Immune checkpoint inhibitors (ICIs) have emerged as a novel therapeutic class for various malignancies. Their immune upregulation promotes significant anti-tumor effect, but simultaneously, can also result in treatment-limiting immune-related adverse events (irAEs). The data on upper gastrointestinal (GI) tract irAEs are sparse. We herein describe a case of steroid-dependent upper GI toxicity with nivolumab (an anti-programmed death [PD] protein-1) that achieved clinical and histological remission with vedolizumab treatment (a GI tract targeted anti-integrin antibody). A 65-year-old male patient with progressive lung cancer was treated with nivolumab and following 16 cycles, developed severe nausea, vomiting, and epigastric abdominal cramps requiring five hospitalizations. His initial esophagogastroduodenoscopy (EGD) showed active inflammation in both the stomach and duodenum. Nivolumab was discontinued, but despite treatment with multiple steroid courses, his symptoms always recurred during prednisone taper. Clinical remission was ultimately achieved with vedolizumab. His last EGD after five infusions of vedolizumab demonstrated resolution of inflammation. His lung cancer has since relapsed and the treatment plan was to resume nivolumab concurrently with vedolizumab. In conclusion, ICIs, such as nivolumab, have emerged as therapy for various malignancies. Their use can be associated with various irAEs including the upper GI adverse events which is uncommon. This case scenario showed that vedolizumab can provide a steroid-sparing therapeutic effect to achieve remission of upper GI irAEs even in cases where multiple steroid courses have failed.
Immune checkpoint inhibitors (ICIs) have emerged as a novel therapeutic class for a wide variety of malignancies with demonstrated high effectiveness. Thus far, three sub-classes have been developed targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed death receptor-1 (PD-1), and PD-ligand 1 (PD-L1).[1,2] Nivolumab is a human monoclonal IgG4 antibody that targets PD-1 and blocks its inhibitory effect on T-cell activity. This interaction releases the “brake” on the immune system imposed by PD-1 with the resultant significant anti-tumor effect, but simultaneously, can also induce toxicities from the nonspecific immunologic activation. The reported toxicities of PD-1 inhibitors include dermatologic, gastrointestinal (GI), hepatic, endocrine, and pulmonary immune-related adverse events (irAEs).[1–4] Notably, among the GI irAEs associated with PD-1 inhibitors, upper GI tract adverse events (defined as nausea and vomiting and/or active inflammation in the stomach and duodenum) are less frequently reported than lower GI tract adverse events (defined as diarrhea and/or inflammation of the colon and distal ileum).[2,5,6] We herein describe a case of nivolumab-induced severe steroid-refractory upper GI irAE that was treated successfully with vedolizumab and achieved clinical and histological remission.
History of present illness
A 65-year-old male patient with metastatic nonsmall-cell lung cancer presented with nausea, vomiting, epigastric pain, decreased appetite, and 12-pound weight loss after 16 infusions of nivolumab therapy.
The patient had a prior medical history of emphysema, essential hypertension, hyperlipidemia, gastroesophageal reflux disease, and prostate cancer treated with leuprolide hormonal injection therapy. His surgical history was significant for prior cholecystectomy and appendectomy. He is a current smoker with 30 pack-year of smoking. Family history was significant only for his father who had stomach cancer.
The previous treatment of his lung cancer involved chemotherapy with pemetrexed and carboplatin at the time of diagnosis in 2013, followed by concurrent paclitaxel, carboplatin, and radiation therapy. He was found to have left upper lobe lung progression with new retroperitoneal lymph nodes and a solitary brain lesion in 2015 and underwent stereotactic radiation therapy with additional pemetrexed and carboplatin. In 2017, he was found to have progressive disease involving retroperitoneal lymphadenopathy, several small brain lesions, and possible liver metastases. Thereafter, nivolumab (at 3 mg/kg) was initiated.
Following the 13th cycle of nivolumab, he complained of the short duration of nausea and abdominal cramping that he attributed to food intolerance. At that time, a whole-body positron-emission tomography/computed tomography (PET/CT) showed no evidence of progressive malignancy but did show diffuse uptake in the stomach compatible with physiologic or inflammatory reaction. He received additional three cycles, and then developed a poor appetite, vomiting twice weekly, diarrhea, and a 12-pound weight loss. The patient received a total of 16 cycles of nivolumab until his first hospitalization for progression of his upper GI symptoms of intractable nausea and vomiting associated with hypotension and epigastric pain. He denied any fever or sick contacts. His nivolumab treatment was discontinued due to the concern of GI toxicity.
On physical examination, he had a temperature of 36.7°C, the pulse of 99 beats/min, blood pressure of 98/69 mmHg, respiratory rate of 18/min, and normal oxygenation on ambient air. He appeared listless and cachectic. The abdomen was soft, nondistended, and tender at both lower quadrants. A CT of the abdomen and pelvis showed enhancement of the gastric mucosa suggestive of gastritis. An esophagogastroduodenoscopy (EGD) revealed a normal esophagus and an erythematous mucosa in the gastric body, antrum, and duodenal bulb; biopsies revealed chronic active gastritis and active duodenitis suggestive of nivolumab therapy-induced gastroenteritis [Figure 1a and b]. Testing for Helicobacter pylori, Cytomegalovirus, and adenovirus was negative. His nausea, vomiting, and epigastric pain improved with empiric antibiotics, ondansetron, prochlorperazine, and pantoprazole, and he was discharged following 4 days hospitalization. After 10 days of discharge, he was hospitalized a second time for recurrent symptoms. Subsequently, 20 days later, he was hospitalized a third time for similar symptoms of nausea, vomiting, and epigastric pain. Two serial CT scans in the second and third hospital admissions showed new findings of mild edematous changes in the distal pancreatic body and tail with mild peripancreatic fat stranding suggesting early signs of uncomplicated pancreatitis, and unchanged gastric mucosal enhancement suggestive of gastritis. There was a new grade 3 elevation of serum lipase since the second admission with a peak of 784 U/L. He was managed as acute pancreatitis with pain control and aggressive intravenous fluid during the second admission; however, he returned within 3 weeks with the same presentation, and this led to his third admission. Intravenous methylprednisolone was started (0.5 mg/kg daily twice daily) for potential ICI-induced gastritis and pancreatitis with immediate symptomatic improvement. After 3 days, he was transitioned to oral budesonide (9 mg daily open capsule) and was discharged following 4 days hospitalization.
Five days following discharge, he reported a recurrence of his nausea and vomiting despite budesonide treatment. Therefore, he was switched to prednisone (50 mg daily) for 2 weeks with a taper plan. However, his upper GI symptoms recurred when the prednisone was tapered down to 10 mg/day around the 6th week, which lead to the fourth hospitalization. A third CT showed submucosal edema of the proximal duodenum, enhancement of the small bowel mucosa with wall thickening, and decreased gastric wall thickening; features still suggestive of gastroenteritis. Repeated blood lipase level was normal. Intravenous methylprednisolone (40 mg every 8 h) was restarted for steroid-dependent gastroenteritis. He had immediate symptomatic improvement and was discharged following 2 days hospitalization with prednisone 60 mg daily on discharge.
Three days following discharge, he was readmitted a fifth time with a recurrence of intractable nausea, vomiting associated with epigastric pain, and new odynophagia. New oral thrush was confirmed, and odynophagia was treated with fluconazole. Intravenous methylprednisolone 60 mg every 12 h was restarted instead of oral prednisone. His nausea, vomiting, and epigastric pain rapidly improved, and he was switched to prednisone 40 mg daily after 4 days with a taper plan. Four days after the initiation of oral prednisone, he developed recurrence of abdominal pain and new-onset grade 1 diarrhea (2–3 loose BMs/day). Examination was significant for hypotension with a blood pressure of 82/50 mmHg, tachycardia with a heart rate of 106, and minimal diffuse abdominal tenderness. Clostridium difficile testing showed positive DNA polymerase chain reaction and toxin (although toxin was negative 10 days prior). GI enteric pathogen testing was negative. He was treated with oral vancomycin intermittently for total 16 days. He remained on oral prednisone during this time. He recovered well with vancomycin and prednisone and was discharged following a 23 days hospitalization. A repeat EGD showed similar findings to the previous examination and pathology showed persistent active gastric and duodenal inflammation.
Given the frequent requirement for high dose steroid treatment, candida and C. difficile infections, and hospital admissions for refractory upper GI irAEs, he was deemed to be a good candidate for a steroid-sparing agent. Approximately 1 month following discharge from his fifth hospitalization, vedolizumab infusion (300 mg) was initiated, and prednisone was tapered off within 1 week. He has remained symptom-free since then while maintaining a regular vedolizumab infusion schedule for the past 7 months. Repeat EGD after three doses of vedolizumab treatment still revealed mild gross inflammation and persistent histologic inflammation. His most recent EGD with biopsy, after five infusions of vedolizumab, confirmed a complete histologic resolution of active inflammation [Figure 2a and b]. The clinical and treatment courses of this case are summarized in Figure 3. Unfortunately, the most recent restaging studies showed new hilar lymphadenopathy concerning for malignancy and increase in the size of right upper lobe metastasis. Given his history of refractory GI toxicity with nivolumab and effective control of the irAEs following vedolizumab treatment, the plan is to resume nivolumab with concurrent vedolizumab treatment. The serial PET/CT scan images of his upper GI toxicities are illustrated in Figure 4.
ICIs, including CTLA-4, PD-1, and PD-L1 have emerged as an effective treatment for a variety of advanced malignancies with manageable toxicities. ICI-induced adverse events can involve any organ system, of which the dermatologic, GI, hepatic, and endocrine systems are most commonly affected.[1–4] GI irAEs are common and can lead to interruption of ICI treatment or even discontinuation.[3,8–10] Most studies evaluating GI irAEs have discussed the adverse effects of the lower GI tract involving colitis and diarrhea.[2–3,8–10] A few case studies have reported upper GI tract injury involving esophagitis, gastritis, and duodenitis. Collins et al. and Gonzalez et al. reported that endoscopic inflammation of the upper GI tract was evident in 68% of the 25 patients who underwent EGD evaluation for GI symptoms.[11,12]
When evaluating for possible upper GI symptoms, the differential can be broad; therefore, a thorough investigation is necessary to delineate other conditions, which may be contributing factors or the primary cause of the symptomatic presentation. For this patient, to determine the cause of his symptoms, diagnostic laboratory tests, microbiologic testing, numerous imaging studies, and endoscopic and histologic evaluation were utilized. Specifically, he underwent evaluation for GI infection, electrolyte disturbance, mechanical obstruction, and malignant progression as potential etiologies for his symptoms. After the exclusion of other competing etiologies for his upper GI symptoms, he was found to have pancreatitis on the basis of diagnostic laboratory and imaging studies. Similarly, he was diagnosed with immune-mediated gastroenteritis on the basis of diagnostic imaging and endoscopic evaluation with histologic confirmation. Hence, it is imperative to perform a thorough diagnostic evaluation to determine the cause of upper GI symptoms to guide an appropriate management plan.
In addition, upper GI symptoms of nausea, vomiting, and epigastric pain are nonspecific, and the current literature has focused on diarrhea and colitis with few studies discussing upper GI symptoms and the associated endoscopic and histologic findings.[2–3,8–13] Collins et al. reported that in a study of 20 patients with GI irAEs, most had diarrhea (90%) followed by abdominal pain (70%) and nausea and vomiting (55%). A total of 19/20 (95%) received EGD with 13/19 (68%) showing abnormalities; however, in the clinical subgroups, only 4/20 (20%) had upper GI tract inflammation, 15/20 (75%) had colitis, and 1/20 (5%) had pseudo-obstruction. Of the patients with colitis, 14/20 received EGD and 9/14 (64%) had upper GI tract abnormalities. Therefore, the lack of upper GI irAE reporting is possibly due to several reasons. The concomitant occurrence of upper and lower GI tract injury where it is considered a lower GI irAE due to the predominance of lower GI symptoms, the lesser severity of many upper GI symptoms (including nausea, anorexia, and dysphagia) relative to lower GI symptoms, and the infrequent use of EGD to investigate GI irAE.[2,10–13] Among the case studies reporting upper GI irAEs, findings on EGD are quite variable ranging from normal-to-severe inflammation with gastric mucosal ulcerations and even necrotizing gastritis.[11–13] Histologic features of gastric and duodenal inflammation include lymphoplasmacytic lamina propria expansion, abscess formation, abundant intra-epithelial neutrophils and lymphocytes, and specific to the duodenum, villous blunting.[11–13]
The occurrence of immune-related pancreatitis in the setting of ICI therapy is quite rare. Michot et al. reported that among a cohort of 909 patients treated with anti-PD-1 or anti-PD-L1 therapy, only 0.3% had immune-related pancreatitis evident by imaging studies. Furthermore, the clinical presentations and outcomes of ICI-induced pancreatitis are only described in a few case reports, and the management of immune-related pancreatitis is not well established.[14–17] The current recommendation of methylprednisolone 1–2 mg/kg/day or equivalent is based on few case reports. Thus, further studies investigating the features of ICI-induced pancreatitis are warranted to develop a systematic approach to the diagnosis and treatment of ICI-induced pancreatitis.
The treatment of upper GI irAEs is not well established. Currently, given that irAEs are mediated by general immunologic activation, the current consensus guidelines for the treatment of GI irAEs recommend 1–2 mg/kg/day methylprednisolone or equivalent for grade 2 or higher adverse events.[3,8,10] However, corticosteroid treatment induces systemic immunosuppression, which is associated with significant morbidity. In this patient, as a consequence of corticosteroid treatment, he suffered from candida esophagitis and C. difficile infection with associated prolonged hospitalizations. Furthermore, GI irAEs, like in this case, might be steroid-refractory or steroid-dependent, which necessitate a long course of steroids, causing increased burden on the patient.[3,8,10] There is also debate on the potential undesirable impact of systemic immunosuppression on the anti-tumor effect of ICI treatment, although this has not been proven in small studies.[18–23] Altogether, the potential adverse effects associated with steroids highlight the importance of an effective steroid-sparing therapy that is safe without inducing systemic immunosuppression. Particularly in steroid refractory diseases, the early introduction of such agent is of significance to avoid unwanted morbidity.
Vedolizumab, a human monoclonal IgG1 antibody against α4 β7 integrin, promotes a gut-specific immunosuppression with a gradual onset of therapeutic effect. It is approved for the treatment of inflammatory bowel diseases, Crohn's and Ulcerative Colitis. Recently, vedolizumab has been described as a treatment for immune-related enterocolitis in a case series and in a case report, as a treatment for immune-related enteritis.[22,23] In this case study, vedolizumab was associated with symptomatic resolution within 2 weeks and eventually, complete histologic remission. The gut-specific activity of vedolizumab could be promising for its use in conjunction with cancer immunotherapy since it does not alter the extra-intestinal immunity.[22,23] The other confounding factor in the favorable outcome of GI irAE, in this case, is the potential waning effect of immunotherapy supported by the evidence of recurrent cancer.
To date, this is the first case study to describe the potential efficacy of vedolizumab in the treatment of upper GI irAEs. However, the significant limitation attached to the nature of any case study precludes any meaningful recommendations regarding the effectiveness of vedolizumab for the treatment of upper GI irAEs. Hence, large-scale studies are needed to investigate further the efficacy and safety of vedolizumab in the treatment of upper GI irAEs.
Gastroenteritis and pancreatitis are uncommon adverse events with ICI treatment. The nonspecific presentation of both and the wide differential of etiologies could lead to the misdiagnosis of these entities. Therefore, a thorough diagnostic evaluation with a high level of awareness of the features of ICI toxicities is crucial to attain the right diagnosis and provide the appropriate treatment. Although steroids are first-line therapy with proven effectiveness in most cases of irAEs, steroid-refractory cases can lead to significant morbidity if appropriate treatment is not provided in a timely manner. We reported the first case of steroid-refractory upper GI injury concurrent with pancreatitis secondary to nivolumab treatment that was successfully treated with vedolizumab achieving clinical and histologic remission at 7 months follow-up. With the increasing number of ICIs in the current clinical practice, it is reasonably anticipated that the incidence of all irAEs will rise. Therefore, it is imperative that all clinicians be made aware of their potential adverse effects to prompt rapid diagnosis and treatment.
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