Fernando Barata

Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data

BACKGROUND Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer. However, the optimum number of treatment cycles remains controversial. Therefore, we did a systematic review and meta-analysis of individual patient data to compare the efficacy of six versus fewer planned cycles of platinum-based chemotherapy. METHODS All randomised trials comparing six versus fewer planned cycles of first-line platinum-based chemotherapy for patients with advanced non-small-cell lung cancer were eligible for inclusion in this systematic review and meta-analysis. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients with an objective response, and toxicity. Statistical analyses were by intention-to-treat, stratified by trial. Overall survival and progression-free survival were compared by log-rank test. The proportion of patients with an objective response was compared with a Mantel-Haenszel test. Prespecified analyses explored effect variations by trial and patient characteristics. FINDINGS Five eligible trials were identified; individual patient data could be collected from four of these trials, which included 1139 patients-568 of whom were assigned to six cycles, and 571 to three cycles (two trials) or four cycles (two trials). Patients received cisplatin (two trials) or carboplatin (two trials). No evidence indicated a benefit of six cycles of chemotherapy on overall survival (median 9·54 months [95% CI 8·98-10·69] in patients assigned to six cycles vs 8·68 months [8·03-9·54] in those assigned to fewer cycles; hazard ratio [HR] 0·94 [95% CI 0·83-1·07], p=0·33) with slight heterogeneity between trials (p=0·076; I(2)=56%). We recorded no evidence of a treatment interaction with histology, sex, performance status, or age. Median progression-free survival was 6·09 months (95% CI 5·82-6·87) in patients assigned to six cycles and 5·33 months (4·90-5·62) in those assigned to fewer cycles (HR 0·79, 95% CI 0·68-0·90; p=0·0007), and 173 (41·3%) of 419 patients assigned to six cycles and 152 (36·5%) of 416 patients assigned to three or four cycles had an objective response (p=0·16), without heterogeneity between the four trials. Anaemia at grade 3 or higher was slightly more frequent with a longer duration of treatment: 12 (2·9%) of 416 patients assigned to three-to-four cycles and 32 (7·8%) of 411 patients assigned to six cycles had severe anaemia. INTERPRETATION Six cycles of first-line platinum-based chemotherapy did not improve overall survival compared with three or four courses in patients with advanced non-small-cell lung cancer. Our findings suggest that fewer than six planned cycles of chemotherapy is a valid treatment option for these patients. FUNDING None.

Phase II, Double-Blinded, Randomized Study of Enzastaurin Plus Pemetrexed as Second-Line Therapy in Patients with Advanced Non-small Cell Lung Cancer

Introduction: We examined the efficacy of enzastaurin plus pemetrexed as second-line therapy in patients with advanced (stage IIIA/B or IV) non-small cell lung cancer in a double-blinded, randomized, phase II study. Methods: Patients received pemetrexed 500 mg/m2 intravenously on day 1 of 21-day cycles (day 8 in cycle 1) plus oral enzastaurin (250 mg two times per day; combination arm) or placebo (pemetrexed arm). Both arms received supplementation with vitamin B12, folic acid, and dexamethasone. An interim analysis was conducted to determine whether efficacy would warrant a phase III study. Results: The interim analysis showed no evidence of improved progression-free survival with enzastaurin. At final analysis (N = 160, 80 in each arm), baseline characteristics were well balanced. There was no significant difference in progression-free survival (3.0 months, p = 0.544) or overall survival (9.6 months in combination arm and 7.4 months in pemetrexed arm, p = 0.171). Drug-related serious adverse events included cerebrovascular accident, palpitations, and renal failure (n = 1, each) in combination arm and neutropenic sepsis, thrombocytopenia, and panniculitis (n = 1, each) in pemetrexed arm. Nonhematologic drug-related grade 3/4 toxicities were similar in both arms. Grade 3/4 hematologic toxicities were higher with the combination, specifically leukopenia (6.3% versus 0%), neutropenia (15.2% versus 5.0%), and thrombocytopenia (8.9% versus 1.3%). Of the 26 deaths reported on-study or within 30 days of discontinuation (10 in combination arm and 16 in pemetrexed arm), none were drug related. Conclusion: The combination regimen of enzastaurin and pemetrexed is well tolerated but does not improve efficacy over pemetrexed and placebo as second-line treatment of unselected patients with advanced non-small cell lung cancer.

An economic analysis of erlotinib, docetaxel, pemetrexed and best supportive care as second or third line treatment of non-small cell lung cancer

AIM Evaluate costs and benefits of erlotinib as 2nd or 3rd line treatment of advanced or metastatic nonsmall cell lung cancer (NSCLC) versus docetaxel, pemetrexed and best supportive care. MATERIALS AND METHODS Cost-minimisation and cost-utility analysis were performed. Time horizon of two years. Portuguese National Health System (NHS) perspective was applied. Survival and time to progression were obtained from three clinical trials. Base-case analysis: 2nd or 3rd line patients with advanced or metastatic NSCLC. Quality Adjusted Life Years (QALYs) were obtained from a UK study. Resource consumption was estimated by a Portuguese panel of experts. Costs were calculated according to official Portuguese databases (updated to 2008). Only direct health costs were applied. Annual discount rate: 5%. Sensitivity analysis included different subpopulations, a three year time horizon and a probabilistic analysis. RESULTS The cost per patient was lower with erlotinib (26,478 euro) than docetaxel (29,262 euro) or pemetrexed (32,762 euro) and higher than best supportive care (16,112 euro). QALYs per patient were higher with erlotinib (0.250) than docetaxel (0.225), pemetrexed (0.241) or best supportive care (0.186). Erlotinib was dominant in the cost-utility analysis, with a lower cost and a higher efficacy than docetaxel and pemetrexed. The sensitivity analysis confirmed the robustness of the base-case analysis results. CONCLUSIONS The use of erlotinib instead of docetaxel or pemetrexed could contribute to annual savings for the NHS (substitution rates: 5%-65%) ranging from 135,046 euro-1,755,602 euro (docetaxel replacement) and 291,801 euro-3,793,409 euro (pemetrexed replacement), with a gain in terms of QALYs.

Phase II Study of Celecoxib with Cisplatin Plus Etoposide in Extensive-Stage Small Cell Lung Cancer

We performed a phase II trial to test whether a cyclooxygenase (COX-2) inhibitor, celecoxib, added to standard first-line combination chemotherapy (CT) and as maintenance therapy would improve outcomes in extensive-stage (ES) small-cell lung cancer (SCLC). This was a multicenter trial in CT-naive patients with ES-SCLC. They received standard cisplatin and etoposide (EP) up to 6 cycles and celecoxib 400 mg PO bid continuously until disease progression. Primary end points were response rate (RR), time to progression (TTP), and toxicity. Secondary were overall survival (OS) and quality of life. Of 74 expected patients, only 24 were enrolled and the study stopped earlier because of the published safety concerns about celecoxib. The patients, all male, were between 38 and 74 years. A total of 130 cycles of CT were administered. Toxicity associated with celecoxib was minimal. The RR was 56.5%. Median TTP and OS were 8.6 and 11.3 months, respectively. These data suggest that celecoxib may safely be combined with EP for treatment of ES-SCLC. This combination showed a promising activity and, despite the safety concerns regarding celecoxib, it would be interesting to further evaluate this regimen.

Avaliação económica do erlotinib, docetaxel, pemetrexedo e tratamento de suporte no tratamento de segunda ou terceira linhas de doentes com cancro do pulmão de não pequenas células

Resumo Objectivo: Avaliar o custo-efectividade de erlotinib na segunda ou terceira linha do tratamento do cancro do pulmao de nao pequenas celulas (CPNPC) avancado ou metastizado versus docetaxel, pemetrexedo ou tratamento de suporte. Material e metodos: Analises de minimizacao de custos e custo-utilidade. Horizonte temporal: dois anos. Perspectiva do Sistema Nacional de Saude (SNS) portugues. Sobrevivencia e tempo ate progressao obtidos a partir de tres ensaios clinicos. Analise-base inclui doentes com CPNPC avancado ou metastizado em segunda ou terceira linhas. Anos de vida ajustados pela qualidade (ou QALY) obtidos a partir de estudo no Reino Unido. Consumo de recursos estimado por painel de peritos portugueses. Incluiram-se apenas custos directos, obtidos a partir de fontes oficiais (precos actualizados para 2008). Taxa de actualizacao anual: 5%. Analises de sensibilidade: diferentes subpopulacoes, horizonte temporal a tres anos e analise probabilistica. Resultados: O custo total/doente foi menor com erlotinib (26 478€) versus docetaxel (29 262€) ou pemetrexedo (32 762€) e superior versus tratamento de suporte (16 112€). Obtiveram-se QALY/doente mais elevados com erlotinib (0,250) versus docetaxel (0,225), pemetrexedo (0,241) ou tratamento de suporte (0,186). Assim, o erlotinib mostrou-se “dominante” em segunda ou terceira linhas versus docetaxel e pemetrexedo. A analise de sensibilidade comprova a robustez dos resultados. Conclusoes: A substituicao de docetaxel ou pemetrexedo por erlotinib poderia contribuir para uma reducao anual dos gastos do SNS que se estima (taxas substituicao: 5%-65%) com uma variacao entre 135 046€-1 755 602€ e entre 291 801€-3 793 409€, respectivamente, e com ganho em termos de QALY. Rev Port Pneumol 2008; XIV (6): 803-827

Carcinoma do pulmão de pequenas células – Estado da arte e perspectivas futuras

Resumo Em Portugal, o cancro do pulmao e a principal causa de morte entre as neoplasias. Em 2006 sao previstos mais de 3500 novos casos, dos quais 20% serao diagnosticados como carcinoma do pulmao de pequenas celulas (CPPC). Destes, 25% a 30% dos doentes serao estadiados como doenca localizada ou regional. Para estes, a opcao terapeutica passa pela combinacao da radioterapia (50 Gy ou 60 Gy) diaria e quimioterapia. A radioterapia hiperfraccionada, em consequencia da sua toxicidade, esta limitada a doentes seleccionados. A combinacao etoposido e cisplatina e sinergica, bem tolerada. E o regimen standard quer na opcao concomitante com a radioterapia, quer isoladamente na doenca disseminada. Apesar da quimiossensibilidade e radiosensibilidade, o prognostico global do CPPC e pobre. Ha um desenvolvimento precoce de resistencia associado a uma elevada predisposicao para a recidiva. A terapeutica de segunda linha para o CPPC e um problema real e actual. Topotecano e hoje uma opcao efectiva e bem tolerada no tratamento em segunda linha do CPPC. Ha um aumento significativo da sobrevivencia mediana versus a terapeutica sintomatica. A sua eficacia e comparavel ao classico regimen CAV. Mostra boa tolerabilidade mesmo quando administrado em doentes idosos, com PS=2. Continua a ser bem tolerado e eficaz quando combinado com a radioterapia holocraniana cerebral ou quando administrado num esquema semanal. Com novas classes de farmacos, como agentes antiangiogenicos como o bevacizumab, inibidores da tirosina quinase e talidomida, decorrem ensaios avaliando a sua associacao com a classica quimioterapia em doentes com CPPC disseminada.

Primary pulmonary melanoma: the unexpected tumour

A 62-year-old woman was referred to our pulmonology team with exertional dyspnoea and chest tightness of 2 months duration. Her medical history included cervical cancer and thyroid nodules. Imaging studies showed collapse of left upper lobe. Fiberoptic bronchoscopy unveiled an endoluminal lesion and bronchial biopsy displayed features of melanoma. She denied a history of melanoma or excision of lesions of skin, mucous membranes or the eye. A thorough evaluation including combined positron emission tomography with CT scan excluded other possible sites of primary melanoma, but there was a metastasis in a thoracic vertebra. Palliative radiotherapy of the spine was performed. Chemotherapy initiation with dacarbazine was postponed by the appearance of a malignant pleural effusion, confirmed by pleural fluid cytology. After four cycles chemotherapy was discontinued due to disease progression. The patient is still alive with a follow-up of 12 months, currently on best supportive care.

Pneumonia associada aos cuidados de saúde versus pneumonia adquirida na comunidade: entidades diferentes, abordagens distintas

Healthcare-associated pneumonia (HCAP) is now identified as a unique entity that differs from community-acquired pneumonia (CAP), and in many ways is similar to nosocomial pneumonia (NP). Patients with the diagnosis of CAP and HCAP admitted to our Pneumology Unit during one year were retrospectively analysed. The objective was to compare the characteristics and the approach of these two entities. 197 patients were included, 144 with CAP and 53 with HCAP. Sex, age, comorbilities, Pneumonia Severity Index (PSI) score, radiological involvement, bacteriology, treatment and outcomes were analysed in the 2 groups. Compared to CAP, HCAP was associated with more severe disease, a higher mortality rate and greater length of hospitalization. HCAP differed from CAP mainly in bacteriology and outcomes.

Pemetrexed em segunda linha no carcinoma do pulmão de não pequenas células

Non small cell lung cancer (NSCLC), which is the leading cause of cancer mortality, is accounts for 85% of all cases of lung cancer. The majority of NSCLC patients present with advanced, unresectable disease. In advanced disease, chemotherapy with platinun (cisplatin or carbo-platin) in combination with a third-generation cytotoxic drug (gemcitabine, vinorelbine, paclitaxel or docetaxel) can provide a modest improvement in survival with quality of life. Response rates of 20%-40% can be expected with a median survival of 8-10 months and a 1 year survival rate of 30% - 40%. Pemetrexed, a multitargeted antifolate agent, has shown clear activity in mesothelioma and NSCLC. In a phase III trial, second line treatment with pemetrexed demonstrated overall survival comparable to docetaxel with a more manageable toxicity profile. Single agent pemetrexed have shown well tolerate in elderly patients, in combination with radiotherapy where we can use full dose pemetrexed. In second line, in nonsquamous NSCLC pemetrexed administrated with folic acid and vitamin B12, has a significant superior survival compared with docetaxel (9.3 vs 8.0 months). Rev Port Pneumol 2008; XIV (Sup.2): S21-S26

Pemetrexed na segunda linha de tratamento do carcinoma do pulmão de não pequenas células – A experiência portuguesa

Until 2004, docetaxel in monotherapy was the standard for second-line treatment of non-small cell lung cancer (NSCLC). Pemetrexed (P) has shown similar activity in this setting with a better adverse event profile. In Portugal, it was introduced in October of 2004. We have carried out a retrospective analysis of patients (pts) who received P for second-line NSCLC in Portugal from October 2004 to December 2006. Data were collected from the records of pts with locally advanced or metastatic NSCLC and failed first-line chemotherapy enrolled in centers participating in the Portuguese Lung Cancer Study Group (GECP). Objective response (OR; complete [CR] or partial [PR] response) was evaluated using RECIST and safety was assessed using serious or non-serious adverse events (SAEs/AEs). By December 2006, 19 GECP centers had enrolled 244 pts who had received P for ≥1cycle, and were considered evaluable for both objective response and safety. Demography: male/female, 175/69; median age, 57.0years (range 20-81); smoking status, y/ex/n, 116/57/71; adenocarcinoma / squamous-cell carcinoma/other histology, 141/72/31; mean time to progression (TTP) 8.07months. Disease control in 209 evaluable pts was observed in 116 (55.5%): 2 CR, 45 PR and 69 SD; mean TTP 4.70months. The majority of AEs were grade 3 anemia (15 pts) and neutropenia (18 pts). The mean overall survival was 17.27months. Our retrospective analysis has observed a similar disease control rate with P in 2nd line (55.5%), and TTP (4.7months) in our current unselected population to that published in the literature. P is an option for second-line NSCLC with a good tolerability. Rev Port Pneumol 2008; XIV (Sup.2): S9-S20.