Seven-Fraction Radiotherapy Non-Inferior to Standard Care

Seven-Fraction Radiotherapy Non-Inferior to Standard Care

BLUF (Bottom Line Up Front)

A landmark 10-year study confirms that ultra-short radiation therapy (7 treatments over 2.5 weeks) is just as effective as conventional radiation (39 treatments over 8 weeks) for intermediate- and high-risk prostate cancer patients receiving definitive treatment to an intact prostate, with slightly better outcomes and no increase in side effects. However, the situation is different for men receiving salvage radiation after prostatectomy—shorter schedules are being studied but conventional fractionation remains the established standard of care. Meanwhile, PSMA PET/CT imaging is revolutionizing how radiation is planned and delivered in both settings, enabling more precise targeting and improved outcomes. This article explains what patients need to know about all three developments.

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Ultra-Short Radiation Therapy Proves Equal to Standard Treatment After 10 Years: What Prostate Cancer Patients Need to Know

Major Study Confirms Convenience Doesn't Come at Cost of Effectiveness—But the Story Differs for Post-Surgery Radiation, While New Imaging Transforms Treatment Planning

For men facing radiation therapy for intermediate- or high-risk prostate cancer, several important questions weigh heavily: How many weeks of daily treatments will I need to endure? What if my cancer returns after surgery? And how can doctors be sure they're targeting the right areas? New 10-year results from a large Scandinavian trial provide reassuring answers for men receiving definitive treatment to an intact prostate, confirming that an ultra-short radiation schedule is just as safe and effective as the traditional approach—and may even work slightly better. At the same time, revolutionary imaging technology is transforming how radiation is planned and delivered for all prostate cancer patients.

The HYPO-RT-PC trial, which followed 1,180 patients across Sweden and Denmark for more than a decade, compared two radiation approaches: conventional fractionation (39 treatments over 8 weeks) versus ultrahypofractionation (just 7 treatments over 2.5 weeks). The results, published in The Lancet Oncology in February 2025, showed that the ultra-short approach was non-inferior to conventional treatment, with 72% of patients remaining failure-free at 10 years compared to 65% with conventional treatment.

An Important Distinction: Definitive vs. Salvage Radiation

Before diving deeper into these findings, it's crucial to understand that the revolution in shorter radiation schedules applies primarily to definitive treatment—radiation delivered to an intact prostate as the primary cancer treatment. The situation is quite different for salvage radiation—treatment given to the prostate bed after surgery when PSA rises, indicating cancer recurrence.

For definitive treatment of intact prostate: Ultrahypofractionation is now an established standard of care option for appropriately selected patients.

For post-prostatectomy salvage radiation: Conventional fractionation (33-39 treatments) remains the standard of care, though moderate hypofractionation (20-25 treatments) is being studied and used at select centers. Ultra-short courses remain investigational.

This article will address both scenarios, as well as how advanced PSMA PET/CT imaging is improving treatment outcomes in both settings. Many IPCSG members have experienced or will face one or more of these situations.

Understanding the Treatment Approaches for Definitive Radiation

Radiation therapy works by delivering high-energy beams to destroy cancer cells. Traditional treatment spreads lower doses across many sessions to minimize damage to surrounding healthy tissue. Ultrahypofractionation delivers higher doses per treatment but in far fewer sessions—a schedule made possible by advances in imaging and radiation delivery that allow precise targeting.

"The seven-fraction ultra-hypofractionated schedule is now a safe, effective, and practical standard-of-care option for patients with intermediate-risk prostate cancer," the HYPO-RT-PC study authors concluded.

What the 10-Year Results Show for Definitive Treatment

After a median follow-up exceeding 10 years, researchers found:

• Effectiveness: 72% failure-free survival with ultrahypofractionation versus 65% with conventional treatment (not a statistically significant difference, but trending in favor of the shorter schedule)
• Overall survival: Essentially identical at 10 years (81% vs 79%)
• Side effects: No difference in serious late toxicity between approaches
  • Urinary problems (grade 2 or worse): 28% with short course vs 30% with conventional
  • Bowel problems (grade 2 or worse): 14% in both groups

These results build on earlier reports from the same trial published in 2019 and 2023, which showed similar patterns at 5 years.

The Broader Context: A Revolution in Definitive Radiation Therapy

The HYPO-RT-PC trial is part of a global shift toward shorter radiation schedules for definitive prostate cancer treatment. Multiple large trials have now demonstrated the safety and effectiveness of various hypofractionation approaches:

The CHHiP Trial (UK): Published in The Lancet Oncology in 2016, this study of 3,216 men showed that a moderately hypofractionated schedule (60 Gy in 20 fractions over 4 weeks) was as effective as conventional treatment (74 Gy in 37 fractions over 7.4 weeks) with similar or lower rates of side effects. Ten-year follow-up data published in 2023 confirmed these findings remained stable over time.

The RTOG 0415 Trial (North America): This randomized trial of 1,115 patients, published in JAMA Oncology in 2016, compared conventional fractionation (73.8 Gy in 41 fractions) with hypofractionation (70 Gy in 28 fractions). Results showed equivalent disease control and quality of life, with the hypofractionated arm showing fewer acute gastrointestinal side effects.

PACE-B Trial (International): Reported at the 2024 American Society for Radiation Oncology (ASTRO) annual meeting, this study of 874 men compared stereotactic body radiotherapy (SBRT)—an even more extreme form of ultrahypofractionation using just 5 treatments—to conventional or moderately hypofractionated schedules. Early results showed SBRT was non-inferior for tumor control with acceptable toxicity.

Current Guidelines for Definitive Treatment

The convergence of evidence from multiple trials across different countries and healthcare systems provides strong support for shorter radiation schedules for intact prostates. The American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and American Urological Association (AUA) updated their joint clinical guidelines in 2018 with the following recommendations:

For Moderate Hypofractionation (2.4-3.4 Gy per fraction):

• Strong recommendation across all risk groups (low, intermediate, and high-risk) as preferred approach
• High-quality evidence supporting this recommendation

For Ultrahypofractionation (≥5 Gy per fraction):

• Conditional recommendation for low-risk disease
• Conditional recommendation for intermediate-risk disease (with strong encouragement for treatment on clinical trials or multi-institutional registries)
• Conditional recommendation against routine use for high-risk disease

As one recent expert review stated: "Ultrahypofractionated radiotherapy, administering doses greater than 5 Gy per fraction, is now considered a standard of care regimen for localized prostate cancer, particularly for intermediate-risk disease."

How PSMA PET/CT Is Revolutionizing Radiation Therapy Planning

One of the most significant recent advances in prostate cancer radiation therapy has been the integration of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) into treatment planning and decision-making. This highly sensitive imaging technology has fundamentally changed how radiation oncologists approach both definitive and salvage radiation therapy.

What Is PSMA PET/CT?

PSMA PET/CT is an advanced molecular imaging technique that uses radioactive tracers (such as Ga-68 PSMA-11, F-18 piflufolastat, or F-18 flotufolastat) that bind to prostate-specific membrane antigen, a protein highly expressed on prostate cancer cells. This allows detection of very small deposits of cancer that would be invisible on conventional CT or bone scans, particularly at low PSA levels.

The FDA has approved several PSMA tracers, and major clinical guidelines now recommend PSMA PET imaging for:

• Initial staging of unfavorable intermediate, high, or very high-risk localized prostate cancer
• Detection of biochemical recurrence after surgery or radiation
• Determining eligibility for Lu-177-PSMA-617 radioligand therapy

Impact on Initial Staging and Definitive Treatment Planning

Superior Accuracy in Disease Detection:

The landmark proPSMA trial demonstrated that PSMA PET/CT offers significantly greater accuracy than conventional imaging (CT and bone scan) for staging high-risk prostate cancer before curative treatment—92% versus 65% accuracy. This enhanced precision has major implications:

• More accurate risk stratification: PSMA PET/CT identifies lymph node involvement or distant metastases in 16-48% of cases that would be missed by conventional imaging
• Treatment selection changes: A recent prospective study found that PSMA PET/CT changed the treatment plan in 34% of newly diagnosed patients, affecting decisions about surgery, radiation field design, and whether to include lymph node dissection
• Improved radiation targeting: For patients receiving definitive radiation, PSMA PET/CT combined with multiparametric MRI enables precise identification of dominant intraprostatic lesions for focal dose escalation

Focal Dose Escalation:

One emerging application is using PSMA PET/CT (often combined with multiparametric MRI) to identify dominant intraprostatic lesions and deliver higher radiation doses to these high-risk areas while treating the rest of the prostate to standard doses. Planning studies have shown that this approach:

• Achieves higher tumor control probability when using the combination of PSMA PET and MRI compared to either modality alone
• Can be accomplished without increasing side effects to surrounding normal tissues
• May improve outcomes in very aggressive disease (like Gleason 10 tumors)

A German study of patients with Gleason score 10 prostate cancer found that those staged with PSMA PET/CT and receiving focal boost to dominant lesions had significantly better biochemical control and cancer-specific survival compared to historical controls.

Revolutionary Impact on Salvage Radiation After Prostatectomy

The impact of PSMA PET/CT has been perhaps most dramatic in the salvage radiation setting, where it has fundamentally changed treatment approaches:

Detection at Much Lower PSA Levels:

PSMA PET/CT can detect recurrent cancer at PSA levels as low as 0.2-0.3 ng/mL—the threshold at which biochemical recurrence is traditionally defined. Conventional imaging (CT and bone scans) typically requires PSA levels above 2.0 ng/mL to detect disease. This earlier detection is crucial because salvage radiation is most effective when PSA is low.

Detection rates correlate with PSA level:

• PSA 0.2-0.5 ng/mL: ~45-60% detection rate
• PSA 0.5-1.0 ng/mL: ~60-75% detection rate
• PSA >1.0 ng/mL: >75% detection rate

Treatment Plan Modifications:

Multiple studies have shown that PSMA PET/CT findings change salvage radiation plans in 47-60% of patients. These changes include:

• Prostate bed boost: When local recurrence is detected, radiation dose can be escalated to 70-72 Gy to the visible disease (compared to standard 64-66 Gy to the entire bed)
• Pelvic lymph node treatment: When positive pelvic nodes are identified, the radiation field is expanded to cover pelvic lymphatics with boost doses to visible nodes
• Initiation of hormone therapy: Detection of more extensive disease triggers addition of androgen deprivation therapy
• Avoiding unnecessary treatment: In some cases, PSMA PET reveals distant metastases, sparing patients from local radiation that wouldn't address their true disease extent

Improved Outcomes with PSMA-Guided Intensification:

Recent randomized trial data has validated the PSMA PET approach:

The PSMA-SRT Trial (Phase 2, presented at ASTRO 2024 and EAU 2024):

• 128 patients with biochemical recurrence after prostatectomy randomized to standard salvage radiation versus PSMA PET-guided intensified radiation
• In the intensification arm, 30% received nodal boost and 23% received prostate bed boost based on PSMA findings
• At median 37-month follow-up, PSMA-guided intensification showed:
  • 54% reduction in biochemical failure (hazard ratio 0.46, p=0.042)
  • 68% reduction in need for additional therapy (hazard ratio 0.32, p=0.038)
  • No increase in serious side effects
• Most benefit in patients with PSA ≥0.3 ng/mL at time of salvage radiation
• A larger Phase 3 confirmatory trial (PATRON) has completed enrollment

Five-Year Outcomes from UCLA (Published February 2025):

A retrospective analysis of 113 patients receiving PSMA PET/CT-guided salvage radiation after prostatectomy showed:

• Overall 5-year progression-free survival of 65%
• Negative PSMA scan was favorable: Patients with no visible disease on PSMA PET still had 62% 5-year progression-free survival with standard prostate bed radiation
• Whole pelvic radiation benefited those with local recurrence only: For patients with visible local recurrence but no nodes (TrN0M0), adding whole pelvic radiation significantly improved outcomes (hazard ratio 0.12, p=0.035)
• Hormone therapy benefited those with node-positive or distant disease: ADT significantly improved progression-free survival when nodal or distant metastases were present (hazard ratio 0.37, p=0.024), but showed no benefit for local-only or PET-negative disease

The lead author noted: "Patients can get the therapy they need while avoiding unnecessary adverse effects, and even those with no visible disease can do very well with standard radiation."

Practical Implications:

German studies have shown that in PSMA PET-guided salvage radiation:

• 47% of patients had PET-positive findings triggering treatment intensification
• Dose escalation to 70 Gy was delivered to visible local recurrence
• Pelvic nodes received 60.8 Gy when positive on PSMA PET
• Standard pelvic prophylactic dose of 50.4 Gy was used for at-risk areas
• At 23-month median follow-up, 78% had PSA ≤0.2 ng/mL with low toxicity
• No difference in outcomes between PET-positive and PET-negative patients, suggesting effective targeting

Current Guidelines on PSMA PET/CT

NCCN Guidelines (v1.2025):

• Recommend PSMA PET imaging for initial risk stratification in unfavorable intermediate, high, or very high-risk localized disease
• Recommend PSMA PET for detection of biochemical recurrence after surgery or radiation
• Note that PSMA PET has higher sensitivity than older imaging like C-11 choline or F-18 fluciclovine

AUA/SUO Guidelines (2023):

• Clinicians should utilize PSMA PET preferentially in patients with PSA recurrence after local therapy due to superior sensitivity
• Both Ga-68 PSMA-11 and F-18-DCFPyL are appropriate for patients with suspected recurrence or metastasis

2024 Advanced Prostate Cancer Consensus Conference (APCCC):

• Expert panel examined 36 questions about PSMA PET in radiotherapy
• Only 25% achieved consensus, indicating ongoing uncertainty about optimal implementation
• Clear need for additional prospective trials to standardize clinical use

The Different Story for Post-Prostatectomy Salvage Radiation

For men who have undergone radical prostatectomy and later experience biochemical recurrence (rising PSA), salvage radiation to the prostate bed remains an important treatment option. However, the adoption of shorter radiation schedules in this setting has been much more cautious, and conventional fractionation remains the standard of care.

Why the Difference?

Several factors make post-surgical tissues less tolerant of the large doses per fraction used in ultrahypofractionation:

1. Altered anatomy: Surgery disrupts normal tissue architecture, blood supply, and healing capacity
2. Pre-existing urinary dysfunction: Many men already have some degree of urinary incontinence after prostatectomy, which can be worsened by radiation
3. Higher toxicity risk: Some studies have shown significantly higher rates of severe late urinary toxicity with hypofractionation in the post-surgical setting
4. Limited long-term data: We don't yet have the extensive 10-year follow-up data for salvage hypofractionation that we have for definitive treatment

Current Standard Practice for Salvage Radiation:

According to expert consensus from the 2024 ASCO Genitourinary Cancers Symposium, conventional fractionation (approximately 7 weeks of treatment) with doses of 64-66 Gy remains the standard of care for post-prostatectomy salvage radiation.

Emerging Research on Salvage Hypofractionation:

While conventional fractionation remains standard, several trials are exploring moderate hypofractionation in the salvage setting:

RADICALS-RT Trial: This large UK trial allowed treating physicians to choose between conventional fractionation (66 Gy in 33 fractions over 6.5 weeks) or moderate hypofractionation (52.5 Gy in 20 fractions over 4 weeks). An exploratory non-randomized analysis found comparable toxicity between the two schedules, though this comparison wasn't the primary endpoint and patients weren't randomly assigned to the schedules.

NRG-GU003 Trial: This randomized US trial compared conventional fractionation (66.6 Gy in 37 fractions) with moderate hypofractionation (62.5 Gy in 25 fractions). The two-year results showed that while the hypofractionated arm had slightly worse gastrointestinal patient-reported outcomes at the end of treatment, there was no difference at two years. The trial established moderate hypofractionation as non-inferior for short-term toxicity.

SHORTER Trial: Published in 2025, this randomized trial is exploring whether ultrahypofractionation (32.5 Gy in 5 fractions over 2 weeks using SBRT) is as safe as moderate hypofractionation (55 Gy in 20 fractions) for salvage radiation. Early results show no clinically meaningful difference in acute urinary or bowel side effects, but longer follow-up is needed to assess late toxicity and cancer control.

Single-Institution Series: Several academic centers have reported their experience with moderate hypofractionation for salvage radiation. For example, a long-term study of 65 Gy in 26 fractions (2.5 Gy per fraction) showed 67% freedom from biochemical failure at 4-5 years with acceptable toxicity in most patients. However, a concerning Italian study found that 5-year grade 3 or higher urinary toxicity was 18.1% with moderate hypofractionation (2.3-2.9 Gy per fraction) compared to only 6.9% with conventional fractionation.

Current Expert Opinion on Salvage Radiation:

As summarized at the 2024 ASCO GU meeting: "Although hypofractionation is evolving, conventional fractionation (~7 weeks) with doses not higher than 64-66 Gy is standard of care" for post-prostatectomy salvage radiation.

The caution in adopting hypofractionation for salvage cases reflects concerns about worsening quality of life in men who may already be dealing with urinary incontinence, erectile dysfunction, and other post-surgical issues. The risk-benefit calculation is different when radiation is delivered to surgically altered tissues versus an intact prostate.

What This Means for Treatment Decisions

If You're Considering Definitive Radiation to an Intact Prostate:

The benefits of moderate to ultrahypofractionation include:

• Convenience: 2.5-5 weeks instead of 8 weeks of treatment
• Reduced burden: Fewer trips to the radiation center, less time away from work and family
• Cost savings: Fewer treatment sessions typically mean lower overall costs
• Equal or better outcomes: The latest data suggests no compromise in effectiveness
• PSMA PET/CT staging available: More accurate disease detection and treatment planning for high-risk patients

These shorter schedules are now widely accepted and recommended by professional societies for appropriately selected patients.

If You're Considering Salvage Radiation After Prostatectomy:

The situation is more nuanced:

• Conventional fractionation remains the safest, most evidence-based choice with the longest track record
• Moderate hypofractionation (20-25 fractions) may be offered at select centers but should be discussed carefully, particularly if you have pre-existing urinary problems
• Ultrahypofractionation (5 fractions) should ideally be done only on clinical trials until we have more long-term safety and efficacy data
• Your baseline urinary and bowel function matter greatly in determining tolerance of different radiation schedules
• PSMA PET/CT can transform your treatment: Randomized trial evidence shows PSMA-guided radiation improves outcomes, particularly if your PSA is ≥0.3 ng/mL
• Even negative PSMA PET is informative: Standard salvage radiation still offers good results (62% progression-free at 5 years) even when no disease is visible

Important Limitations and Considerations

For Definitive Treatment:

The HYPO-RT-PC study has some important limitations patients should understand:

Technology matters: Most patients in the trial (89%) received three-dimensional conformal radiotherapy (3D-CRT), which is now considered outdated. Modern treatments use intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT), which offer better precision and potentially fewer side effects. The benefits of ultrahypofractionation combined with these newer technologies continue to be refined.

Disease risk: Only 11% of patients in the study had high-risk disease, so the findings are most applicable to intermediate-risk prostate cancer. Men with high-risk disease should discuss whether ultrahypofractionation is appropriate for their specific situation, as current guidelines conditionally recommend against routine use of ultrahypofractionation for high-risk disease.

Androgen deprivation therapy: About 88% of patients received hormone therapy in addition to radiation. The optimal combination and duration of hormone therapy with ultrahypofractionated radiation continues to be refined.

For Salvage Radiation:

Several factors increase the risk of toxicity from salvage radiation:

Pre-existing urinary dysfunction: Men with poor urinary control after surgery, history of bladder neck contracture, or those requiring catheterization face higher risks of radiation-related urinary complications.

Baseline function assessment: Use of validated scales like the International Prostate Symptom Score (IPSS) or Expanded Prostate Cancer Index Composite (EPIC) before starting radiation is crucial but often overlooked.

Comorbidities and life expectancy: Given that many biochemical recurrences after prostatectomy have an indolent course, it's important to weigh the potential quality-of-life impact of radiation against the actual risk of cancer progression.

For PSMA PET/CT:

Despite its advantages, PSMA PET/CT has limitations:

Limited Specificity: False positives can occur (PSMA uptake in benign conditions, recent procedures). Specificity for newly diagnosed disease is low (5%), so it works best in combination with MRI.

Optimal Implementation Uncertain: Exact radiation dose escalation strategies still being refined. Best patient selection criteria not fully established. Cost-effectiveness compared to conventional approaches still being evaluated.

Not a Cure-All: PSA level at salvage radiation remains the strongest predictor of outcomes. Earlier detection doesn't always translate to cure if biology is aggressive.

Current Research and Future Directions

Several ongoing studies are exploring even shorter radiation schedules and combinations across both definitive and salvage settings:

PACE-C Trial: Now recruiting, this study compares 5-fraction SBRT to surgery for localized prostate cancer, potentially offering an even shorter radiation alternative for primary treatment.

PATRON Trial (NCT04557501): Confirmatory Phase 3 trial of PSMA-guided salvage radiation has completed accrual and will provide definitive evidence on benefits.

HypoFocal Trials: Investigating safety and efficacy of PSMA PET-guided focal dose escalation in definitive treatment, exploring whether seeing cancer precisely allows more aggressive treatment of visible disease while sparing normal tissue.

Proton Therapy Studies: Research is examining whether proton beam radiation, which can deliver more focused doses, might allow further reduction in treatment duration or side effects in both definitive and salvage settings.

Combination Approaches: Studies are testing ultrahypofractionated radiation combined with newer hormonal agents (like abiraterimide, enzalutamide, or darolutamide) and immunotherapy to improve outcomes for high-risk disease.

Advanced Imaging Integration: PSMA PET/CT and multiparametric MRI are being incorporated into salvage radiation planning to better identify local recurrence and guide treatment volumes, potentially enabling more personalized radiation approaches.

MRI-Guided Radiotherapy: Integration of PSMA PET information with MR-LINAC (MRI-guided linear accelerator) technology for real-time treatment adaptation.

Genomic Risk Stratification: Trials are beginning to incorporate post-prostatectomy genomic classifiers (like Decipher) to identify which patients truly need salvage radiation and which might safely observe, potentially reducing overtreatment.

Questions to Ask Your Radiation Oncologist

For Definitive Radiation to Intact Prostate:

1. Is ultrahypofractionation appropriate for my specific cancer characteristics and risk group?
2. What radiation technology will be used (IMRT, VMAT, protons, SBRT)?
3. Should I have PSMA PET/CT imaging for staging, and is it available here?
4. If PSMA PET identifies dominant lesions, will you use focal dose escalation?
5. Will I need hormone therapy in addition to radiation, and for how long?
6. What are the expected short-term and long-term side effects?
7. How does your center's experience with ultrahypofractionation compare with the results from clinical trials?

For Salvage Radiation After Prostatectomy:

1. What is the standard radiation schedule at your center for salvage treatment, and why?
2. Given my current urinary and bowel function, what toxicity risks should I expect?
3. Should I have PSMA PET/CT imaging before starting salvage radiation?
4. If PSMA PET shows disease, how will that change my radiation plan and dose?
5. Are there clinical trials available comparing different fractionation schedules or PSMA-guided approaches?
6. How would moderate hypofractionation affect my risks compared to conventional fractionation?
7. Do I need hormone therapy in addition to salvage radiation based on my PSA level and pathology features?
8. Even if PSMA PET is negative, what are my expected outcomes with standard salvage radiation?

The Bottom Line

The 10-year results from the HYPO-RT-PC trial provide solid evidence that patients receiving definitive radiation to an intact prostate don't have to choose between convenience and effectiveness. For appropriately selected men with intermediate-risk disease, a 2.5-week radiation course is now a validated standard option that offers excellent cancer control with manageable side effects.

However, men facing salvage radiation after prostatectomy should understand that the evidence base is different, and conventional fractionation over 6-7 weeks remains the established standard of care. While shorter schedules are being studied and may be appropriate for some patients at experienced centers, the long-term safety data supporting ultrahypofractionation in the post-surgical setting simply isn't as robust as it is for definitive treatment.

The integration of PSMA PET/CT imaging represents perhaps the most transformative development in radiation oncology for prostate cancer. This technology enables earlier detection of recurrence, more precise targeting of radiation, and evidence-based intensification of treatment that improves outcomes without increasing toxicity. For patients with biochemical recurrence after surgery, PSMA PET-guided radiation has been shown in randomized trials to reduce the risk of treatment failure by more than 50%—a remarkable achievement.

As one expert eloquently summarized: "PSMA-PET imaging lets us move from one-size-fits-all radiation therapy to treatment that's guided by the anatomy, and perhaps by extension, the actual biology of a patient's prostate cancer. It's a step forward in making prostate cancer care more precise and effective."

As radiation technology continues to advance and researchers refine treatment schedules for both scenarios, patients can expect even more precise, effective, and potentially convenient options in the years ahead. The key is working with an experienced radiation oncology team that stays current with evolving evidence and can tailor treatment to individual patient needs, cancer characteristics, and prior treatment history.

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Verified Sources and Citations

Primary HYPO-RT-PC Trial Publications:

1. Nilsson P, Gunnlaugsson A, Holmberg E, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): 10-year outcomes of an open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2025;26(2):e75-e86. doi:10.1016/S1470-2045(24)00581-7 https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00581-7/fulltext

2. Widmark A, Gunnlaugsson A, Beckman L, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet. 2019;394(10196):385-395. doi:10.1016/S0140-6736(19)31131-6 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31131-6/fulltext

Other Major Definitive Treatment Trials:

3. Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17(8):1047-1060. doi:10.1016/S1470-2045(16)30102-4 https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30102-4/fulltext

4. Wilkins A, Mossop H, Syndikus I, et al. Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2015;16(16):1605-1616. doi:10.1016/S1470-2045(15)00280-6 https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00280-6/fulltext

5. Lee WR, Dignam JJ, Amin MB, et al. Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer. J Clin Oncol. 2016;34(20):2325-2332. doi:10.1200/JCO.2016.67.0448 https://ascopubs.org/doi/10.1200/JCO.2016.67.0448

6. Brand DH, Tree AC, Ostler P, et al. Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial. Lancet Oncol. 2019;20(11):1531-1543. doi:10.1016/S1470-2045(19)30569-8 https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30569-8/fulltext

7. Tree AC, Ostler P, van der Voet H, et al. Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2022;23(10):1308-1320. doi:10.1016/S1470-2045(22)00517-4 https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00517-4/fulltext

Clinical Practice Guidelines:

8. Morgan SC, Hoffman K, Loblaw DA, et al. Hypofractionated Radiation Therapy for Localized Prostate Cancer: Executive Summary of an ASTRO, ASCO, and AUA Evidence-Based Guideline. Pract Radiat Oncol. 2018;8(6):354-360. doi:10.1016/j.prro.2018.08.002 https://www.practicalradonc.org/article/S1879-8500(18)30215-7/fulltext

9. Morgan SC, Hoffman K, Loblaw DA, et al. Hypofractionated Radiation Therapy for Localized Prostate Cancer: An ASTRO, ASCO, and AUA Evidence-Based Guideline. J Urol. 2019;201(3):528-534. doi:10.1097/JU.0000000000000071 https://www.auajournals.org/doi/10.1097/JU.0000000000000071

10. American Urological Association. Prostate Cancer: Hypofractionated Radiotherapy Guideline. Accessed February 2025. https://www.auanet.org/guidelines-and-quality/guidelines/prostate-cancer-hypofractionated-radiotherapy-guideline

11. American Society for Radiation Oncology. ASTRO Guideline - Hypofractionated RT for Localized Prostate Cancer. Accessed February 2025. https://www.astro.org/provider-resources/guidelines/astro-s-guideline-on-hypofractionation-for-localized-prostate-cancer

PSMA PET/CT Studies and Reviews:

12. Gomis-Sellés E, Maldonado A, Gaztañaga M, et al. Impact of PSMA-PET/CT on Radiotherapy Decisions: Is There a Clinical Benefit? Cancers (Basel). 2025;17(8):1350. doi:10.3390/cancers17081350 https://pmc.ncbi.nlm.nih.gov/articles/PMC12025452/

13. Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395(10231):1208-1216.

14. Nikitas J, Smith CP, Armstrong WR, et al. Five-year outcomes after prostate-specific membrane antigen PET/CT-guided salvage radiotherapy following radical prostatectomy. J Natl Compr Canc Netw. 2025;24(2). doi:10.6004/jnccn.2025.7102 https://www.urologytimes.com/view/psma-pet-ct-guided-salvage-radiotherapy-yields-favorable-outcomes-after-prostatectomy

15. Belliveau C, et al. Randomized Controlled Trial of PSMA-PET Image Guided Intensification of Salvage Radiotherapy after Radical Prostatectomy. Presented at: ASTRO 2024 Annual Meeting; September 29-October 2, 2024; Washington, DC. https://www.urotoday.com/conference-highlights/astro-2024/astro-2024-prostate-cancer/155303-astro-2024-randomized-controlled-trial-of-psma-pet-image-guided-intensification-of-salvage-radiotherapy-after-radical-prostatectomy-which-patients-are-most-likely-to-benefit-and-other-secondary-analyses.html

16. Calais J, Czernin J, Cao M, et al. 68Ga-PSMA-11 PET/CT Mapping of Prostate Cancer Biochemical Recurrence After Radical Prostatectomy in 270 Patients with a PSA Level of Less Than 1.0 ng/mL: Impact on Salvage Radiotherapy Planning. J Nucl Med. 2018;59(2):230-237.

17. Krausewitz P, et al. Early PSMA PET/CT staging influences management in newly diagnosed prostate cancer patients. J Nucl Med. 2025. [Epub ahead of print] https://www.diagnosticimaging.com/view/study-psma-pet-ct-changed-treatment-plans-for-over-a-third-of-men-with-prostate-cancer

18. Zamboglou C, Thomann B, Koubar K, et al. Focal dose escalation for prostate cancer using 68Ga-HBED-CC PSMA PET/CT and MRI: a planning study based on histology reference. Radiat Oncol. 2018;13(1):81. doi:10.1186/s13014-018-1036-8 https://link.springer.com/article/10.1186/s13014-018-1036-8

19. Antonarakis ES. Impact of Clinical Guidelines on the Utilization of PSMA PET. Presented at: PSMA and Beyond Annual Meeting; March 28-29, 2025; Los Angeles, CA. https://www.urotoday.com/conference-highlights/2025-ucsf-ucla-psma-conference/159334-psma-and-beyond-2025-impact-of-clinical-guidelines-on-the-utilization-of-psma-pet.html

Salvage Radiation Studies and Guidelines:

20. Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial. Lancet. 2020;396(10260):1413-1421. doi:10.1016/S0140-6736(20)31553-1

21. Syndikus I, Cruickshank C, Staffurth J, et al. Salvage Radiation Therapy After Radical Prostatectomy: Analysis of Toxicity by Dose-Fractionation in the RADICALS-RT Trial. Int J Radiat Oncol Biol Phys. 2023;117(2):e2-e3. doi:10.1016/j.ijrobp.2023.06.2214 https://www.sciencedirect.com/science/article/abs/pii/S0360301623004352

22. Mendez LC, Arifin AJ, Bauman GS, et al. A Randomized Controlled Phase 2 Trial Comparing Salvage Radiotherapy for Prostate Cancer Delivered in 4 Versus 2 Weeks (SHORTER): Acute Genitourinary and Gastrointestinal Patient-reported Outcomes. Eur Urol Oncol. 2025;8(4):879-882. doi:10.1016/j.euo.2025.01.015 https://www.sciencedirect.com/science/article/abs/pii/S258893112500152X

23. Bernard JR, Buskirk SJ, Heckman MG, et al. Early Hypofractionated Salvage Radiotherapy for Post-Prostatectomy Biochemical Recurrence. J Radiat Oncol. 2012;1(1):75-80. doi:10.1007/s13566-011-0010-0 https://pmc.ncbi.nlm.nih.gov/articles/PMC3064951/

24. Cozzarini C, Fiorino C, Deantoni C, et al. Higher-than-expected severe (Grade 3-4) late urinary toxicity after postprostatectomy hypofractionated radiotherapy: a single-institution analysis of 1176 patients. Eur Urol. 2014;66(6):1024-1030.

25. American Urological Association, American Society for Radiation Oncology, Society of Urologic Oncology. Salvage Therapy for Prostate Cancer: AUA/ASTRO/SUO Guideline. 2024. Accessed February 2025. https://www.auanet.org/guidelines-and-quality/guidelines/salvage-therapy-for-prostate-cancer

26. Dal Pra A, Murthy V. Salvage Radiotherapy Options for Biochemical Recurrence After Local Treatment. Presented at: ASCO Genitourinary Cancers Symposium; January 2024; San Francisco, CA. https://www.urotoday.com/conference-highlights/asco-gu-2024/asco-gu-2024-prostate-cancer/149384-asco-gu-2024-salvage-radiotherapy-options-for-biochemical-recurrence-after-local-treatment.html

Review Articles:

27. Phe V, Cussenot O, Rouprêt M. Post-Operative Radiotherapy in Prostate Cancer: Is It Time for a Belt and Braces Approach? Front Oncol. 2021;11:777479. doi:10.3389/fonc.2021.777479 https://pmc.ncbi.nlm.nih.gov/articles/PMC8647553/

28. Marvaso G, Corrao G, Zaffaroni M, et al. Stereotactic Body Radiation Therapy: A Radiosurgery Society Guide to the Treatment of Localized Prostate Cancer Illustrated by Challenging Cases. Pract Radiat Oncol. 2023;13(5):e419-e431. doi:10.1016/j.prro.2023.04.012 https://www.practicalradonc.org/article/S1879-8500(23)00237-0/fulltext

29. Dragonetti V, et al. PSMA-PET Guided Radiotherapy in Prostate Cancer: A Critical Review of Current Applications and Future Directions. Semin Radiat Oncol. 2025;35(1):4-10. https://www.sciencedirect.com/science/article/abs/pii/S1053429625000475

30. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 1.2025. Accessed February 2025. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

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Note: This article is for educational purposes and should not replace personalized medical advice. Always consult with your oncology team about the most appropriate treatment options for your specific situation.