Adjuvant chemotherapy in high-risk malignant melanoma

Fifty-nine patients with regional or hematogenous recurrence of malignant melanoma following resection of all the gross tumor were randomized to observation or chemotherapy. The chemotherapy consisted of BCNU 80 mg/M2 I.V. every 4 weeks, actinomycin-D 0.01 mg/kg and vincristine 1.0 mg/M2 I.V. every 2 weeks, for a total of 6 months. The chemotherapy protocol was tolerated well without appreciable objective side effects. At a median follow-up period of 11.5 months, the disease-free survival time for the chemotherapy treated group is significantly longer than for the control group (P = 0.01). The estimated median disease-free survival time is 4 months in the surgical control group and 9 months in the chemotherapy group. At present, the proportion of patients remaining disease-free is 43% for the surgical control and 55% for the chemotherapy treated group. More patients and follow-up are needed, but this preliminary report suggests that nitrosourea-based protocols need to be evaluated further as adjuvant treatment of malignant melanoma.     

Adjuvant chemotherapy in the management of primary malignant melanoma.

In a prospective randomized study, the effect of chemotherapy (either systemic or combined intraarterial and systemic) was studied in 117 patients undergoing a curative resection of Clark's level III, IV or V malignant melanoma. Systemic chemotherapy was started one month after surgery one week courses with an I.V. injection of Vinblastin 6 mg/m2, Thiotepa 6 mg/m2, Rufocromomycine 60 microgram/m2, Methotrexate 15 mg/m2 on day one with procarbazine 30 mg/m2 orally daily were given every other week for three months and later every four weeks. Intraarterial chemotherapy of DTIC 80 mg/kg day for ten days was given 28 days prior to surgery. 65 patients with limb malignant melanoma were treated either by surgery only (27 patients), or by systemic chemotherapy (23 patients) or by preoperative intraarterial chemotherapy and systemic chemotherapy (15 patients): 52 patients with non limb malignant melanoma were treated either by surgery only (28 patients) or by systemic chemotherapy (24 patients). We drew curves of disease free survival following surgery and studied the levelling off of the curves, 24 months after surgery 65% of the patients treated by surgery alone were alive and free of disease whereas 81% of the patients treated by surgery and chemotherapy were alive and free of disease (p less than 0.05) suggesting a possible benefit of adjuvant chemotherapy. Intraarterial preoperative chemotherapy has not proved of additional benefit to date.     

Adjuvant chemotherapy in ocular malignant melanoma. Study of 20 cases

The frequency of hematogenously propagated hepatic metastases occurring from ocular melanoma led us to treat 20 patients with adjuvant chemotherapy, 19 patients starting chemotherapy during the month following enucleation and 1 patient, a year after enucleation. With a median follow-up of 6 years, 17 patients (80%) are disease-free. Three patients developed hepatic metastases at 24, 24 and 30 months, respectively. The results suggest that adjuvant chemotherapy is effective in preventing metastases from ocular melanoma.     

PALA, vindesine, and cisplatin combination chemotherapy in advanced malignant melanoma. A pilot study

Twenty-two patients with advanced malignant melanoma were entered in a pilot study receiving combination chemotherapy with PALA, vindesine, and cisplatin (PVP). Treatment consisted of PALA 3000 mg/m2 IV on days 1 and 2, vindesine 3 mg/m2 IV on days 1 and 8, cisplatin 30 mg/m2 IV on days 1 through 5, with treatment cycles repeated on day 21 every 3 weeks. Of 22 patients, 3 had non-visceral disease confined to iuxtaregional tumor growth (Stage III), and 19 had disseminated and/or visceral disease (Stage IV). The male/female sex distribution was 13/9; median age was 45 years. All 22 patients had measurable disease; 21 were evaluable for response and toxicity. Five patients (24%) had a complete response (CR) with a median duration of 5 months, and four patients (19%) had a partial response (PR) with a median duration of 3 months. Seven patients showed disease stabilization (33%) with a median duration of 2 months. Progressive disease was seen in five patients (24%) and was commonly due to widespread visceral disease. CR could be found predominantly in non-visceral disease, whereas PR could be observed in visceral disease also. Survival time from the onset of PVP chemotherapy cannot be estimated finally, since some of the responses are continuing at the present time, and 7 of 21 patients are still alive. Currently, median survival time for responders is 8 months, and for nonresponders, 5 months. Toxicity of PVP chemotherapy is mild to moderate and allows cytotoxic drug administration on an outpatient basis. PVP chemotherapy appears to have significant activity against malignant melanoma and may therefore be an alternative regimen in the management of advanced disease. However, despite the relative high remission rate especially in non-visceral disease, response duration remains disappointingly low.     

Adjuvant immunotherapy of malignant melanoma.

A vaccine made of irradiated Vibrio cholerae neuroaminidase (VCN) treated autochthonous tumor cells plus BCG was utilized in combination with surgery or with chemotherapy for Stage II and Stage III malignant melanoma, respectively. A few patients with Stage I melanoma were treated with surgery and BCG. Most of the studies were carried out on a prospective, randomized protocol. When the results with conventional therapy were compared with the results of conventional therapy plus immunotherapy, no beneficial effects of the immunotherapy were seen. Stratification insured comparability in both immunotherapy and nonimmunotherapy groups. We conclude that VCN treated tumor cells plus BCG, when administered according to the protocol utilized here, offer patients with malignant melanoma no substantial benefit when compared with conventional therapy.     

Adjuvant therapy for malignant melanoma

Malignant melanoma is increasing in incidence worldwide, and many patients remain at a significant risk of recurrence following surgical resection. Over the past 30 years, interferon-alpha has been the only agent approved for adjuvant therapy of melanoma. This review summarizes the rationale for adjuvant therapy, and discusses the roles of interferon, immunotherapy, chemotherapy and radiation therapy in the adjuvant setting. New approaches and novel combinations that appear promising for the adjuvant therapy of malignant melanoma are also outlined.     

Active immunotherapy as an adjunct to chemotherapy in the treatment of disseminated malignant melanoma: a pilot study.

In patients with disseminated malignant melanoma an optimal method of immunization with irradiated tumour cells was developed by reference to an in vitro assay for circulating specific serum inhibitors of cell mediated cytotoxicity. This immunization protocol consisted of the intradermal inoculation of 2 times 10(7) irradiated allogeneic melanoma cells admixed with 50 mug of percutaneous BCG. This method of immunization induced a significant but transient fall in the specific inhibitory effects of the sera on tumour directed cytotoxic activity of the patients' lymphocytes. In a pilot group of 30 patients with disseminated malignant melanoma being treated with chemotherapy (DTIC and vincristine) the immunotherapy was given midway between courses of the cytotoxic drugs. There was a correlation between the effects on circulating inhibitor and clinical outcome. The number of objective regressions occurring in this small pilot group was surprisingly high (17/30) and these clinical effects, although obtained in a series without concurrent controls, are presented for discussion. We suggest that the approach illustrated by this study, employing in vitro assays of tumour directed immune responses, may provide a suitable rational basis for the use of active immunotherapy as an adjunct to chemotherapy in the treatment of malignant disease.     

Adjuvant irradiation for axillary metastases from malignant melanoma

PURPOSE: To evaluate the outcome and treatment-related toxicity for patients with axillary lymph node metastases from malignant melanoma treated with surgery and radiation, with or without systemic therapy. MATERIALS AND METHODS: The medical records of 89 consecutive patients with axillary lymph node metastases from malignant melanoma were retrospectively reviewed. All patients underwent axillary dissection and postoperative radiation to a median dose of 30 Gy at 6 Gy/fraction delivered twice weekly. In 3 patients referred with microscopic residual disease, a single boost (4-6 Gy) was given to a reduced field. All but 2 patients were referred because their axillary dissections revealed features believed to predict a 30-50% risk of subsequent axillary recurrence: lymph nodes >/=3 cm in size (54 patients), >/=4 lymph nodes positive (44), the presence of extracapsular extension (69), recurrent disease after initial surgical resection (23), or multiple risk factors (77). Fifty-one patients received systemic therapy before or after radiation therapy. RESULTS: At a median follow-up of 63 months, 47 patients had relapsed and 43 patients had died. The actuarial overall and disease-free survival rates at 5 years were 50% and 46%, respectively. The actuarial axillary control and distant metastasis-free survival rates at 5 years were 87% and 49%, respectively. Univariate analysis revealed that the probability of axillary control was inferior when the axillary disease measured >6 cm in size (72% vs. 93%, p = 0.02), the location of the primary tumor was unknown (74% vs. 93%, p = 0.02), the axillary failure occurred within 18 months from diagnosis of the primary melanoma (84% vs. 100%, p = 0.04), or the Breslow thickness was >4 mm (80% vs. 96%, p = 0.04). Additionally, there was an inferior distant metastasis-free and disease-free survival when there were >2 nodes positive for metastatic disease, the primary lesion had a Breslow thickness >4 mm, or the axillary failure occurred within 18 months from diagnosis of the primary melanoma. On multivariate analysis, the significantly inferior distant metastasis-free and disease-free survival seen when >2 nodes were positive or the recurrence occurred within 18 months remained significant. The small number of axillary failures precluded multivariate analysis for axillary control; however, stratified analysis suggested that size >6 cm was the factor most closely associated with subsequent axillary failure. Twenty-six patients developed treatment-related arm edema. Classification according to the severity of edema yielded 5-year actuarial arm edema rates of 21%, 19%, and 1%, for Grade 1 (transient or asymptomatic), Grade 2 (requiring medical intervention), or Grade 3 (requiring surgical intervention) edema, respectively. CONCLUSION: Adjuvant radiation therapy using a hypofractionated regimen resulted in an 87% 5-year axillary control rate, superior to the 50-70% local control achieved with surgery alone for lymph node metastases from melanoma when high-risk features are present. Improvements are needed for patients with bulky nodal masses >6 cm in size. Mild-to-moderate arm edema was common, but manageable. The degree to which radiotherapy adds to the risk of arm edema after axillary dissection alone cannot be addressed in the present analysis.     

Adjuvant therapy for patients with high-risk malignant melanoma

The role of adjuvant therapy in the treatment of patients with high-risk malignant melanoma remains an area of intense investigation. The initial enthusiasm for high-dose interferon has been tempered by the results of more recent studies that allow for conflicting interpretations. Vaccine therapy trials have failed to clearly demonstrate a survival benefit, although several trials are currently ongoing. Recent studies of the role of chemotherapy suggest there may be combinations that have a survival benefit which deserve further study. This article will address patient selection and staging workup, and review options for treatment.     

Adjuvant chemoimmunotherapy after regional lymphadenectomy for malignant melanoma

Thirty patients with malignant melanoma metastatic to regional lymph nodes who underwent either a full or partial node dissection were treated with adjuvant chemoimmunotherapy (CIT). In this pilot study, 11 patients were given intravenous (i.v.) DTIC plus intradermal (i.d.) BCG (D/BCG), 19 patients received i.v. DTIC, BCNU, and hydroxyurea plus oral BCG (DBH/BCG). Their overall survival (OS) and disease-free interval (DFI) following node dissection and CIT were compared with 33 historical control (HC) patients from the preceding 4 years, matched for the known prognostic factors in melanoma. The D/BCG group received a median of five courses, the DBG/BCG group six courses. Minimum follow-up of all patients is in excess of 7 years. No significant differences were observed in either DFI or OS from diagnosis between the two treatment groups or between CIT patients and HC patients. A highly significant difference was observed in DFI and OS in favor of the partial node dissection (PND) group when compared with full node dissection (FND) group. No other known variables in the PND group accounting for their improved survival are noted. Five patients in DBH/BCG and three in D/BCG group are still alive 84-114 months after completing therapy.     

Adjuvant interferon-alpha in malignant melanoma: current status

High-risk surgically resected primary or loco-regional cutaneous malignant melanoma, although uncommon, can be associated with less than 50% 5-year survival; adjuvant therapy of proven efficacy is therefore appropriate. Since immunological control mechanisms seem to be important in the natural history of melanoma, biological agents have been the subject of many adjuvant studies. Most popular has been recombinant interferon. Well over 4000 patients have been entered into randomized studies. Results suggest that there may be a clinical benefit, most clearly in relapse-free but also perhaps in overall survival. More precise estimates of the magnitude of any benefits are needed. The doses, schedules and cost-benefits have yet to be fully evaluated. Interferon cannot yet be recommended as standard adjuvant therapy in high-risk malignant melanoma.     

Combination chemotherapy plus levamisole in the treatment of disseminated malignant melanoma. A Southwest Oncology Group study

Two hundred-eighty patients were randomized to receive either BCNU, hydroxyurea and imidazole carboxamide (BHD), BHD plus levamisole, or high-dose DTIC plus actinomycin D. There was no difference in response rate in the three groups (24%, 25% and 22%). Females responded better than males and, as expected, those with a better performance status responded more favorably than those with poor performance status. Patients whose primary site of melanoma was on the extremities did significantly better than those melanomas originating on the trunk or head and neck. Patients with lymphocyte counts greater than 2000/mm3 fared better than those with lymphopenia. Those responders who received high-dose DTIC plus actinomycin D had a significantly longer length of response than those receiving the immunotherapy limb. This was also true in those patients who had a prior disease-free interval of greater than 6 months before being placed in this study. Although there was no difference in survival from the start of treatment in all patients, those patients receiving high-dose DTIC plus actinomycin D and who had a prior disease-free interval of greater than 6 months, had significantly superior survival when compared to the immunotherapy limb. It is concluded that the addition of Levamisole to BHD does not improve response rate and may in certain subsets be detrimental to disease-free response and survival. High-dose DTIC plus actinomycin D is equally effective to BHD.     

恶性黑色素瘤化疗研究进展

恶性黑色素瘤(Malignant melanoma,MM)是一种恶性程度极高的实体肿瘤,它极具侵袭性,预后差。尽管晚期黑色素瘤的治疗已经进入靶向和免疫治疗的时代,但是化疗仍然不可摒弃。恶性黑色素瘤的化疗经历了从单药化疗、两药或三药甚至四药的联合化疗、再到生物化疗这一发展过程。本文综述恶性黑色素瘤化疗研究进展,对主要的化疗方案进行比较,展望化疗未来发展的方向。     

Aminoglutethimide in malignant melanoma. A phase II study.

The role of steroid hormones has been suggested in the growth of malignant melanoma, and since aromatase activity has been found in melanoma tissue, we carried out a phase II study of aminoglutethimide, an aromatase inhibitor in malignant melanoma patients. Fifteen heavily pretreated patients entered the study. No response was observed--the treatment was well tolerated. We concluded that aminoglutethimide is very unlikely to be useful in melanoma patients.     

A preliminary report of a pilot trial in adjuvant chemotherapy of primary melanoma.

It is well known that level of skin invasion and tumor thickness are significant prognostic factors in the evolution of primary melanoma. The prognosis of primary melanoma Clark III to V skin invasion level and more than 1.5 mm thick confirms this statement. Even the prophylactic dissection of regional lymph nodes has not improved results. In an attempt to obtain better results in the treatment of primary melanomas, a pilot trial was carried out combining surgery and adjuvant chemotherapy. A group of 21 patients with Clark III, IV and V level primary melanoma who underwent adjuvant polychemotherapy (velba + dactinomycin + procarbazine) for 1 year after surgery showed a very low incidence of recurrences (5%) after 24 months of observation. The historical control group, with the same level of tumor skin invasion, treated only surgically had in the same follow-up period a recurrence rate of 65%. This difference was statistically significant (p less than 0.01). All patients who received adjuvant chemotherapy survived 2 years whereas survival was 77% (p less than 0.05) in the surgical historical control group. Favorable results with the same protocol of adjuvant chemotherapy were not obtained in the group of 16 patients with stage II melanoma when compared with primary tumors. However, 4 recurrences were observed after 12 months of observation; toxic side effects of adjuvant chemotherapy were mild and tolerable. Considering the insufficient number of clinical trials with adjuvant chemotherapy, as well as sometimes controversial results, further randomized clinical studies are needed to establish the actual value of this conbined method in the treatment of primary melanoma with a high risk of dissemination.     

Adjuvant interferon therapy for malignant melanoma: the debate

Based on the results of the Kirkwood high-dose interferon alpha-2b (HDI) adjuvant therapy trial of the Eastern Cooperative Oncology Group 1684, the US Food and Drug Administration (FDA) approved HDI as the postoperative adjuvant therapy for high-risk melanoma. Unfortunately, controversies continue regarding the use of interferon (IFN) as adjuvant therapy for melanoma owing to the inconsistent results of subsequent trials. Numerous trials of adjuvant interferon therapy demonstrated a benefit in terms of rela...     

Adjuvant immunotherapy with BCG in stage II malignant melanoma

Forty-one patients were treated with BCG immunotherapy following block dissection of lymph nodes involved with malignant melanoma. A control group of similar patients who received no immunotherapy was drawn from a population consisting of all patients with malignant melanoma diagnosed in Western Australia in the period from January 1, 1975 to December 31, 1976. The disease-free survival and overall survival of BCG-treated patients were not different from that of the control group, who received no immunotherapy. The findings do not support the use of this type of immunotherapy as an adjuvant to surgery in the treatment of patients with stage II malignant melanoma.     

Desmoplastic malignant melanoma. A clinicohistopathologic study of 25 cases

A clinical and histologic review of 25 patients with melanocytic lesions classified as desmoplastic malignant melanoma is reported. All of the lesions were located in sun-exposed sites. The average age was 61.2 years (range, 38 to 83), with a median age of 56. There were 14 female and 11 male patients. Desmoplastic malignant melanoma is a melanocytic and fibroblastic proliferation that occurs predominantly in the head and neck area. The bland constituent cells resemble fibroblasts and are often arranged in bundles or fascicles, which may be arrayed perpendicularly to the overlying epidermis. Enlarged and/or atypical cells are usually scattered among the spindled cells. Most, but not all, of the tumors (24 of 25 in this series) are associated with lentigo maligna or an atypical junctional melanocytic proliferation. Mitotic figures are always found within the constituent cells of the fibrous-appearing mass, and neurotropism may be present. Patients with desmoplastic melanoma typically present with a mass, which is occasionally associated with a pigmented lesion. The lesions in our series were deeply invasive to level IV or V. Lentigo maligna and a dermal fibroblastic-appearing mass containing atypical cells arranged in fascicles are the most common morphologic features found in desmoplastic melanoma. Follow-up data is available for 23 patients. The average length of follow-up was 2.7 years (range, 0.1 to 9 years). Eighteen patients were observed for 3 or more years. Twelve patients developed local recurrences, and five developed metastases; three of the patients with metastases had a local recurrence before the development of metastases. Three of the patients with metastatic melanoma died of tumor between 2 and 4 years after their initial excision. Eight of the 12 locally recurring lesions were either diagnosed initially as a benign lesion or histologic examination was not performed on the initial excision specimen. It appears that recurrence may be related to inadequate initial therapy.     

Combination chemotherapy in metastatic malignant melanoma: a randomized study of three DTIC-containing combination.

The activity of three DTIC-containing combinations was compared in a prospective randomized study. Of 101 patients randomized to receive one of the three regimens, 95 received adequate trials. Response rates were as follows: DTIC + cyclophosphamide 7/29 (24%); DTIC + vinblastine 6/34 (18%); DTIC + procarbazine 4/32 (13%). None of these response rates is significantly superior to any of the others. When the activity of the combination is analyzed by sex, DTIC + cyclophosphamide appears more active in females than the other regimens, but the difference is not statistically significant. Response to treatment is associated with significant prolongation of life; the median survival among responders was 11 months, while those who progressed lived a median of 4 months from the start of therapy. Toxicity of all regimens appeared to be about the same; therapy with DTIC + procarbazine was associated with significantly more nausea and vomiting. This study has failed to demonstrate clearly that any of three combinations is superior to any of the others.