Preoperative versus Postoperative Chemotherapy in Patients with Resectable Non-small Cell Lung Cancer: Systematic Review and Indirect Comparison Meta-Analysis of Randomized Trials

Lim, Eric; Harris, Grace; Patel, Amit N.; Adachi, Iki; Edmonds, Lyn; Song, Fujian

doi:10.1097/jto.0b013e3181b9ecca

Cited by 165 publications

(95 citation statements)

References 59 publications

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“…Despite having been studied separately in the past, accumulating evidence suggests that tumour metastasis and chemoresistance not only commonly present simultaneously clinically but might also be intrinsically associated biological events45. It was observed, for example, that NSCLC patients with stage IV disease exhibit a substantially lower overall response rate to chemotherapy than patients with locally advanced disease67, suggesting that metastatic NSCLC patients are prone to be more resistant to chemotherapy in the clinic. In parallel, several biological events causing concurrent tumour metastasis and chemoresistance have been reported89.…”

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confidence: 99%

Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC

et al. 2017

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Cancer chemoresistance and metastasis are tightly associated features. However, whether they share common molecular mechanisms and thus can be targeted with one common strategy remain unclear in non-small cell lung cancer (NSCLC). Here, we report that high levels of microRNA-128-3p (miR-128-3p) is key to concomitant development of chemoresistance and metastasis in residual NSCLC cells having survived repeated chemotherapy and correlates with chemoresistance, aggressiveness and poor prognosis in NSCLC patients. Mechanistically, miR-128-3p induces mesenchymal and stemness-like properties through downregulating multiple inhibitors of Wnt/β-catenin and TGF-β pathways, leading to their overactivation. Importantly, antagonism of miR-128-3p potently reverses metastasis and chemoresistance of highly malignant NSCLC cells, which could be completely reversed by restoring Wnt/β-catenin and TGF-β activities. Notably, correlations among miR-128-3p levels, activated β-catenin and TGF-β signalling, and pro-epithelial-to-mesenchymal transition/pro-metastatic protein levels are validated in NSCLC patient specimens. These findings suggest that miR-128-3p might be a potential target against both metastasis and chemoresistance in NSCLC.

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confidence: 99%

Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC

et al. 2017

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“…Although this difference makes a formal indirect comparison of the effects of preoperative and postoperative chemotherapy difficult, the benefit noted is on a similar scale. Others have attempted formal comparison based on aggregate data 8 and concluded the effect of chemotherapy on overall or recurrence-free survival is similar, irrespective of chemotherapy timing. However, they did not include key large trials, published more recently, and have included a trial confounded by the use of radiotherapy in only one arm 40 …”

Section: Discussionmentioning

confidence: 99%

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

2014

The Lancet

683

254

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SummaryBackgroundIndividual 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.MethodsWe 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.FindingsAnalyses 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.InterpretationFindings, 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.FundingMedical Research Council UK.

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“…In addition, an indirect methodology meta-analysis had shown that NCT was similar to adjuvant chemotherapy in terms of survival benefit provided [32]. These findings taken together suggest that when chemotherapy is indicated in stage 2 or 3 disease, NCT or adjuvant chemotherapy are reasonable options in suitable patients.…”

Section: Discussionmentioning

confidence: 99%

The correlates of benefit from neoadjuvant chemotherapy before surgery in non-small-cell lung cancer: a metaregression analysis

2012

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BackgroundAlthough neoadjuvant chemotherapy (NCT) is widely used, it is not clear which subgroup of locally advanced non-small-cell lung cancer (NSCLC) patients should be treated with this approach, and if a particular benefit associated with NCT exists. In this study, we aimed to investigate the potential correlates of benefit from NCT in patients with NSCLC.MethodsAll randomized clinical trials (RCTs) utilizing a NCT arm (without radiotherapy) versus a control arm before surgery were included for metaregression analysis. All regression analyses were weighed for trial size. Separate analyses were conducted for trials recruiting patients with different stages of disease. Previously published measures of treatment efficacy were used for the purpose of this study, regardless of being published in full text or abstract form.ResultsA total of 14 RCTs, consisting of 3,615 patients, were selected. Histology, stage, various characteristics of the NCT protocol, and different trial features including trial quality score were not associated with the benefit of NCT. However, in trials of stage 3 disease only, there was a greater benefit in terms of reduction in mortality from NCT, if protocols with three chemotherapeutics were used (B = −0.18, t = −5.25, P = 0.006).ConclusionsWe think that patients with stage 3 NSCLC are served better with NCT before surgery if protocols with three chemotherapy agents or equally effective combinations are used. In addition, the effect of neoadjuvant chemotherapy is consistent with regard to disease and patient characteristics. This finding should be tested in future RCTs or individual patient data meta-analyses.

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Preoperative versus Postoperative Chemotherapy in Patients with Resectable Non-small Cell Lung Cancer: Systematic Review and Indirect Comparison Meta-Analysis of Randomized Trials

Abstract: In patients with resectable lung cancer, there was no evidence of a difference in overall and disease-free survival between the timing of administration of chemotherapy (postoperative versus preoperative).

Cited by 165 publications

References 59 publications

Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC

Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC

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

The correlates of benefit from neoadjuvant chemotherapy before surgery in non-small-cell lung cancer: a metaregression analysis

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