ONCOLOGY Vol 17 No 11

Rash is a class effect of HER1/epidermal growth factor receptor(EGFR)-targeted agents, and has occurred with high frequency and ina dose-dependent manner in clinical trials of these agents in cancerpatients. Analysis of phase II trials of erlotinib (Tarceva) in non–smallcelllung cancer, head and neck cancer, and ovarian cancer shows asignificant association between rash severity and objective tumor response.Rash severity was highly significantly associated with survivalin patients with non–small-cell lung cancer receiving erlotinib; mediansurvival in patients with no rash was 46.5 days, compared with257 days in those with grade 1 rash (P < .0001) and 597 days in thosewith grade 2/3 rash (P < .0001). Similarly, for the combined non–smallcelllung cancer, head and neck cancer, and ovarian cancer studies,median survival in patients with no rash was 103 days, compared with191 days in those with grade 1 rash (P = .0001) and 266 days in thosewith grade 2/3/4 rash (P = .0001). Similar findings have been madewith cetuximab (Erbitux) and in some settings with gefitinib (Iressa).The strong association of rash severity with response/survival suggeststhat rash may serve as a marker of response to erlotinib treatment andmay be used to guide treatment to obtain optimal response. Dosingerlotinib at the maximum tolerated dose, which is associated with morefrequent and more severe rash, may improve response rates and survivaldurations. Further study of the potentially important associationbetween rash and outcome of treatment with EGFR-targeted agents isneeded.

Erlotinib (Tarceva) is an orally available selective small-moleculeinhibitor of HER1/EGFR tyrosine kinase with a 50% inhibitory concentrationof 2 nM for purified tyrosine kinase. This agent has beenshown to produce stasis or regression of tumor growth in human cancerxenograft models, including non-small-cell lung cancer models.Ongoing preclinical investigations indicate that inhibition of the MAPKand Atk signaling pathways downstream of HER1/EGFR may be requiredfor optimal antitumor effects. Erlotinib exhibits inhibition ofMAPK and Atk kinases at concentrations higher than those requiredfor HER1/EGFR tyrosine kinase inhibition; such findings suggest thatmaximal inhibition of HER1/EGFR, requiring high erlotinib doses, isnecessary for optimum antitumor activity. These considerations aresupported by tumor models, including non-small-cell lung cancermodels, showing dose-related antitumor effects up to high doses oferlotinib. Erlotinib exhibits additive antitumor effects when combinedwith chemotherapeutic agents (cisplatin, doxorubicin, paclitaxel,gemcitabine [Gemzar], and capecitabine [Xeloda]), radiation therapy,and other targeted agents (eg, bevacizumab [Avastin]). Recent studiesindicate that erlotinib inhibits the EGFRvIII mutant at concentrationshigher than those required for inhibition of wild-type receptor. Ongoinginvestigation will help to determine optimal dosing and dose frequencyof erlotinib in various cancers in the clinical setting.

Non–small-cell lung cancer represents a growing global burden andremains a therapeutic challenge. Only small improvements in survivalhave been made with standard chemotherapeutic approaches to advanceddisease in recent history. Novel biologic targeted therapies offerthe potential of improving patient management and treatment outcomesin non–small-cell lung cancer. Prominent among these novelagents are the HER1/epithelial growth factor receptor (EGFR) inhibitors.One of these agents, gefitinib (Iressa), is already approved for usein advanced, refractory non–small-cell lung cancer. Erlotinib (Tarceva)is a promising HER1/EGFR inhibitor in phase III evaluation as firstlinetherapy combined with chemotherapy and as second-/third-linemonotherapy in advanced non–small-cell lung cancer. In addition,erlotinib is being evaluated in combination with the angiogenesis inhibitorbevacizumab (Avastin), a strategy combining two new modalitiesin cancer treatment. Results of these trials will provide importantinformation on optimal use of these new targeted therapies and mayoffer the promise of improving the treatment of non–small-cell lungcancer.

In phase I trials in healthy volunteers and patients with refractorycancers, erlotinib (Tarceva) was well tolerated and showed activityagainst non–small-cell lung cancer and other tumors. The dose identifiedfor further clinical development was 150 mg/d; at this dose, erlotinibachieves high exposure, with maximum concentrations greater than2,000 ng/mL and 24-hour area under the concentration-time curvegreater than 35,000 ng • h/L. In a phase II trial in 57 patients withpreviously treated advanced non–small-cell lung cancer, erlotinib treatmentproduced an objective response rate of 12.3% and a stable diseaserate of 38.6%, with median duration of response of 19.6 weeks;median overall survival was 8.4 months and 1-year survival was 40%,with 9 patients remaining alive over follow-up of greater than 18 months.No grade 4 toxicity was observed, and grade 3 toxicity was minimal. Inan ongoing phase II trial in bronchioloalveolar carcinoma, erlotinibtreatment has produced objective response in 26% of 50 evaluable patients,with median duration of response not yet having been reached.An ongoing phase II trial is examining the combination of erlotinibwith the angiogenesis inhibitor bevacizumab (Avastin) in previouslytreated non–small-cell lung cancer; phase I evaluation revealed no doselimitingtoxicities at tested doses and provided evidence of antitumoractivity. Two phase III trials are examining erlotinib in combinationwith carboplatin (Paraplatin)/paclitaxel (the TRIBUTE trial) orcisplatin/gemcitabine (Gemzar) (the TALENT trial) as first-line treatmentin advanced non–small-cell lung cancer. The phase III BR.21trial is assessing erlotinib monotherapy in advanced refractory non–small-cell lung cancer. Results of these phase II trials will soon beavailable.

The identification of predictive or surrogate markers of response toHER1/epidermal growth factor receptor (EGFR) inhibitor treatmentwould permit selection of patients most likely to respond to such treatment.Markers could consist of tumor characteristics (eg, characteristicsof the receptor or downstream signaling molecules and determinantsof resistance) or host characteristics (eg, pharmacokinetic parametersand toxicities). The occurrence of rash may constitute a surrogatemarker of response to erlotinib (Tarceva) treatment in patientswith non–small-cell lung cancer and other cancers. The erlotinib markeridentification program has been designed to identify and investigateother candidate markers by analysis of a large number of clinicalsamples from patients enrolled in erlotinib trials in non–small-cell lungcancer, including the phase III TALENT and TRIBUTE trials oferlotinib combined with chemotherapy and the phase III BR.21 trial oferlotinib monotherapy in advanced non–small-cell lung cancer. Thisprogram should both contribute to understanding of the molecular biologyof HER1/EGFR inhibition and result in identification of potentialmarkers that can be evaluated in the clinical setting.

Why does the debate over theappropriate treatment ofductal carcinoma in situ(DCIS) continue? Three widely publicizedmulti-institutional randomizedtrials have addressed this question,[1-4]and all have reached largely the sameconclusion. Radiation therapy reducesthe risk of local recurrence of DCISby approximately 50%. Despite thisfact, a significant percentage of DCISpatients (50% or more in many settings)in consultation with their cliniciansopt to undergo excision aloneand forgo radiotherapy.

The major conclusion to bedrawn from the extensivelypublished University of SouthernCalifornia (USC)/Van Nuys databaseon ductal carcinoma in situ(DCIS) is that, to the extent that DCIScan be totally excised, the ipsilaterallocal control rate will approach 100%with surgery alone, regardless of tumorgrade or size or patient age. Thisconclusion, noted by Dr. Silverstein,was achieved only through prospectivemammographic/pathologic correlationand a meticulous pathology protocolthat required orientation, selectiveinking of margins, sequential sectioningand processing of the entirespecimen, and prospective calculationof size and margin status.

The article by Trimble andTrimble nicely summarizes thestate of knowledge on ovariantumors of low malignant potential(LMP) and underscores the fact thatgaps in that knowledge have led toconfusion and controversy regardingseveral issues related to these interestingneoplasms. Many of these controversiescan be characterized as debatesbetween the "lumpers" and the "splitters.'The Johns Hopkins group haslong been at the forefront of researchon ovarian LMP tumors. In this review,I will attempt to place some of theauthors' comments into perspectiveand, at times, present a different pointof view.

In his article, Dr. Silverstein reviewsthe changing incidence of ductalcarcinoma in situ (DCIS) in theUnited States over the past 25 years,discusses the results of various clinicaltrials evaluating treatment optionsfor the disease, and, using the VanNuys Prognostic Index (VNPI), identifiesa subgroup of DCIS patientstreated by lumpectomy who, he feels,may be able to avoid breast irradiation.During several presentations atnational meetings, I have had the opportunityto debate Dr. Silverstein onthis topic. He is a powerful and articulateproponent of the idea thatcertain DCIS patients could be exemptedfrom radiation therapy withoutconsequences.

Myelosuppression and neutropenia represent the major dose-limitingtoxicity of cancer chemotherapy. Chemotherapy-induced neutropeniamay be accompanied by fever, presumably due to life-threateninginfection, which generally requires hospitalization for evaluationand treatment with empiric broad-spectrum antibiotics. The resultingfebrile neutropenia is a major cause of the morbidity, mortality, andcosts associated with the treatment of patients with cancer. Furthermore,the threat of febrile neutropenia often results in chemotherapydose reductions and delays, which can compromise long-term clinicaloutcomes. Prophylactic colony-stimulating factor (CSF) has been shownto reduce the incidence, severity, and duration of neutropenia and itscomplications. Guidelines from the American Society of Clinical Oncologyrecommend the use of CSF on the basis of the myelosuppressivepotential of the chemotherapy regimen. The challenge in ensuring theappropriate and cost-effective use of prophylactic CSF is to determinewhich patients would be most likely to benefit from it. A number ofpatient-, disease-, and treatment-related factors are associated with anincreased risk of neutropenia and its complications. A number of clinicalpredictive models have been developed from retrospective datasetsto identify patients at greater risk for neutropenia and its complications.Early studies have demonstrated the potential of such models toguide the targeted use of CSF to those patients who are most likely tobenefit from the early use of these supportive agents. Additional prospectiveresearch is needed to develop more accurate and valid riskmodels and to evaluate the efficacy and cost-effectiveness of modeltargeteduse of CSF in high-risk patients.

Cancer is a disease of the elderly, and its incidence and mortalityincrease with age. The number of persons with cancer is expected todouble between 2000 and 2050, from 1.3 million to 2.6 million, withthe elderly accounting for most of this increase. Studies have shownthat otherwise-healthy older patients treated with chemotherapy of similarintensity obtain benefits comparable to those obtained by youngerpatients. However, chemotherapy-induced neutropenia and its complicationsare more likely in older patients; they are also more often hospitalizedbecause of life-threatening infectious complications. Furthermore,most neutropenic episodes in elderly patients occur in the earlycycles of chemotherapy. To minimize the occurrence of chemotherapyinducedneutropenia, older patients are often treated with less-aggressivechemotherapy and with dose reductions and delays, which maycompromise treatment outcome. The proactive management ofmyelosuppression is therefore essential in elderly patients. Research todetermine the predictors for neutropenia has found that age itself is asignificant risk factor. The benefit of treating elderly patients withcolony-stimulating factors is well established, with their use beginningin the first cycle of chemotherapy being crucial for minimizing neutropeniaand its complications and facilitating the delivery of full-dosechemotherapy. Such prophylaxis should be routinely considered in elderlypatients with cancer treated with myelosuppressive chemotherapy.

The Trimbles have provided auseful overview of the majorclinical and pathobiologic issuesinvolving ovarian borderlinetumors (also termed atypical proliferativetumors or tumors of low malignantpotential). The borderline category ofovarian tumors comprises a heterogeneousgroup of neoplasms that, whensubdivided according to histologicappearance and the presence of peritoneallesions, form distinctive subgroups,each with characteristicpathologic features and a distinctiveclinical course. Thus, retrospectivereviews of thousands of reported caseshave shown that borderline tumors ofall types that are confined to the ovaries(ie, lack peritoneal “implants”)are associated with virtually 100%survival and an extremely low recurrencerate.[1]

Anumber of novel and targeted agents for treating cancer have been introducedin recent years. Nevertheless, chemotherapy remains the mainstayof treatment in the majority of patients, and myelosuppression-especially neutropenia-represents the primary dose-limiting toxicity of chemotherapy.Therefore, chemotherapy-induced neutropenia remains a central concernin the safe and effective delivery of chemotherapy.

Although their overall incidence is uncommon, gastrointestinal stromaltumors (GIST) are the most frequently encountered mesenchymaltumors of the GI tract. Their pathology has been recently defined bythe presence of KIT (transmembrane receptor tyrosine kinase). Themajority of GISTs have c-kit gain-of-function mutations mainly in exon11 (highly conserved juxtamembrane region) that eventuates in constitutiveactivation of KIT, promoting proliferation and antiapoptotic signaling.Imatinib mesylate (Gleevec) is a specific inhibitor of KIT kinaseactivation, and in phase II clinical trials has proven to be remarkablyefficacious in heavily pretreated GIST patients with advanced disease.The molecular and genomic determinants of response/resistancepatterns are the subject of ongoing studies, and adjuvant studies arealso under way. The initial evaluations of imatinib provide proof ofconcept for the hypothesis-driven design of selective molecularly targetedtherapies for solid tumor malignancies.

Dr. Eisenberg has produced anexcellent, concise, yet comprehensivereview of the evolutionof the KIT inhibitor imatinibmesylate (Gleevec) and the preoperativeand postoperative treatmentdilemmas surrounding mesenchymalgastrointestinal stromal tumors(GISTs), particularly in the face ofadvanced disease and recurrences. Thefocus of the article is on the naturalhistory of GISTs, from a molecularand pathobiologic perspective, toclarify the rationale for the use ofimatinib.

Molecularly targeted therapy isa hot topic in oncology, andthe development of imatinibmesylate (Gleevec) for gastrointestinalstromal tumors (GISTs) is one ofour best examples of the successfultranslation of basic science researchinto effective treatment of malignancy.Dr. Eisenberg has thoroughly researchedthe impetus for the use ofimatinib in GISTs and has methodicallyreviewed the results of severalcompleted trials. He broadly discussesmechanisms of resistance to the drugand talks about future directions inGIST research. Dr. Eisenberg has successfullycaptured much of the earlyexcitement surrounding the success ofimatinib, and he appropriately mentionsthe possibility of applying targetedtherapy to other solid tumors.

Hematopoietic growth factors have transformed the practice of oncology.The two major factors in clinical use are recombinant human(rh) granulocyte colony-stimulating factor (G-CSF, filgrastim[Neupogen]) and granulocyte-macrophage colony-stimulating factor(GM-CSF, sargramostim [Leukine]). These factors differ significantly intheir role in hematopoiesis and the regulation of mature effector cell function.G-CSF regulates both basal and neutrophil production and increasedproduction and release of neutrophils from the marrow in response toinfection. GM-CSF mediates its effects on the neutrophil lineage throughits effects on phagocytic accessory cells and its synergy with G-CSF, but itdoes not appear to have a role in basal hematopoiesis. Part 1 of this twopartseries focuses on the use of the myeloid growth factors rhG-CSF andrhGM-CSF to shorten the duration of chemotherapy-induced neutropeniaand thus prevent infection in cancer patients. In randomized trials,rhG-CSF has consistently decreased the duration of neutropenia duringall cycles of chemotherapy and reduced the risk of infection by 50% ormore. Trials of rhGM-CSF have not reported consistent results.

Breast cancer is the most common noncutaneous malignancy inwomen in industrialized countries. Chemotherapy prolongs survival inpatients with early-stage breast cancer, and maintaining the chemotherapydose intensity is crucial for increasing overall survival. Manypatients are, however, treated with less than the standard dose intensitybecause of neutropenia and its complications. Prophylactic colonystimulatingfactor (CSF) reduces the incidence and duration of neutropenia,facilitating the delivery of the planned chemotherapy doses.Targeting CSF to only at-risk patients is cost-effective, and predictivemodels are being investigated and developed to make it possible forclinicians to identify patients who are at highest risk for neutropeniccomplications. Both conditional risk factors (eg, the depth of the firstcycleabsolute neutrophil count nadir) and unconditional risk factors(eg, patient age, treatment regimen, and pretreatment blood cell counts)are predictors of neutropenic complications in early-stage breast cancer.Colony-stimulating factor targeted toward high-risk patients startingin the first cycle of chemotherapy may make it possible for fulldoses of chemotherapy to be administered, thereby maximizing patientbenefit. Recent studies of dose-dense chemotherapy regimens with CSFsupport in early-stage breast cancer have shown improvements in disease-free and overall survival, with less hematologic toxicity than withconventional therapy. These findings could lead to changes in how earlystagebreast cancer is managed.

Clinical and laboratory reports suggest that ovarian tumors of lowmalignant potential (LMP) represent a “grab bag” of tumors, withdifferent etiologies, molecular biologies, and prognoses. As a result,data on incidence and prognosis may be quite unreliable. Diagnosis isbest made on permanent section. Half of women under age 40 undergoconservative, fertility-sparing surgery when diagnosed with anovarian tumor of LMP, but no adjuvant therapy has been shown toprolong survival in this population. In addition to the various controversiessurrounding LMP tumors, this review will address prognosticmarkers, risk of malignant transformation, treatment of progressivedisease, surveillance after conservative surgery, and future directionsfor research.

Non-Hodgkin’s lymphoma is primarily a disease of the elderly, with61% of the new cases reported in patients 60 years old or older. Aggressivecombination chemotherapy can cure some patients, but there arefrequently treatment failures and overall survival is low. Retrospectivestudies have found that treatment with less than standard chemotherapydoses is associated with lower survival, and surveys of practice patternshave found that many patients, especially elderly ones, are treated withsubstandard regimens and doses. Neutropenia is the major dose-limitingtoxicity of chemotherapy in patients with non-Hodgkin’s lymphoma.First-cycle use of colony-stimulating factor (CSF) can reduce the incidenceof neutropenia and its complications and help maintain the chemotherapydoses. Researchers have investigated risk factors in patientswith non-Hodgkin’s lymphoma to determine which patients are at highestrisk for neutropenia and would benefit from targeted first-cycle CSFsupport. It has been shown in several studies that advanced age, poorperformance status, and high chemotherapy dose intensity are risk factors.Other trials suggest that low serum albumin levels, elevated lactatedehydrogenase levels, bone marrow involvement, and high levelsof soluble tumor necrosis factor receptor are also risk factors. Doseintensity has also been shown in many studies to be an important predictorof survival in patients with non-Hodgkin’s lymphoma. Managingthe toxicity of chemotherapy with CSF has facilitated the deliveryof planned dose on time, as well as dose-intensified chemotherapy regimens.The promising results from recent clinical trials of dose-denseregimens with CSF support suggest that this could prove to be the beststrategy for improving patient outcomes.