High-risk prostate cancer (PCa) is well defined, but opinions vary on whether radical prostatectomy or radiation therapy is the best treatment approach.


“As a high volume radical prostatectomist and urologic oncologist, I feel that a modern-day radical prostatectomy yields better long-term overall quality-of-life than radiotherapy,” said Judd Moul, MD, professor of surgery and anesthesiology in the division of urology at Duke University Medical Center in Durham, North Carolina. “However, I am also a die-hard fan and believer in multi-disciplinary care for men with prostate cancer and feel that all men with localized prostate cancer deserve to be seen by both a surgeon and a radiation oncologist and ideally a medical oncologist if applicable before making an informed decision.”


High-risk PCa is defined as bilaterally clinically palpable tumors extending beyond the prostatic capsule, with PSA levels of 20 ng/mL or higher or a Gleason score of 8 or higher. Dr Moul and colleagues have examined which approach may be the best and found that treatment options for high-risk disease continue to be refined and remain controversial.1


Among the best arguments in favor of surgery over radiation is the use of androgen deprivation therapy (ADT), particularly for most intermediate and high-risk men. “I applaud the radiation oncology community for doing outstanding randomized clinical trials showing a benefit of adding ADT to radiotherapy alone, but this is also an Achilles' heel regarding quality-of-life,” Dr Moul told Renal & Urology News.


In a recently published study of 1424 men who underwent open or robotic-assisted RP from 2004 to 2015, Dr Moul and collaborators found that 61.5% of patients with clinical Gleason 8 disease on prostate biopsy were downgraded on RP, with 58.8% downgraded to Gleason 7.2


“If all of these clinical high-risk men had elected radiotherapy, they could have been subjected to 18 months or more of ADT. In my mind, this sampling error and ascertainment error in clinical risk assessment is the biggest selling point for surgery, particularly for men who are characterized as high-risk by biopsy alone,” Dr Moul said. 


James Mohler, MD, professor of oncology in the department of urology at Roswell Park Cancer Institute in Buffalo, New York, and chair of the National Comprehensive Cancer Network Guidelines Panel for Prostate Cancer, said “nomograms usually demonstrate lower 5-year biochemical progression-free survival (PFS) rates for surgery than radiation with 2–3 years of neoadjuvant/concurrent/adjuvant androgen deprivation therapy.” The nomograms suffer somewhat from the relative rarity of RP for high-risk PCa, since operation has been uncommon until the last few years. “I generally recommend operation over radiation for younger men who wish their cancer gone, who want to try to avoid the need for 2 to 3 years ADT, and who want to avoid radiation, although as many as half the men who choose operation will require later adjuvant or salvage radiation,” Dr Mohler said.


The ProtecT (Prostate Testing for Cancer and Treatment) trial is the only randomized controlled trial showing no difference between surgery and radiotherapy at 10-year follow up. The trial, however, was not applicable to high-risk patients.3 Sam S. Chang, MD, MBA, professor of urologic surgery and oncology at Vanderbilt University Medical Center in Nashville, Tennessee, said although there are no head-to-head data specifically for high-risk patients, it is possible to look at multiple studies that used propensity score matching. “Prostatectomy seems to have better cancer outcomes,” Dr Chang said. “Large randomized trials of localized prostate cancer as a large group show no benefit of one treatment over the other with different side effects.”


In patients who are appropriate candidates for surgery, the pathologic data obtained allows better risk stratification, Dr Chang said. Such data may obviate the need for multimodality therapy.  “Newer diagnostic tools such as multiparametric MRI as well as genetic prognostic tests may help us better individualize the appropriate therapy,” he said. 


According to Suneil Jain, MD, from the Centre for Cancer Research & Cell Biology at Queen's University Belfast in Belfast, Northern Ireland, only 2% of patients in the ProtecT study had high-risk disease, so no conclusions can be drawn from it. Still, he believes the evidence for the use of radiotherapy to treat high-risk PCa is stronger than for surgical treatments. “Well-powered clinical trials have clearly demonstrated that radiation plus ADT improves overall survival compared to ADT alone,” Dr Jain said.


Retrospective and population-based studies are subject to multiple biases, including gatekeeper bias, he said. Data from the STAMPEDE study presented at the European Society for Medical Oncology (ESMO) 2017 conference in September demonstrated the best results for high-risk localized PCa to date. Investigators reported data from patients with high-risk localized PCa randomized to radiotherapy and ADT or radiotherapy, ADT, and 2 years of abiraterone with prednisone. “Amazingly, 3-year failure free survival improved from 80% to 98% with the addition of abiraterone,” Dr Jain said.


Michael Zelefsky, MD, professor of radiation oncology and chief of brachytherapy at Memorial Sloan Kettering Cancer Center in New York, said there is no Level I evidence to support one form of therapy over the other for patients with high-risk disease. “Nevertheless, the retrospective data comparing surgery and radiotherapy suggesting inferior survival outcomes among patients receiving radiotherapy are flawed because of the very different patient populations and their co-morbidities and age as well as the less intense radiation dose levels used years ago,” Dr Zelefsky said.


In a study of high-risk patients who were excluded from the ProtecT trial, he noted, investigators found no difference in PCa-specific or overall survival between surgery and radiation therapy.5


Prior studies of high-risk patients only compared surgery to external beam radiation therapy (EBRT), Dr Zelefsky said. Recently published results from the ASCENDE-RT (Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy) trial—which compared external beam radiation therapy (EBRT) alone and brachytherapy plus EBRT in high-risk patients— demonstrated a marked improvement in the 10-year PSA relapse free survival for the combined regimen. “It is not surprising that radiotherapy in the prior comparison studies didn't do as well,” Dr Zelefsky said. “The studies never compared surgery with the most optimal form of radiotherapy for high-risk disease.”


References


1.  Qi R, Moul J. High-risk prostate cancer: Role of radical prostatectomy and radiation therapy. Oncol Res Treat 2015;38:639-644 doi: 10.1159/000441736


2. Qi R, Foo WC, Ferrandino MN, et al. Over half of contemporary clinical Gleason 8 on prostate biopsy are downgraded at radical prostatectomy. Can J Urol. 2017; 24:8982-8989.


3. Hamdy FC, Donovan JL, Lane JA, et al. ProtecT Study Group. 10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl  J Med. 2016;375:1415-1424.


4.ESMO 2017: Adding Abiraterone Acetate or Docetaxel Plus Prednisone to Standard of Care in Patients with High-Risk Prostate Cancer [news release]. European Study for Medical Oncology; September 8, 2017.


5. Johnston TJ, Shaw GL, Lamb AD, et al. Mortality among men with advanced prostate cancer excluded from the ProtecT trial. Eur Urol. 2017;71:381-388.