CUA 2018: Optimizing Therapy in Localized Prostate Cancer – ProtecT Study

Halifax, Nova Scotia ( Freddie Hamdy, MD gave an overview of the PROTECT study.1 He began with some examples of real-life cases of prostate cancer (PC) patients who were over or under-treated. These led him to explain what men worried about PC want to know:

  1. Whether they need to be screened
  2. What is the optimal way to be tested
  3. How accurate are the tests
  4. Do they have PC
  5. They want more detailed information about cancer itself (PSA, grade, clinical stage)
  6. The prognostic significance of the information they receive
  7. The best treatment to prevent them from dying from the cancer 
  8. The advantages and disadvantages of the treatments on offer
  9. The balance of risks when making management decisions
The big screening and treatment trials (SPCG-4, PIVOT, ERSPC, PLCO) had several fundamental factors missing. These include:

  1. Non-screen detected cases (SPCG-4 and PIVOT)
  2. Cohorts are no longer contemporary (SPCG-4 and PIVOT)
  3. Surveillance was watchful waiting
  4. Radiotherapy was not evaluated against other options
  5. Competing morbidity high and randomization low (PIVOT)
  6. Genomic diversity unknown, poor risk stratification
  7. ‘Trade-off’ insufficiently considered between oncological outcomes and patient-reported outcomes 
  8. Effective but unacceptable over-detection and over-treatment by PSA testing/biopsy (ERSPC)
  9. Heavy contamination in control arm (PLCO)
The PROTECT trial took place in the UK, between 1998-2008, encompassing 82,429 men, with 2,965 PC cases diagnosed. To date, this is the largest randomized controlled trial comparing active monitoring, surgery, and radiotherapy for PSA-detected localized PC. The 3 compared treatment arms included active monitoring (AM), which is a surveillance program, with men followed up with PSA testing and re-evaluation of their disease. The purpose was to avoid unnecessary treatment, but keep patients in a ‘window-of-curability’ if treatment became necessary. The other two treatment arms included surgery, in the form of open radical prostatectomy with routine follow-up and additional treatments as needed; and radiotherapy with neoadjuvant androgen deprivation therapy (ADT) and 74 Gray 3-D conformal external beam, with regular follow-up and additional interventions as required. 

The study consort diagram is shown in Figure 1.

Figure 1- PROTECT study Consort diagram:
UroToday CUA 2018 PROTECT study

The main results included 1% disease-specific mortality in all arms, 10% all-cause mortality in all arms, and 50% reduction in metastasis in the radical treatment arms. In the AM arm, more than 50% had received treatment by 10 years, approximately 80% of the AM arm had no sign of progression, and 44% of AM patients avoided treatment.

Significant differences were demonstrated in the erectile dysfunction (ED) and urinary incontinence rates between the arms, with the surgery arm having significantly higher rates of ED, and urinary incontinence, and the radiotherapy arm having significantly lower bowel function score. No significant difference was demonstrated in the anxiety and depression rates between the different arms.

To prevent one man from developing metastasis, 27 radical prostatectomies (RPs) had to be performed, or 33 radiotherapies. To prevent one man from developing clinical progression, 9 RPs needed to be performed. Hamdy also mentioned that economic evaluations of the PROTECT trial are currently being performed, and will be published soon.

The major points learned from the PROTECT study include:

  1. The PROTECT cohort represents patients with low and intermediate risk clinically localized disease
  2. The risk stratification at diagnosis was inaccurate and may be improved by pre-biopsy imaging, targeting, and genomics
  3. Patient-reported outcomes are like those reported by patients who receive modern treatments
  4. Patients over 65 years benefit from radical treatment
  5. The risk of death from PC over an average of 10 years is very low – 1%.
  6. Surgery and radiotherapy reduce the risk of cancer progression and spread, but cause bothersome urinary, sexual and bowel symptoms
  7. AM avoids treatment side effects, but there is increased risk of cancer progression and spread.
  8. The results are generalizable, and there is a place for each of the 3 treatment arms in disease management
  9. Longer follow-up (15-20 years) is essential in PROTECT to provide data about the ‘trade-off’ between the shorter-term effects of radical treatments, the risks of disease progression, and if any, the long-term benefits in cancer cure and survival.

Presented by: Freddie Hamdy, MD, University of Oxford, UK

1. Freddie C. Hamdy, et al. N Engl J Med 2016; 375:1415-1424

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 73rd Canadian Urological Association Annual Meeting - June 23 - 26, 2018 - Halifax, Nova Scotia