Critical appraisal:Cormier JN, Xing Y, Feng L, Huang X, Davidson L, Gershenwald JE, et al 2006

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Critical Appraisal

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Cormier JN, Xing Y, Feng L, Huang X, Davidson L, Gershenwald JE, et al. Metastatic melanoma to lymph nodes in patients with unknown primary sites. Cancer 2006 May 1;106(9):2012-20 Available from:

Applicable clinical question

Key Facts

Study Design

cohort study

Study aims:

To determine retrospectively the incidence of MUP to a regional lymph node, to examine the prognostic factors for MUP, and to define the long-term outcomes of patients with MUP compared with the outcomes in a contemporary cohort of patients who were treated during the same time interval and who had a known site or primary melanoma with matched lymph node (N) status according to the current American Joint Committee on Cancer (AJCC) staging system.20

Number of Patients:


MUP (N=71)
Controls: Stage III Known Primary Melanoma (N=466)
Reported outcome(s):

Disease-free survival (DFS)
Disease-specific survival (DSS)
Overall survival (OS)

Results of outcome(s):

DFS: Recurrence in 40 (56%) with MUP: 10 (25%) regional recurrences (in basin), 28 (70%) had distant recurrences, and 2 (5%) had synchronous regional and distant recurrences. Controls: Of 282 (61%) who developed disease recurrences, 82 (29%) had regional recurrences, 175 (62%) had distant recurrences, and 7 (3%) had synchronous regional and distant recurrences. Local disease recurred in 18 (6%) who had known primary tumor sites. Kaplan–Meier estimates for 5-year and 10-year DFS MUP: 43% and 33%. Controls 5-year and 10-year DFS rates 30% and 26% DFS in MUP and controls examined according to lymph node category. MU. N1b disease similar for both groups (P = .9). N2b and N3 disease not statistically significant (P = .22 and P = .32). DFS in the control group according to disease stage, estimated 5-year and 10-year DFS rates: Stage IIIB disease were 37% and 32%, Stage IIIC= 25% and 23%. MUP was similar to the survival of patients in control with Stage IIIB (P = .67) and differed statistically from the control group who had Stage IIIC disease (P = .002). Univariate analyses: age, gender, lymph node basin, N category, and treatment. Only male gender (hazard ratio [HR], 2.70; 95% confidence interval [95% CI], 1.58–3.81; P = .017) and N3 category (HR, 1.92; 95% CI, 1.34–2.51; P = .031) proved to be adverse factors in MUP. Multivariate analyses. MUP fared better than controls, not statistical significance (HR, 0.73; 95% CI, 0.53–1.01; P = .057). Age < 50 years (HR, 0.78; 95% CI, 0.63–0.97; P = .025) had better a DFS than > 50 years, male patients (HR, 1.59; 95% CI, 1.27–1.99; P<.001) and N2b disease (HR, 1.55; 95% CI, 1.15–2.08; P = .004) and N3 disease (HR, 2.25; 95% CI, 1.73–2.91; P<.001) fared worse in this regard.
DSS: 35 (49%) MUP and 267 (57%) controls died of melanoma. Median DSS duration was 7.60 years MUP and 3.56 years for controls. Estimated 5-year and 10-year DSS rates, MUP: 56% and 47%, respectively, controls 44% and 36%, respectively, (P = .04). Adjusted by other factors, DSS duration for MUP was significantly better than control patients (HR, 0.60; 95% CI, 0.41–0.86; P = .006). Patients < 50 years (HR, 0.79; 95% CI, 0.62–1.00; P= .048) had a better DSS in the multivariate analysis, male patients (HR, 1.48; 95% CI, 1.15–1.90; P = .002) and N2b disease (HR, 1.47; 95% CI, 1.06–2.05; P = .022) and N3 disease (HR, 2.15; 95% CI, 1.62–2.86; P<.001) fared worse than comparison groups.
OS: There were 37 deaths (52%) in MUP group, 269 deaths (58%) in control group. Median OS was 6.36 years MUP and 2.96 years for control group. Estimated 5-year and 10-year OS rates in MUP: 55% and 44%, and 42% and 33%, respectively, for controls (P = .04). Kaplan–Meier survival curves show no difference in OS between MUP and controls with N1b disease. Patients with N2b disease: (P = .11). Patients in MUP with N3 disease fared significantly better with respect to OS compared with controls (P = .02). When control were stratified according Stage IIIB or IIIC, 5-year and 10-year OS rates: Stage IIIB disease were 50% and 42%, OS rates of 55% and 44%, for MUP (P = .67). 5-year and 10-year OS rates for patients with Stage IIIC disease were significantly lower, at 37% and 26%, than the rates in the MUP (P = .002).
When adjusted for factors, OS duration, MUP was significantly better than controls (HR, 0.61; 95% CI, 0.42–0.86; P = .006). Multivariate analyses showed patients < 50 years (HR, 0.76; 95% CI, 0.61–0.96; P = .020) had a better OS, males (HR, 1.48; 95% CI, 1.17–1.89; P = .001) and patients with N2b disease (HR, 1.47; 95% CI, 1.07–2.03; P = .018) and N3 disease (HR, 2.21; 95% CI, 1.67–2.91; P<0.001) fared worse than patients in the comparison groups

Includes an economic evaluation


Evidence ratings

Level of evidence


Risk of bias
Moderate risk of bias Comments: Please replace this text and include any additional comments in regards to your risk of bias rating

Risk of bias assessment: cohort study

Subject selection
"New technology" group
Selected group
Comparison group
Selected group
Comparability of groups on demographic characteristics and clinical features
Not comparable but adjusted analysis used
Measurement of outcomes
Outcome measures blind to technology used
No, but objective measures used
Same method of measurement used across comparison groups
Completeness of follow-up
Was follow-up complete and were all patients included in the analysis?
Yes (follow-up >95%) or survival analysis using all patients

Relevance of evidence
1 Additional comments: Please replace this text and briefly describe the reasons for your rating
Result of appraisal

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Completed by

Jackie Buck

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Cormier JN, Xing Y, Feng L, Huang X, Davidson L, Gershenwald JE, et al. Metastatic melanoma to lymph nodes in patients with unknown primary sites. Cancer 2006 May 1;106(9):2012-20 Available from:
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