ONCOLOGY Vol 18 No 4

VIENNA-Yes, size does matter, but it is certainly not the only way to monitor the effi cacy of cancer treatment. Th e way in which lesions are measured is extremely important as well, according to a special focus session on the assessment of tumor response at the 2009 European Congress of Radiology.

VIENNA-Image-guided intensity-modulated radiotherapy, high-intensity focused ultrasound, and cryotherapy are increasing the curative treatment options for men with prostate cancer. The problem is how to determine which patients are most suitable for these therapies.

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.

Biomedical research is in themidst of unprecedented transformationstemming from theoverall impact of molecular biologyon medical research, including theemerging high-throughput genomicsbasedtechnologies. These new paradigmsare leading to better definitionof the disease state as well as moreprecise and less toxic therapeutic strategies.But even as we begin to understandthe implications of gene-basedinformation on the genesis, pathophysiology,and progression of disease andon the development of novel therapeuticapproaches, the dawn of theera of proteomics is heralding evenmore radical changes.

The past decade has given rise toan explosion of rationally designed,molecularly targetedtherapeutic agents. The epidermalgrowth factor receptor (EGFR) hasserved as the principal platform forthe development of such novel targetedtherapies, resulting in a paradigmshift in the treatment of a vast array ofsolid malignancies. Damjanov andMeropol have provided a comprehensiveand insightful overview of the roleof EGFR-directed therapeutics in colorectalcancer. They have chosen tofocus their discussion on the compoundsthat are furthest along in clinicaldevelopment and, hence, havereviewed the monoclonal antibodiescetuximab (Erbitux), ABX-EGF, andEMD 72000, as well as the small-moleculetyrosine kinase inhibitors gefitinib(Iressa) and erlotinib (Tarceva).

Damjanov and Meropol havedone an excellent job of reviewingboth the complex biologyof epidermal growth factor signalingand the current status ofepidermal growth factor receptor(EGFR, ErbB-1) inhibition for thetreatment of colorectal cancer. As theypoint out, several factors have madeEGFR a potentially high-value targetin cancer therapy. In addition, theyreview several phase II studies thathave demonstrated clinical activity foranti-EGFR antibodies in patients withadvanced colorectal cancer.

The epidermal growth factor receptor (EGFR) is commonly expressedin colorectal cancers but not in most normal tissues, raising the possibilitythat this receptor could serve as a target for highly selective therapy.Based on preclinical studies demonstrating that antagonists of EGFRresulted in the inhibition of tumor growth, the development of clinicalreagents has been aggressively pursued. Early clinical studies demonstratedantitumor activity of EGFR inhibitors in patients with advancedcolorectal cancer, with acceptable toxicity. This early success fueledrapid clinical development. In this article, we will review the currentstatus of EGFR inhibitors in the treatment of patients with colorectalcancer, in an effort to describe both how far we have come as well aswhere we need to go in optimizing this promising therapeutic approach.

Much excitement has beengenerated in the past fewyears around the potential of“omics technologies” to produce advancesin medicine. For example, globalprofiling using DNA microarrayshas uncovered patterns of gene expressionthat may have clinical utility. However,it has become clear that numerousobstacles must be overcome beforefindings from these studies have a substantialimpact on clinical practice.

For the clinician who is facedwith treating individual patients,the article by Ornstein and Petricoinmight raise the famous questionfrom the Wendy’s commercial:Where’s the beef? When we hear ofthese Star Wars technologies and complexexplanations, we are often frustrated.On the one hand, we havenothing to offer our patients right now,and on the other, our patients readabout these technologies and expectthem to be applied right now.

Introduction: In 1975, Durie and Salmon (DS)developed a staging system that has remained, forover 25 years, the gold standard for stratificationof MM patients. However the system does notcontain B2M, widely recognized as the most usefulprognostic factor. Acceptance of staging systemsutilizing B2M has been impeded by lack ofagreement on the merits of other components.Similar to what has been done in other malignancies,an international cooperative effort gathereddata on 11,171 cases from 17 institutions in Asia,Africa, Europe, and North America; 8,270 receivedstandard treatment, and 2,901 receivedhigh dose therapy as initial planned treatment.

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.

Locally advanced breast canceraccounts for up to 70% ofbreast cancer cases worldwide.[1] In the past decade, neoadjuvantsystemic therapy has emerged asa therapeutic option for early breastcancer. The main goal of neoadjuvanttreatment is to downstage breast tumors,rendering them operable or permittingbreast-conserving surgery.The therapy has been used increasinglyin patients who have large breasttumors and are candidates for mastectomy,but in whom tumor shrinkageallows for less extensive surgeryand better cosmetic results.[2] Thedegree of the tumor’s responsivenessto preoperative therapy could serveas a surrogate for the response ofmicrometastasis to therapy and theconsequent outcome.[3]

Breast cancer mortality has declinedin recent years due toadvances in screening and adjuvantsystemic therapy. Based on anoverall estimated risk of relapse foran individual woman, her age, comorbidities,and tumor characteristics,she may be offered adjuvant hormonetherapy, chemotherapy, or both.

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]

Proteomics is a rapidly emerging scientific discipline that holds greatpromise in identifying novel diagnostic and prognostic biomarkers forhuman cancer. Technologic improvements have made it possible to profileand compare the protein composition within defined populationsof cells. Laser capture microdissection is a tool for procuring pure populationsof cells from human tissue sections to be used for downstreamproteomic analysis. Two-dimensional polyacrylamide gel electrophoresis(2D-PAGE) has been used traditionally to separate complex mixturesof proteins. Improvements in this technology have greatly enhancedresolution and sensitivity providing a more reproducible and comprehensivesurvey. Image analysis software and robotic instrumentationhave been developed to facilitate comparisons of complex protein expressionpatterns and isolation of differentially expressed proteins spots.Differential in-gel electrophoresis (DIGE) facilitates protein expressionby labeling different populations of proteins with fluorescent dyes.Isotope-coded affinity tagging (ICAT) uses mass spectroscopy for proteinseparation and different isotope tags for distinguishing populationsof proteins. Although in the past proteomics has been primarilyused for discovery, significant efforts are being made to developproteomic technologies into clinical tools. Reverse-phase protein arraysoffer a robust new method of quantitatively assessing expressionlevels and the activation status of a panel of proteins. Surface-enhancedlaser-desorption/ionization time-of-flight (SELDI-TOF) mass spectroscopyrapidly assesses complex protein mixtures in tissue or serum. Combinedwith artificial intelligence–based pattern recognition algorithms,this emerging technology can generate highly accurate diagnostic information.It is likely that mass spectroscopy–based serum proteomicswill evolve into useful clinical tools for the detection and treatment ofhuman cancers.

For many oncologists, neoadjuvant treatment for breast cancer issynonymous with preoperative cytotoxic chemotherapy, regardless oftumor characteristics. Preoperative therapy with an endocrine agent isgenerally considered suitable only for the frail elderly or the medicallyunfit. However, favorable information regarding third-generationaromatase inhibitors in the treatment of all stages of breast cancerprompts a reconsideration of this bias. In light of the fact thatneoadjuvant therapy with aromatase inhibitors is restricted to postmenopausalwomen with strongly estrogen-receptor–positive tumors, the assumptionthat neoadjuvant combination chemotherapy is more efficaciousthan a third-generation aromatase inhibitor can be reasonablyquestioned. It is particularly remarkable that the outcome of a comparisonof adjuvant tamoxifen vs anastrozole (Arimidex)-the Arimidex,Tamoxifen Alone or in Combination (ATAC) trial-in more than 6,000patients was predicted by a neoadjuvant trial that showed an efficacyadvantage for a third-generation aromatase inhibitor (letrozole[Femara]) compared to tamoxifen in a sample of 337 patients afteronly 4 months of treatment. The potential of the neoadjuvant setting inefforts to identify new biologic agents that could build on the effectivenessof adjuvant aromatase inhibitors is therefore beginning to be appreciated.Finally, neoadjuvant therapy with an aromatase inhibitorcould be considered a sensitivity test of endocrine therapy that might beincorporated into strategies to individualize treatment according to response.For this possibility to be realized, however, a better understandingof the relationship between surrogates from the neoadjuvant settingand the long-term outcome of adjuvant aromatase inhibitor therapywill have to be established through practice-setting clinical trials.