Abeloff's Clinical Oncology, 4th Edition

Part I – Science of Clinical Oncology

Section D – Preventing and Treating Cancer

Chapter 30 – Systemic Therapy

Carl E. Freter,Michael C. Perry

SUMMARY OF KEY POINTS

History of Drug Discovery

  

   

The history of cancer chemotherapy and of the disciplines of medical oncology has been that of drug discovery.

Development of Combination Chemotherapy

  

   

Virtually all of the curative chemotherapy regimens that have been developed for hematologic malignancies and for advanced solid tumors use combinations of active agents.

  

   

Mathematical models describing tumor cell kinetics and tumor cell drug resistance have had a strong influence on the development of clinical regimens.

  

   

A series of principles for the development of effective combination regimens was developed in the 1970s and continues to be used today.

  

   

The concepts of alternating, non-cross-resistant chemotherapy, hybrid chemotherapy, dose-intense chemotherapy, and dose-dense chemotherapy have generated hypothesis-driven clinical research that has led in some cases to superior chemotherapy regimens.

Targeted Agents and New Directions in Drug Development

  

   

New categories of agents include tyrosine kinase and multikinase inhibitors, differentiating agents, antiangiogenesis agents, monoclonal antibodies, gene therapy, and vaccines.

  

   

An increasing number of these targeted agents are becoming established in standard therapy, often as part of combination chemotherapy regimens.

  

   

Computer modeling and combinatorial chemistry are powerful new tools for drug development.

  

   

The roles of pharmacogenetics, pharmacogenomics, pharmacoproteomics, pharmacokinetics, and pharmacodynamics are likely to become increasingly important in oncology.

Clinical Uses of Chemotherapy

  

   

Adjuvant chemotherapy is the logical extension of the use of chemotherapy in patients who remain at high risk of recurrence after all clinically detectable disease has been eradicated (Box 30-1 ).

  

   

In specific cancers, the application of chemotherapy prior to any other anticancer therapy (neoadjuvant therapy) can provide improved survival and/or organ sparing and preservation of function.

  

   

The most common use of cancer chemotherapy is in the management of advanced and metastatic disease. Although curative for several advanced cancers, chemotherapy is largely palliative for metastatic disease.

Chemotherapeutic Process

  

   

The choice of chemotherapy for a specific patient must take into account physiologic age, performance status, nutritional status, prior therapy, pharmacogenetics, and comorbid conditions.

  

   

The principles of drug selection include the pharmacologic characteristics of the individual agents, the route of administration, and the toxicity profile.

  

   

Information regarding individual chemotherapeutic agents is presented according to drug class, mechanism of action, dosage forms, drug interactions, pharmacokinetics and metabolism, indications, and toxicity.

Box 30-1 

MANAGEMENT APPROACH: CANCERS THAT ARE TREATED EFFECTIVELY BY ADJUVANT CHEMOTHERAPY

  

 

Wilms’ tumor

  

 

Osteosarcoma

  

 

Breast cancer

  

 

Colorectal cancer

INTRODUCTION

Systemic therapy is defined as chemotherapy, hormonal therapy, or targeted therapy. Although chemotherapy is a relatively recent addition to the therapeutic armamentarium for the treatment of patients with cancer, its role is expanding, and cytotoxic agents are used at some point during treatment for most patients with cancer. Historically, chemotherapy was used principally as therapy for metastatic cancer after failed local therapies, and it remains the treatment of choice for such patients. However, the evolution of cancer therapy over the past several decades has resulted in increased recognition of the important role that chemotherapy can play in the management of apparently localized and surgically resectable disease. This recognition has led to the development of other applications for systemic therapy designed to decrease postsurgical recurrences, when given as adjuvant therapy, or to allow more limited organ- and function-sparing surgical procedures when chemotherapy is given preoperatively or concurrently with radiation therapy. The recent addition of molecularly targeted therapies raises new possible therapeutic options.

Perhaps more than any other disease, cancer requires close interaction among medical specialties. As our knowledge of how to combine available therapies evolves and as the efficacy and specificity of available chemotherapeutic agents improve, chemotherapy will play an even greater role in improving both the survival and quality of life for patients with cancer.

HISTORY OF DRUG DISCOVERY

Paul Ehrlich coined the term chemotherapy in reference to the systemic treatment of both infectious diseases and neoplasia. Although the concept of treating cancers with drugs can be traced back several centuries, there were no examples of truly successful systemic cancer chemotherapy until the 1940s. Gilman and Philips[1] conducted the first clinical trial of nitrogen mustard in patients with malignant lymphomas at Yale University in 1942. The use of nitrogen mustard as a chemotherapeutic agent was suggested by the serendipitous findings of marrow and lymphoid hypoplasia in seamen who had been exposed to mustard gas after the explosion of a ship that contained material manufactured for use in chemical warfare in World War II.[2] This discovery supported previous evidence of a systemic lympholytic effect from alkylating agents of this type. The dramatic regressions of the lymphomas that were noted in this original study generated tremendous excitement for this new field of medicine, although enthusiasm was dampened by the fact that regrowth of tumor seemed inevitable. The results, initially published in 1946, could be said to mark the beginning of modern chemotherapy.

Other “experiments of nature” and the observations of well-trained scientists have yielded a number of other important leads, including the recognition by Farber and colleagues[3] of the importance of folates in cell growth in acute leukemia in children and the subsequent development of the first antifolate antimetabolites. This class of compounds produced perhaps the first examples of drug-induced cures of a metastatic cancer in gestational choriocarcinoma, and they remain in wide clinical use today.[4] For their recognition of the importance of nucleic acid synthesis to inhibition of cell growth and for the development of effective antipurine analogs for cancer and other diseases, Elion[5] and Hitchings were awarded the Nobel Prize for Medicine in 1988. Serendipity also played a role in the recognition of the potential of vinca alkaloids, epipodophyllotoxins, and platinum coordination complexes as chemotherapy agents. [6] [7] This scenario has been repeated with sufficient frequency that drug discovery programs such as that of the National Cancer Institute have made extensive use of the approach of mass screening of both natural products and synthetic compounds to identify lead compounds with potent antitumor activity and unique mechanisms of action.

Screening is key to the process of drug development because it narrows the enormous number of candidate drugs to a more manageable number for further study and possible clinical evaluation. Traditionally, this screening system has used transplantable murine tumors to search for evidence of biologic activity.[8] Although this system identified a series of compounds for clinical trial, there was continued uncertainty regarding the relevance of these murine cell lines to human cancers. The current screening system employs a panel of human cancer cell lines grown in culture that represent the major histologic subtypes and sites of origins of human cancer. It is also possible, and probably important, to include cell lines that express various drug resistance phenotypes, such as multidrug resistance, to evaluate new agents against tumor cells that manifest these potentially clinically important cellular characteristics. It also has been possible to automate the testing of candidate drugs in this system so that high-volume screening can be maintained.[9] Because this screening system uses human cancer cell lines, it is hoped that it will identify agents that have unique promise against advanced solid tumors that would not be identified by using other methods.

This organized approach to random screening of large numbers of compounds must be complemented in the drug development effort, however, by attempts to exploit new therapeutic targets that are identified in ongoing basic cancer research. When a putative target is identified on the basis of its biologic significance in the cancer cell, this strategy suggests that the ability of potential therapeutic agents to interact with this target and to inhibit or modify its function should be evaluated as a primary screening procedure. This mechanism-based screening is often performed in simple cell-free systems in which the target and effector are isolated. Drugs that have been identified as promising candidates by this mechanism-based approach to drug development also require test systems that have been developed to validate their biologic activity in whole cells and experimental animal tumor models. Active new agents are needed for the treatment of all common human cancers. The ongoing work in drug development is crucial if our use of chemotherapy is to continue to improve and if its role in potentially curative therapy is to expand. A number of promising and novel strategies are undergoing clinical trials, including antiangiogenesis factors, drugs that affect intracellular signaling pathways, differentiating agents, agents that affect a cell's ability to undergo apoptosis, and gene-specific therapies such as antisense oligonucleotides and ribozymes. These approaches and others that will undoubtedly follow offer great promise for the future of cancer treatment.

DEVELOPMENT OF COMBINATION CHEMOTHERAPY

Chemotherapy initially involved the use of single agents that were associated with responses but almost universal disease progression and dose-limiting toxicity. The development of new agents quickly led to the birth of the concept of combination chemotherapy. However, single-agent therapy retains an important place especially in palliative therapy after initial combination chemotherapy fails. The principles of combination chemotherapy were developed both empirically and with a theoretical basis provided by the fields of tumor cell growth kinetics and drug resistance.

Tumor Cell Growth Kinetics

More than 30 years ago, Skipper and Schabel used a murine leukemia model to define the concept of logarithmic cancer cell growth with the corollary concept that a specific dose of a chemotherapeutic agent would produce an associated specific log cell kill that was independent of the number of cells in the tumor.[10] These studies established the important concepts of growth rate, tumor bulk (or cell number), and chemotherapy dose as determinants of therapeutic outcome. While appealing in its mathematical simplicity, pure logarithmic tumor cell growth is, in fact, the exception rather than the rule. This is particularly true in solid tumors, whose growth involves complex functions of heterogeneous growth kinetics, cell death, and development of cancer-promoting growth properties, including the capacity for invasion, metastases, angiogenesis, elaboration of growth factors, and development of mechanisms of chemotherapy resistance (see later discussion). Hence, most of the available data suggest that cancers generally do not grow with a constant doubling time. [11] [12] [13] [14] [15] In these cases, the data support a Gompertzian model of tumor growth and regression. In Gompertzian growth, the doubling time increases and the growth fraction of tumor decreases as the tumor becomes larger. Experimental models suggest that this observation is the result of decreased cell production rather than of increased cell loss in larger tumors. [16] [17] A tumor theoretically responds to therapy depending on where it lies on the Gompertzian growth curve. In a patient with an advanced cancer and large tumor bulk, this model predicts a lower growth fraction and a lower fraction of cells killed by a given dose of therapy than would be the case with a smaller tumor. The Norton-Simon [18] [19] [20] model for the response of tumors to chemotherapy has used the concept of Gompertzian growth to explain clinically observed phenomena and to suggest treatment strategies. The Norton-Simon model predicts that the log cell kill will be greater for very small cancers than for large cancers and favors, particularly for small tumors, multiple sequential agents at high doses and alternating regimens over more than one cycle to achieve optimum cell kill. The Norton-Simon model has also afforded useful insights into clinical cancer biology. For example, Gompertzian growth kinetics have clarified the rate of tumor regrowth from residual cells that remain after chemotherapy that fails to achieve a cure. [19] [20] The increased rate of tumor cell growth that is seen when tumors are small will minimize the differences in survival among patients with advanced disease who achieved complete versus partial responses to systemic chemotherapy, because the residual tumor in the complete responders grows back faster.

Drug Resistance

The earliest experience with chemotherapy made it clear that cancers that are initially sensitive to chemotherapy unfortunately eventually become resistant. The process of bacterial mutation rates of resistance to bacteriophage killing, which was studied and mathematically modeled by Luria and Delbruck,[21] formed the conceptual basis for the Goldie-Coldman model, a mathematical model of genetic resistance of cancer cells to chemotherapy drugs. The Goldie-Coldman hypothesis mathematically describes the likelihood that drug-resistant cancer cells are present in a patient at diagnosis.[22] A fundamental tenet of the Goldie-Coldman model is that chemotherapy mutations that confer chemotherapy resistance occur in 103 to 106 cells, substantially lower than the limit of clinical detection, which is about 109 cells or a 1 cm3 mass. Goldie and Coldman proposed that tumor cells could acquire drug resistance before drug exposure on the basis of the spontaneous mutation rate that is intrinsic to the genetic instability of a particular tumor. The likelihood that resistant cells are present can be modeled as a function of tumor size or the number of tumor cells and the spontaneous mutation rate of the cells. The predicted frequency of spontaneous mutation of 1:10-5 to 1:10-6 divisions in proliferative tumor cells is consistent with in vitro studies of this phenomenon.[23] Although this discussion has focused on this phenomenon as a means by which cells might acquire drug resistance, it is equally plausible that the same type of genetic events could lead to an increase in vascular invasion and local spread or to an increased tendency to develop systemic metastases.[24] Preclinical studies have demonstrated clearly that the development of the metastatic potential can be the result of genetic instability.[25]

The Goldie-Coldman model predicts that to overcome cancer cell drug resistance most effectively, (1) multiple active agents should be given over the shortest period of time as early in the growth of a cancer as possible, and (2) multiple agents that are given simultaneously will be more effective than sequential agents given at individually higher doses.

Principles of Combination Chemotherapy

Combination chemotherapy has developed both empirically and through the application of principles and predictions of cancer cell kinetics (Norton-Simon hypothesis), and drug resistance (Goldie-Coldman model), into the following principles for combination chemotherapy regimens ( Box 30-2 ):

  

   

All drugs must be active as single agents. The practice of adding an ineffective drug to promote biochemical synergy has rarely produced effective regimens.

  

   

Drugs should be chosen for nonoverlapping toxicity. This spreads toxicity over multiple organ systems, allowing recovery for chemotherapy on schedule, and avoids damaging toxicity to any single organ.

  

   

Drugs should be chosen for different or synergistic mechanisms of action. This achieves the attacking of multiple different cellular targets and the overcoming of resistance at any single target or biochemical pathway.

  

   

Drugs should be chosen that have different mechanisms or patterns of resistance. Cancer cells with resistance to one drug can be attacked by other drugs to which resistance has not developed.

  

   

Drugs should be given according to the optimum dose and schedule. This allows maximum cell kill with a given drug dose and avoids unnecessary toxicity, drug resistance, and “kinetic” chemotherapy failure.

  

   

Drug doses should be individually titrated to end-organ toxicity in individual patients. Reproducible standard toxicity criteria are used for individual organ systems (bone marrow, gastrointestinal, neurologic, dermatologic, etc.). This allows adequate recovery from toxicity to allow cyclic chemotherapy on schedule at the maximum tolerated dose.

Box 30-2 

MANAGEMENT APPROACH: PRINCIPLES OF COMBINATION CHEMOTHERAPY

  

1.   

Only agents that have been proven effective should be used.

  

2.   

Each agent used should have a different mechanism of action.

  

3.   

Each drug should have a different spectrum of toxicity and (ideally) of resistance.

  

4.   

Each drug should be used at maximum dose.

  

5.   

Agents with similar dose-limiting toxicities can be combined safely only by reducing doses, resulting in decreased effects.

  

6.   

Drug combinations should be administered in the shortest interval between therapy cycles to allow for the recovery of normal tissue.

Clinical application of the preceding principles has led to a number of concepts with testable hypotheses for the design of chemotherapy regimens. These have included alternating non-cross-resistant chemotherapy, hybrid chemotherapy, dose-intense chemotherapy (increased total dose of chemotherapy during a fixed cycle period), and dose-dense chemotherapy (increasing dose per unit time, generally by shortening cycle interval). Alternating non-cross-resistant chemotherapy involves the use of multiple active chemotherapy agents with different mechanisms of action organized into two different combination chemotherapy regimens administered on an alternating basis. The Goldie-Coldman hypothesis would suggest frequent alternation of these regimens (e.g., every second cycle), and this has been the general approach taken in prospective clinical trials that have examined this question. A more recent variation on this theme has been the development of hybrid regimens, in which elements of each regimen are administered during each cycle (e.g., on day 1 and day 8) rather than during every second cycle.

In small cell lung cancer, several chemotherapy regimens are available that have roughly equal antitumor efficacies, and alternating chemotherapy regimens have been studied frequently in this disease. Early trials of this strategy in extensive small cell lung cancer demonstrated minimal survival benefit from the use of alternating chemotherapy regimens and a short prolongation of the duration of initial remission in some studies. [26] [27] [28] [29] Other studies have suggested that the benefits of using more than one chemotherapy regimen in small cell lung cancer might be more apparent in limited-stage disease, in which a survival advantage has been shown in several small studies. [30] [31] In Hodgkin's disease, randomized trials of MOPP versus ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) versus MOPP alternated with ABVD have shown superiority of the alternating regimen and ABVD to MOPP alone in terms of both survival and complete remission.[32] A hybrid regimen of MOPP-ABVD has been shown to be superior to MOPP followed by ABVD.[33] In both cases, however, the testing of the hypothesis is clouded by the fact that in these cooperative group studies, the MOPP regimen consistently required significant dosage reductions. In metastatic breast cancer, studies with a similar design have failed to demonstrate an advantage of alternating cycles of CMFVP (cyclophosphamide, methotrexate, 5-fluorouracil [5-FU], vincristine, prednisone) and VATH (vinblastine, doxorubicin, thiotepa, halotensin) to either CAF (cyclophosphamide, doxorubicin, 5-FU) or VATH alone.[34]Collectively, these data suggest that the use of alternating non-cross-resistant chemotherapy regimens is an acceptable, but still not mandatory, alternative therapeutic strategy for these diseases.

The Norton-Simon approach advocates a crossover strategy by which each active regimen is used for a longer period of time (i.e., several cycles) before switching to the alternative regimen. Theoretically, this approach accomplishes two important goals. First, it maintains the most dose-intense administration of each regimen by giving it during every cycle rather than during alternate cycles. Second, it addresses the heterogeneous populations of cells, killing the most sensitive, rapidly growing cells first and then treating the slower-growing, more resistant cells as efficiently as possible.

The concept of dose-dense chemotherapy received additional support with the recent publication of a Cancer and Leukemia Group B study in the adjuvant therapy of node-positive breast cancer.[35] A 2 × 2 factorial design was used, with patients randomized to receive concurrent adriamycin/cyclophosphamide followed by paclitaxel, each for four cycles, or sequential single-agent adriamycin, cyclophosphamide, and paclitaxel, each for four cycles. Patients were also randomized to receive their therapy at 3-week (standard) or 2-week (dose-dense) intervals. Growth factor support was added to the 2-week schedule. Dose-dense treatment improved disease-free survival and overall survival compared with the 3-week cycles. There were no differences in terms of outcome between concurrent or sequential schedules.

The lack of difference between sequential and concurrent therapies raises fundamental questions about the conventional wisdom of combination therapies always being superior to sequential single agents. Although the results might be drug- and disease-specific, the data are consistent with the Norton-Simon predictions that dose density would improve therapeutic results and that giving drugs in sequence while maintaining dose density would maintain efficacy and reduce toxicity.[35]

These concepts have not been definitively tested clinically, and the available results do not totally support either approach. A direct comparison of alternating and sequential chemotherapy in the adjuvant chemotherapy of breast cancer was conducted by using doxorubicin and the CMF (cyclophosphamide, methotrexate, and 5-FU) regimen.[35] In one arm of this study, patients received four courses of doxorubicin followed by eight courses of CMF; in the second arm, patients received two cycles of CMF alternating with one course of doxorubicin. This sequence was repeated four times, for a total of 12 cycles of chemotherapy. The total dose of all drugs was equal, but the patients in the first arm experienced significantly better disease-free and overall survival. In this case, the sequential approach was superior to the alternating schedule.

An intergroup trial involving patients with Hodgkin's disease came to a different conclusion.[33] In this study, a hybrid MOPP-ABV chemotherapy regimen was superior in terms of complete remission, failure-free survival, and overall survival, compared with the sequential use of MOPP followed by ABVD. Whether this study is a valid test of the concept or whether the results reflect the significant dose modifications in the MOPP arm remains unclear.

The Goldie-Coldman and Norton-Simon hypotheses have provided an important paradigm for hypothesis-driven clinical trials in cancer research. Taken together, the results of these trials have been limited by the lack of “ideal” drugs and combination regimens with which to test these hypotheses and perhaps the simplicity of these models in the face of the biological complexity of cancer. The study of drug resistance and tumor cell kinetics has provided important insights into the mechanisms of “chemotherapy failure.” However, developing insights into cancer biology suggest that chemotherapy resistance and “kinetic failure” might not be the only mechanisms by which chemotherapy can fail. The existence of tumor stem cells that have different properties and chemosensitivity than their progeny,[36] for example, continues the challenge to develop effective chemotherapy based on hypothesis-driven clinical research.

TARGETED AGENTS AND NEW DIRECTIONS IN DRUG DEVELOPMENT

The term targeted agents has come to refer to a growing class of drugs that specifically target cancer cell-specific pathways on a molecular level, including gene expression, growth regulation, cell cycle control, apoptosis, and angiogenesis. The targeting of specific molecular pathways on which cancer cells are differentially dependent offers the attractive advantage of cancer-specific therapy with reduced toxicity to normal tissues. This disparate and growing group of drugs and treatment approaches includes small molecule tyrosine kinase and multikinase inhibitors, differentiating agents, angiogenesis inhibitors, monoclonal antibodies, proteosome inhibitors, histone deacetylase inhibitors, gene therapy strategies, and vaccines. The developing experience with kinase inhibitors, angiogenesis inhibitors, and monoclonal antibodies is that while they produce responses, they are generally not curative and are associated with the development of resistance. This has led to efforts to understand how best to combine these agents with more conventional chemotherapy agents to capitalize on the strengths of each.

Tyrosine Kinase and Multikinase Inhibitors

Basic oncology research has given us many important clues as to the molecules that drive the malignant phenotype. Although the basic defect is in the genome, the expression of that defect is manifested in how the cell interacts with its surrounding milieu, which can include other malignant cells, nearby normal cells, the extracellular matrix, and humoral factors. This interaction affects the cell via surface membrane receptors and second messengers within the cell. These second messengers affect gene expression and cell phenotype via kinase cascades (signal transduction pathways) that are specific to the receptor/second messenger system that is activated. Within these receptor/second messenger systems, many oncogenes are mutated proteins that confer abnormal cellular responses to malignant cells.

An important paradigm for drug discovery in oncology has been identifying recurrent specific chromosomal markers as guideposts to discovery of the biology of their associated genetic alterations in a specific cancer. This might then allow the development of molecularly designed therapy to correct or circumvent biologic changes sustaining the cancer phenotype. A striking example of this approach has been the development of the tyrosine kinase inhibitor imatinib to inactivate the constitutively expressed fusion protein BCR-abl, the biologic abnormality that drives CML, defined decades earlier by the Philadelphia chromosome.[37] Imatinib has subsequently been used to target c-Kit in gastrointestinal stromal tumors,[38] and the success of this approach has driven the development of a growing number of tyrosine kinase inhibitors, including dasatinib, a multikinase inhibitor that targets BCR-Abl, SRC-family kinases, c-kit, EPHA2, and PDGFR-beta, indicated for treatment of CML with resistance to prior therapy including imatinib and resistant Ph+ ALL.[39] Erlotinib, an oral tyrosine kinase inhibitor targeting the epidermal growth factor receptor, has been approved for treatment of non-small-cell lung and pancreatic cancers. [40] [41] Sorafenib is an oral multikinase inhibitor that targets Raf, tumor signaling, and tumor vasculature and is approved in advanced renal carcinoma.[42] Sunitinib is another multikinase and angiogenesis inhibitor that is approved in renal cell and gastrointestinal stromal tumors.[43] Lapatinib, a tyrosine kinase inhibitor of HER2/neu and EGFR, has activity in HER2/neu-positive breast cancer progressing after trastuzumab-based therapy (see later discussion).[44] Other members of this family of small molecule kinase and multikinase inhibitors are in active clinical development.

Differentiating Agents

Several classes of compounds have potent in vitro and in vivo differentiating effects on the malignant cell phenotype. These include retinoids, vitamin D analogs, cyclooxygenase inhibitors, and hypomethylating agents. These agents do not eliminate the malignant clone or affect its genotype, but their continued application can cause regression of malignancy, and they might have a role in chemoprevention. All-trans retinoic acid represents an example of a targeted therapy that causes striking granulocytic differentiation of the leukemic cells in acute promyelocytic leukemia, in which the chromosomal translocation 15:17 results in the expression of an aberrant fusion gene involving the retinoic acid receptor PML-RAR-α.[45] 5-Azacytidine and decitabine are DNA hypomethylating agents that act to restore cellular differentiation in myelodysplastic syndrome and certain leukemias.[46] The COX-2 inhibitor celecoxib has activity in reducing polyps in familial adenomatous polyposis[47] and is being tested in other chemoprevention settings.

Angiogenesis Inhibitors

Solid tumors must stimulate the growth of new blood vessels, a process called neovascularization, to obtain oxygen, nutrients, and growth factors to be able to grow and successfully metastasize. Study of the molecular basis of tumor angiogenesis has led to important insights into tumor biology as well as targeted molecular strategies to inhibit tumor angiogenesis. An established agent is bevicizumab, a humanized monoclonal antibody that targets the angiogenic growth factor VEGF. Bevicizumab has modest single-agent activity but has been associated with survival prolongation when combined with conventional chemotherapy for lung, colon, and breast cancer. [48] [49] Thalidomide and lenalidomide, established agents in multiple myeloma, have complex mechanisms of action, including inhibition of tumor necrosis factor-α, interleukin-6, basic fibroblast growth factor, and antiangiogenic activity through inhibition of vascular endothelial growth factor (VEGF).[50]

Monoclonal Antibodies

Malignant cells are vulnerable to treatments that are directed at unique antigens expressed on their surface. Monoclonal antibodies that are directed against growth factor receptors or other specific cancer cellular targets have increasingly established roles in therapy. Antibody binding to the surface of the malignant cell can lead to complement-mediated lysis, antibody-dependent cellular cytotoxicity, or signal transduction-mediated apoptosis. The monoclonal antibody can either be of murine origin or, through recombinant DNA techniques, be made partly human (chimeric) or nearly completely human (humanized). Rituxan, directed against the lymphoid cell surface marker CD20, is widely used in chemotherapy of lymphoid malignancies, [51] [52] as well as in other settings for its immunosuppressive properties. Alemtuzumab, defined by the lymphoid marker CD52w against which it is directed, is approved for treatment of CLL. [53] Trastuzumab, a humanized monoclonal antibody against the HER2 protein, is established in treatment of HER2/neu-positive breast cancer.[54] Cetuximab, a recombinant human/mouse chimeric monoclonal antibody is directed against the extracellular domain of the human epidermal growth factor receptor (EGFR), and has activity in colorectal and head and neck cancers. [55] [56] Panitumumab is another EGFR-directed monoclonal antibody that is indicated for treatment of patients with EGFR-expressing metastatic colorectal cancer that is resistant to conventional chemotherapy.[57] Monoclonal antibodies have also been used to “target” cancer cell antigens with attached cytotoxic moieties, including radionuclides, as in the case of anti-CD20 conjugates, I-131-conjugated tositumomab,[58] or yttrium-90-conjugated ibritumomab tiuxetan[59] for β-cell lymphomas. Immunoconjugates have also been constructed with biological toxins or antitumor antibiotics as in the case of the anti-CD-33-calicheamicin conjugate gemtuzumab ozogamicin for acute myelogenous leukemia.[60] Denileukin diftitox is an example of a recombinant fusion product with cellular binding and toxic moieties combining interleukin-2 and diphtheria toxin to inhibit cellular protein synthesis and induce apoptosis in the treatment of cutaneous T-cell lymphomas.[61]

Proteosome Inhibitors

The ubiquitin-proteosome pathway involves targeted proteolysis of “ubiquitin-tagged” intracellular proteins. Inhibition of the normal essential function of this pathway leads to disruption of multiple intracellular signaling pathways and programmed cell death. Bortezomib, the first approved drug in the proteosome inhibitor class, is a reversible inhibitor of the 26S proteosome, and an established agent in multiple myeloma and some non-Hodgkin's lymphomas.[50]

Histone Deacetylase Inhibitors

The family of histone deacetylases catalyzes the deacetylation of lysine residues on protein substrates including histones and transcription factors. Histone deacetylation is believed to control expression of oncologically relevant genes, including tumor suppressors, and genes involved in differentiation, proliferation, and cell cycle control. Inhibition of overexpressed histone deacetylases in cancer cells is thought to lead to cell cycle arrest and apoptosis. Vorinostat is an oral histone deacetylase inhibitor with activity against a spectrum of histone deacetylases with an indication for treatment of refractory cutaneous T-cell lymphoma.[62]

Gene Therapy

Treatment strategies incorporating specific ribonucleotide sequences come in many different varieties, such as antisense therapy (RNA). An example is the antisense oligonucleotide against bcl-2 RNA, oblimersen, being studied in CLL, melanoma, and other malignancies as a strategy to increase sensitivity to apoptosis with conventional chemotherapy drugs.[63] Other approaches that are under study include systemic viral vector transfection (RNA or DNA), DNA injection into tumors, and ex vivo transfected and selected tumor cells, immune cells, or bone marrow progenitors (DNA). Most of these techniques have demonstrated some effectiveness in animal models, and clinical trials are ongoing. No proof of efficacy has been shown, however, and the technical hurdles are still daunting.

Vaccines

Vaccine strategies to treat cancers have been used for more than 100 years. The principles of immune surveillance and tumor rejection have been well demonstrated in animal models and form the justification for human vaccine strategies. In the last 10 years, many human tumor antigens (and the humoral and cellular immune responses to them) have been characterized. To date, no convincing clinical evidence exists for sufficient efficacy of cancer vaccines, and the ability to correlate immune response to a vaccine and clinical effectiveness has been elusive. Recent advances in molecular immunology might hold the key to solving the puzzles of reinstating and measuring clinically relevant tumor immunogenicity. Several possibly effective cancer vaccines are currently in large phase III trials, which could lead to FDA approval. The recent approval of a vaccine against human papillomavirus to prevent HPV-associated cervical cancer represents the first application of a cancer prevention vaccine.

PHARMACOLOGIC APPROACHES

Drug Development

Although approximately 100 drugs are now in use to treat human cancers, the vast majority of cancers are not cured by chemotherapy. Since it no longer seems possible to identify one specific abnormalitybetween cancerous and normal cells, additional agents with different modes of action must be sought. Although some chemotherapeutic agents (e.g., 5-FU) have been designed rationally, others (e.g., cisplatin) have been found by chance. The National Cancer Institute is developing a chemical screening system that permits the identification of a compound of interest—a lead compound—that can then be modified or enhanced, and the interaction of the compound with its target (enzyme, growth factor, or oncogene product) can be characterized. Appropriate bioassays are required for each lead agent as it is developed.

A significant fraction of our currently available chemotherapeutic agents are either natural products or derived from natural products, which often have complex structures that complicate synthesis efforts. Problems commonly arise in supply of starting material, the development of drug synthesis methods, and successful formulation of the drug so that it is absorbed and distributed appropriately. The problems of chemistry compound the difficulty in bringing drugs to clinical trials.

Computer Modeling and Combinatorial Chemistry

The pioneering discoveries of the early days of chemotherapy have permitted the development of a paradigm for drug discovery that persists, with modifications, to the present day. This organized approach to random screening of large numbers of compounds, however, must be complemented in the drug development effort by attempts to exploit new therapeutic targets that are identified in ongoing basic cancer research.

The molecular basis for antineoplastic therapy has been rapidly being unveiled since the 1990s. For many chemotherapy agents, the molecules that are responsible for drug transport, binding, effector mechanism, detoxification, and efflux out of cells are known. Therefore, new and better agents that result in tumor cell death and clinical response can be designed to exploit these known targets. This effort requires powerful computer programs, advanced chemistry techniques, three-dimensional modeling capabilities, and nucleotide sequences of all the relevant target protein genes. With these tools in place, one can create new small or large molecules or modify existing molecules by the addition or subtraction of functional groups to direct the binding, specificity, inhibition, duration of action, and toxicity of these molecules on the basis of chemical interactions with the target molecules. This process is called mechanistic drug development, and it uses computer modeling to predict the chemical composition of the new drugs, whether they be small molecule inhibitors, peptides, proteins, or nucleotide sequences.

A related endeavor that is occurring in the pharmaceutical industry and elsewhere is called combinatorial chemistry. [64] [65] [66] [67] [68] [69] This process tests for binding interactions between new compounds or molecules and known targets that result in the desired cellular and clinical effect. The target is usually placed on a solid phase, and the candidate molecule is tested for binding to this solid phase. Once specific binding is documented, this compound is then tested for in vitro and in vivo biologic modulation (inhibition or stimulation) of the target molecule function. From there, standard testing of preclinical and clinical activity can be carried out with existing or new methods.

This ongoing work in drug development is crucial if our use of chemotherapy is to continue to improve and if its role in potentially curative therapy is to expand. Standard approaches and mechanistically based drug development will continue in parallel, and many new agents will undoubtedly follow, offering great promise for the future of cancer treatment.

Pharmacogenetics

It is now clear that much of the variability in response to drugs is inherited. The genetically determined variability of drug response characterizes a research area known as pharmacogenetics. Phase III clinical trials frequently report grade 4 toxicities in various solid tumors and hematologic malignancies that have been traditionally regarded as an acceptable alternative to underdosing with ineffective therapy. Identifying genes and allelic variants of genes that affect response to cancer chemotherapy drugs holds great promise for more individualized therapy to avoid untoward toxicity as well as underdosing. One of the first clinically important applications of pharmacogenetics was the identification of single-nucleotide polymorphisms in the gene for the enzyme thiopurine methyltransferase, which is responsible for metabolism of the antitumor agents, 6-thioguanine and 6-mercaptopurine. Children with inherited thiopurine methyltransferase deficiency develop severe hematologic toxicity when exposed to such drugs, while those with high levels of the enzyme require higher doses to achieve the desired effect.[70] Identification of children with thiopurine methyltransferase polymorphisms has the potential to ameliorate toxicity and improve therapeutic outcome.[71] To be clinically useful, such a polymorphism needs to be identified as associated with a correctable untoward clinical outcome and be rapidly detectable with a sensitive, specific test of reasonable cost. Early in the clinical experience with irinotecan in colorectal cancer, an unacceptable early death rate attributable to diarrhea and neutropenia was observed.[72] This was identified as being due to a polymorphism in the gene that encodes uridine diphosphate glucuronosyltransferase 1A1, patients who were homozygous for UGT1A1*28 allele being at increased risk. A genetic test performed on genomic DNA from peripheral blood is available and recommended to screen such patients.[73]

While this patient-tailored approach to chemotherapy drugs is developing, the related fields of pharmacogenomics and pharmacoproteomics hold promise for large-scale genomic and proteomic screening for heritable variation in drug metabolism and other areas of cancer biology. Either technique allows the formulation of a pattern of phenotypic or genotypic expression of the cancer cell, from which patterns of gene expression and therapeutic targets can be discerned. For example, reverse-phase protein microarrays can be used to analyze patient biopsy specimens to measure hundreds of phosphorylated proteins in multiple signaling pathways relevant to the malignant phenotype.[74]

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics is the relationship between plasma concentration of a drug and time and is concerned with the drug's absorption, distribution, metabolism, and excretion. It is what the body does to the drug. The interpretation of pharmacokinetic data is usually based on assessment of total plasma clearance, by measurement of either the area under the plasma concentration–time curve or the steady-state plasma concentration during a constant infusion. A critical issue is intersubject variability in clearance; here, several factors come into play, including saturation of the major metabolic or excretory sites, protein binding, and body size. The evidence for the use of body surface area in dosing oncology drugs is scarce, and other methods could be preferable.

Conversely, pharmacodynamics—the relationship between plasma concentration of the drug and its effects—is what the drug does to the body. Pharmacodynamics analyses have increasingly been incorporated into cancer drug development and complement pharmacokinetic studies, as pharmacodynamics, in conjunction with pharmacokinetics, permits a better prediction and understanding of effect, rather than evaluating plasma concentrations of unclear significance. To date, the influence of pharmacodynamics in oncology has been relatively limited, owing to the tendency to use combination chemotherapy for most malignancies and to the considerable heterogeneity of the cancer population. Many oncology patients are older and have comorbidities that could affect pharmacokinetic-pharmacodynamic variability; hepatic metastases could alter drug metabolism; and there is often a significant lag time between the last measured plasma concentration and the first major therapeutic or toxic effect. The net result is that such studies are often not practical at the present time. This is a field of active investigation, however, and advances in this area might yield great benefits in tailoring treatment to the individual patient.

CLINICAL USES OF SYSTEMIC THERAPY

Adjuvant Therapy

Systemic therapy can be used in a number of ways in the treatment of cancer. The vast majority of cancer chemotherapy treatments or hormonal therapies are administered to patients with clinically obvious disease. The notable exception is adjuvant therapy, which uses chemotherapy or hormonal therapy for patients who remain at high risk of recurrence after the primary tumor and all evidence of cancer have been surgically removed or treated definitively with radiation. Despite an apparently successful resection of primary breast, colon, or other primary cancers along with the regional lymph nodes, patients can be prospectively identified who are at high risk of recurrence of their disease. These criteria might differ for each tumor, but in general, the degree of local extension of the primary tumor, the presence of positive lymph nodes, and certain morphologic or biologic characteristics of the individual cancer cells are important determinants of that risk. The need for effective adjuvant therapy is strongly emphasized by the fact that systemic therapy usually fails to cure these cancers once recurrence has taken place. The theoretical advantage of treating patients with small total body tumor burden is very compelling, but, in fact, some patients who will receive adjuvant therapy have already been rendered disease free by the local therapy and would be cured without it ( Box 30-3 ).

Box 30-3 

MANAGEMENT APPROACH: PRINCIPLES OF ADJUVANT CHEMOTHERAPY

  

1.   

Effective chemotherapy must be available.

  

2.   

Known tumor should be removed by surgery.

  

3.   

Chemotherapy should be started as soon as possible postoperatively.

  

4.   

Chemotherapy should be given in maximally tolerated doses.

  

5.   

Chemotherapy should continue for a limited time period.

  

6.   

Chemotherapy should be intermittent, when possible, to minimize immunosuppression.

The use of chemotherapy when the tumor burden is minimal avoids the problems of increasing tumor cell number, decreasing growth fraction, decreased vascular supply, hypoxia, tumor cell heterogeneity, and the likelihood of emergence of drug resistance, all of which occur with increasing frequency as tumors enlarge. Considerable experimental evidence suggests that cancers are most sensitive to chemotherapy during the early stages of growth. This increased sensitivity is believed to be the result of the high growth fraction and shorter cell cycle times, so a given dose of drug might exert a greater therapeutic effect than it would in a larger, quiescent tumor.[75]

The selection of the specific chemotherapy or hormonal therapy regimen to be used as part of adjuvant therapy for a particular cancer is based on objective response rates observed for patients with advanced cancers of the same type. These regimens should be selected carefully, as it is unrealistic to expect a chemotherapy regimen to be effective in preventing recurrences in the adjuvant setting if the regimen does not have a substantial response rate in advanced disease. The selection of patients for adjuvant therapy is based on the expected rate of recurrence for their initial clinical stage of cancer after local treatment alone. Initial demonstration of the efficacy of an adjuvant therapy regimen requires comparison with a control group that receives no therapy beyond local management in a prospective clinical trial. Historical controls are notoriously unreliable in this regard and are not adequate to prove efficacy.

The typical endpoints of systemic therapy—shrinkage of measurable tumor on physical examination or serial radiographic studies—are not available in this situation; in clinical trials of adjuvant therapy, relapse-free survival and overall survival are the principal measures of treatment effect. For an individual patient, there are no means to determine whether the adjuvant therapy and its resultant toxicity and expense have been beneficial or necessary.

This strategy of adjuvant therapy has been attempted in a wide variety of pediatric and adult tumors with some success, and the principles of adjuvant therapy strategy are well established. In the cases of breast cancer and colon cancer, the number of lives saved by the adjuvant therapy approach is significant because of the large number of affected patients, despite the modest differences that are seen between treated and control patients with current treatment programs.

Neoadjuvant Chemotherapy

A second strategy that acknowledges the presence of micrometastatic disease at sites remote from the primary tumor at diagnosis is that of neoadjuvant chemotherapy ( Box 30-4 ).[76] As with adjuvant chemotherapy, treatment is directed at the possibility of systemic disease in patients with apparently localized disease, although in this instance, chemotherapy is administered before surgery is performed. This approach has several potential advantages over conventional postoperative adjuvant chemotherapy. First, neoadjuvant or preoperative chemotherapy provides earlier exposure of potential micrometastases to chemotherapy than is achieved with the standard adjuvant approach. If the advantages of early chemotherapy treatment that are observed in the laboratory are exportable to the clinic, this should be an optimal approach to the treatment of micrometastases. Second, an objective response to chemotherapy in the primary lesion provides important in vivo evidence that the therapy that is being used has antitumor activity and suggests that the tumor at remote subclinical sites will be sensitive as well. By contrast, if the primary lesion does not respond, the likelihood of success of the initial chemotherapy regimen in eradicating micrometastases would seem to be greatly diminished. Monitoring the response thus provides an early opportunity to consider alternative chemotherapy approaches. This approach has perhaps best been described for osteosarcoma.[77] Third, significant regression of the primary tumor might allow local management to be tailored to the individual patient. For example, surgery might be technically easier because of the reduced tumor bulk, a more conservative surgical procedure could be considered, or radiation therapy might be administered in lieu of surgery. The recent use of the aromatase inhibitors in locally advanced breast cancers is another example of the utility of this approach.

Box 30-4 

MANAGEMENT APPROACH: CANCERS THAT ARE TREATED EFFECTIVELY BY NEOADJUVANT CHEMOTHERAPY

  

 

Soft-tissue sarcoma

  

 

Osteosarcoma

  

 

Anal cancer

  

 

Bladder cancer

  

 

Larynx cancer

  

 

Esophageal cancer

  

 

Locally advanced breast cancer

The latter two approaches could permit organ sparing and function preservation for some patients. In some situations, preoperative chemotherapy is administered concurrently with radiation therapy toimprove local disease control and to treat systemic micrometastases. For cancer of the anal canal and bladder cancer, this approach has allowed organ-sparing procedures for a high percentage of patients. It has also served as highly effective preoperative therapy for esophageal cancer and squamous cell cancer of the head and neck.

The potential disadvantages of the neoadjuvant approach are also very real. First, chemotherapy is being used as initial therapy for a group of patients with cancers that are potentially curable by surgery alone in a small percentage of patients. If chemotherapy proves ineffective and the cancer becomes unresectable during treatment, great harm could be done. Second, the use of preoperative chemotherapy could obscure the true pathologic stage of the cancer by altering tumor size and margins and converting histologically positive nodes to negative. The inaccuracy of clinical staging for many cancers makes it difficult to be confident that a homogeneous group of patients has been treated, and this fact might confound interpretation of results of clinical trials. Third, if a dramatic clinical response results in the performance of an inappropriately conservative procedure or poor patient acceptance of the recommended procedure and if the cancer then recurs, a significant disservice has been done to the patient.

Approximately seven types of cancers have been managed effectively by using neoadjuvant chemotherapy. In all cases, this “effectiveness” might not imply improved survival. In some cases, organ sparing or function preservation is routinely possible and is ample justification for the use of this approach.

Management of Advanced and Metastatic Disease

The most common use of systemic therapy is for the management of advanced or metastatic disease after failed local therapies or in treating disease for which no alternative therapy has been found. This is perhaps the sternest test for chemotherapy, as tumor volume is significant and patients are often physically compromised by the effects of their disease. It is this clinical situation, however, in which the activity of new anticancer agents and combination chemotherapy regimens are initially evaluated. In treating patients with advanced cancer, it is possible both to determine the antitumor activity of the therapy on an individual patient basis and to define the response rate for the therapy accurately by entering an appropriate number of patients with the same diagnosis and similar pretreatment characteristics in a clinical trial. The benefit of systemic therapy to patients can be inferred by the degree to which measurable or evaluable tumor responds to therapy.

Clearly, the most important measure of the efficacy of systemic therapy is the achievement of a complete response, defined as the disappearance of all radiographic and clinical evidence of measurable or evaluable tumor ( Box 30-5 ). It is the necessary first step to achieving a clinical cure. The achievement of a complete response results in a significant decrease in or disappearance of disease-related symptoms and generally translates into a meaningful prolongation of survival, even for patients who ultimately relapse. Therapy can be said to be curative only when the complete response is maintained after treatment is discontinued. The clinical importance of a complete response is therefore measured by the disease-free or relapse-free survival time. Partial responses are defined as a 50% decrease in cross-sectional area of measurable tumor masses and also can result in symptomatic benefit for patients, although survival is rarely significantly prolonged. Continued administration of the chemotherapy regimen is usually required to maintain the partial response. Unless the regimen is extremely well tolerated, the cumulative effects of therapy might ultimately limit the benefit to the patient. The median duration of response among the complete and partial responders is often used as an endpoint in clinical trials of therapies.

Box 30-5 

MANAGEMENT APPROACH: CANCERS THAT ARE CURABLE OR OCCASIONALLY CURABLE WITH CHEMOTHERAPY ALONE

Cancers That Are Curable with Chemotherapy Alone

  

 

Gestational choriocarcinoma

  

 

Hodgkin's disease

  

 

Germ cell cancer of the testis

  

 

Acute lymphoid leukemia

  

 

Non-Hodgkin's lymphoma (some subtypes)

  

 

Hairy cell leukemia (probable)

Cancers That Are Occasionally Cured with Chemotherapy

  

 

Acute myeloid leukemia

  

 

Ovarian cancer

  

 

Small cell lung cancer (with radiation)

Perhaps the greatest value to clinical investigators of documenting partial responses is in the evaluation of investigational new drugs, in which preliminary evidence for antitumor activity of new drugs is often first observed. New agents that produce partial responses in patients with advanced cancer in phase I or II trials might warrant further evaluation at earlier stages of disease or in combination with other active agents. Patients who have stable disease while receiving therapy—that is, responses that do not meet the criteria for either an objective response or progressive disease—are reported in some clinical trials, although the scientific value of this measure in evaluating therapy can be legitimately questioned. For individual patients who experience extended periods of stable disease and symptomatic palliation on treatment after a period of rapid progression, the clinician (and patient) might consider the therapy of value and continue it on that basis. The importance of this endpoint has increased as novel agents that are not truly cytotoxic, such as antimetastatic agents, differentiating agents, or agents that affect intracellular signaling, enter clinical trials. In these cases, it is possible that evidence of biologic effect will take a different form from that to which we have become accustomed with conventional cytotoxic agents.

Although objective responses, duration of survival, and cure rates have been our traditional systemic therapy endpoints, it has become increasingly clear that clinical researchers and clinicians caring for patients must consider other outcomes or endpoints also. These generally fall under the rubric of palliation of symptoms and improved quality of life. [78] [79] Although these endpoints might be more subjective than the traditional ones, it is important that criteria for their evaluation be agreed on and that they be used routinely in clinical trials in which an improved cure rate is not a likely outcome. The palliative benefit to patients who do not have a curable disease is not well defined by our current criteria, and the addition of a semiquantitative means of assessing palliative benefit is critical.

Despite the obvious limitations of our current cytotoxic agents, chemotherapy is curative for several advanced human cancers. These diseases include gestational trophoblastic disease and several hematologic malignancies, but only one advanced solid tumor—germ cell cancer of the testis—can be said to be routinely curable with chemotherapy alone. Another group of cancers, such as small cell lung cancer and ovarian cancer, is occasionally cured with chemotherapy. The most common solid tumors, however—for example, cancers of the breast, lung, prostate, or gastrointestinal tract—when metastatic are not curable with current therapies. These diseases will provide the greatest challenge to the process of drug development and the practice of chemotherapy in the future and will continue to be the focus of active investigative efforts.

The reader is directed to the discussions of the management of individual cancers in Part III of this textbook, “Specific Malignancies.” General principles regarding selection of systemic therapy and characteristics of specific drugs are discussed later in this chapter.

CHEMOTHERAPEUTIC PROCESS

The choice of chemotherapy as the treatment modality for a given patient has significant implications and requires a detailed knowledge of the patient and his or her medical problems and social and emotional background, a general knowledge of chemotherapy, a specific knowledge of the program to be used, and the availability of laboratory and support services ( Box 30-6 ). The occasional therapist cannot expect to become an expert, any more than one can expect to become an accomplished chef simply by using a cookbook. Indicator lesions may be physical findings (e.g., lymphadenopathy, hepatomegaly, splenomegaly, subcutaneous nodules), radiologic abnormalities, or tumor markers in body fluids.

Box 30-6 

MANAGEMENT APPROACH: REQUIREMENTS FOR CHEMOTHERAPY

  

1.   

Biopsy-proven residual or metastatic disease[*]

  

2.   

Indicator lesion[*]

  

3.   

Satisfactory performance score and nutrition

  

4.   

Patient capable of informed consent

  

5.   

Minimal bone marrow, renal, and hepatic function (occasionally pulmonary or cardiac function important)

  

6.   

Available monitoring and support functions

*  Exception: adjuvant chemotherapy.

Patient Selection

Physiologic Age

Advanced age alone is seldom a valid criterion for excluding patients from chemotherapy. Nevertheless, age-related alterations (in addition to disease-related changes) in organ function suggest that aggressive (or even nonaggressive) programs could result in unacceptable toxicity. Examples of such changes include decreased bone marrow reserve with the possibility of enhanced myelosuppression, reduced renal function with the possibility of enhanced methotrexate or cisplatin toxicity, variable gastrointestinal absorption of oral chemotherapeutic agents, and altered drug metabolism by the liver, resulting in possible decreased effectiveness of chemotherapy.[80] Treatment decisions must also take into account the likelihood of benefit. The decision to treat acute granulocytic leukemia in an elderly patient, for whom toxicity is certain and the likelihood of benefit is small, is an example of a difficult situation.

Performance Score

Whether the Karnofsky or Zubrod scale is used, performance status or score ( Table 30-1 ) correlates closely with survival in certain settings. This is most clearly expressed in non-small-cell lung cancer, in which each decrement of 10% in the Karnofsky score results in a measurable decrease in survival. The implication is that patients with Zubrod performance scores of 3 or 4 or Karnofsky scores of less than 30% are usually not candidates for chemotherapy unless the tumor is untreated and especially likely to respond.


Table 30-1   -- Patient Performance Score Using Zubrod and Karnofsky Scales

Zubrod

Karnofsky (%)

Definition

0

100

Asymptomatic

1

80–90

Symptomatic, fully ambulatory

2

60–70

Symptomatic, in bed <50% of day

3

40–50

Symptomatic, in bed >50% of day, but not bedridden

4

20–30

Bedridden

 

 

Nutrition

Although maintenance of usual body weight might be impossible in the setting of advanced malignancy, the ingestion of 1500 to 2000 calories daily is necessary to permit a satisfactory chance of tumor response. This is best accomplished through oral intake, if possible, using supplemental sources as necessary. If the patient cannot ingest enough calories, enteral or parenteral feeding should be considered.

Obesity

Chemotherapy in the massively obese patient carries a potential risk of overdosage if the patient's actual weight is used, whether dosing is on a milligram-per-kilogram basis or according to body surface area. There are no guidelines for this situation, and the pharmacokinetics of antineoplastic drugs in obese patients are poorly understood. It has been suggested that when patients are to be treated with curative intent, they should receive full-dose intensity, using body surface area calculated on actual body weight or on ideal body weight, with dose escalations if tolerated.[81] Patients who are to receive palliative therapy can more safely be given doses based on ideal body weight.[82]

Prior Therapy

In breast cancer, in spite of positive estrogen/progesterone receptors, failure to respond to a hormonal manipulation decreases the likelihood of a response to subsequent hormonal treatment. Similarly, in virtually all malignancies, failure to respond to a first chemotherapy program lessens the probability of a response to second-line therapy, often because of the development of multidrug resistance.

Organ Function

Altered end-organ function (bone marrow, renal, hepatic, cardiac, pulmonary) could eliminate the use of some chemotherapeutic agents entirely or require dose modification.[83] To avoid undue toxicity, it is essential to know the process of drug disposition and metabolism in this setting. Most oncologists find it useful to determine baseline bone marrow function by peripheral blood counts, hepatic and renal function by chemistry profiles, and (occasionally) cardiac function by echocardiography and gated pool cardiac scans or pulmonary function by chest radiography and spirometry.

Coexisting Illnesses

Other nonneoplastic illnesses might modify the choice of chemotherapeutic agents, even if they do not eliminate the rationale of the use of chemotherapy. For instance, congestive heart failure rules out the possibility of the cardiotoxic drug doxorubicin, and severe chronic obstructive pulmonary disease should eliminate the use of the pulmonary toxin bleomycin. Similarly, diabetes might be aggravated by the use of corticosteroids.

Pharmacogenetics

The evolving field of pharmacogenetics has revealed that unexpectedly severe toxicity from 5-FU could be due to a deficiency of dihydropyrimidine dehydrogenase.[84] The prevalence of this enzyme deficiency in the general population is unknown, as is the impact of the heterozygous state on susceptibility to 5-FU toxicity. Similarly, determination of acetylator phenotype as defined by caffeine metabolism can accurately predict the extent of acetylation of amonafide, a DNA-intercalating agent.[85] Determination of acetylation phenotype can thus be used to modify drug dosing to prevent excess toxicity.

Principles of Drug Selection

Single-agent therapy has largely been replaced by combination chemotherapy when cure is the goal of treatment. There are, however, circumstances in which single agents can be used with curative intent. These include methotrexate or dactinomycin in choriocarcinoma and interferon, pentostatin, or cladribine (chlorodeoxyadenosine) in hairy cell leukemia.

Combination therapy is now the standard for the treatment of many disseminated or metastatic diseases and is curative in some.[86] Unfortunately, most of these diseases are relatively uncommon hematologic or pediatric malignancies, and the more common neoplasms of adults, such as cancers of the colon and rectum, lung, or breast, once metastatic, are seldom cured.

Chemohormonal therapy is the use of chemotherapeutic agents and hormonal agents, such as prednisone in the MOPP combination program, or prednisone with vincristine and daunorubicin in the treatment of acute lymphocytic leukemia (ALL). The inclusion of tamoxifen after cytoxan and doxorubicin in the chemotherapeutic program for breast cancer is another example. Biologic response modifiers, such as interferon or interleukin-2, are used singly or in combination with chemotherapeutic agents.

Differentiating agents, the newest class of anticancer therapies, are currently represented by just one compound, all-trans-retinoic acid, which is effective in acute progranulocytic leukemia.

Route of administration has been usually a straightforward decision. Most chemotherapeutic agents are given intravenously, eliminating problems of compliance and absorption. Many of the hormonal agents and some chemotherapeutic agents, such as alkeran, chlorambucil, myleran, 6-mercaptopurine, and 6-thioguanine, are given by the oral route. More recently, oral etoposide and capcitibine, an oral form of 5-FU, have been added to the armamentarium of oral cytotoxic drugs. Absorption could be enhanced if these drugs are taken on an empty stomach. Methotrexate can be given orally, intravenously, intramuscularly, or intrathecally. Interferon and interleukin-2 are usually given subcutaneously. Some chemotherapeutic agents can be instilled in body cavities to treat effusions, as in the example of bleomycin to treat pleural effusions. Continuous infusion therapy offers a potential advantage for cell cycle-specific drugs, such as antimetabolites, in which prolonged exposure might increase cell kill. Cytosine arabinoside is most effective in the treatment of acute granulocytic leukemia, for example, when used as a continuous infusion over 7 days.

Venous access must also be considered, and intravenous therapy might not be feasible if this cannot be established. Fortunately, the development of subcutaneously implanted venous access devices (central or peripheral), multilumen external catheters, and peripherally inserted catheters (PIC lines) has permitted the use of chemotherapy in many circumstances in which this was not possible previously.[87]

Drug programs, including dose, should be extracted from published articles and modified according to the patient's end-organ function ( Table 30-2 ).


Table 30-2   -- Dose Modifications for Chemotherapy (% of Dose to Be Given)

HEMATOLOGIC TOXICITY

 

 

Granulocytes/Total WBC

 

 

Platelet Count (/mm3)

>2000/3500

1500–1999/3000–3499

1000–1499/2500–2999

<1000/2499

>100,000

100

75

50

0

50,000–90,000

50

50

50

0

<50,000

0

0

0

0

NEPHROTOIXCITY

 

 

Creatinine Clearance

 

 

Drug

>60 mL/min

30–60 mL/min

10–30 mL/min

<10 mL/min

Bleomycin

NC

75

75

50

Cisplatin

NC

50

Omit

Omit

Cyclophosphamide

NC

NC

NC

50

Methotrexate

NC

50

Omit

Omit

Mithramycin

NC

75

75

50

Mitomycin

NC

75

75

50

Nitrosoureas

NC

Omit

Omit

Omit

HEPATOTOXICITY

 

 

 

 

Drug

 

 

Bilirubin (mg/dL)

SGOT (IU)

Adriamycin

Daunorubicin

Vinblastine + Vincristine + VP-16

Cyclophosphamide + Methotrexate

5-FU

<1.5

<60

100

100

100

100

100

1.5–3.0

60–180

75

75

50

100

100

3.1–5.0

>180

50

50

Omit

175

100

5.0

 

Omit

Omit

Omit

Omit

Omit

5-FU, 5-fluorouracil; NC, no change; SGOT, serum glutamic-oxaloacetic transaminase.

 

 

 

Dose Modification Guidelines

Drug doses are routinely modified for decreases in blood counts and for changes in renal or hepatic function. Individual protocols should be consulted for possible modifications. Table 30-2 outlines commonly used guidelines for dose reductions. The occurrence of certain toxicities, such as neurotoxicity from the vinca alkaloids or mucositis from methotrexate, is also used as an indication for reduction in dose or cessation of the drug.

Response Criteria

Complete response implies disappearance of all measurable or evaluable disease, signs, symptoms, and biochemical changes related to the tumor for at least 4 weeks, during which time no new lesions may appear. Partial response implies a reduction of greater than 50% in the sum of the products of the perpendicular diameters of all measurable lesions (compared with pretreatment measurements) lasting at least 4 weeks, during which no new lesions may appear and no existing lesion may enlarge. For hepatic lesions, a reduction of greater than 30% in the sum of the measured distances from the costal margin at the midclavicular line and at the xiphoid process to the edge of the liver is required. Stable disease is a less than 50% reduction or a less than 25% increase in the sum of the products of the two perpendicular diameters of all measured lesions and the appearance of no new lesions for 8 weeks. Progression or relapse is defined as an increase in the product of two perpendicular diameters of any measurable lesion by more than 25% over the size that is present at entry into the study, or, for patients who respond, over the size at time of maximum regression, or the appearance of new areas of malignant disease (usually excluding central nervous system metastases). A two-step deterioration in performance status, greater than 10% loss of pretreatment weight, or increasing symptoms in and of themselves, do not constitute progression. Their appearance, however, should initiate a new evaluation for disease extent.

Follow-up

Adjuvant therapy is usually given for a set number of cycles, such as six cycles (or months) of chemotherapy after a modified radical mastectomy or lumpectomy for stage I or II breast cancer. For other situations, such as metastatic disease, it is common to reevaluate the patient after two to three cycles (months) of therapy to determine its effectiveness. If therapy has clearly produced a response (using the criteria discussed previously) and is tolerable for the patient, it is usually continued for a set number of cycles or for two courses past a complete response (to eliminate any remaining microscopic tumor). If the disease has progressed during this interval, therapy is discontinued, and a reevaluation is undertaken. Stable disease after therapy represents the most difficult clinical situation that is encountered. If the patient can tolerate the therapy in terms of side effects, then a mutual decision to continue is reasonable, with the realization that eventually, progressive disease will be seen.

CHEMOTHERAPEUTIC AGENTS

The information about the agents in the following list is taken from multiple sources, but the latest information from the manufacturer should be sought before initiating therapy. [82] [88] [89] [90] [91] [92] [93]Unless otherwise specified, all chemotherapeutic agents are capable of producing some degree of nausea and/or vomiting with administration and myelosuppression, alopecia, and mucositis and/or diarrhea after treatment. Because most agents are also harmful to the gonads and fetus, these toxicities will not be spelled out. Administration of chemotherapy during pregnancy is warranted only in special circumstances and requires a particularly high level of expertise.[94] The increasing incidence of second malignancies as a late complication following successful chemotherapy should also be noted.

  

 

Alemtuzumab (Campath)

  

 

Drug Class: Recombinant humanized monoclonal antibody that targets the CD 52 antigen present on most normal and malignant β- and T-cell lymphocytes. This results in antibody-dependent cellular toxicity and complement binding, then apoptosis and activation of T-cell-induced cytotoxicity.

  

 

Dosage Form: 30-mg vial.

  

 

Drug Interactions: None.

  

 

Pharmacokinetics/Metabolism: Metabolic fate unknown.

  

 

Toxicity: Anaphylactoid reactions. Immunosuppression with decreased CD4 and CD8 counts with resulting increase in opportunistic infections. Myelosuppression. GI toxicity: nausea, vomiting, diarrhea. Constitutional symptoms.

  

 

Indications: Food and Drug Administration (FDA) approved for treatment of relapsed or refractory β-cell chronic lymphocytic leukemia and refractory T-cell prolymphocytic leukemia.

  

 

Dosing: 30 mg/day IV infusion three times weekly for up to 12 weeks.

  

 

Altretamine (Hexalen)—Hexamethylmelamine, HMM

  

 

Drug Class: Alkylating agent.

  

 

Dosage Form: 50-mg capsules.

  

 

Drug Interactions: Metabolism may be slowed by cimetidine or enhanced by Phenobarbital.

  

 

Pharmacokinetics/Metabolism: Well absorbed by mouth, metabolized in the liver. Elimination half-life 4 to 13 hours. Metabolites largely excreted in the urine.

  

 

Toxicity: Myelosuppression is dose limiting. Leukopenia, thrombocytopenia, nausea, and vomiting are common. Neurologic toxicity, including confusion, lethargy, weakness, and sensory changes, is common.

  

 

Indications: FDA approved for refractory ovarian carcinoma.

  

 

Dosing: 4 to 12 mg/kg/day in divided doses for 3 to 6 weeks or 150 mg/m2/day for 14 days each cycle; higher doses have been used.

  

 

Amifostine (Ethyol)—WR-2721, ethiofos

  

 

Drug Class: Cytoprotectant; free-radical scavenger.

  

 

Dosage Form: 500 mg of powder in vial.

  

 

Drug Interactions: Not known to decrease the effectiveness of any cytotoxic drug but not yet adequately studied.

  

 

Pharmacokinetics/Metabolism: Poorly absorbed in the GI tract. After IV infusion, the drug is metabolized to inactive forms in the plasma. Metabolites are cleared in the urine.

  

 

Toxicity: Transient hypotension is dose limiting. Nausea, vomiting, and somnolence are common. Sneezing, hypocalcemia, and flushing can be seen.

  

 

Indications: FDA approved for pretreatment with cisplatin. Useful as a bone marrow, kidney, and nerve cytoprotectant. Useful with other alkylators as well. Also FDA approved as a radiation protectant to reduce xerostomia.

  

 

Dosing: 740 mg/m2 IV infusion over 15 minutes given 15 to 30 minutes before the cytotoxic agent or radiation. Lower doses and subcutaneous administration have also been used.

  

 

Anagrelide (Agrylin)

  

 

Drug Class: Inhibitor of platelet aggregation with an exploitable side effect of thrombocytopenia, for which the mechanism is unclear.

  

 

Dosage Form: 0.5-mg capsules.

  

 

Drug Interactions: Sucralfate may decrease absorption.

  

 

Pharmacokinetics/Metabolism: Good oral bioavailability; maximum plasma concentration occurs after 1 hour. The plasma half-life is 1.3 hours. The drug is metabolized extensively in the liver. Metabolites are excreted in the urine.

  

 

Toxicity: Other than thrombocytopenia, common toxicities include hypotension, headache, and palpitations. Rare toxicities include anemia, arrhythmias, angina pectoris, and congestive heart failure.

  

 

Indications: FDA approved for treatment of essential thrombocytosis as an orphan drug.

  

 

Dosing: 0.5 mg four times daily or 1 mg twice daily.

  

 

Anastrazole (Arimidex)

  

 

Drug Class: Nonsteroidal aromatase inhibitor; blocks estrogen production selectively.

  

 

Dosage Form: 1-mg tablets.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Well absorbed from the GI tract, with maximum plasma levels achieved within 2 hours. Terminal elimination half-life is 50 hours. The drug is extensively metabolized in the liver and is eliminated in the urine as metabolites and 10% unchanged drug. Despite hepatic and renal clearance being important, no adjustments are needed for abnormal function of these organs due to the wide therapeutic index of this drug. Eliminated in the urine as metabolites and 10% unchanged drug.

  

 

Toxicity: The drug is very well tolerated. Asthenia, headache, and hot flashes occur in fewer than 15% of women. Diarrhea, abdominal pain, anorexia, nausea, and vomiting occur in 10% or fewer. Thrombophlebitis has been reported.

  

 

Indications: As adjuvant therapy of breast cancer and for treatment of postmenopausal women with breast carcinoma who have progressed on tamoxifen therapy.

  

 

Dosing: 1 mg PO every day. Higher doses are no more effective.

  

 

Arsenic Trioxide (Trisenox)

  

 

Drug Class: Novel arsenical differentiating agent.

  

 

Dosage Form: Ampules containing 10 mg of drug in 10 mL solution.

  

 

Drug Interactions: None known.

  

 

Pharmacokinetics/Metabolism: Half-life of this compound is unknown. It is methylated in the liver and eliminated in the urine.

  

 

Toxicity: The “differentiation syndrome” is dose limiting and includes leukocytosis, fever, dyspnea, chest pain, tachycardia, hypoxia, and sometimes death. Corticosteroids seem to benefit this syndrome. QT prolongation is common. Common side effects include rash, pruritus, headache, arthralgias, anxiety, bleeding, nausea, and vomiting. Liver and renal toxicity are uncommon.

  

 

Indications: FDA approved for relapsed acute promyelocytic leukemia.

  

 

Dosing: 0.15 mg/kg/day in 100 to 250 mL of D5W until remission, not to exceed 60 doses, then up to 25 doses over five weeks for consolidation starting 3 to 6 weeks after achievement of remission.

  

 

L-Asparaginase (Elspar)—colaspase

  

 

Drug Class: Naturally occurring enzyme derived from Escherichia coli or Erwinia carotovora that cleaves the amino acid asparagine, which is an essential amino acid required by rapidly proliferating cells.

  

 

Dosage Form: 10,000-IU vial of lyophilized cake.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Not orally bioavailable. After IV or IM injection, the drug is metabolized intravascularly by proteolysis. Elimination half-life of 8 to 30 hours. No excretion is required.

  

 

Toxicity: Hypersensitivity can be life threatening, requiring anaphylaxis precautions and a 2-unit test dose. Coagulopathy is common and requires monitoring. Nausea, vomiting, abdominal cramps, anorexia, elevated liver function tests, and transient renal insufficiency are common. Lethargy, somnolence, fatigue, depression, and confusion are seen, as are pancreatitis and fever.

  

 

Indications: FDA approved for acute lymphoblastic lymphoma (ALL); also used in AML, late-stage chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), and non-Hodgkin's lymphomas.

  

 

Dosing: After a 2-unit intradermal test dose, an IM dose of 6000 to 10,000IU/m2 every 3 days for nine doses, or 1000IU/kg/day IV over 30 minutes for 10 days, has been used.

  

 

PEG-Asparaginase (Oncaspar)—pegaspargase

  

 

Drug Class: Naturally occurring enzyme, covalently linked to polyethylene glycol to reduce immunogenicity, slow metabolism, and prolong half-life. The enzyme cleaves the amino acid asparagine, which is an essential amino acid required by rapidly proliferating cells.

  

 

Dosage Form: 750IU/mL in a 5-mL vial No reconstitution or dilution necessary.

  

 

Drug Interactions: None noted. Can reduce effectiveness of methotrexate if given beforehand, due to inhibition of cell division.

  

 

Pharmacokinetics/Metabolism: The drug is not absorbed by the GI tract. When given by IM injection, it has an elimination half-life of approximately 5 days and is not detected in urine or bile. Metabolized completely, clearance not dependent on renal or hepatic function.

  

 

Toxicity: Although less immunogenic that the non-PEGylated form, hypersensitivity and anaphylaxis can still occur. Toxicities similar to those of the non-PEGylated forms are seen, including elevated liver enzymes, coagulopathy, hypercholesterolemia, pancreatitis, hyperglycemia, fever, chills, anorexia, lethargy, confusion, headache, seizures, and azotemia.

  

 

Indications: FDA approved for treatment of ALL, and, like asparaginase, is also used for other leukemias and non-Hodgkin's lymphomas.

  

 

Dosing: 2,500IU/m2 IM every 14 days with other chemotherapy agents for induction or maintenance.

  

 

Azacitadine—NSC-102816 (investigational)

  

 

Drug Class: Antimetabolite, cytidine analog; incorporated into nucleic acids, causing interruption of or errors in transcription and replication of DNA.

  

 

Dosage Form: 100-mg vial of lyophilized powder: 100-mg vial diluted to 20 mL in sterile water, and then rapidly diluted to a final concentration of 0.2 to 2 mg/mL in normal saline or 5% dextrose in water.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Not orally bioavailable. When administered by IV infusion, the drug is activated inside cells to the triphosphate form. It is deaminated in the liver. The elimination half-life is 3 to 6 hours. Parent drug and metabolites are excreted in the urine.

  

 

Toxicity: Myelosuppression is dose limiting. Leukopenia can be prolonged. Nausea and vomiting are common and can be severe. Diarrhea is common; stomatitis is rare. Hepatic enzyme elevation and liver function compromise are common. Transient azotemia is seen. Lethargy, confusion, and coma have been reported.

  

 

Indications: Investigational agent for AML.

  

 

Dosing: 150 to 300 mg/m2/day for 5 days every 3 weeks, or 150 to 200 mg/m2 twice weekly for several weeks.

  

 

Azacytidine (Vidaza)

  

 

Drug Class: Antimetabolite. 5-AZA induces hypomethylation of DNA, which may either induce apoptosis or restore normal function. At higher doses, it acts as a cytidine analog.

  

 

Dosage Form: 100-mg vial of lyophilized powder: 100-mg vial diluted to 20 mL in sterile water, and then rapidly diluted to a final concentration of 0.2 to 2 mg/mL in normal saline or 5% dextrose in water.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Not orally bioavailable. Metabolized by the liver and excreted in urine. Elimination half-life of 4 hours.

  

 

Toxicity: Myelosuppression is dose limiting. Leukopenia, thrombocytopenia, and transient elevation of liver function tests are common; nausea and vomiting and abdominal pain are common.

  

 

Indications: Myelodysplastic syndromes.

  

 

Dosing: 75 to 100 mg/m2 for 7 days; repeated every 4 weeks for 4 to 6 cycles.

  

 

Azathioprine (Imuran)

  

 

Drug Class: Purine analog antimetabolite, which is converted to 6-mercaptopurine in vivo.

  

 

Dosage Form: 50-mg tablets and 100-mg vials of lyophilized powder.

  

 

Drug Interactions: Azathioprine may inhibit the anticoagulant effects of warfarin. Allopurinol blocks the xanthine oxidase-mediated metabolism of azathioprine, requiring reduction of dose for patients taking allopurinol. Angiotensin-converting enzyme inhibitors may exaggerate the myelosuppressive effects of azathioprine.

  

 

Pharmacokinetics/Metabolism: Azathioprine has good oral bioavailability and is rapidly converted to mercaptopurine in the blood compartment. The parent drug and thiol metabolites have a half-life of about 5 hours, but the metabolism of active forms is very rapid, with virtually no azathioprine detectable in urine after a dose. Metabolism occurs in blood and liver. Inactive metabolites are excreted in the urine.

  

 

Toxicity: Myelosuppression is expected and dose limiting. Due to chronic dosing of this drug, the effects on leukocytes, platelets, and to a lesser extent red cells are slow in onset and usually rapidly reversible. A rare metabolic disorder called thiopurine methyltransferase deficiency results in extreme sensitivity to this drug in affected persons. Nausea and vomiting are common but usually mild and transient during chronic therapy. Opportunistic infections are uncommon. Diarrhea, fever, myalgias, skin rashes, and interstitial pneumonitis are rare. Secondary malignancies have been reported. This drug should not be used during pregnancy or nursing.

  

 

Indications: FDA approved for renal transplant recipients and for rheumatoid arthritis. Also used in some hematologic malignancies.

  

 

Dosing: Chronic dosing for the preceding indications is in the range of 1 to 3 mg/kg/day. Higher doses, using the intravenous formulation, are used in the immediate post-transplant period.

  

 

Bacillus Calmette-Guérin (TICE BCG, TheraCys)—BCG

  

 

Drug Class: Immunostimulant/vaccine; induces a cellular immune response at the site of instillation.

  

 

Dosage Form: Freeze-dried powder in vials, 27 mg/vial, supplied with diluent.

  

 

Drug Interactions: Immunosuppressive drugs may block the reaction to BCG and also make the patient more prone to clinical infection from viable BCG organisms.

  

 

Pharmacokinetics/Metabolism: BCG is a live, attenuated bacteria culture, and as such, it does not enter the body in viable form in any quantity. Therefore, it has no detectable pharmacokinetic fate. In rare cases, however, a clinical infection can result from treatment, indicating invasion of the body at the site of administration into the systemic circulation.

  

 

Toxicity: Urinary symptoms predominate, including dysuria, hematuria, hesitancy, urgency, frequency, and secondary infection. Other toxicities include fever, chills, malaise, myalgias/arthralgias, anorexia, nausea, vomiting, and anemia. Clinical mycobacterial infection is rare and generally seen only in immunocompromised patients.

  

 

Indications: Intravesical instillation is FDA approved for noninvasive bladder cancer after removal of papillary tumors. Also used for some experimental vaccine programs as an adjuvant to the vaccine.

  

 

Dosing: 81 mg per treatment, in 53 mL total volume, instructions as previously given. Given once weekly for 6 doses and then at 3, 6, 12, 18, and 24 months after the induction.

  

 

Bevacizumab (Avastin)

  

 

Drug Class: Recombinant humanized monoclonal antibody that binds to all human forms of vascular endothelial growth factor (VEGF), preventing binding to it receptors.

  

 

Dosage Form: 100-mg and 400-mg vials of lyophilized powder: 100-mg vial diluted to 20 mL in sterile water and then rapidly diluted to a final concentration of 0.2 to 2 mg/mL in normal saline or 5% dextrose in water.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Administered by IV infusion. Half-life is 20 days. The fate of parent drug and metabolites is unknown.

  

 

Toxicity: Most common: asthenia, pain, nausea/vomiting, diarrhea, anorexia, stomatitis, dermatitis, hypertension, proteinuria. Infusion-related reactions are rare. Hemoptysis, hemorrhage, delayed wound healing, gastrointestinal perforations; increased risk of thromboembolic events can be severe or fatal.

  

 

Indications: FDA approved for metastatic colorectal cancer, breast cancer and non-small-cell lung cancer.

  

 

Dosing: 5 to 15 mg/m2/day IV every 3 weeks.

  

 

Bexarotene (Targretin)

  

 

Drug Class: Synthetic retinoid, differentiating agent.

  

 

Dosage Form: 75 mg capsules.

  

 

Drug Interactions: No formal studies done. Drugs which inhibit cytochrome P450 3A4 such as ketoconazole, erythromycin, and gemfibrozil expected to increase plasma levels and half-life of bexarotene. Known to decrease plasma levels of tamoxifen with concomitant administration.

  

 

Pharmacokinetics/Metabolism: Good oral bioavailability increased by a high-fat meal. Metabolized in the liver to oxidative metabolites by cytochrome P450 3A4, glucuronidated, eliminated in the bile.

  

 

Toxicity: Hyperlipidemia is dose-limiting and should be monitored while on therapy and treated as appropriate. Pruritus, leukopenia, diarrhea, fatigue, headache, and liver function test elevation can also be dose limiting. Rash, edema, fever, chills, and nausea are uncommon. Excessive bleeding and back or abdominal pain are rare.

  

 

Indications: FDA approved for treatment of cutaneous T-cell lymphoma (mycosis fungoides) refractory to at least one prior therapy.

  

 

Dosing: 300 mg/m2/day orally, dose adjusted for toxicity.

  

 

Bicalutamide (Casodex)

  

 

Drug Class: Nonsteroidal antiandrogen.

  

 

Dosage Forms: 50-mg tablet.

  

 

Drug Interactions: Bicalutamide may enhance the anticoagulant effects of warfarin.

  

 

Pharmacokinetics/Metabolism: Bicalutamide is well absorbed after oral administration. It is highly protein-bound. It undergoes conversion to inactive metabolites in the liver via oxidation and glucuronidation. It has a terminal half-life of several days. Parent drug and metabolites are excreted in the urine and feces.

  

 

Toxicity: Constitutional symptoms predominate, including hot flashes, decreased libido, depression, weight gain, edema, gynecomastia, early disease-site pain (flare reaction), and constipation. Nausea, vomiting, anorexia, diarrhea, and dizziness are uncommon. Dyspnea, anemia, fever, and rashes are rare.

  

 

Indications: FDA approved for stage D2 prostate cancer, in combination with a luteinizing hormone–releasing hormone (LHRH) agonist agent.

  

 

Dosing: 50 mg by mouth daily, in combination with an LHRH agonist agent.

  

 

Bleomycin (Blenoxane)—Bleo

  

 

Drug Class: Antitumor antibiotic; causes DNA strand breaks directly in normal and neoplastic cells.

  

 

Dosage Forms: Available as 15-unit (15-mg) vials of lyophilized powder.

  

 

Drug Interactions: None noted.

  

 

Phamakokinetics/Metabolism: Bleomycin is not orally bioavailable. After an IV infusion, it has an elimination half-life of 3 to 5 hours. Bleomycin is incompletely metabolized by intracellular aminopeptidases. It is excreted in the kidney as unchanged drug and metabolites.

  

 

Toxicity: Pulmonary toxicity, including reversible and irreversible fibrosis, is dose limiting. Other common toxicities include fever, chills, rash, exfoliation, and anorexia. Nausea, vomiting, myelosuppression, anaphylaxis, and mucositis are rare.

  

 

Indications: FDA approved for germ cell tumors, Hodgkin's disease, and squamous cell cancers; used off-label for melanoma, ovarian cancer, and Kaposi's sarcoma. Also used as a sclerosing agent for malignant pleural or pericardial effusions

  

 

Dosing: After 1 to 6 hours of observation following a 2-unit IV test dose given over 15 minutes, the full dose can be given. The usual dose is 10 to 20 units/m2 IV, IM, or SC one to two times per week, or 15 to 20 units/m2/day as a continuous infusion over 3 to 7 days. As a sclerosing agent 60 units is generally used.

  

 

Buserelin (Suprefact)—HOE 766

  

 

Drug Class: LHRH agonist; shuts off luteinizing hormone and follicle-stimulating hormone secretion, thereby resulting in chemical castration.

  

 

Dosage Form: Available as vials for injection at 1 mg/mL and as an intranasal spray in a 10-mL canister.

  

 

Drug Interactions: May cause pain flares in bone metastases if not given with a direct hormonal antagonist.

  

 

Pharmacokinetics/Metabolism: Intravascular and extravascular proteolysis.

  

 

Toxicity: Flare reactions as noted previously, which can be prevented. Castration symptoms such as hot flashes and decreased libido common. Other nonspecific symptoms include headache, nausea, vomiting, diarrhea, constipation, and weakness.

  

 

Indications: FDA approved for prostatic cancer.

  

 

Dosing: 500 mg SC tid for the first week, then 200 mg/day, or intranasally 800 mg tid followed by 400 mg tid.

  

 

Busulfan (Myleran)—BSF

  

 

Drug Class: Alkylating agent.

  

 

Dosage Form: 2-mg scored tablets (an IV form is not yet widely available).

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Excellent oral bioavailability, with peak levels in serum occurring at about 1 hour. Elimination half-life of 2.5 hours. Metabolized partially in liver. Parent drug and metabolites excreted in the urine.

  

 

Toxicity: Myelosuppression, partly chronic and cumulative, is dose limiting. Other common toxicities include nausea, vomiting, anorexia, mucositis, hyperpigmentation, and elevated liver function tests (or veno-occlusive disease of the liver at transplant doses). Neurologic toxicity, including blurred vision, dizziness, and confusion, and interstitial lung disease are less common.

  

 

Indications: Regular-dose therapy in CML (FDA approved) and polycythemia vera. High-dose therapy in bone marrow transplant.

  

 

Dosing: Regular dose: 4 to 8 mg/day. High dose: 8 to 16 mg/kg total dose.

  

 

Capecitibine (Xeloda)

  

 

Drug Class: Oral antimetabolite prodrug.

  

 

Dosage Form: 150-mg and 500-mg tablets.

  

 

Drug Interactions: Capecitibine increases the half-life, area under the curve (AUC), and prothrombin time effect of warfarin. Maalox, when given immediately after capecitibine, increases the oral bioavailability of capecitibine.

  

 

Pharmacokinetics/Metabolism: Readily absorbed by the GI tract, metabolized in vivo to fluorouracil in the liver by carboxylesterase and cytidine deaminase, and then in turn in the peripheral tissues and tumor tissue by thymidine phosphorylase. Capecitibine appears to produce higher levels of fluorouracil in tumor tissue than in normal tissues, probably because thymidine phosphorylase is expressed at higher levels in most tumor tissues.

  

 

Toxicity: Myelosuppression and palmar-plantar erythrodysesthesia are dose limiting. Diarrhea, fatigue, stomatitis, and hyperbilirubinemia are uncommon. Nausea, vomiting, and rash are rare.

  

 

Indications: FDA approved for metastatic breast cancer and metastatic colorectal cancer. Used also in head and neck squamous cell cancer.

  

 

Dosing: The approved dose and schedule is 1250 mg/m2 every 12 hours for 14 days every 21 days. Dose reductions are often required. Treatment delays are sometimes required. Other doses and schedules have been used.

  

 

Carboplatin (Paraplatin)—Carbo, CBDCA

  

 

Drug Class: Atypical alkyator; produces intrastrand and interstrand cross-links in DNA via association bonds with the platinum molecule, leading to DNA strand breakage during replication.

  

 

Dosage Form: Available as powder in glass vials: 50, 150, and 450 mg/vial.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Carboplatin is not orally bioavailable. It is rapidly cleared from the bloodstream after IV infusion, with a terminal half-life of 2.5 hours. It is cleared largely as unchanged drug by the kidneys.

  

 

Toxicity: Myelosuppression, especially thrombocytopenia, is dose limiting. Nausea and vomiting are mild. Renal and neuronal toxicity are rare.

  

 

Indications: FDA approved for ovarian cancer and used extensively in testicular cancer, squamous cell cancers of the head and neck and cervix, and lung cancer.

  

 

Dosing: Dosing can be done on a per-meter-squared basis or through several formulas that take into account renal function and desired level of thrombocytopenia (such as Calvert's formula). Typical doses with normal renal function are in the 300- to 500-mg/m2 range as an IV infusion.

  

 

Carmustine (BiCNU)—BCNU, bis-chloronitrosourea

  

 

Drug Class: Alkylator agent in the nitrosourea class. Cell cycle-independent mechanism.

  

 

Dosage Form: 100-mg vial of carmustine powder and 3-mL vial of ethanol.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Poorly available by the oral route. After an IV infusion, the drug is rapidly taken up by tissues, including the CNS. Extensively metabolized in the liver. The serum half-life is only 15 to 20 minutes. The parent drug and metabolites are cleared by the kidney.

  

 

Toxicity: Myelosuppression, which is slow in onset and cumulative, is dose limiting. Nausea and vomiting are common and can be severe. Hyperpigmentation and renal toxicity can be seen. Interstitial lung disease, including fibrosis, is rare but can occur with any dose. Transplant doses can cause severe liver toxicity and more frequent lung toxicity.

  

 

Indications: FDA approved for brain tumors, multiple myeloma, Hodgkin's disease, lymphoma. Also used for breast cancer, melanoma, stomach cancer, colon cancer, and liver cancer.

  

 

Dosing: Single-agent dose is 150 to 200 mg/m2 every 6 weeks. For transplant, the dose is as high as 600 mg/m2, along with other drugs.

  

 

Carmustine impregnated wafer (Gliadel)—polifeprosan 20 with carmustine implant.

  

 

Drug Class: Novel delivery mechanism for classical nitrosourea alkylating agent.

  

 

Dosage Form: Each individually packaged, sterile wafer contains 7.7 mg of carmustine.

  

 

Drug Interactions: None known.

  

 

Pharmacokinetics/Metabolism: More than 70% of the copolymer degrades by 3 weeks. Gliadel wafers produce minimal systemic exposure to carmustine. The copolymer itself is biodegradable, but metabolites of the polymer have no known or expected pharmacologic implications.

  

 

Toxicity: None.

  

 

Indications: FDA approved for adjuvant treatment of recurrent glioblastoma multiforme. Being tested in the setting of initial resection.

  

 

Dosing: Up to eight wafers are placed in the resection cavity at the time of craniotomy and operative resection.

  

 

Cetuximab (Erbitux)

  

 

Drug Class: Monoclonal antibody.

  

 

Dosage Form: IV.

  

 

Drug Interactions: None known.

  

 

Pharmacokinetics/Metabolism: A recombinant humanized monoclonal antibody targeted against the epidermal growth factor receptor. It competitively inhibits growth factor binding and inhibiting autophosphorylation and cell signaling. Metabolism is poorly understood. Half-life is 5 to 7 days with minimal clearance by kidneys or liver.

  

 

Toxicity: Infusion reaction, characterized by rapid onset dyspnea, fever, chills, urticaria, flushing, angioedema, and hypotension is seen in 40% to 50% of patients. Acneiform rash is common. Constitutional symptoms. Hypomagnesemia. Interstitial lung disease is rare.

  

 

Indications: Metastatic colorectal cancer, head and neck cancer in combination with radiation.

  

 

Dosing: 400 mg/m2 IV, followed by 250 mg/m2 weekly.

  

 

Chlorambucil (Leukeran)

  

 

Drug Class: Alkylating agent. Cell cycle independent.

  

 

Dosage Form: 2-mg tablets.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Excellent oral bioavailability; maximum plasma level at 1 hour. Elimination half-life of 1 to 2 hours. Extensively metabolized in the liver to active and inactive metabolites, which are excreted via the kidneys.

  

 

Toxicity: Myelosuppression is dose limiting and universal, and it can be cumulative. Nausea, vomiting, and diarrhea are mild and uncommon. Sterility and alopecia occur in a minority of patients. Pulmonary fibrosis and neurologic side effects are quite rare.

  

 

Indications: FDA approved for CLL and low-grade lymphomas. Also used for Waldenstrom's macroglobulinemia, multiple myeloma, hairy cell leukemia, and rarely in some solid tumors.

  

 

Dosing: 16 mg/m2/day for 5 days every 4 weeks, or 0.4 mg/kg every 2 to 4 weeks, or 0.1 to 0.2 mg/kg/day for 3 to 6 weeks.

  

 

Cisplatin (Platinol)—cDDP, DDP, cisplatinum, cis-diamminedichloroplatinum (II)

  

 

Drug Class: Atypical alkyator; produces intrastrand and interstrand cross-links in DNA via association bonds with the platinum molecule, leading to DNA strand breakage during replication.

  

 

Dosage Form: Lyophilized powder in sealed vials of 10 and 50 mg, and as a 1-mg/mL solution in bottles of 50 and 100 mg/bottle.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Poor oral bioavailability. After IV infusion, rapid distribution to tissues takes place, and the drug is over 90% protein bound. While the distribution half-life is less than 1 hour, the terminal half-life is 60 to 90 hours due to tissue retention. Not extensively metabolized. Elimination is via the kidneys.

  

 

Toxicity: Nephrotoxicity is dose limiting for an individual dose, while neurotoxicity, especially painful peripheral neuropathy, is dose limiting for cumulative doses. Myelosuppression is mild. Nausea and vomiting are common but manageable, and anorexia and diarrhea are common. Cumulative ototoxicity is also common. Chronic renal magnesium and potassium wasting is common and sometimes not reversible. Elevated liver transaminases can be seen, while alopecia and cardiac conduction abnormalities are rare.

  

 

Indications: Used for almost every class of solid tumor and lymphoma. FDA approved for testicular and ovarian cancer and transitional cell carcinoma.

  

 

Dosing: Cisplatin can be given all in one IV infusion or given daily as an IV infusion for several days for each cycle. Daily divided doses are somewhat better tolerated. The total dose per cycle ranges from 80 to 160 mg/m2. Continuous infusion can also be used. Dose should be reduced for a creatinine clearance below 60 mL/min. Adequate renal perfusion and urine output are critical for minimizing renal toxicity; therefore, prehydration and adequate post-treatment hydration are used, usually with normal saline with or without mannitol, potassium, and magnesium, along with the cisplatin. Cisplatin 100 to 200 mg/m2 is also used intraperitoneally for ovarian cancer.

  

 

Cladribine (Leustatin)—chlorodeoxyadenosine, 2-CdA

  

 

Drug Class: Antimetabolite, purine analog; cytotoxic to dividing and nondividing cells via disruption of DNA function.

  

 

Dosage Form: 1-mg/mL solution in 20-mL vials.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Not orally bioavailable. After IV administration, it has a distribution half-life of 36 minutes and an elimination half-life of 7 hours. Resistant to adenosine deaminase. Chemical conversion to the active form takes place intracellularly in all cells that have deoxycytidine kinase activity. Further information on metabolism and excretion is not available.

  

 

Toxicity: Renal toxicity is dose limiting, but at the typical doses used, myelosuppression is most prominent, including universal lymphopenia and common neutropenia and thrombocytopenia. Fever is common, while nausea and vomiting are rare and mild, and neurologic reactions are rare.

  

 

Indications: FDA approved for hairy cell leukemia. Also used in chronic and acute leukemias, lymphoma, and mycosis fungoides.

  

 

Dosing: For hairy cell leukemia, the dose is 0.1 mg/kg/day for 7 days as a continuous IV infusion, as a single treatment or repeated once. Other doses have ranged from 0.1 to 0.3 mg/kg/day for 5 to 7 days. Can also be given subcutaneously.

  

 

Clofarabine (Clolar)

  

 

Drug Class: Antimetabolite.

  

 

Dosage Form: IV 20-mL vials.

  

 

Drug Interactions: None known.

  

 

Pharmacokinetics/Metabolism: Purine nucleoside antimetabolite. Metabolized intracellularly to the 5′ monophosphate metabolite and then phosphorylated to active triphosphate form. Inhibits DNA synthesis by decreasing deoxynucleoside triphosphate pools by inhibiting ribonucleotide reductase. Incorporates into DN, inhibiting DNA repair. Negligible hepatic metabolism. Most of drug is excreted unchanged in the urine.

  

 

Toxicity: Myelosuppression. Nausea and vomiting. Hepatobiliary toxicity. Cardiac toxicity (decrease in ejection fraction and tachycardia). Capillary leak syndrome.

  

 

Indications: Relapsed or refractory acute lymphoblastic leukemia in children.

  

 

Dosing: 52 mg/m2 IV over 2 hours daily for 5 days, repeated every 2 to 6 weeks.

  

 

Cyclophosphamide (Cytoxan, Neosar)—CTX, CPM, Cy

  

 

Drug Class: Prototypical alkylator drug. Cell cycle independent.

  

 

Dosage Form: 25-mg and 50-mg tablets for oral use, and vials of powder in 100, 200, 500, 1000, and 2000-mg sizes for IV administration.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: 75% oral bioavailability; peak serum levels occur approximately 1 hour after administration. Activated by hepatic enzymes and metabolized to inactive forms in the liver as well. Elimination half-life is 3 to 10 hours. Parent drug and metabolites are excreted in the urine.

  

 

Toxicity: Myelosuppression is dose limiting, leukopenia being most significant. Nausea and vomiting are common and can be chronic with oral administration. Hemorrhagic cystitis is uncommon with standard doses but is common with doses over 2 g/m2. Other toxicities of high-dose therapy include syndrome of inappropriate secretion of antidiuretic hormone, pulmonary fibrosis, and hemorrhagic myocarditis. Secondary malignancies are rare but well documented.

  

 

Indications: FDA approved for many malignancies and used for even more. Most commonly used for breast carcinoma, non-Hodgkin's lymphoma, ovarian carcinoma, and testicular cancer.

  

 

Dosing: Doses range from 50 mg/m2 for 14 days every 28 days, to standard IV doses of 600 to 2000 mg/m2 once every 21 to 28 days, to transplant doses of 60 mg/kg IV for 2 days.

  

 

Cytarabine (Cytosar-U)—AraC, cytosine arabinoside

  

 

Drug Class: Antimetabolite; incorporated into DNA during replication, leading to strand termination. This drug is S-phase specific.

  

 

Dosage Form: Comes in 100-mg through 2000-mg vials of powdered drug.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Parenteral bioavailability only. After an IV dose, it is rapidly distributed into tissues, where it is converted to AraC triphosphate and rapidly deaminated in the blood. It has an elimination half-life of 2 to 3 hours. Eliminated through the kidneys.

  

 

Toxicity: Myelosuppression, often severe and prolonged, is dose limiting. It affects all lineages. Nausea, vomiting, anorexia, mucositis, and diarrhea are common. Skin erythema with exfoliation is common. Keratitis and conjunctivitis are common. Hepatic inflammation and elevation of liver function tests are common. Flu-like syndrome with fever is common. Neurologic toxicity, mostly central with ataxia being predominant, is common and usually mild, but it is dose dependent and may leave permanent dysfunction. It is more common with intrathecal administration. Pulmonary infiltrates after administration are uncommon but can be fatal. Cardiac complications are rare.

  

 

Indications: AML, ALL, and non-Hodgkin's lymphoma. Intrathecal use in acute leukemia.

  

 

Dosing: Doses range from 100 mg/m2/day for 7 days as bolus or continuous infusion to 3 g/m2 every 12 hours for 3 days. Doses less than 500 mg/m2 are considered standard, while doses of 1 g/m2 or more are considered high. The intrathecal dose is generally from 12 mg total dose up to 30 mg/m2, given intermittently during systemic treatment.

  

 

Cytarabine, liposomal (DepoCyt)

  

 

Drug Class: Novel liposomal preparation of an antimetabolite for extended exposure to cancer cells in the cerebrospinal fluid.

  

 

Dosage Form: Vials containing 50 mg of drug in aqueous liposomal solution.

  

 

Drug Interactions: Minimal systemic exposure after intrathecal administration. Drug interactions are not considered clinically important.

  

 

Pharmacokinetics/Metabolism: After intrathecal administration of liposomes, peak levels of cytarabine occur in the CSF at 5 hours, and the half-life of cytarabine in the CSF is 100 to 200 hours. Cytarabine and metabolites eventually enter the plasma compartment, where they are eliminated in the urine.

  

 

Toxicity: Chemical arachnoiditis is common and dose limiting. Headache and back pain are the major clinical manifestations. Myelosuppression is common but usually mild. Fever, nausea, and vomiting are uncommon. Neurologic side effects are also uncommon.

  

 

Indications: FDA approved for treatment of lymphomatous meningitis. Appears to active in leukemic meningitis and carcinomatous meningitis, but published experience is limited.

  

 

Dosing: 50 mg intrathecally via spinal needle or Ommaya reservoir over 1 to 5 minutes every 14 days for up to 9 doses and then every 28 days for up to 4 doses.

  

 

Dacarbazine (DTIC-Dome)—DTIC, DIC, imidazole carboxamide

  

 

Drug Class: Atypical alkylator; methylates guanine bases preferentially. Non-cell cycle dependent.

  

 

Dosage Form: Vials of lyophylized drug containing 100, 200, or 1000 mg.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Not orally bioavailable. After IV administration, the drug is activated by demethylation by microsomal enzymes in the liver and further metabolized to inactive forms. The elimination half-life is 3 to 5 hours. Active and inactive metabolites are largely excreted in the urine.

  

 

Toxicity: Myelosuppression is dose limiting. Nausea and vomiting are severe without aggressive antiemetic therapy. Fever is common, and flu-like syndrome is uncommon, as are diarrhea, stomatitis, alopecia, rash, or significant liver or renal toxicity.

  

 

Indications: FDA approved for the treatment of malignant melanoma and Hodgkin's disease; also used for adult sarcomas and neuroblastoma.

  

 

Dosing: Given by intravenous piggyback in doses of 375 to 1450 mg/m2 every 2 to 3 weeks or 50 to 250 mg/m2/day for 5 to 10 days every 3 to 4 weeks.

  

 

Dactinomycin (Cosmegen)—actinomycin D, ACT-D

  

 

Drug Class: Antitumor antibiotic, inhibits transcription by complexing with DNA.

  

 

Dosage Form: Available in vials of 0.5 mg of lyophilized drug.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Poor oral bioavailability. After an IV dose, the drug is widely distributed except to the cerebrospinal fluid. It is metabolized in the liver. It has an elimination half-life of 30 to 40 hours. Dactinomycin and its metabolites are excreted in both bile and urine.

  

 

Toxicity: This drug is a moderate vesicant. Myelosuppression is dose limiting. Nausea, vomiting, skin erythema, acneiform lesions, and hyperpigmentation are common, while mucositis, diarrhea, and anorexia are uncommon. Hepatitis, ascites, fever, and hypocalcemia are rare.

  

 

Indications: FDA approved for Wilms’ tumor, Ewing's sarcoma, rhabdomysarcoma, uterine carcinoma, germ cell tumors, and sarcoma botryoides; also used for other sarcomas, melanoma, acute myeloid leukemia, ovarian cancer, and trophoblastic neoplasms.

  

 

Dosing: 1 to 2 mg/m2 every 3 weeks or continuous infusions of 0.25 to 0.6 mg/m2/day for 5 days every 3 to 4 weeks.

  

 

Darbopoetin alfa (Arenesp)

  

 

Drug Class: Erythropoietic growth factor, modified recombinant DNA peptide product.

  

 

Dosage Form: Vials containing 25, 40, 60, 100, 150, 200, 300, and 500 mg of drug in 1 mL of either albumin or polysorbate aqueous solution.

  

 

Drug Interactions: No formal drug studies have been done. Exogenous testosterone and erythropoietin products used together could cause polycythemia.

  

 

Pharmacokinetics/Metabolism: After subcutaneous administration, absorption into the bloodstream is slow and dose limiting. Peak concentration occurs at approximately 30 hours and half-life in the bloodstream is 30 to 90 hours. Metabolic fates and routes of elimination have not been formally studied.

  

 

Toxicity: Polycythemia can occur and thus hemoglobin must be monitored during therapy. No other form of dose limiting toxicity is known. Either hypertension or hypotension are common. Headache is uncommon. Cardiovascular events including myocardial infarction, arrhythmia, or stroke are uncommon but can be serious. Fever, edema, or pain are rare.

  

 

Indications: FDA approved for anemia caused by cancer chemotherapy for nonmyeloid malignancies and anemia associated with chronic renal insufficiency.

  

 

Dosing: For anemia and renal insufficiency, the indicated dose is 0.45 mg/kg SC or IV once weekly, titrated upward to achieve the target hemoglobin level of 12 g/dL. For anemic cancer patients receiving chemotherapy, the recommended dose is 2.25 mg/kg SC once weekly, again with slow upward titration as needed to achieve a specific hemoglobin goal. Every other week and every 3 week doses are currently under evaluation.

  

 

Dasatinib (Sprycel)

  

 

Drug Class: Anthracycline antitumor antibiotic, intercalating agent.

  

 

Dosage Form: 20-mg vials of powdered drug for reconstitution.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Not orally bioavailable. After IV bolus, the drug is widely distributed and is metabolized in the liver to active and inactive metabolites. The elimination of the parent drug is 18 hours, and that of the active metabolite daunorubicinol is about 25 hours. Elimination of parent drug and metabolites is via the biliary and renal routes.

  

 

Toxicity: Daunorubicin is a vesicant. Precautions are necessary. Myelosuppression is dose limiting. Alopecia, nausea, vomiting, and stomatitis are common. Diarrhea, rash, elevated liver function tests, and transient arrhythmias are uncommon. Dose-related cardiomyopathy is uncommon below cumulative doses of 400 to 500 mg/m2.

  

 

Indications: FDA approved for AML and ALL.

  

 

Dosing: Given as a single IV injection daily for 1 to 5 days. Total dose per course up to 150 mg/m2. A typical dose would be 45 mg/m2/day for 3 days.

  

 

Daunorubicin, liposomal (Daunosome)

  

 

Drug Class: Novel liposomal preparation of the anthracycline DNA intercalating agent daunorubicin which modifies the pharmacokinetics and toxicities of the drug.

  

 

Dosage Form: Single-use vials containing 50 mg of daunorubicin in an aqueous liposomal solution at a concentration of 2 mg/mL.

  

 

Drug Interactions: Significant interactions of liposomal daunorubicin and other drugs have not been observed.

  

 

Pharmacokinetics/Metabolism: Daunorubicin liposomes have a small volume of distribution after IV administration but are rapidly cleared from the plasma compartment into peripheral tissues with a half-life of about 4 hours. Low levels of metabolites are detected in the plasma, likely due to slow distribution of parent drug from the peripheral tissues to the liver for metabolism. Metabolic fates are the same as for the conventional drug.

  

 

Toxicity: In general, this agent has a milder side effect and toxicity profile that conventional daunorubicin. Myelosuppression is mild but still dose limiting. An acute syndrome of back pain, chest tightness, and flushing can occur uncommonly during administration, which can usually be treated symptomatically. Other cardiac side effects are rare. Skin rashes are rare. Nausea, vomiting, and alopecia are rare.

  

 

Indications: FDA approved for treatment of AIDS-associated Kaposi's sarcoma. Some experience in other solid tumors.

  

 

Dosing: 0 mg/m2 IV infusion over 60 minutes every 2 weeks, with reduction and delay for significant myelosuppression.

  

 

Decitabine (Dacogen)

  

 

Drug Class: Antimetabolite.

  

 

Dosage Form: Oral.

  

 

Drug Interactions: None known.

  

 

Pharmacokinetics/Metabolism: Inhibits DNA methyltransferase, causing hypomethylation of DNA. This may induce apoptosis or restore normal function to genes that control cellular differentiation and proliferation. Deaminated by cytidine deaminase, found in liver, granulocytes, gut, and blood. Elimination half-life is 30 minutes.

  

 

Toxicity: Myelosuppression. Nausea, vomiting, abdominal pain. Constitutional symptoms. Elevated liver functions, blood sugar, low serum magnesium, low serum potassium. Respiratory toxicity.

  

 

Indications: Myelodysplastic syndromes.

  

 

Dosing: 15 mg/m2 by continuous infusion over 3 hours, every 8 hours for 3 days, repeated every 6 weeks for a minimum of 4 cycles.

  

 

Denileukin diftitox (Ontak)

  

 

Drug Class: Recombinant DNA peptide fusion product combining interleukin-2 and a diphtheria toxin, allowing relative specificity of diphtheria toxin toward interleukin-2 receptor-expressing cells.

  

 

Dosage Form: Vials of 300 mg in 2 mL frozen aqueous solution.

  

 

Drug Interactions: None known.

  

 

Pharmacokinetics/Metabolism: After IV administration, the plasma half-life of denileukin diftitox is about 80 minutes. Radiolabeling studies show that the drug accumulates in the vasculature, liver, and kidneys, but its specific metabolic fates are unknown. Antibodies against the drug have been shown to slow its clearance.

  

 

Toxicity: Denileukin diftitox has a broad range of toxicities similar to other peptide biologic response modifiers, with hypotension and other manifestations of vascular leak syndrome being dose limiting. Fever, chills, edema, rash, fatigue, headache, nausea, vomiting, anorexia, and diarrhea are common. Dyspnea, cough, arthralgias, myalgias, and pharyngitis are uncommon. Infections associated with drug administration are common. Arrhythmias and significant neurologic, hepatic, or renal complications are rare.

  

 

Indications: FDA approved for recurrent cutaneous T-cell lymphoma (mycosis fungoides).

  

 

Dosing: 9 or 18 mg/kg/day for 5 days as an IV infusion over at least 15 minutes, repeated every 21 days.

  

 

Dexamethasone (Decadron)—Dex, DXM

  

 

Drug Class: Corticosteroid that has pleiotrophic properties in various body tissues. Directly toxic to benign and malignant lymphocytes. Potent anti-inflammatory action.

  

 

Dosage Form: Tablets ranging from 0.25 to 6 mg are available, as well as an oral solution at 0.1 mg/mL and a solution for injection at 4 to 24 mg/mL.

  

 

Drug Interactions: Drugs that induce hepatic microsomal enzymes can enhance the metabolism of dexamethasone and decrease its effectiveness. This includes phenytoin, tegretol, and dilantin.

  

 

Pharmacokinetics/Metabolism: Well absorbed by the GI tract. Metabolized in the liver. Elimination half-life is 3 to 4 hours. Elimination of metabolites is primarily renal, with some biliary component.

  

 

Toxicity: Toxicities are shared with other corticosteroids and include leukocytosis, hyperglycemia, mood changes, euphoria, insomnia, increased appetite, weight gain, dyspepsia, exacerbation of peptic ulcer disease, cataracts, adrenal suppression, edema, and osteoporosis.

  

 

Indications: Used for many purposes in oncology and hematology patients, including treatment of multiple myeloma, CLL and ALL, non-Hodgkin's lymphoma, immune thrombocytopenic purpura, and hemolytic anemia. Also used to alleviate symptoms from brain or spinal cord metastases and other metastatic sites where edema and inflammation exist. Used as an adjunctive antiemetic medication as well.

  

 

Dosing: Oral and parenteral dosing are equivalent. Dosage for acute indications or active treatment involves total daily doses of 16 to 40 mg, sometimes with an initial “bolus” dose of up to 100 mg. Tapering treatments will decrease down to 1 to 2 mg/day. As an antiemetic, 10 to 20 mg is the standard dose.

  

 

Dexrazoxane (Zinecard)—ADR-529, ICRF-187

  

 

Drug Class: Iron-chelating agent that serves as a free-radical scavenger/cytoprotectant.

  

 

Dosage Form: Lyophilized powder, 500 mg/vial, with diluent.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: The drug is not bioavailable by the oral route. After an IV dose, distribution in the body is widespread and rapid. Metabolism is predominantly hepatic. The terminal half-life is 3 to 4 hours. Parent drug and metabolites are excreted by the kidneys.

  

 

Toxicity: Dexrazoxane appears to worsen slightly the leukopenia induced by doxorubicin. Mild nausea and vomiting are common, fever, stomatitis, fatigue, anorexia, and hypotension are uncommon. Seizure, respiratory arrest, deep venous thrombosis, and significant liver toxicity are rare.

  

 

Indications: FDA approved as an “orphan drug” to prevent doxorubicin-induced cardiomyopathy.

  

 

Dosing: Administered just prior to a dose of doxorubicin as a 15- to 30-minute infusion at a dose of 500 to 1000 mg/m2.

  

 

Docetaxel (Taxotere)—RP-56976

  

 

Drug Class: Docetaxel is a semisynthetic taxane, a class of compounds that inhibit the mitotic spindle apparatus by stabilizing tubulin polymers, leading to death of mitotic cells.

  

 

Dosage Form: 20 and 80-mg vials at a concentration of 40 mg/mL in polysorbate 80 solvent.

  

 

Drug Interactions: Docetaxel given concurrently with cisplatin has been reported to increase the incidence and severity of peripheral neuropathy.

  

 

Pharmacokinetics/Metabolism: The drug has poor oral bioavailability. After a 1-hour infusion, docetaxel is widely distributed and has a triphasic elimination course, with a distribution half-life of 4 minutes, an elimination half-life of 1 hour, and a terminal half-life of 18 hours. The extent and by-products of metabolism are not well known. The main excretion route is biliary.

  

 

Toxicity: Myelosuppression is universal and dose limiting. Alopecia is also universal. Edema and fluid accumulation, including pleural effusions and ascites, are common and can be dose limiting. Fluid accumulation is partially preventable with corticosteroid treatment before and after each cycle of docetaxel. Mild sensory or sensorimotor neuropathy is common. Mucositis and diarrhea are common and usually mild. Hypersensitivity reactions are uncommon and can largely be prevented through premedication with corticosteroids and antihistamines. Rash and elevated liver function tests are uncommon.

  

 

Indications: FDA approved for metastatic breast cancer and first and second line non-small-cell lung cancer. Clinical experience is increasing in ovarian cancer and other epithelial neoplasms.

  

 

Dosing: The standard dose is 100 mg/m2 IV over 1 hour every 3 weeks. Higher doses and other schedules have been used.

  

 

Doxorubicin (Adriamycin, Rubex)—Adria, hydroxydaunorubicin

  

 

Drug Class: Anthracycline antitumor antibiotic, intercalating agent.

  

 

Dosage Form: Available in vials of lyophilized powder containing 10 to 150 mg of drug and as vials of 2-mg/mL solution in 10 to 200-mg vials.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: The drug has poor oral bioavailability. After an IV dose, it is widely distributed in tissues and is 70% protein bound. It is metabolized in the liver to active and inactive forms. It has an elimination half-life of 18 hours or more. Most of the drug and metabolites are excreted through the biliary route.

  

 

Toxicity: Doxorubicin is a potent vesicant, and extravasation precautions are a must. Myelosuppression is universal and usually dose limiting with each individual cycle. Cardiotoxicity is common and can be dose limiting, though usually subclinical. Chronic, cumulative cardiomyopathy is expected when total dose exceeds 400 to 500 mg/m2. This toxicity can be lessened by the addition of dexrazoxone or by longer infusions. Acute cardiac effects, including arrhythmias, are less often seen and are unpredictable. Nausea and vomiting are common but manageable. Diarrhea and stomatitis are common but usually mild. Alopecia, rash, and hyperpigmentation are common.

  

 

Indications: FDA approved for a variety of cancers and used for many more. Most commonly used for breast carcinoma, adult sarcomas, pediatric solid tumors, Hodgkin's disease, non-Hodgkin's lymphomas, and ovarian cancer.

  

 

Dosing: Standard doses range from 60 to 90 mg/m2 IV as a bolus or continuous infusion over 48 to 72 hours every 3 to 4 weeks. Weekly and biweekly schedules are also used, with lower doses. Doses are usually reduced for elevated bilirubin levels.

  

 

Doxorubicin, liposomal (Doxil)

  

 

Drug Class: Novel liposomal preparation of the anthracycline DNA intercalating agent doxorubicin.

  

 

Dosage Form: Vials of 20 mg in 10 mL and 50 mg in 25 mL of doxorubicin in aqueous liposomal dispersion.

  

 

Drug Interactions: No formal drug interaction studies have been conducted. No important drug interactions have been reported.

  

 

Pharmacokinetics/Metabolism: The parent drug, doxorubicin, is metabolized in the liver and excreted primarily in the bile. Significant levels of the principal metabolite doxorubicinol, have not been observed with the liposomal preparation, likely due to the slow distribution of free doxorubicin to the liver. Half-life of the liposomes in the plasma compartment is approximately 55 hours.

  

 

Toxicity: Myelosuppression is mild but dose limiting. Palmar plantar erythrodysesthesia is common and can occasionally be severe and dose limiting. Stomatitis and nausea are common but usually mild. Alopecia is uncommon. Acute infusion reactions including chest pain, back pain, dyspnea, and wheezing can occur uncommonly.

  

 

Indications: FDA approved for recurrent metastatic ovarian cancer and AIDS-related Kaposi's sarcoma. Also used commonly in metastatic breast cancer and multiple myeloma.

  

 

Dosing: 50 mg/m2 IV infusion over 1 hour for ovarian cancer, 20 mg/m2 IV infusion over 30 minutes for Kaposi's sarcoma.

  

 

Epirubicin (Ellence)

  

 

Drug Class: Anthracycline DNA intercalating agent.

  

 

Dosage Form: Vials of 50 mg in 25 mL or 200 mg in 100 mL of aqueous solution.

  

 

Drug Interactions: Additive toxicities with other cytotoxic drugs should be expected. Cardiac toxicity of epirubicin can be enhanced when used with other drugs that can temporarily or permanently impair cardiac function. Cimetidine increases the AUC of epirubicin and should be stopped before starting epirubicin.

  

 

Pharmacokinetics/Metabolism: Epirubicin is metabolized primarily by the liver. The parent drug and metabolites are glucuronidated and are excreted in the bile much more than via renal clearance. Doses should be reduced for patients with mild to moderate hepatic dysfunction. Severe hepatic dysfunction is a contraindication for using epirubicin. Half-life of plasma levels is about 30 to 35 hours after IV administration.

  

 

Toxicity: Myelosuppression is universal and dose limiting. Alopecia is expected. This drug is a vesicant, and precaution must be taken to avoid extravasation into soft tissue around veins. Nausea and vomiting are common but usually manageable. Stomatitis is common. Fatigue is common. Detectable cardiac dysfunction is uncommon to rare. Secondary leukemia is rare.

  

 

Indications: FDA approved for adjuvant therapy after optimal surgical treatment of localized breast cancer with involved axillary lymph nodes.

  

 

Dosing: 100 to 120 mg/m2 by intravenous infusion every 3 to 4 weeks. Usually combined with cyclophosphamide and 5-fluorouracil.

  

 

Erlotinib (Tarceva)

  

 

Drug Class: Targeted agent.

  

 

Dosage Form: 25-mg, 100-mg, 150-mg tablets.

  

 

Drug Interactions: Drugs that stimulate or inhibit liver CYP3A4 enzymes. Warfarin.

  

 

Pharmacokinetics/Metabolism: Inhibits the tyrosine kinase domain of the epidermal growth factor receptor, leading to inhibition of EGFR autophosphorylation and signaling.

  

 

Toxicity: Acneiform rash. Diarrhea. Interstitial lung disease.

  

 

Indications: Second- or third-line therapy of non-small-cell lung cancer. Pancreatic cancer, in combination with gemcitabine.

  

 

Dosing: Lung cancer: 150 mg/day. Pancreatic cancer: 100 mg/day.

  

 

Erythropoietin (Epogen, Procrit)—EPO, epoitin alpha

  

 

Drug Class: Hematopoietic growth factor. Stimulates erythrocytic precursors.

  

 

Dosage Form: Vials of 2000, 4000, and 10,000 units in solution.

  

 

Drug Interactions: Erythropoietin may temporarily decrease the effectiveness of heparin when the two drugs are given simultaneously. Oral aluminum-containing antacids may decrease the effectiveness of erythropoietin.

  

 

Pharmacokinetics/Metabolism: This peptide must be given parenterally. After IV or subcutaneous dosing, it is detectable in plasma for 24 hours. It is distributed to a volume approximating the total blood volume. It is degraded by proteolysis within the blood compartment. Half-life ranges from 4 to 27 hours. Onset of therapeutic effect takes at least 7 days. Excretion of intact peptide is negligible.

  

 

Toxicity: Hypertension is common but usually mild and not dose limiting. Injection site pain is common but mild. Flu-like syndrome and diaphoresis are uncommon. Nausea and vomiting are rare. Seizures have been reported in dialysis patients receiving the drug. Iron deficiency anemia can occur after prolonged therapy, and concomitant iron administration may increase the effectiveness of erythropoietin. Hematocrit values should be monitored closely while on therapy to prevent polycythemia and hyperviscosity.

  

 

Indications: The oncology indication is chemotherapy-induced anemia that is symptomatic. Also used for anemia of chronic renal failure and human immunodeficiency virus (HIV)-associated anemia.

  

 

Dosing: Starting doses of 150 units/kg SC three times per week were recommended, with increases up to 300 units/kg if there is suboptimal effect after 6 to 8 weeks, although 40,000 units weekly with increases to 60,000 units is the most commonly used program.

  

 

Estramustine (Emcyt)

  

 

Drug Class: A conjugate of estrogen and an alkylating moiety, estramustine appears to work through estrogen-binding proteins to kill malignant cells through a nonalkylator mechanism, perhaps by inhibition of microtubules.

  

 

Dosage Form: 140-mg capsules.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Well absorbed by mouth, subject to hepatic metabolism, with a terminal half-life of about 20 hours. Excretion route is not clearly delineated.

  

 

Toxicity: Nausea and vomiting are common and dose limiting but diminish over time. Headache, edema, decreased libido, and impotence are common. Gynecomastia and breast tenderness can be seen. Rash, alopecia, myelosuppression, hepatic toxicity, and thromboembolic events are rare.

  

 

Indications: FDA approved for the treatment of prostate cancer. Not used commonly for any other types of cancer.

  

 

Dosing: The usual dose for prostate cancer is 15 mg/kg/day, which is typically given as 420 mg PO tid for most men.

  

 

Etoposide (Vespid)—VP-16, epipodophyllotoxin; also available as etoposide phosphate (Etopophos)

  

 

Drug Class: Plant alkaloid; topoisomerase II inhibitor. Partially cell cycle dependent.

  

 

Dosage Form: Etoposide comes in oral form as 50-mg capsules and in parenteral form as 100-mg multidose vials in solution at 20 mg/mL. Etoposide phosphate is available in 100-mg single-dose vials as lyophilized powder.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Etoposide phosphate is rapidly converted to etoposide after IV infusion. Etoposide itself is extensively protein bound, is metabolized in the liver, and has an elimination half-life of about 10 hours. About 50% of oral etoposide is absorbed via the GI tract, requiring oral doses to be twice as high as parenteral doses. Excreted both unchanged in the urine and as metabolites in the bile.

  

 

Toxicity: Myelosuppression, primarily leukopenia, is universal and dose limiting. Nausea and vomiting are common with PO administration but rare when the drug is given IV. Stomatitis and diarrhea are rare with normal doses but common with high doses. Alopecia is mild or absent. Hepatic toxicity and neurologic effects (peripheral neuropathy and CNS changes) are rare. Hypotension can occur with rapid administration of etoposide but does not occur commonly when etoposide phosphate is infused over 5 minutes. Secondary AML has been reported after etoposide.

  

 

Indications: FDA approved for germ cell tumors and SCLC. Also used for lymphomas, AML, brain tumors, non-SCLC, and as high-dose therapy in the transplant setting for breast cancer, ovarian cancer, and lymphomas.

  

 

Dosing: Etoposide can be given either over several days or at lower doses over many days. Typical doses are 50 to 120 mg/m2/day for 3 to 5 days given IV. Oral doses are generally twice the IV doses. A typical protracted oral course would be 50 mg/m2/day for 21 days given every 28 days. Transplant doses up to 1200 mg/m2 over 1 to 3 days have been used.

  

 

Exemestane (Aromasin)

  

 

Drug Class: Hormonal agent, steroidal aromatase inhibitor.

  

 

Dosage Form: 25-mg tablets.

  

 

Drug Interactions: In spite of the fact that exemestane is metabolized by cytochrome P450 3A4, ketoconazole does not affect its half-life or AUC, and no other drug-drug interactions have been identified.

  

 

Pharmacokinetics/Metabolism: After oral administration, approximately 40% of exemestane is absorbed from the gastrointestinal tract. Absorption is increased by a fatty meal. It is highly protein bound in the plasma. Exemestane is metabolized in the liver by cytochrome P450 3A4 and aldoketoreductase. Metabolites are eliminated equally in urine and feces.

  

 

Toxicity: Though generally well tolerated, exemestane is expected to cause or exacerbate hot flashes or intermittent flushing in some women. Fatigue and mild nausea are common. Vomiting, headache, and dyspnea are uncommon. It is teratogenic and should not be used in premenopausal women.

  

 

Indications: FDA approved for treatment of estrogen-responsive metastatic breast cancer in postmenopausal women who have progressed on prior hormonal therapy.

  

 

Dosing: 25 mg orally once daily after a meal.

  

 

Filgrastim (Neupogen)—G-CSF

  

 

Drug Class: Hematopoietic growth factor, relatively specific for the granulocyte lineage.

  

 

Dosage Form: Available in single-use vials of 300 and 480 mg, in solution.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: After a bolus SC injection, peak plasma levels of filgrastim occur in 2 to 6 hours, while the elimination half-life is generally 7 hours or less. Metabolism is via proteolysis in the blood compartment. The intact molecule is largely absent from bile or urine.

  

 

Toxicity: Mild bone pain is common. Low-grade fever, myalgias, arthralgias, and transient hypotension are uncommon, as are hyperuricemia and elevations of lactate dehydrogenase and alkaline phosphatase. Leukocytosis leading to hypoxia or capillary leak syndrome has been reported. Anaphylaxis or allergic reaction are rare.

  

 

Indications: FDA approved for minimization of granulocytopenia after myelosuppressive chemotherapy. Also used to speed recovery of granulocytes in the setting of neutropenic fever after chemotherapy, for myelodysplastic syndromes, for congenital agranulocytosis, for cyclic neutropenia, and for mobilization of peripheral blood stem cells from patients or donors for transplant.

  

 

Dosing: Starting dose is 5μg/kg/day until neutrophil recovery (discontinue the drug after an absolute neutrophil count of 10,000 or greater has been achieved), although generally either the whole 300μg or 480μg vial is used. For post-transplant or high-dose chemotherapy applications, 10μg/kg/day is the typical dose. There is no known maximum dose.

  

 

Floxuridine (FUDR)—FdUR, fluorodeoxyuridine

  

 

Drug Class: Pyrimidine nucleotide analog, antimetabolite. Cell cycle dependent.

  

 

Dosage Form: Available in 500-mg vials of lyophilized powder.

  

 

Drug Interactions: Leucovorin will enhance the toxicity of floxuridine.

  

 

Pharmacokinetics/Metabolism: After infusion into the hepatic artery, the drug is phosphorylated to the active monophosphate form and incorporated into cells. Further hepatic metabolism to inactive forms is rapid. The elimination half-life is 30 minutes. Metabolites are cleared by the kidneys.

  

 

Toxicity: When given as a bolus, myelosuppression is dose limiting, while diarrhea and stomatitis are the dose-limiting toxicities of the more common protracted infusions. Other GI toxicities, all rare, include nausea, vomiting, anorexia, gastritis, cramping, enteritis, and duodenal ulcers. Liver toxicity, usually a cholestatic picture, is dose limiting with intrahepatic arterial infusions. Serious neurologic side effects, including ataxia and visual changes, are rare, as is fever.

  

 

Indications: FDA approved for regional (intra-arterial) treatment of GI adenocarcinomas metastatic to the liver. Sometimes used intravenously for the same tumors.

  

 

Dosing: Protracted intra-arterial infusions are generally given at 0.1 to 0.6 mg/kg/day until grade III toxicity, sometimes according to a circadian schedule. IV doses range up to 60 mg/kg/week by various infusion schedules.

  

 

Fludarabine (Fludara)—FAMP

  

 

Drug Class: Purine nucleotide analog antimetabolite. Only partially cell cycle dependent.

  

 

Dosage Form: Vials containing 50 mg each of lyophilized drug. Add 2 mL of sterile water to the vial to make a 25-mg/mL solution, and then dilute the desired dose further to a concentration of 0.04 to 1 mg/mL (depending on the infusion schedule).

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Fludarabine is available only by the parenteral route. After IV administration, the drug is metabolized to 2-fluoro-araA and widely distributed in tissues. It has an elimination half-life of 9 to 10 hours. The drug and metabolite are excreted primarily by the kidneys.

  

 

Toxicity: Neurotoxicity, including cortical blindness, confusion, somnolence, coma, and demyelinating lesions, is dose limiting, but the lower doses that are conventionally used rarely produce these side effects. At these doses, mild myelosuppression is the most common toxicity, cumulative lymphopenia being the most clinically important. Nausea, vomiting, and other GI toxicities are rare. Alopecia and rash are also rare.

  

 

Indications: FDA approved for the treatment of CLL. Also used for low-grade lymphomas and for AML.

  

 

Dosing: The standard regimen is 25 mg/m2/day for 5 days by short IV infusion. Prolonged infusions have also been used.

  

 

5-Fluorouracil (Adrucil, Efudex)—5-FU

  

 

Drug Class: Pyrimidine antimetabolite; inhibitor of thymidylate synthase. Partially cell cycle dependent.

  

 

Dosage Form: Available in solution in 0.5- to 5-γ ampules or vials at a concentration of 50 mg/mL.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Parental bioavailability only. After an intravenous dose, 80% of the drug is metabolized to the inactive dihydro-5-FU by dihydropyrimidine dehydrogenase in the liver. The rest of the drug is activated to fluorodeoxyuridine monophosphate in the target cells. The elimination half-life is about 20 minutes. Excretion is via the kidneys.

  

 

Toxicity: GI toxicities, primarily mucositis for bolus injections and diarrhea for prolonged infusions, are dose limiting. Rare patients with dihydropyrimidine dehydrogenase deficiency have excessive GI toxicity. Myelosuppression is generally less with continuous infusion schedules. Nausea and vomiting are uncommon and mild. Dermatitis and other cutaneous toxicities, including hand-foot syndrome, are common. Cerebellar ataxia and myocardial ischemia are rare.

  

 

Indications: FDA approved for colon, rectum, gastric, pancreas, and breast carcinomas and used for a wide range of other neoplasms in combination regimens. Used for intrahepatic arterial infusion for liver metastases from GI tumors; also used topically for various cutaneous neoplasms and disorders.

  

 

Dosing: IV dosing schemes include weekly bolus, 5 days of bolus every 28 days, 4 to 5 day continuous infusions. Doses range from 300 to 3000 mg/m2/day depending on the dosing scheme and schedule.

  

 

Fluoxymesterone (Halotestin, Oro-Testryl)

  

 

Drug Class: Synthetic steroidal androgen. Antagonizes estrogenic effects in estrogen-dependent target cells.

  

 

Dosage Form: 2-, 5-, and 10-mg tablets.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: The drug is available by the oral route, is metabolized in the liver, and has an elimination half-life of about 10 hours. Route of excretion is unknown.

  

 

Toxicity: Androgenic effects predominate. Hirsutism, amenorrhea, hoarseness, acne, and increased libido occur in women; men may have gynecomastia. Mild edema is common. Liver abnormalities, including transaminitis, fatty change, cholestatic jaundice, and rarely carcinoma, are not uncommon. Polycythemia may occur.

  

 

Indications: FDA approved for the treatment of hormone-sensitive breast cancer and for hypogonadism in males.

  

 

Dosing: The total daily dose for breast cancer is usually between 10 and 40 mg, divided into two or three doses per day.

  

 

Flutamide (Eulexin)

  

 

Drug Class: Nonsteroidal antiandrogen.

  

 

Dosage Form: 125-mg capsules.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Good oral bioavailability, with peak plasma levels after an oral dose at 1 to 2 hours. The drug is metabolized to active and inactive forms in the liver. The elimination half-life is 8 to 10 hours. Parent drug and metabolites are excreted in the urine.

  

 

Toxicity: Generally well tolerated. Gynecomastia, galactorrhea, and impotence are common. Nausea, vomiting, diarrhea, mild myelosuppression, myalgias, and elevated liver function tests are rare.

  

 

Indications: FDA approved for prostate carcinoma.

  

 

Dosing: The standard dose is 250 mg PO three times daily. Often given in conjunction with an LHRH agonist such as leuprolide to create complete androgen blockade.

  

 

Fulvestrant (Faslodex)

  

 

Drug Class: Estrogen receptor antagonist.

  

 

Dosage Form: 250 mg/5 mL and 125 mg/2.5 mL prefilled syringes.

  

 

Drug Interactions: None known.

  

 

Pharmacokinetics/Metabolism: Binds to the estrogen receptor (ER), leading to degradation and loss of ER from the cell. Peak plasma levels reached in 7 days, half-life is 40 days. Metabolized by the liver microsomal P4503A4 system and excreted primarily in the feces.

  

 

Toxicity: Constitutional symptoms, including hot flashes. Peripheral edema. Nausea, vomiting.

  

 

Indications: Estrogen receptor positive metastatic breast cancer in postmenopausal women.

  

 

Dosing: 250 mg IM monthly.

  

 

Gallium Nitrate (Ganite)

  

 

Drug Class: Heavy metal that antagonizes iron metabolism in tumor cells preferentially. Causes hypocalcemia by a similar mechanism.

  

 

Dosage Form: 500-mg vials (20-mL vials of a 25-mg/mL solution).

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: This drug is not metabolized and has an elimination half-life of about 5 hours. Cleared unchanged in the urine.

  

 

Toxicity: Renal toxicity, including glomerular and tubular defects, is dose limiting but partly preventable with adequate hydration during therapy. Hypocalcemia is expected and common and can be dose limiting. Nausea, vomiting, diarrhea, and anorexia are not uncommon. Mild myelosuppression, rashes, hearing loss or tinnitus, visual disturbances, and transient neurologic symptoms are rare.

  

 

Indications: FDA approved for the treatment of malignancy-related hypercalcemia. Also used for advanced bladder carcinoma.

  

 

Dosing: The standard dose and schedule is 300 mg/m2/day for 7 days by continuous IV infusion in a volume of 1000 mL of normal saline.

  

 

Gemcitibine (Gemzar)

  

 

Drug Class: Antimetabolite. Gemcitibine is a nucleoside analog that exhibits cell cycle-dependent and S-phase-specific cytotoxicity, likely due to inhibition of DNA synthesis.

  

 

Dosage Form: Supplied as lyophilized powder in vials containing 200 and 1000 mg of drug.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Gemcitibine has poor oral bioavailability. After IV infusion, the drug is rapidly distributed and has a half-life of less than 2 hours. It is metabolized throughout the body to inactive forms. Parent drug and metabolite are excreted principally by the kidneys.

  

 

Toxicity: Myelosuppression, including anemia, is mild but dose limiting. Nausea and vomiting are mild but common. Diarrhea and edema are sometimes seen. Elevated transaminases are common, as is fever during drug administration. Hematuria and proteinuria are uncommon. Acute dyspnea and rash are uncommon. Paresthesias and CNS depression are rare.

  

 

Indications: FDA approved for advanced pancreatic adenocarcinoma, NSCLC, and metastatic breast cancer; extensively used in bladder cancer also.

  

 

Dosing: The usual dose in pancreatic cancer is 1000 mg/m2 as an IV bolus weekly for up to 7 weeks, followed by a week of rest before another cycle is begun. Similar doses in combination with or without platinating agents are used for the other indications.

  

 

Gemtuzumab ozogamicin (Mylotarg)

  

 

Drug Class: Novel toxin-conjugated monoclonal antibody directed at myeloid lineage cells.

  

 

Dosage Form: Amber single use vials containing 5 mg of drug as a lyophilized powder.

  

 

Drug Interactions: No formal studies done, and no important drug interactions yet noted. Other medications that cause myelosuppression would be expected to worsen myelosuppression caused by gemtuzumab.

  

 

Pharmacokinetics/Metabolism: Gemtuzumab is given as a 2-hour IV infusion, after which the total calicheamycin (ozogamicin released from the antibody by hydrolysis) has a half-life of 45 hours for the first dose and 60 hours after the second dose. Metabolism of the toxin is hepatic. The elimination routes of the toxin and the antibody are unknown.

  

 

Toxicity: This peptide antibody linked to a toxin, given in a group of patients with poor prognosis who are often medically fragile, can have marked acute toxicities. These include somewhat common typical antibody infusion side effects, including fever, chills, hypotension, dyspnea, and wheezing, and other uncommon toxicities including tachycardia, renal insufficiency, hepatic compromise (including hepatic veno-occlusive disease), dizziness, headache, and rash. Leukopenia is expected and can be prolonged, causing a high risk of bacterial, fungal, and sometimes viral infections. Thrombocytopenia and anemia are common also. Nausea and vomiting and diarrhea are common. Serious coagulopathy or hemorrhage are rare.

  

 

Indications: FDA approved for relapsed AML.

  

 

Dosing: 9 mg/m2 as a 2-hour IV infusion given once up front and then again in 14 days.

  

 

Goserelin Acetate (Zoladex)

  

 

Drug Class: LHRH that inhibits pituitary-gonadal axis function. This drug causes steroid hormone withdrawal from dependent tissues, including prostate cancer and breast cancer cells.

  

 

Dosage Form: 3.6-mg prefilled syringes.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: After the contents of the syringe are injected SC into adipose tissue, the depot of drug is slowly released over 28 days, peaking at 12 to 15 days. The elimination half-life is 4 hours, and the drug is not appreciably metabolized. Excretion in almost entirely by the urinary route.

  

 

Toxicity: Toxicity is mild. Endocrine side effects are most prominent and include hot flashes, diminished libido, impotence, gynecomastia, amenorrhea, and breakthrough vaginal bleeding. Other toxicities include flares of pain early during treatment in sites of disease, local tenderness at injection sites, headache, nausea, depression, and elevated cholesterol levels.

  

 

Indications: FDA approved for advanced prostate cancer; used also in metastatic breast cancer.

  

 

Dosing: 3.6 mg SC usually in the abdomen, every 28 days.

  

 

Hydroxyurea (Hydrea)—hydrocarbamide

  

 

Drug Class: Antimetabolite; inhibitor of ribonucleotide reductase, which converts nucleotides to the deoxyribose forms for DNA synthesis. Cell cycle dependent.

  

 

Dosage Form: 500-mg capsules.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: After oral administration, the drug is well absorbed, and drug levels peak in the blood 2 hours after a dose. The elimination half-life is 2 to 5 hours. Metabolism to inactive forms occurs in the liver. Renal excretion is the route of elimination.

  

 

Toxicity: Myelosuppression is common and dose limiting. Other toxicities include rash, headache, fever, and hyperuricemia. Nausea and vomiting are uncommon. Liver toxicity and serious neurologic toxicity are rare.

  

 

Indications: FDA approved for CML; commonly used for other myeloproliferative disorders; also used occasionally for metastatic melanoma, refractory ovarian carcinoma, and squamous cell carcinoma of the cervix and the head and neck.

  

 

Dosing: For CML, the dose is 1000 to 3000 mg/day; in solid tumors, the dose is either 80 mg/kg every third day or 1.25 g/m2 every 8 hours for five doses once a week.

  

 

Ibritumomab tiuxetan—Yttrium-90 (Zevalin)

  

 

Drug Class: Monoclonal antibody directed to the β-cell surface antigen CD20 linked to beta-emitting radionuclide yttrium-90.

  

 

Dosage Form: Kits for preparation of either the In-111 (used for predicting drug distribution) or Y-90 (used for therapy) form of the drug include a vial containing 3.2 mg of the antibody in saline solution along with three other vials for mixing. Y-90 is sent with the Y-90 kit. Rituxan and In-111 must be ordered separately.

  

 

Drug Interactions: None known. Formal studies have not been conducted.

  

 

Pharmacokinetics/Metabolism: Optimal irbitumomab/Y-90 binding and clinical effect require pretreatment with unconjugated ibritumomab. The physical half-life of Y-90 is 64 hours, but the biological half-life of the agent in the body in terms of radioactivity detected is 30 hours. Metabolic and excretory fates of the radionuclide and antibody are not known.

  

 

Toxicity: Ibritumomab/Y-90 should not be administered if the biodistribution of ibritumomab/In-111 is altered significantly. Antibody toxicities can include fever, chills, dyspnea, wheezing, urticaria, and rash. Radionuclide or total agent side effects include lymphopenia, and myelosuppression of other cell lines, which can be prolonged. Infection risk is increased accordingly. Nausea, vomiting, and diarrhea are uncommon, as are arthralgias, myalgias, or neurologic side effects.

  

 

Indications: FDA approved for treatment of relapsed and/or transformed follicular β-cell lymphomas.

  

 

Dosing: The first step of therapy is administration of a 250 mg/m2 dose of rituximab, followed by a 1.6 mg/5 mCi dose of ibritumomab/In-111 as a 10-minute infusion; 9 days later, if biodistribution of the In-111-labeled product is normal, the same dose of rituximab is followed by a 1.6 mg/0.4 mCi/kg dose of ibritumomab/Y-90 as a 10-minute infusion.

  

 

Idarubicin (Idamycin)—4-demethoxydaunorubicin

  

 

Drug Class: Anthracycline intercalating agent. Non-cell cycle dependent.

  

 

Dosage Form: Lyophilized powder in vials of 5 and 10 mg.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Idarubicin has poor oral bioavailability. After an IV dose, the drug is metabolized in the liver to active and inactive forms. The elimination half-life of the parent compound is 13 to 26 hours. Metabolites and some of the unchanged drug are almost exclusively excreted in bile.

  

 

Toxicity: Myelosuppression is common and generally dose limiting for each dose. The cumulative dose-limiting toxicity is cardiomyopathy, but idarubicin is less cardiotoxic than daunorubicin or doxorubicin. Nausea and vomiting are common but usually mild. Diarrhea and stomatitis are sometimes seen. Idarubicin is a weak vesicant or irritant.

  

 

Indications: FDA approved for the treatment of AML.

  

 

Dosing: The standard dose as part of a “7 plus 3” regimen (with cytarabine) is 12 mg/m2/day for 3 days for induction or reinduction/intensification. Other doses have been used.

  

 

Ifosfamide (Ifex)

  

 

Drug Class: Classic alkylating agent. Non-cell cycle dependent.

  

 

Dosage Form: Available in 1- and 3-γ vials of powdered drug.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: After an intravenous dose, ifosfamide is activated by hepatic microsomal enzymes. It is then converted to inactive metabolites in the liver. The active form of the drug is the same as that for cyclophosphamide. The elimination half-life of the drug is 7 to 15 hours. The metabolites and some unchanged drug are excreted in the urine.

  

 

Toxicity: Myelosuppression, hemorrhagic cystitis, and CNS toxicity are all fairly common and can be dose limiting. Hemorrhagic cystitis can largely be prevented by coadministration of the uroprotective agent mesna, and nausea and vomiting are minimized with modern antiemetic regimens. The CNS toxicity, including lethargy, stupor, coma, myoclonus, and seizures, is usually mild and completely reversible. It is worse with impaired renal function. Renal dysfunction, usually reversible, is also seen with ifosfamide. Hepatic toxicity, diarrhea, and rash are rare.

  

 

Indications: FDA approved for the treatment of recurrent germ cell tumors. Used for many other tumor types, including adult sarcomas, lymphoma, Hodgkin's disease, breast cancer, and ovarian cancer.

  

 

Dosing: fosfamide is generally given IV over 3 to 5 days with a total dose of 8 to 12 g/m2/cycle, repeated every 3 to 4 weeks. It can be given as a short infusion each day or as a continuous infusion. Mesna is given IV concurrently, also by short infusion or continuous infusion. Hydration of greater than 3L/day total, with saline or alkali solutions, is also recommended.

  

 

Imatinib mesylate (Gleevec)

  

 

Drug Class: Specific receptor tyrosine kinase inhibitor, which selectively inhibits the tyrosine kinases of bcr-abl, c-kit, and PDGF receptors.

  

 

Dosage Form: 100-mg capsules.

  

 

Drug Interactions: Imatinib plasma levels are enhanced by ketoconazole, and imatinib increases the plasma levels of other drugs that are metabolized by cytochrome P450 3A4. Inducers of this enzyme such as phenytoin would be expected to lower the plasma levels of imatinib.

  

 

Pharmacokinetics/Metabolism: Imatinib has good oral bioavailability, reaches peak serum levels in about 3 hours, and has an elimination half-life of 18 hours. It is metabolized in the liver by cytochrome P450 3A4 among other isoforms, with the demethylated metabolite showing activity similar to that of the parent drug. The parent drug and major metabolite are excreted primarily in the feces.

  

 

Toxicity: Imatinib has no definite dose-limiting toxicity. Myelosuppression is significant in chronic myelogenous leukemia (CML) but mild in gastrointestinal stromal tumors. Hepatotoxicity is common but usually mild. Liver function tests should be monitored closely during therapy. Fluid retention is common but usually mild, as are nausea, vomiting, and diarrhea. Rash and fever are uncommon.

  

 

Indications: FDA approved for treatment of CML in the front-line setting, in accelerated phase, and in blast crisis. It is also approved for the treatment of recurrent inoperable or metastatic gastrointestinal stromal tumors.

  

 

Dosing: Total daily doses of 400 mg to 800 mg, once daily, or divided.

  

 

Interferon-α (IntronA, Roferon)—a-interferon, IFN-α

  

 

Drug Class: Biologic response modifier, antiviral, immunostimulant.

  

 

Dosage Form: Available in vials of lyophilized powder or aqueous solution in quantities from 3 million to 50 million IU/vial.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: After parenteral administration, peak levels of IFN-α in the blood occur in 30 minutes to 8 hours depending on the route. The elimination half-life is 2 to 9 hours. IFN-α is catabolized throughout the body through proteolysis but primarily in the renal tubules. Excretion of intact drug is minimal and not significantly affected by organ function.

  

 

Toxicity: Constitutional symptoms are predominant side effects and are dose limiting in both the short and long term in lower dose schedules. Acute side effects include fever, chills, nasal congestion, diarrhea, and malaise. Chronic side effects include fatigue, anorexia, weight loss, and depression. Neutropenia and thrombocytopenia, both of which are transient, are dose limiting at higher doses. Anemia may also occur, albeit with more chronic administration. Cardiac toxicity, including congestive heart failure and arrhythmias, is rare and almost always reversible. Serious CNS toxicity, including delirium and psychosis, or peripheral neuropathies are also rare and reversible. Hypocalcemia and hyperglycemia can also occur.

  

 

Indications: FDA approved for nonmalignant conditions and malignancies including melanoma, CML, hairy cell leukemia, Kaposi's sarcoma, and cutaneous T-cell lymphoma. Also used in multiple myeloma and low-grade lymphomas.

  

 

Dosing: Dose depends on both the diagnosis and the brand or type of IFN-α. The doses for malignant conditions range from 2 million up to 30 million units/m2 by the SC, IM, or IV route from three times per week to every day. Adjustments are made on the basis of patient tolerance and laboratory parameters.

  

 

Interleukin-2 (Proleukin)—aldesleukin, IL-2

  

 

Drug Class: IL-2 is a glycoprotein cytokine, previously known as T-cell growth factor, that stimulates antigen-specific and nonspecific T-cell and other lymphocyte subsets and also triggers an inflammatory cytokine cascade. Its antineoplastic effects are dependent on an intact immune system.

  

 

Dosage Form: Vials of lyophilized drug containing 18 million IU.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: IL-2 is available by the parenteral route only. It has an elimination half-life of 30 to 60 minutes. It is catabolized by proteolysis throughout the body. Negligible amounts of intact drug are found in urine or bile.

  

 

Toxicity: IL-2 has a wide range of moderate to severe toxicities that are both dose and schedule dependent. Toxicities tend to follow immediately after a bolus dose but gradually accumulate during a continuous infusion. Toxicities are higher for a given dose with continuous infusion as compared to bolus dosing. Capillary leak syndrome, which is dose limiting for most IL-2 administration schedules, results in hypotension, edema, pulmonary congestion, renal insufficiency, arrhythmias, diarrhea, and possibly some of the CNS and hepatic toxicity seen with IL-2. Transient myelosuppression or more prolonged anemia occurs commonly, as does transient hyperbilirubinemia, elevation of transaminases, and electrolyte imbalances. Other constitutional symptoms that occur with IL-2 include fever, chills, malaise, arthralgia/myalgias, erythroderma, nasal congestion/rhinorrhea, and nausea/vomiting. Other serious and less common toxicities include lethargy or delirium, angina pectoris, congestive heart failure, frank respiratory failure, and infections, particularly gram-positive bacteremia.

  

 

Indications: FDA approved for high-dose bolus treatment of metastatic renal cell cancer and metastatic melanoma. Also used at lower doses for metastatic melanoma and for maintenance treatment of acute myeloid leukemia.

  

 

Dosing: The FDA-approved dose for renal cell carcinoma and melanoma is a 600,000 to 720,000IU/kg IV bolus every 8 hours for a maximum of 14 doses on days 1 to 5 and 11 to 15 every 6 weeks. Lower doses are more commonly used, especially continuous infusions of 3 million to 18 million IU/m2/day for 96 hours. SC administration at similar daily doses has also been attempted with reasonable patient tolerance.

  

 

Irinotecan (Camptosar)—CPT-11

  

 

Drug Class: A semisynthetic camptothecin, which functions as a topoisomerase I inhibitor. Partly cell cycle dependent.

  

 

Dosage Form: Available in 100-mg vials as a 20-mg/mL aqueous solution.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Irinotecan is available only by the parenteral route. After IV administration, the drug is converted partially from the active lactone form to the inactive carboxylate form through hydrolysis. The parent drug is metabolized in the intestine, liver, and plasma. The active metabolite of irinotecan, SN-38, also exists in the lactone and inactive carboxylate form in equilibrium in plasma. SN-38 is inactivated by glucuronidation in the liver. SN-38 is responsible for the majority of antitumor activity attributed to the parent drug. The elimination half-life of irinotecan is 8 hours, while the elimination half-life of SN-38 is about 12 hours. Excretion of parent drug and metabolites is largely via the bile.

  

 

Toxicity: Myelosuppression, primarily neutropenia, is common and dose limiting. Diarrhea is also common and can be dose limiting. Diarrhea can occur as part of a cholinergic syndrome, along with cramping, nausea, and vomiting, during or immediately after drug administration or for several days after drug administration. Anticholinergics and antidiarrheals will curtail the immediate diarrhea and other GI symptoms partially but are less effective in treating the delayed diarrhea. Flushing, rash, and alopecia are common. Significant hepatic, renal, neurologic, or pulmonary toxicities are rare.

  

 

Indications: Irinotecan is FDA approved for refractory or recurrent metastatic colon cancer, and it has now been used in other malignancies, including lung cancer, ovarian cancer, and lymphoma.

  

 

Dosing: The recommended dosage for recurrent colon cancer is 125 mg/m2 as a 90-minute IV infusion every week for 4 weeks, with this cycle repeated every 6 weeks. Other doses and schedules have been used.

  

 

Isotretinoin (Accutane)—13-cis-retinoic acid, 13-CRA

  

 

Drug Class: Isotretinoin is a retinoid derivative of vitamin A that binds to specific nuclear receptors and leads to changes in gene expression. This results in apoptosis or differentiation of many malignant or premalignant cell lines.

  

 

Dosage Form: 10, 20, and 40-mg capsules.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Oral bioavailability is about 25%, and the drug is highly protein bound in plasma. It is metabolized in the liver and has an elimination half-life of 10 to 20 hours. Parent compound and metabolite are excreted in both the urine and feces.

  

 

Toxicity: Isotretinoin is teratogenic and should not be given to women of childbearing age without adequate contraception. Mucocutaneous side effects are common and dose limiting and include xerostomia, stomatitis, conjunctivitis, dry skin, pruritus, cheilitis, rash, patchy alopecia, fragility of nails and skin, photosensitivity, and epistaxis. Other less common side effects include elevations in transaminases and bilirubin or frank hepatitis, hyperlipidemia, nausea, vomiting, anorexia, diarrhea, headache, fatigue, depression, and myalgias/arthralgias. Anemia and pseudotumor cerebri are rare.

  

 

Indications: FDA approved for acne vulgaris. Has shown some effectiveness in chemoprevention of aerodigestive malignancies. Ongoing studies are testing its chemopreventive potential in other malignancies.

  

 

Dosing: Daily oral doses of 0.5 to 4 mg/kg/day have been used in the chemoprevention trials for durations of 2 to 6 months.

  

 

Ketoconazole (Nizoral)

  

 

Drug Class: Oral antifungal agent that also acts as an androgen antagonist at high doses.

  

 

Dosage Form: 200-mg tablets.

  

 

Drug Interactions: Ketoconazole is a potent inhibitor of cytochrome P450 3A4. As such, it increases the potency of other drugs that are metabolized by that enzyme isoform, including terfenadine, astemizole, cisapride, midazolam, triazolam, and loratadine and possibly cyclosporin, tacrolimus, methylprednisolone, and warfarin. Rifampin and isoniazid decrease the potency of ketoconazole. Ketoconazole has been reported to cause a disulfiram-type reaction when used with alcohol.

  

 

Pharmacokinetics/Metabolism: Ketoconazole has good oral bioavailability. Its level peaks in the plasma in about 2 hours. It has a terminal half-life of about 8 hours. It is metabolized in the liver to several inactive metabolites. The metabolites are excreted in the bile.

  

 

Toxicity: This drug is not strictly an antineoplastic drug and is generally very well-tolerated. Nausea, vomiting, headache, dizziness, fever, chills, impotence, gynecomastia, leukopenia, hemolytic anemia, urticaria, and anaphylaxis are all rare. Hepatic toxicity is also rare. It has been fatal in unusual cases. Administration with terfenadine and astemizole has resulted in prolonged QT interval, arrhythmias, and deaths in rare cases. Other potential drug interactions are possible, as listed previously.

  

 

Indications: FDA approved for fungal infections, primarily yeast infections. Used in doses of up to 1200 mg/day for androgen-dependent or -independent prostate cancer.

  

 

Dosing: As per preceding instructions, used alone or in combination with chemotherapy, including doxorubicin.

  

 

Lenalidomide (Revlimid)

  

 

Drug Class: Antiangiogenesis agent, immunomodulator.

  

 

Dosage Form: 5-mg, 10-mg capsules.

  

 

Drug Interactions: None known.

  

 

Pharmacokinetics/Metabolism: Mechanism of action not fully characterized. An immunomodulatory agent that inhibits angiogenesis in some cells. Inhibits bone marrow secretion of IL-6, VEGF, and TNF-α.

  

 

Toxicity: Myelosuppression. Diarrhea, rash, fatigue. Increased risk of DVT and PE.

  

 

Indications: Transfusion dependent anemia due to low or intermediate risk myelodysplasia with 5q deletion. Multiple myeloma.

  

 

Dosing: For MDS: 10 mg daily. For myeloma: 25 mg daily for 21 of 28 days.

  

 

Letrozole (Femara)

  

 

Drug Class: Nonsteroidal aromatase inhibitor.

  

 

Dosage Form: 2.5-mg tablets.

  

 

Drug Interactions: Studies have revealed no interactions between letrozole and warfarin or cimetidine. No other formal drug interaction studies have been done.

  

 

Pharmacokinetics/Metabolism: Letrozole has nearly 100% bioavailability, is metabolized in the liver, is glucuronidated, and is excreted by the kidneys. It has a terminal half-life of about 2 days. With daily administration, steady-state plasma levels are reached in 2 to 6 weeks.

  

 

Toxicity: This drug is generally well tolerated. Muscle aches and nausea are uncommon; hot flashes and fatigue are uncommon; weight change, urticaria, and dyspepsia are rare.

  

 

Indications: FDA approved for treatment of metastatic estrogen-responsive breast cancer in postmenopausal patients.

  

 

Dosing: 2.5 mg orally once daily.

  

 

Leucovorin Calcium (Wellcovorin)—citrovorum factor, folinic acid, FA, LV

  

 

Drug Class: Tetrahydrofolate derivative and enzyme cofactor for thymidylate synthase and other purine and pyrimidine synthesis steps. Leucovorin bypasses the dihydrofolate reductase step, which is inhibited by methotrexate and therefore can be used to “rescue” normal cells from the toxicity of methotrexate after high doses are administered. In addition, leucovorin potentiates the toxicity of fluoropyrimidines such as fluorouracil by strengthening the association of the drug with its target enzyme, thymidylate synthase.

  

 

Dosage Form: Tablets in 5- to 25-mg sizes, powder for oral solution, and as vials of powdered drug in 3- to 350-mg sizes.

  

 

Drug Interactions: Reduces the effectiveness and toxicity of dihydrofolate reductase inhibitors such as methotrexate.

  

 

Pharmacokinetics/Metabolism: Leucovorin has excellent bioavailability by the oral or parenteral route. It is oxidized in cofactor reactions throughout the body, and is also partly metabolized. It has an elimination half-life of 2 to 4 hours. Excreted in the urine.

  

 

Toxicity: Leucovorin is generally very well tolerated. It occasionally causes stomach upset or nausea, rash, diarrhea, and headache. Allergic reactions have been reported.

  

 

Indications: Used for rescue of high-dose methotrexate therapy for a variety of neoplasms and as a potentiator of fluoropyrimidine therapy in gastrointestinal malignancies, particularly colorectal cancer.

  

 

Dosing: For rescue from methotrexate, the usual dose is 10 to 25 mg/m2 orally or IV every 6 hours starting up to 24 hours after the methotrexate, until methotrexate levels are less than 1 × 10-8 molar. When used to potentiate 5-FU, doses ranging from 20 to 500 mg/m2, usually given IV, have been used, depending on the 5-FU dose.

  

 

Leuprolide Acetate (Leupron)—leuprorelin acetate

  

 

Drug Class: Gonadotropin-releasing hormone agonist, which serves to paradoxically shut down the pituitary release of gonadotropins with chronic exposure. This results in a dramatic decrease in gonadal estrogens and androgens and growth inhibition of hormone-dependent neoplasms.

  

 

Dosage Form: Available in vials for monthly administration (depot) containing 3.75 and 7.5 mg of powder, along with diluent and syringe. A multidose vial containing 2.8 mL of a 5-mg/mL solution along with syringes is also available for daily administration.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Leuprolide is bioavailable only by the parenteral route. After a SC injection, about 90% of the drug is eventually absorbed. The depot form of the drug is absorbed slowly over days, while the injectable solution is absorbed over several hours. The elimination half-life of the drug once in the serum is 3 hours. Metabolism and excretion are not well delineated but are clinically unimportant.

  

 

Toxicity: Usually well tolerated, but side effects can affect many systems, including endocrine (hot flashes, impotence, gynecomastia, breast tenderness, diminished libido, amenorrhea, atrophic vaginitis, increased cholesterol); GI (nausea, constipation, anorexia, diarrhea); hepatic (elevation of transaminases); dermatologic (rash, changes in body hair composition, pruritus); and neuropsychiatric (insomnia, depression, emotional lability, lethargy, memory loss). Significant cardiac toxicity is rare.

  

 

Indications: FDA approved for the treatment of hormone-dependent advanced prostate cancer. Also used for breast cancer and endometriosis.

  

 

Dosing: The usual dose for prostate cancer is 7.5 mg of the depot form by SC injection once every month or 1 mg of the injectable solution SC daily.

  

 

Lomustine (CeeNU)—CCNU

  

 

Drug Class: Nitrosourea alkylating agent. Cell cycle independent.

  

 

Dosage Form: Available as 10, 20, and 100-mg capsules.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Well absorbed after oral administration. Widely distributed in the body, including the cerebrospinal fluid. Metabolized extensively in the liver to active metabolites. Elimination half-life is 72 hours. Metabolites are excreted in the urine.

  

 

Toxicity: Myelosuppression is dose limiting and tends to be cumulative. Nausea and vomiting are common but usually mild to moderate. Anorexia is also common but short lived. Pulmonary fibrosis can occur with long-term administration. Other toxicities, including CNS effects, hepatic or renal dysfunction, and secondary leukemia, are rare.

  

 

Indications: FDA approved for primary brain tumors and Hodgkin's disease. Also used in melanoma, multiple myeloma, other lymphomas, and breast cancer.

  

 

Dosing: The recommended dose for brain tumors is 100 to 130 mg/m2 orally every 6 weeks. Other doses and schedules have been used.

  

 

Mechlorethamine (Mustargen)—nitrogen mustard, HN2

  

 

Drug Class: Classic alkylating agent. Cell cycle independent.

  

 

Dosage Form: Vials of lyophilized powder containing 10 mg of drug.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Mechlorethamine is not orally bioavailable. After an IV dose, the drug is rapidly deactivated in the blood by reaction with biomolecules. It has an elimination half-life of 15 minutes and has no significant organ metabolism. Virtually no excretion of the drug is detected in urine or stool.

  

 

Toxicity: This drug is a powerful vesicant, so optimal extravasation precautions are a must, as well as rapid infusion. Tissue necrosis will occur if the drug extravasates, although sodium thiosulfate is a somewhat effective antidote. Vein discoloration and scarring are common. Nausea and vomiting are common, potentially severe, and often dose limiting. Myelosuppression is expected and also often dose limiting. Alopecia and infertility are often seen. Less common toxicities include anorexia, diarrhea, jaundice, tinnitus, and skin rash (common with topical treatment). Secondary leukemia and permanent hearing loss are rare.

  

 

Indications: FDA approved for a variety of hematologic malignancies and solid tumors but generally used less in the last decade. Still used for Hodgkin's disease and topically for cutaneous T-cell lymphoma.

  

 

Dosing: The standard dose for Hodgkin's disease as part of the MOPP regimen is 6 mg/m2 IV over 1 to 5 minutes on day 1 and day 8 of a 28-day cycle. The topical form is usually a 10-mg/60-mL solution or 10-mg/dL ointment.

  

 

Medroxyprogesterone acetate (Provera, Depo-Provera)

  

 

Drug Class: Steroidal progestational agent.

  

 

Dosage Form: Available as tablets in sizes of 2.5, 5, and 10 mg, and as a suspension for depot injection as 100 or 400 mg/m.

  

 

Drug Interactions: The metabolism of medroxyprogesterone acetate may be enhanced by aminoglutethamide, leading to decreased effect for a given dose.

  

 

Pharmacokinetics/Metabolism: This drug has good oral bioavailability. It is metabolized in the liver to inactive metabolites and has an elimination half-life of up to 60 hours. Parent drug and metabolites are excreted in the urine and bile.

  

 

Toxicity: Toxicities are mostly constitutional and not dose limiting. They include menstrual changes, amenorrhea, gynecomastia, hot flashes, edema, weight gain, fatigue, acne, hirsutism, anxiety, depression, sleep disturbance, and headache. Nausea, significant skin reactions or allergy, jaundice, and thrombophlebitis are uncommon.

  

 

Indications: FDA approved for treatment of advanced endometrial or renal cell carcinoma. Also used occasionally for breast or prostate cancer.

  

 

Dosing: Loading doses of up to 1000 mg IM weekly and 400 mg IM every month have been used, while oral doses range from 100 to 300 mg/day. Much lower doses are used for gynecologic indications.

  

 

Megestrol Acetate (Megace)—megestrol

  

 

Drug Class: Steroidal progestational agent.

  

 

Dosage Form: 20 and 40-mg tablets and 40-mg/mL oral solution.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: The drug is well absorbed by mouth, is metabolized in the liver to inactive compounds, and has an elimination half-life of 15 to 20 hours. Parent drug and metabolites are excreted in the urine.

  

 

Toxicity: Toxicities are similar to those of other progestins as noted previously. They include menstrual changes, hot flashes, edema, weight gain, fatigue, acne, hirsutism, anxiety, depression, sleep disturbance, and headache. Urinary frequency can also occur. Nausea, vomiting, diarrhea, skin rash or allergy, jaundice, and thrombophlebitis are uncommon.

  

 

Indications: FDA approved for treatment of breast and endometrial carcinoma. Also used for renal cell carcinoma and for appetite stimulation in HIV disease and cancer patients.

  

 

Dosing: The standard dose for cancer treatment is 160 mg/day in divided doses or a single dose. The dose for appetite stimulation may be as high as 800 mg/day, which is where the concentrated oral solution is useful.

  

 

Melphalan (Alkeran)—l-PAM, l-phenylalanine mustard, l-sarcolysin

  

 

Drug Class: Classical alkylating agent. Cell cycle independent.

  

 

Dosage Form: 2-mg tablets and vials for injection at 50 mg/vial.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Melphalan has unpredictable GI absorption, is highly protein bound, and is rapidly autometabolized by hydrolysis in the plasma. It has an elimination half-life of about 2 hours. Ten percent to 15% is excreted as unchanged drug in the urine.

  

 

Toxicity: Myelosuppression is expected and is dose limiting. Recovery may be prolonged, and effects can be cumulative. Large doses may cause significant nausea and vomiting. Diarrhea and stomatitis are uncommon. Vein reactions including scarring may occur, but this agent is not known as a vesicant. Other skin reactions are uncommon, as are pulmonary fibrosis, vasculitis, infertility, alopecia, and secondary leukemia.

  

 

Indications: Used primarily for multiple myeloma, but also FDA approved for ovarian carcinoma. May also be useful in high-dose chemotherapy/transplant settings and in regional perfusion of extremities for melanoma and sarcoma.

  

 

Dosing: Doses for myeloma are typically in the range of 0.1 mg/kg/day for 2 to 3 weeks or up to 6 mg/m2/day for 5 days every 6 weeks. Transplant doses (IV or PO) range up to 140 mg/m2 total. Doses for perfusion are either 0.45 to 0.9 mg/kg or dosed for a certain concentration in the perfusate.

  

 

Mercaptopurine (Purinethol)—6-MP, 6-mercaptopurine

  

 

Drug Class: Purine analog antimetabolite; predominantly S-phase specific.

  

 

Dosage Form: 50-mg tablets. An IV formulation is investigational.

  

 

Drug Interactions: Allopurinol inhibits first-pass metabolism of mercaptopurine in the liver by xanthine oxidase, and therefore dose reduction is required if allopurinol is also being given.

  

 

Pharmacokinetics/Metabolism: 6-MP has good oral bioavailability, undergoes extensive first-pass metabolism in the liver, and has an elimination half-life of about 7 hours. Intact drug and metabolites are excreted by the kidneys.

  

 

Toxicity: Myelosuppression is common and dose limiting. Nausea and vomiting occur occasionally but are usually mild. Diarrhea, anorexia, and stomatitis are less common. Headache and rash are uncommon. Fulminant hepatic toxicity is very rare, but lesser degrees of cholestasis and hepatitis are sometimes seen.

  

 

Indications: Mercaptopurine is FDA approved for treatment of acute lymphoblastic leukemia. It is occasionally used for other hematologic malignancies. There is an investigational IV formulation that does not yet have clinical indications.

  

 

Dosing: The usual dose is 70 to 100 mg/m2/day for a defined period of days during induction or maintenance.

  

 

Mesna (Mesnex)—mercaptoethanesulfonate sodium, uromitexan

  

 

Drug Class: Thiol uroprotectant; binds to and inactivates acrolein, the highly reactive metabolite of cyclophosphamide and ifosfamide, helping to prevent hemorrhagic cystitis.

  

 

Dosage Form: Available as aqueous solution at a concentration of 100 mg/mL.

  

 

Drug Interactions: Mesna does not decrease the effectiveness of cytotoxic drugs or radiation.

  

 

Pharmacokinetics/Metabolism: Mesna has an oral bioavailability of about 50% and is usually given IV. After an IV dose, mesna is converted in the plasma to dimesna, is filtered by the kidneys, and is converted back into mesna in the urine. It has an elimination half-life of 1 hour.

  

 

Toxicity: Mesna is usually very well tolerated. It has been described to occasionally cause nausea, vomiting, diarrhea, rash, fatigue, headache, hypotension, or arthralgias.

  

 

Indications: FDA approved for use as a uroprotectant when administering ifosfamide. Also effective for high-dose cyclophosphamide.

  

 

Dosing: The usual daily dose of mesna is 60% of the daily milligram amount of the ifosfamide, given by IV bolus before, 4 hours after, and 8 hours after the chemotherapy or as a continuous infusion with a loading dose before the chemotherapy. Mesna may be continued for up to 24 hours after the chemotherapy has been completed.

  

 

Methotrexate (Mexate, Folex, others)—MTX, amethopterin

  

 

Drug Class: Antifolate antimetabolite; interferes with nucleotide synthesis by inhibiting dihydrofolate reductase. Cell cycle dependent.

  

 

Dosage Form: 2.5-mg tablets, vials of powder for injection of 20 to 1000 mg/vial, and as a 2.5- and 25-mg/mL aqueous solution for injection.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Methotrexate has good oral bioavailability at low doses. After oral or IV dosing, it is distriuted throughout the body water compartment. It will accumulate in “third-space” fluid compartments and exhibit prolonged toxicity and therefore should be used with caution, if at all, in patients with significant pleural or peritoneal fluid. The drug is minimally metabolized in the liver and has an elimination half-life of about 3 hours, and even low concentrations of drug after most of the drug is eliminated can contribute to significant toxicity. Therefore, dosing based on renal function is critical. Excretion of this drug is entirely renal.

  

 

Toxicity: Myelosuppression is expected and is usually dose limiting. Stomatitis and diarrhea are common. Nausea and vomiting are uncommon. Renal toxicity is uncommon and usually reversible but can be severe. Many types of skin reactions can occur but are uncommon. Pulmonary fibrosis and hepatic fibrosis are rare. Encephalopathy is rare with moderate to low-dose therapy but is more common with high doses, intrathecal administration, or concomitant CNS radiation. It can be severe and permanent.

  

 

Indications: FDA approved for a wide spectrum of malignant and nonmalignant diseases. Most often used for acute leukemias, lymphomas, breast cancer, bladder cancer, squamous cell cancers, and sarcomas.

  

 

Dosing: For malignant conditions, doses up to 100 mg/m2 are considered low dose, 100 to 1000 mg/m2 moderate dose, and over 1000 mg/m2 high dose. Moderate and high doses require leucovorin rescue. Doses can be given weekly or at longer intervals. IV infusions can be 30 minutes or longer, including 24-hour continuous infusions. Methotrexate is also commonly given intrathecally, usually as a 12-mg dose in 10 mL of preservative-free saline.

  

 

Mitomycin C (Mutamycin)

  

 

Drug Class: Antitumor antibiotic; inhibits DNA and RNA synthesis.

  

 

Dosage Form: Vials of powder in 5-, 20, and 40-mg sizes.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Poor oral bioavailability. After an IV dose, mitomycin C is rapidly metabolized to inactive forms in the liver, spleen, and kidneys, with an elimination half-life of about 1 hour. Parent drug and inactive metabolites are excreted in the urine.

  

 

Toxicity: Mitomycin C is a vesicant; extravasation precautions are a must. Myelosuppression is expected and is dose limiting, with a white blood cell nadir at 4 weeks and full recovery at 6 to 7 weeks. Mild nausea, vomiting, anorexia, and fatigue are common. Uncommon toxicities include diarrhea, stomatitis, rash, fever, and renal insufficiency. Rare toxicities include veno-occlusive disease of the liver, hemolytic-uremic syndrome, and interstitial pneumonitis.

  

 

Indications: FDA approved for adenocarcinomas of the stomach and pancreas. Also used commonly in breast cancer and lung cancer.

  

 

Dosing: The usual dose is 10 to 20 mg/m2 IV over 2 to 5 minutes every 6 to 8 weeks.

  

 

Mitotane (Lysodren)—o,p′-DDD

  

 

Drug Class: Adrenal cortical cytotoxin.

  

 

Dosage Form: 500-mg tablets.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: This drug has moderate oral bioavailability, with a peak plasma level about 4 hours after an oral dose. Significant therapeutic effect is not seen until up to 4 weeks of continuous usage. Mitotane is metabolized in the liver and has a variable elimination half-life (due to storage of the drug in adipose tissue) of up to 160 hours. Mitotane is eliminated in the urine and bile.

  

 

Toxicity: Adrenal insufficiency is expected and must be abrogated with concomitant oral glucocorticoid usage (and sometimes mineralocorticoids as well). Anorexia, nausea, vomiting, sedation, and lethargy are common. Hypercholesterolemia and elevation of liver function tests are also common. Rash is seen frequently but is usually mild. Myelosuppression, diarrhea, fever, wheezing, changes in blood pressure, and flushing are uncommon. Permanent CNS changes, retinopathy, nephrotoxicity, and hemorrhagic cystitis are rare.

  

 

Indications: FDA approved for adrenal cortical carcinoma.

  

 

Dosing: The initial dose is usually 1 g/day in four divided doses; this is increased up to 10 g/day as tolerated.

  

 

Mitoxantrone (Novantrone)—DHAD, dihydroxyanthracenedione

  

 

Drug Class: Anthracycline antitumor antibiotic.

  

 

Dosage Form: Vials of 2-mg/mL solution.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Mitoxantrone has poor oral bioavailability. After an IV dose, it exhibits a large volume of distribution, undergoes metabolism in the liver, and has an elimination half-life of 24 to 37 hours. Mitoxantrone is eliminated through the bile.

  

 

Toxicity: Mitoxantrone is not a tissue vesicant. Myelosuppression, mostly limited to leukopenia, is expected and dose limiting. Nausea and vomiting are common but mild, stomatitis is common, and diarrhea and anorexia are less common. Elevated liver function tests are common, but significant hepatic toxicity is rare. Cardiotoxicity is uncommon and dose dependent. Pulmonary or neurologic toxicity is rare.

  

 

Indications: FDA approved for AML and prostate carcinoma. Also used for breast cancer, lymphoma, and hepatocellular carcinoma.

  

 

Dosing: For AML, the typical dose is 10 to 12 mg/m2/day for 3 days by 30-minute infusion, along with AraC. For solid tumors, 12 mg/m2 is given over 30 minutes every 3 to 4 weeks.

  

 

Nelarabine (Arranon)

  

 

Drug Class: Antimetabolite.

  

 

Dosage Form: IV.

  

 

Drug Interactions: None known.

  

 

Pharmacokinetics/Metabolism: A prodrug of deoxyguanosine analog 9-β-d-arabinofuranosylguanine (ara-G). After demethylation by adenosine deaminase to ara-G, it is converted to its active triphosphate form ara-GTP. Incorporation of ara-GTP into DNA inhibits DNA synthesis and function.

  

 

Toxicity: CNS toxicity is dose limiting, with somnolence, headache, dizziness, peripheral neuropathy, seizures, and coma, which may be severe and permanent. Myelosuppression. GI toxicities. Respiratory toxicity. Fatigue, fever, asthenia, blurred, vision, and edema.

  

 

Indications: Refractory or resistant T-cell acute lymphoblastic leukemia/lymphoma as third-line therapy.

  

 

Dosing: 1500 mg/m2 IV over 2 hours days 1, 3, and 5 every 21 days.

  

 

Nilutamide (Nilandron)

  

 

Drug Class: Orally administered nonsteroidal antiandrogen.

  

 

Dosage Form: 50-mg and 150-mg tablets.

  

 

Drug Interactions: Inhibits activity of several cytochrome P450 isoenzymes and thus may increase the potency of several potentially toxic drugs such as warfarin, theophylline, and phenytoin. Caution and careful monitoring are advised during concomitant use of nilutamide with such medications.

  

 

Pharmacokinetics/Metabolism: Rapid and complete GI absorption has been demonstrated. Elimination half-life is about 45 hours. The drug is metabolized in the liver and eliminated in the urine.

  

 

Toxicity: Hot flashes, body hair loss, fatigue, loss of libido, and weight gain are common but usually mild. Loss of visual adaptation to the darkness is common but transient, and nausea and fever and dyspepsia are uncommon. Interstitial pneumonitis is rare.

  

 

Indications: FDA approved for treatment of metastatic prostate cancer.

  

 

Dosing: The usual dose is 300 mg once daily for 30 days followed by 150 mg daily.

  

 

Octreotide, Octreotide long-acting (Sandostatin, Sandostatin LA)—L-cysteinamide

  

 

Drug Class: Synthetic peptide analog of somatostatin; inhibits other GI peptide actions, such as serotonin, insulin, glucagon, and gastrin.

  

 

Dosage Form: Ampules containing 0.05, 0.1, and 0.5 mg in 1 mL of aqueous solution.

  

 

Drug Interactions: May interfere with insulin action, requiring increase in insulin dosage.

  

 

Pharmacokinetics/Metabolism: Not orally bioavailable but rapidly absorbed after SC administration. Metabolized by hydrolysis throughout the body. No active metabolites. Half-life of elimination is about 1.5 hours. Intact drug is cleared via the kidneys.

  

 

Toxicity: GI side effects are dose limiting and include abdominal pain, vomiting, loose stool, occasional fat malabsorption, bloating, and cholelithiasis. Elevations of liver function tests can also occur, but frank hepatitis is rare. Skin reactions, such as pain at the injection site or flushing, rash, or skin thinning, are sometimes seen. Constitutional symptoms, including rhinorrhea, xerostomia, sweating, throat discomfort, and vertigo, can be bothersome. Either hyperglycemia or hypoglycemia can occur. Cardiac side effects, including angina, congestive heart failure, and hypotension or hypertension, are uncommon. Anxiety, depression, fatigue, and anorexia are uncommon, and seizures are rare.

  

 

Indications: FDA approved for carcinoid tumors causing carcinoid syndrome and for vasoactive peptide-secreting tumors. Also used for refractory diarrhea, either cancer related or treatment related, in cancer patients.

  

 

Dosing: Doses from 50 mg twice a day to 1000 mg four times a day injected SC have been used. Continuous IV infusions or administration of drug in total parenteral nutrition solutions has also been used.

  

 

Oprelvekin (Neumega)—interleukin-11, IL-11

  

 

Drug Class: Recombinant polypeptide cytokine molecule; multiple cellular actions, including stimulation of megakaryocyte proliferation and platelet production from megakaryocytes.

  

 

Dosage Form: Vials containing 5 mg of lyophilized powder.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Oprelvekin is available only by parenteral routes. With SC administration, it is absorbed into the circulation with a peak plasma concentration of 3 hours and has an elimination half-life of about 7 hours. This polypeptide agent is metabolized throughout the body by proteolysis. Excretion of drug is not substantial, owing to degradation.

  

 

Toxicity: Headache, fever, malaise, dyspnea, rash, conjunctival irritation, fluid retention, and edema are common during administration but are not usually severe. Oral thrush, dizziness, diarrhea, pleural effusions, and transient anemia are uncommon. Paresthesias, ocular hemorrhage, atrial arrhythmias, and exfoliative dermatitis are rare.

  

 

Indications: FDA approved for prevention of severe chemotherapy-related thrombocytopenia.

  

 

Dosing: 50 mg/kg/day SC injection until the postnadir platelet count is greater than 50,000/mm3, starting 1 day after the completion of chemotherapy.

  

 

Oxaliplatin (Eloxatin)

  

 

Drug Class: New generation platinating agent. Disrupts DNA via intrastrand and interstrand cross-links with two strong platinum association bonds in the molecule, which induces apoptosis beyond a certain level of DNA damage in malignant cells.

  

 

Dosage Form: Clear glass single-use vials containing 50 mg or 100 mg of drug as a lyophilized powder.

  

 

Drug Interactions: No drug-drug interaction studies have been done, and no interactions have yet been identified. Expected additive toxicities with other antineoplastic agents and neurotoxic drugs. Nephrotoxic drugs may slow clearance of oxaliplatin.

  

 

Pharmacokinetics/Metabolism: Oxaliplatin has poor oral bioavailibility. After IV administration, rapid distribution into tissues occurs, as well as rapid spontaneous conversion via hydrolysis into active drug and metabolites. The terminal half-life is long (>300 hours) but represents minimal plasma levels of the hydrolyzed drug. Elimination of platinum metabolites is via the kidneys.

  

 

Toxicity: Neurotoxicity, in the form of a transient neuropathy with each dose and a persistent, cumulative typical sensory polyneuropathy, is very common and dose limiting. Myelosuppression is expected but mild and only sometimes dose limiting. Fatigue and nausea are common but mild. Diarrhea, stomatitis, edema, cough, hypersensitivity reactions, and extravasation injury are rare.

  

 

Indications: FDA approved for metastatic colorectal cancer in combination with 5-fluorouracil/leucovorin. Has been used as a single agent in this disease and is being studied in other malignancies.

  

 

Dosing: With 5-fluorouracil and leucovorin, the dose and schedule is 85 mg/m2 IV every 2 weeks as a 2-hour infusion in 250 to 500 mL of D5W. As a single agent, the most studied doses are the same 2-week dose or 130 mg/m2 IV every 3 weeks.

  

 

Paclitaxel (Taxol, Onxol)

  

 

Drug Class: Naturally occurring taxane molecule; inhibits depolymerization of tubulin in the spindle apparatus, thereby inducing apoptosis in dividing cells.

  

 

Dosage Form: Vials containing 30 and 100 mg of drug in nonaqueous solution.

  

 

Drug Interactions: Cisplatin administered before paclitaxel may enhance the myelosuppressive effect of paclitaxel. Coadministration of paclitaxel and doxorubicin may enhance the cardiotoxicity of doxorubicin.

  

 

Pharmacokinetics/Metabolism: Paclitaxel has poor oral bioavailability. After IV administration, the drug exhibits a large volume of distribution and undergoes metabolism in the liver. The elimination half-life is 15 to 50 hours. Excretion of drug and metabolites is predominantly via the bile.

  

 

Toxicity: Paclitaxel is an irritant or mild vesicant when extravasated into subcutaneous tissue. Myelosuppression, predominantly neutropenia, is expected and is dose limiting. Shorter infusions of the same dose produce less neutropenia. Mucositis is also very common, particularly with longer infusions. Peripheral neuropathy is common, usually mild, and increases with cumulative dose. Acute neuromyopathy is also common and occurs for several days after each dose. This syndrome may require opiate analgesics to control pain. Cardiovascular side effects, including hypertension, hypotension, premature contractions, and bradyarrhythmias, are common but rarely require intervention. Hypersensitivity reactions to paclitaxel, including urticaria, wheezing, chest pain, dyspnea, and hypotension, are common but are reduced in frequency and severity by premedication with corticosteroids and histamine1 and histamine2 antihistamines (the recommended regimen is dexamethasone 20 mg PO 12 and 6 hours prior to paclitaxel and diphenhydramine 50 mg and cimetidine 300 mg IV 30 minutes prior to paclitaxel). Alopecia, usually complete, is expected. Other toxicities are uncommon and include nausea, vomiting, diarrhea, liver toxicity, and interstitial pneumonitis.

  

 

Indications: FDA approved for salvage therapy in ovarian cancer and for breast cancer in both the metastatic and adjuvant settings. Used also in lung cancer, head and neck cancer, and bladder cancer.

  

 

Dosing: 135 to 250 mg/m2 IV over 3 hours or 24 hours every 3 weeks. Weekly schedules and longer infusions have also been used.

  

 

Paclitaxel, Protein bound (Abraxane)

  

 

Drug Class: Taxane; an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nanometers.

  

 

Dosage Form: 100-mg vial.

  

 

Drug Interactions: Potential interactions with substrates or inhibitors of CYP2C8 and CYP3A4.

  

 

Pharmacokinetics/Metabolism: Not studied in patients with hepatic or renal dysfunction.

  

 

Toxicity: Neutropenia, thrombocytopenia, anemia, hypersensitivity reactions, hypotension, cardiovascular events, dyspnea, cough, sensory neuropathy, arthralgias/myalgias, nausea/vomiting, asthenia.

  

 

Indications: Treatment of metastatic breast cancer after failure of combination chemotherapy or relapse with 6 months of adjuvant chemotherapy.

  

 

Dosing: 260 mg/m2 IV over 30 minutes every 3 weeks.

  

 

Pamidronate (Aredia)—APD, aminohydroxypropylidene diphosphonate

  

 

Drug Class: Organic bisphosphonate; inhibitor of bone resorption by osteoclasts.

  

 

Dosage Form: Vials of lyophilized powder containing 30 mg of drug.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Pamidronate is available only by the parenteral route. After IV administration, the drug concentrates in the bone, spleen, and liver. Its metabolism is not well characterized. It has a terminal half-life of about 27 hours. Fifty percent of the parent drug is eliminated in the urine.

  

 

Toxicity: Pamidronate is usually quite well tolerated. Hypotension, syncope, tachycardia, and even atrial fibrillation have been reported uncommonly during the infusion. Hypocalcemia, hypophosphatemia, hypokalemia, and hypomagnesemia occur commonly but only rarely require intervention. Nausea, vomiting, and somnolence are rare.

  

 

Indications: FDA approved for malignancy-induced hypercalcemia. May lead to pain relief and even tumor shrinkage of bone metastases in multiple myeloma, breast cancer, and prostate cancer.

  

 

Dosing: 60 to 90 mg/m2 IV over 24 hours, although the clinical experience with infusions of 1 to 3 hours is extensive. Treatment may be repeated every 1 to 3 weeks. Peak effect occurs 3 to 7 days after a dose.

  

 

Panitumumab (Vectibix)

  

 

Drug Class: Monoclonal antibody.

  

 

Dosage Form: IV.

  

 

Drug Interactions: None known.

  

 

Pharmacokinetics/Metabolism: A recombinant, fully humanized IgG2 kappa monoclonal antibody that binds to the epidermal growth factor receptor. Binds specifically to EGFR, competitively inhibiting ligand binding to the receptor. Steady-state levels are reached by the third infusion. Elimination half-life is about 7.5 days.

  

 

Toxicity: Rash, which may be severe. Diarrhea. Infusion reactions. Hypomagnesemia. Pulmonary fibrosis.

  

 

Indications: Previously treated EGFR expressing metastatic colorectal cancer.

  

 

Dosing: 6 mg/m2 IV every 2 weeks.

  

 

Pegfilgrastim (Neulasta)

  

 

Drug Class: Long-acting (PEGylated) recombinant DNA granulocytic growth factor polypeptide.

  

 

Dosage Form: Syringes containing 6 mg of drug in 0.6 mL aqueous solution with a 27-gauge needle.

  

 

Drug Interactions: No formal drug interaction studies have been done.

  

 

Pharmacokinetics/Metabolism: PEGylation of filgrastim increases its half-life by decreasing renal clearance. After subcutaneous administration, half-life is between 15 and 80 hours, with biologic activity lasting much longer.

  

 

Toxicity: Toxicity and side effect profile is essentially no different than those of filgrastim. Bone pain is common and usually mild and treatable but can be dose limiting. Nausea, fatigue, weakness, and diarrhea are rare. Very rare instances of adult respiratory distress syndrome, sickle cell crisis, splenic rupture, and severe allergic reaction have been seen with the parent drug filgrastim.

  

 

Indications: FDA approved for prevention of severe granulocytopenia from cytotoxic chemotherapy for nonmyeloid malignancies.

  

 

Dosing: 6 mg SC after each chemotherapy cycle (generally used for a 3- or 4-week cycle duration).

  

 

Pemetrexed (Alimta)

  

 

Drug Class: Antimetabolite.

  

 

Dosage Form: 500-mg vials.

  

 

Drug Interactions: Salicylates and NSAIDS may decrease the renal excretion, increasing toxicity. Nephrotoxic drugs may also lead to decreased renal clearance. Thymidine rescues the toxic effects of pemetrexed.

  

 

Pharmacokinetics/Metabolism: Inhibits folate-dependent enzymes thymidlylate synthetase, dihyrofolate reductase and glycinamide ribonucleotide formyltransferase which are involved in the de novo synthesis of thymidine and purine nucleotides, leading to inhibition of DNA and RNA synthesis and function. Metabolized intracellularly to its highly active polyglutamated form. Excreted in urine with 90% of drug unchanged.

  

 

Toxicity: Myelosuppression. Nausea, vomiting, diarrhea. Rash. Dyspnea and fatigue.

  

 

Indications: Mesothelioma and non-small-cell lung cancer.

  

 

Dosing: 500 mg/m2 IV every 3 weeks. Note: All patients must be given folic acid and vitamin B12 supplementation to decrease toxicity, starting 1 week prior to therapy.

  

 

Pentostatin (Nipent)

  

 

Drug Class: Antimetabolite, purine antagonist.

  

 

Dosage Form: 10-mg vial.

  

 

Drug Interactions: Toxicity is increased with vidarabine, and fatal pulmonary toxicity has resulted from the concomitant use of fludarabine.

  

 

Pharmacokinetics/Metabolism: Enzyme adenosine deaminase, found in high concentration in lymphocytes, leading to accumulation of deoxyadenosine and deoxyadenosine triphosphate (dATP), which are cytotoxic to lymphocytes. Elevated dATP levels inhibit ribonucleotide reductase, which inhibits DNA synthesis and function. Undergoes little metabolism, and more than 90% of the drug is excreted in the urine with an elimination half-life of about 5 hours.

  

 

Toxicity: Myelosuppression. Increased risk of opportunistic infections. Hypersensitivity reactions. CNS toxicity. Ophthalmologic and otologic complications.

  

 

Indications: Hairy cell leukemia, chronic lymphocytic leukemia, cutaneous T-cell leukemia.

  

 

Dosing: 4 mg/m2 IV every 2 weeks.

  

 

Plicamycin (Mithracin)—mithramycin

  

 

Drug Class: Antitumor antibiotic. Partly cell cycle dependent.

  

 

Dosage Form: Supplied as lyophilized powder in vials containing 2.5 mg of drug.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Available only by the intravenous route. After an IV dose, the drug is metabolized by the liver and has an elimination half-life of about 2 hours. Parent drug and metabolites are eliminated via the kidneys.

  

 

Toxicity: Plicamycin is a vesicant if extravasated into soft tissues. Hemorrhage, due to both thrombocytopenia and coagulopathy, is dose limiting. Other hematologic toxicities are uncommon. Nausea and vomiting are common but not severe. Stomatitis, diarrhea, and anorexia are less common. Rash is common, but severe cutaneous reactions, such as toxic epidermal necrolysis, are rare. Depletion of calcium, potassium, phosphate, and magnesium are expected but rarely require intervention. Renal toxicities, including proteinuria and azotemia, are uncommon. Elevated liver function tests and neurologic toxicity (including lethargy, weakness, anxiety, somnolence, and headache) are uncommon.

  

 

Indications: FDA approved for treatment of malignancy-induced hypercalcemia, and also for treatment of germ cell tumors. Also has been used for CML in blast crisis.

  

 

Dosing: The typical dose for germ cell tumors is 25 to 30 mg/kg/day IV infusion over 60 minutes for 8 to 10 days. For hypercalcemia, the same dose is given one to three times per week.

  

 

Prednisone (Deltasone, others)

  

 

Drug Class: Corticosteroid.

  

 

Dosage Form: Tablets in sizes from 1 to 50 mg and oral solution.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Prednisone has good oral bioavailability and is extensively metabolized in the liver, primarily to the active form of the drug, prednisolone. It has an elimination half-life of approximately 4 hours. Liver disease may decrease conversion to the active form, requiring use of prednisolone instead of prednisone. Routes of excretion are not well delineated.

  

 

Toxicity: Toxicity is mostly in the form of constitutional symptoms, including mood changes (depressive, anxious, or euphoric), insomnia, indigestion, enhanced appetite, weight gain, acne, and cushingoid features. Other side effects may be more serious but are less common. Hyperglycemia and increased stomach acid predisposing to ulceration occur acutely, while osteopenia, cataracts, skin atrophy, and adrenal insufficiency occur with prolonged use.

  

 

Indications: FDA approved for a wide variety of malignant and nonmalignant conditions. Used in oncology for lymphoid malignancies, for palliative care, and for management of side effects/toxicities.

  

 

Dosing: Lympholytic doses are generally in the range of 50 to 100 mg/m2/day for 5 to 14 days. Higher or lower doses are also used, depending upon the indication.

  

 

Procarbazine (Matulane)—N-methylhydrazine

  

 

Drug Class: Alkylating agent. Cell cycle independent.

  

 

Dosage Form: 50-mg capsules.

  

 

Drug Interactions: This drug has monoamine oxidase inhibitory activity and therefore should not be taken with certain types of food, including beer, wines, fermented cheese, chocolate, and fava beans, or with certain medications, including ethanol, decongestants, tricyclic antidepressants, antihypertensives, antihistamines, narcotics, barbiturates, phenothiazines, or other monoamine oxidase inhibitors.

  

 

Pharmacokinetics/Metabolism: Well absorbed by the oral route, reaching peak plasma levels in 1 hour, with good distribution to the cerebrospinal fluid. Procarbazine is metabolized by the liver and has an elimination half-life of about 1 hour. Largely excreted in the urine.

  

 

Toxicity: Myelosuppression is expected and dose limiting, but anemia is uncommon. Nausea and vomiting are common and can be dose limiting as well. Rash, hives, and photosensitivity sometimes occur. Other side effects are uncommon and include anorexia, diarrhea, stomatitis, hypotension, tachycardia, syncope, flu-like syndrome, interstitial pneumonitis, CNS excitation including seizures, and secondary malignancies.

  

 

Indications: FDA approved for Hodgkin's disease, and may also be useful in non-Hodgkin's lymphoma, multiple myeloma, brain tumors, melanoma, and lung cancer.

  

 

Dosing: In Hodgkin's disease regimens such as MOPP, the dose is 100 mg/m2/day for 14 days during each cycle.

  

 

Rituximab (Rituxan)

  

 

Drug Class: Monclonal antibody directed against the β-cell surface antigen CD20.

  

 

Dosage Form: Sterile vials containing 100 and 500 mg of antibody in aqueous solution (10 mg/mL).

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Not available by the oral route, but when given IV, it is taken up by B lymphocytes and then degraded throughout the body by proteolysis, with a wide ranging serum half-life of 11 to 105 hours (mean 60 hours) with the first dose. There is no appreciable excretion of this polypeptide.

  

 

Toxicity: Fever, chills, and malaise are common during administration, even with premedication with acetaminophen and diphenhydramine. Other infusion-related symptoms include nausea, vomiting, flushing, urticaria, angioedema, hypotension, dyspnea, bronchospasm, fatigue, headache, rhinitis, and pain at disease sites. These symptoms are generally self-limited, improve with slowing of the infusion, and resolve after infusion. Short-lived myelosuppression, abdominal pain, and myalgia are uncommon. Arrhythmias and angina pectoris are rare.

  

 

Indications: FDA approved for relapsed or refractory low-grade or follicular, CD20-positive, β-cell lymphomas.

  

 

Dosing: The recommended dose is 375 mg/m2 by IV infusion (starting at 50 mg/hr and increasing to 400 mg/hr maximum) weekly for 4 weeks. Higher doses, more doses, and longer courses are being used in other lymphoid malignancies.

  

 

Sargramostim (Leukine, Leukomax)—granulocyte-macrophage colony-stimulating factor (GM-CSF)

  

 

Drug Class: Cytokine; exhibits pleiotropic stimulatory effects on bone marrow progenitor cells.

  

 

Dosage Form: Vials containing 250, 400, and 500 mg of lyophilized GM-CSF.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Not available by the oral route but has similar bioavailability when given IV or SC. Degraded throughout the body, predominantly in the liver and kidneys, with an elimination half-life of 2 hours. No appreciable excretion of this peptide occurs.

  

 

Toxicity: Constitutional symptoms, which tend to decrease over time, predominate at standard doses. Higher doses may cause capillary leak syndrome. Side effects include flushing, hypotension (or hypertension), dyspnea, fever, nausea, vomiting, fatigue, myalgias, bone pain, headache, and skin rash. Thrombocytopenia may also occur. Fluid retention and edema rarely occur at standard doses. Progression of myelodysplastic syndrome has been documented in patients on GM-CSF.

  

 

Indications: FDA approved for the treatment of myelosuppression after ABMT. May be useful to minimize myelosuppression after standard-dose chemotherapy or to shorten the course of neutropenic fever. Immunostimulatory properties of GM-CSF are still being investigated.

  

 

Dosing: 250μg/m2/day for 21 days or 5μg/kg/day for 10 to 14 days.

  

 

Sorafenib (Nexavar)

  

 

Drug Class: Targeted agent: Multikinase inhibitor.

  

 

Dosage Form: 200-mg tablets.

  

 

Drug Interactions: The AUC of doxorubicin is increased by 21% with concomitant use of sorafenib.

  

 

Pharmacokinetics/Metabolism: An oral multikinase inhibitor that interacts with multiple intracellular (CRAD, BRAF) and cell surface kinases (KIT, FLT-3, VEGFR-2, VEGFR-2, and PDGFR-β. May inhibit angiogenesis. Metabolized in the liver. Drug and metabolites are excreted primarily in the feces.

  

 

Toxicity: Skin toxicity with rash and hand-foot syndrome. Nausea, vomiting, anorexia, diarrhea. Asthenia, pain, arthralgias. Hypertension. Bleeding events, especially in anticoagulated patients. Cardiac ischemia. Myelosuppression.

  

 

Indications: Advanced renal cell carcinoma.

  

 

Dosing: 400 mg twice daily.

  

 

Streptozocin (Zanosar)

  

 

Drug Class: Alkylating agent. Cell cycle independent.

  

 

Dosage Form: Vials containing 1 g of lyophilized streptozocin.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Streptozocin is bioavailable only by the IV route. It is metabolized primarily in the liver and has an elimination half-life of less than 1 hour. Parent drug and metabolites are excreted in the urine.

  

 

Toxicity: GI side effects (nausea, vomiting, and cramping) or nephrotoxicity (glomerular and tubular damage) are common and potentially dose limiting. Myelosuppression is less often dose limiting. Elevated liver function tests can occur occasionally but are rarely clinically significant. Fever, delirium, and depression occur rarely. Streptozocin is an irritant if extravasated into perivenous soft tissue.

  

 

Indications: FDA approved for metastatic islet cell carcinoma and may also be useful for advanced carcinoid tumor, pancreatic carcinoma, and Hodgkin's disease.

  

 

Dosing: The usual dose is 500 to 1000 mg/m2/day by IV bolus for 5 days every 4 weeks.

  

 

Sunitinib maleate (Sutent)

  

 

Drug Class: Receptor tyrosine kinase inhibitor.

  

 

Dosage Form: 50-mg tablets.

  

 

Drug Interactions: Medications that inhibit or induce CYP3A4; St John's wort.

  

 

Pharmacokinetics/Metabolism: Inhibits multiple receptor tyrosine kinases. Inhibits PDGFRa and PDGFRb, VEGFR1–3, stem cell factor receptor, FLT-3, CSF-1R, and the neurotrophic factor receptor. This inhibition inhibits tumor growth and metastases. Metabolized in the liver with elimination primarily in the feces. Half-life is 40 to 60 hours for the drug and 80 to 110 hours for its primary metabolite.

  

 

Toxicity: Cardiotoxicity-usually reversible. Bleeding event, epistaxis most common. Hypertension. Myelosuppression. Nausea, vomiting. Rash. Liver function test alterations.

  

 

Indications: Advanced renal cell carcinoma. Second-line therapy for gastrointestinal stromal (GIST) cell tumors.

  

 

Dosing: 50 mg daily for 4 weeks, with a 2-week rest.

  

 

Tamoxifen (Nolvedex)

  

 

Drug Class: Nonsteroidal antiestrogen; cytostatic effects on estrogen-dependent and nondependent malignant cells.

  

 

Dosage Form: 10-mg tablets.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Tamoxifen has good oral bioavailability, is metabolized in the liver, and has an elimination half-life of about 7 days. Neither tamoxifen nor its major metabolite is found in the bile or urine.

  

 

Toxicity: Tamoxifen is usually very well tolerated. Constitutional symptoms are most prevalent and usually dose limiting. Hot flashes, sweating, mood changes, weight gain or loss, and stomach upset are most common. Nausea, vomiting, diarrhea, and constipation are less common. Menstrual changes, including significant vaginal bleeding, are uncommon. Venous thromboembolism, myelosuppression, and retinopathy are rare.

  

 

Indications: FDA approved for the treatment of breast cancer, generally in postmenopausal patients or those with estrogen receptor-positive tumors. The same dose has been approved for chemoprevention of breast cancer in high-risk individuals. Higher doses are used for melanoma and pancreatic cancer.

  

 

Dosing: The standard dose for breast cancer is 10 mg PO bid (or 20 mg once a day).

  

 

Temozolomide (Temodar)

  

 

Drug Class: Atypical alkylator (semiselective DNA methylator) drug sharing the same active metabolite as dacarbazine, MTIC but, unlike dacarbazine, is spontaneously converted to MTIC and also penetrates the blood-brain barrier effectively.

  

 

Dosage Form: Capsules containing 5 mg, 20 mg, 100 mg, and 250 mg of temozolomide.

  

 

Drug Interactions: Coadministration with valproic acid results in decreased oral bioavailability of temozolomide by a minor amount. No other drug interactions have been identified.

  

 

Pharmacokinetics/Metabolism: Temozolomide had good bioavailability, enhanced by an empty stomach. After absorption into the bloodstream, it is spontaneously converted to the active moiety MTIC. Peak plasma concentrations occur in about 1 hour. The elimination half-life is about 1.8 hours. Parent drug, MTIC, and other metabolites are eliminated in the urine.

  

 

Toxicity: Myelosuppression is expected and dose-limiting. It may be cumulative. Nausea is common but generally mild and treatable. Headache and fatigue are common. Rash or other cutaneous reactions are uncommon. Infections are common in this population, and some are probably caused by immunosuppression that is known to occur with temozolomide.

  

 

Indications: FDA approved for treatment of recurrent high-grade astrocytomas. Used commonly for other gliomas and also for metastatic melanoma.

  

 

Dosing: 200 mg/m2 PO on an empty stomach daily for 5 days on a 28-day cycle. Other doses and schedules have been used with similar clinical results.

  

 

Teniposide (Vumon)—VM-26, PTG

  

 

Drug Class: Inhibitor of topoisomerase II; similar in action to etoposide.

  

 

Dosage Form: Vials of 10-mg/mL solution containing 50 mg of drug.

  

 

Drug Interactions: Metabolism of teniposide is increased by inducers of liver microsomal enzymes such as phenobarbital and carbamazepine.

  

 

Pharmacokinetics/Metabolism: Teniposide is only available by the IV route. It is extensively protein bound in the plasma and undergoes near-complete metabolism in the liver. It has an elimination half-life of 5 hours. Metabolites are excreted in the bile and urine.

  

 

Toxicity: Myelosuppression, predominantly leukopenia, is universal and dose limiting. Otherwise usually well tolerated. Nausea, vomiting, diarrhea, stomatitis, and anorexia are uncommon. Alopecia is generally mild. Elevated liver function tests can occur but are not usually clinically significant. Allergic reactions, hypotension, fatigue, seizures, somnolence, fever, renal insufficiency, and secondary leukemia are all rare.

  

 

Indications: FDA approved for childhood ALL. Not used commonly for other malignancies, but does have activity against SCLC.

  

 

Dosing: 100 mg/m2 once or twice weekly or 20 to 60 mg/m2/day for 5 days as a slow IV infusion (at least 30 minutes).

  

 

Thalidomide (Thalomid)

  

 

Drug Class: Novel antiangiogenic and immunomodulating agent.

  

 

Dosage Form: 50-mg tablets.

  

 

Drug Interactions: Increases the sedative properties of barbiturates, chlorpromazine, and ethanol.

  

 

Pharmacokinetics/Metabolism: While it has acceptable bioavailibility, thalidomide is slowly and incompletely absorbed from the GI tract. Metabolism appears to be via spontaneous hydrolysis, with an elimination half-life of about 6 hours. Exact quantification of elimination routes are unknown.

  

 

Toxicity: Historical teratogenicity has led to required strict evaluation and monitoring for those taking thalidomide, called the S.T.E.P.S. Program. Strict procedures to prevent conception include barrier contraception for men, since the drug is present in semen of men who are taking it. Fatigue and peripheral neuropathy are the main toxicities and are dose limiting. Myelosuppression is uncommon and usually mild. Rash and headache uncommon.

  

 

Indications: FDA approved for cutaneous leprosy. Used in oncology for multiple myeloma, renal cell carcinoma, metastatic melanoma, and malignant gliomas. Also used as a treatment for cachexia owing to its mild anabolic and appetite-stimulating properties.

  

 

Dosing: Oncology doses range for 50 mg/day up to 1200 mg/day.

  

 

Thioguanine (Tabloid)—6-TG, aminopurine-6-thiol hemihydrate

  

 

Drug Class: Purine analog antimetabolite. Cell cycle dependent.

  

 

Dosage Form: 40-mg tablets.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Thioguanine has modest but slow oral route absorption. It is almost completely metabolized in the liver and has an elimination half-life of up to 11 hours. Metabolites are excreted in the urine.

  

 

Toxicity: Thioguanine is usually well tolerated. Leukopenia and thrombocytopenia are common and dose limiting. Nausea and vomiting, stomatitis, diarrhea, rash, elevated liver function tests, hyperuricemia, and renal insufficiency are uncommon.

  

 

Indications: FDA approved for AML in all phases of treatment. May be useful in other leukemias. An injectable formulation does not yet have FDA approval.

  

 

Dosing: The usual dose for leukemias is 2 to 3 mg/kg/day as part of an ongoing multidrug regimen.

  

 

Thiotepa (TESPA)—triethylenethiophosphoramide, TSPA

  

 

Drug Class: Classical alkylating agent. Cell cycle independent.

  

 

Dosage Form: Available as lyophilized powder in vials containing 15 mg of drug.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: With poor oral bioavailability, thiotepa is available only by the parenteral route. Extensive metabolism occurs in the liver, and the drug has an elimination half-life of 2 to 3 hours. Metabolites are excreted in the urine.

  

 

Toxicity: Myelosuppression, predominantly leukopenia, is expected and dose limiting and may be cumulative. Nausea, vomiting, anorexia, stomatitis, and diarrhea are uncommon. Infertility, fever, and angioedema or urticaria are uncommon. Second malignancies such as acute leukemia are rare. With high-dose therapy and bone marrow rescue, stomatitis and cognitive impairment can be severe. Intravesical administration leads to predominant urinary symptoms, including pain, hematuria, hemorrhagic cystitis, and rare ureteral obstruction.

  

 

Indications: FDA approved for the treatment of breast and ovarian carcinoma, as well as Hodgkin's disease and non-Hodgkin's lymphoma. Used for intravesical therapy of superficial bladder cancer and may also be used for intracavitary and intrathecal administration. Used in the transplant setting for ovarian and breast carcinoma.

  

 

Dosing: The usual dose is 12 to 16 mg/m2 IV over 10 minutes every 1 to 4 weeks. In the transplant setting, doses up to 900 mg/m2 have been used. The bladder instillation dose is 30 to 60 mg once weekly for 4 weeks. The intrathecal dose is 1 to 10 mg/m2 one to two times per week.

  

 

Topotecan (Hycamtin)—hycamptamine

  

 

Drug Class: Semisynthetic camptothecin molecule; an inhibitor of topoisomerase I, which is required by cells for both transcription and replication.

  

 

Dosage Form: 5-mg vials of lyophilized powder.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: No oral form of this drug is available. After IV administration, the drug is not extensively metabolized, and it has an elimination half-life of about 3 hours. A significant portion of the drug is excreted unchanged in the urine.

  

 

Toxicity: Myelosuppression, especially leukopenia, is expected and dose limiting. Thrombocytopenia and anemia are common but mild. Nausea, vomiting, and diarrhea are common but usually not severe. Headache, fever, fatigue, anorexia, malaise, and elevated liver function tests are also common. Hypertension, tachycardia, urticaria, renal insufficiency, hematuria, neuropathy, and mucositis are uncommon.

  

 

Indications: FDA approved for the treatment of refractory, relapsed ovarian carcinoma and for relapsed small cell lung cancer. Also used in myeloid leukemias.

  

 

Dosing: The standard dose for ovarian cancer is 1.5 mg/m2/day for 5 days as a 30-minute infusion.

  

 

Toremifene (Fareston)

  

 

Drug Class: Nonsteroidal antiestrogen; cytostatic effects on estrogen-dependent and nondependent malignant cells.

  

 

Dosage Form: 60-mg tablets.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Toremifene has good oral bioavailability and is extensively bound to plasma proteins. It is metabolized in the liver to active metabolites and has an elimination half-life of about 5 days. Parent drug and metabolites are excreted in the bile.

  

 

Toxicity: Toremifene is usually very well tolerated. Hot flashes, nausea, sweating, dizziness, and fatigue are the most common side effects. Vomiting, diarrhea, anorexia, vaginal discharge, vaginal bleeding, and headache are less common. Venous thrombosis and pulmonary embolism are rare.

  

 

Indications: FDA approved for the treatment of postmenopausal or estrogen receptor-positive metastatic breast cancer.

  

 

Dosing: 60 mg PO every day.

  

 

Trastuzumab (Herceptin)

  

 

Drug Class: A genetically engineered humanized mouse monoclonal antibody directed against the her2/neu growth factor receptor that is overexpressed in many invasive breast carcinomas. Mechanism of action for clinical activity in breast cancer is unknown but may be complement mediated cell lysis, antibody-dependent cellular cytotoxicity, or induction of apoptosis.

  

 

Dosage Form: Vials of 440 mg.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Binding studies show strong binding to cells overexpressing her2/neu molecules. Very little else is known regarding the distribution and metabolic fates of this molecule. Half-life should be very short with minimal distribution outside the vascular compartment and minimal clearance by kidneys or liver (similar to other monoclonal antibodies and polypeptide agents).

  

 

Toxicity: Common toxicities include acute fever, chills, nausea, vomiting, and headache. Trastuzumab seems to worsen leukopenia, anemia, and diarrhea when given with chemotherapy compared to chemotherapy alone. Also, trastuzumab may have uncommon acute cardiotoxicity, which may add to the more common anthracycline-induced cardiotoxicity; therefore, the use of trastuzumab with doxorubicin is not indicated by the FDA.

  

 

Indications: FDA approved for her2/neu overexpressing metastatic or locally advanced breast cancer; has shown clinical benefit as a single agent and in conjunction with paclitaxel-based chemotherapy.

  

 

Dosing: Loading dose of 250 mg or 4 mg/kg by intravenous infusion followed by weekly intravenous infusions of 100 mg or 2 mg/kg for up to 10 weeks (or longer).

  

 

Tretinoin (Vesanoid)—ATRA, all-trans-retinoic acid.

  

 

Drug Class: A naturally occurring retinoid; induces differentiation and apoptosis of malignant promyelocytes in acute promyelocytic leukemia.

  

 

Dosage Form: 10-mg capsules.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: This drug has good oral bioavailability and a very short elimination half-life of about 40 minutes. It induces its own metabolism in the liver, leading to decreased levels and clinical effect with continued administration. No appreciable excretion of the parent compound is evident.

  

 

Toxicity: Tretinoin is teratogenic, so women of childbearing age who take this drug must be on optimal contraceptive measures. Leukostasis and hemorrhage due to leukocytosis are dose limiting but uncommonly life threatening if the drug is stopped. “Retinoic acid syndrome,” although not common, can be dose limiting and consists of fever, chest pain, dyspnea, hypoxia, pulmonary infiltrates, and pleural/pericardial effusions. It can be lethal but improves with cessation of the drug and is treatable with corticosteroids. Dry skin, exfoliation, xerostomia, and cheilitis are common. Elevations in liver function tests and hyperlipidemias are also common. Headache is often seen, but pseudotumor cerebri or other neurologic occurrences are uncommon.

  

 

Indications: FDA approved induction therapy for acute promyelocytic leukemia. Also of benefit in the maintenance phase of this disorder and may have clinical activity in other hematologic malignancies.

  

 

Dosing: For induction, the dose is 45 mg/m2/day PO for 30 to 90 days, depending on the clinical response.

  

 

Vinblastine (Velban, Velsar, others)—VLB, vincaleukoblastine

  

 

Drug Class: Vinca alkaloid; inhibitor of tubulin polymerization and thereby mitosis. G2-phase specific.

  

 

Dosage Form: Vials of drug in solution (1 mg/mL), or lyophilized powder containing 10 mg of drug.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: Poor oral bioavailability. After an IV dose, the drug undergoes deacetylation in the liver to an active metabolite, followed by further metabolism. The elimination half-life is about 20 hours. Excretion is predominantly via the bile.

  

 

Toxicity: Vinblastine is a soft tissue vesicant, requiring extravasation precautions during administration. Myelosuppression, especially leukopenia, is expected and dose limiting. Anemia and thrombocytopenia are less common. Peripheral and autonomic neuropathy are less common than that observed with vincristine. Nausea and vomiting are uncommon, but constipation is more often seen. Acute reactions during administration, including dyspnea, wheezing, chest pain, tumor pain, and fever, are uncommon. Syndrome of inappropriate antidiuretic hormone secretion occurs rarely, as does angina pectoris.

  

 

Indications: FDA approved for multiple hematologic and solid neoplasms. Most often used for Hodgkin's disease, non-Hodgkin's lymphoma, germ cell tumors, and breast cancer.

  

 

Dosing: Typical doses are between 6 and 10 mg/m2 by IV push every 2 to 4 weeks, combined with other drugs. Can also be given as a continuous infusion over 96 hours at a dose of 1.7 to 2.0 mg/m2/day.

  

 

Vincristine (Oncovin, Vincasar)—leurocristine, VCR

  

 

Drug Class: Vinca alkaloid; inhibitor of tubulin polymerization and thereby mitosis. G2-phase specific.

  

 

Dosage Form: Available as solution (1 mg/mL) in vials containing 1 to 5 mg of drug and in syringes containing 1 or 2 mg.

  

 

Drug Interactions: L-Asparaginase may decrease hepatic metabolism of vincristine.

  

 

Pharmacokinetics/Metabolism: Vincristine is bioavailable only by the IV route. It is metabolized by the liver. The elimination half-life is variable but usually greater than 10 hours. Parent drug and metabolites are primarily excreted in the bile.

  

 

Toxicity: Vincristine is a vesicant and should be administered with extravasation precautions. Neurotoxicity is dose limiting in the form of peripheral neuropathy, which is related to total cumulative dose. Autonomic neuropathy is less common, and CNS toxicity is rare. Myelosuppression is mild. Nausea and vomiting are rare, but constipation is fairly common. Acute cardiopulmonary or pain symptoms occurring during administration are uncommon. Transient elevation of liver function tests is sometimes seen.

  

 

Indications: FDA approved for Hodgkin's disease and other lymphomas, acute leukemias, rhabdomyosarcoma, neuroblastoma, and Wilms’ tumor. Used for many other neoplasms as well.

  

 

Dosing: The usual dose is 0.5 to 1.4 mg/m2 IV push every 1 to 4 weeks. A continuous infusion of 0.5 mg/m2/day over 96 hours has also been used.

  

 

Vinorelbine (Navelbine)—5′-noranhydrovinblastine, NVB

  

 

Drug Class: Semisynthetic vinca alkaloid; inhibitor of tubulin polymerization and thereby mitosis. G2-phase specific.

  

 

Dosage Form: Available as vials of 10-mg/mL solution.

  

 

Drug Interactions: None noted.

  

 

Pharmacokinetics/Metabolism: This drug has fair oral bioavailability but is currently available only as an IV preparation. It is metabolized by the liver and has an elimination half-life of about 24 hours. Excretion is predominantly in the bile.

  

 

Toxicity: Vinorelbine is a mild vesicant, requiring extravasation precautions. Myelosuppression, mostly leukopenia, is expected and dose limiting. Significant nausea and vomiting are uncommon. Neurotoxicity in the form of neuropathy is less common and milder than that seen with vincristine. Tumor pain during administration has been reported. Acute reaction such as dyspnea, chest pain, and wheezing have occurred during administration and may be prevented by premedication with corticosteroids.

  

 

Indications: FDA approved for the treatment of relapsed metastatic breast cancer and for NSCLC as a single agent or combined with a platinating agent.

  

 

Dosing: The recommended dose is 30 mg/m2 IV over 20 minutes every week, with dose adjustments based on leukocyte counts.

  

 

Zolendronic Acid (Zometa)

  

 

Drug Class: Bisphosphonate inhibitor of bone metastases.

  

 

Dosage Form: Vials containing 4 mg of zolendronic acid in powder form.

  

 

Drug Interactions: No studies have identified interactions. Theoretical concerns include exacerbation of hypocalcemia if zolendronic acid is coadministered with aminoglycosides or thiazide diuretics. Also, zolendronic acid could exacerbate the renal effects of other nephrotoxic drugs.

  

 

Pharmacokinetics/Metabolism: Zolendronic acid is poorly absorbed by the GI tract and is therefore given as an intravenous infusion. It is not metabolized and is excreted by the kidneys. It has a plasma terminal elimination half-life of about 150 hours.

  

 

Toxicity: Zolendronic acid is generally well tolerated. The most common infusional side effect is fever, which is usually mild and treatable. Nausea and constipation are also common. Dyspnea, fatigue, diffuse pain, rash, and headache are uncommon. Renal insufficiency is uncommon and generally reversible after discontinuation of the drug, but it is more likely with higher doses than with the approved and recommended 4-mg dose.

  

 

Indications: FDA approved for treatment of hypercalcemia of malignancy and for prevention of pathologic fractures in multiple myeloma and solid tumors with known bone metastases.

  

 

Dosing: 4 mg IV injection over 15 minutes once monthly.

REFERENCES

  1. Gilman A, Philips FS: The biological actions and therapeutic applications of β-chloroethyl amines and sulfides.  Science1946; 103:409-415.
  2. Infield GB: Disaster at Bari,  New York, Macmillan, 1971.
  3. Farber S, Diamond LK, Mercer RD, et al: Temporary remissions in acute leukemia in children produced by the folic acid antagonist, 4-aminopteroyl-glutamic acid.  N Engl J Med1948; 238:787-793.
  4. Hertz R, Lewis J, Lippsett M: Five years experience with the chemotherapy of metastatic choriocarcinoma and related trophoblastic tumors in women.  Am J Obstet Gynecol1961; 82:631-640.
  5. Elion GB: The purine path to chemotherapy.  Science1989; 144:41-47.
  6. Johnson IS, Armstrong JG, Gorman M, et al: The vinca alkaloids: a new class of oncolytic agents.  Cancer Res1963; 23:1390-1427.
  7. Rosenberg B, Van Camp L, Trosko JE, et al: Platinum compounds: a new class of potent antitumor agents.  Nature1969; 222:385-386.
  8. Driscoll JS: The preclinical new drug research program of the National Cancer Institute.  Cancer Treat Rep1984; 68:63-76.
  9. Shoemaker RH, Wolpert-DeFilippes MK, Kern DH, et al: Application of a human tumor colony forming assay to new drug screening.  Cancer Res1985; 45:2145-2153.
  10. Skipper HE, Schabel Jr FM, Wilcox WS: Experimental evaluation of potential anticancer agents: XII. On the criteria and kinetics associated with curability of experimental leukemia.  Cancer Chemother Rep1964; 35:1-111.
  11. Collins VP, Loeffler K, Tivey H: Observations on growth rates of human tumors.  Am J Roentgenol1956; 76:988-1000.
  12. Tubiana M: Tumor cell proliferation kinetics and tumor growth rate.  Acta Oncol1989; 28:113-121.
  13. Sullivan PW, Salmon SE: Kinetics of tumor growth and regression in IgG multiple myeloma.  J Clin Invest1972; 51:1697-1708.
  14. Spratt JS, Greenberg RA, Henser LS: Geometry, growth rates, and duration of cancer and carcinoma in situ of the breast before detection by screening.  Cancer Res1986; 46:970-974.
  15. DeMicheli R: Growth of testicular neoplasm lung metastases: tumor specific relation between two Gompertzian parameters.  Eur J Cancer1980; 16:1603-1608.
  16. LaLa PK: Age-specific changes in the proliferation of Ehrlich ascites cells grown as solid tumors.  Cancer Res1972; 32:628-636.
  17. Watson JV: The cell proliferation kinetics of the EMT6/M/AC mouse tumor at four volumes during unperturbed growth in vivo.  Cell Tissue Kinet1976; 9:147-156.
  18. Norton L, Simon R: Tumor size, sensitivity to therapy, and the design of treatment schedules.  Cancer Treat Rep1977; 61:1307-1317.
  19. Norton LA: A Gompertzian model of human breast cancer growth.  Cancer Res1988; 48:7067-7071.
  20. Norton L, Simon R: The Norton-Simon hypotheses revisited.  Cancer Treat Rep1986; 70:163-169.
  21. Luria SE, Delbruck M: Mutations of bacteria from virus sensitivity to virus resistance.  Genetics1943; 28:491-511.
  22. Goldie JH, Coldman AJ: A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate.  Cancer Treat Rep1979; 63:1727-1733.
  23. Schimke RT: Gene amplification in cultured mammalian cells.  Cell1984; 37:705-713.
  24. Poste G, Fidler I: The pathogenesis of cancer metastases.  Nature1980; 283:139-146.
  25. DeVita VT, Young RC, Canellos GP: Combination vs. single agent chemotherapy: a review of the basis for selection of drug treatment of cancer.  Cancer1975; 35:98-110.
  26. Elliott JA, Österlind K, Hansen HH: Cyclic alternating non-cross-resistant chemotherapy in the management of small cell anaplastic carcinoma of the lung.  Cancer Treat Rev1984; 11:103-113.
  27. Österlind K, Sörenson S, Hansen HH, et al: Continuous versus alternating combination chemotherapy for advanced small cell carcinoma of the lung.  Cancer Res1983; 43:6085-6089.
  28. Daniels JR, Chak LY, Sikic BL, et al: Chemotherapy of small cell carcinoma of the lung: a randomized comparison of alternating and sequential combination chemotherapy programs.  J Clin Oncol1984; 2:1192-1199.
  29. Ettinger DS, Finkelstein DM, Abeloff MD, et al: A randomized comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive stage small-cell lung cancer: a Phase III study of the Eastern Cooperative Oncology Group. J Clin Oncol 990;8:230–240.
  30. Roth BJ, Johnson DH, Einhorn LH, et al: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alteration of these two regimens in extensive small-cell lung cancer: a Phase III trial of the Southeastern Cancer Study Group.  J Clin Oncol1992; 10:282-291.
  31. Fukuoka M, Furuse K, Saijo N, et al: Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer.  J Natl Cancer Inst1991; 83:855-861.
  32. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD.  N Engl J Med1992; 327:1478-1484.
  33. Glick J, Young ML, Schilsky R, et al: MOPP/ABV hybrid chemotherapy for advanced Hodgkin's disease significantly improves failure-free and overall survival: the 8-year results of the intergroup trial.  J Clin Oncol1998; 16:19-26.2283 [comment]
  34. Aisner J, Cirrincione C, Perloff M, et al: Combination chemotherapy for metastatic or recurrent carcinoma of the breasts: randomized phase III trial comparing CAF versus VATH versus VATH alternating with CMFVP: cancer and Leukemia Group B Study 8281.  J Clin Oncol1995; 13:1443-1452.
  35. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial 9741/Cancer and Leukemia Group B Trial 9741.  J Clin Oncol2003; 21:1431-1439.
  36. Wicha MS, Liu S, Dontu G: Cancer stem cells: an old idea—a paradigm shift.  Cancer Res2006; 66:1883-1890.
  37. Drucker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specific inhibitor of BCR-ABL kinase in chronic myeloid leukemia.  N Engl J Med2001; 344:1031-1037.
  38. Demitri GD, Von Mehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.  N Engl J Med2002; 347:472-480.
  39. Jabbour E, Cortes J, Kantarjian H: Dasatinib for the treatment of Philadelphia chromosome-positive leukaemias.  Expert Opin Investig Drugs2007; 16:679-687.
  40. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer.  N Engl J Med2005; 353:123-132.
  41. Hochster HS, Haller DG, de Gramont A, et al: Consensus report of the International Society of Gastrointestinal Oncology on therapeutic progress in advanced pancreatic cancer.  Cancer2006; 107:676-685.
  42. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell carcinoma.  N Engl J Med2007; 356:125-134.
  43. Motzer RJ, Hutson TE, Tonczak P, et al: Sunitinib versus interferon alfa in metastatic renal cell carcinoma.  N Engl J Med2007; 356:115-124.
  44. Geyer CE, Foraster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer.  N Engl J Med2006; 355:2783-2785.
  45. Degos L, Wang ZY: All-trans-retinoic acid in acute promyelocytic leukemia.  Oncogene2001; 20:7140-7145.
  46. Kantarjian H, Oki Y, Garcia-Manero G, et al: Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia.  Blood2007; 109:52-57.
  47. Phillips RK, Wallace MH, Lynch PM, et al: A randomized, double blind, placebo-controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis.  Gut2001; 50:857-860.
  48. Kabbinavar FF, Hanbleton J, Mass RD, et al: Combined analysis of efficacy: The addition of bevacizumab to flourouracil/leocovorin improves survival for patients with metastatic colorectal cancer.  J Clin Oncol2005; 3:20-29.
  49. Lyseng-Williamson KA, Robinson DM: Spotlight on bevacizumab in advanced colorectal cancer, breast cancer, and non-small cell lung cancer.  Bio/Drugs2006; 20:193-195.
  50. Ghobrial IM, Leleu X, Hatjiharissi E, et al: Emerging drugs in multiple myeloma.  Expert Opin Emerg Drugs2007; 12:155-163.
  51. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al: IDEC-C2B8: results of a phase I multidose trial in patients with relapsed non-Hodgkin's lymphoma.  J Clin Oncol1997; 15:3266-3274.
  52. McLaughlin P, Grillo-Lopez A, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four dose treatment program.  J Clin Oncol1998; 16:2825-2833.
  53. Rai KR, Freter CE, Mercier RJ, et al: Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine.  J Clin Oncol2002; 20:3891-3897.
  54. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.  J Clin Oncol2002; 20:719-726.
  55. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.  N Engl J Med2004; 351:337-345.
  56. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck.  N Engl J Med2006; 354:567-578.
  57. Saadeh CE, Lee HS: Panitumumab: a fully human monoclonal antibody with activity in metastatic colorectal cancer.  Ann Pharmacother2007; 41:606-613.
  58. Kaminski MS, Zelenetz AD, Press OW, et al: Pivotal study of iodine I-131 tositumomab for chemotherapy-refractory low-grade or transformed β-cell non-Hodgkin's lymphomas.  J Clin Oncol2001; 19:3918-3928.
  59. Witzig TE, Gordon LI, Cabanillas F, et al: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed β-cell non-Hodgkin's lymphoma.  J Clin Oncol2002; 20:2453-2467.
  60. Sievers E, Larson R, Stadtmauer E, et al: Efficacy and safety of gemtuzumab ozogamicin in patients with CD-33 positive acute myeloid leukemia in first relapse.  J Clin Oncol2001; 19:3244-3254.
  61. Kreitman RJ, Pastan I: Immunotoxins in the treatment of hematologic malignancies.  Curr Drug Targets2006; 7:1301-1311.
  62. Fouladi M: Histone deacetylase inhibitors in cancer therapy.  Cancer Invest2006; 24:521-527.
  63. Kim R, Emi M, Matsuura K, Tanabe K: Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy.  Cancer Gene Ther2007; 14:1-11.
  64. Maghfoor I, Doll DC: Chemotherapy in pregnancy.   In: Perry MC, ed. The Chemotherapy Sourcebook,  3rd ed.. Philadelphia: Lippincott Williams & Wilkins; 2001:537-546.
  65. Brown D: Future pathways for combinatorial chemistry.  Mol Diversity1997; 2:217-222.
  66. Combinatorial chemistry to develop new drugs.  Cancer J Sci Am1997; 3:312-313.
  67. Hruby VJ, Shenderovich M, Lam KS, Lebl M: Design considerations and computer modeling related to the development of molecular scaffolds and peptide mimetics for combinatorial chemistry.  Mol Diversity1996; 2:46-56.
  68. Kick EK, Roe DC, Skillman AG, et al: Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsin D.  Chem Biol1997; 4:297-307.
  69. Plunkett MJ, Ellman JA: Combinatorial chemistry and new drugs.  Sci Am1997; 276:68-73.
  70. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM: Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia.  Lancet1990; 336:225-229.
  71. Stanulia M, Schaeffeler E, Flohr T, et al: Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia.  JAMA2005; 293:1485-1489.
  72. Rothenberg ML, Meropol NJ, Poplin EJ, et al: Mortality associated with irinotecan plus bolus flourouracil/leucovorin: summary findings of an independent panel.  J Clin Oncol2001; 19:3801-3807.
  73. O'Dwyer PJ, Catalano RP: Uridine diphosphate glucuronyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy.  J Clin Oncol2006; 24:4534-4538.
  74. Wulfkuhle JD, Edmiston KH, Liotta LA, Petricoin EF: Technology insight: pharmacoproteomics for cancer-promises of patient-tailored medicine using protein microarrays.  Nat Clin Pract Oncol2006; 3:256-268.
  75. Salmon SE: Kinetics of minimal residual disease.  Recent Results Cancer Res1979; 67:1-15.
  76. Frei III E, Clark JR, Miller D: The concept of neoadjuvant chemotherapy.   In: Salmon SE, ed. Adjuvant Therapy of Cancer, vol 5. Orlando, Fla: Grune & Stratton; 1987:67-75.
  77. Rosen G, Caparos B, Huvos AG, et al: Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy.  Cancer1982; 49:1221-1230.
  78. Aaronson NK, Meyerowitz BE, Bard M, et al: Quality of life research in oncology: past achievements and future priorities.  Cancer1991; 67:839-843.
  79. Gough IR, Dalgleish LI: What value is given to quality of life assessment by health professionals considering response to palliative chemotherapy for advanced cancer.  Cancer1991; 68:220-225.
  80. Buzzoni R, Bonadonna G, Valagussa P, et al: Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive nodes.  J Clin Oncol1991; 9:2134-2140.
  81. Walsh SJ, Begg CB, Carbone PP: Cancer chemotherapy in the elderly.  Semin Oncol1989; 16:66-75.
  82. Baker DS, Grochow LB, Donehower RC: Should anticancer drug dose be adjusted in the obese patient?.  J Natl Cancer Inst1995; 87:333-334.
  83. Smith TJ, Desch CE: Neutropenia-wise and pound-foolish: safe and effective chemotherapy in massively obese patients.  South Med J1991; 84:883-885.
  84. In: Perry MC, ed. The Chemotherapy Sourcebook,  9th ed.. Philadelphia: Wolters Kluwer; 2008.
  85. Diasio RB, Beavers TL, Carpenter JT: Familial deficiency of dihydropyrimidine dehydrogenase: biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity.  J Clin Invest1988; 81:47-51.
  86. Ratain MJ, Mick R, Berezin F, et al: Paradoxical relationship between acetylator phenotype and amonafide toxicity.  Clin Pharm Ther1991; 50:573-579.
  87. Burris III HA: Combination chemotherapy.   In: Perry MC, ed. The Chemotherapy Sourcebook,  3rd ed.. Philadelphia: Lippincott Williams & Wilkins; 2001:69-73.
  88. Groeger JS, Lucas AB, Coit DC: Venous access in the cancer patient.   In: De Vita Jr VT, Hellman S, Rosenberg SA, ed. PPO Updates, Principles and Practice of Oncology, vol 5. Philadelphia: JB Lippincott; 1991:1-14.
  89. AskRx Drug Information Program : Information Derived from the United States Pharmacopedial Dispensing Information, vol I (USP DI),  Warrendale, Penn, Camdat Corporation, 1992.
  90. In: Baltzer L, Berkery R, ed. Oncology Pocket Guide to Chemotherapy,  2nd ed.. St. Louis: Mosby-Year Book; 1995.
  91. Clinical Pharmacology Online, Version 1.13. Gold Standard Multimedia, Inc, October 14, 1997.
  92. In: Fischer DS, Knobf MF, Durivage HJ, ed. The Cancer Chemotherapy Handbook,  4th ed.. St. Louis: Mosby-Year Book; 1993.
  93. Thompson Micromedex Greenwood Village, Colorado, 2007.
  94. Physicians' Desk Reference,  57th ed.. Montvale, Medical Economics, 2003.