ONCOLOGY Vol 17 No 10

In this issue of ONCOLOGY, Dr.Aman Buzdar provides a timelysynopsis of current perspectiveson breast cancer in men. I would onlyadd or expand upon a few points.

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]

Dr. Hevezi has outlined someexciting new developments inthe field of radiation oncologyin his thorough review. Since its inception,radiation oncology has beengeographically based, ie, related to theradiation exposure of tumor vs normaltissue. It is therefore a logical extensionof new radiographic technologythat allows for more preciseplacement of radiation fields than everbefore. Further, as outlined by Dr.Hevezi, the development of treatmentplanning computers coupled to verificationcomputers on the liner acceleratoris associated with precise radiationdelivery that exploits the relativeradiation dose between the tumorand normal tissue, allowing higherdoses to be used without increasedtoxicity.

Management of patients with neoplastic disease has shifted from searchand-destroy approaches employing radical surgery, chemotherapy,and radiotherapy to novel strategies that target specific molecular orgenetic characteristics or modify growth factors, angiogenesis, and cell-cell interactions.Attention has also been focused on modifying the production and function ofcertain enzymes pivotal to the genesis of disseminated disease.

This is a period of rapid developments in radiotherapy for malignantdisease. New methods of targeting tumors with computed tomography(CT) virtual simulation, magnetic resonance imaging (MRI), andpositron-emission tomography (PET) fusion provide the clinician withinformation heretofore unknown. Linear accelerators (linacs) withmultileaf collimation (MLC) have replaced lead-alloy blocks. Indeed,new attachments to the linacs allow small, pencil beams of radiation tobe emitted as the linac gantry rotates around the patient, conforming tothree-dimensional (3D) targets as never before. Planning for these deliverysystems now takes the form of "inverse planning," with CT informationused to map targets and the structures to be avoided. In thearea of brachytherapy, techniques utilizing the 3D information providedby the new imaging modalities have been perfected. Permanentseed prostate implants and high-dose-rate (HDR) irradiation techniquestargeting bronchial, head and neck, biliary, gynecologic, and otheranatomic targets are now commonplace radiotherapy tools. CT-guidedpermanent seed implants are being investigated, and a new method oftreating early breast cancer with HDR brachytherapy via a ballooncatheter placed in the lumpectomized cavity is coming to the forefront.Newer modalities for the treatment of malignant and benign diseaseusing stereotactic systems and body radiosurgery are being developed.Targeted radionuclides using microspheres that contain radioemittersand other monoclonal antibody systems tagged with radioemitters havebeen recently approved for use by the Food and Drug Administration.

Traditional therapies for breast cancer have generally relied uponthe targeting of rapidly proliferating cells by inhibiting DNA replicationor cell division. Although this strategy has been effective, its innate lackof selectivity for tumor cells has resulted in diminishing returns, approachingthe limits of acceptable toxicity. A growing understanding ofthe molecular events that mediate tumor growth and metastases has ledto the development of rationally designed targeted therapeutics thatoffer the dual hope of maximizing efficacy and minimizing toxicity tonormal tissue. Promising strategies include the inhibition of growthfactor receptor and signal transduction pathways, prevention of tumorangiogenesis, modulation of apoptosis, and inhibition of histone deacetylation.This article reviews the development of several novel targetedtherapies that may be efficacious in the treatment of patients with breastcancer and highlights the challenges and opportunities associated withthese agents.

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.

Most men with breast cancer present with a mass in the breast, theevaluation of which should include a tissue diagnosis. If the presence ofinvasive cancer is established, adequate local therapy includes totalremoval of the breast. Most tumors are hormone-receptor positive. Inhigh-risk patients, the use of endocrine adjuvant therapy and/or combinedendocrine and chemotherapy should be considered. Patients withestrogen-receptor (ER)-negative disease should be offered chemotherapy.In patients with metastatic disease and ER-positive tumors, initialtreatment should be endocrine therapy; systemic chemotherapy shouldbe used in patients who are either hormone-receptor negative or resistantto available endocrine therapies.

Syed and Rowinsky present acomprehensive review of newtargeted therapies for breast cancer.This is an important review thatsummarizes new biologic targets andcurrent drugs in development for thetreatment of breast cancer-a rapidlyevolving field. Among the targets addressedin the article are epidermalgrowth factor receptor (EGFR), Ras/Raf/mitogen-activated protein (MAP)kinase, phosphatidylinositol 3-kinase(PI3K)/protein kinase B (AkT)/moleculartarget of rapamycin (mTOR), tumorangiogenesis, apoptosis, andhistone deacetylases. The list shouldalso be expanded to include differentiatingagents and inhibitors of invasionand metastasis. It is critical toemphasize the future of customizedtherapy and the use of biologic agentsalone, together, or in combination withchemotherapy for the treatment ofbreast cancer.

Together, parts 1 and 2 of thearticle by Drs. Wilson andSmith on the “Management ofMycosis Fungoides” serve as an excellentreference for the diagnosis andmanagement of this subtype of cutaneousT-cell lymphoma. Part 1, whichdeals with the diagnosis, staging, andprognosis of mycosis fungoides, appearedin the September 2003 issue ofthis journal. Part 2, which deals withtreatment, appears in the current issue.The article is a concise overviewof the numerous treatment strategiesand specific treatments available forvarious stages and presentations ofmycosis fungoides.

Dr. Hevezi provides a broadoverview of the numeroustechnical innovations thathave been commercialized and arenow available to many centers for theradiation treatment of cancers. Hisreview describes computed tomography(CT) simulation, stereotactic radiosurgery,intensity-modulated radiotherapy(IMRT), and advances inbrachytherapy. The article's breadth ofcoverage necessarily limits details.

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]

The review by Dr. Buzdar emphasizesa variety of clinicalfeatures observed in male breastcancer. Although this is an uncommondiagnosis even in a busy oncologypractice (representing less than 1%of all breast cancers), it is occasionallyseen.

As noted by Dr. Buzdar, breastcancer rarely affects men. Accordingto the most recent datafrom the National Cancer Institute’sSurveillance Epidemiology and EndResults program and the National Programof Cancer Registries, the incidenceof invasive breast cancer is 1.5cases per 100,000 men vs 134 casesper 100,000 women.[1] Breast cancerin women is a far greater public healthproblem and understandably has receivedthe lion’s share of researchfunding and public attention.

The article by Drs. Syed andRowinsky is well written andcomprehensive. They introduceseveral biologic pathways that are importantin breast cancer and focus onnew pharmaceutical agents designedto disrupt these pathways. Patients andphysicians hope that agents that targetthe tyrosine kinase signal transductionpathways, block tumor angiogenesis,modulate apoptosis, and inhibithistone deacetylation will be effective,nontoxic therapies for breastcancer. These molecularly targeted approacheshold promise, but deliveringon this promise requires that we movebeyond histologic characterization ofthe disease and rethink the design ofclinical trials.

Mycosis fungoides is a low-grade lymphoproliferative disorder ofskin-homing CD4+ lymphocytes that may produce patches, plaques,tumors, erythroderma, and, ultimately, systemic dissemination. Treatmentselection is generally guided by institutional experience, patientpreference, and toxicity profile, as data from phase III clinical trials arelimited. Effective topical treatments currently include mechlorethamine(Mustargen), carmustine (BCNU, BiCNU), corticosteroids, bexarotene(Targretin, a novel rexinoid), psoralen plus ultraviolet A, ultraviolet B,and total-skin electron-beam radiotherapy. Effective systemic treatmentsinclude interferon, retinoids, bexarotene, denileukin diftitox(Ontak), extracorporeal photopheresis, chemotherapy, and high-dosechemotherapy with allogeneic bone marrow transplant. Each of thesetreatments is discussed in detail, followed by specific recommendationsfor each stage of mycosis fungoides.

Conservation of blood is apriority during surgery, owingto shortages of donor bloodand risks associated with transfusionof blood products.[9,10] However,blood transfusions have been linkedto a number of negative postoperativesequelae, including poorer prognosisafter cardiac and cancer surgery.[11-21] In this context, recognition thatallogeneic transfusion-associatedimmunomodulation can increasemorbidity in allogeneically transfusedpatients has become a major concernin transfusion medicine.[9,22,23]