ONCOLOGY Vol 17 No 3

Anyone who attended the2002 American Society ofHematology (ASH) meetingin Philadelphia couldnot help but be impressedby the number of reportsof clinical trials of biologicagents. In particular,monoclonal antibody–based strategies were describedin a broad range of malignant andbenign conditions. As the reports of singleagentactivity of drugs such as rituximab (Rituxan)diminished for lymphoma trials, thenumber of chemotherapy regimens to which theantibody has been added blossomed. Whensingle-agent data were presented, they oftenrepresented longer-term follow-up with additionalpatients, confirming the safety and efficacyof these agents. Some studies describedattempts at improving the activity of antibodies,whereas others have been evaluating their rolein new malignant and benign indications.

The 107th Congress, by general agreement, was not a majorcontributor to medical and health policy. However, legislation itfailed to pass serves as a prologue to some of the issues the new108th Congress will consider during the next 2 years, said SusanErickson, acting director of the National Cancer Institute's (NCI's)Office of Policy Analysis and Response. "We will probably continue tosee these themes, no matter what specific pieces of legislation comeback," she said at a meeting of the National Cancer Advisory Board.

The use of aromatase inhibitorshas increased dramatically inthe past few years as a resultof the emergence of new, more specificagents, such as anastrozole(Arimidex), exemestane (Aromasin),and letrozole (Femara). This class ofagents effectively blocks the peripheralformation of estradiol, decreasingits concentration to less than 10%,while maintaining selectivity.[1]Evaluation of these selective aromataseinhibitors as adjuvant therapyfor early-stage breast cancer wasbased on the findings of trials inmetastatic breast cancer, summarizedby Visvanathan and Davidson, thatdemonstrated the equivalence and,in some cases, superiority of thearomatase inhibitors comparedwith megestrol and tamoxifen,including their superior side-effectprofile.[2-4]

In the early 1980s, McElwain andcolleagues demonstrated thathigh-dose melphalan (Alkeran,100–400 mg/m2) was very effectivein patients with aggressive (plasmacell leukemia) or refractory myeloma.[1] Other researchers subsequentlyconfirmed these results.[2-4]Unfortunately, the duration of cytopeniaassociated with such treatmentwas excessive (3 to 4 weeks), leadingto a treatment-related mortalityrate of 10% to 20%.

Bolaños-Meade et al provide aconcise review of tandemtransplantation for patientswith multiple myeloma. High-dosechemotherapy with autologous stemcell support has been shown to improveresponse rates, event-free survival,and overall survival overconventional chemotherapy in a majorrandomized clinical trial-the IntergroupeFrançais du Myélome(IFM)-90 trial.[1] This procedure isnow accepted as the standard of carefor newly diagnosed myeloma patientsyounger than age 70 years. However,the same study demonstrated the needto improve upon single autografts, asthe overall survival rate at 7 years inthe transplant group was only 43%.Conceptual Basis ofTandem AutograftsUsing tandem transplants, investigatorshave aimed to improve outcomesby incrementally achievinghigher complete response rates withrepeated cycles of high-dose therapyrequiring stem cell support. With theirTotal Therapy protocol-a series ofnon–cross-resistant chemotherapyregimens culminating in tandemtransplantation-researchers from theArkansas Cancer Research Centershowed that the complete responserate increased from 26% to 41%following the first and second transplant,respectively.[2] On multivariateanalysis, complete response wasa significant prognostic factor forimproved outcome.

Infections are major causes of morbidityand mortality in patientswith cancer. In certain instances,the malignancy itself can predisposepatients to severe or recurrent infections.For example, acute leukemiamay cause neutropenia and ensuingbacterial or fungal infection. Hypogammaglobulinemiaof chroniclymphocytic leukemia may be complicatedby infections due to encapsulatedbacteria. Patients withHodgkin’s lymphoma may sufferfrom recurrent varicella-zoster infections.Solid tumors may obstruct thelumens of respiratory, digestive, andurinary tracts, leading to bacterial infections.Nevertheless, the principalrisk of infectious complications is relatedto the intensity and duration ofimmunosuppressive chemotherapy.Patients with cancer constitute ahighly varied population, both interms of the underlying malignancyand in terms of their immunosuppression.In addition, a single patientmay have multiple predisposing factors,thus increasing the spectrum oflikely pathogens. When evaluating apatient with cancer for a possible infection,it is essential to develop aconceptual framework of quantitativeand qualitative immune defectsthe patient is likely to have, and thento stratify the risk for specific pathogensin the context of the history,physical exam, and laboratorydata.[1]

Breast cancer oncologists makechoices between agents withinthe same therapeutic classevery day-eg, paclitaxel vs docetaxel(Taxotere), doxorubicin vs epirubicin(Ellence), tamoxifen vs anaromatase inhibitor. In the case ofchemotherapeutic agents, we do notyet have results from adequately powereddirect comparisons, and so, decisionsare based on indirectcomparisons between trials, safetyconsiderations, side-effect profiles,cost considerations, and clinical experience.In the case of adjuvantaromatase inhibitor therapy vs tamoxifen,the results of a huge trial areavailable to consider and, indeed, reconsider.In the years to come, theArimidex, Tamoxifen Alone or inCombination (ATAC) trial experiencewill be augmented with resultsfrom multiple other trials that addressalmost all the worthwhile clinicalquestions (except 5 vs 10 yearsof an aromatase inhibitor).

The US Preventive Services Task Force has concluded that notenough scientific evidence exists to promote routine screening ofall men over age 40 for prostate cancer via standard prostatespecificantigen test and/or digital rectal exam. The task force-sponsoredby the Agency for Healthcare Research and Quality-concludedthat the tests are effective for diagnosis but that there is insufficientevidence to show that they affect long-term health or survival. The taskforce noted that results of the ongoing Prostate, Colorectal, Lung, andOvarian Screening Trial, designed to answer this question, will notbecome available until later in this decade.

Each year, 2.4 million patients in the United States develop healthcare–associated infections (HAIs), requiring treatment at an annualcost of approximately $4.5 billion. HAI is the primary cause of deathin approximately 30,000 patients and contributes to the death of 70,000annually. Oncology patients are more susceptible than other patientsto HAIs due to compromised immune systems, surgery (drains),invasive technology (catheters), and environmental factors. This paperwill review each of these risk factors and discuss preventive steps suchas a predictive index, antibiotic therapy, and infection control practices.

The aromatase inhibitors are regarded as standard approaches tofirst- or second-line endocrine therapy in women with hormoneresponsivemetastatic breast cancer. Their efficacy and apparent lackof toxicity have led to their evaluation as adjuvant therapy. Althoughinitial results with these agents in early breast cancer are promising,our collective long-term experience documenting tamoxifen’s benefitsand our uncertainty about the long-term effects of aromatase inhibitorssuggest that it is too early to recommend their routine use in theadjuvant setting. However, anastrozole is also a reasonable therapeuticoption in the adjuvant setting, particularly in individuals with acontraindication to tamoxifen such as those with thromboembolicdisease or those who develop breast cancer while receiving tamoxifenor raloxifene (Evista) therapy. Anastrozole (Arimidex) was recentlyapproved by the Food and Drug Administration for the adjuvanttreatment of postmenopausal women with hormone-receptor–positiveearly breast cancer. Ongoing trials are assessing the potential role ofaromatase inhibitors in the adjuvant, neoadjuvant, and preventivesettings.

The use of high-dose chemotherapy and autologous stem cellsupport in the past decade has changed the outlook for patients withmultiple myeloma. In newly diagnosed patients, complete remissionrates of 25% to 50% can be achieved, with median disease-free andoverall survivals exceeding 3 and 5 years, respectively. Despite theseresults, autologous transplantation has not changed the ultimatelyfatal outcome of the disease, as there is no substantial evidence of“cure” in most published studies. An additional high-dose chemotherapycourse (with tandem transplants) appears to improve progressionfreesurvival, although the effect is not discernible until 3 to 5 yearsposttransplant. The recent reports of tandem autologous transplant formaximum cytoreduction followed by nonmyeloablative allogeneictransplant for eradication of minimal residual disease appears promisingand deserve further investigation. A central issue of tandemtransplants, whether they involve autologous or allogeneic transplants,revolves around defining the subsets of patients who will benefitfrom the procedure. Good-risk patients (defined by normal cytogeneticsand low beta-2–microglobulin levels), especially those who achievea complete or near-complete response after the first transplant, appearto benefit the most from a second cycle. High-risk patients (defined bychromosomal abnormalities usually involving chromosomes 11 and 13and high beta-2–microglobulin levels) whose median survival aftertandem transplant is less than 2 years should be offered novel therapeuticinterventions such as tandem “auto/allo” transplants. Until theefficacy and safety of this procedure is fully established, it should belimited to high-risk patients.

Drs. Guinan, McGuckin, andNowell have nicely reviewedthe risk factors associatedwith increased susceptibility to hospital-acquired infection in oncologypatients and also discussed preventivesteps to attenuate those risks.We agree that patients with malignanciespresent a challenge to thehealth-care provider, as infection willdevelop at some point in almost allcancer patients[1] and may be associatedwith significant mortality.[2]

Non–small-cell lung cancer (NSCLC) accounts for approximately80% of all lung tumors. Patients diagnosed with early-stage diseasegenerally undergo surgery, but up to 50% develop local or distantrecurrences. The benefit of chemotherapy in this disease is modest, butnew drugs and combined strategies offer hope of improved survivalrates. Because the disease recurs outside the chest in 70% of cases, oneof the foremost goals of therapy is to prevent distant dissemination. Tothis end, chemotherapy may be administered preoperatively or afterresection of the tumor. The first part of this article, which concludesnext month, will address adjuvant and neoadjuvant chemotherapy inearly-stage non–small-cell lung cancer.

A phase II study to determine safety and efficacywith the combination of 6 cycles of rituximab (Rituxan)375 mg/m2 (day 1) and CHOP chemotherapy(cyclophosphamide [Cytoxan, Neosar] 750 mg/m2day 3, doxorubicin HCl 50 mg/m2 day 3, vincristine[Oncovin] 1.4 mg/m2 day 3, prednisone 100 mg days3–7) was administered to 33 patients with aggressivenon-Hodkin’s lymphoma (NHL) as frontline therapy.Twently four patients were stage III/IV, 8 stage II, and1 bulky stage IE. Ten patients had one single mass> 10 cm. The histologies of the patients includedfollicular large cell (7), diffuse large cell (22), immunoblastic(2), and other aggressive NHL (2). The medianage of patients was 52 years (range: 20–79 years) with15/33 patients having an International Prognostic Index(IPI) of 0 or 1 and 18/33 having an IPI of 2.