Patterns of Progression and Feasibility of Re-biopsy After First-line Erlotinib for Advanced EGFR Mutation-positive Non-small-cell Lung Cancer.

AIM: To assess the patterns of disease progression in advanced/metastatic epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) on first-line treatment with erlotinib and identify potential prognostic factors for progression-free survival (PFS). PATIENTS AND METHODS: Patients with stage IIIB/IV EGFR-mutation-positive NSCLC receiving first-line erlotinib were followed-up until 24 months after the last patient was enrolled or until premature withdrawal for any cause. RESULTS: A total of 127 evaluable patients were enrolled. The median PFS and overall survival were 8.8 and 19.1 months, respectively. Disease progression was asymptomatic in 57.6% of patients and 53.3% developed new sites of metastasis. The presence of liver metastasis was identified as an independent prognostic factor for poor PFS. CONCLUSION: Metastatic progression with asymptomatic disease seems to be the predominant pattern of disease progression on first-line erlotinib in real-life practice in patients with advanced/metastatic EGFR-mutant NSCLC. Additionally, the presence of liver metastases may negatively affect PFS in these patients.

[Evidence on afatinib in patients progressing on a first-line treatment]. / Evidencia de afatinib en pacientes que progresan a un tratamiento de primera línea.

After description of the importance of EGFR mutations in non-small cell lung cancer and confirmation that tyrosine-kinase inhibitors are more beneficial than chemotherapy in patients with EGFR+ tumours, treatment with one of these drugs has become the standard recommendation. Despite this advance, patients continue to progress and consequently there is a need to search for alternative treatments. Some studies have analysed afatinib activity after first-generation TKI therapy, as well as its administration in combination with conventional chemotherapy. Afatinib produces significant response rates and progression-free survival times after the development of clinical resistance, which are independent of the presence of the T790M resistance mutation and can be attributed to continued pan-HER inhibition. In addition to the initial clinical trial, LUX-LUNG-1, data are available from the use of afatinib in routine clinical practice, within extended use programs. Overall, response rates of between 7 and 15% can be expected with a duration of approximately 24 months and a median progression-free time of about 4 months. A study combining afatinib with cetuximab has obtained a high response rate. Afatinib toxicity in second-line treatment is similar to that appears when the drug is used as first-line therapy (mainly mucocutaneous and diarrhoea) and can be managed with routine measures. In conclusion, afatinib should be considered as a treatment option in patients with EGFR mutations who show disease progression after a first tyrosine-kinase inhibitor.

Evidencia de afatinib en pacientes que progresan a un tratamiento de primera línea / Evidence on afatinib in patients progressing on a first-line treatment

Tras la descripción de la importancia de las mutaciones en EGFR en el carcinoma de pulmón no microcítico y una vez comprobado que los inhibidores de la tirosincinasa superan el beneficio producido por quimioterapia en pacientes con tumores EGFR+, el tratamiento con uno de estos fármacos se ha convertido en la recomendación estándar. A pesar de este avance, los pacientes acaban progresando, por lo que es necesario buscar alternativas de tratamiento. Existen estudios que han analizado la actividad de afatinib después de un tratamiento con un inhibidor de la tirosincinasa de primera generación e incluso de la administración también de quimioterapia convencional. Produce una tasa de respuestas y un tiempo de control de la enfermedad significativos tras la aparición de resistencia clínica, que son independientes de la existencia de la mutación de resistencia T790M y que podemos atribuir a mantener el control pan-HER. Además del ensayo clínico inicial, LUX-Lung 1, tenemos datos de utilización en la práctica clínica habitual dentro de programas de uso expandido. En conjunto, podemos esperar tasas de respuesta de entre el 7 y el 15% con una duración de alrededor de 24 semanas y una mediana del tiempo hasta progresión de unos 4 meses. Un estudio que lo combina con cetuximab ha obtenido una alta tasa de respuestas. La toxicidad de afatinib en segunda línea es semejante a cuando se utiliza en primera (fundamentalmente mucocutánea y diarreas) y manejable con las medidas habituales. En conjunto hay que considerar afatinib como una opción de tratamiento en pacientes con mutación de EGFR que progresan tras un primer inhibidor de la tirosincinasa (AU)

After description of the importance of EGFR mutations in non-small cell lung cancer and confirmation that tyrosine-kinase inhibitors are more beneficial than chemotherapy in patients with EGFR+ tumours, treatment with one of these drugs has become the standard recommendation. Despite this advance, patients continue to progress and consequently there is a need to search for alternative treatments. Some studies have analysed afatinib activity after first-generation TKI therapy, as well as its administration in combination with conventional chemotherapy. Afatinib produces significant response rates and progression-free survival times after the development of clinical resistance, which are independent of the presence of the T790M resistance mutation and can be attributed to continued pan-HER inhibition. In addition to the initial clinical trial, LUX-LUNG-1, data are available from the use of afatinib in routine clinical practice, within extended use programs. Overall, response rates of between 7 and 15% can be expected with a duration of approximately 24 months and a median progression-free time of about 4 months. A study combining afatinib with cetuximab has obtained a high response rate. Afatinib toxicity in second-line treatment is similar to that appears when the drug is used as first-line therapy (mainly mucocutaneous and diarrhoea) and can be managed with routine measures. In conclusion, afatinib should be considered as a treatment option in patients with EGFR mutations who show disease progression after a first tyrosine-kinase inhibitor (AU)

Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.

BACKGROUND: Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population. METHODS: In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993. FINDINGS: Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7-16·4) for atezolizumab versus 9·7 months (8·6-12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53-0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event. INTERPRETATION: Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy. FUNDING: F Hoffmann-La Roche/Genentech Inc.

Adjuvant chemotherapy in non-small cell lung cancer: state-of-the-art.

Adjuvant chemotherapy (AC) plays now a significant role in the treatment of resected non-small cell lung cancer (NSCLC) patients and has become standard in clinical practice. It took more than two decades of clinical research to show its value, but it is has been well established that its benefit translates into a 4-5% absolute increase in 5-year survival according to published meta-analysis. This improvement is obtained with two-drug, Cisplatin-based regimens (multiples choices are acceptable but vinorelbine is the drug with more reported evidence) and usually four courses are recommended. Survival increase is restricted to cases in which there is involvement of lymph nodes (both N1 and N2 levels). For N0 cases AC might be considered, with a lower level of evidence, for tumors larger than 4 cm in diameter. At the present time, molecular predictive factors and gene signatures are investigational. Patient selection is of paramount importance. Proper recovery from surgery and the absence of major comorbidities are essential features. Toxicity is significant, but manageable and transient. Neutropenia is the most relevant side effect due to the risk of febrile neutropenia. The role of timing of administration, adjuvant radiotherapy (RT) and of newer drugs under evaluation is also reviewed.

Heparinas de bajo peso molecular en la profilaxis de episodios tromboembólicos en pacientes con cáncer portadores de catéter venoso central / Role of low molecular weight heparins in prophylaxis of thromboembolic events on oncological patients with indwelling central venous catheter

Fundamento y objetivo: Este estudio pretende analizar la incidencia de trombosis de extremidades superiores y de embolia pulmonar en pacientes oncológicos portadores de catéter venoso central, así como valorar si las heparinas de bajo peso molecular (HBPM) podrían ser útiles en prevenir este tipo de episodios. Pacientes y método: Pacientes oncológicos portadores de catéter tipo porth a cath se trataron con bemiparina o no de forma no aleatorizada; se realizó seguimiento clínico y radiológico mediante flebografía el día 1 y ecografía Doppler los días 1, 45 y 90 tras la implantación. Se determinó la incidencia de trombosis en pacientes con o sin tratamiento con bemiparina sódica (3.500 U/día) y su relación con posibles factores de riesgo. Resultados: Se encontraron 19 episodios trombóticos en 148 pacientes elegibles: el 5,41% de trombosis venosa profunda de extremidad superior sintomática y el 2,03% asintomática; un caso de embolia pulmonar (0,68%); el 2,70% de disfunción del catéter, y el 2,03% de trombosis de extremidades inferiores. Hubo mayor porcentaje de episodios trombóticos en el grupo de tratamiento con HBPM (15,5%) que en el grupo sin profilaxis (9,4%); la diferencia no fue significativa (p=0,272). Los únicos factores de riesgo significativos fueron el tiempo de protrombina, la hipertensión arterial y el sobrepeso. Conclusiones: La colocación de catéteres venosos centrales es una técnica de gran utilidad, con bajo porcentaje de complicaciones trombóticas clínicamente manifiestas. La bemiparina sódica no presenta una relación favorable para disminuir el riesgo de trombosis en estos enfermos (AU)

Background and objective: Our study was designed to assess the incidence of thrombosis in the upper limbs and of pulmonary embolism in oncological patients with indwelling central venous catheters, and to evaluate, also, the potential role of LMWH to prevent these events. Patients and methods: Oncological patients undergoing placement of a central venous acccess (port-a-cath type) were treated with or without bemiparin in a non-randomized fashion. Assessment included clinical and radiological follow-up. A phlebography on the first day and ecodoppler on days 1th, 45th and 90th were performed. Patients received or not prophylactic bemiparin (3500UI/day) in a non-randomized way. The incidence of thrombosis in both groups was assessed as well as its relation with some risk factors. Results: One hundred and forty eight patients were eligible; 19 thrombotic events were found. The incidence of symptomatic upper extremity thrombosis was 5.41%, asymptomatic thrombosis in 2.03% ; there was one case of pulmonary embolism ( 0,68%); catheter failure occurred in 2.70%; incidence of lower extremities deep venous thrombosis was 2.03%. There was a higher percentage of events in the group of patients treated with bemiparin than in the not treated individuals (9.4%), although the difference did not reach statistical significance (p=0.27). The only risk factors reaching statistical significance were the prothrombin time, high blood pressure and overweight. Conclusions: Central venous catheters are very useful in oncology. The procedure was related with a low percentage of thrombotic complications. Sodic bemiparin does not reduce the thrombotic risk in these patients (AU)

[Role of low molecular weight heparins in prophylaxis of thromboembolic events on oncological patients with indwelling central venous catheter]. / Heparinas de bajo peso molecular en la profilaxis de episodios tromboembólicos en pacientes con cáncer portadores de catéter venoso central.

BACKGROUND AND OBJECTIVE: Our study was designed to assess the incidence of thrombosis in the upper limbs and of pulmonary embolism in oncological patients with indwelling central venous catheters, and to evaluate, also, the potential role of LMWH to prevent these events. PATIENTS AND METHODS: Oncological patients undergoing placement of a central venous acccess (port-a-cath type) were treated with or without bemiparin in a non-randomized fashion. Assessment included clinical and radiological follow-up. A phlebography on the first day and ecodoppler on days 1th, 45th and 90th were performed. Patients received or not prophylactic bemiparin (3500UI/day) in a non-randomized way. The incidence of thrombosis in both groups was assessed as well as its relation with some risk factors. RESULTS: One hundred and forty eight patients were eligible; 19 thrombotic events were found. The incidence of symptomatic upper extremity thrombosis was 5.41%, asymptomatic thrombosis in 2.03% ; there was one case of pulmonary embolism ( 0,68%); catheter failure occurred in 2.70%; incidence of lower extremities deep venous thrombosis was 2.03%. There was a higher percentage of events in the group of patients treated with bemiparin than in the not treated individuals (9.4%), although the difference did not reach statistical significance (p=0.27). The only risk factors reaching statistical significance were the prothrombin time, high blood pressure and overweight. CONCLUSIONS: Central venous catheters are very useful in oncology. The procedure was related with a low percentage of thrombotic complications. Sodic bemiparin does not reduce the thrombotic risk in these patients.

[Novel therapeutic targets in metastatic renal cell carcinoma. Results of the treatment with single-agent bevacizumab in a single institution]. / Nuevas dianas terapéuticas para el carcinoma de células renales metastásico. Resultados del tratamiento con bevacizumab en monoterapia en un único centro hospitalario.

AIM: Along the past decade a number of new agents have been developed showing promising results in the treatment of metastatic renal cell carcinoma. We describe our experience with the use of bevacizumab in monotherapy in the Urology and Medical Oncology departments of our institution. MATERIAL AND METHODS: A consecutive series of patients treated with Bevacizumab 10 mg/Kg every 14 days between January 2006 and January 2008 has been assessed. Data concerning the type of surgery, histological subtype, tumor stage, Motzer's risk group, metastatic sites number of bevacizumab courses given, time to progression and overall survival were collected. RESULTS: 25 patients (16 male, 9 female) were analyzed. Median age was 59 years. Nineteen of them (75%) had prior surgery: radical nephrectomy 14, cytoreductive 4 y tumorectomy 1). Clear cell carcinoma was the most frequent subtype (22 patients). According to Motzer's prognostic index 14 had good prognosis, 8 intermediate and 3 poor prognosis. Median time to progression was 19 weeks. Overall median survival since metastatic disease was diagnosed 8,7 months. CONCLUSIONS: Bevacizumab offers, as single agent, modest activity in the metastatic renal cell carcinoma. The recently labeled use in combination with interferon as well as the newer targeted agents will improve the results of the treatment of this disease in the next future.

Nuevas dianas terapéuticas para el carcinoma de células renales metastásico. Resultados del tratamiento con bevacizumab en monoterapia en un único centro hospitalario / Novel therapeutic targets in metastatic renal cell carcinoma. Results of the treatment with single-agent bevacizumab in a single institution

Objetivos: En la última década se están desarrollando multitud de nuevas moléculas que ofrecen resultados esperanzadores para el tratamiento del CCR metastásico. Este estudio describe nuestra experiencia en 25 pacientes tratados con bevacizumab en monoterapia. Material y métodos: Se analizan los resultados obtenidos en 25 pacientes con CCR metastásico tratados con Bevacizumab (10 mg/Kg quincenal) entre enero del 2006 y enero del 2008. Se recogieron datos acerca del tipo de cirugía practicada, tipo histológico, estadio tumoral, grupo de riesgo de Motzer, localizaciones metastásicas, número de ciclos administrados, tiempo hasta la progresión y supervivencia global. Resultados: Se analizaron 25 pacientes (16 varones y 9 mujeres), con una mediana de edad de 59 años. Más de la mitad de ellos (19) se había sometido a algún tipo de intervención quirúrgica (14 nefrectomía radical, 4 citorreductora y 1 tumorectomía). La mayor parte de los enfermos presentaban histología de células claras (22). 14 pacientes pertenecían al grupo de buen pronóstico de Motzer, 8 al grupo de pronóstico intermedio y 3 al de mal pronóstico. La mediana de tiempo hasta la progresión fue de 19 semanas, con una mediana de supervivencia global desde el inicio de tratamiento de 8,7 meses. Conclusiones: El bevacizumab en monoterapia ofrece unos resultados modestos para el tratamiento del CCR metastásico. Su reciente aprobación en combinación con Interferon, y la aparición progresiva de distintas dianas terapéuticas, permitirá optimizar los resultados en los próximos años (AU)

Aim: Along the past decade a number of new agents have been developed showing promising results in the treatment of metastatic renal cell carcinoma. We describe our experience with the use of bevacizumab in monotherapy in the Urology and Medical Oncology departments of our institution. Material and methods: A consecutive series of patients treated with Bevacizumab 10 mg/Kg every 14 days between January 2006 and January 2008 has been assessed. Data concerning the type of surgery, histological subtype, tumor stage, Motzer’s risk group, metastatic sites number of bevacizumab courses given, time to progression and overall survival were collected. Results: 25 patients (16 male, 9 female) were analyzed. Median age was 59 years. Nineteen of them (75%) had prior surgery: radical nephrectomy 14, cytoreductive 4 y tumorectomy 1). Clear cell carcinoma was the most frequent subtype (22 patients). According to Motzer’s prognostic index 14 had good prognosis, 8 intermediate and 3 poor prognosis. Median time to progression was 19 weeks. Overall median survival since metastatic disease was diagnosed 8,7 months. Conclusions: Bevacizumab offers, as single agent, modest activity in the metastatic renal cell carcinoma. The recently labeled use in combination with interferon as well as the newer targeted agents will improve the results of the treatment of this disease in the next future (AU)

Retrospective study of efficacy and toxicity on patients older than 70 years within a randomized clinical trial of two cisplatin-based combinations in patients with small-cell lung cancer.

A retrospective analysis based on the Spanish Lung Cancer Group (SLCG) clinical trial of high-dose epirubicin/cisplatin in patients with small-cell lung cancer (SCLC) was performed. Patients younger than 70 years vs. older than 70 years old were analyzed to evaluate the influence of age on response to treatment, toxicity, time to progression (TTP) and overall survival (OS) of the chemotherapy schedule. Three hundred and thirty eight patients <70 years and sixty-four >70 years, were analyzed. Objective responses were similar in both groups. In patients less than 70 years higher TTP (36 weeks vs. 32 weeks) and OS (47 weeks vs. 42 weeks) were seen, attributable to the improved results observed in the subgroup of patients with limited disease (LD). No significant differences were observed when toxicity profile of both groups was compared, except for a higher rate of febrile neutropenia observed in the elderly group with extensive disease (4.6% vs. 8.8%, p=0.01). In the subgroup of patients with LD, elderly patients received less total cisplatin dose (401 vs. 508 mg/m(2), p=0.01) although less treatment delays were reported (10 days vs. 15 days, p=0.05). Age was likely to be a negative prognostic factor for OS of elderly patients with LD. It also seemed to be related to a greater dose reduction, which may explain that toxic episodes and delays occurred more frequently in the younger patients receiving the full scheduled dose. However, the definitive reason to explain this could not be established due to the characteristics of our analysis.

Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.

BACKGROUND: Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer (NSCLC) is not known. We aimed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC. METHODS: 840 patients with stage IB-IIIA NSCLC from 101 centres in 14 countries were randomly assigned to observation (n=433) or to 30 mg/m(2) vinorelbine plus 100 mg/m(2) cisplatin (n=407). Postoperative radiotherapy was not mandatory and was undertaken according to every centre's policy. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN95053737. FINDINGS: 367 patients in the chemotherapy group and 431 in the control group received their assigned treatment. 301 (36%) patients had stage IB disease, 203 (24%) had stage II disease, and 325 (39%) had stage IIIA disease. Tolerance to chemotherapy mainly included neutropenia in 335 (92%) patients and febrile neutropenia in 34 (9%); seven (2%) toxic deaths were also recorded. Compliance was greater with cisplatin than with vinorelbine (median dose intensity 89% [range 17-108] vs 59% [17-100]). After a median follow-up of 76 months (range 43-116), median survival was 65.7 months (95% CI 47.9-88.5) in the chemotherapy group and 43.7 (35.7-52.3) months in the observation group. Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls (hazard ratio 0.80 [95% CI 0.66-0.96]; p=0.017). Overall survival at 5 years with chemotherapy improved by 8.6%, which was maintained at 7 years (8.4%). INTERPRETATION: Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy.

Serum markers and prognosis in locally advanced breast cancer.

BACKGROUND: Locally advanced breast cancer (LABC) represents a heterogeneous subgroup of breast cancer with an often dismal outcome. Identifying prognostic factors has acquired great significance for the selection of optimal treatment in individual patients. METHODS: Between January 1993 and December 1997, 103 patients were treated in our institution with multimodality treatment consisting of neoadjuvant chemotherapy followed by surgery, adjuvant chemotherapy and radiotherapy; tamoxifen was added in hormone receptor-positive cases. In the search for prognostic factors well-established parameters (clinical, pathological and treatment-related) as well as new features with potential value (c-erbB-2, baseline serum levels of CA 15.3 and CEA) were included in the univariate and multivariate analysis. RESULTS: At a median follow-up of 92 months (range, 8-130), the estimated five-year cancer-specific overall survival (OS) and disease-free survival (DFS) were 71.34% and 57.7%, respectively. Among the 22 different variables studied, only 10 were significantly correlated with OS and DFS. In multivariate analysis five retained independent prognostic value for both OS and DFS: tumor grade, serum markers, features of inflammatory breast cancer (IBC), response to neoadjuvant chemotherapy and lymph node status. With cutoff values of 35 U/mL for CA 15.3 and 5 ng/mL for CEA, the probability of five-year OS (Cox hazard ratio 3.91, P = 0.0009) and DFS (Cox hazard ratio 2.40, P = 0.02) decreased from 78% to 52% and from 68% to 47%, respectively, when at least one of these markers was abnormal. CONCLUSIONS: Baseline serum levels of CEA and CA 15.3 emerged from this study as strong independent predictors of outcome in LABC, whose value adds to other established prognostic factors such as postoperative nodal status, IBC, histological grade and response to neoadjuvant chemotherapy.

Prospective randomized phase III trial of etoposide/cisplatin versus high-dose epirubicin/cisplatin in small-cell lung cancer.

High-dose epirubicin plus cisplatin was compared with the reference regimen of etoposide/cisplatin in small-cell lung cancer (SCLC). Four hundred two previously untreated patients with SCLC were randomized to receive etoposide 100 mg/m(2) on days 1-3 and cisplatin 100 mg/m(2) on day 1 or epirubicin 100 mg/m(2) and cisplatin 100 mg/m(2) on day 1 every 21 days for a total of 6 cycles. Patients were stratified according to treatment center and extent of disease (limited disease, n = 207; extensive disease, n = 195). Patients with limited disease were treated with thoracic radiation therapy after completion of chemotherapy, and those who exhibited a complete response were advised to receive prophylactic cranial irradiation. The primary endpoint was survival, and secondary endpoints were time to progression (TTP), response, toxicity, and costs. Patient characteristics were generally well balanced in the 2 arms, even though more patients in the epirubicin/cisplatin arm had > 5% weight loss and poor Karnofsky performance index compared with the etoposide/cisplatin arm. One hundred thirty-four patients (66.3%) in the etoposide/cisplatin arm and 126 (63.0%) in the epirubicin/cisplatin arm received all 6 planned cycles of chemotherapy. Response rate, TTP, and survival did not differ significantly between the 2 arms. Grade 3/4 neutropenia and toxic deaths occurred more frequently in the etoposide/cisplatin arm. Epirubicin/cisplatin showed a similar activity with a slightly lower toxicity profile than the reference regimen of etoposide/cisplatin. The epirubicin/cisplatin regimen may be recommended in the treatment of SCLC.

Increasing-dose gemcitabine plus low-dose cisplatin in metastatic non-small cell lung cancer.

UNLABELLED: Gemcitabine, a pyrimidine analog active in non-small cell lung cancer (NSCLC), is widely used with cisplatin. The potential activity of the combination has not been fully assessed: gemcitabine is not used at its maximum tolerated dose (MTD) and cisplatin shows a clearly dose-related toxicity. This trial was designed to assess the MTD and dose-limiting toxicity (DLT) of low-dose cisplatin and increasing gemcitabine dose. CHEMOTHERAPY: cisplatin 50 mg/m2 on day 1, gemcitabine starting at 1400 mg/m on days 1 and 8 every 21 days. Subsequent levels were increased by 200 mg/m2. Forty-two patients with metastatic NSCLC were enrolled (37 males; median age 61 years; squamous cell carcinoma 19 patients; performance status 2, in 13 patients; 18 patients had significant weight loss). MTD was found to be 2600 mg/m2 because of DLT in three of six patients: two neutropenic fever and one massive bleeding. Overall toxicity was generally mild consisting mainly of neutropenia. Asthenia was the most common non-hematological effect. Overall response rate was 19 out of 41 patients (46.3%) and median survival was 31 weeks. We conclude that the recommended dose for a phase II dose is gemcitabine 2400 mg/m2 days 1 and 8 as a 30-min infusion when given with cisplatin 50 mg/m2.