Pancreatic cancer is one of the most common gastrointestinal malignant tumors, and characterized by insidious early onset, high-degree malignancy and poor prognosis. Although the pancreatic cancer is currently treated by multidisciplinary therapy, the long-term prognosis for patients remains poor. The distant metastasis rate of pancreatic cancer patients after radical R0 resection is as high as 76%[2]. Since pancreatic cancer cells are neurotropic and prone to distant metastasis in the early stage, it is difficult to achieve the real "radical resection", and 16%-85% of patients are still pathologically confirmed as R1 resection after radical resection[3]. Tumor residue is the major cause of postoperative recurrence and metastasis in pancreatic cancer, and microscopic residual infiltration is often found in posterior peritoneal vessels and peripheral nerves, which seriously affects the long-term survival of patients[4]. Hisbinuma et al. carried out an autopsy analysis on 24 patients who received radical pancreatectomy, among which 18 (75%) patients had local relapse after radical pancreatectomy[5]. Therefore, reducing the postoperative local residue of pancreatic cancer becomes crucial in improving patient prognosis. Due to the large number of protective organs around the pancreas, increased radiotherapy doses may cause serious complications in conventional EBRT. Therefore, for patients with resectable pancreatic cancer, there is an urgent need for a novel radiotherapy regimen that can deliver a high-dose radiation, kill residual tumor cells and do not increase gastrointestinal adverse reactions.
As early as 1905, Comas and Prio reported the feasibility of IORT in cancer treatment[6]. IORT is a safe and effective treatment technique that can be performed without additional increased risks of morbidity or death and can result in significantly improved local control rate[7]. With the progress of technology, IORT equipment has gradually become more secure, effective, and convenient. The INTRABEAM system, a low-energy X-ray mobile IORT system, was used as the IORT equipment in our hospital. The INTRABEAM system could generate 50Kv low-energy X-rays to eliminate tumor micro-residue during surgery. Radiation with high linear energy transfer may cause greater damage to cells[8]. Moreover, unlike electron beam radiotherapy, the use of low-energy X-rays does not have a build-up region for dose deposition. The dose drops to approximately 10% at a depth of less than 2 centimeters, with the highest surface dose in the irradiation field. This is in line with the concept of eliminating residual tumor in the tumor bed or pancreatic bed. During pancreatic cancer surgery, after the tumor is removed by the surgeon, the applicator is immediately placed in the tumor bed/pancreatic bed to ensure direct contact between the radiation beam and the target tissue. The radiotherapy is then performed for approximately 15–30 minutes to eliminate residual tumor cells[9]. In addition, Lee et al. found that IORT could inhibit the self-repair of pancreatic tumor cells, activate immune responses, and suppress the release of tumor-related cytokines, thus improving the local microenvironment[10]. In this study, among 28 patients in the C group, 3 (10.7%) patients developed gastrointestinal emptying syndrome, 9 (32.1%) patients developed myelosuppression, 10 (35.7%) patients developed vomiting, 12 (42%) patients developed abnormal liver function, and 5 (17.1%) patients developed pancreatic fistula; there were no Grade 3 or above adverse reactions, and no Grade C pancreatic fistula or Grade C impaired gastric emptying syndrome. All patients had good prognosis after conservative treatment. Statistical analysis showed no statistical difference in adverse reactions among all groups, indicating that IORT would not increase the probability of perioperative complications and was safe and feasible. Chen et al. conducted a retrospective analysis on the efficacy of IORT (10–20 Gy) on 247 patients with non-metastatic pancreatic cancer. The results showed that there was no significant correlation between IORT (10–20 Gy) and postoperative complications[11]. In this study, most patients received IORT doses of 15-25Gy, which may be the reason why there were no serious complications in patients with IORT. Currently, IORT is considered relatively safe within the range of 12-20Gy, and doses above 20Gy may increase the incidence of adverse reactions, especially the doses above 30Gy, which may significantly increase the necrosis rate of irradiated pancreatic tissue[12, 13]. These results indicate that IORT is safe on the premise of improving the efficacy in treatment of resectable pancreatic cancer. With the rapid development of IORT technology in recent years, the safety of IORT is expected to be further guaranteed.
In this study, Subgroup analysis showed that among the 28 patients in the C group, they had significantly better OS and PFS compared to other subgroups. Besides the effect of IORT, this analysis may also be related to the higher intensity of chemotherapy in Group C patients compared to other subgroups. In addition, both the 1-year OS and the 1-year PFS of surgery combined with postoperative chemotherapy were superior to those of the surgery alone group, indicating that patients could benefit from postoperative adjuvant chemotherapy. It is recommended that patients with good tolerance and physical conditions should be treated with multi-drug combination chemotherapy. The recommended chemotherapy should be carried out within 3 months after surgery, with a duration of more than 6 months[14].
In this study, surgery combined with adjuvant EBRT after chemotherapy did not improve survival prognosis. ESPAC-1 is a large trial comparing the efficacy of postoperative adjuvant chemoradiotherapy vs chemotherapy in treatment of pancreatic cancer. Results showed that the median OS (15.9 months vs 17.9 months) and the 5-year survival rate (10% vs 20%) of patients in the rchemoradiotherapy group were inferior to the non-chemoradiotherapy group[15]. Although some clinical studies showed the opposite results, demonstrating that adjuvant EBRT may improve the local control rate, the application of EBRT is still inconclusive after postoperative chemotherapy for treatment of pancreatic cancer. The reason may be that the chemotherapy regimens in most studies are not uniform, and different chemotherapy regimens may lead to different prognosis of patients. Since pancreatic cancer is prone to systemic metastasis in early postoperative period, and the peak of local relapse occurs after half a year, radiotherapy also needs effective support from systemic chemotherapy to exert its effects, making standardization difficult to achieve. Secondly, the different applications of radiotherapy technology, different radiotherapy doses and radiation ranges may have a significant effect on the prognosis of patients.
In addition, in the studies on IORT, it was not clear whether additional EBRT could improve the treatment outcome. As there were few patients in our hospital who received IORT combined with postoperative chemotherapy and then received supplementary EBRT, they was not included into the cohort study. Positive surgical margins or regional lymph node metastasis are closely associated with early metastasis or recurrence. Some argue that IORT can not adequately cover residual tumors due to the rapid attenuation of X-rays or electron rays, or irregular tumor areas[16]. However, some argue that these patients are able to accept supplementary EBRT since they have fewer complications, better physical conditions, and good prognosis, which may interfere with the results. Therefore, the current recommended treatment for resectable pancreatic cancer is surgery combined with IORT combined with postoperative chemotherapy. Further prospective studies are needed to determine whether to increase EBRT.
In conclusion, this study found that compared with other therapies in the treatment of resectable pancreatic cancer, the application of IORT significantly reduced the relapse rate and improved the survival prognosis of patients without increasing the incidence of gastrointestinal adverse reactions. Our study further confirmed the feasibility, efficacy and safety of IORT in the treatment of resectable pancreatic cancer, suggesting the great potential value of IORT in the field of pancreatic cancer resection treatment.