Surgical Margins in Cutaneous Melanoma (2 cm Versus 5 cm for Lesions Measuring Less Than 2.1-mm Thick)

1941 Surgical Margins in Cutaneous Melanoma (2 cm Versus 5 cm for Lesions Measuring Less Than 2.1-mm Thick) Long-Term Results of a Large European Multicentric Phase III Study David Khayat, M.D., Ph.D. 1 Olivier Rixe, M.D. 1 Ginette Martin, M.D., Ph.D. 2 Claude Soubrane, M.D., Ph.D. 1 Martine Banzet, M.D. 1 Jacques-André Bazex, M.D. 3 Philippe Lauret, M.D. 4 Olivier Vérola, M.D. 5 Gérard Auclerc, M.D. 1 Peter Harper, M.D. 6 Pierre Banzet, M.D. 7 for the French Group of Research on Malignant Melanoma 1 Service d Oncologie Médicale, Hôpital Pitié-Salpêtrière, Paris, France. 2 Service de Chirurgie, Centre Hospitalier de l Université de Montréal, Montréal, Quebec, Canada. 3 Service de Dermatologie, Hôpital Purpan, Toulouse, France. 4 Service de Dermatologie, Hôpital Charles Nicolle, Rouen, France. 5 Service d Anatomopathologie, Hôpital Saint- Louis, Paris, France. 6 Medical Oncology Department, Guy s and Saint Thomas Hospital, London, United Kingdom. 7 Service de Chirurgie Plastique Reconstructive et Esthétique, Hôpital Saint-Louis, Paris, France. Supported by the Association Pour la Vie-Espoir Contre le Cancer (A.V.E.C.). Dr. Peter Harper is an advisory board member for Lilly, Adventis, Glaxo Smithkline, Bristol-Myers Squibb, Roche, and Johnson & Johnson. Address for reprints: David Khayat, M.D., Ph.D., Department of Medical Oncology, Salpetriere Hospital, 47, Boulevard de l Hopital, 75013 Paris, France; Fax: (011) 3301-42-16-04-65; E-mail: david.khayat@psl.ap-hop-paris.fr Received February 15, 2002; revision received February 11, 2002; accepted February 12, 2002. 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. Cancer 2003;97:1941 6. 2003 American Cancer Society. DOI 10.1002/cncr.11272 KEYWORDS: malignant melanoma, surgery, immunotherapy, prognostic factors. The incidence of malignant melanoma is increasing. Therefore, it is important to optimize the surgical management of patients with this tumor. For decades, a wide local excision with a margin as large as 3 5 cm around the lesion was recommended, resulting in significant morbidity. Retrospective and prospective studies have emphasized the importance of tumor thickness in predicting local disease recurrence, 1 3 raising the hypothesis that significantly less mutilating approaches could be sufficient for thin lesions. Two large multicenter prospective trials have evaluated margins in TNM Stage I malignant melanoma. The World Health Organization (WHO) 4 melanoma program studied the effectiveness of a 1-cm margin for thin melanomas ( 1 mm). Balch et al. 5 evaluated 2-cm versus 4-cm margins for 1 4-mm thick primary melanomas. In their multifactorial analysis of prognostic factors, they reported that thickness, the presence of ulceration, and anatomic site were important prognostic factors and 2003 American Cancer Society

1942 CANCER April 15, 2003 / Volume 97 / Number 8 that a 2-cm or 4-cm margin demonstrated no statistical difference in overall survival or local disease recurrence. Although incidence of malignant melanoma is increasing, the use of prevention campaigns has resulted in lesions being diagnosed at an earlier stage. 6 8 As a consequence of earlier diagnosis, the number of lesions measuring 2 mm or less in thickness is expected to increase. 9 11 Optimal management of this group of tumors is essential, with a major impact on cosmesis, quality of life, and cost. This study was designed to address the margin of excision (2 cm vs. 5 cm) for primary melanoma measuring 2 mm or less in thickness. A secondary end point of our trial was to evaluate the role of adjuvant immunotherapy using isoprinosine, a nonspecific immunostimulant that has shown promising results in preclinical models. 12 A double randomization study was performed to independently test the two therapeutic interventions (surgical margin and adjuvant isoprinosine). MATERIALS AND METHODS A prospective multicenter randomized clinical trial was initiated in 1981 in nine European centers. Patients younger than 70 years, with a maximum tumor thickness of 2 mm (Breslow 2 mm), were eligible. All patients were Stage I by TNM criteria. Excluded were toe, nail, or finger lesions and melanomas arising from melanosis, lentigo, and acral lesions. Before entry, all patients underwent a clinical examination, chest X-ray, and liver ultrasound. Patients were randomized to either wide (5 cm) or limited (2 cm) excision surgery. All biopsy specimens were reviewed to confirm the tumor thickness and histologic classification. According to the surgical protocol guidelines, the resection was performed within the month of the initial biopsy. Excisions extended down to the muscular fascia. A total resection margin means that, if the tumor primarily was resected with a 2-cm margin, no further resection was performed if the patient was randomized to the limited excision group. By contrast, if the patient was randomized to the 5-cm excision margin group, a complementary resection of at least 3 cm was performed. The reported excision margin is the summarized excision margins for each patient, when available. Lymph node dissections were not performed. A second randomization allocated the patient to either 12 months of adjuvant treatment with isoprinosine or to no adjuvant treatment (Fig. 1). Isoprinosine was used as a pulse immunotherapy, the dose being one tablet (500 mg)/10 kg per day for 5 days every 15 days. Patients characteristics, including FIGURE 1. Randomization of melanoma patients. surgical margins, were balanced between the two groups based on the immunotherapy randomization. Three hundred thirty-seven patients entered the trial with a median follow-up of 192 months (range, 2 228 months). The cut off date for data collection was December 2000. Local disease recurrence was defined as recurrence within 2 cm of the scar. In-transit metastases were defined as disease recurrence between the primary tumor site and the regional lymph nodes. Local or regional tumors that recurred were removed surgically and follow-up medical treatment was not provided. Metastatic tumors were treated with chemotherapy (dacarbazine, fotemustine, or a combination) or with biochemotherapy (a combination of cisplatin, interleukin-2, and interferon-alpha). The survival analysis (overall survival and progression-free survival) was performed using the actuarial Kaplan Meier method and differences between the curves were analyzed using the log rank test. Survival times were calculated from the date of inclusion until death. Time to disease progression was calculated from the date of inclusion to the date of disease progression. All results are quoted as two-sided P values and differences were considered significant if P values were less than 0.05. The statistical power of this study to detect a 10% difference in survival and recurrence rate was estimated at 70%. The Cox proportional hazards model was used to evaluate prognostic factors and contingency tables were analyzed by an appropriate chisquare test or exact t test. RESULTS Of the 337 patients enrolled, 11 were not eligible (6 were randomized to the narrow excision arm and 5 to the wide excision arm). Exclusion criteria included lesions thicker than 2.0 mm (four patients),

Cutaneous Melanoma/Khayat et al. 1943 TABLE 1 Clinical Characteristics by Randomized Arms (n 326) 2cm(n 161) 5 cm (n 165) Characteristics (n 85) (n 76) Total (n 76) (n 89) Total P value Age (mean) 43 45 0.31 Gender Men (n 122) 29 32 61 27 34 61 Women (n 204) 56 44 100 49 55 104 0.97 Location (missing 16) Head and neck (n 16) 5 5 10 1 5 6 Trunk (n 93) 22 25 47 25 21 46 Upper extremity (n 68) 17 15 32 13 23 36 0.35 Lower extremity (n 138) 32 23 55 34 39 73 Other (n 5) 3 2 5 0 0 0 Clark level of invasion (missing 3) I(n 1) 1 0 1 0 0 0 0.43 II (n 54) 12 12 24 17 18 35 III (n 181) 43 50 93 39 51 90 IV (n 80) 28 14 42 20 19 39 Histology (missing 1) Superficial spreading (n 281) 71 68 139 68 74 142 Nodular (n 41) 14 17 21 8 12 20 0.98 No class (n 3) 0 0 0 0 2 2 Breslow tumor thickness (mm) 0.5 4 4 8 5 5 10 0.51 1.0 34 38 72 33 36 69 0.95 1.01 1.5 27 24 51 23 32 55 1.51 20 10 30 15 16 31 : treated with isoprinosine; : not treated with isoprinosine. Dubreuilh s melanosis based lesions (three patients), age older than 70 years (one patient), and toe or nail lesions (three patients). Therefore, 326 patients were evaluated. There were 122 men and 204 women. The mean age of the sample was 44 years (standard deviation 13 years). One hundred and sixty-one patients were assigned to limited surgical excision (2 cm) and 165 were assigned to wide local excision (5 cm). Both surgical groups were comparable for gender, age, location of the tumor, Clark level of invasion, histologic type, and tumor thickness (Table 1). After nearly 20 years of follow-up, 40 patients (12%) were lost to follow-up. Another 36 patients had missing information regarding the date of their tumor recurrences. However, their death certificate data were evaluable for survival analysis (17 patients in the limited excision arm and 19 in the wide excision arm). Therefore, 243 patients were evaluable for disease-free survival and 286 patients were evaluable for survival (139 for the 2-cm margin and 147 for the 5-cm margin). Ninety-five and 93 patients were free of disease for the 2-cm and 5-cm margins, respectively (Table 2). Fifty-five patients had disease recurrence after a mean TABLE 2 Tumor Recurrences and Deaths in Each Surgical Arm Follow-up 2cm (n 161) (%) 5cm (n 165) (%) Total (n 326) (%) No tumor recurrence 95 (59) 93 (56.3) 188 (57.6) Tumor recurrences 22 (13.6) 33 (20) 55 (16.8) Death 32 (19.8) 29 (17.5) 61 (18.7) Lost to follow-up 22 (13.6) 18 (10.9) 40 (12.3) disease-free interval of 33 months (range, 5 113 months). Of these 55, had local tumor recurrences, 38 had distant or regional lymph node involvement, and 12 were unknown. Twenty-two patients had tumor recurrence in the 2-cm margin arm versus 33 in the 5-cm margin group. Local tumor recurrence occurred in four patients (Breslow thickness: 0.95 mm, 1.05 mm, 1.22 mm, and 1.5 mm) who had wide excision and in only one patient with a narrow excision (Breslow thickness: 2 mm). The type of tumor recurrences and surgery performed were independent on statistical analysis (P

1944 CANCER April 15, 2003 / Volume 97 / Number 8 TABLE 3 Types of Tumor Recurrences for Each Surgical Arm Type or recurrence 2cm (n 161) (%) 5cm (n 165) (%) Total (n 326) (%) Local 1 4 5 Breslow thickness 1mm 0 1 Breslow thickness 1mm 1 3 Distant 4 (2.5) 10 (6.1) 14 (4.3) Regional lymph node 13 (8.1) 11 (6.7) 24 (7.4) Unknown 4 (2.5) 8 (4.8) 12 (3.7) Total 22 (13.6) 33 (20) 55 (16.9) FIGURE 3. Disease-free survival according to the extent of surgery. Statistical analysis was performed using the log-rank test (P 0.83). FIGURE 2. Overall survival according to the extent of surgery. Statistical analysis was performed using the log-rank test (P 0.56) 0.22) (Table 3). The median time to tumor recurrence was 42.1 months (range, 37.6 43 months). The disease-free survival rates at 10 years were 85% in the 2-cm arm and 83% in the 5-cm arm. This difference was not significant (P 0.83) (Fig. 2). On follow-up, 31 deaths were related to melanoma and 23 deaths were unrelated to melanoma. Seven deaths for which the cause was not specified were evaluated as related. Survival was not modified by surgical margin. Overall survival rates at 10 years were 87% for the 2-cm excision and 86% for the 5-cm excision groups (P 0.56) (Fig. 3). Clinical and pathologic prognostic factors were evaluated using previously defined factors. 1 3 In univariate analysis, the number of tumor recurrences was higher according to tumor thickness and male gender (P 0.03 and P 0.01, respectively; Fig. 4 and 5). Survival was influenced by the same factors (P 0.03 and P 0.02, respectively). Other a priori known prognostic factors (e.g., location, histologic type, or age) FIGURE 4. Disease-free survival according to gender. Statistical analysis was performed using the log-rank test (P 0.01). did not appear to statistically influence either overall or disease-free survival. We evaluated the risk of death and tumor recurrence among patients with 1 2-mm thick lesions compared with patients with less than 1-mm thick lesions. A univariate Cox regression model showed that the relative risk of death was 3.6 for patients with melanomas 1 2-mm thick compared with those with lesions less than 1-mm thick (P 0.001; 95% confidence interval [CI], 1.56 8.84). The risk of tumor recurrence estimated at 4.0 was also significantly higher in that subgroup (P 0.0001; 95% CI, 1.91 8.36). The outcome (tumor recurrence, death) was not statistically different for these two subgroups based on the excision margin. The second randomization to receive or not to

Cutaneous Melanoma/Khayat et al. 1945 FIGURE 5. Disease-free survival according to tumor thickness (P 0.032). receive isoprinosine did not appear to affect the outcome of these patients. The median survival periods with or without the drug were 190 months and 192 months respectively (P 0.9) and the disease-free survival periods were 149.5 months and 153.3 months, respectively, (P 0.89). No statistically significant influence of this adjuvant immunotherapy was noted on any subgroup analysis (e.g., extent of surgery, location, and thickness). DISCUSSION The WHO 4 melanoma program studied 612 patients with malignant melanoma of 2 mm or less in thickness. The mean follow-up was 90 months. Veronesi et al. 4 concluded that a 1-cm radial margin for thin melanoma ( 1 mm) was as safe as a 3-cm margin or more. In patients with lesions thicker than 1 mm who underwent a 1-cm excision margin, 4 of 307 lesions metastasized. In a prospective study of 486 patients with a median follow-up of 6 years, Balch et al. 5 showed that a 2-cm margin for lesions 1 4-mm thick was as good as a 4-cm margin. There were two local tumor recurrences in the 2-cm margin group, both with a thickness of 2.1 mm or less. There were three local tumor recurrences in the 4-cm margin group, all with thicknesses greater than 2.3 mm. Balch et al. concluded that a 2-cm or 4-cm margin demonstrated no statistical difference with regard to overall survival and local tumor recurrence. However, for lesions measuring less than 2 mm, some questions remained regarding long-term prognosis. In accordance with other studies, we found that in Stage I melanoma patients, both gender and tumor thickness (Breslow) were prognostically significant. The Swedish Melanoma Study group published a long-term follow-up (median follow-up for survival of 11 years) of a trial of 989 patients with a tumor thickness of 0.8 2.0 mm. It found no advantage of performing a 5-cm margin over a 2-cm margin. 13 The prognostic factor analysis in that study did not show Clark level to be important in thin melanomas. Veronesi et al. 4 compared a 2-cm margin with a 1-cm margin and demonstrated no survival difference. The WHO trial for lesions measuring 1 2.1 mm reported a slightly higher risk of local tumor recurrence in the 1-cm cohort without any apparent impact on survival. They confirmed that lesions 1 mm or smaller have better overall and disease-free survival rates compared with lesions of 1 2 mm. Our study, which compared a 2-cm margin with a 5-cm margin, did not show a difference in local tumor recurrence rates, disease-free survival, or overall survival for lesions measuring less than 2 mm in thickness. For lesions measuring less than 1 mm, a more limited excision may be sufficient. 2 In 1987, isoprinosine was shown in vitro to immunostimulate natural killer cells against melanoma cells. We, therefore, prospectively randomized the use of isoprinosine in our trial. The trend toward a significant clinical benefit related to the use of adjuvant isoprenosine was found to vanish completely with longer follow-up. We conclude that an excision margin larger than 2 cm for lesions of less than 2 mm depth is unnecessary. For lesions measuring less than 1 mm, a more conservative 1-cm margin may be used. Systemic adjuvant isoprinosine did not prevent tumor recurrence or death in patients with thin melanoma and in our opinion should not be used in that setting. REFERENCES 1. Balch CM, Murad TM, Soong S-J, et al. A multifactorial analysis of melanoma: prognostic histopathological features comparing Clark s and Breslow s staging methods. Ann Surg. 1978;188:732 742. 2. Balch CM, Soong S-J, Milton GW, et al. A comparison of prognostic factors and surgical results in 1786 patients with localized (Stage I) melanoma treated in Alabama, USA and New South Wales, Australia. Ann Surg. 1982;196:677 684. 3. Balch CM, Murad TM, Soong S-J, et al. Tumor thickness as a guide to surgical management of clinical Stage I melanoma patients. Cancer. 1979;43:883 888. 4. Veronesi U, Cascinelli N. Narrow excision (1 cm margin) a safe procedure for thin cutaneous melanoma. Arch Surg. 1991;126:438 441. 5. Balch CM, Urist MM, Constantine P, et al. Efficacy of a2cm surgical margin for intermediate thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg. 1993;218:262 269. 6. Armstrong BK, Kricker A. Cutaneous melanoma. Cancer Surv. 1994;19:219 240.

1946 CANCER April 15, 2003 / Volume 97 / Number 8 7. Elwood JM. Recent developments in melanoma epidemiology. Melanoma Res. 1993;3:149 156. 8. Mackie RM, Hole D. Audit of public education campaign to encourage earlier detection of malignant melanoma. BMJ. 1992;304:1012 1015. 9. Mackie RM, Hunter JAA, Blessing K, et al. Changing tumor thickness in melanomas in Scotland 1979-1989. Melanoma Res. 1993;3(Suppl 1):60. 10. Burton RC, Armstrong BK. Recent incidence trends imply a non-metastasizing form of invasive melanoma. Melanoma Res. 1994;4:107 113. 11. Burton RC. Analysis of public education and the implications with regard to nonprogressive thin melanomas. Curr Opin Oncol. 1995;7:170 174. 12. Pompidou A, Soubrane C, Cour V, Telvi L, Meunier C, Jacquillat C. Immunological effects of isoprinosine as a pulse immunotherapy in melanoma and ARC patients. Cancer Detect Prev. 1987;(Suppl 1):457 462. 13. Cohn-Cedermark G, Rutqvist LE, Andersoson R, et al. 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. Cancer. 2000:89: 1495 1501.