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Reply to F.C.M. Cananzi et al.

We thank Cananzi et al for their careful examination of and especially for their interest in the ARTIST (Adjuvant Chemoradiotherapy in Stomach Tumors) trial. Our updated analyses published in Journal of Clinical Oncology confirmed that, after a median follow-up of 7 years, the addition of chemoradiotherapy (XPRT) to adjuvant capecitabine/cisplatin (XP) chemotherapy did not significantly reduce the recurrence rate after curative D2 gastrectomy in patients with gastric cancer. In patients with gastric cancer who had undergone D2 lymph node dissection, a procedure already considered standard in Asian countries but lacking convincing evidence, two phase III trials demonstrated a prolongation of survival with adjuvant chemotherapy involving either S-1 monotherapy or a capecitabine/oxaliplatin combination. On the basis of the results altogether, currently, when a patient has undergone curative gastrectomy with D2 dissection, our recommendation is adjuvant chemotherapy, reserving adjuvant chemoradiotherapy for those who had undergone suboptimal surgery. However, one cannot completely rule out the possibility that certain subgroups of patients derive benefit from the addition of XPRT even if D2 surgery was performed. Our ARTIST trial was undoubtedly motivated by the assumption that adjuvant chemotherapy, with or without concurrent radiotherapy, provides a postgastrectomy survival benefit. Considering that much of the benefit of adjuvant chemoradiotherapy, or chemotherapy, was linked to the reduction in the occurrence of regional recurrence, which included peritoneal and hepatic metastases, it remains unclear whether the chemotherapy or radiotherapy component provided the main benefit. We found that locoregional recurrence developed less frequently in the XPRTarm (15 in XPRT v 29 in XP, P 5 .03). In a subgroup analysis, we also found that adjuvant XPRTmay be of benefit for patients with node-positive disease as well as high lymph node (N) ratio. This is one of the questions being addressed in our subsequent study, the multi-institutional ARTIST II trial (ClinicalTrials.gov identifier: NCT01761461), which compares adjuvant S-1 monotherapy with S-1/oxaliplatin (SOX) and SOX plus radiotherapy (SOXRT) in 900 patients with node-positive gastric cancer who had undergone D2 surgery. Another question raised by Cananzi et al was the prognostic value of N ratio. Although the therapeutic efficacy of D2 lymph node dissection has been questioned in randomized studies, adequate surgical resection with at least 15 lymph nodes examined is an important issue in gastric cancer. Lymph node assessment is affected by the extent of dissection as well as the technique used by surgeons and pathologists. In the ARTIST trial, 99% of patients had at least 15 lymph nodes removed. In patients with curatively resected gastric cancer, N ratio has been reported to have a prognostic role independent of the type of lymph node dissection. As stated, we used a dichotomous classification on the basis of the mean value of the ratio (ie, , 0.083 v $ 0.083), including node-negative patients into a heterogeneous low-ratio group also encompassing node-positive patients. As expected, a significant interaction was observed between the N ratio and the nodal status. In addition, we admit that this two-tier classification is limited in the selection of patients who are at high risk of recurrence. We analyzed the disease-free and overall survival of the patients by using the N ratio categories provided by Marchet et al and depicted the Kaplan-Meier curves in Figure 1. In patients with advanced lymph node involvement (ie, N ratio. 25%), the 5-year disease-free survival rates were 55% and 28% for the XPRT and XP arms, respectively (hazard ratio, 0.527; 95% CI, 0.307 to 0.904; P5 .020). More detailed evaluation of the prognostic value of N ratio for the ARTIST study population will be presented in another publication. As described in the ARTIST article, in patients with D2 resected gastric cancer, we believe that adjuvant chemotherapy should be considered as a standard of care. In an individualized approach for adjuvant treatment, only patients at risk for locoregional failure and recurrence should be considered as candidates