- Email: [email protected]
Subcutaneous recombinant interleukin-2 (rIL-2) in out-patients with metastatic renal cell carcinoma
Annals of Oncology 7: 525-528, 1996. O 1996 Kluwer Academic Publishers. Printed in the Netherlands.
Short report Subcutaneous recombinant interleukin-2 (rIL-2) in out-patients with metastatic renal cell carcinoma Results of a multicenter SCAPP1 trial J. M. Tourani,1 V. Lucas,2 D. Mayeur,3 B. Dufour,4 M. Di Palma,5 C. Boaziz,6 P. Grise,7 C. Varette,8 J. M. Pavlovitch,9 E. Pujade-Lauraine,10 D. Larregain,11 E. Ecstein,12 M. Untereiner,13 E. Vuillemin,14 S. Merran15 & J. M. Andrieu1 1
evaluable patients (18%) had objective responses (95% CI: 9% to 37%) with one complete response. Treatment was Background: This multicenter phase II trial was conducted in interrupted or reduced due to toxicity for seven patients: order to evaluate the efficacy and toxicity of the subcutane- Neuropsychiatric symptoms (3 patients), joint pain (1 paous route of administration of rIL-2 in the treatment of tient), major asthenia and anorexia (1 patient), stroke (1 patients with metastatic renal cell carcinoma and to check patient), and septicemia (1 patient). Other systemic side whether an increased cumulative dose of rIL-2 increases effi- effects in the remaining patients were acceptable. Seventeen patients received maintenance treatment. In none of the cacy. Patients and methods: Thirty-nine patients with metastatic patients did the response status improve during this mainrenal cell carcinoma were included in this study. During the tenance period. The median follow-up of all of the patients induction period, rIL-2 was administered subcutaneously 5 included was 19 months. The one- and two-year survivals days a week for 8 weeks. The weekly dosages were 90 MTU were 65% and 33%, respectively, ad the median duration of during weeks 1 and 6; 63 MTU during weeks 2 to 4 and 7 to response was 11 months (5 to 16+). 9. After evaluation, responders and patients with stable disConclusions: This multicentric study confirms the efficacy ease received maintenance treatment which was discontinued of subcutaneously-administered rIL-2 in patients with metaupon the appearance of disease progression or unacceptable static renal cell carcinoma in terms of both response rate and toxicity. During the maintenance period, rIL-2 was adminis- survival. The role of a maintenance therapy needs further tered 5 days a week for 4 weeks followed by a 2-week rest evaluation. period. The weekly dosages were 90 MIU in week 1 and 63 MIU in weeks 2 to 4. Key words: interleukin-2, out-patient, renal cell carcinoma, Results: After completion of induction treatment, 7 of 39 subcutaneous administration, survival Summary
The prognosis of metastatic renal cell carcinoma is very poor. Since the mid-1980s, recombinant interleukin-2 (rIL-2) has been used to treat patients with metastatic renal cell carcinoma. The initial protocols were based on the principles of chemotherapy administration, with intravenous bolus or continuous infusion of maximal tolerable doses [1, 2]. These studies demonstrated (depending on schedule), objective response rates of 15%-30% and complete response rates of 3%-5%. These protocols produced pulmonary, renal, cardiac and hemodynamic toxic effects requiring hospitalization, sometimes even in an intensive care unit. In order to improve tolerance, many authors have proposed that rIL-2 be subcutaneously administered on an out-
patient basis [3, 4]. The results of these monocentric studies show that the subcutaneous route of administration has comparable efficacy, with objective response rates of 20% to 29% and complete response rates of 2% to 5%, with less toxicity. We report the results of our phase II trial using rIL-2 given subcutaneously in patients with metastatic renal cell carcinoma The original aim of our multicentric study was to test the dose/efficacy concept by giving, over a 10-week period, a cumulative dose of rIL-2 analogous to that administered intravenously over the same duration of time according to the reference protocol of West etal. [2].
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 19, 2016
Oncology Unit, Laennec Hospital, Paris; 2 Oncology Unit, La Source Hospital, Orleans; 3Internal Medicine Unit, A. Mignot Hospital, Le Chesnay; * Urology Unit, Necker Hospital, Paris; 3 Oncology Unit, P. Brousse Hospital, VMejuifi 6 Oncology Unit, Avicenne Hospital, Bobigny; 1 Oncology Unit, C. Nicolle Hospital, Rouen; 8Oncology Unit, St. Antoine Hospital, Paris; ''Oncology Unit, Troyes Hospital, Troyes; w'Oncology Unit, Hotel Dieu Hospital, Paris; "Oncology Unit, Cote Basque Hospital, Bayonne; nUrology Unit, H. Mondor Hospital, Creteil; ^Oncology Unit, C. Bernard Hospital, Metz; uOncology Unit, Pitie-Salpitriere Hospital, Paris; "Radiology Department, F.M.P., Paris, France
526 Patients and methods
Statistical analysis Clinical response and toxicity were evaluated according to WHO criteria. Complete response (CR) was defined as the complete disappearance of all clinical and/or radiological disease for at least 4 weeks; partial response (PR) was defined as a 50% or greater decrease in the sum of the products of the longest perpendicular diameters of measurable lesions for at least one month; stable disease (SD) was defined as a decrease of less than 50% or an increase of less than 25% in measurable lesions; progressive disease (PD) was defined as an increase of more than 25% or the development of new lesions. Responses were evaluated by investigators as well as by independent reviewers to assess the results of treatment The duration of response was calculated from the day the response was first documented to the day of documented progressive disease. The overall survival was calculated from the start of treatment Survival curves were plotted by using the Kaplan-Meier method and statistical differences were estimated using the log-rank test
Results Patient characteristics From April 1993 to April 1994, 39 patients with metastatic renal cell carcinoma, from 11 different centers, were included in this study. The initial characteristics of these patients are summarized in Table 1. Eleven of
Delivered dose and toxicity During the induction period, the cumulative planned dosage of rIL-2 administered subcutaneously was 558 MIU. For 5 of the 39 patients treatment had to be interrupted due to an obvious progression of the disease. For the 39 patients the mean cumulative dose of rIL-2 was 489 MIU (87% of the planned dose). Seven patients received 29%, 44%, 50%, 72%, 82%, 82% and 90% of the planned dose because treatment was interrupted or decreased due to toxicity. These toxic effects included neuropsychiatric manifestations (3 cases), stroke (1 case) septicemia (1 case) joint pain (1 case) and major weakness (1 case). Table 2 summarizes the side effects observed during the induction phase. There were five instances of thyroid dysfunction, namely, biological and clinical hypothyroidism in 2 patients requiring substitute treatments, and biologica 1 hyperthy-
Table 1. Patient characteristics. Number of patients Untreated patients Male/female Age (years) Mean Range Functional performance status (World Health Organization) 0 1 2 Previous nephrectomy (time from nephrectomy) <1 year >1 year Sites of metastatic disease Lung Kidney Lymph nodes Liver Bone Adrenal Pleura Soft tissue Spleen Number of metastatic sites 1 2 3 4 Number of bad prognosis factors 0 1 2 3
39 28 30/9 58 38-74 22 13 4 28 11 24 2 19 7 4 8 3 2 1 19 11 7 2 3 15 11 10
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 19, 2016
Patients with progressive, histologjcally proven, metastatic renal cell carcinoma and clinically measurable or evaluable disease were included in this study. The study was approved by the Paris Necker Enfants-Malades ethical committee, and patients were entered after their written informed consent was obtained. Those with brain metastases, second neoplasms, functional performance status (PS) >2, uncontrolled cardiovascular disease (congestive heart failure, coronary artery disease), severe renal dysfunction or who had previously been treated with rIL-2 were excluded. Prior to study entry, each patient's disease stage was determined by full clinical examination, determination of blood cell counts, serum electrolytes, liver, renal and thyroid functions, chest X-ray, technetium pyrophosphate bone scan, and thoracic, abdominal and brain computed tomographic scanning. During the treatment, tumor volume was evaluated clinically and radiologically after the induction period and after the second, fourth, and sixth maintenance cycles. The rIL-2 (Aldesleukin, Chiron, BV, Amsterdam, The Netherlands) was administered subcutaneously during the first and sixth weeks at a dose of 9 million international units (MIU), twice daily for 5 consecutive days and during the second, third, fourth, seventh, eighth, and ninth weeks at 9 MIU twice daily, on days 1 and 2, followed by 9 MIU once daily, on days 3, 4, and 5. The fifth week was free of treatment The daily dose of rIL-2 was reduced to 9 MIU in patients who developed severe toxicity (grade HI or IV). After induction evaluation and a 2-week rest period, in the absence of progression or unacceptable toxicity despite reduction of the rIL-2 dose, patients received maintenance therapy until progression or the advent of unacceptable toxic effects (grades IH or IV). Maintenance therapy was administered for a maximum of 7 cycles. Each cycle of the maintenance phase was separated by a 2-week rest period. During each maintenance cycle, rIL-2 was given subcutaneously on the same schedule as during the first, second, third, and fourth induction weeks. Paracetamol (500 mg orally every 4 to 6 hours) was given concomitantly in an attempt to ameliorate pyretic reactions.
these patients had previously received treatment: radiotherapy (n - 4), and/or chemotherapy (n - 6), and/or alpha interferon therapy (n ™ 10). According to Palmer et al. classification [5], 3 patients (8%) had no poorprognosis factors, 15 (38%) had 1,11 (28%) had 2 and 10 (26%) had 3 poor-prognosis factors.
527 Table 2. Toxicity and side effects during induction period.
Progression and survival
Event
The median follow-up of all included patients was 19 months. The response durations in the 7 responding patients were 5, 9, 11, 12, 13, 15+, 16+ months. The overall one-year survival and two-year survival were 65% (CI: 0.2437) and 33%, respectively. The one-year survivals for responders and non-responders were, respectively, 100% and 58% (P: 0.05). No significant differences in terms of survival were observed with respect to functional performance status, number of metastatic sites, the time between diagnosis and treatment of the metastatic disease and to administration of maintenance therapy.
0
I
n
m
IV
_ 18 28 7 5 31 38 38 14 26 31 34 37 37 36 38 35 36
14 11 5 11 8 6 1 12 5 5 3 1 2 3 -
20 9 6 17 23 2 1 12 8 1 2 2 1 1 -
3 1 4 3 _ 1 2 1 1 3
2 _ -
Discussion
Recombinant interleukin-2 has been used since 1984 for the treatment of metastatic renal cell carcinoma. The response rates with the intravenous route of administration schedules are around 20% [1, 2, 6] with " Painful swelling at the injection site. a benefit in terms of survival [7]. The protocols using high doses of rIL-2 given by bolus have significant toxic roidism in 3. All of these problems disappeared within effects requiring hospitalization, sometimes even in an a few weeks after the completion of rIL-2 treatment. intensive care unit. Continuous infusion, with interNone of the patients developed hemodynamic or grade mediate doses of rIL-2, improves tolerance but reHI or IV renal toxicity (WHO) during the induction quires a close follow-up on an in-patient basis. phase. Since the beginning of the 1990s, several authors have used the subcutaneous route of administration Response to induction treatment with lower doses of rIL-2. Due to very low toxicity, it has been possible to perform these subcutaneous trials All 39 patients were evaluable for response. Seven on an out-patient basis. The efficacy, based on the repatients (18%) had objective responses, and there was sponse rates, seems identical to those observed with one complete response (95 confidence limit 9% to the intravenous schedules. This modality allows the 37%); 17 patients (43%) had stabilization of their dis- treatment of older patients, or patients with cardiac or ease and 15 (38%) tumor progression. The sites of renal dysfunction who are usually excluded from intraobjective response were lymph nodes (3/19), pulmo- venous programs [4]. nary metastases (8/24) and primary renal tumor (1/2). Sleijfer et al., in their subcutaneous program, obtained a response rate of 20% with cumulative doses of Maintenance period rIL-2 between 306 MIU and 450 MIU according to the four- or six-week regimen [4]. Lissoni et al. reported Of the 24 patients with objective response or stable dis- a response rate of 29% after six weeks of treatment ease at the completion of the induction period, 17 re- using a cumulative dose of 216 MIU [3]. The continuceived a maintenance treatment For the 7 others, treat- ous infusion schedule as proposed by W.H. West ment was interrupted because of toxicity during the allowed the administration of 612 MIU over 10 weeks induction phase (5 cases) or by the patient's decision (2 with response rates of around 20%. In this study, durcases). Seventeen patients (pts) received 1 cycle; 13 pts: ing the 10 week induction period the patients received 2 cycles; 10 pts: 3 cycles; 7 pts: 5 cycles; 5 pts: 6 cycles 489 MIU (87% of the planned dose: 558 MIU). These and 3 pts received 7 cycles. The maintenance therapy doses did not improve the efficacy (18% of objective was interrupted in 11 patients because of an obvious response rate) and increased the toxicity, but the progression of the disease, and by the patient's decision median survival (20 months) and the two-year survival in 3 cases. A decrease in doses and/or a delay of 1-2 (33%) observed with this program seem promising. weeks in the treatment occurred in 8 patients because No improvement was observed during maintenance of side effects. During this maintenance period, one treatment among the 17 patients with objective regrade m toxic effect (infection) was observed. All other sponses or stabilization of disease. Sleijfer and Lissoni side effects were of grades I or II (WHO). In none of did not report data on the evolution of the disease stathe patients was the response status better than the one tus during the maintenance therapy. The role of such a at the end of the induction phase. treatment in patients with metastatic renal cell carci-
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 19, 2016
Fever Nausea/vomiting Diarrhea Asthenia Anorexia Chills Dyspnea Headache Local toxicity" Skin toxicity Cholestasis Elevated transaminase level Thrombocytopenia Stiffness Hypotension Infection Creatinine increase Neuropsychiatric symptoms
WHO grade of toxicity (Number of patients)
528 noma with an objective response or stabilization should be evaluated in further studies. In conclusion, this multicentric study confirms the efficacy of the subcutaneous rIL-2 programs in patients with metastatic renal cell carcinoma, with a response rate of around 20%, similar to those already published. Moreover, to our knowledge, this study is the first to confirm in terms of survival, the efficacy of subcutaneous rIL-2 programs. The role of a maintenance therapy needs further evaluation. To improve these results, combinations of rIL-2 and other drugs or cytokines have been suggested. Preliminary reports of such trials of rIL-2 combined with alpha interferon [8, 9] and with 5-fluorouracil and alpha interferon [10, 11] seem promising.
5. 6. 7. 8. 9.
10.
References
Received 19 February 1996; accepted 10 April 1996. Correspondence to: J. M. Tourani, MD Oncology Unit Laennec Hospital 42 rue de Sevres 75007 Paris, France
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 19, 2016
11. 1. Rosenberg SA, Lotze MT, Muul LM et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987; 316: 889-97. 2. West WH, Tauer KW, Yannelli JR et al. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy on advanced cancer. N Engl J Med 1987; 316: 898-905. 3. Lissoni P, Barni S, Ardizzoia A et al. Prognostic factors of the clinical response to subcutaneous immunotherapy with interleukin-2 alone in patients with metastatic renal cell carcinoma. Oncology 1994; 51: 59-62. 4. Buter J, Sleijfer DT, Van der Graaf WTA et al. A progress
report on the outpatient treatment of patients with advanced renal cell carcinoma using subcutaneous recombinant interleukin-2. Semin Oncol 1993; 20 (Suppl 9): 16-21. Palmer PA, Winke J, Philip T et al. Prognostic factors for survival in patients with advanced renal cell carcinoma treated with recombinant interleukin-2. Ann Oncol 1992; 3:475-80. Rosenberg SA, Lotze MT, Yang JC et al. Experience with the use of high-dose interieukin-2 in the treatment of 652 cancer patients. Ann Surg 1989; 210:474-85. Jones M, Philip T, Palmer P et al. The impact of interleukin-2 on survival in renal cancer. A multivariable analysis. Cancer Biother 1993; 8: 275-88. Atzpodien J, Kofrer A, Franks C et al. Home therapy with recombinant interleukin-2 and interferon-alfa 2b in advanced human malignancies. Lancet 1990; 335:1509-12. Figlin RA, Belldegrun A, Moldawer N, al. Concomitant administration of recombinant human interleukin-2 and recombinant interferon-alfa 2a: An active outpatient regimen in metastatic renal cell carcinoma. J Clin Oncol 1992; 10:414-21. Atzpodien J, Kirchner H, Hanninen LE et al. Interleukin-2 in combination with interferon-alfa and 5-fluorouracil for metastatic renal cell cancer. Eur J Cancer 1993; 29A (Suppl 5): 6-8. Sella A, Kilboura RG, Gray I et al. Phase I study of interleukin-2 combined with interferon-alfa and 5-fluorouracil in patients metastatic renal cell cancer. Cancer Biother 1994; 9: 103-11.
Short report Subcutaneous recombinant interleukin-2 (rIL-2) in out-patients with metastatic renal cell carcinoma Results of a multicenter SCAPP1 trial J. M. Tourani,1 V. Lucas,2 D. Mayeur,3 B. Dufour,4 M. Di Palma,5 C. Boaziz,6 P. Grise,7 C. Varette,8 J. M. Pavlovitch,9 E. Pujade-Lauraine,10 D. Larregain,11 E. Ecstein,12 M. Untereiner,13 E. Vuillemin,14 S. Merran15 & J. M. Andrieu1 1
evaluable patients (18%) had objective responses (95% CI: 9% to 37%) with one complete response. Treatment was Background: This multicenter phase II trial was conducted in interrupted or reduced due to toxicity for seven patients: order to evaluate the efficacy and toxicity of the subcutane- Neuropsychiatric symptoms (3 patients), joint pain (1 paous route of administration of rIL-2 in the treatment of tient), major asthenia and anorexia (1 patient), stroke (1 patients with metastatic renal cell carcinoma and to check patient), and septicemia (1 patient). Other systemic side whether an increased cumulative dose of rIL-2 increases effi- effects in the remaining patients were acceptable. Seventeen patients received maintenance treatment. In none of the cacy. Patients and methods: Thirty-nine patients with metastatic patients did the response status improve during this mainrenal cell carcinoma were included in this study. During the tenance period. The median follow-up of all of the patients induction period, rIL-2 was administered subcutaneously 5 included was 19 months. The one- and two-year survivals days a week for 8 weeks. The weekly dosages were 90 MTU were 65% and 33%, respectively, ad the median duration of during weeks 1 and 6; 63 MTU during weeks 2 to 4 and 7 to response was 11 months (5 to 16+). 9. After evaluation, responders and patients with stable disConclusions: This multicentric study confirms the efficacy ease received maintenance treatment which was discontinued of subcutaneously-administered rIL-2 in patients with metaupon the appearance of disease progression or unacceptable static renal cell carcinoma in terms of both response rate and toxicity. During the maintenance period, rIL-2 was adminis- survival. The role of a maintenance therapy needs further tered 5 days a week for 4 weeks followed by a 2-week rest evaluation. period. The weekly dosages were 90 MIU in week 1 and 63 MIU in weeks 2 to 4. Key words: interleukin-2, out-patient, renal cell carcinoma, Results: After completion of induction treatment, 7 of 39 subcutaneous administration, survival Summary
The prognosis of metastatic renal cell carcinoma is very poor. Since the mid-1980s, recombinant interleukin-2 (rIL-2) has been used to treat patients with metastatic renal cell carcinoma. The initial protocols were based on the principles of chemotherapy administration, with intravenous bolus or continuous infusion of maximal tolerable doses [1, 2]. These studies demonstrated (depending on schedule), objective response rates of 15%-30% and complete response rates of 3%-5%. These protocols produced pulmonary, renal, cardiac and hemodynamic toxic effects requiring hospitalization, sometimes even in an intensive care unit. In order to improve tolerance, many authors have proposed that rIL-2 be subcutaneously administered on an out-
patient basis [3, 4]. The results of these monocentric studies show that the subcutaneous route of administration has comparable efficacy, with objective response rates of 20% to 29% and complete response rates of 2% to 5%, with less toxicity. We report the results of our phase II trial using rIL-2 given subcutaneously in patients with metastatic renal cell carcinoma The original aim of our multicentric study was to test the dose/efficacy concept by giving, over a 10-week period, a cumulative dose of rIL-2 analogous to that administered intravenously over the same duration of time according to the reference protocol of West etal. [2].
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 19, 2016
Oncology Unit, Laennec Hospital, Paris; 2 Oncology Unit, La Source Hospital, Orleans; 3Internal Medicine Unit, A. Mignot Hospital, Le Chesnay; * Urology Unit, Necker Hospital, Paris; 3 Oncology Unit, P. Brousse Hospital, VMejuifi 6 Oncology Unit, Avicenne Hospital, Bobigny; 1 Oncology Unit, C. Nicolle Hospital, Rouen; 8Oncology Unit, St. Antoine Hospital, Paris; ''Oncology Unit, Troyes Hospital, Troyes; w'Oncology Unit, Hotel Dieu Hospital, Paris; "Oncology Unit, Cote Basque Hospital, Bayonne; nUrology Unit, H. Mondor Hospital, Creteil; ^Oncology Unit, C. Bernard Hospital, Metz; uOncology Unit, Pitie-Salpitriere Hospital, Paris; "Radiology Department, F.M.P., Paris, France
526 Patients and methods
Statistical analysis Clinical response and toxicity were evaluated according to WHO criteria. Complete response (CR) was defined as the complete disappearance of all clinical and/or radiological disease for at least 4 weeks; partial response (PR) was defined as a 50% or greater decrease in the sum of the products of the longest perpendicular diameters of measurable lesions for at least one month; stable disease (SD) was defined as a decrease of less than 50% or an increase of less than 25% in measurable lesions; progressive disease (PD) was defined as an increase of more than 25% or the development of new lesions. Responses were evaluated by investigators as well as by independent reviewers to assess the results of treatment The duration of response was calculated from the day the response was first documented to the day of documented progressive disease. The overall survival was calculated from the start of treatment Survival curves were plotted by using the Kaplan-Meier method and statistical differences were estimated using the log-rank test
Results Patient characteristics From April 1993 to April 1994, 39 patients with metastatic renal cell carcinoma, from 11 different centers, were included in this study. The initial characteristics of these patients are summarized in Table 1. Eleven of
Delivered dose and toxicity During the induction period, the cumulative planned dosage of rIL-2 administered subcutaneously was 558 MIU. For 5 of the 39 patients treatment had to be interrupted due to an obvious progression of the disease. For the 39 patients the mean cumulative dose of rIL-2 was 489 MIU (87% of the planned dose). Seven patients received 29%, 44%, 50%, 72%, 82%, 82% and 90% of the planned dose because treatment was interrupted or decreased due to toxicity. These toxic effects included neuropsychiatric manifestations (3 cases), stroke (1 case) septicemia (1 case) joint pain (1 case) and major weakness (1 case). Table 2 summarizes the side effects observed during the induction phase. There were five instances of thyroid dysfunction, namely, biological and clinical hypothyroidism in 2 patients requiring substitute treatments, and biologica 1 hyperthy-
Table 1. Patient characteristics. Number of patients Untreated patients Male/female Age (years) Mean Range Functional performance status (World Health Organization) 0 1 2 Previous nephrectomy (time from nephrectomy) <1 year >1 year Sites of metastatic disease Lung Kidney Lymph nodes Liver Bone Adrenal Pleura Soft tissue Spleen Number of metastatic sites 1 2 3 4 Number of bad prognosis factors 0 1 2 3
39 28 30/9 58 38-74 22 13 4 28 11 24 2 19 7 4 8 3 2 1 19 11 7 2 3 15 11 10
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 19, 2016
Patients with progressive, histologjcally proven, metastatic renal cell carcinoma and clinically measurable or evaluable disease were included in this study. The study was approved by the Paris Necker Enfants-Malades ethical committee, and patients were entered after their written informed consent was obtained. Those with brain metastases, second neoplasms, functional performance status (PS) >2, uncontrolled cardiovascular disease (congestive heart failure, coronary artery disease), severe renal dysfunction or who had previously been treated with rIL-2 were excluded. Prior to study entry, each patient's disease stage was determined by full clinical examination, determination of blood cell counts, serum electrolytes, liver, renal and thyroid functions, chest X-ray, technetium pyrophosphate bone scan, and thoracic, abdominal and brain computed tomographic scanning. During the treatment, tumor volume was evaluated clinically and radiologically after the induction period and after the second, fourth, and sixth maintenance cycles. The rIL-2 (Aldesleukin, Chiron, BV, Amsterdam, The Netherlands) was administered subcutaneously during the first and sixth weeks at a dose of 9 million international units (MIU), twice daily for 5 consecutive days and during the second, third, fourth, seventh, eighth, and ninth weeks at 9 MIU twice daily, on days 1 and 2, followed by 9 MIU once daily, on days 3, 4, and 5. The fifth week was free of treatment The daily dose of rIL-2 was reduced to 9 MIU in patients who developed severe toxicity (grade HI or IV). After induction evaluation and a 2-week rest period, in the absence of progression or unacceptable toxicity despite reduction of the rIL-2 dose, patients received maintenance therapy until progression or the advent of unacceptable toxic effects (grades IH or IV). Maintenance therapy was administered for a maximum of 7 cycles. Each cycle of the maintenance phase was separated by a 2-week rest period. During each maintenance cycle, rIL-2 was given subcutaneously on the same schedule as during the first, second, third, and fourth induction weeks. Paracetamol (500 mg orally every 4 to 6 hours) was given concomitantly in an attempt to ameliorate pyretic reactions.
these patients had previously received treatment: radiotherapy (n - 4), and/or chemotherapy (n - 6), and/or alpha interferon therapy (n ™ 10). According to Palmer et al. classification [5], 3 patients (8%) had no poorprognosis factors, 15 (38%) had 1,11 (28%) had 2 and 10 (26%) had 3 poor-prognosis factors.
527 Table 2. Toxicity and side effects during induction period.
Progression and survival
Event
The median follow-up of all included patients was 19 months. The response durations in the 7 responding patients were 5, 9, 11, 12, 13, 15+, 16+ months. The overall one-year survival and two-year survival were 65% (CI: 0.2437) and 33%, respectively. The one-year survivals for responders and non-responders were, respectively, 100% and 58% (P: 0.05). No significant differences in terms of survival were observed with respect to functional performance status, number of metastatic sites, the time between diagnosis and treatment of the metastatic disease and to administration of maintenance therapy.
0
I
n
m
IV
_ 18 28 7 5 31 38 38 14 26 31 34 37 37 36 38 35 36
14 11 5 11 8 6 1 12 5 5 3 1 2 3 -
20 9 6 17 23 2 1 12 8 1 2 2 1 1 -
3 1 4 3 _ 1 2 1 1 3
2 _ -
Discussion
Recombinant interleukin-2 has been used since 1984 for the treatment of metastatic renal cell carcinoma. The response rates with the intravenous route of administration schedules are around 20% [1, 2, 6] with " Painful swelling at the injection site. a benefit in terms of survival [7]. The protocols using high doses of rIL-2 given by bolus have significant toxic roidism in 3. All of these problems disappeared within effects requiring hospitalization, sometimes even in an a few weeks after the completion of rIL-2 treatment. intensive care unit. Continuous infusion, with interNone of the patients developed hemodynamic or grade mediate doses of rIL-2, improves tolerance but reHI or IV renal toxicity (WHO) during the induction quires a close follow-up on an in-patient basis. phase. Since the beginning of the 1990s, several authors have used the subcutaneous route of administration Response to induction treatment with lower doses of rIL-2. Due to very low toxicity, it has been possible to perform these subcutaneous trials All 39 patients were evaluable for response. Seven on an out-patient basis. The efficacy, based on the repatients (18%) had objective responses, and there was sponse rates, seems identical to those observed with one complete response (95 confidence limit 9% to the intravenous schedules. This modality allows the 37%); 17 patients (43%) had stabilization of their dis- treatment of older patients, or patients with cardiac or ease and 15 (38%) tumor progression. The sites of renal dysfunction who are usually excluded from intraobjective response were lymph nodes (3/19), pulmo- venous programs [4]. nary metastases (8/24) and primary renal tumor (1/2). Sleijfer et al., in their subcutaneous program, obtained a response rate of 20% with cumulative doses of Maintenance period rIL-2 between 306 MIU and 450 MIU according to the four- or six-week regimen [4]. Lissoni et al. reported Of the 24 patients with objective response or stable dis- a response rate of 29% after six weeks of treatment ease at the completion of the induction period, 17 re- using a cumulative dose of 216 MIU [3]. The continuceived a maintenance treatment For the 7 others, treat- ous infusion schedule as proposed by W.H. West ment was interrupted because of toxicity during the allowed the administration of 612 MIU over 10 weeks induction phase (5 cases) or by the patient's decision (2 with response rates of around 20%. In this study, durcases). Seventeen patients (pts) received 1 cycle; 13 pts: ing the 10 week induction period the patients received 2 cycles; 10 pts: 3 cycles; 7 pts: 5 cycles; 5 pts: 6 cycles 489 MIU (87% of the planned dose: 558 MIU). These and 3 pts received 7 cycles. The maintenance therapy doses did not improve the efficacy (18% of objective was interrupted in 11 patients because of an obvious response rate) and increased the toxicity, but the progression of the disease, and by the patient's decision median survival (20 months) and the two-year survival in 3 cases. A decrease in doses and/or a delay of 1-2 (33%) observed with this program seem promising. weeks in the treatment occurred in 8 patients because No improvement was observed during maintenance of side effects. During this maintenance period, one treatment among the 17 patients with objective regrade m toxic effect (infection) was observed. All other sponses or stabilization of disease. Sleijfer and Lissoni side effects were of grades I or II (WHO). In none of did not report data on the evolution of the disease stathe patients was the response status better than the one tus during the maintenance therapy. The role of such a at the end of the induction phase. treatment in patients with metastatic renal cell carci-
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 19, 2016
Fever Nausea/vomiting Diarrhea Asthenia Anorexia Chills Dyspnea Headache Local toxicity" Skin toxicity Cholestasis Elevated transaminase level Thrombocytopenia Stiffness Hypotension Infection Creatinine increase Neuropsychiatric symptoms
WHO grade of toxicity (Number of patients)
528 noma with an objective response or stabilization should be evaluated in further studies. In conclusion, this multicentric study confirms the efficacy of the subcutaneous rIL-2 programs in patients with metastatic renal cell carcinoma, with a response rate of around 20%, similar to those already published. Moreover, to our knowledge, this study is the first to confirm in terms of survival, the efficacy of subcutaneous rIL-2 programs. The role of a maintenance therapy needs further evaluation. To improve these results, combinations of rIL-2 and other drugs or cytokines have been suggested. Preliminary reports of such trials of rIL-2 combined with alpha interferon [8, 9] and with 5-fluorouracil and alpha interferon [10, 11] seem promising.
5. 6. 7. 8. 9.
10.
References
Received 19 February 1996; accepted 10 April 1996. Correspondence to: J. M. Tourani, MD Oncology Unit Laennec Hospital 42 rue de Sevres 75007 Paris, France
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11. 1. Rosenberg SA, Lotze MT, Muul LM et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987; 316: 889-97. 2. West WH, Tauer KW, Yannelli JR et al. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy on advanced cancer. N Engl J Med 1987; 316: 898-905. 3. Lissoni P, Barni S, Ardizzoia A et al. Prognostic factors of the clinical response to subcutaneous immunotherapy with interleukin-2 alone in patients with metastatic renal cell carcinoma. Oncology 1994; 51: 59-62. 4. Buter J, Sleijfer DT, Van der Graaf WTA et al. A progress
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