Cancer Chemotherapy & Biotherapy: Principles & Practices, 4th Edition

Cisplatin, Carboplatin, and Oxaliplatin

Eddie Reed

Rosenberg and colleagues1, 2 in a set of experiments involving Escherichia coli, discovered the dramatic inhibitory effects of platinum compounds on cellular replication. Following those seminal studies, a rapid series of basic, preclinical, and clinical studies resulted in Food and Drug Administration (FDA) approval for the treatment of testicular cancer. Within 15 years, cisplatin's effectiveness in ovarian cancer, lung cancer, head and neck cancer, bladder cancer, and other malignancies led to its becoming the most widely used anticancer drug in North America and in Europe.

Because of the particularly troublesome toxicities of renal damage, nausea and vomiting, deafness, and peripheral neuropathy, efforts were made to develop analogs of the drug that would have equivalent clinical effectiveness, but without the toxicities of the parent compound. The first cisplatin analog to meet with widespread clinical use was carboplatin (Figure 14.1). Well-performed clinical studies have shown that carboplatin is equally effective as cisplatin in ovarian cancer, lung cancer, and several other malignancies. However, for unclear reasons, carboplatin is less effective than cisplatin in the treatment of germ cell malignancy. Carboplatin is less neurotoxic, emetogenic, and nephrotoxic than cisplatin. However, carboplatin is not toxicity-free, as will be discussed.

A number of additional platinum analogs have been synthesized for potential clinical use. Of these, only oxaliplatin (Figure 14.1) has reached the stage of FDA approval, as of this writing. For unclear reasons, oxaliplatin is particularly effective in colon cancer, in combination with other agents. Colon cancer is a disease for which neither cisplatin nor carboplatin show meaningful levels of effectiveness. Understanding the molecular basis for these peculiarities for these three compounds could potentially unlock a treasure trove of new insights as to how cancer cells fight off the effects of DNA-damaging agents.

SUBCELLULAR PHARMACOLOGY

The cellular effects of platinum compounds (and the effects of the cell on platinum compounds) have been extensively studied using cisplatin, carboplatin, and oxaliplatin as the experimental tools. Cisplatin is able to cross cellular barriers because of its simple chemistry, although there have been a number of reports of specific transmembrane transport systems that promote efflux of the drug,3, 4, 5 such as the copper efflux transporter described by Kruh.3 At physiologic pH of 7.4, the chemistry of the molecule is such that dissociation of the chlorides (along with replacement of these chlorides by -OH molecules) results in cisplatin having a neutral charge (Figure 14.2). This makes it possible for ready diffusion across the cellular membrane, flowing with the cisplatin gradient from a high concentration outside the cell to a lower concentration inside the cell. Several important aspects of platinum chemistry are summarized in Table 14.1.

Once inside the cell, three different fates await the compound.3, 5 One fate is to be exported from the cell by one of several specific active transport systems that have been described. A second fate is to be chemically neutralized by proteins that have active sulfhydryl groups, such as glutathione or metallothioneins. A third fate is to react in a relatively nonspecific way with a number of intracellular molecules, which include a range of proteins, RNAs, and DNA (cellular and mitochondrial).

Through this relatively nonspecific interaction of this highly reactive platinum moiety with a range of subcellular molecules, cisplatin exerts its effects on the cell. In terms of affinity for these different classes of reactive subcellular moieties, the measured affinity for RNA is greater than that for DNA, which, in turn, is greater than that for proteins. Because of time of transit from cellular membrane into the nucleus, the sum total of reactions with DNA is lower than that with intracellular protein on a molar basis.

Figure 14.1 Two-dimensional structures are shown for cisplatin, carboplatin, and oxaliplatin. The core structures are the same based on the cisconfiguration of Pt(II). The leaving groups are different for the three compounds. The carrier ligand is different for oxaliplatin

It is widely accepted that in most circumstances, the reactions with cellular DNA determine the bulk of cisplatin-related cellular effects. One exception was noted with a Burkitt's lymphoma cell line, in which protein binding was reported to effect cell death in a time frame that could not be explained by DNA damage.3 This is presumed to be the exception, rather than the rule.

TABLE 14.1 IMPORTANT ISSUES REGARDING PLATINUM CHEMISTRY

1. Analogs in the cis configuration are clinically active. Analogs in the trans configuration are not.

2. The bond angles for the platinum core of these drugs are fixed; therefore, DNA bends to accommodate the structure of the drug.

3. The leaving group is important in platinum pharmacology and the specific carrier ligand is important as well.

4. The aquation chemistry of the cisplatin compound suggests movement of the drug across cellular membranes against a concentration gradient. No need exists for active transport into the cell.

5. The aquation chemistry for oxaliplatin is similar to that of cisplatin. For carboplatin, esterase activity for the carboxylato leaving group is necessary to generate the reactive species of the compound.

6. All clinically active platinum compounds that have been studied form bifunctional intrastrand DNA adducts. which appear to be responsible for the cell-killing effect of these analogs.

Figure 14.2 Aquation and hydrolysis equilibria of cisplatin (pka values are from ref. 187). Note that reactions 3 and 6 are favored at physiologic pH and yield products that have a neutral charge and that theoretically could readily cross cell membranes.

In early studies comparing cisplatin with transplatin (utilizing a technique called alkaline elution), it was demonstrated that the DNA-damaging effects of cisplatin were responsible for its cell-killing effects.3 Further, it was found necessary for reactive groups to be in the cis configuration to generate effective cell killing. In subsequent, more detailed studies, it was shown by several different groups that the intrastrand N7-d(GpG) and the N7-d (ApG) intrastrand adducts were probably responsible for cell killing of the drug (Figure 14.3).5 The relative contribution of these adducts to cell killing, as well as other specific DNA lesions such as interstrand cross-links, have never been completely worked out. But it is clear that the intrastrand adducts are more highly correlated with drug-induced cell killing.

Figure 14.3 Bifunctional adducts of cisplatin with DNA. Lesions indicated in panels A, B, and C represent different intrastrand adducts, which together account for more than 90% of total platinum binding to DNA. The lesion indicated in panel D is the interstrand cross-link measured by alkaline elution and accounts for less than 5% of total platinum binding to DNA. See text for discussion

The N7-d(GpG) and the N7-d(ApG) adducts account for more than 80% of total platinum-DNA damage that forms after an exposure of cisplatin to isolated DNA;1, 6 or to cells in tissue culture;7, 8 or to cells from patients in clinical settings.9, 10, 11 These two adducts are associated with severe kinking of the DNA double helix.12 This kinking is recognized and repaired by the nucleotide excision repair pathway, which involves the genes ERCC1, XPA, and others.13, 14, 15Table 14.2 summarizes the relative proportions of the DNA lesions formed after exposure to cisplatin, carboplatin, or oxaliplatin.

Kinking of the DNA is caused by the fact that the bond angles within the cisplatin molecule are relatively rigid as compared with the DNA double-helix.12 The DNA double-helix thereby bends to conform to the structure of the platinum molecule. This is in contrast to most bifunctional alkylating agents within which the pivotal carbon molecule has bond angles that “breathe” and allow for the drug to bend to accommodate the structure of the DNA. In addition to the fixed angle bending of the DNA helix, there is evidence for local denaturation of the DNA strand at the site of intrastrand adduct binding.

In addition to cisplatin, carboplatin and oxaliplatin are FDA-approved for the treatment of one or more human malignancies. Carboplatin is similar to cisplatin in most respects. The major subcellular differences between these two drugs include the need for an esterase activity to release the carboxylato moiety of the carboplatin molecule, and thereby to expose the reactive arms for covalent binding to target sites, and a delayed time frame for the formation of the specific DNA lesions such as the N7-d (GpG) and N7-d(GpG) adducts, as compared with cisplatin.16 Differences in clinical pharmacology and in clinical toxicity are discussed in this chapter. For almost all matters, the subcellular behaviors of cisplatin and carboplatin appear to be practically the same.

Oxaliplatin is FDA-approved for the treatment of colorectal cancer. The major subcellular differences between cisplatin and oxaliplatin include the carrier ligand effects involving the nonreactive moiety of the oxaliplatin compound,17, 18 and differences in the rates of formation and repair of oxaliplatin-DNA damage, as compared with cisplatin.17, 19, 20 Diffferences in clinical pharmacology and in clinical toxicity are also discussed in this chapter.

MECHANISM(S) OF ACTION

The consensus is that cisplatin and its analogs exert their cytotoxic effects by covalently binding to purine DNA bases and disrupting the normal functions of cellular DNA. Platinum analogs that have therapeutic activity form a preponderance of DNA intrastrand adducts as opposed to DNA interstrand cross-links or DNA–platinum-protein cross-links.3, 5 Cisplatin binding to mitochondrial DNA has been described,21, 22, 23, 24 but is of unclear biologic significance. Binding to cellular proteins has been suggested as being of primary importance in one Burkitt's lymphoma cell line in which cell death occurred shortly after cellular exposure and appeared to result from loss of cell membrane integrity.

Early studies of cisplatin and transplatin compared the relative importance of DNA damage versus protein binding in terms of causing tumor cell kill in tissue culture.3 Some laboratories have sought to correlate tumor cell kill with one or more of the different intrastrand lesions, the N7-d(GpG) adduct or the N7-d(ApG) adduct or the N7-d (GpXpG) adduct.5 There are conflicting reports over which lesion(s) may be more associated with the cytotoxic effects of these drugs and which lesion(s) may be more associated with the mutagenic effects of these drugs. These studies have not been definitive because of the complexity of the mix of DNA adducts after cisplatin exposure, as shown in Table 14.2. When platinum agents are allowed to react with isolated DNA or cells, or are given to animals, the proportions of the various DNA adducts are relatively constant, which is also listed in Table 14.2.

Cell death may occur through apoptotic or nonapototic pathways. The apoptotic pathways may be mediated through mismatch repair genes.25, 26, 27, 28 p53,29or bcl2/bax.30, 31 Overwhelming DNA damage is associated with acute, nonapoptotic cell death. Reports going back more than 3 decades show that cisplatin exerts a positive effect on immune-mediated killing of tumor cells.3, 4, 5 These effects have been reported in vitro in animal models and in human clinical trials. Detailed discussion of these considerations is given in this chapter.

TABLE 14.2 TYPES OF DNA LESIONS CAUSED BY CISPLATIN, CARBOPLATIN, AND OXALIPLATIN

DNA Lesion

% of Total DNA Damage

(Comment)

N7-d(GpG)-intrastrand adduct

~60

Possibly lethal to cells

N7-d(ApG)-intrastrand adduct

~30

Possibly lethal to cells

N7-d(GpXpG)-intrastrand adduct

~10

Potential lethality unclear

N7-d(X)-d(X)-interstrand cross-link

<2

Biologic importance unclear

Levels correlate with cellular toxicity

With the advent of oxaliplatin, the nature of effects of different carrier ligands on platinum's ability to induce cellular damage, and evade DNA repair processes, have been of particular interest. Saris and colleagues19 were the first to demonstrate that a ligand bound to the platinum core, when opposite the cis configuration of the reactive bonds, can exert tremendous influence on subcellular pharmacology of the drug. The carrier ligand has effects on DNA repair efficiency and on cell-killing efficiency.17, 18, 19, 20, 27 It is not clear why oxaliplatin should be particularly active in cases of colon cancer when cisplatin and carboplatin have very limited activity in this disease. One possible explanation has to do with the relative inability to perform replicative bypass over an oxaliplatin-DNA lesion as compared with a cisplatin-carboplatin–DNA lesion. The carrier ligand of oxaliplatin makes replicative bypass of this DNA lesion much more difficult. Thus, cells that depend on replicative bypass as a major mechanism of platinum resistance may be comparatively more sensitive to oxaliplatin than the other platinum compounds. Others have shown that the carrier ligand has substantial effects on the clinical pharmacology of platinum analogs, as will be discussed later.

Platinum agents give additive or synergistic activity with a range of other anticancer agents. Cisplatin is thought to be relatively non–cell cycle-specific in terms of its cell-killing effects. However, it tends to synergize with agents that reduce the intracellular levels of precursors that are needed for DNA replication or repair. This includes antimetabolites such as 5-fluorouracil32, 33 and gemcitabine.34 Platinums also synergize with agents that alter mitosis, such as paclitaxel, DNA repair activity,35 and with ERCC1 inhibitors.36, 37, 38, 39 Positive interactions with topoisomerase inhibitors have been described,40 as well as with agents from other drug classes.3, 5

In summary, the primary mechanism of cell killing for this class of compounds is covalent binding to purine bases of cellular DNA. This covalent binding leads to bending of the DNA helix at a fixed angle, with local denaturing of the DNA strand. This DNA damage is detected by components of the repair complex and is converted into a strand break. Adducts are removed and breaks are repaired by the nucleotide-excision repair process. When not effectively repaired, cell killing may occur through apoptotic or nonapoptotic pathways. The possible contribution of drug-induced, immune-mediated cell killing, which may occur in the intact host, is discussed later.

IMMUNE EFFECTS OF PLATINUM AGENTS

The first human clinical studies of positive immune modulation by cisplatin were done in a group of 34 patients by Kleinerman and colleagues.41 They showed that, after receiving cisplatin-based therapy, patients' monocyte function improved by sixfold; this was particularly striking in patients with epithelial ovarian cancer.41 In subsequent studies, they showed that cisplatin directly stimulated monocytes and did not stimulate other subsets of immune cells.42 Follow-up in vitro studies showed that cisplatin and adriamycin had similar monocyte-stimulating effects, but that this effect was not seen with irradiation, L-phenylalanine mustard, mAMSA, or actinomycin D.43 Similar studies have been reported in murine systems and other preclinical models.3, 5

Recently, Merritt and colleagues44 attempted to dissect out the possible mechanism for the observations of Kleinerman and colleagues.41 In there studies, gene knock-out mice were used in a Lewis lung cancer model. The mice were either Fas-negative or Fas-positive. In these studies, the ability of intraperitoneal cisplatin to effect tumor cell kill depended on the presence of Fas. It was concluded that cisplatin-induced cell killing, in this model, depended on the presence of Fas ligand in the tumor cells.

Li and colleagues45, 46 have shown that Jun/JunK is up-regulated after exposure to cisplatin. Several recent studies have shown that up-regulation of Jun/JunK may lead to up-regulation of Fas in Fas-competent cells.47, 48, 49 Collectively, the data suggest a flow in which up-regulation of Jun/JunK may lead in either of three general directions in terms of downstream molecular pathways. In some cells, up-regulation of Jun/JunK may activate DNA repair processes; in some cells, Fas ligand-mediated immunogenicity may dominate; and in other cells, global stress response processes may be activated. In cells where up-regulation of Fas is a major element of the Jun/JunK response, this could lead to greater immunogenicity and greater immune-mediated cell killing after cisplatin treatment. Among the tumor cell types that demonstrate greater immune-mediated cell killing after cisplatin exposure are esophageal cancer,50mesothelioma,51 gastric cancer, 52 melanoma, 53 colorectal cancer,54 and cervical cancer.55

MECHANISMS OF RESISTANCE

The mechanisms of resistance to platinum agents have been studied most extensively for cisplatin. There are four generic pathways through which cells become resistant, or are intrinsically resistant, to platinum compounds: altered cellular accumulation of drug, cytosolic inactivation of drug, increased DNA repair, or an altered apoptotic process that results in increased tolerance to DNA damage.

Eastman and colleagues6, 7 studied the relative contributions of the first three of these processes in L1210 murine leukemia cells. Johnson et al.56 and Ferry et al.57 studied the relative contributions of these first three processes in human ovarian cancer cells. In both systems, the observations were very similar. At all levels of cisplatin resistance (up to 100-fold over baseline), all three components of resistance (DNA repair, cytosolic inactivaton, and cellular accumulation of drug) appeared to contribute somewhat to the overall pattern of resistance. However, there were differences regarding the relative contribution of a particular mechanism in the two model systems.

At low levels of cisplatin resistance (about 10- to 15-fold over baseline), the primary determinant of cellular resistance was DNA repair. At intermediate levels of resistance (up to 40- to 50-fold over baseline), the primary determinant of cellular resistance was reduced cellular accumulation of drug. At very high levels of resistance, cytosolic inactivation of drug became the primary determinant of resistance. Each item will be briefly reviewed in turn, moving from the cell membrane in toward the nucleus.

Altered Cellular Accumulaton

Chemically, the pH of the blood compartment is such that the redox state of cisplatin in the blood stream favors the uptake of a neutral species of drug, from the blood into the cell. This uptake is mediated by the drug concentration gradient, from high levels in the blood to the lower levels within the cells.5 There are no reports of an active uptake process for cisplatin or any of its analogs.

Active efflux of cisplatin has been described in vitro, particularly as medicated by CuH transporters, ATP7A and ATP7B,4 and other less well-definied systems.5Reduced drug accumulation appears to be a consistent observation in cisplatin-resistant tumor cell lines.

Cytosolic Inactivation of Drug

Proteins or peptides with increased levels of sulfhydryl groups may confer cellular resistance to cisplatin through covalent binding to the active moieties of the compound. Such molecules include glutathione58, 59 and metallothionein.60, 61 Up-regulation of either results in inactivation of the drug before it can reach the nucleus and leads to decreased DNA damage levels after a given level of drug exposure.

DNA Repair

Platinum compounds form bulky lesions with cellular DNA, which are repaired by nucleotide-excision repair (NER).15, 34 This is the same pathway that repairs DNA damage from polycyclic aromatic hydrocarbons and from ultraviolet light. There are 16 proteins involved in the DNA repairosome that repairs cisplatin-DNA adduct. They include ERCC1, XPA, XPF, XPB, XPD, and others.15 In sequence, the platinum-DNA lesion is recognized by the repairosome, the 3′ cut into the DNA strand is made 15 to 23 bases from the site of the lesion, the helicase function is implemented, and then the 5′ cut is made.13, 15 The 5′ cut is implemented by the ERCC1-XPF heterodimer, which is the last substep in the excision of cisplatin-DNA damage. Gap-filling and ligase activity follows.

Platinum-DNA adduct repair temporally occurs in two phases in vitro.62, 63 The first phase occurs over the first 6 to 8 hours after the drug exposure, during which 60 to 80% of all DNA damage is removed from the cells. The second phase occurs more slowly and may last for many hours. It is not complete after 24 hours. A similar pattern was observed in a study of the in vitro removal of platinum from the DNA of peripheral blood cells,9 indicating that what happens in vitro parallels what happens in human patients.

Zehn and colleagues64 and Jones and colleagues65 showed that the first phase of cisplatin-DNA adduct repair is predominated by transcription-coupled, or gene-specific, repair. In this process, transcriptionally active genes are repaired first, before the rest of the genome. The quiescent parts of cellular DNA are repaired in a more leisurely fashion by the cell, taking many hours. This is a function of the three-dimensional state of DNA structure in which transcriptionally active genes are more open and can be readily accessed by the DNA repair protein machinery. The gene-specific repair of cisplatin-DNA damage occurs over the first 6 to 8 hours after the cisplatin exposure and is most prominent in cisplatin-resistant cells.

Altered Apoptosis/Increased Tolerance To DNA Damage

Apoptosis in response to cisplatin is mediated through the mismatch repair (MMR)25, 26, 27, 28 and other genes as previously discussed. Data exist to suggest that sensitivity to drug-induced apoptosis may be altered in cells that have one or more of several defined defects in MMR. This altered sensitivity to apoptosis results in enhanced tumor cell survival and, therefore, greater resistance to chemotherapy. It has been reported that in each cell line in which this alteration in MMR exists, there is a concurrent enhancement of the activity of NER, thus clouding the issue of which is more important, MMR or NER.

Enhanced replicative bypass of platinum-DNA lesions has been suggested to be a mechanism of tumor cell resistance to platinum compounds. Although demonstrated elegantly in the laboratory, it is not yet clear whether this is important in human tissues. The central considerations related to platinum drug resistance are summarized in Table 14.3.

COMMON END ORGAN TOXICITIES

Kidney Toxicity

Renal toxicity is common with all clinically utilized platinum analogs, and particularly so with cisplatin.66, 67, 68 Kidney damage from carboplatin and from oxaliplatin tend to be less severe, and may be subclinical in many cases. Preclinical models suggest that the proximal renal tubule is less sensitive to platinum damage than the distal tubule, although both are affected by platinum exposures.

Renal clearance may be substantially reduced after several cycles of therapy with cisplatin or carboplatin, even in the face of a normal serum creatinine. Alternatively stated, the serum creatinine may remain normal in a patient who has had several cycles of platinum therapy, and the concurrent renal clearance may remain dramatically reduced. This phenomenon has been observed with a number of heavy metals, such as lead. This is important because drugs of other classes (such as antibiotics) may be needed by cancer patients and require adequate renal clearance. Cation loss in the urine is a common component of platinum-related renal toxicity and may include Mg2+, Ca2+, and other heavy metals. The treating physician should consider regular replacement of these cations during the course of treatment, along with over-the-counter supplements such as zinc and selenium. Symptomatic hypomagnesemia and hypocalcemia may result.

TABLE 14.3 MECHANISMS OF CELLULAR RESISTANCE TO PLATINUM COMPOUNDS

Alterations in transmembrane cellular accumulation of drug
   No specific transmembrane carrier for cisplatin has ever been identified. The Cu++ carrier may play a role.
   Altered cellular accumulation has been associated with inhibition of a variety of membrane proteins, including Na, K-adenosine triphosphatase.
   Facile transmembrane transit of drug can be explained by the aquation of cisplatin in water.
Cytosolic inactivation of drug
   Glutathione conjugation of activated platinum occurs with possible active transport out of the cell for drug conjugated to reduced glutathione by the multidrug resistance protein class of adenosine triphosphate-dependent transporters.
   Metallothioneins glutathione and inactivate platinum.
   Other sulfhydryl-containing groups, such as proteins, inactivatedrug.
DNA repair
   Nucleotide excision repair increases (NER; this pathway is responsible for the repair of cisplatin-DNA damage).
   Clinical data show enhanced mRNA expression in platinum-resistant tumors.
   Increased NER is associated with high levels of resistance (more than 10-fold over baseline) in cultured cells.
   Defective MMR may be responsible for failure to recognize platinum-DNA adducts and for the failure to link unrepaired DNA damage to apoptotic pathways.
   Clinical data show enrichment of MMR-defective cells in tumors after platinum therapy.
   Defective MMR is associated with low levels of resistance (twofold to threefold over baseline) in cultured cells.
   Translesional DNA synthesis is observed to occur preferentially in cisplatin-resistant cells.
   In many cell lines, increased NER and defective MMR occur in tandem.
Resistance to apoptosis
   Resistance may be mediated through defective MMR proteins, p53bcl/bax, or other mechanisms.
   Apoptotic response may be p53-dependent or p53-independent, and caspase-dependent or caspase-independent.

Methods used to minimize this toxicity include vigorous intravenous hydration before and after administering cisplatin, and in cases where renal compromise has been discovered or is suspected, using this same approach with carboplatin and oxaliplatin. The use of mannitol to enhance urine flow may be beneficial, but the use of furosemide may be counterproductive in many patients. Furosemide tends to decrease total body water, which would increase tissue-drug exposure per dose and thereby enhance toxicity. Dosing based on area under the curve (AUC) is particularly important for carboplatin, which is eliminated primarily by renal clearance.

Nausea and Vomiting

Cisplatin is clearly the more emetogenic of the platinum analogs, although severe nausea may be seen with carboplatin and with oxaliplatin.5, 69, 70, 71 It is not clear whether this emetogenic effect is mediated primarily through the CNS or through peripheral mechanisms. However, for cisplatin in particular, the most aggressive antiemetic regimens are necessary to ensure patient comfort and patient compliance with future treatment. For cisplatin-containing regimens, it is best to premedicate the patient with dexamethasone, an HT3 antagonist and a substance P antagonist. This approach will address immediate and delayed nausea and vomiting caused by the platinum drugs. Premedication for this side effect should be aggressive and focused on preventing the development of symptoms. Some centers will use H1 and H2 antagonists as well. A less aggressive approach can be used for carboplatin and for oxaliplatin, but the strategy of a preventive approach should be maintained.

Neurotoxicity

Neurotoxicity is a major side effect of cisplatin, and is a frequent problem with carboplatin and oxaliplatin.5, 69, 72, 73, 74 This can be ameliorated in some cases by amifostine (adisulfide activated in normal cells preferentially). Neurotoxicity can be manifested as peripheral sensory or, less commonly, meta neuropathy, auditory impairment, visual disturbances and, less commonly, cortical blindness, seizures, papilledema, and retrobulbarneuritis. Auditory impairment is discussed later.

The toxicity profile from single-agent oxaliplatin is dominated by peripheral neuropathy with little nephrotoxicity and minimal ototoxicity or hematologic toxicity. This neurotoxicity is manifested in either of two ways. An acute neurotoxicity that appears to be related to dose and duration of drug infusion presents as paresthesias or dysesthesias, commonly triggered by exposure to cold and occurring in the extremities and perioral region. This may also be associated with laryngopharyngeal dysesthesias, which cause difficulty breathing or swallowing. These toxicities are usually associated with the maximal drug doses.

Oxaliplatin generates a chronic neurotoxicity that is associated with cumulative platinum dose. This side effect is virtually identical to cisplatin-related neurotoxicity, with the exception that oxaliplatin-induced neurotoxicity is usually fully reversible over 3 to 4 months after stopping the drug. For cisplatin, peripheral neuropathy can persist for several years after stopping the medication.

Cisplatin-related peripheral neuropathy has been treated by a number of maneuvers over time, all with less-than-desired results. No approach is clearly satisfactory with respect to preventing this toxicity, or treating it once it occurs. This is usually managed by cisplatin dose reductions and/or dose delays. One study assessed the effect of vitamin B6 on preventing peripheral neuropathy in patients with ovarian cancer who received platinum-based combination chemotherapy.75 The group randomized to received vitamin B6 had significantly less toxicity than the similarly treated group that did not receive vitamin B6. However, the group receiving vitamin B6 also had a significantly reduced response rate and a significantly reduced survival.

Myelosuppression

Trilineage cumulative myelosuppression is commonly seen with cisplatin and with carboplatin, but less so with oxaliplatin. With cisplatin in particular, thrombocytopenia is prominent. Leukopenia can be ameliorated by granulocyte colony-stimulating factor, and anemia responds to erythropoietin. Platinum-based therapy of ovarian cancer is associated with a fourfold increase in the risk of developing acute myelogenous leukemia.76

Ototoxicity

Auditory impairment can be overt, with clinically dramatic reductions in auditory acuity after several cycles of cisplatin-based therapy, or they can be more subtle. Some patients may complain of the loss of the ability to filter out extraneous noises during a conversation, for example, in a restaurant. High-frequency tones (4,000 to 8,000 Hz) are most affected.

The chinchilla is thought to be a good model for cisplatin-based hearing loss in humans.77, 78 Studies in this animal model suggest that the mechanism of ototoxicity for platinum compounds is loss of hair cells in the cochlea. At low doses of platinum compounds (50 mg/kg intraperitoneally in the chinchilla), loss of inner hair cells in the cochlea is readily seen. At low doses, observers reported a one-third reduction in the amplitude of conduction within nerve fibers of the eighth nerve. This reduction in amplitude was not accompanied by changes in conduction threshold or in the latency of conduction. At doses fivefold higher, loss of outer hair cells were observed, along with reductions in all three parameters measured in these nerve fibers.

Acute Hypersensitivity

Acute hypersensitivity reactions, including anaphylaxis, can occur with platinum compounds. When this occurs, it is usually after the seventh or eighth exposure to the drug. The frequency of this occurrence is directly related to the number of cycles of platinum therapy a patient has received, beyond six. If treatment with platinum-based therapy is of crucial importance, three are several desensitization regimens published in the older literature. Rarely, hemolytic anemia can be seen with drugs in this class. Acute laryngopharngeal dysesthesias can be seen with oxaliplatin, resulting in difficulty swallowing or breathing. This side effect, when it occurs, is usually completely reversible.

CLINICAL PHARMACOLOGY

The clinical pharmacology profiles of cisplatin, carboplatin, and oxaliplatin are summarized in Tables 14.4,14.5, and 14.6. The detailed pharmacology of cisplatin and carboplatin has been described in previous chapters of this book and elsewhere.3, 4, 5, 69 For oxaliplatin, the volume of distribution is 50-fold greater than for cisplatin. Oxaliplatin undergoes extensive nonenzymatic conversion to reactive species, as does cisplatin and carboplatin. Oxaliplatin is excreted mainly by the kidneys (>50% of excreted drug), and less than 2% is excreted in the feces. About 40% of administered oxaliplatin is sequestered in red blood cells, and this fraction appears to have no clinical significance. Studies in patients with varying levels of renal dysfunction show that for single-agent oxaliplatin, dose reduction is not necessary if the patient has a creatinine clearance of >20 mL/minute.

Drug Infusion Issues

The specifics of the intravenous infusion of cisplatin or carboplatin are not well standardized from institution to institution. However, several matters are clear. Platinum agents should be administered using normal saline, which stabilizes the parent compound; the infusion should specifically exclude Mg2+, aluminum needles, and other reactive species that might chemically neutralize the compound. Vigorous intravenous hydration should be given immediately before and during each infusion.

For all three platinum analogs, shorter infusions (less than 1 hour) appear to be associated with greater acute toxicities. Continuous intravenous infusions for long periods of time (24 hours or more) are associated with dramatic reductions in efficacy. For these reasons, the infusion times for all three of these agents tend to range from 1 hour to approximately 4 hours. There are no prospective randomized trials that show that one specific duration of infusion, between 1 and 4 hours, provides the best therapeutic index for cisplatin or carboplatin. Two-hour infusions appear best for oxaliplatin.

At my institution, cisplatin or carboplatin is administered as a 1-hour intravenous infusion in 250 mL of normal saline. Prehydration and posthydration are essential for cisplatin, and probably should be used for carboplatin as well because 50% reductions in renal clearance may occur in the absence of preinfusion and postinfusion hydration. Platinum-induced reductions in renal function are characteristically nonoliguric and the extent of damage may not be fully reflected by changes in serum creatinine.

TABLE 14.4 KEY FEATURES OF CISPLATIN

Dosage:

50–75 mg/m2 IV every 3–4 weeks.

Other dosing regimens may be used in selected situations.

Usually administered in normal saline with vigorous IV prehydration (at least 0.5 L of saline with 125 mg of mannitol).

Mechanism of action:

Covalently binds to DNA bases and disrupts DNA function.

Toxicity may be related to DNA damage and/or protein damage.

Metabolism:

Inactivated intracellularly and in the bloodstream by conjugation to sulfhydryl groups.

Drug covalently binds to glutathione, metallothionein, and sulfhydryls on proteins.

Pharmaco-kinetics:

After IV bolus, t1/2α = 20–30 min; t1/2β = approximately 60 min; t1/2γ = approximately 24 hr.

Elimination:

Approximately 25% of an IV dose is excreted from the body during the first 24 hr.

Of that portion eliminated, excretion is renal > 90%, and bile < 10%.

Extensive long-term protein binding has been observed in many tissues.

Drug interactions:

Thiosulfates administered IV may inactivate drug systemically.

Amifostine (WR2721) may also act to inactivate drug, but preferentially in healthy tissues.

May show enhanced efficacy, and increased toxicity, with a range of other cytotoxic agents.

Toxicity:

Renal insufficiency with cation wasting.

Nausea and vomiting.

Peripheral neuropathy.

Auditory impairment (high tone loss).

Myelosuppression (thrombocytopenia > WBC > RBC).

Visual impairment (rare).

Hypersensitivity (rare).

Seizures (rare).

Leukemia.

Precautions:

Use with caution in the presence of other nephrotoxic drugs (such as aminoglycosides).

Monitor serum electrolytes and cations (especially Mg2+ and Ca2+), and creatinine.

Maintain high urine flow during cisplatin administration.

Aggressive premedication with antiemetics is recommended.

Caution should be used if the 24-hr creatinine clearance is <60 mL/min. Consideration should be given to using alternative agents in this setting, although cisplatin can be safely administered if extensive precautions are used.

RBC, red blood cell count; t1/2, half-life; WBC, white blood cell count.

The acute neurotoxicity of oxaliplatin is directly related to dose and to the duration of drug infusion. The more severe toxicities are seen at higher doses and with shorter infusion times. Therefore, oxaliplatin doses should never exceed 85 mg/m2 every 2 weeks, or 130 mg/m2 every 3 weeks. The oxaliplatin infusion should always be at least over 2 hours in duration.

Platinum-Dosing Strategies

Carboplatin is now most commonly dosed by the AUC for the drug. The most common AUCs for dosing are 5 or 6. The AUC dose is calculated using the Calvert formula, which is: carboplatin dose = target AUC (GFR + 25).77 An older approach, though currently a less well-accepted alternative, is to use 300 mg/m2 per dose when the drug is given in combination with a taxane, or 400 mg/m2 per dose as a single agent. This is based on the clinical observation that, in terms of antitumor efficacy, 1 mg of cisplatin appears to be equivalent to 4 mg of carboplatin; that is, a 75-mg dose of cisplatin is therapeutically equivalent to 300 mg of carboplatin.

Whether one bases dose on AUC or the milligrams per square meter method, the calculated total milligram dosage for any individual tends to be similar if the creatinine clearance is nearly normal. The carboplatin dose should be administered every 21 or 28 days, depending on blood count recovery. In a percentage of patients, cumulative thrombocytopenia will result in dose reductions, or dosing delays, by the fourth or fifth cycle of therapy.

For cisplatin, the dosage should be 50, 60, or 70 mg/m2 per dose, given every 21 or 28 days depending on blood count recovery. Whereas many institutions give cisplatin over 30 minutes, some data suggest that this shorter infusion may be associated with a higher rate of severe side effects. This author recommends a 1-hour infusion time. Prehydration and posthydration with a total of at least 1 L of normal saline are essential. The preventive approach should be taken with respect to immediate and delayed nausea and vomiting. Such therapy should consist of the combination of a steroid, a HT3 inhibitor, and a substance P inhibitor. Once nausea and vomiting develop from cisplatin, they are very difficult to manage.

Oxaliplatin dosing guidelines are provided in Table 14.6. When given in combination with other agents, as in the treatment of colorectal cancer, these doses should never be exceeded. A number of oxaliplatin-based combination therapy regimens are under investigation in a range of diseases.

CLINICAL CONCEPTS OF PLATINUM RESISTANCE

In the treatment of gynecologic malignancies, specifically in ovarian cancer, the disease may be clinically platinum-sensitive or clinically platinum-resistant.79,80 Data show that if a patient with ovarian cancer is more than 2 years out from the most recent dose of platinum (having responded to that therapy), there is a >70% likelihood that the disease will respond to retreatment with cisplatin- or carboplatin-based therapy.79 The percentage of patients who will respond decreases with the shortening of the disease-free period. Persons who have disease recurrence within the first 6 months after the most recent dose of platinum have a low likelihood of response to retreatment with cisplatin or carboplatin and are considered to have platinum-resistant disease. This concept is firmly established for cases of epithelial ovarian cancer. The applicability of this concept to other diseases commonly treated with platinum-based therapy is less well established.

TABLE 14.5 KEY FEATURES OF CARBOPLATIN

Dosage:

Generally dosed by AUC, in mg/m2 × min. Usual dosing range is 4–6 mg/m2 × min.

Calvert formula is generally used for calculating the AUC. A measured creatinine clearance is recommended.

Calvert formula is: AUC (carboplatin) = dose/(creatinine clearance + 25).

The older dosing method is 1 mg cisplatin = 4 mg carboplatin. This approach is not recommended. AUC dosing is associated with greater patient safety, particularly with respect to myelosuppression.

Mechanism of action:

Covalent binding to DNA.

Metabolism:

Conversion to a DNA-reactive species occurs more quickly in cells than in IV solutions, which suggests the activity of esterases in cleavage of the dicarboxylate side group.

Pharmacokinetics:

After IV bolus, t1/2α = 12–24 min; t1/2β = 1.3–1.7 hr; t1/2γ = 22–40 hr.

Elimination:

Approximately 90% is excreted in the urine in 24 hr.

Drug interactions:

See cisplatin (Table 14-5).

Toxicity:

Myelosuppression is more prominent than with cisplatin.

Nausea and vomiting may occur, but are much less prominent than with cisplatin.

Nephrotoxicity can occur, particularly at higher dosages and in patients with prior renal dysfunction.

Precautions:

AUC dosing is very important in the setting of preexistent renal dysfunction.

AUC, area under the concentration × time curve; t1/2, half-life.

Platinum-DNA Adduct and NER Gene Expression Studies

Several groups have conducted a number of studies to assess the possible relationships between platinum-DNA adduct levels in tissues from cancer patients and clinical end points in those patients.9, 10, 81, 82, 83, 84, 85, 86, 87, 88 In some studies, adduct was measured with the use of an enzyme-linked immunosorbent assay that measured only a fraction of the total amount of DNA damage. In other studies, including this author's laboratory adduct was measured by atomic absorbance spectrometry with Zeeman background correction, which measures total DNA-bound platinum.81, 82

Generally, platinum-DNA adduct levels in peripheral blood cell DNA appeared to parallel the adduct levels formed in tumor tissues taken from the same patients. Consistent with this observation, platinum-DNA adduct levels in peripheral blood cell DNA correlated well with independent assessments of tumor response or the duration of progression free survival: the higher the adduct level, the greater the likelihood of response. The correlation between platinum-DNA adduct levels and disease response was consistently seen using treatment programs that were totally or predominantly platinum-based. In treatment regimens that merely contained a platinum agent as one of several clinically active drugs, this relationship did not clearly suggest that the molecular contributions of the non–DNA-damaging agent(s) was critically important to the success of the treatment regimen.

As previously discussed, NER is responsible for the repair of cisplatin-DNA adduct and ERCC1 is an essential gene in the NER pathway. The mRNA expression of ERCC1 in tumor tissues directly correlates with clinical resistance to platinum therapy in ovarian cancer,89, 90 gastric cancer,91 colorectal cancer,92 and lung cancer.93, 94 Up-regulation of ERCC1 and other genes in the NER process suggests increased levels of DNA repair activity, which has been clearly demonstrated in vitro,95, 96 and loss of NER proficiency is associated with cisplatin sensitivity of ovarian cancer cells in vitro.97

Several studies show that other genes critical to the NER process, such as XPAXPD, and others, show up-regulation of mRNA expression concurrent with clinical resistance to platinum-based therapy.88, 89 These studies are fully consistent with a large number of in vitro studies showing a similar direct relationship between ERCC1 mRNA expression and cellular resistance to platinum, which has been reviewed in other reports.15, 36

TABLE 14.6 KEY FEATURES OF OXALIPLATIN

Dosage:

Up to 85 mg/m2 q2weeks; or up to 130 mg/m2 q3weeks.

Given as a 2-, 4-, or 6-hr infusion; 6-hr infusions are used most commonly.

Administer in a 5% dextrose IV solution.

Mechanism of action:

DNA damage. May have unique properties based on unique carrier ligand.

1,2-diaminocyclohexane carrier ligand is the nonleaving group.

Metabolism:

Not fully characterized. Drug accumulates in red blood cells of humans and rats but does not accumulate in plasma (cisplatin accumulates in plasma with repeated dosing).

Pharmacokinetics:

With a 4-hr infusion:
   Free platinum levels decrease in a triphasic fashion.
   Terminal t1/2 = 27.3 hr.
   Volume of distribution = 349 L.
   Total clearance = 222 mL/min; renal clearance = 121 mL/min.

Elimination:

Renal elimination is important. Characterization in humans is not complete.

Drug interactions:

Most effective in gastrointestinal malignancies, given in combination with fluorouracil analogs.

Synergizes with antimetabolites; additional studies warranted.

Toxicity:

When given with 5-fluorouracil, major toxicities include:

Myelosuppression (neutropenia primarily).

Diarrhea ± stomatitis.

Peripheral neuropathy (sensory much greater than motor).

Nausea and vomiting, mild to moderate.

Rare toxicities: anaphylaxis, hemolytic anemia, laryngopharyngeal dysesthesias.

Precautions:

Similar to those for cisplatin and carboplatin (Tables 14-5 and 14-6).

t1/2, half-life.

 

COMMON CLINICAL USES

The platinum compounds constitute the mainstay of therapy for a wide range of malignancies. This includes potentially curative therapies for advanced-stage testicular and ovarian germ cell tumors, epithelial ovarian cancer, and small-cell lung cancer. Effective platinum-based therapies also are in place for advanced stages of non-small cell lung cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, and head and neck malignancies. Cisplatin, in conjunction with radiation, is curative for early-stage head and neck malignancies and cervical cancer. A better understanding of the molecular processes that underlie the clinical differences between cisplatin, carboplatin, and oxaliplatin may open the door for the development of future agents in this class, with an even better therapeutic index and broader efficacy.

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