Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

115. Renal Cell Carcinoma

Christine M. Walko and Ashley E. Simmons


KEY CONCEPTS

 Images Renal cell carcinoma (RCC) predominantly occurs later in life, with 70% of all cases diagnosed between the ages of 55 and 84 years.

 Images The most established risk factors for RCC are smoking, obesity, and hypertension.

 Images Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is the hallmark of the most common type of RCC, the clear cell subtype.

 Images More than 50% of RCC cases are diagnosed by incidental findings on routine imaging for unrelated reasons.

 Images The Memorial Sloan-Kettering Cancer Center Prognostic Factors Model for Survival classifies patients into low-, intermediate-, and high-risk groups based on five clinical factors and can predict survival in untreated patients and those treated with immunotherapy and targeted agents.

 Images Surgical removal of the primary tumor, either by total or partial nephrectomy, is the preferred initial treatment for all stages of RCC.

 Images Immunotherapy used to be considered first-line therapy for metastatic RCC but has largely been replaced by targeted agents because of their improved efficacy and tolerability.

 Images Sunitinib and pazopanib are oral small molecule inhibitors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor and are each treatment options as first-line therapy for metastatic RCC.

 Images The VEGFR–tyrosine kinase inhibitor axitinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus are both second-line therapy options for metastatic RCC patients who progress on a targeted therapy or cytokine-based therapy first-line regimen.

 Images Temsirolimus is an IV administered mTOR inhibitor indicated for first-line therapy in patients with high-risk metastatic RCC.


INTRODUCTION

Renal cell carcinoma (RCC) is a less common malignancy that, until recently, had few treatment options that were poorly tolerated and resulted in few positive outcomes for patients. However, treatment for the disease has been revolutionized by an increased understanding of the pathophysiology of RCC. Clear cell is the predominant subtype of RCC and is the result of inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene on chromosome 3p25, which leads to increased production of growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF), and others responsible for angiogenesis and cell growth.1 Before 2005, the primary therapy option for patients with advanced RCC after nephrectomy was immunotherapy with few responses and high toxicity. However, seven new drugs have been approved as first- or second-line therapy for RCC: sorafenib, sunitinib, temsirolimus, bevacizumab (in combination with interferon-α[IFN-α]), everolimus, pazopanib, and axitinib.27 Each drug is an example of targeted therapy against growth factors important in the pathophysiology of RCC and has yielded much needed progress in a disease with few therapeutic options. RCC serves as an example of rational development of targeted agents based on knowledge of tumor biology for the treatment of other malignancies.

EPIDEMIOLOGY

About 65,000 new cases of kidney and renal pelvis cancer are diagnosed each year in the United States, with two-thirds of these cases occurring in men. More than 13,000 people in the United States will die of kidney cancer each year.8 RCC is the fifth most commonly occurring cancer in men, and the number of new cases diagnosed each year is similar to non-Hodgkin lymphoma and melanoma. In women, kidney cancer is the sixth most common cancer, occurring at a rate similar to the rates for ovarian and pancreatic cancers. The incidence of RCC has increased over the past three decades. The rate has increased more rapidly in blacks than whites and in women than men. In the United States, between 2002 and 2006, the age-adjusted incidence rate in black men was 21.3, white men 19.2, black women 10.3, and white women 9.9 per 100,000 person years.9 This increase may be related to improved imaging techniques and greater use of these imaging modalities, although the higher prevalence of some risk factors may also explain the increased incidence.

Kidney cancer is most commonly diagnosed between the ages of 40 and 70 years, with a peak in the sixth and seventh decades of life. Nearly 70% of all cases of kidney cancer are diagnosed in people between the ages of 55 and 84 years, with less than 3% of all cases diagnosed in patients younger than 34 years.9 Images

One of the primary factors influencing overall survival (OS) is the extent of disease spread. When the tumor is confined to the kidney at the time of diagnosis, surgical resection can result in a 5-year OS rate of about 85%. That figure falls to 64% when localized spread has occurred beyond the kidney and to less than 23% when metastatic disease is present.10 The 5-year relative survival rate of kidney cancer in general improved from 40% in the early 1960s to nearly 70% in 2005.9 Survival is expected to improve with the growing availability of numerous targeted agents.

ETIOLOGY

The incidence rates of RCC vary more than 10-fold worldwide, with the highest incidence rates in Western and European countries and the lowest in Asia and Africa, which suggests that lifestyle and possibly the environment are important factors. The most established risk factors associated with RCC are smoking, obesity, and hypertension.

Images Smoking remains the most consistently established risk factor and is estimated to be responsible for 20% to 30% and 10% to 20% of RCC cases diagnosed in men and women, respectively.11,12 Smoking is associated with a relative risk of 1.54 for men and 1.22 for women with a strong dose-dependent relationship. Heavy smoking, defined as 21 or more cigarettes per day, was associated with an increased relative risk of 2.03 and 1.58 for men and women, respectively.13 Smoking cessation has been demonstrated to reduce the risk of RCC with a 15% to 30% decrease after 10 to 15 years after cessation and a 50% decrease for those who quit for 30 years or more.13,14

Obesity is also linked to RCC development in observational studies and appears to be equally associated in men and women. Compared with a body mass index (BMI) of 20.75 kg/m2 or less, men with a BMI between 22.86 and 27.75 kg/m2 had a relative risk of 1.3 to 1.7, and those with a BMI of 27.76 kg/m2 or greater had a relative risk of 1.9.15 A separate analysis reported a relative risk of 2.5 for those with a BMI of 30 kg/m2 or greater.16 It is estimated that 30% to 40% of RCC cases may be attributed to obesity, which suggests that increasing rates of obesity in the United States may be partially responsible for the increased incidence seen over the past 3 decades.12 Numerous mechanisms explaining the link between obesity and the development of RCC have been proposed. Obesity has been linked to increased lipid peroxidation, which can result in carcinogenesis of the proximal renal tubules. Byproducts of the lipid peroxidation pathway have also been shown to result in DNA adducts in the kidney, which can result in oncogene and tumor suppressor gene mutations and eventually malignancy.17 Adipose tissue, when stimulated, can release numerous substances to regulate energy balance and lipid metabolism. Insulin resistance and compensatory elevated insulin levels result in increased levels of insulin-like growth factor-1 (IGF-1), which regulates cell proliferation and can inhibit cellular apoptosis.16 Finally, the kidneys of obese men and women are more susceptible to carcinogenesis because of higher glomerular filtration rates, renal perfusion, and atrophic scarring of the kidneys.12

The risk of RCC is associated with increased duration and severity of elevated blood pressure. Patients with a diastolic blood pressure (DBP) greater than 90 mm Hg had a relative risk of 2.1 compared with DBP less than 70 mm Hg. A systolic blood pressure (SBP) greater than 150 mm Hg was associated with a relative risk of 1.6 compared with SBP less than 120 mm Hg.15 The exact mechanism explaining the causality of hypertension to RCC is unknown, but it is believed to be related to hypertension-induced renal injury and lipid peroxidation.12,17 Medications commonly used to treat hypertension do not appear to be associated with RCC.

The analgesic phenacetin has a historical link to RCC. The drug was introduced in 1887 and used until the 1970s, when increased concerns for carcinogenesis resulted in replacement with safer analgesics, such as the major metabolite of phenacetin, acetaminophen. Despite its association with the known carcinogen, acetaminophen has not been associated with an increased risk of RCC.12

A well-defined genetic link has also been described. Although most RCC cases are not associated with hereditary factors and are considered “sporadic,” 2% to 3% of cases are secondary to inherited syndromes.18,19 Kidney tumors arising from a genetic etiology are most commonly the result of an autosomal dominant transmission of the diseased gene from a carrier to the offspring. Initially, one carrier parent has one healthy chromosome and one chromosome with the diseased gene. When this carrier has offspring with a healthy individual with two healthy chromosomes, the offspring each have a 50% chance of also being a carrier. These carriers with one healthy chromosome and one chromosome with the diseased gene are then more sensitive to developing RCC after being exposed to additional somatic mutations that can affect the remaining healthy chromosome.

SUBTYPES AND PATHOPHYSIOLOGY

About 85% of kidney cancers affect the parenchyma of the kidney and are classified as RCC. The renal pelvis is less commonly affected, making up 12% of the cases of kidney cancer diagnosed each year, with other rare malignancies affecting other parts of the kidney and making up the remaining 3%. The subtypes of RCC include clear cell, papillary (also known as chromophilic), chromophobic, and oncocytic. Each subtype has a unique genetic pathophysiology that results in a different clinical course and response to therapy.18

Clear Cell Renal Cell Carcinoma: The Role of the von Hippel-Lindau Gene

Clear cell is the predominant subtype responsible for most cases of RCC. These tumors typically affect the proximal tubule of the kidney and are more likely to metastasize than other subtypes. The initial finding of an association between clear cell histology and losses in the short arm of chromosome 3 eventually led to the gene responsible for this subtype being mapped to the location 3p24-25 and termed the VHL gene in 1993.2022 Inactivation of this tumor suppressor gene is now recognized as the hallmark of clear cell RCC. The Knudson and Strong two-hit model explains the development of clear cell RCC after inactivation of both copies of the tumor suppressor gene VHL.22 In patients with sporadic disease, the two copies of VHL present in a healthy kidney can be inactivated via loss of chromosome 3p, gene silencing via hypermethylation, missense mutations, and premature truncation or nonsense mutations. Additional mutations can result in a single, unilateral tumor. In patients with hereditary disease, one copy of VHL has already been deleted via a germline mutation. Fewer events are then needed to delete the remaining gene copy, which explains why patients with hereditary disease are more likely to present with multicentric, bilateral tumors.18,19

The VHL gene produces the VHL protein (pVHL), which is expressed ubiquitously throughout the body and is part of the complex that selects substances for ubiquitination and subsequent destruction by the proteasome.23Because of this role, VHL regulates cellular response to oxygen. In a normal oxygen environment, the target for proteasome destruction is hypoxia-inducible factor (HIF)-1α. Hydroxylated HIF-1α binds to pVHL and is destroyed by the proteasome (Fig. 115-1). When the cellular environment is hypoxic, HIF-1α is not hydroxylated and does not bind to pVHL. The unbound HIF-1α can then initiate transcription of hypoxia-inducible genes in the cell nucleus, which enables the cell to adapt and survive a hypoxic insult23,24 (Fig. 115-2). Images In the case of clear cell RCC, when VHL is mutated or silenced, pVHL is unable to bind and target HIF-1α for degradation regardless of the oxygen presence in the environment. HIF-1α therefore becomes abundant and activates transcription of hypoxia-inducible genes, including VEGF, PDGF, TGF, glucose transporters, erythropoietin, and other factors that promote angiogenesis and tumor development23,24 (Fig. 115-3). Numerous therapies for RCC target these hypoxia-inducible genes that are activated by HIF and are discussed later in the chapter.

Images

FIGURE 115-1 The role of von Hippel-Lindau (VHL) protein and hypoxia-inducible factor (HIF): normal oxygen, normal VHL. In a normal oxygen environment, HIF is hydroxylated. This enables binding of the VHL protein and subsequent attachment of a polyubiquitin chain, a process called ubiquitination. This allows the ubiquitin-tagged HIF to be recognized for destruction by the proteasome. The proteasome acts as a garbage disposal for compounds labeled by the ubiquitination process.

Images

FIGURE 115-2 The role of von Hippel-Lindau (VHL) and hypoxia-inducible factor (HIF)-1α: low oxygen, normal VHL. In a low oxygen environment, the cell wants to increase production of substances to promote a switch to anaerobic metabolism, including enzymes involved in glycolysis and glycerol metabolism. In this situation, HIF-1α is not hydroxylated and cannot bind to VHL. HIF-1α is then able to translocate into the nucleus of the cell. In the nucleus, HIF-1α combines with the HIF-β subunit and the p300 transcriptional cofactor on the hypoxia response element (HRE) that promotes the transcription of HIF-1α target genes. More than 100 genes can be activated by this complex and include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), erythropoietin (EPO), and glucose transporter 1.

Images

FIGURE 115-3 The role of von Hippel-Lindau (VHL) and hypoxia-inducible factor (HIF)-1α: normal oxygen, mutated VHL. When VHL is mutated, it is not able to bind to the hydroxylated HIF-1αregardless of the presence of oxygen in the environment. Because HIF-1α is not bound to VHL, it is not destroyed by the proteasome and is thus free to translocate into the nucleus, combine with the HIF-βsubunit and the p300 transcriptional cofactor on the HRE, and initiate gene transcription. Because a hypoxia situation is not present, production of these genes involved in angiogenesis, cellular survival, and glucose metabolism can result in an oncogenic process. (ADRP, adipose differentiation-related protein [responsible for neutral lipid accumulation in the cell cytoplasm, resulting in the clear cell appearance]; EPO, erythropoietin; PDGF, platelet-derived growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.)

In addition to VHL, other growth factors and cell adhesion pathways control HIF-1α activity.23 TGF is a ligand for the epidermal growth factor receptor (EGFR) and, upon binding, activates the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, in addition to other protein kinase pathways. Activation of the mTOR pathway increases production of HIF-1α, which can drive the oncogenic process described earlier.23,25,26 The mTOR is another pathway targeted for the therapy of RCC.

Papillary Renal Cell Carcinoma Types 1 and 2

Papillary subtypes account for 5% to 10% of RCC cases and occur in the proximal tubule. They are most commonly diagnosed as localized disease and have a more favorable prognosis than the clear cell subtype. Unlike a single mutation driving the development of clear cell disease, papillary RCC has been associated with multiple genetic abnormalities. These tumors are further subclassified into types 1 and 2. Chromophilic type 1 patients are more likely to have multiple, bilateral tumors of lower grade and have a better prognosis compared with the higher grade, singular, unilateral poor prognosis type 2 tumors.17,19,23

The majority (>80%) of hereditary papillary type 1 RCC cases are associated with germline activating mutations in the mesenchymal–epithelial transition (MET) oncogene, located at chromosome 7q31-34.27These mutations are responsible for about 13% of sporadic type 1 disease, but chromosome 7 duplications have been found in 75% of these cases, further supporting the role of MET.23 Activation of the c-MET receptor results in increased cell proliferation and motility and decreased cellular apoptosis.26 Stabilization of HIF can also play a role in the oncogenic potential of the c-MET receptor.28

The papillary type 2 subtype occurs in patients with hereditary leiomyomatosis, which initially presents as multiple skin and uterine leiomyomas when patients are in their 20s and 30s and eventually results in formation of RCC. The associated gene for this subtype is the fumarase hydratase (FH) gene, located at chromosome 1q42.3-45. FH is a tumor suppressor gene that encodes the enzyme FH responsible for catalyzing fumarate to malate in the Krebs cycle. The gene is predominantly inactivated by loss-of-function mutations, which ultimately results in stabilization of HIF and subsequent oncogenesis.29,30

Chromophore and Oncocytoma Renal Cell Carcinoma

The chromophore and oncocytoma subtypes combined are responsible for 5% to 10% of all RCC cases and occur in the intercalated cells of the collecting system. Both are associated with a wide variety of chromosomal abnormalities, including deletions and translocations. Oncocytomas are relatively benign and rarely metastasize.31 Hereditary forms of these subtypes are associated with the Birt-Hogg-Dube (BHD) syndrome, which is characterized by hair follicle fibrofolliculomas of the face and neck and lung cysts in addition to RCC in 15% to 30% of affected individuals. The BHD gene is located on the short arm of chromosome 17 and encodes the tumor suppressor BHD gene that is responsible for the protein folliculin.17

CLINICAL PRESENTATION AND DIAGNOSIS

Imaging modalities, such as computed tomography (CT) scans, are widely used in the medical work-up of numerous conditions. Images As a result, most cases of RCC are now diagnosed incidentally after radiographic imaging for unrelated reasons compared with 10% in 1970.32 Fewer than 10% of patients currently present with the classic triad of flank pain, hematuria, and a palpable abdominal mass. Incidentally diagnosed tumors, or those diagnosed in the absence of signs and symptoms commonly associated with RCC, are usually smaller in size, of a lower stage, and more localized than those seen in patients who present with symptoms such as the classic triad. In addition to the classic triad, common presenting complaints are nonspecific signs and symptoms, including fatigue, weight loss, anemia, hypertension, fever, and lower extremity edema. Bone pain, adenopathy, and pulmonary symptoms are indicators of metastatic disease spread to the mediastinum or lung parenchyma.32

As noted earlier, RCC can be either sporadic or hereditary. Several differences exist between the two etiologies in terms of patterns of development. Sporadic RCC most often presents as a single tumor affecting one kidney in a patient who is at least 60 years of age. These lesions may or may not be cystic in histology, and a family history is usually not reported. In contrast, those with a hereditary etiology more commonly present with numerous cystic tumors affecting both kidneys. These patients are more likely to be younger than age 50 years and may also have other malignancies or have a strong family history of RCC, in addition to other malignancies, including retinal angiomas, hemangioblastomas, and pheochromocytomas.19,32


CLINICAL PRESENTATION

Symptoms

    • Flank pain

    • Fatigue

    • Absence of symptoms is often seen with early disease

Symptoms of Disease Progression

    • Bone pain

    • Pulmonary symptoms, including shortness of breath and cough

    • Types of symptoms differ depending on location of disease spread

Signs

    • Weight loss

    • Anemia

    • Hypertension

    • Fever

    • Lower extremity edema

    • Hematuria

    • Palpable abdominal mass

Sign of Advanced Disease

    • Adenopathy

Diagnostic Tests

    • Complete blood count

    • Serum calcium

    • Serum creatinine

    • Liver function tests

    • Lactate dehydrogenase

    • Coagulation profile

    • Urinalysis

    • Contrast and non-contrast CT or MRI of the chest, abdomen pelvis

    • Fine-needle biopsy only in select cases

Laboratory evaluation should include a complete blood count, serum calcium, serum creatinine, liver function tests, lactate dehydrogenase (LDH), coagulation profile, and urinalysis. Imaging studies, including contrast and noncontrast CT or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis, are also performed to further characterize the renal tumor, assess involvement of the inferior vena cava, and determine the patient’s disease stage. Fine-needle biopsy is used only in rare selected cases.

STAGING AND PROGNOSIS

The factors associated with prognosis are positive margins after surgery, evidence of metastatic spread, presence of sarcomatoid architecture, tumor subtype, tumor grade, and tumor stage, with the latter being the most powerful prognostic indicator.33 The Union Internationale Contre le Cancer/International Union Against Cancer (UICC) and the American Joint Committee for Cancer Staging and End Results Reporting (AJCC) introduced the tumor–nodes–metastasis (TNM) staging system for RCC in 1978. The 7th edition was published most recently in 2010.34,35 The AJCC staging classification considers tumor size, number of lymph nodes involved, and the presence or absence of distant metastases. Subdivisions in the tumor (T) classification further describe the structures of the kidney that have been invaded by the tumor, including the adrenal gland, Gerota’s fascia (the layer of connective tissue surrounding the kidneys), and perinephric fat that lies between the fascia and renal capsule.35 Table 115-1 summarizes the AJCC TNM staging definitions, and Table 115-2 shows the TNM stage and corresponding 5-year OS rates.

TABLE 115-1 American Joint Committee for Cancer Staging and End Results Reporting Sixth Edition Staging

Images

TABLE 115-2 American Joint Committee for Cancer Staging and End Results Reporting Stage Grouping

Images

Images In patients with metastatic disease, the Memorial Sloan-Kettering Cancer Center (MSKCC) Prognostic Factors Model was developed from a retrospective analysis of 670 patients with advanced RCC from 24 different trials at MSKCC between 1975 and 1996. The model identified five factors associated with poor prognosis: Karnofsky performance status (KPS), LDH, hemoglobin, corrected serum calcium, and nephrectomy status (later interchanged with duration of time from diagnosis to initial treatment). Patients with none of the poor prognostic risk factors are considered low risk, one or two factors are intermediate risk, and three or more factors are high risk (Table 115-3). In this analysis, 25% of patients were classified as low risk and had a median OS of 20 months, 53% were intermediate risk with a median OS of 10 months, and 22% were high risk with a median OS of 4 months. Three-year OS for the low-, intermediate-, and high-risk groups was 31%, 7%, and 0%, respectively.36 This model has been validated externally and can be used to predict survival outcomes for patients treated with IFN-based therapy.37 Another retrospective study in 353 patients with untreated RCC confirmed the MSKCC model but identified two additional independent prognostic factors: prior radiation and number of metastatic sites (none or one compared with two or more). Low risk was defined as the presence of no or one risk factor, intermediate risk as two risk factors, and high risk as the presence of three or more risk factors. Based on these criteria, 37% of the patients were classified as low risk (median OS, 26 months), 35% as intermediate risk (median OS, 14.4 months), and 28% as high risk (median OS, 7.3 months).38 In an updated analysis of metastatic RCC patients treated with targeted agents, the MSKCC model confirmed the importance of hemoglobin, corrected serum calcium, KPS, and time from diagnosis to treatment as prognostic factors for OS. Elevated neutrophil and platelet counts were also independent survival prognostic factors. Of the 586 evaluable patients treated with targeted agents (sunitinib, sorafenib, or bevacizumab), 23% were low risk with an OS that was not reached after a median follow up of 24.5 months, 51% were intermediate risk with a median OS of 27 months, and 26% were high risk with a median OS of 8.8 months. Corresponding 2-year OS rates for the low-, intermediate-, and high-risk groups were 75%, 53%, and 7%, respectively.39

TABLE 115-3 Memorial Sloan-Kettering Cancer Center Poor Prognostic Factors

Images


Clinical Controversy…

Traditionally, the Response Evaluation Criteria in Solid Tumors (RECIST) model has been used to evaluate treatment response rates in solid tumors. Whether this remains the optimal method of assessing response rates in patients receiving targeted therapies is unknown because the drugs may result in tumor death and internal tumor necrosis without much change in the tumor size itself.

The MSKCC criteria, with minor additions as discussed earlier, are currently used in practice to determine optimal therapy for patients and are incorporated into the National Comprehensive Cancer Network (NCCN) guidelines. For example, temsirolimus is currently recommended for patients with high-risk disease. Additionally, the criteria are used to determine eligibility or stratification for clinical trials in an effort to further individualize and optimize patient therapy.

Current efforts have focused on the identification of predictive biologic biomarkers for therapy. In contrast to the prognostic factors discussed earlier that correlate with survival regardless of intervention, predictive biomarkers correlate with response to a specific therapy. Predictive biomarkers can help clinicians to optimize therapy choices for patients. No clinically validated biomarkers for RCC are available, but numerous factors are under investigation, including the HIF target carbonic anhydrase IX; angiogenic proteins linked to HIF-associated signaling; and biologic participants in the mTOR signaling pathway, such as phosphorylated-AKT, phosphorylated-S6 kinase, phosphatase and tensin homologue (PTEN), and cytoplasmic p27.4043


Clinical Controversy…

The VEGFR inhibitors are recommended as first-line therapy for treatment of advanced or metastatic RCC. A known adverse effect of VEGF and VEGFR inhibition is hypertension and is commonly reported with both bevacizumab and the tyrosine kinase inhibitors of this pathway. Preliminary data have suggested that development of treatment-associated hypertension may be associated with improved response rates of VEGF-directed therapy. However, prospective correlations are needed to determine the degree of hypertension and magnitude of PFS benefit before this can be translated into clinical practice.

TREATMENT

Surgical excision of the renal tumor remains the primary method of local disease control and is performed in patients with stage I, II, or III disease.44 In patients with advanced disease, treatment options for patients after nephrectomy had historically been limited to immunotherapy approaches with IFN-α, interleukin-2 (IL-2), or both. However, novel VEGFR-targeted tyrosine kinase inhibitors (TKIs), including sunitinib, sorafenib, pazopanib, and axitinib, in addition to the mTOR inhibitors temsirolimus and everolimus have provided numerous therapy options and remain the cornerstone of therapy for advanced and metastatic disease.

Desired Outcomes

The goal of therapy for RCC depends on the stage of disease at diagnosis and other patient-specific factors, including age, performance status, and comorbidities. In patients with localized disease confined to the kidney (stages I, II, and III), the initial treatment recommendation is surgical removal with curative intent. In patients with initially localized disease who undergo nephrectomy, 20% to 30% will relapse, with most relapses occurring in the first 2 years after surgery. When patients have developed metastatic disease, the goal of therapy is to control disease burden and prolong survival while maximizing quality of life.44 Even within patients with metastatic disease, survival outcomes depend on patient specific factors, including the MSKCC-adapted model for targeted agents and the specific therapy chosen.39 The selection of each line of therapy and even agents within the same line of therapy should be weighed against the risks and benefits for each individual patient.

Regardless of the first-line and subsequent therapies, optimizing quality of life is always a goal of treatment. Symptoms differ based on disease stage, sites of distant disease, and treatment. Patients with bone involvement may experience pain in the areas of metastatic disease that can be addressed with the use of bone modifying agents, such as bisphosphonates or denosumab, or palliative radiation therapy, along with optimizing daily pain medication regimens. Adherence with oral targeted therapies should be emphasized with patients, both in terms of taking the medication regularly as prescribed but also following administration recommendations such as taking medication with or without food and avoiding interacting medications. Treatment-related toxicities should also be aggressively addressed to optimize the benefits of therapy. Hypertension, skin related effects, and diarrhea are common toxicities of the VEGFR-TKIs, and hypercholesterolemia and hyperglycemia are common with the mTOR inhibitors. These effects should be anticipated with preventative treatment when appropriate or close monitoring and therapeutic intervention when needed to improve tolerability to these agents and optimize patient quality of life. The subjective nature of many of these treatment-related and disease-related effects can make consistent assessment challenging, but trials incorporating quality of life outcomes using validated patient-reported assessments will improve our ability to optimize survival as well as quality of outcomes for patients with RCC.

Surgery

Images Surgery represents the initial therapy for most patients with RCC regardless of stage. Surgical options include total nephrectomy and nephron-sparing surgery and depend on numerous patient-specific factors, including the size and location of the renal tumor, whether multiple tumors are present, and whether the patient has a single kidney or has a concurrent disease with a risk of multiple kidney tumors, such as a known genetic predisposition. Radical nephrectomy involves excision of the total kidney, Gerota’s fascia, and ipsilateral adrenal gland after ligation of the renal vein and artery. Nephrectomy is preferred for patients with large tumors (4–7 cm), depending on the location of the tumor. Centrally located tumors are more amenable to total resection than partial nephrectomy.44,45 Regardless of the functional capacity of the remaining kidney, total nephrectomy has been associated with a higher risk of developing chronic kidney disease, which explains why nephron-sparing techniques have become more common.46

Nephron-sparing surgery usually refers to partial nephrectomy, but it can also be used to describe probe-based thermal ablation procedures such as radiofrequency ablation (RFA) and cryoablation. The long-term efficacy of these two techniques has not yet been established, with some reports suggesting higher local recurrence rates than actual surgical excision.47 Because RFA and cryoablation can result in localized fibrotic reactions, surgical salvage after relapse can be compromised, and these procedures are typically reserved for patients who are not surgical candidates but still desire aggressive localized therapy. The most common nephron-sparing procedure is partial nephrectomy, which has been shown, in appropriately selected patients, to have equivalent outcomes as those seen in patients receiving total nephrectomy.48 Partial nephrectomy candidates are those with smaller lesions (usually less than 4 cm) that are located in the cortical region of the kidney. Patients with bilateral tumors and those with already compromised renal function are also partial nephrectomy candidates.

In addition to surgical removal of the tumor, some surgeons recommend extended lymphadenectomy. The procedure is controversial if there is no known lymph node involvement, but supporters suggest the procedure can be prognostic because positive nodal findings on lymphadenectomy can indicate systemic involvement, which often results in distant metastatic disease even after lymph nodes removal.44,49Although nearly one-third of patients relapse after surgery, adjuvant therapy does improve relapse-free survival in patients who initially present with localized disease. Radiation therapy is not recommended. As a result, observation is the recommended strategy, with imaging of the chest and abdomen every 4 to 6 months after surgery and then as clinically indicated.44,50

Surgery is still used for patients with distant (stage IV) disease and may consist of surgical resection of the renal tumor, metastectomy (or removal of metastatic sites), or both. Ideal candidates are those who have minimal regional lymphadenopathy and a solitary site of metastatic disease. Metastatic sites amenable to resection include the lung, bone, brain, and soft tissue.44,49 The benefits of surgical resection in patients with metastatic disease treated with IFN-α have been demonstrated in two randomized trials. Patients with metastatic RCC in both studies were randomized to nephrectomy followed by IFN-α or IFN-α alone. In a combined analysis, the median OS was 13.6 months for the nephrectomy followed by IFN-α group as compared with 7.8 months for the IFN-α alone group (hazard ratio = 0.69; 95% confidence interval = 0.55–0.87; P = 0.002).5153 Patients with metastatic disease only involving the lung, good prognostic features, and a performance status of 0 or 1 appear to benefit the most from nephrectomy followed by IFN-α. The mechanism for the apparent improved OS is unknown, but nephrectomy may reduce total tumor burden and increase the time for tumor burden to develop or may eliminate the primary source of immunosuppressive cytokines and tumor-producing growth factors. The benefit of newer targeted therapies is also being evaluated in this setting.50 Finally, palliative nephrectomy may be an option for patients with symptoms related to their primary tumor when removal can provide symptom relief.

Chemotherapy

Traditional cytotoxic therapy has demonstrated minimal efficacy in the treatment of RCC. Numerous agents have been investigated, the most active being gemcitabine, vinblastine, and 5-fluorouracil. However, response rates of more than 4% to 6% were rarely observed with single agents.19 Intrinsic resistance to chemotherapy may be partially explained by increased expression of the multidrug resistance gene (mdr1), which encodes for a P-glycoprotein (Pgp) transmembrane pump involved in drug efflux. Variable expression of the mdr1 gene has been found throughout many normal human tissues and in a number of different tumor types. Normal kidney tissue and various carcinomas of the kidney express high levels the mdr1 gene.54,55 A number of different chemotherapeutic agents have shown high levels of resistance in RCC tumors expressing the Pgp drug transporter. Overexpression of other drug transporter proteins, including the multidrug-resistance–associated proteins, may also play a role in the development of resistance, along with other mechanisms, such as alterations in glutathione metabolism and proteins involved with regulation of apoptosis, ultimately leading to failure of cells to undergo programmed cell death.56

Immunotherapy

Patients with RCC occasionally experience spontaneous regression of their disease, which has led researchers to hypothesize that RCC evokes a host immune response and to study immunotherapy for RCC.57 Images IFN-α and IL-2 have been investigated in numerous trials and combinations and were the standard of care for patients with metastatic RCC until the recent emergence of targeted therapy. Their low response rates and high toxicity have resulted in their current roles being limited, with ongoing trials to determine their potential in combination regimens.

Interleukin-2 (aldesleukin) is a glycoprotein primarily produced by helper T lymphocytes that stimulates the growth and cytotoxicity of T lymphocytes. IL-2 has been associated with response rates of 6% to 30%. Although the complete response rate is only about 4% to 6%, some of these complete responses are durable.50,58 The FDA-approved dose of IL-2 is 600,000 international units/kg IV over 15 minutes given every 8 hours for a maximum of 14 doses. After this initial treatment, the schedule is repeated 9 days later for an additional 14 doses as tolerated. Because of the significant toxicity of IL-2, treatment delays and discontinuations are frequent. The most common reported toxicities are hypotension (71%), diarrhea (67%), chills (52%), vomiting (50%), dyspnea (43%), and peripheral edema (28%) in addition to increases in bilirubin (40%), serum creatinine (33%), and electrolyte abnormalities.59 Many of these effects are related to capillary leak syndrome. Inpatient administration and intensive monitoring and supportive care are required, and many institutions administer IL-2 in an intensive care setting. Many patients are not candidates for IL-2 therapy because of their age (>60 years), comorbidities, organ function, and poor performance status.

Interferons are naturally occurring glycoproteins produced by macrophages and lymphocytes in response to foreign antigens as part of the host immunity. They exert their antitumor effects by activating cytotoxic T and natural killer cells, enhancing expression of cell surface antigens (i.e., major histocompatibility class I), and modulating gene expression.60,61 A number of different IFNs have been studied for the treatment of metastatic RCC, including IFN-α, -β, and -γ. The response rates are similar among the different IFNs, but IFN-α is most commonly used to treat RCC.

Although IFN has been used to treat RCC for 2 decades, it is not approved by the FDA for the treatment of advanced or metastatic RCC. Overall response rates to IFN generally range from 5% to 20%.58,60,62Two randomized trials demonstrated a survival benefit with IFN. IFN-α plus vinblastine was compared with vinblastine alone in 160 patients with advanced RCC. Both groups received vinblastine at 0.1 mg/kg IV every 3 weeks, and the combination group also received IFN at a dose of 3 million units subcutaneously or intramuscularly 3 times a week for the first week and then 18 million units subcutaneously 3 times a week thereafter. The median OS was significantly improved in the combination group compared with the vinblastine alone group at 67.6 weeks and 37.8 weeks (P = 0.005), respectively.63 In another study, IFN-α was compared with medroxyprogesterone acetate 300 mg/day in 350 patients with metastatic RCC. IFN-α was dosed at 5 million units for two doses and then increased to 10 million units 3 times a week for a total of 12 weeks. The median OS was 8.5 months compared with 6 months for IFN-α and medroxyprogesterone, which translated into a 28% reduction in the risk of death in the IFN-α group (P = 0.017).64 Based on these studies, IFN remains the comparator for novel treatments in metastatic RCC. It is better tolerated than IL-2 and can be self-administered at home. However, more than 90% of patients experience chills, fever, asthenia, fatigue, headache, diarrhea, and liver function abnormalities, and some patients develop depression and other neuropsychiatric symptoms.

Targeted Therapy

Images Since 2005, seven new drugs have been approved either as first- or second-line therapy: sunitinib, sorafenib, pazopanib, axitinib, bevacizumab (in combination with IFN), temsirolimus, and everolimus (Table 115-4 and Fig. 115-4).

TABLE 115-4 Comparison and Dosing of Targeted Agents in Patients with Metastatic Renal Cell Carcinoma

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Images

FIGURE 115-4 First and second line therapy recommendations for relapsed or Stage IV and medically or surgically unresectable RCC. (IFN, interferon; IL, interleukin; NCCN, National Comprehensive Cancer Network; RANK, receptor activator of nuclear factor-κB.)

Sunitinib

Sunitinib is an orally administered antiangiogenic agent that inhibits multiple tyrosine kinases, including VEGFR and platelet-derived growth factor receptor (PDGFR).65 Sunitinib is approved for the first-line treatment of metastatic RCC (NCCN guidelines, category I).44 That approval was based on a randomized, phase III clinical trial, which compared sunitinib with IFN-α2a as first-line therapy in 750 patients with clear cell metastatic RCC.66 Sunitinib was administered in a 6-week cycle at 50 mg orally given daily for 4 weeks followed by 2 weeks without treatment. IFN was administered subcutaneously 3 times weekly on nonconsecutive days, with a gradual dose increase from 3 million units to 9 million units over a 3-week period. Sunitinib was found to be superior to IFN, with median progression-free survival (PFS) of 11 months and 5 months (P <0.001), respectively. The improved PFS with sunitinib was observed regardless of baseline characteristics and prognostic factors. Both treatments were generally well tolerated with a low incidence of grade 3 or 4 adverse events. The sunitinib group had higher rates of diarrhea, vomiting, hypertension, hand–foot syndrome, hair discoloration, and myelosuppression than IFN-treated patients. Health-related quality of life was significantly better in the sunitinib group (P <0.001) compared with the IFN group. Sunitinib-treated patients also had prolonged OS as compared with IFN-treated patients (26 vs. 22 months; P = 0.05) even though 25 patients in the IFN group crossed over to the sunitinib group.5 Sunitinib has been evaluated in three clinical trials as either first- or second-line therapy after progression on cytokine therapy, with response rates of 30% to 45%, which was considerably higher than the response rates observed for cytokines.50,6668 In addition to the high response rate, sunitinib was relatively well tolerated, with most adverse events managed by supportive care or dose modification and fewer than 10% requiring treatment discontinuation. As a result, the NCCN guidelines recommend sunitinib for first-line therapy in patients with metastatic RCC who have never received systemic therapy (category 1) and for second-line therapy in patients who have progressed on cytokine (category 1) or TKI (category 2A) therapy.44 Images

Sorafenib

Sorafenib is another orally administered antiangiogenic agent that inhibits multiple tyrosine kinases, including VEGFR, PDGFR, Raf-1, fms-like tyrosine kinase receptor-3 (Flt-3), and c-kit. Sorafenib is approved for second-line treatment of metastatic RCC after progression on cytokine therapy. The approval was based on a phase III double-blind clinical trial in which 903 patients with metastatic RCC who had progressed after first-line systemic therapy were randomized to treatment with sorafenib or placebo. Study patients received sorafenib 400 mg orally twice daily continuously or placebo twice daily until disease progression or intolerable toxicities. Of note, 48% of patients in the placebo arm crossed over to the sorafenib arm when interim analyses demonstrated a significant PFS benefit with sorafenib compared with placebo (5.5 months vs. 2.8 months; P <0.01). The final primary end point analysis for OS showed no difference between sorafenib and placebo therapy (17.8 months vs. 15.2 months; P = 0.15), but censoring for patients who crossed over showed a significant OS benefit favoring sorafenib therapy (17.8 months vs. 14.3 months; P = 0.03). Sorafenib was generally well tolerated with few grade 3 or 4 adverse events, although about 5% of patients reported cardiac infarct or ischemic events.69 Sorafenib was also studied as first-line therapy for metastatic RCC in a phase II randomized clinical trial comparing sorafenib with IFN-α2a. Study patients received oral sorafenib 400 mg twice daily or subcutaneous IFN-α2a 9 million units 3 times weekly. Patients were allowed to cross over from the placebo arm to the sorafenib arm, and dose escalations up to 600 mg twice daily were permitted. The primary end point of PFS showed no difference between sorafenib and IFN-α therapy. However, patients reported better quality of life with sorafenib compared with IFN-α therapy.4 As a result, sorafenib is recommended as second-line therapy for metastatic RCC after progression on initial systemic cytokine therapy (category 1) or TKI therapy (category 2A) and as first-line therapy only in select patients (category 2A).44

Pazopanib

Pazopanib is another orally administered TKI that was recently approved for the treatment of metastatic RCC. Pazopanib also inhibits multiple kinase receptors, including VEGFR, PDGFR, fibroblast growth factor receptor (FGFR), c-kit, IL-2 receptor inducible T-cell kinase (Itk), and leukocyte-specific protein tyrosine kinase (Lck). Pazopanib was evaluated in a phase III double-blind clinical trial in which 435 patients with metastatic RCC were randomized to treatment with pazopanib 800 mg/day or placebo. The study population included 233 treatment-naive and 202 cytokine-pretreated patients. The primary end point of PFS showed a significant benefit in the pazopanib group compared with placebo, with a median PFS of 9.2 months versus 4.2 months, respectively (P <0.001). The PFS benefit was significant in both treatment-naive (11.1 vs. 2.8 months; P <0.001) and cytokine-pretreated (7.4 vs. 4.2 months; P<0.001) populations. Pazopanib was generally well tolerated, with few grade 3 or 4 adverse events.9 It is an option for the first-line treatment of metastatic RCC (category 1) and as second-line therapy after progression on cytokines (category 1) or TKI (category 3).44 A randomized, double-blind, placebo-controlled cross-over trial in patients with metastatic RCC assessing patient preference between pazopanib and sunitinib demonstrated that 70% of patients preferred pazopanib compared with 22% who preferred sunitinib and 8% who had no preference. The most common reasons patients gave for pazopanib preference were improved quality of life and less fatigue.70 A phase III clinical trial comparing the efficacy of these two agents as first-line treatment of metastatic RCC was anticipated to complete data collection in 2012 with final results available in 2014. Pazopanib is also being studied for neoadjuvant therapy and in a single-arm phase II clinical trial as second-line therapy in patients who have progressed on sunitinib or bevacizumab therapy.

Although sunitinib, sorafenib, and pazopanib are all orally administered antiangiogenic multikinase inhibitors, clinical studies have clearly demonstrated that these agents have different efficacy and toxicity profiles (Tables 115-4and 115-5). Whereas sunitinib and pazopanib have been reported to improve PFS in both first- and second-line treatment settings, sorafenib has demonstrated improved PFS only in the second-line treatment setting. In addition to differences in efficacy, these agents have subtle differences in their side effect profile.71 Sunitinib and pazopanib are associated with higher rates of hypertension and hair discoloration than sorafenib. Sunitinib is also associated with higher rates of hypothyroidism than sorafenib. Sorafenib is associated with higher rates of gastrointestinal side effects and hand–foot syndrome than sunitinib and pazopanib. It is also important to note that sunitinib is administered intermittently in a 6-week cycle (4 weeks on treatment, 2 weeks off treatment), but sorafenib and pazopanib are both administered continuously. Both sunitinib and sorafenib appear to have benefit in the subgroup of patients with non–clear cell histology.

TABLE 115-5 Drug Monitoring Recommendations for Renal Cell Carcinoma Therapy

Images

Axitinib

Images Axitinib is the newest orally administered TKI approved in January 2012 for the treatment of advanced RCC after progression on one prior systemic therapy. Axitinib is a second-generation, selective inhibitor of VEGFR 1, 2, and 3 and has been shown to be 50 to 450 times more potent than first-generation VEGFR inhibitors such as sorafenib and sunitinib. Unlike first-generation agents, axitinib has limited activity beyond VEGFR blockade, potentially reducing off-target toxicity.72 Axitinib was compared with sorafenib in a randomized, open-label, phase III trial in 723 patients with clear cell RCC who had progressed on a previous first-line regimen of sunitinib, bevacizumab plus IFN, temsirolimus, or cytokine-based therapy. Most of the patients enrolled received either sunitinib-based therapy (54%) or cytokine-based therapy (35%). The primary end point of PFS assessed by blinded, independent radiology review was superior in the axitinib treated patients with a PFS of 6.7 months compared with 4.7 months in the patients who received sorafenib (P <0.0001). This benefit was seen in both the patients who received prior therapy with sunitinib and cytokines. Additionally, fewer patients discontinued axitinib because of toxic effects compared with sorafenib (4% vs. 8%). The most common adverse effects seen with axitinib were diarrhea, hypertension, fatigue, nausea, and dysphonia, and patients had notably less hand–foot syndrome and alopecia compared with those treated the multikinase inhibitor sorafenib.73 Based on these results, axitinib is now recommended as an additional therapeutic option for subsequent therapy following progression on a first-line regimen that is either targeted therapy or cytokine-based (category 1).44 Ongoing trials are assessing pazopanib in the adjuvant and neoadjvuant settings as well as first-line for poor risk patients with metastatic disease.

Bevacizumab

Bevacizumab is a humanized monoclonal antibody that binds circulating VEGF and thus inhibits the effects of VEGF.65 Bevacizumab was studied in a phase III double-blind clinical trial in which 649 treatment-naive patients with metastatic disease were randomized to receive bevacizumab plus IFN-α2a or placebo plus IFN-α2a. Bevacizumab was administered IV at 10 mg/kg every 2 weeks until disease progression or intolerable toxicity; no dose reductions were allowed. IFN was administered subcutaneously at 9 million units three times weekly with dose reduction to 6 million or 3 million units for treatment-related toxicity.7 The primary end point of OS was not statistically different between the two treatment groups, 23.3 months versus 21.3 months for bevacizumab plus IFN and placebo plus IFN, respectively (P = 0.13).71 However, the secondary end points showed a significant benefit with the addition of bevacizumab to IFN therapy, with a PFS of 10.2 months as compared with 5.4 months with IFN plus placebo therapy (P = 0.0001). In addition, objective response rates were higher with the addition of bevacizumab to IFN, 31% compared with 13% in the placebo plus IFN group. The most common adverse effects were related to IFN therapy, and the addition of bevacizumab did not significantly increase the toxicity of IFN. However, treatment discontinuations because of adverse events occurred more often in the bevacizumab group, with proteinuria, hypertension, and gastrointestinal perforation as the most common causes.7,74 Bevacizumab plus IFN-α2a was studied in another clinical trial (Cancer and Leukemia Group B 90206), which compared it with IFN-α2a monotherapy as first-line treatment.75 The results of this study were similar, with improvements in PFS and objective response rates but no difference in OS. The combination of bevacizumab plus IFN-α2a is an option for the first-line treatment of metastatic RCC (category 1), and bevacizumab monotherapy is an option as second-line therapy (category 2B).44

Temsirolimus

Images Temsirolimus is an IV administered agent that inhibits mTOR. As discussed previously, mTOR is a downstream component of the PI3K/AKT pathway that ultimately results in HIF regulation.23,27Temsirolimus was compared with IFN-α2a or the combination of the two agents in a phase III multicenter trial of 626 treatment-naive patients with higher risk metastatic RCC. About 75% of patients were considered high risk (three or four of five factors), and 25% were considered intermediate risk (one or two of five factors), based on the MSKCC risk classification. The IFN-α2a group received 3 million units subcutaneously 3 times weekly for the first week, 9 million units the second week, and 18 million units thereafter. The temsirolimus group received 25 mg IV once weekly, and the combination group received IFN-α2a at 3 million units subcutaneously 3 times weekly for the first week and 6 million units subcutaneously 3 times weekly and temsirolimus 15 mg IV once weekly. The study was discontinued early after the second interim analysis based on temsirolimus benefit.6 Single-agent temsirolimus was found to be superior for the primary end point, with an OS of 10.9 months compared with 7.3 months for IFN alone and 8.4 months for the combination. The median PFS for the temsirolimus, IFN, and combination groups was 5.5, 3.1, and 4.7 months, respectively. Serious adverse effects were more common in the IFN groups than in the temsirolimus group, resulting in fewer dose reductions and dose delays compared with the IFN and combination groups. Patients receiving temsirolimus were more likely to experience hyperlipidemia, hyperglycemia, and hypercholesterolemia, which were expected based on the role of mTOR in the regulation of glucose and lipid metabolism. The results of this study support the use of temsirolimus for first-line treatment of patients with poor prognostic features, making it the first therapy specifically approved for this patient population. Historical data on patients with three or more poor-risk features, such as those in this study, have resulted in a median OS of 4 to 8 months compared with 7.3 months in this study.38,7678 Based on these results, temsirolimus is recommended by NCCN for first-line treatment in patients with metastatic RCC with poor prognosis (category 1) and as an option for select patients of other risk groups (category 2B).44

Everolimus

Images Everolimus is another mTOR inhibitor, but it is available in an oral formulation. A phase II trial of everolimus in patients with predominantly clear cell histology metastatic RCC with no more than one prior therapy resulted in a modest number of partial responses or stable disease.79 Based on these data, everolimus was compared with placebo in 410 patients who experienced disease progression within 6 months of stopping sunitinib or sorafenib. This international, multicenter, double-blind, phase III trial randomized patients to everolimus or placebo. Those randomized to the everolimus group received everolimus 10 mg orally once daily continuously while in the fasting state or with a light, fat-free meal. The trial was halted after the second interim analysis based on benefit seen in the everolimus group.8Everolimus was found to be superior to placebo for the primary endpoint, with a median PFS of 4 months as compared with 1.9 months (P <0.0001). Patients in the everolimus group had a 26% probability of being progression free at 6 months compared with 2% in the placebo group. At the time of analysis, median OS had not been reached in the everolimus group and was 8.8 months in the placebo group. Partial responses were rare and were seen in only three patients in the everolimus group and none in the placebo group. Health-related quality of life was assessed using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-30 and Functional Assessment of Cancer Therapy Kidney Symptom Index—Disease-Related Symptoms (FKSI-DRS) questionnaires.80,81 Although the time to definitive deterioration of patient-reported outcomes was not different between the two groups, quality of life was sustained during treatment with everolimus relative to placebo as assessed by the EORTC QLQ-C30 and FKSI-DRS questionnaires. All adverse events occurred more frequently in the everolimus group than in the placebo group, but severe adverse effects were uncommon.8 Elevations in glucose and lipids were seen because of everolimus’ ability to inhibit mTOR.82 Based on these results, the NCCN guidelines recommend everolimus for patients with metastatic RCC who have failed treatment with sunitinib, sorafenib, or both (category 1).44


Clinical Controversy…

The majority of patients with advanced or metastatic RCC will receive first-line therapy with a VEGFR–tyrosine kinase inhibitor; however, disease progression will inevitably occur, and therapy with a different VEGFR-targeted agent or mTOR inhibitor will be initiated. This raises the question of optimal therapy sequencing because few head-to-head studies have been done addressing this problem. The AXIS trial demonstrated superior PFS with the selective VEGFR tyrosine kinase inhibitor axitinib compared with sorafenib in the second-line setting, and RECORD-1 reported superiority of the oral mTOR inhibitor everolimus compared with placebo in the same patient population.6,73 Both axitinib and everolimus are classified as category 1 level recommendations by NCCN in patients progressing on a first-line tyrosine kinase inhibitor regimen.44 Ongoing trials are needed to determine the optimal sequencing of these distinct agents beyond the first-line setting.

Temsirolimus and everolimus are both mTOR inhibitors, but they have several important differences. First, everolimus is administered orally once daily, but temsirolimus is administered as an IV infusion once weekly. Second, although most patients in the temsirolimus trial had clear cell histology (80%), the trial also included patients with other histologies (20%). Everolimus was studied only in patients with RCC exhibiting clear cell histology. Third, whereas temsirolimus was studied in the first-line setting in patients with poor prognosis based on clinical features, everolimus was studied in the second-line setting in patients who had progressed after sorafenib or sunitinib.

PERSONALIZED PHARMACOTHERAPY

Given the numerous treatment options for advanced and metastatic RCC, the utilization of patient-related factors to guide treatment selection would be beneficial, but no validated predictors of treatment response have been determined. The use of therapeutic drug monitoring (TDM) for the TKIs and mTOR inhibitors is an attractive option given the numerous factors that can cause variation in drug exposures. For example, differences in first-pass liver metabolism, variation in activation and deactivation pathways, and drug interactions can result in differences in the pharmacokinetics of these agents. Barriers of implementation in current practice are numerous and include a well-defined and validated therapeutic target concentration and availability of reliable analytic assays that can be implemented into clinical practice.83 However, there is some evidence with sunitinib and everolimus that this may be a future possibility.82

A meta-analysis of sunitinib in patients with RCC or gastrointestinal stromal tumors was performed to explore the relationship between exposures of sunitinib and its active metabolite, SU12662, and clinical outcomes. Steady-state area under the curve (AUC) of sunitinib and SU12662 were associated with time to progression, OS, and toxicity. Higher AUC was associated with longer time to progression and OS; increased response rate; and increased incidence of fatigue, hypertension, and neutropenia.84 This type of analysis may help to select agents that may be included in prospective dose-targeting trials.

Everolimus is a derivative of sirolimus, an immunosuppressant agent used in the prevention of solid organ transplant rejection. TDM is commonly used in clinical practice to optimize dosing of sirolimus, which suggests that the same may be possible and beneficial with everolimus. In a phase I pharmacodynamic trial in solid tumor patients, plasma trough concentrations of everolimus were correlated with inhibition of mTOR as evidenced by decreased concentrations of downstream mTOR pathway proteins.85 The linear pharmacokinetics of everolimus also makes pharmacokinetic-directed therapy an attractive and feasible future option.85

In summary, current clinical applications of personalized therapy for RCC are limited, but properties of the agents currently used for management of the disease make them attractive options for future pharmacodynamic studies.

EVALUATION OF THERAPEUTIC OUTCOMES

The outcome of treatment in patients with RCC depends on the extent of disease at the time of diagnosis. Whereas localized RCC has a 5-year OS of about 85%, metastatic RCC has a 5-year OS of less than 23%.10 The standard of care in patients with localized RCC (stage I–III) is surgical removal with a goal of long-term survival and cure. However, 20% to 30% of patients will relapse within 3 years, and 50% to 60% of these patients will have distant recurrence to the lungs. The NCCN Kidney Cancer Panel recommends that patients undergo a medical history; physical examination; comprehensive metabolic panel (including blood urea nitrogen, serum creatinine, calcium levels, and liver function tests); and abdominal, pelvic, and chest imaging every 6 months for the first 2 years after surgery and annually thereafter.44For patients with stage IV and unresectable RCC, the goal of treatment is to control disease burden and prolong survival while maximizing quality of life. Current treatment options depend on RCC histology, comorbidities, patient performance status, and prognosis and include enrollment in a clinical trial; immunotherapy (IFN-α, IL-2); or targeted therapy with VEGFR-TKIs (sunitinib, sorafenib, pazopanib, axitinib), mTOR inhibitors (everolimus, temsirolimus), or a monoclonal antibody VEGF inhibitor (bevacizumab). If a patient has disease progression on the initial treatment regimen, subsequent treatment from a different medication class should be considered. At each patient visit, adherence to medication regimens must be strongly emphasized, and treatment-related toxicities should be closely monitored and prevented, if possible. Because optimizing quality of life is usually the therapeutic end point in metastatic RCC, best supportive care should be given to all patients, which may include palliative radiation, metastasectomy, and bisphosphonates or receptor activator of nuclear factor-κB ligand inhibitors for the treatment of bony metastases.44

ABBREVIATIONS

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