ONCOLOGY Vol 19 No 12

The review by Vergote et al[1]presents a well-organized andcomprehensive summary of thedata addressing neoadjuvant chemotherapyfor ovarian cancer. The timingof debulking surgery for thisdisease is a common and clinicallyimportant question, but one that lacksdefinitive trial data. The assembleddata suggest a rationale for decisionmaking.The European Organizationfor Research and Treatment of Cancer(EORTC) and Gynecologic OncologyGroup (GOG) 152 trialspresent compelling evidence supportinga “maximal surgical effort” by anexperienced gynecologic surgeon,preferably at a specialty hospital, atsome point during primary therapy.

Continuing advances in immunology and molecular biology duringthe past several decades have provided optimism that immunomodulatorystrategies may be clinically useful in patients with cancer.Key advances have included: (1) recognition of the critical role of theantigen-presenting cell and greatly improved understanding of antigenprocessing and presentation, including the molecular interactionsbetween HLA molecules and antigenic epitopes on the antigen-processingcell and the receptors on T cells, and (2) the roles ofcostimulatory molecules such as B7.1, ICAM-1, and LFA-3 in the inductionand maintenance of an immune response. In addition, newtechniques have allowed us to identify immunogenic antigenic determinants,alter their binding affinities, and evaluate the overall successof the intervention through both in vivo and in vitro assays.Carcinoembryonic antigen (CEA) is overexpressed in a large numberof gastrointestinal, lung, and breast cancers. Clinical trials have establishedtreatment protocols using viral vectors to immunize patients toCEA without producing deleterious autoimmune phenomena. By combiningvarious vectors to include MUC-1 and/or CEA plus costimulatorymolecules in a prime-and-boost regimen, we are beginning to see signsthat this intervention can not only produce changes in immune functionbut also potentially improve clinical outcomes. Phase III studies totest these hypotheses are under way.

In this review of hepatic resectionfor metastatic breast cancer, theauthors argue that a small groupof women with isolated liver metastasesmay be appropriate candidates forsurgical resection. Although some datahave been reported, the few publishedstudies represent small, retrospectivesingle-institutional series with no standardizedcriteria for resection. Nevertheless,the potential prospect ofimproved patient outcome in the settingof liver metastases from breastcancer deserves further consideration.

Kauh and colleagues nicely outlinethe major problems facingclinicians who treat humanimmunodeficiency virus (HIV)-positivepatients with squamous cell carcinomaof the anus. This is a highly curabledisease with combined-modality therapy,though the HIV-positive populationpresents unique challenges. Weagree with the approaches outlined bythe authors and would also like to emphasizeseveral principles in the managementof anal cancer.

Squamous cell anal cancer remains an uncommon entity; however,the incidence appears to be increasing in at-risk populations, especiallythose infected with human papillomavirus (HPV) and human immunodeficiencyvirus (HIV). Given the ability to cure this cancer using synchronouschemoradiotherapy, management practices of this disease arecritical. This article considers treatment strategies for HIV-positive patientswith anal cancer, including the impact on chemoradiation-inducedtoxicities and the role of highly active antiretroviral therapy in the treatmentof this patient population. The standard treatment has beenfluorouracil (5-FU) and mitomycin (or cisplatin) as chemotherapy agentsplus radiation. Consideration to modifying the standard treatment regimeis based on the fact that patients with HIV tend to experience greatertoxicity, especially when CD4 counts are below 200; these patients alsorequire longer treatment breaks. Additional changes to the chemotherapydosing, such as giving 5-FU continuously and decreasing mitomycin dose,are evaluated and considered in relation to radiation field sizes in an effortto reduce toxicity, maintain local tumor control, and limit need forcolostomy. The opportunity for decreasing the radiation field size andusing intensity-modulated radiation therapy (IMRT) is also considered,particularly in light of the fact that IMRT provides dose-sparing whilemaximizing target volume dose to involved areas. The impact of the immunesystem in patients with HIV and squamous cell carcinoma of theanus and the associated response to therapy remains unknown. Continuedstudies and phase III trials will be needed to test new treatment strategiesin HIV-infected patients with squamous cell cancer of the anus todetermine which treatment protocols provide the greatest benefits.

Dr. Marshall has done an excellentjob in his review of thecurrent status of the design,development, and delivery of cancervaccines with emphasis on vaccinesfor the treatment of gastrointestinalcancers. He has clearly delineated boththe promise and potential limitationsof this actively emerging field ofinvestigation.

Dr. Marshall has written a clearand concise review of the rationalefor and preliminarydata from studies using therapeuticvaccines in patients with establishedgastrointestinal (GI) malignancies.He has summarized the recent advancesleading to a better understandingof basic immunology. These have hadan important influence on the possibilitythat an effective therapeutic vaccineor vaccines can be developed.

The identification of key signaltransduction pathways and, inparticular, specific proteins thatare involved in the regulation of cancercell growth has provided unprecedentedopportunities for researchersinterested in targeted cancer treatment.The identification of molecular target-specific therapy offers the potentialof maximal therapeutic benefitwhile minimizing toxicity to normalcells. The accomplishment that led tothe sequencing and analysis of theentire human genome in 2001 has providedresearchers with the basic criticaltools to begin to identify anddifferentiate cancer from normal tissueat the genetic level.[1,2] Whilethe implications of this landmarkachievement are still being realized,it has become evident that the identificationof critical genes and proteinsinvolved in cell division and growthare just the beginning. The complexrelationships between multiple signaltransduction pathways, the surroundingtumor microenvironment, andpathways involved in immune-systemregulation have gained new appreciation.The ability to manipulate thesemultiple interactive systems with targetedtherapies represents a new treatmentparadigm in oncology.

The article by Kauh and colleaguesprovides a timely reviewof the therapeutic approachto invasive carcinoma of theanus in human immunodeficiency virus(HIV)-infected patients, which isan emerging clinical problem. Importantlimitations of the published experience,however, need to be pointedout; given the present pursuit of moretargeted anticancer therapy, new avenuesare being explored, even in themanagement of HIV-associated analcancer.

Neoadjuvant, or induction, chemotherapyhas been usedextensively in selected carcinomas,particularly head andneck cancer (recently reviewed inONCOLOGY)[1] and locally advancedbreast cancer. Despite beneficialeffects on morbidity, long-termsurvival has not been significantly improvedby neoadjuvant chemotherapy.

Primary debulking surgery by a gynecologic oncologist remains thestandard of care in advanced ovarian cancer. Optimal debulking surgeryshould be defined as no residual tumor load. In retrospective analyses,neoadjuvant chemotherapy followed by interval debulking surgerydoes not seem to worsen prognosis compared to primary debulking surgeryfollowed by chemotherapy. However, we will have to wait for theresults of future randomized trials to know whether neoadjuvant chemotherapyfollowed by interval debulking surgery is as good as primarydebulking surgery in stage IIIC and IV patients. Interval debulking isdefined as an operation performed after a short course of induction chemotherapy.Based on the randomized European Organization for Researchand Treatment of Cancer–Gynecological Cancer Group (EORTC-GCG)trial, interval debulking by an experienced surgeon improves survival insome patients who did not undergo optimal primary debulking surgery.Based on Gynecologic Oncology Group (GOG) 152 data, intervaldebulking surgery does not seem to be indicated in patients who underwentprimarily a maximal surgical effort by a gynecologic oncologist.Open laparoscopy is probably the most valuable tool for evaluating theoperability primarily or at the time of interval debulking surgery.

Few would question the statementthat the role of surgery in themanagement of epithelial ovariancancer is unique in solid tumoroncology.

Podnos and Wagman provide acomprehensive review of surgicalresection for hepatic breastcancer metastases. The authors presentthe disparate data accrued by variouscenters in the United States, Europe,and Asia, and then attempt to consolidatethese experiences to draw conclusionsand provide guidelines. Thisreview is well-written, thorough, andinteresting; however, as with anyreview of a topic devoid of level 1evidence, the authors raise more questionsthan answers.

In general, surgery has no role inthe curative treatment of metastaticbreast cancer. Metastatic breastcancer is considered incurable, associatedwith an average survival of 18 to24 months. Certain factors such as hormone-receptor negativity, HER2/neupositivedisease, and a short disease-freeinterval portend a poor prognosis. Theliver is not usually a site of initialfailure-less than 15% of patients fitthis pattern.[1] Even fewer are candidatesfor surgical resection due toextrahepatic disease. Eventually, overhalf of all patients with metastatic diseasewill have liver metastasis duringtheir clinical course.

Tremendous gains have been made regarding the treatment of breastcancer. The combination of chemotherapy, radiation therapy, and surgeryhave vastly improved patient course. Hepatic manifestations ofmetastatic breast cancer are extremely difficult to treat. Traditionally,chemotherapy and hormonal treatment of hepatic metastases of breastcarcinoma have not significantly improved survival. For patients withbreast cancer metastases isolated to the liver, operative treatment isincreasingly being used to prolong life and disease-free intervals. Thisarticle reviews the use of surgery for treatment of isolated breast cancermetastases to the liver.