Abstract
Background/Aim: To evaluate the incidence and grade of radiation pneumonitis after volumetric modulated arc therapy (VMAT) performed for the treatment of non-small cell cancer (NSCLC). Patients and Methods: Fifty consecutive non-surgical candidates with NSCLC underwent VMAT. Thirty-five patients had stage-III tumors and 15 had recurrent tumors. The prescribed radiation dose for the gross tumor and the elective nodal area was 69 Gy in 30 fractions and 51 Gy in 30 fractions, respectively. Results: Radiation pneumonitis developed in 38 patients (76%, 38/50), and grade ≥2 radiation pneumonitis developed in 11 patients (22%, 11/50). The percentage of lung volume that received a dose in excess of 5 Gy (V5), V10, V20, V30, and the mean lung dose (MLD) in the bilateral and ipsilateral lung were significantly associated with the development of grade ≥2 radiation pneumonitis. Conclusion: The incidence and degree of radiation pneumonitis are acceptable following treatment of NSCLC with VMAT.
Chemoradiotherapy is the most widely used therapeutic option for the treatment of locally advanced non-small cell lung cancer (NSCLC) (1, 2). Radiation-induced lung injury including radiation pneumonitis and radiation fibrosis is one of major adverse effects after thoracic radiation therapy. Grade ≥2 radiation pneumonitis develops in up to 20% of patients who receive 3-dimensional conformal radiation therapy (3D-CRT) (3–7). The incidence and grade of radiation pneumonitis have been reported to be related to the percentage of lung volume receiving a dose in excess of 20 Gy (V20) (3, 7, 8).
After the recent advent of intensity modulated radiotherapy (IMRT), which enables high conformity in the radiation dose distribution, IMRT has been widely used for the treatment of localized prostate cancers and head and neck squamous cell carcinoma (9, 10). Volumetric modulated arc therapy (VMAT) is a sophisticated application of IMRT, which can provide a comparable dose distribution to conventional IMRT with a shorter treatment time (11–13). Despite this advantage, a concern precluded the use of VMAT for the treatment of NSCLC. It might increase the risk of radiation pneumonitis caused by the expansion of low-dose exposure in the bilateral lung due to the rotational irradiation technique (14).
We introduced VMAT for the treatment of NSCLC and evaluated the incidence and grade of radiation pneumonitis to ensure the safety of this irradiation technique.
Patients and Methods
Study design and endpoints. We designed a prospective single-arm non-comparative phase-II study (UMIN000041875) at our institute, which was approved by the institutional review board (approval no. 2146) in accordance with the Declaration of Helsinki.
Although the primary endpoint of the designed study was 3-year overall survival after VMAT, we planned to evaluate the occurrence of radiation pneumonitis after this treatment in the initial consecutive 50 patients to secure the safety and continuity of this treatment and study. This evaluation was listed in the secondary endpoints of this study. This study reports the incidence and grade of radiation pneumonitis after VMAT in patients with NSCLC.
Patients. The eligibility criteria of this study were as follows: 1) patient with pathologically proven clinical stage-III NSCLC or loco-regional tumor recurrence after surgery, 2) non-surgical candidate, 3) age ≥20 years, and 4) performance status 0-1. The exclusion criteria were as follows: 1) history of thoracic irradiation, 2) uncontrollable co-morbidity, 3) other active double primary cancer, 4) interstitial pneumonitis or pulmonary fibrosis, and 5) pregnancy.
Treatment protocol. Written informed consent was obtained from all patients before the patient was included in this study and received radiation therapy. Patients were treated in the supine position with their arms up and were fixed using positioning cushions (Vaclok, CIVCO Medical Solutions, Orange City, IA, USA) and thermoplastic resin. Treatment plans were made using the radiation treatment planning system (Monaco, Elekta CMS, Maryland Heights, MO, USA) after acquiring CT images (Aquilion LB, Canon Medical Systems, Otawara, Japan). CT images (thickness: 2 mm) were acquired in 3 different respiration phases (inhale, exhale, and free breath). The gross tumor volume (GTV) of each respiration phase was delineated, and an 8-mm margin for adenocarcinoma or 6-mm margin for squamous cell carcinoma was added to create a clinical target volume (CTV) 1. The sum of each CTV1 was an internal target volume (ITV) 1. Elective nodal irradiation (ENI) for the mediastinal and ipsilateral hilar lymph nodes was performed except for the lymph nodes in the case of recurrent cancer. The volume of the elective node was delineated as the CTV2 in the CT images of each respiration phase, and the sum of each CTV2 was ITV2. The planning target volume (PTV) 1 and PTV2 were created by adding 5-mm margin to ITV1 and ITV2, respectively. In this study, the simultaneously integrated boost (SIB) technique was applied, and the prescribed radiation dose for PTV1 and PTV2 was 69 Gy in 30 fractions at 2.3 Gy per fraction and 51 Gy in 30 fractions at 1.7 Gy per fraction, respectively. Fifty percent of the PTV1 received 100% of the prescribed dose (69 Gy), while 95% of the PTV1 exceeded 95% of the prescribed dose, and 95% of the PTV2 exceeded 95% of the prescribed dose for PTV2 (51 Gy).
The radiation dose constraints of the bilateral lungs for the VMAT plan, which were set according to our institutional criteria, with modification based on the NCCN guidelines, were as follows: V20 and V5 were limited to 30% and 50% (tolerance value: <40% and <65%), respectively, and the mean lung dose (MLD) was ≤20 Gy. CT images obtained under free breathing were used for both VMAT planning and dose evaluation, and the X-ray voxel Monte Carlo (XVMC) algorithm was used for dose calculation.
VMAT was delivered by a linear accelerator (Elekta Synergy, ELEKTA, Stockholm, Sweden) using a 6 MV photon beam, and the image-guided radiotherapy technique using cone-beam CT, and the robotic patient positioning system with six degrees of freedom for correction (HexaPOD™ evo, ELEKTA, Stockholm, Sweden) was used for correction of the inter-fractional error.
Combination with chemotherapy, immune checkpoint inhibitor therapy, and supportive care was allowed. In patients who completed radiation therapy after September 2018, durvalumab (Imfinzi, AstraZeneca PLC, Cambridge, UK), an immune checkpoint inhibitor, was administered as a consolidation therapy after chemoradiotherapy.
Follow-up. Patients received follow-up examinations at 1 to 3 months after the completion of radiation therapy, and then every 3 months. Physical examination and laboratory tests were performed at the time of follow-up. FDG-PET/CT was performed at 3 months after the completion of radiotherapy, and thoracic and abdominal CT with contrast enhancement were performed every 3-6 months.
Evaluation and statistical analysis. The incidence and grade of radiation pneumonitis were evaluated at least up to the follow-up period of 6 months after the completion of radiation therapy. The grade of radiation pneumonitis was scored according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (15). The radiological evaluation of radiation pneumonitis was performed by chest X-ray or thoracic CT. In this study, the differential diagnosis of radiation pneumonitis and drug-induced pneumonitis on CT images was performed based on the following criteria: radiation pneumonitis appeared in the radiation field, and the drug-induced pneumonitis spread outside of the radiation field.
A univariate analysis was performed to evaluate the association between the incidence of radiation pneumonitis and each clinical factor (age, sex, histological type (adenocarcinoma or squamous cell carcinoma), emphysema, chronic obstructive pulmonary disease (COPD), smoking history, epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) re-arrangement, programmed cell death ligand 1 (PD-L1) expression, chemotherapy regimen, administration of durvalumab, V30 in the bilateral lung using a logistic regression model. For data with complete or quasi-complete separation, the exact logistic regression model was used for the univariate analysis. The relationship between radiation pneumonitis and dose-volume parameters, such as MLD, V5, V10, V20, V30 and the absolute lung volume spared from a 5 Gy dose (AVS5) in the bilateral lung, the ipsilateral lung, and the contralateral lung were also evaluated using an exact logistic regression model.
The Pearson’s correlation coefficients between dose-volume parameters were calculated. The Spearman’s rank correlation between disease type and each dose-volume parameter was evaluated because the irradiated lung volume in the patients who had recurrent cancer without a tumor in the lung was considered to be smaller than that in patients who had primary lung cancer with a tumor in the lung.
A receiver operating characteristic (ROC) analysis was performed to determine the cut-off values of dose-volume parameters associated with the occurrence of grade ≥2 radiation pneumonitis, and the cut-off value was determined as the point with the maximum Youden index.
p-Values of <0.05 were considered to indicate statistical significance. Data analyses were performed with SPSS version 19.0 (SPSS Inc., Chicago, IL, USA), JMP® 15, and SAS software (SAS Institute, Cary, NC, USA).
Results
Patient and tumor characteristics. From February 2016 to October 2019, 51 patients with Stage-III NSCLC (n=36) and loco-regional recurrence of NSCLC (n=15) underwent radiation therapy. One patient was excluded from this study after registration, because he indicated his wish to withdraw from the study. Therefore, 50 patients (98.0%, 50/51) were enrolled in this study (Table I). Forty patients were men and 10 were women. The median age was 72 years (range=54-89 years). The histological classification was adenocarcinoma in 31 patients (62.0%, 31/50) and squamous cell carcinoma in 19 patients (38.0%, 19/50). No patient developed interstitial pneumonia before undergoing radiation therapy.
Patient characteristics.
The planned course of radiation therapy was completed in all but 2 patients (96.0%, 48/50) who had to have a short-term interruption of radiation therapy due to chemotherapy-induced myelosuppression.
Chemotherapy was not performed in 8 patients (8/50, 16%) due to refusal of drug therapy in 1 patient, comorbid disease in 3 patients, and previous history of chemotherapy in 4 patients. The remaining 42 (42/50, 84%) patients received drug therapy (Table I). The standard chemotherapeutic regimen was carboplatin (Carboplatin, Sawai Pharmaceutical Co., Ltd, Osaka, Japan) plus paclitaxel (Paclitaxel, Sawai Pharmaceutical Co.); this was administered to 39 patients (78.0%, 39/50). The other 3 patients with loco-regional recurrence received other chemotherapies, which included cisplatin (Cisplatin, Yakult Pharmaceutical Industry Co., Ltd., Tokyo, Japan) plus tegaful/gimeracil (S-1, Taiho, Okayama Taiho Pharmaceutical Co., Ltd., Okayama, Japan) in 1 patient (2.0%, 1/50), docetaxel (Docetaxel, Yakult Pharmaceutical Industry Co., Ltd.) in 1 patient (2.0%, 1/50) monotherapy, and tegafur/uracil (UFT E, Taiho Pharmaceutical Co., Ltd.) monotherapy in 1 patient (2.0%, 1/50).
In 25 patients who completed the radiation therapy from September 2018, when the 1-year consolidation therapy consisting of immune check point inhibitor durvalumab administration (Imfinzi, AstraZeneca PLC, Cambridge, UK) was approved, 20 patients received durvalumab starting from 3 to 42 days (median, 15 days) after the completion of chemoradiotherapy. However, 5 patients did not receive durvalumab due to the following reasons: 1 patient refused this treatment, while it was contraindicated in 4 patients due to the occurrence of grade ≥2 radiation pneumonitis.
Incidence of radiation pneumonitis. Forty-nine patients (98%, 49/50) survived at least 6 months after radiation therapy and had been followed-up. One patient (2%, 1/50) died of cancer progression within 3 months from the completion of radiation therapy and after experiencing radiation pneumonitis. Therefore, this patient was also included in this study.
Radiation pneumonitis developed in 38 patients (76.0%, 38/50) at a median of 3 months (range=1-6 months) after radiation therapy. No patients experienced grade 4 or 5 radiation pneumonitis. Twenty-seven patients (54.0%, 27/50) developed grade 1 radiation pneumonitis, 10 patients (20.0%, 10/50) developed grade 2 radiation pneumonitis, and 1 patient (2.0%, 1/50) developed grade 3 radiation pneumonitis (Table II).
The incidence of radiation pneumonitis.
Five (62.5%, 5/8) and 1 (12.5%, 1/8) of the 8 patients who underwent radiation therapy alone experienced any grade and grade ≥2 radiation pneumonitis, respectively. Sixteen (72.7%, 16/22) and 8 (36.4%, 8/22) of the 22 patients who underwent chemoradiotherapy experienced any grade and grade ≥2 radiation pneumonitis, respectively. Seventeen (85.0%, 17/20) and 2 (10.0%, 2/20) of the 20 patients who underwent chemoradiotherapy with durvalumab experienced any grade and grade ≥2 radiation pneumonitis, respectively. The usage of durvalumab did not significantly increase the incidence of radiation pneumonitis (Table III and Table IV). The incidence of grade ≥2 radiation pneumonitis in patients with primary lung cancer (31.4%, 11/35) was significantly higher than that in patients with recurrent cancer (0.0%, 0/15), and the V30 of the bilateral lung was significantly associated with the occurrence of grade ≥2 radiation pneumonitis (odds ratio:1.335, p=0.0053) (Table V and Table VI). The incidence of any grade radiation pneumonitis in patients with EGFR mutations (89.5%, 17/19) was significantly higher than that in patients without EGFR mutations (0.0%, 0/2); however, there was no significant difference in the incidence of grade ≥2 radiation pneumonitis between patients with and without EGFR mutations. No other clinical factors affected the occurrence of any grade and grade ≥2 radiation pneumonitis.
The incidence of radiation pneumonitis according to the use of anticancer drugs and durvalumab.
The incidence of radiation pneumonitis according to the use of anticancer drugs and durvalumab.
Comparison of the incidence of any grade radiation pneumonitis according to the clinical factors.
Comparison of the incidence of grade ≥2 radiation pneumonitis based on the clinical factors.
The dose-volume parameters, including V5, V10, V20, V30 and MLD in the bilateral lung and ipsilateral lung were significantly associated with grade ≥2 radiation pneumonitis according to a univariate analysis (Table VII). The cut-off values of V5, V10, V20, V30, and mean dose of bilateral lung by dividing patients according to the occurrence of grade ≥2 radiation pneumonitis were 50.1% (AUC 0.730), 36.5% (AUC 0.762), 24.6% (AUC 0.848), 22.3% (AUC 0.862) and 16.0 Gy (AUC 0.851), and those of V5, V10, V20, V30 and mean dose of ipsilateral lung were 62.6% (AUC 0.744), 56.8% (AUC 0.811), 50.6% (AUC 0.853), 43.9% (AUC 0.874) and 25.6 Gy (AUC 0.841), respectively (Table VIII).
The associations between radiation pneumonitis and the dose–volume parameters in the bilateral lung, ipsilateral lung, and contralateral lung.
Cut-off values of predictive dosimetric parameters for grade ≥2 radiation pneumonitis.
High Pearson’s correlation coefficients were observed between dose-volume parameters (e.g., MLD, V5, V10, V20, and V30) in the bilateral and the ipsilateral lung (range=0.748-0.986). The Spearman’s rank correlations between disease type and these dose-volume parameters in the bilateral and ipsilateral lung ranged from –0.651 to –0.44, and disease type was significantly correlated with MLD, V5, V10, V20, and V30 in the bilateral and the ipsilateral lung. The V30 in the bilateral lung showed a strong correlation with the disease type (Table IX).
The correlation between the disease type and dosimetric parameters of the lung.
Discussion
This study showed that the incidence and grade of radiation pneumonitis induced by VMAT are acceptable. Previous studies showed that 3D-CRT induces grade ≥2 and grade ≥3 radiation pneumonitis in 11.5-18.6% of patients and 2.3-7.9% of patients, respectively (3–5, 16). On the other hand, the incidence of grade ≥2 and grade ≥3 radiation pneumonitis induced by IMRT has been reported to be 29.6-32.5% and 3.5%-11.7%, respectively (16–18). Chun et al. reported that the incidence of grade ≥3 radiation pneumonitis after 3D-CRT and IMRT was 7.9% and 3.5%, respectively (p=0.039), and IMRT significantly reduced the risk of radiation pneumonitis (p=0.046) in the secondary analysis of the RTOG0617 trial (16). Rades et al. reported that the incidence of symptomatic radiation pneumonitis after VMAT was 7.6% (21/278) and comparatively low (19). This study showed results similar to those observed after IMRT. In this study, the rates of grade 2 and 3 radiation pneumonitis were 20.0% and 2.0%, respectively. A retrospective study also showed no significant differences in the incidence and grade of radiation pneumonitis between IMRT and VMAT in patients with advanced stage non-small cell lung cancer. The incidence of grade ≥3 late pulmonary toxicity after IMRT and VMAT was 9.8% and 17.7%, respectively (p=0.14) (20).
Concurrent chemoradiotherapy is recommended for patients with stage II (node-positive) or III NSCLC (2). In the meta-analysis, concurrent chemotherapy, in particular carboplatin/paclitaxel (relative to cisplatin/etoposide; p<0.001 and p<0.001), and the V20 (p=0.028 and p=0.008) were identified as risk factors for symptomatic radiation pneumonitis based on univariate and multivariate analyses. On the other hand, age (per 10-year increase) was identified as a significant risk factor according to a univariate analysis (p=0.027), but it did not remain a significant risk factor according to a multivariate analysis (p=0.090) (6). In this study, chemotherapy regimen, age, sex, histological type, emphysema, COPD, smoking history, ALK re-arrangement and PD-L1 expression were not significant risk factors for occurrence of any grade and grade ≥2 radiation pneumonitis. The incidence of any grade radiation pneumonitis in patients with EGFR mutation was significantly higher than that in patients without EGFR mutation. However, only two patients had EGFR mutations and it is unclear whether EGFR mutation was associated with the occurrence of radiation pneumonitis in this study.
The administration of durvalumab has been reported to provide a survival benefit after definitive concurrent chemoradiotherapy for unresectable NSCLC (21, 22), and the incidence of any grade radiation pneumonitis in the patients who received durvalumab and in those who received placebo were 20.2% and 15.8%, respectively, while the incidence of grade 3 or 4 radiation pneumonitis in these patients was 1.5% and 0.4% (21). Saito et al. reported that the incidence of grade 1, 2, 3, 4 and 5 radiation pneumonitis was 44%, 28%, 5%, 0% and 3%, and that durvalumab did not increase the incidence of radiation pneumonitis, regardless of its severity (23). Tamiya et al. reported the correlation of radiation pneumonitis before the administration of nivolumab, an immune checkpoint inhibitor, with interstitial lung disease (ILD) and the progression-free survival; a history of radiation pneumonitis was found to be associated with ILD and a prolonged PFS (24). The use of durvalumab after definitive concurrent chemoradiotherapy is recommended as consolidation immunotherapy for patients with unresectable NSCLC (2). However, the influence of durvalumab on radiation pneumonitis is still controversial. Although further studies are required, durvalumab did not increase the incidence of radiation pneumonitis in this study.
No patient with recurrent cancer developed grade ≥2 radiation pneumonitis and the V30 in the bilateral lung, which was significantly correlated with the disease type (primary lung cancer or recurrent cancer), was found to be a significant risk factor for grade ≥2 radiation pneumonitis. A higher lung dose was associated with a higher incidence of radiation pneumonitis after VMAT. As previous studies have shown that dose-volume parameters influence the occurrence of radiation pneumonitis, the V5, V10, V20, V30, and MLD values in bilateral and ipsilateral lung were significantly associated with occurrence of grade ≥2 radiation pneumonitis in this study as well (6, 16, 18, 25, 26). In this study, the V30 in the bilateral lung significantly predicted the occurrence of grade ≥2 radiation pneumonitis; the cutoff value was 22.3%. Tsujino et al. reported that a V20 of ≤25% was associated with a relatively low incidence of grade ≥2 radiation pneumonitis (3). Shintani et al. reported that the optimal cutoff lung V20 value in the ROC curve analysis was 26% (7). Generally, The V20 and MLD in the bilateral lung are used as dose constraints for the lung based on the NCCN guidelines (2). In this study, the cutoff value of V20 in bilateral lung was 24.6% and was similar to that of a previous study (3, 7). In this study, the V30 in the bilateral and ipsilateral lung showed a higher AUC in the ROC analysis of each dose-volume parameter and was a significant predictor of grade ≥2 radiation pneumonitis. Thus, when planning VMAT for lung cancer, a V30 of 22.3% in the bilateral lung and 43.9% in the ipsilateral lung may also be an effective dose constraint.
Chen et al. have reported that the AVS5 in the ipsilateral lung is a prognostic factor for grade ≥2 radiation induced lung injury after 5-beam IMRT (17); however, AVS5 in the ipsilateral lung after VMAT did not predict radition-induced lung injury in this study.
The present study has some limitations, including the limited number of eligible participants with heterogeneous characteristics and the relatively short follow-up period. The median follow-up period of this study, which was 14.5 months, seemed sufficient for the aim of assessing the incidence of radiation pneumonitis, since radiation pneumonitis typically occurs within 12 months (5). A multivariable analysis was not performed to evaluate the association between the occurrence of radiation pneumonitis and dose-volume parameters and patient characteristics because the high correlation of each of the dose-volume parameters had the potential to cause multicollinearity and the events per variable were not sufficient to perform a further statistical analysis.
In conclusion, although the bilateral lung and ipsilateral lung dose requires attention, the incidence and degree of radiation pneumonitis was acceptable in advanced NSCLC patients treated by VMAT. V30 in the bilateral and ipsilateral lung were predictors of the occurrence of grade ≥2 radiation pneumonitis and it will be necessary to clarify the dose constraint of the lung after VMAT for locally advanced NSCLC.
Footnotes
Authors’ Contributions
Masayuki Fujiwara; Study design, treatment of the patients, data assembly and interpretation, writing of the article, and approval of the final article. Hiroshi Doi; Study design, data assembly and interpretation, writing of the article, and approval of the final article. Masataka Igeta; Statistical analyses and interpretation, writing of the article, and approval of the final article. Hitomi Suzuki; Treatment of the patients, data assembly, and approval of the final article. Kazuhiro Kitajima; Study design, revision of the article, and approval of the final article. Masao Tanooka; Study design, three-dimensional treatment planning, treatment of the patients, and approval of the final article. Toshihisa Ishida; Three-dimensional treatment planning, treatment of the patients, and approval of the final article. Tsukasa Wakayama; Three-dimensional treatment planning, treatment of the patients, and approval of the final article. Takashi Yokoi; Treatment of the patients, and approval of the final article. Kozo Kuribayashi treatment of the patients, and approval of the final article. Takashi Kijima; Treatment of the patients, revision of the article, and approval of the final article. Masaki Hashimoto, Nobuyuki Kondo, Seiji Matsumoto, Seiki Hasegawa; Treatment of the patients, and approval of the final article. Norihiko Kamikonya; Revision of the article, and approval of the final article. Koichiro Yamakado; Revision of the article, and approval of the final article.
Conflicts of Interest
All Authors have no conflicts of interest directly relevant to the content of this article.
- Received August 10, 2021.
- Revision received September 11, 2021.
- Accepted September 15, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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