Prostate Cancer

Radical prostatectomy and ultrasound-guided transperinealbrachytherapy are both commonly used for the treatment of localizedprostate cancer. No randomized trials are available to compare thesemodalities. Therefore, the physician must rely on institutional reportsof results to determine which therapy is most effective. While some investigatorshave concluded that both therapies are effective, others haveconcluded that radical prostatectomy should remain the gold standardfor the treatment of this disease. This article reviews the major seriesavailable for both treatments and discusses the major controversiesinvolved in making these comparisons. The data indicate that for lowriskdisease, both treatments are effective, controlling disease in over80% of the cases, with no evidence to support the use of one treatmentover the other. Similarly, for intermediate-risk disease, the conclusionthat one treatment is superior to the other cannot be drawn. Brachytherapyshould be performed in conjunction with external-beam radiationtherapy in this group of patients. For patients with high-risk disease,neither treatment consistently achieves biochemical control rates above50%. Although radical prostatectomy and/or brachytherapy may playa role in the care of high-risk patients in the future, external-beamradiation therapy in combination with androgen deprivation has thebest track record to date.

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.

BETHESDA, Maryland-Convincing evidence indicates that physical activity can significantly reduce the risk of colon and breast cancer, according to a newly released National Cancer Institute (NCI) fact sheet. Moreover, studies also suggest a link between exercise and a reduced risk of cancers of the prostate, lung, and endometrium. However, despite the documented cancer and other health benefits of exercise, "recent studies have shown that more than 60% of Americans do not engage in enough regular physical activity," NCI said. The new publication summarizes the evidence supporting the role of exercise in cancer risk reduction and the possible underlying biological mechanisms

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]

Drs. Merrick, Wallner, and Butlerhave compiled informationregarding patient selection forprostate brachytherapy[1] and concludethat, “While there is no shortageof opinions regarding symptomsor circumstances that render the useof brachytherapy inadvisable, most arebaseless.” They go on to say that,“Reports to date have failed to establishany firm contraindication.” I amimpressed with the certainty such astatement projects for a disease as heterogeneousas 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.