The use of external beam radiation therapy (EBRT) in a fractionated manner provides a therapeutic advantage over the single large IORT dose. That advantage is well explained by the “4Rs” of classical radiobiology (normal tissue repair, tumor re-oxygenation, tumor redistribution, and normal tissue repopulation). The large doses per fraction in case of IORT may result in an increased risk of late effects probably due to small blood vessel injury (4), so careful planning and administration of IORT should be applied for limiting the radiation dose to non-target tissues by its exclusion from the radiation field whether by direct inspection, mobilization or shielding (10).
By reviewing our data, it is appeared that the intent of treatment is almost curative in most of cases. The majority,102 (54.2%) patients had GIT cancers (49(26%) had gastric/esophageal, 35 (18.6%) had colorectal, 9(4.8%) had gall bladder/cholangiocarcinoma and 9(4.8%) had pancreatic cancer). Major surgery with curative intent was performed in nearly all patients (except for two patients; 1 gastric/ esophageal and 1 colorectal).
The philosophy of using IORT in rectal cancer is to improve tumor local control, especially in patients with locally advanced disease (those with T4b disease) where pelvic recurrence are high. Multiple studies have addressed the value of using IORT in rectal cancer management (11–15). A recent meta-analysis extensively reviewed IORT studies in rectal cancer with a positive interpretation of the results (16), however, the only randomized trial done failed to show an advantage for IORT use in this trial 142 patients diagnosed with rectal cancer were included and randomly assigned into 2 groups after receiving preoperative EBRT(40Gy) (one group underwent surgery alone, the other one received IORT 18 Gy at the time of surgery). No difference between the 2 groups regarding the 5 years local control rate as it was 91.8% in IORT group vs 92.8% in surgery alone group (p=0.6018) (17).
Thirty five colorectal cancer cases were included in this study (22 patients with primary while 13 with recurrent disease). Majority of them (97%) underwent major surgery with curative treatment intent (7 patients required multiple IORT fields). HIPEC was performed in 21 (57%) patients (11 primary and 10 recurrences). Four patients performed multiple surgeries with repeated HIPEC. Regarding postoperative complications grades,19 (54.2%) patients developed grade II, while 10 (28.5%) patients developed grade IIIa requiring intervention with local anesthesia, 4 (11.4%)patients developed grade IIIb (3 patients had bowel leakage required exploration and one patient developed wound infection required debridement). No reported grade IV B or V complications. Most of these complications could be attributed to the complexity of the surgical procedures and/or HIPEC. These complex cytoreductive surgeries with HIPEC were performed in a high percentage of cases (57%) (47% of them had presented with recurrent disease with repeated surgeries and re HIPEC). This was reported previously in a randomized trial conducted by Vic J. Verwaal et al in which they reported that most of the complications from the complex surgical procedures done and HIPEC were related to bowel leakage (18) .
EBRT has an established role for years in the postoperative management of gastric cancer patients with significant improvement of local control rate, disease-free survival (DFS), and overall survival (OS) in comparison to surgery alone (19, 20). Multiple studies support using IORT as a treatment option in gastric cancer resulting in a decrease loco-regional recurrence without an increase in complications incidence, however it does not appear to have an impact on overall survival (21-25).
Forty nine (26%) patients having gastro esophageal cancer were included in our study, Majority of them (97.9%) underwent major surgery with curative treatment intent. Forty patients underwent HIPEC. Regarding postoperative complications, grades 65% developed grade II complications with reported 4 patients died post-operatively (All these patients were more than 70 years). This might raise the question again about the safety of HIPEC in combination with cytoreductive surgery in these old people, actually this question was addressed in many studies; Spiliotis et al (26) and Arslan et al. (27) who concluded a higher incidence of postoperative mortality (12.9%) in those elderly people versus (7.2%) in younger patients.
IORT has been used as a part of multi-modality treatment approach in patients with soft-tissue sarcoma, especially retroperitoneal site, taking advantage of higher radiation dose to the target volume with lower dose to surrounding healthy tissues with encouraging local control rate and survival (28-32). Sarcomas beside gastro-esophageal cancer are the most treated tumors in 49(27%) patients (57.1% of them had recurrent disease) ,30/49(61.2%) patients had retroperitioneal site, The intent of the treatment was almost curative with radical resection in majority (98%) of patients. HIPEC was performed in 23 patients (47%) with proved peritoneal sarcomatosis. Regarding IORT technical aspects, 23 patients (47%) required 10 cm applicator diameters that could be related to the large tumor extension and large post-resection tumor bed. Moreover, 9 patients required complex irradiation with multiple fields by high energy electrons up to 12Mev and doses up to 15 Gy in 20 cases (40.8%). The 30 days postoperative complications grades were as follow; 30 (66.6%) patients developed grade II and 18 (36.7%) patients developed grade III complications or more.
The role of cytoreductive surgery (with removal of all macroscopic visible diseases) in advanced primary epithelial ovarian cancer (EOC) has been established with significant improvement of both DFS and OS (33-35), however its value in relapsed epithelial ovarian cancer remains controversial and is not considered as a standard of care because this approach has not been demonstrated in prospective trials. In a retrospective analysis, surgery at first relapse appears to be associated with a survival benefit only when a complete tumor resection can be obtained (36,37). IORT use in gynecological malignancies has been investigated in many series, especially in recurrent disease with better loco regional control rate compared to surgery alone without significant increase in toxicity apart from neuropathy which was more frequent in IORT dose > 20 Gy (38). The largest series evaluating HIPEC for recurrent EOC included 246 patients (184 with platinum-sensitive recurrent EOC), 92% of whom underwent optimal cytoreductive surgery. HIPEC treatment resulted in a median overall survival (OS) of 49 months; 52 months for platinum-sensitive patients. There was a 12% incidence of serious (grade 3/4) complications, including leukopenia (3%), intra-abdominal hemorrhage (2%), and postoperative complications (5%), including one postoperative death due to an anastomotic leak resulting in peritonitis and acute renal failure (39).
Gynecological malignancy was reported in 16 patients in our study (10 patients had ovarian cancer and 6 patients had uterine sarcoma). Nine (56.2%) patients had recurrent disease, All patients had major surgery with curative intent. HIPEC performed in most of the cases (93.7%), with multiple field IORT in two cases. The majority (56%) of cases developed grade II complications post-operatively, with 4 (25%) developed grade IIIb complication requiring intervention under general anesthesia.
Pancreatic cancer is one of the most aggressive malignancies with poor outcome, 5 years OS is less than 5%. The resectability rate is only 20–40% with a maximum 5-year survival of 30% in those patients with R0 resection. The need of IORT use in pancreatic cancer may come from the higher incidence of local recurrence (rate is nearly 50% in 5 years) despite the use of preoperative or postoperative EBRT. IORT could be an interesting therapeutic option for this disease for the purpose of dose intensification to the tumor /tumor bed for better local tumor control, especially in locally advanced cases. The benefits of using IORT in selected pancreatic cancers were widely reported in some trials with significant improvement of both local control and survival (40-42).
Pancreatic cancer was reported in 9 patients in our study. All patients had major surgery with curative intent. HIPEC was performed in 3(33%) patients with possible carcinomatosis. Multiple IORT fields applied only in one case. Regarding the technical character of IORT, it was found that most of the patients required a larger applicator diameter (≥ 7.5 cm), probably due to the large surgical field with high incidence of lymph node metastasis. Two thirds of cases developed grade II complications, with only 2 (22.2%) developed grade IIIb complications (bowel leakage) requiring intervention under general anesthesia.
The main limitations of our study are: 1. Relatively small sample size given the high number of cancer types (low number of subjects per cancer type or per group). 2. Retrospective design. 3. Inability to generalize the results to different populations. 4. Potential selection bias due to recruitment of patients from only one center.