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Challenge of Locally Persistent Prostate Cancer: An Unresolved Clinical Dilemma

University of Texas Health Science Center, San Antonio, TX

THE ARTICLE BY Coen et al¹ addresses an important issue in the management of prostate cancer. The hypothesis intuitively seems clinically valid but is difficult to prove. The investigators hypothesize that a subset of patients with localized prostate cancer will experience a late wave of metastasis attributable to persistence of cancer within the prostate. Furthermore, their conclusions suggest that effective control of the primary would reduce the rate of delayed metastasis.

Many clinical investigators have speculated on the relationship of persistence of primary cancer to later metastases. As the authors note, several lines of clinical evidence implicate persistence of prostate cancer in later relapse. The competing, and equally compelling, hypothesis to explain the observed phenomenon is that resistance to radiation therapy is also predictive of metastasis. There are clinical and laboratory data to support this view as well. Clinically, both tumor grade and tumor stage are predictive of metastases as well as failure to respond to the definitive radiation therapy.^2-4

The primary objective of the study was to determine whether locally persistent tumor after radiation was the cause of distant metastasis. A total of 1,469 patients were available for study, and it seems that data quality and follow-up were good. The patient sample size was adequate to address this issue. The problem, however, is that the statistical issues raised by these questions are complex. The investigators have made the simplistic assumption that detection of local disease at any time in the disease course, before or after discovery of distant metastasis, exclusively categorizes patients as failures for local control. There are many obvious problems with this, including the length of follow-up available, biases introduced by extent of surveillance, and impact of intervening treatment once local control is detected. There are statistical methods for consideration of competing risks and time-dependent effects that might add more confidence to the conclusions, even though the application of these methods may leave the question unresolved.^5-8

From a clinical perspective, the duration of follow-up, absence of a prospective definition of local control and standardization of assessment intervals, and the effect of the widespread application of prostate-specific antigen may have had an impact on these results. Although the data does not conclusively support the authors’ argument, further follow-up of these patients may help elucidate some of the issues. Thus, one must conclude that the central question the authors ask has not been critically tested. However, the observations they report may become the foundation for design of studies to address the problem. The authors have attempted to assess the impact of a single element of a complex treatment strategy in an environment of evolving medical practice. Effectively addressing this question could help clarify specific clinical dilemmas for patients with prostate cancer. The availability of new technology for the safe delivery of radiation therapy allows clinicians to maximally and safely explore the radiation dose-response relationship to effectively control the primary. However, the therapeutic options in patients with persistent cancer after radiation therapy have significant clinical complications. Salvage surgery or cryotherapy result in significant complications, as does continuous and sustained androgen.⁹ If the evidence were stronger in support of the effects of local control on metastasis, one would be more inclined to recommend an intervention. Unfortunately, the current state of knowledge continues to leave clinicians and patients in a quandary. Future studies will benefit from a more thorough characterization of the heterogeneous patient population by cellular and molecular predictors of outcome. Integrating those observations with clinical investigation up to the task of detecting the impact of individual elements of complex therapy strategies provides promise for the resolution of these important clinical questions.

REFERENCES

1. Coen JJ, Zietman AL, Thakral H, et al: Radical radiation for localized prostate cancer: Local persistence of disease results in a late wave of metastases. J Clin Oncol 20: 3199-3205, 2002[Abstract/Free Full Text]

2. Hanks GE, Hanlon AL, Horwitz EM: Evidence for cure of ‘young’ men with prostate cancer. Oncology 15:563-567; discussion 571-574, 2001

3. Han M, Partin AW, Pound CR, et al: Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy: The 15-year Johns Hopkins experience. Urol Clin North Am 28: 555-565, 2001[CrossRef][Medline]

4. Kattan MW, Zelefsky MJ, Kupelian PA, et al: Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer. J Clin Oncol 18: 3352-3359, 2000[Abstract/Free Full Text]

5. Gaynor JJ, Feuer EJ, Tan CC, et al: On the use of cause-specific failure and conditional failure probabilities: Examples from clinical oncology data (in applications and case studies). J Am Stat Assoc 88: 400-409, 1993[CrossRef]

6. Kay R: Treatment effects in competing-risks analysis of prostate cancer data. Biometrics 42: 203-211, 1986[CrossRef][Medline]

7. Lunn M, McNeil D: Applying Cox regression to competing risks. Biometrics 51: 524-532, 1995[CrossRef][Medline]

8. Gelman R, Gelber R, Henderson IC, et al: Improved methodology for analyzing local and distant recurrence. CO 8: 548-555, 1990

9. Cespedes RD, Pisters LL, von Eschenbach AC, et al: Long-term followup of incontinence and obstruction after salvage cryosurgical ablation of the prostate: Results in 143 patients. J Urol 157: 237-240, 1997[Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Logothetis, C. J. Search for Related Content PubMed PubMed Citation Articles by Logothetis, C. J. Social Bookmarking                            What's this?