Contemporary Management of Prostate Cancer With Lethal Potential

June 1, 2004

Virtually every management decisionrelated to prostate canceris highly controversial.Should we screen men for prostatecancer with prostate-specific antigen(PSA)? If so, what are the proper cutoffvalues? If we detect an early prostatecancer, is treatment warranted? Ifwe find an aggressive cancer, is treatmenteffective? If treatment is deemedwarranted, what is the optimal managementstrategy (radical prostatectomyvs radiation therapy)? If radicalprostatectomy is selected, should theprocedure be performed roboticallyor via an open approach? If radiationtherapy is selected, does eitherbrachytherapy or external-beamirradiation offer an advantage? Isthere a role for neoadjuvant hormonaltherapy in men undergoing definitiveintervention?

Virtually every management decisionrelated to prostate canceris highly controversial.Should we screen men for prostatecancer with prostate-specific antigen(PSA)? If so, what are the proper cutoffvalues? If we detect an early prostatecancer, is treatment warranted? Ifwe find an aggressive cancer, is treatmenteffective? If treatment is deemedwarranted, what is the optimal managementstrategy (radical prostatectomyvs radiation therapy)? If radicalprostatectomy is selected, should theprocedure be performed roboticallyor via an open approach? If radiationtherapy is selected, does eitherbrachytherapy or external-beamirradiation offer an advantage? Isthere a role for neoadjuvant hormonaltherapy in men undergoing definitiveintervention?It is imperative that we rely onevidence-based approaches for insightinto the management of prostate cancer.Because of the typically protractednatural history of prostate cancersdetected in the modern era, long-termstudies are mandatory in order to demonstratethe survival advantage ofintervention. To eliminate selectionbias, these studies should be randomizedand appropriately powered todetect clinically significant outcomes.They require tremendous human andfinancial resources. A major frustrationrelated to these long-term, randomizedstudies is that because ofconcurrent advances in the field, theirconclusions often lose clinical relevancebefore they are completed andpublished.High-Risk Prostate Cancer
The optimal management of highriskprostate cancer is also highly controversial.Davis et al provide ascholarly and balanced summary ofthe management of prostate cancerpatients at high risk. They present acomprehensive review of the literature,highlighting the strengths andpitfalls of pivotal studies.It is generally agreed that men withhigh PSA levels (> 20 ng/mL), highgradecancers (Gleason score ≥ 8),and/or large tumor volumes based ondigital rectal examination or a reviewof the biopsy cores are at greater riskfor disease progression and death ifuntreated. In selected high-risk subgroups,radical prostatectomy and radiationtherapy increase survival.Unfortunately, due to the lack of untreatedcontrols, the magnitude of thesurvival advantage is unknown. Diseasewill progress in many of thesemen despite aggressive intervention.One of the limitations of nonconcurrentstudies comparing differenttreatment options in high-risk patientsis the lack of a uniform definition ofhigh-risk and the lack of homogeneityin the treatment groups. For example,a man with a PSA of 4.1 ng/mL, aGleason score of 8, disease in a singlebiopsy core, and a normal prostate ondigital rectal exam, and a man with aPSA of 40 ng/mL, an extensive Gleason8 cancer, and a diffusely induratedpalpable prostate gland might bothbe considered high risk. Most likely,differences in outcome between thesetwo men would depend more on thedifference in baseline characteristicsthan in the treatment selected. Therefore,one must be very cautious ofselection bias when examining nonconcurrentstudies.Treatment Considerations
Because some men with high-riskprostate cancer are cured following radicalprostatectomy and radiation therapy,this group of patients should not bearbitrarily denied curative intervention.Although many of these men will failradical prostatectomy and radiationtherapy, the morbidity of treatment, especiallyin centers of excellence, is nowquite low. Therefore, it is reasonable toembark on a potentially curative interventionfor men with high-risk tumors,recognizing that there will be a relativelyhigh failure rate. This is particularlytrue if the alternative is anexperimental, unproven therapy. Sucha therapy might be better delivered ifa conventional therapy fails.It is intuitive that the ability ofradical prostatectomy and radiationtherapy to cure high-risk disease dependson total extirpation or total destructionof the local tumor burdenand the absence of metastatic disease.The ability of radiation therapy to curehigh-risk disease depends on the relativedegree of risk, the amount of radiationtherapy delivered, and the useof adjuvant hormonal therapy. Thecompilation of data suggests that neoadjuvanthormonal therapy providesa survival advantage prior to radiationtherapy but not prior to surgery.The authors appropriately questionwhether the survival advantage of neoadjuvanthormonal therapy is solely dueto the effect of hormonal therapy or asynergistic effect between radiationtherapy and neoadjuvant therapy.Future Study Design
Unfortunately, no randomizedstudies have compared radical prostatectomyto radiation therapy (withor without neoadjuvant hormonal therapy)for the treatment of high-riskdisease. Would such a study definitivelyresolve the question of optimaltherapy for high-risk disease? Mostlikely, the answer is no. First, the studywould require several years to organizeand complete enrollment. In addition,follow-up would have to span atleast 5 years to determine any survivaladvantages. It is unlikely that allhigh-risk patients respond uniformlyto different treatments; thus, it is conceivablethat high-risk patients withorgan-confined disease would respondbetter to radical prostatectomy, whereasthose with extensive extraprostaticdisease, with or without involvedlymph nodes, would respond better toradiation therapy.As different subgroups respond differentlyto therapy, the study wouldrequire extremely large patient numbersto achieve statistical power sufficientto identify clinically relevantdifferences in therapeutic outcome. Itis also likely that within the next decade,effective neoadjuvant chemotherapywill be identified for high-riskprostate cancer. In addition, it is likelythat researchers will identify biochemicalor genetic factors that morereliably distinguish men with systemicmetastasis. These advances wouldhave a significant impact on the managementof high-risk men and, therefore,would likely render therandomized study obsolete.Treatment Plan
The obvious dilemma is how tomanage men with high-risk prostatecancer based upon the available evidence.I believe that all men with alife expectancy of 5 years are at riskfor disease progression and death ifuntreated. Moreover, I believe thatradical prostatectomy alone, neoadjuvanthormonal therapy and radiotherapyappear to be effective insubsets of men with high-grade prostatecancer. Because of the high likelihoodof coexisting systemic disease,effective chemotherapy will likelyimprove survival outcomes. Aggressiveintervention should be offered,providing morbidity is minimal.Fortunately, in this era of PSAscreening, few men are initially diagnosedwith high-risk disease. I rely onthe Partin table to predict the likelihoodof extraprostatic disease.[1] Ifthe likelihood of achieving negativemargins is high, then I recommendradical prostatectomy. If men fail radicalprostatectomy, I consider adjuvantradiation therapy. For men inwhom it is unlikely that negativesurgical margins can be achieved, Irecommend a combination of neoadjuvanthormone therapy, docetaxel(Taxotere), and external-beam irradiation.Although there is no long-termfollow-up to justify this treatment algorithm,it is a sensible approach tothe management of the high-risk groupbased upon common sense and theexisting literature, which was reviewedin such a scholarly fashion byDavis and associates.

Disclosures:

The author has no significantfinancial interest or other relationshipwith the manufacturers of any productsor providers of any service mentioned in thisarticle.

References:

1.

Partin AW, Kattan MV, Subing EN, et al:Combination of prostate-specific antigen, clinicalstage, and Gleason score to predict pathologicalstage of localized prostate cancer: Amulti-institutional update. JAMA 227:1445-1451, 1997.