ONCOLOGY Vol 18 No 5

The authors begin their articleby presenting the current stateof affairs regarding lung cancerand the rationale as to why itwould seem to be an obvious candidateto benefit from a program ofearly diagnosis followed by earlytreatment. Briefly summarized, thedisease is the number one cancer killer,it is nearly uniformly fatal whendiagnosis is symptom-prompted, andit is highly curable when found in itsearly stage.

I would like to compliment the authorson their comprehensive reviewof cytoreductive surgery forovarian cancer. However, some oftheir interpretation of the literaturewarrants amplification, and some conclusionsmerit presentation of an alternativeperspective.

Despite the remarkable resultsso ably described by Ghobrialand Witzig in this issue ofONCOLOGY, radioimmunotherapyfor low-grade and transformed lowgradelymphoma is a treatment thatappears to be currently underutilizedby clinicians. The two US Food andDrug Administration (FDA)-approvedanti-CD20 radiolabeled antibodies,Y-90 ibritumomab tiuxetan (Zevalin)and tositumomab/iodine-131 (I-131)tositumomab (Bexxar), have producedresponse rates from 50% to 80% andcomplete response rates from 20% to40% in studies of patients with varyingresistance to chemotherapy as wellas rituximab (Rituxan), making theseagents probably the most active systemicagents we have available forlow-grade B-cell lymphoma.

Tumor resection without expectationof complete excision violatesthe traditional tenets ofsurgical oncology. The concept of operabilitycarries the implication ofcomplete tumor excision with a marginof normal tissue. This classic viewwas challenged by Griffith’s landmark1975 paper showing an improved survivalwith surgical cytoreduction-atechnique that cut across tumor andrarely attained negative margins.[1] Heshowed in 70 patients that survival timewas inversely proportional to the sizeof the residual tumor after surgery.

Chugh and Baker have presenteda concise and contemporaryreview of the commonnonepithelial malignancies of thebreast, focusing mainly on the managementof this heterogeneous groupof neoplasms. Needless to say, appropriatemanagement of any neoplasmis entirely dependent on accurate pathologicdiagnosis. Due to the rarity ofthese nonepithelial malignancies of thebreast, they commonly present difficultiesin pathologic diagnosis. Issuesrelating to the diagnosis of these tumorsmay not be obvious to nonpathologists,and deserve comment.

Primary nonepithelial malignancies of the breast comprise an importantminority of breast neoplasms, including primary breast sarcomas,therapy-related breast sarcomas, the phyllodes tumors, and primarybreast lymphomas. With widespread mammographic detection ofbreast lesions, these tumors represent critical elements of the differentialdiagnosis of even benign-appearing lesions. Each has a distinctclinical profile, including presentation, available therapeutic options,and prognosis, further underscoring the importance of timely recognition.The increasing incidence of breast carcinomas and the subsequenttherapy thereof may be contributing to an increase in the numberof therapy-related breast tumors. This review discusses various featuresof these uncommon malignancies and their treatment, with thegoal of increasing understanding of their clinical behavior andmanagement.

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.

We applaud Ghobrial andWitzig for their comprehensiveand balanced article on"Radioimmunotherapy: A New TreatmentModality for B-cell Non-Hodgkin's Lymphoma." Theseauthors have provided a review thatwill serve the oncologist and oncologypatient well. They have not engagedin arcane and tedious discussionof which anti-CD20 monoclonal antibody(ibritumomab tiuxetan [Zevalin]or tositumomab/iodine-131[I-131] tositumomab [Bexxar]), or radionuclide(yttrium-90 [Y-90] orI-131), or dosing method is better.Wisely, Ghobrial and Witzig have providedaccurate distillates of the manypublications on these exciting drugs.Because no rigorous body of dataclearly indicates that one drug is betterthan the other, these debates onlyconfuse the oncologist and are betterleft to the "technocrat."

Drs. Chugh and Baker's concisereview highlights diseaseentities we hear little of, andmay never see, but of which we mustbe cognizant. The article serves as avaluable reminder that not every breastmass that is palpated or detected byradiologic screening represents eithera carcinoma or benign entity such as afibroadenoma. Although rare, the nonepithelialmalignancies must beconsidered in a complete differentialdiagnosis.

At this time, two positions aboutlung cancer screening are defensiblebased on current evidence.First, it is quite reasonable todefend the position that there is insufficientevidence to recommend population-based screening for lung cancerwith spiral computed tomography(CT) for individuals at increased riskfor lung cancer.[1] Despite very favorableresults from observationalstudies,[2-4] broad consensus aboutpolicy depends, at a minimum, on resultsfrom a prospective randomizedtrial comparing lung cancer mortalityin an experimental group with a controlgroup. Ideally, this comparison isbetween a group invited to screeningand a group receiving usual care, andsuch trials have begun in France, theNetherlands, and Italy, but decisionsalso may be made for alternative comparisonsif circumstances warrant adifferent randomization scheme. TheNational Lung Screening Trial has justcompleted recruiting 50,000 individualsat elevated risk to a prospectiverandomized trial comparing chest radiographyto spiral CT.[5]

Yttrium-90 (Y-90) ibritumomabtiuxetan (Zevalin) radioimmunotherapywas approvedby the US Food and DrugAdministration (FDA) in February2002 and tositumomab/iodine-131(I-131) tositumomab (Bexxar) was approvedby the FDA in June 2003 forthe treatment of patients with relapsedor refractory low-grade, follicular, orCD20-positive transformed B-cellnon-Hodgkin’s lymphoma (NHL),and rituximab (Rituxan)-refractoryfollicular NHL. In this excellentreview, Drs. Ghobrial and Witzigdescribe the rationale for radioimmunotherapyand the relevant clinicaltrials that formed the basis forFDA approval.

The majority of ovarian cancer patients present with advanced-stagedisease, for which the goal of surgery is not only to document the extentof disease but also to perform surgical cytoreduction or tumordebulking. Cytoreductive surgery for ovarian cancer is generally performedat the time of diagnosis, when it is referred to as primarycytoreduction. It is also performed during primary chemotherapy (intervalcytoreduction) and after disease recurrence (secondarycytoreduction). Over the past 3 decades, numerous retrospective analyseshave established the role of primary cytoreduction in the managementof advanced-stage ovarian cancer. However, recent studies havereported that certain patients benefit from a neoadjuvant chemotherapeuticapproach, in which chemotherapy is given to those with presumedadvanced ovarian cancer prior to cytoreductive surgery. Althoughseveral theoretical advantages of this approach over primarycytoreduction have been reported, significant concerns remain. Therole of neoadjuvant chemotherapy is being investigated in a randomizedstudy currently being conducted by the European Organizationfor the Research and Treatment of Cancer (EORTC) and the NationalCancer Institute of Canada. The benefit of interval cytoreduction wasinvestigated in two randomized prospective trials conducted by theEORTC and the Gynecologic Oncology Group (GOG). Final resultswere somewhat conflicting, but both studies supported an extensiveattempt at surgical cytoreduction during primary therapy. In the managementof recurrent disease, the majority of retrospective studies demonstratea benefit to secondary cytoreduction. The GOG is currentlyattempting to better define the role of secondary cytoreduction in aprospective, randomized trial.

Given that there is no validated test for early lung cancer detection,the current standard approach to lung cancer detection is to wait forsigns or symptoms to develop. In that setting, newly detected lung canceris generally rapidly fatal resulting in over 157,000 deaths annually.Sole dependence on tobacco control is an insufficient public healthresponse to lung cancer, since most newly diagnosed individuals areeither former smokers or never smokers. Finding a more effective wayto diagnose premetastatic lung cancer would be a crucial step towardan improved lung cancer-related mortality rate. Based on studies ofbreast cancer screening, we know that achieving optimal benefit fromearly cancer detection also involves defining the most effective, efficient,and safest approach to the clinical management of screen-identifiedlung cancer. In this review, we consider how to build on the successesof other cancer screening efforts to detect and manage earlylung cancer. This involves outlining the specific elements for lung cancerthat could make a screening program safe, affordable, and effective.We also explore the current standards of early lung cancer managementand target areas where potential pitfalls and opportunities forimprovement exist.

The field of radioimmunotherapy for the treatment of non-Hodgkin'slymphoma (NHL) has advanced significantly over the past decade, andseveral radioimmunoconjugates are being tested in clinical trials. Twoof these antibodies target CD20: yttrium-90 (Y-90)-labeled ibritumomabtiuxetan (Zevalin) and tositumomab/iodine-131 (I-131)-labeledtositumomab (Bexxar). Other agents target either CD22 (Y-90epratuzumab) or human leukocyte antigen (HLA)-DR (I-131 Lym-1),respectively. In February 2002, Y-90-labeled ibritumomab tiuxetanbecame the first radioimmunoconjugate to be approved by the US Foodand Drug Administration (FDA) for the treatment of cancer.Tositumomab/I-131 tositumomab was approved in June 2003. Thus,two radioimmunoconjugates have been approved for the treatment ofNHL. Both agents, when administered as a single dose, have producedimpressive tumor response rates with an acceptable toxicity profile. Themain side effect is reversible myelosuppression. Radioimmunotherapyproduces overall response rates of approximately 80% in patients withlow-grade lymphomas, and 25% to 30% of patients achieve a completeremission. Lower response rates (approximately 40%) have been reportedin patients with large-cell lymphomas. This review discusses theclinical trials of radioimmunotherapeutic agents for NHL that demonstratedtheir safety and efficacy and outlines the current status of theseagents.

In this paper, Dr. Kuban et al addresscontroversies surroundingthe use of posttreatment prostatespecificantigen (PSA) in determiningoutcome after radiotherapy. They basemost of their discussion on their ownobservations of prostate cancer outcomesin more than 4,000 patients followingexternal-beam radiotherapyalone.[1,2] I had the privilege of writingan editorial on their earlier companionpapers, and I made the argumentthen that although some definitionswere slightly better than the AmericanSociety for Therapeutic Radiology andOncology (ASTRO) definition, the differenceswere not impressive enoughto recommend changing the standardfor determining outcome after external-beam radiotherapy.[3]