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Treatment of metastatic renal cell cancer patients with recombinant subcutaneous human interleukin-2 and interferon-α
Annals of Oncology 1: 377-378, 1990. © 1990 Kluwer Academic Publishers. Printed in the Netherlands.
Short report Treatment of metastatic renal cell cancer patients with recombinant subcutaneous human interleukin-2 and interferon-a J. Atzpodien,1 A. Korfer,1 P.A. Palmer,2 C.R. Franks,2 H. Poliwoda1 & H. Kirchner1 * Department of Hematology & Oncology M H H Univ. Medical Center, Hannover, Germany; *• EuroCetus BV, Amsterdam, The Netherlands
Summary, We treated 17 patients who had progressive metastatic renal carcinoma with a combination of subcutaneous recombinant human interleukin-2 (administered every 12 hours, at 9.0 million IU/m2 on days one and two, followed by 1.8 million IU/m2, five days per week, over six consecutive weeks) and interferon-a2b (given at 5 million U/m2 three times weekly, for six consecutive weeks). Treatment courses were repeated in patients presenting with stable or regressive disease after the six weeks of combination therapy (11 of 14 evaluable). Two and three of 14 evaluable patients achieved complete and partial remissions, respectively. Toxicity of this regimen was moderate, with local inflammation of the injection sites, grade I-II (WHO) fevers, chills, malaise, nausea/vomiting, and anorexia in more than two-thirds of the patients treated. Key words: renal cell carcinoma, interleukin-2, interferon-a
Introduction Metastatic renal cell carcinoma is a poor-prognosis disease with survival rates of approximately 26% and 4% at one and three years, respectively [1]. Therapeutic strategies have included hormonal treatment and various chemotherapeutic agents, with response rates below 10% [1—3]. Rosenberg and colleagues reported a response rate of 33% when using high-dose recombinant human interleukin2 (rDL-2, 600,000 IU/kg/day 3x daily) in conjunction with lymphokine-activated killer cells [4]. We have now evaluated the safety, tolerance, and clinical effects of a combination of low dose s.c. rIL-2 and s.c. recombinant interferon-a2b (rIFN-a2b) in metastatic renal cell cancer. The results of the study are the subject of this report.
Patients and methods Patients Seventeen patients with metastatic renal carcinoma, all of them evaluated for safety and tolerance, were treated in this study. Response to treatment was assessed in the 14 patients who completed one or more treatment cycles according to protocol. All patients had histologically confirmed tumors and presented with clinically evaluable progressive disease as demonstrated by standard radiographic procedures. Recombinant interleukin-2 and rIFN-a2b were self-administered in an outpatient setting. Patients received s.c.
rIL-2 (EuroCetus, Amsterdam) at 9.0 million IU/m2 twice daily x 2 days, followed by six weeks of combined administration of s.c. rIL-2 (1.8 million IU/m2 twice daily, x5 days/week), and s.c. rIFN-a2b (Essex-Schering, Miinchen) at 5.0 million U/m2 x3/week. A re-evaluation of tumor status was performed at regular ten-week intervals.
Results Treatment response Five of fourteen evaluable patients had a greater than 50% reduction in metastatic disease after one cycle of rIL-2 and rIFN-a2b, and two of these five subsequently achieved complete remissions. The median response durations have been 6+ months (range 3 to 11+ mos.) in patients with complete or partial remissions and four months (range 3 to 8) in those with stable disease. The median time from diagnosis of metastatic disease was calculated at 10+ months (patients with CR and PR; range of 7+ to 22+), and 18+ months (stable-disease patients, n=6; range of 7+ to 49+). Adverse effects As summarized in Table 1, systemic toxicity was moderate, and mostly limited to WHO grades I and n. Fevers, chills, malaise, anorexia, nausea and/or vomiting occurred in more than 70% of patients treated. None of these, however, required inpatient treatment. In a total of three treatment courses, grade HI WHO toxicity was observed, resulting in
378 a 50% dose reduction. No toxic deaths occurred. Patients were administered 96.7% and 93.6% of the projected total doses of rIL-2 and rIFN-a2b, respectively. Table 1. Systemic toxicity. Side effect
Fever Anorexia Chills Malaise Nausea/vomiting Liver toxicity Diarrhea Hypotension Dyspnea
Number of treatment cycles WHO grade I/II
Grade III
27 27 23 20 21 14 12 10 10
0 0 0 3 1 0 1 1 1
A total of 17 patients and 28 treatment cycles were evaluated for toxicity. No grade IV toxicity was observed.
Discussion In this trial the adverse effects of systemic rIL-2 reported previously by Rosenberg and colleagues were substantially reduced [4]. While both the number of patients evaluable and the median follow-up time were limited, objective tumor remissions were induced in 36% (95% confidence limits, 13-65%) of patients receiving the combination of subcutaneous rIL-2 and rIFN-a2b. In addition, a significant proportion of patients with progressive renal carcinoma exhibited stable disease upon treatment Only longer
follow-up, however, will permit ascertainment of a survival benefit in patients who continue on treatment in the absence of objective tumor response. It also appears that a larger patient accrual will be needed to further assess the therapeutic efficacy of outpatient s.c. rIL-2 [5] and rlFNa2b in patients with metastatic renal carcinoma.
References 1. Buzaid AC, Todd MB. Therapeutic Options in Renal Cell Carcinoma. Semin Oncol 1989; 16: 12-9. 2. Harris DT. Hormonal therapy and chemotherapy of renal cell carcinoma. Semin Oncol 1983; 10:422-30. 3. Krown SE. Therapeutic options in renal cell carcinoma. Semin Oncol 1985; 12: 13-7. 4. Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE. A progress report on the treatment of 157 patients with advanced cancer using lympbokine-activated killer cells and interieuldn-2 or high-dose interleukin-2 alone. N Engl J Med 1987; 316: 889-97. 5. Atzpodien J, KSrfer A, Evers P, Franks CR, KnOver-Hopf J, LopezHanninen E, Fischer M, Mohr H, Dallmann I, Hadam M, Poliwoda H, Kirchner H. Low dose subcutaneous recombinant interleukin-2 in advanced human malignancy: a Phase II outpatient study. Mol Biother 1990; 2: 18-26. Received 26 March 1990; accepted 3 April 1990. Correspondence to: Dr. Jens Atzpodien Abt Hamatologie u. Onkologie (6860) Medizinische Hochschule Hannover D-3000 Hannover 61, Germany
Note of the Editor While this "Short report" was already in press, the authors published another paper (Lancet 1990; 1:1509): the 17 patients with renal cell cancer included in that article are the same as those discussed in this short report They should therefore be accounted only once in any future compilation of literature data.
Short report Treatment of metastatic renal cell cancer patients with recombinant subcutaneous human interleukin-2 and interferon-a J. Atzpodien,1 A. Korfer,1 P.A. Palmer,2 C.R. Franks,2 H. Poliwoda1 & H. Kirchner1 * Department of Hematology & Oncology M H H Univ. Medical Center, Hannover, Germany; *• EuroCetus BV, Amsterdam, The Netherlands
Summary, We treated 17 patients who had progressive metastatic renal carcinoma with a combination of subcutaneous recombinant human interleukin-2 (administered every 12 hours, at 9.0 million IU/m2 on days one and two, followed by 1.8 million IU/m2, five days per week, over six consecutive weeks) and interferon-a2b (given at 5 million U/m2 three times weekly, for six consecutive weeks). Treatment courses were repeated in patients presenting with stable or regressive disease after the six weeks of combination therapy (11 of 14 evaluable). Two and three of 14 evaluable patients achieved complete and partial remissions, respectively. Toxicity of this regimen was moderate, with local inflammation of the injection sites, grade I-II (WHO) fevers, chills, malaise, nausea/vomiting, and anorexia in more than two-thirds of the patients treated. Key words: renal cell carcinoma, interleukin-2, interferon-a
Introduction Metastatic renal cell carcinoma is a poor-prognosis disease with survival rates of approximately 26% and 4% at one and three years, respectively [1]. Therapeutic strategies have included hormonal treatment and various chemotherapeutic agents, with response rates below 10% [1—3]. Rosenberg and colleagues reported a response rate of 33% when using high-dose recombinant human interleukin2 (rDL-2, 600,000 IU/kg/day 3x daily) in conjunction with lymphokine-activated killer cells [4]. We have now evaluated the safety, tolerance, and clinical effects of a combination of low dose s.c. rIL-2 and s.c. recombinant interferon-a2b (rIFN-a2b) in metastatic renal cell cancer. The results of the study are the subject of this report.
Patients and methods Patients Seventeen patients with metastatic renal carcinoma, all of them evaluated for safety and tolerance, were treated in this study. Response to treatment was assessed in the 14 patients who completed one or more treatment cycles according to protocol. All patients had histologically confirmed tumors and presented with clinically evaluable progressive disease as demonstrated by standard radiographic procedures. Recombinant interleukin-2 and rIFN-a2b were self-administered in an outpatient setting. Patients received s.c.
rIL-2 (EuroCetus, Amsterdam) at 9.0 million IU/m2 twice daily x 2 days, followed by six weeks of combined administration of s.c. rIL-2 (1.8 million IU/m2 twice daily, x5 days/week), and s.c. rIFN-a2b (Essex-Schering, Miinchen) at 5.0 million U/m2 x3/week. A re-evaluation of tumor status was performed at regular ten-week intervals.
Results Treatment response Five of fourteen evaluable patients had a greater than 50% reduction in metastatic disease after one cycle of rIL-2 and rIFN-a2b, and two of these five subsequently achieved complete remissions. The median response durations have been 6+ months (range 3 to 11+ mos.) in patients with complete or partial remissions and four months (range 3 to 8) in those with stable disease. The median time from diagnosis of metastatic disease was calculated at 10+ months (patients with CR and PR; range of 7+ to 22+), and 18+ months (stable-disease patients, n=6; range of 7+ to 49+). Adverse effects As summarized in Table 1, systemic toxicity was moderate, and mostly limited to WHO grades I and n. Fevers, chills, malaise, anorexia, nausea and/or vomiting occurred in more than 70% of patients treated. None of these, however, required inpatient treatment. In a total of three treatment courses, grade HI WHO toxicity was observed, resulting in
378 a 50% dose reduction. No toxic deaths occurred. Patients were administered 96.7% and 93.6% of the projected total doses of rIL-2 and rIFN-a2b, respectively. Table 1. Systemic toxicity. Side effect
Fever Anorexia Chills Malaise Nausea/vomiting Liver toxicity Diarrhea Hypotension Dyspnea
Number of treatment cycles WHO grade I/II
Grade III
27 27 23 20 21 14 12 10 10
0 0 0 3 1 0 1 1 1
A total of 17 patients and 28 treatment cycles were evaluated for toxicity. No grade IV toxicity was observed.
Discussion In this trial the adverse effects of systemic rIL-2 reported previously by Rosenberg and colleagues were substantially reduced [4]. While both the number of patients evaluable and the median follow-up time were limited, objective tumor remissions were induced in 36% (95% confidence limits, 13-65%) of patients receiving the combination of subcutaneous rIL-2 and rIFN-a2b. In addition, a significant proportion of patients with progressive renal carcinoma exhibited stable disease upon treatment Only longer
follow-up, however, will permit ascertainment of a survival benefit in patients who continue on treatment in the absence of objective tumor response. It also appears that a larger patient accrual will be needed to further assess the therapeutic efficacy of outpatient s.c. rIL-2 [5] and rlFNa2b in patients with metastatic renal carcinoma.
References 1. Buzaid AC, Todd MB. Therapeutic Options in Renal Cell Carcinoma. Semin Oncol 1989; 16: 12-9. 2. Harris DT. Hormonal therapy and chemotherapy of renal cell carcinoma. Semin Oncol 1983; 10:422-30. 3. Krown SE. Therapeutic options in renal cell carcinoma. Semin Oncol 1985; 12: 13-7. 4. Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE. A progress report on the treatment of 157 patients with advanced cancer using lympbokine-activated killer cells and interieuldn-2 or high-dose interleukin-2 alone. N Engl J Med 1987; 316: 889-97. 5. Atzpodien J, KSrfer A, Evers P, Franks CR, KnOver-Hopf J, LopezHanninen E, Fischer M, Mohr H, Dallmann I, Hadam M, Poliwoda H, Kirchner H. Low dose subcutaneous recombinant interleukin-2 in advanced human malignancy: a Phase II outpatient study. Mol Biother 1990; 2: 18-26. Received 26 March 1990; accepted 3 April 1990. Correspondence to: Dr. Jens Atzpodien Abt Hamatologie u. Onkologie (6860) Medizinische Hochschule Hannover D-3000 Hannover 61, Germany
Note of the Editor While this "Short report" was already in press, the authors published another paper (Lancet 1990; 1:1509): the 17 patients with renal cell cancer included in that article are the same as those discussed in this short report They should therefore be accounted only once in any future compilation of literature data.