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Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 6759472, 5 pages https://doi.org/10.1155/2019/6759472 Case Report Nivolumab-Induced, Late-Onset, Steroid-Sensitive, High-Grade Pneumonitis and Durable Tumor Suppression in Metastatic Renal Cell Carcinoma: A Case Report 1 1 2 Vincent Louie Mendiola , Meghana Kesireddy , and Bagi Jana Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA Hematology/Oncology, University of Texas Medical Branch, Galveston, TX, USA Correspondence should be addressed to Vincent Louie Mendiola; email@example.com Received 2 May 2019; Accepted 11 December 2019; Published 26 December 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 Vincent Louie Mendiola 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. Nivolumab, an antiprogrammed death-1 checkpoint inhibitor, has been approved for use in unresectable/metastatic renal cell carcinoma (RCC). Nivolumab-induced pneumonitis, a rare, but often severe and potentially life-threatening immune-related adverse event, has been reported, typically, early during the treatment. Due to its low incidence, more studies are needed to better elucidate this condition and its possible eﬀects on cancer progression. We now present a 57-year-old Hispanic male th patient with metastatic RCC-clear cell type who, after his 34 cycle of nivolumab (16 months after being on nivolumab), developed a late-onset, immune-related adverse event (IRAE) including a grade 3 pneumonitis, which resolved completely, clinically, and on serial lung imaging with steroids and drug discontinuation. His cancer remained stable with no progression for 18 months despite discontinuation of nivolumab which showed tumor progression resistance. This case report is aimed at providing further information regarding the rare phenomena of a late-onset IRAE, in particular, a grade 3 nivolumab-induced pneumonitis which also responded rapidly to treatment, as well as at discussing this immunotherapy’s durable tumor suppressive eﬀect and a possible associated factor to this phenomenon. 1. Background 2. Case Presentation RCC-clear cell (CC) type is the most common type of kidney A 57-year-old Hispanic male was diagnosed with RCC-CC cancer among adults with a global incidence of about 337,000 type and underwent radical nephrectomy. His RCC was cases and 143,000 deaths annually . staged as stage III (pT3N0M0) and graded as Fuhrman grade Nivolumab, a monoclonal antibody that selectively 3. He was lost to follow-up, and four years later, he was found inhibits programmed cell death-1 (PD1) activity, is approved to have a soft tissue mass at the nephrectomy surgical bed, for patients with metastatic/unresectable renal cell carcinoma indicating local cancer recurrence (Figure 1). This, along (RCC) who failed prior antiangiogenic therapy. Pneumonitis, with multiple spiculated nodules in the right and left lung, a rare immune-related adverse event (IRAE) that is life- is the largest being 1.4 cm (Figure 2(a)). MRI brain and bone threatening, occurred in 5% of 406 patients [2–4] and the scan were negative. Fine needle aspiration of the lung nodule median duration of treatment before pneumonitis onset is conﬁrmed metastatic RCC-clear cell type. His international typically 2.8 months . metastatic RCC database consortium (IMDC) score at repre- 2 Case Reports in Oncological Medicine Figure 1: CT abdomen and pelvis w/ contrast; arrow showing heterogenous density 2:5×3:5cm lesion in vicinity of the right nephrectomy bed compressing the inferior vena cava. (a) (b) Figure 2: (a) CT chest w/ contrast. Arrow showing a 1.4 cm peripherally enhancing, partially speculated nodule in the left upper lung apex. (b) CT chest w/ contrast; ~18 months post discontinuation of nivolumab with the following ﬁndings: arrow showing a 0.4 cm enhancing nodule in the left upper lung lobe. sentation was 2-3 (patient could have had metastases >1 year evaluated for these respiratory symptoms in the outpatient before representation for systemic therapy as he was lost to setting, in a span of 2 days, he developed a rash on his bilat- follow-up for years, Karnofsky <80%, hemoglobin less than eral palms and soles and got admitted to the hospital for normal, while his calcium levels, neutrophil, and platelet acute hypoxic respiratory failure (a respiratory rate of 30, counts were low-normal), suggesting intermediate to poor O saturation of 81 on room air, partial O of 57 on arterial 2 2 risk of mortality, with a median survival of 7.8-22.5 months. blood gas) requiring a nonrebreather mask (with 100% frac- He was initially started on antiangiogenic agents, pazopa- tion of inspired oxygen (FiO ) on 15 L/minute ﬂow). Physical nib followed by everolimus, which he did not tolerate due to examination revealed bilateral diﬀuse crackles and thick side eﬀects of vomiting, diarrhea, mouth ulcers, and palmar- plaques/callouses of his bilateral palms and soles. CT chest plantar erythrodysesthesia. He was then treated with bevaci- showed conﬂuent ground-glass and reticular opacities in zumab plus interferon alfa-2b but had cancer progression on bilateral lungs predominantly in the bases (Figure 3) con- this therapy. Finally, nivolumab (3 mg/kg, q2 weekly cycles) cerning for pneumonitis from nivolumab therapy. Follow- was started which he tolerated well, and surveillance imaging up serologic tests, sputum, and blood cultures were negative, showed stable pulmonary nodules with a decrease in the size and bronchoscopy was not done due to suggestive ﬁndings of the tumor at his nephrectomy site. on imaging. th Seventeen days after his 34 cycle (after 16 months), he He was started on high-dose steroids, methylpredniso- presented to the clinic with a 10-day history of productive lone IV 2 mg/kg (160 mg) daily, which resulted in signiﬁcant cough (clear sputum) and shortness of breath. While being improvement of his cough, dyspnea, hypoxia, and skin rash Case Reports in Oncological Medicine 3 Figure 3: CT chest w/ contrast, lung window, showing initial acute pneumonitis ﬁndings: extensive ground-glass opacities and Figure 5: CT chest w/ contrast, lung window, showing lung ﬁndings interlobular septal thickening with bilateral traction bronchiectasis. post ~4 months of initial pneumonitis ﬁndings: mild emphysematous Pulmonary nodules are not well seen due to ground-glass opacities. changes noted. 3. Discussion Regarding our patient’s pneumonitis onset, the typical median duration of treatment before pneumonitis was 2.6 months in non-RCC patients and 5.5 months in RCC patients [6–9]. Our patient developed pneumonitis along with synchronous dermatological manifestations 16 months after nivolumab initiation implying late-onset toxicity which is extremely rare. Our case report highlights that nivolumab- induced pneumonitis, an IRAE, can occur at any time after therapy initiation, even late in its treatment, and can co-occur with other IRAEs as well. The pathological mecha- nism involved and the factors predisposing to late-onset IRAE are yet to be determined. In addition, due to this phe- nomenon’s rarity, it is important to rule out any infectious etiologies including fungal or viral as a diﬀerential, especially Figure 4: CT chest w/ contrast, lung window, showing lung ﬁndings in immunosuppressed patients, by using a combination of post ~1.5 months of initial pneumonitis ﬁndings: signiﬁcant clinical judgement in terms of patient presentation, proxim- improvement in scattered interstitial thickening and ground-glass ity of factors to inciting event, along with laboratory and opacities. radiographic tests such as serologic tests, cultures, and response to treatments. In our patient, cultures were nega- in a couple of days. After ﬁve days of IV steroids, he was tive, imaging showed the classic ground-glass opacities noted switched to prednisone 40 mg oral daily. On day ten of in pneumonitis features, and, although proximity to nivolu- mab treatment was atypical, our patient still improved with steroids, he was successfully weaned oﬀ supplemental oxygen and discharged with a prolonged prednisone taper of 40 mg just steroids, with no antibiotics being given. He also did PO daily for two weeks followed by 20 mg PO daily for two not have any aspiration risks putting chemical-induced weeks, and then 10 mg PO daily for one week. Nivolumab pneumonitis lower on his diﬀerential as well. was discontinued and held indeﬁnitely. Regarding his pneumonitis management, about 42% of A CT chest obtained 1.5 months after his hospital dis- nivolumab-induced grade 3/4 pneumonitis patients died charge showed signiﬁcantly improved ground-glass opacities despite therapy with steroids and immunosuppressants in both lungs, while his pulmonary nodules remained [5, 10]. Our patient’s grade 3 pneumonitis and skin rash unchanged (Figure 4). He was monitored closely with CT responded rapidly to high-dose steroids and completely chest, abdomen, and pelvis, and after four months (post resolved (both clinically and radiologically). This excellent pneumonitis admission), the ground-glass opacities have steroid response in our patient could be associated with improved signiﬁcantly (Figure 5), along with stable pulmo- diﬀerent pathological mechanisms involved in the develop- nary nodules, and a stable nephrectomy site mass that ment of late-onset IRAEs compared to the typical/early remained unchanged on serial imaging. onset IRAEs and needs further elucidation. 4 Case Reports in Oncological Medicine (a) (b) (c) (d) Figure 6: (a) CT abdomen and pelvis w/ contrast; ~1.5 months post discontinuation of nivolumab with the following ﬁndings: arrow showing a heterogenous density 3:5×1:0cm lesion in the right retroperitoneal space unchanged from prior imaging (around time of acute pneumonitis occurrence). (b) CT abdomen and pelvis w/ contrast; ~4 months post discontinuation of nivolumab with the following ﬁndings: arrow showing a 3×1:0cm soft tissue lesion posterior to inferior vena cava, stable in size. (c) CT abdomen and pelvis w/ contrast; ~9 months post discontinuation of nivolumab with the following ﬁndings: arrow showing a 3:1×1:3cm soft tissue lesion posterior to inferior vena cava, stable in size. Of note, supra renal inferior vena cava tumor thrombus was noted measuring 2:8× 1:5cm. (d) CT abdomen and pelvis w/ contrast; ~18 months post discontinuation of nivolumab with the following ﬁndings: arrow showing a 2:8×1:5cm soft tissue lesion posterior to inferior vena cava, stable in size. The supra renal inferior vena cava tumor thrombus measured at 2.1 × 1.4 cm, improved from prior imaging. Regarding nivolumab therapeutic durability, Takagi et al. during his pneumonitis treatment or from the durable anti- tumor eﬀect of nivolumab in and of itself. showed a durable response of 6 months after discontinuation of the drug before a metastatic RCC patient had disease Of note, the tumor suppressor eﬀect of glucocorticoids progression . Our patient had stable cancer burden with has been elucidated in animal experimental models in the no progression for 18 months and ongoing, despite disconti- past and may be playing a crucial role in tumor suppression nuing nivolumab therapy (Figures 2(b) and 6(a)–6(d)). This durability resulting to glucocorticoids being commonly used in chemotherapy regimens in hematologic and solid tumor therapeutic durability could be related to the following: the antitumor eﬀect of the pathological immune mechanism malignancies [12–15]. In terms of our patient, more informa- responsible for his late-onset IRAE (pneumonitis in our tion is needed to elucidate if the rapid response of his rare, case), from the additional antitumor eﬀect of steroids used late-onset IRAE along with his ongoing stable metastatic Case Reports in Oncological Medicine 5 ligand 1 therapy,” Journal of Clinical Oncology, vol. 35, no. 7, cancer, oﬀ his nivolumab and any other current therapy, may pp. 709–717, 2017. be due to steroids in particular.  Lexicomp, Nivolumab: Drug Information, Lexicomp, Inc., UpToDate. 1978 2018, https://www.uptodate.com/contents/ 4. Conclusion nivolumab-drug-information. Further studies are necessary to understand the predisposing  C. K. Toh, E. H. Wong, W. T. Lim et al., “The impact of smok- factors and pathological mechanisms involved in late-onset ing status on the behavior and survival outcome of patients IRAE. In addition, further elucidation is needed to see if these with advanced non-small cell lung cancer: a retrospective anal- mechanisms are also responsible for the excellent steroid ysis,” Chest, vol. 126, no. 6, pp. 1750–1756, 2004. response of this patient’s late-onset IRAE or even the durable  D. Bouros, K. Hatzakis, H. Labrakis, and K. Zeibecoglou, suppressive eﬀect on metastatic RCC-CC tumor as seen in “Association of malignancy with diseases causing interstitial pulmonary changes,” Chest, vol. 121, no. 4, pp. 1278–1289, our patient. Abbreviations  L. M. Coussens and Z. Werb, “Inﬂammation and cancer,” Nature, vol. 420, no. 6917, pp. 860–867, 2002. RCC: Renal cell carcinoma  J. R. Brahmer, C. Lacchetti, B. J. Schneider et al., “Management CC: Clear cell of immune-related adverse events in patients treated with RCT: Randomized control trial immune checkpoint inhibitor therapy: American Society of OS: Overall survival Clinical Oncology Clinical Practice Guideline,” Journal of Clinical Oncology, vol. 36, no. 17, pp. 1714–1768, 2018. IRAE: Immune-related adverse event IV: Intravenous  T. Takagi, K. Yoshida, H. Kobayashi et al., “Durable response PO: Per oral after discontinuation of nivolumab therapy in patients with metastatic O : Oxygen renal cell carcinoma,” Japanese Journal of Clinical Oncology, vol. 48, no. 9, pp. 860–863, 2018. FiO : Fraction of inspired oxygen.  I. Rogatsky, A. B. Hittelman, D. Pearce, and M. J. Garabedian, “Distinct glucocorticoid receptor transcriptional regulatory Consent surfaces mediate the cytotoxic and cytostatic eﬀects of gluco- corticoids,” Molecular and Cellular Biology, vol. 19, no. 7, Written informed consent was obtained from the patient for pp. 5036–5049, 1999. publication of this case report and any accompanying images. A copy of the written consent is available for review  A. Yemelyanov, J. Czwornog, D. Chebotaev et al., “Tumor sup- pressor activity of glucocorticoid receptor in the prostate,” by the Editor-in-Chief of this journal. Oncogene, vol. 26, no. 13, pp. 1885–1896, 2007. Conflicts of Interest  P. Crowley, N. Y. Lai, N. De Young, P. Pearce, J. W. Funder, and P. G. Gill, “Inhibition of growth of B16 melanoma by glu- The authors declare that they have no competing interests. cocorticoids does not result directly from receptor-mediated inhibition of tumour cells,” Oncology, vol. 45, no. 4, pp. 331– 335, 1988. Authors’ Contributions  S. Greenstein, K. 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