What is the significance of 55 Gy in 20 fractions (Gray (Gy) in fractions) radiation dose in the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial for prostate cancer treatment?

55 Gy in 20 Fractions in the STAMPEDE Trial

The STAMPEDE trial used 55 Gy in 20 fractions over 4 weeks as one of two radiotherapy schedules for treating the primary prostate tumor in men with newly diagnosed metastatic prostate cancer, but this approach did not improve overall survival in the unselected metastatic population. 1

STAMPEDE Trial Design and Radiotherapy Schedules

The STAMPEDE trial randomized 2,061 men with newly diagnosed metastatic prostate cancer between January 2013 and September 2016 to either standard androgen deprivation therapy (ADT) alone or ADT plus radiotherapy to the prostate. 1

Two radiotherapy schedules were pre-specified before randomization:

• Daily schedule: 55 Gy in 20 fractions over 4 weeks 1
• Weekly schedule: 36 Gy in 6 fractions over 6 weeks 1

Approximately 52% of participants (1,082 patients) nominated the daily 55 Gy/20 fraction schedule before randomization, while 48% (979 patients) selected the weekly schedule. 1

Trial Outcomes and Clinical Implications

Primary outcome: Radiotherapy to the prostate did not improve overall survival (HR 0.92,95% CI 0.80-1.06; p=0.266) in the overall metastatic population. 1

Secondary outcomes showed benefit:

• Failure-free survival was significantly improved with radiotherapy (HR 0.76,95% CI 0.68-0.84; p<0.0001) 1
• The treatment was well-tolerated, with only 5% experiencing grade 3-4 acute toxicity during radiotherapy and 4% after completion 1
• The proportion of patients with severe adverse events (grade 3 or worse) was similar between control (38%) and radiotherapy (39%) groups 1

Context: Hypofractionation as Standard Practice

The 55 Gy in 20 fractions regimen represents moderate hypofractionation, which is now considered standard of care for localized prostate cancer. 2 This dose-fractionation schedule:

• Provides equivalent cancer control and toxicity compared to conventional fractionation (74-78 Gy in 37-39 fractions) 2
• Offers significant advantages in treatment duration (4 weeks vs 7-8 weeks) and patient convenience 2
• Is recommended across all risk categories (low, intermediate, and high-risk) based on high-quality randomized controlled trial evidence 2

Technical requirements for safe delivery:

• Image-guided radiation therapy (IGRT) with daily prostate localization is mandatory 2
• Intensity-modulated radiation therapy (IMRT) or more advanced techniques must be used 2
• At least 2 dose-volume constraint points for rectum and bladder are required 2

Comparison to Other Hypofractionated Schedules

The 55 Gy/20 fraction schedule used in STAMPEDE is biologically equivalent to other validated moderate hypofractionation regimens:

• 60 Gy in 20 fractions (3 Gy per fraction) 2
• 70 Gy in 28 fractions (2.5 Gy per fraction) 2

This differs from the older, suboptimal regimen of 55 Gy in 20 fractions mentioned in earlier guidelines for localized disease, which was compared unfavorably to brachytherapy boost in a single institution trial where external beam techniques were suboptimal (half the patients did not receive conformal radiotherapy). 3

Critical Distinction: Metastatic vs Non-Metastatic Disease

The STAMPEDE trial specifically addressed metastatic prostate cancer, where the role of prostate radiotherapy remains controversial. 1 In contrast, for high-risk non-metastatic prostate cancer:

• Radiotherapy to the prostate is standard treatment, typically combined with 2-3 years of ADT 2
• Recent STAMPEDE data in non-metastatic high-risk disease showed that adding abiraterone and prednisolone to ADT significantly improved metastasis-free survival (6-year rate: 82% vs 69%, HR 0.53, p<0.0001) 4
• However, emerging data suggest that in the PSMA-PET era, appropriately intensified local treatment (hypofractionated RT with median 82 Gy equivalent) combined with long-term ADT may achieve excellent outcomes (6-year metastasis-free survival 80.7%) without abiraterone in selected patients 5

Common Pitfalls to Avoid

Do not extrapolate the negative overall survival results from STAMPEDE's metastatic cohort to non-metastatic high-risk disease, where prostate radiotherapy remains a cornerstone of curative treatment. 2, 4

Do not use 55 Gy in 20 fractions without proper image guidance and IMRT techniques, as inadequate technique increases toxicity risk without improving outcomes. 2

Do not assume all hypofractionated schedules are equivalent—the 55 Gy/20 fraction schedule delivers a lower biological dose than the 60 Gy/20 fraction regimen now commonly used for definitive treatment of localized disease. 2