Preoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysis of individual participant data

BACKGROUND: Individual participant data meta-analyses of postoperative chemotherapy have shown improved survival for patients with non-small-cell lung cancer (NSCLC). We aimed to do a systematic review and individual participant data meta-analysis to establish the effect of preoperative chemotherapy for patients with resectable NSCLC. METHODS: We systematically searched for trials that started after January, 1965. Updated individual participant data were centrally collected, checked, and analysed. Results from individual randomised controlled trials (both published and unpublished) were combined using a two-stage fixed-effect model. Our primary outcome, overall survival, was defined as the time from randomisation until death (any cause), with living patients censored on the date of last follow-up. Secondary outcomes were recurrence-free survival, time to locoregional and distant recurrence, cause-specific survival, complete and overall resection rates, and postoperative mortality. Prespecified analyses explored any variation in effect by trial and patient characteristics. All analyses were by intention to treat. FINDINGS: Analyses of 15 randomised controlled trials (2385 patients) showed a significant benefit of preoperative chemotherapy on survival (hazard ratio [HR] 0.87, 95% CI 0.78-0.96, p=0.007), a 13% reduction in the relative risk of death (no evidence of a difference between trials; p=0.18, I2=25%). This finding represents an absolute survival improvement of 5% at 5 years, from 40% to 45%. There was no clear evidence of a difference in the effect on survival by chemotherapy regimen or scheduling, number of drugs, platinum agent used, or whether postoperative radiotherapy was given. There was no clear evidence that particular types of patient defined by age, sex, performance status, histology, or clinical stage benefited more or less from preoperative chemotherapy. Recurrence-free survival (HR 0.85, 95% CI 0.76-0.94, p=0.002) and time to distant recurrence (0.69, 0.58-0.82, p<0.0001) results were both significantly in favour of preoperative chemotherapy although most patients included were stage IB-IIIA. Results for time to locoregional recurrence (0.88, 0.73-1.07, p=0.20), although in favour of preoperative chemotherapy, were not statistically significant. INTERPRETATION: Findings, which are based on 92% of all patients who were randomised, and mainly stage IB-IIIA, show preoperative chemotherapy significantly improves overall survival, time to distant recurrence, and recurrence-free survival in resectable NSCLC. The findings suggest this is a valid treatment option for most of these patients. Toxic effects could not be assessed. FUNDING: Medical Research Council U

The accuracy of clinical staging of stage I-IIIa non-small cell lung cancer: An analysis based on individual participant data

BACKGROUND: Clinical staging of NSCLC helps determine prognosis and management of patients; few data exist on accuracy of clinical staging and the impact on treatment and survival of patients. We assessed whether participant or trial characteristics were associated with clinical staging accuracy as well as impact on survival. METHODS: We used individual participant data from RCTs, supplied for a meta-analysis of pre-operative chemotherapy (+/- radiotherapy) versus surgery alone (+/- radiotherapy) in NSCLC. We assessed agreement between clinical TNM (cTNM) stage at randomization and pathological TNM (pTNM) stage, for participants in the control group. RESULTS: Results are based on 698 patients who received surgery alone (+/- radiotherapy) with data for cTNM and pTNM stage. 46% of cases were cTNM stage I, 23% cTNM stage II and 31% cTNM stage IIIa. cTNM stage disagreed with pTNM stage in 48% of cases, with 34% clinically understaged and 14% clinically over-staged. Agreement was not associated with age (p=0.12), gender (p=0.62), histology (p=0.82), staging method (p=0.32) or year of randomisation (p=0.98). Poorer survival in understaged patients was explained by the underlying pTNM stage. Clinical staging failed to detect T4 disease in 10% of cases and misclassified nodal disease in 38%. CONCLUSIONS: This study demonstrates suboptimal agreement between clinical and pathological staging. Discrepancies between clinical and pathological T and N-staging could have led to different treatment decisions in 10% and 38% of cases respectively. There is therefore a need for further research into improving staging accuracy for patients with stage I-IIIa NSCLC

Discussing potential recurrence after lung cancer surgery: uncertainties and challenges

Patients with lung cancer who undergo surgery may potentially be cured. The resulting pathological staging gives an indication of 5-year survival and whether further treatment is recommended. To date, there is little research evidence regarding the way potential recurrence is communicated to patients by staff. This qualitative research used case studies to explore how information disclosure about possible recurrence was managed following lung cancer surgery and aimed to identify practice implications for clinical teams. Twelve patients were recruited and first post-operative surgical and subsequent oncology or follow-up consultations were recorded and transcribed. The perspective of the professionals involved in these clinics was ascertained through 30 in-depth interviews. Key themes in the data were identified using Framework Analysis. Recurrence risk was communicated to patients in a number of ways and levels of clarity and openness. Information provided by participants about early warning signs of recurrence varied. Findings indicate information provided was linked to the patient’s prognosis and individual professionals’ underlying communication approach. This study provides a unique insight into the views of lung cancer specialists regarding information disclosure and reveals the challenging nature and complexity of discussing recurrence following lung cancer surgery

YangZheng XiaoJi exerts anti-tumour growth effects by antagonising the effects of HGF and its receptor, cMET, in human lung cancer cells

BACKGROUND: Hepatocyte growth factor (HGF) is a cytokine that has a profound effect on cancer cells by stimulating migration and invasion and acting as an angiogenic factor. In lung cancer, the factor also plays a pivotal role and is linked to a poor outcome in patients. In particular, HGF is known to work in combination with EGF on lung cancer cells. In the present study, we investigated the effect of a traditional Chinese medicine reported in cancer therapies, namely YangZheng XiaoJi (YZXJ) on lung cancer and on HGF mediated migration and invasion of lung cancer cells. METHODS: Human lung cancer cells, SKMES1 and A549 were used in the study. An extract from the medicine was used. Cell migration was investigated using the EVOS and by ECIS. Cell–matrix adhesion and in vitro invasion were assessed. In vivo growth of lung cancer was tested using an in vivo xenograft tumour model and activation of the HGF receptor in lung tumours by an immunofluorescence method. RESULTS: Both lung cancer cells increased their migration in response to HGF and responded to YZXJ by reducing their speed of migration. YZXJ markedly reduced the migration and in vitro invasiveness induced by HGF. It worked synergistically with PHA665752 and SU11274, HGF receptor inhibitors on the lung cancer cells both on HGF receptor activation and on cell functions. A combination of HGF and EGF resulted in a greater increase in cell migration, which was similarly inhibited by YZXJ, and in combination with the HGF receptor and EGF receptor inhibitors. In vivo, YZXJ reduced the rate of tumour growth and potentiated the effects of PHA665752 on tumour growth. It was further revealed that YZXJ significantly reduced the degree of phosphorylation of the HGF receptor in lung tumours. CONCLUSION: YZXJ has a significant role in reducing the migration, invasion and in vivo tumour growth of lung cancer and acts to inhibit the migratory and invasive effects induced by HGF and indeed by HGF/EGF. This effect is likely attributed to the inhibition of the HGF receptor activation. These results indicate that YZXJ has a therapeutic role in lung cancer and that combined strategy with methods to block HGF and EGF should be considered. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-015-0639-1) contains supplementary material, which is available to authorized users