Top

Published in:

01-02-2022 | NSCLC | Short Report

Planning target volume as a predictor of disease progression in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy and concurrent and/or sequential immune checkpoint inhibition

Authors: Julian Taugner, Lukas Käsmann, Monika Karin, Chukwuka Eze, Benedikt Flörsch, Julian Guggenberger, Minglun Li, Amanda Tufman, Niels Reinmuth, Thomas Duell, Claus Belka, Farkhad Manapov

Published in: Investigational New Drugs | Issue 1/2022

Summary

Background. The present study evaluates outcome after chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (CPI) for inoperable stage III NSCLC patients depending on planning target volume (PTV). Method and patients. Prospective data of thirty-three consecutive patients with inoperable stage III NSCLC treated with CRT and sequential durvalumab (67%, 22 patients) or concurrent and sequential nivolumab (33%, 11 patients) were analyzed. Different PTV cut offs and PTV as a continuous variable were evaluated for their association with progression-free (PFS), local–regional progression-free (LRPFS), extracranial distant metastasis-free (eMFS) and brain-metastasis free-survival (BMFS). Results. All patients were treated with conventionally fractionated thoracic radiotherapy (TRT); 93% to a total dose of at least 60 Gy, 97% of patients received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 19.9 (range: 6.0–42.4) months; median overall survival (OS), LRFS, BMFS and eMFS were not reached. Median PFS was 22.8 (95% CI: 10.7–34.8) months. Patients with PTV ≥ 900ccm had a significantly shorter PFS (6.9 vs 22.8 months, p = 0.020) and eMFS (8.1 months vs. not reached, p = 0.003). Furthermore, patients with PTV ≥ 900ccm and stage IIIC disease (UICC-TNM Classification 8th Edition) achieved a very poor outcome with a median PFS and eMFS of 3.6 vs 22.8 months (p < 0.001) and 3.6 months vs. not reached (p = 0.001), respectively. PTV as a continuous variable also had a significant impact on eMFS (p = 0.048). However, no significant association of different PTV cut-offs or PTV as a continuous variable with LRPFS and BMFS could be shown. The multivariate analysis that was performed for PTV ≥ 900ccm and age (≥ 65 years), gender (male), histology (non-ACC) as well as T- and N-stage (T4, N3) as covariates also revealed PTV ≥ 900ccm as the only factor that had a significant correlation with PFS (HR: 5.383 (95% CI:1.263–22.942, p = 0.023)). Conclusion. In this prospective analysis of inoperable stage III NSCLC patients treated with definitive CRT combined with concurrent and/or sequential CPI, significantly shorter PFS and eMFS were observed in patients with initial PTV ≥ 900ccm.

Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA A Cancer J Clin 69(1):7–34. https://doi.org/10.3322/caac.21551CrossRef

Taugner J, Eze C, Käsmann L et al (2020) Pattern-of-failure and salvage treatment analysis after chemoradiotherapy for inoperable stage III non-small cell lung cancer. Radiat Oncol 15(1):148. https://doi.org/10.1186/s13014-020-01590-8CrossRefPubMedPubMedCentral

Käsmann L, Taugner J, Eze C et al (2019) Performance Status and Its Changes Predict Outcome for Patients With Inoperable Stage III NSCLC Undergoing Multimodal Treatment. Anticancer Res 39(9):5077–5081. https://doi.org/10.21873/anticanres.13701CrossRefPubMed

Taugner J, Käsmann L, Eze C et al (2019) Survival score to characterize prognosis in inoperable stage III NSCLC after chemoradiotherapy. Transl Lung Cancer Res 8(5):593–604. https://doi.org/10.21037/tlcr.2019.09.19CrossRefPubMedPubMedCentral

Antonia SJ, Villegas A, Daniel D et al (2017) Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 377(20):1919–1929. https://doi.org/10.1056/NEJMoa1709937 CrossRefPubMed

Peters S, Felip E, Dafni U et al (2019) Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial. Lung Cancer 133:83–87. https://doi.org/10.1016/j.lungcan.2019.05.001CrossRefPubMed

Peters S, Felip E, Dafni U et al (2020) Progression-free and overall survival for concurrent nivolumab with standard concurrent chemo-radiotherapy in locally advanced stage IIIA/B NSCLC: Results from the European Thoracic Oncology Platform NICOLAS phase II trial (ETOP 6–14). J Thorac Oncol. https://doi.org/10.1016/j.jtho.2020.10.129CrossRefPubMedPubMedCentral

Käsmann L, Eze C, Taugner J et al (2020) Chemoradioimmunotherapy of inoperable stage III non-small cell lung cancer: immunological rationale and current clinical trials establishing a novel multimodal strategy. Radiat Oncol 15(1):167. https://doi.org/10.1186/s13014-020-01595-3CrossRefPubMedPubMedCentral

Antonia SJ, Villegas A, Daniel D et al (2018) Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med 379(24):2342–2350. https://doi.org/10.1056/NEJMoa1809697CrossRefPubMed

10.

Gray JE, Villegas A, Daniel D et al (2020) Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC-Update from PACIFIC. J Thorac Oncol 15(2):288–293. https://doi.org/10.1016/j.jtho.2019.10.002CrossRefPubMed

11.

Jung HA, Noh JM, Sun J-M et al (2020) Real world data of durvalumab consolidation after chemoradiotherapy in stage III non-small-cell lung cancer. Lung Cancer 146:23–29. https://doi.org/10.1016/j.lungcan.2020.05.035CrossRefPubMed

12.

Offin M, Shaverdian N, Rimner A et al (2020) Clinical outcomes, local-regional control and the role for metastasis-directed therapies in stage III non-small cell lung cancers treated with chemoradiation and durvalumab. Radiother Oncol 149:205–211. https://doi.org/10.1016/j.radonc.2020.04.047CrossRefPubMedPubMedCentral

13.

Käsmann L, Eze C, Taugner J, Roengvoraphoj O, Belka C, Manapov F (2020) Implementation of durvalumab maintenance treatment after concurrent chemoradiotherapy in inoperable stage III non-small cell lung cancer (NSCLC)-a German radiation oncology survey. Transl Lung Cancer Res 9(2):288–293. https://doi.org/10.21037/tlcr.2020.03.25CrossRefPubMedPubMedCentral

14.

Salama JK, Stinchcombe TE, Gu L et al (2011) Pulmonary toxicity in Stage III non-small cell lung cancer patients treated with high-dose (74 Gy) 3-dimensional conformal thoracic radiotherapy and concurrent chemotherapy following induction chemotherapy: a secondary analysis of Cancer and Leukemia Group B (CALGB) trial 30105. Int J Radiat Oncol Biol Phys 81(4):e269–e274. https://doi.org/10.1016/j.ijrobp.2011.01.056CrossRefPubMedPubMedCentral

15.

Bradley JD, Paulus R, Komaki R et al (2015) Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 16(2):187–199. https://doi.org/10.1016/S1470-2045(14)71207-0CrossRefPubMedPubMedCentral

16.

Bradley JD, Hu C, Komaki RR et al (2020) Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. J Clin Oncol 38(7):706–714. https://doi.org/10.1200/JCO.19.01162CrossRefPubMed

17.

Karin M, Taugner J, Käsmann L et al (2020) Association of Planning Target Volume with Patient Outcome in Inoperable Stage III NSCLC Treated with Chemoradiotherapy: A Comprehensive Single-Center Analysis. Cancers (Basel) 12(10). https://doi.org/10.3390/cancers12103035.

18.

Wiersma TG, Dahele M, Verbakel WFAR et al (2013) Concurrent chemoradiotherapy for large-volume locally-advanced non-small cell lung cancer. Lung Cancer 80(1):62–67. https://doi.org/10.1016/j.lungcan.2013.01.006CrossRefPubMed

19.

Nestle U, de Ruysscher D, Ricardi U et al (2018) ESTRO ACROP guidelines for target volume definition in the treatment of locally advanced non-small cell lung cancer. Radiother Oncol 127(1):1–5. https://doi.org/10.1016/j.radonc.2018.02.023CrossRefPubMed

20.

Ursula Nestle, Cecile Le Pechoux, Dirk De Ruysscher (2020) Evolving target volume concepts in locally advanced non-small cell lung cancer. Transl Lung Cancer Res 0(0). https://doi.org/10.21037/tlcr-20-805

21.

Werner-Wasik M, Swann RS, Bradley J et al (2008) Increasing tumor volume is predictive of poor overall and progression-free survival: secondary analysis of the Radiation Therapy Oncology Group 93–11 phase I-II radiation dose-escalation study in patients with inoperable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 70(2):385–390. https://doi.org/10.1016/j.ijrobp.2007.06.034CrossRefPubMed

22.

Hui R, Özgüroğlu M, Villegas A et al (2019) Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study. Lancet Oncol 20(12):1670–1680. https://doi.org/10.1016/S1470-2045(19)30519-4CrossRefPubMed

23.

Shaverdian N, Thor M, Shepherd AF et al (2020) Radiation pneumonitis in lung cancer patients treated with chemoradiation plus durvalumab. Cancer Med 9(13):4622–4631. https://doi.org/10.1002/cam4.3113CrossRefPubMedPubMedCentral

24.

Shaverdian N, Offin MD, Rimner A et al (2020) Utilization and factors precluding the initiation of consolidative durvalumab in unresectable stage III non-small cell lung cancer. Radiother Oncol 144:101–104. https://doi.org/10.1016/j.radonc.2019.11.015CrossRefPubMed

25.

Durm GA, Jabbour SK, Althouse SK et al (2020) A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14–179. Cancer 126(19):4353–4361. https://doi.org/10.1002/cncr.33083CrossRefPubMed

26.

Anouti B, Althouse S, Durm G, Hanna N (2020) Prognostic Variables Associated With Improved Outcomes in Patients With Stage III NSCLC Treated With Chemoradiation Followed by Consolidation Pembrolizumab: A Subset Analysis of a Phase II Study From the Hoosier Cancer Research Network LUN 14–179. Clin Lung Cancer 21(3):288–293. https://doi.org/10.1016/j.cllc.2019.06.009CrossRefPubMed

27.

Assess the Safety of Immunotherapy Induction With Tremelimumab and Durvalumab Prior to Chemoradiotherapy and/or Resection in the Treatment - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04287894?term=induction&cond=NSCLC&draw=2&rank=1. Updated February 23, 2021. Accessed February 23, 2021.

28.

Mario Negri Institute for Pharmacological Research, AstraZeneca, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano. BRIDGE Trial: Phase II Trial of durvalumaB and chemotheRapy Induction Followed by Durvalumab and Radiotherapy in larGe volumE Stage III NSCLC: NCT04765709, IRFMN-NSCLC-8187. https://clinicaltrials.gov/ct2/show/NCT04765709. Updated February 21, 2021. Accessed February 23, 2021.

29.

Phase-II Trial of Induction Chemotherapy and Chemoradiotherapy Plus/Minus Durvalumab and Consolidation Immunotherapy in Patients With Resectable Stage III NSCLC. - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04202809?term=induction&cond=NSCLC&draw=2&rank=4. Updated February 23, 2021. Accessed February 23, 2021.

30.

Durvalumab Followed by Chemoradiation and Consolidation Durvalumab for Stage III Non-small Cell Lung Cancer - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04364048?term=induction&recrs=abdf&cond=NSCLC&draw=3&rank=13. Updated February 23, 2021. Accessed February 23, 2021.

31.

Intensified Chemo-immuno-radiotherapy With Durvalumab for Stage III Non-Small Cell Lung Cancers - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04230408?term=induction&recrs=abdf&cond=NSCLC&draw=3&rank=19. Updated February 23, 2021. Accessed February 23, 2021.

Title: Planning target volume as a predictor of disease progression in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy and concurrent and/or sequential immune checkpoint inhibition
Authors: Julian Taugner
Lukas Käsmann
Monika Karin
Chukwuka Eze
Benedikt Flörsch
Julian Guggenberger
Minglun Li
Amanda Tufman
Niels Reinmuth
Thomas Duell
Claus Belka
Farkhad Manapov
Publication date: 01-02-2022
Publisher: Springer US
Keywords: NSCLC
NSCLC
Published in: Investigational New Drugs / Issue 1/2022
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-021-01143-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Summary

Please log in to get access to this content

Other articles of this Issue 1/2022

Anaphylactic shock in a small cell lung cancer patient receiving atezolizumab therapy: a rare but potentially fatal complication

Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies

A phase I trial of lurbinectedin in combination with cisplatin in patients with advanced solid tumors

KAT2B is an immune infiltration-associated biomarker predicting prognosis and response to immunotherapy in non‐small cell lung cancer

In vitro selection of DNA aptamers against human osteosarcoma

Author Correction: Antineoplastic activity of products derived from cellulose‑containing materials: levoglucosenone and structurally‑related derivatives as new alternatives for breast cancer treatment

Keynote webinar | Spotlight on antibody–drug conjugates in cancer