Treatment options for early-stage non-small cell lung cancer (ES-NSCLC) are generally well-tolerated. Minimally-invasive surgical techniques, stereotactic ablative radiotherapy (SABR) and radiofrequency ablation (RFA) can all achieve post-treatment mortality of <1% in clinical trial settings. There has been increasing evidence to suggest that patients with interstitial lung disease (ILD) suffer severe toxicity after treatment for NSCLC. Treatment-related toxicity may result in death and may take the form of acute exacerbations of existing ILD following surgery or RFA, or severe radiation pneumonitis following SABR. We performed a systematic review of literature in compliance with PRISMA guidelines to investigate the rate of treatment-related toxicity and mortality following treatment for ES-NSCLC. The Medline and EMBASE databases were queried from respective dates of inception to January 2016. Treatment modalities included in the search strategy were surgery, SABR, RFA, particle beam therapy and conventionally-fractionated radiotherapy. Results were summarized with weighted statistics according to the sample size of individual studies. A total of 3,054 unique records were screened and 282 full texts were reviewed. Forty-nine journal articles were included in the final analysis, with 92% of studies being retrospective in design. Thirty surgical studies with 1716 patients, 13 SABR studies with 122 patients, 3 RFA studies with 46 patients, 2 proton beam therapy (PBT) studies with 17 patients and one carbon ion beam therapy (CIBT) study with 5 patients were included. Most patients in non-surgical studies were medically inoperable. Treatment-related or 30-day post-operative mortality was 2.3%, 15.5%, 8.7%, 5.8% and 0%, respectively, for surgery, SABR, RFA, PBT and CIBT. Treatment-related acute exacerbation of ILD or radiation pneumonitis ≥ grade 3 was 12%, 25%, 25%, 12.5% and 20%, respectively. For patients treated with surgery, 5-year overall survival (OS) was 31.4% to 61.6% (median 54.2%) for patients with ILD and 70.5% to 88.3% (median 83.0%) for patients without ILD. For medically inoperable patients treated with SABR, 2 to 3-year OS was 0% to 53.8% (median 48.8%) for patients with ILD and 54% to 86.7% (median 70.8%) for patients without ILD. Studies that included only patients with idiopathic pulmonary fibrosis reported higher treatment-related toxicity compared to other studies. An elevated level of treatment-related toxicity is observed in patients treated for ES-NSCLC with co-existing ILD. Medically inoperable patients experienced high levels of treatment-related mortality. For surgery and SABR, overall survival was worse for patients with ILD compared to those without ILD.
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