The recent study by Nam et al in The Lancet Oncology—reviewed in this issue of The ASCO Post—provides a fresh perspective on complications other than incontinence or erectile dysfunction that commonly arise after primary treatment of localized prostate cancer.1 The authors conducted a population-based retrospective cohort study using administrative databases to compare 5-year cumulative incidences of hospital admissions, minimally invasive urologic procedures, rectal or anal procedures, open surgical procedures, and secondary neoplasms. Strikingly, the authors uncovered the fact that the rates of these complications may be far higher than previously thought.
The authors are to be commended for looking beyond the two most common adverse events after primary therapy to other complications that are perhaps less appreciated by clinicians and patients alike but that can have serious, detrimental effects on future quality of life.2 The study provides sound, detailed methodologic approaches to allow others to validate these results in additional populations.
Notable Implications
The population-based nature of the data with age-matched controls provides a clear picture of what a patient can expect in the 5 years following treatment for prostate cancer. Specifically, patients undergoing treatment were 17.9 times more likely to be admitted to the hospital, 6.8 times more likely to undergo a urologic procedure, twice as likely to have a rectal or anal procedure, and 6.0 times as likely to have an open surgical procedure as compared to the general population.
While these data do not elucidate any information on stage or grade of prostate cancer, the implications from the standpoint of any overdiagnosis and subsequent overtreatment of prostate cancer are astounding, primary treatment modality aside.3 While capturing similar data for patients who choose active surveillance might be impossible with an administrative dataset (there are no such procedural billing codes, to these authors’ knowledge, that would capture patients on active surveillance), one must wonder whether these numbers would hold true. With these data at hand, the principle of primum non nocere should weigh even more heavily on those who administer prostate cancer treatment.
Divergence of Experience
If a patient does choose to undergo treatment, these data demonstrate a divergence of experience between radiation and surgery. Patients who received both surgery and radiation were excluded. Those choosing forms of radio-therapy experienced higher 5-year incidences of hospital admissions (≥ 1 day), rectal or anal procedures, open surgical procedures, and secondary malignancies than those who chose radical prostatectomy, implying increased rates of urethral and ureteral stricture, proctitis and rectal problems, and refractory cystitis.
The study is limited by an inability to specify what form of radiotherapy was delivered (external-beam conformal radiation, intensity-modulated radiation therapy, image-guided radiation therapy, brachytherapy, or stereotactic radiation). Some forms of radiotherapy likely provide differing rates of toxicity, but this study does not elucidate such differences.
Those opting for radiation were, however, less likely to undergo subsequent urologic procedures (cystoscopy, catheterization, urethral dilation or incision, or calculi or clot removal) than the surgical group (hazard ratio = 0.66, 95% confidence interval [CI] = 0.63–0.69). Furthermore, while longer lengths of stay were more common in the radiotherapy group, this is not entirely unexpected given the older age and increased comorbidity in these patients.
Contentiously, the authors did opt to count post-radiation prostate biopsy as a complication (accounting for 6% of all complication events in that group). The authors note that biopsy after radiation is not “expected or routine.” One could argue against inclusion of these events on the basis that they represent patients with biochemical failure, which is a feature of any prostate cancer treatment. Still, omission would detract from the totality of post-treatment procedures. Conversely, one could argue that the authors should have considered adjuvant or salvage radiation after prostatectomy as a complication, but they state quite correctly they wanted to avoid contamination of the two groups.
One curiosity in this large, population-based study is how 35 patients underwent open bladder neck repair after radiotherapy, whereas no prostatectomy patients suffered a similar fate, despite a larger incidence of catheterization and urethral dilation/incision in the surgical cohort—proving that bladder neck contracture occurs commonly with both treatments. This speaks highly to the biases of treatment sought and received when patients are under the care of a urologist as opposed to a radiation oncologist.
This same argument applies to the control group population: Patients who did not receive regular care by a urologist might have avoided some procedures that would have otherwise been delivered or indicated. Prostate cancer patients are often highly motivated to seek attention and treatment, more so than the general population. This form of spectrum bias may speak to the higher-than-expected incidence of complications reported in this study.4
Elephant in the Room
Addressing the elephant in the room, the authors studied the rate of secondary malignancy after radiation treatment, comparing the incidence from years 5 through 9 (accounting for lag time after delivery of radiation) in both the control population and surgically treated patients. Risk of secondary cancer was 309 per 100,000 person-years in the radiotherapy group and 113 per 100,000 person-years in the surgery group, with a standardized incidence ratio (comparing incidence in each group to expected rates of cancer in an age-adjusted general population) of 2.0 (95% CI = 1.7–2.3) for radiotherapy and 0.8 (95% CI = 0.6–1.0) for surgery.
The authors determined there was no improvement in rate of secondary malignancy when the analysis was restricted to patients who received contemporary radiation treatment with three-dimensional treatment planning. The literature cites rates ranging from 1.9% to 9% after radiotherapy for prostate cancer.5-8 Despite the large range within the literature, given the lag time, one can assume older patients with shorter life expectancies to suffer lower rates of secondary neoplasm than younger, healthier patients, confirming previous data.8 These data, however small, show that the risk of secondary cancer attributable to radiation is not zero, and this will likely generate much discussion within the radiation oncology community.
This study is limited in the degree of certainty in tying secondary events to treatment for prostate cancer, as the use of administrative databases may overestimate the risk of these events.9,10 Unfortunately, androgen-deprivation therapy could not be accounted for due to a lack of data on all patients. Robotic-assisted laparoscopic prostatectomy was also excluded given lack of broad adoption during the study period. Including these patients for subanalysis might further influence the results and provide insight into the modern delivery of prostate cancer treatment. Still, this study provides a unique global view of activities following treatment of prostate cancer on a population scale.
Informed Decision-Making
In an era of patient-centered medicine, informed decision-making is key. This study demonstrates that there are vastly different types and rates of complications between primary treatment modalities across a modern population of prostate cancer patients. To address these differences, clinicians must have an open conversation with patients that details possible adverse effects of treatment, including urinary incontinence and erectile dysfunction.
Furthermore, we know that patient retention of information after any single clinic visit can be dismally low, owing to a number of factors including socioeconomic status, patient anxiety, and foreignness of information to be digested. Given the complexity of discussing treatments, a multidisciplinary approach (some combination of urologist, radiation oncologist, medical oncologist, pathologist, radiologist, and patient advocate) is paramount to providing the patient with an unbiased, accurate picture of treatment and expectations that allows careful consideration of the risks and benefits of each treatment approach.11-13
Disclosure: Drs. Higuchi and Crawford reported no potential conflicts of interest. Dr. Rove receives honoraria from UBM Medica.
References
1. Nam RK, Cheung P, Herschorn S, et al: Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer. Lancet Oncol 15: 223-231, 2014.
2. Elliott SP, McAninch JW, Chi T, et al: Management of severe urethral complications of prostate cancer therapy. J Urol 176:2508-2513, 2006.
3. Bangma CH, Roemeling S, Schröder FH: Overdiagnosis and overtreatment of early detected prostate cancer. World J Urol 25:3-9, 2007.
4. Potosky AL, Davis WW, Hoffman RM, et al: Five-year outcomes after prostatectomy or radiotherapy for prostate cancer. J Natl Cancer Inst 96:1358-1367, 2004.
5. Baxter NN, Tepper JE, Durham SB, et al: Increased risk of rectal cancer after prostate radiation. Gastroenterology 128:819-824, 2005.
6. Liauw SL, Sylvester JE, Morris CG, et al: Second malignancies after prostate brachytherapy. Int J Radiat Oncol Biol Phys 66:669-673, 2006.
7. Abdel-Wahab M, Reis IM, Hamilton K: Second primary cancer after radiotherapy for prostate cancer—a SEER analysis of brachytherapy versus external beam radiotherapy. Int J Radiat Oncol Biol Phys 72:58-68, 2008.
8. de Gonzalez AB, Curtis RE, Kry SF, et al: Proportion of second cancers attributable to radiotherapy treatment in adults. Lancet Oncol 12:353-360, 2011.
9. Resnick MJ, Koyama T, Fan K-H, et al: Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med 368:436-445, 2013.
10. Sewell JM, Rao A, Elliott SP: Validating a claims-based method for assessing severe rectal and urinary adverse effects of radiotherapy. Urology 82:335-340, 2013.
11. Gomella LG: Prostate cancer. Nat Rev Urol 9:360-362, 2012.
12. Magnani T, Valdagni R, Salvioni R, et al: The 6-year attendance of a multidisciplinary prostate cancer clinic in Italy. BJU Int 110:998-1003, 2012.
13. Stewart SB, Bañez LL, Robertson CN, et al: Utilization trends at a multidisciplinary prostate cancer clinic. J Urol 187:103-108, 2012.
Dr. Rove is a resident in general urology; Dr. Higuchi is Assistant Professor, Surgery/Urology; and Dr. Crawford is Professor of Radiation Oncology, Division of Urology, University of Colorado, Anschutz Medical Campus, Aurora.
