Prostate Cancer

Reviewing the Literature

RIU0378_03-14.qxd 3/15/08 3:00 AM Page 81 REVIEWING THE LITERATURE News and Views from the Literature Prostate Cancer Focal Therapy for Prostate Cancer Reviewed by Danil V. Makarov, MD, Alan W. Partin, MD, PhD such therapy. Two recent articles in the literature address some of the issues involved with focal therapy of prostate cancer. Focal Therapy for Localized Prostate Cancer: A Critical Appraisal of Rationale and Modalities The James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD Eggener SE, Scardino PT, Carroll PR, et al; International Task Force on Prostate Cancer and the Focal Lesion Paradigm. [Rev Urol. 2008;10(1):81-82] J Urol. 2007;178(6):2260-2267. © 2008 MedReviews, LLC lthough it is a significant health threat and cause of mortality, newly diagnosed prostate cancer has undergone a stage migration, with more and more small volume tumors diagnosed at presentation than ever before.1 Despite great advances in techniques for prostatectomy and radiotherapy, there remains a risk of morbidity from techniques designed to ablate cancer from the entire gland. Recently, patients have been offered ablative therapies targeted to focal lesions within the prostate, leaving much of the gland untreated and minimizing the side effects from treatment. However, there is very little documentation of the long-term oncologic outcomes after A This paper by Eggener and colleagues is the summary of recommendations made by a multidisciplinary group of experts (surgeons, radiotherapists, medical oncologists, radiologists, pathologists, and epidemiologists) assembled to review the current state of focal therapy for prostate cancer. The group reviewed 152 articles collected from a search of the medical literature and then summarized their findings and consensus opinion. The group began by identifying prostate cancer as a worldwide health problem and a potentially lethal disease (68,000 deaths in the European Union in 2004)2 and then described current trends in overdetection of prostate cancer (estimated to be between 15% and 84%)3 and the potential harm that treatment of prostate cancer may VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 81 RIU0378_03-14.qxd 3/15/08 3:00 AM Page 82 Prostate Cancer continued cause. They then discussed the rationale for focal therapy based on decreasing tumor volumes (shrinking from 6.0 to 2.2 cm3 between 1989 and 2001)4 and evidence that nonindex lesions tend to be much smaller and presumably less aggressive than those identified on biopsy.5 With newer imaging technology6 and more thorough biopsy samples,7 preoperative estimates of final pathology are becoming more accurate. Despite these advances they note the concerns about the high rate of bilateral cancer among men with seemingly focal disease and the potential for even non-index lesions to metastasize.8 They then discuss the 4 leading technologies currently employed for focal therapy: high-intensity focused ultrasound (HIFU), cryotherapy, radio frequency ablation (RFA), and photodynamic therapy (PDT). All of these modalities seem able to destroy prostate cancer tissue quite well, but almost every study utilizing one of these modalities also uses androgen deprivation therapy. It is thus impossible to tell, with such short follow-up, whether these patients have been cured or whether they are experiencing a temporary PSA depression secondary to hormonal manipulation. The expert panel concludes by recommending further research on these modalities and defining the characteristics that these studies should have. These men should have nonaggressive, unifocal tumors and should have extensive follow-up to determine whether cancer is still present after therapy. Predicting Unilateral Prostate Cancer Based on Biopsy Features: Implications for Focal Ablative Therapy—Results From the SEARCH Database Scales CD Jr, Presti JC Jr, Kane CJ, et al; SEARCH Database Study Group. They identified 261 men with these favorable parameters and determined that only 35.1% of them demonstrated no prostate cancer on the contralateral side, the obvious implication being that almost 65% of men undergoing a “curative” procedure for prostate cancer are left with prostate cancer in situ. The authors next attempted to determine whether any preoperative characteristics predicted more extensive disease upon pathological examination. They found neither age, prostate specific antigen, clinical stage, body mass index, nor number of positive biopsy cores predicted bilateral disease. They conclude that most men with prostate cancer, even very favorable risk prostate cancer, have bilateral disease and that there is no way to tell a man with unilateral disease from one with bilateral disease a priori. The review by Eggener and coworkers does a good job of placing the Scales article into context. It is indeed very difficult, given the long natural history that even aggressive prostate cancer follows, to tell this early whether focal therapy will be a successful modality. It is possible to argue that the lesions detected on the side of the gland contralateral to the initial biopsy are not clinically significant and would pose no threat to the patient within his lifetime, but it is also possible to make this same argument regarding the index lesion in these patients. At least 65% of the time, however, patients and physicians are de facto electing watchful waiting for undetected, contralateral cancer. Although this may be a reasonable option or a reasonable risk to take for some men, it must only occur with their informed consent. References 1. 2. J Urol. 2007;178:1249-1252. 3. Adding new research to the debate is the article from Scales and colleagues. They reason that unilateral ablative therapy, when practiced on men with low-risk prostate cancer, presumes that only a single focus of prostate cancer exists, which can be eradicated. Because unilateral ablative therapy leaves the contralateral prostate completely spared, they undertook to determine how often the contralateral prostate had concomitant prostate cancer. They studied a cohort of men with low-risk prostate cancer (clinical stage T1c or T2a prostate cancer, prostate specific antigen less than 10 ng/ml, Gleason score  6, and only 1 or 2 ipsilateral positive cores on at least a sextant biopsy) from the SEARCH database who had all undergone radical prostatectomy. 82 VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 4. 5. 6. 7. 8. Cooperberg MR, Lubeck DP, Meng MV, et al. The changing face of low-risk prostate cancer: trends in clinical presentation and primary management. J Clin Oncol. 2004;22:2141-2149. Boyle P, Ferlay J. Cancer incidence and mortality in Europe, 2004. Ann Oncol. 2005;16:481-488. Miller DC, Gruber SB, Hollenbeck BK, et al. Incidence of initial local therapy among men with lower-risk prostate cancer in the United States. J Natl Cancer Inst. 2006;98:1134-1141. Loeb S, Gonzalez CM, Roehl KA, et al. Pathological characteristics of prostate cancer detected through prostate specific antigen based screening. J Urol. 2006;175:902-906. Wise AM, Stamey TA, McNeal JE, Clayton JL. Morphologic and clinical significance of multifocal prostate cancers in radical prostatectomy specimens. Urology. 2002;60:264-269. Kirkham AP, Emberton M, Allen C. How good is MRI at detecting and characterising cancer within the prostate? Eur Urol. 2006;50:1163-1174; discussion 1175. King CR, McNeal JE, Gill H, Presti JC, Jr. Extended prostate biopsy scheme improves reliability of Gleason grading: implications for radiotherapy patients. Int J Radiat Oncol Biol Phys. 2004;59:386-391. Gburek BM, Kollmorgen TA, Qian J, et al. Chromosomal anomalies in stage D1 prostate adenocarcinoma primary tumors and lymph node metastases detected by fluorescence in situ hybridization. J Urol. 1997;157:223-227. RIU0378_03-14.qxd 3/15/08 3:00 AM Page 83 Prostate Cancer Testosterone Therapy in Men With Localized Prostate Cancer Reviewed by Jacob Rajfer, MD Department of Urology, University of California at Los Angeles, Los Angeles, CA [Rev Urol. 2008;10(1):83] © 2008 MedReviews, LLC ne of the major clinical dilemmas facing urologists who see patients with prostate cancer is what to do with them after they become hypogonadal, either biochemically or symptomatically. It is known that as men age, the incidence of hypogonadism increases at the same time that the incidence of prostate cancer increases. Ever since Huggins and Hodges showed the link between testosterone and prostate cancer more than 6 decades ago,1 it is considered verboten to treat anyone who has a diagnosis of prostate cancer with exogenous testosterone, regardless of whether or not they are hypogonadal. Indeed, all forms of testosterone carry such a warning label, and there have been very few reports attesting to the fact that treatment of men who have localized prostate cancer with exogenous testosterone causes a flare of the cancer. This is in contradistinction to men who have metastatic disease where the treatment with LHRH agonists can cause such a flare, which is presumed to be due to the transient elevation of the serum testosterone right after initiation of LHRH agonist treatment. O Testosterone Replacement for Hypogonadism After Treatment of Early Prostate Cancer With Brachytherapy Sarosdy MF. prostate cancer and have an unmeasurable PSA can be safely treated with exogenous testosterone as long as the PSAs are carefully monitored.2 The assumption here is that there is no remaining prostate cancer following the radical prostatectomy and, therefore, this type of treatment is safe in these patients. In fact, it would be unheard of to treat such post–radical prostatectomy men who have measurable PSAs with exogenous testosterone because of the belief that exogenous testosterone would stimulate the cells that are producing the measurable PSA in those patients. This latter notion is now being challenged by the recent report of Sarosdy, who treated 31 men who underwent brachytherapy with or without external beam radiation therapy with exogenous androgens despite there being a measurable PSA in many of these patients. In these patients, there was no evidence of metastatic disease, and the prostate cancer was assumed to be 100% localized to the prostate. What Sarosdy found was that none of these patients demonstrated any stimulation of the PSA, even though 1 patient had a PSA of 1.0 while on therapy. This observation is remarkable and puts our entire mindset about testosterone therapy and prostate cancer on hold. At the same time it gives some ammunition to those patients who are so severely impacted by their hypogonadism that they demand relief from those debilitating hypogonadal symptoms. The findings in this landmark paper will obviously need to be reproduced by others and, if confirmed, will add to the growing controversy of the questionable import of testosterone in “causing” prostate cancer. References 1. Cancer. 2007;109:536-541. Recent reports have trickled out to show that men who have undergone radical prostatectomy for localized 2. Huggins C, Hodges CV. The effects of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-297. Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 2004;172: 920-922. VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 83