The present study firstly reported the clinical outcomes of 25 patients treated with CIRT for pelvic recurrence of rectal cancer in Chinese patients. With a median follow-up of 19.6 months, the 2-year LC rate and OS rate were 71.8% and 65.1%, respectively. CIRT achieved favorable LC and survival comparable to surgery. Otherwise, adverse events were self-limited during the treatment of CIRT, without any grade 4 or higher toxicity. The results are promising and suggest that CIRT is an optional therapy for patients with pelvic recurrence of rectal cancer.
In our study, for patients with pelvic recurrent rectal cancer the LC rates at 1 and 2 years were 90.4% and 71.8%. The OS rates at 1 and 2 years were 82.9% and 65.1%, respectively. Previous clinical results for locally recurrent rectal cancer (LRRC) treated by CIRT were reported by Heidelberg Ion Beam Therapy Center (HIT) in Germany and National Institutional of Radiological Sciences Hospital (NIRS) in Japan. In HIT’s study, 19 patients received carbon ion irradiation to treat LRRC. All patients had a history of surgery and pelvic radiotherapy of at least 50.4 Gy. The range of CIRT dose was 36-51Gy (RBE), 3 Gy (RBE) per fraction. With median follow-up of 8 months, local progression-free survival was 20.6 months . In NIRS’s study ,Shinoto et al. investigated the efficacy and safety of CIRT for LRRC. 224 patients were enrolled in the study and the prescribed dose was 70.4 or 73.6 Gy (RBE) in 16 fractions. The results showed that LC rates were 93% at 3 years and 88% at 5 years. OS rates were 73% at 3 years and 51% at 5 years. The prescribed dose of CIRT was relatively low and the follow-up duration was short in HIT’s study. Compared with the results of the previous two studies, as the first study in patients receiving CIRT for LRRC in China, our study yielded acceptable and encouraging results in the efficacy of CIRT in treating LRRC.
For LRRC, there are other radiation modalities except CIRT. Cai et al. evaluated the efficacy and safety of irinotecan and capecitabine with concurrent intensity-modulated radiation therapy (IMRT) for the treatment of recurrent rectal cancer without prior pelvic irradiation. Radiotherapy was delivered to the pelvis, and IMRT of 45 Gy (1.8 Gy per fraction), followed by a boost of 10 Gy to 16 Gy, was delivered to the recurrent sites. For medically fit patients without extra-pelvic metastases, they would be recommended to receive radical surgery. After chemoradiation, the LC rates at 1 and 3 years were 74.2% and 33.9%, the OS rates at 1 and 3 years were 80.1% and 36.5%, respectively . 2 patients experienced grade 4 leukopenia. No acute toxicity over grade 3 was reported. Sun et al. evaluated the efficacy and treatment-related toxicity of accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for LRRC. Surgery would be performed after radiation if the disease was resectable. 3-year LC and OS were 31.19% and 45.12% . Incidence of grade 3–4 diarrhea and granulocytopenia was 9.7% and 8.3%. Small bowel obstruction was severely late toxicity, and the incidence was 1.4%. Although the LC and OS rates in these two studies were acceptable, it should be noted that after IMRT and hyperfractionation re-irradiation, radical surgery would be performed if the lesion was evaluated as resectable. Defoe et al. evaluated the safety and efficacy of stereotactic body radiotherapy (SBRT) in LRRC patients with prior pelvic radiation. 11 patients were treated with 36 Gy in 3 fractions and 3 patients were treated with single fraction of 12, 16 or 18 Gy. 1y- and 2y- LC rates were 90.9% and 68.2% and the 1y- and 2y- OS rates were 90% and 78.8%, respectively. No acute toxicity over grade 3 was observed . Compared with conventional photon modalities, our results showed that CIRT was effective as a radical treatment modality for LRRC with or without prior pelvic radiation.
In our study, there was a significant correlation between dose and local control rates. Overall LC at 1- and 2-year using the Kaplan Meier method were 76.2% and 30.5% for patients whose prescribed tumor doses of CIRT < 66 Gy (RBE), 100% and 100% for patients whose prescribed doses of CIRT ≥ 66 Gy (RBE). Actually, among patients whose prescribed doses of CIRT ≥ 66 Gy (RBE), only one patient progressed after 31.2 months’ follow-up. In HIT’s study , the results showed that applied dose (36 Gy (RBE) vs. ≥36Gy (RBE), 20.2 vs. 15.2 months, respectively) were not predictive of local failure. In NIRS’s study , no correlation between prescribed dose and local control was noted. It should be noted that in HIT’s study, the applied does was relatively low and in NIRS’s study, the prescribed dose were almost the same. It was reasonable that in our results, patients received ≥ 66 Gy (RBE) had obviously better LC rates than those received < 66 Gy (RBE). It suggests that the currently applied dose of CIRT (≥ 66 Gy) in our center is feasible for patients with LRRC.
The toxicities of CIRT in treating LRRC were mild in our study. Systemic treatment before and after CIRT was suggested for LRRC patients. With less hematological toxicities caused by CIRT, more systemic treatment could be applied to decrease distant metastases, which might have benefits for LRRC patients in OS. Tumors that were close to gastrointestinal tract might cause gastrointestinal toxicity and pelvic infection in our study. Neuroinjury was reported mostly in high biological equralent dose (BED) radiation therapy such as SBRT and CIRT in Japan. One of the patients enrolled in our study suffered neuropathy 11 months after CIRT. By reviewing CT scan, we found that the injured nerve located by electromyography was in the high BED region during treatment, which reminded us that we should pay more attention to organs at risk which are usually safe in conventional radiotherapy.
There are some limitations in the present study, which need to be acknowledged. First, this is a retrospective study with a relatively short follow-up time. Longer follow-up on clinical outcomes is needed. Second, the sample size of this study is small. Larger and well-designed prospective studies are required to further evaluate the role of CIRT in treating LRRC. Third, systemic treatment before or after CIRT might affect OS of LRRC patients, which was not further analyzed in this study.
To sum up, the results of the present study suggest that CIRT is effective for LRRC and can provide LC and OS rates that are comparable to those of the prior studies of CIRT. The incidence of acute and late toxicities was also tolerable. CIRT should be considered as a safe, effective treatment option for LRRC and can provide an alternative to surgery.