Journal of Clinical Oncology, Vol 17, Issue 9
(September), 1999: 2859
© 1999 American Society for Clinical Oncology
Prospective Randomized Trial of Interferon Alfa-2a Plus Vinblastine Versus Vinblastine Alone in Patients With Advanced Renal Cell Cancer
Seppo Pyrhönen,
Eeva Salminen,
Mirja Ruutu,
Timo Lehtonen,
Martti Nurmi,
Teuvo Tammela,
Harri Juusela,
Erkki Rintala,
Päivi Hietanen,
Pirko-Liisa Kellokumpu-Lehtinen
From the Helsinki University Central Hospital, Helsinki; Turku University Central Hospital, Turku; Tampere University Hospital, Tampere; Jorvi Hospital, Espoo; and Helsinki City Hospital, Helsinki, Finland.
Address reprint requests to Seppo Pyrhönen, MD, Department of Oncology, Turku University Central Hospital, PO Box 52, Fin-20521 Turku, Finland; email terttu.alakoski{at}tyks.fi
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ABSTRACT
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PURPOSE: The combination of interferon alfa-2a (IFN 2a) plus vinblastine (VLB) induces objective tumor responses in patients with advanced renal cell cancer. However, no prospective randomized trial has shown that this treatment prolongs overall survival. We compared overall survival after treatment with IFN2a plus VLB versus VLB alone in patients with advanced renal cell cancer.
PATIENTS AND METHODS: We prospectively randomized 160 patients with locally advanced or metastatic renal cell cancer to receive either VLB alone or IFN2a plus VLB for 12 months or until progression of disease. In both groups, VLB was administered intravenously at 0.1 mg/kg every 3 weeks, and in the combination group IFN2a was administered subcutaneously at 3 million units three times a week for 1 week, and 18 million units three times a week thereafter for the second and subsequent weeks. For patients unable totolerate IFN2a at 18 million units per injection, the dose was reduced to 9 million units.
RESULTS: Median survival was 67.6 weeks for the 79 patients receiving IFN2a plus VLB and 37.8 weeks for the 81 patients treated with VLB (P = .0049). Overall response rates were 16.5% for patients treated with IFN2a plus VLB and 2.5% for patients treated with VLB alone (P = .0025). Treatment with the combination was associated with constitutional symptoms and abnormalities in laboratory parameters, but no toxic deaths were reported.
CONCLUSION: The combination of IFN2a plus VLB is superior to VLB alone in the treatment of patients with locally advanced or metastatic renal cell carcinoma. This is the first study to demonstrate that survival can be prolonged by using IFN2a for these patients.
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INTRODUCTION
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RENAL CELL CANCER (RCC) accounts for approximately 2% of all malignancies and for 80% to 85% of kidney tumors in adults.1,2 The incidence of RCC is increasing, and worldwide mortality is expected to exceed 100,000 by the year 2,000.3 Localized RCC can often be cured with surgery.4 However, renal cell carcinoma is characterized by a lack of early warning signs, and approximately 50% of patients present with locally advanced or metastatic disease.2 In addition, 20% to 30% of patients presenting with localized RCC relapse after radical nephrectomy, usually with distant metastases.2 Five-year survival for patients with stage IV disease is 0% to 10%.1
RCC is characteristically unresponsive to chemotherapy.1,2 Of all chemotherapeutic agents tested, vinblastine (VLB) has been found to be one of the most consistently active, inducing objective responses in 7% to 15% of patients when administered as a single agent or in combination with other chemotherapy agents.5,6 Despite the low activity of VLB, its use as a palliative agent was a common feature of patient management before the widespread availability of recombinant biologic response modifiers (BRMs).
Certain BRMs are active in RCC, in particular interleukin-2 (IL-2) and interferon alfa (IFN). IL-2 induces objective responses in approximately 15% to 20% of patients,7,8 with enduring remissions in some patients and higher response rates in selected patients with favorable prognostic factors.8 Serious side effects of high-dose intravenous IL-2 have limited its use in daily practice. IFN produces responses in approximately 15% of patients, also with some enduring remissions9 and more favorable results in patients with good prognostic factors, including low erythrocyte sedimentation rate (ESR), good performance status, and no recent weight loss.10 The combination of IL-2 and IFN led to higher response rates than either agent alone in a recent study, although increased activity did not translate into a significant prolongation of survival or of time to progression.11
The presumption that VLB and BRMs acted through different antitumor mechanisms prompted investigations of combined biologic and chemotherapeutic agents. Preclinical studies indicated that the combination of IFN plus VLB was synergistic in inhibiting the growth of tumor cells.12 Early phase I and II studies13-15 indicated that response rates with IFN plus VLB consistently exceeded 20% to 25%, and median overall survival was 70 weeks in one study.14 Because these results were among the best response rates and median survival durations reported for RCC, further exploration of the activity and effect on survival of this combination seemed justified. Therefore, we conducted a phase III clinical trial to test the hypothesis that interferon alfa-2a (IFN2a) added to a palliative regimen of VLB would prolong overall survival compared with VLB chemotherapy alone in patients with advanced RCC. This report presents the final results of this prospective randomized trial.
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PATIENTS AND METHODS
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Patients
The patients eligible for this study had histologically or cytologically confirmed measurable or nonmeasurable but assessable advanced renal cell carcinoma. Patients were required to be younger than 75 years of age, have a Karnofsky performance status greater than 50% (Eastern Cooperative Oncology Group performance status of 0 to 2), a life expectancy greater than 3 months, and no abnormalities worse than mild (grade 1) in leukocyte, granulocyte, and platelet count, serum creatinine, and serum urea. Patients with brain metastases, other malignancies, serious concomitant illnesses or radiotherapy involving more than 25% of the bone marrow reserve were excluded. The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by institutional ethical committees at all participating clinical institutes, and patients gave witnessed verbal informed consent.
Treatment
Patients were randomly assigned to receive either IFN2a plus VLB or VLB alone. Patients in both groups received VLB at 0.1 mg/kg intravenously every 3 weeks. In the combination arm, patients received IFN at 3 million units subcutaneously or intramuscularly three times a week (TIW) for the first week, then 18 million units subcutaneously for subsequent weeks. Patients who were unable to tolerate 18 million units TIW were allowed to decrease the dose to 9 million units TIW. Commercially available VLB (Velbe, Eli Lilly and Co, Indianapolis, IN) and IFN2a (Roferon-A, Hoffmann-La Roche LTD, Basel, Switzerland) were used. The duration of treatment was either 12 months, until the development of progressive disease (PD), or for 3 months after the first observation of a complete response. Prolongation of therapy beyond 12 months was permitted for individual patients with partial responses or stable disease.
Evaluation of Patients
Patients were evaluated at baseline and monthly during treatment. Routine evaluations included a history and physical examination, bone scan, abdominal imaging (either ultrasound or CT scan), and laboratory tests, including hemoglobin, WBC with differential, platelet count, ESR, alkaline phosphatase, gamma-glutamyltransferase, serum creatinine, serum calcium, and urinalysis. Tumor measurements were obtained every 2 months. Chest x-rays and ECGs were obtained as clinically indicated. Response data were collected as a secondary end point using World Health Organization (WHO) criteria. Films of patients with objective responses were reviewed by a single central radiologist and the principal investigators from the two centers not treating the patient. Duration of response was calculated using standard WHO criteria. Toxicity was assessed by the investigators using WHO criteria where applicable. Toxicities for which specific WHO criteria did not exist were assigned grades: grade 1 = mild, grade 2 = moderate, grade 3 = severe, and grade 4 = life-threatening.
Statistical Analysis
The primary end point for the study was overall survival. The sample size calculation in the protocol stated that the study had 80% power to detect a difference between treatment groups in median survival of 12 versus 8 months, assuming recruitment of 160 patients at a rate of 40 patients per year and a follow-up period of 1 year. This calculation envisaged a one-sided statistical test, but all statistical analyses described in this report are two-sided. Secondary end points included response rates, duration of response, and time to progression. All enrolled patients were assessable for overall survival and time to progression. To be assessable for tumor response, patients must have been treated for at least 22 days with at least two infusions of VLB.
Overall survival was assessed from the date of randomization to the date of death. Time to progression was calculated from the date of randomization to the time when PD was observed. Results for overall survival and time to progression were analyzed according to Kaplan-Meier estimates and compared by use of the log-rank test, using life-table methods. Response rates are presented as frequency tables and were compared using Fisher's exact test. The Cox proportional hazards model was applied to test for interactions between prognostic factors and survival within each treatment group and between prognostic factors and the effects of treatment on overall survival.
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RESULTS
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Patients and Treatment
A total of 160 patients were enrolled at three university clinics in Finland between April 1988 and October 1994. Of these, 81 were randomized to VLB and 79 were randomized to the combination of IFN2a plus VLB. All enrolled patients had PD that required therapy in the opinion of the treating physician, and all patients received at least one dose of study medication. All patients are included in all analyses. Baseline demographic and disease characteristics for these patients are listed in Table 1. The treatment groups were well balanced for all measured characteristics.
No patients were lost to follow-up at the time of this report, and follow-up of all surviving patients is continuing. Of the 81 patients randomized to VLB, four patients (4.9%) were treated for 12 months, whereas 69 (85%) withdrew after developing PD, six (7.4%) died of progressive RCC during treatment, and two (2.5%) withdrew for other reasons. Treatment was prolonged beyond 12 months for one patient in the VLB group and was later stopped after development of PD. Of the 79 patients randomized to the IFN2a plus VLB, 18 (23%) were treated for 12 months, whereas 50 (63%) withdrew after developing PD, two (2.5%) died of progressive RCC during treatment, five (6.3%) withdrew for adverse events, and four (5.1%) withdrew for other reasons. Treatment with IFN2a plus VLB was prolonged beyond 12 months for six patients and was later stopped due to adverse events (one patient), death (one patient), or development of PD (four patients).
The median dose-intensity of IFN2a was 32.7 million units per week (range, 8.3 to 53.4 million units), and the median cumulative IFN2a dose was 774 million units. For patients receiving combination therapy, the median dose intensity of VLB was 2.3 mg/wk (range, 1.3 to 3.7 mg/wk), and the median cumulative dose was 62 mg. For patients treated with VLB alone, the median dose-intensity of VLB was 2.4 mg/wk (range, 1.7 to 3.3 mg), and the median cumulative dose was 36 mg. The median duration of treatment was 173 days (range, 19 to 413 days) for patients treated with IFN2a plus VLB and 85 days (range, 1 to 414 days) for patients treated with VLB alone.
Efficacy
Overall survival for all patients is presented in Fig 1. Median survival was 67.6 weeks for patients treated with IFN2a plus VLB and 37.8 weeks for patients treated with VLB alone (P = .0049). Survival rates for patients treated with IFN2a plus VLB or VLB alone were, respectively, 55.7% and 38.3% after 1 year, 11.7% and 5.1% at 3 years, 8.1% and 1.3% at 4 years, and 4.1% and 0% at 5 years.
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Fig 1. Survival of patients with renal cell carcinoma treated with IFN2a plus VLB or VLB alone. All 160 patients randomly assigned to the treatments are represented, regardless of any protocol violation or cause of death (the P value was determined by a two-sided log-rank test).
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Table 2 lists tumor response frequencies. Among all patients, overall response rates were 16.5% for the IFN2a plus VLB treatment group and 2.5% for the VLB group (P = .0025). The difference between groups was also statistically significant when nonassessable patients were counted as nonresponders. In the IFN2a plus VLB group, the median duration of response were 27 weeks for the seven patients who achieved complete responses (range, 12 to 281 weeks) and 24 weeks for the six patients who achieved partial responses (range, 18 to 63 weeks). In the VLB group, the response durations were 100+ weeks for the patient who achieved a complete response and 24 weeks for the patient who achieved a partial response. Sites of metastases among responders in the IFN2a plus VLB group were lung only (five patients, including one with pleural effusion and one with pleural metastases), lung and bone (two patients), lung and other tissues excluding bone (four patients), bone and other tissues excluding lung (one patient), and sites other than lung or bone (one patient).
Progression-free survival for all patients is presented in Fig 2. The median time to progression was 13 weeks for patients treated with IFN2a plus VLB and 9 weeks for those treated with VLB alone (P = .0001), and the difference between groups increased markedly after the median was reached.
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Fig 2. Progression-free survival of patients with renal cell carcinoma treated with IFN2a plus VLB or VLB alone. All 160 patients randomly assigned to the treatments are represented, regardless of any protocol violation or cause of death (the P value was determined by a two-sided log-rank test).
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The number of patients with objective tumor response seemed too small to account entirely for the effect of treatment on overall survival. For this reason, we compared overall survival between treatment groups for nonresponding patients. Results indicated significantly longer survival for nonresponding patients treated with IFN2a plus VLB compared with patients treated with VLB alone (P = .0338; data not shown).
Toxicity led to IFN2a dose reductions in 42 patients. Patients were considered to have received a reduced dose if they received doses that were less than 18 million units, including missed treatments, for more than 6 consecutive days. No difference in survival was apparent between patients who received 18 million units of IFN2a throughout therapy as planned, compared with patients for whom doses were reduced to 9 million units (results not shown).
The Cox proportional hazards model was applied to test for interactions between survival and seven prognostic factors that were identified in earlier phase II studies.10,16 Results listed in Table 3 indicate that survival in both treatment groups was correlated (P < .1) with low ESR, good performance status, and absence of liver metastases. Other factors were correlated only in one treatment group or were not significant in this population. In separate analyses, the Cox model was applied to identify correlations between prognostic factors and the difference in survival between treatment groups. Results of this analysis, listed in Table 4, indicated that increases in survival associated with IFN2a plus VLB treatment were correlated with advanced age (> 60 years), high ESR, prompt treatment after an initial diagnosis of RCC, poor performance status, male sex, and absence of liver metastases (P < .05 in all cases). Marginal significance was found for patients who had undergone prior nephrectomy. A comparison of Tables 3 and 4 reveals that some factors that were associated with poor survival, notably poor performance status and high ESR, were correlated with significantly better treatment benefit, indicating that IFN2a plus VLB had its greatest effect in patients who were generally considered to have a poor survival prognosis. In addition, risk reduction factors for improved survival with IFN2a plus VLB are positive for all prognostic groups (Table 4), indicating that combination therapy had no adverse effect on survival in any group, compared with VLB alone.
Toxicity
Adverse events noted in patients treated with the combination of IFN2a plus VLB were characteristic of IFN toxicity and similar in type and frequency to toxicities described in previous studies of this combination. The most frequent events were fatigue, fever, and flu-like symptoms. No patient died as a result of treatment toxicity in either group. Grade 4 toxicity was reported for 15 patients treated with IFN2a plus VLB and comprised neutropenia (12 patients), abnormal transaminase level (ALT) (two patients), and one case of grand mal epilepsy, which was classified as being unrelated to therapy. Grade 4 toxicity was reported for two patients in the VLB group and comprised abnormal alkaline phosphatase and ALT levels in one patient each. Abnormalities in laboratory parameters were reversible in all patients in both treatment groups. Five patients in the combination group and no patients in the VLB group were withdrawn from treatment before 12 months for adverse events, and a sixth patient in the combination group was withdrawn from prolonged (> 12 months) treatment. Treatment-related adverse events leading to withdrawal were fatigue and fever in four patients, peripheral neuropathy in two patients, and among these six patients, weakness in extremities, depression, confusion, memory loss, alopecia, anorexia, nausea and vomiting, and local erythema.
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DISCUSSION
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This prospective randomized trial indicates that overall survival is significantly prolonged in patients with advanced renal cell carcinoma when IFN2a is used in combination with a palliative regimen of VLB, compared with survival with VLB therapy alone. The increase in median survival from 37.8 to 67.6 weeks was statistically and clinically significant, and long-term survivors who remain in remission after 4 to 5 years were noted. Survival was prolonged in the overall patient population, even in the subset of patients who did not have objective tumor responses, and was not decreased in patients who required a reduction of their IFN2a dose from 18 million units to 9 million units per injection to improve tolerability. The combination was also associated with higher response rates, a larger number of complete responses, and prolonged time to progression. The gain in survival was achieved without toxic deaths or substantial serious toxicity. Treatment was generally well tolerated and easily administered in an ambulatory setting, although most patients treated with the combination did experience adverse events commonly associated with IFN therapy, such as fatigue, fever, flu-like symptoms, or reversible granulocytopenia.
Results of this study do not seem to be attributable to an imbalance in baseline characteristics between patients in the two treatment groups. The demographic features, baseline disease characteristics and history, and major prognostic factors of patients enrolled in this study seem to be consistent with those described in surveys of newly diagnosed advanced RCC patients17 and in other studies of nonpretreated advanced RCC patients.2,16
Prognostic factors associated with survival within treatment groups were not identical to those associated with prolonged survival that were attributable to treatment with IFN2a plus VLB, and in some cases, the patients with the poorest overall survival prognosis derived the greatest survival benefit from combination therapy. For example, survival was positively correlated with good performance status and low ESR, whereas the analysis of treatment interaction revealed that poor performance status and high ESR were prognostic of a prolongation of survival associated with IFN2a plus VLB treatment. In general, results of the treatment interaction analysis indicate that patients who are most likely to benefit from therapy with the combination of IFN2a plus VLB are those who are older than 60 years and have high ESR ( 50 mm/h), began treatment within 12 months of their initial diagnosis of RCC, have poor performance status (Zubrod = 2), are male, and are without liver metastases. Results of a previous analysis indicate that increases rather than decreases in the CD4+/CD8+ ratio were correlated with increased survival among patients treated in this study with IFN2a plus VLB.18
The results of this trial are consistent with those reported in previous studies with a variety of treatments, including the combination of IFN2a plus VLB. In a survey of 416 patients treated with IFN plus VLB, the overall response rate was 22%, and median survival (when reported) usually exceeded 1 year (Table 5). By comparison, a median survival duration of 229 days was reported in an Eastern Cooperative Oncology Group database for 610 patients who received experimental treatments that were subsequently judged to have little therapeutic value.26 In other surveys of experimental treatments, median survival duration for patients with advanced RCC has been generally less than 1 year.27,28
This study was designed to verify the therapeutic value of IFN when combined with VLB, but it does not specifically address the role of VLB in the combination. Two randomized studies have compared the activities and patient benefit of IFN2a with or without VLB but have not completely resolved this question.19,20 In a study in which IFN2a was administered at a dose regimen similar to the one used here, Fosså et al19 found no statistically significant differences in activity or survival between IFN2a as monotherapy or IFN2a plus VLB, but the combination was associated with a numerically higher response rate (24% v 11%) and a trend to longer survival (median, 55 v 47 weeks). Importantly, the toxicity of IFN2a was not substantially increased by the addition of VLB at 0.1 mg/m2 every 3 weeks in the combination. In another comparative trial using various species of naturally occurring IFN (IFNn1) and an intermittent dosing scheme administered over a shorter period of 12 weeks, Niedhart et al24 found that high doses of VLB (10 mg/m2 every 2 weeks) did not increase response rates or overall survival over IFNn1 alone. In this trial, however, only 39% of patients completed the full treatment course. In light of these different results from comparative trials, it is relevant to note that one of these phase III trials19 seems to be consistent with extensive phase II data that suggest a modestly higher activity and greater benefit for the combination. A survey of phase II studies (Table 6) indicates that IFN monotherapy, at dose-intensities approximating those used here (range, 9 to 108 million units per week) induced overall response rates of 14% to 15%, with median survival durations of generally less than 1 year. This differs from the 21% to 22% response rate and median survival duration of greater than 1 year reported in studies with the combination of IFN2a plus VLB (Table 5), which are consistent with the results of Fosså et al.19 Accordingly, although the role and value of VLB in the combination remains to be further clarified, available evidence supports the view that it may contribute modestly to antitumor activity, and that its use remains a justified option.
A preliminary report shows that IFN2b alone prolongs overall survival when compared with medroxyprogesterone acetate,40 indicating that IFN alone may improve survival over less effective or purely palliative treatment. However, the degree of therapeutic gain reported was modest (consisting of an increase of 10 weeks in overall survival) when compared with the benefit of IFN2a plus VLB reported here. However, the lower survival benefit reported for IFN2b monotherapy versus medroxyprogesterone acetate may be due to the lower dose of IFN2b (10 million units), and shorter treatment period (12 weeks), rather than due to the absence of VLB.
This study provides no direct information on the therapeutic role of IFN2a plus VLB compared with IL-2 in advanced RCC. However, the results of this trial indicate that IFN2a plus VLB can lead to prolonged remission in some patients, as has been reported for IL-2.8 The combination of IFN2a plus IL-2 induced higher response rates than either agent alone in a recent randomized trial, but the combination did not induce a significant prolongation of survival or of time to progression.11 Notably, IFN2a and IL-2 monotherapies had similar effects in this study on tumor response, disease progression, and overall survival, which is consistent with the view that these agents have similar activity in comparable patients. IFN2a did not increase the incidence of serious toxicity in the combination relative to IL-2 alone.
Despite the improved survival noted in this study and the promising development of combination therapies with IFN, IL-2, and fluorouracil,41 only a minority of patients respond to therapy of any sort, and the current treatment options for patients with advanced RCC are unsatisfactory. Further development of new agents and treatment strategies remains essential.
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ACKNOWLEDGMENTS
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Supported in part by a grant from Hoffmann-La Roche and by research grants from the Finnish Cancer Society.
We are greatly indebted to Raija Husa for her great help as a study nurse. We also thank Martine Wahl and Elisabeth Wassner Fritsch for their support in data collection, Paul Smith for statistical analyses, and Thomas Brown for his editorial assistance in preparing the manuscript.
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NOTES
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Presented in part at the Annual Meeting of the American Society of Clinical Oncology, May 18-21, 1996, Philadelphia, PA.
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Submitted September 8, 1998;
accepted April 27, 1999.
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TOP
ABSTRACT
INTRODUCTION
