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© 2003 American Society for Clinical Oncology
Renal Cell Carcinoma: A Priority Malignancy for Development and Study of Novel TherapiesMemorial Sloan-Kettering Cancer Center, New York, NY MESSING ET AL1 report in this issue of the Journal of Clinical Oncology the results of a randomized, phase III trial of adjuvant interferon alfa compared with observation for patients with locally advanced renal cell carcinoma completely resected by nephrectomy. Interferon alfa given as adjuvant therapy after complete resection by nephrectomy was compared with observation in two other phase III randomized trials as well.2,3 None showed a delay in time to relapse or improvement in overall survival associated with interferon alfa therapy.1–3 Data are lacking for study of interleukin-2 adjuvant therapy in a randomized trial. Thus, the standard management for localized tumors after nephrectomy remains surveillance. Success of an adjuvant treatment program depends on drugs capable of eradicating metastases. More than 30,000 individuals are diagnosed with kidney cancer annually in the United States, and more than 40% have metastases at diagnosis.4 The outcome of three adjuvant trials1–3 reflects the lack of effective systemic therapy to treat metastatic disease. Three decades of extensive clinical investigation have identified only two agents that have an effect on survival for patients with metastatic renal cell carcinoma.5 Treatment with high-dose bolus interleukin-2 achieved durable responses in a small proportion of highly selected patients.6 A modest survival benefit for interferon alfa therapy in metastatic renal cell carcinoma was observed in two phase III trials comparing interferon alfa with vinblastine or medroxyprogesterone.7,8 The deficiency of these two therapies is evidenced by their low response proportion and the paucity of long-term survivors. Using the Memorial Sloan-Kettering Cancer Center experience as an example, the overall response rate for 463 patients treated with interferon alfa as first-line treatment was 11%, and the 3-year survival rate was 19%.9 Over a 21-year period at Memorial Sloan-Kettering Cancer Center, 670 patients were treated on clinical trials with interferon alfa, interleukin-2, or chemotherapy for metastatic disease.10 Thirty patients were identified among the 670 who had survival time greater than 5 years, of which only 12 patients were disease-free.10 A recently completed Kidney Cancer Progress Review Group report conducted by the National Cancer Institute highlighted the need for preclinical and clinical research directed toward this disease to develop mechanism-driven therapies based on molecular features.11 Renal cell carcinoma consists of a heterogeneous group of tumors composed of clear-cell, papillary, chromophobe, and collecting duct cell types. These cell types have different molecular features and warrant individual consideration in drug development. (von Hippel Lindau (VHL) gene mutations are associated with clear-cell renal cancers, which comprise more than 90% of metastatic renal cell carcinomas. Hypoxia-inducible factors HIF1a and HIF2a are substrates of the VHL protein and are potent inducers of angiogenic and growth factor peptides. Targeting this pathway represents a unique opportunity to develop specific therapy for a causative mutation. Also, papillary renal cancer is characterized by mutations in the MET proto-oncogene.12 It is hoped that therapies directed at these and other pathways relevant to specific renal cancer histologies will identify new active agents. This is contingent on laboratory-based efforts to define the molecular profiles of these tumors. Given the poor outcome associated with metastases, renal cell carcinoma must be regarded as a priority malignancy for the development and study of novel therapies. Several features bear particular relevance in interpreting results of new treatments in clinical trials for renal cell carcinoma. First, spontaneous regression and stable disease as a part of the natural history are considered when the results of a treatment program indicate a low-level response activity.13 A randomized trial comparing interferon gamma with placebo in 197 patients with metastatic renal cell carcinoma showed a 7% response rate in the group treated with placebo, which was higher than the group treated with interferon gamma.14 Second, response proportions vary among phase II trials according to patient selection. Reports of response to high-dose interleukin-2 given by bolus administration in phase II trials range from 33%15 to 0%.16 Patients showing response by shrinkage of metastatic disease in the setting of a relatively stable bulky renal primary tumor may not meet standard criteria for partial response because of the large bidimensional area of the primary tumor.17 This contributes to higher response proportions associated with agents studied in phase II trials containing a high proportion of nephrectomized patients. The relative efficacy of one treatment program compared with another cannot be assessed by comparison of response proportions taken from individually conducted phase II trials. Phase III randomized trials are required for definitive comparison of treatment programs. Third, new treatment strategies, including angiogenesis inhibitors, could show antitumor effect by producing prolonged stabilization of disease or by slowing tumor regression over the course of many months. Therefore, time to progression is being considered as a valid therapeutic end point in phase II clinical trials for renal cell carcinoma. A challenge facing the clinical investigator is deciding what length of disease stabilization observed in a phase II trial constitutes a favorable outcome sufficient to justify further study in a large phase III trial. In summary, this report1 highlights three critical points regarding renal cell carcinoma treatment: (1) effective systemic therapy against metastases is lacking; (2) given the high proportion of patients with metastases and the associated poor survival, this malignancy must be regarded as a priority for studies in tumor biology and development of novel, mechanism-driven therapies; and (3) randomized trials are essential to evaluate promising new agents or combinations. REFERENCES
1. Messing EM, Manola J, Wilding G, et al: Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: An Eastern Cooperative Oncology Group/Intergroup Trial. J Clin Oncol 21:1214–1222, 2003 2. Porzsolt F: Adjuvant therapy of renal cell cancer with interferon alfa-2a. Proc Am Soc Clin Oncol 11:202, 1992 (abstr 622) 3. Pizzocaro G, Piva L, Costa A, et al: Adjuvant interferon to radical nephrectomy in Robson’s stage II and III renal cell cancer: A multicenter randomized study with some biological evaluations. Proc Am Soc Clin Oncol 16:318a, 1997 (abstr 1132)
4. Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Med 335:865–875, 1996 5. Motzer RJ, Russo P: Systemic therapy for renal cell carcinoma. J Urol 163:408–417, 2000[CrossRef][Medline] 6. Fisher RI, Rosenberg SA, Fyfe G: Long-term survival update for high dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 6:S55–S57, 2000 (suppl)
7. Pyrhonen S, Salminen E, Ruutu M, et al: Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 17:2859–2867, 1999 8. Medical Research Council and Collaborators: Interferon-alfa and survival in metastatic renal carcinoma: Early results of a randomised controlled trial. Lancet 353:14–17, 1999[CrossRef][Medline]
9. Motzer R, Bacik J, Murphy BA, et al: Interferon alfa as a comparative treatment for clinical trials of new therapies against renal cell carcinoma. J Clin Oncol 20:289–296, 2002
10. Motzer RJ, Mazumdar M, Bacik J, et al: Effect of cytokine therapy on survival for patients with advanced renal cell carcinoma. J Clin Oncol 18:1928–1935, 2000 11. Jones P, Vogelzang N: Priorities of the kidney/bladder cancer progress review group. Bethesda, MD, National Cancer Institute, 2002; http://prg.nci.nih.gov/kidney/finalreport.html 12. Schmidt L, Junker K, Nakaigawa N, et al: Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 18:2343–2350, 1999[CrossRef][Medline] 13. Vogelzang NJ, Priest ER, Borden L: Spontaneous regression of histologically proved pulmonary metastases from renal cell carcinoma: A case with 5-year followup. J Urol 148:1247–1248, 1992[Medline]
14. Gleave ME, Elhilali M, Fradet Y, et al: Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. N Engl J Med 338:1265–1271, 1998
15. Rosenberg SA, Lotze MT, Yang JC, et al: Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 85:622–632, 1993
16. Abrams JS, Rayner AA, Wiernik PH, et al: High-dose recombinant interleukin-2 alone: A regimen with limited activity in the treatment of advanced renal cell carcinoma. J Natl Cancer Inst 82:1202–1206, 1990 17. Stadler WM, Kuzel T, Dumas M, et al: A multi-center phase II trial of interleukin-2, interferon-alpha, and 13 cis-retinoic acid in patients with metastatic renal cell carcinoma. J Clin Oncol 16:1820–1825, 1998[Abstract]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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