Franz Schramel

Randomized Controlled Trial of Resection Versus Radiotherapy After Induction Chemotherapy in Stage IIIA-N2 Non–Small-Cell Lung Cancer

BACKGROUND Induction chemotherapy before surgical resection increases survival compared with surgical resection alone in patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC). We hypothesized that, following a response to induction chemotherapy, surgical resection would be superior to thoracic radiotherapy as locoregional therapy. METHODS Selected patients with histologic or cytologic proven stage IIIA-N2 NSCLC were given three cycles of platinum-based induction chemotherapy. Responding patients were subsequently randomly assigned to surgical resection or radiotherapy. Survival curves were estimated using Kaplan-Meier analyses from time of randomization. RESULTS Induction chemotherapy resulted in a response rate of 61% (95% confidence interval [CI] = 57% to 65%) among the 579 eligible patients. A total of 167 patients were allocated to resection and 165 to radiotherapy. Of the 154 (92%) patients who underwent surgery, 14% had an exploratory thoracotomy, 50% a radical resection, 42% a pathologic downstaging, and 5% a pathologic complete response; 4% died after surgery. Postoperative radiotherapy was administered to 62 (40%) of patients in the surgery arm. Among the 154 (93%) irradiated patients, overall compliance to the radiotherapy prescription was 55%, and grade 3/4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7%; one patient died of radiation pneumonitis. Median and 5-year overall survival for patients randomly assigned to resection versus radiotherapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (hazard ratio = 1.06, 95% CI = 0.84 to 1.35). Rates of progression-free survival were also similar in both groups. CONCLUSION In selected patients with pathologically proven stage IIIA-N2 NSCLC and a response to induction chemotherapy, surgical resection did not improve overall or progression-free survival compared with radiotherapy. In view of its low morbidity and mortality, radiotherapy should be considered the preferred locoregional treatment for these patients.

Three-Arm Randomized Study of Two Cisplatin-Based Regimens and Paclitaxel Plus Gemcitabine in Advanced Non–Small-Cell Lung Cancer: A Phase III Trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group—EORTC 08975

PURPOSE To compare the therapeutic efficacy of paclitaxel plus cisplatin (arm A) versus gemcitabine plus cisplatin (arm B) and arm A versus paclitaxel plus gemcitabine (arm C) in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS Patients were randomly assigned to receive either paclitaxel 175 mg/m2 (3-hour infusion, day 1) or gemcitabine 1,250 mg/m2 (days 1 and 8) both combined with cisplatin 80 mg/m2 (day 1) or paclitaxel 175 mg/m2 (3-hour infusion, day 1) combined with gemcitabine 1,250 mg/m2 (days 1 and 8). Primary end point was comparison of overall survival for B versus A and C versus A. Secondary end points included response rate and duration, progression-free survival, toxicities, quality of life [QoL], and cost of treatment. RESULTS Four hundred eighty patients (arm A, 159; arm B, 160; arm C, 161 patients) were enrolled; all baseline characteristics were balanced. Median survival times were as follows: arm A, 8.1 months; arm B, 8.9 months; arm C, 6.7 months. Response rates were 31.8% for arm A, 36.6% for arm B, and 27.7% for arm C. Other than myelosuppression (B v A, P <.005), no statistically or clinically significant differences were observed for secondary end points. The average treatment costs were 25% higher in arm C as compared with arms A and B. CONCLUSION Gemcitabine plus cisplatin and paclitaxel plus gemcitabine do not increase overall survival in patients with advanced NSCLC as compared with paclitaxel plus cisplatin. Treatment was well tolerated, and most QoL parameters were similar, but costs associated with the nonplatinum arm were highest.

Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review

BACKGROUND Although surgery offers the best chance of cure for patients with non-small cell lung cancer (NSCLC), the overall 5-year survival rate is modest, and improvements are urgently needed. In the 1990s, much interest was generated from two small trials that reported striking results with neo-adjuvant chemotherapy, and therefore our intergroup randomised trial was designed to investigate whether, in patients with operable non-small cell lung cancer of any stage, outcomes could be improved by giving platinum-based chemotherapy before surgery. METHODS Patients were randomised to receive either surgery alone (S), or three cycles of platinum-based chemotherapy followed by surgery (CT-S). Before randomisation, clinicians chose the chemotherapy that would be given from a list of six standard regimens. The primary outcome measure was overall survival, which was analysed on an intention-to-treat basis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN25582437. RESULTS 519 patients were randomised (S: 261, CT-S: 258) from 70 centres in the UK, Netherlands, Germany, and Belgium. Most (61%) were clinical stage I, with 31% stage II, and 7% stage III. Neo-adjuvant chemotherapy was feasible (75% of patients received all three cycles of chemotherapy), resulted in a good response rate (49% [95% CI 43%-55%]) and down-staging in 31% (25%-37%) of patients, and did not alter the type or completeness of the surgery (lobectomy: S: 56%, CT-S: 60%, complete resection: S: 80%, CT-S: 82%). Post-operative complications were not increased in the CT-S group, and no impairment of quality of life was observed. However, there was no evidence of a benefit in terms of overall survival (hazard ratio [HR] 1.02, 95% CI 0.80-1.31, p=0.86). Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant chemotherapy (1507 patients, HR 0.88, 95% CI 0.76-1.01, p=0.07), equivalent to an absolute improvement in survival of 5% at 5 years INTERPRETATION Although there was no evidence of a difference in overall survival with neo-adjuvant chemotherapy, the result is statistically consistent with previous trials, and therefore adds considerable weight to the current evidence.

Gemcitabine and Cisplatin as Induction Regimen for Patients With Biopsy-Proven Stage IIIA N2 Non–Small-Cell Lung Cancer: A Phase II Study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group (EORTC 08955)

PURPOSE Our objective was to better define the activity/feasibility of gemcitabine/cisplatin (GC) as induction chemotherapy in patients with stage IIIA N2 non-small-cell lung cancer (NSCLC) followed by surgery or radiotherapy within a large, ongoing comparative study (EORTC 08941). PATIENTS AND METHODS Forty-seven chemotherapy-naive patients with NSCLC, median age of 58 years, stage IIIA N2 disease, World Health Organization performance status of 0 or 1, and the ability to tolerate a pneumonectomy received gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 and cisplatin 100 mg/m(2) on day 2, every 4 weeks. Patients received induction chemotherapy (three cycles) before re-evaluation and randomization to surgery or radiotherapy. RESULTS Grade 3/4 thrombocytopenia, the main hematologic toxicity, occurred in 60% of patients but was not associated with bleeding. Full-dose gemcitabine was given in 48% of the courses. Severe nonhematologic toxicity was uncommon. Two patients with preexisting, autoimmune pulmonary fibrosis had deterioration of pulmonary function after radiotherapy. Thirty-three (70.2%; 95% confidence interval, 55.1% to 82.7%) of the 47 eligible patients had objective responses (three complete responses and 30 partial responses). Mediastinal nodes were tumor-free after induction therapy in 53% of cases. Resections were considered complete in 71% of the patients who underwent thoracotomy after induction therapy. Median survival for all recruited patients (N = 53) was 18.9 months, with an estimated 1-year survival rate of 69%. CONCLUSION In patients with N2 stage IIIA NSCLC, GC is a highly active and well-tolerated induction regimen. GC should be explored in combination with surgery or radiotherapy in stage I and II patients.

Radiographically occult lung cancer treated with fibreoptic bronchoscopic electrocautery: a pilot study of a simple and inexpensive technique

The curative potential of bronchoscopic intervention, e.g. photodynamic therapy (PDT) and brachytherapy, for resectable radiographically occult lung cancer has been reported previously. Bronchoscopic electrocautery is currently feasible using an insulated flexible bronchoscope to coagulate and vaporize tumour tissue. Since the lesions are usually small, noninvasive bronchoscopic electrocautery may be able to eradicate radiographically occult lung cancer completely. In a prospective study, 13 patients with 15 radiographically occult lung cancer lesions were treated with bronchoscopic electrocautery. The duration of follow-up was > or = 16 months. The median age of the patients was 69 yrs (range 48-79 yrs). Fibreoptic bronchoscopy under local anaesthesia was used to coagulate the occult lung cancer. Approximately 30 W of energy was applied until visible necrosis of the tumour area became apparent. There were no immediate complications. In 10 patients with 12 lesions, a complete response (CR) was obtained (CR rate 80%; 95% confidence interval (95% CI) 52-96%). Median duration of follow-up was 21 months (range 16-43 months). Bronchoscopic electrocautery did not obtain a CR in the remaining three patients, but PDT also failed to achieve CR. Two patients underwent radical resection, and the tumours were histologically confirmed to be more invasive. One patient received external radiotherapy. Three patients with a CR died during follow-up, two as a result of myocardial infarction and apoplexy, and one because of metastasis from his previously resected T3N1 primary large cell cancer. Current data show bronchoscopic electrocautery to be equally effective and potentially as curative as photodynamic therapy for treating patients with radiographically occult lung cancer. Obvious advantages are that it is an inexpensive and simple procedure, which does not cause photosensitivity.

Cost-effectiveness of video-assisted thoracoscopic surgery versus conservative treatment for first time or recurrent spontaneous pneumothorax

The aim of this study was to analyse differences in efficacy and costs in treating first time or recurrent spontaneous pneumothorax by conservative therapy (pleural drainage or observation) and video-assisted thoracoscopic surgery (VATS). Retrospectively, 112 patients treated by conservative therapy during 1985-1989 (Period 1) were compared with 97 patients treated by VATS during 1991-1994 (Period 2). Mean follow-up time in each period was more than 2 yrs. Patients in both periods had comparable clinical characteristics. Irrespective of first time or recurrent spontaneous pneumothorax at presentation, drainage and hospitalization times were longer, and complication and recurrence rates were higher in Period 1. When costs due to the waiting time before VATS were excluded, the total costs in Period 1 were higher than in Period 2. Video-assisted thoracoscopic surgery is more effective in treating patients with first time or recurrent spontaneous pneumothorax, with less morbidity and total costs compared to conservative therapy. In view of cost-effectiveness, we feel that a different management of first time or recurrent spontaneous pneumothorax is not justified.

Fibreoptic bronchoscopic electrosurgery under local anaesthesia for rapid palliation in patients with central airway malignancies: a preliminary report.

BACKGROUND--Obstruction of a major airway by tumour causes serious morbidity. There is still scope for a widely applicable, simple and effective treatment to provide rapid palliation. METHODS--A fibreoptic bronchoscope prototype with an insulated inner sheath was used under local anaesthesia in 17 patients with locally advanced tracheobronchial malignancies. An insulated flexible electro-surgery probe was used to coagulate intraluminal tumour mass using standard electrosurgery equipment. RESULTS--Immediate reopening of the airway was obtained in 15 of the 17 patients. Two appeared to have extraluminal disease. Eleven patients had an obvious bronchoscopic response in whom a > 75% reopening of the normal airway diameter was achieved. Eight patients had subjective improvement of their dyspnoea, but only in four cases was there an objective improvement in physiological parameters. Haemoptysis resolved in four. There were no deaths resulting from treatment. Minor bleeding occurred in one patient and an aspiration pneumonia occurred in one. Three patients received additional treatment. CONCLUSIONS--Fibreoptic bronchoscopic electrosurgery is a simple technique for rapid palliation and immediate tumour debulking in patients with central tracheobronchial tumours. Further work is needed to compare its efficacy with other techniques.

Randomized, Placebo-Controlled Phase III Study of Docetaxel Plus Carboplatin With Celecoxib and Cyclooxygenase-2 Expression As a Biomarker for Patients With Advanced Non–Small-Cell Lung Cancer: The NVALT-4 Study

PURPOSE Cyclooxygenase-2 (COX-2) protein expression in patients with non-small-cell lung cancer (NSCLC) may be not only a prognostic marker but also predictive for COX-2 inhibition. We hypothesized that COX-2 expression is associated with shorter survival and that celecoxib, being a potent COX-2 inhibitor, increases tumor response and survival. PATIENTS AND METHODS A phase III study was performed in patients with stage IIIb/IV NSCLC who had pathologic confirmation, no prior chemotherapy, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Treatment consisted of docetaxel and carboplatin every 3 weeks for five cycles. Patients were randomly assigned to receive celecoxib 400 mg or placebo twice daily. COX-2 expression on tumor cells was detected by immunohistochemistry. Primary end point was overall survival (OS). RESULTS From July 2003 to December 2007, 561 patients were randomly assigned. Toxicity was mild, and no increase in cardiovascular events was observed. Tumor response was 38% in the celecoxib arm and 30% in the placebo arm (P = .08). Median progression-free survival was 4.5 months (95% CI, 4.0 to 4.8) for the celecoxib arm and 4.0 months (95% CI, 3.6 to 4.9) for the placebo arm (hazard ratio [HR], 0.8; 95% CI, 0.6 to 1.1; P = .25). Median OS was 8.2 months (95% CI, 7.5 to 8.8) for both treatment arms (HR, 0.9; 95% CI, 0.6 to 1.2; P = .32). COX-2 expression did not independently predict survival. Benefit from celecoxib, restricted to patients with low COX-2 expression, was not significant when adjusted for prognostic factors. CONCLUSION In advanced NSCLC, celecoxib does not improve survival. In this study, COX-2 expression was not a prognostic biomarker and had no predictive value when celecoxib was added to chemotherapy.

Distribution of talc suspension during treatment of malignant pleural effusion with talc pleurodesis

Talc pleurodesis is an effective technique for the management of symptomatic malignant pleural effusions. It is assumed that a good dispersion of talc suspension contributes to the final success of this treatment. For this purpose, guidelines often advise to rotate the patient after intra-pleural instillation of the sclerosant. This prospective, randomized study analyses the dispersion of talc suspension and the overall success rate in patients with malignant effusions. After instillation of 99mTc-sestamibi-labeled talc suspension ten subjects were rotated for 1 h, while the ten other patients remained in a stable supine body position. Scintigraphic imaging was done in two directions immediately after instillation and after 1 h with a clamped drain. The overall success of the treatment was assessed 1 month after the pleurodesis. The dispersion of talc was limited and unequal in 75% of the subjects. In two patients with apparently good distribution on anterior views, the lateral views of the scintigraphy showed only limited distribution. Rotation of the patients did not influence the dispersion of sludge after 1 min or 1 h. Pleurodesis was successful in 85% of the patients after 1-month follow-up. Standard rotation protocols for patients with malignant pleural effusion do not affect the overall dispersion of talc suspension and should be abolished because of the discomfort caused to the patients.

Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study.

BACKGROUND Standard chemotherapy does not lead to long-term survival in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma is strongly dependent on vasculature with high vessel counts and high concentrations of serum vascular growth factors. Thalidomide has shown antiangiogenic activity, and we hypothesised that its use in the maintenance setting could improve outcomes. METHODS In this open-label, multicentre, randomised phase 3 study, eligible patients had proven malignant pleural or peritoneal mesothelioma and had received a minimum of four cycles of first-line treatment containing at least pemetrexed, with or without cisplatin or carboplatin, and had not progressed on this treatment. Patients were randomly assigned (in a 1:1 ratio, stratified by previous first-line chemotherapy, histological subtype, and recruiting hospital) to receive thalidomide 200 mg per day (including a 2 week run in of 100 mg per day) plus active supportive care or active supportive care alone until disease progression. Patients were required to be registered and to start treatment with thalidomide within 10 weeks after the end of the first-line chemotherapy. Thalidomide was given for a maximum of 1 year or until unacceptable toxicity. The primary endpoint was time to progression. The primary analyses were by intention to treat. The study is registered, ISRCTN13632914. FINDINGS Between May 11, 2004, and Dec 23, 2009, we randomly assigned 222 patients, 111 in each group (one patient on active supportive care later withdrew consent and was excluded from analyses). At the time of this final analysis, median follow-up was 33.1 months (IQR 22.3-66.8), and physician-reported disease progression had occurred in 104 patients in the thalidomide group and 107 in the active supportive care group; 92 patients in the thalidomide group and 93 in the active supportive care group had died. Median time to progression in the thalidomide group was 3·6 months (95% CI 3.2-4.1) compared with 3.5 months (2.3-4.8) in the active supportive care group (hazard ratio 0.95, 95% CI 0.73-1.20, p=0.72). 43 (39%) grade 3 or 4 adverse events were reported in the thalidomide group and 31 (28%) in the active supportive care group; neurosensory events were reported by two (2%) patients on thalidomide and none on active supportive care, cardiac events by two (2%) patients on thalidomide and three (3%) on active supportive care, and thromboembolic events by three (3%) patients on thalidomide and none on active supportive care. INTERPRETATION No benefit was noted in time to progression with the addition of thalidomide maintenance to first-line chemotherapy. Different treatment strategies are needed to improve outcomes in patients with malignant mesothelioma. FUNDING Dutch Cancer Society (KWF), Eli Lilly, NSW Dust Disease Compensation Board, University of Sydney, and Cancer Australia.