Radiation Pneumonitis after Intensity-Modulated Radiotherapy for Esophageal Cancer: Institutional Data and a Systematic Review.
Topic: Radiation/Chemotherapy

Radiation pneumonitis (RP) is a serious complication that can occur after thoracic radiotherapy. The goal of this study is to investigate the incidence of RP after radiochemotherapy with intensity modulated radiotherapy (IMRT) in patients with esophageal cancer and correlate this with dose volume histogram (DVH) related parameters. For this purpose, the clinical course of 73 patients was evaluated and irradiation doses to the lungs were extracted from radiotherapy treatment plans. Furthermore, a systematic review on this topic was conducted across PubMed. In our institutional cohort, Common Terminology Criteria for Adverse Events (CTCAE) grade II or higher RP occurred in four patients (5.5%). The systematic review identified 493 titles of which 19 studies reporting 874 patients qualified for the final analysis. No grade IV or V RP after radiochemotherapy with IMRT for esophageal cancer was reported in the screened literature. Grade II or higher RP is reported in 6.6% of the patients. A higher incidence can be seen with increasing values for lung V20. In conclusion, our institutional data and the literature consistently show a low incidence of symptomatic RP after radiochemotherapy in patients with esophageal cancer treated with IMRT. However, efforts should be made to keep the lung V20 below 23% and specific caution is warranted in patients with pre-existing lung conditions.

PICO
Population: Patients with esophageal cancer undergoing radiochemotherapy with intensity modulated radiotherapy (IMRT)
Intervention: Incidence of radiation pneumonitis (RP) and correlation with dose volume histogram (DVH) related parameters
Comparison: N/A
Outcomes: To investigate the occurrence of RP after IMRT in patients with esophageal cancer, specifically looking at the incidence of CTCAE grade II or higher RP, the relationship with lung V20 values, and the overall symptomatic RP rate

Included studies:
title: The efficacy and safety of simultaneous integrated boost intensity-modulated radiation therapy for esophageal squamous cell carcinoma in Chinese population: A single institution experience.
abstract: To evaluate the clinical efficacy and toxicity of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) in patients with esophageal squamous cell carcinoma (ESCC) in Chinese population.
title: Expert Consensus Contouring Guidelines for Intensity Modulated Radiation Therapy in Esophageal and Gastroesophageal Junction Cancer.
abstract: Current guidelines for esophageal cancer contouring are derived from traditional 2-dimensional fields based on bony landmarks, and they do not provide sufficient anatomic detail to ensure consistent contouring for more conformal radiation therapy techniques such as intensity modulated radiation therapy (IMRT). Therefore, we convened an expert panel with the specific aim to derive contouring guidelines and generate an atlas for the clinical target volume (CTV) in esophageal or gastroesophageal junction (GEJ) cancer.
title: Phase I study of concurrent selective lymph node late course accelerated hyper-fractionated radiotherapy and pemetrexed, cisplatin for locally advanced esophageal squamous cell carcinoma.
abstract: The optimized concurrent chemoradiotherapy has not been established for patients with advanced esophageal squamous cell carcinoma (SCC). The aim of the present study was to evaluate the safety and efficacy of concurrent chemotherapy and selective lymph node (SLN) late course accelerated hyperfractionated (LCAF) intensity modulated radiotherapy (IMRT) for the patients with thoracic SCC. Twelve patients with T3-4N0-1M0-1a thoracic esophageal SCC were included. The total dose of SLN LCAF IMRT was 59.6 Gy/34 fractions in 5.4 weeks. The concurrent chemotherapy protocol was as following: cisplatin 10 mg/m(2) on days 1-5 and 22-26, pemetrexed in escalating doses, from the base level of 500 mg/m(2) once every 21 days. The primary objectives were to determine the maximum tolerated dose (MTD), recommended dose (RD), and dose limiting toxicities (DLTs). Secondary end point included determination of preliminary radiographic response rates. As a result, three patients were enrolled in dose level 1 with pemetrexed 500 mg/m(2) and nine patients in dose level 0 with 400 mg/m(2) , respectively. At dose level 1, DLTs occurred in two of three patients. However, only two of nine patients in Level 0 developed DLTs. The complete response and partial response were observed in eight and four patients, respectively. Furthermore, no patient experienced cancer progression with a median follow-up of 9 months. In conclusion, the concurrent SLN LCAF IMRT and chemotherapy is feasible. The MTD of pemetrexed in this regimen was 500 mg/m(2) and RD was 400 mg/m(2) . Although toxicities were common, the protocol was safe, well tolerated, and achieved an encouraging outcome.
title: Intracranial chordoma: an unusual confirmation of the diagnosis.
title: Comparison of dosimetric parameters and toxicity in esophageal cancer patients undergoing 3D conformal radiotherapy or VMAT.
abstract: Volumetric-modulated arc therapy (VMAT) achieves high conformity to the planned target volume (PTV) and good sparing of organs at risk (OAR). This study compares dosimetric parameters and toxicity in esophageal cancer (EC) patients treated with VMAT and 3D conformal radiotherapy (3D-CRT).
title: INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy.
abstract: To compare the local/regional control, survival, and toxicity of combined-modality therapy using high-dose (64.8 Gy) versus standard-dose (50.4 Gy) radiation therapy for the treatment of patients with esophageal cancer.
title: [Pyridine nucleotide concentrations in the muscles of rats following corticotropin and hydrocortisone administration].
title: Analysis of dose-volume parameters predicting radiation pneumonitis in patients with esophageal cancer treated with 3D-conformal radiation therapy or IMRT.
abstract: Multimodality therapy for esophageal cancer can cause various kinds of treatment-related sequelae, especially pulmonary toxicities. This prospective study aims to investigate the clinical and dosimetric parameters predicting lung injury in patients undergoing radiation therapy for esophageal cancer.
title: Simultaneous integrated boost intensity-modulated radiotherapy in esophageal carcinoma: early results of a phase II study.
abstract: The safety and efficacy of using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for patients with esophageal squamous cell carcinoma were evaluated in a single-institution phase II setting.
title: ATM polymorphisms predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy.
abstract: The ataxia telangiectasia mutated (ATM) gene mediates detection and repair of DNA damage. We investigated associations between ATM polymorphisms and severe radiation-induced pneumonitis (RP).
title: Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial.
abstract: Purpose Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non-small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities. Results The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P = .005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distant metastasis-free survival were not different between IMRT and 3D-CRT. IMRT was associated with less ≥ grade 3 pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses ( P < .05), and the volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis ( P < .05). The lung V5 was not associated with any ≥ grade 3 toxicity, whereas the lung V20 was associated with increased ≥ grade 3 pneumonitis risk on multivariable analysis ( P = .026). Conclusion IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC.
title: Phase I study of concurrent selective lymph node late-course accelerated hyperfractionated radiotherapy and S-1 plus cisplatin for locally advanced oesophageal squamous cell carcinoma.
abstract: This Phase I study aimed to assess the safety and efficacy of concurrent selective lymph node (SLN) late-course accelerated hyperfractionated (LCAF) intensity-modulated radiotherapy (IMRT) and S-1 plus cisplatin (CDDP) for the locally advanced oesophageal squamous-cell carcinoma (ESCC).
title: Feasibility of using intensity-modulated radiotherapy to improve lung sparing in treatment planning for distal esophageal cancer.
abstract: To evaluate the feasibility whether intensity-modulated radiotherapy (IMRT) can be used to reduce doses to normal lung than three-dimensional conformal radiotherapy (3 DCRT) in treating distal esophageal malignancies.
title: Phase II study of concurrent selective lymph node late course accelerated hyper-fractionated radiotherapy and pemetrexed and cisplatin for locally advanced oesophageal squamous cell carcinoma.
abstract: To determine the clinical efficacy and toxicity of pemetrexed combined with low-dose cisplatin (CDDP) concurrent with late-course accelerated hyperfractionated (LCAF) intensity-modulated radiation therapy (IMRT) in patients with inoperable locally advanced oesophageal squamous cell carcinoma (ESCC).
title: Challenges in defining radiation pneumonitis in patients with lung cancer.
abstract: To assess the difficulty of assigning a definitive clinical diagnosis of radiation (RT)-induced lung injury in patients irradiated for lung cancer.
title: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC).
title: Prospective assessment of dosimetric/physiologic-based models for predicting radiation pneumonitis.
abstract: Clinical and 3D dosimetric parameters are associated with symptomatic radiation pneumonitis rates in retrospective studies. Such parameters include: mean lung dose (MLD), radiation (RT) dose to perfused lung (via SPECT), and pre-RT lung function. Based on prior publications, we defined pre-RT criteria hypothesized to be predictive for later development of pneumonitis. We herein prospectively test the predictive abilities of these dosimetric/functional parameters on 2 cohorts of patients from Duke and The Netherlands Cancer Institute (NKI).
title: Volumetric modulated arc radiotherapy for esophageal cancer.
abstract: A treatment planning study was performed to evaluate the performance of volumetric arc modulation with RapidArc (RA) against 3D conformal radiation therapy (3D-CRT) and conventional intensity-modulated radiation therapy (IMRT) techniques for esophageal cancer. Computed tomgraphy scans of 10 patients were included in the study. 3D-CRT, 4-field IMRT, and single-arc and double-arc RA plans were generated with the aim to spare organs at risk (OAR) and healthy tissue while enforcing highly conformal target coverage. The planning objective was to deliver 54 Gy to the planning target volume (PTV) in 30 fractions. Plans were evaluated based on target conformity and dose-volume histograms of organs at risk (lung, spinal cord, and heart). The monitor unit (MU) and treatment delivery time were also evaluated to measure the treatment efficiency. The IMRT plan improves target conformity and spares OAR when compared with 3D-CRT. Target conformity improved with RA plans compared with IMRT. The mean lung dose was similar in all techniques. However, RA plans showed a reduction in the volume of the lung irradiated at V(₂₀Gy) and V(₃₀Gy) dose levels (range, 4.62-17.98%) compared with IMRT plans. The mean dose and D(₃₅%) of heart for the RA plans were better than the IMRT by 0.5-5.8%. Mean V(₁₀Gy) and integral dose to healthy tissue were almost similar in all techniques. But RA plans resulted in a reduced low-level dose bath (15-20 Gy) in the range of 14-16% compared with IMRT plans. The average MU needed to deliver the prescribed dose by RA technique was reduced by 20-25% compared with IMRT technique. The preliminary study on RA for esophageal cancers showed improvements in sparing OAR and healthy tissue with reduced beam-on time, whereas only double-arc RA offered improved target coverage compared with IMRT and 3D-CRT plans.