Individualizing Therapy For Patients With Advanced Rcc
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Individualizing Therapy For Patients With Advanced Rcc

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  • It is wonderful to see the advances in knowledge that make my treatment for Met. RCC possible.

    The kink that causes the cancer; malfuntioning gene (s) may be the only key to a CURE for the disease in individuals.
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  • US estimates for 2008 indicate that 54,390 individuals will be diagnosed with cancer of the kidney and renal pelvis, and 13,010 individuals will die from the disease. 1 The median age of individuals at diagnosis is 65 years; the median age of individuals at death is 71 years. 1 Kidney and renal pelvis cancer is the 3rd most common genitourinary cancer after prostate cancer and bladder cancer. 2 It is 1 of the 10 most-common cancers affecting both men and women. 2 National Cancer Institute. SEER cancer statistics fact sheet: Cancer of the kidney and renal pelvis. Available at http://seer.cancer.gov/statfacts/html/kidrp.html?statfacts_page=kidrp.html&x=22&y=16. Accessed July 27, 2008. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin . 2008;58:71-96.
  • At diagnosis, 56% of kidney and renal pelvis cancer cases have disease that is confined to the primary site (ie, localized stage); 19% are diagnosed after the cancer has spread to regional lymph nodes or directly beyond the primary site; 20% are diagnosed after the cancer has already metastasized (distant stage). 1 The corresponding 5-year relative survival rates based on historic data are 89.9% for localized disease, 61.3% for regional disease, and 9.9% for distant (metastatic) disease. National Cancer Institute. SEER cancer statistics fact sheet: Cancer of the kidney and renal pelvis. Available at http://seer.cancer.gov/statfacts/html/kidrp.html?statfacts_page=kidrp.html&x=22&y=16. Accessed July 27, 2008.
  • Unfortunately, because RCC is clinically silent for much of its natural history, many individuals present with unresectable disease, metastatic disease, or locally advanced RCC prone to recurrence. 1,2 Individuals with metastatic RCC have a very poor prognosis, with a 5-year survival rate of only 9.9%. 1 This poor outlook stems from the fact that, up until recently, these individuals had very few treatment options. Surgery is not a potential option for cure, chemotherapy and radiotherapy play little to no role in treatment, and immunotherapy produces limited benefit at the expense of considerable toxicity. These significant unmet treatment needs for patients with advanced RCC drove investigators to acquire a greater understanding of the biologic basis of renal oncogenesis in order to guide rational approaches to treatment. National Cancer Institute. SEER cancer statistics fact sheet: Cancer of the kidney and renal pelvis. Available at http://seer.cancer.gov/statfacts/html/kidrp.html?statfacts_page=kidrp.html&x=22&y=16. Accessed July 27, 2008. Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and m anagement of recurrent disease. Urol Clin North Am . 2003;30:843-852.
  • RCC is a heterogeneous disease. There are 5 distinct subtypes of RCC that reflect differences in morphology, growth pattern, cellular origin, histochemical features, and molecular features in renal adenocarcinomas. 1-3 The most common genetic abnormality in clear cell carcinoma involves the von Hippel-Lindau (VHL) gene. Papillary-type carcinomas (i.e., types 1 and 2) are characterized by abnormalities in c-Met or fumarate hydratase. The Birt-Hogg-Dube syndrome is associated with both chromophobe and oncocytoma. BHD: Birt-Hogg-Dubé; VHL: von Hippel Lindau. Thoenes W, Störkel S, Rumpelt HJ. Histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas). The basic cytological and histopathological elements and their use for diagnostics. Pathol Res Pract . 1986;181:125-143. Störkel S, van den Berg E. Morphological classification of renal cancer. World J Urol . 1995;13:153-158. Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol . 2003;170:2163-2172.
  • Researchers have come to appreciate the role of the VHL gene in RCC, which in turn has led to a better understanding of the pathogenesis of RCC. VHL is a tumor suppressor gene located on chromosome 3p25. Several lines of evidence point to the importance of VHL in RCC pathology. Studies show that loss of heterozygosity of the VHL gene locus is detected in approximately 85%-95% of informative cases of clear-cell RCC. 1,2 Other studies show that VHL genetic abnormalities are present in 60%-90% of all patients with sporadic RCC. 3,4 In these studies, VHL was mutated in roughly 50%-70% of individuals, whereas it was silenced by hypermethylation in 5%-20%. Inactivation of VHL is thought to be a very early event in clear-cell tumorigenesis. 1. Shuin T, Kondo K, Torigoe S, et al. Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res . 1994;54:2852-2855. 2. Brauch H, Weirich G, Brieger J, et al. VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. Cancer Res . 2000;60:1942-1948. 3. Yao M, Yoshida M, Kishida T, et al. VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst . 2002;94:1569-1575. 4. Banks RE, Tirukonda P, Taylor C, et al. Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer Res . 2006;66:2000-2011.
  • The VHL gene encodes a tumor suppressor protein that binds to several other proteins (elongin B, elongin C, Cul2, Rbx1, NEDD8) to form a multiprotein complex (VEC) that targets various proteins for destruction including hypoxia inducible factor 1  (HIF-1  ), a transcription factor that controls genes that allow cells to grow and survive in hypoxic conditions. Under normoxic conditions, HIF-1  is hydroxylated at specific amino acid resides, which allows the VHL complex to bind and ubiquitinate HIF-1  , thus targeting the protein for degradation by the proteasome. As a consequence, VHL controls hypoxia-inducible genes involved in angiogenesis, glycolysis, erythropoiesis, pH, cell adhesion, and extracellular membrane assembly. Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer . 2005;104:2323-2333.
  • Loss of VHL function, either through mutation or silencing (ie, hypermethylation), is functionally equivalent to hypoxic conditions. That is, VHL is unable to bind to HIF-1  to target the protein for destruction. As a consequence, HIF-1  accumulates and binds to its abundantly expressed partner, HIF-1  , in the cell nucleus to then induce gene transcription. Proteins upregulated by transcriptionally active HIF-1  /HIF-1  include VEGF, PDGF, transforming growth factor-  (TGF-  ), the glucose transporter protein GLUT-1, and carbonic anhydrase IX, among others. The effects of mutant VHL and HIF-1  on angiogenic factors such as VEGF and PDGF are thought to account for the high degree of vascularization seen in RCC tumors. Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer . 2005;104:2323-2333.
  • Upregulation of VEGF, PDGF, and EGFR by HIF-1  leads to the activation of several molecular pathways that contribute to cellular proliferation, cell survival, cell migration, and angiogenesis. 1,2 Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer . 2005;104:2323-2333. Vignot S, Faivre S, Aguiire D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol . 2005;16:525-537. [after fade] The most important of these pathways for growth stimulation, and the ones that have undergone the most intensive therapeutic investigation, include the Raf/MEK/ERK pathway and the PI3K/AKT pathway. 1,2 Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer . 2005;104:2323-2333. Vignot S, Faivre S, Aguiire D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol . 2005;16:525-537.
  • Downstream of PI3K and AKT lies mTOR, a central modulator that relays angiogenesis and nutrient-uptake signals to downstream proteins controlling transcription and translation. The mTOR pathway contributes to angiogenesis in 2 distinct ways: it mediates endothelial proliferation through VEGF signaling, and it activates activates angiogenic growth factors through increased production of the HIF-1  transcription factor. 1-3 Expression of the PTEN tumor suppressor gene, which is an upstream regulator of mTOR, has been shown to be downregulated and/or inactivated in RCC. 4,5 Seeliger H, Guba M, Kleespies A, Jauch KW, Bruns CJ. Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. Cancer Metastasis Rev . 2007;26:611-621. Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol . 2002;22:7004-7014. Mita MM, Mita A, Rowinsky EK. The molecular target of rapamycin (mTOR) as a the rapeutic target against cancer. Cancer Biol Ther . 2003;2:S169-S177. Yu Y, Sato JD. MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor. J Cell Physiol . 1999;178:235-246. Brenner W, Färber G, Herget T, Lehr HA, Hengstler JG, Thüroff JW. Loss of tumor suppressor protein PTEN during renal carcinogenesis. Int J Cancer . 2002;99:53-57.
  • Knowledge of biologic basis of renal oncogenesis has facilitated the transition from a nonspecific immune approach using cytokines (ie, IL-2, IFN-  ) to a molecular approach that targets the specific pathways involved in RCC pathology. Some of these agents have been FDA approved for the treatment of advanced RCC, whereas others are still considered investigational for this indication. 1 1. Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer . 2005;104:2323-2333.
  • RCC staging enhances disease management by providing clinicians with the ability to predict tumor behavior, prognosticate with regard to patient outcomes, stratify patients into risk categories, and select treatment options based on these risk categories. 1 In addition, using standardized RCC staging as inclusion criteria for clinical trials ensures that patients are appropriate candidates for such trials and facilitates cross-study comparisons of the results. 1. Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS. The role of molecular markers in the staging of renal cell carcinoma. BJU Int . 2007;99:1208-1211.
  • The 3 primary factors used to determine RCC prognosis are the anatomic extent of disease, histopathology, and clinical factors. 1 1. Shuch BM, Lam JS, Belldegrun AS, Figlin RA. Prognostic factors in renal cell carcinoma. Semin Oncol . 2006:33:563-575.
  • Several models have been developed that integrate information on anatomic staging, histopathology, and clinical parameters to determine prognosis. The most widely used of these models is the validated UCLA integrated staging system (UISS). 1,2 The UISS uses the TNM classification scheme, Fuhrman grade, and ECOG performance status to classify patients into 5 prognostic categories that correlate with postnephrectomy outcomes. Zisman A, Pantuck AJ, Dorey F, et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol . 2001;19:1649-1657. Patard JJ, Kim HL, Lam JS, et al. Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study. J Clin Oncol . 2004;22:3316-3322.
  • An example of survival rates based on the UISS prognostic model is shown above. 1 ECOG PS: Eastern Cooperative Oncology Group performance status. Zisman A, Pantuck AJ, Dorey F, et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol . 2001;19:1649-1657.
  • There are several molecular prognostic factors in RCC, as listed on this slide. Currently, these factors are useful for investigating the biology of RCC; they are not yet well established enough for use by practicing clinicians in patient selection. CAIX: carbonic anhydrase IX; COX-2: cyclo-oxygenase-2; LDH: lactose dehydrogenase; PFS: progression-free survival; PTEN: phosphatase and tensin homolog; VEGF: vascular endothelial growth factor. Bui MH, Seligson D, Han KR, et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res. 2003;9:802-811. Patard JJ, Fergelot P, Karakiewicz PI, et al. Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma. Int J Cancer. 2008;123:395-400. Bui MH, Visapaa H, Seligson D, et al. Prognostic value of carbonic anhydrase IX and KI67 as predictors of survival for renal clear cell carcinoma. J Urol. 2004;171:2461-2466. Weiss RH, Borowsky AD, Seligson D, et al. p21 is a prognostic marker for renal cell carcinoma: implications for novel therapeutic approaches. J Urol. 2007;177:63-68. Shvarts O, Seligson D, Lam J, et al. p53 is an independent predictor of tumor recurrence and progression after nephrectomy in patients with localized renal cell carcinoma. J Urol. 2005;173:725-728. Kim HL, Seligson D, Liu X, et al. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol. 2005;173:1496-1501. Bukowski RM, Eisen T, Szczylik C, et al. Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: survival and biomarker analysis. Program and abstracts of the 43th American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Illinois. Abstract 5023. Klatte T, Seligson DB, Riggs SB, et al. Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma. Clin Cancer Res. 2007;13:7388-7393. Thompson RH, Zang X, Lohse CM, et al. Evaluation of soluble B7x as a serum marker in patients with clear cell renal cell carcinoma. Program and abstracts of the 44th American Society of Clinical Oncology Annual Meeting; May30-June 3, 2008; Chicago, Illinois. Abstract 5052. Kim H, Yi S, Jun H, et al. Use of biomarkers to predict outcomes of immunotherapy for metastatic renal cell carcinoma. Program and abstracts of the 44th American Society of Clinical Oncology Annual Meeting; May30-June 3, 2008; Chicago, Illinois. Abstract 16015. Tanimoto S, Fukumori T, El-Moula G, et al. Prognostic significance of serum hepatocyte growth factor in clear cell renal cell carcinoma: comparison with serum vascular endothelial growth factor. J Med Invest. 2008;55:106-111. Pantuck AJ, Seligson DB, Klatte T, et al. Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer. 2007;109:2257-2267.
  • CAIX serves as a good example of a prognostic molecular marker. Immunohistochemical analysis using a CAIX monoclonal antibody was performed on tissue specimens taken from 321 patients treated by nephrectomy for clear-cell RCC. 1 CAIX staining was correlated with the response to treatment, clinical factors, pathologic features, and survival. CAIX staining was detected in 94% of clear-cell RCCs, but not in normal-looking renal tissue. In patients with metastatic disease, high CAIX staining (>85% of cells) was associated with a median disease-specific survival of 24.8 months, whereas low CAIX staining (≤85%) was associated with a median survival of only 5.5 months (P < 0.001). Low CAIX staining was a strong, independent prognostic factor associated with poor survival for patients with metastatic RCC--much stronger than performance status, tumor grade, tumor stage, and nodal status. CI: confidence interval; ECOG PS: Eastern Cooperative Oncology Group performance status; HR: hazard ratio. Bui MH, Seligson D, Han KR, et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res . 2003;9:802-811.
  • Just as there are molecular prognostic factors that can indicate clinical outcomes in patients with RCC, there are also molecular and genetic markers that can predict the response to treatment, as shown on this slide. CAIX: carbonic anhydrase IX; COX-2: cyclo-oxygenase-2; HIF: hypoxia inducible factor; VEGF: vascular endothelial growth factor. Kim HL, Seligson D, Liu X, et al. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol . 2005;173:1496-1501. Patel PH, Chadalavada RS, Ishill NM, et al. Hypoxia-inducible factor (HIF) 1α and 2α levels in cell lines and human tumor predicts response to sunitinib in renal cell carcinoma (RCC). Program and abstracts of the 44th American Society of Clinical Oncology Annual Meeting; May30-June 3, 2008; Chicago, Illinois. Abstract 5008. Faber PW, Vaziri SA, Wood L, et al. Potential non-synonymous single nucleotide polymorphisms (nsSNPs) associated with toxicity in metastatic clear cell renal cell carcinoma (MCCRCC) patients (pts) treated with sunitinib. Program and abstracts of the 44th American Society of Clinical Oncology Annual Meeting; May30-June 3, 2008; Chicago, Illinois. Abstract 5009. Jaeger E, Waldman F, Roydasgupta R, et al. Array-based comparative genomic hybridization (CGH) identifies chromosomal imbalances between Interleukin-2 complete and non-responders. Program and abstracts of the 44th American Society of Clinical Oncology Annual Meeting; May30-June 3, 2008; Chicago, Illinois. Abstract 5043. Choueiri TK, Vaziri SA, Jaeger E, et al. von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma. J Urol . 2008. [Epub ahead of print]
  • Certain clinical factors are very useful for determining prognosis. The prognostic value of several clinical factors has been validated using patient data. The Memorial Sloan-Kettering Cancer Center criteria and the Cleveland Clinic Foundation criteria are detailed above. 1,2 These simple clinical characteristics enable practitioners to easily determine disease risk, which may then be used to tailor therapy. KPS: Karnosfsky performance status; LDH: lactose dehydrogenase; LLN: lower limit of normal; ULN: lower limit of normal. Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol . 2004;22:454-463. Mekhail TM, Abou-Jawde RM, Boumerhi G, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol . 2005;23:832-841.
  • Both the Memorial Sloan-Kettering Cancer Center risk criteria and the Cleveland Clinic Foundation risk criteria allow patients to be categorized according to good, intermediate, or poor risk. This stratification can facilitate decisions as to the aggressiveness of therapy based on a patient’s risk status. OS: overall survival. Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol . 2004;22:454-463. Mekhail TM, Abou-Jawde RM, Boumerhi G, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol . 2005;23:832-841.
  • RCC has a highly variable natural history with no available systemic cure. Among the agents currently available for treatment, none are predicted to be uniformly potent in all patient populations. Because of this, tailoring therapy to each individual patient is likely to provide the best chance of disease control balanced with the best possible quality of life.
  • There are several important issues to consider when thinking about how to individualize therapy for a patient. First, it is important to keep in mind the overall goals of treatment for metastatic RCC, which include delaying the life-threatening burden of disease for as long as possible and optimizing the chance of long-term disease control while maximizing patient quality of life and convenience. Second, the benefits and risks of each therapeutic agent must be weighed to identify the most appropriate agent for a given patient. Third, clinicians should bear in mind that most patients will likely receive a sequence of several agents to help control their disease, thus warranting thoughtful selection of first-, second-, and subsequence lines of therapy. Last, the development of targeted agents has outpaced our understanding of how to use these agents optimally. As such, it is important to keep in mind that broad regulatory approval of an agent does not equate to broad activity across all patients; some agents are likely to be more effective in certain patient subgroups than other agents.
  • There are 4 targeted agents available for the treatment of advanced RCC. These agents are the first new drugs to be approved for RCC in almost 2 decades. Three of these agents target the VEGF pathway, whereas 1 targets the mTOR pathway. All of these agents significantly prolong the time to disease progression in comparison with either placebo or IFN-a. 1-5 As such, these agents represent the new standard of care for metastatic disease. ORR: overall response rate; PBO: placebo; TTP: time to progression. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet . 2007;370:2103-2111. 2. Rini BI, Halabi S, Rosenberg JE, et al. CALGB 90206: a phase III trial of bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in metastatic renal cell carcinoma. Program and abstracts of the 2008 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 14-16, 2008; San Francisco, CA. Abstract 350. 3. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med . 2007;356:115-124. 4. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med . 2007;356:125-134. 5. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med . 2007;356:2271-2281.
  • Although there are now several active agents available to treat RCC, their inability to durably suppress disease means that most individuals will require chronic therapy. As such, the benefits of treatment must be weighed against the overall burden of treatment, including toxicity, cost, and time. It may not be necessary to immediately start systemic treatment following diagnosis in all patients, particularly those with low-volume, slow-growing disease. There is evidence indicating that the benefit of treatment is still preserved when treatment is delayed. In the randomized phase II discontinuation trial of sorafenib, 28 patients who were initially assigned to the placebo arm initiated sorafenib at a median of 7 weeks after randomization when they experienced disease progression. 1 The median duration of progression-free survival in these individuals was 24 weeks, which was identical to the progression-free survival duration of patients initially assigned to the sorafenib arm from the outset. These findings suggest that asymptomatic patients may be able to delay the start of treatment without jeopardizing the ability to attain a clinical benefit from therapy. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol . 2006;24:2505-2512.
  • All of the targeted therapies have been compared with either placebo or interferon in clinical trials. Head-to-head comparisons of the targeted agents have yet to be conducted, making it somewhat difficult to answer the question as to which agent is best to use in metastatic RCC. At this point, comparing the pros and cons of each agent for a given patient is likely to be the best approach for selecting the appropriate therapy. 1 1. Rini BI, Bukowski RM. Targeted therapy for metastatic renal cell carcinoma: a home run or a work in progress? Oncology (Williston Park) . 2008;22:388-396.
  • Based on the results of phase III trials, a treatment algorithm has been designed that takes into consideration the efficacy of the different systemic therapies across various disease settings and patient populations. 1 Hutson TE, Figlin RA. Renal cell cancer. Cancer J . 2007;13:282-286.
  • This proposed treatment algorithm for targeted therapy is consistent with the National Comprehensive Cancer Network guidelines, 1 which advocate sunitinib, bevacizumab with or without interferon, or temsirolimus (for patients with poor prognosis) as first-line therapy in patients with clear-cell RCC. Sorafenib may also be considered for select patients. NCCN Clinical Practice Guidelines in Oncology 2007;v.1.2008.
  • 1. NCCN Clinical Practice Guidelines in Oncology 2007;v.1.2008.
  • For subsequent therapy, sorafenib or sunitinib are strongly recommended, and temsirolimus or bevacizumab may also be considered. NCCN Clinical Practice Guidelines in Oncology 2007;v.1.2008.
  • The use of sequential targeted agents has become the de facto treatment approach in metastatic disease, despite the lack of prospective clinical trials supporting this approach. There are many unresolved issues concerning the sequence of targeted agents to use. First, the ideal sequence of agents is unknown. Second, while all targeted agents have been shown to be active after cytokine therapy, it is unclear whether immunotherapy is active after targeted therapy. Third, it is unknown whether RCC tumor biology changes after exposure to a targeted agent and whether this affects the effectiveness of subsequent therapy. Fourth, the mechanisms of resistance to targeted agents remains to be elucidated, which may have implications for what agents may be used in the setting of resistance. Fifth, it is unknown whether adverse reactions to 1 targeted agent affect the tolerability of subsequent agents.
  • To summarize the information presented, there are several patient factors to consider when individualizing therapy for a given patient. These factors include the risk status of a patient; the molecular characteristics of a patient’s tumor, if available; whether first-line or a subsequent line of therapy is being selected; and the patient’s preference regarding when to start treatment, which clinical outcomes are most important to them, and which side effects they are and are not willing to tolerate.

Individualizing Therapy For Patients With Advanced Rcc Individualizing Therapy For Patients With Advanced Rcc Presentation Transcript

  • Individualizing Therapy for Patients With Advanced RCC Robert A. Figlin, MD Arthur and Rosalie Kaplan Chair in Oncology Professor and Chair, Medical Oncology and Therapeutics Research City of Hope National Medical Center and Beckman Research Institute Associate Director for Clinical Research City of Hope Comprehensive Cancer Center Duarte, California
  • Overview
  • RCC Statistics
    • US estimates for 2008 1
      • 54,390 individuals will be diagnosed with cancer of the kidney and renal pelvis
        • Median age at diagnosis: 65 years
      • 13.010 individuals will die from cancer of the kidney and renal pelvis
        • Median age at death: 71 years
    • Accounts for 3.5% of all cancers in the US 2
      • 3 rd most common genitourinary cancer after prostate cancer and bladder cancer
      • 7 th most common cancer in men
      • 9 th most common cancer in women
    1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008. 2. Jemal A et al. CA Cancer J Clin . 2008;58:71.
  • Stage Distribution National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008. 35.5% 5% Unknown 9.9% 20% Distant 61.3% 19% Regional 89.9% 56% Localized 5-Year Relative Survival Rate At Diagnosis Disease Distribution
  • Advanced RCC
    • 1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008.
    • 2. Janzen N et al. Urol Clin North Am . 2003;30:843.
    • 20-30% of patients present with metastatic disease 1
      • Another 25-50% of individuals treated for localized disease experience recurrence 2
    • Prognosis for patients with metastatic RCC is dismal, with a 5-year survival rate of 9.9% 1
      • Surgery not an option for cure
      • RCC resistant to radiotherapy and chemotherapy
      • Immunotherapy results in limited benefit with marked toxicity
    • Prompted need for rational therapeutic approaches based on disease biology
  • Biologic Basis of Renal Oncogenesis
  • Subtypes 1-3 1. Thoenes W et al. Path Res Pract . 1986;181:125. 2. Störkel S, van den Berg E. World J Urol . 1995;13:153. 3. Linehan WM et al. J Urol. 2003;170:2163. Very rare Collecting duct tumors (a.k.a. Bellini’s duct) BHD Uncommon (≤2%) Oncocytomas BHD 5 – 10% Chromophobic carcinomas c-Met , fumarate hydratase 10 – 15% Chromophilic (papillary) carcinomas VHL 75 – 85% Clear cell carcinoma Microscopic Features Genetic Defect Prevalence Subtype
  • VHL and RCC
    • VHL is a tumor suppressor gene located on chromosome 3p25
    • Loss of heterozygosity of VHL gene locus detected in ~85-95% of clear-cell RCCs 1,2
    • VHL genetic abnormalities present in 60-90% of patients with sporadic RCC 1,2
      • VHL mutated in 52-71% of patients with sporadic RCC
      • VHL silenced by hypermethylation in an additional 5-20%
    • Inactivation of VHL thought to be a very early event in clear-cell RCC tumorigenesis
    1. Shuin T et al. Cancer Res . 1994;54:2852. 2. Brauch H et al. Cancer Res . 2000;60:1942. 3. Yao M et al. J Natl Cancer Inst . 2002;94:1569. 4. Banks RE. Cancer Res . 2006;66:2000. VHL = von Hippel-Lindau
  • Normal VHL Function Stadler WM. Cancer . 2005;104:2323. O 2 VEC NEDD8 Degradation by proteasome
    • Hypoxia Response:
    • Angiogenesis
    • Glycolysis
    • Erythropoiesis
    • pH
    • Cell adhesion
    • ECM assembly
    Cul2 VHL Rbx1 Elongin B Elongin C OH HIF-1  OH x Ub
  • Mutant VHL Stadler WM. Cancer . 2005;104:2323. O 2 VEC NEDD8 Degradation by proteasome X X X Mutant VHL mimics conditions of hypoxia HIF-1  mRNA transcription Cul2 Mutant VHL Rbx1 Elongin B Elongin C HIF-1  HIF-1  VEGF PDGF TGF-  EGFR Ub
  • Pathways Activated by HIF-1  1,2 1. Stadler WM. Cancer . 2005;104:2323. 2. Vignot S et al. Ann Oncol . 2005;16:525. Endothelial/ Tumor cells Angiogenesis/Cell proliferation Angiogenesis Cell survival Upregulation in response to HIF-1 transcription PDGF VEGF EGF Ras RAF MEK Erk PLC RAC P38MAPK Cell migration PKC Cell proliferation Cell survival PI3K AKT/PKB SRC JAK STAT Cell survival
  • mTOR Pathway Seeliger H et al. Cancer Metastasis Rev . 2007;26:611. PI3K Growth factors = insulin, IGF, VEGF, IL-2 Protein synthesis Upregulation in response to HIF-1 transcription Growth Factor AKT mTOR S6K1 PTEN HIF-1  eIF-4E
  • Targeting the Molecular Pathways of RCC Oncogenesis Proposed CME slide Stadler WM. Cancer . 2005;104:2323. Angiogenesis/Cell proliferation/Cell survival bevacizumab gefitinib, cetuximab, erlotinib, panitimumab Gene expression rapamycin, temsirolimus, everolimus, AP23573 CI-1040 sorafenib, ISIS-5132 Endothelial/ Tumor cells Upregulation in response to HIF-1 transcription sorafenib, sunitinib, PTK/ZK PDGF VEGF EGF Ras RAF PI3K AKT MEK ERK mTOR
  • RCC Prognostic Factors and Risk Stratification
  • Rationale for RCC Staging
    • Predict tumor behavior
      • Patient prognosis
    • Stratify patients into risk categories
      • Predict disease recurrence and cancer-related death
    • Select treatment approach
      • Choose therapy based on molecular markers expressed by tumor
      • Predict response to therapy
      • Minimize treatment exposure to avoid unnecessary toxicity
    • Standardize inclusion criteria for clinical trials
    Leppert JT et al. BJU Int . 2007;99:1208.
  • Determinants of RCC Prognosis Shuch BM et al. Semin Oncol. 2006;33:563.
    • Tumor necrosis
    • Venous involvement
    • Thrombocytosis
    • Microvascular invasion
    • Metastasis
    • Cachexia-related symptoms
    • Morphology
    • Lymph node involvement
    • Performance status
    • Fuhrman grade
    • Tumor size
    Clinical Factors Histopathology Anatomic Extent of Disease
  • Integrated Prognostic Models
    • Various prognostic models developed that integrate information on anatomic staging, histopathology, and clinical parameters
    • Most widely used model is the validated UCLA integrated staging system (UISS) 1,2
      • Uses TNM classification scheme, Fuhrman grade, and ECOG performance status to classify patients into 5 prognostic categories that correlate with post-nephrectomy outcome
    1. Zisman A et al. J Clin Oncol . 2001;19:1649. 2. Patard JJ et al. J Clin Oncol . 2004;22:3316. TNM = tumor node metastasis ECOG = Eastern Cooperative Oncology Group
  • UISS and Survival Zisman A et al. J Clin Oncol . 2001;19:1649. RCC Prognosis Stratified by UISS Stage PS = performance status 0 ± 4.0% ≥ 1 4 IV V ≥ 1 1-3 IV 23 ± 3.1% 0 3, 4 IV IV 0 1, 2 IV 39 ± 2.8% ≥ 1 2-4 III III ≥ 1 1 III 0 Any III Any Any II Any 3, 4 I 67 ± 6.4% ≥ 1 1, 2 I II 94 ± 2.5% 0 1, 2 I I 5-Year Survival ECOG PS Fuhrman Grade TNM Stage UISS Stage
  • Biomolecular Prognostic Factors in RCC 1. Bui MH et al. Clin Cancer Res . 2003;9:802. 2. Patard JJ et al. Int J Cancer . 2008;123:395. 3. Bui MH et al. J Urol . 2004;171:2461. 4. Weiss RH et al. J Urol . 2007;177:63. 5. Shvarts O et al. J Urol . 2005;173:725. 6. Kim HL et al. J Urol . 2005;173:1496. 7. Bukowski RM et al. ASCO 2007; Abstract 5023. 8. Klatte T et al. Clin Cancer Res . 2007;13:7388. 9. Thompson RH et al. ASCO 2008; Abstract 5052. 10. Kim H et al. ASCO 2008; Abstract 16015. 11. Tanimoto S et al. J Med Invest . 2008;55:106. 12. Pantuck AJ et al. Cancer . 2007;109:2257. Poor survival Low PTEN 6,12 Poor survival High cytoplasmic levels Akt 12 Poor survival High Hepatocyte growth factor 11 Non-response, poor survival Low COX (cyclooxygenase)-2 10 Advanced tumor stage High B7x 9 Poor survival High HIF (hypoxia-inducible factor)-1  8 Shorter progression free survival (PFS) High serum levels VEGF 7 (vascular endothelial growth factor) Higher recurrence rate High P53 5,6 Poor survival High p21 (metastatic disease) 4 Poor survival High Ki67 3 Poor survival Low CAIX 1,2 Predicted Response to Treatment Expression Level Marker
  • CAIX Expression Bui MH et al. Clin Cancer Res . 2003;9:802. .033 1.32 (1.02-1.71) Nodal status .005 1.44 (1.12-1.87) Tumor stage .004 1.52 (1.15-2.01) Grade .003 1.62 (1.18-2.24) ECOG PS <.001 3.17 (2.07-4.86) Low CAIX staining P Value HR (95% CI) Factor
  • Predicting Response to Treatment Based on Molecular/Genetic Markers nsSNPs: nonsynonymous single nucleotide polymorphisms 1. Kim HL et al. J Urol . 2005;173:1496. 2. Patel PH et al. ASCO 2008. Abstract 5008. 3. Faber PW et al. ASCO 2008. Abstract 5009. 4. Jaeger E et al. ASCO 2008. Abstract 5043. 5. Choueiri TK et al. J Urol . 2008; [Epub ahead of print]. Good response to VEGF therapy VHL loss-of-function mutation 5 Non-response to interleukin-2 (IL-2) Loss of chromosomes 4, 9, or 17p 4 Significant sunitinib toxicity Various nsSNPs 3 Predicted Response to Treatment Genetic Marker Good response to sunitinib High HIF-1  /HIF-2  2 Good response to immunotherapy High COX-2 1 Good response to immunotherapy High CAIX 1 Predicted Response to Treatment Expression Level Molecular Marker
  • Poor-Risk Clinical Features of Advanced RCC * In liver, lungs, or retriperitoneal lymph nodes MSKCC = Memorial Sloan Kettering Cancer Center CCF = Cleveland Clinic Foundation 1. Motzer RJ et al. J Clin Oncol . 2004;22:454. 2. Mekhail TM et al. J Clin Oncol . 2005;23:832. Yes Presence of metastasis* Yes Prior radiotherapy <12 months Time from diagnosis to interferon (IFN)-  >1.5 x upper limit of normal Lactose dehydrogenase <80% Karnofsky performance status >10.0 mg/dL Corrected serum calcium ≥ 10.0 mg/dL Corrected serum calcium <lower limit of normal Hemoglobin ≤ 13.0 g/dL men, ≤ 11.5 g/dL women Hemoglobin CCF Criteria 2005 2 MSKCC Criteria 2004 1
  • Comparison of MSKCC 1 and CCF 2 Criteria 1. Motzer RJ et al. J Clin Oncol . 2004;22:454. 2. Mekhail TM et al. J Clin Oncol . 2005;23:832.
    • MSKCC risk groups
    • Favorable: 0 risk factors
    • Intermediate: 1 risk factor
    • Poor: 2-3 risk factors
    • CCF risk groups
    • Favorable: 0-1 risk factor
    • Intermediate: 2 risk factors
    • Poor: ≥3 risk factors
    OS = overall survival CCF Criteria MSKCC Criteria Median OS, mo Proportion, % Median OS, mo Proportion, % Risk Group 73 28 5.4 23 Poor 14.4 35 11.9 35 Intermediate 26 37 22 42 Favorable
  • Individualizing Therapy for Metastatic RCC
  • Rationale for Individualizing Therapy
    • RCC has a highly variable natural history with no available systemic cure
    • No one therapy predicted to be uniformly active in all patient populations
    • Individualizing therapy offers patients the best chance of disease control balanced with the best possible quality of life
  • Issues to Consider
    • Overall goals of treatment for metastatic RCC
      • Delay life-threatening burden of disease
      • Optimize chance of long-term disease control
      • Maximize quality of life and patient convenience
    • Weigh benefits vs risks to identify optimal therapeutic for a given patient
    • Most patients will likely receive a sequence of several agents to help control disease
    • Development of targeted agents has outpaced an understanding of their optimal use
      • Broad approval ≠ broad activity
  • Clinically Available Targeted Agents for Advanced RCC 1. Escudier B et al. Lancet . 2007;370:2103. 2. Rini BI et al. 2008 ASCO Genitourinary Cancers Symposium. Abstract 350. 3. Motzer RJ et al. N Engl J Med . 2007;356:115. 4. Escudier B et al. N Engl J Med. 2007;356:125. 5. Hudes G et al. N Engl J Med . 2007;356:2271. ORR = overall response rate TTP = time to progression 8.5 vs 5.2; P < .0001 26% vs 13% 732 Bevacizumab + IFN-  vs IFN-  2 3.7 vs 1.9 (IFN-  ); P = .001 9% vs 7% vs 11% 626 Temsirolimus vs IFN-  vs both agents 5 mTOR Temsirolimus 5.5 vs 2.8; P = .000001 10% vs 2% 903 Sorafenib vs PBO 4 VEGF receptor Sorafenib 11.1 vs 5; P = .00001 37% vs 9% 750 Sunitinib vs IFN-  3 VEGF receptor Sunitinib 10.2 vs 5.4; P = .0001 31% vs 13% 649 Bevacizumab + IFN-  vs placebo (PBO) + IFN-  1 VEGF Bevacizumab TTP (mos) ORR No. Treated Comparison Efficacy in Randomized Phase III Trials Target Agent
  • When Should Systemic Therapy Be Started?
    • Immediately start treatment or delay therapy to offset treatment burden?
    • Evidence suggests that treatment benefit may be preserved even if treatment initiation is delayed in asymptomatic patients
      • Randomized phase II discontinuation trial of sorafenib vs placebo
      • 28 patients initially randomized to placebo arm subsequently received sorafenib upon disease progression at a median of 7 weeks
      • Median PFS = 24 weeks
        • PFS identical to that of patients in original sorafenib arm
    Ratain MJ et al. J Clin Oncol . 2006;24:2505.
  • Which Agent Is Best? Rini BI, Bukowski RM. Oncology (Williston Park) . 2008;22:388.
    • Only active in a subset of patients
    • Considerable toxicity
    • Requires infusion
    • Higher ORR in patients with high CAIX expression – requires clinical trial confirmation
    High-dose IL-2
    • Less efficacy in front-line setting
    • Active in cytokine-refractory disease
    • Oral dosing
    • Favorable toxicity profile
    Sorafenib
    • Requires infusion
    • Often requires combination therapy with IFN- 
    • Favorable toxicity profile
    Bevacizumab
    • Activity appears to be restricted to patients with poor-risk disease
    • Requires infusion
    • Survival advantage
    • Active in patients with poor-risk disease
    Temsirolimus
    • Long-term disease control may not be robust
    • Highest ORR
    • Oral dosing
    • Survival advantage
    Sunitinib Cons Pros Agent
  • Which Agent Is Best? Hutson TE, Figlin RA. Cancer J . 2007;13:282.
      • Everolimus
      • Prior VEGF therapy
      • Sorafenib, Sunitinib
      • Prior cytokine therapy
    Second-line therapy
      • Temsirolimus
      • Poor risk
      • Sunitinib
      • Bevacizumab ± IFN- 
      • High-dose IL-2
      • Low + intermediate risk
    First-line therapy Therapy Setting
  • NCCN Practice Guidelines in Oncology: Kidney Cancer Relapse or Stage IV and medically or surgically unresectable Predominant clear cell histology Clinical trial or Sunitinib (category 1) or Temsirolimus for poor-prognosis patients * (category 1) or Bevacizumab + IFN or High-dose IL-2 for selected patients or Sorafenib for selected patients and Best supportive care  FIRST-LINE THERAPY * Temsirolimus indicated for poor-prognosis patients, defined as those with ≥3 predictors of short survival  Best supportive care can include palliative radiation therapy (RT), metastasectomy or biphosphonates for bony metastasis NCCN Clinical Practice Guidelines in Oncology. 2007;v.1.2008.
  • NCCN Practice Guidelines in Oncology: Kidney Cancer Relapse or Stage IV and medically or surgically unresectable Clinical trial (preferred) or Temsirolimus * (category 1 for poor-prognosis, category 2A for other risk groups) or Sorafenib or Sunitinib or Chemotherapy (category 3): gemcitabine or capecitabine or floxuridine or 5-FU or doxorubicin (in sarcomatoid only) and Best supportive care  FIRST-LINE THERAPY (cont.) Non clear cell histology * Temsirolimus indicated for poor-prognosis patients, defined as those with ≥3 predictors of short survival  Best supportive care can include palliative RT, metastasectomy or biphosphonates for bony metastasis NCCN Clinical Practice Guidelines in Oncology. 2007;v.1.2008.
  • NCCN Practice Guidelines in Oncology: Kidney Cancer Clinical trial (preferred) or Sorafenib (category 1 following cytokine therapy and category 2A following TKI) or Sunitinib (category 1 following cytokine therapy and category 2A following TKI) or Temsirolimus (category 2A following cytokine therapy and category 2B following TKI) or IFN (category 2B) or High dose IL-2 (category 2B) or Low dose IL-2 + IFN (category 2B) or Bevacizumab and Best supportive care* SUBSEQUENT THERAPY (use crossover regimen) Progression * Best supportive care can include palliative RT, metastasectomy or biphosphonates for bony metastasis NCCN Clinical Practice Guidelines in Oncology. 2007;v.1.2008.
  • Does the Sequence of Agents Matter?
    • Use of sequential targeted agents has become the de facto treatment approach in metastatic disease
      • Ideal sequence of agents unknown
    • Many unresolved issues
      • Is immunotherapy active after targeted therapy?
      • Does the biology of a tumor change after exposure to an agent?
      • Does this affect the effectiveness of subsequent therapy?
      • What are the mechanisms of drug resistance?
      • Does the toxicity profile of 1 agent affect the tolerability of subsequent agents?
  • Factors to Consider When Individualizing Therapy
    • Risk status
      • Extent of disease
      • Histopathology
      • Clinical factors
    • Tumor molecular characteristics
    • First-line, second-line, subsequent lines of therapy
    • Patient preference
      • Regarding start of treatment
      • Desired clinical outcomes
      • Acceptable/unacceptable toxicities
  • Summary
    • Accurately predicting patient outcomes is important for individualizing therapy
      • Enables patients to be informed about their prognosis
      • Enables educated decision-making regarding treatment
    • RCC staging will evolve as factors defining patient prognosis are better understood
    • Patient prognosis will become more accurate as molecular marker information is incorporated into staging systems
    • Additional molecular marker research needed to better facilitate individualized therapy selection
      • Current goal of individualized therapy is to maximize treatment effectiveness and minimize toxicity