Surgical Margins in Cutaneous Melanoma(2 cm Versus 5 cm for Lesions MeasuringLess 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-Andre Bazex, M.D.3

Philippe Lauret, M.D.4

Olivier Verola, M.D.5

Gerard Auclerc, M.D.1

Peter Harper, M.D.6

Pierre Banzet, M.D.7

for the French Group of Research onMalignant Melanoma

1 Service d’Oncologie Medicale, Hopital Pitie-Sal-petriere, Paris, France.

2 Service de Chirurgie, Centre Hospitalier del’Universite de Montreal, Montreal, Quebec, Canada.

3 Service de Dermatologie, Hopital Purpan, Tou-louse, France.

4 Service de Dermatologie, Hopital Charles Nicolle,Rouen, France.

5 Service d’Anatomopathologie, Hopital Saint-Louis, Paris, France.

6 Medical Oncology Department, Guy’s and SaintThomas’ Hospital, London, United Kingdom.

7 Service de Chirurgie Plastique Reconstructive etEsthetique, Hopital Saint-Louis, Paris, France.

Supported by the Association Pour la Vie-EspoirContre le Cancer (A.V.E.C.).

Dr. Peter Harper is an advisory board member forLilly, Adventis, Glaxo Smithkline, Bristol-MyersSquibb, Roche, and Johnson & Johnson.

Address for reprints: David Khayat, M.D., Ph.D.,Department of Medical Oncology, Salpetriere Hos-pital, 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 receivedFebruary 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 random-

ized 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 immu-

nostimulant, 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 demon-

strate 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 isimportant to optimize the surgical management of patients with

this tumor. For decades, a wide local excision with a margin as largeas 3–5 cm around the lesion was recommended, resulting in signifi-cant morbidity. Retrospective and prospective studies have empha-sized the importance of tumor thickness in predicting local diseaserecurrence,1–3 raising the hypothesis that significantly less mutilatingapproaches could be sufficient for thin lesions. Two large multicenterprospective trials have evaluated margins in TNM Stage I malignantmelanoma. The World Health Organization (WHO)4 melanoma pro-gram studied the effectiveness of a 1-cm margin for thin melanomas(�1 mm). Balch et al.5 evaluated 2-cm versus 4-cm margins for1– 4-mm–thick primary melanomas. In their multifactorial analysis ofprognostic factors, they reported that thickness, the presence of ul-ceration, and anatomic site were important prognostic factors and

1941

© 2003 American Cancer Society

that a 2-cm or 4-cm margin demonstrated no statisti-cal difference in overall survival or local disease recur-rence.

Although incidence of malignant melanoma is in-creasing, the use of prevention campaigns has re-sulted in lesions being diagnosed at an earlierstage.6 – 8 As a consequence of earlier diagnosis, thenumber of lesions measuring 2 mm or less in thick-ness is expected to increase.9 –11 Optimal managementof this group of tumors is essential, with a majorimpact on cosmesis, quality of life, and cost.

This study was designed to address the margin ofexcision (2 cm vs. 5 cm) for primary melanoma mea-suring 2 mm or less in thickness. A secondary endpoint of our trial was to evaluate the role of adjuvantimmunotherapy using isoprinosine, a nonspecific im-munostimulant that has shown promising results inpreclinical models.12 A double randomization studywas performed to independently test the two thera-peutic interventions (surgical margin and adjuvantisoprinosine).

MATERIALS AND METHODSA prospective multicenter randomized clinical trialwas initiated in 1981 in nine European centers. Pa-tients younger than 70 years, with a maximum tumorthickness of 2 mm (Breslow � 2 mm), were eligible. Allpatients were Stage I by TNM criteria. Excluded weretoe, nail, or finger lesions and melanomas arising frommelanosis, lentigo, and acral lesions.

Before entry, all patients underwent a clinical ex-amination, chest X-ray, and liver ultrasound. Patientswere randomized to either wide (5 cm) or limited (2cm) excision surgery. All biopsy specimens were re-viewed to confirm the tumor thickness and histologicclassification. According to the surgical protocolguidelines, the resection was performed within themonth of the initial biopsy. Excisions extended downto the muscular fascia. A total resection margin meansthat, if the tumor primarily was resected with a 2-cmmargin, no further resection was performed if thepatient was randomized to the limited excision group.By contrast, if the patient was randomized to the 5-cmexcision margin group, a complementary resection ofat least 3 cm was performed. The reported excisionmargin is the summarized excision margins for eachpatient, when available. Lymph node dissections werenot performed. A second randomization allocated thepatient to either 12 months of adjuvant treatment withisoprinosine or to no adjuvant treatment (Fig. 1). Iso-prinosine was used as a pulse immunotherapy, thedose being one tablet (500 mg)/10 kg per day for 5days every 15 days. Patients’ characteristics, including

surgical margins, were balanced between the twogroups based on the immunotherapy randomization.Three hundred thirty-seven patients entered the trialwith a median follow-up of 192 months (range, 2–228months). The cut off date for data collection was De-cember 2000.

Local disease recurrence was defined as recur-rence within 2 cm of the scar. In-transit metastaseswere defined as disease recurrence between the pri-mary tumor site and the regional lymph nodes. Localor regional tumors that recurred were removed surgi-cally and follow-up medical treatment was not pro-vided. Metastatic tumors were treated with chemo-therapy (dacarbazine, fotemustine, or a combination)or with biochemotherapy (a combination of cisplatin,interleukin-2, and interferon-alpha). The survivalanalysis (overall survival and progression-free sur-vival) was performed using the actuarial Kaplan–Meiermethod and differences between the curves were an-alyzed using the log rank test. Survival times werecalculated from the date of inclusion until death. Timeto disease progression was calculated from the date ofinclusion to the date of disease progression. All resultsare quoted as two-sided P values and differences wereconsidered 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 esti-mated at 70%. The Cox proportional hazards modelwas used to evaluate prognostic factors and contin-gency tables were analyzed by an appropriate chi-square test or exact t test.

RESULTSOf the 337 patients enrolled, 11 were not eligible (6were randomized to the narrow excision arm and 5 tothe wide excision arm). Exclusion criteria includedlesions thicker than 2.0 mm (four patients),

FIGURE 1. Randomization of melanoma patients.

1942 CANCER April 15, 2003 / Volume 97 / Number 8

Dubreuilh’s melanosis based lesions (three patients),age older than 70 years (one patient), and toe or naillesions (three patients). Therefore, 326 patients wereevaluated. There were 122 men and 204 women. Themean age of the sample was 44 years (standard devi-ation � 13 years). One hundred and sixty-one patientswere assigned to limited surgical excision (2 cm) and165 were assigned to wide local excision (5 cm). Bothsurgical groups were comparable for gender, age, lo-cation of the tumor, Clark level of invasion, histologictype, and tumor thickness (Table 1).

After nearly 20 years of follow-up, 40 patients(12%) were lost to follow-up. Another 36 patients hadmissing information regarding the date of their tumorrecurrences. However, their death certificate datawere evaluable for survival analysis (17 patients in thelimited excision arm and 19 in the wide excision arm).Therefore, 243 patients were evaluable for disease-freesurvival and 286 patients were evaluable for survival(139 for the 2-cm margin and 147 for the 5-cm mar-gin). Ninety-five and 93 patients were free of diseasefor the 2-cm and 5-cm margins, respectively (Table 2).Fifty-five patients had disease recurrence after a mean

disease-free interval of 33 months (range, 5–113months). Of these 55, had local tumor recurrences, 38had distant or regional lymph node involvement, and12 were unknown. Twenty-two patients had tumorrecurrence in the 2-cm margin arm versus 33 in the5-cm margin group.

Local tumor recurrence occurred in four patients(Breslow thickness: 0.95 mm, 1.05 mm, 1.22 mm, and1.5 mm) who had wide excision and in only one pa-tient with a narrow excision (Breslow thickness: 2mm). The type of tumor recurrences and surgery per-formed were independent on statistical analysis (P

TABLE 2Tumor Recurrences and Deaths in Each Surgical Arm

Follow-up2 cm(n � 161) (%)

5 cm(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)

TABLE 1Clinical Characteristics by Randomized Arms (n � 326)

Characteristics

2 cm (n � 161) 5 cm (n � 165)

P valueIso�

(n � 85)Iso�

(n � 76) TotalIso�

(n � 76)Iso�

(n � 89) Total

Age (mean) 43 45 0.31Gender

Men (n � 122) 29 32 61 27 34 61Women (n � 204) 56 44 100 49 55 104 0.97

Location (missing 16)Head and neck (n � 16) 5 5 10 1 5 6Trunk (n � 93) 22 25 47 25 21 46Upper extremity (n � 68) 17 15 32 13 23 36 0.35Lower extremity (n � 138) 32 23 55 34 39 73Other (n � 5) 3 2 5 0 0 0

Clark level of invasion (missing 3)I (n � 1) 1 0 1 0 0 0 0.43II (n � 54) 12 12 24 17 18 35III (n � 181) 43 50 93 39 51 90IV (n � 80) 28 14 42 20 19 39

Histology (missing 1)Superficial spreading (n � 281) 71 68 139 68 74 142Nodular (n � 41) 14 17 21 8 12 20 0.98No class (n � 3) 0 0 0 0 2 2

Breslow tumor thickness (mm)� 0.5 4 4 8 5 5 100.51–1.0 34 38 72 33 36 69 0.951.01–1.5 27 24 51 23 32 55� 1.51 20 10 30 15 16 31

Iso�: treated with isoprinosine; Iso�: not treated with isoprinosine.

Cutaneous Melanoma/Khayat et al. 1943

� 0.22) (Table 3). The median time to tumor recur-rence was 42.1 months (range, 37.6 – 43 months). Thedisease-free survival rates at 10 years were 85% in the2-cm arm and 83% in the 5-cm arm. This differencewas not significant (P � 0.83) (Fig. 2).

On follow-up, 31 deaths were related to mela-noma and 23 deaths were unrelated to melanoma.Seven deaths for which the cause was not specifiedwere evaluated as “related.” Survival was not modifiedby surgical margin. Overall survival rates at 10 yearswere 87% for the 2-cm excision and 86% for the 5-cmexcision groups (P � 0.56) (Fig. 3).

Clinical and pathologic prognostic factors wereevaluated using previously defined factors.1–3 In uni-variate analysis, the number of tumor recurrences washigher 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 � 0.03and P � 0.02, respectively). Other a priori known prog-nostic factors (e.g., location, histologic type, or age)

did not appear to statistically influence either overallor disease-free survival.

We evaluated the risk of death and tumor recur-rence among patients with 1–2-mm–thick lesionscompared with patients with less than 1-mm–thicklesions. A univariate Cox regression model showedthat the relative risk of death was 3.6 for patients withmelanomas 1–2-mm thick compared with those withlesions less than 1-mm thick (P � 0.001; 95% confi-dence interval [CI], 1.56 – 8.84). The risk of tumor re-currence estimated at 4.0 was also significantly higherin that subgroup (P � 0.0001; 95% CI, 1.91– 8.36). Theoutcome (tumor recurrence, death) was not statisti-cally different for these two subgroups based on theexcision margin.

The second randomization to receive or not to

TABLE 3Types of Tumor Recurrences for Each Surgical Arm

Type or recurrence2 cm(n � 161) (%)

5 cm(n � 165) (%)

Total(n � 326) (%)

Local 1 4 5Breslow thickness � 1 mm 0 1Breslow thickness � 1 mm 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 2. Overall survival according to the extent of surgery. Statistical

analysis was performed using the log-rank test (P � 0.56)

FIGURE 3. Disease-free survival according to the extent of surgery. Statis-

tical analysis was performed using the log-rank test (P � 0.83).

FIGURE 4. Disease-free survival according to gender. Statistical analysis was

performed using the log-rank test (P � 0.01).

1944 CANCER April 15, 2003 / Volume 97 / Number 8

receive isoprinosine did not appear to affect the out-come of these patients. The median survival periodswith or without the drug were 190 months and 192months respectively (P � 0.9) and the disease-freesurvival periods were 149.5 months and 153.3 months,respectively, (P � 0.89). No statistically significant in-fluence of this adjuvant immunotherapy was noted onany subgroup analysis (e.g., extent of surgery, location,and thickness).

DISCUSSIONThe WHO4 melanoma program studied 612 patientswith malignant melanoma of 2 mm or less in thick-ness. The mean follow-up was 90 months. Veronesi etal.4 concluded that a 1-cm radial margin for thin mel-anoma (�1 mm) was as safe as a 3-cm margin ormore. In patients with lesions thicker than 1 mm whounderwent a 1-cm excision margin, 4 of 307 lesionsmetastasized. In a prospective study of 486 patientswith a median follow-up of 6 years, Balch et al.5

showed that a 2-cm margin for lesions 1– 4-mm thickwas as good as a 4-cm margin. There were two localtumor recurrences in the 2-cm margin group, bothwith a thickness of 2.1 mm or less. There were threelocal tumor recurrences in the 4-cm margin group, allwith thicknesses greater than 2.3 mm. Balch et al.concluded that a 2-cm or 4-cm margin demonstratedno statistical difference with regard to overall survivaland local tumor recurrence. However, for lesions mea-suring less than 2 mm, some questions remained re-garding long-term prognosis.

In accordance with other studies, we found that inStage I melanoma patients, both gender and tumorthickness (Breslow) were prognostically significant.The Swedish Melanoma Study group published a

long-term follow-up (median follow-up for survival of11 years) of a trial of 989 patients with a tumor thick-ness of 0.8 –2.0 mm. It found no advantage of perform-ing a 5-cm margin over a 2-cm margin.13 The prog-nostic factor analysis in that study did not show Clarklevel to be important in thin melanomas.

Veronesi et al.4 compared a 2-cm margin with a1-cm margin and demonstrated no survival difference.The WHO trial for lesions measuring 1–2.1 mm re-ported a slightly higher risk of local tumor recurrencein the 1-cm cohort without any apparent impact onsurvival. They confirmed that lesions 1 mm or smallerhave better overall and disease-free survival ratescompared with lesions of 1–2 mm.

Our study, which compared a 2-cm margin with a5-cm margin, did not show a difference in local tumorrecurrence rates, disease-free survival, or overall sur-vival for lesions measuring less than 2 mm in thick-ness. For lesions measuring less than 1 mm, a morelimited excision may be sufficient.2

In 1987, isoprinosine was shown in vitro to immu-nostimulate natural killer cells against melanomacells. We, therefore, prospectively randomized the useof isoprinosine in our trial. The trend toward a signif-icant clinical benefit related to the use of adjuvantisoprenosine was found to vanish completely withlonger follow-up.

We conclude that an excision margin larger than 2cm for lesions of less than 2 mm depth is unnecessary.For lesions measuring less than 1 mm, a more conser-vative 1-cm margin may be used. Systemic adjuvantisoprinosine did not prevent tumor recurrence ordeath in patients with thin melanoma and in ouropinion should not be used in that setting.

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analysis of melanoma: prognostic histopathological featurescomparing Clark’s and Breslow’s staging methods. AnnSurg. 1978;188:732–742.

2. Balch CM, Soong S-J, Milton GW, et al. A comparison ofprognostic factors and surgical results in 1786 patients withlocalized (Stage I) melanoma treated in Alabama, USA andNew South Wales, Australia. Ann Surg. 1982;196:677– 684.

3. Balch CM, Murad TM, Soong S-J, et al. Tumor thickness asa guide to surgical management of clinical Stage I mela-noma patients. Cancer. 1979;43:883– 888.

4. Veronesi U, Cascinelli N. Narrow excision (1 cm margin) asafe procedure for thin cutaneous melanoma. Arch Surg.1991;126:438 – 441.

5. Balch CM, Urist MM, Constantine P, et al. Efficacy of a 2 cmsurgical margin for intermediate thickness melanomas (1 to4 mm). Results of a multi-institutional randomized surgicaltrial. Ann Surg. 1993;218:262–269.

6. Armstrong BK, Kricker A. Cutaneous melanoma. CancerSurv. 1994;19:219 –240.

FIGURE 5. Disease-free survival according to tumor thickness (P � 0.032).

Cutaneous Melanoma/Khayat et al. 1945

7. Elwood JM. Recent developments in melanoma epidemiol-ogy. Melanoma Res. 1993;3:149 –156.

8. Mackie RM, Hole D. Audit of public education campaign toencourage earlier detection of malignant melanoma. BMJ.1992;304:1012–1015.

9. Mackie RM, Hunter JAA, Blessing K, et al. Changing tumorthickness in melanomas in Scotland 1979-1989. MelanomaRes. 1993;3(Suppl 1):60.

10. Burton RC, Armstrong BK. Recent incidence trends imply anon-metastasizing form of invasive melanoma. MelanomaRes. 1994;4:107–113.

11. Burton RC. Analysis of public education and the implica-

tions with regard to nonprogressive thin melanomas. CurrOpin Oncol. 1995;7:170 –174.

12. Pompidou A, Soubrane C, Cour V, Telvi L, Meunier C, Jac-quillat C. Immunological effects of isoprinosine as a pulseimmunotherapy in melanoma and ARC patients. CancerDetect 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 SwedishMelanoma Study Group on 2-cm versus 5-cm resectionmargins for patients with cutaneous melanoma with atumor thickness of 0.8 –2.0 mm. Cancer. 2000:89:1495–1501.

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