The relationship between dosimetric factors, side effects, and survival in patients with non–small cell lung cancer treated with definitive radiotherapy

doi:10.1016/j.meddos.2017.02.002

Medical Dosimetry

Volume 42, Issue 3, Autumn 2017, Pages 169-176

https://doi.org/10.1016/j.meddos.2017.02.002 Get rights and content

Abstract

The patients with non–small cell lung cancer (NSCLC) treated with definitive conformal radiotherapy (RT) were evaluated in terms of side effects and survival. Normal tissue complication probability (NTCP) was calculated for 68 patients treated between 2009 and 2012. Clinical and dosimetric factors were analyzed. The median dose of 63 Gy (range: 54 to 70 Gy) was given with conformal RT with blocks (n = 37), 3-dimensional conformal RT (3DCRT) (n = 11), or intensity-modulated RT (IMRT) (n = 20). Acute grade 1 to 2 radiation pneumonitis (RP) was seen in 13% of the patients. No significant relationship was found between RP and treatment and dosimetric factors (p > 0.05). There was a positive correlation between median “mean lung dose” (MLD) (17 Gy), lung V30 (20.5%), and NTCP (14%) (p < 0.001). Median and 2-year overall survival (OS) and progression-free survival (PFS) were 27 and 18 months and 51% and 42%, respectively. In univariate analysis, significant dose range for survival was found between 59.4 and 63 Gy (p < 0.01). In multivariate analysis, response (p = 0.001), fraction dose of 1.8 Gy (p = 0.002), MLD <18 Gy (p = 0.04) for OS and response (p < 0.001), total dose > 59.4 Gy (p = 0.01), and tumor biologically effective dose (BED)3_(Gy) ≤ 100.8 (p = 0.01) for PFS were found to be favorable factors. In our study, we found a linear correlation between NTCP and MLD for RP risk estimation in patients with NSCLC. Therapeutic dose range where MLD can be kept under 20 Gy with significant survival benefit was found between 59.4 and 63 Gy. Increased therapeutic efficacy will be possible using risk-adaptive RT techniques.

Introduction

Standard treatment of locally advanced non–small cell lung cancer (NSCLC) is definitive radiotherapy (RT) with concurrent chemotherapy (CHE).¹ Delivery of high “biologically effective dose (BED)” using different dose and fractionation (fx) schedules has been shown to improve local control (LC) and survival.² However, it is known that increase in radiation dose may have unfavorable effects on survival owing to treatment-related side effects.3, 4 Severe radiation pneumonitis (RP) is the most important treatment-related complication seen at a rate of 10% to 20%, and it has been reported that half of the cases die of this complication.⁵

Lung tolerance dose has been estimated from patients receiving only RT with 2-dimensional techniques, and normal tissue complication probability (NTCP) has been calculated using the Lyman-Kutcher-Burman (LKB) model until the 2000s.6, 7 With the advances in RT techniques, dose-volume histograms (DVH) have been started to be used to define normal tissue doses.¹ The specific DVH parameters to assess risk of RP include relative volumes of lung that receive more than a threshold dose (V_dose) (i.e., V20, V30) and mean lung dose (MLD). NTCP is calculated by converting the physical dose derived from DVH to an equivalent dose by using the linear-quadratic model.⁸ However, Rodrigues et al. reported that an ideal parameter for DVH has not been identified yet.⁹ Cutoff values for V20, MLD, and NTCP were found to be 30%, 20 Gy, and 10%, respectively, and positive and negative predictive values for identifying RP risk have been reported to be 50% to 71% and 85% to 89%, respectively.1, 10, 11

The Quantitative Analysis of Normal Tissue Effects in the Clinic study has raised the question of how many doses will be given to where, and it has been emphasized that large volumes should be taken into consideration, as the lung is considered as a parallel organ.¹² Studies on biomarkers and genetic variations are ongoing, and the use of individualized cutoff values for toxicity will be possible in the future.1, 13

In the light of these studies, we aimed to evaluate the clinical and dosimetric factors and their relationship with treatment-related side effects and survival in patients with NSCLC who received definitive RT with or without CHE and survived for at least 6 months.

Section snippets

Methods and Materials

A total of 68 patients treated between January 2009 and May 2012 were evaluated retrospectively. The study was approved by the ethics committee.

Eligibility criteria for this study were as follows: age ≥ 18 years; inoperable patients with histopathologically confirmed NSCLC; a Karnosfky performance status (KPS) ≥ 60; no previous RT or CHE; received at least ≥ 50 Gy; and written informed consent.

Staging had been performed based on computed tomography (CT) scan of the chest and abdomen or positron

Results

The median age was 59 (range: 36 to 81) years, and 60% of the patients had squamous cell carcinoma (Table 1). Staging was carried out according to the American Joint Committee on Cancer staging system v.7, 2010. Tumor and nodal maximum standardized uptake value (SUVmax) was recorded in 54 cases diagnosed with PET/CT.

One patient with postoperative relapse also received definitive RT. The median total dose was 63 Gy (range: 54 to 70 Gy). Except for 1 case, neoadjuvant, concurrent, and adjuvant

Discussion

The goal of definitive RT in patients with locally advanced NSCLC is to provide the highest tumor control without complication. Individualized treatment will be possible with the identification of predictive factors.⁵

The relationship between NTCP model, symptomatic RP, and dose distribution in 3-dimensional planning was first defined by Martel et al.¹⁵ Hernando et al. reported the probability of RP with 64% accuracy with dosimetric factors.¹⁶ Kong et al. demonstrated that the incidence of RP

Conflict of interest

None declared.

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: This study has not been previously presented elsewhere.

: Author contributions: Concept—D.O., S.S.; Design—D.O., S.S.; Supervision—S.S.; Resource—D.O.; S.S.; Materials—D.O., S.G.; Data collection and/or Processing—D.O., S.G., S.S.; Analysis and/or Interpretation—D.O., S.S., D.S.; Literature Search—D.O., S.S.; Critical reviews—S.S.; Writing—D.O., S.S.

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Dosimetry Contribution:The relationship between dosimetric factors, side effects, and survival in patients with non–small cell lung cancer treated with definitive radiotherapy

Abstract

Introduction

Section snippets

Methods and Materials

Results

Discussion

Conflict of interest

Int. J. Radiat. Oncol. Biol. Phys

Int. J. Radiat. Oncol. Biol. Phys

Int. J. Radiat. Oncol. Biol. Phys

Radiother. Oncol

Int. J. Radiat. Oncol. Biol. Phys

Int. J. Radiat. Oncol. Biol. Phys

Int. J. Radiat. Oncol. Biol. Phys

Int. J. Radiat. Oncol. Biol. Phys

Int. J. Radiat. Oncol. Biol. Phys

Int. J. Radiat. Oncol. Biol. Phys

Int. J. Radiat. Oncol. Biol. Phys

Int. J. Radiat. Oncol. Biol. Phys

Int. J. Radiat. Oncol. Biol. Phys

Lung

Dosimetry Contribution:
The relationship between dosimetric factors, side effects, and survival in patients with non–small cell lung cancer treated with definitive radiotherapy