Excision margins in high-risk malignant melanoma. Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick). Margin of resection in the management of primary melanoma. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. Do public media campaigns designed to increase skin cancer awareness result in increased skin excision rates? Surgical excision vs Mohs' micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial. Final results of the EORTC 18871/DKG 80-1 randomised phase III trial. rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis.
Controversy exists concerning the necessary margin of excision for cutaneous melanoma 2 mm or greater in thickness.
                We conducted a randomized clinical trial comparing 1-cm and 3-cm margins.
                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=0.05). 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=0.1); overall survival was similar in the two groups (hazard ratio for death, 1.07; 95 percent confidence interval, 0.85 to 1.36; P=0.6).
                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 Large, prospective, randomized trials with long term follow-up are required to obtain an unbiased evaluation of the significance of resection margins in patients with cutaneous melanoma.
                The Swedish Melanoma Study Group performed a prospective, randomized, multicenter study of patients with primary melanoma located on trunk or extremities and with a tumor thickness > 0.8 mm and </= 2 mm. Patients were allocated randomly to a 2-cm excision margin or a 5-cm excision margin. In total, 989 patients were recruited during the period 1982-1991. The median follow-up was 11 years (range, 7-17 years) for estimation of survival and 8 years (range, 0-17 years) for evaluation of recurrent disease.
                The crude rate of local recurrence, defined as a recurrence in the scar or transplant, was < 1% (8 of 989 patients). Twenty percent of the patients (194 of 989 patients) experienced any disease recurrence, and 15% (146 of 989 patients) died of melanoma. There were no statistically significant differences between the two treatment arms. In a multivariate Cox analysis with patients allocated to wide excision as the reference group, the estimated relative hazards for overall survival and recurrence free survival among those allocated to a 2-cm resection margin were 0.96 (95% confidence interval, 0.75-1.24), and 1.02 (95% confidence interval, 0.80-1.30), respectively.
                In this long term follow-up study, local recurrences were found to be rare among patients with tumors > 0.8 mm thick and </= 2.0 mm thick. No difference in recurrence rate or survival between the two treatment groups was found. Patients in this category can be treated with a resection margin of 2 cm as safely as with a resection margin of 5 cm. The Intergroup Melanoma Surgical Trial began in 1983 to examine the optimal surgical margins of excision for primary melanomas of intermediate thickness (i.e., 1-4 mm). There is now a median 10-year follow-up.
                There were two cohorts entered into a prospective multi-institutional trial: (1) 468 patients with melanomas on the trunk or proximal extremity who randomly received a 2 cm or 4 cm radial excision margin and (2) 272 patients with melanomas on the head, neck, or distal extremities who received a 2 cm radial excision margin.
                A local recurrence (LR) was associated with a high mortality rate, with a 5-year survival rate of only 9% (as a first relapse) or 11% (anytime) compared with an 86% survival for those patients who did not have a LR (P < .0001). The 10-year survival for all patients with a LR was 5%. The 10-year survival rates were not significantly different when comparing 2 cm vs. 4 cm margins of excision (70% vs. 77%) or comparing the management of the regional lymph nodes (observation vs. elective node dissection). The incidences of LR were the same for patients having a 2 cm vs. 4 cm excision margin regardless of whether the comparisons were made as first relapse (0.4% vs. 0.9%) or at anytime (2.1% vs. 2.6%). When analyzed by anatomic site, the LR rates were 1.1% for melanomas arising on the proximal extremity, 3.1% for the trunk, 5.3% for the distal extremities, and 9.4% for the head and neck. The most profound influence on LR rates was the presence or absence of ulceration; it was 6.6% vs. 1.1% in the randomized group involving the trunk and proximal extremity and was 16.2% vs. 2.1% in the non-randomized group involving the distal extremity and head and neck (P < .001). A multivariate (Cox) regression analysis showed that ulceration was an adverse and independent factor (P = .0001) as was head and neck melanoma site (P = .01), while the remaining factors were not significant (all with P > .12).
                For this group of melanoma patients, a local recurrence is associated with a high mortality rate, a 2-cm margin of excision is safe and ulceration of the primary melanoma is the most significant prognostic factor heralding an increased risk for a local recurrence. 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.
                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.
                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.
                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. In the last 20 years, it has become evident that the continued use of 4 to 5 cm margins of resection around a primary melanoma is not justified. A prospective randomized trial by the World Health Organization (WHO) Melanoma Group showed that for melanomas up to 2 mm thick, a 1 cm margin provides local control similar to that observed after a 3 cm margin. Another prospective randomized trial by the Melanoma Intergroup Committee in the United States concluded that for melanomas 1 to 4 mm in thickness, a 2 cm margin of resection provides local control that is as good as a 4 cm margin. For melanomas thicker than 4 mm, the current evidence suggests that a 2 cm margin is adequate, the chief manifestation of recurrence for these thick lesions being hematogenous and lymphogenous spread. The adoption of the narrower surgical margins suggested above should reduce the morbidity caused by the radical margins of the past without compromising local control of the disease. Patients with primary cutaneous melanoma with a Breslow thickness > or = 1.5 mm have only a 30% to 70% probability of survival after surgery, and no adjuvant therapy has so far improved this outcome. Since interferon alfa-2a (IFNalpha2a) exhibits antitumor activity in metastatic melanoma, we investigated whether adjuvant IFNalpha2a diminishes the occurrence of metastases and thus prolongs disease-free survival in melanoma patients after excision of the primary tumor.
                In a prospective randomized study, 311 melanoma patients with a Breslow thickness > or = 1.5 mm were assigned to either adjuvant IFNalpha2a treatment (n = 154) or observation (n = 157) after excision of the primary tumor. IFNalpha2a was given daily at a dose of 3 mIU subcutaneously (s.c.) for 3 weeks (induction phase), after which a dose of 3 mIU s.c. three times per week was given over 1 year (maintenance phase).
                Prolonged disease-free survival was observed in patients treated with IFNalpha2a versus those who underwent surgery alone. This difference was significant (P = .02) for all patients enrolled onto the study (intention-to-treat analysis) at a mean observation time of 41 months. Subgroup analysis showed that Breslow tumor thickness had no influence on treatment results in the groups of patients investigated.
                Adjuvant IFNalpha2a treatment diminishes the occurrence of metastases and thus prolongs disease-free survival in resected primary stage II cutaneous melanoma patients. We report on an observational study of one city in Queensland over a 30-month period to evaluate the effects of two public skin cancer campaigns on the excision rates of melanocytic skin lesions. The numbers of melanomas, the numbers of potentially malignant melanocytic lesions (Hutchinson's melanotic freckles and dysplastic naevi) whose excision might have benefited the patient, and the total number of melanocytic skin lesions submitted to pathology services were recorded. A total of 3221 melanocytic skin lesions were excised. More lesions were excised during summer than non-summer periods (rate ratio 1.22, 95% CI 1.06, 1.40) and, independently, during campaign periods than non-campaign periods (rate ratio 1.24, 95% CI 1.11, 1.37). There were 145 melanomas (4%), of which 116 were < 0.76 mm thick, and an additional 53 (2%) other potentially malignant lesions. During campaigns, proportions of neither type increased significantly, nor was there a significant reduction in excised melanoma thickness. Doctors reported more often that the reason for excision was to exclude malignancy during the campaigns, although they felt themselves to be under less pressure from patients to excise lesions. There may be considerable cost associated with primary prevention campaigns in the form of increased excision of benign skin lesions, which should be addressed in future skin cancer public awareness campaigns. Rates of recurrence of facial basal-cell carcinoma are consistently lower after Mohs' micrographic surgery (MMS) than after other treatments, such as surgical excision (SE). However, MMS is more time-consuming and therefore more expensive than SE. We investigated the types of facial basal-cell carcinomas in which MMS was more effective than SE.
                408 primary and 204 recurrent facial carcinomas (374 and 191 patients, respectively) were analysed separately in this prospective randomised study. Patients were assigned SE or MMS (each 204 primary, 102 recurrent), and received treatment at two hospitals in the Netherlands. The primary outcome was recurrence of carcinoma. Analysis was by intention to treat.
                Of the basal-cell carcinomas included in the trial, 397 primary (198 MMS, 199 SE) and 201 recurrent (99, 102) tumours were actually treated. Of patients with primary carcinomas, 21 had both MMS and SE on different tumours. Nine with recurrent carcinomas had both treatments on different skin tumours. 66 primary and 13 recurrent carcinomas were lost to follow-up. Of the primary carcinomas, five (3%) recurred after SE compared with three (2%) after MMS during 30 months of follow-up. Of the recurrent carcinomas, three (3%) recurred after SE and none after MMS during 18 months of follow-up. Four recurrent carcinomas randomly assigned to the SE group were treated with MMS. Although both differences favoured MMS, they were not significant (primary, difference 1% [95% CI -2.5% to 3.7%], p=0.724; recurrent, 3.2% [-2.0% to 5.0%], p=0.119). Total operative costs of MMS were higher than those of SE (primary 405.79 Euros vs 216.86 Euros, recurrent 489.06 Euros vs 323.49 Euros; both p<0.001).
                No definitive conclusion on recurrence rates of primary or recurrent basal-cell carcinomas is yet possible. Although recurrence rates were lower after MMS than after SE, the differences were not significant. Between 1988 and 1996, the European Organisation for Research and Treatment of Cancer Melanoma Group (EORTC-MG) performed a prospective, randomised phase III adjuvant trial to evaluate the efficacy and toxicity of low dose recombinant interferon-alpha 2 b (rIFN-alpha2b) (1 MU) or recombinant interferon gamma (rIFN-gamma), (0.2 mg) both given subcutaneously (s.c.), every other day (qod), for 12 months in comparison with an untreated control group. The German Cancer Society (DKG) added a fourth arm with Iscador M, a popular mistletoe extract. High-risk stage II patients (thickness >3 mm) and stage III patients (positive lymph nodes) without distant metastasis were randomised and followed until their first progression or death. An intention-to-treat analysis was performed. From 1988 to 1996, a total of 830 patients were randomised: 423 in the three-arm EORTC 18871 trial and 407 patients in the four-arm DKG 80-1 trial. The median follow-up was 8.2 years and a total of 537 relapses and 475 deaths were reported. At 8 years, the disease-free interval (DFI) rate was 32.4% and the overall survival (OS) rate was 40.0%. In terms of the DFI, the hazard ratio estimates (95% Confidence Intervals (CI)) were: 1.04 (0.84, 1.30) for the comparison of rIFN-alpha2b versus control, 0.96 (0.77, 1.20) for rIFN-gamma versus control, and 1.32 (0.93, 1.87) for Iscador M versus control. In terms of OS, the corresponding estimates (95% CI) for the 3 treatment comparisons were: for IFN-alpha2b 0.96 (0.76, 1.21), for rIFN-gamma 0.87 (0.69, 1.10) and for Iscador M 1.21 (0.84, 1.75), respectively. The results show no clinical benefit for adjuvant treatment with low dose rIFN-alpha2b or rIFN-gamma or with Iscador M in high-risk melanoma patients.
This systematic review summarises the evidence regarding width of excision margins for primary cutaneous melanoma. None of the five published trials, nor our meta-analysis, showed a statistically significant difference in overall survival between narrow or wide excision.
The summary estimate for overall survival favoured wide excision by a small degree [Hazard Ratio 1.04; 95% confidence interval 0.95 to 1.15; P = 0.40], but the result was not significantly different. This result is compatible with both a 5% relative reduction in overall mortality favouring narrower excision and a 15% relative reduction in overall mortality favouring wider excision. Therefore, a small (but potentially important) difference in overall survival between wide and narrow excision margins cannot be confidently ruled out.
The summary estimate for recurrence free survival favoured wide excision [Hazard Ratio 1.13; P = 0.06; 95% confidence interval 0.99 to 1.28] but again the result did not reach statistical significance (P < 0.05 level).
Current randomised trial evidence is insufficient to address optimal excision margins for primary cutaneous melanoma.