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© 2001 American Society for Clinical Oncology Outpatient Biochemotherapy With Interleukin-2 and Interferon Alfa-2b in Patients With Metastatic Malignant Melanoma: Results of Two Phase II Cytokine Working Group TrialsByFrom the Karmanos Cancer Institute, Wayne State University, Detroit, MI; Beth Israel Deaconess Medical Center, Boston, MA; University of Illinois at Chicago and Loyola University, Chicago, IL; University of Texas, San Antonio, TX; City of Hope National Medical Center, Duarte, CA; New York Medical College, Bronx, NY; University of Arizona, Phoenix, AZ; and University of Pittsburgh, Pittsburgh, PA. Address reprint requests to Lawrence E. Flaherty, MD, Division of Hematology and Oncology, 516-Hudson, Harper Hospital, 3990 John R, Detroit, MI 48201; email: flaherty{at}karmanos.org
PURPOSE: The Cytokine Working Group performed a randomized phase II trial of two outpatient biochemotherapy regimens to identify an outpatient regimen with high antitumor activity and less toxicity than inpatient regimens which might be compared with chemotherapy or inpatient biochemotherapy regimens in future phase III trials. PATIENTS AND METHODS: Eighty-one patients with metastatic malignant melanoma received dacarbazine 250 mg/m2/d intravenously (IV) and cisplatin 25 mg/m2/d IV on days 1, 2, and 3, plus interferon (IFN) alfa-2b 5 mU/m2 subcutaneously (SC) on days 6, 8, 10, 13, and 15, given every 28 days. Interleukin-2 (IL-2) was given daily on days 6 to 10 and 13 to 15. In group 1, IV IL-2 was given at 18.0 MU/m2, and in group 2, SC IL-2 was given at 5.0 mU/m2. RESULTS: In group 1 (IV IL-2), there were five complete responses (CRs) and 11 partial responses (PRs) among 44 patients (objective response rate [ORR], 36%; 95% confidence interval [CI], 22% to 51%). In group 2 (SC IL-2), there was one CR and five PRs among the 36 patients (ORR, 17%; 95% CI, 4% to 29%). The median survival was 10.7 months in group 1 and 7.3 months in group 2. Eleven patients in group 1 and four patients in group 2 remain alive as of the last follow-up. Toxicities in both groups were similar. No patient required hospitalization for neutropenic fever. CONCLUSION: Biochemotherapy has activity in these outpatient regimens with acceptable toxicity. The antitumor activity observed with the IV IL-2 regimen seems similar to that of inpatient biochemotherapy regimens. If inpatient biochemotherapy regimens develop an established role in the management of melanoma, future phase III trial comparisons with this outpatient IV IL-2 regimen would be appropriate.
METASTATIC MELANOMA responds poorly to the currently available standard systemic therapies. Treatment options consist of chemotherapy, biologic agents, or investigational therapies. Several single-agent chemotherapies have produced response rates in the range of 10% to 20%, but there are few long-term survivors.1-3 The search for more effective agents and therapeutic combinations remains important in this field.
In recent years, trials have evaluated the role of combination chemotherapy, the addition of tamoxifen to chemotherapy, and the addition of interferon alfa-2b (IFN
Extensive experience has been gained in recent years with the use of interleukin-2 (IL-2) in patients with metastatic melanoma. With the high-dose intravenous (IV) bolus schedule, response rates of 16% have been identified with durable complete remission in approximately one third of responders.13 Many investigators have combined IL-2 with both IFN The present trials were designed to evaluate two outpatient biochemotherapy regimens in a multi-institutional setting to better evaluate their antitumor activity and toxicities. These trials were performed by use of a randomized phase II design so that patient characteristics in both groups would be similar and data with regard to their activity and survival would be available at similar time points. The purpose of a randomized phase II trial is to select a treatment for eventual phase III tests. This trial design is not an end in itself and does not allow comparison between treatment arms. It serves as a screening function toward a simple, phase III study when multiple experimental regimens hold promise. The treatment with the best outcome, regardless of the magnitude, is selected for further tests in a phase III setting to meet the burden of statistical significance and larger sample size.33 Therefore, this study was not designed with sufficient power to permit a direct comparison of these two regimens.
The eligibility criteria for these trials included the following clinical parameters: histologically confirmed, surgically incurable metastatic malignant melanoma with measurable disease confirmed by physical examination or noninvasive radiographic procedure, and Southwest Oncology Group performance status of 0 or 1. Exclusion factors included seizure disorders, human immunodeficiency virus–positive condition, psychiatric illness, CNS metastasis, corticosteroid or beta-blocker therapy, symptomatic pleural effusion or ascites, major organ allografts, other malignancies within 3 years other than in situ malignancies or basal cell or squamous cell carcinoma of the skin, history of serious cardiac arrhythmia, congestive heart failure, angina, and significant cardiovascular limitations (New York Heart Association class 3 or 4). At least 21 days from the completion of previous radiation therapy must have elapsed and patients must have recovered from any previous surgery.
Initial eligibility required that patients who had received adjuvant IFN All patients were required to undergo tumor staging that included a contrast computed tomographic scan or magnetic resonance imaging of the brain within 28 days before treatment. Pulmonary function test and stress test, if indicated, must have been performed within 8 weeks before registration. All patients provided voluntary written informed consent to participate in this study. The institutional review boards of each of the participating institutions approved the protocol and the informed consent forms.
Each treatment cycle was 28 days in length. Both treatment regimens consisted of cisplatin 25 mg/m2 and DTIC 250 mg/m2 IV on days 1, 2, and 3 (day 1 was typically a Wednesday), so that the biologic agents could be initiated on a Monday. The cisplatin was administered over 1 hour in a minimum of 250 mL of 0.9 normal saline. A minimum hydration of 1 L of 0.9 normal saline was administered before and after each cisplatin dose. Mannitol 12.5 g IV push was administered before, and 25 g IV push was administered after cisplatin. Immediately after cisplatin was given, DTIC was administered in 250 mL of dextrose 5% in water over 30 minutes. Pretreatment with IV ondansetron or ganisetron was recommended before each treatment. Corticosteroids were excluded. Patients in both groups also received IFN DTIC and cisplatin chemotherapy was administered in either the inpatient or outpatient units of the participating institutions to assure adequate hydration and management of patient’s volume and electrolyte status. Vital signs were obtained before treatment and then hourly for 6 hours on day 6 (first day of IL-2 and IFN administration) of the first cycle. For patients without grade 3 toxicity on day 6, blood pressure measurements were obtained on subsequent days after IL-2 administration and the patient was discharged when stable. The following medications were given to patients on the days they received IL-2: acetaminophen 650 mg orally (PO) 30 minutes before IL-2 and IFN, then every 4 hours in case of fever; naproxen 375 mg PO 30 minutes before treatment, then every 12 hours (for fever or myalgia), and ranitidine 150 mg PO every 12 hours. Meperidine was used if necessary to control rigors, and IV or oral antiemetics (excluding corticosteroids) were used at the discretion of the investigator. Guidelines for dose adjustments after the first cycle of therapy are listed in Table 1. Additional treatment cycles were initiated at 28-day intervals if the absolute granulocyte count was greater than or equal to 1,500/µL, the platelet count was greater than or equal to 100,000/µL, and the estimated or calculated creatinine clearance was greater than or equal to 40 mL/min. All patients were instructed to drink a minimum of 2 L of fluid in the 24 hours that preceded each chemotherapy treatment. Patients who did not meet the above criteria had treatment delayed for 1 week and parameters rechecked; patients who required more than 2 weeks’ delay were removed from protocol therapy.
Patients had the following clinical and laboratory examinations performed on days 6, 9, 13, and 15 and once between days 20 and 24: a complete blood count, creatinine, calcium, and serum chemistry panel to include a total bilirubin, AST, lactate dehydrogenase (LDH), and alkaline phosphatase. History and physical examination were repeated at the beginning of each cycle. Toxicity was assessed with the National Cancer Institute common toxicity criteria (original version) on days 1, 6, 9, 13, and 15 and on one day between days 20 and 24 of each cycle. Scans for tumor measurement were repeated at the end of every second cycle. A complete response (CR) was defined as the disappearance of all measurable and assessable disease, without the appearance of any new lesions for at least 4 weeks. A partial response (PR) was defined as a decrease of 50% or greater under the baseline in the sum of the products of the perpendicular diameters of all measured lesions for at least 4 weeks, without progression of assessable lesions or new lesions. All measurable and assessable lesions and sites must have been assessed. Stable disease was defined as not qualified for CR, PR, or progression. Progression was defined as an increase of 50% or greater or an increase of 10 cm2 in the sum of products of measurable lesions over the smallest sum observed, or the reappearance of a lesion, worsened assessable disease, the appearance of a new lesion, or nonreturn for evaluation because of deteriorating clinical condition. All measurements for response were confirmed by one of the coauthors (C.A.), who also was responsible for collection of data from individual centers. The primary objective of this study was to assess the response rates of these regimens as well as the duration of response. The secondary objective was to assess the qualitative and quantitative toxicities associated with these treatment regimens. Progression-free and overall survival were also secondary end points. Patients were randomly assigned to group 1 or 2 after prestratification for known prognostic factors for stage IV disease at the time the study was initiated: performance status (0 v 1) and disease site (based on American Joint Committee on Cancer staging criteria), ie, nonvisceral versus visceral (M1a v M1b). After the first 40 patients were entered onto the study, the eligibility was amended to allow patients whose melanoma recurred during adjuvant high-dose IFN therapy. At that time, an additional stratification for adjuvant IFN (yes v no) was included. The statistical design and analysis plan for the two treatment arms was identical but independent. Eighty patients were to be registered onto this treatment trial in an effort to have a sample size of 40 assessable patients per treatment arm. This would provide an 87% power with a 5% significance level to identify a regimen of no further interest if the response rate was less than 20% or a regimen of definite interest with a response rate of 40% or more. The second objective was to assess the toxicity for each arm separately after the first 20 patients completed the first cycle of treatment. If seven or more patients in either group experienced toxicities that required hospitalization, patient accrual would be discontinued for that group, and the regimen would be declared unacceptably toxic or modified and re-evaluated. Patients were observed for progression-free survival and overall survival. The estimate of survival curves was performed by the Kaplan-Meier method.
Between April 1996 and July 1998, 82 patients were registered and 81 patients were eligible (one patient was ineligible because of incorrect histology). Forty-four patients were randomized to group 1 and 37 to group 2. All forty-four patients were assessable in group 1, and 36 were assessable in group 2. One eligible patient never received treatment because brain metastasis developed within 48 hours of registration. The clinical characteristics of all eligible patients are listed in Table 2.
The overall objective response rate for group 1 was 36% (95% confidence interval [CI], 21% to 53%). There were five CRs (11%; 95% CI, 2% to 21%) with a median duration of more than 15 months (4, 10+, 15+, 16+, and 29+ months). There were 11 PRs (25%; 95% CI, 12% to 38%) with durations of 2 to 11 months (median, 5.0 months) for the nine patients who eventually exhibited disease progression. One patient in partial remission after 4 months had all sites of known metastatic disease resected and remains alive and disease free more than 21 months after registration. One additional patient in partial remission received radiation therapy to involved sites and remains alive and relapse free more than 26 months after registration. The median survival duration for all patients was 10.1 months (Fig 1). The median survival exceeded 19 months for the patients with CR (range, 14.2 to 36.0+ months), was 14.2 months for PR (range, 10.8 to 26.2+ months), and exceeded 17 months for all patients who responded (range, 10.8 to 36.0+ months). A listing of the response rate by patient characteristic for the patients in group 1 is provided in Table 3.
In group 2, the overall objective response rate was 17% (95% CI, 4% to 29%). There was one CR (3%) that lasted 12+ months. There were five PRs (14%; 95% CI, 3% to 25%) with durations of 3.0, 3.5, 5, 6, and 8.0 months. The median response duration was 5.0 months for patients with PR and 5.5 months for the overall group. The median survival for all patients treated with this regimen was 7.3 months (Fig 1). The survival for the single patient who achieved complete remission was 27+ months, and the median survival for the patients who attained a PR was 14.5 months (range, 7.8 to 20.3 months). Table 3 lists the response rate by patient characteristic for patients in group 2. The CR occurred in a patient who had soft tissue metastasis only. The median number of treatment cycles in group 1 was four. Two patients received less than one full cycle, five patients received one cycle, 10 patients received two cycles, three patients received three cycles, 16 patients received four cycles, and nine patients received six cycles of treatment. In group 2, the median number of treatment cycles was 2.5. Four patients received one cycle, 14 patients received two cycles, four patients received three cycles, eight patients received four cycles, two patients received five cycles, and four patients received six cycles of treatment. The serum LDH has been recognized recently as an important prognostic factor for stage IV disease by the American Joint Committee on Cancer,34-37 but this information was not available at the time of our study and therefore was not used as a stratification factor. In group 1, nine of the 43 assessable patients were identified with elevated LDH. In group 2, 16 of the 36 assessable patients were identified with elevated LDH, 19 did not have elevated LDH, and one LDH level was unknown. In group 1, 148 treatment cycles were administered. Table 4 lists all toxicities of grade 1 or 2 that occurred in 20% or more of cycles or grade 3 or 4 that occurred in 10% or more cycles. The toxicity profile was as anticipated for a regimen that involved both chemotherapeutic and biologic agents. Grade 3 or 4 toxicities of note included a 23% incidence of neutropenia and a 6% incidence of thrombocytopenia, but no patients were admitted to the hospital for neutropenic fever or infection. Grade 3 nausea, vomiting, and fatigue occurred in 2% or less of cycles. The majority of patients experienced low-grade constitutional symptoms and gastrointestinal complaints that occasionally extended over the entire 2-week duration of the treatment cycle. Grade 1 or 2 nephrotoxicity was identified in 20% of cycles and was reversible in all cases; there was only one episode of grade 3 nephrotoxicity, which also was reversible. Thirteen dose reductions were required in treatment cycles 2 to 6 for the management of toxicity. Six reductions of the biotherapy agents and seven adjustments in the chemotherapy were necessary; six involved the DTIC and one involved the cisplatin. Two deaths possibly related to treatment occurred in the group; the deaths were unrelated to disease progression. One involved a 38-year-old man who developed adult respiratory distress syndrome during the first treatment cycle at the completion of the chemotherapy but before any biotherapy was administered. Additional treatment was withheld. The second occurred in a 54-year-old man with a normal pretreatment treadmill test who completed six cycles of treatment and experienced a myocardial infarction while on vacation, shortly after the completion of his last cycle of treatment. No histologic evaluation of his myocardium was obtained.
In group 2, 119 treatment cycles were administered. Hematologic, constitutional, and gastrointestinal toxicities were most common. Eleven percent of cycles were associated with grade 3 or higher neutropenia, and 7% of cycles were associated with grade 3 or higher thrombocytopenia. No hospitalizations were required for neutropenic fever or infection. Gastrointestinal and constitutional toxicities were the most frequent side effects, and occasionally they lasted for the entire 2 weeks of the therapeutic component of the treatment cycle. There was only one episode of reversible grade 3 nephrotoxicity. Eleven dose reductions in the chemotherapy or biotherapy were required because of toxicity. There were five reductions in the biotherapy and six reductions in the chemotherapy (five DTIC reductions and one cisplatin reduction). No deaths associated with treatment occurred in this group.
Biochemotherapy regimens that contain IL-2 have been associated with 40% to 60% response rates in stage IV melanoma in a large number of phase II trials, the majority of which were from single institutions.14-23 Several phase III trials that compared chemotherapy alone with biochemotherapy also have been reported recently. Rosenberg et al38 compared DTIC, cisplatin, and tamoxifen with the same chemotherapy combined with high-dose IL-2 and IFN in a small phase III trial of 102 patients designed to compare response rates. The response rate for the biochemotherapy regimen was superior (44% v 27%) although not statistically significant (P = .071). Overall survival, however, favored the chemotherapy-alone arm (P = .052). A larger European Organization for Research and Treatment of Cancer phase III trial39 has accrued 325 patients and compares DTIC, cisplatin, and IFN with or without infusional IL-2. An interim analysis of the first 118 registered patients demonstrated a response rate for the IL-2-containing regimen of 22% versus 28% for the non-IL-2 group (P = .12). At 2 years, however, there were 10 relapse-free patients on the IL-2 arm compared with two patients on the non-IL-2 arm (P = .028). Eton et al40 recently reported a phase III trial with 190 patients from the M.D. Anderson Cancer Center group. Chemotherapy that consisted of cisplatin, DTIC, and vinblastine was compared with the same chemotherapy with sequential infusional IL-2 and IFN. The IL-2–containing arm demonstrated superior response rates (48% v 25%; P = .001), time to treatment failure (4.9 v 2.4 months; P = .004), and median survival (11.9 v 9.2 months; P = .033). These phase II and III trial results support the continued interest in IL-2–based biochemotherapy regimens in a clinical trial setting. Most of these trials have required inpatient administration of IL-2 in an IV bolus or continuous infusion schedule. Although these biochemotherapy regimens have led to durable complete remissions in 5% to 10% of patients in phase II trials and encouraging results in some phase III trials, widespread use of these regimens has been limited by their complexity and associated toxicity. Modification of one inpatient biochemotherapy regimen19,23 to reduce its toxicity has permitted the activation of a large United States Intergroup trial in stage IV melanoma to compare cisplatin, vinblastine, and DTIC chemotherapy with the same chemotherapy combined with IL-2 by continuous IV infusion and SC IFN (Eastern Cooperative Oncology Group 3695). This trial, with the results of the phase III trials mentioned above, will help to define the role of biochemotherapy in the initial management of patients with metastatic melanoma. Despite the modifications incorporated into this regimen, moderate toxicity persists and treatment on an inpatient basis is necessary. In recent years, several investigators have developed biochemotherapy regimens that could be administered in the outpatient setting. Flaherty et al24 combined IV DTIC at 1,000 mg/m2 over 24 hours given on day 1 with IV IL-2 administered over 15 minutes at doses that ranged from 12 to 30 MU/m2 daily on days 15 to 19 and days 22 to 26 of a 28-day cycle. The maximum tolerated dose of IL-2 in the investigation was 24 MU/m2/d. Several other investigators have examined biochemotherapy regimens in which SC IL-2 was administered on an outpatient basis (Table 5). 25-31 A large body of clinical data exists that consists of more than 300 patients, treated predominantly in single-institution trials that examine the effectiveness of outpatient biochemotherapy. These trials have explored various doses of SC or IV IL-2 with or without SC IFN combined with chemotherapy that usually included DTIC and cisplatin and frequently included carmustine and tamoxifen. Response rates have ranged from 34% to 55% (average, 41%) with CR rates from 8% to 19% (average, 13%).
The optimal dose and route of IL-2 administration in combination with other biologic agents or chemotherapy remain unresolved. The Food and Drug Administration–approved schedule of IL-2 as a single agent involves its administration at high doses by IV bolus. No previously reported or ongoing phase III trials have examined whether SC IL-2 administration is comparable to IV administration. A substantial number of phase II biochemotherapy trials have incorporated IL-2 as administered in a variety of routes, schedules, and doses combined with chemotherapy and other biologic agents. The contribution of the IL-2 dose and route becomes difficult to assess in this setting, because it is only one of several active agents that contribute to the overall benefit associated with a given regimen.
The present investigation was performed as two parallel multi-institutional trials, which differed only in the dose and route of IL-2 administration. Both were performed to confirm the individual activity of these regimens in a multi-institutional setting. Randomization of patients was performed to prevent large imbalances of known prognostic factors for stage IV melanoma patients. During the time frame of trial registration, the proportion of patients who had received adjuvant IFN as previous therapy increased. Although the impact of previous IFN The toxicity of inpatient biochemotherapy and the lack of its proven survival benefit in phase III trials has been an impediment to more widespread acceptance by patients and physicians. The present United States Intergroup phase III trial (E-3695), which uses a modification of the Legha regimen,19,23 requires prophylactic antibiotics and granulocyte colony-stimulating factor support to manage the anticipated hematologic toxicity. The phase II trials reported herein are noteworthy for their lack of significant hematologic toxicity. Although grade 3 and occasional grade 4 neutropenia and thrombocytopenia were noted (Table 4), no patient in either trial group required hospitalization for neutropenic fever. In addition, neither prophylactic antibiotics nor colony-stimulating factor support was used routinely in patients on these protocols. Nephrotoxicity was also minimal in both treatment groups despite the use of two drugs associated with renal dysfunction (cisplatin and IL-2). The major side effects for which dose adjustment or additional supportive management were required comprised the constitutional symptom of fatigue and the gastrointestinal side effects of anorexia, nausea, and vomiting. The modest toxicity identified with these regimens also suggests that additional active agents or modest dose escalations of existing agents could be considered in future investigations. No major differences in the toxicity profiles of these regimens were noted. The response data for both treatment groups is of interest. Responses were more common in the patients who had not failed adjuvant IFN (five CRs and nine PRs; overall response rate, 42%) than in those who had (two PRs, overall response rate, 18%) in group 1. In group 2, there were no responses (0%) among the seven patients who had received previous adjuvant IFN, and 21% of patients who had not received previous adjuvant IFN responded. These differences for both groups may suggest that prior adjuvant IFN may be an important negative predictor of response to therapies that include biologic agents, and they support our initial decision to stratify patients enrolled onto this trial for that characteristic. Should other investigators confirm this finding, it may become an important factor for stratification in future phase III trials. The 40% response rate in treatment group 1 patients who presented with visceral involvement (M1b), the 47% response rate in patients with two or three organ sites of involvement, and the 30% response rate in patients with more than three organ sites of involvement are particularly encouraging. In group 2, the response rate in patients with M1b disease was 12%, the response rates in patients with two or three organs involved was 20%, and the response rate in patients with more than three organs involved was 9%. Among group 2 patients in the most favorable subsets, the response rates for those with performance status 0, a normal LDH, or M1a (nonvisceral metastasis) were 29%, 21%, and 27%, respectively. The median overall survival for treatment group 1 was 10.7 months (95% CI, 7.8 to 15.0 months) (Fig 1), which is within the range noted in many of the inpatient biochemotherapy regimens. Of additional importance is the number of patients who remain alive in this particular group,11 including four of the five patients in continued complete remissions. The large percentage of patients in group 1 who have remained in complete remission or durable partial remissions to date seems to match or exceed previous experiences with inpatient regimens and supports the notion that outpatient regimens may have equivalent activity. The median overall survival for patients in group 2 was 7.3 months (95% CI, 4.5 to 10.1 months) (Fig 1). To date, four patients who remain alive, only one of whom exhibited a response to treatment (CR) in this group. In summary, outpatient chemotherapy regimens can be administered with modest toxicity and with little risk of neutropenic fever, hypotension, or renal toxicity. These regimens are likely to be more acceptable to patients and physicians. Based on the response rate, activity in patients with unfavorable prognostic characteristics, median overall survival, and durability of responses to date, we favor advancement of the group 1 regimen with IV IL-2 for future trial consideration. Previous adjuvant IFN administration may influence the response rate of patients treated for this stage of disease. It should be identified in future treatment reports and considered as a stratification factor for phase III trials if other investigators confirm these preliminary data.
Supported by unrestricted educational grants from Chiron Corporation and Schering Oncology Biotech.
1. Ahmann DL, Creagan ET, Hahn RG, et al: Complete responses and long-term survivals after systemic chemotherapy for patients with advanced malignant melanoma. Cancer 63: 224-227, 1989[Medline] 2. Balch CM, Reinthgen DS, Kirkwood JM, et al: Cutaneous melanoma, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology ( ed 5 ). Philadelphia, PA, Lippincott, 1997, pp 1947-2011 3. Mastrangelo MJ, Bellet RE, Kane MJ, et al: Chemotherapy of melanoma, in Perry MC (ed): The Chemotherapy Source Book. Baltimore, MD, Williams & Wilkins, 1992, pp 886-907 4. DelPrete SA, Maurer LH, O’Donnell J, et al: Combination chemotherapy with cisplatin, carmustine, dacarbazine, and tamoxifen in metastatic melanoma. Cancer Treat Rep 68: 1403-1405, 1984[Medline] 5. McClay EF, Mastrangelo MJ, Berd D, et al: Effective combination chemo/hormonal therapy for malignant melanoma: Experience with three consecutive trials. Int J Cancer 50: 553-556, 1992[Medline] 6. Cocconi G, Bella M, Calabresi F, et al: Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med 327: 516-523, 1992[Abstract] 7. Falkson CI, Falkson G, Falkson HC: Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma. J Clin Oncol 9: 1403-1408, 1991[Abstract] 8. McClay EF, Mastrangelo MJ, Bellet RE, et al: Combination chemotherapy and hormonal therapy in the treatment of malignant melanoma. Cancer Treat Rep 71: 465-469, 1987[Medline] 9. Margolin KA, Liu PY, Flaherty LE, et al: Phase II study of carmustine, dacarbazine, cisplatin, and tamoxifen in advanced melanoma: A Southwest Oncology Group study. J Clin Oncol 16: 664-669, 1998[Abstract]
10.
Rusthoven JJ, Quirt IC, Iscoe NA, et al: Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. J Clin Oncol 14: 2083-2090, 1996 11. Falkson CI, Ibrahim J, Kirkwood JM, et al: Phase III trial of dacarbazine versus dacarbazine with interferon alfa-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alfa-2b and tamoxifen in patients with metastatic malignant melanoma: An Eastern Cooperative Oncology Group study. J Clin Oncol 16: 1743-1751, 1998[Abstract]
12.
Chapman PB, Einhorn LH, Meyers ML, et al: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17: 2745-2751, 1999
13.
Atkins MB, Lotze MT, Dutcher JP, et al: High-dose recombinant interleukin-2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17: 2105-2116, 1999
14.
Atkins MB, O’Boyle KR, Sosman JA, et al: Multi-institutional phase II trial of intensive combination chemotherapy for metastatic melanoma. J Clin Oncol 12: 1553-1560, 1994 15. Antoine EC, Benhammouda A, Bernard A, et al: Salpetriere Hospital experience with biochemotherapy in metastatic melanoma. Cancer J Sci Am 3: S16-S21, 1997 (suppl 1)
16.
Richards JM, Mehta N, Ramming K, et al: Sequential chemoimmunotherapy in the treatment of metastatic melanoma. J Clin Oncol 10: 1338-1343, 1992 17. Legha SS, Ring S, Eton O, et al: Development and results of biochemotherapy in metastatic melanoma: The University of Texas M.D. Anderson Cancer Center experience. Cancer J Sci Am 3: S9-S15, 1997 (suppl 1)
18.
Keilholz U, Goey SH, Punt CJ, et al: Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: A randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. J Clin Oncol 15: 2579-2588, 1997 19. McDermott DF, Mier JW, Lawrence DP, et al: A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine (CVD), interleukin-2 (IL-2), and interferon alfa-2b (IFN) in patients with metastatic melanoma. Proc Am Soc Clin Oncol 17: 507a, 1998 (abstr 1956) 20. O’Day SJ, Boasberg P, Guo M, et al: Phase II trial of concurrent biochemotherapy (c-BC) with decrescendo interleukin-2 (d-IL-2), tamoxifen (T), and G-CSF support in patients with metastatic melanoma (MM). Proc Am Soc Clin Oncol 16: 490a, 1997 (abstr 1763)
21.
Keilholz U, Conradt C, Legha S, et al: Results of interleukin-2-based treatment in advanced melanoma: A case record-based analysis of 631 Patients. J Clin Oncol 16: 2921-2929, 1998 22. Allen IE, Kupelnick B, Kumashiro M: Efficacy of interleukin-2 in the treatment of metastatic melanoma: Systemic review and meta-analysis. Cancer Ther 1: 168-173, 1998 23. Legha SS, Ring S, Eton O, et al: Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol 16: 1752-1759, 1998[Abstract] 24. Flaherty LE, Redman BG, Chabot GG, et al: A phase I-II study of dacarbazine in combination with outpatient interleukin-2 in metastatic malignant melanoma. Cancer 65: 2471-2477, 1990[Medline] 25. Flaherty LE, Robinson W, Redman BG, et al: A phase II study of dacarbazine and cisplatin in combination with outpatient administered interleukin-2 in metastatic malignant melanoma. Cancer 71: 3520-3525, 1993[Medline] 26. Thompson JA, Gold PJ, Markowitz DR, et al: Updated analysis of an outpatient chemoinnumotherapy regimen for treating metastatic melanoma. Cancer J Sci Am 3: S29-S34, 1997 (suppl 1) 27. Atzpodien J, Lopez Hanninen E, Kirchner H, et al: Chemoinnumotherapy of advanced malignant melanoma: Sequential administration of subcutaneous interleukin-2 and interferon-alpha after intravenous dacarbazine and carboplatin or intravenous dacarbazine, cisplatin, carmustine and tamoxifen. Eur J Cancer 31A: 876-881, 1995 28. Bernengo MG, Doveil GC, Bertero M, et al: Low-dose integrated chemoimmuno-hormonotherapy with cisplatin, subcutaneous interleukin-2, alpha-interferon and tamoxifen for advanced metastatic melanoma: A pilot study. Melanoma Res 6: 257-265, 1996[Medline] 29. Guida M, Latorre A, Mastria A, et al: Subcutaneous recombinant interleukin-2 plus chemotherapy with cisplatin and dacarbazine in metastatic melanoma. Eur J Cancer 32A: 730-733, 1996 30. Dillman R, Soori G, Schulof R, et al: Cancer Biotherapy Research Group (CBRG) trial 94-11: Outpatient subcutaneous interleukin-2 [Proleukin] and interferon alfa-2b [Intron A] with combination chemotherapy plus tamoxifen in the treatment of metastatic melanoma. Proc Am Soc Clin Oncol 18: 530a, 1999 (abstr 2045) 31. Kamanabrou D, Straub C, Heinsch M, et al: Sequential biochemotherapy of IFN-alfa/IL-2, cisplatin (CDDP), dacarbazine (DTIC) and carmustine (BCNU): Results of a monocenter phase II study in 109 patients with advanced metastatic malignant melanoma (MMM). Proc Am Soc Clin Oncol 18: 530a, 1999 (abstr 2044) 32. Flaherty LE, Liu PY, Unger J, et al: Comparison of patient characteristics and outcome between a single-institution phase II trial and a cooperative-group phase II trial with identical eligibility in metastatic melanoma. Am J Clin Oncol 20: 600-604, 1997[Medline] 33. Liu PY, LeBlanc M, Desai M: False positive rates of randomized phase II designs. Control Clin Trials 20: 343-352, 1999[Medline]
34.
Deichmann M, Benner A, Bock M, et al: S100-beta melanoma-inhibiting activity and lactate dehydrogenase discriminate progressive from nonprogressive stage IV melanoma. J Clin Oncol 17: 1891-1896, 1999 35. Franzke A, Probst-Kepper M, Buer J, et al: Elevated pretreatment serum levels of soluble vascular cell adhesion molecule 1 and lactate dehydrogenase as predictors of survival in cutaneous metastatic melanoma. Br J Cancer 78: 40-45, 1998[Medline] 36. Balch CM, Buzaid AC, Atkins MB, et al: A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer 88: 1484-1491, 2000[Medline] 37. Eton O, Legha SS, Moon TE, et al: Prognostic factors for survival of patients treated systemically for disseminated melanoma. J Clin Oncol 16: 1103-1111, 1998[Abstract]
38.
Rosenberg SA, Yang JC, Schwartzentruber J, et al: Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 17: 968-975, 1999 39. Keilholz U, Punt CJA, Gore M, et al: Dacarbazine, cisplatin, and interferon alfa with or without interleukin-2 in advanced melanoma: Interim analysis of EORTC Trial 18951. Proc Am Soc Clin Oncol 18: 530a, 1999 (abstr 2043) 40. Eton O, Legha S, Bedikian A, et al: Phase III randomized trial of cisplatin, vinblastine, and dacarbazine (CVD) plus interleukin-2 (IL2) and interferon-Alfa-2b (INF) versus CVD in patients (pts) with metastatic melanoma. Proc Am Soc Clin Oncol 19: 552a, 2000 (abstr 2174) Submitted August 8, 2000; accepted April 4, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) to chemotherapy.
