Abstract
Background/Aim: The safety of carbon-ion radiotherapy (CIRT) for patients with prostate cancer after rectal cancer surgery remains unknown. This is a retrospective analysis of the safety of CIRT in patients with prostate cancer after rectal cancer surgery. Patients and Methods: The subjects were 13 consecutive patients with prostate cancer who underwent CIRT after rectal cancer surgery at the Kanagawa Cancer Center from December 2015 to April 2022. A total dose of 51.6 Gy (relative biological effectiveness) was administered in 12 fractions over 3 weeks. The criteria stated in the Common Terminology Criteria for Adverse Events, version 5.0, were used to assess toxicity. Fisher’s exact test was performed to assess the associations between patient clinical factors and rectal toxicity. Results: The median patient age was 71 years (range=66-83 years). The median observation period was 27.4 months (range=10.6-82.4 months). The median duration from rectal surgery to CIRT was 6.9 years (1.0-16.8 years). Five (38.5%) and six (46.2%) patients had a planning target volume (PTV)-adjacent rectal anastomosis and diabetes mellitus, respectively, and two (15.4%) patients had both. Grades 1 and 2 late gastrointestinal toxicities were observed in one case each. Development of gastrointestinal toxicity was significantly associated with both a PTV adjacent rectal anastomosis and diabetes mellitus (p=0.013). Conclusion: Late gastrointestinal toxicity was tolerable in patients with prostate cancer treated with CIRT after rectal cancer surgery. Patients with both a PTV adjacent rectal anastomosis and diabetes mellitus were more likely to experience late gastrointestinal toxicity.
Prostate cancer ranks second globally in morbidity and fifth in mortality in men (1). The definitive treatments for prostate cancer are surgery or radiation therapy (RT) (2). Colorectal cancer accounts for approximately 10% of all cancers diagnosed and cancer-related deaths worldwide (1). It is the third most common cancer in men, with 25% lower incidence and mortality rates in women than in men (3). Surgery is the standard treatment for resectable colorectal cancer and has been shown to improve survival (4). With this background, we have often experienced some cases of prostate cancer after surgery for rectal cancer. Previous surgery for rectal cancer makes surgery for prostate cancer difficult because of fibrosis in the pelvic region. Therefore, RT may be a useful option for prostate cancer after rectal cancer surgery. However, the rectal toxicity, including rectal bleeding and anastomotic leakage, of RT for patients with prostate cancer after rectal cancer surgery is unknown. Several studies have demonstrated that a history of abdominal or pelvic surgery was significantly associated with rectal bleeding (5-7). In these previous studies, three-dimensional conformal RT (3DCRT) was administered for RT and the rectal toxicity was found to be dose-dependent.
Carbon-ion RT (CIRT) has physical and biological advantages over conventional X-rays. Physically, CIRT delivers better dose distribution to the target volume than X-rays due to Bragg peaks and sharp penumbra (8, 9). Moreover, the relative biological effectiveness (RBE) is approximately three times higher for CIRT than for X-rays (10). Several studies have reported promising clinical results with CIRT for prostate cancer, and the sharp dose distribution of CIRT minimized rectal toxicity (11-14). Thus, it is expected that CIRT can reduce rectal toxicity in patients with prostate cancer after rectal cancer surgery. However, there have been no reports of CIRT for prostate cancer after rectal cancer surgery, and its safety is unknown. We retrospectively investigated the toxicity and safety of CIRT in patients with prostate cancer after rectal cancer surgery.
Patients and Methods
Patients. The subjects were patients with prostate cancer and a history of surgery for rectal cancer who initiated CIRT at our center between December 2015 and April 2022. The eligibility criteria were as follows: (i) histopathologically diagnosed prostate cancer, (ii) cT1bN0M0 to cT4 (excluding rectal invasion) N0M0 according to the 7th UICC classification, (iii) performance status of 0-2, (iv) age >20 years, and (v) a history of surgery for rectal cancer prior to CIRT. Clinical data were collected in February 2023. Written informed consent was obtained from all patients. The hospital institutional review board approved this study (approval number: 2022-153).
CIRT. The details of CIRT are described in our previous study (13). The gross tumor volume was not delineated. The clinical target volume (CTV) included the entire prostate and proximal seminal vesicle; in case T3b, the entire ipsilateral seminal vesicle was included in the CTV. Planning target volume (PTV)1 was created by adding 10 mm anterior and lateral to the CTV and 5 mm cephalad and posterior to the CTV; PTV2 was reduced from PTV1 as follows: the posterior edge of PTV2 was set in front of the anterior wall of the rectum. The total dose was 51.6 Gy (RBE) in 12 fractions: 34.4 Gy (RBE) in eight fractions for PTV1, and 17.2 Gy (RBE) in four fractions for PTV2. In addition, the irradiation method was modified to set a single PTV (mPTV) from January 2019. The mPTV was defined as PTV1 minus a structure enlarged 4 mm on each side and 1 mm cephaloventral to the rectum. The mPTV was irradiated with a total dose of 51.6 Gy (RBE) in 12 fractions. A PTV and an anastomosis were considered to be adjacent if the anastomosis of the rectum was seen on the same horizontal section of the PTV. All treatment plans were designed so that the PTVs were covered at 95% of the prescribed dose. The rectum was delineated as an organ at risk from 10 mm above the upper margin of the PTV to 10 mm below the lower margin of the PTV. The dose constraint for the rectum was set at the volume irradiated with 80% of the prescribed dose (V80) <10 cc. The anastomosis of the rectum was identified by postoperative anastomotic clipping. Scanning CIRT was performed in all cases.
A laxative and an antiflatulent were given to the patient before each session to empty the rectum as much as possible, and the patients were given an enema if they had not defecated within 24 h of treatment. The patients were asked to urinate and drink water 1 hour before CIRT.
Follow-up. After completion of CIRT, the patients were followed up by a radiation oncologist and a urologist every 3 months up to 3 years after the initiation of CIRT, every 6 months from 3 to 5 years, and every year thereafter. Prostate-specific antigen (PSA) was measured at each visit. The Phoenix definition (15) was used to define biochemical relapse, i.e., an increase ≥2 ng/ml from the nadir PSA was diagnosed as biochemical relapse. Imaging studies were considered when biochemical recurrence was observed. Clinical relapse was determined by consultation between a radiation oncologist and urologist. The Common Terminology Criteria for Adverse Events version 5.0 was used to assess toxicity, and toxicity within 3 months of CIRT initiation was considered to be acute, and if it occurred later, as late toxicity. The worst toxicity grade was judged as the final grade of toxicity. The period of observation and time to each event were calculated from the date of CIRT initiation.
Statistical analysis. The associations between patient clinical factors and toxicity were assessed by performing Fisher’s exact test. A p-value of <0.05 was considered to be significant. Statistical analysis was performed using STATA software (version 17.0, College Station, TX, USA).
Results
Patient characteristics. Table I summarizes the patient characteristics, and Figure 1 shows a representative dose distribution. Thirteen patients were included in this study. The median follow-up period was 27.4 months (range=10.5-82.4 months). The median age was 71 (range=66-83 years). According to the D’Amico classification, 0 (0%), 5 (38.5%), and 8 (61.5%) were in the low-, intermediate-, and high-risk groups, respectively. The median duration from rectal cancer surgery to the initiation of CIRT was 6.9 years (range=1.0-19.8 years). Eleven (84.6%) patients had anastomosis confirmed by computed tomography. In five (38.5%) patients, the anastomosis was adjacent to the PTV. Diabetes mellitus (DM) comorbidity was present in seven (46.2%) patients. Two (15.4%) patients had both anastomosis adjacent to the PTV and DM.
Survival and recurrence. During the observation period, there was one death, which occurred 67.6 months after the initiation of CIRT; it was caused by newly diagnosed esophageal gastric junction cancer after the CIRT was completed. During the observation period, one case of biochemical relapse occurred 37.1 months after CIRT initiation. This patient had pelvic and para-aortic lymph node metastases at 40.2 months after CIRT initiation. The patient was in the high-risk group with a Gleason score of 9, and he underwent rectal cancer surgery 5.4 years before CIRT, and its anastomosis was adjacent to the PTV.
Toxicity. Table II summarizes the toxicities. The only acute toxicity observed was Grade 1 genitourinary (GU) toxicity in four (30.8%) patients.
Late Grade 2 GU toxicity was observed in one (7.7%) patient. Late Grade 1 and 2 gastrointestinal (GI) toxicities were observed in one (7.7%) case each. Grade 1 and 2 GI toxicities were observed 18.4 and 6.8 months after CIRT initiation, respectively, and both were rectal hemorrhages. Anastomosis adjacent to the PTV was not associated with GI toxicity occurrence (p=0.128), and there was no association between DM and GI toxicity (p=0.192). The two patients with GI toxicity had both a PTV adjacent to the anastomosis and DM. The occurrence of GI toxicity was significantly associated with patients who had both an adjacent anastomosis and DM (p=0.013).
Discussion
In this study, the safety of CIRT in patients with prostate cancer and a history of previous rectal cancer surgery was investigated: 13 patients were analyzed, and Grade 1 and 2 late GI toxicities were observed in one patient each. The presence of both anastomosis adjacent to the PTV and DM was significantly associated with the occurrence of GI toxicity. To the best of our knowledge, this is the first report on the safety of CIRT for prostate cancer after rectal cancer surgery in the literature.
Several studies have investigated the association between the history of abdominal or pelvic surgery and late GI toxicity after RT for prostate cancer. Valdagni et al. investigated the association between the history of abdominal surgery and late GI toxicity after RT for prostate cancer and found that a history of appendectomy and/or cholecystectomy was significantly associated with Grade 3 late GI toxicity (5). That study suggested that cytokines elicited by surgery may modulate RT toxicity may explain the result. Defraene et al. similarly found that a history of abdominal surgery was a significant factor associated with late GI toxicity (6). They mentioned the possibility that a history of surgery prior to irradiation may reduce the ability of the rectum to repair itself. Fellin et al. also revealed that a history of pelvic and abdominal surgery was associated with Grade 3 rectal bleeding (7). In all three of these studies, 3DCRT was administered for RT. Recently, a study on the safety of intensity-modulated RT (IMRT) for prostate cancer after rectal cancer surgery showed that Grade 1 late GI toxicity occurred in 25% of 20 patients under observation, with no Grade ≥2 late GI toxicity (16). In our study, rectal bleeding after CIRT occurred in 15.4% of the patients. In contrast, the 3-year cumulative incidence of Grade ≥1 rectal bleeding was 6.1% in our previous study (13). Thus, a history of abdominal surgery or rectal cancer surgery may be a risk factor for late GI toxicity. However, no serious late GI toxicity was observed in this study; therefore, the toxicity of CIRT for prostate cancer after rectal cancer surgery was considered to be acceptable.
In a study on risk factors for rectal bleeding after CIRT, Ishikawa et al. showed that the use of anticoagulation therapy and rectal V50% were significant risk factors for the development of Grades 1-2 GI toxicity (17). In that study, DM and androgen-deprivation therapy were not associated with GI toxicity. In contrast, none of the patients in our study had a history of anticoagulant medication. In addition, due to the small number of cases, we did not examine the parameters of the dose-volume histogram. However, Akimoto et al. investigated the association between clinical factors and dosimetric parameters and Grade ≥2 GI toxicity in X-ray RT (18). In that study, univariate analysis showed that rectal dosimetric parameters were associated with GI toxicity in addition to the presence of DM, but in multivariate analysis, DM was the most statistically significant risk factor for the occurrence of GI toxicity. Maki et al. also investigated the association between IMRT for prostate cancer and late GI toxicity (19). That study concluded that strict rectal wall dose constraints should be considered in patients with DM. Although DM alone was not associated with late GI toxicity in our study as well, it may influence the occurrence of late GI toxicity.
There are several limitations in this study. This was a single-center retrospective study with an insufficient number of cases and a short observation period. In addition, this study did not set a dose constraint for the rectal anastomosis. Furthermore, the dosimetric parameter was not considered in this study because of the small number of late GI toxicity cases. Further analysis with a larger number of patients in a longer observation period is needed to establish the safety of CIRT for prostate cancer after rectal surgery.
Conclusion
We investigated the safety of CIRT for prostate cancer after rectal cancer surgery and concluded that the toxicity was acceptable. However, patients with both PTV adjacent to rectal anastomosis and DM may be more prone to late GI toxicity.
Footnotes
Authors’ Contributions
YT collected and analyzed the data and drafted the manuscript. H Katoh, DY, and TK analyzed the data and contributed to the final draft of the manuscript. H Koge, KK, and SS collected, and analyzed the clinical data. KT and NM aided in writing the manuscript and contributed to the final draft of the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
Hiroyuki Katoh and Daisaku Yoshida received research funding from Toshiba Energy Systems and Solutions Corporation (Kanagawa, Japan).
- Received March 17, 2023.
- Revision received March 27, 2023.
- Accepted March 28, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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