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© 2002 American Society for Clinical Oncology Results From a Randomized Phase III Study Comparing Combined Treatment With Histamine Dihydrochloride Plus Interleukin-2 Versus Interleukin-2 Alone in Patients With Metastatic MelanomaByFrom the Melanoma Center of the University of Pittsburgh Cancer Institute, Pittsburgh, PA; Bowyer Oncology Center, University of California at Los Angeles, Los Angeles; John Wayne Cancer Institute, Santa Monica; Sidney Kimmel Cancer Center, and Maxim Pharmaceuticals, San Diego; and University of California, Irvine Comprehensive Cancer Center, Orange, CA; Karmanos Cancer Institute, Detroit, MI; Washington University and The Melanoma Center of St. Louis, St Louis; and Oncology/Hematology Associates of Kansas City, Kansas City, MO; University of Colorado, Denver, CO; Arizona Cancer Center, Tucson, AZ; University of Miami Sylvester Cancer Research Center, Miami, FL; Department of Virology, University of Göteborg, Göteborg; and Department of Surgery, Umea University, Umea, Sweden. Address reprint requests to Sanjiv S. Agarwala, MD, Melanoma Center, University of Pittsburgh Cancer Institute, 200 Lothrop St, Pittsburgh, PA 15213-2582; email: agarwalass{at}msx.upmc.edu
PURPOSE: Reactive oxidative species (ROS) produced by phagocytic cells have been ascribed a role in the localized suppression of lymphocyte function within malignant tumors. Histamine has been shown to inhibit ROS formation and possibly synergize with cytokines to permit activation of natural killer cells and T cells. This study was designed to determine whether the addition of histamine to a subcutaneous (SC) regimen of interleukin-2 (IL-2) would improve the survival of metastatic melanoma patients. PATIENTS AND METHODS: A phase III, multicenter, randomized, parallel group study comparing IL-2 plus histamine with IL-2 alone was conducted in 305 patients with advanced metastatic melanoma. Patients were randomized to IL-2 (9 MIU/m2 bid SC on days 1 to 2 of weeks 1 and 3, and 2 MIU/m2 bid SC on days 1 to 5 of weeks 2 and 4) with or without histamine (1.0 mg bid SC days 1 to 5, weeks 1 to 4). The primary end point, survival, was prospectively applied to all randomized patients (intent-to-treat–overall population, ITT-OA) and all patients having liver metastases at randomization (ITT-LM population). Secondary end points included safety of the combined treatment, time to disease progression, and response rate. RESULTS: Combined treatment with histamine plus IL-2 significantly improved overall survival in the ITT-LM population (P = .004) and showed a trend for improved survival in the ITT population (P = .125). Grade 3 and 4 adverse events were comparable in the two arms. CONCLUSION: Use of histamine as an adjunct to IL-2 is safe, well tolerated, and associated with a statistically significant prolongation of survival compared with IL-2 alone in metastatic melanoma patients with liver involvement. Further trials to confirm and understand the role of histamine in this combination treatment are underway.
THERE WILL BE approximately 51,400 new cases of malignant melanoma diagnosed in the United States in 2001, resulting in approximately 7,800 deaths.1 Approximately 7,500 patients per year are diagnosed with distant metastases (American Joint Committee on Cancer [AJCC] stage IV). The prognosis for these patients is poor, with a 5-year survival rate of approximately 6% and a reported median survival duration of 7.5 months.2 Interleukin (IL)-2 has been shown to have clinical activity in metastatic melanoma. The high-dose bolus regimen investigated by the National Cancer Institute can potentially produce long-term remissions in less than 10% of patients.3 However, data from randomized trials indicating superiority of this treatment over other therapeutic modalities for metastatic melanoma are lacking. Furthermore, the substantial toxicity and expense of this regimen has precluded its widespread use outside of specialized treatment centers. Lower-dose, subcutaneously administered regimens of IL-2 have not been adequately studied in this disease. The mechanism of action of IL-2 in melanoma may be related to its activating effects on antineoplastic lymphocytes such as natural killer (NK) and T cells. Functional inhibition of intratumoral T cell and NK cell cytotoxic activity has been demonstrated and correlated to down-modulation of the CD3 zeta signaling pathway.4,5 Monocyte/macrophage (MO)–derived reactive oxygen species (ROS) have been shown to be important mediators of this inhibitory signal.5 More recently, in vitro studies have demonstrated that MO-derived ROS inhibit NK and T-cell functions, including the activation of antitumor cytotoxicity, cell cycle proliferation and cytokine gene transcription induced by IL-2.5,6 The inhibition is irreversible and eventually leads to NK and T-cell apoptosis.7,8 Histamine, acting via H2-receptors on MO, has been shown to protect NK cells and T-cells from MO-induced functional inhibition and apoptosis.6,7,9,10 In addition, treatment of tumor-bearing rodents with histamine has been shown to enhance the antitumor efficacy of IL-2 in mice with malignant melanoma and lymphoma11 and in rats with prostate adenocarcinoma12 and malignant glioma.13 The histamine-induced potentiation of IL-2–induced activation of NK cells and T cells is mediated through H2 receptors on MO and is antagonized by H2 receptor antagonists such as ranitidine and cimetidine.7
Phase II studies combining histamine with IL-2 and/or interferon alfa (IFN-
Patients and Eligibility Criteria Patients had to satisfy the following inclusion criteria: age  18 years; histologically proven stage IV malignant melanoma; World Health Organization performance status of 0 or 1 (Karnofsky of 70), anticipated life expectancy of more than 3 months; and adequate hematologic (hemoglobin 10 g/dL, WBC count > 2,500/µL; absolute granulocyte count > 1,500/µL; platelet count > 100,000/µL), renal (serum creatinine 1.5 mg/dL), cardiac (normal cardiac stress test for patients > 50 years of age), hepatic (serum bilirubin and AST within normal limits or serum bilirubin < 1.5 times the upper limits of normal and AST < three times the upper limits of normal values for patients with hepatic metastases), and pulmonary function (arterial oxygen percent saturation 90% or forced expiratory volume in one second/forced vital capacity 70% of predicted). Patients with confirmed metastases from choroidal melanoma or those with controlled brain metastases were not excluded. Previous systemic therapy except for IL-2 was permitted, but patients must have recovered from any toxicity from previous therapy (minimum of 4 weeks from previous systemic therapy). Female patients of childbearing potential were to be neither nursing nor pregnant. All patients signed full informed consent. Patients with the following criteria were excluded from the study: active malignancies except in situ carcinoma of the cervix and localized squamous or basal cell carcinomas of the skin, clinically significant active infection that required specific therapy, untreated brain metastases at study entry, history of asthma requiring active treatment within the previous 5 years, or any other significant medical or psychiatric condition that could preclude compliance on the protocol. Patients with active peptic ulcer disease or those with a positive human immunodeficiency virus test were also excluded. Patients older than 50 years were required to undergo cardiac testing.
Study Design
Each patient was treated in the outpatient clinic on days 1 and 8 for the first cycle for monitoring during study drug administration. Subsequent therapy was self-administered at home, and if required, with the help of home care nursing. Patients continued treatment for up to 12 months or until clinically significant progression, CR, or unacceptable toxicity occurred, leading to discontinuation. Ancillary medications including acetaminophen, diphenoxylate, and antiemetics were prescribed as needed. Most patients received omeprazole to suppress gastric acid production; use of H2 receptor antagonists were not permitted while on study. Medications such as beta-blockers and corticosteroids were discontinued at least 24 hours before the first dose of study medications.
Study End Points
Treatment Duration
Statistical Analysis
Secondary parameters such as TTP were also analyzed using Kaplan-Meier procedures as described above. Overall response rates were compared between the two treatment groups using a
Safety Analysis
Patient Characteristics Three hundred five patients were enrolled at 56 centers in the United States between July 1997 and March 1999. One hundred fifty-two patients were enrolled onto the histamine plus IL-2 group and 153 were enrolled onto the IL-2–alone group. Within the ITT-OA population, the two groups were comparable, with no statistically significant differences except for the metastatic site of liver (Table 2). Comparison of the patient characteristics between the two groups within the ITT-LM population also showed no significant differences, except for the number of organ sites equal to one (Table 2). All known prognostic factors and all demographic characteristics between treatment groups were tested using the Cox proportional hazards model. These adjusted multivariate analyses failed to demonstrate any prognostic factor or demographic difference that impacted on the treatment effect of histamine plus IL-2 or statistical significance for duration of survival in either of the primary analysis populations (Tables 3 and 4). The number of patients who discontinued treatment because of adverse events, toxicity, or progressive disease was similar for both study groups; there were six deaths on study, three in each arm.
Efficacy The primary efficacy variable was duration of survival, which was applied to two primary populations, ITT-OA and ITT-LM. The cutoff date for data analysis was 12 months after completion of accrual, which corresponded to approximately an 80% event rate. No patients were lost to follow-up for survival. Kaplan-Meier survival distribution curves for the ITT-OA population demonstrate a trend for improved survival for the histamine plus IL-2 group compared with the IL-2–alone group (Fig 1), but the difference between the two groups was not statistically significant (P = .125). Median survival was improved from 245 days (8.2 months) for the IL-2 group to 272 days (9.1 months) for the histamine plus IL-2 group. The ITT-LM population was prospectively identified as a subgroup of the overall study population in the original protocol and final statistical plan that would be considered in the primary analysis. Data from this population presented in the Kaplan-Meier survival distribution curves (Fig 2) demonstrate that the duration of survival for the patients in the histamine plus IL-2 group was significantly longer than for the IL-2 group (P value adjusted for multiple comparisons = .008). Median survival was improved from 154 days (5.1 months) for IL-2 to 283 days (9.4 months) for histamine plus IL-2. Secondary end points included TTP for both the ITT-OA and ITT-LM populations. Analysis of TTP demonstrated a significant difference in favor of histamine plus IL-2 for both the ITT-OA and ITT-LM populations (P = .038 and P = .007, respectively; data not shown). Details of the best tumor response achieved by patients within the ITT-OA population are given in Table 5. Forty-nine patients on the IL-2 arm and 43 patients on the histamine plus IL-2 group were not assessable for response as they did not complete two cycles (12 weeks) of therapy as required for the first response assessment, mostly because of progressive melanoma. All randomized patients were included in the survival and toxicity analyses. The numbers of patients achieving a CR or PR was identical in each treatment group. In the combined total of all responses apart from PD, there was a higher percentage of patients in the IL-2 group reporting PD, and consequently there was a higher percentage of patients in the histamine plus IL-2 group who recorded a lack of disease progression. Details of the best tumor response achieved by patients within the ITT-LM population are given in Table 5. There was a higher percentage of patients in the histamine plus IL-2 group (38%) than in the IL-2–alone group (20%) (P = .085) who demonstrated a lack of disease progression.
Safety Serious adverse events were experienced by 59 patients (39%) in the IL-2 group and 53 patients (34%) in the histamine plus IL-2 group. The distribution of serious adverse events among body systems was similar between the two treatment groups, as were grade 3 and 4 toxicities (National Cancer Institute common toxicity criteria). Table 6 lists grade 3 or 4 adverse events by severity. Three patients, one in the IL-2 group and two in the histamine plus IL-2 group, died because of causes other than melanoma while enrolled on the study. Three patients in the IL-2 group and five patients in the histamine plus IL-2 group died during the 28 days after study discontinuation.
Adverse events related to administration of histamine were mild to moderate (grade 1 and 2), and included flushing, palpitations, mild hypotension, headache, injection site reaction, and dyspepsia. Histamine-related effects were transient (30 to 60 minutes), required no treatment, and were without sequelae.
Current systemic therapeutic options for metastatic melanoma have used chemotherapy (single agents and combinations), immunotherapy (IL-2 and IFN), and concurrent or sequential chemoimmunotherapy regimens. Although chemotherapeutic agents such as dacarbazine demonstrate response rates in the range of 10% to 20%, no meaningful impact on survival has been demonstrable to date,18,19,20 and combination chemotherapy has not been proven superior to single-agent dacarbazine in randomized trials.19,20
Immunotherapy with single-agent high-dose bolus IL-2 (600,000 to 720,000 IU/kg every 8 hours for 14 doses over 5 days) has demonstrated sustained objective responses in a minority of patients with metastatic melanoma. In the most recently published review of 270 patients treated between 1985 and 1993, the overall response rate was 16%, with 17 CRs and 26 PRs.3 The overall median survival was 11.4 months and the survival rate at 24 months was approximately 22%. Data were not available on patients having liver metastases. In a separate analysis of 631 patients with advanced melanoma receiving either high-dose IL-2 alone or in combination with IFN-
Combinations of chemotherapy and immunotherapy (biochemotherapy) have also been evaluated for metastatic melanoma. Although phase II data with this approach seemed promising, two recent randomized trials of biochemotherapy have not produced statistically significant improvements in survival.22 A recently reported trial comparing the combination of cisplatin/vinblastine/dacarbazine (CVD) to CVD plus IL-2/IFN- One of the proposed limitations of cytokine-based therapies may involve inactivation of peritumoral and intratumoral cytotoxic T cells and NK cells. In vitro studies have demonstrated that ROS generated by MO populations may inhibit cytotoxic activity within the tumor, leading to the hypothesis that cytokine-based immunotherapy may be more effective if the generation of ROS were inhibited.5,7 Histamine dihydrochloride is a potent inhibitor of ROS formation through interaction with the H2 receptor on phagocytic cells.6,24 The ability of histamine to downregulate ROS may improve the efficacy of various immunotherapeutics such as cytokines and vaccines. Clinical evidence in support of this hypothesis came from phase II studies combining histamine with cytokine-based therapies for metastatic melanoma, acute myelogenous leukemia, and renal cell carcinoma.14,15,25-27 These early studies suggested a prolongation of survival or remission duration, particularly in patients with liver metastases, and led to the design of this phase III trial in advanced metastatic melanoma.
In the study reported herein, we have demonstrated that the addition of histamine to a subcutaneous regimen of IL-2 is associated with a statistically significant survival benefit for metastatic melanoma patients with liver metastases at study entry (P = .008; adjusted for multiple comparisons). A beneficial survival trend was noted for the entire ITT population, but the difference was not statistically significant (P = .125). Further examination of the survival data according to the modified AJCC staging system demonstrates that those patients with M1b (lung alone) median survival was improved from 463 days to 565 days for patients treated in the histamine plus IL-2 group (P = .071), and for the patients classified M1c (visceral disease plus all patients with LDH It is intriguing to hypothesize regarding the underlying mechanism responsible for the potential benefit seen specifically in these patients with liver metastases. The liver is a common site for metastases from melanoma and carries a predictable and unfavorable outcome. This is reflected in the recent modification of the AJCC staging system, which assigns patients with visceral involvement, including the liver, to a separate substage, M1c. The results observed in this trial may be explained in part by the possibility that the presence of liver metastases establishes a more homogenous patient population with a predictably short survival duration where the impact of treatment may be more clinically evident. When the data were analyzed using the new modified AJCC M1c category, the benefit of the histamine IL-2 treatment was also statistically significant (P = .026), as mentioned above. Interestingly, the improvement in overall survival with histamine plus IL-2 seen in this trial was not correlated with an increased response rate. It is also notable that in most randomized trials, response rates have been a poor surrogate for a survival benefit. This was evident in the recently reported United States Cooperative Group randomized trial of combination chemotherapy with the Dartmouth regimen of dacarbazine, cisplatin, carmustine, and tamoxifen versus dacarbazine alone, where a doubling of the response rate with the combination was not associated with an increase in survival.19 A more accurate assessment of response in studies using low-dose immunotherapy and other cytostatic therapies might be a lack of disease progression, which would comprise all patients without PD as defined in this protocol. Using this criteria, there was a trend toward improvement for the number of patients who lacked disease progression in both the ITT-OA and ITT-LM populations in the histamine/IL-2 group, but the improvement was not statistically significant. However, time to disease progression was significantly improved for both the ITT-OA (P = .038) and ITT-LM (P = .007) populations. Assessment of the various prognostic factors between the two groups in this trial did not reveal any significant factors that influenced the final survival outcomes when examined in the Cox proportional hazards model. In particular, LDH, age greater than 65 years, number of metastatic sites more than two, prior chemotherapy, and male sex, which have been shown previously to significantly impact on treatment outcome and survival,3,28,29 were not significantly different between the two treatment arms. As expected, bone, CNS metastases, liver metastases, performance status, and elevated LDH were significant predictors of survival in this study population. The control arm in our study was subcutaneously administered IL-2 using a schedule designed to maximize ease of outpatient administration and to duplicate as far as possible the continuous-infusion regimen evaluated by other investigators.30,31 The choice of this control treatment could be criticized because of the lack of data demonstrating efficacy of this regimen in metastatic melanoma. However, it is worth noting that the median survival of the IL-2–alone control arm of our study is very similar to survival data obtained in other randomized trials in stage IV melanoma. Indeed, the median survival of the IL-2–alone arm for our study (8 months for the ITT-OA population) was similar to other representative trials using dacarbazine as the control arm (6.4 to 8.9 months)19,20,32 despite our inclusion of previously treated patients. Furthermore, the median survival of 9 months for the histamine/IL-2 group compares favorably to that achieved with single-agent continuous infusion IL-2 used in other regimens.31 With regard to liver metastases, the median survival for patients in the ITT-LM group treated with IL-2 alone was 5.1 months, which is comparable to the 2 to 5 months previously reported for studies of stage IV melanoma patients with metastases to the liver.33,14,21,34 Overall toxicities in this study were mild, perhaps because of the low doses of IL-2 administered. Toxicities traditionally associated with higher doses of IL-2, including hypotension, oliguria, and diarrhea, were infrequent on this trial on both arms, and the treatment was administered on an outpatient basis at home. Advances in the therapy for stage IV melanoma have been tempered by the recurring observation that phase III randomized trials cannot confirm promising results previously seen in phase II studies. In particular, higher response rates have not proven to be a marker for improvement in survival, yet response rate continues to be considered a major end point of ongoing trials in this area. We have presented data from a large prospective, multicenter, randomized trial showing a significant improvement in median survival for an important subset of patients with metastatic melanoma and liver involvement which was achieved with modest toxicity in an outpatient (in-home) setting. Clearly, more studies are needed to better understand the potential mechanisms underlying this observation, and a second randomized trial of histamine and IL-2 compared with IL-2 alone in patients with melanoma metastatic to the liver was initiated in 2001.
We thank the other investigators participating in this study: T. Amatruda, C. Anderson, F. Arena, R. Asbury, N. Bartlett, R. Belt, D. Bodkin, A. Brown, A. Chang, N. Chowhan, A. Deisseroth, M. Ernstoff, L. Fehrenbacher, M. Graham, D. Irwin, V. Jones, A. Keller, D. Lawson, J. Lutzky, K. McMasters, F. Nathan, R. Oratz, J. Polikoff, W.J. Poo, J. Richards, J. Rosenblatt, F. Sanchez, N. Savaraj, P. Schaefer, L. Sutton, H. Terebelo, M. Thant, and R. Weinstein. We also thank the people at Maxim Pharmaceuticals, San Diego, CA, and Omnicare, King of Prussia, PA, who managed this clinical trial.
1. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer Statistics, 2001. Ca Cancer J Clin 51: 15-36, 2001 2. Barth A, Wanek LA, Morton DL: Prognostic factors in 1,521 melanoma patients with distant metastases. J Am Col Surg 181: 193-201, 1995
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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
4.
Mizoguchi H, O’Shea JJ, Longo DL, et al: Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258: 1795-1798, 1992 5. Kono K, Salazar-Onfray F, Petersson M, et al: Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell- and natural killer cell-mediated cytotoxicity. Eur J Immunol 26: 1308-1313, 1996[Medline] 6. Hellstrand K, Asea A, Dahlgren C, et al: Histaminergic regulation of NK cells: Role of monocyte-derived reactive oxygen metabolites. J Immunol 153: 4940-4947, 1994[Abstract] 7. Hansson M, Hermodsson S, Brune M, et al: Histamine protects T cells and natural killer cells against oxidative stress. J Interferon Cytokine Res 19: 1135-1144, 1999[CrossRef][Medline] 8. Hansson M, Asea A, Ersson U, et al: Induction of apoptosis in NK cells by monocyte-derived reactive oxygen metabolites. J Immunol 156: 42-47, 1996[Abstract] 9. Hellstrand K, Hermodsson S: Cell-to-cell mediated inhibition of natural killer cell proliferation by monocytes and its regulation by histamine H2-receptors. Scand J Immunol 34: 741-752, 1991[CrossRef][Medline] 10. Hellstrand K, Hermodsson S: Synergistic NK cell activation by histamine and interleukin-2. Int Arch Allergy Appl Immunol 92: 379-389, 1990[Medline] 11. Asea A, Hermodsson S, Hellstrand K: Histaminergic regulation of natural killer cell-mediated clearance of tumour cells in mice. Scand J Immunol 43: 9-15, 1996[CrossRef][Medline] 12. Johansson S, Landstrom M, Hellstrand K, et al: The response of Dunning R3327 prostatic adenocarcinoma to IL-2, histamine and radiation. Br J Cancer 77: 1213-1219, 1998[Medline] 13. Johansson M, Henriksson R, Bergenheim AT, et al: Interleukin-2 and histamine in combination inhibit tumor growth and angiogenesis in malignant glioma. Br J Cancer 83: 826-832, 2000[CrossRef][Medline] 14. Hellstrand K, Naredi P, Lindner P, et al: Histamine in immunotherapy of advanced melanoma: A pilot study. Cancer Immunol Immunother 39: 416-419, 1994[CrossRef][Medline] 15. Hellstrand K, Hermodsson M, Brune M, et al: Histamine in cancer immunotherapy. Scand J Clin Lab Invest 57: 193-202, 1997[Medline] 16. Balch CM, Soong S, Shaw HM, et al: An analysis of prognostic factors in 4000 patients with cutaneous melanoma, in Balch CM, Milton GW (eds): Cutaneous Melanoma: Clinical Management and Treatment Results Worldwide. Philadelphia, PA, JB Lippincott Co, 1985, pp 321-352 17. Ludbrook J: Multiple comparison procedures updated. Clin Exp Pharmacol Physiol 25: 1032-1037, 1998[Medline] 18. Balch CM, Reintgen DS, Kirkwood JM, et al: Cutaneous melanoma, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, JB Lippincott Co, 1997, pp 1947-1994
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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 20. Falkson CI, Ibrahim J, Kirkwood JM, et al: Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: An Eastern Cooperative Oncology Group study. J Clin Oncol 16: 1743-1751, 1998[Abstract]
21.
Keilholz U, Conradt C, Legha SS, 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. Keilholz, U, Punt C, Gore M, et al: Dacarbazine, cisplatin and IFN-alfa with or without IL-2 in advanced melanoma (EORTC trial 18951). Ann Oncol 11:S4, 2000 (suppl 4, abstr) 23. Eton O, Legha S, Bedikian A, et al: Phase III randomized trial of cisplatin, vinblastine and dacarbazine (CVD) plus interleukin-2 (IL2) and interferon-alpha-2B (INF) versus CVD in patients (pts) with metastatic melanoma. Proc Am Soc Clin Oncol 19: 552a, 2000 (abstr 2174)
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Mellqvist U-H, Hansson M, Brune M, et al: Natural killer cell dysfunction and apoptosis induced by chronic myelogenous leukemia cells: Role of reactive oxygen species and regulation by histamine. Blood 96: 1961-1968, 2000 25. Hellstrand K, Hermodsson S, Naredi P, et al: Histamine and cytokine therapy. Acta Oncol 37: 347-353, 1998[CrossRef][Medline] 26. Hellstrand K, Mellqvist UH, Wallhult E, et al: Histamine and interleukin-2 in acute myelogenous leukemia. Leuk Lymphoma 27: 429-438, 1997[Medline] 27. Hellstrand K, Brune M, Naredi P, et al: Histamine: A novel approach to cancer immunotherapy. Cancer Invest 18: 347-355, 2000[Medline] 28. Richards JM, Parkinson DR, Abrams J, et al: Interleukin-2 therapy in patients with metastatic malignant melanoma: A phase II study. J Clin Oncol 8: 1650-1656, 1990[Abstract] 29. ;4>O’Day SJ, Gammon G, Boasberg PD, et al: Advantages of concurrent biochemotherapy modified by decrescendo interleukin-2, granulocyte colony-stimulating factor, and tamoxifen for patients with metastatic melanoma. J Clin Oncol 17:2752-2761, 1999 30. West WH: Continuous infusion recombinant interleukin-2 (rIL-2) in adoptive cellular therapy of renal carcinoma and other malignancies. Cancer Treat Rev 16: 83-89, 1989 (suppl A) 31. Legha SS, Gianan MA, Plager C, et al: Evaluation of interleukin-2 administered by continuous infusion in patients with metastatic melanoma. Cancer 77:89-96, 1996, 1996
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33.
Sparano J, Fisher R, Sunderland M, et al: Randomized phase III trial of treatment with high dose interleukin-2 alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 11: 1969-1977, 1993 34. Mansfield PF, Lee JE, Balch CM: Cutaneous melanoma: Current practice and surgical controversies, in Wells Jr SA (ed): Current Problems in Surgery (vol 31). St Louis, MO, Mosby-Year Book Inc, 1994, pp 253-374 Submitted November 20, 2000; accepted July 9, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) in metastatic melanoma have indicated positive activity with the combination.
2 test. 
