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© 2000 American Society for Clinical Oncology Adjuvant Therapy of Stage III and IV Malignant Melanoma Using Granulocyte-Macrophage Colony-Stimulating FactorByFrom the Northern California Melanoma CenterSan Francisco, CA; Massachusetts General Hospital, Boston, MA; Dartmouth Hitchcock Medical Center and Norris Cotton Cancer Center, Lebanon, NH; Immunex R & D Corp, Seattle, WA; and University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL. Address reprint requests to Lynn E. Spitler, MD, Northern California Medical Center, St Francis Memorial Hospital, 900 Hyde St, San Francisco, CA 94109; email lynn{at}drspitler.com
PURPOSE: To evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as surgical adjuvant therapy in patients with malignant melanoma who are at high risk of recurrence. PATIENTS AND METHODS: Forty-eight assessable patients with stage III or IV melanoma were treated in a phase II trial with long-term, chronic, intermittent GM-CSF after surgical resection of disease. Patients with stage III disease were required to have more than four positive nodes or a more than 3-cm mass. All patients were rendered clinically disease-free by surgery before enrollment. The GM-CSF was administered subcutaneously in 28-day cycles, such that a dose of 125 µg/m2 was delivered daily for 14 days followed by 14 days of rest. Treatment cycles continued for 1 year or until disease recurrence. Patients were evaluated for toxicity and disease-free and overall survival. RESULTS: Overall and disease-free survival were significantly prolonged in patients who received GM-CSF compared with matched historical controls. The median survival duration was 37.5 months in the study patients versus 12.2 months in the matched controls (P < .001). GM-CSF was well tolerated; only one subject discontinued drug due to an adverse event (grade 2 injection site reaction). CONCLUSION: GM-CSF may provide an antitumor effect that prolongs survival and disease-free survival in patients with stage III and IV melanoma who are clinically disease-free. These results support institution of a prospective, randomized clinical trial to definitively determine the value of surgical adjuvant therapy with GM-CSF in such patients.
PATIENTS WITH metastatic melanoma have a dismal prognosis and respond poorly to currently available chemotherapies and biologic agents, which result in median survivals durations of between 6 and 9 months.1-3 In contrast, patients who undergo complete surgical resection of metastatic disease (stage IV) enjoy prolonged survival durations of between 11 and 19 months.1,4-7 It has been suggested that adjuvant treatment with immune modulators such as vaccines and cytokines after complete surgical resection may further prolong median survival rates.3,8,9 Such agents are believed to have their greatest potential in the setting of minimal residual disease. Therefore, complete surgical resection of metastatic melanoma offers an ideal setting in which to evaluate immune modulatory agents for efficacy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multifunctional molecule and plays a vital role in various functions of the immune system. One of the most important activities relative to cancer therapy is the ability of GM-CSF to activate macrophages. GM-CSF stimulates peripheral-blood monocytes in vitro to become cytotoxic for human melanoma cells.10,11 The in vivo administration of GM-CSF results in an increase in the functional capacity of monocytes, as determined by the cytotoxicity of monocytes against antibody-coated xenogeneic cells12 and HT29 colon carcinoma cells.13 GM-CSF also serves as the principal mediator of proliferation, maturation, and migration of dendritic cells,14-16 which are antigen-presenting cells that play a major role in the induction of primary and secondary T-cell immune responses. Finally, GM-CSF causes increased production of matrix metalloelastase elastase by tumor infiltrating macrophages,17 which results in the production of angiostatin by the macrophages.18 The angiostatin inhibits angiogenesis and suppresses the growth of pulmonary metastases. Here, we report the results of an open-label, multicenter, phase II trial evaluating long-term intermittent GM-CSF therapy in patients with advanced melanoma after surgical resection. These results suggest that GM-CSF may have a role in the surgical adjuvant treatment of patients with melanoma.
Patient Population Eligible patients were those with stage III or IV malignant melanoma as defined by the American Joint Committee on Cancer (AJCC). Patients with stage III (node-positive) disease were required to have more than four positive nodes and/or a nodal mass greater than 3 cm in diameter. Patients were clinically disease-free at the time of study entry, having undergone surgical resection of nodal or metastatic disease. Patients in whom residual disease was suspected postoperatively may have received adjuvant radiotherapy. Some patients were given prophylactic whole-brain irradiation. Patients were not excluded if they had received prior chemotherapy, radiation therapy, or immunotherapy, although they must have completed therapy at least 1 month before study entry. The institutional review boards at the participating institutions approved the protocol, and all patients provided written informed consent.
Treatment Regimen
Historical Controls
Statistical Methods
Characteristics of the Study Population Fifty-one patients were entered onto the study and 48 patients were assessable, having received at least one dose of GM-CSF. The other three patients were found to be ineligible due to the presence of gross disease (two patients) or inappropriate disease stage (one patient). The 48 patients treated with GM-CSF were matched with 48 control patients (Table 1). The patient populations were identical in terms of stage of disease (14 patients with stage III disease and 34 patients with stage IV disease in the treatment and control groups) and were comparable in terms of age and sex. There were more patients in whom the location of the primary tumor was unknown in the treated patients and more in whom the location of the primary tumor was classified as "other" in the control patients. There were more patients with "thin" primary tumors (< 1.5-mm thickness) in the treated than in the control population, but neither the histopathology or location of the primary tumor is a prognostic factor in this population of patients who have already developed metastatic disease.19
For the patients with stage III melanoma, there was complete agreement in the study and control populations with regard to the number of nodes involved (Table 2). The number of nodes involved with melanoma is well accepted as the most important prognostic indicator for patients with stage III disease.20 Patients with stage IV disease were perfectly matched for site of metastases (visceral v subcutaneous) and closely matched for the number of anatomic sites (Table 2). These are recognized as the most important prognostic indicators for this patient population.19 The time from diagnosis of the primary tumor to study entry was comparable in the stage III patients but quite different in the stage IV patients, largely because of the wide differences in the range. Other variables could not be matched. For example, there were eight patients with fewer than five nodes among the patients in the experimental group with stage III disease, and those patients were required to have bulky lymph node disease with a mass of a diameter greater than 3 cm. The control patients could not be matched for this characteristic because the information was not collected in the database. Also, three of the 14 patients with stage III melanoma in the study group were known to have had one resected lymph node metastasis before the second resected lymph node metastasis that qualified them for entry onto the study; those in the matched controls did not. Ten of the patients with stage IV disease in the study group had prior visceral metastases; those in the control group did not. The patients with stage IV disease in the study group had undergone a number of prior therapies; 44% had undergone prior radiation therapy, 29% had undergone prior surgical procedures for metastatic disease, and some patients had received biotherapy or chemotherapy. These data were not available for the patients in the control group.
GM-CSF Therapy Patients received GM-CSF for a median duration of 11.5 cycles (range, two to 49 cycles). Twenty-four received fewer than 12 cycles; twenty-three discontinued therapy because of disease progression after a median of six cycles, and one patient discontinued therapy because of an adverse event (grade 2 injection site reaction) after three cycles. Seven patients received 12 cycles, and seventeen (35%) received more than 12 cycles, with a median of 24 cycles. Three patients interrupted the dosing schedule for more than 2 months.
Side Effects
Hematologic Response
Survival
Recurrences Thirty-five patients had at least one disease recurrence on study (Table 4). In 18 patients, the disease recurrence was localized and could be excised completely. In five of these 18 patients, there were further localized recurrences, which also could be excised. The remainder had multiple lesions that required systemic therapy. Combination chemotherapy was the most common type of treatment (11 patients), and in most patients, this consisted of the combination of dacarbazine, carmustine, cisplatin, and tamoxifen. Only four patients received biochemotherapy.
These results indicate that the administration of GM-CSF to patients with metastatic malignant melanoma who are at high risk for recurrence after surgical resection of metastatic disease results in a statistically significant prolongation of overall and disease-free survival compared with matched historical controls. Furthermore, GM-CSF is well tolerated and results in minimal toxicity. Because of the potential impact of prognostic variables on the clinical outcome, we used a statistical analysis in which each patient treated with GM-CSF was paired with a control subject. Pairs were matched for number of nodes (patients with stage III disease)20 or location and number of metastatic sites (patients with stage IV disease)1,4,5,19,21; these are the two most important prognostic indicators for these patient populations. The groups were generally well matched demographically. The stage III patients were well matched for the time between diagnosis of the primary tumor and the first lymph node recurrence, but the stage IV patients had a substantially longer time between diagnosis of the primary tumor and the first distant metastasis. There have been several reports indicating that remission time before metastasis is not a significant prognostic indicator of survival,5,20-22 and one report claims that it is.7 Despite these matching characteristics, there were a number of features that would indicate that the population treated with GM-CSF might have a worse prognosis than the control patients. For example, in the population of patients with stage III melanoma, there were eight patients with fewer than five nodes in both the treatment and control groups. In the treatment group, these patients all had bulky nodal disease, which placed them in the N2 category according to the AJCC staging system. The patients included in the study reported herein are not typical of the overall population of patients with stage IV disease; they represent a selected subpopulation of patients who present with metastatic disease that can be surgically excised. This is demonstrated by the fact that in the database used here as historical controls, only 32% of the patients were in this group. Patients in this subpopulation who undergo complete resection of all gross disease have a longer median survival than patients who are treated by other means, such as chemotherapy. Median survival after complete resection of metastatic melanoma has been reported by various centers to range from 11 to 19 months when the patients were treated with surgery alone (Table 5). The reason for this wide range in median survival may rest in the distribution of the location of the metastatic sites and whether or not the metastases were solitary or multiple in the patient population under investigation, because it is recognized that the outcome is dependent on these prognostic indicators.
Because the treatment options that are available for therapy of metastatic melanoma are different now from those that were available at the time when the historical controls were treated, one must consider whether the improved survival might be due to improved therapeutic options. Combination chemotherapy regimens have had little impact on survival,23 and attention has recently focused on combination biochemotherapy regimens.24-27 Because only four (8%) of the 48 patients in the GM-CSF treatment group were given biochemotherapy, we think it is unlikely that this could be the sole explanation for the improved survival of the study patients. The effect of surgical adjuvant therapy with GM-CSF seemed to have a greater impact on survival than on disease-free survival. The same seems to be the case in the study with the polyvalent melanoma cell vaccine, although the authors didn’t comment on that aspect of their therapy.8,28 We postulate that therapy with GM-CSF may be changing the biology of the behavior of metastatic melanoma. Recurrences in the treated population were often localized and could be treated with localized means rather than requiring systemic therapy. Data regarding this aspect of the nature of recurrences were not in the database of the matched controls or in any other database of which we are aware, so we could not conduct a comparative analysis. Nonetheless, it is reasonable to postulate that the macrophages activated by the GM-CSF could eradicate small metastatic tumor nodules that would have appeared as systemic metastases, although they could not overcome a nodule that was larger at the time of treatment and would subsequently appear as a localized metastasis. This postulate is supported by the observation that small tumors are infiltrated with a relatively large number of macrophages, whereas large tumors are not.29-31 Physicians caring for patients with melanoma face a dilemma in determining which adjuvant therapy to recommend. The only agent currently approved in the United States for adjuvant therapy of melanoma is interferon alfa-2b, and it is recommended for use in a high-dose regimen. The efficacy of this regimen is modest9 and the treatment is associated with considerable toxicity, especially in older patients. Moreover, a follow-up study confirmed disease-free survival benefit but failed to confirm overall survival benefit of this regimen or of a low-dose interferon regimen in prolonging survival in patients with high-risk melanoma.32 Low-dose interferon alfa has also been evaluated in a large, randomized study in adjuvant therapy of patients with stage II melanoma and results have been promising, although the low-dose regimen does not seem effective in higher-risk patients.33 In a large, prospective, randomized trial, levamisole was been reported to be effective in the adjuvant therapy of patients with high-risk melanoma,34 and on the basis of that study, levamisole has been approved for this purpose in Canada, but not in the United States. A similar prospective, randomized, placebo-controlled trial failed to show benefit of levamisole in the adjuvant treatment of melanoma, but the dose used was slightly different.35 There is current enthusiasm for the potential of vaccines for adjuvant therapy of melanoma, but the only large-scale, prospective, randomized, placebo-controlled study reported to date has been negative.36 There have been a number of positive reports of efficacy of vaccines in phase II trials, but none of these have yet been established to be effective in properly designed phase III trials. These include a GM2 ganglioside-keyhole limpet hemocyanin conjugate vaccine,37 a polyvalent melanoma vaccine administered with Bacillus Calmette-Guérin,21 a polyvalent melanoma antigen vaccine consisting of shed antigens,38 a hapten-modified autologous vaccine,39 and a synthetic peptide vaccine administered with interleukin-2.40 A number of other vaccines for adjuvant therapy of melanoma are in earlier stages of testing. Although results are encouraging, none of these vaccines is approved for marketing and they are generally not available outside of clinical trials. Because of the success of biochemotherapy in the treatment of patients with advanced melanoma,25 this regimen is now being tested in the adjuvant setting, but results are not yet available. Toxicities demonstrated in this study were substantially less severe than those reported for other biologic agents (interleukin-2 and interferon alfa). In fact, only one patient prematurely discontinued treatment because of an adverse event (grade 2 injection site reaction). This safety profile allows long-term maintenance therapy to be delivered in the majority of patients. The results reported herein suggest that GM-CSF may have efficacy as surgical adjuvant treatment of melanoma, and a properly designed, prospectively randomized clinical trial is warranted.
Supported in part by the Melanoma Research Institute, San Francisco, CA, and Immunex R & D Corp, Seattle, WA. We thank Vera Byers and Mark Gilbert for critical assistance in the preparation of this manuscript and Kelly Otto and Linda Austin for statistical analysis. We also thank Robert Allen, James Good, and John Meyers for helping with the care of the patients treated on this protocol and Sister Patrice Burns for overall support.
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Berd D, Maguire HCJ, Schuchter LM, et al: Autologous hapten-modified melanoma vaccine as postsurgical adjuvant treatment after resection of nodal metastases. J Clin Oncol 15:2359-2370, 1997 40. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al: Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma [see comments]. Nat Med 4:321-327, 1998[Medline] Submitted October 12, 1999; accepted February 1, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
ecogdba/general/e1690_abstract.html
