Conversion Therapy of Unresectable Pancreatic Cancer: A Retrospective Study of the Real World

Objective: A retrospective study of the real world was conducted to analyze whether patients with unresectable pancreatic cancer (URPC) can benet from conversion therapy, and to screen out pancreatic cancer patients who are suitable for conversion therapy. Patients and Methods: Inquired about patients with URPC who visited Zhejiang Provincial People's Hospital from January 2015 to April 2021. We selected 25 patients with URPC who underwent conversion therapy, and 19 patients with locally advanced pancreatic cancer (LAPC) who directly underwent surgery to conducted a retrospective analysis. Results: The median overall survival (OS) of 25 patients with URPC who received conversion therapy was 28 months (95%CI: 15.46-40.54 months), and the median progression-free survival (PFS) was 12 months (95%CI: 9.26-14.74 months). The curative resection (R0) rate was 84% (22/25). Conclusions: Conversion therapy improves the R0 rate of patients with URPC, and prolongs OS and PFS.


Introduction
Pancreatic ductal adenocarcinoma (PDAC) is one of the most highly malignant solid malignancies with the fourth fatality rate among all cancer types in the United States (1). It is estimated that pancreatic cancer will become the second leading cause of cancer-related deaths by 2030 in the United States (2).
Pancreatic cancer is the cancer with the highest mortality rate in China, the 5-year relative survival rate (7.2%) is lower than that of the United States (8.5%) (3,4).
Surgery is the only way to cure pancreatic cancer, only 10% -20% of patients with pancreatic cancer have the opportunity of surgical resection, unresectable pancreatic cancer (URPC) patients accounted for the majority of newly diagnosed patients (5). The prognosis of URPC is poor, the median overall survival (mOS) without special treatment is 3-11 months(6, 7). Palliative treatment is mainly used to improve quality of life for patients with pancreatic cancer who do not have the opportunity of surgical treatment initially. In recent years, with the development of chemotherapy, conversion therapy has been paid more and more attention. Clinicians have found that some patients with URPC have achieved a tumor-lowering phase during chemotherapy, which gives them the opportunity to have their tumors surgically removed.
Suker et al. found that FOLFIRINOX as a rst-line chemotherapy regimen can achieve the R0 rate of 22.5% and the mOS can be prolonged to 13.7-24.2 months in patients with LAPC(8). Schneitler et al. reported that 2 patients with liver metastasis of pancreatic cancer achieved complete remission after receiving FOLFIRINOX regimen chemotherapy, achieved R0 of the primary tumor, and obtained overall survival of 22 and 26 months, respectively (9). Conversion therapy has brought hope to patients with URPC, but it is still in the immature stage. Therefore, we conducted a retrospective study to analyze the e cacy and safety of URPC patients who have undergone conversion therapy, and explore new treatment options for patients with inoperable pancreatic cancer.

Patients And Methods
Patients 44 patients with URPC who were admitted to Zhejiang Provincial People's Hospital from January 1, 2015 to April 1, 2021 were retrospectively analyzed. Clinical staging of patients according to the American Joint Committee on Cancer (AJCC) guidelines (10). 25 patients with URPC underwent surgical resection after conversion therapy, and 19 patients with LAPC chose surgery at initial diagnosis. The de nition of URPC excludes metastatic disease, but also refers to tumors that invades superior mesenteric artery (SMA), portal vein (PV), celiac artery (CA) and common hepatic artery or their main branches (11). Here, URPC included LAPC. Statistical analysis OS was de ned as the time from the start of chemotherapy or surgery to death or the last follow-up. For the conversion therapy group, progression-free survival (PFS) referred to the time from the start of chemotherapy to the rst progression of the disease. For the surgery group, PFS referred to the time from surgery to the rst progression of the disease. OS and PFS were calculated using the Kaplan-Meier method, and the survival was compared using the log-rank test. Continuous variables are expressed in terms of mean with standard deviation and were compared using the independent Student's t test. All statistical analyses were performed using the SPSS version 25 (IBM, Chicago, IL, USA). A p value <0.05 (two-sided) was de ned as statistically signi cant.

Patient demographics
We reviewed the clinical data of 44 patients with URPC, of which 25 cancer patients received conversion therapy, and the remaining 19 patients chose direct surgery ( Figure 1). Of the 25 patients who received conversion therapy, 11 patients are still alive, 10 patients died, and 4 patients were lost to follow-up. Of the 19 patients who underwent surgical treatment, 4 patients are still alive, 9 patients died, and 5 patients were lost to follow-up.  (Figure 2). Our subjects included 9 patients with metastatic pancreatic cancer (mPC) with mOS of 29 months and mPFS of 12 months. The mOS and mPFS of 16 patients with LAPC were 23 months and 15 months respectively. The Kaplan-Meier survival curve showed that the survival time of patients with metastatic pancreatic cancer after conversion therapy is not necessarily shorter than that of patients with locally advanced pancreatic cancer ( Figure 4). The R0 rate of patients with LAPC is greater than that of patients with mPC (87.50% vs.77.78%).
The mOS of the 6 patients who chose FOLFIRINOX as the conversion treatment regimen was 14 months, and the mPFS was 7.5 months. The mOS of 14 patients who took gemcitabine as the basis of the conversion treatment plan was 23 months, and the mean PFS was 12 months. The OS and PFS of the gemcitabine-based chemotherapy regimen were slightly longer than those of the FOLFIRINOX regimen, but there is no signi cant statistical difference (p>0.05) ( Table 2).
We found that the OS and PFS of patients with pancreatic cancer whose preoperative serum carbohydrate antigen 19-9(CA19-9) level observably decreased from baseline or remained in the normal range were prolonged after conversion therapy (OS: 22.00 months vs. 13.09 months, p=0.008, PFS: 11.46 months vs. 8.41 months, p=0.033). The mean OS of patients with lymph node metastasis less than or equal to 2 was longer than that of patients with lymph node metastasis more than 2(OS: 20.47 months vs. 13.00 months, p=0.044). There were no signi cant differences in the effects of age, gender, T staging, and distant metastasis on the OS and PFS of conversion therapy. Discussion 25 patients received surgical treatment after conversion therapy and achieved a R0 rate of 84%, of which the R0 rate of patients with LAPC was 87.50%. The R0 rate of patients with surgery rst was 73.68%. The R0 rate in the patients with unresectable pancreatic cancer was improved to some extent by conversion therapy. Studies have reported that appropriate chemotherapy can increase the possibility of surgical resection of initial unresectable pancreatic cancer, which is bene cial to prognosis and long-term survival (17)(18)(19).
Currently, the main treatment for URPC is chemotherapy combined with or without radiotherapy. For patients with unresectable LAPC receiving chemotherapy and radiotherapy, the mOS was 11-15 months, and the mPFS was 10.4-12 months (20,21). For patients with mPC, with the application of FOLFIRINOX and gemcitabine plus albumin paclitaxel, the mOS was extended to 5 -11.1 months, and the mPFS was extended to 3.7-5.5 months (13,22,23). The prognosis and long-term survival of pancreatic cancer are still unsatisfactory. The subjects of this study were 25 patients with URPC who had no chance of surgical resection. The mOS was 28 months and the mPFS was 12 months. The survival time after conversion therapy is signi cantly longer than that of pancreatic cancer patients after traditional palliative care. After conversion therapy, the median OS and PFS of patients with mPC were not signi cantly different from those of patients with LAPC. We found that conversion therapy can signi cantly improve the OS and PFS of patients with mPC.
Whether surgical resection is an option for patients with LAPC has been discussed for a long time (24,25). In 2004, a multicenter randomized controlled study in Japan showed that the effect of surgery for LAPC was better than that of radiotherapy and chemotherapy(26). Surgery is also being tried for advanced pancreatic cancer. Shrikhande et al reported that the median survival time of patients with liver metastases from pancreatic cancer after R0/R1 resection was longer than without surgical resection (11.4 months vs. 5.9 months, p=0.0384) (27). With the advancement of surgical technology and the improvement of chemotherapy regimens, surgery has gradually become a treatment option for patients with URPC. 19 patients with LAPC chose to receive surgery rst, achieving an R0 rate of 73.68%, with mOS of 16.5 months and mPFS of 8 months. 25 patients with URPC underwent surgical resection after conversion therapy, and 9 of them had distant metastases. The Kaplan-Meier survival curve showed that conversion therapy prolonged the OS and PFS of patients with URPC compared with surgical treatment. One patient with liver metastases of pancreatic cancer achieved R1 resection, with an OS of 29 months and a PFS of 5 months. One patient with bone metastasis of pancreatic cancer only underwent resection of the primary lesion, with an OS of 35 months and a PFS of 4.5 months. Radical surgery for patients with metastatic pancreatic cancer may bene t the long-term survival of patients even if R0 resection cannot be achieved(28, 29). The preoperative CA19-9 level is an independent factor that affects the OS and PFS achieved by conversion therapy. The number of lymph node metastases is an independent factor that affects the OS.
It has been reported in the literature that low preoperative CA19-9 levels and fewer lymph node metastases are associated with a good prognosis after conversion therapy (19,30). We found that age, gender, T stage, and distant metastasis are not independent prognostic factors for conversion therapy.
This study has several limitations. First, this is a single-center retrospective study, the small sample size limits the credibility of the conclusions drawn. Second, the 25 patients involved in this study who received conversion therapy were not all assessed as resectable before surgery, and most of the patients' condition was relieved or remained stable. Third, there are individual differences in the response of patients to treatment. Fourth, there may be selection bias.

Conclusion
Conversion therapy may become an important role in the treatment of URPC in the future. Conversion therapy is currently not widely used clinically. Conversion therapy has the potential to bene t long-term survival and prognosis in URPC from limited clinical studies (18,19,30). Screening out patients with URPC suitable for conversion therapy is the key. The purpose of conversion therapy is not necessarily to transform unresectable tumors into resectable tumors. Even if R0 resection is not achieved, it can extend the survival time of the patients and improve the prognosis.

Declarations Funding
This study has no nancial support.

Con icts of interest
The authors declare that they have no con ict of interest.

Data sharing statement
No additional data are available.
Code availability Not applicable.

Authors' contributions
The authors acknowledge Liu Yang, Zhe-ling Chen and Peng-fei Zhu for their assistance with the preparation of the manuscript. Liu Yang and Zhe-ling Chen contributed to the conception of the study.
Peng-fei Zhu helped to collected the data.

Ethics approval
The study was based on the principles outlined in the Declaration of Helsinki. The protocol was approved by the ethics committee of the Zhejiang Provincial People's Hospital (2017KY007).

Consent to participate
All patients expressed their informed understanding of this study and agreed to participate in this study, and obtained their informed consent.

Consent for publication
All patients agree to publish their data in this paper. All authors read and approved the nal manuscript.