The study showed a significantly higher overall death rate, prostate cancer–specific death rate, and rate of distant metastases in the watchful waiting group. However, many patients in this group did not develop metastases or die of cancer. As is often the case in prostate cancer, there are few absolute truths.
—Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
I have spent my career working with urologists. Over a long period of time, I have concluded that they are fine and interesting people who work hard, live well, support interesting hobbies, generally take good care of their families, and are very enjoyable company at parties.
The recent discussion of prostate-specific antigen (PSA) and prostate screening, with a host of encyclicals and guidelines decrying the utility of these tools, accompanied by the development of a series of novel treatment agents, has led to discussions of whether the domain of urology is really necessary for cancer management, beyond the role of initial diagnosis.
Pioneers of Uro-oncology
I have had the good fortune to work with some very fine uro-oncology surgical thinkers and technicians of the modern era, including Don Skinner, Paul Lange, Elwin Fraley, John Rogers, the late Bruce Pearson, and the late John Stein, among others. Each of them had the gift of looking beyond the cystoscope, or the tools of laparotomy and laparoscopy, and thinking about the biology and management of the range of urologic malignancies, and the interplay of those broader issues with their own technical craft.
Skinner, Stein, and their colleagues thought carefully about the evolution of invasive bladder cancer and its association with gene mutation, and developed a superb technical approach to local control, augmented by strategic thinking about prediction, prognostication, and management of occult metastases.1,2 Similarly Lange, Fraley and their teams advocated multidisciplinary management of genitourinary cancer, predicated on outstanding surgical skill, rational use of molecular predictors, and thoughtful interplay with basic scientists focused on extensions of basic biology of testis,3 bladder,4 and prostate cancer.5 Rogers and Pearson, both technically excellent, worked with me 30 years ago to develop the early paradigms of neoadjuvant therapy for bladder cancer,6,7 interspersed with their support of extensive preclinical modeling,8 and then tested those paradigms in a series of randomized trials.9,10
What has united these fine fellows is the quest for understanding, and their preparedness to test hypotheses carefully, integrating strong basic science with carefully constructed and executed clinical trials. In addition, they had the ability to undertake complex postchemotherapy surgery (for example, extensive retroperitoneal lymph node dissection after chemotherapy for advanced germ cell tumors), with sure hands and the ability to avoid apologies for being unable to resect the residual masses. This made Skinner, Stein, and Rogers absolutely invaluable in the curative treatment of testis cancer. We surely know how important that contribution is.11
Prostate cancer is more puzzling, and the issues of PSA and screening, while appropriately under attack, remain conundrums for further investigation.12 That said, it is clear that aggressive prostate cancers do require treatment.
Recently there has been an increasing trend toward watchful waiting—or even the more aggressive “active surveillance”—for newly diagnosed stage I-II prostate cancer. In an important, planned update of their randomized trial, Bill-Axelson and colleagues13 from Scandinavia have shown quite clearly the importance of surgery in achieving cure of prostate cancer, and the potential dangers of loosely structured watchful waiting.
This is a well-designed and meaningful study. Over a 10-year period from 1989, this team randomly assigned 695 men younger than 75 years of age with clinical stage T1-T2 prostate cancer to radical prostatectomy or watchful waiting. Of importance, all patients were required to have a PSA level less than 50 ng/mL and a negative bone scan, and the PSA cutoff may have had important implications for the outcome of the study. PSA values greater than 20 ng/mL can easily reflect nodal or more distant involvement, and this could have influenced some of the outcomes of the trial.
The study showed a significantly higher overall death rate, prostate cancer–specific death rate, rate of distant metastases, and rate of use of androgen-deprivation therapy in the watchful waiting group. However, also of importance, many patients in this surveillance group did not develop metastases or die of cancer. As is often the case in prostate cancer, there are few absolute truths.
Another important caveat is that the study population may differ somewhat from that found in the United States, and watchful waiting, in a potentially less anxious and less test-oriented population, could be less intense and less effective (but also much cheaper) than in the U.S. This study certainly signals the need for caution and structured follow-up when placing patients with localized prostate cancer into observational protocols.
After 30 years in the field, I still don’t know whether radical prostatectomy, image-guided external-beam radiotherapy, or brachytherapy is the best option for the definitive treatment of localized prostate cancer, nor am I able to easily define the exact population requiring active treatment. However, I do realize that there are cases where something active needs to be done by someone with expertise. I just wish that more urologists would be prepared to test hypotheses, secure structured data, and practice evidence-based medicine like the wonderfully valuable pioneers and statesmen of uro-oncology mentioned above. ■
Disclosure: Dr. Raghavan reported no potential conflicts of interest.
Dr. Raghavan is President, Levine Cancer Institute, Charlotte, North Carolina.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.
1. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 19:666-675, 2001.
2. Stadler WM, Lerner SP, Groshen S, et al: Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on P53 status. J Clin Oncol 29:3443-3449, 2011.
3. Lange PH, Vogelzang NJ, Goldman A, et al: Marker half-life analysis as a prognostic tool in testicular cancer. J Urol 128:708-711, 1982.
4. Lange PH, Ercole CJ, Lightner DJ, et al: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J Urol 141:873-879, 1989.
5. Limas C, Lange P, Fraley EE, et al: A, B, H antigens in transitional cell tumors of the urinary bladder: Correlation with the clinical course. Cancer 44:2099-2107, 1979.
6. Raghavan D, Pearson B, Coorey G, et al: Intravenous cisplatinum for invasive bladder cancer: Safety and feasibility of a new approach. Med J Aust 140:276-278, 1984.
7. Raghavan D, Pearson B, Duval P, et al: Initial intravenous cis-platinum therapy: Improved management for invasive high risk bladder cancer? J Urol 133:399-402, 1985.
8. Russell PJ, Raghavan D, Gregory P, et al: Bladder cancer xenografts: A model of tumor cell heterogeneity. Cancer Res 46:2035-2040, 1986.
9. Wallace DM, Raghavan D, Kelly KA, et al: Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Br J Urol 67:608-615, 1991.
10. International Collaboration of Trialists: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: Long-term results of the BA06 30894 trial. J Clin Oncol 29:2171-2177, 2011.
11. Riggs SB, Burgess EF, Gaston KE, et al: Postchemotherapy surgery for germ cell tumors—what have we learned in 35 years? Oncologist. April 9, 2014 (early release online).
12. Raghavan D: PSA: Please stop agonizing (over prostate-specific antigen interpretation). Mayo Clin Proc 88:1-3, 2013.
13. Bill-Axelson A, Holmberg L, Garmo H, et al: Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 370:932-942, 2014.
The long-term benefits of radical prostatectomy vs watchful waiting in men with localized prostate cancer has remained a debated issue. As reported in The New England Journal of Medicine by Anna Bill-Axelson, MD, of Uppsala University Hospital, and colleagues, additional long-term follow-up in the...