ONCOLOGY Vol 17 No 12

To begin with, let me acknowledgethat Drs. Epstein andSchubert are experienced doctorsof dental medicine who have beeninvolved in the evaluation and therapyof cytotoxic therapy–related mucositisfor a long time. I fully agree withthem that cytotoxic therapy–associatedmucositis is a major clinicalproblem and that there is a dearth ofgood studies that address ways to alleviatethe condition. Drs. Epstein andSchubert do an excellent job describingthe incidence, causative factors, and etiology of cytotoxic therapy–relatedoral mucositis, and they are tobe congratulated for this. Nonetheless,I view a few points differently, as discussedbelow.

In the introduction to his book,The Order of Things, the Frenchstructuralist philosopher MichelFoucault posed the question: "Whenwe establish a considered classification,when we say that a cat and adog resemble each other less thantwo greyhounds do, on what groundsare we able to establish the validityof this classification with completecertainty?" He went on: "On whattable, according to what grid of identities,similarities, analogies do wesort out so many different and similarthings."

Dr. Rosenwald presents a timelyand highly lucid review ofrecent findings in molecularprofiling-a powerful new tool that ishelping to unravel the clinical andbiologic heterogeneity of lymphomas.Although histologic classificationsprovide a framework for the organizationof lymphomas into distinct diseaseentities with shared pathogenesisand clinical behavior, many ofthese entities continue to display significantclinical and diagnostic variability.Molecular profiling representsthe next step in the evolution of lymphomaclassification that has advancedfrom exclusively morphologic to thecurrent World Health Organizationclassification that incorporates immunophenotypeand genetic endpoints.[1] This evolution is the directresult of insights into the molecularpathogenesis of lymphoma, includingthe identification of "hallmark"genetic abnormalities.

This timely and elegant articleby Glaspy reviews current datasupporting the clinical role ofhematopoietic growth factors. As theauthor thoroughly discusses, the introductionof myeloid and erythroidregulatory proteins more than a decadeago has had a dramatic impacton the care of patients with a varietyof cancers and hematologic disorders,as well as other diseases. A large bodyof research allows us to draw someimportant conclusions about the rationaland appropriate use of theseagents. However, as stated in thisarticle, a number of important questionsremain.

The US Senate has designated February 2004 as National CancerPrevention Month to underscore the fact that over 70% of allcancers are preventable through diet and lifestyle. Senator Ernest"Fritz" Hollings (D-SC), who sponsored the resolution, said, "We havemade great advances in recent years in our understanding of cancer, itsroot causes, and the steps that individuals can take to prevent it. Fromimproved nutrition and exercise to smoking cessation and appropriatescreening procedures, there is much every person can do to decreasetheir risk of developing cancer. A month specifically dedicated tocancer prevention awareness will help us elevate public understandingand decrease the terrible toll that cancer takes on our society."

As the major regulator of erythropoiesis in man, erythropoietin inhibitsthe programmed cell death of committed erythroid precursors.In cancer patients, a relative erythropoietin deficiency is coupled witha decreased responsiveness to the substance mediated by the effects ofinflammatory cytokines on the marrow and on ferrrokinetics, leadingto a high incidence of anemia. Two recombinant human erythropoietin(rhEPO) preparations-epoetin alfa (Epogen, Procrit) and epoetinbeta (Marogen)-as well as a modified erythropoietic compound(darbepoetin alfa [Aranesp]) are in clinical use. Part 2 of this two-partseries on hematopoietic agents reviews the use of these erythropoieticfactors and their effect on the anemia that develops in cancer patients.Thrombopoietic factors and progenitor cell-mobilizing factors are alsobriefly addressed.

Gene expression profiling using cDNA microarrays has the potentialto improve current lymphoma classification schemes by establishinga molecular diagnosis of these malignancies. The use of this technologyled to the discovery of biologically and clinically distinct subtypesof diffuse large B-cell lymphoma (DLBCL). Gene expression datacan also be used to formulate powerful mathematical algorithms thatpredict the clinical outcome in patients with DLBCL and mantle celllymphoma. In B-cell chronic lymphocytic leukemia, gene expressionprofiling identified ZAP70, an important prognostic marker whose expressioncorrelates with the mutational status of the immunoglobulinheavy chain gene and, therefore, with survival in these patients. Theseexamples illustrate that gene expression profiling may pave the way fordetailed molecular characterization of lymphoid malignancies that willultimately lead to tailored, disease-specific therapies.

Chemotherapeutic agents that are highly responsive to ionizing radiationand enhance the effectiveness of radiation treatment are termedradiation sensitizers. Radiation sensitizers act in a number of ways tomake cancer cells more susceptible to death by radiation than surroundingnormal cells, and several such compounds are now available forthe treatment of solid tumors. This review discusses the biology thatunderlies chemotherapy and radiation interactions for oneradiosensitizerSMQ-8212-SMQgemcitabine (Gemzar). It also provides a brief assessmentof how to modify treatment regimens for various cancers to maximizethe radiosensitization potential of gemcitabine in order to furtherincrease efficacy. Newer molecularly targeted agents and their antitumorpotential as monotherapy or in combination with radiation arealso reviewed.

Oropharyngeal mucositis is a common and treatment-limiting sideeffect of cancer therapy. Severe oral mucositis can lead to the need tointerrupt or discontinue cancer therapy and thus may have an impacton cure of the primary disease. Mucositis may also increase the risk oflocal and systemic infection and significantly affects quality of life andcost of care. Current care of patients with mucositis is essentially palliativeand includes appropriate oral hygiene, nonirritating diet andoral care products, topical palliative mouth rinses, topical anesthetics,and opioid analgesics. Systemic analgesics are the mainstay of painmanagement. Topical approaches to pain management are under investigation.The literature supports use of benzydamine for prophylaxisof mucositis caused by conventional fractionationated head andneck radiotherapy, and cryotherapy for short–half-life stomatoxic chemotherapy,such as bolus fluorouracil. Continuing studies are investigatingthe potential use of biologic response modifiers and growth factors,including topical and systemic delivery of epithelial growth factorsand agents. Progress in the prevention and management of mucositiswill improve quality of life, reduce cost of care, and facilitate completionof more intensive cancer chemotherapy and radiotherapy protocols. Inaddition, improved management of mucositis may allow implementationof cancer treatment protocols that are currently excessively mucotoxicbut may produce higher cure rates. Continuing research related to thepathogenesis and management of mucositis will undoubtedly lead to thedevelopment of potential interventions and improved patient care.

Both paclitaxel and gemcitabine (Gemzar) have shown activity andmanageable toxicity when used as single agents in heavily pretreatedpatients with metastatic breast cancer. This phase II study evaluatedtheir use in combination for metastatic breast cancer patients whosedisease recurred or progressed following treatment with anthracyclinecontainingregimens.

Both advanced nonSMQ-8211-SMQsmall-cell lung cancer and pancreatic cancer pose significanttherapeutic challenges to clinicians due to their high mortalityrates. The past 2 decades witnessed an evolution in the approach to thetreatment of these diseases. In metastatic nonSMQ-8211-SMQsmall-cell lung cancer, trials ofrecently developed chemotherapy regimens have shown increased response ratesand improved quality of life. Several large, randomized phase III trials in unresectablenonSMQ-8211-SMQsmall-cell lung cancer have demonstrated that treatment with chemotherapyand radiation in combination leads to superior outcomes compared with radiationalone. This supplement highlights current treatment options with chemoradiationfor patients with advanced nonSMQ-8211-SMQsmall-cell lung cancer and pancreatic cancer.

Cigarette sales dropped more than twice as much during the1990s in four states with strongly funded tobacco control programsthan elsewhere in the United States, according to theCenters for Disease Control and Prevention (CDC). A new studyreports that cigarette sales fell 43% in Arizona, California, Massachusetts,and Oregon vs 20% in all other states between 1990 and 2000.The study is the first to include cigarette sales data from all states and toisolate the effects of tobacco control programs by controlling for excisetaxes, cross-border cigarette sales, and other state-specific factors. Itwas conducted by researchers at CDC, the Research Triangle Institute,and the University of Illinois at Chicago.

Oropharyngeal mucositis hasbeen reported as the mostbothersome side effect by patientsundergoing myeloablative regimens,and it remains a therapy-limitingtoxicity of radiation and chemotherapyfor head and neck cancer. JoelEpstein and Mark Schubert providean informative review of progressmade over more than a decade of researchon the pathophysiology andmanagement of oropharyngeal mucositisin patients undergoing cancertreatment.

It is an honor to have the opportunityto comment on this review byDrs. Epstein and Schubert onoropharyngeal mucositis. This paperwill serve as an excellent teaching toolfor physicians and dentists in that itprovides comprehensive backgroundinformation on the topic. In addition,it presents a commonsense approachto prevention and management,which should serve as a guide topractitioners.

It is fair to say that combination chemotherapy is the standard of care inmetastatic breast cancer. In many ways, however, the burden of proof that it isthe standard of care remains with those who advocate combination therapy.Some of the push to consider combination therapy as the standard is provided by ameta-analysis of trials comparing single-agent and combination therapy in thissetting, which was reported by Fossati et al in 1998.[1] Although the vast majorityof individual trials included in the analysis did not show significant differences inhazard ratios for death, the meta-analysis showed a significant mortality advantagefor combination therapy. Yet the total population considered in this meta-analysis(990 patients in combination groups, 996 in single-agent groups) is not largecompared with some recent phase III trials in metastatic breast cancer, includingone reported by Sledge et al that showed that sequential doxorubicin and paclitaxelwas equivalent to the concurrent combination.[2] Further, no studies includingtaxanes are included in the meta-analysis, raising questions about the application ofits findings to contemporary oncology. In addition, the trials included did notexamine sequential single-agent treatment, an approach that clearly has merit andthat requires additional consideration and study.

Krag and Harlow believe thatsentinel lymph node biopsyfor breast cancer is still an experimentalprocedure because “longtermrandomized trials comparing thesurvival outcome of this procedurewith that of conventional axillary noderesection have not been completed.”Specifically, they are awaiting the resultsof the American College of SurgeonsOncology Group (ACOSOG)Z0011 trial and the National SurgicalAdjuvant Breast and Bowel Project(NSABP) B-32 trial before they makea determination about the “safety” ofthis procedure.[1] This is a commonmisconception, because these studieswill not prove whether sentinel nodebiopsy results in equivalent survivalcompared to standard level I/II axillarydissection in patients with clinicallynode-negative breast cancer. Thetime has come for clear thinking aboutthe design of these trials and precisereasoning about the interpretation oftheir ultimate results.

The federal patient privacy rule that went into effect in April is"wreaking havoc on crucial aspects of cancer research" and "isseverely derailing 'the progress of knowledge,' " according to areport prepared by an ad hoc subcommittee of the National Cancer AdvisoryBoard. The full board pledged to pursue the issue with the Departmentof Health and Human Services (HHS), which enforces the rule.

In this issue of ONCOLOGY,Rosenwald describes in detail thecurrent state of gene expressionprofiling and its role in the classificationand prediction of outcome in lymphoidmalignancies. Since the firstpublication describing the use of geneexpression signatures to predict outcomein diffuse large B-cell lymphoma(DLBCL), a few subsequent papershave appeared, detailing comprehensivefindings in other lymphoma subtypes.[1-4] Together these works bringclarity to the molecular taxonomyof the non-Hodgkin's lymphomas(NHL). Insights gleaned from thesestudies not only provide an improvedunderstanding of the biology of thesetumors, but have also led to a significantimprovement in our ability to assignrisk for individual patients withlymphoma.[2]

The biologic rationale for sentinellymph node biopsy, althoughit may ultimately stagethe axilla more accurately, is essentiallythat a positive lymph node representssystemic disease. Removal ofaxillary lymph nodes is of little, if any,therapeutic value, and most patients with tumors greater than 1 cm are offeredchemotherapy regardless ofnodal status. Thus, the risks of lymphedemaand neurologic deficit outweighany prognostic information derivedfrom an axillary node dissection whenthis same information can be accuratelyobtained in a less invasive, lessmorbid procedure.

Gemcitabine (Gemzar) and paclitaxel exhibit good activity and goodsafety profiles when used alone and together in the treatment of advancedbreast cancer. In a phase II trial, 45 patients with metastaticbreast cancer received gemcitabine at 1,200 mg/m2 on days 1 and 8 andpaclitaxel at 175 mg/m2 on day 1 every 21 days. Twenty-seven patients(60.0%) had prior adjuvant therapy. Objective response was observedin 30 patients (objective response rate 66.7%, 95% confidence interval[CI] = 52%–71%), including complete response in 10 (22.2%) and partialresponse in 20 (44.4%). Median duration of response was 18 months(95% CI = 11–26.7 months), median time to tumor progression for theentire population was 11 months (95% CI = 7.1–18.7 months), medianoverall survival was 19 months (95% CI = 17.3–21.7 months), and the1-year survival rate was 69%. Treatment was well tolerated, with grade3/4 toxicities being infrequent. Grade 3/4 leukopenia, neutropenia, andthrombocytopenia were each observed in six patients (13.3%). No patientwas discontinued from the study due to hematologic ornonhematologic toxicity. Thus, the gemcitabine/paclitaxel combinationshows promising activity and tolerability when used as first-line treatmentin advanced disease. The combination recently has been shownto be superior to paclitaxel alone as first-line treatment in anthracyclinepretreatedadvanced disease according to interim results of a phase IIItrial and it should be further evaluated in comparative trials in breastcancer.

Sentinel node surgery potentially increases the accuracy of identifyinglymph nodes that contain breast cancer and decreases morbiditycompared to conventional axillary lymph node resection. However, nolong-term comparisons of the two modalities have been carried out,and the survival benefit associated with one protocol vs the other remainsunknown. Although sentinel node surgery is not expected to increasethe cure rate of breast cancer patients, a significant reduction inthe incidence of permanent side effects associated with axillary noderesection will be a considerable advance. The completion of clinicaltrials establishing that no meaningful reduction in survival is associatedwith the decrease in side effects is important.

Patients with locally advanced or metastatic nonSMQ-8211-SMQsmall-cell lungcancer (stage III and IV) who are not candidates for surgery and exhibitgood performance status are typically treated with concurrent radiationand platinum-based chemotherapy for disease palliation. Platinum-based chemotherapies, used alone or with radiation therapy, offera small but significant survival benefit compared with supportivecare. The incorporation of first-line agents such as gemcitabine(Gemzar), vinorelbine (Navelbine), and paclitaxel, as well as secondlineagents such as docetaxel (Taxotere), in doublet and triplet combinationshas had a further significant therapeutic impact. Randomizedtrials have shown that cisplatin-based therapy in combination with newagents results in improved 1- and 2-year survival rates in patients withadequate performance status. The 1-year survival benefit has significantlyimproved, with greater symptom relief and improved quality oflife in these patients. Thus, delaying disease progression with combinationchemotherapy appears both beneficial and cost-effective in patientswith advanced nonSMQ-8211-SMQsmall-cell lung cancer. Newer approachesSMQ-8212-SMQincluding targeting critical signaling pathways, such as tyrosine kinasereceptors, angiogenesis, and downstream signal transductionmechanismsSMQ-8212-SMQmay provide novel agents with an improved toxicity profileand the potential for better disease management.

Cancer of the pancreas remains a formidable challenge in oncology.This malignancy ranks as the fourth leading cause of cancer deathin the United States in 2003, with an estimated 30,700 new cases to bediagnosed and 30,000 deaths. Although gains have been achieved inthe clinical management of these patients, this malignancy is rarelycurable. Long-term survival is limited to patients undergoing resection.For patients with localized but unresectable malignancy, radiationtherapy combined with fluorouracil, gemcitabine (Gemzar), orpaclitaxel has shown modest improvements in survival and symptompalliation. However, there has been significant progress in the diagnosticevaluation of pancreatic cancer patients, which has aided cliniciansin caring for these patients and in selecting therapies. The use ofcomputed tomography, endoscopic ultrasonography, and laparoscopytechniques will be discussed. Newer techniques of radiation therapy,such as intraoperative electron-beam radiation therapy and threedimensionalconformal radiation therapy, with the integration of newbiologically targeted agents may provide new avenues of research andprogress in this disease.

In patients with advanced breast cancer, treatment with paclitaxeland doxorubicin has been shown to produce impressive overall responserates (up to 94%) and to prolong overall survival significantly over acombination of fluorouracil (5-FU), doxorubicin, and cyclophosphamide(Cytoxan, Neosar) in one prospective phase III clinical study.

Gemcitabine has been evaluated in combination with paclitaxel,docetaxel, anthracyclines, vinorelbine, and cisplatin as first-line treatmentand after prior chemotherapy in patients with metastatic breastcancer. Results with gemcitabine/taxane combinations have been especiallyencouraging, with these combinations providing promising outcomeswith regard both to tumor response and tolerability. The combinationof gemcitabine and paclitaxel has garnered particular interestfor further phase III evaluation on the basis of high response rates anddurable responses in both treatment-naive and treatment-experiencedpatients, including anthracycline-pretreated patients.

Survival for patients with stage III nonSMQ-8211-SMQsmall-cell lung cancer hasgradually improved in recent years, with median survival times increasingfrom less than 10 months to more than 18 months. These increasesare thought to result primarily from advances in chemoradiation. Thisarticle reviews major advances in the development of chemoradiationfor patients with locally advanced nonSMQ-8211-SMQsmall-cell lung cancer. Resultsfrom cooperative group trials suggest that concurrent chemoradiationis superior to sequential therapy and may replace sequential therapy asthe new standard of care in patients with good performance status.Technological advances such as 18F-fluorodeoxyglucose positron emissiontomography (PET) staging can be used to improve patient selectionand predict survival. Locoregional control may be improved byaltering radiation fractionation or delivery (eg, hyperfractionation, highdoseinvolved-volume radiotherapy, 3D conformal radiotherapy). Novelagents and regimens in combination with radiation are being investigatedto further improve therapeutic outcomes.

The year 1991 was truly a watershed year in medical oncology,as three events resulted in aparadigm shift in the tolerability,safety, and symptom management ofchemotherapy delivery. The first twoevents moved chemotherapy administrationfrom a user-unfriendly hospitalinpatient environment to whatevolved into a highly efficient, sophisticated,outpatient system led by privatepractitioners of medical oncology.Ondansetron (Zofran), the first of the5HT3-receptor antagonists, providedreliable prophylaxis of immediatechemotherapy-induced nausea andvomiting in highly emetogenic regimens.[1] Recombinant human granulocytecolony-stimulating factor(rhG-CSF, filgrastim [Neupogen]),[2]if dosed appropriately, significantlyreduced the duration of severe neutropeniathrough its role as the primaryregulator of increased production andrelease of granulocytes from the bonemarrow.

Gemcitabine (Gemzar) and paclitaxel show good activity as singleagents and combined in metastatic breast cancer, and the combinationof paclitaxel/trastuzumab (Herceptin) has been shown to prolong timeto disease progression and survival significantly in this setting. Preclinicaldata indicate additive or synergistic effects of gemcitabine andtrastuzumab in HER2-positive human breast cancer cell lines. In aphase II trial, patients with HER2-overexpressing metastatic breastcancer who had received no prior chemotherapy for metastatic diseasereceived gemcitabine at 1,200 mg/m2 on days 1 and 8 and paclitaxel at175 mg/m2 on day 1 every 21 days for six cycles plus trastuzumab at aninitial loading dose of 4 mg/kg followed by 2 mg/kg weekly; patientswithout progressive disease after six cycles continued to receivetrastuzumab until disease progression. Overall, objective response wasobserved in 28 (67%) of 42 evaluable patients, including complete responsein 4 (10%) and partial response in 24 (57%); stable disease wasobserved in 7 (17%) and progressive disease was observed in 6 (14%).Median time to treatment failure was 9+ months. Median overall survivalhas not yet been reached, but is estimated at approximately 27months. Significant toxicities apart from neutropenia were uncommon.The triplet combination of gemcitabine, paclitaxel, and trastuzumab ishighly active and well tolerated in patients with HER2-overexpressingmetastatic breast cancer.