Summary Background Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide ...improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. Methods The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4–12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00409188. Findings From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25·6 months (95% CI 22·5–29·2) with tecemotide versus 22·3 months (19·6–25·5) with placebo (adjusted HR 0·88, 0·75–1·03; p=0·123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30·8 months (95% CI 25·6–36·8) compared with 20·6 months (17·4–23·9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0·78, 0·64–0·95; p=0·016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19·4 months 95% CI 17·6–23·1 vs 24·6 months 18·8–33·0, respectively; adjusted HR 1·12, 0·87–1·44; p=0·38). Grade 3–4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 5% of 1024 patients in the tecemotide group vs 21 4% of 477 patients in the placebo group), metastases to central nervous system (29 3% vs 6 1%), and pneumonia (23 2% vs 12 3%). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 3% in the tecemotide group vs 14 3% in the placebo group), dyspnoea (29 3% vs 13 3%), and metastases to central nervous system (32 3% vs 9 2%). Serious immune-related adverse events did not differ between groups. Interpretation We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. Funding Merck KGaA (Darmstadt, Germany).
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Maximum tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses given on a frequent schedule) acts on tumour vascular endothelial cells by increasing the ...anti-tumour effect of anti-angiogenic agents. This multicentre, phase 2 study investigated the effectiveness of MTD gemcitabine combined with metronomic capecitabine plus the multikinase inhibitor sorafenib for the treatment of metastatic renal-cell carcinoma (RCC). Methods Patients were enrolled at eight centres across Spain between Dec 13, 2006, and April 17, 2008. Patients were aged 18 years or older, had confirmed metastatic RCC with clear-cell histology, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had not undergone previous therapy, and were unsuitable for, or intolerant to, immunotherapy. Treatment consisted of intravenous gemcitabine 1000 mg/m2 (days 1 and 8), oral capecitabine 500 mg/m2 twice a day (final dose after adjustment, days 1–14), and oral sorafenib 400 mg twice a day (days 1–21), for six cycles, followed by sorafenib monotherapy (at the investigator's discretion if clinical benefit was maintained). The primary endpoint was median progression-free survival (PFS) analysed in a population of all patients who received treatment. The trial is registered with ClinicalTrials.gov , number NCT00496301. Findings 44 patients enrolled in the study, 40 of whom received treatment. Median PFS for these patients was 11·1 months (95% CI 7·9–17·1). A partial response was achieved in 20 patients, and stable disease in 17 patients. Most adverse events were grade 1 or 2. Grade 3 adverse events were fatigue or asthenia (n=9), hand–foot skin reaction (n=11), mucositis (n=3), diarrhoea (n=2), infection (n=2), and allergic reaction, hypertension, and rash (all n=1). Grade 3 haematological toxicity was noted in nine patients. One death due to pulmonary embolism was reported as grade 5 dyspnoea possibly related to study drug. Interpretation PFS and response rates were greater than those previously observed with gemcitabine and capecitabine or sorafenib monotherapy in patients with metastatic RCC. Adverse events were manageable in most patients. These findings provide preliminary confirmation of the synergistic activity of the chemo-switch concept seen in preclinical studies, and merit further exploration. Funding Spanish Oncology Genitourinary Group (SOGUG).
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
SCLC is one of the most lethal malignancies. Classically, staging has been performed using a dual classification distinguishing limited from the extensive stage. This study aimed to evaluate the ...prognostic value of TNM staging in a real-world population of patients with SCLC.
Patients were selected from the Surveillance Epidemiology and End Results database. Chi-square bivariate analysis was used for the association of binary qualitative variables. A multivariate Cox regression analysis was performed to determine the impact of these prognostic factors on median overall survival (mOS) and long-term survival.
A total of 26,221 patients were included (50.7% men, 55.7% ≥65 y, 82% White). At diagnosis, 18,574 (70.83%) presented metastases, which were more frequent in the liver (n = 11,896, 64%). In the overall population, mOS was 8 (7.86–8.14) months, which decreased according to each increasing category of TNM staging (p < 0.0001). The worse mOS was found among patients with stage IV SCLC (6 mo, 95% confidence interval: 5.83–6.17). Long-term survival decreased according to TNM staging, with patients having stage IV SCLC exhibiting the lowest survival rates at all follow-up time points. Within stage IV, the lowest mOS values were found in patients greater than or equal to 65 years and in those with liver metastases. Among the TNM stages corresponding to the limited stage, stage IB revealed the lowest hazard ratios value for risk of death compared with stage IA (hazard ratio = 1.161, 95% confidence interval: 0.97–1.40, p = 0.114), which increased gradually within the limited-stage SCLC. In the multivariate analysis, TNM staging, male sex, and older age resulted in poor prognostic factors for survival.
TNM staging seems to define prognosis in patients with SCLC in the real-world setting, particularly for those patients with earlier disease.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
