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© 2000 American Society for Clinical Oncology Effect of Cytokine Therapy on Survival for Patients With Advanced Renal Cell CarcinomaFrom the Genitourinary Oncology Service, Division of Solid Tumor Oncology, and Departments of Medicine, Biostatistics and Epidemiology, and Urology, Memorial Sloan-Kettering Cancer Center, and Department of Medicine, Cornell University Medical College, New York, NY. Address reprint requests to Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.
PURPOSE: To evaluate the relationship between treatment with cytokine therapy and survival, investigate the effect of nephrectomy on survival, and identify long-term survivors among a cohort of 670 patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: A total of 670 patients with advanced RCC treated on 24 clinical trials of systemic chemotherapy or cytokine therapy were the subjects of this retrospective analysis. Treatment was categorized as cytokine (containing interferon alfa and/or interleukin-2) in 396 patients (59%) and as chemotherapy (cytotoxic or hormonal therapy) in 274 (41%). Among the 670 patients, those with survival times of greater than 5 years were identified as long-term survivors. RESULTS: Patients treated with cytokine therapy had a longer survival time than did those treated with chemotherapy, regardless of the year of treatment or risk category based on pretreatment features. The median survival times for favorable-, intermediate-, and poor-risk patients were 27, 12, and 6 months for those treated with cytokines and 15, 7, and 3 months for those treated with chemotherapy, respectively. The magnitude of difference in median survival was greater in the favorable- and intermediate-risk groups. The median survival time was less than 6 months in the poor-risk group for both treatment programs. Median survival time was 14 months among patients with prior nephrectomy plus time from diagnosis to treatment greater than 1 year versus 8 months among those with time from diagnosis to treatment less than 1 year, regardless of pretreatment nephrectomy status. Thirty patients (4.5%) among the 670 patients were identified as long-term survivors; 12 were free of disease after nephrectomy and treatment with interferon alfa, interleukin-2, or surgical resection of metastasis. CONCLUSION: The low proportion of patients with advanced RCC who achieve long-term survival emphasizes the need for clinical investigation to identify more effective therapy.
THE OUTLOOK FOR patients with advanced renal cell carcinoma (RCC) is poor, with a 5-year survival proportion of less than 10% for patients who present with stage IV disease.1,2 RCC is resistant to chemotherapy and hormonal therapy, because no agent consistently achieves a response in more than 10% of patients.3 Treatment with cytokines, ie, interleukin-2 and interferon alfa, achieves responses in 10% to 20% of patients.3,4 The impact of treatment on survival is controversial, but two recent phase III trials have reported modest prolongation of survival associated with interferon alfa compared with vinblastine or medroxyprogesterone.5,6 The low proportion of patients who respond and achieve long-term survival emphasizes the need for clinical trials in the treatment of this highly resistant malignancy. We have reported on a prognostic stratification model derived from 670 patients treated in clinical trials of cytokine or chemotherapy at our center.7 Based on pretreatment features, patients were stratified into favorable-, intermediate-, and poor-risk categories.7 This categorization helps to identify patients who might achieve longer survival times after treatment, which is important in interpreting the results of clinical trials and in directing clinical investigations. Herein, we report on the relationship between type of therapy (cytokine v chemotherapy) and survival in each of the risk groups to determine if cytokine therapy benefits patients selected by risk group. In addition, the role of nephrectomy before systemic therapy remains controversial.3 Prior nephrectomy as a favorable prognostic feature for survival was compared according to time from initial diagnosis to treatment. Last, we identified patients treated for metastatic RCC who achieved long-term survival; their clinical features are reported in this article.
Six hundred seventy patients with advanced RCC treated with cytokine therapy or chemotherapy on 24 consecutive clinical trials at Memorial Sloan-Kettering Cancer Center were the subjects of this analysis.8-28 The Institutional Review Board–approved clinical trials accrued patients between September 1975 and July 1996. Patients who were entered onto more than one clinical trial were considered assessable for this study at the time of entry onto their first Memorial Sloan-Kettering Cancer Center trial. Eligibility criteria for all protocols included histologic confirmation of RCC, stage IV disease with measurable lesions, adequate Karnofsky performance status, lack of severe comorbid conditions, and adequate hematologic, renal, and hepatic function. The eligibility, treatment program, and results were reported in the individual trials. The methods and development of the model based on pretreatment features are reported elsewhere.7 In summary, a stepwise modeling approach based on Cox regression was used to form a multivariate model.7 It was determined that hemoglobin, lactate dehydrogenase, corrected calcium (total calcium - 0.707[albumin - 3.4]),29 nephrectomy, and Karnofsky performance status were the independent risk factors that predicted survival.7 These prognostic factors were used to categorize patients by risk into three different groups. In the development of the model, the relationship of survival to treatment program and to the year systemic treatment was initiated was studied. Patients were grouped according to whether they had treatment with cytokine therapy or chemotherapy and according to when they received treatment (1975 to 1980, 1981 to 1990, or 1991 to 1996). The program was classified as cytokine therapy when interferon alfa and/or interleukin-2 were included in the treatment regimen. Treatment was classified as chemotherapy when it consisted of cytotoxic therapy or hormonal therapy and when no interferon alfa or interleukin-2 was given. To account for these effects, type and year of therapy were included as strata in the Cox model when the prognostic model was developed.7 Herein, the effect of type of treatment program on survival is investigated by year of therapy and by risk group.
Status of prior nephrectomy and the interval from diagnosis to treatment ( Patients with survival times greater than 5 years were considered long-term survivors. The clinical features and treatment for these patients were recorded. The treatment history for those long-term survivors with no evidence of disease was tabulated.
The clinical features of the 670 patients are summarized in Table 1. Three hundred ninety-six patients (59%) were treated with cytokine therapy and 274 (41%) with chemotherapy (or hormonal therapy). Cytokine therapy consisted of interferon alfa for 294 patients, interleukin-2 for 68 patients, and interferon alfa plus interleukin-2 for 34 patients. The median overall survival time for these patients was 10 months (95% confidence interval, 9 to 11 months). Fifty-seven (8%) of the 670 patients remained alive at the time of this writing, and the median follow-up time for the survivors was 33 months (range, 1 to 187 months).
The model for predicting survival was based on five pretreatment risk factors (Table 2).7 The median times to death in the favorable-, intermediate-, and poor-risk groups were 20, 10, and 4 months, respectively. Survival was longer for patients treated with cytokine therapy (P < .0001) (Table 3, Fig 1) and for patients treated in more recent years (P < .0001) (Table 3). Therefore, these factors were included as strata in the Cox model when developing the prognostic model.
To further examine the effect of cytokine therapy, median survivals for the two types of therapy were estimated according to year of treatment (Table 4). Because cytokine therapy was not used in clinical trials conducted during the 1970s, statistics for that group cannot be estimated. However, the results showed that patients treated with cytokine therapy had a longer survival compared with patients treated with chemotherapy, both in the 1980s and in the 1990s.
Survival according to treatment was studied when patients were classified by risk group based on the model developed from pretreatment features (Table 4). The median survival times for favorable-risk, intermediate-risk, and poor-risk patients treated with cytokine therapy were 27, 12, and 6 months, respectively. In comparison, the median survival times for patients treated with chemotherapy were 15, 7, and 3 months for favorable-risk, intermediate-risk, and poor-risk patients, respectively. Therefore, in each of the risk groups, there was an approximate doubling of median survival when patients treated with cytokine therapy were compared with those treated with chemotherapy. The magnitude of difference in median survival was greater in the favorable- and intermediate-risk groups. The median survival time was less than 6 months in the poor-risk group, regardless of treatment program.
Four hundred thirty-four (65%) of the 670 patients had undergone nephrectomy before entry onto this study, and 422 (63%) had intervals from diagnosis to treatment of less than 1 year. Both prior nephrectomy and interval from initial diagnosis to treatment of greater than 1 year were associated with longer survival in univariate analysis (P = .001) (Table 5). Patients were stratified by nephrectomy status and length of interval from diagnosis to treatment (
Of the 670 patients, 30 were identified who had survival times greater than 5 years (Table 6). Twenty-six (87%) had Karnofsky performance status of 80% or greater, and 27 (90%) had undergone prior nephrectomy. Sixteen (53%) and 14 (47%) had been categorized as favorable and intermediate risk, respectively. None of the long-term survivors had been assigned to the poor-risk category. Twenty-one patients (70%) were treated on a clinical trial that included interferon alfa and/or interleukin-2, and nine (30%) were treated with chemotherapy or hormonal therapy. Fourteen patients (47%) remained alive at the time of this writing, including 12 who were free of disease, and 16 (53%) had died.
The clinical features and complete list of treatment programs administered throughout the clinical history of the 12 patients who were alive and free of disease at 5 years are summarized in Table 7. All had undergone prior nephrectomy, and 11 had Karnofsky performance status of 80% or 90%. The most frequent site of metastasis was lung, with five having lung as the only site of metastasis. The treatments that rendered patients continuously free of disease were interferon alfa in four patients, surgical resection of metastasis in three patients, interleukin-2 in two patients, interferon alfa plus interleukin-2 in two patients, and flutamide in one patient. The survival times ranged from 64 to 188 months.
The role of cytokine therapy with interleukin-2 and/or interferon alfa in prolonging survival for patients with metastatic RCC remains controversial. Selection factors influence treatment outcome, and phase III randomized trials are required for definitive comparison of treatment programs. Several randomized trials failed to show benefit,30-32 but the two largest trials showed that interferon alfa resulted in a modest prolongation in survival compared with medroxyprogesterone or vinblastine.5,6 Factors that could influence the outcome for these randomized trials include differences in sample size, prognostic clinical features of the patient population, and treatment programs. In this retrospective study, patients treated with cytokine therapy experienced longer survival compared with patients treated with chemotherapy. When survival after cytokine or chemotherapy treatment was considered according to pretreatment risk status,7 the difference in median survival was greater in the group with the more favorable prognostic features, characterized by the fewest number of risk factors. In contrast, survival for patients with poor-risk features was short, with a median survival time of less than 6 months, regardless of treatment type. These observations suggest that patients with favorable prognostic features according to the model7 may derive therapeutic benefit from cytokine therapy. Prospective identification of patients who are more likely to benefit from cytokine therapy could be used as a stratification factor in phase III trials and in risk-directed therapy. Several prior reports support the concept of risk-directed therapy of cytokines for patients with metastatic RCC. One of these reports applied a prognostic model to 246 patients treated with interferon, interleukin-2, and fluorouracil.33 The group with favorable prognostic features had a relatively longer survival compared with patients with poor prognostic features, and treatment directed to the favorable-risk group was recommended.33 Two other reports compared survival for patients treated with interferon alfa34 and interleukin-235 with external data sets of patients treated with chemotherapy, and stratified patients according to risk based on the criteria of Elson et al.36 In both studies,34,35 survival was longer in patients treated with cytokine therapy and the difference in survival was greater in patients with more favorable prognostic features. Controversy exists regarding the use of nephrectomy to reduce tumor bulk before treatment with immunotherapy.3 Theoretical advantages include the reduction of large, potentially immunosuppressive tumor burdens and the prevention of complications related to the primary tumor during systemic therapy. Disadvantages of the approach include the proportion of patients precluded from receiving systemic therapy because of rapid progression, perioperative complications, and surgical mortality. The proportion of patients precluded from systemic therapy by cytoreductive nephrectomy ranges from 9% to 40% and depends on patient selection by tumor size, performance status, and comorbid conditions.37-43 This issue is being addressed in a randomized phase III trial by the Southwest Oncology Group, which is comparing interferon treatment with intact primary tumor versus nephrectomy followed by interferon therapy.3 In our study, prior nephrectomy was associated with increased survival after systemic therapy on the clinical trial. When considered according to time interval from diagnosis to start of systemic therapy, survival was greater when nephrectomy was performed more than 1 year before initiation of systemic therapy for metastases. In contrast, the patients with less than 1 year from diagnosis to treatment had similar survival regardless of whether nephrectomy had been performed. The increased survival associated with prior nephrectomy observed in our study may reflect a more indolent tumor biology in patients who initially underwent nephrectomy for clinically localized disease and subsequently relapsed, rather than a direct consequence of resection of the primary tumor. Few patients achieved long-term survival, regardless of risk group or type of therapy. The median survival of the 670 patients was 11 months, and 30 (4.5%) were identified who had survival times of 5 years or longer. These long-term survivors were characterized by prior nephrectomy, favorable- or intermediate-risk classification according to the model,7 and treatment on a clinical trial with cytokine therapy. Among the 30 patients, 12 (2%) were alive and continuously free of disease after treatment with interleukin-2, interferon alfa, and surgical resection of metastasis. The rarity of such patients highlights the resistant nature of this malignancy and the need to identify more effective systemic therapy. In summary, the overall low proportion of patients with stage IV RCC who achieve long-term survival in response to systemic therapy emphasizes the need for clinical investigations to identify more effective therapy for all patients with metastatic RCC. Ongoing clinical research against RCC includes combination programs of interferon alfa or interleukin-2 with other agents, new cytokines, and novel immunotherapy programs. Patients with favorable- or intermediate-risk features may be more likely to benefit from these investigative approaches. In contrast, patients with poor-risk features experience a dismal survival, regardless of type of treatment. In these patients, clinical trials of novel treatment strategies can be considered a priority.
Supported in part by National Institutes of Health grant no. CA-05826. We thank Carol Pearce for reviewing the article.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1 year v > 1 year) were both found to be significant in univariate analysis for this group of patients. The interplay between these two variables was examined by dividing patients into four categories based on whether they had undergone a nephrectomy and whether their interval from diagnosis to treatment was less than or greater than 1 year. Survival curves for the four categories were then estimated. 
