José Maestre

A Randomized Trial Comparing Preoperative Chemotherapy Plus Surgery with Surgery Alone in Patients with Non-Small-Cell Lung Cancer

BACKGROUND The efficacy of surgery for patients with non-small-cell lung cancer is limited, although recent studies suggest that preoperative chemotherapy may improve survival. We conducted a randomized trial to examine the possible benefit of preoperative chemotherapy and surgery for the treatment of patients with non-small-cell lung cancer. METHODS We studied 60 patients (59 men and 1 woman) with stage IIIA non-small-cell lung cancer. The patients were randomly assigned to receive either surgery alone or three courses of chemotherapy (6 mg of mitomycin per square meter of body-surface area, 3 g of ifosfamide per square meter, and 50 mg of cisplatin per square meter) given intravenously at three-week intervals and followed by surgery. All patients received mediastinal radiation after surgery. The resected tumors were evaluated by means of K-ras oncogene analysis and flow cytometry. RESULTS The median period of survival was 26 months in the patients treated with chemotherapy plus surgery, as compared with 8 months in the patients treated with surgery alone (P < 0.001); the median period of disease-free survival was 20 months in the former group, as compared with 5 months in the latter (P < 0.001). The rate of recurrence was 56 percent in the group treated with chemotherapy plus surgery and 74 percent in the group treated with surgery alone. The prevalence of mutated K-ras oncogenes was 15 percent among the patients receiving preoperative chemotherapy and 42 percent among those treated with surgery alone (P = 0.05). Most of the patients treated with chemotherapy plus surgery had tumors that consisted of diploid cells, whereas the patients treated with surgery alone had tumors with aneuploid cells. CONCLUSIONS Preoperative chemotherapy increases the median survival in patients with non-small-cell lung cancer.

A Novel Anti-Apoptosis Gene: Re-expression of Survivin Messenger RNA as a Prognosis Marker in Non–Small-Cell Lung Cancers

PURPOSE The survivin gene is a novel apoptosis inhibitor, related to the baculovirus gene, which is believed to play a pivotal role in fetal development and in cancer. We hypothesised that survivin would be expressed in tumors of patients with non-small-cell lung cancer (NSCLC), and we attempted to determine the influence of survivin re-expression on clinical outcome in patients with up to stage IIIA NSCLC who had undergone radical surgery. METHODS We designed a reverse transcriptase polymerase chain reaction (RT-PCR) assay to study the expression of the survivin gene in 83 NSCLC tumor samples and compared the results with relevant clinical and pathologic data. RESULTS The RT-PCR identified survivin gene transcript in 71 (85. 5%) of the tumor samples and in only 10 (12%) of the paired, histopathologically normal lung samples. There was no relationship between histologic subtype (squamous v nonsquamous) and survivin gene expression. The 12 patients without survivin expression had significantly better overall survival than the 71 patients with survivin expression (P =.01 by univariate analysis; relative risk, 2. 1). There was no significant correlation between survivin expression and age, sex, cigarette smoking, histologic subtype, tumor differentiation, tumor size, or the presence of mediastinal lymph node metastases in surgical specimens. CONCLUSION The survivin gene was expressed in a vast majority of NSCLC tumors. We conclude that survivin transcript is a defining diagnostic marker for NSCLC that may also yield prognostic information and, as an apoptosis inhibitor, be an important target in cancer therapy.

Preresectional chemotherapy in stage IIIA non-small-cell lung cancer : a 7-year assessment of a randomized controlled trial

In 1989, we began a multicenter study to evaluate the potential benefit of preoperative chemotherapy with cisplatin, ifosfamide and mitomycin over surgery alone in CT-visible N2 non-small-cell lung cancer. We present here a 7-year assessment of this randomized trial. Sixty patients were randomized to receive either surgery alone or three cycles of mitomycin 6 mg/m2, ifosfamide 3 g/m2 and cisplatin 50 mg/m2, given intravenously on day 1 of each cycle at 3-week intervals and followed by surgery. All patients received thoracic irradiation after surgery. The resected tumors were evaluated for the presence of K-ras gene point mutations. Treatment arms were well-balanced in characteristics such as gender, age, histology, and tumor size. Mediastinoscopy and/or mediastinotomy (Chamberlain procedure) with a biopsy was performed in all patients with N2 stage detected by CT scan of the chest (83% of the patients in the preresectional chemotherapy arm and 63% of those in the surgery arm). In eight of the 25 patients (32%) who had mediastinoscopy in the preresectional chemotherapy arm, the initially positive mediastinal lymph nodes were downstaged. For the 30 patients who received preresectional chemotherapy, overall median survival was 22 months (95% CI, 13.4 30.6). Of the 30 patients who received surgery alone, overall median survival was 10 months (95% CI, 7.4-12.6; P = 0.005 by the log rank test). Updated survival data reveals a plateau in the preresectional chemotherapy group, and this still significant long-term survival benefit prompts us to hypothesize that even with short-term preresectional chemotherapy, the natural history of still resectable CT-visible N2 non-small cell lung cancer is favorably altered. The results of our study mirror the long-term survival recently reported in the MD Anderson randomized study.

Preoperative Chemotherapy Plus Surgery Versus Surgery Plus Adjuvant Chemotherapy Versus Surgery Alone in Early-Stage Non–Small-Cell Lung Cancer

PURPOSE To address whether preoperative chemotherapy plus surgery or surgery plus adjuvant chemotherapy prolongs disease-free survival compared with surgery alone among patients with resectable non-small-cell lung cancer. PATIENTS AND METHODS In this phase III trial, 624 patients with stage IA (tumor size > 2 cm), IB, II, or T3N1 were randomly assigned to surgery alone (212 patients), three cycles of preoperative paclitaxel-carboplatin followed by surgery (201 patients), or surgery followed by three cycles of adjuvant paclitaxel-carboplatin (211 patients). The primary end point was disease-free survival. RESULTS In the preoperative arm, 97% of patients started the planned chemotherapy, and radiologic response rate was 53.3%. In the adjuvant arm, 66.2% started the planned chemotherapy. Ninety-four percent of patients underwent surgery; surgical procedures and postoperative mortality were similar across the three arms. Patients in the preoperative arm had a nonsignificant trend toward longer disease-free survival than those assigned to surgery alone (5-year disease-free survival 38.3% v 34.1%; hazard ratio [HR] for progression or death, 0.92; P = .176). Five-year disease-free survival rates were 36.6% in the adjuvant arm versus 34.1% in the surgery arm (HR 0.96; P = .74). CONCLUSION In early-stage patients, no statistically significant differences in disease-free survival were found with the addition of preoperative or adjuvant chemotherapy to surgery. In this trial, in which the treatment decision was made before surgery, more patients were able to receive preoperative than adjuvant treatment.

Gene Expression as a Predictive Marker of Outcome in Stage IIB-IIIA-IIIB Non-Small Cell Lung Cancer After Induction Gemcitabine-Based Chemotherapy Followed By Resectional Surgery

Purpose: The first suggestions of a relationship between gene mRNA expression and differential sensitivity to gemcitabine/cisplatin are now emerging. ERCC1, RRM1, and XPD are involved in the nucleotide excision repair pathways, and tumor up-regulation of these genes leads to chemotherapy failure. In the present study, we have examined the potential correlation and predictive value of ERCC1, RRM1, and XPD mRNA expression in resected specimens from 67 stage IIB, IIIA, and IIIB non-small cell lung cancer patients treated with neoadjuvant gemcitabine/platinum followed by surgery Experimental Design: ERCC1, RRM1, and XPD expression was quantified using real-time quantitative reverse transcription-PCR. Results: A good correlation was found between mRNA expression levels of the three genes. For RRM1 levels, patients in the bottom quartile had a decreased risk of death compared with those in the top quartile (risk ratio = 0.30; P = 0.033). Median survival for the 17 patients in the bottom quartile was 52 months, whereas for the 15 in the top quartile, it was 26 months (P = 0.018). When the characteristics of these 17 patients were compared with all of the other 50 patients, no differences in initial staging were observed. However, the 17 patients in the bottom quartile had better outcomes, including more radiographic responses (65% versus 54%; P = 0.24), complete resections (94% versus 72%; P = 0.03), lobectomies (71% versus 34%; P = 0.004), and pathological complete responses (29% versus 0%; P = 0.00001) Conclusions: Patients with RRM1 levels in the bottom quartile benefited significantly from gemcitabine/cisplatin neoadjuvant chemotherapy, leading us to conclude that RRM1 mRNA levels should be additionally validated to proceed with tailored chemotherapy.

Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors

BACKGROUND Aspergillus infection remains a major cause of morbidity and mortality after lung transplantation. Therefore, some strategies have been attempted, one of which is nebulized amphotericin B (nAB); however, the efficacy of this prophylaxis has not been shown clearly. The aim is to study whether nAB can protect against Aspergillus infection in lung transplant recipients. PATIENTS AND METHODS A study of risk factors was conducted in 55 consecutive lung allograft recipients. Twenty-three potential risk factors were analyzed. In 44 (80%) patients, nAB was indicated as prophylaxis. Multivariate analysis using logistic regression was performed. RESULTS Eighteen of the 55 patients (33%) developed infection due to Aspergillus spp. Multivariate analysis showed nAB to be a preventive factor (odds ratio: 0.13; 95% confidence interval [CI] 0.02-0.69; p < 0.05) and cytomegalovirus (CMV) disease was an independent risk factor for developing Aspergillus infection (odds ratio: 5.1; 95% CI 1.35-19.17; p < 0.05). Only 1 patient required withdrawal of the prophylaxis owing to bronchospasm. nAB was well-tolerated in the remaining patients with only a few, mild, easily controlled side effects. CONCLUSIONS The present results show that nAB prophylaxis may be efficient and safe in preventing Aspergillus infection in lung-transplanted patients, and CMV disease increases the probability of Aspergillus infection.

Donor-to-host transmission of bacterial and fungal infections in lung transplantation.

The purpose of this study was to evaluate the incidence and etiology of bacterial and fungal infection or contamination in lung allograft donors and to assess donor‐to‐host transmission of these infections. Recipients who survived more than 24 h and their respective donors were evaluated. The overall incidence of donor infection was 52% (103 out of 197 donors). Types of donor infection included isolated contamination of preservation fluids (n = 30, 29.1%), graft colonization (n = 65, 63.1%) and bacteremia (n = 8, 7.8%). Donor‐to‐host transmission of bacterial or fungal infection occurred in 15 lung allograft recipients, 7.6% of lung transplants performed. Among these cases, 2 were due to donor bacteremia and 13 to colonization of the graft. Twenty‐five percent of donors with bacteremia and 14.1% of colonized grafts were responsible for transmitting infection. Excluding the five cases without an effective prophylactic regimen, prophylaxis failure occurred in 11 out of 197 procedures (5.58%). Donor‐to‐host transmission of infection is a frequent event after lung transplantation. Fatal consequences can be avoided with an appropriate prophylactic antibiotic regimen that must be modified according to the microorganisms isolated from cultures of samples obtained from donors, grafts, preservation fluids and recipients.

The role of chemotherapy in early non-small-cell lung cancer management

Great advances have been made in chemotherapy in advanced and metastatic non-small-cell lung cancer (NSCLC), and a major milestone was reached with the administration of neoadjuvant chemotherapy in stage IIIA N2 disease. The systemic nature of lung cancer has been confirmed by many genetic analyses documenting micrometastases in negative lymph nodes and bone marrow, and mRNA gene overexpression as a surrogate of cancer cells has been identified in peripheral blood. Furthermore, serum or plasma cell-free tumor DNA has been observed even in tumors with a diameter of less than 2 cm. Pharmacogenetic screening can lead to tailored chemotherapy even in patients with early disease through the use of a genetic tool kit that will allow us to optimize the use of chemotherapy by using serial measurements of serum DNA that can help to detect residual disease and re-assess the chemosensitivity of sub-clinical micrometastatic disease. The ongoing (neo)adjuvant taxol/carboplatin hope (NATCH) trial is testing the value of three cycles of chemotherapy given pre- or post-operatively compared with surgery alone and will analyze genetic abnormalities in serum DNA at three different points during patient follow-up. Our major concern in this review is to analyze the pros and cons of chemotherapy in NSCLC. Although this review is not a formal meta-analysis, we have discussed the most relevant published studies in this field. We conclude that not only is there no evidence of detrimental effects of chemotherapy, in fact, there are many indications that chemotherapy induces response in up to 80% of patients and downgrades N2 disease in up to 50% of patients. This translates into significantly better survival when accompanied by complete resection. Since at least 50% of patients with stage IB disease develop distant metastases, it seems logical to explore the role of chemotherapy in early disease.

Experiencia piloto de benchmarking en cirugía torácica: comparación de la casuística e indicadores de calidad en resección pulmonar

Objetivo En el presente articulo se describen los metodos y las conclusiones del primer estudio espanol de benchmarking en cirugia toracica. Los objetivos propuestos fueron: describir la casuistica de reseccion pulmonar desarrollada en 9 hospitales espanoles, comparar indicadores de calidad entre los 9 centros participantes e identificar y proponer areas de mejora comunes para los procesos de reseccion pulmonar. Metodos Se utilizo como fuente de informacion el conjunto minimo basico de datos de los anos 2002 y 2003 de los procesos de lobectomia o neumonectomia. Los indicadores de resultados seleccionados fueron: mortalidad hospitalaria, morbilidad, estancia y readmisiones urgentes en los 30 dias siguientes al alta, ajustadas por complejidad de los casos. Una vez presentados los resultados entre los participantes, se identificaron las unidades con mejores resultados y se discutieron diversas propuestas de mejora. Resultados Se ha estudiado un total de 1.666 procedimientos (1.276 lobectomias y 390 neumonectomias). Se detectaron diferencias en estancia media, mortalidad, tasa de readmisiones y morbilidad, que permitieron identificar unidades, de complejidad equiparable o superior, con baja mortalidad y estancia. Sin embargo, en estas unidades se apreciaron tasas de morbilidad y readmision mas elevadas. Conclusiones Se propusieron medidas encaminadas a registrar todos los diagnosticos relevantes en los informes de alta, disminuir las estancias inadecuadas y estandarizar los procedimientos que permitiran en el futuro establecer criterios fiables para mejorar la calidad de los procesos de reseccion pulmonar.

Isoniazid prophylaxis in lung transplantation

The incidence of tuberculous disease (TD) is higher in lung-transplant patients than in the general population. During a 7-year period, we included 61 patients who underwent lung transplantation in a prospective isoniazid prophylaxis protocol. Isoniazid was prescribed to infected and anergic patients not previously treated when added to the waiting list. Six of 61 patients (10%) developed tuberculosis. We observed no differences in tuberculous disease incidence between infected-anergic and non-infected patients. In our tuberculous-endemic area, isoniazid prophylaxis is safe and offers protection from TD to infected and anergic patients who must be enrolled in a lung transplantation program.