PRONTOX – proton therapy to reduce acute normal tissue toxicity in locally advanced non-small-cell lung carcinomas (NSCLC): study protocol for a randomised controlled trial

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Abstract

Background

Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients’ quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects.

Methods/design

This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week.

Discussion

The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects.

Trial registration

Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016.

Electronic supplementary material

The online version of this article (doi:10.1186/s13063-016-1679-4) contains supplementary material, which is available to authorized users.

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Most cited references 13

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Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis.

David A. Palma, Suresh Senan, Kayoko Tsujino … (2013)

Radiation pneumonitis is a dose-limiting toxicity for patients undergoing concurrent chemoradiation therapy (CCRT) for non-small cell lung cancer (NSCLC). We performed an individual patient data meta-analysis to determine factors predictive of clinically significant pneumonitis. After a systematic review of the literature, data were obtained on 836 patients who underwent CCRT in Europe, North America, and Asia. Patients were randomly divided into training and validation sets (two-thirds vs one-third of patients). Factors predictive of symptomatic pneumonitis (grade ≥2 by 1 of several scoring systems) or fatal pneumonitis were evaluated using logistic regression. Recursive partitioning analysis (RPA) was used to define risk groups. The median radiation therapy dose was 60 Gy, and the median follow-up time was 2.3 years. Most patients received concurrent cisplatin/etoposide (38%) or carboplatin/paclitaxel (26%). The overall rate of symptomatic pneumonitis was 29.8% (n=249), with fatal pneumonitis in 1.9% (n=16). In the training set, factors predictive of symptomatic pneumonitis were lung volume receiving ≥20 Gy (V(20)) (odds ratio [OR] 1.03 per 1% increase, P=.008), and carboplatin/paclitaxel chemotherapy (OR 3.33, P 0.65). On RPA, the highest risk of pneumonitis (>50%) was in patients >65 years of age receiving carboplatin/paclitaxel. Predictors of fatal pneumonitis were daily dose >2 Gy, V(20), and lower-lobe tumor location. Several treatment-related risk factors predict the development of symptomatic pneumonitis, and elderly patients who undergo CCRT with carboplatin-paclitaxel chemotherapy are at highest risk. Fatal pneumonitis, although uncommon, is related to dosimetric factors and tumor location. Copyright © 2013 Elsevier Inc. All rights reserved.

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Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients.

A. Auperin, C Le Péchoux, J.P. Pignon … (2006)

Despite several randomised trials comparing radiotherapy alone with concomitant radio-chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC), it is not clear whether the addition of chemotherapy improves survival. This meta-analysis was based on individual patient data from published and unpublished randomised trials which compared radiotherapy alone with the same radiotherapy combined with concomitant cisplatin- or carboplatin-based chemotherapy. Trials with accrual completed after 2000 were excluded. Trials were sought in electronic databases, clinical trial registries and by additional manual searches. The primary endpoint was overall survival analysed using the log-rank test stratified by trials. There were twelve eligible trials that included a total of 1921 patients. The data from 3 trials were not available. Therefore, the analysis was based on 9 trials including 1764 patients. Median follow-up was 7.2 years. The hazard ratio of death among patients treated with radio-chemotherapy compared to radiotherapy alone was 0.89 (95% confidence interval, 0.81-0.98; P = 0.02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. There was some evidence of heterogeneity among trials and sensitivity analyses did not lead to consistent results. The combination of platin with etoposide seemed more effective than platin alone. Concomitant platin-based radio-chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.

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Mature results of an individualized radiation dose prescription study based on normal tissue constraints in stages I to III non-small-cell lung cancer.

Angela Baardwijk, S. Wanders, Wiel Geraedts … (2010)

We previously showed that individualized radiation dose escalation based on normal tissue constraints would allow safe administration of high radiation doses with low complication rate. Here, we report the mature results of a prospective, single-arm study that used this individualized tolerable dose approach. In total, 166 patients with stage III or medically inoperable stage I to II non-small-cell lung cancer, WHO performance status 0 to 2, a forced expiratory volume at 1 second and diffusing capacity of lungs for carbon monoxide >or= 30% were included. Patients were irradiated using an individualized prescribed total tumor dose (TTD) based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8 Gy fractions twice daily. Only sequential chemoradiation was administered. The primary end point was overall survival (OS), and the secondary end point was toxicity according to Common Terminology Criteria of Adverse Events (CTCAE) v3.0. The median prescribed TTD was 64.8 Gy (standard deviation, +/- 11.4 Gy) delivered in 25 +/- 5.8 days. With a median follow-up of 31.6 months, the median OS was 21.0 months with a 1-year OS of 68.7% and a 2-year OS of 45.0%. Multivariable analysis showed that only a large gross tumor volume significantly decreased OS (P < .001). Both acute (grade 3, 21.1%; grade 4, 2.4%) and late toxicity (grade 3, 4.2%; grade 4, 1.8%) were acceptable. Individualized prescribed radical radiotherapy based on normal tissue constraints with sequential chemoradiation shows survival rates that come close to results of concurrent chemoradiation schedules, with acceptable acute and late toxicity. A prospective randomized study is warranted to further investigate its efficacy.

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Author and article information

Contributors

Sebastian Zschaeck: sebastian.zschaeck@uniklinikum-dresden.de

Monique Simon: m.simon@dkfz-heidelberg.de

Steffen Löck: steffen.loeck@oncoray.de

Esther G. C. Troost: esther.troost@uniklinikum-dresden.de

Kristin Stützer: kristin.stuetzer@oncoray.de

Patrick Wohlfahrt: patrick.wohlfahrt@oncoray.de

Steffen Appold: steffen.appold@uniklinikum-dresden.de

Sebastian Makocki: sebastian.makocki@uniklinikum-dresden.de

Rebecca Bütof: rebecca.buetof@uniklinikum-dresden.de

Christian Richter: christian.richter@oncoray.de

Michael Baumann: michael.baumann@uniklinikum-dresden.de

Mechthild Krause: mechthild.krause@uniklinikum-dresden.de

Journal

Journal ID (nlm-ta): Trials

Journal ID (iso-abbrev): Trials

Title: Trials

Publisher: BioMed Central (London )

ISSN (Electronic): 1745-6215

Publication date (Electronic): 15 November 2016

Publication date PMC-release: 15 November 2016

Publication date Collection: 2016

Volume: 17

Electronic Location Identifier: 543

Affiliations

[1 ]Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden – Rossendorf, German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Partner Site Dresden, Fetscherstr. 74, Dresden, 01307 Germany

[2 ]German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, National Center for Tumor Diseases (NCT), Partner Site Dresden, Fetscherstr. 74, Dresden, 01307 Germany

[3 ]OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden – Rossendorf, National Center for Tumor Diseases (NCT), Partner Site Dresden, Fetscherstr. 74, Dresden, 01307 Germany

[4 ]Helmholtz-Zentrum Dresden – Rossendorf, Institute of Radiooncology, Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, OncoRay – National Center for Radiation Research in Oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Partner Site Dresden, Bautzner Landstr. 400, Dresden, 01328 Germany

[5 ]OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden – Rossendorf, Fetscherstr. 74, PF 41, Dresden, 01307 Germany

[6 ]Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, National Center for Tumor Diseases (NCT), Partner Site Dresden, Fetscherstr. 74, Dresden, 01307 Germany

[7 ]Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden – Rossendorf, National Center for Tumor Diseases (NCT), Partner Site Dresden, Fetscherstr. 74, Dresden, 01307 Germany

[8 ]OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus and Helmholtz-Zentrum Dresden – Rossendorf, Technische Universität Dresden,German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), Heidelberg, Helmholtz-Zentrum Dresden – Rossendorf, Institute of Radiooncology, Fetscherstr. 74, Dresden, 01307 Germany

[9 ]Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden – Rossendorf, German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ) Heidelberg, Helmholtz-Zentrum Dresden – Rossendorf, Institute of Radiooncology, National Center for Tumor Diseases (NCT), Partner Site Dresden, Fetscherstr. 74, Dresden, 01307 Germany

[10 ]Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden – Rossendorf German Cancer Consortium (DKTK) Dresden, German Cancer Research Center (DKFZ) Heidelberg, Helmholtz-Zentrum Dresden – Rossendorf, National Center for Tumor Diseases (NCT), Partner Site Dresden, Fetscherstr. 74, Dresden, 01307 Germany

Article

Publisher ID: 1679

DOI: 10.1186/s13063-016-1679-4

PMC ID: 5111266

PubMed ID: 27846903

SO-VID: b5b59e7f-79a2-4c9f-b5c7-acd81f870b64

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 26 May 2016

Date accepted : 3 November 2016

Funding

Funded by: German Cancer Consortium (DKTK) Dresden

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: proton radiotherapy,non-small-cell lung cancer (nsclc),locally advanced,photon radiotherapy,toxicity,randomised clinical trial,phase ii trial

Data availability:

ScienceOpen disciplines: Medicine

Keywords: proton radiotherapy, non-small-cell lung cancer (nsclc), locally advanced, photon radiotherapy, toxicity, randomised clinical trial, phase ii trial

PRONTOX – proton therapy to reduce acute normal tissue toxicity in locally advanced non-small-cell lung carcinomas (NSCLC): study protocol for a randomised controlled trial

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Abstract

Background

Methods/design

Discussion

Trial registration

Electronic supplementary material

Related collections

Herbal Medicines Journal (Herb Med J)

Most cited references 13

Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis.

Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients.

Mature results of an individualized radiation dose prescription study based on normal tissue constraints in stages I to III non-small-cell lung cancer.

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