With the advent of intensive regimens such as mFOLFIRINOX and GnP, the ORR has increased considerably compared with that using gemcitabine monotherapy. As a result, the prognosis of PC patients has improved significantly12,13. However, the increase in survival has been only a matter of months.
Surgery is the only treatment to cure PC but it has never been an optimal option for UPC. The clinical benefits of surgery for patients with unresectable disease are controversial6,14. Accompanied with a good response to treatment, some (including UPC) patients regain the opportunity to undergo surgery. Novel combination treatments bring hope to UPC patients and confidence to surgeons. Hence, research on the clinical benefit of CS for UPC has become a hot topic in recent years.
Preoperative systemic treatment can reduce the accuracy of imaging in the evaluation of resectability after treatment owing to treatment-related fibrosis15,16. Moreover, vessel involvement is observed in most UPC patients, and R0 resection is required for combined resection and reconstruction of relevant vessels17. Therefore, a lower accuracy of preoperative evaluation and a more invasive procedure may lead to a longer duration of procedure and greater blood loss. However, del Chiaro et al. demonstrated that an aggressive procedure did not result in higher postoperative mortality (2.9% vs. 2.6%, P = 0.9) or postoperative surgical complications (38.2% vs. 25.6%, P = 0.2) compared with that using a palliative procedure17. Rangelova et al. reported a prevalence of total surgical postoperative complications of 48% in patients who had CS, and 90-day mortality reached 6%18. The prevalence of severe complications and postoperative death was 24% and 2%, respectively, in our study, which was relatively low. DP and DP-CAR was undertaken in 49% of patients in our study. Until recently, development of DP-CAR significantly increased the CS rate for tumors of the body or tail of the pancreas that involved the CA. In high-volume centers, the overall prevalence of complications after DP-CAR has been reported to be 42.6%, and only 18.5% of patients developed complications of grade III or worse19. Therefore, DP-CAR is accepted widely to be a safe and feasible procedure for UPC patients with downstaging treatment20. In our study, 14% of MPC patients developed postoperative complications of grade III or worse, which was significantly lower than that for LAPC cases (26%). One of the most important reasons is that the local tumor in 86% of MPC patients was resectable or borderline-resectable. A pancreatic fistula was one of the most common postoperative complications, and a pancreatic fistula was observed in 13 cases, with one patient dying due to pancreatic fistula-related hemorrhage. Taken together, these data suggest that CS is safe for carefully selected UPC patients in high-volume centers.
Several reports have affirmed the survival benefit of CS for UPC patients6. In the present study, the long-term outcomes of UPC patients who underwent tumor resection after systemic treatment were encouraging. Median OS of 32.1 months and median PO-OS of 31.2 months were documented for UPC patients, which were similar to the outcomes for patients with resectable disease. Moreover, there was no significant difference in OS between LAPC patients and MPC patients who had CS (P = 0.28). Yanagimoto et al. reported similar results to our findings9.
Recently, some scholars have reported on resection of local pancreatic tumors with synchronous metastases. A review by Sakaguchi et al. focused on the usefulness of surgery in MPC patients. They looked at studies involving 428 patients who underwent resection for liver metastases, lung metastases and peritoneal dissemination. Median OS in patients with liver metastases was > 30 months21. Surgery for MPC remains controversial. Four criteria of CS for MPC patients are important: (i) a few metastases or occult metastases which were not diagnosed in the preoperative evaluation; (ii) no evidence of multiple-organ disease; (iii) a high probability of obtaining radical excision with an acceptable surgical risk; (iv) good physical status of the patient22. In the present study, for 14 MPC cases, PO-PFS was 7.10 months while OS did not reach, which implied that “super-responders” with metastastic disease could also be surgical candidates (Supplementary Fig. 3).
CS was carried out only for an extremely select group of patients who were super-responders to systemic treatment. An important indication for surgery in UPC patients is that radical excision of the tumor can be achieved. Imaging is the most widely used method to evaluate resectability, but the accuracy of imaging decreases markedly after systemic treatment. White et al. demonstrated that restaging unresectability based on CT findings deprived ~ 20% of patients the opportunity for curative resection22. Hence, patients without progressive disease who undergo aggressive systemic treatment should be considered as CS candidates. All patients in our study achieved a PR or SD and, finally, a high prevalence of a negative margin of 81% was achieved. Moreover, patients with a PR showed longer PO-OS than patients with SD in the univariate analysis. Our findings are similar to the results documented by Takano and colleagues: early tumor shrinkage during systemic treatment was the only independent prognostic factor for patients with unresectable LAPC who had CS23.
The clinical response must also be taken into consideration. Changes in tumor marker levels likely represent a tumor-specific response to systemic treatment. Tsai et al. found that patients with normal preoperative or postoperative CA19-9 levels experienced a doubling in OS compared with patients who did not have normal levels24. Similar results were reported by Truty and colleagues: patients with an increased CA19-9 level that was normalized after treatment experienced much longer recurrence-free survival (RFS; 32.8 months) and OS (72.1 months) than that of patients who had an increased CA19-9 level post-treatment (RFS = 11.2 months and OS = 38.4 months)25. PFS of patients with a normalized postoperative tumor marker was extended significantly compared with that of patients who did not have a normalized tumor marker level (11.0 vs. 6.13 months, P < 0.05) in our study.
The pathological response is the “gold standard” for assessing tumor degeneration/necrosis, and is a prognostic factor. Chatterjee et al. postulated that the major pathological response (CAP grade = 0–1) in tumor specimens was strongly correlated with longer survival in PC patients26. In our study, four patients achieved pathological complete remission (CAP grade = 0) and 10 patients had minimal residual tumors (CAP grade = 1). However, there was no significant difference in PO-PFS or PO-OS between patients who achieved a major pathological response and those who did not. Mataki et al. reported no significant differences in survival between patients with different pathological responses, which is similar to our findings27. A pCR is defined as the absence of any observable cancer cells on final pathology, but disease recurrence is observed28. Blair et al. reported a recurrence prevalence of 46.7% in patients with a pCR28. Among the four patients with a pCR in our study, one suffered tumor recurrence to the lungs. The recurrence prevalence of patients with a pCR was 25%.
Our study had three main limitations. First, there was a selection bias for patients. Second, the cohort size was small. Third, international consensus on CS for UPC is not available, so when and how to carry out a surgical procedure is controversial. CS may be the most effective way to lengthen survival in UPC patients, and systemic treatment is the best way to select surgical candidates at this stage. CS prevalence varies among regimens and treatment protocols, but GnP and mFFX are recommended. Several types of systemic treatment, including chemo-immunotherapy, have been applied recently, but the role of immunotherapy is not clear. The usefulness of adjuvant therapy in patients who have completed preoperative systemic treatment and radical excision is not clear.