The surgical approach for PDAC mainly depends on the anatomical location of the tumor. Although the surgical resection rate and surgical safety of PDAC have been significantly improved, and the incidence of serious complications during perioperative period has been significantly reduced in the past 30 years, the main goal still remains the same: removal of all lesions visible to the naked eye and microscopically within the pancreas and drainage of the lymph nodes, known as marginal negative or R0 resection14. However, even after R0 resection, the prognosis of PDAC is not significantly improved, and the treatment of PDAC remains extremely challenging9. In this study, patients with non-metastatic PDAC who received surgery alone had the worst prognosis. The main reason for this poor prognosis is local recurrence or distant metastasis of PDAC after surgery, which is a key factor affecting the long-term survival of patients. This showed that only surgical treatment of PDAC is far from enough, and we need to combine systematic adjuvant therapy. Therefore, the application value of neoadjuvant radiotherapy in PDAC has gradually become a hot topic, but there is still a big controversy.
The focus of this study was to determine whether neoadjuvant radiotherapy had a better effect on OS than postoperative radiotherapy, but the existing evidence remains controversial. Currently, it is generally accepted that neoadjuvant radiotherapy is superior to adjuvant radiotherapy mainly related to tumor response and preservation of normal tissues, including the following points. (1). The goal of neoadjuvant radiotherapy is to reduce the stage of the tumor and, in combination with R0 resection, increase the chance of survival. With effective treatment, a percentage of potentially unresectable tumors may be reduced in staging in order to be surgically resectable. (2). Neoadjuvant radiotherapy is more effective on well-oxygenated cells that cannot be surgically removed. (3). In approximately 25% of patients, postoperative adjuvant radiotherapy may be affected due to delayed postoperative recovery. However, delayed postoperative recovery does not affect the implementation of neoadjuvant radiotherapy14. (4). The use of neoadjuvant radiotherapy may help identify PDAC patients at high risk of early metastasis.
Therefore, neoadjuvant radiotherapy is considered to be applicable to borderline resectable PDAC and locally advanced PDAC. Some studies demonstrated that neoadjuvant radiotherapy can improve the R0 resection rate and the prognosis of patients with borderline resectable PDAC. After neoadjuvant radiotherapy, the median rate of resection and R0 resection of PDAC patients can reach 68% and 89% respectively. For patients who received neoadjuvant therapy and underwent surgical resection, the median OS range was 15.6 to 35 months. Compared with the group without neoadjuvant radiotherapy, the difference in median OS was statistically significant15, 16.In this study, patients with non-metastatic PDAC were divided into T1-3N0M0, T1-3N + M0, T4N0M0, T4N + M0 according to TNM stages, and the effects of different treatment regimens including neoadjuvant radiotherapy on the prognosis were analyzed. The results proved that neoadjuvant radiotherapy improves OS for T1-4N + M0/T4N0M0 PDAC patients. Moreover, for T4 patients, the effect of neoadjuvant radiotherapy on OS was significantly better than that of adjuvant radiotherapy and surgery plus chemotherapy. Therefore, the necessity of neoadjuvant radiotherapy should be emphasized in clinical practice for PDAC patients with stage T4.
However, the survival of T1-3N0M0 patients couldn’t benefit from neoadjuvant radiotherapy according to the results of this study. Some scholars also questioned the use of neoadjuvant radiotherapy in early PDAC. Patients with resectable PDAC can initially be surgically removed, but neoadjuvant radiotherapy may delay the patient's surgical opportunity, making the lesions that could have been resected with R0 become unresectable or even distant metastases17. Especially in the process of neoadjuvant radiotherapy, if the patient has serious complications, such as biliary tract obstruction, this may aggravate the development of the disease, or even make the patient's physical condition worse, not suitable for surgical treatment. Another problem that must be considered is that, unlike surgery, the initiation of neoadjuvant radiotherapy requires definite pathological results. Given the anatomical location and structure of the tumor, biopsy is sometimes difficult to perform and may delay treatment. The specificity of endoscopic ultrasound-guided biopsy is 96 percent, but the sensitivity is only 85.92 percent and repeated examinations are required in 11 percent of cases18.
A prospective, randomized, controlled phase II trial in Germany comparing neoadjuvant chemoradiotherapy with surgical priority for resectable pancreatic cancer was prematurely discontinued after 73 patients were enrolled. The existing results showed that there was no significant difference in R0 removal rate and median overall survival time between the two groups19. A meta-analysis published in 2019 included 11 clinical studies involving 2666 patients from the university of Texas southwestern medical center, Montefiore medical center, erlangen university hospital, Germany, Tohoku university school of medicine, Japan, and others. The results showed that the R0 resection rate was improved in patients of resectable PDAC treated with neoadjuvant radiotherapy, but the overall survival time of the patients was not significantly increased20. Combined with the results of this study, the overall survival of surgery plus chemotherapy is significantly better than neoadjuvant radiotherapy and adjuvant radiotherapy, so it is recommended that patients with T1-3N0M0 should choose surgery plus chemotherapy as the priority.
A consensus has been reached on the mode of systemic therapy for PDAC under MDT21. For borderline resectable and locally advanced PDAC, neoadjuvant radiotherapy may transform patients who cannot be R0 resected or even inoperable into R0 resectable patients, thus extending survival time and benefiting the patients. In this study, a combination of neoadjuvant radiotherapy was recommended for patients with stage T4 PDAC. Whether neoadjuvant therapy can benefit patients with early resectable PDAC is still controversial. Our study suggested that T1-3N0M0 stage PDAC patients were preferred to receive surgery plus chemotherapy, while neoadjuvant radiotherapy was not recommended. In addition, T1-3N + M0 stage PDAC patients were preferentially recommended postoperative adjuvant radiotherapy. However, this study is only a retrospective analysis from a large database, and the results need to be further verified by prospective experiments. With the development of large clinical trials, high level of evidence-based medical evidence will continue to be presented, and the understanding of neoadjuvant radiotherapy for PDAC will be deepened, which may lead to a consensus on the existing controversies and treatment options in the future.
Previous studies had repeatedly shown that uninsured and underinsured PDAC patients have lower rates of surgery and survival22, 23. This study confirmed once again that uninsured PDAC patients have a worse prognosis. Numerous studies had shown that marital status affects survival of patients with a variety of cancers, including PDAC24. In this study, marital status was an independent predictor of prognosis in patients with PDAC, and those who were unmarried status had a worse prognosis. Non-modifiable prognosis risk factors of PDAC include increasing age25. This study also confirmed that age was an important factor affecting the prognosis of PDAC patients. The prognosis of patients with PDAC was relatively worse with age.
Patients with high tumor grade had poor prognosis in this study. This may be because higher-grade tumors are more aggressive, leading to early local and distant metastases26. Differences in embryonic development lead to significant differences in blood supply, cell composition, lymphatic and venous reflux, and innervation of the head and body/tail of the pancreas27. This difference may account for the difference in prognosis between pancreatic head and pancreatic body/tail cancers. Our study found that patients with pancreatic head cancer had a worse prognosis. Retrospective clinical studies suggested that adequate lymph node dissection can reduce lymph node metastasis in the surgical area, reduce the rate of postoperative recurrence, and bring survival benefits28. The International Study Group on Pancreatic Surgery (ISGPS) consensus recommended that the number of lymph nodes examined should be at least > 1529. The results of this study showed that patients with ≥ 15 regional nodes examined have a better prognosis.
Similar to other studies using the SEER database as a data source, our study has limitations and requires careful interpretation of the results. First, while the SEER data included information about surgery, radiation, and chemotherapy, the details of these treatments (such as surgical margins, radiation dose, chemotherapy regiments, and chemotherapy sequence) were not recorded in the database. Second, the SEER database lacks some key clinical information that may be important for prognosis, such as tumor markers (CA19-9), the relationships between tumor and important blood vessels, and so on.