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© 2002 American Society for Clinical Oncology Phase II Trial of Thalidomide for Patients With Advanced Renal Cell CarcinomaByFrom the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine; Departments of Radiology, Urology, and Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center; and Department of Medicine, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY. Address reprint requests to Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: motzerr{at}mskcc.org
PURPOSE: To assess efficacy and toxicity of thalidomide in patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: Twenty-six patients with RCC were treated with thalidomide at a starting dose of 200 mg daily. Thalidomide was increased by 200 mg every 2 weeks until a maximum dose of 800 mg or prohibitive toxicity was reached. Fifteen patients had prior nephrectomy, 11 patients had no prior systemic therapy, and 15 had received one prior systemic regimen. RESULTS: A maximum dose of 800 mg, 600 mg, 400 mg, and 200 mg was reached in five, 10, eight, and three patients, respectively. Grade 2 and 3 dyspnea occurred in four and three patients, respectively. Grade 2 and 3 neurologic toxicity was observed in five and two patients, respectively. Of the 25 assessable patients, the best response was stable disease in 16 (95% confidence interval [CI], 43% to 82%) patients. The 6-month progression-free survival rate was 32% (95% CI, 14% to 50%). Three patients achieved prolonged stable disease of 16, 16+, and 18+ months, including two patients who were refractory to previous cytokine therapy. Fifty-seven percent were alive at 1 year (95% CI, 37% to 76%). CONCLUSION: This trial does not support the routine use of thalidomide to induce partial response for metastatic RCC. Because disease stabilization occurs as a part of the natural history of metastatic RCC, the potential effect of thalidomide on progression-free and overall survival for patients with advanced RCC is being addressed in a randomized phase III trial. New immunomodulatory analogs of thalidomide that have shown potentially greater antitumor effects in preclinical models warrant study in metastatic RCC.
SMALL NUMBERS of patients with advanced renal cell carcinoma (RCC) exhibit complete or partial responses to interferon-alfa and/or interleukin-2.1 However, most patients do not respond to treatment, and there are few long-term RCC survivors.2 Therefore, clinical investigations of novel treatment strategies are of the highest priority in this refractory disease. The majority of RCC is composed of clear-cell carcinoma, which is characterized by mutation in the VHL gene.1 Because the VHL protein has been shown to stabilize vascular endothelial growth factor3 and because RCC is a highly vascular tumor with an angiographic pattern that is considered diagnostic,4 the study of angiogenesis inhibitors seems particularly relevant in RCC. Thalidomide is a potent angiogenesis inhibitor in vivo.5 After there were reports of clinical response in patients with advanced RCC treated with thalidomide,6,7 we performed a phase II trial to assess antitumor activity in 25 assessable patients. Although the exact mechanism by which thalidomide inhibits angiogenesis is unknown, thalidomide has been shown to affect levels of tumor necrosis factor-alfa and interferon-gamma8,9 and has shown antitumor activity in patients with refractory multiple myeloma,10 a disease that is characterized by prominent bone vascularization. The dose and schedule of thalidomide in our study was derived from a trial in multiple myeloma.10
Patients Between December 1999 and June 2000, 26 patients with advanced RCC entered this phase II trial that was approved by the institutional review board at Memorial Sloan-Kettering Cancer Center (MSKCC). Eligibility criteria included informed consent; measurable disease; Karnofsky performance status  70%; and adequate hematologic, renal, and hepatic function. The latter criteria were defined as WBC count 3,000 cells/mm3, granulocytes 1,500 cells/mm3, platelet count 100,000 cells/mm3, normal serum bilirubin, transaminase levels  2.5 times normal, and a serum creatinine concentration of 1.5 times normal or creatinine clearance 50 mL/min. Exclusion criteria included active brain metastases, pregnancy, or patients of child-bearing potential unwilling to use effective means of contraception.
Dose and Treatment Schedule In the case of nonhematologic grade 1 toxicity thought to be drug-related, treatment was maintained or escalated one dose level according to the discretion of the investigator. In the case of nonhematologic grade 2 toxicity, treatment was continued at the same dose or reduced by one dose level at the discretion of the investigator. For nonhematologic grade 3 or greater toxicity, treatment was withheld until recovery to grade 1 or less toxicity, then resumed at one dose level lower. Hematologic toxicity that required interruption of thalidomide treatment included grade 3 or 4 neutropenia and grade 3 or 4 thrombocytopenia. In these cases, treatment was withheld until resolution to grade 1 or less, then restarted at the next lower dose level. Patients given dose reductions were not re-escalated. Each cycle consisted of 28 days of thalidomide administered daily. On the basis of assessment of tumor size after cycle 2, patients with stable disease or greater response received additional cycles of therapy until evidence of disease progression or unacceptable toxicity. Patients were monitored with physical examination, complete blood count, and serum chemistry. A serum HCG for women of childbearing potential was performed every week during the first month and monthly thereafter. Each patient was reassessed for measurable disease after 8 weeks of treatment, then every 8 weeks thereafter. Response was assessed according to bidimensional measurements11 and toxicity according to National Cancer Institute common toxicity criteria. Duration of stable disease was measured from start of treatment until disease progression or last follow-up date. Progression-free survival was defined as time from start of therapy to disease progression or last follow-up. The purpose of the trial was to assess the partial plus complete response proportion associated with thalidomide. The target accrual was 25 assessable patients, a sample size associated with a 95% confidence interval (CI), for a response rate of ± 20%.
Patient Characteristics Twenty-six patients were treated with thalidomide (Table 1). The median age was 58 years (range, 40 to 78 years). Fifteen patients (58%) had received a prior nephrectomy. Assignment to MSKCC risk group on the basis of pretreatment clinical features2 showed that all but two patients had favorable-risk or intermediate-risk clinical features. Eleven patients (42%) were previously untreated, and 15 patients (58%) had been treated with one prior systemic therapy. This therapy consisted of cytokine therapy in 14 patients and a monoclonal antibody therapy in one patient.
Response and Survival Twenty-five patients were assessable for response. One patient was not assessable because she withdrew consent after receiving 14 days of treatment. No patient achieved a partial or complete response (95% CI, 0% to 14%) (Table 2). Stable disease was observed in 16 patients (64%; 95% CI, 43% to 82%), and disease progression was seen in nine patients. The median duration of stable disease for the 16 patients was 6 months (range, 3 to 18+ months) The median time to progression was 4 months (95% CI, 2 to 6 months) (Fig 1). The 6-month progression-free survival rate was 32% (95% CI: 14% to 50%). Three patients remained progression-free with stable disease at 16, 16+, and 18+ months of therapy; two continue treatment with thalidomide. Two of these three patients had progressive RCC after treatment with cytokine therapy, and one patient was previously untreated. Fourteen of 26 patients remain alive, with median follow-up of 17 months (range, 10 to 19 months) (Fig 2). The proportion of patients alive at 1 year is 57% (95% CI, 34% to 76%).
Treatment Administered and Toxicity The median duration of therapy administered to 26 patients was 3.8 months (range, 0.4 to 18 months), and two patients remain on treatment. A maximum dose of 800 mg, 600 mg, 400 mg, and 200 mg was reached in five (19%), 10 (38%), eight (31%), and three patients (12%), respectively. During the course of treatment, the side effect profile was moderate in intensity. Toxicities included fatigue, constipation, edema, ataxia, and sensory neuropathy (Table 3). Grade 2 and 3 dyspnea occurred in four and three patients (total, 27%), respectively. Grade 2 and 3 neurologic toxicity was observed in five and two patients (total, 27%), respectively. Four patients (15%) experienced grade 2 skin toxicity. One patient developed grade 3 bradycardia, and another developed lower extremity deep venous thrombosis. There was no grade 4 toxicity.
Phase II trials of thalidomide against metastatic RCC were prompted by reports that thalidomide had potent antiangiogenic properties,5 patients with cytokine-resistant metastatic RCC had achieved clinical responses,6,7 and treatment was relatively well tolerated,6,7,10 Since the first study of single-agent thalidomide in advanced RCC by Eisen et al,6 our trial and four others have investigated thalidomide in comparable patients.12-14 Collectively, the overall response rate in these studies was 6%, with eight of 144 assessable patients achieving a partial response (Table 4).6,12-15 Progressive metastatic RCC after treatment with cytokine therapy is characterized by a high degree of resistance to systemic therapy. In 14 phase II trials at MSKCC that involved 237 patients with advanced RCC, the overall response rate to chemotherapy or hormone therapy was 1.7%.16 The lack of response in our study and low cumulative response rate in the combined experience do not support the routine use of thalidomide to induce partial response in patients with metastatic RCC.
Stable disease was observed in our trial and in the other studies of thalidomide in advanced RCC in patients who had not responded to cytokine treatment.6,12-15 In three of these studies, 24% to 32% of patients had more than 5-month progression-free survival (Table 4). Antiangiogenesis agents like thalidomide may only be able to achieve disease stabilization by cytostatic inhibition of further tumor growth. Therefore, long-term stable disease might be a more appropriate treatment end point than objective responses on the basis of tumor shrinkage.17,18 In another study of a single-agent angiogenesis inhibitor in metastatic RCC, stable disease was also the best treatment effect observed, and that was consistent with preclinical expectations.18 Stabilization of disease is recognized as a part of the natural history of RCC.2 However, it is less likely to occur in patients who have progressed through cytokine therapy. The 1-year survival rate for patients treated on this trial was 57%. Treatment outcome proportions vary among phase II trials according to patient selection.19 Nearly all the patients treated on this trial had favorable (27%) or intermediate (65%) risk factors, according to the MSKCC model.2 The 1-year survival rates for patients with these features in the MSKCC data set were 71% and 42%, respectively.2 Phase III randomized trials are required for definitive comparison of treatment programs. In this regard, the role of thalidomide in extending time to progression and survival in patients with advanced RCC is currently being studied in a phase III randomized trial of the Eastern Cooperative Oncology Group that compares low-dose interferon-alfa with or without thalidomide. In summary, the lack of response in our study does not support the routine use of thalidomide to induce partial response for metastatic RCC. Because disease stabilization occurs as a part of the natural history of metastatic RCC, the potential effect of thalidomide on progression-free and overall survival for patients with advanced RCC is being addressed in the Eastern Cooperative Oncology Group randomized phase III trial. New immunomodulatory analogs of thalidomide that have shown potentially greater antitumor effects in preclinical models20 also warrant study in metastatic RCC.
Supported by Celgene Corp, Warren, NJ, and by grant no. K24 CA82431 from the National Institutes of Health, Bethesda, MD. We thank Patricia Fischer and Beth Goodkin for nursing support and Carol Pearce for her review of the manuscript.
1. Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Med 335: 865-875, 1996
2.
Motzer RJ, Mazumdar M, Bacik J, et al: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17: 2530-2540, 1999 3. Linehan WM: Renal cell carcinoma, in Vogelstein B, Kinzler K (eds): The Genetic Basis of Human Cancer. New York, NY, McGraw-Hill, 1998, pp 455-473 4. Campbell SC: Advances in angiogenesis research: Relevance to urological oncology. J Urol 158: 1663-1674, 2001
5.
D’Amato RJ, Loughman MS, Flynn J: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91: 4082-4085, 1994 6. Eisen T, Boshoff C, Sapunar F, et al: Continuous low-dose thalidomide: A phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer 82: 812-817, 1999 7. Amato D: Thalidomide for recurrent renal cell cancer in a 40-year-old man. Oncology 12: 33-36, 2000 (suppl 13)
8.
Sampaio EP, Sarno EN, Galilly R, et al: Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 173: 699-703, 1991 9. McHugh SM, Rifkin IR, Deighton J, et al: The immunosuppressive drug thalidomide induces T helper cell type 2 (TH2) and concomitantly inhibits Th1 cytokine production in mitogen- and antigen-stimulated human peripheral blood mononuclear cell cultures. Clin Exp Immunol 99: 160-167, 1995[Medline]
10.
Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341: 1565-1571, 2000 11. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[CrossRef][Medline] 12. Minor D, Elias L: Thalidomide treatment of metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 19: 352a, 2000 (abstr 1384) 13. Li Z, Amato R, Papandreou C, et al: Phase II study of thalidomide for patients with metastatic renal cell carcinoma progressing after interleukin-2–based therapy. Proc Am Soc Clin Oncol 20: 180a, 2001 (abstr 717) 14. Escudier B, Lassau N, Couanet D, et al: Phase II trial of thalidomide in renal cell carcinoma. Proc Am Soc Clin Oncol 20: 180a, 2001 (abstr 718) 15. Novik Y, Dutcher JP, Larkin M, et al: Phase II study of thalidomide in advanced refractory metastatic renal cell carcinoma: A single institution experience. Proc Am Soc Clin Oncol 20: 265a, 2001 (abstr 1057) 16. Murray Law T, Motzer RJ, Minasian LM, et al: Risk stratification in advanced renal cell carcinoma: A single-institution study of 237 patients. Proc Am Soc Clin Oncol 13: 243, 1994 (abstr 759)
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Korn EL, Arbuck SG, Pluda JM, et al: Clinical trial designs for cytostatic agents: Are new approaches needed? J Clin Oncol 19: 265-272, 2001
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Stadler WM, Kuzel T, Shapiro C, et al: Multi-institutional study of the angiogenesis inhibitor TNP-470 in metastatic renal cell carcinoma. J Clin Oncol 17: 2541-2545, 1999 19. Motzer RJ, Russo P: Systemic therapy for renal cell carcinoma. J Urol 163: 408-417, 2000[CrossRef][Medline]
20.
Hideschima T, Chauhan D, Shima Y, et al: Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96: 2943-2950, 2000 Submitted April 2, 2001; accepted August 23, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
