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Referring to the article published on pp. 1–7 of this issueReferring to the article published on pp. 1–7 of this issue

Defining and Treating High-Risk Prostate Cancer: Can We Do Better?

By: Leah Gerbera c, Lionel L. Bañeza c and Stephen J. Freedlanda b c lowast

European Urology, Volume 58 Issue 1, July 2010, Pages 8-9

Published online: 01 July 2010

Abstract Full Text Full Text PDF (91 KB)

Refers to article:

Outcome Predictors of Radical Prostatectomy in Patients With Prostate-Specific Antigen Greater Than 20 ng/ml: A European Multi-Institutional Study of 712 Patients

Martin Spahn, Steven Joniau, Paolo Gontero, Steffen Fieuws, Giansilvio Marchioro, Bertrand Tombal, Burkhard Kneitz, Chao-Yu Hsu, Katie Van Der Eeckt, Pia Bader, Detlef Frohneberg, Alessandro Tizzani and Hein Van Poppel

Accepted 1 March 2010

July 2010 (Vol. 58, Issue 1, pages 1 - 7)

Currently, one in four deaths in both Europe and the United States is the result of cancer. The American Cancer Society identified prostate cancer (PCa) as the most commonly diagnosed non-dermatologic malignancy among American men, and it remains the second most fatal cancer. Similar incidence and mortality figures are reported by the European Association of Urology (EAU).

The goal of PCa screening is to detect potential fatal cancers at a time when they may still be curable. The downside of screening is the diagnosis and overtreatment of tumours destined to pose no threat to the man during his lifetime. The upside of screening is the detection of high-risk cancers while still clinically localised. In a heavily screened population, this “high-risk” group accounts for 15% of men with clinically localised disease and likely a higher percentage in less heavily screened populations [1]. Ultimately, the best treatment for this group of men is unclear, though we would suggest that they are at risk for undertreatment.

The exact definition of high risk is a matter of debate. High-risk, clinically localised disease was classically defined by D’Amico et al as any combination of the following factors: a prostate-specific antigen (PSA) score >20 ng/ml, a Gleason score of 8–10, or clinical stage T2C or greater [2]. More recently, the National Comprehensive Cancer Network and EAU have modified this definition to include any combination of a clinical T3, a PSA score >20 ng/ml, or a Gleason score of 8–10. Regardless of the definition used, the optimal treatment for these men remains unknown, although common treatments include surgery, radiation, or primary androgen-deprivation therapy. However, it is clear that regardless of the treatment used, some men fair well while others possess disease that continues to progress rapidly.

With the goal of further stratifying a high-risk group in mind, Spahn et al in this issue of European Urology sought to use combinations of the classic PCa predictive triad (PSA, Gleason score, and clinical stage) to predict outcome after radical prostatectomy (RP) in patients with a PSA ≥20 [3]. They postulate that the use of a single criterion may overestimate the risk of recurrence and may not accurately tease out the true high-risk patient. Indeed, the authors found marked heterogeneity within this group. For example, men with a high PSA and a Gleason grade ≤7 had very low risks for cancer progression. Alternatively, men with multiple high-risk features (ie, PSA >20, biopsy Gleason score 8–10, or clinical stage T3 disease) had poor outcomes despite surgery. These multi-institutional European data mirror similar results from a multi-institutional series from the United States composed of men treated with either RP or external-beam radiation therapy (RT) showing that the presence of more high-risk features is associated with poorer outcomes [4].

Beyond helping to further risk stratify high-risk men, another main strength of the study is its contribution to the growing body of evidence showing that managing high-risk PCa with surgery is a viable option. In addition to the current investigation, other studies with high-risk men defined by a single criterion (ie, Gleason score 8–10 or clinical T3 disease) have shown reasonably good long-term PSA and cancer control with surgery [5], [6], and [7]. In a more comprehensive review, Yossepowitch et al found that 35–76% of high-risk patients were alive 10 yr after surgery as the only therapy (with survival rates dependent on the definition of high-risk disease) [8].

Traditionally, surgery has often not been considered a good option for high-risk men because of the high risk of treatment failure. However, as the above data indicate, surgery can provide reasonable cancer control for many men. Thus, we have moved from asking whether surgery is a viable treatment option for high-risk men to asking whether it might actually be the preferred treatment. A population-based study found that after adjusting for disease aggressiveness, those treated with surgery had a low rate of PCa mortality [9]. Most recently, a single-institution study found that RP resulted in a 65% risk reduction for metastasis compared to high-dose RT [10]. Although these studies are limited by their retrospective nature and nonrandomised data, it is important to note that there is no evidence that high-risk patients might, in fact, have higher rates of metastases or death from PCa with surgical intervention than other therapeutic modalities.

Another point that is clear from the Spahn et al article is that despite surgery, many men continue to progress. Thus, what does the future hold for the treatment of high-risk PCa? Most studies, including the current investigation, addressing high-risk PCa treatment are limited, as they focus on a single primary therapy. It is time to shift focus from debating which primary treatment is the most useful for this group to open discussions on developing confidence in risk stratification and the possibility of moving towards multimodal therapy. The best way to treat patients based on risk stratification still eludes us. Current approaches to dealing with high-risk disease have succeeded in stratifying risk and predicting outcome. Unfortunately, these risk categories do not inform us regarding the best treatment, just that a man is at high or low risk for progression. Traditional multimodal therapy has focused on RT plus hormone therapy (HT). However, given the side-effects of HT, we believe that the time is ripe to explore other combinations of multimodal therapy that do not use HT up front—specifically, surgery with adjuvant RT. Indeed, the combination of adjuvant RT for high-risk men improves overall survival relative to surgery alone [11]. Ultimately, the goal is to match the treatment intensity to the level of disease threat. Research energy should be shifted to focus on further stratifying the high-risk group and assessing which patients might achieve better long-term control with multimodal therapy. To accomplish this, we will need to move beyond simply PSA, stage, and grade and look to molecular markers and gene expression signatures. By studying gene expression signatures, we begin to learn not just about disease aggressiveness but tumour biology. This information can in turn be used not only to risk stratify men but to identify the optimal treatment. For example, a man with a tumour biology known to be resistant to RT can be guided to surgery. As the future of medicine—let alone cancer care and PCa care—will be focused on customisation of care tailored to the individual, future scientific advancements originating from fields such as genomics, proteomics, metabolomics, and nanotechnology may further enhance risk stratification with identification of an optimal, personalised therapeutic strategy.

A final point that must be kept in mind is that even high-risk PCa exists within a human, and a poor outcome is defined as deaths within years rather than decades. As such, the context of the patient—his age, race, comorbidities, body habitus—and the side-effects of the treatment must be considered in all of our treatment decision planning. Thus, not all “high-risk” PCa should be treated equally. As such, it is important to remember that we are not simply PCa doctors but doctors. Our number one goal should be to promote overall wellness. Indeed, there is a teachable moment at the time of diagnosis—especially of a high-risk PCa—for patients to make lifestyle changes (eg, weight loss, exercise). We know such approaches reduce cardiovascular disease, which remains the number one killer of men—even men with localised, high-risk PCa. Thus, through a combination of lifestyle changes and an aggressive but tailor-designed multimodal treatment strategy, we can best optimise care of our men with high-risk PCa.

Conflicts of interest

The authors have nothing to disclose.

References

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Footnotes

a Duke Prostate Center, Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA

b Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA

c Department of Surgery, Durham Veterans Administration Hospital, Durham, North Carolina, USA

lowast Corresponding author. Division of Urologic Surgery and the Duke Prostate Center, Department of Surgery, Duke University Medical Center, Box 2626, MSRB-I Room 475, 571 Research Drive, Durham, NC 27710, USA. Tel. +1 919 668 8361; Fax: +1 919 668 7093.

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