Original Research

Acute toxicities of moderately hypofractionated radiotherapy in the treatment of localised prostate cancer

Elsabi L. Roos, Krishantha Pillay, Sheynaz Bassa

Received: 02 Mar. 2025; Accepted: 20 Aug. 2025; Published: 16 Oct. 2025

Copyright: © 2025. The Authors. Licensee: AOSIS.
This work is licensed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/).

Abstract

Background: Moderately hypofractionated radiotherapy (MHRT) is the standard of care for localised prostate cancer. It is valuable in resource-constrained settings where prostate cancer is the most prevalent cancer in males.

Aim: This study aims to evaluate the incidence and severity of acute genitourinary toxicity (GUT) and gastrointestinal toxicity (GIT) in patients receiving moderately hypofractionated radiotherapy for localised prostate cancer.

Setting: This study was conducted at the Department of Radiation Oncology, Steve Biko Academic Hospital.

Methods: This study involves a retrospective review of 120 patients with localised prostate cancer treated using a 60 Gy in 20 fraction HRT regimen. Acute GU and GI toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) morbidity scale. The correlation between dose–volume histogram (DVH) constraints for the bladder and rectum and the severity of acute toxicity were analysed.

Results: Gastrointestinal toxicity was minimal, with only four cases during radiotherapy. Genitourinary toxicity was more prevalent, peaking at week 4 of treatment (n = 44, 37%), declining at week 6 (n = 21, 18%) and again at week 12 (n = 9, 8%). Bladder dose constraints were frequently exceeded, with V30 > 30 Gy in 36% (n = 43) and V60 > 60 Gy in 33% (n = 30) of cases. There was no statistically significant relationship between bladder dose parameters and the odds of grade 1 or 2 GU toxicity (p = 0.98, p = 0.70, p = 0.28 and p = 0.43, respectively).

Conclusion: Moderately hypofractionated radiotherapy can be effectively implemented in high-volume centres.

Contribution: This study validated the successful implementation of MHRT in a busy academic centre.

Keywords: prostate cancer; radiotherapy; moderate hypofractionation; bladder toxicity; bowel toxicity; acute radiotherapy toxicity.

Introduction

Prostate cancer is the most common malignancy among South African males.¹ Many patients present with advanced disease, and access to surgical treatment is often limited in state health care centres. Radiotherapy plays a critical role in the management of localised prostate cancer and is increasingly used for local treatment even in the setting of oligometastatic disease. The management approach of localised disease is based on the National Comprehensive Cancer Network (NCCN) risk grouping which is based on the primary tumour stage (T stage) baseline prostate-specific antigen (PSA) level, histological Grade Group score, PSA density and percentage positive cores.² This categorises localised disease into five distinct categories which guide both local and adjuvant systemic therapy decision-making.

External beam radiotherapy (EBRT) is a commonly prescribed local treatment targeting both the primary disease and pelvic nodes where clinically indicated. Conventionally fractionated radiotherapy with dose escalation was found to improve prostate cancer control rates and freedom from biochemical failure. However, it often requires at least 7 weeks of treatment, increasing radiotherapy waiting times.

Driven both by the radiobiological features of prostate cancer cells and the need to offer shorter treatment schedules to large numbers of patients, hypofractionated radiotherapy (HRT) using high dose per fraction delivered in fewer fractions became an area of increasing research, more especially in countries with state-driven health care systems.³

Hypofractionated radiotherapy is an attractive treatment option for prostate cancer because of its low α/β ratio, relative to surrounding organs at risk (OAR). This makes tumour cells more sensitive to higher doses per fraction while sparing surrounding critical structures.³ Several prospective randomised trials have demonstrated the non-inferiority of moderately hypofractionated radiotherapy compared to conventional fractionation in terms of local control, biochemical control and toxicity, without compromising the quality of life.^4,5,6

Successful implementation of hypofractionation requires strict bladder filling and rectal emptying protocols as well as image-guided radiotherapy (IGRT) to ensure accurate dose delivery while minimising exposure to OAR.⁷ Daily cone beam computed tomography (CBCT) is a key component of IGRT, allowing precise verification of planning target volume (PTV) coverage and OAR dose constraints. While the use of fiducial markers and rectal spacers can further enhance imaging accuracy and reduce OAR doses, these technologies are not widely available in resource-limited settings.⁸ Consequently, adherence to well-established dose–volume histogram (DVH) constraints remains a fundamental aspect of treatment planning.

Sinzabakira et al. analysed 17 prospective studies published between 2011 and 2022. These 17 included 10 Phase II trials and 7 Phase III randomised controlled trials, involving a total of 7796 patients.⁹ Among these, 10 studies directly compared HRT and standard fractionation radiotherapy (SFRT), while 7 were single-arm studies. Most patients were treated with intensity modulated radiotherapy (IMRT) or volumetric arc radiotherapy (VMAT), while a few received three-dimensional conformal radiotherapy (3DCRT). Toxicities were graded using Radiation Therapy Oncology Group (RTOG) and/or CTCAE systems, although only three studies included patient-reported outcomes. Their analysis revealed a modest, but statistically significant increase in acute ≥ Grade 2 gastrointestinal toxicity (GIT) in the HRT arm (risk difference +6.3%, p = 0.004), while no significant difference was observed in genitourinary toxicity (GUT) (risk difference +1.3%, p = 0.27). This supports the safe use of HRT in patients with localised prostate cancer.

In this study, we present the incidence of acute GUT and GIT in patients treated with moderately hypofractionated EBRT with daily CBCT image guidance at the Department of Radiation Oncology, Steve Biko Academic Hospital, between 01 January 2022 and 31 December 2023.

Methods

This was a retrospective analysis of 120 case files of patients treated for localised prostate cancer with a 60 Gy in 20 fractions moderately hypofractionated radiotherapy protocol between 01 June 2022 and 31 December 2023. Males over the age of 18 years with localised prostate cancer, no prior history or history of contraindication to radiotherapy and who consented to radiotherapy were included in the study. Because of local referral patterns, all patients included in this study had either intermediate or high-risk prostate cancer. All patients received radiotherapy to the prostate and seminal vesicles if clinically indicated. Postoperative cases, patients receiving conventionally fractionated radiotherapy or patients receiving pelvic nodal radiotherapy were excluded, as well as case files that lacked required clinical data.

All patients received a dose of 60 Gy in 20 fractions to the prostate PTV. The seminal vesicles were included in the clinical target volume (CTV) for all patients with high-risk disease or those with an estimated risk of involvement of >15% based on the Roach formula. All patients were scanned using a bladder filling and rectal emptying protocol. The prostate (± seminal vesicles) was contoured on axial CT images. Radiotherapy was delivered using a volumetric arc (VMAT) therapy with a maximum of 2 arcs per treatment. All treatments were planned to use the Elekta Monaco^® treatment planning system. The PTV included the CTV with an anterior and lateral margin of 7 mm and a posterior margin of 5 mm. The OAR dose constraints were derived from the French Genitourinary Group (GETUG) recommendations.¹⁰ The target constraints for rectum were V57 ≤ 15% and V30 ≤ 50%. The bladder constraints included the following: V60 ≤ 5%, V50 ≤ 30%, V40 ≤ 50% and V30 ≤ 50%. These constraints correlate with the risk of Grade ≥ 2 late GIT and GUT, as there are no defined criteria for acute toxicity. Treatment was delivered using an Elekta Versa HD® Linear Accelerator using 10 MV photons. Quality assurance included daily CBCT images to ensure adequate bladder filling (at least 2/3rd full) and rectal emptying (anterior–posterior distension < 4 cm). The CBCT image was compared to the planning image using soft tissue reconstruction settings. A deviation of PTV < 3 mm was considered acceptable at the time of treatment. Cone beam computed tomography images were taken daily with an actionable threshold of > 3 mm. Images were reviewed offline and approved by the treating oncologist.

Acute toxicity was assessed at several time points: weekly during treatment, and post-treatment at week 6 and week 12. Bladder and bowel toxicities were evaluated using the RTOG Acute Radiation Scoring Criteria (Grades 0–4). Patients were reviewed weekly during radiotherapy and at 6- and 12-weeks following treatment completion.¹¹

Toxicity grading was defined as follows:

• Grade 0: No documented side effects.
• Grade 1: Toxicity documented without need for therapeutic intervention
• Grade 2: Toxicity requiring medical intervention (e.g., prescription of symptomatic medication).
• Grade 3: Toxicity leading to interruption of radiotherapy.
• Grade 4: Severe toxicity requiring inpatient admission for management.

We also documented the clinical characteristics of the patients (age, performance status and presence of co-morbid disease) and the disease characteristics. Disease was staged as per the tumour, node, metastasis (TNM) staging system, and patients were risk-stratified as per the NCCN risk grouping system.

All patients with unfavourable and high-risk disease received androgen deprivation therapy (ADT) as per institutional protocol.

Statistical analysis

Data were collected through a Redcap® generated data collection sheet. Data were extracted in Excel format and analysed using Stata® Basic edition version 18.

Descriptive statistics were used to report clinical characteristics. The highest grade of GIT and GUT reported from the start of radiotherapy up to 12 weeks post completion of radiotherapy for each subject was graded according to the 4-point RTOG scale (Grade 0–4). The frequency of Grade ≤ 2 and ≥ 3 GUT and GIT toxicities was assessed at each time point, and toxicity was grouped as a categorical variable. Volume of tissue receiving the prescribed dose D was expressed in percentages and grouped as continuous variable. Logistic regression was used to determine the correlation between the volume receiving the prescribed dose and the severity of GIT or GUT toxicity. A p-value of < 0.05 was deemed significant.

Ethical considerations

This study was approved by the University of Pretoria’s Ethics Review Committee (Protocol number (724/2023). A waiver for informed consent was obtained from the Ethics Review Committee based on the retrospective nature of the study.

Results

The final analysis included data from 120 treated patients. The mean age of participants was 67 years (range: 45–83 years, s.d.: 6.89).

Clinical and disease characteristics

Among the cohort, 29 patients (24%) had co-morbid diabetes mellitus, 95 patients (79%) had pre-existing hypertension and 5 patients (4%) had other, unspecified co-morbid conditions.

Most patients presented with clinically staged T2c disease (n = 86, 72%), followed by T2b disease (n = 17, 14%) depicted in Figure 1. The mean baseline PSA at first consultation was 47.4 ng/mL (range: 0.6 ng/mL – 38.5 ng/mL, s.d.: 55 ng/mL). On average, 5% of biopsy cores were involved (range: 2% – 100%, s.d.: 26.8%).

FIGURE 1: Pie graph demonstrating T stage as per AJCC TNM staging system.

Most patients were diagnosed with Grade Group 2 prostate cancer (33%), followed by Grade Group 1 disease (31%), corresponding to Gleason scores of 3 + 4 and 3 + 3, respectively.

Based on the NCCN risk stratification, nearly two-thirds of the cohort (n = 80) were classified as high risk. The remaining patients were evenly distributed between unfavourable intermediate risk and very high-risk categories, each comprising 14% (N = 17) of the population (Figure 2).

FIGURE 2: Risk grouping based on the National Comprehensive Cancer Network (NCCN) classification system.

None of the patients had received prior local therapy. The mean referral time from biopsy to the first consultation was 531 days (range: 155 to 3845 days, s.d.: 573).

A total of 118 patients (98%) received ADT. Among these, 88 patients (73%) initiated ADT before referral with a mean duration of 258 days (range: 2–3293 days, s.d.: 405), and 30 patients (25%) started ADT within a mean of 63 days from the first consultation (range: 0–1141 days, s.d.: 215).

Baseline PSA values at diagnosis ranged from 0.6 ng/mL to 385 ng/mL, with a mean of 47.4 ng/mL. The baseline International Prostate Symptom Score (IPSS) of the cohort is depicted in Figure 3.

FIGURE 3: Distribution of baseline International Prostate Symptom Score for treated cohort.

FIGURE 4: Adherence to protocol organs at risk constraints for rectum and bladder where V represents the volume of organ in percentage and dose D represents the dose limit.

Radiotherapy treatment characteristics

All patients received 60 Gy in 20 fractions to the prostate with the seminal vesicles included based on the Roach score. The mean duration of treatment was 22 days (range 18–34 days, s.d. 2.6).

The mean PTV equalled 111 cm³ with a range of 57 cm³ – 190 cm³, s.d. 33. The dose–volume constraints for the rectum and bladder are summarised in Table 1.

Rectum constraints were most often met with only 1 (1%) case exceeding the V57 Gy. Bladder constraints were most often not met with 76 (63%) cases exceeding the V30 Gy, 41 (34%) cases exceeding the V40 Gy and 74 (62%) cases exceeding the V60 Gy as depicted in Figure 1.

Based on Pearson’s correlation model, rectum V30 was the only DVH characteristic to show a moderate positive correlation with PTV volume (r = 0.3785, p < 0.001). All other DVH criteria demonstrated weak positive correlations.

Gastrointestinal toxicity side effects

Gastrointestinal toxicity side effects were uncommon, with only 4 (3%) documented cases of Grade 1 toxicity during weeks 1 and 4 of treatment. No side effects were reported at weeks 6 and 12 post-treatment as depicted in Figure 5.

FIGURE 5: Incidence and severity of acute gastrointestinal toxicity at week 1, 4, 6 and 12 from the start of radiotherapy.

Genitourinary toxicity side effects

Genitourinary toxicity side effects were more frequent, peaking at week 4 of treatment (n = 44, 37%). The frequency of Grade 1 side effects decreased by 50% at week 6 (n = 21, 18%) and further improved by week 12 (n = 9, 8%) (Figure 6).

FIGURE 6: Incidence and severity of acute genitourinary toxicity at week 1, 4, 6 and 12 from the start of radiotherapy.

The logistic regression model did not identify a statistically significant relationship between bladder dose parameters (V60, V50, V40, V30) and the odds of Grade 1 or 2 GUT (p = 0.98, p = 0.70, p = 0.28, and p = 0.43, respectively).

Follow-up prostate-specific antigen

The mean PSA at 6 weeks was 0.72 (95% confidence interval [CI]: 0.07–1.43) which was a clinically significant reduction from the baseline PSA (p = 0.000).

Discussion

In this retrospective review of 120 cases, acute toxicities associated with moderately hypofractionated radiotherapy were predominantly Grade 2 GUT side effects. These toxicities peaked during the final week of treatment and declined thereafter. The cohort primarily consisted of high-risk prostate cancer patients, reflecting referral patterns at our institution. Prostate volume did not appear to influence the severity of GIT or GUT.

The HYPRO trial reported 23% acute GUT and 13% GIT in a similar patient population.¹² At 3 months post-treatment, toxicity levels were comparable between the hypofractionated and conventionally fractionated groups. A key difference between our study and the HYPRO trial is the fractionation scheme; we used a prescribed dose of 3 Gy per fraction, compared with 3.4 Gy per fraction in the HYPRO trial.¹²

Several other pivotal studies including PROFIT, CHHiP and RTOG 0415 that have demonstrated the non-inferiority of moderately hypofractionated radiotherapy compared to conventional fractionated radiotherapy.^4,13,14 Notably, HYPRO had the highest proportion of high-risk patients (74%), with two-thirds receiving ADT.¹⁵ In contrast, the PROFIT and RTOG 0415 studies included only intermediate- and low-risk patients, respectively, and neither trial incorporated ADT into the treatment protocols.¹⁵ The rate of Grade ≥ 3 toxicity was ≤ 5% in both PROFIT and RTOG 0415 studies, whereas HYPRO reported a 41.3% incidence, which was not significantly different from the control arm.¹⁵

One limitation in our study was the lack of magnetic resonance imaging (MRI)-based target delineation because of limited accessibility. MRI has been shown to improve prostate target definition, whereas CT-based imaging tends to overestimate target volumes.¹⁶ The mean PTV in our series was 111 cm³.

Our findings align with other published studies that report a low incidence of predominantly Grade 2 acute toxicity.¹⁷ Specifically, they observed a 20% Grade ≤ 2 GIT and 6.9% incidence of GUT. To mitigate toxicity risks, our institutional protocol incorporates strict bladder filling and rectal emptying protocols, alongside daily CBCT image guidance to ensure accurate radiation delivery. We have also conducted further studies to determine if a reduction of CTV to PTV margin can maintain adequate PTV coverage while minimising dose to bladder and rectum.

A key limitation of this study is its retrospective nature, which relies on clinical case notes that may have led to underreporting of toxicity incidence and severity. Future prospective studies with systematic toxicity assessments are warranted to validate these findings.

Acknowledgements

The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.

E.L.R. contributed to the protocol design, approval, data collection and manuscript development. S.B. contributed to the secondary data analysis and manuscript editing. K.P. was a co-supervisor in the research project. All authors contributed to the article, discussed the results and approved the final version for submission and publication.

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

The data that support the findings of this study are not openly available because of privacy and/or ethical restrictions and are available from the corresponding author, E.L.R., upon reasonable request.

The views and opinions expressed in this article are those of the authors and are the product of professional research. It does not necessarily reflect the official policy or position of any affiliated institution, funder, agency or publisher. The authors are responsible for this article’s results, findings and content.

References