Acute and Late Rectal Toxicity Following Hypofractionated Radiotherapy in Patients With Prostate Cancer: Results of a Prospective Study

Abstract

Background/Aim: Previous randomized clinical trials have shown that moderate hypofractionation has a non-inferior or even superior efficacy to conventionally fractionated external beam radiation therapy (EBRT) in low and intermediate-risk prostate cancer. We herein aimed to evaluate the acute and late gastrointestinal (GI) toxicity of hypofractionated radiotherapy (HRT) in a real-world setting.

Patients and Methods: Patients with intermediate-risk prostate adenocarcinoma eligible to receive HRT were prospectively enrolled. All patients were submitted to rectoscopy after completion of HRT, every three months after radiotherapy for the first year and every six months for the second year. Toxicity events were classified as acute, when presenting during radiotherapy or within the first three months following its completion, and as late when appearing three months to three years post-HRT.

Results: Twenty prostate cancer patients participated in this study and received 22 sessions of HRT (5 sessions a week; 2.75 Gy per session) and an overall dose of 60.5 Gy. None of our patients developed acute GI toxicity; late GI toxicity (RTOG/EORTC grade 3 rectal bleeding) was observed in 1 patient only (1/20, 5%), at 6- and 12-months post-HRT. No rectal mucosa damage was observed on follow-up rectoscopy in the acute phase in any of our patients; five patients (5/20, 25%) developed late telangiectasias. Vienna retroscopy score (VRS) was 1 in 4/5 patients (80%) and 2 in 1/5 (20%).

Conclusion: Minimal radiation-induced rectal mucosal damage was observed in our patient population, and only as a late event, further attesting to the safety of HRT in this setting.

According to the latest epidemiological estimates, prostate cancer is the second commonest cancer type and the fifth leading cause of cancer-related deaths in men worldwide (1). Prognosis largely depends on disease stage at the time of diagnosis, with 10-year survival rates often exceeding 95% in organ-confined disease (2). External beam radiation therapy (EBRT) is a widely employed non-surgical treatment modality in localized prostate cancer, achieving largely comparable clinical outcomes to radical prostatectomy, particularly in low- and intermediate-risk patients (3,4). Although EBRT is sparing the patient from surgical risks, it nevertheless carries its own risk of radiation-induced injury to pelvic organs, such as the bowel or the urinary bladder, a condition known as pelvic radiation disease (PRD) (5,6).

Clinical symptoms and signs of PRD may vary significantly, depending on the time interval since the initiation of radiotherapy, the specific organ(s) involved, and the extent of tissue damage inflicted (7). Within the entire spectrum of PRD three distinct phases have been mainly recognized, i.e., the acute, chronic, and delayed (latent) phase. Acute toxicity may present either during radiotherapy or within the first three months following its completion, with symptoms of nausea, diarrhea, tenesmus, abdominal cramps, fecal urgency or bleeding, with the latter often resulting from radiation-induced telangiectasias (5-8). The chronic PRD phase may appear three months to three years post-radiotherapy, and is marked by severe bleeding, colon perforation, adhesions, fissures, or colon wall strictures, while the latent stage may arise years or decades later with an increased incidence of radiation–induced malignancies of any organ-at-risk (7-9).

New techniques of EBRT, such as hypofractionation, aiming to potentiate the efficacy of radiotherapy without significantly increasing PRD risk, have been recently developed and introduced in routine clinical practice. According to data derived from randomized clinical trials and observational studies, hypofractionation may have a non-inferior or even superior efficacy to conventionally fractionated external beam radiation therapy (EBRT) in low and intermediate-risk prostate cancer and a generally favorable safety profile, especially in the acute phase, but its potential negative effect on late toxicity remains controversial (10,11).

The primary objective of the present study was to prospectively evaluate the real-world toxicity of hypofractionated radiotherapy (HRT), both in the acute and the chronic phase, in patients with intermediate-risk localized prostate cancer.

Patients and Methods

Study design and inclusion criteria. The study protocol was approved by the institutional review boards of Attikon University Hospital (7708/5-5-2015) and “Sotiria” Athens General Hospital (1428/15-6-2015) and written informed consent was obtained by all participants prior to enrollment. Patients with histologically confirmed, clinically localized intermediate-risk prostate adenocarcinoma (T2b-T2c N0 tumors or Gleason score 7 or PSA: 10-20 ng/ml) scheduled to receive HRT were considered eligible for participation (12,13). Patients with a history of previous pelvic irradiation, prostatectomy, collagen vascular or inflammatory bowel disease, or with follow-up time less than 12 months were excluded from the study.

Radiation therapy, endoscopy and toxicity evaluation. Androgen deprivation therapy was initiated to all patients prior to administration of HRT. Radiation therapy was delivered using a 15 MV linear accelerator and a three-dimensional conformal technique. Each patient received a total radiation dose of 60.5 Gy in 22 fractions (2.75 Gy/day). Radiation-induced gastrointestinal (GI) side effects were scored according to the Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) (RTOG/EORTC) (14).

All patients were submitted to colonoscopy before the administration of HRT (for the evaluation of pre-treatment lesions); subsequently, rectoscopy was performed immediately after radiotherapy, every three months after radiotherapy completion for the first year and every six months for the second year. The endoscopy findings of rectal mucosal damage were graded according to Vienna rectoscopy score (VRS) (Table I) (15). Any toxicities observed within the initial 3-month period were classified as acute events, while those observed after this time period were classified as chronic.

Table I. Vienna rectoscopy score (15).

Results

Patient characteristics and baseline evaluations. Twenty prostate cancer patients, fulfilling the predetermined inclusion and exclusion criteria, were prospectively enrolled. Mean age was 69 years (range=56-78 years). Patient’s characteristics, including T stage at diagnosis, baseline (pretreatment) prostate specific antigen (PSA) values and Gleason score are summarized in Table II. Mean time of follow-up was 22.2 months (range=12-24 months); 17/20 (85%) were followed for the entire study period of 24 months, while 3 patients were lost to follow-up after the fourth post-HRT rectoscopy (12 months post-HRT).

Table II. Clinicopathological features of our patient population.

PSA: Prostate specific antigen.

All patients were submitted to colonoscopy before administration of HRT. The results were within normal limits in 10/20 patients (50%), whereas sigmoid colon diverticula were found in 5/20 (25%), sigmoid colon angiodysplasias in 1/20(5%), and rectal, sigmoid or ascending colon polyps were found in 4/20 patients (20%) (Table III).

Table III. Results of pre-treatment colonoscopy.

Grading of GI toxicity and scoring of rectal mucosal damage. None of our patients (0/20, 0%) developed symptoms of GI toxicity in the acute phase (during HRT and within the first 3 months following its completion). With regard to late toxicity, rectal bleeding (RTOG/EORTC grade 3) was observed in 1 patient only (1/20, 5%), at the time points of 6- and 12-months post-HRT, controlled in each occasion with a session of argon plasma coagulation (APC). All remaining patients were asymptomatic throughout the entire study period (Table IV).

Table IV. Description and grading of gastrointestinal toxicity events (RTOG/EORTC).

HRT: Hypofractionated radiotherapy.

According to the results of follow-up endoscopy, no acute mucosal damage was observed during rectoscopy in any of our patients (VRS: 0 in all patients). Rectoscopy of our single symptomatic patient showed telangiectasias at 6, 9, 12, 18, and 24months post-HRT (VRS grade 2, 1, 2, 1 and 1, respectively); grade 2 telangiectasias at 6and 12 months post-HRT were accompanied by rectal bleeding, controlled each time by APC (as described above). Four additional patients showed telangiectasias (VRS grade 1) at 12 months post-HRT, persisting at 18- and 24-months post-HRT. The remaining patients (15/20, 75%) showed no mucosal rectal damage on rectoscopy throughout the entire study period (Table V). Three of these patients (3/20, 15%) were lost to follow-up after the 12-month post-HRT time point.

Table V. Follow-up endoscopy findings.

HRT: Hypofractionated radiotherapy; VRS: Vienna rectoscopy score.

Discussion

In the present study, we aimed to prospectively document the acute and late GI toxicity of HRT in a real-world series of patients with localized intermediate-risk prostate cancer. For this purpose, we performed consecutive endoscopy evaluations at pre-determined time points, as well as a systematic recording and grading of GI side effects developed during the same period. Our results showed absence of adverse events in the acute phase and a highly tolerable late toxicity profile, limited to a single symptomatic case only. Most importantly, rectoscopy showed minimal rectal mucosal damage (telangiectasias) in a small subset of cases, and only as a late finding.

The low alpha/beta ratio for prostate cancer (1.5 Gy), compared to the respective ratio for the rectum (3-5 Gy for late and 10 Gy for acute toxicity), theoretically provides an adequate “safety window” for dose escalation with hypofractionation (16-20). Delivering increased fraction doses in fewer fractions carries the potential of augmenting the therapeutic efficacy of radiotherapy, while reducing not only the duration of treatment but also health care costs (20-23). However, concerns regarding the potential enhancement of long-term complications in the organs-at-risk do remain. According to a recent systematic review and meta-analysis (24), most –but not all– previous clinical trials have shown that moderate hypofractionation may be largely equivalent to conventional fractionation with regard to GI toxicity, while pooled analysis of their data showed a trend to increased GI toxicity associated with hypofractionation. The latter finding was attributed mostly to dose-escalation rather than the hypofractionation itself (24). In line with these findings, an earlier meta-analysis showed that dose-escalated HRT may increase late GI toxicity, when compared to conventional RT, whereas no dose-escalated HRT may actually lower the rate of late toxicity events (25).

Rectal toxicity, most commonly presenting with rectal bleeding, is a significant radiation-induced adverse event, with a major impact on morbidity and quality of life, and is frequently used as a toxicity endpoint in clinical trials evaluating radiotherapy outcomes in prostate cancer (26,27). The reported rates of rectal bleeding events –particularly RTOG/EORTC grade 2 or higher- among prostate cancer patients treated with HRT remain in the low range and intervention for bleeding control is only rarely required (27). In cases that fail to respond to non-invasive medical treatment (such as sucralfate), endoscopic therapy (mainly APC, as in our reported case) or even surgery may be employed, with the latter typically reserved for refractory bleeding or when life-threatening complications (e.g., obstruction, sepsis) develop (27,28).

Although PRD is far from rare, it clearly does not affect all patients receiving radiotherapy for pelvic malignancies (7). A variety of patient-related clinicopathological factors, including but not limited to diabetes mellitus, inflammatory bowel or collagen vascular diseases, or previous pelvic or abdominal surgery, have been found to predispose to the development of PRD, whereas treatment-related parameters, such as radiation dose, volume of healthy tissue irradiated, time-dose fractionation factors or timing of chemotherapy administration are among the main determinants of the severity of ultimate injury (5,7,29). Since our study was not powered to investigate the above risk factors for the development of PRD, patients with any of the above clinicopathological features were excluded from enrollment.

Some additional limitations of our work that need to be emphasized include the small sample size of our patient population and the lack of toxicity data beyond the 3-year time point, precluding the evaluation of delayed complications. However, significant strengths of our study are its prospective design, the homogeneity of patients’ characteristics and the inclusion of longitudinal endoscopy data in a routine clinical setting.

In conclusion, our results further attest to the safety and tolerability of HRT for treatment of localized, intermediate-risk prostate cancer. Rectal mucosal damage appeared only as a late event and in a minority of our cases and, with the exception of a single symptomatic case, was limited to asymptomatic telangiectasias. Additional larger-scale prospective observational data are undoubtedly needed to confirm these findings.

Conflicts of Interest

The Authors have no conflicts of interest to declare in relation to this study.

Authors’ Contributions

The Authors G.K., A.K., G.B. and G.P. conceived and designed the study; G.K. and A.K. collected the data; G.K., A.K., G.B, D.G. and N.S. analyzed the data; D.G., N.S. and A.K. drafted the paper; G.K., G.B., G.P. and I. K. revised the paper; All Authors approved the final article.