a.Sunitinib is associated with a 30% to 40% overall RECIST response rate in this subtype of RCC.

b.Sorafenib is associated with better long-term outcomes than sunitinib in papillary type I RCC.

c.mTOR inhibitors improve survival in patients with metastatic papillary RCC.

d.Enrollment in a phase 2 trial evaluating a novel inhibitor of MET activity is a reasonable consideration in this patient.

.Which of the following statements about agents targeting components of the VHL pathway is TRUE in patients with metastatic clear cell RCC?

a.The combination of sunitinib and temsirolimus is associated with higher progression-free and overall survival than sunitinib alone.

b.The addition of IFN-α to bevacizumab has been shown in randomized trials to improve progression free survival compared with bevacizumab alone.

c.Overlapping toxicity may limit maximal tolerated doses when two agents targeting this pathway are combined.

d.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

cell RCC patients undergoing sunitinib therapy is approximately 30% to 40%, as demonstrated in a randomized phase 3 study comparing sunitinib with interferon.

.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.

.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.

.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.

.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.

.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.

.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.

.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.

.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 VHL gene 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 tumorassociated 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.

PART XI

The Adrenals