Primary melanoma

Current surgical margins are based on several randomized trials that were described in the 2002 review article and are listed in Table 1 . These studies demonstrated increased local recurrence rates as the melanoma increases in thickness and the excision margin decreases. No trial has clearly demonstrated a difference in survival with more aggressive surgical margins, and yet local recurrence is associated with poor overall survival, therefore investigation into the appropriate margin has continued. Since 2001, there have been two additional randomized trials addressing the effect of excision margins of the primary lesion on outcome in patients with melanoma. A large European multicentric phase 3 study from nine European centers investigated the difference between 2-cm and 5-cm excision margins for melanomas less than 2.1 mm thick. No significant difference was found in the number of recurrences, recurrence-free survival, or overall survival between the two excision margin groups. Another trial from the UK studied patients with melanomas 2 mm or greater in thickness, randomized to 1-cm or 3-cm margins. This trial demonstrated no significant difference in overall survival or melanoma-specific survival, but did demonstrate an increase in LR in the 1-cm margin group compared with the 3-cm margin group (hazard ratio [HR] 1.26; P = .05). The results of all the randomized trials on excision margins suggest that reasonable practice is still a 1-cm margin for lesions less than 1 mm in thickness, and 2-cm margins for thicker lesions. Whether 1-cm margins may yield equivalent outcomes to those of 2-cm margins for 1- to 2-mm lesions remains to be addressed specifically by a randomized trial.

Regional metastatic disease

As shown in Table 2 , elective lymph node dissection (ELND) has not been shown to improve survival in patients with melanoma. Only the long-term follow-up of the Intergroup trial suggested a survival benefit in younger patients with nonulcerated, intermediate-thickness melanomas. The sentinel lymph node (SLN) biopsy technique has supplanted the need for further investigations into the merits of ELND. SLN biopsy is the standard approach to evaluate clinically negative lymphatic basins. The Melanoma Selective Lymphadenectomy Trial (MSLT)-1 trial randomized patients with intermediate-thickness melanomas to either wide local excision (WLE) with nodal observation, or WLE in combination with SLN biopsy. Those patients with metastatic disease detected in the sentinel node underwent immediate completion lymph node dissection, whereas the patients in the observation arm underwent a therapeutic lymphadenectomy for clinically evident nodal disease. The study confirmed the high prognostic value of the sentinel-node status for patients with intermediate-thickness melanomas. MSLT-I did not demonstrate any difference in melanoma-specific survival between the two groups, which was the primary end point of the trial. In a subset analysis of all patients with nodal metastases, however, there was a statistically significant improved 5-year survival rate in those patients who underwent SLN biopsy and immediate lymphadenectomy versus those who underwent delayed lymphadenectomy on clinically evident disease (72.3% vs 52.4%).

The benefits of prophylactic regional hyperthermic isolated limb perfusion (ILP) for patients with high-risk melanomas were examined in a cooperative-group trial that randomized 832 patients to ILP with melphalan. No significant difference in survival was reported at the conclusion of the trial. Since 2001, the results of one additional randomized trial have been performed using ILP in the treatment of locally advanced melanoma (ACOSOG trial Z0020). This trial randomized patients with locally advanced melanoma to standard hyperthermic limb perfusion with either melphalan alone or melphalan in combination with tumor necrosis factor (TNF). The trial was stopped early because of an increase in grade 4 toxicities, including amputations, in the combined treatment arm. The survival data, with short follow-up, was not different between the two groups.

Adjuvant treatment of high-risk melanoma

Chemotherapies are toxic and ineffective in melanoma, and therefore adjuvant strategies have focused on immunotherapy. The rationale for immunotherapy in the treatment of melanoma stems from observations of rare, but spontaneous, regression of melanoma in patients. In addition, patients with tumor infiltrating lymphocytes, vitiligo, or other evidence of immune activation, may have improved survival. Therefore, adjuvant immunotherapies aim to activate the host immune system through vaccines, interferons (IFNs), and compounds such as bacillus Calmette-Guérin (BCG).

IFN is a protein that is produced by the immune system in response to viral infection and foreign proteins. Exogenous administration of this compound is intended to stimulate the immune system to recognize melanoma antigens. The results of adjuvant IFN treatment usually fail to demonstrate a survival benefit, but do demonstrate a modest improvement in recurrence-free survival. Investigations have therefore continued to attempt to identify whether there is a subset of patients and a dosing regimen that will improve outcomes. IFN α-2b was approved by the US Food and Drug Administration (FDA) as adjuvant treatment of high-risk patients with deep primary melanomas or regional lymph node metastatic disease after ECOG trial E1684. This trial compared high-dose IFN α-2b with observation, and found a significant improvement in disease-free and overall survival. The follow-up study compared observation, low-dose IFN α-2b, and high-dose IFN α-2b, and found improved relapse-free survival but no overall survival difference.

The continued inconsistency in results of IFN trials is demonstrated by two recent studies with no significant results: the AIM HIGH Study and EORTC 18952. The AIM HIGH Study randomized patients to long-term low-dose IFN or observation after resection of stage IIB or III melanoma. In this trial there was an initial benefit in recurrence-free survival that disappeared after 3 years of follow-up and was not significant. Fifteen percent of patients in the IFN group withdrew from the study, and toxicities were modest. These results are similar to those of the EORTC 18952 trial which randomized patients after resection with stage IIb or III melanoma to 13 months or 25 months of intermediate dose IFN or observation. Recent results from EORTC 18991, which randomized patients with stage III melanoma after resection to pegylated IFN or observation, also demonstrated additional promise for this immunotherapy. The trial demonstrated a small (6% at 4 years) improvement in recurrence-free survival with the pegylated IFN, which is potentially best noted in the subgroup of patients with N1 disease. It is possible that long-term follow-up of pegylated IFN will continue to show an improvement in patients with early stage III disease, and, therefore, it may have a more definitive role in the adjuvant setting than standard IFN, because it is also better tolerated.

IFN has also been combined with other immunologic and chemotherapeutic agents. Garbe and colleagues randomized patients with stage III disease following surgery to adjuvant low-dose IFN, with or without dacarbazine, or to observation. Overall survival was significantly higher by multivariate analysis in patients with adjuvant low-dose IFN compared with surgery alone, but the addition of dacarbazine removed this survival benefit. In another trial, high-dose IFN was compared with a ganglioside vaccine, GM2-KLH/QS-21, in patients with resected stage IIB and III melanomas. The trial was halted on an interim analysis because of a significant recurrence-free survival, and overall survival, benefit in the high-dose IFN arm. In 2007, Mitchell reported on 604 patients who were randomized to 2 years of treatment with an allogeneic melanoma lysate and low-dose IFN or high-dose IFN. Overall and recurrence-free survival were the same between the two arms, providing another trial without any clear benefit to vaccine use in the adjuvant setting. Other immunotherapy trials have examined BCG in the adjuvant setting. Early trials reported improvements in disease-free survival (DFS) with BCG use. To test this hypothesis, Agarwala randomized 734 patients with stage I to III melanoma into four groups that were assembled into two cohorts: (1) BCG versus BCG plus dacarbazine; and (2) BCG versus. observation. There was no benefit to BCG or BCG plus dacarbazine with any patients in the stage I to III categories of melanoma patients.

The Canvaxin vaccine consisted of allogeneic melanoma cells with high antigen expression. Phase 2 studies showed an improvement in survival when used as an adjuvant in stage III patients, which generated considerable interest. However, a multicenter randomized phase 3 trial failed to confirm these results, and this therapy is no longer used.

Treatment of metastatic melanoma

In the prior review, the Dartmouth regimen (cisplatin, carmustine, dimethyltriazenyl imidazole carboxamide [DTIC], and tamoxifen) and its components were the most commonly studied regimen in several large prospective RCTs. The only positive trial was Cocconi’s study, which showed improved response rates and median survival with DTIC plus tamoxifen compared with DTIC alone. Chapman then performed a study that showed no difference between the Dartmouth regimen and DTIC regarding tumor response, toxicity, or survival. At that time, DTIC alone was felt to be the optimal treatment. Temozolamide has also been used to treat patients with metastatic melanoma, and DTIC was compared with temozolomide in a study by the Royal Marsden Hospital. Patients treated with temozolomide demonstrated equivalent progression-free survival, response rates, toxicity, and survival. Temozolomide was also studied in combination with cisplatin, with no benefit found in the combined regimen. Recently, imatinib mesylate was also used in a phase 2 trial with 21 patients who had melanoma cells that expressed c-kit. At 400 mg twice a day, imatinib had little clinical efficacy, although it did have individual responders, suggesting a possible role for imatinib in patients with specific kit mutations.

Additional agents that have been investigated outside the published randomized trials include sorafenib and bevacizumab. Sorafenib was evaluated by Eisen and found to be well tolerated but with little to no antitumor activity in patients with advanced melanoma. Bevacizumab was studied in a trial that randomized to bevacizumab with or without low-dose IFN α-2b. There was no benefit to combining IFN with bevacizumab, but bevacizumab alone caused prolonged disease stabilization in approximately 25% of patients in the bevacizumab-alone group. Currently, the benefits of using this drug are limited. Trials using anti-CTLA-4 for the treatment of patients with metastatic disease, and as an adjuvant in stage III disease, are in progress. Although not FDA approved, durable clinical responses have been noted with CTLA-4 blockade, and there is hope that this field will continue to evolve.

Investigators have combined treatments with biologic agents and chemotherapies in an effort to maximize activity against melanoma. Unfortunately, most of these studies have not improved survival. As reviewed in the previous article, studies comparing IL-2/IFN α and chemotherapy to IL-2/IFN α alone, or IL-2 to IL-2/IFN α, showed no difference in overall survival. This review includes a biochemotherapy trial that is similar to other trials, such as EORTC 18951, in structure and outcomes, in that it compared cisplatin, vinblastine, dacarbazine with cisplatin, vinblastine, dacarbazine, IL-2, and IFN α and found no significant alteration in overall survival or durable responses. There were higher response rates and a longer median progression-free survival rate with the biochemotherapy, but there were significant toxicities associated with these regimens. The conclusion from these trials is that biochemotherapy with IL-2 and IFN α are not recommended for treating metastatic melanoma.

Level Ia evidence in melanoma

Surgical Trials

1. Surgical margins in cutaneous melanoma (2-cm versus 5-cm for lesions measuring less than 2.1-mm thick). Khayat D, Rixe O, Martin G, et al. Cancer 2003 Apr 15;97(8):1941–6.

Hypothesis: A smaller excision margin (2-cm) of the primary tumor for patients with melanomas less than 2.1 mm in thickness may yield similar outcomes regarding disease recurrence and survival to a wider (5-cm) excision margin.

Number of Patients Randomized	Study Groups	Stratification	Significance Demonstrated	% Change Identified in Trial
337	2-cm margins N = 161	Histology	None Equivalent	None
	5-cm margins N = 165

Published abstract: BACKGROUND: This study addressed the question of whether limited surgery for primary malignant melanoma with a 2-cm margin is as good as a 5-cm margin. An update of a 16-year follow-up is provided. METHODS: Nine European Centers, over a period of 5 years, prospectively randomized 337 patients with melanoma measuring less than 2.1 mm in thickness to undergo a local excision with either a 2-cm or a 5-cm margin. Three hundred twenty-six patients were eligible for statistical analysis. Excluded from the trial were patients older than 70 years; those with melanomas from the toe, nail, or finger; and those with acral-lentiginous melanoma. A separate randomization was performed to independently test an adjuvant treatment with a nonspecific immunostimulant, isoprinosine, compared with observation. The median follow-up time was 192 months (16 years) for the estimation of survival and disease recurrences. RESULTS: There were 22 tumor recurrences in the 2-cm arm and 33 in the 5-cm arm. The median time to disease recurrence was 43 months and 37.6 months, respectively. The 10-year disease-free survival rates were 85% for the group with a 2-cm margin and 83% for the group with a 5-cm margin. There was no difference in the 10-year overall survival rates (87% vs. 86%). Isoprinosine did not demonstrate any activity in this setting. CONCLUSIONS: The authors concluded that for melanoma less than 2.1-mm thick, a margin of excision of 2 cm is sufficient. A larger margin of 5 cm does not appear to have any impact on either the rate or the time to disease recurrence or on survival. (Copyright 2003 American Cancer Society. Reprinted with permission.)

Editor’s summary and comments: This multicenter European trial investigated the role of surgical margins for melanoma lesions less than 2.1 mm in thickness by randomizing patients to either 2-cm or 5-cm excisional margins in patients (those >70 years and with acral-lentiginous lesions were excluded). There was no difference in local tumor recurrence rates, DFS or overall survival between the two excision margin groups, with a median follow-up of 16 years. This study reinforces the results of the Swedish Melanoma Study group (2-cm versus 5-cm margin groups for 0.8-mm to 2-mm thickness lesions), and the WHO trial discussed earlier. As a secondary randomization, patients in each excisional margin arm were assigned to receive isoprinosine, shown to have immunostimulation properties toward natural killer cells against melanoma in vitro, or to observation. No difference was seen in median overall survival or DFS between the groups receiving adjuvant immunotherapy and those followed with observation alone, using any subgroup analysis of tumor characteristics or surgery extent, although the numbers in each final randomized group were fairly small (76–89 patients).

2. Excision margins in high-risk malignant melanoma. Thomas JM, Newton-Bishop J, A’Hern R, et al. N Engl J Med 2004 Feb 19;350(8):757–66.

Hypothesis: Narrow (1-cm) excision margins for high-risk melanoma lesions (>2 mm) may be insufficient compared with wider (3-cm) margins.

Number of Patients Randomized	Study Groups	Stratification	Significance Demonstrated	% Change Identified in Trial
453	1-cm margin (N = 453)	Histology	Increase in locoregional recurrence (LR) with 1-cm margin	HR 1.26 for LR in 1-cm vs 3-cm margin group ( P = .05)
	3-cm margin (N = 447)

Published abstract: BACKGROUND: Controversy exists concerning the necessary margin of excision for cutaneous melanoma 2 mm or greater in thickness. METHODS: We conducted a randomized clinical trial comparing 1-cm and 3-cm margins. RESULTS: Of the 900 patients who were enrolled, 453 were randomly assigned to undergo surgery with a 1-cm margin of excision and 447 with a 3-cm margin of excision; the median follow-up was 60 months. A 1-cm margin of excision was associated with a significantly increased risk of locoregional recurrence. There were 168 locoregional recurrences (as first events) in the group with 1-cm margins of excision, as compared with 142 in the group with 3-cm margins (hazard ratio, 1.26; 95 percent confidence interval, 1.00 to 1.59; P = .05). There were 128 deaths attributable to melanoma in the group with 1-cm margins, as compared with 105 in the group with 3-cm margins (hazard ratio, 1.24; 95 percent confidence interval, 0.96 to 1.61; P = .1); overall survival was similar in the two groups (hazard ratio for death, 1.07; 95 percent confidence interval, 0.85 to 1.36; P = .6). CONCLUSIONS: A 1-cm margin of excision for melanoma with a poor prognosis (as defined by a tumor thickness of at least 2 mm) is associated with a significantly greater risk of regional recurrence than is a 3-cm margin, but with a similar overall survival rate. (Copyright [2004] Massachusetts Medical Society. All rights reserved.)

Editor’s summary and comments: This well-designed randomized trial addresses the important question of whether 1-cm margins are adequate for higher risk melanoma lesions greater than 2 mm in thickness. The comparison arm to the 1-cm margin is a 3-cm margin, and not 2-cm, which is the standard margin size routinely performed for intermediate-thickness lesions (adapted largely from the results of the Intergroup trial). The study design directly complements the design of the WHO trial, which compared 1-cm to 3-cm margins for lesions less than 2 mm. The investigators found a decrease in the incidence of locoregional recurrence (which included local, in transit or regional nodal recurrences) favoring the 3-cm margin group. However, this finding did not translate into a statistically different DFS, or overall survival, between the two randomized arms, although there was a trend toward an increased disease-specific mortality associated with the narrow margin (HR 1.24, P = .1). Patients in the study were not permitted to undergo SLN biopsy, and it remains unclear how the use of this technique, which is routinely performed in this patient population, would have affected the results.

3. Sentinel-node biopsy or nodal observation in melanoma. Morton DL, Thompson JF, Cochran AJ, et al. N Engl J Med 2006 Sep 28;355(13):1307–17.

Hypothesis: Patients with intermediate-thickness melanomas undergoing SLN biopsy for staging with immediate lymphadenectomy for SLN metastases would have an improved survival compared with patients with simple excision of their primary lesion and therapeutic lymphadenectomy on detection of clinically evident regional nodal disease.

Number of Patients Randomized	Study Groups	Stratification	Significance Demonstrated	% Change Identified in Trial
1347	Nodal observation with therapeutic lymphadenec-tomy for clinically evident disease (N = 500)	Histology	None	None (see editor’s comments)
	SLN biopsy and immediate lymphadenec-tomy for SLN metastases (N =769)

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