What is the best treatment for prostate cancer?

15 year outcome of ProtecT Study

Prostate cancer is one of the most common cancers in men. The ProtecT study is a landmark study led by Professor Hamdy of Oxford University, which has evaluated by randomization, the three most common treatments for early or localized prostate cancer; radical prostatectomy (surgery carried out to remove the prostate, normally performed as keyhole surgery with the help of a robot), radical radiotherapy or active surveillance. Active surveillance means that no treatment is started but patients are closely monitored until they ever show any signs of disease progression, then they can go on to active treatment, usually prostatectomy or radiotherapy. The advantage of active surveillance is that treatment, with its associated risks and complications may be avoided or delayed until necessary, thereby minimising the impact on quality of life.

Prostate cancer studies require very long follow up as it is often a slowly progressing disease, and its evaluation is complicated by its nature as a disease of the elderly, who may have other illnesses which pose a greater risk to their health than the prostate cancer.

The 15-year outcomes were recently published in the New England Journal of Medicine.

So, what are the main findings?

The good news is that the prostate cancer specific mortality was lower than expected (3.0% of people died of prostate cancer after 15 years, less than the 10%+ expected).

There is an equivalence between the three treatment groups. No treatment option has been proven to better than the other yet. The trial can give patients, who have been started on active surveillance, confidence that they are unlikely to have caused any harm to themselves by deferring treatment. On the other hand, 61% of people started on active surveillance eventually went on to have treatment (largely radical prostatectomy or radiotherapy), so some patients will see that they are likely to require treatment eventually and may choose to cross that hurdle at an early opportunity. Follow up needs to be prolonged as disease progression can occur many years later and there has sometimes been a tendency to reduce the intensity of follow up in the later years.

One of the problems with long studies, is the inevitable changes in technology and medical practice which occur over time which no one can predict but can catch up with any study and it is off course easy to highlight them with the benefit of hindsight.

Soon after the ProtecT study was initiated, the use of MRI prostate prior to carrying out a prostate biopsy became more common which means that patients today can be assessed more precisely before they are treated, than the patients who were recruited to the ProtecT study. When compared to current patients, It is more likely that patients recruited to the ProtecT study had the amount and aggressiveness of cancer in the prostate underappreciated, if they were not randomised to have their prostate removed, in which cases a thorough evaluation of the whole prostate is made. Despite this, the ProtecT study cohort mainly consists of lower risk patients which may not reflect the current trends where it is more likely that higher risk cancer is detected rather than missed because of MRI which acts a lens which can highlight significant disease in the prostate whilst ignoring lower risk disease which may not need to be diagnosed.

The ProtecT study is a huge undertaking. 82000 men between the ages of 50 and 69 were recruited to the study and screened for prostate cancer. However, in retrospect, though it is the largest trial of its kind, there is probably insufficient volume of patients with higher risk disease, to allow a differentiation between the three treatment groups that are being compared.

When the ProtecT study was designed, it was expected that roughly 10% of patients would die of prostate cancer at 10 years. Prostate cancer death is the primary outcome. A study can have only one primary outcome, but several secondary outcomes can also be evaluated. Some of the secondary study outcomes were death form any cause, disease progression, evidence of spread of disease outside of the prostate and starting hormonal treatment.

This expected mortality rate was a reasonable assumption based on previous trial data. Thankfully much lower rates of prostate cancer deaths occurred. In the active surveillance group (total 545), 419 have low risk disease (grade group 1) and the prostate cancer specific mortality is 2.6% at 15 years. There are 93 with intermediate risk disease (grade group 2) with a 4.6% prostate cancer specific mortality and 33 patients with high-risk disease (grade group ≥3) who had a 6.1% mortality.

Most of the ProtecT trial patients have low risk disease, which makes the trial less powerful, as the main outcome that is being evaluated occurs infrequently, and in retrospect a larger number of patients would likely have been needed to prove a difference, but 15 years follow up is still early days for a prostate cancer trial and there will be some divergence in outcome with time between the different groups, but whether this difference becomes large enough so that it can be declared to have arisen without chance remains to be seen. There was a difference between the groups with regards to secondary outcomes, with a higher number of patients who had diseases that spread outside of the prostate and disease progression in the active surveillance group compared to the two upfront treatment groups.

So we don’t know which is the best treatment as such and it remains a personal choice that patients will need to make based on their preferences and evaluation of the different side effects of treatment.

The mystery remains why there is a less than 1% absolute difference in cancer specific mortality between upfront and delayed treatments and the study makes prostate cancer seem like a very indolent disease, yet 10000 men die each year from prostate cancer in the UK, which means our current practice is less than optimal, and there is still plenty of work to de done to find the right patients who will benefit most form treatment. The paper alludes to yet undiscovered lethality factors, that could facilitate prognosis and patient selection for treatment.

References

1.            Hamdy FC,Donovan JL, Lane JA, et al. Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. [cited 2023 May 1];388(17):1547–58.

2.            Klotz L,Chin J, Black PC, et al. Comparison of Multiparametric Magnetic Resonance Imaging–Targeted Biopsy With Systematic Transrectal Ultrasonography Biopsy for Biopsy-Naive Men at Risk for Prostate Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol [Internet] 2021 [cited 2023 May 1];7(4):534–42.

3.            Hamdy FC,Donovan JL, Lane JA, et al. 10-Year Outcomes after Monitoring, Surgery, orRadiotherapy for Localized Prostate Cancer. New England Journal of Medicine[Internet] 2016 [cited 2023 May 1];375(15):1415–24.