Kong FM, Ten Haken R, Eisbruch A, Lawrence TS.
Non-small cell lung cancer therapy-related pulmonary toxicity: an update on radiation pneumonitis and fibrosis.
Semin Oncol. 2005 Apr;32(2 Suppl 3):S42-54. doi: 10.1053/j.seminoncol.2005.03.009.
Abstract/Text
Successful treatment of non-small cell lung cancer requires adequate local and systemic disease control. Although it has been shown to have superior results, high-dose radiation therapy is not a current practice largely because of concerns of normal tissue toxicity. This article reviews and updates the possible mechanism of radiation-induced pneumonitis and fibrosis, their associations with dose intensity, and the role they may play in making treatment decisions. The commonly used clinical terminology and grading systems are summarized. Pneumonitis and fibrosis after 3-dimensional conformal high-dose radiation are reviewed, including recent updates from radiation dose escalation trials. Chemotherapy- and chemoradiation-related lung toxicities are also discussed. Individual susceptibility and potential predictive models are examined; dose and 3-dimensional dosimetric parameters are reviewed along with estimation of normal tissue complication probability and biologic predictive assays. Based on the risk levels of toxicity for each patient, future clinical trials may be designed to maximize individual therapeutic gain.
Nagata Y, Hiraoka M, Mizowaki T, Narita Y, Matsuo Y, Norihisa Y, Onishi H, Shirato H.
Survey of stereotactic body radiation therapy in Japan by the Japan 3-D Conformal External Beam Radiotherapy Group.
Int J Radiat Oncol Biol Phys. 2009 Oct 1;75(2):343-7. doi: 10.1016/j.ijrobp.2009.02.087.
Abstract/Text
PURPOSE: To recognize the current status of stereotactic body radiotherapy (SBRT) in Japan, using a nationwide survey conducted by the Japan 3-D Conformal External Beam Radiotherapy Group.
METHODS AND MATERIALS: The questionnaire was sent by mail to 117 institutions. Ninety-four institutions (80%) responded by the end of November 2005. Fifty-three institutions indicated that they have already started SBRT, and 38 institutions had been reimbursed by insurance.
RESULTS: A total of 1111 patients with histologically confirmed lung cancer were treated. Among these patients, 637 had T1N0M0 and 272 had T2N0M0 lung cancer. Metastatic lung cancer was found in 702 and histologically unconfirmed lung tumor in 291 patients. Primary liver cancer was found in 207 and metastatic liver cancer in 76 patients. The most frequent schedule used for primary lung cancer was 48 Gy in 4 fractions at 22 institutions (52%), followed by 50 Gy in 5 fractions at 11 institutions (26%) and 60 Gy in 8 fractions at 4 institutions (10%). The tendency was the same for metastatic lung cancer. The average number of personnel involved in SBRT was 1.8 radiation oncologists, including 1.1 certified radiation oncologists, 2.8 technologists, 0.7 nurses, and 0.6 certified quality assurance personnel and 0.3 physicists. The most frequent amount of time for treatment planning was 61-120 min, for quality assurance was 50-60 min, and for treatment was 30 min. There were 14 (0.6% of all cases) reported Grade 5 complications: 11 cases of radiation pneumonitis, 2 cases of hemoptysis, and 1 case of radiation esophagitis.
CONCLUSION: The current status of SBRT in Japan was surveyed.
Nagata Y, Hiraoka M, Shibata T, Onishi H, Kokubo M, Karasawa K, Shioyama Y, Onimaru R, Kozuka T, Kunieda E, Saito T, Nakagawa K, Hareyama M, Takai Y, Hayakawa K, Mitsuhashi N, Ishikura S.
Prospective Trial of Stereotactic Body Radiation Therapy for Both Operable and Inoperable T1N0M0 Non-Small Cell Lung Cancer: Japan Clinical Oncology Group Study JCOG0403.
Int J Radiat Oncol Biol Phys. 2015 Dec 1;93(5):989-96. doi: 10.1016/j.ijrobp.2015.07.2278. Epub 2015 Nov 11.
Abstract/Text
PURPOSE: To evaluate, in Japan Clinical Oncology Group study 0403, the safety and efficacy of stereotactic body radiation therapy (SBRT) in patients with T1N0M0 non-small cell lung cancer (NSCLC).
METHODS AND MATERIALS: Eligibility criteria included histologically or cytologically proven NSCLC, clinical T1N0M0. Prescribed dose was 48 Gy at the isocenter in 4 fractions. The primary endpoint was the percent (%) 3-year overall survival. The threshold % 3-year survival to be rejected was set at 35% for inoperable patients, whereas the expected % 3-year survival was 80% for operable patients.
RESULTS: Between July 2004 and November 2008, 169 patients from 15 institutions were registered. One hundred inoperable and 64 operable patients (total 164) were eligible. Patients' characteristics were 122 male, 47 female; median age 78 years (range, 50-91 years); adenocarcinomas, 90; squamous cell carcinomas, 61; others, 18. Of the 100 inoperable patients, the % 3-year OS was 59.9% (95% confidence interval 49.6%-68.8%). Grade 3 and 4 toxicities were observed in 10 and 2 patients, respectively. No grade 5 toxicity was observed. Of the 64 operable patients, the % 3-year OS was 76.5% (95% confidence interval 64.0%-85.1%). Grade 3 toxicities were observed in 5 patients. No grade 4 and 5 toxicities were observed.
CONCLUSIONS: Stereotactic body radiation therapy for stage I NSCLC is effective, with low incidences of severe toxicity. This treatment can be considered a standard treatment for inoperable stage I NSCLC. This treatment is promising as an alternative to surgery for operable stage I NSCLC.
Copyright © 2015 Elsevier Inc. All rights reserved.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators.
Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.
N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.1056/NEJMoa1709937. Epub 2017 Sep 8.
Abstract/Text
BACKGROUND: Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy.
METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety.
RESULTS: Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events.
CONCLUSIONS: Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).
Gray JE, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, Cho BC, Planchard D, Paz-Ares L, Faivre-Finn C, Vansteenkiste JF, Spigel DR, Wadsworth C, Taboada M, Dennis PA, Özgüroğlu M, Antonia SJ.
Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC-Update from PACIFIC.
J Thorac Oncol. 2020 Feb;15(2):288-293. doi: 10.1016/j.jtho.2019.10.002. Epub 2019 Oct 14.
Abstract/Text
INTRODUCTION: In the phase 3 PACIFIC study of patients with unresectable stage III NSCLC without progression after chemoradiotherapy, durvalumab demonstrated significant improvements versus placebo in the primary end points of progression-free survival (hazard ratio [HR] = 0.52, 95% confidence interval [CI]: 0.42-65, p < 0.0001) and overall survival (OS) (HR = 0.68, 95% CI: 0.53-0.87, p = 0.00251), with manageable safety and no detrimental effect on patient-reported outcomes. Here, we report 3-year OS rates for all patients randomized in the PACIFIC study.
METHODS: Patients, stratified by age, sex, and smoking history, were randomized (2:1) to receive durvalumab, 10 mg/kg intravenously every 2 weeks, or placebo for up to 12 months. OS was analyzed by using a stratified log-rank test in the intention-to-treat population. Medians and rates at 12, 24, and 36 months were estimated by the Kaplan-Meier method.
RESULTS: As of January 31, 2019, 48.2% of patients had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). The median duration of follow-up was 33.3 months. The updated OS remained consistent with that previously reported (stratified HR = 0.69 [95% CI: 0.55-0.86]); the median OS was not reached with durvalumab but was 29.1 months with placebo. The 12-, 24- and 36-month OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively. All secondary outcomes examined showed improvements consistent with previous analyses.
CONCLUSIONS: Updated OS data from PACIFIC, including 3-year survival rates, demonstrate the long-term clinical benefit with durvalumab after chemoradiotherapy and further establish the PACIFIC regimen as the standard of care in this population.
Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
J. Vansteenkiste, J. Naidoo, C. Faivre-Finn, M. Özgüroğlu, A. Villegas, D. Daniel,et al., MA05. 02 PACIFIC Subgroup Analysis: Pneumonitis in Stage III, Unresectable NSCLC Patients Treated with Durvalumab vs. Placebo After CRT, J. Thorac. Oncol 13 S370-S1.
Murakami S, Özgüroğlu M, Villegas A, et al. PACIFIC: A double-blind, placebo-controlled Phase III study of durvalumab as consolidation therapy after chemoradiation in patients with locally advanced, unresectable NSCLC（ESMO Asia 2017 Congress, 403O）. Ann oncol 2017; 28（suppl_10） mdx670.
Tsukita Y, Yamamoto T, Mayahara H, Hata A, Takeda Y, Nakayama H, Tanaka S, Uchida J, Usui K, Toyoda T, Tamiya M, Morimoto M, Oya Y, Kodaira T, Miyauchi E, Jingu K, Sugiura H.
Intensity-modulated radiation therapy with concurrent chemotherapy followed by durvalumab for stage III non-small cell lung cancer: A multi-center retrospective study.
Radiother Oncol. 2021 Jul;160:266-272. doi: 10.1016/j.radonc.2021.05.016. Epub 2021 May 21.
Abstract/Text
BACKGROUND AND PURPOSE: Intensity-modulated radiation therapy (IMRT) is increasingly applied in concurrent chemoradiotherapy (CCRT) for locally-advanced non-small cell lung cancer (NSCLC), with improvement of target coverage and better sparing of normal tissue. IMRT tends to have a larger low-dose irradiation volume than 3D conformal radiotherapy, but the incidence of and risk factors for pneumonitis remain unclear, especially following the approval of durvalumab.
MATERIALS AND METHODS: We retrospectively reviewed the records of NSCLC patients treated by CCRT using IMRT at seven Japanese institutions. Primary outcomes were incidence of symptomatic pneumonitis and progression-free survival (PFS). Multivariate logistic regression analysis was used to identify risk factors for ≥grade 2 pneumonitis.
RESULTS: Median follow-up from the start of CCRT was 14.3 months (n = 107 patients; median age 70 years, 29% female). Median lung V5 and V20 was 49.2% and 19.5%, respectively. Durvalumab was administered to 87 patients (81%). Pneumonitis developed in 95 (89%) patients of which 53% had grade 1, 28% grade 2, 6.5% grade 3, and 0.9% grade 4. Durvalumab had been discontinued in 16 patients (18.4%) due to pneumonitis. By multivariate analysis, age ≥70 years, male sex, and V5 ≥58.9% were identified as significantly associated with ≥grade 2 pneumonitis (p = 0.0065, 0.036 and 0.0013 respectively). The median PFS from the start of CCRT was not reached (95% CI, 14.2 months to not reached) in patients receiving durvalumab.
CONCLUSION: CCRT using IMRT followed by durvalumab was generally effective and tolerable; V5 <60% would be recommended to avoid symptomatic pneumonitis.
Copyright © 2021 Elsevier B.V. All rights reserved.
Shintani T, Kishi N, Matsuo Y, Ogura M, Mitsuyoshi T, Araki N, Fujii K, Okumura S, Nakamatsu K, Kishi T, Atsuta T, Sakamoto T, Narabayashi M, Ishida Y, Sakamoto M, Fujishiro S, Katagiri T, Kim YH, Mizowaki T.
Incidence and Risk Factors of Symptomatic Radiation Pneumonitis in Non-Small-Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy and Consolidation Durvalumab.
Clin Lung Cancer. 2021 Sep;22(5):401-410. doi: 10.1016/j.cllc.2021.01.017. Epub 2021 Feb 4.
Abstract/Text
INTRODUCTION: Data on the risk factors for symptomatic radiation pneumonitis (RP) in non-small-cell lung cancer (NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) and consolidation durvalumab are limited; we aimed to investigate these risk factors.
MATERIALS AND METHODS: This multicenter retrospective study, conducted at 15 institutions in Japan, included patients who were ≥20 years of age; who started definitive CCRT for NSCLC between July 1, 2018, and July 31, 2019; and who then received durvalumab. The primary endpoint was grade 2 or worse (grade 2+) RP.
RESULTS: In the 146 patients analyzed, the median follow-up period was 16 months. A majority of the patients had stage III disease (86%), received radiation doses of 60 to 66 Gy equivalent in 2-Gy fractions (93%) and carboplatin and paclitaxel/nab-paclitaxel (77%), and underwent elective nodal irradiation (71%) and 3-dimensional conformal radiotherapy (75%). RP grade 2 was observed in 44 patients (30%); grade 3, in four patients (3%); grade 4, in one patient (1%); and grade 5, in one patient (1%). In the multivariable analysis, lung V20 was a significant risk factor, whereas age, sex, smoking history, irradiation technique, and chemotherapy regimen were not. The 12-month grade 2+ RP incidence was 34.4% (95% confidence interval [CI], 26.7%-42.1%); the values were 50.0% (95% CI, 34.7%-63.5%) and 27.1% (95% CI, 18.8%-36.2%) in those with lung V20 ≥ 26% and < 26%, respectively (P = .007).
CONCLUSION: The incidence of grade 2+ RP was relatively high in this multicenter real-world study, and its risk increased remarkably at elevated lung V20. Our findings can aid in RP risk prediction and the safe radiotherapy treatment planning.
Copyright © 2021. Published by Elsevier Inc.
Saito G, Oya Y, Taniguchi Y, Kawachi H, Daichi F, Matsumoto H, Iwasawa S, Suzuki H, Niitsu T, Miyauchi E, Yokoi T, Yokoyama T, Uenami T, Sakata Y, Arai D, Okada A, Nagata K, Teraoka S, Kokubo M.
Real-world survey of pneumonitis and its impact on durvalumab consolidation therapy in patients with non-small cell lung cancer who received chemoradiotherapy after durvalumab approval (HOPE-005/CRIMSON).
Lung Cancer. 2021 Nov;161:86-93. doi: 10.1016/j.lungcan.2021.08.019. Epub 2021 Sep 5.
Abstract/Text
OBJECTIVES: The incidence of real-world pneumonitis and durvalumab rechallenge during chemoradiotherapy and durvalumab consolidation for non-small cell lung cancer is unknown.
MATERIALS AND METHODS: We retrospectively evaluated the medical records of 302 consecutive patients diagnosed with non-small cell lung cancer who started chemoradiotherapy between May 2018 and May 2019.
RESULTS: Median age was 70 (range: 40-87) years. Volume of lung parenchyma that received 20 Gy (V20) exceeded 35% in 2% and mean lung dose exceeded 20 Gy in 1% of patients. Durvalumab consolidation was delivered to 225 patients (75%). Overall, 83% (n = 251), 34% (n = 103), 7% (n = 21), and 1% (n = 4) of the patients developed any grade of pneumonitis, symptomatic pneumonitis, ≥grade 3 pneumonitis, and fatal (grade 5) pneumonitis, respectively. Corticosteroids were administered to 25% of the patients to treat pneumonitis. Multivariate analysis identified the predictive factors for the development of symptomatic pneumonitis: V20 Gy or more ≥ 25% (odds ratio [OR]: 2.37, P = 0.008) and mean lung dose (MLD) ≥ 10 Gy (OR: 1.93, P < 0.0047). Of the 52 patients who received corticosteroids for pneumonitis after durvalumab initiation, 21 were rechallenged with durvalumab. Overall, 81% of patients met the PACIFIC study's rechallenge criteria and did not experience a severe pneumonitis relapse.
CONCLUSION: High V20 and MLD were independent risk factors of symptomatic pneumonitis. More than 80% of the patients who were rechallenged with durvalumab after pneumonitis met the PACIFIC study's rechallenge criteria. Consequently, severe relapse did not occur. Cooperation between radiation and medical oncologists is important for safe chemoradiotherapy and the safe completion of durvalumab consolidation therapy.
Copyright © 2021 Elsevier B.V. All rights reserved.
Oshiro Y, Mizumoto M, Sekino Y, Maruo K, Ishida T, Sumiya T, Nakamura M, Ohkawa A, Takizawa D, Okumura T, Tamaki Y, Sakurai H.
Risk factor of pneumonitis on dose-volume relationship for chemoradiotherapy with durvalumab: Multi-institutional research in Japan.
Clin Transl Radiat Oncol. 2021 Jul;29:54-59. doi: 10.1016/j.ctro.2021.05.009. Epub 2021 May 29.
Abstract/Text
OBJECTIVES: To estimate appropriate dose-volume parameters for avoidance of pneumonitis in use of chemoradiotherapy and durvalumab for treatment of lung cancer.
MATERIALS AND METHODS: Patients with non-small cell lung cancer treated with concurrent chemoradiotherapy followed by durvalumab at 9 centers were enrolled in the study. Three-dimensional radiotherapy, intensity modulated radiotherapy, and proton beam therapy were used. The frequency and severity of pneumonitis and the dose-volume relationship for normal lung were evaluated. Univariable and multivariable analyses were conducted to identify risk factors. A covariate adjusted hazard ratio was then estimated for the percentages of normal lung volume irradiated at ≥ X Gy (Vx) (X = 5-40) and lung volume non-irradiated at ≥ X Gy (X = 5-40), with the covariates selected in the variable selection. Cumulative incidence functions and covariate adjusted hazard ratios were also estimated for dichotomized variables, with estimated cut-off points.
RESULTS: A total of 91 patients were enrolled in the study. The median time from the start of radiotherapy to development of pneumonitis was 4.1 months. Pneumonitis was observed in 80 patients (88%), including grade 2 or severe pneumonitis in 31 (34%) and ≥ grade 3 pneumonitis in 11 (12%). Pneumonitis was inside the irradiation field in 73 of the 80 patients (91%). The selected factors for ≥ grade 2 pneumonitis were V20, and primary site (upper lobe) in multivariable analysis. The cut off value of V20 was 18.99%, and there was a significant difference between V20 of < 18.77 and ≥ 18.77.
CONCLUSION: Though there are some limitation of this study, the basic concept of concurrent chemoradiotherapy with an emphasis on V20 remains unchanged in use of durvalumab. However, we recommend reduction of V20 to as small a value as possible in use of this therapy.
© 2021 The Author(s).
Horinouchi H, Atagi S, Oizumi S, Ohashi K, Kato T, Kozuki T, Seike M, Sone T, Sobue T, Tokito T, Harada H, Maeda T, Mio T, Shirosaka I, Hattori K, Shin E, Murakami H.
Real-world outcomes of chemoradiotherapy for unresectable Stage III non-small cell lung cancer: The SOLUTION study.
Cancer Med. 2020 Sep;9(18):6597-6608. doi: 10.1002/cam4.3306. Epub 2020 Jul 30.
Abstract/Text
There are limited real-world data on the treatment practices, outcomes, and safety of chemoradiotherapy (CRT) alone in potential candidates for immune checkpoint inhibitors (ICI) for unresectable non-small cell lung cancer (NSCLC). In this study, we analyzed the safety and efficacy of CRT in patients who underwent CRT and would satisfy the key eligibility criteria for maintenance therapy with durvalumab (eg, no progression after CRT) in real-world settings (m-sub) for unresectable Stage III NSCLC between 1 January 2013 and 31 December 2015 at 12 sites in Japan. The m-sub comprised 214 patients with a median follow-up of 31.6 months (range 1.9-65.8 months). Median overall survival (OS) and progression-free survival (PFS) from completing CRT were 36.4 months (95% confidence interval [CI] 28.1 months to not reached) and 9.5 months (95% CI 7.7-11.7 months), respectively. Consolidation chemotherapy did not influence OS or PFS. Median PFS was 16.9 vs 9.1 months in patients with vs without epidermal growth factor receptor (EGFR) mutations, with PFS rates of ~20% at 3-4 years. Pneumonitis was the most common adverse event (according to MedDRA version 21.0J), and about half of events were grade 1. Pneumonitis mostly occurred 10-24 weeks after starting CRT, peaking at 18-20 weeks. Esophagitis and dermatitis generally occurred from 0 to 4 weeks, peaking at 2-4 weeks after starting CRT. Pericarditis was rare and occurred sporadically. In conclusion, the results of the m-sub provide real-world insight into the outcomes of CRT, and will be useful for future evaluations of ICI maintenance therapy after CRT.
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Wang Y, Zhang T, Huang Y, Li W, Zhao J, Yang Y, Li C, Wang L, Bi N.
Real-World Safety and Efficacy of Consolidation Durvalumab After Chemoradiation Therapy for Stage III Non-small Cell Lung Cancer: A Systematic Review and Meta-analysis.
Int J Radiat Oncol Biol Phys. 2022 Apr 1;112(5):1154-1164. doi: 10.1016/j.ijrobp.2021.12.150. Epub 2021 Dec 26.
Abstract/Text
PURPOSE: Consolidation durvalumab after chemoradiation therapy (CRT) has improved patient outcomes in stage III non-small cell lung cancer (NSCLC) since the practice-changing results of the PACIFIC trial, whereas real-world evidence regarding the PACIFIC regimen has not been systematically reviewed. This meta-analysis comprehensively investigated the real-world toxicity and efficacy of this regimen and identified differences between the real world and clinical trials.
METHODS AND MATERIALS: Real-world studies (RWSs) on patients with stage III NSCLC treated with durvalumab after CRT were identified in MEDLINE, EMBASE, PubMed, and Cochrane Library databases. We summarized the differences in demographic and therapeutic characteristics between RWSs and the PACIFIC trial. A meta-analysis of short-term efficacy and adverse event rates was performed. Subgroup analyses were conducted to identify potential influencing factors.
RESULTS: Thirteen studies involving 1885 patients were included. More elderly and poor-performance-status patients, prolonged interval from CRT completion to durvalumab exceeding 42 days, median infusions of durvalumab <20 cycles, and sequential CRT were observed in the real world. The pooled 12-month overall survival (OS) and progression-free survival (PFS) rates were 90% (95% confidence interval [CI], 83%-98%) and 62% (95% CI, 56%-68%), respectively. Subgroup analysis determined that delay in durvalumab initiation beyond 42 days did not affect 12-month OS (P = .068) or PFS (P = .989). Pooled incidences of all-grade and grade ≥3 pneumonitis were 35% (95% CI, 22%-48%) and 6% (95% CI, 3%-8%), respectively. Higher all-grade pneumonitis rates were observed in the studies of patients with a median age of >65 years (P = .008) and from Asian regions (P = .017), whereas expanded access program-related studies reported significantly lower rates (P = .024).
CONCLUSIONS: The safety and short-term efficacy of consolidation durvalumab in real-life use aligns with the PACIFIC trial. RWSs can be helpful for understanding the true efficacy and toxicity of consolidation durvalumab given the less-restrictive eligibility criteria.
Copyright © 2021. Published by Elsevier Inc.
Cheng Y, Spigel DR, Cho BC, Laktionov KK, Fang J, Chen Y, Zenke Y, Lee KH, Wang Q, Navarro A, Bernabe R, Buchmeier EL, Chang JW, Shiraishi Y, Sezgin Goksu S, Badzio A, Shi A, Daniel DB, Hoa NTT, Zemanova M, Mann H, Gowda H, Jiang H, Senan S; ADRIATIC Investigators.
Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer.
N Engl J Med. 2024 Oct 10;391(14):1313-1327. doi: 10.1056/NEJMoa2404873. Epub 2024 Sep 13.
Abstract/Text
BACKGROUND: Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy.
METHODS: In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded.
RESULTS: A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = 0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = 0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group.
CONCLUSIONS: Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.).
Copyright © 2024 Massachusetts Medical Society.
Ozturk B, Egehan I, Atavci S, Kitapci M.
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 Jan 1;58(1):213-9. doi: 10.1016/s0360-3016(03)01444-5.
Abstract/Text
PURPOSE: Pentoxifylline (Ptx) is thought to be helpful in preventing radiotoxicity by inhibiting platelet aggregation and tumor necrosis factor. We assessed whether prophylactic use of Ptx could prevent early and late normal lung tissue damage due to radiotherapy in a double-blind, randomized trial.
METHODS AND MATERIALS: A total of 40 patients with lung or breast cancer were randomized to receive Ptx (400 mg) or a placebo, 3 times daily, during the entire period of radiotherapy. We used the late effects normal tissue-subjective, objective, management, and analytic (LENT-SOMA) scale to evaluate and compare toxicity, including the findings of pulmonary function tests and radiologic and scintigraphic evaluations performed before and at 3 and 6 months of follow-up.
RESULTS: According to the LENT score, a statistically significant difference was found between the two groups in favor of Ptx (p = 0.016). The difference in diffusing capacity of the lung for carbon monoxide and regional perfusion scan results were found to be statistically significant between the groups at 3 and 6 months (p <0.05). The use of Ptx resulted in a noticeable reduction in the higher degrees of lung injury detected radiologically.
CONCLUSION: Our study showed a significant protective effect of Ptx for both early and late lung radiotoxicity. We recommend the prophylactic use of Ptx, finding it to be safe and effective.
Sasse AD, Clark LG, Sasse EC, Clark OA.
Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis.
Int J Radiat Oncol Biol Phys. 2006 Mar 1;64(3):784-91. doi: 10.1016/j.ijrobp.2005.06.023. Epub 2005 Sep 29.
Abstract/Text
PURPOSE: To evaluate the efficacy of amifostine in diminishing radiotherapy side effects and whether or not it protects the tumor.
METHODS AND MATERIALS: We performed a systematic review and meta-analysis of 14 included randomized controlled trials, comprising 1451 patients, comparing the use of radiotherapy vs. radiotherapy plus amifostine for cancer treatment.
RESULTS: The use of amifostine significantly reduced the risk of developing mucositis (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.29-0.48; p < 0.00001), esophagitis (OR, 0.38; CI, 0.26-0.54; p < 0.00001), acute xerostomia (OR, 0.24; CI, 0.15-0.36; p < 0.00001), late xerostomia (OR, 0.33; CI, 0.21-0.51; p < 0.00001), dysphagia (OR, 0.26; CI, 0.07-0.92; p = 0.04), acute pneumonitis (OR, 0.15; CI, 0.07-0.31; p < 0.00001) and cystitis (OR, 0.17; CI, 0.09-0.32; p < 0.00001). There was no difference in overall response rate between the groups. However, complete response rate was superior for patients using amifostine (OR, 1.81; CI, 1.10-2.96; p = 0.02).
CONCLUSIONS: This systematic review shows that amifostine significantly reduces the side effects of radiation therapy. The efficacy of radiotherapy was not itself affected by the use of this drug and patients receiving amifostine were able to achieve higher rates of complete response.
Kma L, Gao F, Fish BL, Moulder JE, Jacobs ER, Medhora M.
Angiotensin converting enzyme inhibitors mitigate collagen synthesis induced by a single dose of radiation to the whole thorax.
J Radiat Res. 2012;53(1):10-7. doi: 10.1269/jrr.11035.
Abstract/Text
Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m(2)/day) or enalapril (19-28 mg/m(2)/day), but not fosinopril (19-28 mg/m(2)/day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation.
Jenkins P, Welsh A.
Computed tomography appearance of early radiation injury to the lung: correlation with clinical and dosimetric factors.
Int J Radiat Oncol Biol Phys. 2011 Sep 1;81(1):97-103. doi: 10.1016/j.ijrobp.2010.05.017. Epub 2011 May 3.
Abstract/Text
PURPOSE: To systematically assess the spectrum of radiologic changes in the lung after radiation therapy for non-small-cell lung cancer.
METHODS AND MATERIALS: We reviewed the cases of 146 patients treated with radical radiotherapy at our institution. All patients had computed tomography (CT) scans performed 3 months after completion of therapy. Radiographic appearances were categorized using a standard grading system. The association of these abnormalities with pretreatment factors and clinical radiation pneumonitis (RP) was investigated.
RESULTS: New intrapulmonary abnormalities were seen in 92 patients (63%). These were ground-glass opacity in 16 (11%), patchy consolidation in 19 (13%), and diffuse consolidation in 57 (39%). Twenty-five patients (17%) developed clinical symptoms of RP. Although 80% of the patients with RP had areas of consolidation seen on the posttreatment CT scan, the majority (74%) of patients with such radiographic changes were asymptomatic. For patients with lung infiltrates, the minimum isodose encompassing the volume of radiologic abnormality was usually ≥27 Gy. Traditional dose-volume metrics, pulmonary function tests, and the coadministration of angiotensin converting enzyme inhibitors (ACE-I) were all strongly correlated with the presence of radiologic injury on univariate analysis (p≤0.002). There was also an inverse correlation between prior smoking history and CT scan changes (p=0.02). On multivariate analysis, dosimetric parameters and the use of ACE-I retained significance (p=0.005).
CONCLUSIONS: Our findings suggest that there is substantial interindividual variation in lung radiosensitivity. ACE-I prevented the radiologic changes seen after high-dose radiation therapy, and their role as radioprotectants warrants further investigation.
Copyright © 2011 Elsevier Inc. All rights reserved.
Kharofa J, Cohen EP, Tomic R, Xiang Q, Gore E.
Decreased risk of radiation pneumonitis with incidental concurrent use of angiotensin-converting enzyme inhibitors and thoracic radiation therapy.
Int J Radiat Oncol Biol Phys. 2012 Sep 1;84(1):238-43. doi: 10.1016/j.ijrobp.2011.11.013. Epub 2012 Jan 31.
Abstract/Text
PURPOSE: Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation.
METHODS AND MATERIALS: Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004-2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors, nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose-volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis.
RESULTS: A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose-volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] ≤37% and mean lung dose ≤20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade 2 or higher pneumonitis.
CONCLUSION: ACE inhibitors may decrease the incidence of radiation pneumonitis in patients receiving thoracic radiation for lung cancer. These findings are consistent with preclinical evidence and should be prospectively evaluated.
Copyright © 2012 Elsevier Inc. All rights reserved.
Sio TT, Atherton PJ, Pederson LD, Zhen WK, Mutter RW, Garces YI, Ma DJ, Leenstra JL, Rwigema JM, Dakhil S, Bearden JD, van der Veen SJ, Ganti AK, Schild SE, Miller RC.
Daily Lisinopril vs Placebo for Prevention of Chemoradiation-Induced Pulmonary Distress in Patients With Lung Cancer (Alliance MC1221): A Pilot Double-Blind Randomized Trial.
Int J Radiat Oncol Biol Phys. 2019 Mar 1;103(3):686-696. doi: 10.1016/j.ijrobp.2018.10.035. Epub 2018 Nov 2.
Abstract/Text
PURPOSE: Chemoradiation (CRT) is an integral treatment modality for patients with locally advanced lung cancer. It has been hypothesized that current use of an angiotensin-converting enzyme inhibitor during CRT may be protective for treatment-related lung damage and pneumonitis.
METHODS AND MATERIALS: We conducted a pilot, double-blind, placebo-controlled, randomized trial. Study-eligible patients receiving curative thoracic radiation therapy (RT) were randomly assigned to 20 mg of lisinopril or placebo once daily during and up to 3 months after RT. All patients received concurrent chemotherapy. The primary endpoint was adverse event profiling. Multiple patient-reported outcome (PRO) surveys, including the Lung Cancer Symptom Scale, Function Assessment of Cancer Therapy-Lung, and the European Organisation for Research and Treatment of Cancer Lung Cancer Questionnaire, were applied with a symptom experience questionnaire. Exploratory comparative statistics were used to detect differences between arms with χ2 and Kruskal-Wallis testing.
RESULTS: Five institutions enrolled 23 patients. However, accrual was less than expected. Eleven and 12 patients were in the placebo and lisinopril arms, respectively (mean age, 63.5 years; male, 62%). Baseline characteristics were balanced. Eighteen patients (86%) were former or current smokers. The primary endpoint was met; neither arm had grade 3 or higher hypotension, acute kidney injury, allergic reaction (medication-induced cough), or anaphylaxis (medication-related angioedema). Few PRO measures suggested that compared with the placebo arm, patients receiving lisinopril had less cough, less shortness of breath, fewer symptoms from lung cancer, less dyspnea with both walking and climbing stairs, and better overall quality of life (for all, P < .05).
CONCLUSIONS: Although underpowered because of low accrual, our results suggest that there was a clinical signal for safety-and possibly beneficial by limited PRO measures-in concurrently administering lisinopril during thoracic CRT to mitigate or prevent RT-induced pulmonary distress. Our results showed that a definitive, larger-scale, randomized phase 3 trial is needed in the future.
Copyright © 2018. Published by Elsevier Inc.
Sheikholeslami S, Aryafar T, Abedi-Firouzjah R, Banaei A, Dorri-Giv M, Zamani H, Ataei G, Majdaeen M, Farhood B.
The role of melatonin on radiation-induced pneumonitis and lung fibrosis: A systematic review.
Life Sci. 2021 Sep 15;281:119721. doi: 10.1016/j.lfs.2021.119721. Epub 2021 Jun 16.
Abstract/Text
PURPOSE: Pneumonitis and lung fibrosis, as the most common compliances of lung irradiation, can affect the quality of life. The use of radio-protective agents can ameliorate these injuries. This study aimed to review the potential protective role of melatonin in the treatment of radiation-induced Pneumonitis and lung fibrosis.
METHODS: The current systematic study was conducted based on PRISMA guidelines to identify relevant literature on " the effect of melatonin on radiation-induced pneumonitis and lung fibrosis" in the electronic databases of Web of Science, Embase, PubMed, and Scopus up to January 2021. Eighty-one articles were screened in accordance with the inclusion and exclusion criteria of the study. Finally, eight articles were included in this systematic review.
RESULTS: The finding showed that the lung irradiation-induced pneumonitis and lung fibrosis. The co-treatment with melatonin could alleviate these compliances through its anti-oxidant and anti-inflammatory actions. Melatonin through upregulation of some enzymes such as catalase, superoxide dismutase, glutathione, NADPH oxidases 2 and 4, dual oxidases 1 and 2, and also downregulation of malondialdehyde reduced oxidative stress following lung radiation. Moreover, melatonin through its anti-inflammatory effects, can attenuate the increased levels of nuclear factor kappa B, tumor necrosis factor alpha, transforming growth factor beta 1, SMAD2, interleukin (IL)-4, IL-4 receptor-a1 (IL4ra1), and IL-1 beta following lung radiation. The histological damages induced by ionizing radiation were also alleviated by co-treatment with melatonin.
CONCLUSION: According to the obtained results, it was found that melatonin can have anti-pneumonitis and anti-fibrotic following lung irradiation.
Copyright © 2018. Published by Elsevier Inc.
Citrin DE, Prasanna PGS, Walker AJ, Freeman ML, Eke I, Barcellos-Hoff MH, Arankalayil MJ, Cohen EP, Wilkins RC, Ahmed MM, Anscher MS, Movsas B, Buchsbaum JC, Mendonca MS, Wynn TA, Coleman CN. Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016. Radiat Res. Radiation Research Society; 2017 Jul;188(1):1–20.
Takeda A, Tsurugai Y, Sanuki N, Enomoto T, Shinkai M, Mizuno T, Aoki Y, Oku Y, Akiba T, Hara Y, Kunieda E. Clarithromycin mitigates radiation pneumonitis in patients with lung cancer treated with stereotactic body radiotherapy. J Thorac Dis. AME Publishing Company; 2018 Jan 1;10(1):247–261.
De Ruysscher D, Granton PV, Lieuwes NG, van Hoof S, Wollin L, Weynand B, Dingemans AM, Verhaegen F, Dubois L. Nintedanib reduces radiation-induced microscopic lung fibrosis but this cannot be monitored by CT imaging: A preclinical study with a high precision image-guided irradiator. Radiother Oncol. Elsevier Ireland Ltd; 2017 Sep 1;124(3):482–487.
Mazeron R, Etienne-Mastroianni B, Pérol D, Arpin D, Vincent M, Falchero L, Martel-Lafay I, Carrie C, Claude L.
Predictive factors of late radiation fibrosis: a prospective study in non-small cell lung cancer.
Int J Radiat Oncol Biol Phys. 2010 May 1;77(1):38-43. doi: 10.1016/j.ijrobp.2009.04.019. Epub 2010 Feb 18.
Abstract/Text
PURPOSE: To determine predictive factors of late radiation fibrosis (RF) after conformal radiotherapy (3D-RT) in non-small cell lung cancer (NSCLC).
METHODS AND MATERIALS: Ninety-six patients with Stage IA-IIIB NSCLC were included in a prospective trial. Clinical evaluation, chest X-ray, and pulmonary functional tests including diffusion parameters were performed before and 6 months after radiotherapy. An independent panel of experts prospectively analyzed RF, using Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic scales classification. Logistic regression analysis was performed to identify relationships between clinical, functional, or treatment parameters and incidence of RF. Variations of circulating serum levels of pro-inflammatory (interleukin-6, tumor necrosis factor alpha, tumor growth factor beta1) and anti-inflammatory (interleukin-10) cytokines during 3D-RT were examined to identify correlations with RF.
RESULTS: Of the 96 patients included, 72 were evaluable for RF at 6 months. Thirty-seven (51.4%) developed RF (Grade >or=1), including six severe RF (Grades 2-3; 8.3%). In univariate analysis, only poor Karnofsky Performance Status and previous acute radiation pneumonitis were associated with RF (p < 0.05). Dosimetric factors (mean lung dose, percentage of lung volume receiving more than 10, 20, 30, 40, and 50 Gy) were highly correlated with RF (p < 0.001). In multivariate analysis, previous acute radiation pneumonitis and dosimetric parameters were significantly correlated with RF occurrence. It was not significantly correlated either with cytokines at baseline or with their variation during 3D-RT.
CONCLUSIONS: This study confirms the importance of dosimetric parameters to limit the risk of RF. Contrary to acute radiation pneumonitis, RF was not correlated to cytokine variations during 3D-RT.
Palma DA, Senan S, Tsujino K, Barriger RB, Rengan R, Moreno M, Bradley JD, Kim TH, Ramella S, Marks LB, De Petris L, Stitt L, Rodrigues G.
Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis.
Int J Radiat Oncol Biol Phys. 2013 Feb 1;85(2):444-50. doi: 10.1016/j.ijrobp.2012.04.043. Epub 2012 Jun 9.
Abstract/Text
BACKGROUND: 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.
METHODS AND MATERIALS: 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.
RESULTS: 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<.001), with a trend for age (OR 1.24 per decade, P=.09); the model remained predictive in the validation set with good discrimination in both datasets (c-statistic >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.
CONCLUSIONS: 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.
Hu X, He W, Wen S, Feng X, Fu X, Liu Y, Pu K. Is IMRT superior or inferior to 3DCRT in radiotherapy for NSCLC? A meta-analysis. PLoS One. Public Library of Science; 2016 Apr 1;11(4).
Chun SG, Hu C, Choy H, Komaki RU, Timmerman RD, Schild SE, Bogart JA, Dobelbower MC, Bosch W, Galvin JM, Kavadi VS, Narayan S, Iyengar P, Robinson CG, Wynn RB, Raben A, Augspurger ME, MacRae RM, Paulus R, Bradley JD.
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.
J Clin Oncol. 2017 Jan;35(1):56-62. doi: 10.1200/JCO.2016.69.1378. Epub 2016 Oct 31.
Abstract/Text
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.
Chun SG, Hu C, Choy H, Komaki RU, Timmerman RD, Schild SE, Bogart JA, Dobelbower MC, Bosch W, Galvin JM, Kavadi VS, Narayan S, Iyengar P, Robinson CG, Wynn RB, Raben A, Augspurger ME, MacRae RM, Paulus R, Bradley JD. 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. J Clin Oncol. American Society of Clinical Oncology; 2017 Jan 1;35(1):56–62.
Meng Y, Luo W, Wang W, Zhou C, Zhou S, Tang X, Hou L, Kong FS, Yang H.
Intermediate Dose-Volume Parameters, Not Low-Dose Bath, Is Superior to Predict Radiation Pneumonitis for Lung Cancer Treated With Intensity-Modulated Radiotherapy.
Front Oncol. 2020;10:584756. doi: 10.3389/fonc.2020.584756. Epub 2020 Oct 15.
Abstract/Text
PURPOSE: Although intensity-modulated radiotherapy (IMRT) is now a preferred option for conventionally fractionated RT in lung cancer, the commonly used cutoff values of the dosimetric constraints are still mainly derived from the data using three-dimensional conformal radiotherapy (3D-CRT). We aimed to compare the prediction performance among different dosimetric parameters for acute radiation pneumonitis (RP) in patients with lung cancer received IMRT.
METHODS: A total of 236 patients treated with IMRT were retrospectively reviewed in two independent groups of lung cancer from January 2014 to August 2018. The primary endpoint was grade 2 or higher acute RP (RP2). Dose metrics were generated from the bilateral lung volume outside GTV (VdoseG) and PTV (VdoseP). The associations of RP2 with clinical variables, dose-volume parameters and mean lung dose (MLD) were analyzed by univariate and multivariate logistic regression. The power of discrimination among each predictor was assessed by employing the bootstrapped area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and the integrated discrimination improvement (IDI).
RESULTS: Thirty-four (14.4%) out of 236 patients developed acute RP2 after the end of IMRT. The clinical parameters were identified as less important predictors for RP2 based on univariate and multivariate analysis. In both studied groups, the significance of association was more convincing in V20P, V30P, and MLDP (smaller Ps) than V5G and V5P. The largest bootstrapped AUC was identified for the V30P. We found a trend of better discriminating performance for the V20P and V30P, and MLDP than the V5G and V5P according to the higher values in AUC, IDI, and NRI analysis. To limit RP2 incidence less than 20%, the V30P cutoff was 14.5%.
CONCLUSIONS: This study identified the intermediate dose-volume parameters V20P and V30P with better prediction performance for acute RP2 than low-dose metrics V5G and V5P. Among all studied predictors, the V30P had the best discriminating power, and should be considered as a supplement to the traditional dose constraints in lung cancer treated with IMRT.
Copyright © 2020 Meng, Luo, Wang, Zhou, Zhou, Tang, Hou, Kong and Yang.
Tatsuno S, Doi H, Okada W, Inoue E, Nakamatsu K, Tanooka M, Tanaka M, Nishimura Y.
Risk factors for radiation pneumonitis after rotating gantry intensity-modulated radiation therapy for lung cancer.
Sci Rep. 2022 Jan 12;12(1):590. doi: 10.1038/s41598-021-04601-0. Epub 2022 Jan 12.
Abstract/Text
The risk factors for severe radiation pneumonitis (RP) in patients with lung cancer who undergo rotating gantry intensity-modulated radiation therapy (IMRT) using volumetric modulated arc therapy (VMAT) or helical tomotherapy (HT) are poorly understood. Fifty-two patients who received rotating gantry IMRT for locally advanced lung cancer were included in this retrospective study. In total, 31 and 21 patients received VMAT and HT, respectively. The median follow-up duration was 14 months (range, 5.2-33.6). Twenty (38%) and eight (15%) patients developed grade ≥ 2 and ≥ 3 RP, respectively. In multivariate analysis, lung V5 ≥ 40% was associated with grade ≥ 2 RP (P = 0.02), and past medical history of pneumonectomy and total lung volume ≤ 3260 cc were independently associated with grade ≥ 3 RP (P = 0.02 and P = 0.03, respectively). Rotating gantry IMRT was feasible and safe in patients with lung cancer undergoing definitive radiotherapy. Reducing lung V5 may decrease the risk of symptomatic RP, and care should be taken to avoid severe RP after radiotherapy in patients with a past medical history of pneumonectomy and small total lung volume.
© 2022. The Author(s).
肺癌放射線治療計画用のリンパ節部位アトラス作成委員会：肺癌放射線治療計画のためのリンパ節部位のCTアトラス. 肺癌．2015；55：189-205.
Yuan S, Sun X, Li M, Yu J, Ren R, Yu Y, Li J, Liu X, Wang R, Li B, Kong L, Yin Y. A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer. Am J Clin Oncol Cancer Clin Trials. Am J Clin Oncol; 2007 Jun;30(3):239–244.
Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H.
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 Feb;16(2):187-99. doi: 10.1016/S1470-2045(14)71207-0. Epub 2015 Jan 16.
Abstract/Text
BACKGROUND: We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer.
METHODS: In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949.
FINDINGS: Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001).
INTERPRETATION: 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients.
FUNDING: National Cancer Institute and Bristol-Myers Squibb.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Li R, Yu L, Lin S, Wang L, Dong X, Yu L, Li W, Li B. Involved field radiotherapy (IFRT) versus elective nodal irradiation (ENI) for locally advanced non-small cell lung cancer: A meta-analysis of incidence of elective nodal failure (ENF). Radiat Oncol. BioMed Central Ltd.; 2016.
Faivre-Finn C, Snee M, Ashcroft L, Appel W, Barlesi F, Bhatnagar A, Bezjak A, Cardenal F, Fournel P, Harden S, Le Pechoux C, McMenemin R, Mohammed N, O'Brien M, Pantarotto J, Surmont V, Van Meerbeeck JP, Woll PJ, Lorigan P, Blackhall F; CONVERT Study Team.
Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.
Lancet Oncol. 2017 Aug;18(8):1116-1125. doi: 10.1016/S1470-2045(17)30318-2. Epub 2017 Jun 20.
Abstract/Text
BACKGROUND: Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer.
METHODS: The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0-2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up.
FINDINGS: Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35-58), median overall survival was 30 months (95% CI 24-34) in the twice-daily group versus 25 months (21-31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95-1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50-62) in the twice-daily group and 51% (45-57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI -3·2% to 13·7%]). The most common grade 3-4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3-4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3-4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group).
INTERPRETATION: Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting.
FUNDING: Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups).
Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC-BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Bogart J, Wang X, Masters G, Gao J, Komaki R, Gaspar LE, Heymach J, Bonner J, Kuzma C, Waqar S, Petty W, Stinchcombe TE, Bradley JD, Vokes E.
High-Dose Once-Daily Thoracic Radiotherapy in Limited-Stage Small-Cell Lung Cancer: CALGB 30610 (Alliance)/RTOG 0538.
J Clin Oncol. 2023 May 1;41(13):2394-2402. doi: 10.1200/JCO.22.01359. Epub 2023 Jan 9.
Abstract/Text
PURPOSE: Although level 1 evidence supports 45-Gy twice-daily radiotherapy as standard for limited-stage small-cell lung cancer, most patients receive higher-dose once-daily regimens in clinical practice. Whether increasing radiotherapy dose improves outcomes remains to be prospectively demonstrated.
METHODS: This phase III trial, CALGB 30610/RTOG 0538 (ClinicalTrials.gov identifier: NCT00632853), was conducted in two stages. In the first stage, patients with limited-stage disease were randomly assigned to receive 45-Gy twice-daily, 70-Gy once-daily, or 61.2-Gy concomitant-boost radiotherapy, starting with either the first or second (of four total) chemotherapy cycles. In the second stage, allocation to the 61.2-Gy arm was discontinued following planned interim toxicity analysis, and the study continued with two remaining arms. The primary end point was overall survival (OS) in the intention-to-treat population.
RESULTS: Trial accrual opened on March 15, 2008, and closed on December 1, 2019. All patients randomly assigned to 45-Gy twice-daily (n = 313) or 70-Gy once-daily radiotherapy (n = 325) are included in this analysis. After a median follow-up of 4.7 years, OS was not improved on the once-daily arm (hazard ratio for death, 0.94; 95% CI, 0.76 to 1.17; P = .594). Median survival is 28.5 months for twice-daily treatment, and 30.1 months for once-daily treatment, with 5-year OS of 29% and 32%, respectively. Treatment was tolerable, and the frequency of severe adverse events, including esophageal and pulmonary toxicity, was similar on both arms.
CONCLUSION: Although 45-Gy twice-daily radiotherapy remains the standard of care, this study provides the most robust information available to help guide the choice of thoracic radiotherapy regimen for patients with limited-stage small-cell lung cancer.
Graham MV, Purdy JA, Emami B, Harms W, Bosch W, Lockett MA, Perez CA.
Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC).
Int J Radiat Oncol Biol Phys. 1999 Sep 1;45(2):323-9. doi: 10.1016/s0360-3016(99)00183-2.
Abstract/Text
PURPOSE: To identify a clinically relevant and available parameter upon which to identify non-small cell lung cancer (NSCLC) patients at risk for pneumonitis when treated with three-dimensional (3D) radiation therapy.
METHODS AND MATERIALS: Between January 1991 and October 1995, 99 patients were treated definitively for inoperable NSCLC. Patients were selected for good performance status (96%) and absence of weight loss (82%). All patients had full 3D treatment planning (including total lung dose-volume histograms [DVHs]) prior to treatment delivery. The total lung DVH parameters were compared with the incidence and grade of pneumonitis after treatment.
RESULTS: Univariate analysis revealed the percent of the total lung volume exceeding 20 Gy (V20), the effective volume (Veff) and the total lung volume mean dose, and location of the tumor primary (upper versus lower lobes) to be statistically significant relative to the development of > or = Grade 2 pneumonitis. Multivariate analysis revealed the V20 to be the single independent predictor of pneumonitis.
CONCLUSIONS: The V20 from the total lung DVH is a useful parameter easily obtained from most 3D treatment planning systems. The V20 may be useful in comparing competing treatment plans to evaluate the risk of pneumonitis for our individual patient treatment and may also be a useful parameter upon which to stratify patients or prospective dose escalation trials.
Tsujino K, Hirota S, Endo M, Obayashi K, Kotani Y, Satouchi M, Kado T, Takada Y.
Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer.
Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):110-5. doi: 10.1016/s0360-3016(02)03807-5.
Abstract/Text
PURPOSE: To clarify whether the percentage of pulmonary volume irradiated to >20 Gy (V20) is related to the incidence and grade of radiation pneumonitis (RP) in cases of lung cancer treated with concurrent chemoradiation.
METHODS AND MATERIALS: The subjects comprised 71 patients with lung cancer who were treated with conventionally fractionated definitive concurrent chemoradiation. The chemotherapy agents were carboplatin or cisplatin combined with taxane for most patients. Radiotherapy was delivered at 1.8-2.0 Gy fractions once daily to a total of 48-66 Gy (median 60). We analyzed the relation between RP grade and V20. Univariate and multivariate analyses were performed to assess patient- and treatment-related factors, including age, gender, smoking history, pulmonary function (forced expiratory volume in 1 s), tumor location (upper lobe vs. middle/lower lobe), chemotherapy regimen (platinum + taxane vs. other), total dose, overall radiation periods in addition to V20.
RESULTS: With a median follow-up of 7.5 months, an RP grade of 0, 1, 2, 3, and 5 was observed in 16, 35, 17, 1, and 2 patients, respectively; the corresponding mean V20 values were 20.1%, 22.0%, 26.3%, 27.0%, and 34.5%. The 6-month cumulative incidence of RP greater than Grade 2 was 8.7%, 18.3%, 51%, and 85% in patients with a V20 of or=31%, respectively (p <0.0001). According to both univariate and multivariate analyses, V20 was the only factor associated with RP of Grade 2 or greater.
CONCLUSION: The incidence and grade of RP are significantly related to the V20 value. Thus, V20 appears to be a factor that can be used to predict RP after concurrent chemoradiation for lung cancer.
Marks LB, Bentzen SM, Deasy JO, Kong FM (Spring), Bradley JD, Vogelius IS, El Naqa I, Hubbs JL, Lebesque J V., Timmerman RD, Martel MK, Jackson A. Radiation Dose-Volume Effects in the Lung. Int J Radiat Oncol Biol Phys. Int J Radiat Oncol Biol Phys; 2010 Mar 1;76(3 SUPPL.).
日本放射線腫瘍学会. 放射線治療計画ガイドライン 2024年版 第6版. 金原出版, 2024.
Tsujino K, Hirota S, Kotani Y, Kado T, Yoden E, Fujii O, Soejima T, Adachi S, Takada Y.
Radiation pneumonitis following concurrent accelerated hyperfractionated radiotherapy and chemotherapy for limited-stage small-cell lung cancer: Dose-volume histogram analysis and comparison with conventional chemoradiation.
Int J Radiat Oncol Biol Phys. 2006 Mar 15;64(4):1100-5. doi: 10.1016/j.ijrobp.2005.09.025. Epub 2005 Dec 20.
Abstract/Text
PURPOSE: The aim of this study was twofold: to determine whether the dose-volume metrics are valuable in predicting radiation pneumonitis (RP) in small-cell lung cancer (SCLC) patients treated with accelerated hyperfractionated radiotherapy and chemotherapy (AHFRT + CT); and to clarify how AHFRT influences the risk of RP in comparison to conventional once-daily radiotherapy and chemotherapy (QDRT + CT).
METHODS AND MATERIALS: Study subjects were 43 patients with SCLC treated with AHFRT + CT. Radiotherapy was delivered at 1.5 Gy/fraction (fr) twice daily to 45 Gy/30 fr/3 weeks. We analyzed the relation between RP incidence and several dosimetric factors. We also compared this series data with our previously published data from lung cancer patients treated with QDRT + CT.
RESULTS: Radiation pneumonitis Grades 1, 2, and 3 were observed in 28 patients, 7 patients, and 1 patient, respectively. Univariate analysis revealed that the percentage of lung volume receiving more than 15 Gy, 20 Gy, and 30 Gy (V15, V20, V30) and normal tissue complication probability were of predictive value for the development of RP. The 12-month cumulative incidences of RP greater than Grade 2 were 0%, 7.1%, 25%, and 42.9% in patients with a V20 of < or =20%, 21-25%, 26-30%, and > or =31%, respectively. These incidences were lower than that of our patients treated with QDRT + CT.
CONCLUSIONS: Dosimetric factors are valuable in predicting RP in SCLC patients treated with AHFRT + CT. Regarding the incidence of RP, AHFRT appears to have some advantage over QDRT.
Sasaki T, Seto T, Yamanaka T, Kunitake N, Shimizu J, Kodaira T, Nishio M, Kozuka T, Takahashi T, Harada H, Yoshimura N, Tsutsumi S, Kitajima H, Kataoka M, Ichinose Y, Nakagawa K, Nishimura Y, Yamamoto N, Nakanishi Y. A randomised phase II trial of S-1 plus cisplatin versus vinorelbine plus cisplatin with concurrent thoracic radiotherapy for unresectable, locally advanced non-small cell lung cancer: WJOG5008L. Br J Cancer. Nature Publishing Group; 2018 Sep 11;119(6):675–682.
Yom SS, Liao Z, Liu HH, Tucker SL, Hu CS, Wei X, Wang X, Wang S, Mohan R, Cox JD, Komaki R. Initial Evaluation of Treatment-Related Pneumonitis in Advanced-Stage Non-Small-Cell Lung Cancer Patients Treated With Concurrent Chemotherapy and Intensity-Modulated Radiotherapy. Int J Radiat Oncol Biol Phys. Int J Radiat Oncol Biol Phys; 2007 May 1;68(1):94–102.
Khalil AA, Hoffmann L, Moeller DS, Farr KP, Knap MM. New dose constraint reduces radiation-induced fatal pneumonitis in locally advanced non-small cell lung cancer patients treated with intensity-modulated radiotherapy. Acta Oncol (Madr). Taylor and Francis Ltd; 2015 Oct 21;54(9):1343–1349.
Chen J, Hong J, Zou X, et al. Association between absolute volumes of lung spared from low-dose irradiation and radiation-induced lung injury after intensity-modulated radiotherapy in lung cancer: a retrospective analysis. J Radiat Res. 2015;56(6):883–888.
Matsuo Y, Shibuya K, Nakamura M, Narabayashi M, Sakanaka K, Ueki N, Miyagi K, Norihisa Y, Mizowaki T, Nagata Y, Hiraoka M. Dose-volume metrics associated with radiation pneumonitis after stereotactic body radiation therapy for lung cancer. Int J Radiat Oncol Biol Phys. Int J Radiat Oncol Biol Phys; 2012 Jul 15;83(4).
Seppenwoolde Y, Lebesque J V., De Jaeger K, Belderbos JSA, Boersma LJ, Schilstra C, Henning GT, Hayman JA, Martel MK, Ten Haken RK. Comparing different NTCP models that predict the incidence of radiation pneumonitis. Int J Radiat Oncol Biol Phys. Elsevier Inc.; 2003 Mar 1;55(3):724–735.
Tucker SL, Liu HH, Wang S, Wei X, Liao Z, Komaki R, Cox JD, Mohan R.
Dose-volume modeling of the risk of postoperative pulmonary complications among esophageal cancer patients treated with concurrent chemoradiotherapy followed by surgery.
Int J Radiat Oncol Biol Phys. 2006 Nov 1;66(3):754-61. doi: 10.1016/j.ijrobp.2006.06.002. Epub 2006 Sep 11.
Abstract/Text
PURPOSE: The aim of this study was to investigate the effect of radiation dose distribution in the lung on the risk of postoperative pulmonary complications among esophageal cancer patients.
METHODS AND MATERIALS: We analyzed data from 110 patients with esophageal cancer treated with concurrent chemoradiotherapy followed by surgery at our institution from 1998 to 2003. The endpoint for analysis was postsurgical pneumonia or acute respiratory distress syndrome. Dose-volume histograms (DVHs) and dose-mass histograms (DMHs) for the whole lung were used to fit normal-tissue complication probability (NTCP) models, and the quality of fits were compared using bootstrap analysis.
RESULTS: Normal-tissue complication probability modeling identified that the risk of postoperative pulmonary complications was most significantly associated with small absolute volumes of lung spared from doses > or = 5 Gy (VS5), that is, exposed to doses < 5 Gy. However, bootstrap analysis found no significant difference between the quality of this model and fits based on other dosimetric parameters, including mean lung dose, effective dose, and relative volume of lung receiving > or = 5 Gy, probably because of correlations among these factors. The choice of DVH vs. DMH or the use of fractionation correction did not significantly affect the results of the NTCP modeling. The parameter values estimated for the Lyman NTCP model were as follows (with 95% confidence intervals in parentheses): n = 1.85 (0.04, infinity), m = 0.55 (0.22, 1.02), and D50 = 17.5 Gy (9.4 Gy, 102 Gy).
CONCLUSIONS: In this cohort of esophageal cancer patients, several dosimetric parameters including mean lung dose, effective dose, and absolute volume of lung receiving < 5 Gy provided similar descriptions of the risk of postoperative pulmonary complications as a function of the radiation dose distribution in the lung.
Palma G, Monti S, Conson M, Pacelli R, Cella L. Normal tissue complication probability (NTCP) models for modern radiation therapy. Semin Oncol. W.B. Saunders; 2019. p. 210–218.
Petit SF, van Elmpt WJ, Oberije CJ, Vegt E, Dingemans AM, Lambin P, Dekker AL, De Ruysscher D.
[¹⁸F]fluorodeoxyglucose uptake patterns in lung before radiotherapy identify areas more susceptible to radiation-induced lung toxicity in non-small-cell lung cancer patients.
Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):698-705. doi: 10.1016/j.ijrobp.2010.06.016. Epub 2010 Sep 29.
Abstract/Text
PURPOSE: Our hypothesis was that pretreatment inflammation in the lung makes pulmonary tissue more susceptible to radiation damage. The relationship between pretreatment [(18)F]fluorodeoxyglucose ([(18)F]FDG) uptake in the lungs (as a surrogate for inflammation) and the delivered radiation dose and radiation-induced lung toxicity (RILT) was investigated.
METHODS AND MATERIALS: We retrospectively studied a prospectively obtained cohort of 101 non-small-cell lung cancer patients treated with (chemo)radiation therapy (RT). [(18)F]FDG-positron emission tomography-computed tomography (PET-CT) scans used for treatment planning were studied. Different parameters were used to describe [(18)F]FDG uptake patterns in the lungs, excluding clinical target volumes, and the interaction with radiation dose. An increase in the dyspnea grade of 1 (Common Terminology Criteria for Adverse Events version 3.0) or more points compared to the pre-RT score was used as an endpoint for analysis of RILT. The effect of [(18)F]FDG and CT-based variables, dose, and other patient or treatment characteristics that effected RILT was studied using logistic regression.
RESULTS: Increased lung density and pretreatment [(18)F]FDG uptake were related to RILT after RT with univariable logistic regression. The 95th percentile of the [(18)F]FDG uptake in the lungs remained significant in multivariable logistic regression (p = 0.016; odds ratio [OR] = 4.3), together with age (p = 0.029; OR = 1.06), and a pre-RT dyspnea score of ≥1 (p = 0.005; OR = 0.20). Significant interaction effects were demonstrated among the 80th, 90th, and 95th percentiles and the relative lung volume receiving more than 2 and 5 Gy.
CONCLUSIONS: The risk of RILT increased with the 95th percentile of the [(18)F]FDG uptake in the lungs, excluding clinical tumor volume (OR = 4.3). The effect became more pronounced as the fraction of the 5%, 10%, and 20% highest standardized uptake value voxels that received more than 2 Gy to 5 Gy increased. Therefore, the risk of RILT may be decreased by applying sophisticated radiotherapy techniques to avoid areas in the lung with high [(18)F]FDG uptake.
Copyright © 2011 Elsevier Inc. All rights reserved.
Chaudhuri AA, Binkley MS, Rigdon J, Carter JN, Aggarwal S, Dudley SA, Qian Y, Kumar KA, Hara WY, Gensheimer M, Nair VS, Maxim PG, Shultz DB, Bush K, Trakul N, Le QT, Diehn M, Loo BW Jr, Guo HH.
Pre-treatment non-target lung FDG-PET uptake predicts symptomatic radiation pneumonitis following Stereotactic Ablative Radiotherapy (SABR).
Radiother Oncol. 2016 Jun;119(3):454-60. doi: 10.1016/j.radonc.2016.05.007. Epub 2016 Jun 3.
Abstract/Text
PURPOSE: To determine if pre-treatment non-target lung FDG-PET uptake predicts for symptomatic radiation pneumonitis (RP) following lung stereotactic ablative radiotherapy (SABR).
METHODS: We reviewed a 258 patient database from our institution to identify 28 patients who experienced symptomatic (grade ⩾ 2) RP after SABR, and compared them to 57 controls who did not develop symptomatic RP. We compared clinical, dosimetric and functional imaging characteristics between the 2 cohorts including pre-treatment non-target lung FDG-PET uptake.
RESULTS: Median follow-up time was 26.9 months. Patients who experienced symptomatic RP had significantly higher non-target lung FDG-PET uptake as measured by mean SUV (p < 0.0001) than controls. ROC analysis for symptomatic RP revealed area under the curve (AUC) of 0.74, with sensitivity 82.1% and specificity 57.9% with cutoff mean non-target lung SUV > 0.56. Predictive value increased (AUC of 0.82) when mean non-target lung SUV was combined with mean lung dose (MLD). We developed a 0-2 point model using these 2 variables, 1 point each for SUV > 0.56 or MLD > 5.88 Gy equivalent dose in 2 Gy per fraction (EQD2), predictive for symptomatic RP in our cohort with hazard ratio 10.01 for score 2 versus 0 (p < 0.001).
CONCLUSIONS: Patients with elevated pre-SABR non-target lung FDG-PET uptake are at increased risk of symptomatic RP after lung SABR. Our predictive model suggests patients with mean non-target lung SUV > 0.56 and MLD > 5.88 Gy EQD2 are at highest risk. Our predictive model should be validated in an external cohort before clinical implementation.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Hirose TA, Arimura H, Ninomiya K, Yoshitake T, Fukunaga JI, Shioyama Y.
Radiomic prediction of radiation pneumonitis on pretreatment planning computed tomography images prior to lung cancer stereotactic body radiation therapy.
Sci Rep. 2020 Nov 24;10(1):20424. doi: 10.1038/s41598-020-77552-7. Epub 2020 Nov 24.
Abstract/Text
This study developed a radiomics-based predictive model for radiation-induced pneumonitis (RP) after lung cancer stereotactic body radiation therapy (SBRT) on pretreatment planning computed tomography (CT) images. For the RP prediction models, 275 non-small-cell lung cancer patients consisted of 245 training (22 with grade ≥ 2 RP) and 30 test cases (8 with grade ≥ 2 RP) were selected. A total of 486 radiomic features were calculated to quantify the RP texture patterns reflecting radiation-induced tissue reaction within lung volumes irradiated with more than x Gy, which were defined as LVx. Ten subsets consisting of all 22 RP cases and 22 or 23 randomly selected non-RP cases were created from the imbalanced dataset of 245 training patients. For each subset, signatures were constructed, and predictive models were built using the least absolute shrinkage and selection operator logistic regression. An ensemble averaging model was built by averaging the RP probabilities of the 10 models. The best model areas under the receiver operating characteristic curves (AUCs) calculated on the training and test cohort for LV5 were 0.871 and 0.756, respectively. The radiomic features calculated on pretreatment planning CT images could be predictive imaging biomarkers for RP after lung cancer SBRT.
Kawahara D, Imano N, Nishioka R, Ogawa K, Kimura T, Nakashima T, Iwamoto H, Fujitaka K, Hattori N, Nagata Y.
Prediction of radiation pneumonitis after definitive radiotherapy for locally advanced non-small cell lung cancer using multi-region radiomics analysis.
Sci Rep. 2021 Aug 10;11(1):16232. doi: 10.1038/s41598-021-95643-x. Epub 2021 Aug 10.
Abstract/Text
To predict grade ≥ 2 radiation pneumonitis (RP) in patients with locally advanced non-small cell lung cancer (NSCLC) using multi-region radiomics analysis. Data from 77 patients with NSCLC who underwent definitive radiotherapy between 2008 and 2018 were analyzed. Radiomic feature extraction from the whole lung (whole-lung radiomics analysis) and imaging- and dosimetric-based segmentation (multi-region radiomics analysis) were performed. Patients with RP grade ≥ 2 or < 2 were classified. Predictors were selected with least absolute shrinkage and selection operator logistic regression and the model was built with neural network classifiers. A total of 49,383 radiomics features per patient image were extracted from the radiotherapy planning computed tomography. We identified 4 features and 13 radiomics features in the whole-lung and multi-region radiomics analysis for classification, respectively. The accuracy and area under the curve (AUC) without the synthetic minority over-sampling technique (SMOTE) were 60.8%, and 0.62 for whole-lung and 80.1%, and 0.84 for multi-region radiomics analysis. These were improved 1.7% for whole-lung and 2.1% for multi-region radiomics analysis with the SMOTE. The developed multi-region radiomics analysis can help predict grade ≥ 2 RP. The radiomics features in the median- and high-dose regions, and the local intensity roughness and variation were important factors in predicting grade ≥ 2 RP.
© 2021. The Author(s).
Zhang Z, Wang Z, Yan M, Yu J, Dekker A, Zhao L, Wee L.
Radiomics and Dosiomics Signature From Whole Lung Predicts Radiation Pneumonitis: A Model Development Study With Prospective External Validation and Decision-curve Analysis.
Int J Radiat Oncol Biol Phys. 2023 Mar 1;115(3):746-758. doi: 10.1016/j.ijrobp.2022.08.047. Epub 2022 Aug 27.
Abstract/Text
PURPOSE: Radiation pneumonitis (RP) is one of the common side effects of radiation therapy in the thoracic region. Radiomics and dosiomics quantify information implicit within medical images and radiation therapy dose distributions. In this study we demonstrate the prognostic potential of radiomics, dosiomics, and clinical features for RP prediction.
METHODS AND MATERIALS: Radiomics, dosiomics, dose-volume histogram (DVH) metrics, and clinical parameters were obtained on 314 retrospectively collected and 35 prospectively enrolled patients diagnosed with lung cancer between 2013 to 2019. A radiomics risk score (R score) and dosiomics risk score (D score), as well as a DVH-score, were calculated based on logistic regression after feature selection. Six models were built using different combinations of R score, D score, DVH score, and clinical parameters to evaluate their added prognostic power. Overoptimism was evaluated by bootstrap resampling from the training set, and the prospectively collected cohort was used as the external test set. Model calibration and decision-curve characteristics of the best-performing models were evaluated. For ease of further evaluation, nomograms were constructed for selected models.
RESULTS: A model built by integrating all of the R score, D score, and clinical parameters had the best discriminative ability with areas under the curve of 0.793 (95% confidence interval [CI], 0.735-0.851), 0.774 (95% CI, 0.762-0.786), and 0.855 (95% CI, 0.719-0.990) in the training, bootstrapping, and external test sets, respectively. The calibration curve image showed good agreement between the predicted and actual values, with a slope of 1.21 and intercept of -0.04. The decision curve image showed a positive net benefit for the final model based on the nomogram.
CONCLUSIONS: Radiomic and dosiomic features have the potential to assist with the prediction of RP, and the combination of radiomics, dosiomics, and clinical parameters led to the best prognostic model in the present study.
Copyright © 2022 Elsevier Inc. All rights reserved.
Vinogradskiy Y, Castillo R, Castillo E, Schubert L, Jones BL, Faught A, Gaspar LE, Kwak J, Bowles DW, Waxweiler T, Dougherty JM, Gao D, Stevens C, Miften M, Kavanagh B, Grills I, Rusthoven CG, Guerrero T.
Results of a Multi-Institutional Phase 2 Clinical Trial for 4DCT-Ventilation Functional Avoidance Thoracic Radiation Therapy.
Int J Radiat Oncol Biol Phys. 2022 Mar 15;112(4):986-995. doi: 10.1016/j.ijrobp.2021.10.147. Epub 2021 Nov 9.
Abstract/Text
PURPOSE: Radiation pneumonitis remains a major limitation in the radiation therapy treatment of patients with lung cancer. Functional avoidance radiation therapy uses functional imaging to reduce pulmonary toxic effects by designing radiation therapy plans that reduce doses to functional regions of the lung. Lung functional imaging has been developed that uses 4-dimensional computed tomography (4DCT) imaging to calculate 4DCT-based lung ventilation (4DCT-ventilation). A phase 2 multicenter study was initiated to evaluate 4DCT-ventilation functional avoidance radiation therapy. The study hypothesis was that functional avoidance radiation therapy could reduce the rate of grade ≥2 radiation pneumonitis to 12% compared with a 25% historical rate, with the trial being positive if ≤16.4% of patients experienced grade ≥2 pneumonitis.
METHODS AND MATERIALS: Lung cancer patients receiving curative-intent radiation therapy (prescription doses of 45-75 Gy) and chemotherapy were accrued. Patient 4DCT scans were used to generate 4DCT-ventilation images. The 4DCT-ventilation images were used to generate functional avoidance plans that reduced doses to functional portions of the lung while delivering the prescribed tumor dose. Pneumonitis was evaluated by a clinician at 3, 6, and 12 months after radiation therapy.
RESULTS: Sixty-seven evaluable patients were accrued between April 2015 and December 2019. The median prescription dose was 60 Gy (range, 45-66 Gy) delivered in 30 fractions (range, 15-33 fractions). The average reduction in the functional volume of lung receiving ≥20 Gy with functional avoidance was 3.5% (range, 0%-12.8%). The median follow-up was 312 days. The rate of grade ≥2 radiation pneumonitis was 10 of 67 patients (14.9%; 95% upper CI, 24.0%), meeting the phase 2 criteria.
CONCLUSIONS: 4DCT-ventilation offers an imaging modality that is convenient and provides functional imaging without an extra procedure necessary. This first report of a multicenter study of 4DCT-ventilation functional avoidance radiation therapy provided data showing that the trial met phase 2 criteria and that evaluation in a phase 3 study is warranted.
Copyright © 2021 Elsevier Inc. All rights reserved.
Huang YS, Chen JL, Lan HT, Tai MH, Kuo SH, Shih JY, Chang YC.
Xenon-Enhanced Ventilation Computed Tomography for Functional Lung Avoidance Radiation Therapy in Patients With Lung Cancer.
Int J Radiat Oncol Biol Phys. 2023 Feb 1;115(2):356-365. doi: 10.1016/j.ijrobp.2022.07.034. Epub 2022 Aug 24.
Abstract/Text
PURPOSE: This phase 2 trial aimed to determine whether xenon-enhanced ventilation computed tomography (XeCT)-guided functional-lung-avoidance radiation therapy could reduce the radiation pneumonitis (RP) rate in patients with lung cancer undergoing definitive chemoradiation therapy.
METHODS AND MATERIALS: Functional lung ventilation was measured via pulmonary function testing (PFT) and XeCT. A standard plan (SP) without reference to XeCT and a functional-lung-avoidance plan (fAP) optimized for lowering the radiation dose to the functional lung at the guidance of XeCT were designed. Dosimetric parameters and predicted RP risks modeled by biological evaluation were compared between the 2 plans in a treatment planning system (TPS). All patients received the approved fAP. The primary endpoint was the rate of grade ≥2 RP, and the secondary endpoints were the survival outcomes. The study hypothesis was that fAP could reduce the rate of grade ≥2 RP to 12% compared with a 30% historical rate.
RESULTS: Thirty-six patients were evaluated. Xenon-enhanced total functional lung volumes positively correlated with PFT ventilation parameters (forced vital capacity, P = .012; forced expiratory volume in 1 second, P = .035), whereas they were not correlated with the diffusion capacity parameter. We observed a 17% rate of grade ≥2 RP (6 of 36 patients), which was significantly different (P = .040) compared with the historical control. Compared with the SP, the fAP significantly spared the total ventilated lung, leading to a reduction in predicted grade ≥2 RP (P = .001) by TPS biological evaluation. The median follow-up was 15.2 months. The 1-year local control (LC), disseminated failure-free survival (DFFS), and overall survival (OS) rates were 88%, 66%, and 91%, respectively. The median LC and OS were not reached, and the median DFFS was 24.0 months (95% confidence interval, 15.7-32.3 months).
CONCLUSIONS: This report of XeCT-guided functional-lung-avoidance radiation therapy provided evidence showing its feasibility in clinical practice. Its benefit should be assessed in a broader multicenter trial setting.
Copyright © 2022 Elsevier Inc. All rights reserved.
Matsuno Y, Satoh H, Ishikawa H, Kodama T, Ohtsuka M, Sekizawa K.
Simultaneous measurements of KL-6 and SP-D in patients undergoing thoracic radiotherapy.
Med Oncol. 2006;23(1):75-82. doi: 10.1385/MO:23:1:75.
Abstract/Text
PURPOSE: Radiation pneumonitis (RP) is a serious complication in patients undergoing thoracic radiotherapy (TRT). Serum KL-6 and SP-D have been shown to increase in several kinds of interstitial pneumonia. To evaluate their clinical usefulness in detecting RP, we serially measured them in patients receiving TRT.
MATERIALS AND METHODS: Thirty-nine patients, who received TRT for lung cancer between July 1999 and April 2004, were prospectively studied. Serum levels of KL-6 and SP-D were measured using enzyme-linked immunosorbent assays. Patients were followed up until August 2004 or their deaths.
RESULTS: During the period, RP occurred in 19 patients. In five patients with diffuse RP extended outside the radiation field, serum KL-6 levels increased, reaching more than 1,000 U/mL. Serum KL-6 levels at 40 Gy in patients who developed RP were higher than those without it (p = 0.0363, Mann-Whitney U test). In addition, serum KL-6 levels at 40 Gy in patients who developed RP were higher than those of pretreatment (p = 0.0126, Wilcoxon signed rank test). On the other hand, there were no statistical differences between sp-d at 40 Gy and those before TRT (P = 0.1165).
CONCLUSIONS: Increased KL-6 at 40 Gy compared with those before treatment in patients undergoing TRT may be of clinical significance. KL-6 proved to be a useful indicator for estimating RP, while usefulness of SP-D was not confirmed in this study.
Hara R, Itami J, Komiyama T, Katoh D, Kondo T.
Serum levels of KL-6 for predicting the occurrence of radiation pneumonitis after stereotactic radiotherapy for lung tumors.
Chest. 2004 Jan;125(1):340-4. doi: 10.1378/chest.125.1.340.
Abstract/Text
To determine the usefulness of serum KL-6 levels for predicting the occurrence of radiation pneumonitis (RP) after the application of single high-dose stereotactic radiation therapy for lung tumors, the serum KL-6 levels were measured in 16 patients before irradiation and every 1 or 2 months thereafter. Three of the 16 patients experienced RP of grade 3 severity according to the European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group toxicity criteria. RP occurred 3 months after the completion of radiation therapy in two patients, and 4 months after completion in one patient. RP occurred at significantly increased frequencies in patients with primary lung cancer (p = 0.01) and adenocarcinoma (p = 0.01), and in those undergoing the concurrent irinotecan therapy (p = 0.02). In all 16 patients, the lactate dehydrogenase level remained normal during the follow-up period. In all three of the patients with RP, KL-6 levels increased by > 1.5-fold compared to the pretreatment value and over the cutoff level of 500 IU. The ratio of the increase in serum KL-6 values 2 months after the patient had undergone irradiation showed a significant correlation with the occurrence of RP (p = 0.04). In conclusion, KL-6 is a useful marker for prediction of the occurrence of RP after single, fractional, high-dose stereotactic irradiation of lung tumors.
Iwata H, Shibamoto Y, Baba F, Sugie C, Ogino H, Murata R, Yanagi T, Otsuka S, Kosaki K, Murai T, Miyakawa A.
Correlation between the serum KL-6 level and the grade of radiation pneumonitis after stereotactic body radiotherapy for stage I lung cancer or small lung metastasis.
Radiother Oncol. 2011 Nov;101(2):267-70. doi: 10.1016/j.radonc.2011.05.031. Epub 2011 Jun 2.
Abstract/Text
Goto K, Kodama T, Sekine I, Kakinuma R, Kubota K, Hojo F, Matsumoto T, Ohmatsu H, Ikeda H, Ando M, Nishiwaki Y.
Serum levels of KL-6 are useful biomarkers for severe radiation pneumonitis.
Lung Cancer. 2001 Oct;34(1):141-8. doi: 10.1016/s0169-5002(01)00215-x.
Abstract/Text
The antigen KL-6, a mucin-like high-molecular-weight glycoprotein, is expressed on type-2 pneumocytes and bronchiolar epithelial cells. Serum levels of KL-6 have been shown to correlate well with the activities of several different kinds of interstitial pneumonia. The purpose of this study was to assess the usefulness of monitoring serum KL-6 levels in patients who had received thoracic radiotherapy (TRT). In particular, the usefulness of such a protocol for the early diagnosis of severe radiation pneumonitis (RP) and the evaluation of its progress and severity was examined. Serum KL-6 levels were retrospectively monitored in 16 patients with lung cancer who had received TRT with or without chemotherapy. Eight of these patients had developed severe RP and eight had developed localized (within the irradiated field) RP. Serum KL-6 levels were measured using a modified sandwich-type enzyme-linked immunosorbent assay. In patients who developed severe RP, serum KL-6 levels showed a consistent tendency to increase after the clinical diagnosis of RP. In four patients, serum KL-6 levels even began to rise before a clinical diagnosis of severe RP had been made. In the patients with localized RP, on the other hand, the serum levels did not show any tendency to increase during or after TRT. Moreover, patients whose serum KL-6 levels rose more than 1.5 times higher than their pre-treatment serum KL-6 level, had a large chance of developing severe RP that was unresponsive to steroid hormones and resulted in death. Serum KL-6 levels, therefore, should be useful indicators for the early diagnosis of severe RP and for estimating its progress and severity in patients treated with TRT.
Kong FM, Ao X, Wang L, Lawrence TS.
The use of blood biomarkers to predict radiation lung toxicity: a potential strategy to individualize thoracic radiation therapy.
Cancer Control. 2008 Apr;15(2):140-50. doi: 10.1177/107327480801500206.
Abstract/Text
BACKGROUND: Radiation-induced lung toxicity (RILT) is an important dose-limiting toxicity during thoracic radiotherapy. Early prediction of radiation lung toxicity will allow physicians to determine a customized treatment regimen for each patient and deliver a radiation dose tailored to that individual's normal tissue sensitivity profile rather than to the average tolerance of the whole population.
METHODS: This review focuses on blood biomarkers in predicting radiation-induced lung toxicity. We searched the literature for data associated with cytokines, and we review the updates of proteomic and genetic polymorphisms in radiation lung toxicity.
RESULTS: Studies from single institutions have demonstrated the significant values of cytokines such as TGF-beta1, IL-6, KL-6, surfactant proteins, and IL-1ra on predicting RILT. The majority of studies focus on the values prior to and at the end of radiation therapy. There is limited data from proteomics and specific genomic single nucleotide polymorphism studies that target individualized radiation therapy for patients with lung cancer.
CONCLUSIONS: Biomarkers or models that can accurately predict radiation-induced lung damage at an early stage, before completion of chemoradiation, would allow physicians to monitor and customize remaining treatment for each patient.
Liu X, Shao C, Fu J.
Promising Biomarkers of Radiation-Induced Lung Injury: A Review.
Biomedicines. 2021 Sep 8;9(9). doi: 10.3390/biomedicines9091181. Epub 2021 Sep 8.
Abstract/Text
Radiation-induced lung injury (RILI) is one of the main dose-limiting side effects in patients with thoracic cancer during radiotherapy. No reliable predictors or accurate risk models are currently available in clinical practice. Severe radiation pneumonitis (RP) or pulmonary fibrosis (PF) will reduce the quality of life, even when the anti-tumor treatment is effective for patients. Thus, precise prediction and early diagnosis of lung toxicity are critical to overcome this longstanding problem. This review summarizes the primary mechanisms and preclinical animal models of RILI reported in recent decades, and analyzes the most promising biomarkers for the early detection of lung complications. In general, ideal integrated models considering individual genetic susceptibility, clinical background parameters, and biological variations are encouraged to be built up, and more prospective investigations are still required to disclose the molecular mechanisms of RILI as well as to discover valuable intervention strategies.
Wang S, Campbell J, Stenmark MH, Zhao J, Stanton P, Matuszak MM, Ten Haken RK, Kong FS.
Plasma Levels of IL-8 and TGF-β1 Predict Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer: A Validation Study.
Int J Radiat Oncol Biol Phys. 2017 Jul 1;98(3):615-621. doi: 10.1016/j.ijrobp.2017.03.011. Epub 2017 Mar 14.
Abstract/Text
PURPOSE AND OBJECTIVES: We previously reported that the combination of mean lung dose (MLD) and inflammatory cytokines interleukin-8 (IL-8) and transforming growth factor-β1 (TGF-β1) may provide a more accurate model for radiation-induced lung toxicity (RILT) prediction in 58 patients with non-small cell lung cancer (NSCLC). This study is to validate the previous findings with new patients and to explore new models with more cytokines.
METHODS AND MATERIALS: One hundred forty-two patients with stage I-III NSCLC treated with definitive radiation therapy (RT) from prospective studies were included. Sixty-five new patients were used to validate previous findings, and all 142 patients were used to explore new models. Thirty inflammatory cytokines were measured in plasma samples before RT and 2 weeks and 4 weeks during RT (pre, 2w, 4w). Grade ≥2 RILT was defined as grade 2, and higher radiation pneumonitis or symptomatic pulmonary fibrosis was the primary endpoint. Logistic regression was performed to evaluate the risk factors of RILT. The area under the curve (AUC) for the receiver operating characteristic curves was used for model assessment.
RESULTS: Sixteen of 65 patients (24.6%) experienced RILT2. Lower pre IL-8 and higher TGF-β1 2w/pre ratio were associated with higher risk of RILT2. The AUC increased to 0.73 by combining MLD, pre IL-8, and TGF-β1 2w/pre ratio compared with 0.61 by MLD alone to predict RILT. In all 142 patients, 29 patients (20.4%) experienced grade ≥2 RILT. Among the 30 cytokines measured, only IL-8 and TGF-β1 were significantly associated with the risk of RILT2. MLD, pre IL-8 level, and TGF-β1 2w/pre ratio were included in the final predictive model. The AUC increased to 0.76 by combining MLD, pre IL-8, and TGF-β1 2w/pre ratio compared with 0.62 by MLD alone.
CONCLUSIONS: We validated that a combination of mean lung dose, pre IL-8 level, and TGF-β1 2w/pre ratio provided a more accurate model to predict the risk of RILT2 compared with MLD alone.
Copyright © 2017 Elsevier Inc. All rights reserved.
Shi A, Zhu G, Wu H, Yu R, Li F, Xu B.
Analysis of clinical and dosimetric factors associated with severe acute radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent chemotherapy and intensity-modulated radiotherapy.
Radiat Oncol. 2010 May 12;5:35. doi: 10.1186/1748-717X-5-35. Epub 2010 May 12.
Abstract/Text
BACKGROUND: To evaluate the association between the clinical, dosimetric factors and severe acute radiation pneumonitis (SARP) in patients with locally advanced non-small cell lung cancer (LANSCLC) treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT).
METHODS: We analyzed 94 LANSCLC patients treated with concurrent chemotherapy and IMRT between May 2005 and September 2006. SARP was defined as greater than or equal 3 side effects and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The clinical and dosimetric factors were analyzed. Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between clinical, dosimetric factors and SARP.
RESULTS: Median follow-up was 10.5 months (range 6.5-24). Of 94 patients, 11 (11.7%) developed SARP. Univariate analyses showed that the normal tissue complication probability (NTCP), mean lung dose (MLD), relative volumes of lung receiving more than a threshold dose of 5-60 Gy at increments of 5 Gy (V5-V60), chronic obstructive pulmonary disease (COPD) and Forced Expiratory Volume in the first second (FEV1) were associated with SARP (p < 0.05). In multivariate analysis, NTCP value (p = 0.001) and V10 (p = 0.015) were the most significant factors associated with SARP. The incidences of SARP in the group with NTCP > 4.2% and NTCP 50% were 5.7% and 29.2%, respectively (p < 0.01).
CONCLUSIONS: NTCP value and V10 are the useful indicators for predicting SARP in NSCLC patients treated with concurrent chemotherapy and IMRT.
柄山正人, 千田金吾: IPF合併肺癌の治療. 放射線療法時の問題点. 日本胸部臨床 2011;70:823-831.
Mehta V.
Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: pulmonary function, prediction, and prevention.
Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):5-24. doi: 10.1016/j.ijrobp.2005.03.047.
Abstract/Text
Although radiotherapy improves locoregional control and survival in patients with non-small-cell lung cancer, radiation pneumonitis is a common treatment-related toxicity. Many pulmonary function tests are not significantly altered by pulmonary toxicity of irradiation, but reductions in D(L(CO)), the diffusing capacity of carbon monoxide, are more commonly associated with pneumonitis. Several patient-specific factors (e.g. age, smoking history, tumor location, performance score, gender) and treatment-specific factors (e.g. chemotherapy regimen and dose) have been proposed as potential predictors of the risk of radiation pneumonitis, but these have not been consistently demonstrated across different studies. The risk of radiation pneumonitis also seems to increase as the cumulative dose of radiation to normal lung tissue increases, as measured by dose-volume histograms. However, controversy persists about which dosimetric parameter optimally predicts the risk of radiation pneumonitis, and whether the volume of lung or the dose of radiation is more important. Radiation oncologists ought to consider these dosimetric factors when designing radiation treatment plans for all patients who receive thoracic radiotherapy. Newer radiotherapy techniques and technologies may reduce the exposure of normal lung to irradiation. Several medications have also been evaluated for their ability to reduce radiation pneumonitis in animals and humans, including corticosteroids, amifostine, ACE inhibitors or angiotensin II type 1 receptor blockers, pentoxifylline, melatonin, carvedilol, and manganese superoxide dismutase-plasmid/liposome. Additional research is warranted to determine the efficacy of these medications and identify nonpharmacologic strategies to predict and prevent radiation pneumonitis.
Sanuki N, Ono A, Komatsu E, Kamei N, Akamine S, Yamazaki T, Mizunoe S, Maeda T.
Association of computed tomography-detected pulmonary interstitial changes with severe radiation pneumonitis for patients treated with thoracic radiotherapy.
J Radiat Res. 2012;53(1):110-6. doi: 10.1269/jrr.110142.
Abstract/Text
We evaluated associations of interstitial changes with radiation pneumonitis (RP) for patients treated with thoracic radiotherapy. Between 2005 and 2009, patients who received thoracic radiotherapy of 40 Gy or more for lung cancer or thymic tumors and were followed-up for more than 6 months were eligible for this study. Possible risk factors for RP included the presence of interstitial changes on computed tomography before radiotherapy, and elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH) levels; these were compared with the incidences of severe RP. A total of 106 patients were included. The incidences of RP were 4 (4%), 0 (0%), and 5 (5%) for grades 3, 4, and 5, respectively. For those with interstitial changes, the incidence of RP ≥ grade 3 was significantly increased from 3% (2/79) to 26% (7/27) (p < 0.001). CRP and LDH levels were also associated with increased RP, as were pulmonary emphysema and performance status ≥ 2. Among 91 patients with RP ≥ grade 1, RP grade ≥ 3 occurred significantly earlier than grades 1 and 2. In conclusion, pulmonary interstitial changes, LDH and CRP levels, pulmonary emphysema, and performance status ≥ 2 were significantly associated with RP ≥ grade 3. RP grade ≥ 3 occurred significantly earlier than grades 1 and 2. The early appearance of interstitial changes requires careful management due to the possibility of severe RP.
Yamashita H, Kobayashi-Shibata S, Terahara A, Okuma K, Haga A, Wakui R, Ohtomo K, Nakagawa K.
Prescreening based on the presence of CT-scan abnormalities and biomarkers (KL-6 and SP-D) may reduce severe radiation pneumonitis after stereotactic radiotherapy.
Radiat Oncol. 2010 May 9;5:32. doi: 10.1186/1748-717X-5-32. Epub 2010 May 9.
Abstract/Text
PURPOSE: To determine the risk factors of severe radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT) for primary or secondary lung tumors.
MATERIALS AND METHODS: From January 2003 to March 2009, SBRT was performed on 117 patients (32 patients before 2005 and 85 patients after 2006) with lung tumors (primary = 74 patients and metastatic/recurrent = 43 patients) in our institution. In the current study, the results on cases with severe RP (grades 4-5) were evaluated. Serum Krebs von den Lungen-6 (KL-6) and serum Surfactant protein-D (SP-D) were used to predict the incidence of RP. A shadow of interstitial pneumonitis (IP) on the CT image before performing SBRT was also used as an indicator for RP. Since 2006, patients have been prescreened for biological markers (KL-6 & SP-D) as well as checking for an IP-shadow in CT.
RESULTS: Grades 4-5 RP was observed in nine patients (7.7%) after SBRT and seven of these cases (6.0%) were grade 5 in our institution. A correlation was found between the incidence of RP and higher serum KL-6 & SP-D levels. IP-shadow in patient's CT was also found to correlate well with the severe RP. Severe RP was reduced from 18.8% before 2005 to 3.5% after 2006 (p = 0.042). There was no correlation between the dose volume histogram parameters and these severe RP patients.
CONCLUSION: Patients presenting with an IP shadow in the CT and a high value of the serum KL-6 & SP-D before SBRT treatment developed severe radiation pneumonitis at a high rate. The reduction of RP incidence in patients treated after 2006 may have been attributed to prescreening of the patients. Therefore, pre-screening before SBRT for an IP shadow in CT and serum KL-6 & SP-D is recommended in the management and treatment of patients with primary or secondary lung tumors.
Zhao J, Yorke ED, Li L, Kavanagh BD, Li XA, Das S, Miften M, Rimner A, Campbell J, Xue J, Jackson A, Grimm J, Milano MT, Spring Kong FM.
Simple Factors Associated With Radiation-Induced Lung Toxicity After Stereotactic Body Radiation Therapy of the Thorax: A Pooled Analysis of 88 Studies.
Int J Radiat Oncol Biol Phys. 2016 Aug 1;95(5):1357-1366. doi: 10.1016/j.ijrobp.2016.03.024. Epub 2016 Mar 25.
Abstract/Text
PURPOSE: To study the risk factors for radiation-induced lung toxicity (RILT) after stereotactic body radiation therapy (SBRT) of the thorax.
METHODS AND MATERIALS: Published studies on lung toxicity in patients with early-stage non-small cell lung cancer (NSCLC) or metastatic lung tumors treated with SBRT were pooled and analyzed. The primary endpoint was RILT, including pneumonitis and fibrosis. Data of RILT and risk factors were extracted from each study, and rates of grade 2 to 5 (G2+) and grade 3 to 5 (G3+) RILT were computed. Patient, tumor, and dosimetric factors were analyzed for their correlation with RILT.
RESULTS: Eighty-eight studies (7752 patients) that reported RILT incidence were eligible. The pooled rates of G2+ and G3+ RILT from all 88 studies were 9.1% (95% confidence interval [CI]: 7.15-11.4) and 1.8% (95% CI: 1.3-2.5), respectively. The median of median tumor sizes was 2.3 (range, 1.4-4.1) cm. Among the factors analyzed, older patient age (P=.044) and larger tumor size (the greatest diameter) were significantly correlated with higher rates of G2+ (P=.049) and G3+ RILT (P=.001). Patients with stage IA versus stage IB NSCLC had significantly lower risks of G2+ RILT (8.3% vs 17.1%, odds ratio = 0.43, 95% CI: 0.29-0.64, P<.0001). Among studies that provided detailed dosimetric data, the pooled analysis demonstrated a significantly higher mean lung dose (MLD) (P=.027) and V20 (P=.019) in patients with G2+ RILT than in those with grade 0 to 1 RILT.
CONCLUSIONS: The overall rate of RILT is relatively low after thoracic SBRT. Older age and larger tumor size are significant adverse risk factors for RILT. Lung dosimetry, specifically lung V20 and MLD, also significantly affect RILT risk.
Copyright © 2016. Published by Elsevier Inc.
Mak RH, Alexander BM, Asomaning K, Heist RS, Liu CY, Su L, Zhai R, Ancukiewicz M, Napolitano B, Niemierko A, Willers H, Choi NC, Christiani DC.
A single-nucleotide polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene is associated with risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy.
Cancer. 2012 Jul 15;118(14):3654-65. doi: 10.1002/cncr.26667. Epub 2011 Dec 5.
Abstract/Text
BACKGROUND: This study examined the association between functional single-nucleotide polymorphisms in candidate genes from oxidative stress pathways and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy for locally advanced lung cancer.
METHODS: A review was conducted of 136 patients treated with radiation therapy for lung cancer between 2001 and 2007, and who had prior genotyping of functional single-nucleotide polymorphisms in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylene tetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of RP of grades ≥2 and ≥3 on univariate and multivariate analysis, respectively. P values were corrected for multiple hypothesis esting.
RESULTS: With a median follow-up of 21.4 months, the incidence of grade ≥2 RP was 29% and grade ≥3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy and consolidation docetaxel, and lung dosimetric parameters such as volume receiving greater than 20 Gy and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of grade ≥2 RP (hazard ratio: 0.37; 95% confidence interval: 0.18-0.76; P = .006, corrected P = .018) and grade ≥3 RP (hazard ratio: 0.21; 95% confidence interval: 0.06-0.70; P = .01; corrected P = .03). SOD2 genotype was not associated with RP.
CONCLUSIONS: This study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP.
Copyright © 2011 American Cancer Society.
McCurdy MR, Wazni MW, Martinez J, McAleer MF, Guerrero T.
Exhaled nitric oxide predicts radiation pneumonitis in esophageal and lung cancer patients receiving thoracic radiation.
Radiother Oncol. 2011 Dec;101(3):443-8. doi: 10.1016/j.radonc.2011.08.035. Epub 2011 Oct 6.
Abstract/Text
BACKGROUND AND PURPOSE: Radiation pneumonitis is a significant toxicity following thoracic radiotherapy with no method to predict individual risk.
MATERIALS AND METHODS: Sixty-five patients receiving thoracic radiation for lung or esophageal cancer were enrolled in a phase II study. Each patient received respiratory surveys and exhaled nitric oxide measurements before, on the last day of, and 30-60 days after completing radiotherapy (RT). Pneumonitis toxicity was scored using the common terminology criteria for adverse events, version 4.0. The demographics, dosimetric factors, and nitric oxide ratio (NOR) of end RT/pre-RT were evaluated for correlation with symptomatic patients (Grade ≥ 2).
RESULTS: Fifty patients completed the trial. The pneumonitis toxicity score was: Grade 3 for 1 patient, Grade 2 for 6 patients, Grade 1 for 18 patients, and Grade 0 for 25 patients. Dosimetric factors were not predictive of symptoms. The NOR was 3.0 ± 1.8 (range 1.47-6.73) for the symptomatic and 0.78 ± 0.29 (range 0.33-1.37) for the asymptomatic patients (p=0.006). A threshold NOR of 1.4 separated symptomatic and asymptomatic patients (p<0.001). The average error was 4%.
CONCLUSIONS: Elevation in eNO on the last day of radiotherapy predicted subsequent symptomatic radiation pneumonitis weeks to months after treatment.
Copyright © 2011. Published by Elsevier Ireland Ltd.
Guerrero T, Martinez J, McCurdy MR, Wolski M, McAleer MF.
Elevation in exhaled nitric oxide predicts for radiation pneumonitis.
Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):981-8. doi: 10.1016/j.ijrobp.2010.08.041. Epub 2011 Mar 4.
Abstract/Text
PURPOSE: Radiation pneumonitis is a major toxicity after thoracic radiotherapy (RT), with no method available to accurately predict the individual risk. This was a prospective study to evaluate exhaled nitric oxide as a predictive biomarker for radiation pneumonitis in esophageal cancer patients.
PATIENTS AND METHODS: A total of 34 patients prescribed neoadjuvant chemoradiotherapy for esophageal cancer were enrolled in the present trial. Each patient underwent respiratory surveys and exhaled nitric oxide (NO) measurements before, at the end of, and 1 to 2 months after completing RT. Pneumonitis toxicity was scored using the Common Terminology Criteria for Adverse Events, version 4.0. The demographics, dosimetric factors, and exhaled NO levels were evaluated for correlation with symptomatic patients (scores ≥ 2).
RESULTS: Of the 34 patients, 28 were evaluable. All had received 50.4 Gy RT with concurrent chemotherapy. The pneumonitis toxicity score was Grade 3 for 1, Grade 2 for 3, Grade 1 for 7, and Grade 0 for 17. The dosimetric factors were not predictive of symptoms. The mean exhaled NO level measured before, at completion, and at restaging was 17.3 ± 8.5 (range, 5.5-36.7), 16.0 ± 14.2 (range, 5.8-67.7), and 14.7 ± 6.2 (range, 5.5-28.0) parts per billion, respectively. The ratio of exhaled NO at the end of RT vs. before treatment was 3.4 (range, 1.7-6.7) for the symptomatic and 0.8 (range, 0.3-1.3) for the asymptomatic (p = .0017) patients. The elevation in exhaled NO preceded the peak symptoms by 33 days (range, 21-50). The interval to peak symptoms was inversely related to the exhaled NO elevation.
CONCLUSIONS: Elevations in exhaled NO at the end of RT was found to predict for radiation pneumonitis symptoms.
Copyright © 2012 Elsevier Inc. All rights reserved.
Castillo R, Pham N, Castillo E, Aso-Gonzalez S, Ansari S, Hobbs B, Palacio D, Skinner H, Guerrero TM.
Pre-Radiation Therapy Fluorine 18 Fluorodeoxyglucose PET Helps Identify Patients with Esophageal Cancer at High Risk for Radiation Pneumonitis.
Radiology. 2015 Jun;275(3):822-31. doi: 10.1148/radiol.14140457. Epub 2015 Jan 13.
Abstract/Text
PURPOSE: To examine the association between pre-radiation therapy (RT) fluorine 18 fluorodeoxyglucose (FDG) uptake and post-RT symptomatic radiation pneumonitis (RP).
MATERIALS AND METHODS: In accordance with the retrospective study protocol approved by the institutional review board, 228 esophageal cancer patients who underwent FDG PET/CT before chemotherapy and RT were examined. RP symptoms were evaluated by using the Common Terminology Criteria for Adverse Events, version 4.0, from the consensus of five clinicians. By using the cumulative distribution of standardized uptake values (SUVs) within the lungs, those values greater than 80%-95% of the total lung voxels were determined for each patient. The effect of pre-chemotherapy and RT FDG uptake, dose, and patient or treatment characteristics on RP toxicity was studied by using logistic regression.
RESULTS: The study subjects were treated with three-dimensional conformal RT (n = 36), intensity-modulated RT (n = 135), or proton therapy (n = 57). Logistic regression analysis demonstrated elevated FDG uptake at pre-chemotherapy and RT was related to expression of RP symptoms. Study subjects with elevated 95% percentile of the SUV (SUV95) were more likely to develop symptomatic RP (P < .000012); each 0.1 unit increase in SUV95 was associated with a 1.36-fold increase in the odds of symptomatic RP. Receiver operating characteristic (ROC) curve analysis resulted in area under the ROC curve of 0.676 (95% confidence interval: 0.58, 0.77), sensitivity of 60%, and specificity of 71% at the 1.17 SUV95 threshold. CT imaging and dosimetric parameters were found to be poor predictors of RP symptoms.
CONCLUSION: The SUV95, a biomarker of pretreatment pulmonary metabolic activity, was shown to be prognostic of symptomatic RP. Elevation in this pretreatment biomarker identifies patients at high risk for posttreatment symptomatic RP.
RSNA, 2015
Kong FM (Spring), Wang S. Nondosimetric Risk Factors for Radiation-Induced Lung Toxicity. Semin Radiat Oncol. W.B. Saunders; 2015. p. 100–109.
Palma DA, Senan S, Tsujino K, Barriger RB, Rengan R, Moreno M, Bradley JD, Kim TH, Ramella S, Marks LB, De Petris L, Stitt L, Rodrigues G. Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: An international individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. Int J Radiat Oncol Biol Phys; 2013 Feb 1;85(2):444–450.
Ozawa Y, Abe T, Omae M, Matsui T, Kato M, Hasegawa H, Enomoto Y, Ishihara T, Inui N, Yamada K, Yokomura K, Suda T. Impact of preexisting interstitial lung disease on acute, extensive radiation pneumonitis: Retrospective analysis of patients with lung cancer. PLoS One. Public Library of Science; 2015 Oct 13;10(10).
Tsujino K, Hashimoto T, Shimada T, Yoden E, Fujii O, Ota Y, Satouchi M, Negoro S, Adachi S, Soejima T. Combined analysis of V20, VS5, pulmonary fibrosis score on baseline computed tomography, and patient age improves prediction of severe radiation pneumonitis after concurrent chemoradiotherapy for locally advanced non-small-cell lung cancer. J Thorac Oncol. Lippincott Williams and Wilkins; 2014;9(7):983–990.
Tomita N, Okuda K, Ogawa Y, Iida M, Eguchi Y, Kitagawa Y, Uchiyama K, Takaoka T, Nakanishi R, Shibamoto Y.
Relationship between radiation doses to heart substructures and radiation pneumonitis in patients with thymic epithelial tumors.
Sci Rep. 2020 Jul 7;10(1):11191. doi: 10.1038/s41598-020-68168-y. Epub 2020 Jul 7.
Abstract/Text
Radiation doses to the heart are potentially high in patients undergoing radiotherapy for thymoma or thymic carcinoma because of their origin site and propensity for pericardial invasion. We investigated potential relationships between radiation pneumonitis (RP) and the dosimetric parameters of lung and heart substructures in patients with thymic epithelial tumors. This retrospective study included 70 consecutive patients who received definitive or postoperative radiotherapy at a median dose of 58.3 Gy. Heart substructures were delineated according to a published atlas. The primary end point of ≥ grade 2 RP was observed in 13 patients (19%) despite a low lung dose; median lung V20 (i.e. percentage of the volume receiving at least 20 Gy) was only 16.6%. In a univariate analysis, four lung parameters, heart V35, three pulmonary artery (PA) parameters, two left ventricle parameters, and left atrium V35 were associated with the development of RP. In a multivariate analysis, only PA V35 remained significant (hazard ratio 1.04; 95% CI 1.01-1.07, p = 0.007). PA V35 of the RP versus non-RP groups were 84.2% versus 60.0% (p = 0.003). The moderate dose sparing of PA could be a candidate as a planning constraint for reducing the risk of RP in thoracic radiotherapy.
Torre-Bouscoulet L, Arroyo-Hernández M, Martínez-Briseño D, Muñoz-Montaño WR, Gochicoa-Rangel L, Bacon-Fonseca L, Pérez-Padilla R, Vergara E, García-Sancho C, Lozano-Ruiz F, Fernández-Plata R, Guzmán-Barragán A, Arrieta O.
Longitudinal Evaluation of Lung Function in Patients With Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation Therapy.
Int J Radiat Oncol Biol Phys. 2018 Jul 15;101(4):910-918. doi: 10.1016/j.ijrobp.2018.04.014. Epub 2018 Apr 12.
Abstract/Text
PURPOSE: In lung cancer patients, radiation therapy modifies lung architecture, resulting in functional deterioration, which worsens symptoms and reduces quality of life.
METHODS AND MATERIALS: A multicenter, prospective, longitudinal study was conducted in a cohort of patients with locally advanced and oligometastatic non-small cell lung cancer treated with concurrent chemoradiation therapy (CCRT). A wide array of pulmonary function tests (forced spirometry, body plethysmography, impulse oscillometry, carbon monoxide diffusing capacity, fraction of exhaled nitric oxide, arterial blood gases, and 6-minute walk test) were used to evaluate lung function at baseline; after radiation therapy; and at 6, 12, 24, and 48 weeks after CCRT. Relative changes in test results (percentages) were estimated at the aforementioned intervals and compared with baseline results.
RESULTS: Thirty-seven patients completed the follow-up and were included in the analysis. After CCRT, patients showed a maximum decline in lung volumes as follows: (1) 31% in forced expiratory volume in the first second after 24 weeks (P = .008), (2) 9.6% in forced vital capacity after 48 weeks (P = .04), and (3) 15.1% in total lung capacity after 48 weeks (P = .0015). Similarly, at 12 weeks after CCRT, patients showed a 21.8% decrease in carbon monoxide diffusing capacity (P = .002). Increases were found in total airway resistance (respiratory system resistance at 5 Hz), frequency dependence of resistance (change in respiratory system resistance at 5 Hz-respiratory system resistance at 20 Hz, P = .012), and reactance (P = .0003 for respiratory system reactance at 5 Hz and P = .001 for reactance area), which together indicate small-airway dysfunction.
CONCLUSIONS: The longitudinal evaluation of lung function through pulmonary function tests detects CCRT-induced damage before the appearance of clinical symptoms associated with CCRT lung toxicity.
Copyright © 2018 Elsevier Inc. All rights reserved.
Scher ED, Kim S, Deek MP, Ahmed I, Kothadia JP, Balasubramanian S, Aisner J, Goyal S, Jabbour SK. Ambulatory pulse oximetry as a clinical aid for the diagnosis and treatment response of radiation pneumonitis. Pract Radiat Oncol. Elsevier Inc.; 2015 Nov 1;5(6):e635–e641.
Lee YH, Choi HS, Jeong H, Kang KM, Song JH, Lee WS, Lee GW, Song HN, Kim HG, Kang MH, Rhee DY, Jeong BK.
Neutrophil-lymphocyte ratio and a dosimetric factor for predicting symptomatic radiation pneumonitis in non-small-cell lung cancer patients treated with concurrent chemoradiotherapy.
Clin Respir J. 2018 Mar;12(3):1264-1273. doi: 10.1111/crj.12660. Epub 2017 Jun 28.
Abstract/Text
OBJECTIVES: To identify the factors that predict the progression of radiological radiation pneumonitis (RP) to symptomatic RP, and to evaluate the usefulness of the neutrophil-lymphocyte ratio (NLR) as a marker of RP severity and prognosis in stage III non-small cell lung cancer (NSCLC) patients treated with definitive concurrent chemoradiotherapy (CCRT).
MATERIALS AND METHODS: We retrospectively reviewed 61 patients treated between January 2010 and December 2015. Patients' demographic characteristics, clinical data, laboratory findings and treatment parameters were analyzed to determine the predictive factors associated with progression from radiological RP to symptomatic RP.
RESULTS: Forty-seven patients (77%) exhibited radiological RP at a median of 78 days after radiation therapy (RT) completion, and 15 (32%) of these patients developed symptomatic RP. The interval between RT completion and radiological RP presentation was shorter in patients who progressed to symptomatic RP (P = .001); progression was highly probable if this latency period was ≤2 months (P = .002). Stage and RT technique correlated with symptomatic RP development (P = .046 and P = .046, respectively). Among dosimetric factors, a V20 (defined as the lung volume receiving ≥20 Gy) of >30% was the most significant predictor of symptomatic RP (P = .001). The NLR and C-reactive protein level at radiological RP were higher in patients who developed symptomatic RP (P = .067 and P = .012, respectively). On multivariate analysis, a V20 >30% and an NLR at radiological RP >6 were associated with symptomatic RP development.
CONCLUSION: The NLR at radiological RP is a useful biomarker for predicting symptomatic RP development after CCRT in stage III NSCLC patients.
© 2017 John Wiley & Sons Ltd.
Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, Garon EB, Lee P. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. Lancet Publishing Group; 2017 Jul 1;18(7):895–903.
Thore P, Godbert B, Petit I, Chaouat A. Radiation recall pneumonitis in a patient treated by nivolumab for non-small-cell lung cancer, no relapse with rechallenge. J. Med. Oncol. 2018;1(3):12.
Shibaki R, Akamatsu H, Fujimoto M, Koh Y, Yamamoto N.
Nivolumab induced radiation recall pneumonitis after two years of radiotherapy.
Ann Oncol. 2017 Jun 1;28(6):1404-1405. doi: 10.1093/annonc/mdx115.
Abstract/Text
Kalisz KR, Ramaiya NH, Laukamp KR, Gupta A. Immune checkpoint inhibitor therapy–related pneumonitis: Patterns and management. Radiographics. Radiological Society of North America Inc.; 2019 Nov 1;39(7):1923–1937.
宮敏路, 大野陽子, 田中穂積, 輿石義彦, 呉屋朝幸: Gefitinib(Iressa)によって想起されたRadiation recall pneumonitis の 1 例. 日呼吸会誌 2003;41:565-568.
Ding X, Ji W, Li J, Zhang X, Wang L.
Radiation recall pneumonitis induced by chemotherapy after thoracic radiotherapy for lung cancer.
Radiat Oncol. 2011 Mar 6;6:24. doi: 10.1186/1748-717X-6-24. Epub 2011 Mar 6.
Abstract/Text
BACKGROUND: Radiation recall pneumonitis (RRP) describes a rare reaction in previously irradiated area of pulmonary tissue after application of triggering agents. RRP remains loosely characterized and poorly understood since it has so far only been depicted in 8 cases in the literature. The objective of the study is to disclose the general characteristics of RRP induced by chemotherapy after thoracic irradiation for lung cancer, and to draw attention to the potential toxicity even after a long time interval from the previous irradiation.
METHODS: Medical records were reviewed. RRP induced by chemotherapy was diagnosed by the history of chemotherapy after radiotherapy, clinical presentation and radiographic abnormalities including ground-glass opacity, attenuation, or consolidation changes within the radiation field, plus that radiographic examination of the thorax before showed no radiation pneumonitis. RRP was graded according to Common Terminology Criteria for Adverse Events version 3.0. The characteristics of the 12 RRP cases were analyzed.
RESULTS: Twelve patients were diagnosed of RRP, of who 8 received taxanes. The median time interval between end of radiotherapy and RRP, between end of radiotherapy and beginning of chemotherapy, and between beginning of chemotherapy and RRP was 95 days, 42 days and 47 days, respectively. Marked symptomatic and radiographic improvement was observed in the 12 patients after withdrawal of chemotherapy and application of systemic corticosteroids. Seven patients were rechallenged with chemotherapy, of whom four with the same kind of agents, and showed no recurrence with steroid cover.
CONCLUSIONS: Doctors should pay attention to RRP even after a long time from the previous radiotherapy or after several cycles of consolidation chemotherapy. Taxanes are likely to be associated with radiation recall more frequently. Withdrawal of causative agent and application of steroids are the treatment of choice. Patients may be rechallenged safely with steroid cover and careful observation, which needs to be validated.
Riviere P, Sumner W, Cornell M, Sandhu A, Murphy JD, Hattangadi-Gluth J, Bruggeman A, Kim SS, Randall JM, Sharabi AB.
Radiation Recall Pneumonitis After Treatment With Checkpoint Blockade Immunotherapy: A Case Series and Review of Literature.
Front Oncol. 2021;11:662954. doi: 10.3389/fonc.2021.662954. Epub 2021 Apr 30.
Abstract/Text
BACKGROUND: Radiation recall pneumonitis (RRP) is a poorly understood clinical syndrome in which patients develop radiation pneumonitis triggered by a systemic agent, often years after the completion of radiation therapy. Immune checkpoint blockade agents have only recently been posited as a trigger for RRP. Here, we present three cases of immunotherapy-induced RRP.
CASE PRESENTATION: Our first patient was diagnosed with primary lung adenocarcinoma, and 4.5 years after completing radiation therapy developed symptomatic RRP immediately following a second dose of nivolumab-containing immunotherapy regimen. Our second patient was diagnosed with primary bladder cancer metastatic to the mediastinum, which was treated twice with radiation therapy. He developed RRP in the days following his second course of ipilimumab-pembrolizumab which was months after his second course of radiation that he received. Our final patient was diagnosed with metastatic small cell lung cancer and received local consolidative radiation therapy in addition to whole-brain radiation. He developed RRP on the 11th day after concluding his 4th cycle of nivolumab-ipilimumab, approximately 7 months after having had completed chest radiation therapy.
CONCLUSIONS: Immunotherapy-induced RRP is a rare diagnosis which can present more focally than traditional immunotherapy pneumonitis and which must be clinically differentiated from other local processes such as pneumonia. Further research should explore the mechanisms underlying these radiation recall reactions as many patients receive radiation and immunotherapy during the course of their cancer treatment.
Copyright © 2021 Riviere, Sumner, Cornell, Sandhu, Murphy, Hattangadi-Gluth, Bruggeman, Kim, Randall and Sharabi.
Noda-Narita S, Naito T, Udagawa H, Goto K, Miyawaki T, Mamesaya N, Nakashima K, Kenmotsu H, Shimokawaji T, Kato T, Hakozaki T, Okuma Y, Nakamura M, Nakayama Y, Watanabe H, Kusumoto M, Ohe Y, Horinouchi H.
Nivolumab-induced radiation recall pneumonitis in non-small-cell lung cancer patients with thoracic radiation therapy.
Cancer Sci. 2023 Feb;114(2):630-639. doi: 10.1111/cas.15621. Epub 2022 Nov 20.
Abstract/Text
The role of previous thoracic radiation therapy as a risk factor of immune-related pneumonitis is unclear. Furthermore, some patients develop radiation recall pneumonitis, which is characterized by a radiation pneumonitis-like imaging pattern with consolidation progressing within a previous radiation field. In this multicenter retrospective study, we analyzed the relationship of previous thoracic radiation therapy with immune-related pneumonitis and the characteristics of radiation recall pneumonitis. The medical records of patients with non-small-cell lung cancer who had received nivolumab between December 2015 and March 2017 at five institutions were retrospectively reviewed. Incidence, imaging patterns, clinical course, and risk factors of immune-related pneumonitis and radiation recall pneumonitis were evaluated. A total of 669 patients were evaluated, and the incidences of all-grade and grade 3 or higher immune-related pneumonitis were 8.8% and 2.6%, respectively. The incidences of immune-related pneumonitis were 13.2% (34/257) and 6.1% (25/412) in patients with and those without previous thoracic radiation therapy, respectively. A history of previous thoracic radiation therapy was associated with immune-related pneumonitis (odds ratio, 2.11; 95% confidence interval, 1.21-3.69 in multivariate analysis). Among the patients with previous thoracic radiation therapy, 6.2% (16/257) showed radiation recall pattern. This study found an increased risk of nivolumab-induced immune-related pneumonitis associated with a history of thoracic radiation therapy. Radiation recall pattern was one of the major patterns of immune-related pneumonitis among the patients with previous thoracic radiation therapy. Incidence, risk factors, and clinical outcome of radiation recall pneumonitis were elucidated.
© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
Shinada K, Murakami S, Yoshida D, Saito H.
Radiation recall pneumonitis after COVID-19 vaccination.
Thorac Cancer. 2022 Jan;13(1):144-145. doi: 10.1111/1759-7714.14239. Epub 2021 Nov 17.
Abstract/Text
Cordier JF, Mornex JF, Lasne Y, Gérard JP, Cordier G, Creyssel R, Touraine R.
Bronchoalveolar lavage in radiation pneumonitis.
Bull Eur Physiopathol Respir. 1984 Jul-Aug;20(4):369-74.
Abstract/Text
Bronchoalveolar lavage (BAL) was carried out in six patients with radiation pneumonitis, the early radiation-induced lung damage that usually leads to radiation fibrosis. Protein analysis by immuno-electrophoresis and polyacrylamide gel electrophoresis of BAL fluid revealed leakage of circulatory proteins, including high molecular weight components. Cell count of BAL fluid showed an increased number of lymphocytes; these proved to be activated on cell cycle analysis in one patient. Collagenolytic activity, assessed by degradation of radiolabelled type I human collagen, was present in BAL fluid of all six patients. The following mechanisms are therefore considered to participate in the pathogenesis of radiation-induced lung damage: 1) permeability oedema, which led to acute respiratory distress syndrome in one case of hyperacute radiation pneumonitis, 2) lymphocyte alveolitis possibly perpetuated by activated lymphocytes, and 3) release of collagenolytic enzymes in alveolar structures contributing to fibrotic processes.
Roberts CM, Foulcher E, Zaunders JJ, Bryant DH, Freund J, Cairns D, Penny R, Morgan GW, Breit SN.
Radiation pneumonitis: a possible lymphocyte-mediated hypersensitivity reaction.
Ann Intern Med. 1993 May 1;118(9):696-700. doi: 10.7326/0003-4819-118-9-199305010-00006.
Abstract/Text
OBJECTIVE: To determine if unilateral thoracic irradiation results in a lymphoid alveolitis in both irradiated and unirradiated lung fields.
DESIGN: A prospective, nonrandomized study.
PATIENTS: Women receiving postoperative radiotherapy for carcinoma of the breast were evaluated both before and 4 to 6 weeks after radiotherapy. Findings after radiotherapy in 15 asymptomatic patients were compared with findings in a group of patients with clinical radiation pneumonitis.
MEASUREMENTS: History, physical examination, chest radiograph, quantitative gallium lung scanning, respiratory function tests, bronchoalveolar lavage, and lavage lymphocyte subset analysis.
RESULTS: After irradiation, lavage lymphocytes increased significantly (34.5% versus 46.8%; P = 0.01) in the 17 patients studied prospectively. There was an associated reduction in vital capacity (102.5% versus 95.5%; P = 0.04). Comparison of results in patients before treatment, after treatment without clinical pneumonitis, and after treatment with clinical pneumonitis showed a dramatic increase in total lymphocytes after irradiation (6.3 versus 9.4 versus 35.2 million, respectively; P = 0.005), particularly in those with clinical pneumonitis. Only in those with clinical pneumonitis was this accompanied by an increase in the gallium index (3.7 versus 3.4 versus 9.0, respectively; P < 0.001). Vital capacity was also progressively reduced (102.5% versus 96.9% versus 76.7%, respectively; P = 0.04), as was diffusing capacity (98.6% versus 91.4% versus 72.6%, respectively; P = 0.003). No statistical differences existed between irradiated and unirradiated sides of the chest in either lavage or gallium lung scan studies.
CONCLUSION: In most patients, a lymphocytic alveolitis develops in both lung fields after strictly unilateral thoracic irradiation; this is more pronounced in patients developing clinical pneumonitis. These findings suggest that radiotherapy may cause a generalized lymphocyte-mediated hypersensitivity reaction.
Toma CL, Serbescu A, Alexe M, Cervis L, Ionita D, Bogdan MA.
The bronchoalveolar lavage pattern in radiation pneumonitis secondary to radiotherapy for breast cancer.
Maedica (Bucur). 2010 Dec;5(4):250-7.
Abstract/Text
BACKGROUND AND PURPOSE: Radiotherapy in breast cancer patients is limited by lung tissue tolerance. Two complications involving the lung are known: radiation pneumonitis (RP) and radiation fibrosis. The aim of the study was to evaluate the pattern of bronchoalveolar lavage (BAL) in patients with RP after radiotherapy for breast cancer in symptomatic and asymptomatic patients.
MATERIAL AND METHODS: Sixty-five female patients (mean age 58.3 yrs) with RP after radiotherapy for breast cancer were included in the study. The majority of patients had previous breast surgery (mastectomy or lumpectomy and axillary dissection) and received doses of radiations of 45-50Gy. All patients had adjuvant chemotherapy with cyclophosphamide, 5-fluorouracil, and epirubicin or methotrexate.
RESULTS: All patients had an infiltrate or consolidation on chest radiography confined to the upper lobe of the irradiated lung, as marker of RP. Based on the presence or absence of symptoms, we divided the patients in 2 groups: 49 patients (75.4%) with symptomatic RP (fever, cough, dyspnea, chest pain and fatigue) and 16 patients (24.6%) without any symptom. Symptomatic RP patients had a BAL with significant increase in total cells (18.0±12.2 x10(6) cells•100mL-1) when compared to BAL in asymptomatic patients (11.9±6.2 x10(6) cells•100mL-1), p=0.01. Lymphocytosis in BAL was significantly increased in symptomatic group, compared with asymptomatic one (35.4±18.7% vs. 26.1±14.3%, p=0.045), with predominance of T lymphocytes (CD3). It was also a predominance of CD4 lymphocytes in all patients, but the CD4/CD8 ratio was inside normal range in the majority of cases. Five patients had clinical features of bronchiolitis obliterans organizing pneumonia (BOOP) secondary to irradiation with increased percentages of lymphocytes, neutrophils, eosinophils, and mast cells in BAL and one patient without history of atopic disease had a percentage of 40% eosinophils. Only a mild reduction in diffusing capacity for carbon monoxide was seen in both groups on pulmonary function tests. The lung volumes were normal in all patients.
CONCLUSIONS: Lymphocytic alveolitis was the marker of radiation pneumonitis in all patients. The degree of the inflammatory reaction of the lungs was correlated with the presence of symptoms. The lymphocytic alveolitis consisted mainly of T lymphocytes, with a predominance of CD4 subset in both groups, but the CD4/CD8 ratio remained mostly into normal range.
Frank A, Lefkowitz D, Jaeger S, Gobar L, Sunderland J, Gupta N, Scott W, Mailliard J, Lynch H, Bishop J.
Decision logic for retreatment of asymptomatic lung cancer recurrence based on positron emission tomography findings.
Int J Radiat Oncol Biol Phys. 1995 Jul 30;32(5):1495-512. doi: 10.1016/0360-3016(94)00622-R.
Abstract/Text
PURPOSE: The purpose of the study was to determine if Positron emission tomography (PET) 2-[F-18] fluoro-2-deoxy-D-glucose (FDG) imaging could detect subclinical local lung cancer recurrence and whether retreatment of such recurrence was feasible and beneficial.
METHODS AND MATERIALS: Twenty patients with biopsy proven lung cancer were studied with Positron emission tomography for the purpose of detecting subclinical lung cancer recurrence over a period of 4.25 years. All patients were treated with external radiation as part or all of their therapy. Twenty patients had baseline PET and computed tomography (CT) studies for comparison with later studies. Surviving patients had a total of 40 sequential PET scans and 35 CT scans. The follow-up interval ranged from 5 to 40 months posttreatment. The differential uptake ratio (DUR) was determined for regions of interest of increased FDG uptake.
RESULTS: The median DUR value of the 20 baseline PET studies was 5.59. The DUR value of greater than 3 was empirically selected as being positive for tumor detection. On baseline studies, PET had a 100% correlation with the CT findings in regard to detection of the site of primary tumor involvement. Four of 20 patients showed areas of discordance in the mediastinal and hilar areas on initial PET and CT studies. Seven of 17 patients showed discordant posttreatment PET-CT findings. Two false positive PET studies were due to radiation pneumonitis and one to macrophage glycolysis in tumor necrosis. For detection of asymptomatic tumor recurrence, analysis of sequential PET and CT studies, biopsy results, and the patient's clinical course suggested that PET had a sensitivity of 100%, specificity of 89.3%, and accuracy of 92.5%. Computerized Tomography was found to have a sensitivity of 67%, specificity of 85%, and accuracy of 82% for detection of such early-stage recurrence. Five patients went on to have retreatment with external irradiation based upon the PET evidence. Four retreated patients had biopsies that corroborated the positive PET findings, and one patient was retreated on the basis of the qualitative appearance of the posttreatment PET study. Two of the five retreated patients remain alive without evidence of tumor to 34 months following initial therapy.
CONCLUSION: Positron emission tomography scanning appears to be effective in detecting and following the progression of recurrent lung cancer. Retreatment of patients with asymptomatic recurrent tumor has resulted in absent or decreased FDG activity. Monitoring of patients with PET may provide prolonged survival in patients who otherwise would fail treatment because of local tumor recurrence.
Choi YW, Munden RF, Erasmus JJ, Park KJ, Chung WK, Jeon SC, Park CK.
Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis.
Radiographics. 2004 Jul-Aug;24(4):985-97; discussion 998. doi: 10.1148/rg.244035160.
Abstract/Text
Radiation-induced lung disease (RILD) due to radiation therapy is common. Radiologic manifestations are usually confined to the lung tissue within the radiation port and are dependent on the interval after completion of treatment. In the acute phase, RILD typically manifests as ground-glass opacity or attenuation or as consolidation; in the late phase, it typically manifests as traction bronchiectasis, volume loss, and scarring. However, the use of oblique beam angles and the development of newer irradiation techniques such as three-dimensional conformal radiation therapy can result in an unusual distribution of these findings. Awareness of the atypical manifestations of RILD can be useful in preventing confusion with infection, recurrent malignancy, lymphangitic carcinomatosis, and radiation-induced tumors. In addition, knowledge of radiologic findings that are outside the expected pattern for RILD can be useful in diagnosis of infection or recurrent malignancy. Such findings include the late appearance or enlargement of a pleural effusion; development of consolidation, a mass, or cavitation; and occlusion of bronchi within an area of radiation-induced fibrosis. A comprehensive understanding of the full spectrum of these manifestations is important to facilitate diagnosis and management in cancer patients treated with radiation therapy.
Copyright RSNA, 2004
Mac Manus MP, Ding Z, Hogg A, Herschtal A, Binns D, Ball DL, Hicks RJ.
Association between pulmonary uptake of fluorodeoxyglucose detected by positron emission tomography scanning after radiation therapy for non-small-cell lung cancer and radiation pneumonitis.
Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1365-71. doi: 10.1016/j.ijrobp.2010.04.021. Epub 2010 Aug 2.
Abstract/Text
PURPOSE: To study the relationship between fluorodeoxyglucose (FDG) uptake in pulmonary tissue after radical radiation therapy (RT) and the presence and severity of radiation pneumonitis.
METHODS AND MATERIALS: In 88 consecutive patients, (18)F-FDG-positron emission tomography was performed at a median of 70 days after completion of RT. Patients received 60 Gy in 30 fractions, and all but 15 had concurrent platinum-based chemotherapy. RT-induced pulmonary inflammatory changes occurring within the radiation treatment volume were scored, using a visual (0 to 3) radiotoxicity grading scale, by an observer blinded to the presence or absence of clinical radiation pneumonitis. Radiation pneumonitis was retrospectively graded using the Radiation Therapy Oncology Group (RTOG) scale by an observer blinded to the PET radiotoxicity score.
RESULTS: There was a significant association between the worst RTOG pneumonitis grade occurring at any time after RT and the positron emission tomograph (PET) radiotoxicity grade (one-sided p = 0.033). The worst RTOG pneumonitis grade occurring after the PET scan was also associated with the PET radiotoxicity grade (one-sided p = 0.035). For every one-level increase in the PET toxicity scale, the risk of a higher RTOG radiation pneumonitis score increased by approximately 40%. The PET radiotoxicity score showed no significant correlation with the duration of radiation pneumonitis.
CONCLUSIONS: The intensity of FDG uptake in pulmonary tissue after RT determined using a simple visual scoring system showed significant correlation with the presence and severity of radiation pneumonitis. (18)F-FDG-PET may be useful in the prediction, diagnosis and therapeutic monitoring of radiation pneumonitis.
Copyright © 2011 Elsevier Inc. All rights reserved.
Takeda A, Kunieda E, Fujii H, Yokosuka N, Aoki Y, Oooka Y, Oku Y, Ohashi T, Sanuki N, Mizuno T, Ozawa Y.
Evaluation for local failure by 18F-FDG PET/CT in comparison with CT findings after stereotactic body radiotherapy (SBRT) for localized non-small-cell lung cancer.
Lung Cancer. 2013 Mar;79(3):248-53. doi: 10.1016/j.lungcan.2012.11.008. Epub 2012 Dec 11.
Abstract/Text
PURPOSE: Stereotactic body radiotherapy (SBRT) is the standard care for medically inoperable early non-small-cell lung cancer (NSCLC). However, it can be difficult to differentiate local recurrence from non-recurrence radiation-induced lung opacity. We retrospectively assessed (18)F-FDG PET/CT to detect local recurrence after SBRT for NSCLC.
METHODS: Between 2005 and 2011, 273 NSCLCs in 257 patients were treated with SBRT. Prescribed doses were 50Gy and 40Gy per 5 fractions for peripheral and central lesions, respectively. Tri-monthly follow-up CT scans were acquired. (18)F-FDG PET/CT scans were scheduled for screening at one year after SBRT or when recurrence was highly suspected. The dual-time-point maximum standardized uptake values (SUVmaxs) and their retention indexes (RIs) were obtained.
RESULTS: A total of 214 (18)F-FDG PET/CT scans were obtained for 164 localized NSCLC tumors in 154 patients. The median follow-up period was 24.9 months (range: 6.3-72.1). Among these, 21 scans of 17 tumors were diagnosed as local recurrence. The median SUVmaxs on early and late images of recurrence and their RI were 5.0 (range: 3.2-10.7), 6.3 (range: 4.2-13.4), and 0.20 (range; 0-0.41), respectively. These were significantly higher than the respective values of non-recurrence images of 1.8 (range: 0.5-4.6), 1.7 (range: 0.5-6.1), and 0.00 (range: -0.37-0.41) (all p<0.05). For SUVmaxs on early and late images, optimal thresholds were identified as 3.2 and 4.2. Using each threshold, the sensitivity and specificity were 100% and 96-98%, respectively. CT findings were classified into ground-glass opacity (N=9), scar or fibrotic change (N=96), consolidation with air-bronchogram (N=34), consolidation only (N=22), and nodule (N=17); the respective numbers of recurrence were 0, 0, 1, 3, and 17.
CONCLUSION: SUVmaxs of (18)F-FDG PET/CT could detect local recurrence after SBRT for localized NSCLC. In contrast, CT scan results had a limited ability to diagnose local recurrence.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Matsuo Y, Nakamoto Y, Nagata Y, Shibuya K, Takayama K, Norihisa Y, Narabayashi M, Mizowaki T, Saga T, Higashi T, Togashi K, Hiraoka M. Characterization of FDG-PET images after stereotactic body radiation therapy for lung cancer. Radiother Oncol. Radiother Oncol; 2010 Nov;97(2):200–204.
Dunlap NE, Yang W, McIntosh A, Sheng K, Benedict SH, Read PW, Larner JM.
Computed tomography-based anatomic assessment overestimates local tumor recurrence in patients with mass-like consolidation after stereotactic body radiotherapy for early-stage non-small cell lung cancer.
Int J Radiat Oncol Biol Phys. 2012 Dec 1;84(5):1071-7. doi: 10.1016/j.ijrobp.2012.01.088. Epub 2012 Aug 14.
Abstract/Text
PURPOSE: To investigate pulmonary radiologic changes after lung stereotactic body radiotherapy (SBRT), to distinguish between mass-like fibrosis and tumor recurrence.
METHODS AND MATERIALS: Eighty consecutive patients treated with 3- to 5-fraction SBRT for early-stage peripheral non-small cell lung cancer with a minimum follow-up of 12 months were reviewed. The mean biologic equivalent dose received was 150 Gy (range, 78-180 Gy). Patients were followed with serial CT imaging every 3 months. The CT appearance of consolidation was defined as diffuse or mass-like. Progressive disease on CT was defined according to Response Evaluation Criteria in Solid Tumors 1.1. Positron emission tomography (PET) CT was used as an adjunct test. Tumor recurrence was defined as a standardized uptake value equal to or greater than the pretreatment value. Biopsy was used to further assess consolidation in select patients.
RESULTS: Median follow-up was 24 months (range, 12.0-36.0 months). Abnormal mass-like consolidation was identified in 44 patients (55%), whereas diffuse consolidation was identified in 12 patients (15%), at a median time from end of treatment of 10.3 months and 11.5 months, respectively. Tumor recurrence was found in 35 of 44 patients with mass-like consolidation using CT alone. Combined with PET, 10 of the 44 patients had tumor recurrence. Tumor size (hazard ratio 1.12, P=.05) and time to consolidation (hazard ratio 0.622, P=.03) were predictors for tumor recurrence. Three consecutive increases in volume and increasing volume at 12 months after treatment in mass-like consolidation were highly specific for tumor recurrence (100% and 80%, respectively). Patients with diffuse consolidation were more likely to develop grade ≥ 2 pneumonitis (odds ratio 26.5, P=.02) than those with mass-like consolidation (odds ratio 0.42, P=.07).
CONCLUSION: Incorporating the kinetics of mass-like consolidation and PET to the current criteria for evaluating posttreatment response will increase the likelihood of correctly identifying patients with progressive disease after lung SBRT.
Copyright © 2012 Elsevier Inc. All rights reserved.
Takeda A, Kunieda E, Takeda T, Tanaka M, Sanuki N, Fujii H, Shigematsu N, Kubo A.
Possible misinterpretation of demarcated solid patterns of radiation fibrosis on CT scans as tumor recurrence in patients receiving hypofractionated stereotactic radiotherapy for lung cancer.
Int J Radiat Oncol Biol Phys. 2008 Mar 15;70(4):1057-65. doi: 10.1016/j.ijrobp.2007.07.2383. Epub 2007 Oct 1.
Abstract/Text
PURPOSE: To retrospectively analyze opacity changes near primary lung cancer tumors irradiated by using hypofractionated stereotactic radiotherapy (HSRT) to determine the presence or absence of tumor recurrence.
METHODS AND MATERIALS: After review-board approval for a retrospective study, we examined data from 50 patients treated with curative intent for proven or highly suspected localized peripheral-lung cancer and followed up for at least 12 months. All patients had received 50 Gy in five fractions (80% isodose) and were followed up monthly with chest X-ray until clinical and X-ray findings stabilized. Follow-up computed tomography scans were performed 1 and 3 months after HSRT and thereafter at 3-month intervals during the first 2 years.
RESULTS: Median follow-up was 30.4 months (range, 12.0-73.8 months). Abnormal opacities that were suspicious for recurrent tumor appeared in 20 patients at a median of 20.7 months (range, 5.9-61.4 months). Only 3 patients were finally found to have recurrence; 14 were recurrence free but were suspected to have fibrosis, and findings for the other 3 patients were considered equivocal because of a short follow-up period (CONCLUSION: Radiation fibrosis, which may occur 1 year or longer after completion of HSRT, is difficult to distinguish from tumor recurrence. Even when opacities increase on follow-up radiologic scans, recurrence cannot be diagnosed conclusively based on image findings; biopsy occasionally is warranted.
Peulen H, Mantel F, Guckenberger M, Belderbos J, Werner-Wasik M, Hope A, Giuliani M, Grills I, Sonke JJ. Validation of High-Risk Computed Tomography Features for Detection of Local Recurrence After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. Elsevier Inc.; 2016 Sep 1;96(1):134–141.
Huang K, Dahele M, Senan S, Guckenberger M, Rodrigues GB, Ward A, Boldt RG, Palma DA. Radiographic changes after lung stereotactic ablative radiotherapy (SABR) - Can we distinguish recurrence from fibrosis? A systematic review of the literature. Radiother Oncol. Radiother Oncol; 2012. p. 335–342.
Mattonen SA, Ward AD, Palma DA. Pulmonary imaging after stereotactic radiotherapy-does RECIST still apply? Br J Radiol. British Institute of Radiology; 2016.
Crestani B, Valeyre D, Roden S, Wallaert B, Dalphin JC, Cordier JF.
Bronchiolitis obliterans organizing pneumonia syndrome primed by radiation therapy to the breast. The Groupe d'Etudes et de Recherche sur les Maladies Orphelines Pulmonaires (GERM"O"P).
Am J Respir Crit Care Med. 1998 Dec;158(6):1929-35. doi: 10.1164/ajrccm.158.6.9711036.
Abstract/Text
Reports of bronchiolitis obliterans organizing pneumonia (BOOP) occurring in women after radiation therapy for breast cancer have suggested that radiation to the lung could participate in the development of BOOP. We now describe the clinical, radiographic, functional, and bronchoalveolar lavage characteristics of this syndrome in a series of 15 patients reported to the Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P) in France. All 15 women (60 +/- 6 yr of age) fulfilled the following inclusion criteria: (1) radiation therapy to the breast within 12 mo, (2) general and/or respiratory symptoms lasting for at least 2 wk, (3) lung infiltrates outside the radiation port, and (4) no specific cause. The patients presented with fever, nonproductive cough, mild dyspnea, and peripheral alveolar opacities on chest radiograph with a characteristic migratory pattern. In five patients, BOOP was found at lung pathologic analysis. In all the patients dramatic improvement was obtained with corticosteroids, but relapses occurred in 12 patients while tapering or after stopping corticosteroids. This report demonstrates that a characteristic BOOP syndrome may occur after radiation therapy to the breast, including tangential radiation to the lung, thus suggesting that radiation therapy may prime the development of BOOP.
Ogo E, Komaki R, Fujimoto K, Uchida M, Abe T, Nakamura K, Mitsumori M, Sekiguchi K, Kaneyasu Y, Hayabuchi N.
A survey of radiation-induced bronchiolitis obliterans organizing pneumonia syndrome after breast-conserving therapy in Japan.
Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):123-31. doi: 10.1016/j.ijrobp.2007.09.003. Epub 2007 Dec 3.
Abstract/Text
PURPOSE: We observed a rare and unique occurrence of radiation-induced pulmonary injury outside the tangential field for early breast cancer treatment. The findings appeared to be idiopathic and were called radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome. We surveyed major hospitals in Japan to review their findings of radiation-induced BOOP, in particular the clinical and pictorial characteristics of the entity.
METHODS AND MATERIALS: We reviewed surveys completed and returned by 20 institutions. The survey responses were based on a total of 37 cases of BOOP syndrome. We also reviewed X-ray and computed tomography scans provided by these institutions. We discussed the information derived from the questionnaire and analyzed patients' characteristics, methods used in the treatment of BOOP syndrome, and prognosis.
RESULTS: The incidence of the radiation-induced BOOP syndrome was about 1.8% (37 of 2,056). We did not find a relationship between the characteristics of patients and the occurrence of radiation-induced BOOP syndrome. The pulmonary findings were classified into four patterns on chest computed tomography scans. Progression of the pulmonary lesions observed on chest X-ray was classified into three patterns. Pneumonitis appeared within 6 months after radiotherapy was completed and disappeared within 6-12 months after its onset. At 5-year follow-up, 2 patients had died, 1 of breast cancer and the other of interstitial pneumonitis, which seemed to be idiopathic and unrelated to the radiation-induced BOOP syndrome.
CONCLUSIONS: Although the incidence of BOOP syndrome and its associated prognosis are not significant, the patients' clinical condition must be carefully followed.
Katayama N, Sato S, Katsui K, Takemoto M, Tsuda T, Yoshida A, Morito T, Nakagawa T, Mizuta A, Waki T, Niiya H, Kanazawa S.
Analysis of factors associated with radiation-induced bronchiolitis obliterans organizing pneumonia syndrome after breast-conserving therapy.
Int J Radiat Oncol Biol Phys. 2009 Mar 15;73(4):1049-54. doi: 10.1016/j.ijrobp.2008.05.050. Epub 2008 Aug 26.
Abstract/Text
PURPOSE: To evaluate factors associated with radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome after breast-conserving therapy.
METHODS AND MATERIALS: A total of 702 women with breast cancer who received radiotherapy after breast-conserving surgery at seven institutions between July 1995 and December 2006 were analyzed. In all patients, the whole breast was irradiated with two tangential photon beams. The criteria used for the diagnosis of radiation-induced BOOP syndrome were as follows: (1) radiotherapy to the breast within 12 months, (2) general and/or respiratory symptoms lasting for >or=2 weeks, (3) radiographs showing lung infiltration outside the radiation port, and (4) no evidence of a specific cause.
RESULTS: Radiation-induced BOOP syndrome was seen in 16 patients (2.3%). Eleven patients (68.8%) were administered steroids. The duration of steroid administration ranged from 1 week to 3.7 years (median, 1.1 years). Multivariate analysis revealed that age (>or=50 years; odds ratio [OR] 8.88; 95% confidence interval [CI] 1.16-67.76; p = 0.04) and concurrent endocrine therapy (OR 3.05; 95% CI 1.09-8.54; p = 0.03) were significantly associated with BOOP syndrome. Of the 161 patients whose age was >or=50 years and who received concurrent endocrine therapy, 10 (6.2%) developed BOOP syndrome.
CONCLUSIONS: Age (>or=50 years) and concurrent endocrine therapy can promote the development of radiation-induced BOOP syndrome after breast-conserving therapy. Physicians should carefully follow patients who received breast-conserving therapy, especially those who are older than 50 years and received concurrent endocrine therapy during radiotherapy.
Park HJ, Kim KJ, Park SH, Kay CS, Oh JS.
Early CT findings of tomotherapy-induced radiation pneumonitis after treatment of lung malignancy.
AJR Am J Roentgenol. 2009 Sep;193(3):W209-13. doi: 10.2214/AJR.08.2298.
Abstract/Text
OBJECTIVE: The objective of our study was to evaluate the early CT findings of tomotherapy-induced radiation pneumonitis.
MATERIALS AND METHODS: Tomotherapy was performed during the study period in 31 patients with peripheral pulmonary malignancies, 25 of whom underwent follow-up CT within the first 3 months after tomotherapy. These 25 patients, with a total of 77 target lesions, were enrolled for the analysis. We evaluated pulmonary toxicity by the Common Toxicity Criteria for Adverse Events (CTCAE) method and retrospectively analyzed the CT findings of radiation pneumonitis, focusing on the appearance (attenuation, shape, degree of fibrosis) and location (concentric vs eccentric, centrifugal vs centripetal) of radiation pneumonitis relative to the target lesions.
RESULTS: Radiation pneumonitis developed around 34 target lesions (34/77, 44%) in 13 patients (13/25, 52%) during the first 3 months after tomotherapy. Five patients needed steroid therapy (CTCAE grade 2, 5/25 [20%]) and the remaining eight patients required no additional treatment (CTCAE grade 0 or 1, 20/25 [80%]). In appearance, the common CT findings were irregular shape (18/34), ground-glass attenuation (19/34), and no or minimal fibrosis (33/34). The location of the radiation pneumonitis was eccentric (22/34) and centrifugal (19/34) relative to the target lesions.
CONCLUSION: Radiation pneumonitis commonly developed with minimal clinical findings within 3 months after tomotherapy. The CT findings were nonspecific: focal, irregular-shaped ground-glass opacities with minimal fibrosis. However, the location of the radiation pneumonitis tended not to correspond to the planned target volume and had a centrifugal distribution. In addition, the immediate area around the target tended to be spared.
Linda A, Trovo M, Bradley JD.
Radiation injury of the lung after stereotactic body radiation therapy (SBRT) for lung cancer: a timeline and pattern of CT changes.
Eur J Radiol. 2011 Jul;79(1):147-54. doi: 10.1016/j.ejrad.2009.10.029. Epub 2009 Dec 1.
Abstract/Text
Stereotactic body radiation therapy (SBRT) is a new radiotherapy treatment method that has been applied to the treatment of Stage I lung cancers in medically inoperable patients, with excellent clinical results. SBRT allows the delivery of a very high radiation dose to the target volume, while minimizing the dose to the adjacent normal tissues. As a consequence, CT findings after SBRT have different appearance, geographic extent and progression timeline compared to those following conventional radiation therapy for lung cancer. In particular, SBRT-induced changes are limited to the "shell" of normal tissue outside the tumor and have a complex shape. When SBRT-induced CT changes have a consolidation/mass-like appearance, the differentiation from tumor recurrence can be very difficult. An understanding of SBRT technique as it relates to the development of SBRT-induced lung injury and familiarity with the full spectrum of CT manifestations are important to facilitate diagnosis and management of lung cancer patients treated with this newly emerging radiotherapy method.
Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.
Ueki N, Matsuo Y, Togashi Y, Kubo T, Shibuya K, Iizuka Y, Mizowaki T, Togashi K, Mishima M, Hiraoka M.
Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer.
J Thorac Oncol. 2015 Jan;10(1):116-25. doi: 10.1097/JTO.0000000000000359.
Abstract/Text
INTRODUCTION: To investigate the impact of pre-existing radiological interstitial lung disease (ILD) findings on the incidence of radiation pneumonitis (RP) and clinical outcomes after stereotactic body radiation therapy (SBRT) for stage I non-small-cell lung cancer.
METHODS: We included 157 consecutive patients who underwent SBRT alone for stage I non-small-cell lung cancer and whose pretreatment lung computed tomography images were available for retrospective review. The pretreatment computed tomography images were evaluated retrospectively for the presence of ILD. The incidence of RP, overall survival (OS) rate, and the incidence of disease progression and local progression were evaluated between patients with ILD (ILD[+]) and without ILD (ILD[-]).
RESULTS: Pre-existing ILD was identified in 20 patients. The median follow-up period was 39.5 months. The incidences of RP worse than grade 2 (≥ Gr2 RP) and worse than grade 3 (≥ Gr3 RP) were significantly higher in ILD(+) than ILD(-) (1 year ≥ Gr2 RP rate, 55.0% versus 13.3%; p < 0.001 and 1year ≥ Gr3 RP rate 10.0% versus 1.5%; p = 0.020). Multivariate analysis also indicated that ILD(+) was a risk factor for ≥ Gr2 and ≥ Gr3 RP, and the volume of the irradiated lung. The OS rate tended to be worse in ILD(+) than ILD(-) (3-year OS, 53.8% versus 70.8%; p = 0.28). No difference was observed in the disease progression or local progression rates.
CONCLUSIONS: Pre-existing ILD was a significant risk factor for symptomatic and severe RP. Prescreening for ILD findings is important for determining the radiation pneumonitis risk when planning SBRT.
Glick D, Lyen S, Kandel S, Shapera S, Le LW, Lindsay P, Wong O, Bezjak A, Brade A, Cho BCJ, Hope A, Sun A, Giuliani M.
Impact of Pretreatment Interstitial Lung Disease on Radiation Pneumonitis and Survival in Patients Treated With Lung Stereotactic Body Radiation Therapy (SBRT).
Clin Lung Cancer. 2018 Mar;19(2):e219-e226. doi: 10.1016/j.cllc.2017.06.021. Epub 2017 Jul 10.
Abstract/Text
INTRODUCTION: The purpose of this study was to determine the impact of interstitial lung disease (ILD) on radiation pneumonitis (RP) and overall survival (OS) in lung stereotactic body radiation therapy (SBRT).
METHODS: Patients treated with lung SBRT from 2004 to 2015 were included. Pretreatment computed tomography scans were reviewed and classified for interstitial changes by thoracic radiologists using American Thoracic Society guidelines and Washko and Kazerooni scores. RP was scored prospectively using Common Terminology Criteria for Adverse Events, version 3.0. Pretreatment imaging characteristics, clinical variables, and dosimetry were assessed by univariate (UVA) and multivariate analysis (MVA). OS was assessed by the log-rank test, and the impact of ILD on OS was assessed by Cox regression.
RESULTS: Of the 537 patients assessed, 39 had interstitial changes (13 usual interstitial pneumonia [UIP], 24 possible UIP, and 2 inconsistent with UIP). RP was significantly higher in patients with ILD than in patients without ILD (grade ≥ 2, 20.5% vs. 5.8%; P < .01; grade ≥ 3, 10.3% vs. 1.0%; P < .01). Two of 3 grade 5 RP had imaging features of ILD. On UVA, ILD, Washko score, lung parameters performance status, and dose were significant predictors of grade ≥ 2 RP. On MVA, ILD (odds ratio, 5.81; 95% confidence interval, 2.28-14.83; P < .01) and mean lung dose (odds ratio, 1.40; 95% confidence interval, 1.14-1.71; P < .01) were predictors of RP. ILD did not significantly affect OS on UVA or MVA. Median survival was 27.4 months in the ILD cohort and 34.8 in the ILD-negative cohort (P = .17).
DISCUSSION: ILD is a significant risk factor for RP in patients treated with lung SBRT. Computed tomography scans should be reviewed for evidence of ILD prior to SBRT.
Copyright © 2017 Elsevier Inc. All rights reserved.
Hagiwara Y, Nakayama Y, Kudo S, Hayakawa T, Nakamura N, Kitamoto Y, Takahashi S, Tsujino K, Kubo N, Tamaki Y, Nagata Y; Japan Radiation Oncology Study Group (JROSG) Working Subgroup for Lung and Mediastinal Tumors.
Nationwide survey of radiation therapy in Japan for lung cancer complicated with interstitial lung disease.
J Radiat Res. 2020 Jul 6;61(4):563-574. doi: 10.1093/jrr/rraa018.
Abstract/Text
The purpose of this study was to clarify the opinions of radiation oncologists in Japan regarding treatment for lung cancer complicated with interstitial lung disease (ILD) by a questionnaire survey, and the risk of acute exacerbation (AE) after radiotherapy. Questionnaires were sent to all of the facilities in which radiation therapy is performed for lung cancer in Japan by using the mailing list of the Japanese Society for Radiation Oncology (JASTRO). The questionnaire survey was conducted to clarify who judges the existence of ILD, the indications for radiation therapy in cases of ILD-combined lung cancer, and the ratio of ILD-combined lung cancer in lung cancer patients treated with radiation therapy. Patients with ILD-combined lung cancer who received radiotherapy during the period from April 2014 to March 2015 were retrospectively analysed. Any cases of AE without any other obvious cause were included. ILD confirmation was performed by central radiologists using computed tomography images. A total of 47 facilities responded to the questionnaire. Radiation therapy was an option in cases of ILD-combined lung cancer in 39 (83%) of the facilities. The indication for radiation therapy was based on image findings in 35 (90%) of the 39 facilities in which radiation therapy was acceptable or was a choice in some cases of ILD. The final indication was based on the opinion of the pulmonologist in 29 (74%) of those 39 facilities. In fiscal year 2014, a total of 2128 patients in 38 facilities received chest irradiation. Seventy-eight (3.7%) of those 2128 patients had ILD-combined lung cancer. Sixty-seven patients were included in patient analysis. AE occurred in 5 patients (7.5%), and one of those 5 patients (20.0%) died from radiation-induced AE. The median period from radiotherapy to AE was 4 months (range, 2-7 months). The following four independent risk factors for AE were identified in univariate analysis: non-advanced age (<75 years), increased C-reactive protein level (≥0.3 mg/dl), adjuvant chemotherapy and ≥ Grade 2 radiation pneumonitis. Radiotherapy was an option for lung cancer even in cases with ILD in 83% (39/47) of the facilities in Japan. Seventy-eight (3.7%) of 2128 patients who received radiation therapy for lung cancer had ILD. Radiotherapy for ILD-combined lung cancer may induce AE at a substantial rate and AE can be life-threatening. Minimizing the risk of radiation pneumonitis might enable the risk of AE to be reduced.
© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.
Yamaguchi S, Ohguri T, Ide S, Aoki T, Imada H, Yahara K, Narisada H, Korogi Y.
Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: the potential risk of extensive radiation pneumonitis.
Lung Cancer. 2013 Nov;82(2):260-5. doi: 10.1016/j.lungcan.2013.08.024. Epub 2013 Sep 7.
Abstract/Text
PURPOSE: To evaluate the toxicity and efficacy of thoracic stereotactic body radiotherapy (SBRT) in patients with subclinical interstitial lung disease (ILD).
METHODS AND MATERIALS: One hundred patients with 124 lung tumors were treated with SBRT at our institution according to our own protocols; patients with subclinical (untreated and oxygen-free) ILD were treated with SBRT, while those with clinical ILD (post- or under treatment) were not. The administration of 48 Gy in four fractions was used in 103 (83%) of the 124 tumors. The presence of subclinical ILD in the pre-SBRT CT findings was reviewed by two chest radiologists. The relationships between radiation pneumonitis (RP) and clinical factors were investigated.
RESULTS: Subclinical ILD was recognized in 16 (16%) of 100 patients. Grade 2-5 RP was recognized in 13 (13%) of 100 patients. Grade 2-5 RP was observed in three (19%) of 16 patients with subclinical ILD. Subclinical ILD was not found to be a significant factor influencing Grade 2-5 RP; however, extensive RP beyond the irradiated field, including the contralateral lung, was recognized in only three patients with subclinical ILD, and the rate of extensive RP was significantly high in the patients with subclinical ILD. Grade 4 or 5 extensive RP was recognized in only two patients with subclinical ILD. Dosimetric factors of the lungs (V5, V10, V15, V20, V25, MLD) were significantly associated with Grade 2-5 RP. The three-year overall survival and local control rates of all patients were 53% and 86%, respectively. No significant differences were seen in either overall survival or local control rates between the patients with ILD and those without ILD.
CONCLUSIONS: Subclinical ILD was not found to be a significant factor for Grade 2-5 RP or clinical outcomes in the current study; however, uncommon extensive RP can occur in patients with subclinical ILD.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Onishi H, Marino K, Yamashita H, Terahara A, Onimaru R, Kokubo M, Shioyama Y, Kozuka T, Matsuo Y, Aruga T, Hiraoka M. Case series of 23 patients who developed fatal radiation pneumonitis after stereotactic body radiotherapy for lung cancer. Technol Cancer Res Treat. SAGE Publications Inc.; 2018 Jan 1;17.
Onishi H, Yamashita H, Shioyama Y, Matsumoto Y, Takayama K, Matsuo Y, Miyakawa A, Matsushita H, Aoki M, Nihei K, Kimura T, Ishiyama H, Murakami N, Nakata K, Takeda A, Uno T, Nomiya T, Takanaka T, Seo Y, Komiyama T, Marino K, Aoki S, Saito R, Araya M, Maehata Y, Tominaga L, Kuriyama K.
Stereotactic Body Radiation Therapy for Patients with Pulmonary Interstitial Change: High Incidence of Fatal Radiation Pneumonitis in a Retrospective Multi-Institutional Study.
Cancers (Basel). 2018 Aug 2;10(8). doi: 10.3390/cancers10080257. Epub 2018 Aug 2.
Abstract/Text
Pretreatment pulmonary interstitial change (PIC) has been indicated as a risk factor of severe radiation pneumonitis (RP) following stereotactic body radiation therapy (SBRT) for early-stage lung cancer, but details of its true effect remain unclear. This study aims to evaluate treatment outcomes of SBRT for stage I non-small cell lung cancer in patients with PIC. A total of 242 patients are included in this study (88% male). The median age is 77 years (range, 55⁻92 years). A total dose of 40⁻70 Gy is administered in 4 to 10 fractions during a 4-to-25 day period. One, two, and three-year overall survival (OS) rates are 82.1%, 57.1%, and 42.6%, respectively. Fatal RP is identified in 6.9% of all patients. The percent vital capacity <70%, mean percentage normal lung volume receiving more than 20 Gy (>10%), performance status of 2⁻4, presence of squamous cell carcinoma, clinical T2 stage, regular use of steroid before SBRT, and percentage predicting forced expiratory volume in one second (<70%) are associated with worse prognoses for OS. Our results indicate that fatal RP frequently occurs after SBRT for stage I lung cancer in patients with PIC.
Saha A, Dickinson P, Shrimali RK, Salem A, Agarwal S.
Is Thoracic Radiotherapy an Absolute Contraindication for Treatment of Lung Cancer Patients With Interstitial Lung Disease? A Systematic Review.
Clin Oncol (R Coll Radiol). 2022 Dec;34(12):e493-e504. doi: 10.1016/j.clon.2022.01.043. Epub 2022 Feb 12.
Abstract/Text
Thoracic radiotherapy decisions in patients with interstitial lung disease (ILD) are complex due to concerns about severe or even fatal radiation pneumonitis. This systematic review analysed the published evidence regarding the incidence of radiation pneumonitis and mortality after thoracic radiotherapy and investigated clinical and dosimetric predictors of radiation pneumonitis in lung cancer patients with ILD. A systematic search was carried out in PubMed, Medline, Embase and the Cochrane database for articles published between January 2000 and April 2021. Two authors independently screened eligible studies that met our predefined criteria. Studies were assessed for design and quality and a qualitative data synthesis was carried out. The search strategy resulted in 1750 articles. After two rounds of screening, 24 publications were included. The median overall incidence of grade ≥3 radiation pneumonitis was 19.7% (range 8-46%). The incidence was greater in conventional radical radiotherapy-treated patients (median 31.8%) compared with particle beam therapy- or stereotactic ablative radiotherapy-treated patients (median 12.5%). The median rate of grade 5 radiation pneumonitis was 11.9% (range 0-60%). The presence of ILD was an independent predictor of severe radiation pneumonitis. Severe radiation pneumonitis was more common in the presence of usual interstitial pneumonia (UIP) pattern or idiopathic pulmonary fibrosis (IPF) than non-UIP or non-IPF subtype. Several other clinical predictors were reported in the literature. V5, V10, V20 and mean lung dose were the most common dosimetric predictors for severe radiation pneumonitis, often with stricter dose constraints than conventionally used. Patients with lung cancer associated with ILD had a poorer overall survival compared with patients without ILD. In conclusion, patients with lung cancer associated with ILD have a poor prognosis. They are at high risk of severe and even fatal radiation pneumonitis. Careful patient selection is necessary, appropriate high-risk consenting and strict lung dose-volume constraints should be used, if these patients are to be treated with thoracic radiotherapy.
Copyright © 2022 The Royal College of Radiologists. All rights reserved.
Kim H, Pyo H, Noh JM, Lee W, Park B, Park HY, Yoo H.
Preliminary result of definitive radiotherapy in patients with non-small cell lung cancer who have underlying idiopathic pulmonary fibrosis: comparison between X-ray and proton therapy.
Radiat Oncol. 2019 Jan 28;14(1):19. doi: 10.1186/s13014-019-1221-4. Epub 2019 Jan 28.
Abstract/Text
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with fatal complications after radiotherapy (RT) for lung cancer patients; however, the role of proton therapy to reduce the incidence of life-threatening complications is unclear. Herein, we present the preliminary results of early-stage lung cancer patients having IPF and treated with RT, with a focus on the comparison between X-ray and proton therapy.
METHODS: From January 2010 to October 2017, we retrospectively reviewed the medical records of 264 patients with stage I-II non-small cell lung cancer (NSCLC) treated with definitive RT alone. Ultimately, 30 patients (11.4%) who had underlying IPF were analyzed. Among these, X-ray and proton RT were delivered to 22 and 8 patients, respectively. Treatment-related complications and survival outcomes were compared between X-ray and proton therapy.
RESULTS: The median follow-up duration was 11 months (range, 2 to 51 months). All living patients were followed-up at least 9 months. Treatment-related death occurred in four patients (18.2%) treated with X-ray but none with proton therapy. Most patients died within one month after the onset of pulmonary symptoms in spite of aggressive treatment. In addition, the 1-year overall survival (OS) rate in patients treated with X-ray and proton was 46.4 and 66.7%, respectively, and patients treated with proton therapy showed a tendency of better survival compared to X-ray (p = 0.081). Especially, in GAP stage II and III subgroups, patients treated with proton therapy showed significantly increased survival outcomes compared to X-ray (1-year OS rate; 50.0% versus 26.4%, p = 0.036) in univariate analysis.
CONCLUSIONS: RT is associated with serious treatment-related complications in patients with IPF. Proton therapy may be helpful to reduce these acute and fatal complications.
TRIAL REGISTRATION: retrospectively registered.
Drakopanagiotakis F, Krauss E, Michailidou I, Drosos V, Anevlavis S, Günther A, Steiropoulos P.
Lung Cancer and Interstitial Lung Diseases.
Cancers (Basel). 2024 Aug 13;16(16). doi: 10.3390/cancers16162837. Epub 2024 Aug 13.
Abstract/Text
Lung cancer continues to be one of the leading causes of cancer-related death worldwide. There is evidence of a complex interplay between lung cancer and interstitial lung disease (ILD), affecting disease progression, management strategies, and patient outcomes. Both conditions develop as the result of common risk factors such as smoking, environmental exposures, and genetic predispositions. The presence of ILD poses diagnostic and therapeutic challenges in lung cancer management, including difficulties in interpreting radiological findings and increased susceptibility to treatment-related toxicities, such as acute exacerbation of ILD after surgery and pneumonitis after radiation therapy and immunotherapy. Moreover, due to the lack of large, phase III randomized controlled trials, the evidence-based therapeutic options for patients with ILDs and lung cancer remain limited. Antifibrotic treatment may help prevent pulmonary toxicity due to lung cancer treatment, but its effect is still unclear. Emerging diagnostic modalities and biomarkers and optimizing personalized treatment strategies are essential to improve outcomes in this patient population.
日本臨床腫瘍研究グループ. 有害事象共通用語規準 v5.0日本語訳JCOG版. [Internet]. Available from: https://jcog.jp/doctor/tool/ctcaev5/
Wang JY, Chen KY, Wang JT, Chen JH, Lin JW, Wang HC, Lee LN, Yang PC.
Outcome and prognostic factors for patients with non-small-cell lung cancer and severe radiation pneumonitis.
Int J Radiat Oncol Biol Phys. 2002 Nov 1;54(3):735-41. doi: 10.1016/s0360-3016(02)02994-2.
Abstract/Text
PURPOSE: Radiation pneumonitis is a serious complication that develops after thoracic irradiation. The purpose of this study was to identify prognostic factors for severe radiation pneumonitis in patients with non-small-cell lung cancer.
METHODS AND MATERIALS: The medical records of patients with non-small-cell lung cancer and severe radiation pneumonitis were reviewed. Variables were analyzed by univariate and stepwise multivariate analysis using the Cox regression model.
RESULTS: Among the 31 patients, the mortality rate approached 50% in the first 2 months after the onset of radiation pneumonitis. The variables significantly associated with survival in the univariate analysis were tumor histologic feature, grade and extent (out-of-field or in-field) of radiation pneumonitis, oxygenation index, and serum albumin (<35 g/L or >or=35 g/L), and uric acid levels at the onset of radiation pneumonitis. Only the extent of radiation pneumonitis and serum albumin level were independently associated with survival in the multivariate analysis.
CONCLUSION: The mortality rate of non-small-cell lung cancer patients with severe radiation pneumonitis is extremely high, and survival is much shorter in patients with out-of-field radiation pneumonitis or a low serum albumin level at the onset. Additional studies to investigate the factors precipitating out-of-field radiation pneumonitis should improve the management of irradiation complications.
Gross NJ.
Pulmonary effects of radiation therapy.
Ann Intern Med. 1977 Jan;86(1):81-92. doi: 10.7326/0003-4819-86-1-81.
Abstract/Text
The cellular effects of irradiating the lungs are rleated to the histologic and clinical sequelae. The occurrence and severity of damage rare semiquantitatively related to the volume of lung irradiated, and the dose rate of irradiation. The clinical syndrome occurs in up to about 10% of patients and consists of an acute transient phase, radiation pneumonitis, usually occurring 6 to 12 weeks after radiation therapy. This is followed by clinical remission except in the most severe cases and gradula radiologic progression to the stage of radiation fibrosis over the next 6 to 12 months. Concommittant chemotherapy, repeat courses of radiation, and steroid wihtdrawal are exacerbating factors. Characteristic changes in pulmonary function and radiographic appearance are described, and management is reviewed.
Sekine I, Sumi M, Ito Y, Nokihara H, Yamamoto N, Kunitoh H, Ohe Y, Kodama T, Saijo N, Tamura T.
Retrospective analysis of steroid therapy for radiation-induced lung injury in lung cancer patients.
Radiother Oncol. 2006 Jul;80(1):93-7. doi: 10.1016/j.radonc.2006.06.007. Epub 2006 Jul 3.
Abstract/Text
PURPOSE: To disclose characteristics of lung cancer patients developing radiation-induced lung injury treated with or without corticosteroid therapy.
METHODS AND MATERIALS: Radiographic changes, symptoms, history of corticosteroid prescription, and clinical course after 50-70 Gy of thoracic radiotherapy were retrospectively evaluated in 385 lung cancer patients.
RESULTS: Radiation-induced lung injury was stable without corticosteroid in 307 patients (Group 1), stable with corticosteroid in 64 patients (Group 2), and progressive to death despite corticosteroid in 14 patients (Group 3). Fever and dyspnea were noted in 11%, 50% and 86% (p<0.001), and in 13%, 44% and 57% (p<0.001) patients in Groups 1-3, respectively. Median weeks between the end of radiotherapy and the first radiographic change were 9.9, 6.7 and 2.4 for Groups 1-3, respectively (p<0.001). The initial prednisolone equivalent dose was 30-40 mg daily in 52 (67%) patients. A total of 16 (4.2%) patients died of radiation pneumonitis or steroid complication with a median survival of 45 (range, 8-107) days.
CONCLUSION: Development of fever and dyspnea, and short interval between the end of radiotherapy and the first radiographic change were associated with fatal radiation-induced lung injury. Prednisolone 30-40 mg daily was selected for the treatment in many patients.
Stephen Keffer, Christopher L. and Elisabeth Weiss. Fatal Radiation Pneumonitis: Literature Review and Case Series. Advances in Radiation Oncology 2019 Article in Press:
Machtay M. Pulmonary complications of anticancer teatment. In: Abeloff’s Clinical Oncology, 4th ed. 2008, Elsevier.P969-981.
Movsas B, Raffin TA, Epstein AH, Link CJ Jr.
Pulmonary radiation injury.
Chest. 1997 Apr;111(4):1061-76. doi: 10.1378/chest.111.4.1061.
Abstract/Text
Machtay M: Pulmonary complications of anticancer treatment. Abeloff’s Clinical Oncology, 4th ed. Elsevier, 2008;969-981.
Tu J, Chen X, Li C, Liu C, Huang Y, Wang X, Liang H, Yuan X.
Nintedanib Mitigates Radiation-Induced Pulmonary Fibrosis by Suppressing Epithelial Cell Inflammatory Response and Inhibiting Fibroblast-to-Myofibroblast Transition.
Int J Biol Sci. 2024;20(9):3353-3371. doi: 10.7150/ijbs.92620. Epub 2024 Jun 11.
Abstract/Text
Radiation-induced pulmonary fibrosis (RIPF) represents a serious complication observed in individuals undergoing thoracic radiation therapy. Currently, effective interventions for RIPF are unavailable. Prior research has demonstrated that nintedanib, a Food and Drug Administration (FDA)-approved anti-fibrotic agent for idiopathic pulmonary fibrosis, exerts therapeutic effects on chronic fibrosing interstitial lung disease. This research aimed to investigate the anti-fibrotic influences of nintedanib on RIPF and reveal the fundamental mechanisms. To assess its therapeutic impact, a mouse model of RIPF was established. The process involved nintedanib administration at various time points, both prior to and following thoracic radiation. In the RIPF mouse model, an assessment was conducted on survival rates, body weight, computed tomography features, histological parameters, and changes in gene expression. In vitro experiments were performed to discover the mechanism underlying the therapeutic impact of nintedanib on RIPF. Treatment with nintedanib, administered either two days prior or four weeks after thoracic radiation, significantly alleviated lung pathological changes, suppressed collagen deposition, and improved the overall health status of the mice. Additionally, nintedanib demonstrated significant mitigation of radiation-induced inflammatory responses in epithelial cells by inhibiting the PI3K/AKT and MAPK signaling pathways. Furthermore, nintedanib substantially inhibited fibroblast-to-myofibroblast transition by suppressing the TGF-β/Smad and PI3K/AKT/mTOR signaling pathways. These findings suggest that nintedanib exerts preventive and therapeutic effects on RIPF by modulating multiple targets instead of a single anti-fibrotic pathway and encourage the further clinical trials to determine the efficacy of nintedanib in patients with RIPF.
© The author(s).
Rimner A, Moore ZR, Lobaugh S, Geyer A, Gelblum DY, Abdulnour RE, Shepherd AF, Shaverdian N, Wu AJ, Cuaron J, Chaft JE, Zauderer MG, Eng J, Riely GJ, Rudin CM, Els NV, Chawla M, McCune M, Li H, Jones DR, Sopka DM, Simone CB 2nd, Mak R, Weinhouse GL, Liao Z, Gomez DR, Zhang Z, Paik PK.
Randomized Phase 2 Placebo-Controlled Trial of Nintedanib for the Treatment of Radiation Pneumonitis.
Int J Radiat Oncol Biol Phys. 2023 Aug 1;116(5):1091-1099. doi: 10.1016/j.ijrobp.2023.02.030. Epub 2023 Mar 7.
Abstract/Text
PURPOSE: Radiation pneumonitis (RP) is the most common dose-limiting toxicity for thoracic radiation therapy. Nintedanib is used for the treatment of idiopathic pulmonary fibrosis, which shares pathophysiological pathways with the subacute phase of RP. Our goal was to investigate the efficacy and safety of nintedanib added to a prednisone taper compared with a prednisone taper alone in reducing pulmonary exacerbations in patients with grade 2 or higher (G2+) RP.
METHODS AND MATERIALS: In this phase 2, randomized, double-blinded, placebo-controlled trial, patients with newly diagnosed G2+ RP were randomized 1:1 to nintedanib or placebo in addition to a standard 8-week prednisone taper. The primary endpoint was freedom from pulmonary exacerbations at 1 year. Secondary endpoints included patient-reported outcomes and pulmonary function tests. Kaplan-Meier analysis was used to estimate the probability of freedom from pulmonary exacerbations. The study was closed early due to slow accrual.
RESULTS: Thirty-four patients were enrolled between October 2015 and February 2020. Of 30 evaluable patients, 18 were randomized to the experimental Arm A (nintedanib + prednisone taper) and 12 to the control Arm B (placebo + prednisone taper). Freedom from exacerbation at 1 year was 72% (confidence interval, 54%-96%) in Arm A and 40% (confidence interval, 20%-82%) in Arm B (1-sided, P = .037). In Arm A, there were 16 G2+ adverse events possibly or probably related to treatment compared with 5 in the placebo arm. There were 3 deaths during the study period in Arm A due to cardiac failure, progressive respiratory failure, and pulmonary embolism.
CONCLUSIONS: There was an improvement in pulmonary exacerbations by the addition of nintedanib to a prednisone taper. Further investigation is warranted for the use of nintedanib for the treatment of RP.
Copyright © 2023 Elsevier Inc. All rights reserved.
Muraoka T, Bandoh S, Fujita J, Horiike A, Ishii T, Tojo Y, Kubo A, Ishida T.
Corticosteroid refractory radiation pneumonitis that remarkably responded to cyclosporin A.
Intern Med. 2002 Sep;41(9):730-3. doi: 10.2169/internalmedicine.41.730.
Abstract/Text
Radiation therapy is commonly used for the treatment of lung cancer. However, radiation pneumonitis frequently occurs as a complication of the radiation therapy. Although corticosteroids are widely used for the treatment of radiation pneumonitis, they are not always effective. In this report, we used cyclosporin A in the treatment of a patient suffering from steroid-refractory radiation pneumonitis. To our knowledge, this is the first report in which cyclosporin A was successfully used in the treatment of radiation pneumonitis.
McCarty MJ, Lillis P, Vukelja SJ.
Azathioprine as a steroid-sparing agent in radiation pneumonitis.
Chest. 1996 May;109(5):1397-400. doi: 10.1378/chest.109.5.1397.
Abstract/Text
Radiation therapy is commonly used for treatment of neoplastic disease involving the thorax. Treatment complications include radiation pneumonitis that may require therapy with corticosteroids which possess significant side effects. We report the use of azathioprine as a steroid-sparing agent in a patient with severe radiation pneumonitis and steroid-induced myopathy.
宮川倫子, 望月吉郎, 守本明枝, 塚本宏壮, 渡部悦子, 後藤孝吉, 中原保治, 真弓哲一郎, 三村一行, 河村哲治, 佐々木信, 田畑寿子, 岡田秀明, 勝田倫子: 重症放射線肺臓炎の 1 例―血漿交換の試み. 日呼吸会誌 2009;47:481-485.
