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Renal Cell Carcinoma Diagnosis And Management

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Renal Cell Carcinoma Diagnosis And Management

  1. 1. Renal Cell Carcinoma Diagnosis & Management Raúl H. Morales - Borges, MD, FICPS, FIACATH Chairman of the Board of Trustees and Lecturer of Pathology, Immunology & Genetics San Juan Bautista School of Medicine Medical Director of The Ashford Institute of Hematology & Oncology Attending Physician and Consultant Ashford Presbyterian Community Hospital
  2. 2. Disclosures <ul><li>Investments: None </li></ul><ul><li>Speaker Bureau: </li></ul><ul><ul><li>Pfizer Caribbean </li></ul></ul><ul><ul><li>Sanofi Aventis </li></ul></ul><ul><ul><li>Astra Zeneca </li></ul></ul><ul><li>Consultant: </li></ul><ul><ul><li>Astra Zeneca Glaxo SmithKline </li></ul></ul><ul><ul><li>Sanofi Aventis Merck </li></ul></ul>
  3. 3. TOPICS TO BE DISCUSSED <ul><li>Overview: Epidemiology, Pathology, and Pathogenesis of Rena Cell Carcinoma (RCC) </li></ul><ul><li>Clinical manifestations, evaluation, and staging of RCC </li></ul><ul><li>Prognosis and Treatment of RCC </li></ul><ul><li>Targeted therapies for RCC </li></ul>
  4. 4. INTRODUCTION <ul><li>Renal cell carcinoma (RCC) has increased its incidence at a rate of 2% per year on the last 65 years as well as its mortality on the last 2 decades. </li></ul><ul><li>Partial Surgery is the new option for localized tumors. 20% to 40% of the operated tumors will develop metastases in a future and will require additional therapy. </li></ul><ul><li>RCC are resistant to chemotherapy and radiotherapy. Hormones doesn’t work too. </li></ul><ul><li>New target therapy agents are available with great responses & survival benefits. </li></ul>
  5. 5. Overview of RCC Epidemiology Pathology Pathogenesis
  6. 6. Epidemiology <ul><li>RCC is the responsible of 2% - 3% of all malignancies in the adults. </li></ul><ul><li>The incidence peak age is: 60 – 80 years old. </li></ul><ul><li>Men : Women ratio of 2:1 </li></ul><ul><li>Incidence & Mortality are rising in African Americans. </li></ul><ul><li>51190 new cases & 12890 deaths on 2007 with 54390 cases and 13010 deaths on 2008 in USA. </li></ul><ul><li>5-year survival rate of 65% by 1995-2000. . </li></ul>
  7. 7. <ul><li>RCC affects more than 150,000 people annually worldwide, resulting in 78,000 deaths each year. </li></ul><ul><li>An individual with positive family history of RCC have a 2.5-fold greater chance for developing renal cancer during their life time. </li></ul><ul><li>Patients with a family history comprise about 4% of all cases of RCC. </li></ul>
  8. 8. Pathology Clear cell (non-papillary) carcinoma is the most common.
  9. 12. Pathogenesis A number of environmental, hormonal, cellular, and genetic factors have been studied as possible causes of RCC.
  10. 13. Etiology <ul><li>Tobacco </li></ul><ul><li>Obesity </li></ul><ul><li>Chronic arterial hypertension </li></ul><ul><li>Diabetes mellitus </li></ul><ul><li>End-Stage Renal Disease on hemodialysis </li></ul><ul><li>High fat, high protein diet, fried food, red meat </li></ul><ul><li>Use of phenacetin chronically as analgesics </li></ul><ul><li>Amphetamines </li></ul><ul><li>Petroleum products </li></ul><ul><li>Cadmiun </li></ul><ul><li>Asbestos </li></ul><ul><li>Aromatic hydrocarbons </li></ul>
  11. 14. <ul><li>Smoking: 30% in men, 24% in women. </li></ul><ul><li>Obesity: Increased BMI is related with RCC, but more favorable prognosis. </li></ul>
  12. 16. Familiar type RCC & von Hippel Lindau <ul><li>Suppressor gene in the short arm of chromosome 3 as autosomic dominant. </li></ul><ul><li>1 in 30,000 births. </li></ul><ul><li>Age of early symptoms: 26.3 years old. </li></ul><ul><li>Penetrance age of 60 years old. </li></ul><ul><li>RCC: bilateral low staging. </li></ul><ul><li>Associated features: retinal angiomas, cerebelar & spinal cord hemagioblastomas, cysts and/or angiomas of solid organs, pheochromocytomas. </li></ul>
  13. 20. Birt-Hogg-Dubé Syndrome <ul><li>Rare autosomal dominant </li></ul><ul><li>Gene located at the short arm of the chromosome 17 </li></ul><ul><li>Chromophobe RCC with low metastatic potential </li></ul><ul><li>Fibrofolliculomas trichodiscomas (benign hamartomas of the hair follicule), pulmonary cysts, spontaneous pneumothorax </li></ul>
  14. 22. Clinical Manifestations Evaluation and Staging Of RCC
  15. 23. Clinical Presentation <ul><li>Small tumors as incidental findings </li></ul><ul><li>Hematuria </li></ul><ul><li>Abdominal pain </li></ul><ul><li>Palpable abdominal mass </li></ul><ul><li>Paraneoplastic syndrome: </li></ul><ul><ul><li>Bone pain </li></ul></ul><ul><ul><li>Hypercalcemia </li></ul></ul><ul><ul><li>Fever </li></ul></ul><ul><ul><li>Weight loss </li></ul></ul><ul><ul><li>Polycythemia </li></ul></ul><ul><ul><li>Neuromyopathy </li></ul></ul><ul><ul><li>Amyloidosis </li></ul></ul>
  16. 25. <ul><li>30% presented with metastatic disease, 25% with locally advanced disease, and 45% with localized disease. </li></ul><ul><li>75% of metastatic disease presents with pulmonary lesions, 36% to soft tissues, 20% to the bones, 18% to the liver, 8% to the skin, and 8% to the CNS. </li></ul>
  17. 26. Diagnostic tests <ul><li>History & Physical Exam </li></ul><ul><li>Laboratory: CBC, CMP, LDH, ESR, U/A </li></ul><ul><li>CXR, Abdomino-pelvic CT Scan </li></ul><ul><li>MRI if IVC thrombosis suspected </li></ul><ul><li>Bone scan if bone metastases suspected </li></ul><ul><li>PET/CT is controversial </li></ul>
  18. 33. Prognosis and Treatment of RCC
  19. 34. Prognostic factors <ul><li>Symptomatic presentation </li></ul><ul><li>Weight loss </li></ul><ul><li>Poor performance status </li></ul><ul><li>ESR > 30 mm/hr </li></ul><ul><li>Anemia </li></ul><ul><li>Elevated alkaline phosphatase </li></ul><ul><li>Tumor size, positive margins, liver & lung metastases, Sarcomatoid tumors </li></ul>
  20. 38. Surgery in RCC <ul><li>We are moving from Radical nephrectomy to partial nephrectomy using laparoscopy. </li></ul><ul><li>We can minimize positive margins in partial nephrectomy using: </li></ul><ul><ul><li>Intraoperative sonography </li></ul></ul><ul><ul><li>Use of cold scissors for parenchymal transection </li></ul></ul><ul><ul><li>Hilum control to avoid vascular leak (bleeding). </li></ul></ul>
  21. 39. <ul><li>The first nephrectomy was performed on June 4 th of 1861. Since then, there have been significant advances in surgical techniques. </li></ul><ul><li>The most common procedure today for treatment of localized renal carcinoma > 4 cm is radical nephrectomy. </li></ul><ul><li>Laparoscopic nephrectomy has become the standard of care for management of most renal tumors not amenable to nephron-sparing surgery. </li></ul>
  22. 40. <ul><li>At present, lymphadenectomy is a safe adjunct to radical nephrectomy and is primarily used for staging. </li></ul><ul><li>Cytoreductive nephrectomy in metastatic RCC is controversial, but depends on the selection of the patient due to insignificant benefit and short term survival. </li></ul>
  23. 41. Angioinfarction <ul><li>Embolization of the renal artery: only for palliation. No definitive benefit. </li></ul>
  24. 42. Chemotherapy <ul><li>NO ROLE !!!!! </li></ul><ul><li>Combination of Vinblatine + Toremifene/ Verapamil/ Nifedipime/ Cyclosporin ????? Due to inhibition of p-glycoprotein which is the responsible for chemo-resistance. </li></ul>
  25. 43. <ul><li>4% SPONTANEOUS REGRESSION RATE. </li></ul><ul><li>IL-2 & IFN-alpha 2a and 2b alone or in combinations: poor response rates. </li></ul><ul><li>TIL’s, LAK cells, and Dendritic cell therapies: very complex and expensive with low response rates. </li></ul>IMMUNOTHERAPY
  26. 44. Targeted Therapies for RCC
  27. 45. New Class of Agents Used in RCC: Tyrosine Kinase Inhibitors (TKI’s) <ul><li>Sorafenib : Approved by FDA in Dec. 2005 </li></ul><ul><li>Sunitinib : Approved by FDA in Jan. 2006 </li></ul><ul><li>Temsirolimus : Approved in May 2007 </li></ul>
  28. 49. Long-term toxicity of TKI’s <ul><li>HYPOTHYROIDISM </li></ul><ul><li>MYELOSUPPRESSION </li></ul><ul><li>FATIGUE </li></ul><ul><li>B.k Vakkalanka et al: Abstract 16045; ASCO 2008 </li></ul>
  29. 50. Adjuvant Therapy
  30. 51. Adjuvant Therapy: Rationale <ul><li>Patients with recurrent disease following nephrectomy have micrometastatic disease at the time of surgery </li></ul><ul><li>There is a 35%-65% recurrence rate* with locally aggressive tumors </li></ul><ul><li>Use of effective therapy may reduce the risk of relapse </li></ul>Lam JS, et al. BJU Int. 2005;96:483-488. * Depending on pathologic stage.
  31. 52. Adjuvant Therapy <ul><li>To date, all adjuvant therapy trials have failed to demonstrate DFS or OS advantage </li></ul><ul><ul><li>High-dose (HD) IL-2 </li></ul></ul><ul><ul><li>Interferon </li></ul></ul><ul><ul><li>Autologous tumor cells + BCG vaccine </li></ul></ul><ul><ul><li>Vitespen (HSPPC-96) vaccine </li></ul></ul><ul><li>Given the risk/benefit profile, no adjuvant treatment is appropriate outside clinical trial </li></ul><ul><li>VHL mutation (and thus VEGF production) is an early oncogenic event in RCC </li></ul><ul><ul><li>Radiation therapy </li></ul></ul><ul><ul><li>Megestrol acetate </li></ul></ul>
  32. 53. ASSURE Trial (Intergroup Sponsored by ECOG) <ul><li>Eligibility: nonmetastatic kidney cancer </li></ul><ul><ul><li>Disease  T1b N any (resectable) M0 by radiologic criteria </li></ul></ul><ul><li>Primary endpoint: DFS </li></ul>Nephrectomy Patients with nonmetastatic kidney cancer Disease stage II-IV (N = 1332) Stratification by UISS stage (II-V) and histologic subtype (clear cell or nonclear cell) Sunitinib 50 mg daily for 4 of 6 wks Sorafenib 800 mg daily continuously Placebo daily continuously Available through www.CTSU.org 1 year
  33. 54. SORCE (MRC Adjuvant trial) <ul><li>Eligibility </li></ul><ul><ul><li>No evidence of residual disease after RCC resection </li></ul></ul><ul><ul><li>Leibovich prognostic score 3-8 (high or intermediate risk of metastatic RCC or death) postsurgery </li></ul></ul><ul><ul><li>≥ 4 weeks and ≤ 4 months since surgery </li></ul></ul><ul><li>Endpoints </li></ul><ul><ul><li>Primary: metastasis-free survival </li></ul></ul><ul><ul><li>Secondary: DFS, toxicity, genomics </li></ul></ul>Patients with high- and intermediate-risk resected RCC (Planned N = 1420) Placebo 3 years Sorafenib Sorafenib Placebo 1 year
  34. 55. ARISER Study <ul><li>Eligibility </li></ul><ul><ul><li>Clear-cell RCC, no metastasis, ECOG status 0 </li></ul></ul><ul><ul><li>RCC patients at high-risk of recurrence* </li></ul></ul><ul><li>Primary endpoints: DFS, OS </li></ul>cG250 (WX-G250) IV over 15 minutes once weekly Placebo IV over 15 minutes once weekly Patients with clear-cell nonmetastatic RCC (N = 600+) * T3b/T3c/T4 N0/XM0; All T stages N+M0; T1b/T2 N0/XM0 with G ≥ 3 and MVI or T3a N0/XM0 with G ≥ 3 Nephrectomy 24 weeks
  35. 56. Neoadjuvant Trials <ul><li>Phase II </li></ul><ul><ul><li>Neoadjuvant sunitinib: Cleveland Clinic Foundation </li></ul></ul><ul><ul><ul><li>For patients with “unresectable” primary renal tumors (with or without metastases) </li></ul></ul></ul><ul><ul><li>Neoadjuvant RAD-001 (mTOR inhibitor): UCLA </li></ul></ul>
  36. 57. Metastatic RCC: Frontline/Monotherapy
  37. 58. CALGB 90206: Interferon alfa-2b ± Bevacizumab in Advanced RCC <ul><li>Endpoints </li></ul><ul><ul><li>Primary: OS </li></ul></ul><ul><ul><li>Secondary: TTP, ORR, toxicity </li></ul></ul><ul><li>Follow-up </li></ul><ul><ul><li>Every 3 months for 2 years </li></ul></ul><ul><ul><li>Annual thereafter (up to 10 years from study entry) </li></ul></ul>Interferon alfa-2b 9 MU SC 3 times weekly (n = 350) Interferon alfa-2b 9 MU SC 3 times weekly + Bevacizumab 10 mg/kg IV Days 1 and 15, every 28 days (n = 350) Patients with untreated, metastatic or unresectable clear-cell RCC (N = 700) Stratified for nephrectomy status and MSKCC risk group
  38. 59. <ul><li>Primary endpoint </li></ul><ul><ul><li>OS (improvement from 13-17 months) </li></ul></ul>European Phase III Trial of IFN/Bevacizumab in RCC (BO17705) Patients with metastatic clear cell RCC, status post nephrectomy (N = 638) Interferon alfa-2a 9 MU 3 times weekly for up to 52 weeks + Placebo every 2 weeks until disease progression Interferon alfa-2a 9 MU 3 times weekly for up to 52 weeks + Bevacizumab 10 mg/kg every 2 weeks until disease progression
  39. 60. <ul><li>Randomized, open-label, multicenter trial </li></ul><ul><ul><li>100 Sites (US, Canada, Europe, Australia, Brazil) </li></ul></ul>Phase III Trial of Sunitinib vs Interferon alfa in Metastatic RCC Patients with metastatic clear cell RCC (N = 690) Sunitinib orally administered daily (4 of every 6 weeks) (n = 345) Interferon alfa administered 3 times weekly (n = 345) <ul><li>Endpoints </li></ul><ul><ul><li>Primary: PFS </li></ul></ul><ul><ul><li>Secondary: TTP, OS, RR, QoL, safety, cost-effectiveness </li></ul></ul>
  40. 61. <ul><li>Phase II trial </li></ul><ul><li>111 patients </li></ul><ul><li>RR: 7% </li></ul><ul><li>TTP: 5.8 months </li></ul><ul><li>OS: 15 months </li></ul><ul><li>Toxicity: rash, fatigue, mucositis, nausea </li></ul>CCI-779: mTOR inhibitor ASK1 Cap-dependent translation 0 2 Schematic from Bjornsti and Houghton Nat Rev Cancer 4L335-348 (2004) Atkins J, et al. J Clin Oncol. 2004;22:909-918. ATP Amino acids Protein stability Phosphatidic acid TOR Mitochondria Transcription-factor translocation Apoptosis S6K1 Translation ribosomal proteins eIF4E Ribosome biogenesis Nutritional-stress response Growth/survival factors Nucleus 4E-BP1 Plasma membrane Cytoplasm
  41. 62. <ul><li>International phase III randomized trial </li></ul><ul><li>Endpoints </li></ul><ul><ul><li>Primary: OS </li></ul></ul><ul><ul><li>Secondary: Safety, PFS, RR, health outcomes </li></ul></ul>Temsirolimus (CCI-779) + Interferon alfa in Advanced RCC 1. Motzer RJ, et al. J Clin Oncol. 2002;20:289-296. CCI-779 IV 25 mg weekly CCI-779 15 mg IV weekly + Interferon alfa 6 MU SC TIW Interferon alfa SC up to 18 MU TIW as tolerated Patients with previously untreated advanced RCC Poor risk criteria [1] (Planned N = 600)
  42. 63. CA IX and Response to Interleukin-2 (IL-2) Therapy in RCC * Including all CRs. Bui MH, et al. Clin Cancer Res. 2003;9:802-811. Atkins M, et al. Clin Cancer Res. 2005;11:3714-3721. 51 80 Nonresponders with high CA IX 78 91 Responders with high CA IX 24 14 Response in low CA IX 51 27* Response in high CA IX 62 77 No of metastatic pts with > 85% CA IX Boston, % (N = 66) UCLA, % (N = 83) Outcome
  43. 64. HD IL-2 “Select” Trial: Study Design rIL-2 600,000 IU/kg q8h by 15-min infusion rIL-2 600,000 or q8h by 15-min infusion Rest 9 days 5 days 5 days <ul><li>Eligibility </li></ul><ul><ul><li>Measurable metastatic RCC; all histologic subtypes </li></ul></ul><ul><ul><li>Consented to provide tumor blocks </li></ul></ul><ul><ul><li>No prior systemic therapy </li></ul></ul><ul><ul><li>Candidate for HD IL-2 </li></ul></ul><ul><ul><li>ECOG PS 0-1 and good organ function </li></ul></ul>Maximum 3 courses per patient. Responses independently audited.
  44. 65. Metastatic RCC: Determining Clinical Cross-Resistance to VEGF-Targeted Agents
  45. 66. Approach to Tyrosine Kinase Inhibitor (TKI) – Resistant Disease KDR HIF VEGF mTOR inhibitor (temsirolimus, CCI-779) Bevacizumab Sorafenib, sunitinib, AG13736 O 2 <ul><li>Hypothesis </li></ul><ul><ul><li>Resistance to 1 TKI will be mediated by pathways sensitive to inhibition by another TKI </li></ul></ul><ul><ul><li>Varying response rates and toxicity profiles suggest some differences between TKIs </li></ul></ul>
  46. 67. <ul><li>Sunitinib in bevacizumab-refractory RCC </li></ul><ul><ul><li>VEGF-R (and other targets like PDGF) after VEGF ligand inhibition </li></ul></ul><ul><ul><li>ASCO 2006: definite activity, data to be presented </li></ul></ul><ul><ul><li>Sorafenib in sunitinib or bevacizumab-refractory RCC </li></ul></ul><ul><ul><ul><li>Multitargeted agent, plus Raf kinase inhibition </li></ul></ul></ul><ul><li>AG013736 in sorafenib-refractory RCC </li></ul><ul><ul><li>More potent VEGFR inhibition </li></ul></ul><ul><li>All 3 are standard clinical trials </li></ul><ul><ul><li>No insights into mechanisms of resistance, etc, are possible </li></ul></ul>A  B Trials
  47. 68. 6-Arm Randomized Phase II Trial (E9805): Sunitinib Failures Patients failing sunitinib Sunitinib daily Arm A Arm B Sunitinib + Bevacizumab Arm C Change to Sorafenib
  48. 69. 6-Arm Randomized Phase II Trial (E9805): Sorafenib Failures Patients failing sorafenib Increase Sorafenib dose Sorafenib + Bevacizumab Arm D Arm E Arm F Change to Sunitinib Arm D Arm D Arm E
  49. 70. Metastatic RCC: Combinations
  50. 71. Phase I and II Combination Studies <ul><li>Sorafenib + bevacizumab </li></ul><ul><li>Sunitinib + bevacizumab </li></ul><ul><li>CCI-779 + bevacizumab </li></ul><ul><li>CCI-779 + sorafenib </li></ul><ul><li>AMG386 (anti-Ang2/Tie2) + bevacizumab, TKI </li></ul><ul><li>HD IL-2 + bevacizumab (Phase II CWG study) </li></ul>
  51. 72. ECOG “BEST” Trial Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15) Patients with advanced RCC (N = 360*) Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15) Sorafenib 400 mg PO twice daily *Accrual goal. † Arm to be added when phase II doses are available from ongoing phase I trials. Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15) and Temsirolimus 25 mg IV weekly (Days 1, 8, 15 and 22) Sorafenib PO twice daily and Temsirolimus IV weekly (Days 1, 8, 15 and 22) † <ul><li>Randomized phase II study </li></ul><ul><li>Endpoints </li></ul><ul><ul><li>Primary: PFS </li></ul></ul><ul><ul><li>Secondary: ORR, OS, correlates (DCE-MRI, biomarkers) </li></ul></ul>Stratified by prior therapy (prior cytokine/vaccine or no prior cytokine) and Motzer risk category (low, intermediate, or high)
  52. 73. Patients with clear cell RCC (N = 499)* 1 year Phase III Renal EFFECT Trial *Initial, nonrandomized dose-finding study for sunitinib and interferon-alfa2b in first 25 patients at 4 sites <ul><li>Primary endpoint: improvement in TTP from 8-12 months; 85% power (hazard ratio = 0.67); 222 events required. </li></ul><ul><li>1 year of follow-up after end of treatment </li></ul>Sunitinib, 50 mg/d orally, 4 weeks on 2 weeks off (n = 149) Sunitinib, daily , 4 weeks on 2 weeks off , plus Interferon alfa-2b every 3 weeks (n = 149) Sunitinib 35 mg/d orally for 6 weeks (n = 149)
  53. 74. Conclusions <ul><li>VEGF and other targeted therapies </li></ul><ul><ul><li>Robust activity in metastatic RCC </li></ul></ul><ul><ul><li>Cornerstone of future therapy </li></ul></ul><ul><li>Currently under investigation </li></ul><ul><ul><li>Value in earlier stages of disease </li></ul></ul><ul><ul><li>Clinical cross-resistance </li></ul></ul><ul><ul><li>Optimal sequencing/combination </li></ul></ul><ul><li>Clinical trials </li></ul><ul><ul><li>Participation mandatory for benefit of all </li></ul></ul>
  54. 75. Thank You THANK YOU !!!

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