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Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: Results of a European multi-center phase III study
Annals of Oncology 3: 301-305, 1992. O 1992 Kluwtr Academic Publishers. Printed in the Netherlands.
Original article Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: Results of a European multi-center phase III study S. D. Fossa,1 G. Martinelli,2 U. Otto,3 G. Schneider,4 H. Wander,5 F. Oberling,6 H. W. Bauer,7 U. Achtnicht & E. E. Holdener8 1
Department of Medical Oncology and Radiotherapy, The Norwegian Radium Hospital, Oslo; 2 Hospital San Giovanni, Bellinzona, Switzerland; ' Department of Urology, University Hospital Eppendorf, Hamburg; 4 Department of Medicine II, Division of Oncology, Augsburg; ^ Department of Internal Medicine, University Hospital, Goettingen, FRG; hDepartment of Onco-Hematology, CHU-Hautepierre, Strasbourg, France; 7Department of Urology, University Hospital Steglitz, Berlin, FRG; "Department of Clinical Research, F. Hoffman-La Roche Ltd., Basel, Switzerland Summary. A total of 178 patients with metastatic renal cell cancer were randomized to receive interferon alfa-2a (rIFN alfa-2a) or interferon alfa-2a + vinblastine (VLB). 1FN alfa2a was injected intramuscularly at a dose of 18 MIU 3 times a week and VLB was given intravenously at a dose of 0.1 mg/kg once every 3 weeks. The response rate was 11% for patients on monotherapy and 24% for those on combination treatment. The 5-year survival for 145 eligible patients was 9%, independently from the treatment arm. The performance status was significantly related to long-term prognosis, and 13% of the patients with performance status 0 were alive at 5 years, as compared to 6% and 0% for patients with a WHO grade of 1 and 2, respectively. The most frequent adverse
events in both treatment arms were flu-like symptoms (95%), fatigue (70%) and gastrointestinal disturbances (68%). Leukopenia was observed more frequently with combination treatment (53%) than with IFN alfa-2a alone (30%). In conclusion, rIFN alfa-2a monotherapy at this dose and schedule has modest antitumor activity in metastatic renal cell cancer. The combination of rIFN alfa-2a + VLB results in a doubling of the response rate, but this does not translate into prolonged survival. Toxicity (except leukopenia) and tolerance were similar in both treatment arms.
Introduction
rates in patients with metastatic renal cell carcinoma treated with either interferon alfa-2a alone, or in combination with vinblastine.
There is no standard treatment for patients with metastatic renal cell carcinoma (MRCC). Although a number of drugs have been tested in MRCC, the overall results are disappointing [1-6]. Vinblastine (VLB) has been claimed to be the most active antineoplastic drug, but more recent trials show that the response rate does not exceed 10% [7, 8]. The rare occurrence of spontaneous regression of metastases from MRCC [9] has resulted in the speculation that an immunologic rejection of an occasionally antigenic tumor may lead to tumor regression. Biologic response modifiers including interferon can produce immunostimulation in humans. Interferon has also direct antiproliferative activity in both normal and malignant cells [10, 11]. Once interferon became available for clinical use, a number of trials using interferon as single agent [12-17] or in combination with vinblastine, were performed [18, 19]. Interferon monotherapy resulted in overall response rates ranging from 5% to 20% depending on dose and schedule, whereas the combination with vinblastine generated response rates up to 40%. The aim of the present multi-center phase III trial was to compare the response and long-term survival
Key words: interferon, ± vinblastine, renal cell carcinoma, response rate, survival
Patients and methods From 1985 to 1986 a total of 178 patients with metastatic renal cell carcinoma were entered into this open phase III study. Eligibility criteria were as follows: age up to 70 years, histologically proven measurable or evaluable MRCC, nephrectomy more than 4 weeks prior to the study entry, performance status WHO grade <2 [20] (Karnofsky performance status of >70%), WBC >3 Giga/1, serum creatinine <150 nmol/1, and bilirubin, ASAT and ALAT within 25% above the upper limit of the normal range. Patients with cerebral metastases, with radiotherapy to the marker lesions or with previous anticancer chemotherapy were not eligible for the study. The study protocol had to be approved by the institutional Ethical Committee and patients had to give at least verbal consent Recombinajit interferon alfa-2a, (rIFN alfa-2a - Roferon*-AJ was supplied by F. Hoffmann La-Roche Ltd., Basel, Switzerland. Vinblastine (Velbe*) was used as commercially available. For 87 patients entered in the combination arm. rIFN alfa-2a was given at a dose of 18 MIU intramuscularly three times a week and VBL was injected intravenously at a dose of 0.1 mg per kilogram body weight once every three weeks. For 91 patients entered in the monotherapy treatment arm, the interferon dosage was the same as in the combination treatment arm. At baseline, a complete medical history was taken and physical
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302 examination performed on every patient. In addition, hematological analysis including hemoglobin, white blood cell count and platelet count were performed together with serum chemistry which included bilirubin, transaminases, alkaline phosphatase, serum creatinine and serum calcium. Additional examinations were performed in order to determine the extent of tumor using chest x-ray, CT-scan, brain scan, ultrasonography as well as x-ray of bone where applicable. WHO response criteria were used to assess tumor responses after at least 2 months' treatment [20). Patients with 'early progression' (vide infra) were included into the progression category. Patients were required to receive a minimum of 2 months treatment in order to be evaluated for response unless disease progression was observed during this period (early progression). Treatment was given until disease progression or in case of 'no change' or partial response for a maximum of one year, unless unacceptable toxicity developed. Completely responding patients (CR) were to be given therapy for further 6 months after demonstration of CR. Toxicity was, whenever possible, assessed in patients according to the WHO classification system for toxicity grading [20|. Flu-like symptoms were arbitarily graded as grade 1: mild; grade 2: moderate; grade 3: severe; grade 4: life-threatening. In cases of grade II toxicity which were thought to be related to IFN treatment, rIFN alfa-2a was discontinued until the patient recovered. Treatment was restarted with 12 MIU of rIFN alfa-2a. In cases of grade IV toxicity which were thought to be related to IFN treatment, retreatment started at a dose of 9 MIU. Grade III myelosuppression thought to be caused by VLB resulted in the subsequent injection being delayed until recovery. No dose reduction was made after grade III toxicity, but subsequent VLB doses had to be reduced by 25% in case of grade IV toxicity. Statistical analyses were carried out using the Statistical Analysis System (SAS). Statistical tests were restricted to the hypothesis that there was no difference between the treatment groups with respect to the following parameters: tumor response (Chi-square test, Fisher's Exact Test), duration of response (Wilcoxon test), survival duration (Wilcoxon test, Log rank test). Objective responses were evaluated in 1987, but the survival was calculated according to the Kaplan-Meyer method with the last cut-off in March 1991. Umvariate and Cox multivariate regression analysis were performed in order to define factors predictive of response and survival.
Results A total of 178 patients were entered by 13 institutions. Twenty-four patients (13%) did not fulfill the protocolstated eligibility criteria and had to be excluded from the response analysis together with 9 patients who had bone metastases as the only site of evaluable disease. Twenty-six of the remaining 145 eligible patients were withdrawn early from the study due to toxicity. They had had treatment for less than 2 months and none of them had disease progression at the time of withdrawal. The total number of patients who were evaluable for response was thus 119 (Table 1). Of these were 85 males and 34 females. The median duration for the disease before entering the trial was 4.3 and 5.4 months for patients on rIFN alpha-2a and combination treatment, respectively. The median Karnofsky performance status was 90% and the majority of the patients had lung metastases as their indicator lesions. The response rate (Table 2) in all patients was 22/ 119 (16%), for rIFN alfa-2a alone it was 6/53 (11%; 95% CI: 4-23%), for the combination of rIFN alfa-2a +
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Table 1. Demographics. Evaluable patients
All patients IFN
IFN + VLB
IFN
IFN + VLB
No. of patients
87
91
53
66
Age (yrs) - median - range
57
57
57
31-74
30-81
31-70
56.5 30-70
64 23
65 26
39 14
46 20
80
90
90
30-100
70-100
70-100
Sex
- male - female
Performance status (Karnofsky) 80 - median - range 70-100 Time from Dx* to Txb (months) - median - range Indicator lesion(s) - Lung — Lymph node - Liver - Bone - Other
5.9
5.1
4.3
5.4
1-110
1-262
1-110
1-208
34 13 9 4 15
45 10
8 5 11
31 13 6 9
42 9 7 10
" Diagnosis. b Treatment start. Table 2. Response to rIFN alfa-2a alone or in combination with vinblastine. Evaluable patients only IFNA alfa-2a
IFN alfa-2a + vinblastine
Response
(n-53)
(n - 66)
Overall response Complete response Partial response No change Progressive disease
6 (1 1%)" 1 (2%) 5 (9%) 32 (60%)
16(24%)h 1 (2%) 15(23%) 29 (44%) 21 d (32%)
15C (25%)
" 95% CI 4%-23%. b 95% CI 15%-36%. c Including 9 early PD. d Including 11 early PD.
vinblastine it was 16/66 (24%; 95% CI 15-36, twotailed Fisher's Exact Test 0.1; Chi square 0.07). Complete responses were seen in 2 patients, one in each treatment arm. Responses were mainly seen in lung metastases and lymph node metastases. The median duration time of partial response was 8.6 months (range 3.7 to 18.3 months) and 6.0 months (range 2.7 to 18.6 months), for rIFN alfa-2a and the combination, respectively. For two patients with a complete response the response duration was 5.3+ months (rIFN alfa-2a alone) and 5.6+ months (rIFN alfa-2a plus vinblastine). There was no difference in survival between the 2 treatment arms independently whether all included patients were considered or only eligible and evaluable
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Fig. 1. Survival in patients with metastatic renal cell carcinoma treated with rIFN alfa-2a or rIFN alfa-2a + vinblastine. a) All included patients; b) Eligible patients; c) Evaluable patients.
(Fig. 1). In all 3 groups performance status (WHO; 20) had a significant impact on survival (Fig. 2). Sex, age, the duration of the disease prior to study entry, previous radiotherapy and the performance status had no significant impact on tumor response using logistic regression analysis. The Cox regression analysis for survival showed that age <60 years and WHO performance status of 0 were significant independent prognostic parameters. Toxicity was analyzed for all 178 patients entered into the trial (Table 3). The median duration of rIFN alfa-2a treatment in all patients entered into the trial was 112 days (1-468 days) for the monotherapy and 132 days (8-500 days) for the combination therapy. The median treatment duration in responders (CR + PR) was 261 (140-467) days with IFN alfa-2a monotherapy and 209 (91-499) days with the combination treatment. The median cumulative dose of rIFN alfa-2a
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0 12
24
36
48
60
72
Months from treatment start Fig. 2. Survival in patients with metastatic renal cell carcinoma treated with rIFN alfa-2a or rIFN alfa-2a + VLB according to performance status. ( • • • ) WHO grade 0; (ooo) WHO grade 1; (* A A) WHO grade 2; a) All included patients; b) Eligible patients; c) Evaluable patients.
was 774 MIU and 882 MIU for monotherapy and combination therapy, respectively. A total of 48 patients treated for at least 60 days with rIFN alfa-2a monotherapy and 49 similar patients receiving IFN alfa-2a + VLB tolerated full dose (- 18 MIU TTW) of rIFN. All responders from the monotherapy arm were in the group of 48 patients who received full dose. In the IFN alfa-2a + VLB arm, 12 of 16 responders received the full dose of IFN during the first 60 days. Thirty-one patients had one or more dose reductions of VLB (median: 2; range: 1-6), usually after 2 or more VLB injections. Concomitant rIFN alfa-2a decrease was necessary in 2 of the 31 patients.
304 Table 3. Spectrum of most frequent clinical side effects observed in 178 patients treated with rIFN alfa-2a (n - 87) or the combination of rIFN alfa-2a + vinblastine (n - 91). % of patients rIFN alfa-2a
rIFN alfa-2a + vinblastine
Class of adverse events (n - 87)
(n-91)
95 (22) 70 (22) 68 (23) 21 (10) 9(10) 7(1) 7(1)
98 (23) 68(10) 70(19) 20(9) 5(1) 7(2) 7(2)
Flu-like symptoms Fatigue Gastrointestinal CNS/PNS Skin + appendages M usculo-skeletal Cardiovascular (
): Percent of patients with grade III or grade IV toxicity.
The most frequent side effects were flu-like symptoms (95%), fatigue (70%) and gastrointestinal disturbances (68%). These side effects were rated as mild or moderate in about 80% of the patients. There was no difference between the two treatment arms. There was also no significant difference in weight loss between the two treatment arms with 23% (IFN alone) and 25% (rIFN + VLB) showing more than 10% weight loss during the treatment. The most frequent laboratory changes were leukopenia and increase in liver enzymes. Leukopenia was seen more frequently in the combination therapy (53%), as compared to the monotherapy (30%). Grade HI leukopenia was observed in 5 patients within the combination arm and in 3 patients treated with IFN alfa-2a alone. No patient developed Grade IV leukopenia.
Discussion
combination with interferon alfa in the clonogenic assay system [36], suboptimal but less toxic doses of both compounds may well result in a higher overall response rate in a clinical setting. This higher response rate with the combination in the current study was due to an increase in partial responses while the complete response rate remained below the 5% level. This may, together with the regrettable lack of any external review of the responses, explain why the higher response rate in the combination arm did not translate into a prolongation of median survival compared to interferon alfa2a monotherapy. On the other hand, a median survival of 12 months in both treatment groups in the present trial compares favourably with other published data [37], where only the best prognostic subgroup (e.g. excellent performance status, time from initial diagnosis >1 year, maximally one metastatic site, no prior chemotherapy and no recent weight loss) showed a similar median survival. As only a small proportion of our patient population fits into this most favourable patient category, this could suggest a survival benefit for both treatments in the present trial as compared to series with patients receiving chemotherapy [37]. However, only prospective randomized trials of interferon or an interferon-cytotoxic drug combination against a no treatment control and stratified for prognostic factors can demonstrate a survival advantage. Such studies, whilst scientifically interesting, may be difficult to perform. Our overall 5-year survival of 9% for eligible patients is in agreement with recent observations by Neidhart et al. [38]. As in other reports [37, 38] patients with an excellent performance status had the best prognosis, independently from treatment. In future studies with interferon MRCC, patients should be stratified according to this criterion. Toxicity and tolerance observed in the present trial were not different compared to previously reported studies using similar dosages for IFN monotherapy and in combination with low dose vinblastine. As expected there was a slight increase in more frequent and more pronounced leukopenia in the combination therapy group, otherwise the spectrum of toxicity was quantitatively and qualitatively similar. In conclusion, the combination of intermediate dose rIFN alfa-2a with low dose vinblastine resulted in doubling of the objective response rate compared to interferon monotherapy (at the same dose), without translating into increased survival. Toxicity and tolerance of both treatments were very similar.
Interferon alfa treatment in MRCC consistently produces objective response rates between 10%-20% [21-23] which is confirmed by the monotherapy arm of the present study. There is a trend of a possible doseresponse relationship for interferon therapy in MRCC [24], with lower doses resulting in less than a 10% objective response, whereas higher doses can generate objective response rates beyond 20% [25]. The combination of interferon alfa-2a with vinblastine has resulted in an increase of the objective response rate in several phase II studies [26-31] with response rates between 16%-36%. The present prospectively randomized study confirms these data by demonstrating a doubling of the response rate to 24% for the combination treatment. Vinca alkaloids as monotherapy in much higher doses as compared to the dose given in this trial have resulted References in very low response rates, usually less than 10% [7, 32, 1. Hahn RG, Bauer M, Wolter J, Creech R, Bennett JM, Wampler 33] with only one exception [34]. Since synergistic efG. Phase II study of single-agent therapy with megestrol fects are seen when cytostatics are combined with inacetate, VP-16-231, cyclophosphaxnide, and dianhydrogalactiterferon alfa [35] and vinblastine showed the highest tol in advanced renal cell cancer. Cancer Treat Rep 1979; 63: additive antiproliferative effect of all vinca alkaloids in 513-5
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305 2. Mittelman A, Alber DJ, Murphy GP. Lomustine treatment of metastatic renal coll carcinoma JAMA 1973; 225: 32-5. 3. Gralla RJ, Yagoda A. Phase II evaluation of chlorozotocin in patients with renal cell carcinoma. Cancer Treat Rep 1979; 63: 1007-8. 4. Moore GE, Bross ID, Ausman R et al. Effects of 5-fluorouracil (NSC-19893) in 389 patients with cancer. Cancer Chemother Rep 1968; 52: 641-53. 5. O'Bryan RM, Luce JK, Talley RW, Gottlieb JA, Baker LH, Bonadonna G. Phase n evaluation of adriamycin in human neoplasia. Cancer 1973; 31:1-8. 6. Johnson DE, Chalbaud RA, Holoye PY, Samuels ML. Clinical trial of bleomycin (NSC-125066) in the treatment of metastatic renal carcinoma. Cancer Chemother Rep 1975; 59:433-5. 7. Tannock IF, Evans WK. Failure of 5-day vinblastine influsion in the treatment of patients with renal cell carcinoma. Cancer Treat Rep 1985; 69: 227-8. 8. Crivellari D, Tumolo S, Frustaci S, Galligioni E, Figoli F, Lo Re G, Veronesi A, Monfardini S. Phase II study of five-day continuous infusion of vinblastine patients with metastatic renal cell carcinoma. Am J Clin Oncol 1987; 10: 231-3. 9. De Kernion JB, Berry D. The diagnosis and treatment of renal cell carcinoma. Cancer 1980; 45: 1947-56. 10. Van t'Hull E, Schellenkens H, Loewenberg B, de Vries MJ. Influence of interferon preparations on the proliferative capacity of human and mouse bone marrow cells in vitro. Cancer Res 1978; 38: 911-4. 11. Holdener EE, Schnell P, Spieler P, Sem H. In vitro effect of interferon-alfa on human granulocyte/macrophage progenitor cells and human clonogenic tumor cells. Recent Res Cancer Res 1984; 94: 205-19. 12. DeKernion JB, Sarna G, Figlin R, Lindner A, Smith RB. The treatment of renal cell carcinoma with human leukocyte alphainterferon. J Urol 1983; 130: 1063-6. 13. Muss HB, Costanzi JJ, Leavitt R et al. Recombinant alfa interferon in renal cell carcinoma: A randomized trial of two routes of administration. J Clin Oncol 1987; 5: 286-91. 14. Kirkwood JM, Harris JE, Vera R et al. A randomized study of low and high dose of leukocyte alfa-interferon in metastatic renal cell carcinoma: The American Cancer Society Collaborative Trial. Cancer Res 1985; 45: 863-71. 15. Vugrin D, Hood L, Taylor W, Laszlo J. Phase II study of hyman lymphoblastoid interferon in patients with advanced renal cell carcinoma. Cancer Treat Rep 1985; 69: 817-20. 16. Quesada JR, Swanson DA, Gutterman JU. Phase II study of interferon alpha in metastatic renal cell carcinoma: A progress report. J Clin Oncol 1985; 3: 1086-92. 17. Krown SE. Interferon treatment of renal cell carcinoma. Cancer 1987; 59:647-51. 18. Fossa SD, De Garis ST. Further experience with recombinant interferon alfa-2a with vinblastine in metastatic renal cell carcinoma. A progress report. Int J Cancer 1987; 1: 35—40. 19. Bergerat JP, Herbrecht R, Dufour P et al. Combination of recombinant interferon alfa-2a and vinblastine in advanced renal cell cancer. Cancer 1988; 62: 2320-4. 20. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results in cancer treatment. Cancer 1981; 47: 207-14. 21. Holdener F.F.. The efficacy and safety of human recombinant interferon alfa-2a in metastatic renal cell carcinoma. In Kaye SB (ed): Progress in the treatment of renal cell carcinoma. Proc NatI Symp Queen's College. Medical Action Communication Ltd, Thorpe UK 1989: pp. 56-61. 22. Hirch FW, Kraaz B, Lohr GW, Bross KJ. Wirksamkeit und Nebenwirkungcn von rekombiniertem Interferon alpha-2a bci
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Received 15 November 1991; accepted 17 January 1992. Correspondence to: Sophie D. Fossa M.D.. Ph.D. The Norwegian Radium Hospital 0310 Oslo Norway
Original article Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: Results of a European multi-center phase III study S. D. Fossa,1 G. Martinelli,2 U. Otto,3 G. Schneider,4 H. Wander,5 F. Oberling,6 H. W. Bauer,7 U. Achtnicht & E. E. Holdener8 1
Department of Medical Oncology and Radiotherapy, The Norwegian Radium Hospital, Oslo; 2 Hospital San Giovanni, Bellinzona, Switzerland; ' Department of Urology, University Hospital Eppendorf, Hamburg; 4 Department of Medicine II, Division of Oncology, Augsburg; ^ Department of Internal Medicine, University Hospital, Goettingen, FRG; hDepartment of Onco-Hematology, CHU-Hautepierre, Strasbourg, France; 7Department of Urology, University Hospital Steglitz, Berlin, FRG; "Department of Clinical Research, F. Hoffman-La Roche Ltd., Basel, Switzerland Summary. A total of 178 patients with metastatic renal cell cancer were randomized to receive interferon alfa-2a (rIFN alfa-2a) or interferon alfa-2a + vinblastine (VLB). 1FN alfa2a was injected intramuscularly at a dose of 18 MIU 3 times a week and VLB was given intravenously at a dose of 0.1 mg/kg once every 3 weeks. The response rate was 11% for patients on monotherapy and 24% for those on combination treatment. The 5-year survival for 145 eligible patients was 9%, independently from the treatment arm. The performance status was significantly related to long-term prognosis, and 13% of the patients with performance status 0 were alive at 5 years, as compared to 6% and 0% for patients with a WHO grade of 1 and 2, respectively. The most frequent adverse
events in both treatment arms were flu-like symptoms (95%), fatigue (70%) and gastrointestinal disturbances (68%). Leukopenia was observed more frequently with combination treatment (53%) than with IFN alfa-2a alone (30%). In conclusion, rIFN alfa-2a monotherapy at this dose and schedule has modest antitumor activity in metastatic renal cell cancer. The combination of rIFN alfa-2a + VLB results in a doubling of the response rate, but this does not translate into prolonged survival. Toxicity (except leukopenia) and tolerance were similar in both treatment arms.
Introduction
rates in patients with metastatic renal cell carcinoma treated with either interferon alfa-2a alone, or in combination with vinblastine.
There is no standard treatment for patients with metastatic renal cell carcinoma (MRCC). Although a number of drugs have been tested in MRCC, the overall results are disappointing [1-6]. Vinblastine (VLB) has been claimed to be the most active antineoplastic drug, but more recent trials show that the response rate does not exceed 10% [7, 8]. The rare occurrence of spontaneous regression of metastases from MRCC [9] has resulted in the speculation that an immunologic rejection of an occasionally antigenic tumor may lead to tumor regression. Biologic response modifiers including interferon can produce immunostimulation in humans. Interferon has also direct antiproliferative activity in both normal and malignant cells [10, 11]. Once interferon became available for clinical use, a number of trials using interferon as single agent [12-17] or in combination with vinblastine, were performed [18, 19]. Interferon monotherapy resulted in overall response rates ranging from 5% to 20% depending on dose and schedule, whereas the combination with vinblastine generated response rates up to 40%. The aim of the present multi-center phase III trial was to compare the response and long-term survival
Key words: interferon, ± vinblastine, renal cell carcinoma, response rate, survival
Patients and methods From 1985 to 1986 a total of 178 patients with metastatic renal cell carcinoma were entered into this open phase III study. Eligibility criteria were as follows: age up to 70 years, histologically proven measurable or evaluable MRCC, nephrectomy more than 4 weeks prior to the study entry, performance status WHO grade <2 [20] (Karnofsky performance status of >70%), WBC >3 Giga/1, serum creatinine <150 nmol/1, and bilirubin, ASAT and ALAT within 25% above the upper limit of the normal range. Patients with cerebral metastases, with radiotherapy to the marker lesions or with previous anticancer chemotherapy were not eligible for the study. The study protocol had to be approved by the institutional Ethical Committee and patients had to give at least verbal consent Recombinajit interferon alfa-2a, (rIFN alfa-2a - Roferon*-AJ was supplied by F. Hoffmann La-Roche Ltd., Basel, Switzerland. Vinblastine (Velbe*) was used as commercially available. For 87 patients entered in the combination arm. rIFN alfa-2a was given at a dose of 18 MIU intramuscularly three times a week and VBL was injected intravenously at a dose of 0.1 mg per kilogram body weight once every three weeks. For 91 patients entered in the monotherapy treatment arm, the interferon dosage was the same as in the combination treatment arm. At baseline, a complete medical history was taken and physical
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302 examination performed on every patient. In addition, hematological analysis including hemoglobin, white blood cell count and platelet count were performed together with serum chemistry which included bilirubin, transaminases, alkaline phosphatase, serum creatinine and serum calcium. Additional examinations were performed in order to determine the extent of tumor using chest x-ray, CT-scan, brain scan, ultrasonography as well as x-ray of bone where applicable. WHO response criteria were used to assess tumor responses after at least 2 months' treatment [20). Patients with 'early progression' (vide infra) were included into the progression category. Patients were required to receive a minimum of 2 months treatment in order to be evaluated for response unless disease progression was observed during this period (early progression). Treatment was given until disease progression or in case of 'no change' or partial response for a maximum of one year, unless unacceptable toxicity developed. Completely responding patients (CR) were to be given therapy for further 6 months after demonstration of CR. Toxicity was, whenever possible, assessed in patients according to the WHO classification system for toxicity grading [20|. Flu-like symptoms were arbitarily graded as grade 1: mild; grade 2: moderate; grade 3: severe; grade 4: life-threatening. In cases of grade II toxicity which were thought to be related to IFN treatment, rIFN alfa-2a was discontinued until the patient recovered. Treatment was restarted with 12 MIU of rIFN alfa-2a. In cases of grade IV toxicity which were thought to be related to IFN treatment, retreatment started at a dose of 9 MIU. Grade III myelosuppression thought to be caused by VLB resulted in the subsequent injection being delayed until recovery. No dose reduction was made after grade III toxicity, but subsequent VLB doses had to be reduced by 25% in case of grade IV toxicity. Statistical analyses were carried out using the Statistical Analysis System (SAS). Statistical tests were restricted to the hypothesis that there was no difference between the treatment groups with respect to the following parameters: tumor response (Chi-square test, Fisher's Exact Test), duration of response (Wilcoxon test), survival duration (Wilcoxon test, Log rank test). Objective responses were evaluated in 1987, but the survival was calculated according to the Kaplan-Meyer method with the last cut-off in March 1991. Umvariate and Cox multivariate regression analysis were performed in order to define factors predictive of response and survival.
Results A total of 178 patients were entered by 13 institutions. Twenty-four patients (13%) did not fulfill the protocolstated eligibility criteria and had to be excluded from the response analysis together with 9 patients who had bone metastases as the only site of evaluable disease. Twenty-six of the remaining 145 eligible patients were withdrawn early from the study due to toxicity. They had had treatment for less than 2 months and none of them had disease progression at the time of withdrawal. The total number of patients who were evaluable for response was thus 119 (Table 1). Of these were 85 males and 34 females. The median duration for the disease before entering the trial was 4.3 and 5.4 months for patients on rIFN alpha-2a and combination treatment, respectively. The median Karnofsky performance status was 90% and the majority of the patients had lung metastases as their indicator lesions. The response rate (Table 2) in all patients was 22/ 119 (16%), for rIFN alfa-2a alone it was 6/53 (11%; 95% CI: 4-23%), for the combination of rIFN alfa-2a +
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Table 1. Demographics. Evaluable patients
All patients IFN
IFN + VLB
IFN
IFN + VLB
No. of patients
87
91
53
66
Age (yrs) - median - range
57
57
57
31-74
30-81
31-70
56.5 30-70
64 23
65 26
39 14
46 20
80
90
90
30-100
70-100
70-100
Sex
- male - female
Performance status (Karnofsky) 80 - median - range 70-100 Time from Dx* to Txb (months) - median - range Indicator lesion(s) - Lung — Lymph node - Liver - Bone - Other
5.9
5.1
4.3
5.4
1-110
1-262
1-110
1-208
34 13 9 4 15
45 10
8 5 11
31 13 6 9
42 9 7 10
" Diagnosis. b Treatment start. Table 2. Response to rIFN alfa-2a alone or in combination with vinblastine. Evaluable patients only IFNA alfa-2a
IFN alfa-2a + vinblastine
Response
(n-53)
(n - 66)
Overall response Complete response Partial response No change Progressive disease
6 (1 1%)" 1 (2%) 5 (9%) 32 (60%)
16(24%)h 1 (2%) 15(23%) 29 (44%) 21 d (32%)
15C (25%)
" 95% CI 4%-23%. b 95% CI 15%-36%. c Including 9 early PD. d Including 11 early PD.
vinblastine it was 16/66 (24%; 95% CI 15-36, twotailed Fisher's Exact Test 0.1; Chi square 0.07). Complete responses were seen in 2 patients, one in each treatment arm. Responses were mainly seen in lung metastases and lymph node metastases. The median duration time of partial response was 8.6 months (range 3.7 to 18.3 months) and 6.0 months (range 2.7 to 18.6 months), for rIFN alfa-2a and the combination, respectively. For two patients with a complete response the response duration was 5.3+ months (rIFN alfa-2a alone) and 5.6+ months (rIFN alfa-2a plus vinblastine). There was no difference in survival between the 2 treatment arms independently whether all included patients were considered or only eligible and evaluable
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Fig. 1. Survival in patients with metastatic renal cell carcinoma treated with rIFN alfa-2a or rIFN alfa-2a + vinblastine. a) All included patients; b) Eligible patients; c) Evaluable patients.
(Fig. 1). In all 3 groups performance status (WHO; 20) had a significant impact on survival (Fig. 2). Sex, age, the duration of the disease prior to study entry, previous radiotherapy and the performance status had no significant impact on tumor response using logistic regression analysis. The Cox regression analysis for survival showed that age <60 years and WHO performance status of 0 were significant independent prognostic parameters. Toxicity was analyzed for all 178 patients entered into the trial (Table 3). The median duration of rIFN alfa-2a treatment in all patients entered into the trial was 112 days (1-468 days) for the monotherapy and 132 days (8-500 days) for the combination therapy. The median treatment duration in responders (CR + PR) was 261 (140-467) days with IFN alfa-2a monotherapy and 209 (91-499) days with the combination treatment. The median cumulative dose of rIFN alfa-2a
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0 12
24
36
48
60
72
Months from treatment start Fig. 2. Survival in patients with metastatic renal cell carcinoma treated with rIFN alfa-2a or rIFN alfa-2a + VLB according to performance status. ( • • • ) WHO grade 0; (ooo) WHO grade 1; (* A A) WHO grade 2; a) All included patients; b) Eligible patients; c) Evaluable patients.
was 774 MIU and 882 MIU for monotherapy and combination therapy, respectively. A total of 48 patients treated for at least 60 days with rIFN alfa-2a monotherapy and 49 similar patients receiving IFN alfa-2a + VLB tolerated full dose (- 18 MIU TTW) of rIFN. All responders from the monotherapy arm were in the group of 48 patients who received full dose. In the IFN alfa-2a + VLB arm, 12 of 16 responders received the full dose of IFN during the first 60 days. Thirty-one patients had one or more dose reductions of VLB (median: 2; range: 1-6), usually after 2 or more VLB injections. Concomitant rIFN alfa-2a decrease was necessary in 2 of the 31 patients.
304 Table 3. Spectrum of most frequent clinical side effects observed in 178 patients treated with rIFN alfa-2a (n - 87) or the combination of rIFN alfa-2a + vinblastine (n - 91). % of patients rIFN alfa-2a
rIFN alfa-2a + vinblastine
Class of adverse events (n - 87)
(n-91)
95 (22) 70 (22) 68 (23) 21 (10) 9(10) 7(1) 7(1)
98 (23) 68(10) 70(19) 20(9) 5(1) 7(2) 7(2)
Flu-like symptoms Fatigue Gastrointestinal CNS/PNS Skin + appendages M usculo-skeletal Cardiovascular (
): Percent of patients with grade III or grade IV toxicity.
The most frequent side effects were flu-like symptoms (95%), fatigue (70%) and gastrointestinal disturbances (68%). These side effects were rated as mild or moderate in about 80% of the patients. There was no difference between the two treatment arms. There was also no significant difference in weight loss between the two treatment arms with 23% (IFN alone) and 25% (rIFN + VLB) showing more than 10% weight loss during the treatment. The most frequent laboratory changes were leukopenia and increase in liver enzymes. Leukopenia was seen more frequently in the combination therapy (53%), as compared to the monotherapy (30%). Grade HI leukopenia was observed in 5 patients within the combination arm and in 3 patients treated with IFN alfa-2a alone. No patient developed Grade IV leukopenia.
Discussion
combination with interferon alfa in the clonogenic assay system [36], suboptimal but less toxic doses of both compounds may well result in a higher overall response rate in a clinical setting. This higher response rate with the combination in the current study was due to an increase in partial responses while the complete response rate remained below the 5% level. This may, together with the regrettable lack of any external review of the responses, explain why the higher response rate in the combination arm did not translate into a prolongation of median survival compared to interferon alfa2a monotherapy. On the other hand, a median survival of 12 months in both treatment groups in the present trial compares favourably with other published data [37], where only the best prognostic subgroup (e.g. excellent performance status, time from initial diagnosis >1 year, maximally one metastatic site, no prior chemotherapy and no recent weight loss) showed a similar median survival. As only a small proportion of our patient population fits into this most favourable patient category, this could suggest a survival benefit for both treatments in the present trial as compared to series with patients receiving chemotherapy [37]. However, only prospective randomized trials of interferon or an interferon-cytotoxic drug combination against a no treatment control and stratified for prognostic factors can demonstrate a survival advantage. Such studies, whilst scientifically interesting, may be difficult to perform. Our overall 5-year survival of 9% for eligible patients is in agreement with recent observations by Neidhart et al. [38]. As in other reports [37, 38] patients with an excellent performance status had the best prognosis, independently from treatment. In future studies with interferon MRCC, patients should be stratified according to this criterion. Toxicity and tolerance observed in the present trial were not different compared to previously reported studies using similar dosages for IFN monotherapy and in combination with low dose vinblastine. As expected there was a slight increase in more frequent and more pronounced leukopenia in the combination therapy group, otherwise the spectrum of toxicity was quantitatively and qualitatively similar. In conclusion, the combination of intermediate dose rIFN alfa-2a with low dose vinblastine resulted in doubling of the objective response rate compared to interferon monotherapy (at the same dose), without translating into increased survival. Toxicity and tolerance of both treatments were very similar.
Interferon alfa treatment in MRCC consistently produces objective response rates between 10%-20% [21-23] which is confirmed by the monotherapy arm of the present study. There is a trend of a possible doseresponse relationship for interferon therapy in MRCC [24], with lower doses resulting in less than a 10% objective response, whereas higher doses can generate objective response rates beyond 20% [25]. The combination of interferon alfa-2a with vinblastine has resulted in an increase of the objective response rate in several phase II studies [26-31] with response rates between 16%-36%. The present prospectively randomized study confirms these data by demonstrating a doubling of the response rate to 24% for the combination treatment. Vinca alkaloids as monotherapy in much higher doses as compared to the dose given in this trial have resulted References in very low response rates, usually less than 10% [7, 32, 1. Hahn RG, Bauer M, Wolter J, Creech R, Bennett JM, Wampler 33] with only one exception [34]. Since synergistic efG. Phase II study of single-agent therapy with megestrol fects are seen when cytostatics are combined with inacetate, VP-16-231, cyclophosphaxnide, and dianhydrogalactiterferon alfa [35] and vinblastine showed the highest tol in advanced renal cell cancer. Cancer Treat Rep 1979; 63: additive antiproliferative effect of all vinca alkaloids in 513-5
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Received 15 November 1991; accepted 17 January 1992. Correspondence to: Sophie D. Fossa M.D.. Ph.D. The Norwegian Radium Hospital 0310 Oslo Norway