Final toxicity results of a radiation-dose escalation study in patients with non–small-cell lung cancer (NSCLC): Predictors for radiation pneumonitis and fibrosis

doi:10.1016/j.ijrobp.2006.01.051

International Journal of Radiation OncologyBiologyPhysics

Volume 65, Issue 4, 15 July 2006, Pages 1075-1086

This work was presented at the 13th European Cancer Conference, November 2nd, 2005.

https://doi.org/10.1016/j.ijrobp.2006.01.051 Get rights and content

Purpose: We aimed to report the final toxicity results on a radiation-dose escalation trial designed to test a hypothesis that very high doses of radiation could be safely administered to patients with non–small-cell lung cancer (NSCLC) by quantifying the dose–volume toxicity relationship of the lung.

Methods and Materials: A total of 109 patients with unresectable or medically inoperable NSCLC were enrolled and treated with radiation-dose escalation (on the basis of predicted normal-lung toxicity) either alone or with neoadjuvant chemotherapy by use of 3D conformal techniques. Eighty-four patients (77%) received more than 69 Gy, the trial was stopped after the dose reached 103 Gy. Estimated median follow-up was 110 months.

Results: There were 17 (14.6%) Grade 2 to 3 pneumonitis and 15 (13.8%) Grade 2 to 3 fibrosis and no Grade 4 to 5 lung toxicity. Multivariate analyses showed them to be (1) not associated with the dose prescribed to the tumor, and (2) significantly (p < 0.001) associated with lung-dosimetric parameters such as the mean lung dose (MLD), volume of lung that received at least 20 Gy (V20), and the normal-tissue complication probability (NTCP) of the lung. If cutoffs are 30% for V20, 20 Gy for MLD, and 10% for NTCP, these factors have positive predictive values of 50% to 71% and negative predictive value of 85% to 89%.

Conclusions: With long-term follow-up for toxicity, we have demonstrated that much higher doses of radiation than are traditionally administered can be safely delivered to a majority of patients with NSCLC. Quantitative lung dose–volume toxicity–based dose escalation can form the basis for individualized high-dose radiation treatment to maximize the therapeutic ratio in these patients.

Introduction

Evidence is emerging regarding a radiotherapeutic dose–response effect for local control of non–small-cell lung cancer (NSCLC) (1, 2, 3, 4, 5, 6, 7, 8). Early supportive evidence came from Radiation Therapy Oncology Group (RTOG) 7301, a four-arm randomized study that compared a 40-Gy split course and 40 Gy, 50 Gy, and 60 Gy continuous courses of radiation (2, 3). This trial demonstrated that the best local disease control occurred after a dose of 60 Gy. Although no randomized trials have been performed at higher dose levels, several retrospective analyses have suggested that doses higher than 60 Gy may improve local disease control and overall survival (4, 5, 6, 7). Schwegler et al. (8) demonstrated the elimination of gross and microscopic tumor in 20.5% of patients after a dose of 60 Gy and 64% of patients after 80 Gy, with improved local relapse–free and overall survival with the higher dose. We have recently reported that higher-dose radiation was associated with improved long- term tumor control and survival within the dose range of 63 Gy to 103 Gy (1).

High-dose radiation treatments, however, are not routinely employed in practice because of concerns about normal-tissue toxicity, largely lung toxicity. For the past 30 years, the most commonly prescribed radiation dose has been 60 Gy to 66 Gy. Radiation pneumonitis, an interstitial pulmonary inflammation that develops in up to 30% of patients after thoracic irradiation (9), is an important dose-limiting toxicity of radiation therapy for NSCLC. Thus, the development of a strategy to deliver high-dose radiation while avoiding radiation pneumonitis would offer the possibility of improving the therapeutic ratio of patients with NSCLC.

We hypothesized that radiation doses much higher than the common prescription dose of 60 Gy to 66 Gy could be safely administered to patients with NSCLC by the use of highly conformal techniques and elimination of elective nodal irradiation. We conducted a radiation-dose escalation trial to determine the maximum safe dose of radiation that could be administered as a function of normal-lung volume irradiated. The interim results of this trial, including data on maximum lung tolerance and part of the acute lung-toxicity results, were reported previously (10, 11, 12). Mature results are now available on all patients enrolled in this study. The purposes of this report are to report the final results of acute and late toxicity and to investigate the lung dose–volume toxicity relationship to identify potential predictors for clinically significant (Grade ≥ 2) radiation pneumonitis and fibrosis.

Section snippets

Study population

Details of protocol eligibility were previously described (10, 11, 12). In brief, subjects had to have newly diagnosed or recurrent Stage I to III, histologically confirmed NSCLC and no prior thoracic radiation. An ECOG performance status of 0 to 2 was required. No restrictions were placed on either the degree of weight loss or pulmonary compromise. Patients with biopsy-proven supraclavicular lymphadenopathy, documented malignant pleural or pericardial effusion, or noncontiguous involvement of

Patient characteristics

Between 1992 and 2000, 122 patients with NSCLC were enrolled into this study at the University of Michigan Hospital and 2 other affiliates. Thirteen patients were taken off the study: 1 died of a myocardial infarction during neoadjuvant chemotherapy; 3 had disease progression at CT simulation; and 9 failed to meet other (than lung) normal-tissue dose constraints (1 heart, 2 spinal cord, 6 esophagus). A total of 109 patients were, therefore, considered treatment eligible at the time of CT

Discussion

With long-term follow-up for toxicity, we have demonstrated that higher doses of radiation than are traditionally administered (60 Gy–66 Gy) can be safely delivered to a majority of patients with NSCLC by use of 3D conformal techniques without inclusion of elective nodal irradiation to minimize the volume of lung treated and by quantifying the relationships among dose, volume irradiated, and risk of toxicity. In 83 patients (76%) who received more than 69.3 Gy (maximum dose of 103 Gy), no Grade

Acknowledgments

The authors are grateful to Mary Martel, John M. Robertson, George Henning, Pete Possert, Fred Littles, Kemp Cease, Dean Brenner, and many others for supporting protocol conduct and recruitment; Molly Sullivan, Olivier Chapet, and Ming Chen for help on reviewing the toxicities; Daniel Normolle for help with data analysis; Julie Wietzke and Howard Sandler for protocol monitoring; The Veterans Administration Medical Center, Ann Arbor and the Center for Hematology-Oncology, Southeast, Michigan for

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Clinical investigationLungFinal toxicity results of a radiation-dose escalation study in patients with non–small-cell lung cancer (NSCLC): Predictors for radiation pneumonitis and fibrosis

Introduction

Section snippets

Study population

Patient characteristics

Discussion

Acknowledgments

High dose radiation improved local tumor control and overall survival in inoperable/unresectable non-small cell lung cancerLong-term results from radiation dose escalation study

Int J Radiat Oncol Biol Phys

Impact of tumor control on survival in carcinoma of the lung treated with irradiation

Int J Radiat Oncol Biol Phys

Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy

Cancer

Prognostic factors in the treatment of node-negative nonsmall cell lung carcinoma with radiotherapy alone

Int J Radiat Oncol Biol Phys

Dose, volume, and tumor control prediction in primary radiotherapy of non-small-cell lung cancer

Int J Radiat Oncol Biol Phys

Gross tumor volume, critical prognostic factor in patients treated with three-dimensional conformal radiation therapy for non-small-cell lung carcinoma

Int J Radiat Oncol Biol Phys

Improved local control with higher doses of radiation in large-volume stage III non-small-cell lung cancer

Int J Radiat Oncol Biol Phys

Inoperable non-small-cell bronchial carcinomaMacroscopic and microscopic tumor behavior during and after radiotherapy with curative intent

Schweiz Rundsch Med Prax

Radiation pneumonitis/fibrosis risk based on dosimetric, clinical, and location-related factors

Int J Radiat Oncol Biol Phys

Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapyUpdate of a phase I trial

J Clin Oncol

Results following treatment to doses of 92.4 or 102.9 Gy on a phase I dose escalation study for non-small cell lung cancer

Lung Cancer

Dose escalation for non-small cell lung cancer using conformal radiation therapy

Int J Radiat Oncol Biol Phys

Use of Veff and iso-NTCP in the implementation of dose escalation protocols

Int J Radiat Oncol Biol Phys

Comparing different NTCP models that predict the incidence of radiation pneumonitis

Int J Radiat Oncol Biol Phys

Do dose-volume metrics predict pulmonary function changes in lung irradiation?

Int J Radiat Oncol Biol Phys

Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer

Radiother Oncol

Radiation-induced pulmonary toxicityA dose-volume histogram analysis in 201 patients with lung cancer

Int J Radiat Oncol Biol Phys

Idiopathic interstitial pneumonia following bone marrow transplantationThe relationship with total body irradiation

Int J Radiat Oncol Biol Phys

Injury to the lung from cancer therapyClinical syndromes, measurable endpoints, and potential scoring systems

Int J Radiat Oncol Biol Phys

Clinical investigation
Lung
Final toxicity results of a radiation-dose escalation study in patients with non–small-cell lung cancer (NSCLC): Predictors for radiation pneumonitis and fibrosis