INTRODUCTION
Immune checkpoint inhibitors (ICIs) are now widely applied in the treatment of a variety of malignant tumors, such as metastatic melanoma, colorectal carcinoma, hepatocellular carcinoma, non-small cell lung cancer, malignant pleural mesothelioma, renal cell carcinoma, urothelial carcinoma, and DNA mismatch repair-deficient tumors. By inhibiting tumor cells’ immune evasion mechanisms, ICIs restore and enhance the ability of effector T cells to recognize and eliminate tumor cells, thereby boosting the body’s anti-tumor immune response[1-4]. This mechanism has led to significant improvements in cancer patient survival rates[5]. However, alongside this enhancement of cellular immunity, ICIs can also activate self-reactive T cells, causing immune system damage across various organ systems and leading to immune tolerance imbalance, which results in immune-related adverse events (irAEs)[6]. Although irAEs can affect multiple tissues and organs-including skin, heart, gastrointestinal tract, and musculoskeletal system-their primary clinical manifestations include symptoms such as abdominal pain, diarrhea, bloody stools, weight loss, and fever, often accompanied by extraintestinal manifestations like joint pain, endocrine disorders, skin lesions, hepatitis, nephritis, and pericarditis[7]. Among these adverse effects, gastrointestinal toxicity (GIT) is one of the most common and severe adverse reactions, affecting any part of the gastrointestinal tract. Lower gastrointestinal symptoms, particularly diarrhea and colitis, are the most common presentations. These conditions can lead to treatment interruption, drug discontinuation, and reduced therapeutic efficacy. In severe case, colitis can lead to life-threatening complications such as bowel obstruction, toxic megacolon, and perforation, requiring surgical intervention.
IN THE APPLICATION OF ICIS FOR MALIGNANT TUMOR TREATMENT, VIGILANCE FOR ICI-ASSOCIATED COLITIS IS ESSENTIAL
In the latest issue of the World Journal of Gastrointestinal Surgery, Hong et al[8] published an article, which provides valuable clinical insights into the use of ICIs in cancer therapy. They reported a newly diagnosed liver cancer patient with pre-existing, well-controlled ulcerative colitis (UC) who had received comprehensive targeted anti-cancer therapy, including five months of tirelizumab, before surgery. About two months into tirelizumab treatment, the patient began experiencing 5-6 episodes of bloody diarrhea per day, though without abdominal pain. Nine days after liver cancer resection, the patient’s condition worsened, with symptoms including new-onset abdominal pain, nausea, and over 10 episodes of bloody diarrhea daily, though without vomiting or fever. Following extensive tests, examinations, and multidisciplinary management, the patient was diagnosed with UC accompanied by ICI-associated colitis. Initial treatments with antibiotics, corticosteroids (CS), and somatostatin were unsuccessful in controlling the bloody diarrhea. Subsequent colonoscopy and biopsy confirmed colitis. Despite developing massive lower gastrointestinal bleeding, the patient declined the recommended surgical intervention and opted for conservative management, including blood transfusions, which ultimately proved lifesaving. Through further multidisciplinary consultations, the patient was treated with infliximab (IFX) and vedolizumab (VDZ), achieving significant clinical improvement as confirmed by colonoscopy. However, the patient later experienced severe pancytopenia and was diagnosed with immune-related pancytopenia. The recurrence and worsening of bloody diarrhea led to a subtotal colectomy with ileostomy and enterolysis. Postoperative pathology confirmed UC accompanied by ICI-associated colitis. This case highlights the importance of vigilance for ICI-associated colitis in patients undergoing ICI therapy for malignant tumors, especially in the presence of symptoms like bloody diarrhea or abdominal pain. Early diagnosis and treatment, facilitated by imaging, endoscopy, biopsy, and stool tests, are crucial. Tailoring treatment strategies to symptom severity can improve clinicians’ ability to prevent, diagnose, and manage these adverse effects, thereby optimizing the safe and effective use of ICIs.
ICIs enhance the body’s anti-tumor immune response by blocking negative regulatory proteins that regulate T cell activation[2]. A prominent example is the programmed cell death protein-1 (PD-1) inhibitor, which intensifies T cell attacks on tumor cells but may also lead to attacks on normal cells, causing a range of inflammatory conditions resembling autoimmune diseases, known as irAEs[9]. These irAEs can affect nearly any organ in the body, with the gastrointestinal tract being one of the most frequently involved[10]. The incidence of ICI-associated colitis varies from 1% to 25%[1], depending on factors such as the specific ICI used, tumor type, gut microbiome composition, concurrent use of non steroidal anti inflammatory drugs[11], and combined use of multiple ICIs.
Incidence, timing and characteristics of ICI-associated colitis
Alorfi and Alourfi[12] found that in patients treated with PD-1/programmed cell death-Ligand 1 (PD-L1) inhibitors, the incidence of colitis ranges from 0.7% to 1.6%, whereas in those treated with cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitors, the incidence is higher, between 5.7% and 9.1%. For patients receiving combined treatment with both CTLA-4 and PD-1/PD-L1 inhibitors, the incidence reaches 13.6%. In addition, studies have shown[13] that the toxicity of CTLA-4 inhibitors may be dose-dependent, while the toxicity of PD-1/PD-L1 inhibitors appears unrelated to dosage. This difference may reflect the unique role of CTLA-4 in maintaining gut homeostasis. The median onset of CTLA-4 inhibitor-associated colitis is about one month after the first dose, usually not exceeding two months[14]. In contrast, PD-1 inhibitor-associated colitis generally occurs 2-4 months after treatment initiation, though some cases have been reported up to one year after treatment onset or even 11 months after discontinuation[15]. Bamias et al[16] found that plasma cells or CD4+ T cells predominated in the mucosal tissue of patients with CTLA-4 inhibitor-associated colitis, whereas Coutzac et al[17] reported a predominance of CD8+ T cells in the mucosal tissue of patients with PD-1 inhibitor-associated colitis. Additionally, tumor necrosis factor (TNF)-α levels in the colonic mucosa were higher in CTLA-4 inhibitor-associated colitis than in PD-1 inhibitor-associated colitis. Moreover, tumor types also affect the occurrence of ICI-associated colitis. Patients with melanoma, particularly those with stage III tumors, experience a higher incidence of colitis compared to those with stage IV tumors. Interestingly, the incidence rate does not seem to be affected by gender or age, but Caucasians are at higher risk for developing ICI-associated colitis[18].
The role of gut microbiota imbalance in ICI-associated colitis
The gut microbiota plays a crucial role in preventing gastrointestinal diseases. It forms a bacterial barrier by adhering to the mucosal layer along the intestinal inner wall, occupying space to deter pathogens and producing antimicrobial substances such as bacteriocins, organic acids, and hydrogen peroxide. This barrier blocks or inhibits the invasion of pathogenic or opportunistic pathogenic bacteria on the intestinal mucosa, providing a nonspecific immune effect. Additionally, as an antigen, gut microbiota can stimulate and promote the development and maturation of the immune system, enabling the body to gain resistance to many pathogenic bacteria and their toxins, thus producing a specific immune effect. Furthermore, gut microbiota helps form lymphoid tissues in the intestine and increases immunoglobulin levels in plasma and intestinal mucosa, keeping the immune system moderately active to maintain an effective defense against invading pathogens. Research shows that patients with high baseline levels of Faecalibacterium and other Firmicutes in their gut microbiota are more susceptible to developing immunotherapy-induced colitis following ipilimumab treatment. This may be due to deficiencies in the polyamine transport system and vitamin B biosynthesis within certain gut bacteria, which increase inflammation risk. Additionally, genetic polymorphisms of the CTLA-4 allele may also increase the risk of GIT after ICI treatment[19]. Therefore, maintaining a balanced gut microbiota is of great significance for preventing a series of digestive system diseases (such as enteritis) and maintaining overall health.
Diagnosis of ICI-associated colitis
Diarrhea is the most common symptom of ICI-associated colitis, often accompanied by nausea, abdominal pain, and bloody stools. Severe cases may lead to life-threatening complications such as intestinal perforation, toxic megacolon, and gastrointestinal hemorrhage. Patient education plays a vital role in early diagnosis, and it is crucial to determine the patient's baseline bowel movement habits before starting immunotherapy[18]. Therefore, during ICI treatment, or even after discontinuation, any occurrence of diarrhea and abdominal pain-regardless of other gastrointestinal symptoms-warrants diagnostic consideration once other gastrointestinal diseases have been ruled out. According to the National Comprehensive Cancer Network (NCCN) guidelines, for grade 1 diarrhea and colitis, diagnostic tests should include a complete blood count, comprehensive metabolism (biochemical and electrolytes), and fecal lactoferrin. Fecal microscopy, culture, and drug sensitivity testing are also recommended to exclude infectious causes of diarrhea, such as Clostridium difficile or other pathogens. For grade 2 or above, additional tests, including fecal calprotectin and fecal infection analysis, are advised. Fecal calprotectin, a non-invasive biomarker, is essential for monitoring disease activity and can help minimize the need for invasive endoscopy[20]. In addition, endoscopic examinations can also be prioritized based on fecal lactoferrin levels, which are strongly correlated with inflammation observed during endoscopy (sensitivity of 70%) and histological findings from endoscopic biopsy specimens (sensitivity of 90%)[21]. For grade 3-4 diarrhea and colitis, a complete colonoscopy is recommended. Endoscopic examination usually shows gastrointestinal inflammation, commonly presenting as ulcers (57%-79%), as well as erosion, erythema, disappearance of vascular pattern, and bleeding. In some cases, the intestinal mucosa may appear normal[22]. However, the severity of diarrhea and immune-related enteritis is not always proportional to endoscopic findings, and routine submucosal biopsy may be necessary for accurate assessment, as a few cases of immune-related colitis can appear normal on endoscopy[23]. Histopathological analysis of the mucosal tissue typically shows acute inflammation, with some cases also displaying chronic inflammation characteristics. Luoma et al[24] found a significant increase in T cells in both inflammatory bowel disease (IBD) and ICI-associated colitis patients, with this increase being more pronounced in the latter. This further confirms that while ICIs enhance T cells’ ability to against tumors, they can also induce autoimmune damage, potentially correlating with improved ICI response and clinical prognosis[25]. Finally, in patients showing signs of colitis complications, such as intestinal perforation or toxic megacolon, an abdominal computed tomography scan should be performed[18]. In this case report, the patient, with a well-controlled history of UC, still developed ICI-associated colitis during treatment, further demonstrating that patients with pre-existing IBD undergoing ICI treatment have a significantly increased risk of developing new or exacerbated ICI-associated colitis[26].
Treatment of ICI-associated colitis
For the treatment of ICI-associated colitis, CSs are the first-line treatment drugs, especially for grade 2 and above[18]. For persistent symptoms lasting for more than two weeks, CS may also be considered in cases of grade 1 diarrhea/colitis[27]. For grade 2 diarrhea/colitis, the NCCN guidelines recommend prednisone/methylprednisolone; for grade 3 or higher, hospitalization is advised to monitor electrolyte balance and administer intravenous methylprednisolone[28]. However, approximately 30% to 60% of diarrheal/colitis patients are resistant to CS[29]. At present, the optimal dose and course of CS treatment remain under investigation, as high dose and prolonged use can lead to complications such as impaired glucose tolerance, infection, and changes in bone metabolism[30]. Therefore, minimizing CS exposure is crucial, and dose tapering is recommended within 4 weeks to 6 weeks once symptoms improve[18]. For patients who do not respond to CS or who experience relapse upon tapering or completion of CS therapy, additional immunosuppressive agents should be considered[18,28].
Biologic therapies usually take effect quickly, with symptom relief often observed within a week[31]. Current guidelines emphasize early assessment of response to first-line treatments, recommending an escalation to biologic therapy for non-responders as soon as possible. Biologic agents used in this context include anti-TNF-α monoclonal antibodies, such as IFX, VDZ, and ustekinumab (UST)[32].
IFX, a monoclonal antibody against TNF-α, has been extensively used in IBD and various rheumatic diseases[33]. IFX acts quickly, achieving rapid clinical remission in severe patients[34]. Multiple clinical studies have demonstrated the high efficacy of IFX for treating refractory colitis, and it is recommended by organizations such as Asian small-clawed otters (ASCO) and NCCN[18,35]. According to statistics, the remission rate of IFX in CS-refractory ICI-associated colitis ranges from 54% to 71.4%[28]. In addition, some authors have described that the combined use of IFX and ICIs effectively manages both tumors and colitis. Bamias et al[16] reported minimal impact of IFX on survival rates, while enhancing the antitumor effect of ICIs. For patients with lymphoma, severe congestive heart failure, suspected extraintestinal infection, or concurrent ICI-induced hepatitis, VDZ is recommended. However, VDZ should be avoided in patients with gastrointestinal infection or known gastrointestinal malignancy or metastasis[34]. In the ASCO and NCCN guidelines, the combined use of VDX and IFX for the treatment of ICI-associated colitis is recommended[16,18]. For cases of refractory ICI-associated colitis intolerant to glucocorticoids, IFX, VDX, or UST may be considered for treatment[32].
Deciding whether to continue ICI treatment after irAEs remission is a major clinical challenge due to the potentially fatal nature and high recurrence risk of irAEs. For patients with grade 2-3 ICI-associated colitis, resumption of ICI treatment may be considered when symptoms regress to grade 0-1, preferably using a different class of ICIs. However, for grade 4 ICI-associated colitis, permanent discontinuation of ICIs is recommended[1]. As ICI-associated colitis remains a leading cause of immunotherapy interruption and treatment-related death, determining the optimal treatment strategy is crucial. Future clinical studies are needed to evaluate the effectiveness and safety of biologics in managing tumor immunotherapy-induced adverse reactions.
The gut microbiota also plays a key role in the pathogenesis of ICI-associated colitis, as already mentioned[33]. Dysbiosis is recognized as a contributor to the onset of colitis, with certain gut bacteria linked to either the induction or remission of ICI-associated colitis[36]. Fecal microbiota transplantation (FMT) from healthy donors aims to restore the intestinal microbiome, potentially inducing immunological changes, such as an increase in regulatory T cells in the colonic mucosa. FMT has been suggested as a treatment method for severe or refractory ICI colitis[33]. However, research on FMT for ICI-associated colitis is currently limited, highlighting the need for further investigation in this area.
Challenges in the diagnosis and treatment of ICI-associated colitis
In this case report, the patient developed abdominal pain and bloody diarrhea two months after initiating ICI treatment. Had an early diagnosis and further treatment been possible, the patient’s prognosis may have been different. However, early diagnosis of ICI-associated colitis remains challenging due to several factors, such as atypical early symptoms, difficulty distinguishing it from IBD, particularly in patients with preexisting conditions, patients’ tendency to overlook symptoms, and poor compliance, all contributing to diagnostic difficulties. Nevertheless, dedicated clinicians promptly organized a multidisciplinary management approach when the patient’s condition worsened. The inclusion of biologics such as IFX and VDX for steroid-refractory ICI-associated colitis significantly improved the patient’s condition. Although immune pancytopenia eventually developed, necessitating surgery due to disease recurrence, the prompt multidisciplinary approach delayed the need for emergency surgery and mitigated the immediate impact of a second surgery. Studies have shown that 1% to 1.5% of cases of ICI-associated colitis may be complicated by colonic perforation, which requires urgent surgical intervention[37]. As described by Hong et al[8], extensive colonic lesions and disease progression in this patient led to subtotal colectomy as a recommended option.
Currently, there are no established preventive measures for ICI-associated colitis. Previous research has shown that prophylactic use of budesonide during ipilimumab treatment did not reduce the frequency of grade 2 or higher diarrhea[38]. Therefore, early identification and treatment of ICI-associated colitis are crucial. The choice of treatment should be based on the severity of diarrhea or colitis. Additionally, close, continuous monitoring of patient condition and prompt organization of multidisciplinary management are essential to creating a more tailored treatment plan that may further improve patient outcomes.
