Does Surgery Have a Role in the Era of High Dose Chemoradiotherapy for Locally Advanced NSCLC?

7019 Background: Modest benefits from concurrent chemoradiotherapy (CRT) in patients with locally advanced NSCLC warrant more effective treatment regimen. Cetuximab, a monoclonal antibody against the epidermal growth factor receptor has shown activity in NSCLC. Feasibility data and toxicity have been published previously. We report treatment outcome of a multicenter phase II study of the combination of high dose accelerated RT and daily dose cisplatin with or without weekly cetuximab. Methods: Patients with locally advanced NSCLC received accelerated RT (66 Gy in 24 fractions) and concurrent daily cisplatin (6 mg/m2) with (Arm A) or without (Arm B) additional weekly cetuximab (400 mg/m2 loading dose one week prior to the RT start followed by weekly 250 mg/m2). The Objective Local Response Control (OLRC) was determined at 6 and 24 weeks after treatment using response evaluation criteria in solid tumours criteria. Results: Between Feb 2009 and May 2011, 102 patients were included. Median follow-up was 13 months. Patients and tumor characteristics are shows in the Table. Stage distribution was: II (8%), IIIa (51%), and IIIb (40%). The CRT was well tolerated. The OLRC at 24 weeks was 79% in Arm A and 80% in Arm B. The one-year progression free survival and overall survival were 58% (45%-76%) and 76% (64%-91%) for Arm A and 49% (35%-68%) and 72% (58%-89%) for Arm B respectively. Conclusions: The addition of cetuximab to low dose cisplation CRT does not improve OLRC in an unselected patient cohort but data on longterm disease control and survival are to be awaited. [Table: see text]

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Automated quantitative analyses (AQUA) of cyclic-AMP-response-element-binding protein (CREB), phosphorylated CREB (pCREB), and ataxia-telangiectasia-mutated protein kinase (ATM) protein expression in patients (pts) undergoing thoracic radiation for locally advanced non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e13537 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e13537-e13537 ◽

Cited By ~ 1

Author(s):

Bo H. Chao ◽

Anne M. Traynor ◽

David T Yang ◽

Chong Zhang ◽

Thomas Pier ◽

...

Keyword(s):

Dna Damage ◽

Protein Expression ◽

Cell Fate ◽

Advanced Nsclc ◽

Control Cell ◽

Locally Advanced ◽

High Dose ◽

Cell Fate Decisions ◽

Locally Advanced Nsclc ◽

Thoracic Radiation

e13537 Background: Increased protein expression of CREB, a DNA damage-regulated transcription factor, has been associated with poor survival in advanced NSCLC. We have demonstrated that exposure of cancer cell lines to low dose ionizing radiation (IR) increased pCREB on a Ser133 residue. However, exposure to high dose IR correlated with pCREB on Ser121 by ATM, a master regulator of the cellular DNA damage response. This unusual bimodal response of CREB to IR, reflected by activation at low doses and attenuation at high doses, suggested that CREB may control cell fate decisions in response to DNA damage. We hypothesized that patterns of protein expression of CREB, pCREB Ser133, and ATM would predict treatment response in pts who have undergone radiotherapy for locally advanced NSCLC. Methods: Diagnostic tumor specimens were obtained from pts who underwent thoracic radiation in a clinical trial for locally advanced NSCLC. Protein expression of CREB, pCREB Ser133, and ATM was assessed by AQUA. Wilcoxon rank sum test was used to assess differences in protein expression. Univariate regression was conducted to evaluate protein expression and clinical outcomes. Kruskal Wallis test was used to assess protein expression and pneumonitis. Results: Sufficient tumor tissue was available for 35 of 79 pts enrolled. Best responses in 6 months included 12% CR, 73% PR, 9% SD, and 6% PD. Pre-treatment protein expression per AQUA analyses of CREB, pCREB Ser133, and ATM were not statistically associated with time to in-field progression, time to out-of-field progression, time to distant metastasis, best response, pneumonitis, or overall survival. Unexpectedly, increased expression of pCREB Ser133 was associated with durable anti-tumor response to radiation at a median duration of 14.6 months (p=0.03). Conclusions: Protein expression per AQUA of CREB, pCREB Ser133, and ATM did not confirm our hypotheses, possibly related to our limited sample size. Further analysis of the role of CREB in response to IR in cancer pts is ongoing.

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A systematic analysis of high-dose radiation in the treatment of surgically unresectable, locally advanced non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.7059 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 7059-7059

Author(s):

Madhusmita Behera ◽

Jonathan Jay Beitler ◽

Chandar Bhimani ◽

Kristin Higgins ◽

Zhengjia Chen ◽

...

Keyword(s):

Lung Cancer ◽

Advanced Nsclc ◽

Locally Advanced ◽

Small Cell ◽

High Dose ◽

Small Cell Lung ◽

Systematic Analysis ◽

Locally Advanced Nsclc ◽

Weighted Median ◽

Dose Radiation

7059 Background: The 5-year survival rate for locally advanced non-small cell lung cancer (NSCLC) is < 25% with concomitant chemoradiotherapy. High-dose radiation appears to confer additional benefit based on surrogate endpoints from relatively small clinical trials. However, survival advantage of higher-dose radiation delivered by conventional fractionation of 1.8-2 Gy is unclear. We conducted a systematic review of pooled outcome data from published results of studies that evaluated the role of high-dose radiation in the management of locally advanced NSCLC. Methods: A detailed search of published clinical trials was conducted using computerized databases (MEDLINE, EMBASE, Cochrane library) and meeting proceedings. Single arm studies using high dose (>66Gy) or randomized trials of high versus standard radiation dose (60-63Gy) for locally advanced NSCLC were selected. A systematic analysis of extracted data was performed using Comprehensive Meta Analysis (Version 2.2.048) software under the random effect model. Clinical outcome in patients treated with high versus standard radiation dose was compared using point estimates for weighted values of median overall survival (OS), progression free survival (PFS), and response rate (RR). Treatment-related toxicities data between the two arms was compared using T-test and chi-square test. Results: Analytic data was retrieved from the results of 44 eligible studies reported between 1994 and 2012. The studies enrolled 3699 patients, 62% males, 2095 and 1604 treated with standard and high dose radiation respectively. The weighted median age was 63 and 61 years (p=0.66) for standard and high dose patients respectively. The weighted median OS was 19.1 vs. 16.4 months (p= 0.97); weighted RR of 76% vs. 70% (p=0.79) and survival rates after up to 3 years of follow up of 39% vs. 46% (p=0.45) for standard and high dose arms respectively. There was no significant difference in the rate of grade ≥3 toxicities between the two treatment groups. Conclusions: High-dose radiation therapy does not result in improved survival over standard radiotherapy dose in patients with locally advanced NSCLC.

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Faculty Opinions recommendation of Prognostic Factors and Long-Term Survival in Locally Advanced NSCLC with Pathological Complete Response after Surgical Resection Following Neoadjuvant Therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.739153253.793581073 ◽

2020 ◽

Author(s):

Paul Van Schil

Keyword(s):

Prognostic Factors ◽

Neoadjuvant Therapy ◽

Surgical Resection ◽

Advanced Nsclc ◽

Pathological Complete Response ◽

Locally Advanced ◽

Complete Response ◽

Term Survival ◽

Locally Advanced Nsclc

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Real-world prospective analysis of treatment patterns in durvalumab maintenance after chemoradiotherapy in unresectable, locally advanced NSCLC patients

Investigational New Drugs ◽

10.1007/s10637-021-01091-9 ◽

2021 ◽

Author(s):

Julian Taugner ◽

Lukas Käsmann ◽

Chukwuka Eze ◽

Alexander Rühle ◽

Amanda Tufman ◽

...

Keyword(s):

Prospective Study ◽

Real World ◽

Maintenance Treatment ◽

Progressive Disease ◽

Advanced Nsclc ◽

Locally Advanced ◽

Contrast Enhanced Ct ◽

Unresectable Stage ◽

Locally Advanced Nsclc

SummaryThe aim of this prospective study is to evaluate the clinical use and real-world efficacy of durvalumab maintenance treatment after chemoradiotherapy (CRT) in unresectable stage, locally advanced non-small cell lung cancer (NSCLC). All consecutive patients with unresectable, locally advanced NSCLC and PD-L1 expression (≥1%) treated after October 2018 were included. Regular follow up, including physical examination, PET/CT and/or contrast-enhanced CT-Thorax/Abdomen were performed every three months after CRT. Descriptive treatment pattern analyses, including reasons of discontinuation and salvage treatment, were undertaken. Statistics were calculated from the last day of thoracic irradiation (TRT). Twenty-six patients were included. Median follow up achieved 20.6 months (range: 1.9–30.6). Durvalumab was initiated after a median of 25 (range: 13–103) days after completion of CRT. In median 14 (range: 2–24) cycles of durvalumab were applied within 6.4 (range 1–12.7) months. Six patients (23%) are still in treatment and seven (27%) have completed treatment with 24 cycles. Maintenance treatment was discontinued in 13 (50%) patients: 4 (15%) patients developed grade 3 pneumonitis according to CTCAE v5 after a median of 3.9 (range: 0.5–11.6) months and 7 (range: 2–17) cycles of durvalumab. Four (15%) patients developed grade 2 skin toxicity. One (4%) patient has discontinued treatment due to incompliance. Six and 12- month progression-free survival (PFS) rates were 82% and 62%, median PFS was not reached. No case of hyperprogression was documented. Eight (31%) patients have relapsed during maintenance treatment after a median of 4.8 (range: 2.2–11.3) months and 11 (range: 6–17) durvalumab cycles. Two patients (9%) developed a local-regional recurrence after 14 and 17 cycles of durvalumab. Extracranial distant metastases and brain metastases as first site of failure were detected in 4 (15%) and 2 (8%) patients, respectively. Three (13%) patients presented with symptomatic relapse. Our prospective study confirmed a favourable safety profile of durvalumab maintenance treatment after completion of CRT in unresectable stage, locally advanced NSCLC in a real-world setting. In a median follow-up time of 20.6 months, durvalumab was discontinued in 27% of all patients due to progressive disease. All patients with progressive disease were eligible for second-line treatment.

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