Genitourinary Cancers

ORLANDO-Being overweight or obese appears to adversely affect a man’s risk of dying from prostate cancer, according to a poster presentation at the 2005 Multidisciplinary Prostate Cancer Symposium (abstract 6). "Men who were overweight

Androgen-deprivation therapy, usually with combined androgenblockade, is standard initial treatment for advanced prostate cancer.With failure of initial treatment, as indicated by rising prostate-specificantigen (PSA) levels, second-line hormonal therapy is usually instituted.Over the past several years, it has become increasingly clear thatsystemic chemotherapy has an important role in hormone-refractorydisease. Phase II trials have demonstrated high PSA and measurabledisease response rates with taxane single-agent and combination treatments.One recent phase III trial showed that docetaxel (Taxotere)/estramustine (Emcyt) significantly improved overall survival, progression-free survival, and PSA response rate compared with mitoxantrone(Novantrone) plus prednisone. Another phase III trial demonstratedthat docetaxel given every 3 weeks plus prednisone significantly improvedoverall survival, PSA response rate, pain relief response rate,and quality of life compared with mitoxantrone and prednisone. Onthe basis of these findings, every-3-week docetaxel plus prednisone isnow considered standard first-line therapy for metastatic hormonerefractorydisease. There is considerable optimism that treatment canbe further improved. Studies of taxane combinations with bevacizumab(Avastin), thalidomide (Thalomid), bortezomib (Velcade), antisenseBcl-2 oligonucleotide, mTOR inhibitors, epidermal growth factor receptorinhibitors, and KDR inhibitors are under way. Randomized phaseIII trials in progress or planned are examining docetaxel in combinationwith imatinib mesylate (Gleevec) or calcitriol and docetaxel/prednisonein combination with bevacizumab and an antisense clusterincompound. Other promising systemic agents include epothilones andatrasentan, and promising vaccines include Provenge, GVAX, andProstvac.

Recent advances in treatment modalities for breast and prostate cancerhave resulted in an increasing number of patients that are cured orthat, despite residual disease, live long enough to start experiencingcomplications from cancer treatment. Osteoporosis is one such problemthat has been increasingly identified in cancer patients. Hypogonadismand glucocorticoid use are the two major causes of bone loss inthese patients. Osteoporosis is characterized by low bone mass and abnormalbone microarchitecture, which results in an increased risk offractures. Vertebral body and hip fractures commonly result in a drasticchange of quality of life as they can result in disabling chronic pain,loss of mobility, and loss of independence in performing routine dailyactivities, as well as in increased mortality. In patients with prostatecarcinoma, androgen-deprivation therapy by either treatment with agonadotropin-releasing hormone (GnRH) or bilateral orchiectomy resultsin increased bone turnover, significant bone loss, and increasedrisk of fractures. Patients with breast cancer are at increased risk forestrogen deficiency due to age-related menopause, ovarian failure fromsystemic chemotherapy, or from the use of drugs such as aromataseinhibitors and GnRH analogs. Several studies have indicated that theprevalence of fractures is higher in breast and prostate cancer patientscompared to the general population. Therefore, patients at risk for boneloss should have an assessment of their bone mineral density so thatprevention or therapeutic interventions are instituted at an early enoughstage to prevent fractures. This article will address the characteristicsof bone loss observed in breast and prostate cancer patients and potentialtreatments.

ORLANDO-A novel therapeutic vaccine therapy (see illustration) increased survival in patients with advanced prostate cancer during a phase III clinical trial, lead investigator Eric J. Small, MD, reported in an oral presentation and a media briefing at the 2005 Multidisciplinary Prostate Cancer Symposium (abstract 264). "This immunotherapy has the potential to provide a new treatment option for a group of patients with precious few options," said Dr. Small, professor of medicine and urology, University of California, San Francisco, School of Medicine. "On a broader scale, this is the first study ever to show a survival advantage for the immune approach in prostate cancer."

It is estimated that, in 1995, about 50,500 new cases of urinary bladder cancer will be diagnosed and that 11,200 patients will die of the diease. The most common malignant tumor of the urinary tract, bladder cancer accounts for 6.5% of all cancers annually. It is the fifth most common cancer among American men [1], and approximately three quarters of all cases occur in men.

The most effective form of therapyfor muscle-invasive bladdercancer is radical surgery andurinary diversion. Numerous clinicalseries demonstrate stage-for-stage 5-and 10-year survival data that are betterthan that seen for other treatmentmodalities.[1] The widespread applicationof continent urinary diversionover the past 2 decades has furtheredthe acceptance of radical surgery, asit provides for the lost function ofvolitional storage and emptying ofurine. Even patients who undergo astandard ileal loop diversion generallytolerate it well and adapt to thealtered body image.[2]

Drs. Fernando and Sandler havewritten a thorough review thathas documented why a bladder-conserving therapy can now bemore widely accepted treatment for patientswith muscle-invading bladdercancer. They have shown that this treatmentapproach, while selective, doeshave a high likelihood of eradicatingthe primary tumor, preserving good organfunction, and not compromisingpatient survival. These successful approacheshave evolved over the past 25years following initial reports of theeffectiveness of cisplatin against transitionalcell carcinoma and then reportsof added efficacy when cisplatinis given concurrently with radiation.

This is a timely review on thecurrent status of selective bladderpreservation for muscleinvasivebladder cancer. Although controversial,the concept is extremely attractiveto patients, and evidence fromretrospective and/or small series demonstrateits efficacy. Most of these trials,however, have included highlyselected patients. Unfortunately, thereare few, if any, ongoing randomizedcontrolled trials comparing radical cystectomyto bladder-preserving protocols.Although the overall 5-yearsurvival rate for radical cystectomy andtrimodality therapy is approximately50%, patients with pure T2 disease frequentlyachieve 5-year survival ratesapproaching 70%.[1-3] While it is clearlybeyond the scope of this editorial togo into an in-depth analysis of all thestudies reported to date, several significantquestions remain.

While organ preservation with nonextirpative surgery, radiotherapy,and frequently, chemotherapy has become a favored strategy in thetreatment of many cancers, bladder preservation for patients with invasivedisease remains controversial. The standard treatment for muscleinvasivebladder cancer in the United States is still radical cystectomywith pelvic lymph node dissection. An alternative to cystectomy ismultimodality bladder preservation with thorough transurethral resection,chemotherapy, and radiation therapy. This review will addressissues raised by a multimodality approach for the treatment of invasivebladder cancer.

The use of hormonal therapy with external-beam radiation (EBRT)to treat prostate cancer is a topic that has been well explored. The potentialuse of hormonal therapy and brachytherapy in the treatment ofprostate cancer, however, continues to be controversial. This review isbased on our current interpretation of the available literature assessingthe outcomes of patients treated with EBRT and brachytherapy withor without hormonal therapy. Extrapolating from the findings of theRadiation Therapy Oncology Group (RTOG) 9413 trial, there appearsto be a favorable interaction between hormonal therapy and irradiationin the lymph nodes. The benefits demonstrated with whole-pelvicEBRT and hormonal therapy are likely to extend to patients treatedwith brachytherapy as well. Studies suggest that the role of hormonaltherapy in brachytherapy is limited without the application of wholepelvicEBRT due to the inability of brachytherapy to address potentiallymph nodes at risk. The potential role of hormonal therapy in conjunctionwith brachytherapy without pelvic radiotherapy, is limited byinconclusive data and abbreviated follow-up times.

In their article, Drs. Matthew Cooperberg,Sangtae Park, and PeterCarroll summarize four nationalregistries that have studied risk migration,practice patterns, outcomepredictions, and quality-of-life outcomesin prostate cancer. Each of thesefour large registries-the Prostate CancerOutcomes Study (PCOS), the Departmentof Defense Center for ProstateDisease Research (CPDR), the Cancerof the Prostate Strategic Urologic ResearchEndeavor (CaPSURE), and theShared Equal Access Regional CancerHospital (SEARCH)-has a particularstrength that complements theothers. As more patients enroll in theseregistries, researchers will gain greaterinsight into the patterns of care andclinical and health-related quality oflife for diverse cohorts of prostate cancerpatients.

The 30 reports in this special supplement to Oncology News International represent highlights of ongoing major clinical trials and new research presented at ASCO 2004 regarding state-of-the-art chemotherapeutic management of gastrointestinal and other cancers. Important developments in capecitabine as adjuvant therapy, novel targeted agents, and new combinations are discussed.

Radical prostatectomy and ultrasound-guided transperinealbrachytherapy are both acceptedtreatment options for men with clinicallylocalized prostate cancer.Investigators continue to argue overthe relative effectiveness of each ofthese procedures, not only from thestandpoint of cure, but also with regardto how each treatment affectsquality of life. With the recent closureof a prospective, randomized trial addressingthese issues (the SurgicalProstatectomy Interstitial RadiationIntervention Trial, or SPIRIT) due tolack of patient accrual, it is unlikelythat a direct comparison of these techniqueswill be performed in the foreseeablefuture.

I am honored and delighted to beable to comment on the outstandingcontribution from Drs. Cooperberg,Park, and Carroll relating recentprostate cancer research fromthe various national efforts in prostatedisease research database efforts.As a former director of the Departmentof Defense Center for ProstateDisease Research (DoD-CPDR), Iwas blessed to be able to lead one ofthese database efforts as well as collaboratewith Dr. Carroll and his colleaguesfrom the Cancer of theProstate Strategic Urologic ResearchEndeavor (CaPSURE). Dr. AnthonyD'Amico and his colleagues headedseveral of our joint collaborationsfrom Harvard. In this light, I wouldlike to focus my editorial commentson providing a more in-depth reviewof work[1] that was briefly mentionedin the article by Cooperberg et al.

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.

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.