Thoracic Radiation Normal Tissue Injury☆
Introduction
Thoracic malignancies are a heterogenous group of cancers that included non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), esophageal cancer, thymoma, thymic carcinoma, and malignant pleural mesothelioma, as well as lymphomas and more rare tumors such as thoracic sarcomas and paragangliomas. Lung cancer is by far the most common thoracic malignancy in both developed and developing countries,1 and it is the leading cause of death among all malignancies, with an estimated 222,500 new cases and 155,870 deaths expected in the United States in 2017.2
Over 85% of patients with lung cancer are histologically classified as having NSCLC, and approximately 15% of patients with NSCLC present with localized disease that is confined to their primary tumor site.3 Among these patients, surgery has been considered the standard treatment modality for curative-intent therapy. However, owing to the high proportion of patients who are determined to be medically inoperable, largely due to comorbidities or advanced age,4, 5 radiation therapy has had an entrenched position as a curative-intent modality for nonoperable patients.
With local control and overall survival rates with conventionally fractionated radiotherapy for stage I NSCLC inferior to that with surgery, there was great interest in assessing first hypofractionation6 and then stereotactic body radiation therapy (SBRT).7, 8 Given the excellent local control rates and early high rates of survival, SBRT, also termed stereotactic ablative radiotherapy, has recently emerged as a potential alternative to surgery in medical operable patients with stage I NSCLC,9, 10 as well as an option for early-stage SCLC.11
The remainder of patients with nonmetastatic NSCLC and SCLC present with nodal metastases or more advanced primary tumors. These patients with NSCLC are considered to have locally advanced disease, whereas those with SCLC are considered to have limited-stage disease. For each of these groups, the standard-of-care treatment is concurrent chemoradiation. A primary study to define this standard for locally advanced NSCLC (LA-NSCLC) was the Radiation Therapy Oncology Group (RTOG) 94-10 trial.12 In that trial, 610 patients were randomized into the following 3 arms: (1) sequential cisplatin and vinblastine followed by radiation therapy to 63 Gy in 34 daily fractions (sequential arm), (2) concurrent cisplatin and vinblastine and radiation therapy to 63 Gy in 34 daily fractions (concurrent arm), and (3) concurrent cisplatin plus etoposide and hyperfractionated radiotherapy to 69.6 Gy in 58 twice-daily fractions (hyperfractionated arm). This landmark study demonstrated improved overall survival in the concurrent arm compared with the sequential arm (17.0 months vs 14.6 months). For limited-stage SCLC (LS-SCLC), the Japanese Cooperative Oncology Group randomized 231 patients to sequential vs concurrent chemotherapy (cisplatin and etoposide) and radiation therapy (45 Gy in 1.5 Gy twice-daily fractions).13 Concurrent therapy had numerically improved median survival (27.2 months vs 19.7 months). Although both studies provide a strong rationale for concurrent chemoradiation, both studies also demonstrated increased rates of toxicities with concurrent compared with sequential chemoradiation.
In this article, I describe the common and the dose-limited toxicities associated with radiation therapy for thoracic malignancies, with a focus on the toxicities of concurrent chemoradiation for lung cancer. Both acute and late toxicities are detailed. I also describe the management of radiation toxicities and the changing patterns of toxicities with advanced radiation delivery modalities such as SBRT, intensity-modulated radiation therapy (IMRT), and proton therapy.
Section snippets
Radiation Pneumonitis
Radiation pneumonitis, an inflammation of the normal lung tissues from radiation therapy, is a dose-limiting toxicity of thoracic radiation therapy. In hours to days after the initiation of irradiation to the lungs, acute inflammation predominates and is manifested by hyperemia, increased capillary permeability, leukocytic infiltration, and cytokine release of factors such as tumor necrosis factor-α, interleukin-6, and interleukin-1α. Subsequent exudative alveolitis and sustained acute
Pulmonary Fibrosis
The aforementioned cascade of acute lung parenchymal changes from irradiation can lead to chronic parenchymal damage. In fact, distinguishing between the resolution of acute pneumonitis and the development of late fibrosis is often not possible to be made clinically, and these 2 entities may constitute a continuous spectrum of radiation-induced lung toxicities or the development of radiation pneumonitis may increase the risk for the development of radiation fibrosis.48, 49
The mechanism of
Advanced Radiotherapy Techniques and Toxicity Implications
Since the publication of several sentinel chemoradiation trials for LA-NSCLC, LS-SCLC, and esophageal cancer that defined the expected rates of toxicities from therapy, multiple advances have been made to radiotherapy delivery that may now allow for lower toxicity rates in the modern era. IMRT is perhaps the most prominent and important such advance. By using inverse-planned computer algorithms to generate highly conformal irradiation dose distributions, IMRT can allow for substantial
Conclusions
Thoracic malignancies are a heterogeneous but difficult group of tumors to treat with radiation therapy, and treatment-induced toxicities are common and potentially life threatening. Factors associated with radiation pneumonitis and radiation esophagitis are relatively well defined, whereas there exists a knowledge gap as to the exact toxicities, mechanisms, and factors associated with the development of treatment-related cardiac toxicities. SBRT has emerged as a standard approach for
References (74)
- et al.
Trends in stereotactic body radiation therapy for stage I small cell lung cancer
Lung Cancer
(2017) - et al.
Stereotactic body radiation therapy for lung cancer
Chest
(2013) - et al.
Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: A pooled analysis of two randomised trials
Lancet Oncol
(2015) - et al.
Multi-institutional experience of stereotactic ablative radiation therapy for stage I small cell lung cancer
Int J Radiat Oncol Biol Phys
(2017) - et al.
Randomized phase III trial of radiation treatment +/− amifostine in patients with advanced-stage lung cancer
Int J Radiat Oncol Biol Phys
(2001) - et al.
Pentoxifylline in prevention of radiation-induced lung toxicity in patients with breast and lung cancer: A double-blind randomized trial
Int J Radiat Oncol Biol Phys
(2004) - et al.
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
(2015) - et al.
Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: An international individual patient data meta-analysis
Int J Radiat Oncol Biol Phys
(2013) - et al.
Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC)
Int J Radiat Oncol Biol Phys
(1999) - et al.
Radiation-induced pulmonary toxicity: A dose-volume histogram analysis in 201 patients with lung cancer
Int J Radiat Oncol Biol Phys
(2001)
Analysis of clinical and dosimetric factors associated with treatment-related pneumonitis (TRP) in patients with non-small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT)
Int J Radiat Oncol Biol Phys
Int J Radiat Oncol Biol Phys
Factors predicting severe radiation pneumonitis in patients receiving definitive chemoradiation for lung cancer
Int J Radiat Oncol Biol Phys
Applications of FDG PET/CT in the assessment and prediction of radiation therapy related complications
PET Clin
Predicting esophagitis after chemoradiation therapy for non-small cell lung cancer: An individual patient data meta-analysis
Int J Radiat Oncol Biol Phys
Palliative thoracic radiotherapy in non-small cell lung cancer. An analysis of 1250 patients. Palliation of symptoms, tolerance and toxicity
Lung Cancer
Effect of overall treatment time on outcomes after concurrent chemoradiation for locally advanced non-small-cell lung carcinoma: Analysis of the Radiation Therapy Oncology Group (RTOG) experience
Int J Radiat Oncol Biol Phys
Dosimetric and clinical predictors for radiation-induced esophageal injury
Int J Radiat Oncol Biol Phys
Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with three-dimensional conformal radiotherapy
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
Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma
Int J Radiat Oncol Biol Phys
Dosimetric predictors of radiation esophagitis in patients treated for non-small-cell lung cancer with carboplatin/paclitaxel/radiotherapy
Int J Radiat Oncol Biol Phys
Radiation dose-volume effects in the esophagus
Int J Radiat Oncol Biol Phys
Dosimetric predictors of esophageal toxicity after stereotactic body radiotherapy for central lung tumors
Radiother Oncol
Esophageal dose tolerance to hypofractionated stereotactic body radiation therapy: Risk factors for late toxicity
Int J Radiat Oncol Biol Phys
Influence of fractionation scheme and tumor location on toxicities after stereotactic body radiation therapy for large (≥5 cm) non-small cell lung cancer: A multi-institutional analysis
Int J Radiat Oncol Biol Phys
Radiation pneumonitis and fibrosis: Mechanisms underlying its pathogenesis and implications for future research
Int J Radiat Oncol Biol Phys
Predictive factors of late radiation fibrosis: A prospective study in non-small cell lung cancer
Int J Radiat Oncol Biol Phys
Radiation-induced lung injury
Semin Radiat Oncol
Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin’s lymphoma: An analysis from the St Jude Lifetime Cohort Study
Lancet Oncol
Radiation-associated cardiovascular disease
Crit Rev Oncol Hematol
Cardiac toxicity in association with chemotherapy and radiation therapy in a large cohort of older patients with non-small-cell lung cancer
Ann Oncol
Heart dose is an independent dosimetric predictor of overall survival in locally advanced non-small cell lung cancer
J Thorac Oncol
Consensus statement on proton therapy in early-stage and locally advanced non-small cell lung cancer
Int J Radiat Oncol Biol Phys
National cancer database analysis of proton versus photon radiation therapy in non-small cell lung cancer
Int J Radiat Oncol Biol Phys
Intensity-modulated proton therapy for elective nodal irradiation and involved-field radiation in the definitive treatment of locally advanced non-small-cell lung cancer: A dosimetric study
Clin Lung Cancer
First clinical investigation of cone beam computed tomography and deformable registration for adaptive proton therapy for lung cancer
Int J Radiat Oncol Biol Phys
Cited by (110)
Melatonin affects the expression of microRNA-21: A mini-review of current evidence
2024, Pathology Research and PracticeMulticenter Phase 1b/2a Clinical Trial of Radioprotectant BIO 300 Oral Suspension for Patients With Non-Small Cell Lung Cancer Receiving Concurrent Chemoradiotherapy
2024, International Journal of Radiation Oncology Biology PhysicsLung cancer reirradiation: Exploring modifications to utilization, treatment modalities and factors associated with outcomes
2024, Journal of Medical Imaging and Radiation SciencesPredicting the Effect of Proton Beam Therapy Technology on Pulmonary Toxicities for Patients With Locally Advanced Lung Cancer Enrolled in the Proton Collaborative Group Prospective Clinical Trial
2024, International Journal of Radiation Oncology Biology PhysicsEnabling ultra-high dose rate electron beams at a clinical linear accelerator for isocentric treatments
2023, Radiotherapy and OncologyDocosahexaenoic Acid Attenuates Radiation-Induced Myocardial Fibrosis by Inhibiting the p38/ET-1 Pathway in Cardiomyocytes
2023, International Journal of Radiation Oncology Biology PhysicsCitation Excerpt :As an essential cancer treatment strategy for thoracic malignant tumors, such as lung cancer and esophageal cancer, thoracic radiation therapy (RT) plays an important role in treating tumor lesions and improving patient overall survival. However, RT inevitably results in various corresponding complications, including radiation-induced heart damage,1-5 which causes noncancer-related mortality.6 As delayed cardiac damage, the development of radiation-induced myocardial fibrosis (RIMF) is a slow but continuous process, with an incidence up to 20% to 80%.7
- ☆
Conflict of interest: none.