What is the role of hypofractionation of radiotherapy (radiation therapy) in the treatment of carcinoma of the prostate?

Hypofractionation in Prostate Cancer Radiotherapy

Moderate hypofractionation (2.4-3.4 Gy per fraction) should be offered to all patients with localized prostate cancer across all risk groups who choose external beam radiotherapy, as it provides equivalent cancer control and toxicity compared to conventional fractionation while offering significant advantages in treatment duration and convenience. 1

Moderate Hypofractionation: The Standard Approach

Strong Recommendation Across All Risk Groups

• Moderate hypofractionation is recommended for low-, intermediate-, and high-risk prostate cancer based on high-quality randomized controlled trial evidence. 1
• Multiple large-scale RCTs demonstrate that moderate hypofractionation achieves prostate cancer control outcomes and late toxicity rates similar to conventional fractionation (75.6-81 Gy in 1.8-2 Gy fractions). 1
• The 2019 ASTRO/ASCO/AUA guideline reached strong consensus (based on high-quality evidence) for offering moderate hypofractionation across all risk categories. 1

Validated Regimens

• Doses of 60 Gy in 20 fractions of 3 Gy over 4 weeks have been validated in randomized trials, showing 5-year biochemical-clinical failure-free survival of 85% with no increase in grade ≥3 toxicity. 2
• 66 Gy in 22 fractions of 3 Gy achieved 5-year biochemical recurrence-free survival of 95.4% in intermediate-risk patients with only 2% grade ≥2 GI toxicity and 7% GU toxicity. 3
• 76.7 Gy at 2.19 Gy/fraction demonstrated 10-year biochemical relapse-free survival of 87.7% overall, with rates of 91.4%, 89.3%, and 76.2% for low-, intermediate-, and high-risk disease respectively. 4
• The 2014 NCCN guideline notes that moderately hypofractionated image-guided IMRT regimens (2.4-4.0 Gy per fraction over 4-6 weeks) have similar efficacy and toxicity to conventional fractionation. 1

No Single Regimen is Superior

• One moderately hypofractionated regimen is not recommended over another for cancer control across specific risk groups. 1
• The efficacy of moderate hypofractionation does not appear to be affected by patient age, comorbidity, anatomy, or urinary function. 1

Ultrahypofractionation: Risk-Stratified Approach

Low-Risk Disease

• Ultrahypofractionation (35-36.25 Gy in 5 fractions of 7-7.25 Gy) may be offered as an alternative to conventional fractionation for patients who decline active surveillance. 1
• This is a conditional recommendation based on moderate-quality evidence. 1

Intermediate-Risk Disease

• Ultrahypofractionation may be offered but patients should strongly be encouraged to enroll in a clinical trial or multi-institutional registry. 1
• This conditional recommendation is based on low-quality evidence, as no prospective comparative studies with published efficacy data exist for intermediate-risk disease. 1

High-Risk Disease

• Ultrahypofractionation should NOT be offered outside of a clinical trial or multi-institutional registry due to insufficient comparative evidence. 1
• This is a conditional recommendation against routine use based on low-quality evidence. 1

Specific Ultrahypofractionation Parameters

• The recommended dose is 35-36.25 Gy in 5 fractions (7-7.25 Gy per fraction) for prostate sizes <100 cm³. 1
• Doses above 36.25 Gy in 5 fractions are NOT recommended outside clinical trials due to increased risk of late toxicity. 1
• Consecutive daily treatments are NOT recommended due to potential increased risk of late urinary and rectal toxicity; treatments should be delivered on alternate days or with gaps. 1

Radiobiological Rationale

The α/β Ratio Advantage

• Prostate cancer has a very low α/β ratio (approximately 1.3 Gy), lower than surrounding normal tissues. 5
• When the α/β ratio for cancer is similar to or lower than surrounding tissues, hypofractionated regimens can achieve similar cancer control with acceptable toxicity profiles. 6
• This radiobiological characteristic makes prostate cancer uniquely suited to hypofractionation compared to other malignancies. 7, 5

Essential Technical Requirements

Image-Guided Radiation Therapy (IGRT)

• IGRT is strongly recommended and considered essential for safe delivery of any hypofractionated regimen. 1
• The vast majority of hypofractionated studies used IGRT, and it is central to safe and effective delivery. 1
• Daily prostate localization using CT, ultrasound, implanted fiducials, electromagnetic targeting/tracking, or endorectal balloon should be employed. 1

Intensity-Modulated Radiation Therapy (IMRT)

• Non-modulated 3-dimensional conformal techniques should be avoided with hypofractionation. 1
• IMRT or more advanced techniques are strongly recommended to minimize toxicity. 1

Dose-Volume Constraints

• At least 2 dose-volume constraint points for rectum and bladder must be used: one at the high-dose end (near total prescribed dose) and one in the mid-dose range. 1
• Deviating from published reference study constraints is strongly discouraged due to risk of increased acute and late toxicity. 1

Clinical Advantages

Patient and System Benefits

• Shorter overall treatment time: 4-6 weeks versus conventional 7-9 weeks. 6, 2
• Improved patient convenience and quality of life during treatment. 1
• Better resource utilization for healthcare systems. 1
• Equivalent biochemical control rates to conventional fractionation. 6, 2

Common Pitfalls to Avoid

Technical Errors

• Inadequate image guidance leads to geographic miss and treatment failure. 6
• Using non-IMRT techniques increases toxicity risk unacceptably. 1
• Exceeding validated dose constraints significantly increases late toxicity. 1

Patient Selection Errors

• Treating high-risk patients with ultrahypofractionation outside trials lacks evidence and should be avoided. 1
• Ignoring prostate size limitations (>100 cm³) for ultrahypofractionation increases toxicity risk. 1
• Using consecutive daily treatments for 5-fraction ultrahypofractionation increases urinary and rectal toxicity. 1

Dose Calculation Errors

• Not accounting for cumulative doses to organs at risk when combining with other radiation modalities. 6
• Attempting to replicate results without matching the technical parameters of published studies. 1

Integration with Androgen Deprivation Therapy

Risk-Stratified ADT Use

• High-risk patients: 2-3 years of neoadjuvant/concomitant/adjuvant ADT (Category 1 recommendation). 1
• Intermediate-risk patients: Consider 4-6 months of neoadjuvant/concomitant/adjuvant ADT. 1
• Low-risk patients: Should not receive ADT. 1
• The randomized trial validating 60 Gy in 20 fractions specifically excluded ADT to isolate the radiation effect. 2