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A Case of Long-Term Survival after Checkpoint Inhibitor Pneumonitis in a Patient with Squamous Cell Lung Cancer

A Case of Long-Term Survival after Checkpoint Inhibitor Pneumonitis in a Patient with Squamous... Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 4836404, 4 pages https://doi.org/10.1155/2019/4836404 Case Report A Case of Long-Term Survival after Checkpoint Inhibitor Pneumonitis in a Patient with Squamous Cell Lung Cancer Hironori Ashinuma , Satoko Mizuno, Yasushi Yoshida, and Masato Shingyoji Division of Respiratory Medicine, Chiba Cancer Center, Chiba, Japan Correspondence should be addressed to Hironori Ashinuma; hashinuma@chiba-cc.jp Received 11 June 2019; Accepted 14 December 2019; Published 27 December 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 Hironori Ashinuma et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The management of grade 1 checkpoint inhibitor pneumonitis (CIP) is to withhold immune checkpoint inhibitors; however, the natural history of this condition is unknown. We herein report the case of a woman with squamous cell lung cancer who was a long-term survivor after CIP. After 4 rounds of treatment with nivolumab, a chest CT revealed a reticular pattern and ground- glass attenuation with shrinkage of the primary nodule. Nivolumab treatment was withheld without the administration of steroids. Although she remained asymptomatic, subsequent images revealed an increasing interstitial shadow until 2 months after the stop of nivolumab treatment. Thereafter, the interstitial shadow began to improve spontaneously without steroid treatment. Moreover, although the patient has not received additional therapy, disease control of lung cancer has been obtained within a follow-up period of more than 3 years. Although the exacerbation of CIP may appear on images for several months, asymptomatic cases can be followed without the administration of steroids. If the tumor had already responded prior to the onset of CIP, a favorable long-term prognosis can be expected. 1. Introduction of a headache and aphasia. A brain magnetic resonance imag- ing (MRI) examination revealed a 30 mm mass in the left- Immune checkpoint inhibitors (ICIs) have been widely used anterior lobe, and a chest computed tomography (CT) exam- for the treatment of non-small-cell lung cancer, but attention ination revealed a 30 mm mass in the left upper lobe with to immune-related adverse events (irAEs) including serious metastasis to the left hilar lymph nodes. A brain metastasis events, such as pneumonitis, is necessary. The incidence of from lung cancer was suspected. A craniotomy was per- checkpoint inhibitor pneumonitis (CIP) has been reported formed, and the presence of a squamous cell carcinoma that to be between 3% and 5% in clinical settings, but a higher fre- was negative for epidermal growth factor receptor mutation quency of 19% was reported in a single retrospective study [1]. or anaplastic lymphoma kinase fusion was confirmed. Long-term results after ICI treatment have been reported Because we were unable to perform immunohistochemistry [2], but data on the natural history and prognosis of patients for programmed cell death 1 (PD-L1) at that time, the PD- with CIP remain inadequate. We herein report a patient with L1 status was unknown. After the addition of localized radia- squamous cell lung cancer who developed CIP; the patient’s tion (50 Gy/25 fractions) to the excised site of the brain, she condition improved after the discontinuation of nivolumab was treated with carboplatin and S-1 and achieved a partial treatment only, and disease control has been achieved for response. After 7 months, the lung mass had increased in size. more than 3 years without treatment. She was treated with docetaxel (DOC) monotherapy and achieved a stable disease condition. After 7 cycles of DOC, however, the lung mass began to increase in size once again. 2. Case Presentation Treatment with nivolumab (3 mg/kg, every 2 weeks) A 64-year-old woman with a smoking history of 40 pack-years was next initiated. On the first day of 5 cycles of nivolu- was admitted to our neurological surgery ward complaining mab, a chest CT examination revealed a reticular pattern 2 Case Reports in Oncological Medicine (a) (b) (c) (d) (e) (f) (g) (h) Figure 1: Changes in chest X-ray images. Before treatment with nivolumab (a), at the onset of CIP (b), 1 week after the onset of CIP (c), 2 weeks after the onset of CIP (d), 1 month after the onset of CIP (e), 2 months after the onset of CIP (f), 3 months after the onset of CIP (g), and 6 months after the onset of CIP (h). The relapsed lung tumor is indicated by the arrows. CIP: checkpoint inhibitor pneumonitis. and ground-glass attenuation with a shrinking lung mass in 3. Discussion the left upper lobe (Figures 1(b) and 2(b)). She had no symptoms at that time. She was afebrile, and her oxygen Here, we report a case depicting the natural history of grade 1 saturation on room air was 96%, which was the same as pre- CIP in which disease control has been achieved for more than vious measurements. Her white blood count was 5900 two and a half years without any therapy and after only 4 cells/μL, and her C-reactive protein level was 0.33 mg/dL. rounds of nivolumab administration. Other blood tests were almost normal except for a sialylated In a meta-analysis, the overall incidence of CIP was 2.7% carbohydrate antigen Krebs von den Lungen-6 (KL-6) level for all-grade [3]. The onset of CIP ranges from 9 days to 27.4 of 606 U/mL (normal range: 500 U/mL or less) and a pul- months [4]. Guidelines [5] for the management of grade 1 monary surfactant protein-D (SP-D) level of 195 ng/mL CIP recommend withholding immune checkpoint inhibitors (normal range: 110 ng/mL or less). Although a bronchoalve- (ICIs). If no improvement is seen, the patient should then be olar lavage fluid test and additional tests were not per- treated as if they have grade 2 CIP. However, the natural his- formed, she was clinically diagnosed as having grade 1 tory of grade 1 CIP is unclear. Because of concerns over pos- CIP. Treatment with nivolumab was discontinued, and a sible deterioration, steroid therapy is often administered repeat chest X-ray and CT were performed. Although she early during the disease course. In a retrospective study remained asymptomatic, her chest X-ray and CT images where 39 out of 205 patients had CIP, all the patients with revealed an increasing interstitial shadow similar in appear- CIP received high-dose steroids [1]. Ricciuti et al. reported ance to that of a cryptogenic organizing pneumonia pattern that patients receiving ≥10 mg of prednisone at baseline until 2 months after the discontinuation of nivolumab had worse outcomes than those receiving 0 to <10 mg of (Figures 1(c)–1(f) and 2(c)). Her KL-6 level increased to a prednisone [6]. In a small study of melanoma patients who maximum of 1300 U/mL at 2 months, and her SP-D level had ipilimumab-induced hypophysitis, patients who received increased to a maximum of 302 ng/mL after one month. a high dose of glucocorticoids had reduced survival than However, three months thereafter, the interstitial shadow those who received a low dose of glucocorticoids [7]. There- began to disappear on the chest X-ray and CT images fore, it is better to avoid using steroids in unnecessary cases. (Figures 1(g) and 2(d)), despite a lack of prednisone treat- Predicting which cases will improve and which cases will ment. The KL-6 and SP-D levels also began to decrease deteriorate is difficult. In the present case, the radiological gradually. After 6 months, almost all the interstitial shadow findings continued to worsen until 3 months after onset, had disappeared and the lung mass was continuing to despite a lack of clinical symptoms, and then improved spon- shrink in size (Figures 1(h) and 2(e)). Although she has taneously. A similar case has been previously reported [8]. In not been treated with additional therapy, the lung mass this previous report, the patient was diagnosed as having sus- has continued to shrink and no new lesions have appeared pected interstitial pneumonia (IP) and was followed up with- for more than 3 years. out treatment; the IP subsequently resolved spontaneously 3 Case Reports in Oncological Medicine 3 (a) (b) (c) (d) (e) Figure 2: Changes in chest computed tomography images. Before treatment with nivolumab (a), at the onset of CIP (b), 1 month after the onset of CIP (c), 3 months after the onset of CIP (d), and 6 months after the onset of CIP (e). The relapsed lung tumor is indicated by the arrows. CIP: checkpoint inhibitor pneumonitis. months after onset. Although details of the patient’s clinical of ICIs was 8 weeks, prior lines of chemotherapy were 2 lines, course were not provided, an improvement in grade 1 CIP ex-smoker, and no other accompanying irAEs. Although irAEs can be lethal, the development of irAEs generally requires several months. However, careful follow- up is still necessary. In the presently reported case, the main has been reported to be associated with a survival benefitin reason why the patient was followed without treatment was patients with non-small-cell lung cancer (NSCLC) [9, 10]. that she remained asymptomatic, despite a worsening in This survival benefit also applies to patients with pneumoni- her radiographic findings. However, it should be noted that tis. Fujimoto et al. reported that lung cancer patients who a fatal case of a patient who was diagnosed as having grade were treated with ICIs and developed CIP ultimately 1 pneumonitis but who did not initially receive steroids has achieved higher response rates and longer progression-free also been reported [8]. Recently, Park et al. reported that survival periods than those who did not develop CIP (37% the CIP patients who never needed to receive steroids had a vs. 18% and 5.8 vs. 2.1 months, respectively) in a multicenter later onset from initiation of ICIs (mean 37.48 weeks vs. retrospective study [11]. Our presently reported case has 25.45 weeks), more prior lines of chemotherapy (median also had a very good survival period. On the other hand, 2.5 vs. 1.0 lines), higher proportion of current/ex-smokers another retrospective study has shown that pneumonitis (83.3% vs. 50.0%), and fewer other accompanying irAEs associated with cytotoxic chemotherapy or targeted therapy (50% vs. 75%) [4]. In the present case, onset from initiation has an adverse impact on survival [12], which seems like a 4 Case Reports in Oncological Medicine [4] C. Park, B. Keam, S. H. Yoon et al., “Clinical insights on out- reasonable association. Therefore, the good prognosis of comes of corticosteroid administration in immune checkpoint patients who develop pneumonitis might be specific to treat- inhibitor-induced pneumonitis by retrospective case series ment with ICIs. analysis,” ESMO Open, vol. 4, no. 6, article e000575, 2019. Whether the readministration of ICIs should be under- [5] J. R. Brahmer, C. Lacchetti, B. J. Schneider et al., “Management taken following recovery from an irAE remains unknown. of immune-related adverse events in patients treated with In the presently reported case, the patient has not been immune checkpoint inhibitor therapy: American Society of retreated with nivolumab because of concerns over pneumo- Clinical Oncology clinical practice guideline,” Journal of nitis relapse and the absence of tumor regrowth. Santini et al. Clinical Oncology, vol. 36, no. 17, pp. 1714–1768, 2018. reported that among patients with early objective responses [6] B. Ricciuti, S. E. Dahlberg, A. Adeni, L. M. Sholl, M. Nishino, prior to serious irAE, the outcomes were similar regardless and M. M. Awad, “Immune checkpoint inhibitor outcomes of whether they were retreated [13]. In cases like ours, it for patients with non-small-cell lung cancer receiving baseline may be reasonable to withdraw readministration. corticosteroids for palliative versus nonpalliative indications,” A limitation of this case is that we diagnosed the patient Journal of Clinical Oncology, vol. 37, no. 22, pp. 1927–1934, as having CIP based only on images and the clinical course. 22, 2019. However, very little is known about the pathological findings [7] A. T. Faje, D. Lawrence, K. Flaherty et al., “High-dose gluco- for CIP in lung biopsy specimens, and the utility of bron- corticoids for the treatment of ipilimumab-induced hypophy- choscopy in establishing a diagnosis of CIP is unknown sitis is associated with reduced survival in patients with [14]. Although infectious diseases are an important differen- melanoma,” Cancer, vol. 124, no. 18, pp. 3706–3714, 18, 2018. tial diagnosis, there were no findings suggestive of an infec- [8] T. Kato, N. Masuda, Y. Nakanishi et al., “Nivolumab-induced tious disease, and the spontaneous improvement makes an interstitial lung disease analysis of two phase II studies patients infectious disease unlikely. with recurrent or advanced non-small-cell lung cancer,” Lung Cancer, vol. 104, pp. 111–118, 2017. [9] K. Haratani, H. Hayashi, Y. Chiba et al., “Association of 4. Conclusions immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer,” JAMA Oncology, vol. 4, no. 3, This case was able to be followed up without the steroid treat- pp. 374–378, 2018. ment as the patient remained asymptomatic (grade 1) though the imaging studies were initially exacerbated. This case [10] S. Teraoka, D. Fujimoto, T. Morimoto et al., “Early immune- related adverse events and association with outcome in showed response to nivolumab at the time of CIP onset, advanced non-small cell lung cancer patients treated with and no relapse has been observed for about 3 years without nivolumab: a prospective cohort study,” Journal of Thoracic any additional anticancer treatment including readministra- Oncology, vol. 12, no. 12, pp. 1798–1805, 2017. tion of nivolumab. [11] D. Fujimoto, H. Yoshioka, Y. Kataoka et al., “Efficacy and safety of nivolumab in previously treated patients with non- Conflicts of Interest small cell lung cancer: a multicenter retrospective cohort study,” Lung Cancer, vol. 119, pp. 14–20, 2018. Hironori Ashinuma received honorarium from Ono Phar- [12] D. Fujimoto, R. Kato, T. Morimoto et al., “Characteristics and maceutical and Bristol-Myers Squibb. Masato Shingyoji prognostic impact of pneumonitis during systemic anti-cancer received honorarium from Ono Pharmaceutical. therapy in patients with advanced non-small-cell lung cancer,” PLoS One, vol. 11, no. 12, article e0168465, 2016. Acknowledgments [13] F. C. Santini, H. Rizvi, A. J. Plodkowski et al., “Safety and effi- cacy of re-treating with immunotherapy after immune-related Writing assistance was provided by the International Medical adverse events in patients with NSCLC,” Cancer Immunology Information Center, Translation Section. This service and Research, vol. 6, no. 9, pp. 1093–1099, 2018. article processing charges were paid for by internal funding. [14] K. Suresh, J. Naidoo, C. T. Lin, and S. Danoff, “Immune check- point immunotherapy for non-small cell lung cancer: benefits and pulmonary toxicities,” Chest, vol. 154, no. 6, pp. 1416– References 1423, 2018. [1] K. Suresh, K. R. Voong, B. Shankar et al., “Pneumonitis in non- small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors,” Journal of Tho- racic Oncology, vol. 13, no. 12, pp. 1930–1939, 2018. [2] S. Gettinger, L. Horn, D. Jackman et al., “Five-year follow-up of Nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study,” Journal of Clinical Oncology, vol. 36, no. 17, pp. 1675–1684, 17, 2018. [3] M. Nishino, A. Giobbie-Hurder, H. Hatabu, N. H. Ramaiya, and F. S. Hodi, “Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced can- cer: a systematic review and meta-analysis,” JAMA Oncology, vol. 2, no. 12, pp. 1607–1616, 2016. 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A Case of Long-Term Survival after Checkpoint Inhibitor Pneumonitis in a Patient with Squamous Cell Lung Cancer

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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 4836404, 4 pages https://doi.org/10.1155/2019/4836404 Case Report A Case of Long-Term Survival after Checkpoint Inhibitor Pneumonitis in a Patient with Squamous Cell Lung Cancer Hironori Ashinuma , Satoko Mizuno, Yasushi Yoshida, and Masato Shingyoji Division of Respiratory Medicine, Chiba Cancer Center, Chiba, Japan Correspondence should be addressed to Hironori Ashinuma; hashinuma@chiba-cc.jp Received 11 June 2019; Accepted 14 December 2019; Published 27 December 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 Hironori Ashinuma et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The management of grade 1 checkpoint inhibitor pneumonitis (CIP) is to withhold immune checkpoint inhibitors; however, the natural history of this condition is unknown. We herein report the case of a woman with squamous cell lung cancer who was a long-term survivor after CIP. After 4 rounds of treatment with nivolumab, a chest CT revealed a reticular pattern and ground- glass attenuation with shrinkage of the primary nodule. Nivolumab treatment was withheld without the administration of steroids. Although she remained asymptomatic, subsequent images revealed an increasing interstitial shadow until 2 months after the stop of nivolumab treatment. Thereafter, the interstitial shadow began to improve spontaneously without steroid treatment. Moreover, although the patient has not received additional therapy, disease control of lung cancer has been obtained within a follow-up period of more than 3 years. Although the exacerbation of CIP may appear on images for several months, asymptomatic cases can be followed without the administration of steroids. If the tumor had already responded prior to the onset of CIP, a favorable long-term prognosis can be expected. 1. Introduction of a headache and aphasia. A brain magnetic resonance imag- ing (MRI) examination revealed a 30 mm mass in the left- Immune checkpoint inhibitors (ICIs) have been widely used anterior lobe, and a chest computed tomography (CT) exam- for the treatment of non-small-cell lung cancer, but attention ination revealed a 30 mm mass in the left upper lobe with to immune-related adverse events (irAEs) including serious metastasis to the left hilar lymph nodes. A brain metastasis events, such as pneumonitis, is necessary. The incidence of from lung cancer was suspected. A craniotomy was per- checkpoint inhibitor pneumonitis (CIP) has been reported formed, and the presence of a squamous cell carcinoma that to be between 3% and 5% in clinical settings, but a higher fre- was negative for epidermal growth factor receptor mutation quency of 19% was reported in a single retrospective study [1]. or anaplastic lymphoma kinase fusion was confirmed. Long-term results after ICI treatment have been reported Because we were unable to perform immunohistochemistry [2], but data on the natural history and prognosis of patients for programmed cell death 1 (PD-L1) at that time, the PD- with CIP remain inadequate. We herein report a patient with L1 status was unknown. After the addition of localized radia- squamous cell lung cancer who developed CIP; the patient’s tion (50 Gy/25 fractions) to the excised site of the brain, she condition improved after the discontinuation of nivolumab was treated with carboplatin and S-1 and achieved a partial treatment only, and disease control has been achieved for response. After 7 months, the lung mass had increased in size. more than 3 years without treatment. She was treated with docetaxel (DOC) monotherapy and achieved a stable disease condition. After 7 cycles of DOC, however, the lung mass began to increase in size once again. 2. Case Presentation Treatment with nivolumab (3 mg/kg, every 2 weeks) A 64-year-old woman with a smoking history of 40 pack-years was next initiated. On the first day of 5 cycles of nivolu- was admitted to our neurological surgery ward complaining mab, a chest CT examination revealed a reticular pattern 2 Case Reports in Oncological Medicine (a) (b) (c) (d) (e) (f) (g) (h) Figure 1: Changes in chest X-ray images. Before treatment with nivolumab (a), at the onset of CIP (b), 1 week after the onset of CIP (c), 2 weeks after the onset of CIP (d), 1 month after the onset of CIP (e), 2 months after the onset of CIP (f), 3 months after the onset of CIP (g), and 6 months after the onset of CIP (h). The relapsed lung tumor is indicated by the arrows. CIP: checkpoint inhibitor pneumonitis. and ground-glass attenuation with a shrinking lung mass in 3. Discussion the left upper lobe (Figures 1(b) and 2(b)). She had no symptoms at that time. She was afebrile, and her oxygen Here, we report a case depicting the natural history of grade 1 saturation on room air was 96%, which was the same as pre- CIP in which disease control has been achieved for more than vious measurements. Her white blood count was 5900 two and a half years without any therapy and after only 4 cells/μL, and her C-reactive protein level was 0.33 mg/dL. rounds of nivolumab administration. Other blood tests were almost normal except for a sialylated In a meta-analysis, the overall incidence of CIP was 2.7% carbohydrate antigen Krebs von den Lungen-6 (KL-6) level for all-grade [3]. The onset of CIP ranges from 9 days to 27.4 of 606 U/mL (normal range: 500 U/mL or less) and a pul- months [4]. Guidelines [5] for the management of grade 1 monary surfactant protein-D (SP-D) level of 195 ng/mL CIP recommend withholding immune checkpoint inhibitors (normal range: 110 ng/mL or less). Although a bronchoalve- (ICIs). If no improvement is seen, the patient should then be olar lavage fluid test and additional tests were not per- treated as if they have grade 2 CIP. However, the natural his- formed, she was clinically diagnosed as having grade 1 tory of grade 1 CIP is unclear. Because of concerns over pos- CIP. Treatment with nivolumab was discontinued, and a sible deterioration, steroid therapy is often administered repeat chest X-ray and CT were performed. Although she early during the disease course. In a retrospective study remained asymptomatic, her chest X-ray and CT images where 39 out of 205 patients had CIP, all the patients with revealed an increasing interstitial shadow similar in appear- CIP received high-dose steroids [1]. Ricciuti et al. reported ance to that of a cryptogenic organizing pneumonia pattern that patients receiving ≥10 mg of prednisone at baseline until 2 months after the discontinuation of nivolumab had worse outcomes than those receiving 0 to <10 mg of (Figures 1(c)–1(f) and 2(c)). Her KL-6 level increased to a prednisone [6]. In a small study of melanoma patients who maximum of 1300 U/mL at 2 months, and her SP-D level had ipilimumab-induced hypophysitis, patients who received increased to a maximum of 302 ng/mL after one month. a high dose of glucocorticoids had reduced survival than However, three months thereafter, the interstitial shadow those who received a low dose of glucocorticoids [7]. There- began to disappear on the chest X-ray and CT images fore, it is better to avoid using steroids in unnecessary cases. (Figures 1(g) and 2(d)), despite a lack of prednisone treat- Predicting which cases will improve and which cases will ment. The KL-6 and SP-D levels also began to decrease deteriorate is difficult. In the present case, the radiological gradually. After 6 months, almost all the interstitial shadow findings continued to worsen until 3 months after onset, had disappeared and the lung mass was continuing to despite a lack of clinical symptoms, and then improved spon- shrink in size (Figures 1(h) and 2(e)). Although she has taneously. A similar case has been previously reported [8]. In not been treated with additional therapy, the lung mass this previous report, the patient was diagnosed as having sus- has continued to shrink and no new lesions have appeared pected interstitial pneumonia (IP) and was followed up with- for more than 3 years. out treatment; the IP subsequently resolved spontaneously 3 Case Reports in Oncological Medicine 3 (a) (b) (c) (d) (e) Figure 2: Changes in chest computed tomography images. Before treatment with nivolumab (a), at the onset of CIP (b), 1 month after the onset of CIP (c), 3 months after the onset of CIP (d), and 6 months after the onset of CIP (e). The relapsed lung tumor is indicated by the arrows. CIP: checkpoint inhibitor pneumonitis. months after onset. Although details of the patient’s clinical of ICIs was 8 weeks, prior lines of chemotherapy were 2 lines, course were not provided, an improvement in grade 1 CIP ex-smoker, and no other accompanying irAEs. Although irAEs can be lethal, the development of irAEs generally requires several months. However, careful follow- up is still necessary. In the presently reported case, the main has been reported to be associated with a survival benefitin reason why the patient was followed without treatment was patients with non-small-cell lung cancer (NSCLC) [9, 10]. that she remained asymptomatic, despite a worsening in This survival benefit also applies to patients with pneumoni- her radiographic findings. However, it should be noted that tis. Fujimoto et al. reported that lung cancer patients who a fatal case of a patient who was diagnosed as having grade were treated with ICIs and developed CIP ultimately 1 pneumonitis but who did not initially receive steroids has achieved higher response rates and longer progression-free also been reported [8]. Recently, Park et al. reported that survival periods than those who did not develop CIP (37% the CIP patients who never needed to receive steroids had a vs. 18% and 5.8 vs. 2.1 months, respectively) in a multicenter later onset from initiation of ICIs (mean 37.48 weeks vs. retrospective study [11]. Our presently reported case has 25.45 weeks), more prior lines of chemotherapy (median also had a very good survival period. On the other hand, 2.5 vs. 1.0 lines), higher proportion of current/ex-smokers another retrospective study has shown that pneumonitis (83.3% vs. 50.0%), and fewer other accompanying irAEs associated with cytotoxic chemotherapy or targeted therapy (50% vs. 75%) [4]. In the present case, onset from initiation has an adverse impact on survival [12], which seems like a 4 Case Reports in Oncological Medicine [4] C. Park, B. Keam, S. H. Yoon et al., “Clinical insights on out- reasonable association. Therefore, the good prognosis of comes of corticosteroid administration in immune checkpoint patients who develop pneumonitis might be specific to treat- inhibitor-induced pneumonitis by retrospective case series ment with ICIs. analysis,” ESMO Open, vol. 4, no. 6, article e000575, 2019. Whether the readministration of ICIs should be under- [5] J. R. Brahmer, C. Lacchetti, B. J. Schneider et al., “Management taken following recovery from an irAE remains unknown. of immune-related adverse events in patients treated with In the presently reported case, the patient has not been immune checkpoint inhibitor therapy: American Society of retreated with nivolumab because of concerns over pneumo- Clinical Oncology clinical practice guideline,” Journal of nitis relapse and the absence of tumor regrowth. Santini et al. Clinical Oncology, vol. 36, no. 17, pp. 1714–1768, 2018. reported that among patients with early objective responses [6] B. Ricciuti, S. E. Dahlberg, A. Adeni, L. M. Sholl, M. Nishino, prior to serious irAE, the outcomes were similar regardless and M. M. Awad, “Immune checkpoint inhibitor outcomes of whether they were retreated [13]. In cases like ours, it for patients with non-small-cell lung cancer receiving baseline may be reasonable to withdraw readministration. corticosteroids for palliative versus nonpalliative indications,” A limitation of this case is that we diagnosed the patient Journal of Clinical Oncology, vol. 37, no. 22, pp. 1927–1934, as having CIP based only on images and the clinical course. 22, 2019. However, very little is known about the pathological findings [7] A. T. Faje, D. Lawrence, K. Flaherty et al., “High-dose gluco- for CIP in lung biopsy specimens, and the utility of bron- corticoids for the treatment of ipilimumab-induced hypophy- choscopy in establishing a diagnosis of CIP is unknown sitis is associated with reduced survival in patients with [14]. Although infectious diseases are an important differen- melanoma,” Cancer, vol. 124, no. 18, pp. 3706–3714, 18, 2018. tial diagnosis, there were no findings suggestive of an infec- [8] T. Kato, N. Masuda, Y. Nakanishi et al., “Nivolumab-induced tious disease, and the spontaneous improvement makes an interstitial lung disease analysis of two phase II studies patients infectious disease unlikely. with recurrent or advanced non-small-cell lung cancer,” Lung Cancer, vol. 104, pp. 111–118, 2017. [9] K. Haratani, H. Hayashi, Y. Chiba et al., “Association of 4. Conclusions immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer,” JAMA Oncology, vol. 4, no. 3, This case was able to be followed up without the steroid treat- pp. 374–378, 2018. ment as the patient remained asymptomatic (grade 1) though the imaging studies were initially exacerbated. This case [10] S. Teraoka, D. Fujimoto, T. Morimoto et al., “Early immune- related adverse events and association with outcome in showed response to nivolumab at the time of CIP onset, advanced non-small cell lung cancer patients treated with and no relapse has been observed for about 3 years without nivolumab: a prospective cohort study,” Journal of Thoracic any additional anticancer treatment including readministra- Oncology, vol. 12, no. 12, pp. 1798–1805, 2017. tion of nivolumab. [11] D. Fujimoto, H. Yoshioka, Y. Kataoka et al., “Efficacy and safety of nivolumab in previously treated patients with non- Conflicts of Interest small cell lung cancer: a multicenter retrospective cohort study,” Lung Cancer, vol. 119, pp. 14–20, 2018. Hironori Ashinuma received honorarium from Ono Phar- [12] D. Fujimoto, R. Kato, T. Morimoto et al., “Characteristics and maceutical and Bristol-Myers Squibb. Masato Shingyoji prognostic impact of pneumonitis during systemic anti-cancer received honorarium from Ono Pharmaceutical. therapy in patients with advanced non-small-cell lung cancer,” PLoS One, vol. 11, no. 12, article e0168465, 2016. Acknowledgments [13] F. C. Santini, H. Rizvi, A. J. Plodkowski et al., “Safety and effi- cacy of re-treating with immunotherapy after immune-related Writing assistance was provided by the International Medical adverse events in patients with NSCLC,” Cancer Immunology Information Center, Translation Section. This service and Research, vol. 6, no. 9, pp. 1093–1099, 2018. article processing charges were paid for by internal funding. [14] K. Suresh, J. Naidoo, C. T. Lin, and S. Danoff, “Immune check- point immunotherapy for non-small cell lung cancer: benefits and pulmonary toxicities,” Chest, vol. 154, no. 6, pp. 1416– References 1423, 2018. [1] K. Suresh, K. R. Voong, B. Shankar et al., “Pneumonitis in non- small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors,” Journal of Tho- racic Oncology, vol. 13, no. 12, pp. 1930–1939, 2018. [2] S. Gettinger, L. Horn, D. Jackman et al., “Five-year follow-up of Nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study,” Journal of Clinical Oncology, vol. 36, no. 17, pp. 1675–1684, 17, 2018. [3] M. Nishino, A. Giobbie-Hurder, H. Hatabu, N. H. Ramaiya, and F. S. Hodi, “Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced can- cer: a systematic review and meta-analysis,” JAMA Oncology, vol. 2, no. 12, pp. 1607–1616, 2016. 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