Genitourinary Cancers

In 2004, the large majority of prostate cancers are detected via prostate-specific antigen (PSA) screening. Most are diagnosed at an earlystage and are amenable to aggressive local treatment. However, thenatural history of the disease may be prolonged, and all available activetreatments exert a potential negative effect on patients’ HRQOL.Management options for localized prostate cancer have become increasinglycomplex in recent years, and rigorous trials are frequently difficultto perform due to the extended follow-up required to reach meaningfuloutcomes. In this context, the advent of the national prostatecancer disease registries-Prostate Cancer Outcomes Study (PCOS),Center for Prostate Disease Research (CPDR), Cancer of the ProstateStrategic Urologic Research Endeavor (CaPSURE), and Shared EqualAccess Regional Cancer Hospital (SEARCH)-has greatly facilitatedclinical research in prostate cancer. This review summarizes key findingsfrom the registries in the areas of risk migration, practice patterns,outcome prediction, and quality-of-life outcomes. The availabilityof these large databases of patients will be a tremendous asset asprostate cancer management continues to evolve in the coming years.

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?

In this issue of ONCOLOGY, Daviset al provide a succinct overviewof the contemporary managementof high-risk prostate cancer patients.[1] As the authors point out, theintroduction and widespread implementationof prostate-specific antigen(PSA) as a tumor marker hasdriven a remarkable stage migrationin how patients present with prostatecancer, yet a significant number ofmen continue to present with featuresplacing them at high risk for localtreatment failure, development ofprostate cancer metastases, and ultimately,death.

The article by Davis et al is importantfor several reasons.First, it reminds us about themost lethal phenotype in patients withapparently localized prostate cancer.This subgroup is easily forgotten intoday's era of PSA screening becausethe majority of patients now diagnosedwith prostate cancer are classified aslow risk. Second, there have been few,if any, good reviews that define theissues, including the definition ofhigh-risk disease, the effectiveness ofthe major treatments (ie, radical prostatectomy,radiation therapy, and theirneoadjuvant or adjuvant supplementaltherapies), and the current gaps inour knowledge of these issues.

Screening for prostate cancer by determining serum prostate-specificantigen (PSA) levels has resulted in a stage migration such thatpatients with high-risk disease are more likely to be candidates for curativelocal therapy. By combining serum PSA, clinical stage, and biopsyinformation-both Gleason score and volume of tumor in the biopsycores-specimen pathologic stage and patient biochemical disease-freesurvival can be estimated. This information can help patients and cliniciansunderstand the severity of disease and the need for multimodaltherapy, often in the context of a clinical trial. While the mainstays oftreatment for local disease control are radical prostatectomy and radiationtherapy, systemic therapy must be considered as well. A randomizedtrial has shown a survival benefit for radical prostatectomy inpatients with positive lymph nodes who undergo immediate adjuvantandrogen deprivation. Clinical trials are needed to clarify whether adjuvantradiation therapy after surgery confers a survival benefit. PSAis a sensitive marker for follow-up after local treatment and has proventhat conventional external-beam irradiation alone is inadequate treatmentfor high-risk disease. Fortunately, the technology of radiationdelivery has been dramatically improved with tools such as three-dimensionalconformal radiation, intensity-modulated radiation therapy,and high-dose-rate brachytherapy. The further contributions of pelvicirradiation and neoadjuvant, concurrent, and adjuvant androgen deprivationtherapy have been defined in clinical trials. Future managementof high-risk prostate cancer may be expanded by clinical trialsevaluating neoadjuvant and/or adjuvant chemotherapy in combinationwith androgen deprivation.

The introduction of prostate-specific antigen (PSA) as a reliabletumor marker for prostate cancer brought significant changes in theend points used for outcome reporting after therapy. With regard to adefinition of failure after radiation, a consensus was reached in 1996that took into account the particular issues of an intact prostate aftertherapy. Over the next several years, the consensus definition issued bythe American Society for Therapeutic Radiology and Oncology(ASTRO) was used and studied. Concerns and criticisms were raised.The sensitivity and specificity of this definition vs other proposals hasbeen investigated, and differences in outcome analyzed and compared.Although the ASTRO definition came from analysis of datasets on external-beam radiation and most of the work on this topic has been withthis modality, failure definitions for brachytherapy must be exploredas well. The concept of a universal definition of failure that might beapplied to multiple modalities, including surgery, should also be investigated,at least for comparative study and research purposes.

In this paper, Dr. Kuban et al addresscontroversies surroundingthe use of posttreatment prostatespecificantigen (PSA) in determiningoutcome after radiotherapy. They basemost of their discussion on their ownobservations of prostate cancer outcomesin more than 4,000 patients followingexternal-beam radiotherapyalone.[1,2] I had the privilege of writingan editorial on their earlier companionpapers, and I made the argumentthen that although some definitionswere slightly better than the AmericanSociety for Therapeutic Radiology andOncology (ASTRO) definition, the differenceswere not impressive enoughto recommend changing the standardfor determining outcome after external-beam radiotherapy.[3]

The options available for patients with recurrent prostate cancerare limited. Men who have failed external-beam irradiation as the primarytreatment are rarely considered for potentially curative salvagetherapy. Traditionally, only palliative treatments have been offered withhormonal intervention or simple observation. A significant percentageof these patients have only locally recurrent cancer and are thus candidatesfor curative salvage therapy. Permanent brachytherapy withiodine-125 or palladium-103 has been used in an attempt to eradicatethe remaining prostate cancer and prevent the need for additional intervention.It is critical in this population to identify patients most likelyto have distant metastases or who are unlikely to suffer death or morbidityfrom their recurrence, in order to avoid potential treatmentmorbidity in those unlikely to benefit from any intervention. Followingsalvage brachytherapy, up to 98% of these cancers may be locally controlled,and 5-year freedom from second relapse is approximately 50%.With careful case selection, relapse-free rates up to 83% may beachieved. A schema is presented, suggesting that it may be possible toidentify the patients most likely to benefit from salvage treatment basedon prostate-specific antigen (PSA) kinetics and other features. Suchfeatures include histologically confirmed local recurrence, clinical andradiologic evidence of no distant disease, adequate urinary function,age, and overall health indicative of at least a 5- to 10-year life expectancy,prolonged disease-free interval (> 2 years), slow PSA doublingtime, Gleason sum ≤ 6, and PSA < 10 ng/mL.

Dr. Beyer has done a good jobof summarizing the issuesconcerning the use of brachytherapyas a salvage modality to treatradiation therapy failures. This willbecome an issue of greater importanceas we continue to diagnose andtreat younger and younger patientswith prostate cancer. This trend canbe primarily attributed to the successof prostate-specific antigen (PSA)screening. With younger patients optingfor radiation treatment, the numberof patients at potential risk forfailure and hence potential candidatesfor salvage brachytherapy will increase.This, coupled with the stagemigration toward early-stage, lower-PSA disease, may result in an increasingpopulation of patients with perhapsmore curable recurrent disease.

Prostate cancer management issurrounded by controversy.From the screening debatethrough choosing the best treatmentoption for localized disease, there islittle consensus on the approach to themost common solid tumor in men. Avariety of predictive models are beingdeveloped to assist in clinical decisionmaking.[1,2] Although transrectal ultrasound(TRUS)-directed prostatebiopsies represent the “gold standard”in the diagnosis of the disease, limitationsof this approach have been recognized.[3] To compensate for theselimitations, the absolute number of needlecores taken has increased from 6 to10–12 or more. TRUS enhancementssuch as color Doppler and the use ofcontrast agents hold promise, but theyhave not yet replaced the TRUS grayscaleapproach.[4]

Arguably the most important step in the prognosis of prostate canceris early diagnosis. More than 1 million transrectal ultrasound (TRUS)-guided prostate needle biopsies are performed annually in the UnitedStates, resulting in the detection of 200,000 new cases per year. Unfortunately,the urologist's ability to diagnose prostate cancer has not keptpace with therapeutic advances; currently, many men are facing theneed for prostate biopsy with the likelihood that the result will beinconclusive. This paper will focus on the tools available to assist theclinician in predicting the outcome of the prostate needle biopsy. We willexamine the use of "machine learning" models (artificial intelligence),in the form of artificial neural networks (ANNs), to predict prostatebiopsy outcomes using prebiopsy variables. Currently, six validatedpredictive models are available. Of these, five are machine learningmodels, and one is based on logistic regression. The role of ANNs inproviding valuable predictive models to be used in conjunction withTRUS appears promising. In the few studies that have comparedmachine learning to traditional statistical methods, ANN and logisticregression appear to function equivalently when predicting biopsyoutcome. With the introduction of more complex prebiopsy variables,ANNs are in a commanding position for use in predictive models. Easyand immediate physician access to these models will be imperative iftheir full potential is to be realized.

Drs. Porter and Crawford carefullyassess the role of artificialneural networks (ANNs)as predictive models of outcomes forinitial prostatic biopsies performed inconjunction with transrectal ultrasound(TRUS). Obviously, the treatmentof prostate cancer rests onestablishing the diagnosis via biopsy,and TRUS-guided core biopsies havebeen the standard of care since Hodgeet al reported the superiority of thistechnique in 1989.[1]

WASHINGTON- Researchers have closed the Prostate Cancer Prevention Trial (PCPT) 15 months early after finding that men who took Proscar (finasteride) had a 25% lower risk of developing the disease, compared with men given placebo. "This trial proves that prostate cancer, at least in part, is preventable. It is a huge step forward for cancer research," Peter Greenwald, MD, DrPH, director of the National Cancer Institute’s Division of Cancer Prevention, said at a press conference announcing the results.

Hormonal treatment of advanced prostate cancer should be consideredfor patients who have stages C and D1 disease, a high risk of recurrenceafter local therapy, or prostate-specific antigen–measured recurrenceafter local treatment. This approach is dependent on most prostatecancer cells being androgen-dependent, but androgen-independentcells may arise after several years of hormonal therapy. Options forandrogen blockade primarily include orchiectomy, luteinizing hormone–releasing agonists and antagonists, and nonsteroidal antiandrogens.There is some controversy regarding combined androgen blockade,intermittent androgen blockade, and the question of whether earlyandrogen blockade is superior to delayed therapy. Convincing data doexist for the use of adjuvant/neoadjuvant hormonal therapy with external-beam radiation therapy. Although hormonal therapy is an importanttreatment modality for advanced prostate cancer, long-termtreatment carries significant side effects that need to be considered.

For many years, prostate cancerhas been known to be sensitiveto androgens. Indeed, endocrinemanipulations aimed at the reductionof serum testosterone to below oraround the castrate range have beenthe mainstay in the management ofadvanced prostate cancer for the past60 years. Despite widespread testing,the advances with this treatment modalityfor prostate cancer over the pastseveral decades have been modest.Unfortunately, the answers to manyrelevant critical questions still lie inthe future. The limiting factor of hormonaltherapy is that a significant proportionof tumor cells are not affectedby androgen deprivation.

The US Preventive Services Task Force has concluded that notenough scientific evidence exists to promote routine screening ofall men over age 40 for prostate cancer via standard prostatespecificantigen test and/or digital rectal exam. The task force-sponsoredby the Agency for Healthcare Research and Quality-concludedthat the tests are effective for diagnosis but that there is insufficientevidence to show that they affect long-term health or survival. The taskforce noted that results of the ongoing Prostate, Colorectal, Lung, andOvarian Screening Trial, designed to answer this question, will notbecome available until later in this decade.

ROCKVILLE, Maryland-The US Preventive Services Task Force has concluded that not enough scientific evidence exists to promote routine screening of all men over age 40 for prostate cancer via standard PSA test and/or digital rectal exam. The task force-sponsored by the Agency for Healthcare Research and Quality-concluded that the tests are effective for diagnosis but that there is insufficient evidence to show that they affect long-term health or survival. The task force noted that results of the ongoing Prostate, Colorectal, Lung, and Ovarian Screening Trial, designed to answer this question, will not become available until later in this decade.

NEW YORK-In patients with androgen-independent prostate cancer, a pulsed regimen of docetaxel (Taxotere) plus high-dose calcitriol is well tolerated and results in disease response by a variety of standard measures, according to results of a phase II trial.

As Dr. Raghavan has emphasizedin his excellent overviewof the current therapyfor testis cancer, it is critical that thesuccess of therapy for this diseasenot be compromised by a desire toavoid the complications of therapy.We would wholeheartedly agree withhis assertion that modifications intherapy must be introduced with athoughtful and structured approachto minimize the risk to efficacy.

Dr. Derek Raghavan, a recognizedexpert in the managementof testicular cancer, isto be congratulated for a clear andconcise overview of the contemporarymanagement of testicular cancer.As a urologist with almost 20years’ experience in the treatment oftesticular cancer, I fully agree withthe concept of not modifying or delayingthe use of proven treatmentprotocols.I can remember as an internand junior resident seeing youngcontemporaries die a horrible deathfrom testicular cancer. Any clinician40 years of age or older can relate tothis scenario, and it probably had thesame impact on them as it did onme-we don’t ever want to “gothere” again.

A6-year prostate cancer research plan released by the NationalInstitutes of Health (NIH) contains a detailed outline of theNational Cancer Institute’s (NCI) future strategy for dealingwith the disease, which includes a shift in the standard treatment modelfrom seek-and-destroy to target-and-control.

The management of germ cell tumors has advanced dramatically,with cure rates approaching 90% to 95%. Treatment of stage I/Aseminomas generally includes orchiectomy and adjuvant radiotherapy.Treatment of stage I/A nonseminomatous germ cell tumors involvesorchiectomy followed by retroperitoneal lymph node dissection oractive surveillance. One of the major advances has been the introductionof cisplatin-based chemotherapy for metastatic disease and thedevelopment of a system of risk attribution. The logical managementof any patient with curable disease is to provide curative therapy andthen follow the patient in a structured manner, to diagnose and treatany complications in a timely manner.

Dr. Raghavan is to be commendedfor a concise andcomprehensive overview ofthe management of germ cell tumors.As he suggests, given the demographicsof this relatively uncommon diseaseand the high cure rate that canbe achieved with proper treatmentand follow-up, it behooves us to maintainthese excellent results, even whilestriving to reduce the toxicity of treatment.We will highlight a few additionalpoints to complement thissuperb review.

BETHESDA, Maryland-A 6-year prostate cancer research plan released by the National Institutes of Health (NIH) contains a detailed outline of the National Cancer Institute’s (NCI) future strategy for dealing with the disease, which includes a shift in the standard treatment model from seek-and-destroy to target-and-control.

FRAMINGHAM, Massachusetts-Genzyme Molecular Oncology has launched a phase I/II vaccine trial in advanced kidney cancer. The vaccine is made by combining the patient’s own cancer cells with dendritic cells using an electrical fusion approach. Up to 20 patients will be enrolled at Beth Israel Deaconess Medical Center and the Dana-Farber Cancer Institute, Boston.

NEW ORLEANS-In the treatment of localized prostate cancer, biochemical failure rates are similar among permanent radioactive seed implantation, high-dose external beam radiation therapy, combination seeds/external radiation, and radical prostatectomy, according to a very large series of patients followed at the Cleveland Clinic Foundation and Memorial Sloan-Kettering Cancer Center.

The addition of high-dose calcitriol (the active form of vitamin D) to weekly treatment with docetaxel (Taxotere) appears to improve response in men with hormone-refractory prostate cancer without compromising safety, according to the results of a

ORLANDO-Adoptive transfer of T cells taken from tumor-draining lymph nodes and secondarily activated and expanded in vitro can shrink established renal cell cancers, according to phase II data reported at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 10). Alfred E. Chang, MD, chief of the Division of Surgical Oncology, University of Michigan Health Systems, Ann Arbor, presented the study.

William Pirl and Jeffrey Mello present an informative overview of the psychological impact of prostate cancer. They also provide a practical framework for distress management, as promulgated by the National Comprehensive Cancer Network (NCCN).

The authors challenge the notion that men with prostate cancer exhibit little psychological difficulty. In fact, we do not know much about actual distress rates in men with prostate cancer because few studies have directly measured distress in this population. Likewise, we do not know if the distress experienced by prostate cancer patients is qualitatively different from that of other cancer patients. By assuming that all men with prostate cancer "do well," we, as clinicians and researchers, may fail to ask patients important questions.