Full lymph-node removal in melanoma did not extend life

Overview

Faries MB et al.. N Engl J Med 2017 · PMID 28591523 · DOI 10.1056/NEJMoa1613210

Completion dissection did not improve melanoma-specific survival but caused more lymphoedema.

Does the study support the specific claim? Partly · Methodological quality: high

Original publication

Plain-language summary

Scientific in-depth review

1. Full reference

Authors

Faries MB et al.

Journal

N Engl J Med

Year

2017

Identifier

PMID 28591523 DOI 10.1056/NEJMoa1613210

Verification

verified – PubMed efetch 2026-10-25

Retracted

no

Corrections

none

Extent checked

full text

Conflicts of interest and funding

NCI grants (CA189163, CA29605) and private foundations (Borstein, Amyx, Adelson, John Wayne Cancer Institute Auxiliary). Several authors report advisory/consulting fees from pharmaceutical companies (e.g. Amgen, BMS, Merck, Novartis, Roche) and patents (incl. on the RT-PCR micrometastasis assay used in the trial).

2. Research question

Does immediate completion lymph-node dissection improve melanoma-specific survival in patients with sentinel-node metastases?

3. Study design and population

Study design

Randomised controlled trial – International multicentre randomised phase 3 trial (MSLT-II, NCT00297895; registered retrospectively on 27 February 2006 after 119 patients were enrolled), 63 centres

Population

Patients aged 18-75 years with clinically localised cutaneous melanoma, ECOG 0-1, non-melanoma life expectancy >=10 years and a tumour-positive sentinel node (by standard pathology or multimarker RT-PCR assay); low nodal tumour burden (median largest deposit 0.61-0.67 mm)

Country

International: USA, Canada, Australia, Italy, Netherlands, UK, Germany, Switzerland, Sweden, Finland, Spain, Israel

Period

Enrolment December 2004 to March 2014; median follow-up 43 months; follow-up data to 30 April 2016

Sample size

3531 screened; 1939 randomised; 1934 evaluable in ITT; 1755 per protocol (143 excluded from per-protocol in dissection group, 140 of whom declined dissection)

Inclusion and exclusion criteria

Randomisation and completion dissection within 140 days of diagnostic biopsy; RT-PCR-only-positive patients no longer randomised from 2012 on DSMB advice (insufficient power).

4. Methods and endpoints

Exposure / intervention

Immediate completion lymph-node dissection

Comparator

Nodal observation with clinical examination and nodal ultrasonography (every 4 months years 1-2, every 6 months years 3-5, then annually), dissection only on nodal recurrence

Endpoints

Primary: melanoma-specific survival; secondary: overall survival, disease-free survival, nodal recurrence-free survival, distant metastasis-free survival, nonsentinel-node metastasis rate; adverse events (lymphoedema)

Statistical methods

Permuted-block 1:1 randomisation stratified by Breslow thickness, ulceration, detection method and MSLT-I centre; log-rank tests and Cox regression; planned sample 1925 for 83% power to detect 5 percentage points difference; per-protocol results reported in main text (ITT in supplement, stated as similar); results released at third interim analysis on DSMB advice.

5. Actual results

Results

3-year melanoma-specific survival (per protocol) 86 +/- 1.3% dissection vs 86 +/- 1.2% observation (P=0.42); adjusted HR for death 1.08 (0.88-1.34). 3-year disease-free survival 68 +/- 1.7% vs 63 +/- 1.7% (P=0.05); regional nodal control 92 +/- 1.0% vs 77 +/- 1.5% (P<0.001); nodal recurrence HR 0.31 (0.24-0.41) in pathology-positive patients; distant metastasis-free survival adjusted HR 1.10 (0.92-1.31). Nonsentinel-node metastases in 11.5% of dissection group, prognostic (HR 1.78, P=0.005). Lymphoedema 24.1% vs 6.3% (P<0.001; 64% mild, 33% moderate, 3% severe). No subgroup benefited in melanoma-specific survival.

Absolute risks

3-year melanoma-specific survival 86% in both groups; 3-year disease-free survival 68% vs 63%; 3-year regional nodal control 92% vs 77%; lymphoedema 24.1% vs 6.3%

Authors' conclusion

Immediate completion lymph-node dissection increased regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with sentinel-node metastases; benefits come at the cost of more complications.

6. Strengths

• Large international RCT with stratified randomisation and survival primary endpoint
• Prespecified power calculation largely achieved (1939 randomised)
• Objective endpoints; ultrasound surveillance protocol standardised

7. Weaknesses

• Short median follow-up (43 months) for melanoma-specific survival; results released at an interim analysis
• Main text reports per-protocol rather than ITT analysis; 140 patients in dissection group declined surgery (differed in prognostic factors)
• Retrospective trial registration (119 patients enrolled before registration)
• Low nodal tumour burden; RT-PCR stratum stopped; limited power for high-burden patients
• Safety of observation not established where intensive ultrasound follow-up is unavailable (authors' caveat)
• Open-label surgical comparison; surveillance intensity differed (ultrasound only in observation group)

8. Risk of bias

Orienting tool

RoB 2

Type of assessment

structured assessment based on the full text by a single reviewer (no formal double review)

Full formal assessment

no

Overall risk of bias

some concerns

Rationale

Overall unchanged. Null primary result is consistent across ITT and per-protocol analyses, so concerns do not change the conclusion. Simplified single-reviewer judgement; a formal RoB 2 needs two independent reviewers and the protocol.

Full-text review (25 October 2026): Added countries, period, eligibility, screening/randomisation numbers, observation protocol, adjusted HRs (MSS 1.08, 0.88-1.34; nodal recurrence 0.31; distant metastasis 1.10), lymphoedema severity, retrospective registration, per-protocol reporting, interim release, funding and author COIs. RoB 2 overall unchanged with domains.

9. Assessment of the statistical interpretation

No melanoma-specific survival difference (HR 1.08, 0.88-1.34); improved regional control with dissection (nodal recurrence HR 0.31) at the cost of more lymphoedema. Follow-up is short for late events.

10. Relevance to the specific claim

Shows that routine extensive lymph-node dissection can cause harm without survival benefit; sentinel biopsy itself was retained and associated with better survival in node-positive intermediate-thickness melanoma (background in abstract).

11. Independent contrary findings

Dissection improved regional control and staging.

12. Transferability to Germany and Europe

International incl. Europe.

13. Overall methodological judgement

High-quality RCT supporting de-escalation of completion lymph-node dissection in melanoma with sentinel-node metastasis, under ultrasound surveillance; sentinel-node biopsy (staging and early treatment) remains standard.

14. Open questions

Longer-term survival; patients with higher nodal tumour burden; settings without access to nodal ultrasonography.

15. Linked fact checks

• Surgical oncologists do not understand what tumours are: they remove the tumour and 'clean out' the lymph nodes, which he regards as wrong. – Studies with mixed or unclear results