Sequential Administration of Recombinant Human Interleukin-2 and Dacarbazine in Metastatic Melanoma: A Multicenter Phase II Study By G. Stoter, S. Aamdal, S. Rodenhuis, F.J. Cleton, S. lacobelli, C.R. Franks, R. Oskam, and E. Shiloni Twenty-five assessable patients with metastatic melanoma have been entered in a multicenter phase II study of two induction cycles of human recombinant interleukin-2 (IL2), 18 x 106 IU/m 2 /d continuous intravenous (IV) infusion on days 1 to 5 and days 12 to 17. Dacarbazine (DTIC), 850 mg/m2 IV bolus was given on day 26. The cycle was repeated at 5 weeks. Maintenance therapy was scheduled 3 weeks after the completion of induction treatment, consisting of IL2, 18 x 106 IU/m 2/d for 5 days alternating with DTIC, 850 mg/m2 IV every 3 weeks, for a total of 18 weeks. Six patients responded (24%); two complete and four partial. Stable disease was seen in five patients. None of the six patients with more than two sites of metastases responded. Maximum response was observed in the first 3 months of treatment. Progression-free
periods of 6 months and longer were seen in the two complete responders (8 and 17+ months), in two of the four partial responders (7 and 12+ months), and in three of the five patients with stable disease (9+, 15, and 17+ months). Toxicity included fever, skin rash, fatigue, anorexia, and diarrhea in most patients. Two patients had a weight gain of more than 10%. Eight patients needed intensive care for the observation and treatment of a myocardial injury (one patient), ventriculartachycardia (one), hypotension and oliguria (four), and sepsis (two). Sequential treatment with 1L2 and DTIC appears to be effective but not clearly better than could be expected of IL2 alone. J Clin Oncol 9:1687-1691. © 1991 by American Society of ClinicalOncology.
T
HE INCIDENCE of melanoma is steadily rising throughout the world. In 1989 the Swedish Cancer Registry reported an annual increase in incidence rates of 5.4% in females and 5.8% in males. In the observation period from 1960 to 1982, this increase corresponded to a rise from 3.7 to 11.2/100,000 females, and from 3.0 to 11.8/100,000 males per year. The age-standardized mortality rates rose from 1.4 to 2.7/100,000 females, and from 2.3 to 3.7/100,000 males per year.' In metastatic melanoma, no life-prolonging therapies exist. Dacarbazine (DTIC) has been reported to have some antitumor activity with response rates in the range of 15%, usually of short duration.2 Following the promising clinical results with human recombinant interleukin-2 (IL2) by Rosenberg et al3 using high-dose bolus therapy, and by West et al 4 using continuous intravenous (IV) administration, we started a multicenter phase II study with the latter approach. The suggestive evidence for increased efficacy of chemotherapy 5 and IL2 provided by Mitchell et al led us to select a combination of IL2 and DTIC as the study
regimen.
MATERIAL AND METHODS Patients Twenty-seven patients were entered. The protocol required histologic or cytologic documentation of metastatic melanoma, measurable progressive metastatic disease, Karnofsky performance status 2 80, WBC count > 4,000/mL, platelet count > 100,000/mL, hematocrit level > 30%, serum bilirubin and creatinine within the institution's normal range, no cardiovascular history, no prior chemotherapy or extensive radiotherapy, and no concomitant local treatment to the sole indicator lesion. Corticosteroids were prohibited. The protocol required a central venous catheter for the administration of IL2. The use of prophylactic antibiotics was at the discretion of the investigators. Two patients were ineligible: one due to unmeasurable
From the Rotterdam Cancer Institute, Rotterdam; Netherlands CancerInstitute,Amsterdam; UniversityMedical Center, Leiden; EuroCetusBV Amsterdam, The Netherlands;Norwegian Radium Hospital, Oslo, Norway; San Camillo Hospital, Chieti, Italy; and Hadassah University Hospital, Jerusalem, Israel. Submitted July 9, 1990; accepted March 20, 1991. Address reprintrequests to G. Stoter,MD, PhD, Department of Medical Oncology, Rotterdam Cancer Institute, PO Box 5201, 3008AE Rotterdam, The Netherlands. © 1991 byAmerican Society of Clinical Oncology. 0732/183X/91/0909-0023$3.00/0
Journalof Clinical Oncology, Vol 9, No 9 (September), 1991: pp 1687-1691
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1687
STOTER ET AL
1688 Table 1. Patient and Tumor Characteristics of Eligible Patients Female:male Karnofsky performance score Median Range Prior treatment No. of metastatic organ sites 1 2 3 4 Distribution of metastatic sites Lung Lymph nodes Skin Liver Abdominal
15:10 100 80-100 4 12 7 4 2 13 11 9 9 4
lesions and one due to brain metastases. Therefore, 25 patients are assessable for toxicity and response. The two ineligible patients are omitted from all analyses. The patient characteristics are shown in Table 1. One patient received prior chemotherapy by limb perfusion, two had prior radiotherapy. A fourth patient had previously received adjuvant therapy with the interferon-inducer poly A-poly U. Median time from initial diagnosis to treatment in this study was 24 months (range, 1 to 161 months), with 32% of patients entered in less than 1 year after diagnosis of the primary tumor. The majority of patients had bulky disease. Seven patients (28%) had nonvisceral disease only. IL2 (Proleukin) was supplied by Eurocetus Ltd, Amsterdam, The Netherlands. The specific activity per milligram of protein is 18 mega international units (MIU), which equals 3 Cetus MU. Treatment Therapy comprised two induction cycles of IL2 18 MIU/ m 2/d continuous IV, days 1 to 5 (120 hours) and days 12 to 17 (108 hours). DTIC 850 mg/m 2 IV bolus was given on day 26. The cycle was repeated at 5 weeks. Maintenance therapy was scheduled 3 weeks after the completion of induction treatment, consisting of IL2 18 MIU/m2/d for 5 days, alternating with DTIC 850 mg/m2 IV on day 22 every 3 weeks, for a total of 18 weeks. Response and Toxicity Response was evaluated after the two induction therapy cycles, and every 8 weeks thereafter. Assessment of response, duration of response, time to progression, survival, and toxicity was performed according to the criteria of the World Health Organization (WHO).' Complete response was defined as the disappearance of all known disease for at least 4 weeks; partial response was defined as a reduction in the sum of the products of the perpendicular largest diameters of each lesion by at least 50% for at least 4 weeks; stable disease was defined as a decrease of less than 50% in total tumor size, or an increase of less than 25% in the size of one or more lesions. Duration of partial response and
stable disease were calculated from the start of treatment to the day of disease progression. Complete response was measured from the day it was first recorded. Time to progression was defined as the period from the start of protocol treatment until the day progressive disease was first noted. Centralized review of the data for response assessment was done by a team of three medical oncologists and two radiologists. For toxicities not included in the WHO guidelines, a grading system was used ranging from mild (grade 1) to life-threatening (grade 4). RESULTS Response
Twenty patients completed at least one treatment cycle of IL2 and DTIC. Sixteen received two full cycles, 10 had three cycles, four had four, and three patients received five cycles, ie, two induction and three maintenance courses. Eighty percent of patients received more than 90% of the
planned treatment dose throughout their treatment period. Five patients (20%) were taken off study early, due to rapid progression (two patients) and WHO grade 3 and 4 side effects (three
patients). Table 2 shows the treatment results in the 25
eligible patients. The complete responses were in patients with lymph node metastases as the only site of disease. One of the partial responders had skin metastases only, two had lung and liver metastases, and one had skin and liver metastases. None of the patients with more than two involved sites responded. All responses occurred in the first two treatment cycles, ie, were documented 3 months after the start of treatment. Four of the responders were female and two were male.
Seventeen patients had baseline lymphocyte counts of 1,400/mL or more, and 18 had rebound
lymphocytosis above 6,000/mL. One complete and one partial responder met both these counts, the other four responders did not. After a maximum follow-up period of 24 months, the duration of complete responses is 6 and 16+
months, respectively. Time to progression for complete responders is 8 and 17+ months; for partial responders, 4, 5, 7, and 12+ months; for stable Table 2. Response to Treatment No. of patients Complete response Partial response Stable disease Progressive disease
25 2 (8%) 4 (16%) 5 13
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1689
IL2 AND DTIC IN MELANOMA
patients, 4, 4, 9+, 15, and 17+ months. The median survival of all eligible patients is 400 days (Fig 1). Toxicity The side effects of treatment were analyzed for all 25 eligible patients and are presented in Table 3. Fever, skin rash, nausea, vomiting, diarrhea, and malaise were common. Many patients had tachycardia associated with fever; one had ECG-proven ventricular tachycardia. Hypotension requiring vasopressors occurred in four patients. Weight gain > 5% developed in eight patients and > 10% in two patients. A 29-year-old woman without cardiovascular risk factors developed a myocardial injury on day 6 from the start of treatment with ST segment elevations in the precardial leads and elevated MB isoenzymes of creatine phosphokinase levels. The patient did not have anginal pain, and the abnormalities disaDoeared in 2 days. Coronary angiography on day 10 was completely normal. This case has been detailed elsewhere. 7 '1Two patients with central venous catheters in situ developed sepsis; one with blood cultures sho 'wing Serratialiquefaciens and one with Staphyloc occus aureus. The first patient was subject to mu ltiple organ failure. Intensive care included me chanical ventilation. The course of the second pat ient was complicated by a mycotic aneurysm of the radial artery, which required surgery. Both pat ients recovered. I7ive patients were removed from the study ear ly, ie, after 5 to 10 days of IL2 treatment; two as %Survival 100 90 80 70 680 50 40 30 20 10 0 100 o
200
300
400
500
600
700
Survival in days Fig 1. Survival curve for 25 eligible patients: median surviva 1,400 days.
Table 3. Side Effects Frequency
WHO Grade 2-4 Toxicity
No. Patients
%
Fever Skin rash/peeling Nausea/vomiting Diarrhea Malaise Weight gain > 10% Hypotension Myocardial injury Creatinine Dyspnea Mental disturbances Sepsis Ventricular tachycardia Alkaline phosphatase Bilirubin Anemia Thrombocytopenia
22 19 14 12 21 2 16 1 6 3 9 2 1 15 6 14 5
88 76 56 48 84 8 64 4 24 12 36 8 4 60 24 56 20
a result of rapidly progressive disease, and three due to toxicity. These toxicities included septic shock, ventricular tachycardia, and myocardial injury, respectively. Ninety percent of patients developed some degree of anemia, and nine patients needed blood transfusions. Lymphocytopenia during IL2 treatment was universal (median nadir, 700/mL; range, 0 to 750), with rebound lymphocytosis at a median peak of 15,300/mL (range, 3,800 to 27,500). Eosinophilia was also common, and counts increased with each IL2 administration episode during induction treatment. Median peak values at cycles IA and IB and IIA and IIB were 900, 5,400, 3,500, and 7,200/mL, respectively. Leukocytopenia was insignificant. The median nadir was 6,000/mL (range, 3,400 to 15,100). Thrombocytopenia occurred in 10 patients and was severe in two (WHO grades 3 and 4). Platelet transfusions were not given. The patient with grade 4 thrombocytopenia developed septic shock and multiple organ failure. Increments in serum creatinine WHO grade 1 were observed in four patients; grade 2, in six. Serum creatinine levels normalized within 7 days after completion of IL2 in all patients but one. Most patients experienced transient elevations of bilirubin, transaminases, and alkaline phosphatase. Grade 4 elevation of alkaline phosphatase only occurred in the patient with multiple organ failure.
DTIC-induced bone marrow and gastrointesti-
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nal toxicity was mild to moderate; re-treatment with IL2 at 10 days after DTIC was never delayed. DISCUSSION This study of sequential use of daily continuous infusion of IL2 and bolus administration of DTIC has yielded a 24% response rate, including 8% complete responses. Restriction of the response analysis to the 20 patients who received at least one combination cycle of IL2 and DTIC results in an overall response rate that is not different, with one complete and four partial responders (25%). All responses were observed in the first two treatment cycles, and less than half of the eligible patients received more than two cycles. This casts doubt on the need for maintenance therapy. In contrast to the observations reported by West et al, 4 we have not found a relationship between baseline and rebound lymphocyte counts. However, the number of sites of metastases appeared to be an important prognostic factor in this study (P = .04). Notably, the two complete responders had lymph node metastases only and no visceral metastases. Four patients remained free from progressive disease between 9 and 17 months from the start of treatment. However, the median time to progression for all eligible patients is only 4 months. The median survival of the whole group is 13 months (400 days). This seems to be better than the 4 to 6 months that has been reported for historical controls,2 but it remains debatable whether this is due to the immunotherapy or to the strict selection criteria in use for IL2 protocols. The treatment results of this study are comparable with those reported for IL2 with ex vivoactivated killer lymphocytes (LAK),8"- and IL2 with chemotherapeutic agents such as cyclophosphamide 5' 12 and DTIC with or without LAK.13,14 One study"3 of IL2 and DTIC reported 30
patients treated with DTIC 200 mg/m2/day as a continuous infusion on days 1 to 5. IL2 was administered in a dose of 24 x 106 IU/d as a 30-minute infusion on days 1 to 5 and 8 to 12, every 4 weeks. Four patients achieved a complete response (13%); six, a partial response (20%). The other study 14 used LAK with IL2 and DTIC. IL2 was given at a similar dose and schedule compared with our regimen, but DTIC was given at a higher dose of 1,200 mg/m 2. Two durable complete responses and five short-lived partial responses were achieved in 27 assessable patients, for an overall response rate of 26%. The median survival for all patients was 10 months. Two other studies of IL2 and chemotherapy including cisplatin have shown response rates around 40%.15,'6
The side effects of the combination of IL2 and DTIC in our study were dominated by IL2. The toxicity observed in this study is of the same magnitude as reported in other studies."11 Intensive care was needed for one patient with ventricular tachycardia, one with a myocardial injury, and four patients to be treated with dopamine. The remaining patients tolerated therapy with IL2 and DTIC reasonably well. Because the protocol required the use of central venous catheters for the administration of IL2, the initial patients were managed accordingly. Prophylactic antibiotic treatment was optional and, in fact, was not given. Two patients with central venous catheters in situ developed sepsis and were admitted to the intensive care unit. This observation led the investigators to avoid central venous catheters whenever possible as IL2 can safely be given through a peripheral intravenous infusion.17 In conclusion, the sequential use of IL2 and DTIC appears feasible and effective. The results of this study and the data from the literature suggest a role for the combined use of IL2 and chemotherapy in melanoma.
REFERENCES 1. Thorn M, Adami HO, Bergstr6m R, et al: Trends in survival from malignant melanoma: Remarkable improvement in 23 years. J Natl Cancer Inst 81:611-617, 1989 2. Legha SS: Current therapy for melanoma. Semin Oncol 16:34-44, 1989 3. 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 316:889-897, 1987 4. West WH, Tauer KW, Yannelli JR, et al: Constant-
infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Eng J Med 316:898-905, 1987 5. Mitchell MS, Kempf RA, Harel W, et al: Effectiveness and tolerability of low-dose cyclophosphamide and lowdose intravenous interleukin-2 in disseminated melanoma. J Clin Oncol 6:409-424, 1988 6. WHO: Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, WHO, 1979 7. Osanto S, Cluitmans FHM, Franks CR, et al: Myocardial injury after interleukin-2 therapy. Lancet 2:48-49, 1988 8. Rosenberg SA, Lotze MT, Yang JC, et al: Experience
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1691
IL2 AND DTIC IN MELANOMA with the use of high dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210:474-485, 1989 9. West WH: Continuous infusion recombinant interleukin-2 in adoptive cellular therapy of renal carcinoma and other malignancies. Cancer Treat Rev 16:83-89, 1989 (suppl A) 10. Dutcher JP, Creekmore S, Weiss GR, et al: A phase II study of interleukin-2 and lymphokine-activated killer cells in patients with metastatic malignant melanoma. J Clin Oncol 7:477-485, 1989 11. Parkinson DR, Abrams JS, Wiernik PH, et al: Interleukin-2 therapy in patients with metastatic malignant melanoma: A phase II study. J Clin Oncol 8:1650-1656, 1990 12. Lindemann A, H6ffken K, Schmidt RE, et al: A phase-II study of low-dose cyclophosphamide and recombinant human interleukin-2 in metastatic renal cell carcinoma and malignant melanoma. Cancer Immunol Immunother 28:275-281, 1989 13. Papadopoulos NEJ, Howard JG, Murray JL, et al:
Phase II DTIC and interleukin-2 trial for metastatic malignant melanoma. Proc Am Soc Clin Oncol 9:277, 1990 (abstr) 14. Dillman RO, Oldham RK, Barth NM, et al: Recombinant interleukin-2 and adoptive immunotherapy alternated with dacarbazine therapy in melanoma: A National Biotherapy Study Group trial. J Natl Cancer Inst 82:1345-1349, 1990 15. Atkins M, Demchak P, Mier J, et al: Phase II study of alternating interleukin-2 and cisplatin with WR-2721 in metastatic melanoma. Proc Am Soc Clin Oncol 8:287, 1989 (abstr) 16. Flaherty L, Robinson W, Redman B, et al: A phase II study of dacarbazine (DTIC), cisplatin (DDP) and outpatient interleukin-2 (IL2) in metastatic malignant melanoma. Proc Am Soc Clin Oncol 9:187, 1990 (abstr) 17. Shiloni E, Gross E, Shapiro M: Reducing central line catheter related nosocomial sepsis in patients receiving interleukin-2 therapy. Ann Intern Med 112:882-883, 1990
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periods of 6 months and longer were seen in the two complete responders (8 and 17+ months), in two of the four partial responders (7 and 12+ months), and in three of the five patients with stable disease (9+, 15, and 17+ months). Toxicity included fever, skin rash, fatigue, anorexia, and diarrhea in most patients. Two patients had a weight gain of more than 10%. Eight patients needed intensive care for the observation and treatment of a myocardial injury (one patient), ventriculartachycardia (one), hypotension and oliguria (four), and sepsis (two). Sequential treatment with 1L2 and DTIC appears to be effective but not clearly better than could be expected of IL2 alone. J Clin Oncol 9:1687-1691. © 1991 by American Society of ClinicalOncology.
T
HE INCIDENCE of melanoma is steadily rising throughout the world. In 1989 the Swedish Cancer Registry reported an annual increase in incidence rates of 5.4% in females and 5.8% in males. In the observation period from 1960 to 1982, this increase corresponded to a rise from 3.7 to 11.2/100,000 females, and from 3.0 to 11.8/100,000 males per year. The age-standardized mortality rates rose from 1.4 to 2.7/100,000 females, and from 2.3 to 3.7/100,000 males per year.' In metastatic melanoma, no life-prolonging therapies exist. Dacarbazine (DTIC) has been reported to have some antitumor activity with response rates in the range of 15%, usually of short duration.2 Following the promising clinical results with human recombinant interleukin-2 (IL2) by Rosenberg et al3 using high-dose bolus therapy, and by West et al 4 using continuous intravenous (IV) administration, we started a multicenter phase II study with the latter approach. The suggestive evidence for increased efficacy of chemotherapy 5 and IL2 provided by Mitchell et al led us to select a combination of IL2 and DTIC as the study
regimen.
MATERIAL AND METHODS Patients Twenty-seven patients were entered. The protocol required histologic or cytologic documentation of metastatic melanoma, measurable progressive metastatic disease, Karnofsky performance status 2 80, WBC count > 4,000/mL, platelet count > 100,000/mL, hematocrit level > 30%, serum bilirubin and creatinine within the institution's normal range, no cardiovascular history, no prior chemotherapy or extensive radiotherapy, and no concomitant local treatment to the sole indicator lesion. Corticosteroids were prohibited. The protocol required a central venous catheter for the administration of IL2. The use of prophylactic antibiotics was at the discretion of the investigators. Two patients were ineligible: one due to unmeasurable
From the Rotterdam Cancer Institute, Rotterdam; Netherlands CancerInstitute,Amsterdam; UniversityMedical Center, Leiden; EuroCetusBV Amsterdam, The Netherlands;Norwegian Radium Hospital, Oslo, Norway; San Camillo Hospital, Chieti, Italy; and Hadassah University Hospital, Jerusalem, Israel. Submitted July 9, 1990; accepted March 20, 1991. Address reprintrequests to G. Stoter,MD, PhD, Department of Medical Oncology, Rotterdam Cancer Institute, PO Box 5201, 3008AE Rotterdam, The Netherlands. © 1991 byAmerican Society of Clinical Oncology. 0732/183X/91/0909-0023$3.00/0
Journalof Clinical Oncology, Vol 9, No 9 (September), 1991: pp 1687-1691
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 20, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1687
STOTER ET AL
1688 Table 1. Patient and Tumor Characteristics of Eligible Patients Female:male Karnofsky performance score Median Range Prior treatment No. of metastatic organ sites 1 2 3 4 Distribution of metastatic sites Lung Lymph nodes Skin Liver Abdominal
15:10 100 80-100 4 12 7 4 2 13 11 9 9 4
lesions and one due to brain metastases. Therefore, 25 patients are assessable for toxicity and response. The two ineligible patients are omitted from all analyses. The patient characteristics are shown in Table 1. One patient received prior chemotherapy by limb perfusion, two had prior radiotherapy. A fourth patient had previously received adjuvant therapy with the interferon-inducer poly A-poly U. Median time from initial diagnosis to treatment in this study was 24 months (range, 1 to 161 months), with 32% of patients entered in less than 1 year after diagnosis of the primary tumor. The majority of patients had bulky disease. Seven patients (28%) had nonvisceral disease only. IL2 (Proleukin) was supplied by Eurocetus Ltd, Amsterdam, The Netherlands. The specific activity per milligram of protein is 18 mega international units (MIU), which equals 3 Cetus MU. Treatment Therapy comprised two induction cycles of IL2 18 MIU/ m 2/d continuous IV, days 1 to 5 (120 hours) and days 12 to 17 (108 hours). DTIC 850 mg/m 2 IV bolus was given on day 26. The cycle was repeated at 5 weeks. Maintenance therapy was scheduled 3 weeks after the completion of induction treatment, consisting of IL2 18 MIU/m2/d for 5 days, alternating with DTIC 850 mg/m2 IV on day 22 every 3 weeks, for a total of 18 weeks. Response and Toxicity Response was evaluated after the two induction therapy cycles, and every 8 weeks thereafter. Assessment of response, duration of response, time to progression, survival, and toxicity was performed according to the criteria of the World Health Organization (WHO).' Complete response was defined as the disappearance of all known disease for at least 4 weeks; partial response was defined as a reduction in the sum of the products of the perpendicular largest diameters of each lesion by at least 50% for at least 4 weeks; stable disease was defined as a decrease of less than 50% in total tumor size, or an increase of less than 25% in the size of one or more lesions. Duration of partial response and
stable disease were calculated from the start of treatment to the day of disease progression. Complete response was measured from the day it was first recorded. Time to progression was defined as the period from the start of protocol treatment until the day progressive disease was first noted. Centralized review of the data for response assessment was done by a team of three medical oncologists and two radiologists. For toxicities not included in the WHO guidelines, a grading system was used ranging from mild (grade 1) to life-threatening (grade 4). RESULTS Response
Twenty patients completed at least one treatment cycle of IL2 and DTIC. Sixteen received two full cycles, 10 had three cycles, four had four, and three patients received five cycles, ie, two induction and three maintenance courses. Eighty percent of patients received more than 90% of the
planned treatment dose throughout their treatment period. Five patients (20%) were taken off study early, due to rapid progression (two patients) and WHO grade 3 and 4 side effects (three
patients). Table 2 shows the treatment results in the 25
eligible patients. The complete responses were in patients with lymph node metastases as the only site of disease. One of the partial responders had skin metastases only, two had lung and liver metastases, and one had skin and liver metastases. None of the patients with more than two involved sites responded. All responses occurred in the first two treatment cycles, ie, were documented 3 months after the start of treatment. Four of the responders were female and two were male.
Seventeen patients had baseline lymphocyte counts of 1,400/mL or more, and 18 had rebound
lymphocytosis above 6,000/mL. One complete and one partial responder met both these counts, the other four responders did not. After a maximum follow-up period of 24 months, the duration of complete responses is 6 and 16+
months, respectively. Time to progression for complete responders is 8 and 17+ months; for partial responders, 4, 5, 7, and 12+ months; for stable Table 2. Response to Treatment No. of patients Complete response Partial response Stable disease Progressive disease
25 2 (8%) 4 (16%) 5 13
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1689
IL2 AND DTIC IN MELANOMA
patients, 4, 4, 9+, 15, and 17+ months. The median survival of all eligible patients is 400 days (Fig 1). Toxicity The side effects of treatment were analyzed for all 25 eligible patients and are presented in Table 3. Fever, skin rash, nausea, vomiting, diarrhea, and malaise were common. Many patients had tachycardia associated with fever; one had ECG-proven ventricular tachycardia. Hypotension requiring vasopressors occurred in four patients. Weight gain > 5% developed in eight patients and > 10% in two patients. A 29-year-old woman without cardiovascular risk factors developed a myocardial injury on day 6 from the start of treatment with ST segment elevations in the precardial leads and elevated MB isoenzymes of creatine phosphokinase levels. The patient did not have anginal pain, and the abnormalities disaDoeared in 2 days. Coronary angiography on day 10 was completely normal. This case has been detailed elsewhere. 7 '1Two patients with central venous catheters in situ developed sepsis; one with blood cultures sho 'wing Serratialiquefaciens and one with Staphyloc occus aureus. The first patient was subject to mu ltiple organ failure. Intensive care included me chanical ventilation. The course of the second pat ient was complicated by a mycotic aneurysm of the radial artery, which required surgery. Both pat ients recovered. I7ive patients were removed from the study ear ly, ie, after 5 to 10 days of IL2 treatment; two as %Survival 100 90 80 70 680 50 40 30 20 10 0 100 o
200
300
400
500
600
700
Survival in days Fig 1. Survival curve for 25 eligible patients: median surviva 1,400 days.
Table 3. Side Effects Frequency
WHO Grade 2-4 Toxicity
No. Patients
%
Fever Skin rash/peeling Nausea/vomiting Diarrhea Malaise Weight gain > 10% Hypotension Myocardial injury Creatinine Dyspnea Mental disturbances Sepsis Ventricular tachycardia Alkaline phosphatase Bilirubin Anemia Thrombocytopenia
22 19 14 12 21 2 16 1 6 3 9 2 1 15 6 14 5
88 76 56 48 84 8 64 4 24 12 36 8 4 60 24 56 20
a result of rapidly progressive disease, and three due to toxicity. These toxicities included septic shock, ventricular tachycardia, and myocardial injury, respectively. Ninety percent of patients developed some degree of anemia, and nine patients needed blood transfusions. Lymphocytopenia during IL2 treatment was universal (median nadir, 700/mL; range, 0 to 750), with rebound lymphocytosis at a median peak of 15,300/mL (range, 3,800 to 27,500). Eosinophilia was also common, and counts increased with each IL2 administration episode during induction treatment. Median peak values at cycles IA and IB and IIA and IIB were 900, 5,400, 3,500, and 7,200/mL, respectively. Leukocytopenia was insignificant. The median nadir was 6,000/mL (range, 3,400 to 15,100). Thrombocytopenia occurred in 10 patients and was severe in two (WHO grades 3 and 4). Platelet transfusions were not given. The patient with grade 4 thrombocytopenia developed septic shock and multiple organ failure. Increments in serum creatinine WHO grade 1 were observed in four patients; grade 2, in six. Serum creatinine levels normalized within 7 days after completion of IL2 in all patients but one. Most patients experienced transient elevations of bilirubin, transaminases, and alkaline phosphatase. Grade 4 elevation of alkaline phosphatase only occurred in the patient with multiple organ failure.
DTIC-induced bone marrow and gastrointesti-
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nal toxicity was mild to moderate; re-treatment with IL2 at 10 days after DTIC was never delayed. DISCUSSION This study of sequential use of daily continuous infusion of IL2 and bolus administration of DTIC has yielded a 24% response rate, including 8% complete responses. Restriction of the response analysis to the 20 patients who received at least one combination cycle of IL2 and DTIC results in an overall response rate that is not different, with one complete and four partial responders (25%). All responses were observed in the first two treatment cycles, and less than half of the eligible patients received more than two cycles. This casts doubt on the need for maintenance therapy. In contrast to the observations reported by West et al, 4 we have not found a relationship between baseline and rebound lymphocyte counts. However, the number of sites of metastases appeared to be an important prognostic factor in this study (P = .04). Notably, the two complete responders had lymph node metastases only and no visceral metastases. Four patients remained free from progressive disease between 9 and 17 months from the start of treatment. However, the median time to progression for all eligible patients is only 4 months. The median survival of the whole group is 13 months (400 days). This seems to be better than the 4 to 6 months that has been reported for historical controls,2 but it remains debatable whether this is due to the immunotherapy or to the strict selection criteria in use for IL2 protocols. The treatment results of this study are comparable with those reported for IL2 with ex vivoactivated killer lymphocytes (LAK),8"- and IL2 with chemotherapeutic agents such as cyclophosphamide 5' 12 and DTIC with or without LAK.13,14 One study"3 of IL2 and DTIC reported 30
patients treated with DTIC 200 mg/m2/day as a continuous infusion on days 1 to 5. IL2 was administered in a dose of 24 x 106 IU/d as a 30-minute infusion on days 1 to 5 and 8 to 12, every 4 weeks. Four patients achieved a complete response (13%); six, a partial response (20%). The other study 14 used LAK with IL2 and DTIC. IL2 was given at a similar dose and schedule compared with our regimen, but DTIC was given at a higher dose of 1,200 mg/m 2. Two durable complete responses and five short-lived partial responses were achieved in 27 assessable patients, for an overall response rate of 26%. The median survival for all patients was 10 months. Two other studies of IL2 and chemotherapy including cisplatin have shown response rates around 40%.15,'6
The side effects of the combination of IL2 and DTIC in our study were dominated by IL2. The toxicity observed in this study is of the same magnitude as reported in other studies."11 Intensive care was needed for one patient with ventricular tachycardia, one with a myocardial injury, and four patients to be treated with dopamine. The remaining patients tolerated therapy with IL2 and DTIC reasonably well. Because the protocol required the use of central venous catheters for the administration of IL2, the initial patients were managed accordingly. Prophylactic antibiotic treatment was optional and, in fact, was not given. Two patients with central venous catheters in situ developed sepsis and were admitted to the intensive care unit. This observation led the investigators to avoid central venous catheters whenever possible as IL2 can safely be given through a peripheral intravenous infusion.17 In conclusion, the sequential use of IL2 and DTIC appears feasible and effective. The results of this study and the data from the literature suggest a role for the combined use of IL2 and chemotherapy in melanoma.
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