ONCOLOGY Vol 18 No 13 | Oncology

Breast Cancer: New Radiation Treatment Options

November 01, 2004

Six published randomized trials[1-6] and one meta-analysis[7] of published and unpublishedtrials have demonstrated thatbreast-conserving therapy (breast-conservingsurgery plus breast irradiation)is equivalent to mastectomy interms of survival. As a result, breastconservingtherapy is the option preferredby many women for thetreatment of early-stage breast cancer.[8] Breast irradiation followingbreast-conserving surgery is an integralpart of breast-conserving therapy.There are seven other publishedrandomized trials demonstrating thatbreast irradiation substantially reducesthe rate of local recurrence andprevents the need for subsequent mastectomy.[9-15] A recent meta-analysisalso supports the conclusion that breastcancer patients who receive breast irradiationhave improved survival.[16]

Induction Chemotherapy for Resectable Non–Small-Cell Lung Cancer

November 01, 2004

Recent advances in molecularclassification and the adventof noncytotoxic molecularlytargeted therapies have offered increasedhope of improving the diagnosis,treatment, and prognosis forpatients with non–small-cell lung cancer(NSCLC).[1] Yet the use of chemotherapyin NSCLC has continuedto evolve over recent years with theappearance of newer cytotoxic agentsthat have improved the outcome forpatients. Doublet combination chemotherapyhas become the standardof care for patients with advanceddisease and good performance status.Prolongation of survival has also beenshown with second-line chemotherapyfor patients whose tumors are refractoryto first-line agents.[1]

Induction Chemotherapy for Resectable Non–Small-Cell Lung Cancer

November 01, 2004

Drs. Patel, Blum, and Argirishave provided a detailed, thoroughreview of induction chemotherapyfor non–small-cell lungcancer (NSCLC). They also discussstaging and the relative merits of avariety of invasive and noninvasivetechniques for staging lung cancer.

Breast Cancer: New Radiation Treatment Options

November 01, 2004

Dr. Arthur and colleagues havepresented a comprehensiveoverview of two of the mostnoteworthy radiotherapy (RT) advancesin the contemporary managementof breast cancer, ie, short-course hypofractionatedRT and intensity-modulatedradiotherapy (IMRT). Althoughboth challenge the conventional RTapproach to early-stage disease, theydiffer considerably in that hypofractionatedRT refers to treatment of eitherthe entire breast or a part of thebreast in a shorter time course thanwith standard fractionation, whereasIMRT refers to an alteration in themethod of treatment delivery. I willdiscuss each in turn.

Commentary (Asgharzadeh/Finlay): Recent Advances in the Treatment of Pediatric Brain Tumors

November 01, 2004

The review by Gururangan andFriedman takes an interestingand informative approach to pediatricbrain tumors in emphasizingthe possible biologic bases for chemotherapyfailure in these neoplasmsin general, and focusing on newer, asyet largely unproven, strategies employing“biologic” therapies to circumventsuch mechanisms of tumor resistance.Many of these newer treatment strategiesare drawn from the work of theauthors and others in the field of adultmalignant gliomas. To date, minimalprogress has been achieved in improvingoutcome for children with malignantsupratentorial gliomas andbrainstem tumors. Hopefully, these newstrategies will have significant benefitin pediatric as well as adult patients.

Hypersensitivity Reactions to Oxaliplatin: Incidence and Management

November 01, 2004

Gowda and colleagues reviewed169 consecutive patients withesophageal or colorectal cancerwho received oxaliplatin-basedtherapy over a 2.5-year period to identifythe incidence of hypersensitivityreactions. Thirty-two patients (19%) experiencedhypersensitivity; some patientsexperienced more than onesymptom, including skin rash (13%),fever (3%), respiratory symptoms (3%),lacrimation/blurring of vision (1%), andlaryngeal/glossal edema (0.6%).

Recent Advances in the Treatment of Pediatric Brain Tumors

November 01, 2004

Central nervous system (CNS) cancers are the second most frequent malignancy in childhood. In recent years, significant advances in surgery, radiotherapy, and chemotherapy have improved survival in children with these tumors. However, a significant proportion of patients with CNS tumors suffer progressive disease despite such treatment.

Hypersensitivity Reactions to Oxaliplatin: Incidence and Management

November 01, 2004

The paper by Gowda et al is anotherwell-done work on allergicreactions in patients treatedwith oxaliplatin (L-OHP, Eloxatin)for advanced colorectal cancer.Oxaliplatin was found to be an activeagent in the treatment of this disease10 years ago,[1] and its role in combinationwith leucovorin and fluorouracil(5-FU) is a cornerstone in thetreatment of advanced colorectalcancer,[2-7] as it will probably alsobecome in the adjuvant setting.[8] Althoughthe drug’s dose-limiting toxicityis a cumulative sensory neuropathy,allergic and idiosyncratic reactions mustalways be considered due to their severityand because they can representan important, irreversible reasonfor treatment discontinuation.

Clinical Update on Pemetrexed

November 02, 2004

The articles in this supplement to ONCOLOGY, “Clinical Update onPemetrexed,” are presented by leading international clinical andpreclinical investigators in the arenas of thoracic, gastrointestinal, breast, andgynecologic cancers. They cover a wide range of topics that focus on the promisingagent pemetrexed (Alimta).

Update on Neutropenia and the Use of Myeloid Growth Factors

November 03, 2004

There has been a remarkable explosion in medicalinformation over the past several years.The rate of new discoveries and improved understandingof the biology and treatment ofcancer is ever-increasing. The same is true inthe area of supportive cancer therapy.[1]

Pemetrexed in Malignant Pleural Mesothelioma

November 02, 2004

Malignant pleural mesothelioma (MPM) is a disease with a poorprognosis, related in part to the aggressiveness of this disease, and inpart due to the lack of drugs that have demonstrated tumor activity.Historically, antifolates such as methotrexate have been the most activedrugs in the treatment of mesothelioma. Newer antifolates haverecently demonstrated higher efficacy than older regimens in the treatmentof this rare disease. One of these agents, pemetrexed (Alimta),has been evaluated both as a single agent and as part of a combinationregimen. Pemetrexed has been studied in three trials in patients withMPM, and two phase I trials included patients with MPM. In a phaseII trial, pemetrexed was studied as a single agent in patients with MPM.Seven of 64 patients achieved partial responses, with a median overallsurvival of 10.7 months. A large, randomized, phase III trial was conductedto compare pemetrexed/cisplatin with cisplatin. The responserate was 41.3% compared with 16.7%, median survival was 12.1 monthscompared with 9.3 months, and 1-year survival was 50.3% vs 38% inthe pemetrexed/cisplatin and cisplatin arms, respectively. The combinationof pemetrexed/cisplatin also demonstrated superiority in qualityof life and pulmonary functioning analysis when compared withcisplatin.

Targeting the Proapoptotic Factor Bcl-2 in Non-Hodgkin's Lymphoma

November 04, 2004

Bcl-2 functions as a key survival factor for lymphocytes and is highlyexpressed in a majority of non-Hodgkin's lymphomas. The ability ofoblimersen sodium (Genasense, previously known as G3139) to targetbcl-2 messenger RNA and decrease Bcl-2 protein levels has the potentialto enhance the activity of cytotoxic chemotherapy. Pretreatmentwith oblimersen followed by cyclophosphamide (Cytoxan, Neosar)markedly improved survival relative to single-agent cyclophosphamidein a murine xenograft model. Oblimersen has also enhanced the cytotoxicityof a variety of other agents against non-Hodgkin's lymphoma,including etoposide, rituximab (Rituxan), and alemtuzumab (Campath).An initial phase I study of oblimersen in non-Hodgkin's lymphomademonstrated modest single-agent activity. Recent reports suggest thatoblimersen may add to the activity of R-CHOP (rituximab-cyclophosphamide/doxorubicin/vincristine/prednisone) in previously untreatedmantle cell lymphoma and to rituximab alone in a variety of subtypesof relapsed non-Hodgkin's lymphoma. Additional studies in both treatment-naive and relapsed patients will define the role of oblimersen inthe treatment of non-Hodgkin's lymphoma.

Breast Cancer: New Radiation Treatment Options

November 01, 2004

Conventional radiotherapeutic treatment for early and advancedbreast cancer has been based on broad-field radiation treatment principlesthat date back several decades. Although these strategies havebeen successful, newer techniques now offer the ability to incorporateimproved target imaging, dosimetric planning, and treatment deliveryinto the treatment design. These newer techniques include acceleratedpartial-breast irradiation and hypofractionated whole-breast irradiationfor early-stage breast cancer, and intensity-modulated radiotherapy(IMRT) for both early and advanced breast cancer. Accelerated partial-breast irradiation and hypofractionated whole-breast radiotherapyare treatment approaches that promise both reduced overall treatmenttimes and the potential for increased use of breast-conservation therapy.IMRT offers unparalleled dose homogeneity and conformality thatenables dose reduction to normal structures with the potential to reducetreatment toxicity and improve cosmesis. Based on the publishedliterature, an increasing number of treatment facilities are offering treatmentwith these techniques. However, further clinical study remainsimportant to thoroughly define the appropriate clinical setting, patientselection criteria, and limitations for each of these innovative treatmentapproaches.

Pemetrexed in Advanced Colorectal Cancer

November 02, 2004

Pemetrexed (Alimta) shows single-agent activity in advancedcolorectal cancer. In two phase II studies in which patients receivedpemetrexed at 600 mg/m2 or 500 mg/m2 as first-line treatment for metastaticdisease, objective response rates were 15.4% and 17.2%.

Bcl-2 Antisense Therapy in Multiple Myeloma

November 04, 2004

Most malignant plasma cells overexpress Bcl-2, which contributesto resistance against apoptosis induced by dexamethasone and otheranticancer agents. Oblimersen sodium (Genasense, previously knownas G3139), an antisense oligonucleotide that specifically binds to bcl-2messenger RNA, decreases production of Bcl-2 protein in both humanmyeloma cell lines, as well as in ex vivo purified myeloma cells, andenhances the cytotoxicity of dexamethasone and doxorubicin. Combiningoblimersen with other anticancer agents represents a therapyenhancingstrategy to reverse the multidrug resistance seen in multiplemyeloma (MM). Phase II trials are evaluating the potential role ofoblimersen in reversing resistance to standard therapies. Preliminaryresults from these trials in patients with refractory or relapsed MMindicate that the combination of oblimersen with dexamethasone/thalidomide (Thalomid) or vincristine/doxorubicin/dexamethasone isactive and well tolerated and that oblimersen may help overcome chemotherapyresistance and restore sensitivity to MM cells. A randomizedphase III clinical trial comparing dexamethasone plus oblimersenwith dexamethasone alone in patients with relapsed or refractory myelomahas completed enrollment, with results expected to be availablein 2004. Future studies will focus on the role of oblimersen in combinationwith novel biologic agents such as bortezomib (Velcade).

Apoptosis Mechanisms: Implications for Cancer Drug Discovery

November 04, 2004

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.

Hypersensitivity Reactions to Oxaliplatin: Incidence and Management

November 01, 2004

Oxaliplatin (Eloxatin) is a novel platinum compound that has activityin a wide variety of tumors. Several hypersensitivity reactions distinctfrom laryngopharyngeal dysesthesia have been described. We retrospectivelyanalyzed 169 consecutive patients who received oxaliplatinfor esophageal or colorectal cancer between 1/1/00 and 7/31/02 andreviewed any significant adverse reactions labeled as hypersensitivityreactions. Thirty-two patients (19%) reportedly experienced hypersensitivity.Skin rash was the most common event (22 patients), occurringafter a median of three infusions. Fever was seen in five patients aftera median of two infusions. Five patients experienced respiratory symptomsat median infusion number 6. Ocular symptoms of lacrimationand blurring of vision were seen in two patients. Five patients experiencedmore than one type of reaction. Treatments prescribed forhypersensitivity were antihistamines, steroids, and topical emollients.One patient developed grade 4 hypersensitivity during cycle 6, characterizedby laryngeal edema, tongue swelling, and labored breathing.This patient underwent a desensitization procedure, adapted from guidelinesfor carboplatin (Paraplatin) allergy. Subsequently, three cycleswere administered over 6 hours and were well tolerated. However,during the fourth infusion postdesensitization, the patient developedrecurrent signs of hypersensitivity. In conclusion, hypersensitivity isfrequently seen with oxaliplatin, but most reactions are mild.

Pemetrexed in Transitional Cell Carcinoma of the Urothelium

November 02, 2004

Currently, the four-drug combination of methotrexate, vinblastine,doxorubicin (Adriamycin), and cisplatin (MVAC) or the two-drug combinationof gemcitabine and cisplatin (GC) represents the standard ofcare for patients with locally advanced and metastatic transitional cellcarcinoma of the urothelium. Recently, there has been a plethora ofdata from other chemotherapeutic regimens. Promising new agents,such as the multitargeted antifolate pemetrexed (Alimta), and new drugcombinations have demonstrated increased efficacy and/or decreasedtoxicity compared with current regimens. Currently, data are availablefrom three phase II studies utilizing pemetrexed or the combination ofpemetrexed/gemcitabine (Gemzar) in patients with locally advanced andmetastatic transitional cell carcinoma of the urothelium. Further investigationof combinations of pemetrexed and other active drugs inthe treatment of patients with locally advanced and metastatic diseaseis warranted.

Translational Research With Pemetrexed in Breast Cancer

November 02, 2004

Pemetrexed (Alimta) is a novel folate antimetabolite that primarilyinhibits the enzymes thymidylate synthase (TS), dihydrofolate reductase(DHFR), and glycinamide ribonucleotide formyl transferase(GARFT), all of which are involved in pyrimidine and purine synthesis.In a phase II trial of patients with T3/4, N0–2 breast cancer, expressionof thymidylate synthase (TS), dihydrofolate reductase (DHFR),glycinamide ribonucleotide formyltransferase (GARFT), p53, andc-erb-B2 (at the mRNA or protein level) was examined in tumor biopsyspecimens before and 24 hours after the first dose of pemetrexed andafter three cycles of single-agent treatment to establish correlations ofbiomarker levels and changes with clinical outcome and toxicity. Althoughfinal data are not available, initial indications are that clinicalresponse may correlate with decreased or low TS expression. The resultsobtained from clinical data are supported by laboratory results inthree cell lines (MDA-231, MCF-7, and ZR-75). These results suggestthat in vitro transcript profiling to identify which genes are importantpredictors of successful cytotoxic chemotherapy, followed by a focusedclinical trial to confirm the in vitro results, may be the best approachfor translational research.

Commentary (Olson): Recent Advances in the Treatment of Pediatric Brain Tumors

November 01, 2004

Sri Gururangan and Henry Friedmanpresent a thoughtful reviewof advances in pediatric neurooncology.Coupled with the recent reviewof pediatric brain tumor biologywritten by Richard Gilbertson, thesearticles highlight the value that thepediatric neuro-oncology communityplaces on translating signal transductionmodifiers into clinical practice.[1]The remainder of this commentaryfocuses on the challenges and opportunitiesassociated with developingmore effective and less toxic therapiesfor children with brain tumors.

Pemetrexed in Gastric Cancer

November 02, 2004

Gastric cancer is a major clinical challenge, with poor overall prognosisand limited life expectancy for patients with advanced disease.Even with surgery and other modalities, palliation is often difficult.Improvement of response rates has evolved with the development ofstandard regimens and those incorporating newer chemotherapy agents,such as oral fluoropyrimidines, the taxanes, camptothecins, novel platinums(eg, oxaliplatin [Eloxatin]), and antifolates (eg, pemetrexed[Alimta]). Ongoing trials with these regimens aim toward improvingsurvival, as well as improving the safety profile. It is hoped that in conjunctionwith molecular research in the pathogenesis of gastric cancerand development of targeted therapies in this disease, these trial datamight lead to the evolution of treatment strategies that could prove effective.

Pemetrexed in Pancreatic Cancer

November 02, 2004

Single-agent gemcitabine (Gemzar) is the standard of chemotherapyfor advanced pancreatic cancer, with no phase III trials to date havingshown significantly improved survival with gemcitabine-based combinationsvs single-agent treatment. The multitargeted antifolate agentpemetrexed (Alimta) shows synergistic effects in vitro in combinationwith gemcitabine, and activity and good tolerability when used as singleagenttreatment in advanced pancreatic cancer. In a phase II trial inpatients with advanced pancreatic cancer, the combination ofgemcitabine at 1,250 mg/m2 on days 1 and 8 plus pemetrexed at 500mg/m2 on day 8 after gemcitabine every 21 days resulted in a mediansurvival of 6.5 months and a 1-year survival rate of 29%. Neutropeniawas the primary toxicity, with grade 4 toxicity in 51% of patients. Thepromising results of this trial prompted the initiation of a phase IIItrial comparing gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 every28 days vs the 21-day gemcitabine/pemetrexed regimen given with vitaminsupplementation in patients with pancreatic cancer. The primaryoutcome measure was overall survival, with secondary measures includingresponse rate, progression-free survival, and quality of life.While an increase in response and time to progression was reported forthe gemcitabine/pemetrexed combination, there were no significantdifferences in survival between treatment arms.

Biochemical Pharmacology of Pemetrexed

November 02, 2004

Pemetrexed (Alimta) is a novel antimetabolite that inhibits the folatedependentenzymes thymidylate synthase, dihydrofolate reductase, andglycinamide ribonucleotide formyltransferase. Pemetrexed has demonstratedactivity in clinical trials in a variety of tumor types, includinglung, breast, colon, mesothelioma, pancreatic, gastric, bladder, headand neck, and cervix. Pemetrexed is rapidly metabolized into activepolyglutamate forms that are potent inhibitors of several tetrahydrofolatecofactor-requiring enzymes critical to the synthesis of purines and thymidine.Functionally, pemetrexed acts as a prodrug for its polyglutamateforms. Two different transporters are known to take extracellular folates,and some antifolates, into the cell. These are the reduced folate carrierand the folate receptor. One of the many attributes that make pemetrexedunique is that methodology has been developed to eliminate and controlmany of its associated clinical toxicities. Multivariate analyses demonstratedthat pretreatment total plasma homocysteine levels significantlypredicted severe thrombocytopenia and neutropenia, with orwithout associated grade 3/4 diarrhea, mucositis, or infection. Routinevitamin B12 and folic acid supplementation have resulted in decreasedfrequency/severity of toxicities associated with pemetrexed without affectingefficacy, making this novel antifolate a safe and efficaciousanticancer agent.

Pemetrexed in Front-Line Chemotherapy for Advanced Non–Small-Cell Lung Cancer

November 02, 2004

Pemetrexed (Alimta) possesses broad antitumor activity. It has beenevaluated in non–small-cell lung cancer (NSCLC) as front-line chemotherapyin a comprehensive phase II evaluation. While variousantifolates have been previously evaluated in clinical trials, drug developmentwas stopped or delayed in light of their lack of efficacy oroccurrence of life-threatening toxicities. While similar trends were observedwith pemetrexed early in development, investigators institutedfolic acid and vitamin B12 supplementation to minimize these toxicitieswithout hampering drug efficacy. This article briefly summarizes thecurrent evidence that supports the role of pemetrexed-based combinationsin clinical trials for chemonaive patients with advanced NSCLC.

Induction Chemotherapy for Resectable Non–Small-Cell Lung Cancer

November 01, 2004

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.

Use of Newer Antifungal Therapies in Clinical Practice: What Do the Data Tell Us?

November 01, 2004

Considering the significant morbidity and mortality associated withinvasive fungal infections in immunocompromised patients, it is particularlyimportant to make the diagnosis as early as possible and tomake best use of the available antifungal drugs for prophylaxis andtreatment. The newer antifungal drugs include the lipid products ofamphotericin B, such as amphotericin B lipid complex (ABLC) andliposomal amphotericin B; voriconazole (a triazole); and caspofungin(an echinocandin). ABLC and liposomal amphotericin B are as effectiveas amphotericin B deoxycholate but are less nephrotoxic; ABLC isprobably the drug of choice for zygomycosis. Voriconazole is approvedfor use in the treatment of invasive aspergillosis and may have a role inpreventing breakthrough fungal infections in patients with persistentfever and neutropenia. Caspofungin is effective against both invasiveaspergillosis and invasive candidiasis.

Pemetrexed in Second-Line Treatment of Non–Small-Cell Lung Cancer

November 02, 2004

According to the updated 2004 guidelines of the American Societyof Clinical Oncology (ASCO) on the treatment of advanced non–smallcelllung cancer (NSCLC), docetaxel (Taxotere) can be considered thestandard second-line chemotherapy in patients relapsing after frontlinetherapy. This was based on two phase III trials (TAX 317 and TAX320) that demonstrated the superiority of docetaxel at 75 mg/m2 in theparameters of survival, quality of life, and disease/symptom controlwhen compared to best supportive care or alternative single-agent chemotherapy.The response rate was approximately 6%, with a mediansurvival time of 7 months and a 1-year survival rate of 30%. Despitethe activity demonstrated, this schedule showed an important toxicityprofile, with grade 3/4 neutropenia and febrile neutropenia occurringin 70% and 11% of patients, respectively. However, the results obtainedby these studies stimulated research interest in new drugs for this diseasesetting. Pemetrexed (Alimta), a new multitargeted antifolate, hasachieved promising results in NSCLC treatment, as a single agent or incombination with other drugs. In the second-line setting, a large phaseII study demonstrated good activity of pemetrexed, with an acceptabletoxicity profile. This led to a phase III registration trial that comparedpemetrexed at 500 mg/m2 to the standard docetaxel dose of 75 mg/m2.While results from this trial demonstrated a similar efficacy of the tworegimens in response rate and survival, pemetrexed achieved a bettersafety profile. These results support the use of pemetrexed as a newoption in the second-line treatment of NSCLC.

Management of Invasive Mycoses in Hematology Patients: Current Approaches

November 01, 2004

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.

Potential Therapeutic Applications of Oblimersen in CLL

November 04, 2004

Bcl-2 protein is upregulated in a wide variety of lymphoid malignancies,including chronic lymphocytic leukemia (CLL). The proteinis thought to be responsible for maintaining the viability of malignantlymphoid cells and may contribute to chemotherapy and radiotherapyresistance. Previous studies have shown that reduction of bcl-2 expressionby antisense therapy sensitizes cells to chemotherapy-inducedapoptosis. In vitro, the Bcl-2 antisense drug oblimersen sodium(Genasense, previously known as G3139) enhances the apoptotic responsein CLL cells to fludarabine (Fludara), corticosteroids,alemtuzumab (Campath), and rituximab (Rituxan). A phase I trial inpatients with refractory/relapsed CLL showed that patients with CLLwere more sensitive to oblimersen than patients with solid tumors. Themaximum tolerated oblimersen dose was 3 mg/kg/d, and the most commondose-limiting reaction was hypotension, frequently in associationwith high spiking fever. In this study, oblimersen displayed limited singleagentactivity, including tumor lysis syndrome, transient decreases incirculating CLL cells, and reduction of splenomegaly and size of lymphnodes. Major responses were observed in 9% of patients. Subsequently,a phase III trial evaluating fludarabine and cyclophosphamide with orwithout oblimersen (3 mg/kg/d for 7 days) was initiated in patients withrelapsed or refractory CLL. This trial recently completed accrual of241 patients.

Overview of Phase I/II Pemetrexed Studies

November 02, 2004

Pemetrexed (Alimta) is an antifolate that is effective in the inhibitionof multiple enzyme targets including thymidylate synthase,dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase.The compound has been evaluated in several phase I trials, bothas single agent and in combination with other cytotoxic agents. Theinitial schedule selected for further investigation in phase II trials waspemetrexed 600 mg/m2 as a 10-minute infusion on day 1 every 21 days.During the subsequent phase II development, the dose of pemetrexedwas adjusted to 500 mg/m2 due to bone marrow and gastrointestinaltoxicities. The adjusted dose of pemetrexed was well tolerated throughoutthe late-phase drug development program. Preclinical evidencesuggests that pemetrexed has additive or synergistic activity when combinedwith many other clinically important anticancer agents, includinggemcitabine (Gemzar), fluorouracil, carboplatin (Paraplatin),oxaliplatin (Eloxatin), paclitaxel, and vinorelbine (Navelbine). Doselimitingtoxicities in these studies were primarily hematologic, and therewas no evidence of cumulative hematologic toxicity. During the drugdevelopment program it was discovered that supplementation with folicacid and vitamin B12 profoundly increased the tolerability ofpemetrexed. The studies discussed in this review demonstrate thatpemetrexed is well tolerated as a single agent and will be an importantcontribution to combination chemotherapy regimens.

The Promise of Pharmacogenomics: Gemcitabine and Pemetrexed

November 02, 2004

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.

Phase II Studies of Pemetrexed in Metastatic Breast and Gynecologic Cancers

November 02, 2004

Pemetrexed (Alimta) is active in a variety of solid tumors, includingbreast and gynecologic cancers. Phase II trials of pemetrexed at a doseof 600 mg/m2 without vitamin B12 and folic acid supplementation inlargely pretreated metastatic breast cancer patients demonstrated objectiveresponse rates of 21% and 28%, with generally manageableneutropenia constituting the primary toxicity. In phase II trials using500 mg/m2 with or without vitamin supplementation in anthracyclineandtaxane-pretreated patients, response rates were lower (approximately9%) and treatment was generally well tolerated irrespective ofvitamin supplementation status. A phase II trial is currently comparingpemetrexed doses of 600 and 900 mg/m2 with vitamin B12 supplementationin patients with previously untreated advanced breast cancer. In aphase II trial in patients with advanced cervical cancer, pemetrexed at600 mg/m2 without vitamin supplementation and 500 mg/m2 with supplementationproduced similar response rates, with the frequency of neutropeniabeing somewhat lower among patients receiving the lower doseand vitamin supplementation. Preliminary results in an ongoing phaseII trial indicate activity of the regimen of gemcitabine (Gemzar) at1,000 mg/m2 plus pemetrexed at 500 mg/m2 with vitamin supplementationin patients with ovarian cancer. Ongoing and future studies willestablish optimal dosing regimens of pemetrexed and potential benefitsof vitamin supplementation in the settings of metastatic breastcancer and gynecologic malignancies.

Apoptotic Mechanisms of Gallium Nitrate: Basic and Clinical Investigations

November 04, 2004

Gallium nitrate inhibits the growth of various lymphoma cell linesin vitro and exhibits antitumor activity in patients with lymphoma.The mechanism(s) of cytotoxicity is (are) only partly understood butappears to involve a two-step process: (1) targeting of gallium to cells,and (2) acting on multiple, specific intracellular processes. Galliumshares certain chemical properties with iron; therefore, it binds avidlyto the iron transport protein transferrin. Transferrin-gallium complexespreferentially target cells that express transferrin receptors on theirsurface. Expression of transferrin receptors is particularly high onlymphoma cells. Cellular uptake of the gallium-transferrin complexleads to inhibition of cellular proliferation primarily via disruption ofiron transport and homeostasis and blockade of ribonucleotidereductase. Recent studies have shown that cellular uptake of galliumleads to activation of caspases and induction of apoptosis. In phase IItrials in patients with relapsed or refractory lymphoma, the antitumoractivity of gallium nitrate is similar to, or better than, that of othercommonly used chemotherapeutic agents. Gallium nitrate is notmyelosuppressive and may be used in patients with neutropenia orthrombocytopenia. A multicenter trial to evaluate the use of galliumnitrate in patients with relapsed non-Hodgkin's lymphoma is currentlyongoing.

Combination Antifungal Therapy: Where Are We Now, and Where Are We Going?

November 01, 2004

Combination therapy with amphotericin B and flucytosine is consideredto be the treatment of choice for cryptococcal infections. However,for other infections and combinations of antifungal infections,the data are less clear-cut. The concurrent use of amphotericin B withan azole has elicited controversy, given the potential of antimicrobialantagonism. The results of one recent candidemia study suggest thatthe potential antagonism may not be an issue; the combination of amphotericinB and fluconazole provided more effective clearance of Candidafrom the bloodstream than did fluconazole used alone. Several invitro and animal studies have shown antagonism between the azolesand amphotericin B for aspergillosis. However, introduction of the newclass of agents that target β-glucan synthase (echinocandins) has invigoratedthe prospects of combination therapy. The echinocandins andpolyenes are not antagonistic, and there is evidence that theechinocandins may provide additive to synergistic activity in combinationwith triazoles. For patients whose aspergillosis is progressing despitemonotherapy, the addition of a second agent, such as anechinocandin, may be reasonable.