Late Gastrointestinal Toxicity During Nivolumab Therapy in Non–Small Cell Lung Cancer: A Rare Case of Inflammatory Bowel Disease
Authors: Giorgia Guaitoli, Cinzia Baldessari, Chiara Tomasello, Fausto Barbieri, Stefano Cascinu, Federica Bertolini, Anna Maria Cesinaro
Journal: Journal of Thoracic Oncology (2018)

Checkpoint inhibitors (CIs) have tremendously changed the management of different malignancies, including NSCLC. Despite reported benefits, this class of drugs has been also associated with a wide spectrum of immune-related adverse events: incidence is up to 70% with anti-PD1/PD-L1 antibodies and usually occurs within 3 to 6 months from initiation of treatment.1Michot J.M. Bigenwald C. Champiat S. et al.Immune-related adverse events with immune checkpoint blockade: a comprehensive review.Eur J Cancer. 2016; 54: 139-148Abstract Full Text Full Text PDF PubMed Scopus (1348) Google Scholar Most of immune-related adverse events are grade 1 or 2 and their management include corticosteroids. CI-induced colitis is an emerging phenotype which shares many features with inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis.2Bertha M. Bellaguara E. Kuzel T. Hanauer S. Checkpoint inhibitor–induced colitis: a new type of inflammatory bowel disease?.ACG Case Rep J. 2017; 4: 3-5Google Scholar Endoscopic findings range from normal mucosa to mild erythema or severe inflammation.3Haanen J.B.A.G. Carbonnel F. Robert C. et al.Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv119-iv142Abstract Full Text Full Text PDF PubMed Scopus (1300) Google Scholar In literature few case reports describe anti – programmed death 1 – induced colitis.2Bertha M. Bellaguara E. Kuzel T. Hanauer S. Checkpoint inhibitor–induced colitis: a new type of inflammatory bowel disease?.ACG Case Rep J. 2017; 4: 3-5Google Scholar, 4Kubo K. Mototsugu K. Katsuhiro M. Nivolumab-associated colitis mimicking ulcerative colitis.Clin Gastroenterol Hepatol. 2017; 15: A35-A36Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 5Kim J. Shia J. Schattner M.A. et al.ANTI-PD-1 induced colitis: a case series of 25 patients.Gastroenterology. 2017; 152: S811Abstract Full Text PDF Google Scholar In July 2014, a Caucasian 64-year-old male was diagnosed with stage IV NSCLC (EGFR and K-RAS wild-type; ALK receptor tyrosine kinase [ALK] and ROS-1 negative; programmed death-ligand 1 (PD-L1) not performed for absence of tissue). At the time of diagnosis he was an active smoker; and was undergoing treatment with atenolol, simvastatin, acetylsalicylic acid, and oral hypoglycemic drugs. Between August 2014 and May 2015, he was treated with three different chemotherapy lines and in June 2015 he underwent radiotherapy treatment on supraclavicular and axillary lymph nodes. In August 2015, after pulmonary and nodal disease progression, he started treatment with nivolumab in the expanded access program according to standard schedule (3 mg/kg every 2 weeks), achieving partial to complete response until December 2016 when thickening of right colon was revealed by computed tomographic scan. In the meantime, the patient started complaining of diarrhea (soft stools evacuation once a day) and he was treated with prednisolone 1 mg/kg due to its persistance.4Kubo K. Mototsugu K. Katsuhiro M. Nivolumab-associated colitis mimicking ulcerative colitis.Clin Gastroenterol Hepatol. 2017; 15: A35-A36Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar In April 2017, after 35 administrations of nivolumab, treatment was discontinued due to the recurrence of gastrointestinal toxicity (diarrhea with blood traces). In the same period, a computed tomography re-assessment was performed and the previous colon thickening was no longer detectable. In the following weeks, the patient continued reporting grade 1 diarrhea and abdominal pain. Symptoms worsened at the discontinuation of steroid and were not responsive to loperamide, but the patient benefitted from mesalazine (800 mg three times a day). In August 2017, a new colonoscopy was performed with random biopsy specimens obtained from both right and left colon: histologic examination revealed plasmacytosis and eosinophil granulocyte infiltration in lamina propria with rare neutrophils (Fig. 1). This assessment was compatible with an early stage IBD. No exposure to new compounds was reported and microbiology on stools was negative; therefore, pharmacological or infectious causes were excluded, so we hypothesized that the colitis could be related to the CI. To our knowledge, this is a rare case of a suspected IBD based on clinical features and histology in a patient treated with immunotherapy. Moreover, the described toxicity presented a late onset, having developed 15 months from the beginning of treatment. This underlines the importance of paying attention to toxicities even in the late phase of treatment, when they seem unexpected, and also remarks the importance of a detailed diagnostic assessment (including histologic diagnosis if indicated) to guarantee patients the best treatment.3Haanen J.B.A.G. Carbonnel F. Robert C. et al.Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv119-iv142Abstract Full Text Full Text PDF PubMed Scopus (1300) Google Scholar, 4Kubo K. Mototsugu K. Katsuhiro M. Nivolumab-associated colitis mimicking ulcerative colitis.Clin Gastroenterol Hepatol. 2017; 15: A35-A36Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar The authors thank Bristol-Myers-Squibb Italy for providing nivolumab.