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Anatomical classification alone is not sufficient for optimal patient selection for neoadjuvant therapy versus upfront resection

We thank Dr. Jonas and colleagues for their insightful comments and suggestions on our article.1 Based on the findings in our article, and the results of their network metaanalysis published recently,2 Dr. Jonas and colleagues hypothesized neoadjuvant therapy (NAT) would be beneficial for all nonmetastatic pancreatic cancer (PC) regardless of tumor extent, and proposed a further study to determine whether NAT can improve the longterm outcomes for patients with resectable PC (RPC) compared to the traditional upfront resection (UFR) approach. Although we agreed with their comments in terms of the need for a study to test the efficacy of NAT for RPC, we would like to pose some cautions for NAT approach for this group of patients. The indication of NAT for borderline resectable (BR)/ locally advanced unresectable (LAUR) PC is simple and straightforward because complete resection (R0) is technically challenging otherwise. In contrast, R0 resection would be most likely possible for RPC without NAT, and thus, the role of NAT for RPC needs to be considered in this separate context and its indication remains controversial. While identification of the patients who are unlikely to benefit from surgical resection is one of the purposes of NAT, can disease progression during NAT be a contraindication for resection for all RPCs? The tumor biology of PC is much more diverse than generally thought; Johns Hopkins group evaluated the autopsy of PC patients and demonstrated that nearly one third of patients did not have widespread systemic metastasis and died of destructive local growth of the tumor.3 This finding indicates the delay of surgery due to NAT can result in loss of opportunity for curative treatment rather than in reasonable selection for patients with PC of this type of biology, and the proportion of such patients is likely not so small that it should be ignored. To avoid nonbeneficial delay of definitive surgery, the patients should be designated appropriately to NAT or UPR according to the risk of treatment failure. Recently, we reported the outcomes of 431 patients with resectable and BR PC who underwent UFR,4 and showed that CA199 ≥500 can stratify the survival and risk of early recurrence regardless of anatomical resectability; RPC with high CA199 had significantly poorer overall survival than those with low CA199 (median survival time: 30 vs 16 months, P < .001), and 36% of the patients with RPC with high CA199 developed recurrence within 6 months after resection, compared to 18% of those with BRPC with low CA199 (P = .0231). Therefore, we concluded that CA199 can be a biomarker to help guide the selection of patients with RPC for NAT or UPR. The paradigm of “resectability” has evolved recently. A recent consensus statement described that new resectability criteria consisted of anatomical, biological, and conditional factors.5 In the era of multidisciplinary care with modern chemotherapy regimens, tailored management strategy is expected, and the type and the duration of chemotherapy and the sequence of treatment modalities should be optimized individually according to the expected operative outcomes and longterm prognosis.