Prostate Cancer

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.

Granulocyte-macrophage colony-stimulating factor (GM-CSF,sargramostim [Leukine]) is a powerful cytokine that is able to stimulatethe generation of dendritic cells. Adjuvant treatment with continuous lowdoseGM-CSF has been shown to prolong survival of stage III/IV melanomapatients. Data on continuous low-dose GM-CSF therapy in tumorsother than prostate cancer are still lacking.

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."

ORLANDO-Higher baseline PSA and rapid PSA doubling time (PSADT) are adversely associated with bone metastasis and death in patients with castrate nonmetastatic prostate cancer, according to a study presented at the 2005

Lung cancer is the most commoncause of cancer-relatedmortality in the United Statesand worldwide.[1] In the UnitedStates, lung cancer was responsiblefor an estimated 160,440 deaths in2004. This surpassed the combinedmortality resulting from colorectal,breast, and prostate cancer.

This special supplement to Oncology News International comprises expertcommentary and selected reports from the 2004 meetings of RSNA andASTRO about new imaging techniques, with a focus on state-of-the-art magneticresonance imaging, positron emission tomography, computed tomography,and complementary modalities for improving the diagnosis, staging, andtreatment of a variety of cancers. Evident in these reports is the increasingcollaboration between the specialties of radiation oncology and diagnosticradiology as imaging technology continues to evolve.

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.

Drs. Andrews and Roach present an excellent review and discussion of the existing literature regarding the role of androgen ablation therapy in patients being treated with external-beam radiation therapy (EBRT) and prostate brachytherapy. However, the indications for, and optimal timing of androgen ablation with radiation therapy remain controversial, particularly in regard to brachytherapy.

Several key areas must be considered in the diagnosis and managementof spinal cord compression. Because the outcome can be devastating,a diagnosis must be made early and treatment initiated promptly.Although any malignancy can metastasize to the spine, clinicians shouldbe aware that this occurs more commonly in certain diseases, ie, lungcancer, breast cancer, prostate cancer, and myeloma. The current algorithmfor early diagnosis of spinal cord compression involves neurologicassessment and magnetic resonance imaging of the entire spine.Treatment generally consists of intravenous dexamethasone followedby oral dosing. Depending on the extent of the metastases, symptomsmay also be managed with nonnarcotic pain medicines, anti-inflammatorymedications, and/or bisphosphonates, with local radiation administeredas needed. Surgery has often led to destabilization of the spine.

Icommend the authors for their excellent review and discussion regarding the integration of hormonal therapy with permanent prostate implants. They address several important issues relating to the sequence and duration of hormonal therapy in combination with externalbeam radiation therapy (EBRT) and its underlying relationships with permanent prostate implants.

NEW ORLEANS-A new analysis of long-term zoledronic acid (Zometa) therapy in advanced prostate cancer patients with bone metastases showed significant ongoing benefit, Fred Saad, MD, reported at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 4575). A second analysis of the data showed that bisphosphonate therapy offers clinical benefit in these patients regardless of whether they had a skeletal-related event (SRE) prior to entry into the study (abstract 4576).

ATLANTA-With the use of highly conformal radiation therapy (RT), men can safely receive a high dose of radiation for early-stage prostate cancer, Anthony L. Zietman, MD, reported at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO abstract 4). Compared with a conventional radiation dose, the high dose was associated with a lower rate of treatment failure.

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.

There are two problems with thepaper by Quaranta et al, neitherof which can be overcomewith discussion or sophistry. The firstconcerns the criteria used to determinewhether a report would be includedin this analysis. Specifically,any series with a median follow-up ofonly 3 years was included if it alsomet the other inclusion criteria. Thisis simply inadequate, as there is greatconsensus that studies with 3-year follow-up miss many recurrences. Thesecond problem with the paper is thedefinition of recurrence. The AmericanSociety for Therapeutic Radiologyand Oncology (ASTRO) criteriaused by the authors has proven inferiorto using a cutoff of 0.2 ng/mL forprostate-specific antigen (PSA) nadirfollowing brachytherapy. The inaccuracyin using ASTRO criteria fordetermining cure by brachytherapy isparticularly pronounced in series withshort follow-up such as the 3-yearmedian follow-up criterion used inthis paper.

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.

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.