Prostate Cancer

Following permanent prostatebrachytherapy with or withoutsupplemental external-beamradiation therapy, encouraging longtermbiochemical outcomes-includinga morbidity profile that comparesfavorably with competing local modalities-have been reported forpatients with low-, intermediate-, andhigh-risk features.[1,2] The efficacyand morbidity of prostate brachytherapyare dependent on implantquality. Substantial differences havebeen reported in the incidence andclinical course of brachytherapyrelatedmorbidities, with many of theconflicts likely related to patientselection, technical differences intreatment planning, intraoperativetechnique, or variation in patient managementphilosophies.[3-6]

The myriad effects of androgendeprivation therapy (ADT) inmen were really not appreciateduntil those without metastatic prostatecancer received such treatment.For example, fatigue-now recognizedas a common toxicity of ADT-was once more likely attributed tometastatic disease. Today, however,patients who are otherwise fully functional,healthy, and asymptomatic arebeing treated for a rising prostate-specificantigen level after primary therapy.In these men, the side effects ofADT can be very dramatic and aremore clearly related to the initiationof therapy.

For the past 60 years, the treatmentof advanced prostate cancerhas consisted of deprivingcancer cells of androgens.[1] The keypremise of androgen ablation is thatmost prostate carcinoma cell growthis initially androgen-dependent. Theandrogen receptor expressed by thesecells binds dihydrotestosterone, whichis then transported into the nucleus,leading to a cascade of events thatinduce cellular growth. If androgen isremoved, cellular death ensues via apoptosisof the androgen-sensitive cells.

Androgen deprivation, as a form of treatment for prostate cancer,has been used for decades. Within the last decade, however, its use hasincreased significantly. Therefore, it is incumbent upon the physicianto be familiar with the side effects associated with this treatment. Someof these side effects (eg, osteoporosis, changes in lipid profiles, andanemia) may be associated with significant morbidity, whereas others(eg, impotence, decreased libido, fatigue, and hot flashes) primarilyaffect the patient’s quality of life. Prevention strategies and treatmentsexist for many of these side effects. In addition, alternative forms ofantiandrogen therapy such as intermittent hormone ablation andantiandrogen monotherapy may be effective, with the added benefit ofminimizing side effects. This review focuses on the wide range of sideeffects associated with androgen ablation as well as preventive and treatmentstrategies.

This special "annual highlights" supplement to Oncology News International is a compilation of some of the major advances in the management of gastrointestinal cancers during 2003–2004, as reported in ONI. Guest editor Dr. James L. Abbruzzesecomments on the reports included herein and discusses advances in the clinical management of GI cancers, with a focus on developments in targeted therapy, newcombinations, adjuvant therapy, and what to watch for in 2004.

Androgen deprivation therapy(ADT) with a gonadotropinreleasinghormone agonist isthe cornerstone of treatment for metastaticprostate cancer. Patterns of carehave changed dramatically over thepast decade, and gonadotropin-releasinghormone agonists are now routinelyadministered to men withoutradiographic evidence of metastases.These agents account for about onethirdof Medicare expenditures for thetreatment of prostate cancer[1]; in1999, that portion exceeded $800 million.The routine use of gonadotropin-releasing hormone agonists in menwith nonmetastatic prostate cancer increasesthe importance of understandingand preventing treatment-relatedadverse effects. In this issue ofONCOLOGY, Dr. Holzbeierlein andcolleagues provide a timely summaryof the adverse effects of ADT.

Dr. Beyer provides an insightful and balanced approach tothe indications for salvageprostate brachytherapy after externalbeamradiotherapy failure. As hepoints out, the challenge for the cliniciancontemplating local salvage therapyto address biochemical failure isto determine whether the biochemicalrelapse represents local relapse onlyor systemic disease. Local salvagetreatment in a patient with micrometastaticdisease would have no appreciableimpact on disease-free survivaland is more likely to be associatedwith significant potential morbidity.Unfortunately, with the current lackof reliable molecular markers or sensitiveimaging modalities, it is impossibleto determine with certainty thesource of a biochemical relapse inmost settings.

Dr. Beyer has presented a thoroughreview of the current literatureon salvage implanttherapy following external-beamtherapy failure. Although the reviewpresents the available data clearly, Iwould characterize the data as preliminaryand suspect. I would questionconclusions drawn from these studiesand would especially question guidelinesfor patient selection based onthese conclusions. It will be necessaryto improve staging at recurrence, improvepathology postradiation, andimprove postimplant dosimetry beforewe can define the appropriate candidatefor salvage therapy.

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.

BETHESDA, Maryland&#151;Newly released data show that the nation’s mortality rate for all cancers combined, which declined between 1994 and 1998, remained stable from 1998 through 2000. However, the mortality rate for the four leading malignancies in the United States&#151;lung, female breast, prostate, and colorectal&#151;continued to decline in the late 1990s, according to the "Annual Report to the Nation on the Status of Cancer, 1975-2000."

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.

CHICAGO-Men with biochemical recurrence of prostate cancer after radical prostatectomy are more likely to develop distant disease if they present with a tumor that has a high Gleason grade or if they have a prostate specific antigen doubling time (PSADT) less than 12 months, Christopher Amling, MD, said at the 98th Annual Meeting of the American Urological Association (abstract 1489).

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]

CHAPEL HILL, North Carolina-Mass spectroscopy-based screening of serum samples from men with elevated PSA levels can distinguish benign from malignant disease and significantly reduce the need for biopsies, according to David Ornstein, MD, and his colleagues at the Food and Drug Administration (FDA) and National Cancer Institute (NCI). Dr. Ornstein is assistant professor of surgery, Division of Urology, University of North Carolina School of Medicine. [See Figure]

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.

Oottamasathien and Crawfordadvance a hypothesis withwhich I heartily agree-androgendeprivation/antagonist (AD/A)strategies should be considered in manymore patients than urologists and oncologiststraditionally teach. However,I think the authors could substantiallysharpen their message. I would like tomake five specific points, and thenoffer a few nitpicking comments.

CHICAGO-Zoledronic acid (Zometa) significantly decreased skeletal complications and bone pain in men with hormone-refractory prostate cancer and bone metastases, compared with placebo, according to an update of a phase III study presented at the 2003 Annual Meeting of the American Urological Association (abstracts 1472 and 1473).

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.

CHICAGO-Black men with localized prostate cancer do just as well as white men when treated with brachy-therapy alone, William Barrett, MD, said at the 88th Annual Scientific Assembly of the Radiological Society of North America (RSNA abstract 252RO-p).

BETHESDA, Maryland-Astra-Zeneca failed to gain backing from the FDA’s Oncologic Drugs Advisory Committee (ODAC) for its effort to expand the indication for Casodex (150 mg bicalutamide) in the treatment of prostate cancer. ODAC members found that the data presented were too premature to recommend that the FDA approve the company’s supplementary new drug application. They suggested, instead, that the agency delay a decision until longer-term data about the drug’s efficacy become available.

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.