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

Trial Summary

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.

What data supports the effectiveness of the treatment Salvage Radiotherapy for Prostate Cancer?

Research shows that salvage radiotherapy (SRT) can improve survival in prostate cancer patients who experience a rise in PSA (a protein that can indicate cancer activity) after surgery, without evidence of cancer spread. This approach may reduce side effects compared to immediate radiation after surgery, as it targets only those with signs of cancer returning. ^{1 2 3 4 5}

Is salvage radiotherapy generally safe for humans?

Salvage radiotherapy (SRT) for prostate cancer has been studied for safety, showing some patients experience urinary and gastrointestinal side effects. In one study, 9% of patients had severe urinary issues, and 7% had moderate gastrointestinal issues, but severe gastrointestinal problems were rare. ^{2 4 6 7 8}

How is salvage radiotherapy different from other treatments for prostate cancer?

Salvage radiotherapy (SRT) is unique because it is specifically used after prostate surgery (radical prostatectomy) to target any remaining cancer cells when prostate-specific antigen (PSA) levels rise, indicating a recurrence. Unlike initial treatments, SRT is applied when cancer returns, and its timing (early vs delayed) can impact its effectiveness. ^{2 9 10 11 12}

What is the purpose of this trial?

The investigators will randomize patients presenting with early BCR with a negative baseline PSMA PET/CT, to upfront SRT or surveillance. Early BCR is defined as a PSA relapse of \>0.1 to \<0.3 ng/mL. Patients in the surveillance arm will be monitored with PSA every 3 months. A repeat PSMA PET/CT will be undertaken when the PSA reaches a target level of \>0.5 to \<1.0 ng/mL. Both early radiation treatment and surveillance with repeat PSMA PET/CT imaging are within patterns of practice locally; therefore, the investigators believe that there is clinical equipoise on this subject.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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 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]

References

1. Switzerland 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. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Long-term rates of undetectable PSA with initial observation and delayed salvage radiotherapy after radical prostatectomy. [2015]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Radiation Therapy After Radical Prostatectomy: What Has Changed Over Time? [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

The Effect of Salvage Radiotherapy and its Timing on the Health-related Quality of Life of Prostate Cancer Patients. [2019]

5. Germany 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. [2018]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Integrating Prostate-specific Antigen Kinetics into Contemporary Predictive Nomograms of Salvage Radiotherapy After Radical Prostatectomy. [2022]

7. Switzerland 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. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Disease Control With Delayed Salvage Radiotherapy for Macroscopic Local Recurrence Following Radical Prostatectomy. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Impact of Early Salvage Radiation Therapy in Patients with Persistently Elevated or Rising Prostate-specific Antigen After Radical Prostatectomy. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

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

11. China pubmed.ncbi.nlm.nih.gov

Outcomes of salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. [2018]

12. United States pubmed.ncbi.nlm.nih.gov

Long-term Outcome of Prostate Cancer Patients Who Exhibit Biochemical Failure Despite Salvage Radiation Therapy After Radical Prostatectomy. [2021]