Final trial report of sentinel-node biopsy versus nodal observation in melanoma

Abstract

Background: Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial.

Methods: We evaluated outcomes in 2001 patients with primary cutaneous melanomas randomly assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (observation group), or wide excision and sentinel-node biopsy, with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). Results No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population (20.8% with and 79.2% without nodal metastases). Mean (± SE) 10-year disease-free survival rates were significantly improved in the biopsy group, as compared with the observation group, among patients with intermediate-thickness melanomas, defined as 1.20 to 3.50 mm (71.3 ± 1.8% vs. 64.7 ± 2.3%; hazard ratio for recurrence or metastasis, 0.76; P=0.01), and those with thick melanomas, defined as >3.50 mm (50.7 ± 4.0% vs. 40.5 ± 4.7%; hazard ratio, 0.70; P=0.03). Among patients with intermediate-thickness melanomas, the 10-year melanoma-specific survival rate was 62.1 ± 4.8% among those with metastasis versus 85.1 ± 1.5% for those without metastasis (hazard ratio for death from melanoma, 3.09; P<0.001); among patients with thick melanomas, the respective rates were 48.0 ± 7.0% and 64.6 ± 4.9% (hazard ratio, 1.75; P=0.03). Biopsy-based management improved the 10-year rate of distant disease-free survival (hazard ratio for distant metastasis, 0.62; P=0.02) and the 10-year rate of melanoma-specific survival (hazard ratio for death from melanoma, 0.56; P=0.006) for patients with intermediate-thickness melanomas and nodal metastases. Accelerated-failure-time latent-subgroup analysis was performed to account for the fact that nodal status was initially known only in the biopsy group, and a significant treatment benefit persisted.

Conclusions: Biopsy-based staging of intermediate-thickness or thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy. Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. (Funded by the National Cancer Institute, National Institutes of Health, and the Australia and New Zealand Melanoma Trials Group; ClinicalTrials.gov number, NCT00275496.).

Figure 1. Trial Design, Enrollment, and Outcomes

Panel A shows the design of the trial. Panel B shows enrollment and outcomes at 10 years of follow-up for patients with intermediate-thickness primary melanomas (1.20 to 3.50 mm) and those with thick primary melanomas (>3.50 mm).

Figure 2. Melanoma-Specific and Disease-free Survival, According to Study Group and Melanoma Thickness

Plus–minus values are means ±SE for the estimated rate of survival at specified time points. OBS denotes nodal observation, and SNB sentinel-node biopsy.

Figure 3. Estimated 10-Year Incidence of Nodal Metastasis and Melanoma-Specific Survival, According to Study Group, Melanoma Thickness, and Presence or Absence of Nodal Recurrence

Panels A and B show the cumulative incidence of nodal metastasis at 10 years among patients with intermediate-thickness melanomas and those with thick melanomas, respectively. Data are from the per-protocol analysis; patients who left the study or were lost to follow-up were excluded. In the biopsy group, nodal recurrence in patients whose sentinel nodes were negative for tumor (i.e., false negative biopsy results) was assessed. Plus–minus values are means ±SE for the estimated rate of nodal metastasis. The abbreviation neg. denotes negative, and pos. positive. Panels C and D show the probability of melanoma-specific survival (i.e., survival until death from melanoma) among patients with intermediate-thickness melanomas and those with thick melanomas, respectively. Numbers (1–4) to the right of the survival curves refer to the numbered comparisons below each graph. Plus–minus values are means ±SE for the estimated probability of melanoma-specific survival.