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Gallbladder carcinoma and carcinoma of the bile ducts are relativelyrare cancers in the United States. These cancers are often diagnosedin an advanced stage due to their nonspecific symptomatologyand until recently have been associated with a dismal prognosis. Recentadvances in imaging and surgical techniques along with emergingoptions in palliative chemotherapy have improved the outlook inthese cancers. While complete surgical resection remains the only hopeof cure in both these cancers, palliative biliary decompression and chemotherapyresult in substantial improvement in quality of life. Part 1 ofthis review provides a relevant and comprehensive update of molecularpathology, imaging modalities, and surgical care. In part 2, which willappear next month, we will review palliative care and systemic therapyin gallbladder and biliary tract carcinomas, as well as the use of livertransplantation in the treatment of cholangiocarcinomas. These strategiesare of relevance to internists as well as oncologists caring forthese patients.

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.

AN ANTONIO-Breast cancer patients with BRCA 1 or 2 mutations undergoing breast-conserving surgery plus radiotherapy do not have more in-breast recurrences or radiotherapy complications than their counterparts without the germ-line mutation, and they derive particular benefits from prophylactic bilateral oophorectomy, according to 10-year results from a large collaborative database reported at the 26th San Antonio Breast Cancer Symposium (abstract 5).

Over the past decade, remarkable advanceshave been made in the biology and treatmentof multiple myeloma.[1] In most, if not all,patients, myeloma evolves from a precursorstage called monoclonal gammopathy of undeterminedsignificance (MGUS); MGUS isasymptomatic, but progresses to myeloma ora related disorder at a rate of 1% per year.[2]Although precise pathogenetic mechanismsremain elusive, recent studies show that aprimary translocation, usually involvingthe immunoglobulin heavy chain locus onchromosome 14q32, or in some cases theimmunoglobulin lambda light chain locus,can be detected at the MGUS stage in 60-65% of individuals.[3] Progression of MGUSto myeloma appears to be a random eventoften accompanied by secondary translocations(eg, c-myc), mutations in RAS or othergenes, as well as changes in the microenvironmentincluding the induction of angiogenesis.

The role of prostate brachytherapyin the treatment of prostatecancer continues to expand andevolve. The increasing clinical use andwider acceptance of this treatmentmodality can be attributed to published10-year data demonstrating cure ratesequivalent to those of radical prostatectomyand to quality-of-life studiesthat demonstrate relatively lowermorbidity from brachytherapy comparedto surgery.[1-4] It is the easeand convenience of treatment, the apparentequivalent cure rates, and theperception of lower morbidity thatmakes this treatment so appealing topatients. However, like all treatments,prostate brachytherapy does have sideeffects, and some patients will suffersignificant complications or severemorbidity.

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.

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.

This special “annual highlights” supplement to Oncology News International is acompilation of some of the major advances in the management of gastrointestinalcancers during 2003–2004, as reported in ONI. Guest editor Dr. James L. Abbruzzesecomments on the reports included herein and discusses advances in the clinicalmanagement 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.

SAN DIEGO-The addition of rituximab (Rituxan) to CHOP chemotherapy has resulted in a dramatic improvement in outcome for patients of all ages with diffuse large B-cell (DLBC) lymphoma in a retrospective study from British Columbia. Improvements were greatest among the elderly population in the study, Laurie Sehn, MD, clinical assistant professor, British Columbia Cancer Agency and University of British Columbia, said at the 45th Annual Meeting of the American Society of Hematology (abstract 88).

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.

NEW ORLEANS-Molecular imaging is rapidly advancing as a biomedical modality that increases the understanding of underlying cellular mechanics and dynamics and adds a new dimension to the diagnosis and treatment of disease. It may be a sensitive and specific method for evaluating cancer by measuring the expression of genes that trigger oncogenesis and stratifying tumors on the basis of their biological characteristics

There was a very rapid response [to CyBorD], which has been typical when you incorporate bortezomib into the initial regimens,” commented Dr. Anderson, from the Dana-Farber Cancer Institute in Boston.

Amgen and Millennium, a subsidiary of Takeda Pharmaceutical Company Limited, have suspended enrollment in the phase III Motesanib NSCLC Efficacy and Tolerability Study.

This special supplement to Oncology News International presents 17 reports fromthe first annual Geriatric Oncology Consortium (GOC) multidisciplinary conference,‘‘Advancing Cancer Care in the Elderly.’’ Reports focus on issues in geriatric oncology,in particular team-based patient assessment and care delivery,adherence to medication, accrual to clinical trials, appropriate dosingthrough supportive therapy, radiation therapy, cognition problems, pain management,reassessment of outcomes, and caregiving issues.

SALT LAKE CITY-A single fraction of 8 Gy of radiation therapy is as efficacious as 30 Gy delivered in 10 fractions for palliation of painful bone metastases and causes less acute toxicity, reported William F. Hartsell, MD, at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (plenary session, abstract 1).

Oropharyngeal mucositis is a common and treatment-limiting sideeffect of cancer therapy. Severe oral mucositis can lead to the need tointerrupt or discontinue cancer therapy and thus may have an impacton cure of the primary disease. Mucositis may also increase the risk oflocal and systemic infection and significantly affects quality of life andcost of care. Current care of patients with mucositis is essentially palliativeand includes appropriate oral hygiene, nonirritating diet andoral care products, topical palliative mouth rinses, topical anesthetics,and opioid analgesics. Systemic analgesics are the mainstay of painmanagement. Topical approaches to pain management are under investigation.The literature supports use of benzydamine for prophylaxisof mucositis caused by conventional fractionationated head andneck radiotherapy, and cryotherapy for short–half-life stomatoxic chemotherapy,such as bolus fluorouracil. Continuing studies are investigatingthe potential use of biologic response modifiers and growth factors,including topical and systemic delivery of epithelial growth factorsand agents. Progress in the prevention and management of mucositiswill improve quality of life, reduce cost of care, and facilitate completionof more intensive cancer chemotherapy and radiotherapy protocols. Inaddition, improved management of mucositis may allow implementationof cancer treatment protocols that are currently excessively mucotoxicbut may produce higher cure rates. Continuing research related to thepathogenesis and management of mucositis will undoubtedly lead to thedevelopment of potential interventions and improved patient care.

This special supplement to Oncology News International presents 17 reports fromthe first annual Geriatric Oncology Consortium (GOC) multidisciplinary conference,‘‘Advancing Cancer Care in the Elderly.’’ Reports focus on issues in geriatric oncology,in particular team-based patient assessment and care delivery,adherence to medication, accrual to clinical trials, appropriate dosingthrough supportive therapy, radiation therapy, cognition problems, pain management,reassessment of outcomes, and caregiving issues.

This special supplement to Oncology News International presents 17 reports fromthe first annual Geriatric Oncology Consortium (GOC) multidisciplinary conference,‘‘Advancing Cancer Care in the Elderly.’’ Reports focus on issues in geriatric oncology,in particular team-based patient assessment and care delivery,adherence to medication, accrual to clinical trials, appropriate dosingthrough supportive therapy, radiation therapy, cognition problems, pain management,reassessment of outcomes, and caregiving issues.

This special supplement to Oncology News International presents 17 reports fromthe first annual Geriatric Oncology Consortium (GOC) multidisciplinary conference,‘‘Advancing Cancer Care in the Elderly.’’ Reports focus on issues in geriatric oncology,in particular team-based patient assessment and care delivery,adherence to medication, accrual to clinical trials, appropriate dosingthrough supportive therapy, radiation therapy, cognition problems, pain management,reassessment of outcomes, and caregiving issues.

This special supplement to Oncology News International presents 17 reports fromthe first annual Geriatric Oncology Consortium (GOC) multidisciplinary conference,‘‘Advancing Cancer Care in the Elderly.’’ Reports focus on issues in geriatric oncology,in particular team-based patient assessment and care delivery,adherence to medication, accrual to clinical trials, appropriate dosingthrough supportive therapy, radiation therapy, cognition problems, pain management,reassessment of outcomes, and caregiving issues.