Campbell-Walsh Urology, 11th Edition

PART X

Neoplasms of the Upper Urinary Tract

63

Treatment of Advanced Renal Cell Carcinoma

  1. Marston Linehan; Ramaprasad Srinivasan

Questions

  1. What is the approximate overall objective response rate to interleukin-2 (IL-2) monotherapy in patients with metastatic renal cell carcinoma (RCC)?
  2. 5%
  3. 10%
  4. 15%
  5. 25%
  6. 35%
  7. Which of the following regarding IL-2 therapy for metastatic RCC is TRUE?
  8. IL-2 has demonstrable efficacy in clear cell as well as papillary RCC.
  9. Randomized studies have demonstrated a survival benefit associated with high-dose IL-2.
  10. Low-dose subcutaneous and high-dose intravenous IL-2 have comparable efficacy.
  11. Durable complete responses are seen in a small proportion of patients receiving high-dose IL-2.
  12. Newer formulations have led to better tolerability of high-dose IL-2.
  13. In the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic scheme for patients with metastatic RCC undergoing therapy with cytokine or chemotherapy, which of the following is NOT a predictor of poor outcome?
  14. Karnofsky performance status greater than 80%
  15. Elevated lactate dehydrogenase
  16. Elevated calcium
  17. Decreased hemoglobin
  18. Absence of prior nephrectomy
  19. In which of the following patients with metastatic RCC is cytoreductive nephrectomy most appropriate?
  20. A 50-year-old male with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, a large 12-cm right renal mass, and four small pulmonary metastases
  21. A 67-year-old female with an ECOG performance status of 0, a 7-cm left renal mass, retroperitoneal adenopathy, and hepatic metastases that have doubled in size over 4 weeks
  22. An 81-year-old man with an asymptomatic 6-cm right renal mass and multiple hepatic metastases who has declined systemic therapy
  23. A 72-year-old man with an ECOG performance status of 2, a 5-cm right renal mass, and mild dyspnea associated with numerous pulmonary metastases
  24. The rationale for cytoreductive nephrectomy followed by immunotherapy with cytokines in patients with synchronous metastatic RCC includes all of the following EXCEPT:
  25. removal of tumor burden.
  26. removal of source of tumor-associated immunosuppressive factors.
  27. reversal of acquired immune dysfunction.
  28. improved tolerance to cytokine therapy.
  29. improved T-lymphocyte function.
  30. Which of the following statements about cytokine therapy for metastatic renal cell carcinoma is TRUE?
  31. Lymphokine-activated killer (LAK) cells augment the efficacy of both interferon-α (IFN-α) and IL-2.
  32. Randomized trials have demonstrated a significant survival advantage for combined IL-2 and interferon versus either agent given as monotherapy.
  33. The combination of IL-2 and interferon leads to higher overall response rates than either agent alone.
  34. The complete response rate with interferon-α monotherapy is 10%.
  35. Which of the following metastatic RCC tumors is most likely to benefit from cytokine therapy?
  36. Papillary carcinoma
  37. Clear cell carcinoma
  38. Medullary carcinoma
  39. Collecting duct carcinoma
  40. Chromophobe carcinoma
  41. A 58-year-old woman had a nephrectomy 6 years previously for a grade 2 clear cell carcinoma. She was incidentally found to have three left-sided pulmonary nodules (two < 1.0 cm, other 2.5 cm). A physical examination is normal, as are all blood chemistries. Computed tomography (CT) of the brain, lungs, abdomen, and pelvis show three pulmonary nodules with no associated hilar or mediastinal adenopathy, and a bone scan is normal. Which of the following is the most appropriate next step in her management?
  42. Therapy with high-dose IL-2
  43. Biopsy of a pulmonary nodule
  44. Mediastinoscopy followed by resection of the pulmonary nodules
  45. Observation
  46. IFN-α therapy
  47. The sirolimus analogues temsirolimus and everolimus act primarily on which of the following pathways?
  48. vascular endothelial growth factor (VEGF)
  49. Platlelet-derived growth factor (PDGF)
  50. Raf-1
  51. mechanistic target of rapamycin (mTOR)
  52. c-met
  53. The overall RECIST response rate in metastatic clear cell RCC patients receiving front-line therapy with sunitinib is:
  54. 15% to 20%.
  55. 30% to 40%.
  56. 60% to 70%.
  57. less than 10%.
  58. greater than 70%.
  59. In patients with previously untreated metastatic clear cell RCC, sunitinib is:
  60. associated with a higher response rate compared with interferon-α.
  61. associated with a longer progression free survival compared with interferon-α.
  62. associated with a better quality of life compared with interferon-α.
  63. all of the above.
  64. none of the above.
  65. Which of the following agents has been shown to prolong progression-free survival in patients with metastatic clear cell RCC who have progressed on first-line therapy with VEGFR antagonists?
  66. Axitinib
  67. Bevacizumab + interferon-α
  68. High-dose IL-2
  69. Everolimus
  70. Low-dose subcutaneous IL-2
  71. Randomized trials in patients with previously untreated metastatic clear cell RCC have demonstrated that sorafenib is:
  72. associated with better overall survival compared with interferon-α.
  73. associated with a longer progression free survival compared with interferon-α.
  74. associated with a better quality of life compared with interferon-α.
  75. all of the above.
  76. none of the above.
  77. Which of the following agents has been shown in randomized phase 3 trials to prolong survival in “poor risk” metastatic RCC patients?
  78. IL-2
  79. Sunitinib
  80. Sorafenib
  81. Temsirolimus
  82. IFN-α
  83. Which of the following molecules is NOT known to be upregulated as a consequence of VHL dysfunction?
  84. VEGF
  85. PDGF
  86. TGF-α
  87. Glut-1
  88. Raf-1
  89. In what proportion of sporadic clear cell tumors are mutations or promoter hypermethylation of the VHLgene seen?
  90. 70% to 90%
  91. 10% to 20%
  92. 100%
  93. Less than 10%
  94. A 47-year-old man presents with multiple metastatic lesions to the lungs and liver 8 months following a radical nephrectomy for a 9-cm papillary type I renal tumor. Which of the following statements about his systemic treatment options is TRUE?
  95. Sunitinib is associated with a 30% to 40% overall RECIST response rate in this subtype of RCC.
  96. Sorafenib is associated with better long-term outcomes than sunitinib in papillary type I RCC.
  97. mTOR inhibitors improve survival in patients with metastatic papillary RCC.
  98. Enrollment in a phase 2 trial evaluating a novel inhibitor of MET activity is a reasonable consideration in this patient.
  99. Which of the following statements about agents targeting components of the VHL pathway is TRUE in patients with metastatic clear cell RCC?
  100. The combination of sunitinib and temsirolimus is associated with higher progression-free and overall survival than sunitinib alone.
  101. The addition of IFN-α to bevacizumab has been shown in randomized trials to improve progression free survival compared with bevacizumab alone.
  102. Overlapping toxicity may limit maximal tolerated doses when two agents targeting this pathway are combined.
  103. MET is an important target in clear cell renal cancer due to the presence of MET mutations in approximately 90% of clear cell renal tumors.

Answers

  1. c. 35%.Although response rates of 30% or more were reported in early phase 2 studies with IL-2, the overall response rate with this agent was determined to be approximately 15% in larger studies and meta-analysis.
  2. d. Durable complete responses are seen in a small proportion of patients receiving high-dose IL-2.Complete responses are seen in 7% to 9% of metastatic clear cell RCC patients receiving high-dose IL-2, with the majority of these remaining disease-free for long periods. The efficacy of IL-2 has not been adequately evaluated in patients with non–clear cell histologies, and the use of this agent is largely restricted to clear cell RCC patients. There are no randomized phase 3 studies demonstrating survival benefit with IL-2.
  3. a. Karnofsky performance status greater than 80%.A Karnofsky performance score below 80% was determined to be an adverse prognostic feature and is one of the factors used to predict outcome in the MSKCC prognostic system for patients with metastatic RCC. All other factors listed have been associated with poor outcome.
  4. a. A 50-year-old male with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, a large 12-cm right renal mass, and four small pulmonary metastases.Cytoreductive nephrectomy is most likely to benefit patients who are good surgical candidates as well as candidates for postnephrectomy systemic therapy, such as those with a good performance status, those with a relatively slow rate of disease progression, and those with relatively low metastatic burden (as demonstrated in a randomized phase III study where interferon was offered post-nephrectomy). Patients described in b-d are less likely to benefit from this approach because they do not satisfy one or more of the above criteria.
  5. d. Improved tolerance to cytokine therapy. Studies suggest patients with synchronous metastatic RCC have a high frequency of acquired immune dysfunction involving T lymphocytes. The abnormalities described include increased T-cell apoptosis, impaired proliferative responses, and tumor-associated immunosuppressive factors. Cytoreductive nephrectomy may improve these abnormalities.No data demonstrate better patient tolerance to cytokine therapy.
  6. c. The combination of IL-2 and interferon leads to higher overall response rates than either agent alone.In a randomized phase 3 study, the combination of IL-2 and interferon was associated with a higher response rate than either agent given alone, although this did not translate to an improved long-term outcome (overall survival) in the combination arm. The addition of LAK cells to cytokine therapy does not appear to improve outcome.
  7. b. Clear cell carcinoma.Clear cell RCC is the histology most likely to respond to cytokine therapy. Although there are inadequate data to make definitive determinations about the activity of cytokines such as IL-2 or interferons in other histologic subtypes, these agents do not appear particularly effective in non–clear cell RCC variants.
  8. c. Mediastinoscopy followed by resection of the pulmonary nodules.Patients with metachronous pulmonary nodules related to remote renal tumors may have prolonged survival following resection of the nodule(s) as demonstrated by several retrospective studies.
  9. d. mTOR.mTOR (mammalian target of rapamycin) is the primary target of sirolimus (rapamycin) and its analogues.
  10. b. 30% to 40%.Objective overall RECIST response rates in metastatic clear cell RCC patients undergoing sunitinib therapy is approximately 30% to 40%, as demonstrated in a randomized phase 3 study comparing sunitinib with interferon.
  11. d. All of the above.A randomized phase 3 study demonstrated that sunitinib was associated with a higher response rate, longer progression free survival and better quality of life compared with interferon-α in the front-line treatment of patients with metastatic clear cell RCC.
  12. d. Everolimus.In a randomized phase 3 trial, everolimus has been shown to prolong progression-free survival compared with placebo (median PFS 4.0 vs. 1.9 months) in patients with metastatic clear cell RCC who have progressed on sunitinib and/or sorafenib.
  13. e. None of the above.In a randomized phase 2 study, sorafenib was not superior to interferon-α in previously untreated patients with metastatic clear cell RCC.
  14. d. Temsirolimus.In a randomized phase 3 study, temsirolimus was associated with better overall survival than interferon-α (median 10.9 vs. 7.3 months) in metastatic RCC patients presenting with three or more predefined factors predictive of poor-prognosis.
  15. e. Raf-1.Raf-1 is a mediator of growth factor signaling pathways but has not been shown to be upregulated in RCC as a consequence of VHL inactivation/HIF upregulation.
  16. a. 70% to 90%. Based on numerous recent studies, it is estimated that VHL inactivation by mutation or promoter hypermethylation occurs in 70% to 90% of clear cell renal tumors.
  17. d. Enrollment in a phase 2 trial evaluating a novel inhibitor of MET activity is a reasonable consideration in this patient. There is no conclusive evidence suggesting that standard agents with activity in clear cell RCC (including VEGF pathway inhibitors and mTOR inhibitors) have a favorable impact on outcome in patients with metastatic papillary RCC, and patients with these tumors are appropriate candidates for rational targeted therapy approaches.The presence of activating c-met mutations in some papillary tumors has kindled interest in the evaluation of c-met pathway antagonists in this patient population.
  18. c. Overlapping toxicity may limit maximal tolerated doses when two agents targeting this pathway are combined. Agents targeting different components of the VHL/HIF pathway often share an overlapping adverse event profile and dictate the need for dose reduction of individual agents when used in combination.Although this is an area under active investigation, there is currently no evidence to suggest that combined therapy with VEGF pathway and mTOR antagonists is superior to either class of agents administered alone. C-met mutations have been identified in some papillary tumors but not in clear cell RCC.

Chapter review

  1. Metastatic RCC is almost always fatal, with a 10-year survival of less than 5%.
  2. In patients with metastatic RCC, long-term survival is generally associated with a long interval between the initial diagnosis and the appearance of metastatic disease and the development of limited sites of metastatic disease.
  3. Nephrectomy as the sole treatment for metastatic RCC is unlikely to affect survival. However, when combined with cytokine therapy in carefully selected patients, there is an improvement in overall survival but not necessarily in cancer-specific survival.
  4. Isolated pulmonary nodules are the most common metastatic site amenable to resection with curative intent.
  5. After nephrectomy, the incidence of spontaneous regression of metastases is less than 1%.
  6. High dose IL-2 causes the vascular leak syndrome.
  7. Patients who overexpress carbonic anhydrase IX are most likely to benefit from IL-2 therapy.
  8. The VHLgene is a tumor suppressor gene. Mutations of this gene promote accumulation of hypoxia-inducible factor, which upregulates a variety of growth factors.
  9. Conventional cytotoxic chemotherapy is generally ineffective for metastatic RCC.
  10. Hormonal therapy for metastatic RCC has no role.
  11. Targeted chemotherapy in clear cell RCC is directed at vascular endothelial growth factor.
  12. Performance status, lactate dehydrogenase, hemoglobin, calcium, and prior nephrectomy may be used to stratify patients as to survival.
  13. The efficacy of IL-2 has not been adequately evaluated in patients with non-clear cell histologies, and the use of this agent is largely restricted to clear cell RCC patients.
  14. The addition of LAK cells to cytokine therapy does not appear to improve outcome.
  15. Patients with metastatic RCC have a high frequency of acquired immune dysfunction involving T-lymphocytes. The abnormalities include increased T-cell apoptosis, impaired proliferative responses, and tumor-associated immunosuppressive factors. Cytoreductive nephrectomy may improve these abnormalities; however, there are no data to demonstrate that cytoreductive nephrectomy improves the patient’s tolerance to cytokine therapy.
  16. There is no conclusive evidence suggesting that standard agents with activity in clear cell RCC (including VEGF pathway inhibitors and mTOR inhibitors) have a favorable impact on outcome in patients with metastatic papillary RCC.
  17. Agents targeting different components of the VHL/HIF pathway often share an overlapping adverse event profile and dictate the need for dose reduction of individual agents when used in combination.