Genitourinary Cancers

In this review, we describe how clinical investigators addressed some of the challenges in prostate cancer chemotherapy trials 20 years ago, and we indicate what has evolved in the field since that time. We consider the impact that prostate-specific antigen measurement had in this setting, evolving clinical paradigms, multidisciplinary programs, and the current armamentarium of cancer treatment, including targeted molecular therapy, for patients with hormone-refractory disease.

In this review, we describe how clinical investigators addressed some of the challenges in prostate cancer chemotherapy trials 20 years ago, and we indicate what has evolved in the field since that time. We consider the impact that prostate-specific antigen measurement had in this setting, evolving clinical paradigms, multidisciplinary programs, and the current armamentarium of cancer treatment, including targeted molecular therapy, for patients with hormone-refractory disease.

In this review, we describe how clinical investigators addressed some of the challenges in prostate cancer chemotherapy trials 20 years ago, and we indicate what has evolved in the field since that time. We consider the impact that prostate-specific antigen measurement had in this setting, evolving clinical paradigms, multidisciplinary programs, and the current armamentarium of cancer treatment, including targeted molecular therapy, for patients with hormone-refractory disease.

Novel prognostic biomarkers for prostate cancer are moving toward the clinic and may eventually join Gleason score and other predictors of relapse to help with treatment decisions, according to data on two candidate markers presented at the 97th Annual Meeting of the American Association for Cancer Research.

A combination of radiation and suicide-gene therapy is eliminating the spread of prostate cancer; and providing a long-term vaccine against the disease, according to a study presented at the American Society of Clinical Oncology's annual prostate cancer meeting in San Francisco recently.

Cytogen Corporation recently announced the presentation of clinical data demonstrating that a high level of prostate-specific membrane antigen (PSMA) in prostate tissue is a strong predictor of prostate cancer recurrence. The data were presented at the 101st American Urological Association (AUA) Annual Meeting held May 20-25 in Atlanta.

The 5-year incidence of biochemical recurrence (BCR) of prostate cancer decreases with increased experience of the surgeon performing the prostatectomy, Fernando Bianco, MD, reported at the 2006 Prostate Cancer Symposium (abstract 272).

Socioeconomic factors predominantly explain racial and ethnic disparities in prostate cancer outcomes, according to a new study.

The US Food and Drug Administration (FDA) recently approved sunitinib malate (Sutent) capsules for two types of cancer: advanced renal cell carcinoma and malignant gastrointestinal stromal tumor (GIST), after disease progression on or intolerance to the frontline drug imatinib mesylate (Gleevec).

For the first time, the US Food and Drug Administration (FDA) has granted a new oncologic drug product approval for indications for two different cancers simultaneously. The agency approved Sutent (suniti-nib, Pfizer) for the treatment of patients with gastrointestinal stromal tumors (GIST) whose disease has progressed on imatinib (Gleevec) or who are unable to tolerate imatinib. It also granted Sutent accelerated approval for treating advanced renal cell carcinoma (RCC).

The Food and Drug Administration (FDA) has approved Nexavar (sorafenib tosylate) tablets for the treatment of patients with advanced renal cell carcinoma. Nexavar, a multikinase inhibitor that has been shown to double progression-free survival in these patients, is the first FDA-approved treatment for this type of cancer in more than a decade, Bayer Pharmaceuticals Corporation and Onyx Pharmaceuticals, Inc.

High-grade urothelial cancer ofthe bladder is not only relativelycommon but unfortunately,is frequently lethal. These tumorsare often diagnosed when thetumors have already invaded the wallof the bladder. Even when they arediagnosed at a time when they areconfined to the mucosa or lamina propria,patients may not respond to abladder-preservation approach. Oftena radical cystectomy with urinary diversionis either not offered at all or notconsidered until the cancer has invadeddeep into the muscularis propria andlocal treatment fails.

Bladder cancer is the fifth most common cancer diagnosed in theUnited States. Prognosis for this disease is dependent on both tumorstage and grade. Radical cystectomy has been the standard treatmentfor muscle-invasive local disease; however, combined-modality approacheswith the use of chemotherapy are gaining momentum withdata suggesting survival improvement. Patients with metastatic diseasehave poor long-term survival rates despite systemic multiagent chemotherapy.A variety of agents, including newer cytotoxic drugs and biologicallytargeted agents, are under investigation to determine the mosteffective regimen. The special needs of specific patient populations,such as the elderly, those with a suboptimal performance status, andpatients with medical comorbidities have gained more attention.Progress in the treatment of this disease is dependent on supportingongoing and future clinical trials.

Drs. Henry, MacVicar, and Hussainprovide a timely reviewof the current management ofmuscle-invasive and metastaticurothelial cancer. The emerging roleof neoadjuvant chemotherapy and thepromise of novel, less toxic targetedtherapies are of particular interest inthe treatment of a disease in whichoutcomes remain poor for locally advancedand metastatic involvementdespite an aggressive multimodalityapproach.[1] We wish to briefly commenton three issues raised by theauthors: (1) the role of surgery in themanagement of invasive disease,(2) the indiscriminate use of neoadjuvantchemotherapy for clinically localizeddisease, and (3) the currentstatus of bladder-sparing approaches.

Optimal therapy for locally advancedbladder cancer aimsto prevent local recurrence,reduce the probability of distant metastasis,and improve survival. Radicalcystectomy coupled with a pelviclymph node dissection is the mainstaytreatment of locally invasive bladdercancer, curing the majority ofpatients with organ-confined bladdertumors, about half with extravesicaldisease, and a significant minoritywith lymph node metastases. Althoughradical cystectomy providesgood local and regional control of invasivebladder cancer, the recurrencefreeand overall survival rates are stillonly 63%–72% and 59%–66%, respectively,among all patients. Themajor predictors for disease-specificsurvival of patients following radicalcystectomy for bladder cancer are thepathologic stage of the primary tumorand status of lymph nodes at time ofcystectomy. Freedom from recurrenceat 5 years after cystectomy is 63%–72% for patients with organ-confineddisease and only 25%-37% for non-organ-confined disease.

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.