ONCOLOGY Vol 18 No 8

In this issue of ONCOLOGY, Kutleret al eloquently address the concept,application, and controversiesof a planned neck dissection inpatients with head and neck carcinomaand nodal metastasis who receivenonsurgical therapy to the primary tumor.As stated lucidly in the article,planned neck dissection arose in thehistorical context of low rates of completeresponse in patients with N2/3neck disease treated with conventionallyfractionated radiotherapy, coupledwith low surgical salvage ratesamong patients who failed in the neck.Hence, the concept evolved that allpatients with N2/3 neck disease shouldundergo a planned neck dissection regardlessof response to radiotherapy.

Dr. Kozuch and coauthors havewritten a comprehensive reviewof gallbladder and biliarytract carcinoma. We would like to updateseveral issues related to this topic,with particular emphasis on new chemotherapystrategies and drug combinationsfor improving outcomes.

Cancers of the gallbladder andbile ducts are uncommon, aggressivemalignancies thatpresent both a diagnostic and therapeuticchallenge. With an annual incidenceof 7,200 cases in the UnitedStates, and the difficulty in diagnosingbiliary tract tumors, there is a paucityof data supporting therapeuticoptions. This comprehensive updateby Daines et al demonstrates the advancesin diagnostic and staging techniques,which have led to appropriatesurgical resection. Despite these advances,the prognosis of gallbladderand cholangiocarcinoma remains bleak,without significant improvement in survival,contrary to the author's optimisticintroduction. There is a lack of activechemotherapy and clinical trials exploringadjuvant and palliative therapy.Guidelines such as those advocated bythe National Comprehensive CancerNetwork (NCCN) help to establish standardsfor the evaluation and treatmentof these uncommon tumors and providea framework for the developmentof clinical trials.[1]

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.

It is well known that the prognosisfor patients with brain metastasesfrom small cell lung cancer(SCLC) is very poor, with mediansurvivals in the range of 3 to 14months.[1-3] As pointed out by Quanet al, brain metastasis is an importantissue, given that approximately 60%of SCLC patients will develop brainmetastases sometime in the course oftheir disease. Quan et al set out towrite an article on the treatment ofbrain metastases from SCLC, but theyoften have to refer to the results ofstudies of brain metastases from othersites. Unfortunately, many studiesspecifically exclude SCLC-relatedbrain metastases, and therefore,advances in their treatment havebeen few.

Gallbladder carcinoma and carcinoma of the bile ducts are relativelyrare cancers in the United States. These cancers are often diagnosedin an advanced stage due to their nonspecific symptomatologyand until recently have been associated with a dismal prognosis. Recentadvances in imaging and surgical techniques along with emergingoptions in palliative chemotherapy have improved the outlook inthese cancers. While complete surgical resection remains the only hopeof cure in both these cancers, palliative biliary decompression and chemotherapyresult in substantial improvement in quality of life. Part 1 ofthis review, which appeared in last month’s issue, provided a relevantand comprehensive update of molecular pathology, imaging modalities,and surgical care. In part 2, we examine palliative care and systemictherapy in gallbladder and biliary tract carcinomas, as well asthe use of liver transplantation in the treatment of cholangiocarcinomas.These strategies are of relevance to internists as well as oncologistscaring for these patients.

The use of chemotherapy in the treatment of early and advancednon–small-cell lung cancer (NSCLC) has increased during the pastdecade. One of the main reasons for the increased acceptance of chemotherapyis the development of several new cytotoxic agents with aunique mechanism(s) of action and high single-agent activity, combinedwith a favorable toxicity profile. Pemetrexed (Alimta) is a novelantifolate that inhibits several enzymes involved in DNA synthesis(thymidylate synthase [TS], dihydrofolate reductase [DHFR], andglycinamide ribonucleotide formyltransferase [GARFT]). Pemetrexed’stoxicity is markedly reduced by folic acid and vitamin B12 supplementation.The compound has been studied extensively in various tumor types,including NSCLC. In NSCLC, pemetrexed at 500 mg/m2, every 3 weeks,given IV over 10 minutes, has shown promising activity, and can safelybe administrated with vitamin supplementation. After registration,single-agent pemetrexed will certainly add to the chemotherapeuticoptions available for pretreated patients and will most likely changesignificantly chemotherapy prescriptions in second-line chemotherapy.In first-line chemotherapy, the role of platinum-based and -free combinationdoublet chemotherapy with pemetrexed still needs to be defined.Phase II data indicate high efficacy combined with favorabletoxicity for pemetrexed in combination with cisplatin, carboplatin(Paraplatin), oxaliplatin (Eloxatin), gemcitabine (Gemzar), andvinorelbine (Navelbine). This review summarizes the clinical experienceobtained thus far during the early clinical development ofpemetrexed in NSCLC.

Standard first-line chemotherapy for the majority of patients withadvanced non–small-cell lung cancer (NSCLC) consists of platinumbasedcombination regimens including one of the newer-generationagents, such as gemcitabine (Gemzar), a taxane, vinorelbine(Navelbine), or irinotecan (Camptosar). Several effective regimens areavailable, the choice of which will depend on treatment goals, individualpatient or disease factors, as well as physician preferences. Thispaper surveys randomized trials of many of the newer-generation chemotherapycombinations in patients with advanced NSCLC to examineseveral issues, such as which new-generation regimen to use, whethera platinum agent is needed, the optimal number of drugs in the combination,and treatment duration.

The novel multitargeted antimetabolite pemetrexed (Alimta), recentlyapproved by the US Food and Drug Administration for the treatment ofmesothelioma when combined with cisplatin, is also active in first- andsecond-line non–small-cell lung cancer (NSCLC). In a phase III trialcomparing single-agent pemetrexed vs docetaxel (Taxotere) as secondlinetherapy in advanced NSCLC, survival was shown to be comparablebetween these agents, but side effects were significantly less frequentand severe for patients who received pemetrexed. In the frontlinesetting, phase II studies have shown significant activity and a veryfavorable toxicity profile of the combination of pemetrexed with a platinumagent. Pemetrexed has been well tolerated at systemic doses as aradiosensitizer when given as concurrent chest radiation, and a phaseI study is under way to assess its tolerability in combination withcarboplatin (Paraplatin) in this setting. Pemetrexed is an importantaddition to the armamentarium of medicines used to treat thoracicmalignancies, and merits study in combination with other drugs havingnovel mechanisms of action.

The purpose of this paper is to provide an overview of the clinical presentation, diagnosis, and treatment of brain metastases in patients with SCLC, with a focus on current trends and developments in the treatment of this disease.

Quan and colleagues have providedan important and timelyreview on the treatment ofbrain metastases in patients with smallcell lung cancer (SCLC). We certainlyagree with the comments and viewsof the authors, but wish to emphasizeseveral aspects of central nervoussystem (CNS) metastases in SCLCpatients.

The recent recognition that theaddition of concurrent chemotherapyto definitive radiationcan improve locoregional control, organpreservation, and survival in patientswith squamous cell head andneck cancer has had a significant impacton our management choices.Chemoradiotherapy data from metaanalyses,cooperative group trials, andlarge tertiary care institutions now suggestthat there is a realistic potentialfor cure in almost all patients withlocoregionally confined disease, and thefocus has increasingly shifted towardthe impact of our treatments on longtermfunction. In the past, control ofneck node involvement often requireda comprehensive neck dissection, a procedureassociated with some degree oflong-term morbidity. In this review,Kutler, Patel, and Shah address the importantquestion of whether the neckdissection should be a planned componentin the management of patientstreated with definitive concurrentchemoradiotherapy.

Malignant mesothelioma is a devastating disease with an onset 20to 60 years after exposure to asbestos. Although most cytotoxic agentshave been evaluated for the treatment of mesothelioma, few single agentshave consistently yielded response rates above 20%. Antimetabolitesare the most active drugs against mesothelioma, and of these, theantifolate group is the most widely studied and effective. Pemetrexed(Alimta), a new antifolate, may be more active because of its differentmechanism of action. Several clinical trials have evaluated pemetrexedalone and in combination with a platinum agent for patients with malignantmesothelioma. A pivotal phase III trial has demonstrated thatcombination chemotherapy with pemetrexed and cisplatin improvessurvival, response rate, pulmonary function, and quality of life comparedwith single-agent cisplatin. Additional trials are evaluatingpemetrexed in the neoadjuvant setting and in combination with othercytotoxic and targeted agents.

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.

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.

Standard first-line chemotherapy regimens in advanced non-smallcelllung cancer (NSCLC) include carboplatin (Paraplatin)/paclitaxel,cisplatin/docetaxel (Taxotere), cisplatin/gemcitabine (Gemzar), andcisplatin/vinorelbine (Navelbine). An informal meta-analysis of 13 randomizedtrials of these regimens in NSCLC indicates no marked differencesin terms of response rates or survival, but toxicity advantageswith cisplatin/gemcitabine and cisplatin/vinorelbine regimens. An informalmeta-analysis to assess the feasibility of substituting carboplatinfor cisplatin in combination with gemcitabine or docetaxel shows nomarked differences in efficacy between cisplatin- and carboplatincontainingregimens, although a slight trend favoring carboplatin/gemcitabine treatment may be observed; comparison of toxicity profilesamong carboplatin-based regimens suggests advantages forcarboplatin/gemcitabine treatment. A formal meta-analysis of 13 trialscomparing gemcitabine/platinum combinations with other platinumbasedregimens in NSCLC indicates significant improvements inprogression-free survival and overall survival with gemcitabine/platinum treatment. On balance, available data suggest that carboplatin/gemcitabine may be the first-line option with the best therapeutic index.

The treatment of advanced non–small-cell lung cancer (NSCLC)has evolved rapidly over the past few years. Systemic chemotherapy isassociated with both quality of life and modest survival benefit for patientswith advanced NSCLC. Platinum-based doublet combinationsare the “standard of care.” The US Food and Drug Administration(FDA) has approved gemcitabine (Gemzar), a pyrimidine analog, to beused in combination with cisplatin for the treatment of advanced NSCLCin the first-line setting. Randomized clinical trials have established comparableefficacy with improved therapeutic index for the carboplatin/gemcitabine regimen when compared with cisplatin/gemcitabine andother platinum doublets. Nonhematologic toxicities occur at a lowerfrequency with carboplatin/gemcitabine combinations compared withother “standard” platinum-based doublets, whereas dose-limitingthrombocytopenia, the most common toxicity, rarely requires therapeuticintervention. Both the 3- and 4-week schedules of carboplatin/gemcitabine result in similar efficacy and toxicity profiles, but the3-week regimen is preferred. The combination of carboplatin andgemcitabine is an effective regimen with an acceptable toxicity profilefor the treatment of advanced NSCLC. This regimen can also be usedas a foundation for the development of innovative combinations withmolecularly targeted agents.

Research to identify the optimal drugs for use in chemoradiotherapyhas led to the development of the potent radiosensitizing agentgemcitabine (Gemzar), which has exhibited excellent activity in non-small-cell cancer. When used in sequential chemoradiotherapy regimens,gemcitabine has been associated with response rates of 57% to68%. A full dose of gemcitabine (1,000 mg/m2) can be safely used asinduction therapy, and there is no definitive indication of enhancementof radiotoxicity. In addition, results from phase I/II trials supportthe efficacy of concurrent gemcitabine/radiation therapy in improvingoverall response rates and overall survival. Rates of 68%, 37%, and28%, respectively, for 1-, 2-, and 3-year survival have been reported forgemcitabine/cisplatin chemotherapy administered concurrently withradiotherapy. Although the optimal dose has yet to be determined, aweekly dose of 300 mg/m2 appears to be effective with an acceptabletoxicity level. Additional clinical trials are warranted to assess the longtermefficacy and safety of gemcitabine in combination with other chemotherapeuticagents and radiation therapy for treatment of non-smallcelllung cancer.

Several new antimetabolites, administered alone or in combination,are changing the therapeutic landscape for thoracic cancer. Two-drugcombinations involving these newer drugs are becoming the standardof care for non–small-cell lung cancer (NSCLC), largely due to improvementsin survival rates, time to disease progression, and responserates as well as an improved safety profile. Gemcitabine (Gemzar) haselicited considerable interest in this disease, as a combination partnerin chemotherapeutic regimens. Another promising agent is pemetrexed(Alimta), a folate-based inhibitor of thymidylate synthase. In preclinicaldevelopment, pemetrexed both alone and in combination with othercytotoxic agents has exhibited activity across a broad range of tumormodels, including NSCLC and mesothelioma. In clinical trials of patientswith NSCLC, pemetrexed has been an effective, well-toleratedagent that can be used as monotherapy or in combination with otheragents at full dose. In clinical trials of patients with mesothelioma, thecombination of pemetrexed and cisplatin demonstrated a significantimprovement in survival, response, and patient quality-of-life parameters.The principle toxicities of pemetrexed can be minimized by folateand vitamin B12 supplements.