Research ArticleClinical Studies

Elective Nodal Irradiation for Non-small Cell Lung Cancer Complicated With Chronic Obstructive Pulmonary Disease Affects Immunotherapy Αfter Definitive Chemoradiotherapy

MASAHIRO MORIMOTO, KAZUMI NISHINO, KENTARO WADA, FUMIO IMAMURA, KOJI KONISHI, HANAKO KUHARA, MOTOHIRO TAMIYA, TAKAKO INOUE, KEI KUNIMASA, MADOKA KIMURA, TAKERO HIRATA, NAOYUKI KANAYAMA, MASAYASU TORATANI, HAYATO KAWACHI, KIKA OHIRA, ERINA NAKANISHI, SHINGO OHIRA, TOMOHIRO SAGAWA, MASAYOSHI MIYAZAKI, TAKASHI MATSUNAGA, TORU KUMAGAI and TERUKI TESHIMA
Anticancer Research December 2020, 40 (12) 6957-6970; DOI: https://doi.org/10.21873/anticanres.14720

Abstract

Background/Aim: The aim of this retrospective study was to detect the frequency, reasons, and significant factors for not receiving immunotherapy after chemoradiotherapy in non-small cell lung cancer (NSCLC) patients. Patients and Methods: Thirty-four patients with NSCLC received definitive chemoradiotherapy. The endpoint of this study was receiving durvalumab within 45 days after chemoradiotherapy for NSCLC. Results: Twenty-five of 34 (73%) patients received immunotherapy within 45 days after chemoradiotherapy. The reasons for not receiving immunotherapy were radiation pneumonitis (50%), radiation esophagitis (10%), and four other reasons (40%). Univariate analysis showed that significant factors for not receiving immunotherapy were elective nodal irradiation (ENI)+ and chronic obstructive pulmonary disease (COPD)+. The rate of immunotherapy was 100% (17/17 cases) in the COPD− and ENI− group, and 16% (1/6 cases) in the COPD+ and ENI+ group. Conclusion: ENI for NSCLC complicated with COPD decreased the rate of immunotherapy after definitive chemoradiotherapy.

Key Words:

The anti-programmed cell death ligand-1 immune checkpoint inhibitor, durvalumab, is a standard treatment for locally advanced non-small cell lung cancer (NSCLC) after chemoradiotherapy (1, 2). However, not all NSCLC patients can receive immunotherapy after chemoradiotherapy for various reasons. In clinical practice, reasons include adverse events from chemoradiotherapy, progressive disease, or other factors.

The characteristics of patients who cannot receive immunotherapy and the significant factors that are correlated with not receiving immunotherapy are not clear. The aim of this retrospective study was to detect the frequency, reasons, and significant factors for not receiving immunotherapy after chemoradiotherapy in NSCLC patients.

Patients and Methods

A total of 34 patients with NSCLC received definitive chemoradiotherapy between May 2018 and January 2019. Institutional review board approval was obtained for this study (number 19020). The patient characteristics and treatment factors are listed in Table I. The diagnosis of NSCLC was confirmed by histologic findings. The patients underwent the following pre-therapeutic procedures: a physical examination and chest radiography; fiberoptic bronchoscopy and endobronchial ultrasonography as needed; complete blood cell count and biochemical tests including tumor markers; electrocardiography; computed tomography (CT) imaging of the chest and abdomen; positron emission tomography/CT. A hematologic status, which included a white blood cell count >3,500/mm3, platelet count >100,000/mm3, and hemoglobin level >10 g/dl, was generally required. When febrile neutropenia or grade 3 non-hematologic adverse events excluding nausea, vomiting, appetite loss, and elevated creatinine or liver enzymes developed, radiotherapy was generally interrupted. Adverse events were evaluated using Common Terminology Criteria for Adverse Events, Version 4.0. Tumor staging was based on TMN classification 7th and 8th edition. The follow-up time was from the day radiotherapy or chemotherapy was started. Any death was counted as an event in the overall survival rate. Any deaths or progression, including distant metastases, were counted as an event in the progression-free survival rate. Any progression in the radiotherapy field was counted as an event in the local control rate. Isolated elective nodal failures (i.e., recurrences) were investigated in all thirty-four patients.

View this table:
Table I.

Patient characteristics and treatment factors.

Radiotherapy. Volumetric modulated arc therapy (VMAT) with mainly Dmean prescription was generally performed. All patients received four-dimensional or three-dimensional CT simulation. Clinical target volume (CTV) 1 was typically a 0.5-cm expansion of the gross tumor volume including the primary tumor and metastatic lymph nodes; planning target volume (PTV) 1 was then a 0.5-cm expansion of CTV1. Then, the radiation oncologist determined whether CTV2 should include elective hilar, mediastinal, or supraclavicular lymph nodes plus CTV1 based on the information of the patient, tumor, and treatment. This protocol is called elective nodal irradiation (ENI) and is intended to treat potential metastatic lymph nodes. The target of the elective nodal area was delineated based on the Japan Lung Cancer Society-Japanese Society for Radiation Oncology consensus-based computed tomographic atlas for defining regional lymph node stations in radiotherapy for lung cancer (3, 4). The total radiation dose of 60 Gy/30 fractions/6 weeks once daily was mainly administered to the patients. Alternatively, a more aggressive dose of 64 Gy/40 fractions/4 weeks twice daily (accelerated hyperfractionated thoracic radiotherapy) was given (5-7); in the morning, 2 Gy with or without ENI, and in the evening, 1.2 Gy with tumor boost radiotherapy were administered to other patients. ENI was performed for a median of 40 Gy/20 fractions/4 weeks. ENI was preferably adopted in good performance patients or patients in whom the tumor was located in the upper lobe, which requires a smaller lung dose compared to those with a primary location in the lower lobe.

Chemotherapy and immunotherapy. The chemotherapy regimen mainly consisted of cisplatin and vinorelbine or carboplatin and paclitaxel. Cisplatin (80 mg/m2) on day 1 combined with vinorelbine (20 mg/m2) on days 1 and 8 in 3- to 4-week intervals were delivered concurrently with radiotherapy. In patients aged >75 years or those with a low performance status, low renal function (creatinine clearance <60 ml/min), or other severe complications, the second choice for concurrent chemotherapy consisted of weekly carboplatin (area under the curve=2) plus paclitaxel (40 mg/m2), which were administered concurrently with radiotherapy. Another regimen, carboplatin (area under the curve=6) on day 1 combined with nab-paclitaxel (100 mg/m2) on days 1, 8, and 15 delivered concurrently with radiotherapy or pre-radiotherapy, was used. After chemoradiotherapy, durvalumab (10 mg/kg) every 2 weeks for up to 12 months was given if possible.

Statistical analysis. The endpoint of this study was that durvalumab was given to patients within 45 days after chemoradiotherapy. Although 42 days (6 weeks) was the longest interval between the end of chemoradiotherapy and start of durvalumab in a previous phase III study (1, 2), the one and a half-month (45 days) interval was adopted in this daily clinical practice study. Univariate logistic regression analyses were performed for 71 clinical and therapeutic factors. Then, selected factors were entered into the multivariate logistic regression analyses. However, the results of multivariate analyses are shown in Table II for reference only, because the sample size was 34 cases, and thus, results might be unstable. Statistical analyses were performed using SPSS, version 24.0 (IBM, Armonk, NY, USA). The 1-year overall survival, 1-year local control, and 1-year progression-free survival rates were estimated, and percentages were calculated with the Kaplan-Meier method.

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Table I.

Patient characteristics and treatment factors.

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Table II.

Univariate and multivariate logistic regression analyses for no use of durvalumab after definitive chemoradiotherapy in non-small cell lung cancer patients.

Results

The median follow-up time was 13 months (range=0-17 months). The 1-year overall survival rate was 89% (range=79-100%). The 1-year progression-free survival rate was 72% (range=56-87%). The 1-year local control rate was 76% (range=60-92%). No isolated elective nodal failures were found in all thirty-four patients.

Twenty-five of 34 (73%) patients received immunotherapy after a median of 8 days (range=1-45 days) from the end of chemoradiotherapy. The reasons for not receiving immunotherapy are shown in Table III. The most frequent reason for not receiving immunotherapy was radiation pneumonitis, which accounted for 50% (5/10 reasons). Adverse events including hematologic toxicities due to chemoradiotherapy are shown in Table IV. Radiation pneumonitis ≥Grade 2 and radiation esophagitis ≥Grade 2 were found in 32% (11/34 cases) and 11% (4/34 cases), respectively. The eight significant factors in univariate analysis that affected administration of immunotherapy are listed in Table V and are as follows: chronic obstructive pulmonary disease (COPD)+, ENI+, using inhaled medicine for COPD, forced expiratory volume in 1 second (FEV1), FEV1%, %FEV1, radiation pneumonitis ≥Grade 2, and radiation esophagitis ≥Grade 2. COPD was defined as FEV1% <70% in this study. Lung dose parameters including lung VS5Gy (cc) (absolute volume of the lung spared from 5 Gy) (8) were not significant factors. To avoid multicollinearity, COPD+, ENI+, and age, were included in the multivariate logistic regression analyses. Although age was not a significant factor in univariate analysis, age was important in clinical practice. After multivariate logistic regression analysis, two significant factors affecting immunotherapy were identified as COPD+ and ENI+ (for reference only; Table II). The actual rates of immunotherapy based on COPD (+ or −) or ENI (+ or −) are shown in Table VI. The rate of immunotherapy was 100% (17/17 cases) in the COPD− and ENI− group, and 16% (1/6 cases) in the COPD+ and ENI+ group. The choice of ENI area and the background of the patients are shown in Table VII. The comparison of lung dose parameters between the group that received durvalumab and the group that did not is shown in Table VIII. No significant differences were found in any of the average lung doses between the two groups.

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Table II.

Univariate and multivariate logistic regression analyses for no use of durvalumab after definitive chemoradiotherapy in non-small cell lung cancer patients.

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Table III.

Frequency and reasons for not receiving durvalumab within 45 days after chemoradiotherapy.

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Table IV.

Adverse events due to chemoradiotherapy.

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Table V.

Univariate logistic regression analyses for not receiving durvalumab after definitive chemoradiotherapy in thirty-four non-small cell lung cancer patients.

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Table V.

Univariate logistic regression analyses for not receiving durvalumab after definitive chemoradiotherapy in thirty-four non-small cell lung cancer patients.

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Table VI.

The rate of use of durvalumab with or without chronic obstructive pulmonary diseases (COPD), and with or without elective nodal irradiation (ENI) after definitive chemoradiotherapy in thirty-four non-small cell lung cancer patients.

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Table VII.

Choice of elective nodal irradiation area and background of twelve patients.

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Table VIII.

Comparison of dosimetric parameters of lung dose between group that used durvalumab and group that did not.

Five patients could not receive immunotherapy because of radiation pneumonitis. Four of these five patients with radiation pneumonitis received ENI. Therefore, for these four patients, the virtual radiation therapy planning was done without ENI (i.e., without PTV2) in order to prove the reduction of the lung dose parameters using their past radiation therapy planning CT with fusion of diagnostic CT images of emergence of their radiation pneumonitis. The radiation pneumonitis area on diagnostic CT with fusion on the radiation therapy planning CT was delineated, and a virtual radiation therapy plan without ENI was made. For all four patients, reduction of the dose in the radiation pneumonitis area, lung dose parameters, and esophagus dose parameters could be achieved by maintaining the effective dose to PTV1 (i.e., the primary tumor and metastatic lymph nodes) (Table IX).

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Table IX.

Comparison of dosimetric factors between virtual radiation therapy plans without elective nodal irradiation (ENI) and actual radiation therapy plans with ENI in the four radiation pneumonitis patients who could not receive durvalumab (N=4).

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Table IX.

Comparison of dosimetric factors between virtual radiation therapy plans without elective nodal irradiation (ENI) and actual radiation therapy plans with ENI in the four radiation pneumonitis patients who could not receive durvalumab (N=4).

Discussion

Although our study size was small, this study calculated the actual rate of immunotherapy, analyzed clinical and dosimetric factors, and demonstrated that ENI and COPD affected whether NSCLC patients did or did not receive immunotherapy after definitive chemoradiotherapy. Radiation pneumonitis was the most common reason for not receiving immunotherapy. Virtual radiation therapy plan without ENI in patients treated with ENI who could not receive immunotherapy because of their radiation pneumonitis, achieved a reduction in the dose parameters of the lung. The results showed the possibility of palliation for their radiation pneumonitis without ENI. Although the follow-up time was short, no isolated elective nodal failures were found in all patients in the current study.

ENI has not been recommended for NSCLC in the guidelines of the European Organization for Research and Treatment of Cancer (9). In the International Atomic Energy Agency report (10), the clinical value of ENI was uncertain. The clinical trial Radiation Therapy Oncology Group 0617 did not permit ENI (11). On the other hand, ENI was regarded as an alternative standard therapy for locally advanced lung cancer in the Japanese radiation therapy planning guideline in 2016 (12) when immunotherapy was not available after definitive chemoradiotherapy. Although ENI has been used traditionally (13), its effectiveness has not been established. Yuan et al. reported that high-dose involved field irradiation (IFI) achieves a better overall response rate (90% vs. 79%, p=0.032), better 5-year local control rate (51% vs. 36%, p=0.032), and better 2-year overall survival rate (39.4% vs. 25.6%, p=0.048) than low-dose ENI in a randomized trial of 200 patients (14). The radiation pneumonitis rate in the IFI group was also lower than that in the ENI group (17% vs. 29%, p=0.044). Topkan et al. reported that isolated elective nodal failures were present in 2.5% of the ENI group (21/844 cases) vs. 2.1% (3/143 cases) of the IFI group (15). They also reported that the overall survival rate (22.3 vs. 23.7 months, p=0.47), locoregional progression-free survival rate (12.6 vs. 13.2 months, p=0.58), and progression-free survival rate (10.7 vs. 10.4 months, p=0.82) were not significantly different between the two groups. In a meta-analysis, Li et al. reported no significant difference in the incidence of elective nodal failure between the IFI and ENI groups in three randomized controlled trials and three cohort studies (16). Schild et al. reported that ENI is associated with worse survival than IFI (median survival 16 vs. 24 months, p=0.002) in a pooled analysis of 16 cooperative group trials involving 3,600 patients (17).

Staging accuracy was achieved with positron emission tomography/CT and endobronchial ultrasonography. The progressed supportive care recommendation for NSCLC patients receiving chemoradiotherapy has been described (18). Radiotherapy technology was developed by four-dimensional CT, intensity modulated radiation therapy (IMRT), VMAT, and daily cone-beam CT. Although ENI compensates for the developing staging accuracy or radiation technology, omission of ENI for decreasing radiation-induced adverse events including pneumonitis is a reasonable idea for introducing immunotherapy after chemoradiotherapy in this era. Although the radiation oncologist should decrease the normal tissue dose including the dose to the lung and concentrate the effective dose on the gross tumor, they should remember which lymph nodes lung cancers tend to spread. This way of thinking may encourage another future study such as a study that includes post-operative radiotherapy.

Around 39-62% of lung cancer patients also have COPD (19, 20). In the current study, one-third of NSCLC patients had COPD, and most of them received an acting anti-muscarinic antagonist, acting beta agonist, or inhaled corticosteroid. COPD and radiation pneumonitis are inflammatory diseases caused mainly by smoking and radiation therapy, respectively. Using univariate analysis, Shi et al. reported that COPD was a significant factor (p<0.05) in 11 patients with severe acute radiation pneumonitis among 94 NSCLC patients treated with IMRT (21). Using multivariate analysis, Inoue et al. reported that COPD was a significant factor (p=0.002) in 44 patients with prolonged minimal radiation-induced pneumonitis after stereotactic body radiation therapy among 136 stage I lung cancer patients (22). Therefore, COPD might be a risk factor in relation to radiation pneumonitis. COPD should be treated along with lung cancer to minimize the influence of loss of normal lung function by chemoradiotherapy. Continuing medications such as an acting anti-muscarinic antagonist, acting beta agonist, or inhaled corticosteroid for COPD is important before and after chemoradiotherapy for NSCLC. Prohibiting smoking and vaccination against influenza and Streptococcus pneumoniae are also important (23).

Conclusion

ENI for NSCLC complicated with COPD decreased the rate of immunotherapy after definitive chemoradiotherapy. To increase the possibility of introducing immunotherapy, ENI should not be used for NSCLC complicated with COPD. Supportive care for NSCLC patients complicated with COPD should be done to minimize the loss of normal tissue function by chemoradiotherapy.

Acknowledgements

This study was supported by JSPS KAKENHI Grant Number 18K15616. The Authors deeply appreciate the investigator Toshiki Ikawa M.D. (Department of Radiation Oncology, Osaka International Cancer Institute, Osaka, Japan) who contributed to this study.

Footnotes

  • Authors’ Contributions

    Conception and design: M Morimoto, and K Nishino. Acquisition of data: M Morimoto, K Nishino, K Wada, F Imamura, K Konishi, H Kuhara, M Tamiya, T Inoue, K Kunimasa, M Kimura, T Hirata, N Kanayama, M Toratani, H Kawachi, K Ohira, E Nakanishi, S Ohira, T Sagawa, M Miyazaki, T Kumagai, and T Teshima. Analysis and interpretation of data: M Morimoto, K Nishino, K Wada, F Imamura, K Konishi, H Kuhara, M Tamiya, T Inoue, K Kunimasa, M Kimura, T Hirata, N Kanayama, M Toratani, H Kawachi, K Ohira, E Nakanishi, S Ohira, T Sagawa, M Miyazaki, T Matsunaga (statistician), T Kumagai, and T Teshima. Writing, review, and/or revision of the manuscript: M Morimoto, K Nishino, K Wada, and K Kunimasa.

  • This article is freely accessible online.

  • Conflicts of Interest

    K Nishino had honoraria from Nippon Boehringer Ingelheim Co., Ltd., AstraZeneca K.K., Novartis Pharma K.K., Eli Lilly Japan K.K., Roche Diagnostics K.K., Chugai Pharma, and ONO PHARMACEUTICAL CO., LTD. K Nishino had research funding from Nippon Boehringer Ingelheim Co., Ltd. F Imamura had research funding from AstraZeneca. T Kumagai received a grant from Ono Pharmaceutical., MSD K.K., Chugai Pharmaceutical Co. Ltd., AstraZeneca K.K., Takeda Pharmaceutical Company Limited., Merck Serono Co., Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., and The Osaka Foundation for The Prevention of Cancer and Life-style related Diseases (Public Interest Incorporated Foundation). T Kumagai received personal fee from Ono Pharmaceutical., AstraZeneca K. K., Taiho Pharmaceutical Co. Ltd., MSD K.K., TEIJIN PHARMA LIMITED, Novartis Pharma K.K., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Pfizer Inc., Chugai Pharmaceutical Co. Ltd., Bristol-Myers Squibb K.K., and Takeda Pharmaceutical Company Limited.

  • Received October 3, 2020.
  • Revision received October 8, 2020.
  • Accepted October 9, 2020.

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Elective Nodal Irradiation for Non-small Cell Lung Cancer Complicated With Chronic Obstructive Pulmonary Disease Affects Immunotherapy Αfter Definitive Chemoradiotherapy
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