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The most common subtype of aggressive non-Hodgkin’s lymphomais diffuse large B-cell lymphoma (DLBCL). Diffuse large B-cell lymphomarepresents a heterogeneous entity, with 5-year overall survivalrates ranging from 26% to 73%. Microarray gene expression studieshave confirmed that biologically distinct subgroups exist within DLBCL,and can be correlated with outcome. Initial management is usuallyguided by stage of disease at presentation. Approximately 25% of patientswith DLBCL present with limited-stage disease and are treatedwith combined-modality therapy (brief chemotherapy and involved-fieldradiation). Most patients present with advanced-stage disease and requiretreatment with an extended course of chemotherapy. The CHOP(cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone)chemotherapy regimen has been the mainstay of therapy sinceits development in the 1970s, as more intensive chemotherapy regimensfailed to show additional benefit. The era of monoclonal antibodieshas transformed treatment practices for aggressive lymphoma andhas led to a significant improvement in outcome. A randomized trialcomparing the use of rituximab (Rituxan), a chimeric anti-CD20 IgG1monoclonal antibody, combined with CHOP chemotherapy vs CHOPchemotherapy alone for elderly patients with advanced-stage DLBCLdemonstrated a significant benefit for the combination approach. Thisfinding has now been confirmed in two additional randomized, controlledtrials and a population-based analysis, making CHOP andrituximab the standard of care for all newly diagnosed patients withDLBCL. Despite this advance, newer therapies are needed and manyare under active investigation. The insights gained from molecular techniquessuch as gene expression profiling should permit identificationof additional lymphoma-specific therapeutic targets and the developmentof novel agents that take into account underlying biology andallow for greater tailoring of therapy.

The most common indolent lymphoma, follicular lymphoma comprises 35% of adult non-Hodgkin’s lymphoma (NHL) in the United States and 22% worldwide. Features associated with adverse outcome include age, male gender, disease stage, and performance status, with the International Prognostic Index being the most widely used risk classification system. Long-term disease-free survival is possible in select patient subgroups after treatment, but very late relapses suggest that quiescent lymphoma cells might be harbored for long periods of time. Radiation therapy is the mainstay of treatment for limited-stage follicular lymphoma, but there is some experience with chemotherapy and combined chemoradiation. When to initiate treatment in patients with advanced disease is controversial, but options include various combined chemotherapy regimens, monoclonal antibodies, radiolabeled antibodies, and bone marrow or stem cell transplantation. Future directions in the treatment of follicular lymphoma include vaccines, antisense therapy, and proteasome inhibitors.

Vaccines are a promising but still experimental treatment for melanoma.They are intended to stimulate immune responses against melanomaand by so doing, increase resistance against and slow the progressionof this cancer. Key requirements for vaccines to be effectiveare that they contain antigens that can stimulate tumor-protective immuneresponses and that some of these antigens are present on thetumor to be treated. Unfortunately, these antigens are still not known.To circumvent this problem, polyvalent vaccines can be constructedcontaining a broad array of melanoma-associated antigens. Severalstrategies are available to construct such polyvalent vaccines; each hasadvantages and disadvantages. Clinical trials have shown that vaccinesare safe to use and have much less toxicity than current therapy formelanoma. Vaccines can stimulate both antibody and T-cell responsesagainst melanoma, with the type of response induced, its frequency,and its magnitude depending on the vaccine and the adjuvant agentused. A growing body of evidence suggests that vaccines can be clinicallyeffective. This evidence includes correlations between vaccineinducedantibody or T-cell responses and improved clinical outcome,clearance of melanoma markers from the circulation, improved survivalcompared to historical controls, and most convincingly, two randomizedtrials in which the recurrence-free survival of vaccine-treatedpatients was significantly longer than that of control groups.

Overexpression of cyclooxygenase-2 (COX-2) is frequently presentin lung cancer and may play a significant role in carcinogenesis, invasion,and metastasis. It has been associated with shortened survival inpatients with resected early-stage adenocarcinoma of the lung. COX-2inhibition decreases tumor cell proliferation in vivo and has been shownto enhance tumor radiosensitivity. Additionally, COX-2 inhibition mayprotect normal pulmonary tissue from radiation fibrosis. Clinical studiesare under way to assess the potential benefits and risks of COX-2inhibition in the treatment of lung cancer. The rationale for COX-2inhibitors in the treatment of lung cancer will be reviewed. The resultsof a phase II study assessing the acute toxicity of concurrent celecoxib(Celebrex) and thoracic irradiation in patients with non–small-cell lungcancer (NSCLC) are reported, and an ongoing Radiation TherapyOncology Group study using celecoxib and concurrent radiation therapyfor NSCLC in patients with intermediate prognostic factors is reviewed.

The epidermal growth factor receptor (EGFR) plays an importantrole in cell growth, differentiation, and survival. Targeting EGFR inpatients with colorectal cancer has become an important therapeutictool. Recently, a monoclonal antibody against the extracellular domainof the receptor (cetuximab [Erbitux]) has been approved for the treatmentof patients with EGFR-positive metastatic disease refractory toirinotecan (Camptosar)-based therapy. The role of other targeted agentsagainst EGFR, including other monoclonal antibodies as well as inhibitorsof the intracellular tyrosine kinase domain, will also be discussed.

Defects in the regulation of apoptosis (programmed cell death) makeimportant contributions to the pathogenesis and progression of mostcancers and leukemias. Apoptosis defects also figure prominently inresistance to chemotherapy, radiotherapy, hormonal therapy, andimmune-based treatments. Apoptosis is caused by activation ofintracellular proteases, known as caspases, that are responsible directlyor indirectly for the morphologic and biochemical events thatcharacterize the apoptotic cell. Numerous proteins that regulate thesecell death proteases have been discovered, including proteins belongingto the Bcl-2, inhibitor of apoptosis, caspase-associated recruitmentdomain, death domain, and death effector domain families. Thesecaspase-regulating proteins provide mechanisms for linkingenvironmental stimuli to cell death responses or to maintenance of cellsurvival. Alterations in the expression and function of several apoptosisregulatinggenes have been demonstrated in cancer, suggesting targetsfor drug discovery. Knowledge of the molecular details of apoptosisregulation and the three-dimensional structures of apoptosis proteinshas revealed new strategies for identifying small-molecule drugs thatmay yield more effective treatments for malignancies. Apoptosisregulatinggenes are also beginning to find utility as targets for antisenseoligonucleotides.

Although no overall differences in survival have been observed betweenthe many chemotherapy combinations in non–small-cell lungcancer, the clinical application of mRNA expression levels of amplifiedgenes may disclose many genetic influences on cytotoxic drug sensitivityand enable clinicians to tailor chemotherapy according to eachindividual’s gene profile. Specifically, the assessment of ribonucleotidereductase subunit M1 and thymidylate synthase mRNA expression levelsmight select patients who benefit from gemcitabine (Gemzar) orpemetrexed (Alimta) combinations. Until recently, clinical prognosticfactors such as performance status, weight loss, and lactate dehydrogenasewere the only parameters used to predict chemotherapy responseand survival. However, accumulated data indicate that overexpressionof genes involved in cancer glycolysis pathways plays an important role,and might be an independent mechanism of chemoresistance. Thedysregulation of glycolytic genes is affected by growth signals involvingthe PI3K/Akt pathway and downstream genes such as hypoxiainduciblefactor-1-alpha. One can thus envision that substantial improvementsin therapeutic outcome could benefit from the integrationof tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotidereductase antisense therapy, and targeted therapy.

Candidiasis and aspergillosis are the most common fungal infectionsin hematopoietic stem cell transplant recipients and other hematology/oncology patients. Strategies for reducing the morbidity and mortalityassociated with these infections include antifungal prophylaxis,empiric therapy in patients with persistent fever and neutropenia, andpreemptive therapy. Antifungal therapies include amphotericin B deoxycholate,lipid formulations of amphotericin B, the triazoles (fluconazole,itraconazole, and voriconazole), and the echinocandins (caspofunginand the investigational agents micafungin and anidulafungin).Fluconazole is a reasonable choice for the treatment of invasive candidiasisif the patient has not previously received a triazole and theinstitution has a low incidence of triazole resistance. If resistance is aconcern, an echinocandin, such as caspofungin, is an appropriate option.Voriconazole may be the initial choice in most patients with invasiveaspergillosis. If patients are intolerant of or refractory to conventionaltherapy, effective alternatives include a lipid formulation of amphotericinB or an echinocandin.

Lung cancer remains the leading cause of cancer death in Americanmen and women. Non–small-cell lung cancer (NSCLC) accountsfor 85% of these cases. Although surgery is the best curative approachfor resectable NSCLC, long-term survival for patients with operabledisease remains poor. More than half of patients who initially presentwith stage I to IIIA disease experience relapse of metastatic disease.Postoperative adjuvant therapy has been evaluated in several randomizedtrials, and provides a survival benefit. It appears reasonable tolook to induction chemotherapy, or preoperative chemotherapy, to providea similar improvement in survival with early treatment ofmicrometastatic disease. Multiple trials of induction therapy have beencarried out with encouraging results. The use of various induction regimenswith chemotherapy alone or chemotherapy combined with radiotherapyfor stage IIIA NSCLC is under investigation. Randomized trialsare under way to better define the role of induction therapy in themultimodality treatment of NSCLC.

The treatment of breast cancer has progressed substantially overthe past 15 years. Data from randomized adjuvant trials have shownthat the risk of disease recurrence and death is significantly reducedwhen adjuvant chemotherapy and/or hormonal therapy is added to treatment.As new strategies are incorporated, one of the continued controversiesin patient management is whether adjuvant anthracyclinesshould be the preferred treatment for all patients. Data from randomizedand translational clinical trials have become available and arehelping to elucidate the proper role of anthracyclines, as well as their acuteand long-term toxicities. In most situations, an anthracycline is currentlypreferred, but other single and combination chemotherapies arecurrently under evaluation and appear promising for use in the adjuvantsetting. Continued breast cancer research using molecular markers(such as topoisomerase II–alpha and gene clusters) as predictors oftreatment response, could help individualize decisions regardingwhether to incorporate anthracyclines into adjuvant therapy regimens.

Iowa City, IA-The development of gene-directed therapy for common genetic ocular diseases that will be deployable on a population scale rests on coordinated research involving a series of steps. However, judging from progress made so far, such modalities might become clinically available soon, said Edwin M. Stone, MD, PhD.

Several decades of chemotherapy trials in non–small-cell lung cancer(NSCLC) have clearly shown a survival benefit for chemotherapyover best supportive care. However, only short-lived responses are attained,with an average of four cycles of chemotherapy, before tumorprogression is observed. Second-line chemotherapy has been demonstratedto improve outcome, with docetaxel (Taxotere) as the predominantcytotoxic drug. A recent randomized trial in second-line NSCLCindicated that the novel drug pemetrexed (Alimta) attained the sameresponse, time to progression, and survival as docetaxel. This findingushers in a new age in second-line treatment that can be further invigoratedby the addition of targeted agents. Accumulated evidence indicatesthat overexpression of epidermal growth factor receptor andHER2/neu, which occurs frequently in NSCLC, leads to the deregulationof PI3K and MAPK, activating Akt and enhancing chemoresistance.Future clinical trials in NSCLC will include tailored andmultitargeted therapy and pemetrexed represents a significant step forSward in this direction.

The presence of regional nodal metastases represents a significantadverse prognostic factor for patients with squamous cell carcinoma ofthe head and neck. Early-stage head and neck cancers, localized to theprimary site without regional lymph node metastases have excellentcure rates with either surgery or radiation therapy. The presence ofregional metastases results in cure rates that are approximately half ofthose obtainable in early-stage disease. Therefore, due to the significantadverse impact of neck metastases on prognosis, the treatment ofthe neck remains a vital part of the decision-making process in determiningtherapy for head and neck cancer.

Data from adjuvant trials clearly indicate that one of the most importantproblems in patients with resected non-small-cell lung cancer(NSCLC) is compliance to chemotherapy. In the postoperative setting,significant comorbidities and incomplete recovery after surgery oftenmake it difficult for patients to tolerate or comply with systemic therapy.Therefore, it may be preferable to deliver chemotherapy before surgeryas "neoadjuvant" or "induction" chemotherapy. The rationale for usinginduction chemotherapy is based on evidence that chemotherapymight reduce tumor burden and possess activity againstmicrometastases, resulting in improved results by surgery, radiotherapy,or a combination. Moreover, induction therapy facilitates in vivo assessmentof tumor response or resistance. Potential drawbacks includethe risk of perioperative complications, and the possibility that the tumormass may become unresectable due to disease progression. Duringthe past decade, four phase III randomized trials evaluated the roleof induction chemotherapy in stage IIIA NSCLC. The first three studiesconsistently showed that induction chemotherapy improves survivalcompared with surgery alone. More recently, a large phase III trialperformed by French investigators suggested a survival benefit in stageI/II patients, but not stage IIIA. The high activity of new platinumbasedchemotherapy-based on response rate and 1-year survival inadvanced disease-reinforces the rationale for the use of these newcombinations in early-stage NSCLC, especially for a subset of patientstraditionally treated with surgery alone. Several phase III trials arecurrently evaluating the role of new doublets as induction chemotherapy;these are discussed in the article. The results of these ongoingphase III trials should help clarify the role of induction chemotherapyin early-stage disease.

Any T-cell-mediated disease benefits from therapy without affecting other inflammatory pathways

Any T cell-mediated disease found to benefit from this therapy without affecting other inflammatory pathways

Any T-cell-mediated disease benefits from therapy without affecting other inflammatory pathways

Lung cancer is a major health problem worldwide. Non–small-celllung cancer (NSCLC) accounts for 80% to 85% of all lung cancers,while small-cell lung cancer (SCLC) accounts for 15% to 20% of cases.For early-stage and locally advanced NSCLC (stages I through III), amultimodality treatment approach is appropriate because it improvessurvival. Combination chemotherapy is currently the standard treatmentfor good performance patients with metastatic disease. Elderlypatients (≥ 70 years) with metastatic NSCLC also benefit from treatment.In SCLC, concurrent radiation therapy and chemotherapy is thestandard for limited disease, while chemotherapy is the treatment forextensive disease. Novel innovative therapies, which could includemolecular targeting agents, are needed to treat both NSCLC and SCLC.

Locally advanced non–small-cell lung cancer represents 30% to 40%of all pulmonary malignancies. Most patients will die of the diseaseafter aggressive contemporary treatments. Therefore, significant improvementin therapeutic methods must be implemented to improveoverall survival rates. The arrival of a new generation of chemotherapeuticagents-including the taxanes, gemcitabine (Gemzar), andtopoisomerase inhibitors such as irinotecan (Camptosar) and topotecan(Hycamtin)-offers the hope of significant advances in the treatmentof lung cancer. Irinotecan and topotecan are camptothecin derivativesthat inhibit topoisomerase I enzyme. It is believed that topoisomerase Iinhibitors stabilize a DNA/topoisomerase I complex and interact withreplication machinery to cause cell death. A significant amount of datademonstrates that these topoisomerase I inhibitors also act asradiosensitizers. With the increasing data that support concurrentchemoradiation treatment for malignancies, including lung cancer andhead and neck cancers, there is an impetus to pursue the additionaldrugs that may potentially improve local control and survival. Irinotecanis undergoing early clinical trials in the combined-modality setting inseveral different disease sites. This paper will review the data on therole of camptothecin derivatives as a radiosensitizer and as a componentof combined-modality therapy for lung cancer. It is hoped thatnewer treatment strategies, like the combination of radiation andtopoisomerase I inhibitors, will have a significant impact on cure ratesin the future.

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.

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.

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.

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.

This review by Dr. Gore emphasizesthe significance of theproblem of brain metastases inpatients with locally advanced non–small-cell lung cancer (NSCLC). Thearticle should prompt medical and radiationoncologists to consider enrollingpatients in the ambitious study ofprophylactic cranial irradiation (PCI)led by the Radiation Therapy OncologyGroup (RTOG L-0214). Statisticsfrom the ongoing RTOG study arecomplicated, but essentially, the researchersare looking for a 20% increasein median survival for patientsreceiving PCI. This would make theimpact of PCI in NSCLC comparableto that observed in limited small-celllung cancer (SCLC).

Ophthalmic drops that combine immediate antihistamine relief with prophylactic care in the form of mast cell inhibition and eosinophil blockage are the mainstay of therapy for allergic conjunctivitis.

High-dose myeloablative therapy with autologous or allogeneicstem cell rescue is an effective treatment strategy for non-Hodgkin’slymphoma (NHL), but NHL is much less likely to stay in remission afteran autologous transplant than after an allogeneic transplant. Thebenefit of undergoing an autologous transplant earlier in the course ofthe disease, especially for patients who present with intermediate orhigh scores on the International Prognostic Index of risk factors, is stillunclear. The addition of immunotherapy, biologic modifiers, andantibody therapy such as rituximab (Rituxan) or radiolabeled antibodyto the autologous transplant are approaches undergoing evaluation.Historically, there has been a high regimen-related mortality rateassociated with myeloablative allogeneic transplant that has made thisapproach a less appealing option for therapy. The use of nonmyeloablativeallogeneic transplants as treatment for NHL is less well studiedand remains to be defined.

Portland, OR-Researchers in the Casey Eye Institute at Oregon Health & Science University (OHSU) began participation in February in a gene therapy trial for patients with age-related macular degeneration (AMD).

Philadelphia-Gene therapy has successfully restored the visual function of blind dogs with a rare congenital retinal disease, according to early research results. This breakthrough holds implications for the treat- ment of several human retinal degenerative diseases within the next several years.

PHILADELPHIA-T-cell depletion had no clear advantage over immunosuppressive drug therapy in patients receiving a matched, unrelated donor bone marrow transplant, John E. Wagner, MD, reported at the 44th Annual Meeting of the American Society of Hematology (ASH abstract 274).

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.