A large meta-analysis from 2016 tried to answer the question of which definitive local therapy is better for prostate cancer (radical prostatectomy or radiotherapy) (1). This meta-analysis included 95,791 patients, demonstrating significant advantages for the surgical modality compared to radiotherapy, in all aspects, including overall survival and cancer-specific survival. However, both speakers pointed out that there are major biases in this publication, which include the fact that no randomized controlled trials were included, and the fact that androgen deprivation therapy (ADT) use was not mentioned. Therefore, this publication does not help us answer this important question. Both speakers agreed that only a randomized controlled trial could attempt to answer this question. Another retrospective study published in JAMA Oncology in 2018 (2), included a large consortium of 1809 very high-risk prostate cancer patients from 12 tertiary US centers, and compared three optional treatment: radical prostatectomy, external beam radiotherapy (EBRT) alone, and EBRT + brachytherapy boost. The mean follow-up ranged between 4.2-6.3 years. This study clearly showed an advantage to the EBRT + brachytherapy group in cancer-specific survival and distant metastasis-free survival. But again, this was a retrospective study, with the usual selection bias, and did not provide us with the data that we seek.
The PROTECT study (3) was a randomized controlled study assessing 1643 patients with localized disease, including 58% with low-risk disease, 40% with intermediate-risk disease, and 2% with high-risk disease. Patients were randomized to either radical prostatectomy, radiotherapy and six months of ADT, or active monitoring. The mean follow-up was ten years, and the results showed no difference in the specific cancer death rate (p=0.48) between surgery (0.9%), radiotherapy with six months of ADT (0.7%) and active monitoring (1.4%). The Kaplan Meier curves for survival were overlying each other, with absolutely no difference. Furthermore, no difference was seen in the quality of life between the three groups, but slight differences were witnessed in the various specific domains, with worse bowel function and worse erectile dysfunction in the radiotherapy and surgery groups, respectively. There was also a significant difference in the rate of metastases, with a higher rate in the active monitoring group (6%) after ten years of follow-up.
An important point raised by the speakers was the rate of additional cancer that is caused by radiotherapy. In the meta-analysis mentioned before (1) and published in European Urology, the odds ratio for developing bladder, colon, and rectal cancers after radiotherapy compared to surgery were 1.39, 1.68, and 1.62, respectively. This could be a major issue, leading patients to choose surgery over radiotherapy. However, the speakers note that these numbers are not relevant to the type of radiotherapy that is given today. Furthermore, there is a significant difference between the various types of radiotherapy modalities, with three-dimensional conformal radiotherapy (3D-CRT) and intensity modulated radiation therapy (IMRT), and stereotactic body radiotherapy (SBRT) resulting in a much higher risk for secondary cancers than brachytherapy.
This figure demonstrates the risk of second cancer, stratified by the organ and radiotherapy modality. Another important flaw in this finding of increased risk of secondary cancer is the fact that the control group was patients who underwent surgery for prostate cancer. These patients’ risk for a secondary malignancy is lower than in the general population, and the comparison is not appropriate. Lastly, in the meta-analysis there is missing information on confounders, comorbidities and other risk factors for cancer such as smoking, and obesity, further questioning the validity of this finding.
The next debate raised was whether the increased age of a patient is a contraindication for surgery, due to the increased risk of side effects. In a large study examining the outcomes of patients, stratified according to their age, it was shown the older men were at increased risk for erectile dysfunction (51% in men older than 70, vs. 92% in men younger than 52), and return of continence (86% in men older than 70 vs. 95% in men younger than 52). (4) Elderly men recover slower and reach lower functional results than younger men.
Whether patients with high-risk disease can undergo surgery was another question raised by Dr. Bossi, the radiation oncologist. In an analysis of 492 patients with high-risk disease that were excluded from the PROTECT study, 54 patients underwent surgery, and 254 patients underwent radiotherapy (with 93% of them receiving ADT as well). Both groups had a high percentage of patients receiving multimodal therapy. The results demonstrated no difference between the surgery and radiotherapy groups regarding cancer-specific survival and overall survival.
Figure 2 – Comparison of high-risk prostate cancer patients treated with radical prostatectomy, radiotherapy, and ADT alone:
Even when there is clinically node-positive disease, surgical therapy is still an equal therapeutic option. (5)
Next, Dr. Mottet raised the question whether a history of a previous TURP is a contraindication for brachytherapy. Limited TURP for men with moderate lower urinary tract symptoms (LUTS) before brachytherapy for prostate cancer is feasible and safe. A study published in 2015 analyzed 2000 patients who underwent limited TURP at a median of 64 days before brachytherapy. The results demonstrated that there was a significant improvement of IPSS, post void residual, uroflow, and quality of life, without an increase in the risk of acute urinary retention following brachytherapy. (6)
Lastly, the speakers concluded their discussion by mentioning the absolute contraindications for surgery and radiotherapy. For radical prostatectomy patients unwilling to accept potential side effects, those who cannot undergo general anesthesia, and patients with major coagulation issues should not undergo surgery. For radiotherapy, patients unwilling to accept potential side effects, patients with significant major voiding problems, and for EBRT – previous pelvic radiotherapy, and for brachytherapy – previous major TURP procedures, should all not undergo radiotherapy. Dr. Mottet also pointed out that salvage prostatectomy after recurrence in patients who underwent radiotherapy is a more difficult procedure, but can be performed in experienced highly trained centers with good results.
The ideal candidate for surgery or radiotherapy is a patient who decides for himself after complete and informed consent, and after hearing all the benefits and drawbacks of both of these modalities.
Speaker:A. Bossi, Villejuif (FR) N. Mottet, Saint-Étienne (FR)
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2nd EAU Update on Prostate Cancer (PCa18)– September 14-15, 2018 – Milan, Italy
1. Wallis et al. Eur Urol 2016
2. Kishan et al. JAMA Oncol, 2018
3. Hamdy et al. N Eng. J. Med, 2016
4. Kundu et al. J Urol 2004
5. Moschini et al. Eur Urol, 2016
6. Brousil et al. BJUI, 2015