Therapeutics
2-cm and 4-cm surgical excision margins
did not differ for survival in cutaneous
melanoma > 2 mm thick
Gillgren P, Drzewiecki KT, Niin M, et al. 2-cm versus 4-cm surgical
excision margins for primary cutaneous melanoma thicker than 2 mm:
a randomised, multicentre trial. Lancet. 2011;378:1635-42.
Clinical impact ratings: O ★★★★★★✩ D ★★★★★★✩
Question
Conclusion
Does surgery with 2-cm excision margins differ from surgery
with 4-cm excision margins for survival in patients with cutaneous melanoma > 2 mm thick?
Radical surgery with 2-cm excision margins did not differ from
that with 4-cm margins for survival in patients with cutaneous
melanoma > 2 mm thick.
Methods
*See Glossary.
Design: Randomized, controlled, equivalency trial. ClinicalTrials.
gov NCT01183936.
Allocation: Concealed.*
Blinding: Unblinded.*
Follow-up period: Median 6.7 years. Trial was stopped early
because of changing clinical practice and decreasing enrollment.
Setting: 53 hospitals in Sweden, Denmark, Estonia, and Norway.
Patients: 936 patients ≤ 75 years of age (median age 59 to 60 y,
64% men) who had a primary, clinically localized cutaneous
melanoma > 2 mm thick on the trunk, arms, or legs. Exclusion
criteria were cutaneous melanoma on hands, feet, head and neck,
or anogenital region; past cutaneous melanoma; or other malignant disease (except basal cell carcinoma or in situ cervical cancer).
Intervention: Radical surgery with a 2-cm (n = 465) or 4-cm
(n = 471) excision margin.
Outcomes: Overall survival and recurrence-free survival. 1000
patients were needed to detect a reduction in 5-year survival
from 60% to 50% (90% power, α = 0.05) at interim analysis.
2000 patients were planned to evaluate treatment equivalency.
Patient follow-up: > 99% (intention-to-treat analysis).
Main results
At 5 years, overall survival was 65% in each group (P = 0.69),
and recurrence-free survival was 56% in each group (P = 0.82).
Results for mortality and recurrence at a median 6.7 years of
follow-up are reported in the Table.
Radical surgery with 2-cm vs 4-cm excision margins in
cutaneous melanoma > 2 mm thick†
Outcomes
All-cause mortality
2-cm
4-cm
At a median 6.7 y of follow-up
RRI (95% CI)
NNH (CI)
39%
38%
4% (−12 to 21)
Not significant
RRR (CI)
NNT (CI)
Recurrence or
melanoma mortality
41.7%
42.5%
2% (−14 to 16)
Not significant
Melanoma mortality
28.8%
29.3%
1% (−21 to 19)
Not significant
†Abbreviations defined in Glossary. RRI, RRR, and CI calculated from hazard ratios and
event rates in the 4-cm group reported in article.
Sources of funding: Swedish Cancer Society and Stockholm
Cancer Society.
For correspondence: Dr. P. Gillgren, Department of Surgery,
Södersjukhuset, Stockholm, Sweden. E-mail peter. gillgren@
sodersjukhuset.se. ■
Commentary
A systematic review and meta-analysis in 2009 concluded that
there was insufficient evidence to determine optimal excision
margins for cutaneous melanomas (1). In the study by Gillgren
and colleagues, 936 patients with melanomas thicker than 2 mm
had surgery with excision margins of either 2 cm or 4 cm. There
were no significant differences in overall survival or recurrencefree survival. Overall survival at 5 years was 65% in both groups,
with a hazard ratio of 1.05, 95% CI 0.85 to 1.29.
At face value, these results suggest that excision margins of 2 cm
and 4 cm are equivalent. Unfortunately, < 1000 patients were accrued
from the original plan of 2000 required to test for equivalence, and
the width of the 95% CIs indicates substantial residual uncertainty.
The data are sufficient to rule out a substantial benefit for excision
margins of 4 cm rather than 2 cm (the hazard rate for death is
unlikely to be > 1.29 times better), but they are insufficient to
rule out a clinically important harm for excision margins of 2 cm
rather than 4 cm (the hazard rate for death could be as much as
1.29 times worse).
This important study adds to our knowledge about the surgical
treatment of melanoma. Current evidence suggests that 1-cm
surgical margins may be adequate for melanomas ≤ 2 mm in
thickness and 2-cm margins may be adequate for melanomas
thicker than 2 mm. Studies designed to establish that narrow
margins are not inferior to wide margins (noninferiority trials)
need to have many more patients than those designed to establish
if wide margins are superior to narrow margins (superiority trials).
Carlos Garcia, MD
Dawson Medical Group
Oklahoma City, Oklahoma, USA
Reference
1. Sladden MJ, Balch C, Barzilai DA, et al. Surgical excision margins
for primary cutaneous melanoma. Cochrane Database Syst Rev.
2009;(4):CD004835.
15 May 2012 | ACP Journal Club | Volume 156 • Number 5
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