Pathologic response rates following definitive dose image-guided chemoradiotherapy and resection for locally advanced non-small cell lung cancer

Shumway, Dean A.; Corbin, Kimberly S.; Salgia, Ravi; Villaflor, Victoria M.; Malik, R.; Haraf, D. J.; Vigneswaren, W.T.; Shaikh, Arif; Connell, Philip P.; Ferguson, Mark K.; Salama, Joseph K.

doi:10.1016/j.lungcan.2011.05.003

Cited by 21 publications

(9 citation statements)

References 32 publications

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“…Although technological advances have improved pathological response rates to advanced conformal therapies compared to standard techniques, there is need to further improve therapeutic ratio by minimising the probability of complications in surrounding normal tissues (3,5). Evasion of cell death is a mechanism by which cancer cells resist anti-cancer therapy (6); targeting resistance to cell death is therefore a potential strategy to preferentially sensitize tumor cells to ionizing radiation (IR)-induced cell death and thereby improve response rates to radiotherapy in NSCLC.…”

Section: Introductionmentioning

confidence: 99%

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

McLaughlin

Németh

Bradley

et al. 2016

Molecular Cancer Therapeutics

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Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor, FLIP, is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway.Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were down-regulated by RNAi, IRinduced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the anti-tumor activity of IR in vivo. Therefore, FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radio-sensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR. KA McLaughlin et al. FLIP-mediated radio-resistance in NSCLC3

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Section: Introductionmentioning

confidence: 99%

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

McLaughlin

Németh

Bradley

et al. 2016

Molecular Cancer Therapeutics

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“…A large number of retrospective studies on neo-adjuvant CHRT in patients with operable stage IIIA NSCLC have been published, using mostly cisplatin doublets while RT schedules mainly included conventional fractionation schemes with a few hyperfractionated schemes, with doses between 43-60 Gy [15][16][17][18][19][20][21][22]. The pCR, when reported, varied 16%-27 % [15,[17][18][19][20]22], except in one study where it was as high as 40% [21]. The median survival time (MST) ranged between 21 and 36 months, and the 5-year overall survival (OS) ranged 31%-40% [15][16][17][18][19][20][21][22].…”

Section: Neoadjuvant Chrt Followed By Surgerymentioning

confidence: 99%

Neoadjuvant Treatment for Resectable, Stage IIIA Non-Small Cell Lung Cancer

Kiladze

2021

CTOIJ

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The optimal treatment of patients with stage IIIA non-small cell lung cancer (NSCLC) remains highly controversial. In resectable stage IIIA NSCLC, there is still a considerable debate regarding the best strategy. Treatment choice is often a function of institutional and/or physician preference. Treatment consists of neo-adjuvant chemotherapy or chemoradiotherapy (CHRT) followed by surgery with or without postoperative radiotherapy (RT), definitive CHRT, or neoadjuvant immunotherapy followed by surgery and several other options. Neo-adjuvant therapy for operable NSCLC has been the subject of a large number of studies in the literature. We summarized existing data and also highlight ongoing trials, focusing on neoadjuvant immunotherapy. Neoadjuvant CHRT seems to be safe and efficient and is associated with an improved pathological outcome, but it has failed to demonstrate any advantage in terms of progression-free survival or overall survival compared to neoadjuvant chemotherapy. Contrary to previous fears, radiotherapy does not add a higher toxicity, nor does it increase post-operative mortality compared to chemotherapy alone. Studies with chemoimmunotherapy provide a higher rate of pathologic responses and downstaging compared to chemotherapy. On the other hand, it remains to be confirmed whether pCR is a sufficient surrogate for OS.Results of ongoing neoadjuvant immunotherapy trials are awaiting and we believe, the next decades will bring much needed improvements for patients. Still the controversy is not being solved and further trials considering a better patients' selection, innovative radiotherapy and more efficient systemic treatments need to be undertaken.

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“…A retrospective study by Shumway et al examined pathologic control rates of patients with stage IIIA/IIIB NSCLC treated preoperatively with and without 4D-CT and IGRT. 6 Only ten patients of the 53 were treated with 4DCT/IGRT, however these patients had higher rates of nodal down-staging and pathologic complete response following resection.…”

Section: Introductionmentioning

confidence: 99%

Image guided radiation therapy may result in improved local control in locally advanced lung cancer patients

Kilburn

Soike

Lucas

et al. 2016

Practical Radiation Oncology

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Purpose Image guided radiotherapy (IGRT) is designed to ensure accurate and precise targeting, but whether improved clinical outcomes result is unknown. Materials and Methods A retrospective comparison of locally advanced lung cancer patients treated with and without IGRT from 2001-2012 was conducted. Median local failure-free survival (LFFS), regional, locoregional failure-free survival (LRFFS), distant failure-free survival (DFFS), progression-free survival, and overall survival (OS) were estimated. Univariate and multivariate models assessed the association between patient and treatment-related covariates and local failure. Results 169 patients were treated with definitive radiotherapy and concurrent chemotherapy with a median follow-up of 48 months in the IGRT cohort and 96 months in the non-IGRT cohort. IGRT was utilized in 36% (62 patients) of patients. OS was similar between cohorts (2-year OS, 47% vs. 49%, p=0.63). The IGRT cohort had improved two year LFFS (80% vs. 64%, p=0.013) and LRFS (75% and 62%, p=0.04). Univariate analysis revealed IGRT and treatment year improved LFFS while group stage, dose, and PET/CT planning had no impact. IGRT remained significant in the multivariate model with an adjusted hazard ratio (aHR) of 0.40 (p=0.01). DFFS (58% vs. 59%, p=0.67) did not differ significantly. Conclusion IGRT with daily CBCT confers an improvement in the therapeutic ratio relative to patients treated without this technology.

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Pathologic response rates following definitive dose image-guided chemoradiotherapy and resection for locally advanced non-small cell lung cancer

Cited by 21 publications

References 32 publications

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

Neoadjuvant Treatment for Resectable, Stage IIIA Non-Small Cell Lung Cancer

Image guided radiation therapy may result in improved local control in locally advanced lung cancer patients

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