Randomized Phase II Study of Preoperative Chemoradiotherapy ± Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIa, N2+) Non–Small Cell Lung Cancer: NRG Oncology RTOG 0839

Martin J. Edelman, Chen Hu, Quynh Thu Le, Jessica S. Donington, Warren D. D'Souza, Adam P. Dicker, Billy W. Loo, Elizabeth M. Gore, Gregory M.M. Videtic, Nathaniel R. Evans, Joseph W. Leach, Maximilian Diehn, Steven J. Feigenberg, Yuhchyau Chen, Rebecca Paulus, Jeffrey D. Bradley

Research output: Contribution to journalArticle

Abstract

Introduction Multimodality therapy has curative potential in locally advanced NSCLC. Mediastinal nodal sterilization (MNS) after induction chemoradiotherapy (CRT) can serve as an intermediate marker for efficacy. NRG Oncology Radiation Therapy Oncology Group (RTOG) 0229 demonstrated the feasibility and efficacy of combining full-dose radiation (61.2 Gy) with chemotherapy followed by resection and chemotherapy. On the basis of that experience and evidence that EGFR antibodies are radiosensitizing, we explored adding panitumumab to CRT followed by resection and consolidation chemotherapy in locally advanced NSCLC with a primary end point of MNS. Methods Patients with resectable locally advanced NSCLC were eligible if deemed suitable for trimodality therapy before treatment. Surgeons were required to demonstrate expertise after CRT and adhere to specific management guidelines. Concurrent CRT consisted of weekly carboplatin (area under the curve = 2.0), paclitaxel (50 mg/m2), and 60 Gy of radiation therapy delivered in 30 fractions. There was a 2:1 randomization in favor of panitumumab at 2.5 mg/kg weekly for 6 weeks. The mediastinum was pathologically reassessed before or at the time of resection. Consolidation chemotherapy was weekly carboplatin (area under the curve = 6) and paclitaxel, 200 mg/m2 every 21 days for two courses. The study was designed to detect an improvement in MNS from 52% to 72%. With use of a 0.15 one-sided type 1 error and 80% power, 97 patients were needed. Results The study was opened in November 2010 and closed in August 2015 by the Data Monitoring Committee after 71 patients had been accrued for futility and excessive toxicity in the experimental arm. A total of 60 patients were eligible: 19 patients (86%) who received CRT and 29 (76%) who received CRT plus panitumumab and underwent an operation. With regard to postoperative toxicity, there were three grade 4 adverse events (13.6%) and no grade 5 adverse events (0%) among those who received CRT versus six grade 4 (15.8%) and four grade 5 adverse events (10.5%) among those who received CRT plus panitumumab. The MNS rates were 68.2% (95% confidence interval: 45.1–86.1) and 50.0% (95% confidence interval: 33.4–66.6) for CRT and CRT plus panitumumab, respectively (p = 0.95). Conclusion The addition of panitumumab to CRT did not improve MNS. There was an unexpectedly high mortality rate in the panitumumab arm, although the relationship to panitumumab is unclear. The control arm had outcomes similar to those in NRG Oncology RTOG 0229.

Original languageEnglish (US)
Pages (from-to)1413-1420
Number of pages8
JournalJournal of Thoracic Oncology
Volume12
Issue number9
DOIs
StatePublished - Sep 1 2017
Externally publishedYes

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Consolidation Chemotherapy
Radiation Oncology
Chemoradiotherapy
Non-Small Cell Lung Carcinoma
Radiotherapy
Radiation Dosage
Arm
Carboplatin
Paclitaxel
Area Under Curve
panitumumab
Clinical Trials Data Monitoring Committees
Confidence Intervals
Medical Futility
Drug Therapy
Mediastinum
Random Allocation

Keywords

  • Chemoradiotherapy
  • EGFR antibody
  • Multimodality
  • NSCLC
  • Panitumumab
  • Preoperative

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Randomized Phase II Study of Preoperative Chemoradiotherapy ± Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIa, N2+) Non–Small Cell Lung Cancer : NRG Oncology RTOG 0839. / Edelman, Martin J.; Hu, Chen; Le, Quynh Thu; Donington, Jessica S.; D'Souza, Warren D.; Dicker, Adam P.; Loo, Billy W.; Gore, Elizabeth M.; Videtic, Gregory M.M.; Evans, Nathaniel R.; Leach, Joseph W.; Diehn, Maximilian; Feigenberg, Steven J.; Chen, Yuhchyau; Paulus, Rebecca; Bradley, Jeffrey D.

In: Journal of Thoracic Oncology, Vol. 12, No. 9, 01.09.2017, p. 1413-1420.

Research output: Contribution to journalArticle

Edelman, MJ, Hu, C, Le, QT, Donington, JS, D'Souza, WD, Dicker, AP, Loo, BW, Gore, EM, Videtic, GMM, Evans, NR, Leach, JW, Diehn, M, Feigenberg, SJ, Chen, Y, Paulus, R & Bradley, JD 2017, 'Randomized Phase II Study of Preoperative Chemoradiotherapy ± Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIa, N2+) Non–Small Cell Lung Cancer: NRG Oncology RTOG 0839', Journal of Thoracic Oncology, vol. 12, no. 9, pp. 1413-1420. https://doi.org/10.1016/j.jtho.2017.06.007
Edelman, Martin J. ; Hu, Chen ; Le, Quynh Thu ; Donington, Jessica S. ; D'Souza, Warren D. ; Dicker, Adam P. ; Loo, Billy W. ; Gore, Elizabeth M. ; Videtic, Gregory M.M. ; Evans, Nathaniel R. ; Leach, Joseph W. ; Diehn, Maximilian ; Feigenberg, Steven J. ; Chen, Yuhchyau ; Paulus, Rebecca ; Bradley, Jeffrey D. / Randomized Phase II Study of Preoperative Chemoradiotherapy ± Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIa, N2+) Non–Small Cell Lung Cancer : NRG Oncology RTOG 0839. In: Journal of Thoracic Oncology. 2017 ; Vol. 12, No. 9. pp. 1413-1420.
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title = "Randomized Phase II Study of Preoperative Chemoradiotherapy ± Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIa, N2+) Non–Small Cell Lung Cancer: NRG Oncology RTOG 0839",
abstract = "Introduction Multimodality therapy has curative potential in locally advanced NSCLC. Mediastinal nodal sterilization (MNS) after induction chemoradiotherapy (CRT) can serve as an intermediate marker for efficacy. NRG Oncology Radiation Therapy Oncology Group (RTOG) 0229 demonstrated the feasibility and efficacy of combining full-dose radiation (61.2 Gy) with chemotherapy followed by resection and chemotherapy. On the basis of that experience and evidence that EGFR antibodies are radiosensitizing, we explored adding panitumumab to CRT followed by resection and consolidation chemotherapy in locally advanced NSCLC with a primary end point of MNS. Methods Patients with resectable locally advanced NSCLC were eligible if deemed suitable for trimodality therapy before treatment. Surgeons were required to demonstrate expertise after CRT and adhere to specific management guidelines. Concurrent CRT consisted of weekly carboplatin (area under the curve = 2.0), paclitaxel (50 mg/m2), and 60 Gy of radiation therapy delivered in 30 fractions. There was a 2:1 randomization in favor of panitumumab at 2.5 mg/kg weekly for 6 weeks. The mediastinum was pathologically reassessed before or at the time of resection. Consolidation chemotherapy was weekly carboplatin (area under the curve = 6) and paclitaxel, 200 mg/m2 every 21 days for two courses. The study was designed to detect an improvement in MNS from 52{\%} to 72{\%}. With use of a 0.15 one-sided type 1 error and 80{\%} power, 97 patients were needed. Results The study was opened in November 2010 and closed in August 2015 by the Data Monitoring Committee after 71 patients had been accrued for futility and excessive toxicity in the experimental arm. A total of 60 patients were eligible: 19 patients (86{\%}) who received CRT and 29 (76{\%}) who received CRT plus panitumumab and underwent an operation. With regard to postoperative toxicity, there were three grade 4 adverse events (13.6{\%}) and no grade 5 adverse events (0{\%}) among those who received CRT versus six grade 4 (15.8{\%}) and four grade 5 adverse events (10.5{\%}) among those who received CRT plus panitumumab. The MNS rates were 68.2{\%} (95{\%} confidence interval: 45.1–86.1) and 50.0{\%} (95{\%} confidence interval: 33.4–66.6) for CRT and CRT plus panitumumab, respectively (p = 0.95). Conclusion The addition of panitumumab to CRT did not improve MNS. There was an unexpectedly high mortality rate in the panitumumab arm, although the relationship to panitumumab is unclear. The control arm had outcomes similar to those in NRG Oncology RTOG 0229.",
keywords = "Chemoradiotherapy, EGFR antibody, Multimodality, NSCLC, Panitumumab, Preoperative",
author = "Edelman, {Martin J.} and Chen Hu and Le, {Quynh Thu} and Donington, {Jessica S.} and D'Souza, {Warren D.} and Dicker, {Adam P.} and Loo, {Billy W.} and Gore, {Elizabeth M.} and Videtic, {Gregory M.M.} and Evans, {Nathaniel R.} and Leach, {Joseph W.} and Maximilian Diehn and Feigenberg, {Steven J.} and Yuhchyau Chen and Rebecca Paulus and Bradley, {Jeffrey D.}",
year = "2017",
month = "9",
day = "1",
doi = "10.1016/j.jtho.2017.06.007",
language = "English (US)",
volume = "12",
pages = "1413--1420",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "9",

}

TY - JOUR

T1 - Randomized Phase II Study of Preoperative Chemoradiotherapy ± Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIa, N2+) Non–Small Cell Lung Cancer

T2 - NRG Oncology RTOG 0839

AU - Edelman, Martin J.

AU - Hu, Chen

AU - Le, Quynh Thu

AU - Donington, Jessica S.

AU - D'Souza, Warren D.

AU - Dicker, Adam P.

AU - Loo, Billy W.

AU - Gore, Elizabeth M.

AU - Videtic, Gregory M.M.

AU - Evans, Nathaniel R.

AU - Leach, Joseph W.

AU - Diehn, Maximilian

AU - Feigenberg, Steven J.

AU - Chen, Yuhchyau

AU - Paulus, Rebecca

AU - Bradley, Jeffrey D.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Introduction Multimodality therapy has curative potential in locally advanced NSCLC. Mediastinal nodal sterilization (MNS) after induction chemoradiotherapy (CRT) can serve as an intermediate marker for efficacy. NRG Oncology Radiation Therapy Oncology Group (RTOG) 0229 demonstrated the feasibility and efficacy of combining full-dose radiation (61.2 Gy) with chemotherapy followed by resection and chemotherapy. On the basis of that experience and evidence that EGFR antibodies are radiosensitizing, we explored adding panitumumab to CRT followed by resection and consolidation chemotherapy in locally advanced NSCLC with a primary end point of MNS. Methods Patients with resectable locally advanced NSCLC were eligible if deemed suitable for trimodality therapy before treatment. Surgeons were required to demonstrate expertise after CRT and adhere to specific management guidelines. Concurrent CRT consisted of weekly carboplatin (area under the curve = 2.0), paclitaxel (50 mg/m2), and 60 Gy of radiation therapy delivered in 30 fractions. There was a 2:1 randomization in favor of panitumumab at 2.5 mg/kg weekly for 6 weeks. The mediastinum was pathologically reassessed before or at the time of resection. Consolidation chemotherapy was weekly carboplatin (area under the curve = 6) and paclitaxel, 200 mg/m2 every 21 days for two courses. The study was designed to detect an improvement in MNS from 52% to 72%. With use of a 0.15 one-sided type 1 error and 80% power, 97 patients were needed. Results The study was opened in November 2010 and closed in August 2015 by the Data Monitoring Committee after 71 patients had been accrued for futility and excessive toxicity in the experimental arm. A total of 60 patients were eligible: 19 patients (86%) who received CRT and 29 (76%) who received CRT plus panitumumab and underwent an operation. With regard to postoperative toxicity, there were three grade 4 adverse events (13.6%) and no grade 5 adverse events (0%) among those who received CRT versus six grade 4 (15.8%) and four grade 5 adverse events (10.5%) among those who received CRT plus panitumumab. The MNS rates were 68.2% (95% confidence interval: 45.1–86.1) and 50.0% (95% confidence interval: 33.4–66.6) for CRT and CRT plus panitumumab, respectively (p = 0.95). Conclusion The addition of panitumumab to CRT did not improve MNS. There was an unexpectedly high mortality rate in the panitumumab arm, although the relationship to panitumumab is unclear. The control arm had outcomes similar to those in NRG Oncology RTOG 0229.

AB - Introduction Multimodality therapy has curative potential in locally advanced NSCLC. Mediastinal nodal sterilization (MNS) after induction chemoradiotherapy (CRT) can serve as an intermediate marker for efficacy. NRG Oncology Radiation Therapy Oncology Group (RTOG) 0229 demonstrated the feasibility and efficacy of combining full-dose radiation (61.2 Gy) with chemotherapy followed by resection and chemotherapy. On the basis of that experience and evidence that EGFR antibodies are radiosensitizing, we explored adding panitumumab to CRT followed by resection and consolidation chemotherapy in locally advanced NSCLC with a primary end point of MNS. Methods Patients with resectable locally advanced NSCLC were eligible if deemed suitable for trimodality therapy before treatment. Surgeons were required to demonstrate expertise after CRT and adhere to specific management guidelines. Concurrent CRT consisted of weekly carboplatin (area under the curve = 2.0), paclitaxel (50 mg/m2), and 60 Gy of radiation therapy delivered in 30 fractions. There was a 2:1 randomization in favor of panitumumab at 2.5 mg/kg weekly for 6 weeks. The mediastinum was pathologically reassessed before or at the time of resection. Consolidation chemotherapy was weekly carboplatin (area under the curve = 6) and paclitaxel, 200 mg/m2 every 21 days for two courses. The study was designed to detect an improvement in MNS from 52% to 72%. With use of a 0.15 one-sided type 1 error and 80% power, 97 patients were needed. Results The study was opened in November 2010 and closed in August 2015 by the Data Monitoring Committee after 71 patients had been accrued for futility and excessive toxicity in the experimental arm. A total of 60 patients were eligible: 19 patients (86%) who received CRT and 29 (76%) who received CRT plus panitumumab and underwent an operation. With regard to postoperative toxicity, there were three grade 4 adverse events (13.6%) and no grade 5 adverse events (0%) among those who received CRT versus six grade 4 (15.8%) and four grade 5 adverse events (10.5%) among those who received CRT plus panitumumab. The MNS rates were 68.2% (95% confidence interval: 45.1–86.1) and 50.0% (95% confidence interval: 33.4–66.6) for CRT and CRT plus panitumumab, respectively (p = 0.95). Conclusion The addition of panitumumab to CRT did not improve MNS. There was an unexpectedly high mortality rate in the panitumumab arm, although the relationship to panitumumab is unclear. The control arm had outcomes similar to those in NRG Oncology RTOG 0229.

KW - Chemoradiotherapy

KW - EGFR antibody

KW - Multimodality

KW - NSCLC

KW - Panitumumab

KW - Preoperative

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