Early vs Delayed Salvage Radiotherapy for Prostate Cancer

(TOPP Trial)

Overseen By Srinivas Raman

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Androgen deprivation

Disqualifiers: Previous pelvic radiotherapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: Varies

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the optimal timing for starting salvage radiotherapy (a type of radiation treatment) in men whose prostate cancer has returned but hasn't spread according to scans. The goal is to compare outcomes between starting radiation treatment immediately and monitoring with regular PSA tests before starting treatment later. Men who have undergone prostate cancer surgery and now have rising PSA levels without signs of cancer on specific scans might be suitable for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are using androgen deprivation therapy, you cannot participate in the trial.

Is there any evidence suggesting that salvage radiotherapy is likely to be safe for humans?

Research has shown that salvage radiotherapy (SRT) is generally safe for treating prostate cancer that returns after surgery. One study found that most patients tolerate SRT well on its own. While some side effects occur, they are usually mild. Common side effects include fatigue and skin irritation, which often resolve after treatment ends.

Another study found that SRT remains safe when used after other treatments, with patients reporting few serious issues. This suggests that SRT is a reliable option for managing recurrent cancer. Overall, evidence supports SRT as a safe treatment choice for many patients with recurring prostate cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the trial comparing early versus delayed salvage radiotherapy for prostate cancer because it aims to refine the timing of this treatment, potentially improving patient outcomes. Unlike the traditional approach where radiotherapy is often administered after clear signs of cancer return, this trial explores whether starting radiotherapy earlier, based on PSA levels before significant cancer progression, might be more beneficial. The trial also investigates the role of surveillance with advanced PSMA PET/CT scans, which could help tailor treatment plans more precisely and avoid unnecessary treatments. These aspects could lead to more personalized treatment strategies, reducing side effects while maintaining or even enhancing effectiveness.

What evidence suggests that salvage radiotherapy could be effective for prostate cancer?

This trial will compare early versus delayed salvage radiotherapy (SRT) for prostate cancer. Studies have shown that SRT can significantly reduce the risk of prostate cancer spreading. In one study, patients who received SRT were less likely to experience cancer spread at both 5 and 15 years compared to those who did not receive the treatment. Another study found that 77.8% of men showed no further signs of cancer at 5 years if their PSA levels (a blood marker used to detect prostate cancer) dropped below 0.1 ng/mL after SRT. Experts suggest that SRT is more effective when administered at lower PSA levels. Overall, these findings indicate that SRT can be a strong option for treating prostate cancer that returns after surgery. Participants in this trial will either receive SRT or be placed under surveillance to determine the optimal timing for SRT. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

Men over 18 with prostate cancer who've had surgery (prostatectomy) and have a specific low PSA level indicating early recurrence, but no signs of cancer spread on advanced imaging. They must be in good physical condition and understand the study's risks.

Inclusion Criteria

I am fully active or can carry out light work.

My cancer is in the early or locally advanced stage but hasn't spread to distant organs.

Informed consent: All patients must sign a document of informed consent indicating their understanding of the investigational nature and risks of the study before any protocol related studies are performed.

Exclusion Criteria

I cannot undergo radiotherapy due to other health issues.

I have had radiation therapy to my pelvic area before.

I am currently using or have used hormone therapy after prostate surgery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to either early salvage radiotherapy or surveillance with delayed PSMA PET/CT imaging

Varies

Regular visits for radiotherapy or PSA monitoring every 3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

7 years

PSA results every 3 months for surveillance patients

What Are the Treatments Tested in This Trial?

Interventions

• Salvage radiotherapy

Trial Overview The trial is testing two approaches after surgery: immediate radiotherapy or monitoring PSA levels closely and only using radiotherapy if PSA rises to a certain point. Patients are randomly assigned to one of these strategies.

How Is the Trial Designed?

Group I: Surveillance Experimental Treatment 1 Intervention

Patients with early biochemical relapse of prostate cancer following radical prostatectomy who have a PSA greater than or equal to 0.1 to less than 0.3 ng/mL with negative PSMA PET/CT will go on surveillance. Routine PSA will be conducted and a repeat PSMA PET/CT imaging will be conducted when the PSA rises to greater than 0.5 to less than 1.0 ng/mL.

Group II: Salvage radiotherapy Active Control 1 Intervention

Patients with early biochemical relapse of prostate cancer following radical prostatectomy who have a PSA of greater than or equal to 0.1 to less than 0.3 ng/mL with negative PSMA PET/CT will receive salvage radiotherapy to the prostate bed. This radiotherapy may or may not include the pelvic lymph nodes.

Salvage radiotherapy is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Salvage Radiation Therapy for:

• Prostate cancer recurrence after prostatectomy

Approved in European Union as Salvage Radiation Therapy for:

• Prostate cancer recurrence after prostatectomy

Approved in Canada as Salvage Radiation Therapy for:

• Prostate cancer recurrence after prostatectomy

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

In the SAKK 09/10 trial involving 350 men with biochemical progression of prostate cancer after surgery, conventional-dose salvage radiotherapy (64 Gy) was found to be equally effective as dose-intensified radiotherapy (70 Gy) in preventing further cancer progression, with similar freedom from biochemical progression rates (62% vs. 61%).

Higher doses of radiation (70 Gy) resulted in increased gastrointestinal toxicity without any significant improvement in clinical outcomes, suggesting that conventional-dose SRT is sufficient and safer for patients with early biochemical progression after radical prostatectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-intensified Versus Conventional-dose Salvage Radiotherapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: The SAKK 09/10 Randomized Phase 3 Trial. Ghadjar, P., Hayoz, S., Bernhard, J., et al.[2022]

In a study of 554 prostate cancer patients who received salvage radiotherapy (SRT) after surgery, escalating the radiation dose to 7000 cGy or more significantly improved progression-free survival compared to lower doses, with a median follow-up of 6.8 years.

Factors such as lower tumor stages and lower Gleason scores were also associated with better progression-free survival, but the study found no significant impact on overall survival, indicating the need for longer follow-up to fully understand the benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Dose Escalation on the Efficacy of Salvage Radiotherapy for Recurrent Prostate Cancer-A Risk-Adjusted, Matched-Pair Analysis. Böhmer, D., Siegmann, A., Scharl, S., et al.[2023]

In a study of 69 prostate cancer patients treated with delayed dose-escalated salvage radiotherapy (SRT) after radical prostatectomy, the 5-year biochemical recurrence-free survival (bRFS) rate was 44%, indicating a moderate level of effectiveness for this treatment approach.

The treatment was associated with manageable toxicity, with only 9% of patients experiencing acute grade 3 urinary toxicity and 1.5% experiencing late grade 3 gastrointestinal toxicity, suggesting that while the treatment is effective, it may not provide as strong tumor control as earlier interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disease Control With Delayed Salvage Radiotherapy for Macroscopic Local Recurrence Following Radical Prostatectomy. Shelan, M., Odermatt, S., Bojaxhiu, B., et al.[2023]

A study of 925 node-negative patients showed that early salvage radiation therapy (SRT) after radical prostatectomy is effective in preventing distant metastasis, but only for specific patient groups based on their prostate cancer characteristics.

The research identified three optimal candidate groups for early SRT: those with undetectable PSA after surgery and a Gleason score of ≤7, those with undetectable PSA and a Gleason score of ≥8, and those with PSA persistence and a Gleason score of ≤7, highlighting the importance of personalized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Early Salvage Radiation Therapy in Patients with Persistently Elevated or Rising Prostate-specific Antigen After Radical Prostatectomy. Fossati, N., Karnes, RJ., Colicchia, M., et al.[2022]

Starting salvage radiotherapy (SRT) at lower prostate-specific antigen (PSA) levels significantly improves relapse-free survival (RFS), with a 2.6% decrease in RFS for each incremental 0.1 ng/mL increase in PSA before treatment.

Higher doses of SRT (70 Gy) are associated with better RFS compared to lower doses (60 Gy), suggesting that dose escalation may enhance tumor control after radical prostatectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The timing of salvage radiotherapy after radical prostatectomy: a systematic review. King, CR.[2022]

In a study of 84 Chinese patients treated with salvage radiotherapy (SRT) for prostate cancer, 56% achieved undetectable PSA levels after treatment, indicating effective biochemical control.

The 5-year survival rates showed that SRT significantly helps prevent biochemical progression (62.7%), the need for androgen deprivation therapy (83.5%), and distant metastasis (86.7%), highlighting its efficacy as a local treatment after radical prostatectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. Lee, EK., Mui, WH., Chan, AW., et al.[2018]

In a study of 859 men who underwent radical prostatectomy and chose initial observation, those with positive surgical margins or extracapsular extension had a 7-year PSA progression-free survival rate of 62%, while those with seminal vesicle invasion had a lower rate of 32%.

For patients who experienced PSA progression and received delayed salvage radiation therapy (SRT), 56% of those with positive surgical margins or extracapsular extension maintained an undetectable PSA for 5 years, indicating that SRT can be an effective treatment strategy for selected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term rates of undetectable PSA with initial observation and delayed salvage radiotherapy after radical prostatectomy. Loeb, S., Roehl, KA., Viprakasit, DP., et al.[2015]

In a study of 61 men treated with salvage radiation therapy (SRT) for recurrent prostate cancer, the long-term outcomes showed that overall survival at 10 years was 67%, indicating that SRT can be effective even after biochemical recurrence.

Patients who experienced early failure (within 1 year after SRT) had significantly worse outcomes, with only 43% distant metastases-free survival at 10 years, suggesting that this group may have more aggressive disease and could benefit from further clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Outcome of Prostate Cancer Patients Who Exhibit Biochemical Failure Despite Salvage Radiation Therapy After Radical Prostatectomy. Ying, J., Wang, CJ., Yan, J., et al.[2021]

Patients who underwent salvage radiotherapy (SRT) after radical prostatectomy (RP) reported poorer recovery in urinary, bowel, and erectile functions compared to those who had RP only, indicating a significant impact on health-related quality of life (HRQoL).

Delaying SRT for at least 7 months after RP was associated with better sexual satisfaction and improved urinary function recovery, suggesting that timing of treatment can influence the severity of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Salvage Radiotherapy and its Timing on the Health-related Quality of Life of Prostate Cancer Patients. van Stam, MA., Aaronson, NK., Pos, FJ., et al.[2019]

In a study of 151 prostate cancer patients who underwent salvage radiotherapy (sRT) after radical prostatectomy, PSA monitoring during treatment did not predict therapeutic success, indicating that PSA levels alone may not be reliable indicators of treatment effectiveness.

Despite the lack of predictive value from PSA kinetics, patients generally experienced a significant prolongation in PSA doubling times after sRT, suggesting that sRT provides a therapeutic benefit for most patients, even those with higher risk factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage radiotherapy in prostate cancer patients with biochemical relapse after radical prostatectomy : Prolongation of prostate-specific antigen doubling time in patients with subsequent biochemical progression. Lohm, G., Neumann, K., Budach, V., et al.[2018]

In a study of 1005 men with prostate cancer, it was found that postoperative PSA levels and the rate at which PSA doubles significantly influence the risk of cancer recurrence after salvage radiotherapy, with specific thresholds indicating higher risks.

Nomograms were developed to help predict the likelihood of biochemical failure, distant metastasis, and prostate cancer-specific mortality based on these PSA kinetics, providing valuable tools for guiding treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrating Prostate-specific Antigen Kinetics into Contemporary Predictive Nomograms of Salvage Radiotherapy After Radical Prostatectomy. Campbell, SR., Tom, MC., Agrawal, S., et al.[2022]

Early salvage radiotherapy (SRT) may be safer than adjuvant radiotherapy (ART) for prostate cancer patients after radical prostatectomy, as it targets only those with biochemical recurrence, potentially reducing side effects without compromising treatment outcomes.

The selection of patients for SRT and the timing of radiotherapy remain uncertain, highlighting the need for further research on the use of novel imaging techniques and genomic classifiers to optimize post-operative management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation Therapy After Radical Prostatectomy: What Has Changed Over Time? Zattoni, F., Heidegger, I., Kasivisvanathan, V., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40567132/

Understanding the Impact of Salvage Radiation on ... After 1:1 propensity score matching (2109 patients per cohort), SRT significantly reduced the risk of metastases at 5 (12.7% vs. 19.3%, p < 0.0001) and 15 years ...

2. thegreenjournal.com thegreenjournal.com/article/S0167-8140(24)00746-1/fulltext

Undetectable PSA predicts outcome after salvage ... Median follow-up after SRT was 5.6 (range 0.1–14.5) years. The 5-year BPFS was 77.8 % in patients with a PSA nadir < 0.1 ng/mL (undetectable) ...

3. mskcc.org mskcc.org/nomograms/prostate/salvage_radiation_therapy

Prostate Cancer Nomograms: Salvage Radiation Therapy Our salvage radiation therapy nomogram predicts whether a recurrence of prostate cancer after radical prostatectomy can be treated successfully with salvage ...

4. auanet.org auanet.org/guidelines-and-quality/guidelines/salvage-therapy-for-prostate-cancer

Salvage Therapy for Prostate Cancer: AUA/ASTRO/SUO ... Clinicians should inform patients that salvage radiation for a detectable prostate-specific antigen (PSA) after RP is more effective when given at lower levels ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa2214122

Fifteen-Year Outcomes after Monitoring, Surgery, or ... Of the 40 men in whom metastases had been diagnosed at 10 years, 14% had died of prostate cancer in the active-monitoring group by 15 years as ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9902708/

Efficacy and safety of salvage radiotherapy combined with ... This systematic review and meta-analysis found superior efficacy associated with adding endocrine therapy to SRT compared with SRT alone in patients with ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2405456925000227

Salvage Radiotherapy Following Nonradiotherapy Ablative ... This study provides new insights into the safety and efficacy of salvage radiotherapy (SRT) following nonradiotherapy ablative interventions ( ...

8. nature.com nature.com/articles/s41391-024-00883-3

Local salvage therapies in patients with radio-recurrent ... Overall, pooled 2-year and 5-year RFS were higher after re-irradiation salvage procedures. Indeed, 2-year RFS were 84% and 69% following salvage ...

9. urotoday.com 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

Salvage Radiotherapy Options for Biochemical Recurrence ... Salvage radiotherapy has been considered the only potentially curative therapy after biochemical failure and has been associated with better outcomes if given ...