PACE-C Trial Reveals Higher Urinary Toxicity with SBRT Compared to Conventional Radiotherapy in Prostate Cancer

The phase III PACE-C trial has revealed significant differences in urinary toxicity between stereotactic body radiotherapy (SBRT) and moderately hypofractionated radiotherapy (MHRT) in men with intermediate- and high-risk localized prostate cancer. The study, which enrolled 1,208 patients, found that while SBRT offers the convenience of a much shorter treatment schedule, it comes with a higher incidence of urinary side effects compared to conventional fractionation.

Study Design and Patient Population

PACE-C enrolled men with localized prostate cancer defined as stage T1c–T3a, Gleason score ≤4+4, and baseline PSA ≤30 ng/mL. Participants were randomly assigned in a 1:1 ratio to receive either SBRT (36.25 Gy in five fractions over one to two weeks) or MHRT (60 Gy in 20 fractions over four weeks). All patients received six to twelve months of androgen deprivation therapy as part of their treatment protocol.

Late toxicity was prospectively evaluated using both RTOG and CTCAE grading systems at multiple time points up to two years after treatment, specifically at 6, 9, 12, 18, and 24 months. The co-primary endpoints were the incidence of grade 2 or higher gastrointestinal and genitourinary toxicities at the two-year mark.

Genitourinary Toxicity Results

The trial demonstrated significantly higher urinary toxicity with SBRT compared to MHRT. Using RTOG criteria, grade 2+ genitourinary toxicity at 2 years was 9% for SBRT versus 3% for MHRT (p<0.0001). When assessed using CTCAE criteria, the rates were 13% versus 4% respectively (p<0.0001).

The cumulative 2-year incidence of urinary toxicity was particularly striking, reaching 24% (RTOG) and 32% (CTCAE) for SBRT compared to 10% and 13% for MHRT. These findings indicate that patients receiving SBRT experienced substantially more urinary complications over the two-year follow-up period.

Gastrointestinal Toxicity and Patient-Reported Outcomes

In contrast to urinary toxicity, gastrointestinal side effects remained similar between treatment groups. RTOG grade 2+ gastrointestinal toxicity at 2 years was 2% for both SBRT and MHRT (p=0.71), while CTCAE grade 2+ rates were 3% for both groups (p=0.67). The cumulative 2-year incidence was 8% (RTOG) and 13% (CTCAE) for SBRT versus 6% and 10% for MHRT.

Patient-reported outcomes using the EPIC-26 questionnaire revealed that minimally clinically important differences in urinary irritative/obstructive scores were more frequent with SBRT (46% versus 27%, p<0.0001). However, there were no meaningful differences in urinary incontinence (32% versus 25%, p=0.012) or bowel function (38% versus 32%, p=0.047).

Safety Profile

Importantly, severe toxicity remained low in both treatment arms, with grade ≥3 gastrointestinal and genitourinary toxicities occurring in less than 2% of patients in both groups. This finding suggests that while SBRT increases the risk of moderate urinary symptoms, it does not substantially increase the risk of severe complications.

Clinical Implications

The PACE-C results provide important evidence on the trade-offs between SBRT and MHRT in managing intermediate- and high-risk prostate cancer. While SBRT offers significant advantages in terms of treatment convenience and resource efficiency, patients and clinicians must weigh these benefits against the potential for increased urinary morbidity.

The findings suggest that SBRT can be delivered safely in this higher-risk population, but it is not without drawbacks, particularly regarding urinary side effects. The results are limited to late toxicity outcomes at two years, and longer-term follow-up will be critical to assess whether SBRT remains non-inferior in terms of both toxicity and oncologic outcomes such as disease control and survival.