Genitourinary Cancers

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.

Over the past decade, interest has been growing in the quality of life of men with prostate cancer. Traditionally considered a group with few psychological complications, 10% to 20% of men with prostate cancer are found to have clinically significant levels of psychological distress. This article reviews the prevalence of psychiatric symptomatology among prostate cancer patients, the psychological challenges of coping with the disease, and general guidelines for treatment. [ONCOLOGY 16:1448-1467, 2002]

Pirl and Mello carefully review the current state of knowledge about the psychological complications of prostate cancer. Their discussion is worth reading, particularly by those who treat patients with the disease. To put this knowledge in context for the general reader, we should give some thought to what this review illustrates about all patients with a serious life-threatening illness.

African-American patients with advanced prostate cancer survived slightly longer than white patients, according to a multi-institutional study led by Dana-Farber Cancer Institute researchers. The findings, which were reported at the 38th annual

UPPSALA, Sweden-In a new study, radical prostatectomy reduced deaths due to prostate cancer but did not increase overall survival in men with newly diagnosed, early-stage disease. The Scandinavian Prostatic Cancer Study Group found that after a median 6.2 years of follow-up, there were no significant differences in overall survival, but patients randomized to radical prostatectomy were less likely to develop distant metastases than those randomized to watchful waiting.

ORLANDO-A new two-stage prostate cancer vaccine should be explored in a phase III study in metastatic prostate cancer patients, based on promising phase II results of an Eastern Cooperative Oncology Group trial (E7897). Howard L. Kaufman, MD, reported the results of the "prime/boost" vaccine trial at the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 12).

SEATTLE-Dendreon Corporation has announced preliminary results from its analysis of its randomized, double-blind, placebo-controlled phase III study of Provenge (APC 8015) for the treatment of hormone-resistant prostate cancer. The trial of the cancer vaccine (D9901) involved 127 men with late-stage, metastatic, hormone-resistant prostate cancer, 82 of whom received Provenge, three vaccinations over a 4-week period.