understanding renal cell carcinoma

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  • 1. Understanding Renal Cell CarcinomaRonald M. Bukowski, MD Emeritus Staff, Consultant Cleveland Clinic Taussig Cancer Center Cleveland, Ohio

2. Overview 3. RCC Statistics

  • US estimates for 2007 1
    • 51,190 individuals diagnosed with cancer of the kidney and renal pelvis
    • 12,890 individuals died from cancer of the kidney and renal pelvis
  • 3 rdmost common genitourinary cancer after prostate cancer and bladder cancer 2
  • Median age at diagnosis: 65 years (2000-2004) 1
  • Median age at death: 71 years (2000-2004) 1
  • An estimated 240,266 US individuals with a history of kidney and renal pelvis cancer were alive in 2004 1
  • 5-year survival has improved 3
    • 50.9% in 1975-1977; 65.7% in 1996-2003

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 . 2007;57:43.3. Ries LAG et al. SEER Cancer Statistics Review, 1975-2004;2007. 4. US Yearly Kidney and Renal Pelvis Cancer Incidence and Mortality

  • Ries LAG et al. SEER Cancer Statistics Review, 1975-2004;2007.

5. US Kidney and Renal Pelvis Cancerin Comparison With Other Cancers

  • 1. Jemal A et al.CA Cancer J Clin . 2007;57:43.
  • Accounts for 3.5% of all cancers in the US 1
    • 7th most common cancer in men 9th most common cancer in women

NHL = non-Hodgkins lymphoma 100 678,060 All sites 100 766,860 All sites 3 19,440 Leukemia 2 18,830 Pancreas 3 19,600 Kidney & renal pelvis 3 24,180 Oral cavity & pharynx 3 22,430 Ovary 3 24,800 Leukemia 4 25,480 Thyroid 4 31,590 Kidney & renal pelvis 4 26,030 Melanoma4 33,910 Melanoma 4 28,990 NHL 4 34,200 NHL 6 39,080 Uterine corpus 7 50,040 Urinary bladder 11 74,630 Colon & rectum 10 79,130 Colon & rectum 15 98,620 Lung & bronchus 15 114,760 Lung & Bronchus 26 178,480 Breast 29 218,890 Prostate % of all New Cases Cancers in Women % of all New Cases Cancers in Men 6. Historical Overview of Treatment 7. Surgery for Localized RCC

  • Nephrectomy
    • Radical: entire kidney removed
    • Partial: only the cancerous portion of the kidney removed along with a margin of healthy tissue
  • Potentially curative for patients with early-stage disease (ie, stage I, II, or III)
    • Ongoing surveillance in these individuals is critical, as 25-50% will develop disease recurrence 1
  • May be used for palliation or in combination with other treatment modalities in metastatic disease

1. Janzen N et al.Urol Clin North Am . 2003;30:843. 8. Advanced RCC

  • 20-30% of patients present with metastatic disease 1
    • Another 25-50% of individuals treated for localized disease experience recurrence 2
  • Additional treatment options aside from surgery
    • Radiotherapy
      • Not an effective option
    • Chemotherapy
      • Not an effective option
    • Immunotherapy
      • Limited/some benefit
    • Targeted therapy
      • Clinical benefit; active area of research and further refinement

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. 9. Radiotherapy

  • RCC characterized as radioresistant
    • No effect on survival when administered pre- or postsurgery

1. Finney R.Br J Urol . 1973;45:258.2. Juusela H et al.Scand J Urol Nephrol. 1977; 11:277 . 3. Stein M et al.Radiother Oncol . 1992;24:41. 4. Janzen N et al.Urol Clin North Am . 2003;30:843.

  • Radiotherapy may have some benefit for 1
    • Painful bone metastases
    • Brain metastases
    • Painful recurrences in renal bed

* Radiotherapy administered postsurgery in Finney & Stein studies; administered presurgery in Juusela study 55% 40% 147 Stein et al. 1992 3 47% 63% 88 Juusela et al. 1977 2 36% 44% 100 Finney 1973 1 Surgery + Radiotherapy Surgery 5-Year Survival Number of Patients Study 10. Chemotherapy

  • RCC has intrinsic resistance to conventional chemotherapy
    • Literature review of 33 chemotherapy agents tested in 1347 patients in 51 phase II trials found no justification for using any drugs as single agents based on poor response rates 1
      • 23 trials reported response rates of 0%
      • 38 trials reported response rates 6%
    • Chemotherapy ineffective even when multidrug resistance modifiers (eg, cyclosporine A, tamoxifen) are used to try and sensitize tumors to therapy 1
      • Response rates 11% seen in all 15 trials assessing this approach
  • As such, chemotherapy is rarely used in RCC

1. Motzer RJ, Russo P.J Urol.2000;163:408. 11. Immunotherapy

  • RCC considered to be an immunogenic disease
    • Spontaneous regression of metastatic lesions observed 1
    • Prolonged stabilization of disease without systemic treatment is seen 2,3
    • Tumor-infiltrating lymphocytes present at site of lesions 4-6
    • Durable responses can be elicited with cytokine therapy 7
  • As such, immunotherapy has long been the principal treatment modality for managing advanced RCC 8

1. de Reise W et al.Int Urol Nephrol . 1991;23:13. 2. Motzer RJ et al.N Engl J Med . 1996;335:865.3. Whang, YE, Godley PACurr Opin Oncol . 2003;15:213. 4. Schoof DD et al.Cell Immunol . 1993;150:114. 5. Kowalczyk D et al.Br J Urol . 1997;80:543. 6. van den Hove LE et al.Clin Ex Immunol.1997;109:501. 7. Coppin C et al.Cochrane Database Syst Rev . 2005;(1):CD001425. 8. Bukowski RM.Oncology . 1999;13:801. 12. Immunotherapy

  • 2 immunotherapies used, either alone or in combination
    • Recombinant human interleukin-2 (IL-2)
    • Recombinant human interferon -2b (IFN- )
  • IL-2
    • Stimulates growth of immune cells and activates them to destroy tumor cells
    • Common sides effects: flu-like symptoms, nausea, diarrhea, hypotension, decreased urine production
  • IFN-
    • Increases antigen presentation on the surface of cancer cells, thereby increasing their susceptibility to attack by the immune system
    • Common side effects: flu-like symptoms, nausea, fatigue, depression

13. Immunotherapy

  • IL-2 and IFN- have limited benefit in RCC
    • Meta-analysis of 58 randomized trials of immunotherapy conducted in 6880 patients with advanced RCC 1
      • ORR of immunotherapy vs active controls: 12.4% vs 2.4%
      • Mean OS with immunotherapy vs active controls: 13 vs 9.5 months
      • Efficacy of IFN- vs controls: mean increase in OS of 3.8 months, 44% reduction in 1-year mortality, 26% reduction in 2-year mortality
      • Efficacy of high-dose IL-2 vs controls: RR as high as 23% observed, but this conferred no improvement in OS
  • Toxicity of these agents often outweighs the potential benefits

1. Coppin C et al.Cochrane Database Syst Rev . 2005;(1):CD001425. OS = overall survival RR = response rate 14. Unmet Treatment Needs

  • Prognosis for patients with metastatic RCC is dismal, with a 5-year survival rate of 9.5% 1
    • Surgery is generally not an option for cure
    • RCC resistant to radiotherapy and chemotherapy
    • Immunotherapy results in limited benefit with marked toxicity
  • Significant unmet treatment needs for patients with advanced RCC prompted research into biologic basis of renal oncogenesis to guide rational therapeutic approaches

1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008. 15. Biologic Basis of Renal Oncogenesis 16. Angiogenesis

  • Angiogenesis is a key determinant in the pathophysiology of RCC 1
  • RCCs are the most vascularized of all solid tumors 2

1. Izawa JI, Dinney CP.CMAJ . 2001;164:662. 2. Cristofanilli M et al.Nat Rev Drug Discov . 2002;1:415. Map of Blood Flow to a Metastatic RCC Lesion 17. Growth Factors

  • Vascular endothelial growth factor (VEGF) is a key growth factor involved in angiogenesis 1,2
    • VEGF mRNA expression correlates with vascularizatio