JNCI: Journal of the National Cancer Institute, Oct 2017

Bhatia, Shailender, Storer, Barry E., Nghiem, Paul

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JNCI J Natl Cancer Inst ( Response Shailender Bhatia 0 1 Barry E. Storer 0 1 Paul Nghiem 0 1 0 The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions , please 1 Affiliation of authors: University of Washington/Fred Hutchinson Cancer Research Center , Seattle, WA , USA - We appreciate the thoughtful comments and additional analyses by Vargo et al. and regret the inadvertent omission of primary surgical details in our original report. We have now reanalyzed our data set of stage I and II Merkel cell carcinoma (MCC) patients including this relevant variable. For the purpose of this analysis, we defined wide local excision (WLE) as any surgical excision with a margin greater than 1 cm. A multivariable analysis was conducted using the same methods as described in the original report. Statistical methods are also the same as described in the original report. The hazard ratios presented below are mortality hazard ratios. Analyses were carried out using SAS software (SAS Institute Inc., Cary, NC). All P values are two-sided and derived from Wald statistics. In stage I MCC, WLE had been performed in 59.0% of the surgery group vs 55.0% of the surgery plus adjuvant radiation therapy (RT) group. In stage II MCC, WLE had been performed in 55.0% of the surgery group vs 54.0% of the surgery plus RT group. After adjustment for the other variables including WLE, patients who had surgery plus RT had statistically significantly improved overall survival (OS) compared with patients who had surgery alone among those with localized MCC (stage I: hazard ratio [HR] ¼ 0.71, 95% confidence interval [CI] ¼ 0.63 to 0.79, P < .001; stage II: HR ¼ 0.77, 95% CI ¼ 0.66 to 0.89, P < .001). These results are virtually identical to our original results, which did not include primary surgical details. Patients who had WLE had statistically significantly improved OS vs other primary surgical approaches in stage I (HR ¼ 0.86, 95% ¼ CI 5 0.77 to 0.96, P ¼ .009), but not in stage II (HR ¼ 0.95, 95% CI ¼ 0.81 to 1.12, P ¼ .0.57). We also agree that carefully considering the timing of postsurgical therapy is important in a study such as this. Our use of time-dependent indicators for adjuvant treatment modalities (as we described in the article) explicitly accounts for this potential source of bias and evaluates the delayed component only among patients who have survived an equal length of time. A landmark analysis can also do this, but it ignores information about events prior to the landmark and changes in therapy thereafter. In conclusion, these findings confirm our original observation of improved OS associated with adjuvant RT, now including WLE vs other surgery in the multivariable analyses. R E S P O N S E

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Bhatia, Shailender, Storer, Barry E., Nghiem, Paul. Response, JNCI: Journal of the National Cancer Institute, 2017, DOI: 10.1093/jnci/djx053