|Year : 2021 | Volume
| Issue : 3 | Page : 113-116
Severe colitis induced by pembrolizumab in a patient with advanced hypopharyngeal squamous cell carcinoma: A case report of an immune-related adverse event
Sing-Ting Wang, Ming-Yu Lien
Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
|Date of Submission||06-Nov-2020|
|Date of Decision||22-Jan-2021|
|Date of Acceptance||26-Jan-2021|
|Date of Web Publication||21-Jul-2021|
Dr. Ming-Yu Lien
Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, China Medical University, No. 2, Yude Road, North District, Taichung 404
Source of Support: None, Conflict of Interest: None
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target downregulators of anticancer immune responses: cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1). Immune-related adverse events (irAEs) can affect multiple organs of the body. Distinct toxicity induced by different ICIs had been observed. Immune-mediated colitis (IMC) is a common irAE and more frequently encountered in anti-CTLA-4 than anti-PD-1 or anti-PD-L1. Owing to a wide range and inconclusive endoscopic and histological findings, the diagnosis of IMC can be made after excluding other possible causes and relies primarily on clinical suspicion. Optimal management of IMC requires early recognition and timely treatment. Corticosteroids are recommended for Grade 2 or more severe colitis while holding the immunotherapy. A better response to corticosteroids has been observed in anti-PD-1-related IMC than in anti-CTLA-4. Herein, we report a case of severe colitis induced by pembrolizumab.
Keywords: Colitis, immune-mediated colitis, immune-related adverse event, pembrolizumab, squamous cell carcinoma
|How to cite this article:|
Wang ST, Lien MY. Severe colitis induced by pembrolizumab in a patient with advanced hypopharyngeal squamous cell carcinoma: A case report of an immune-related adverse event. J Cancer Res Pract 2021;8:113-6
|How to cite this URL:|
Wang ST, Lien MY. Severe colitis induced by pembrolizumab in a patient with advanced hypopharyngeal squamous cell carcinoma: A case report of an immune-related adverse event. J Cancer Res Pract [serial online] 2021 [cited 2022 Oct 3];8:113-6. Available from: https://www.ejcrp.org/text.asp?2021/8/3/113/322012
| Introduction|| |
Immune checkpoint proteins, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death protein-1 (PD-1), and programmed death-ligand 1 (PD-L1), initiate signaling pathways that suppress T-cell function and are related to cancer growth. Immune checkpoint inhibitors (ICIs) have demonstrated a durable response and significantly improved clinical outcomes in different cancer types. To date, there are eight approved checkpoint inhibitors: anti-CTLA-4 (ipilimumab and tremelimumab), anti-PD-1 (pembrolizumab, nivolumab, and cemiplimab), and anti-PD-L1 (atezolizumab, avelumab, and durvalumab). With more extended treatment indications, the adverse events related to ICIs have become an important issue. Toxicities from ICIs include infusion reactions and side effects associated with increased activity of the immune system caused by ICIs, known as immune-related adverse events (irAEs). IrAEs can affect multiple organ systems of the body, including endocrine (hypothyroidism and hyperthyroidism and pituitary and adrenal dysfunction), gastrointestinal (diarrhea, colitis, and nausea), lung (pneumonitis), skin (rash, pruritus, and vitiligo), liver (hepatitis), and musculoskeletal (arthralgia and myalgia). Distinct toxicity induced by different ICIs has been observed. For example, any grade of colitis, hypophysitis, and skin rash are more frequently encountered in anti-CTLA-4 therapy; whereas pneumonitis, hypothyroidism, arthralgia, and vitiligo are more common in anti-PD-1 or anti-PD-L1 therapy. The incidence of immune-mediated colitis (IMC) ranges from 0.3% to 19.7%, depending on the type of ICI and if used in combination.
Pembrolizumab is a humanized monoclonal antibody that acts against PD-1. Based on the promising results of clinical trials that have shown the efficacy and safety of pembrolizumab, it has been approved as a treatment for various types of cancers including advanced head-and-neck squamous cell carcinoma. Treatment-related AEs from pembrolizumab have been demonstrated in approximately 60% of patients, and the majority have been classified as Grade 1 or 2. The most common pembrolizumab treatment-related AEs include fatigue, rash or pruritus, and decreased appetite., Pneumonitis or severe skin reactions have often been reported among AEs classified as Grade 3 or higher; however, the incidence of this grade of AE is very rare (<2%–3%)., Herein, we report a case of severe colitis after receiving pembrolizumab.
| Case Report|| |
A 51-year-old male with a history of alcohol drinking and heavy smoking presented to our hospital with the chief complaint of a progressive husky voice along with lump sensation and left neck nontender mass enlargement for 1 month. He was subsequently diagnosed with squamous cell carcinoma of the hypopharynx, clinical-stage T3N2M0, based on the 7th Edition of the American Joint Committee on Cancer 7 Staging.
The patient underwent five cycles of induction chemotherapy with the docetaxel, cisplatin, fluorouracil (TPF) regimen followed by left neck modified radical neck dissection, right neck level II-IV lymph node dissection, subsequent bioradiotherapy with eight cycles of cetuximab, and achieved complete remission after the above treatment.
Tumor recurrence was noted 18 months later, and combination therapy with cisplatin, fluorouracil, cetuximab, and pembrolizumab (100 mg per month) was arranged. After five cycles of treatment, the patient presented with watery diarrhea and bloody stool 7–9 times for 4 days, and Grade 3 IMC was impressed. Stool examinations were negative for infectious agents including Clostridium difficile. Colonoscopy revealed multiple ulcers and erosions from the anus to the sigmoid colon [Figure 1]a. The pathologic report of the colonoscopy biopsy showed chronic active colitis, with active neutrophilic cryptitis, crypt microabscesses, mixed neutrophils, lymphoplasmacytic cells, and eosinophil infiltration [Figure 1]b. Periodic acid–Schiff stain, Grocott's methenamine silver stain, and cytomegalovirus immunostain were negative. According to the history of recent pembrolizumab injection and a lack of evidence of infection or cancer involvement, IMC associated with pembrolizumab was suspected. Hence, pembrolizumab was discontinued, and methylprednisolone 1 mg/kg/day was infused for 10 days. Upon the improvement of diarrhea, we gradually tapered the dose of steroids over 6 weeks.
|Figure 1: (a) The first colonoscopy revealed multiple ulcers and erosion from the anus to the sigmoid colon. (b) Microscopic figures (×200) revealed active colitis with neutrophils in the lamina propria (black arrows) and crypt abscess (arrowhead) and neutrophils within epithelial cells (cryptitis) (white arrows)|
Click here to view
Recurrent bloody stool 3 times per day developed 2 months later. Colonoscopy revealed pancolitis (Mayo subscore: 3) [Figure 2]a, and the biopsy showed active colitis with neutrophils, lymphoplasmacytic cells, and eosinophil infiltration, as in the first episode [Figure 2]b. Steroid infusion was given and gradually tapered over a 4-week period as the symptoms improved. There was no recurrence of diarrhea or bloody stool; however, the patient died of tumor progression 8 months later.
|Figure 2: (a) The second colonoscopy revealed pancolitis (Mayo subscore: 3). (b) Microscopic figures revealed active colitis with neutrophils in the lamina propria (black arrows) and crypt abscess (arrowhead) and neutrophils within epithelial cells (cryptitis) (white arrows)|
Click here to view
| Discussion|| |
Among the patients receiving ICIs, the risk of developing colitis is higher in those receiving anti-CTLA-4 than anti-PD-1 or anti-PD-L1., The incidence of pembrolizumab-related colitis ranges from 0.6% to 2.3% according to previous studies,,,, and most AEs have been classified as Grade 1 or 2. Pembrolizumab-associated perforating colitis has also been reported.
In general, irAEs occur quite early, mostly within 3 months after the initiation of ICIs. Ipilimumab-induced colitis typically occurs between 4 and 8 weeks after the first infusion and is almost never seen >2 months after the last treatment dose. Ipilimumab-induced hypophysitis typically emerges between 6 and 14 weeks, neurological irAEs occur between 1 and 7 weeks, and acute interstitial nephritis occurs between 2 and 12 weeks. In a case series including 19 patients with gastrointestinal toxicity after anti-PD-1 therapy, the median time from drug initiation to symptom onset was 3 months. The most common symptoms were diarrhea, nausea, vomiting, and abdominal pain.
The diagnosis of IMC can be made after excluding other possible causes. Patients with diarrhea on ICIs therapy should undergo a workup including complete blood count, serum electrolyte profile, and stool analysis for enteropathogens, including Clostridium difficile toxin. Endoscopic findings range from mild erythema to severe inflammation (mucosal friability or ulceration), although microscopic colitis with normal endoscopic findings has also been reported. Histological findings included lamina propria expansion, villus blunting, intra-epithelial neutrophils, increased crypt/gland apoptosis, intraepithelial lymphocytes, and patchy loss of mucosal absorptive cells. Anti-CTLA-4- and anti-PD-1-induced colitis have been reported to have distinct immunological characteristics. CD8+ T-cells have been found in the lamina propria and epithelium in anti-PD-1-induced colitis, whereas CD4+ T-cells have been found in the lamina propria in anti-CTLA-4-induced colitis. High mucosal tumor necrosis factor-α concentrations have been observed in anti-CTLA-4-induced colitis. In our case, the microscopic figure showed chronic active colitis, with active neutrophilic cryptitis, crypt microabscesses, mixed neutrophils, lymphoplasmacytic cells, and eosinophil infiltration. Special stains were not performed on our patients, and the diagnosis was made mainly based on clinical history.
The patient underwent five cycles of the TPF regimen (docetaxel, cisplatin, and 5-FU) as induction chemotherapy, during which there was no record of diarrhea. In a phase I/II study of cetuximab in combination with cisplatin and fluorouracil in patients with recurrent or metastatic squamous cell carcinoma of the head and neck, the AE rate of any grade of diarrhea was 41%, but grade ¾ diarrhea was observed in only 7% of the patients. Although diarrhea is a common side effect of 5-FU, there are few case reports of 5-FU-induced colitis. High-dose 5-FU-based chemotherapy has been reported to induce colitis and also possibly be involved in the upper small intestine tract. However, colitis developed within a few days in this case series. A systemic assessment of the risk of immune-related colitis with anti-PD-1 or anti-PD-L1 versus chemotherapy in solid tumors revealed that compared with chemotherapy, there was an increased risk of all grade colitis for pembrolizumab. Taken together, based on the results of these studies and the timing sequence of the development of colitis in our patient, a diagnosis of pembrolizumab-related colitis was more favored.
Patients with nonsevere diarrhea should be treated with anti-diarrheals, fluid, and electrolyte supplementation if needed. Patients with persistent Grade 2 diarrhea or severe diarrhea should discontinue ICI therapy and receive systemic corticosteroids (prednisolone 1–2 mg/kg per day intravenously or equivalent dose of methylprednisolone). Patients who have a response to intravenous corticosteroids within 3–5 days should be switched to the oral form and tapered over 8–12 weeks., In our case, we tapered methylprednisolone gradually over 6 weeks, which may have contributed to the development of the second episode of colitis. Tapering more slowly may be required to prevent recurrent colitis.
Anti-inflammatory agents (e.g., infliximab) should also be considered in steroid-refractory disease. ICIs should be discontinued permanently in Grade 4 colitis. It has been reported that one-third to two-thirds of patients do not respond to high-dose intravenous corticosteroids or have a relapse requiring an increase in the corticosteroid dosage during the course of steroid tapering., The presence of colonic ulcers on the endoscopic examination of patients with ipilimumab-induced colitis can predict a steroid-refractory course., However, Collins et al. reported that 87.5% of patients with gastrointestinal irAEs associated with anti-PD-1 responded to corticosteroid treatment.
We report a case of severe colitis induced by pembrolizumab with a good response to systemic corticosteroid treatment. In the era of immunotherapy, clinicians should be more aware of different presentations of irAEs, as the discontinuation of the offending drug is crucial in severe cases, and some patients respond well to systemic corticosteroid treatment.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378:158-68.
Khoja L, Day D, Wei-Wu Chen T, Siu LL, Hansen AR. Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: A systematic review. Ann Oncol 2017;28:2377-85.
Som A, Mandaliya R, Alsaadi D, Farshidpour M, Charabaty A, Malhotra N, et al
. Immune checkpoint inhibitor-induced colitis: A comprehensive review. World J Clin Cases 2019;7:405-18.
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al
. Pembrolizumab as Second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015-26.
Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, et al
. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18:1483-92.
Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, et al
. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: Results from a single-arm, phase II study. J Clin Oncol 2017;35:1542-9.
Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, et al
. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 clinical KEYNOTE-059 trial. JAMA Oncol 2018;4:e180013.
Collins M, Michot JM, Danlos FX, Champiat S, Mussini C, Soularue E, et al
. P315 Gastrointestinal immune related adverse events associated with programmed-Death 1 blockade. J Crohns Colitis. 2017;11:S237.
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al
. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-28.
Celli R, Kluger HM, Zhang X. Anti-PD-1 therapy-associated perforating colitis. Case Rep Gastrointest Med 2018;2018:3406437.
Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al
. Adverse effects of immune-checkpoint inhibitors: Epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16:563-80.
Majem M, García-Martínez E, Martinez M, Muñoz-Couselo E, Rodriguez-Abreu D, Alvarez R, et al
. SEOM clinical guideline for the management of immune-related adverse events in patients treated with immune checkpoint inhibitors (2019). Clin Transl Oncol 2020;22:213-22.
Ahmed M, Francis G. Pembrolizumab-induced microscopic colitis. Am J Gastroenterol 2018;113:629-30.
Gonzalez RS, Salaria SN, Bohannon CD, Huber AR, Feely MM, Shi C. PD-1 inhibitor gastroenterocolitis: Case series and appraisal of 'immunomodulatory gastroenterocolitis'. Histopathology 2017;70:558-67.
Coutzac C, Adam J, Soularue E, Collins M, Racine A, Mussini C, et al
. Colon immune-related adverse events: Anti-CTLA-4 and anti-PD-1 blockade induce distinct immunopathological entities. J Crohns Colitis 2017;11:1238-46.
Bourhis J, Rivera F, Mesia R, Awada A, Geoffrois L, Borel C, et al
. Phase I/II study of cetuximab in combination with cisplatin or carboplatin and fluorouracil in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2006;24:2866-72.
Madisch A, Wiedbrauck F, Marquard F, Stolte M, Hotz J. 5-Fluorouracil-induced colitis–A review based upon consideration of 6 cases. Z Gastroenterol 2002;40:59-66.
Su Q, Zhang X, Shen X, Hou Y, Sun Z, Gao ZH. Risk of immune-related colitis with PD-1/PD-L1 inhibitors vs chemotherapy in solid tumors: Systems assessment. J Cancer 2018;9:1614-22.
Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al
. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv119-42.
Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P, Bhatia S, et al
. NCCN guidelines insights: Management of immunotherapy-related toxicities, version 1.2020. J Natl Compr Canc Netw 2020;18:230-41.
Puzanov I, Diab A, Abdallah K, Bingham CO 3rd
, Brogdon C, Dadu R, et al
. Managing toxicities associated with immune checkpoint inhibitors: Consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017;5:95.
Marthey L, Mateus C, Mussini C, Nachury M, Nancey S, Grange F, et al
. Cancer Immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease. J Crohns Colitis 2016;10:395-401.
Geukes Foppen MH, Rozeman EA, van Wilpe S, Postma C, Snaebjornsson P, van Thienen JV, et al
. Immune checkpoint inhibition-related colitis: Symptoms, endoscopic features, histology and response to management. ESMO Open 2018;3:e000278.
Jain A, Lipson EJ, Sharfman WH, Brant SR, Lazarev MG. Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis. World J Gastroenterol 2017;23:2023-8.
[Figure 1], [Figure 2]