Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation

INTRODUCTION — Gastrointestinal (GI) toxicity due to chemotherapeutic drugs is a common problem in cancer patients. The high proliferation index of the GI mucosa makes it particularly susceptible to toxicity from chemotherapy [1]. The specific chemotherapy-related GI complications that are reviewed here include diarrhea, constipation, and intestinal perforation. Evaluation and management of patients with acute chemotherapy-related diarrhea is discussed separately, as is enterotoxicity related to immunotherapy with checkpoint inhibitors, chemotherapy-induced oral toxicity (mucositis), and chemotherapy-induced nausea and vomiting. (See "Management of acute chemotherapy-related diarrhea" and "Oral toxicity associated with systemic anticancer therapy" and "Immune checkpoint inhibitor colitis" and "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting" and "Prevention of chemotherapy-induced nausea and vomiting in adults".)

DIARRHEA — Chemotherapy-related diarrhea (CRD) is most commonly described with fluoropyrimidines (particularly fluorouracil [FU] and capecitabine) and irinotecan. Diarrhea is the dose-limiting and major toxicity of regimens containing a fluoropyrimidine with irinotecan. However, in addition to conventional cytotoxic drugs, many molecularly targeted agents (including tyrosine kinase inhibitors [TKIs] and monoclonal antibodies) are also associated with CRD. (See 'Risk with conventional cytotoxic agents' below.)

Pathogenesis/mechanisms — CRD generally occurs through three major mechanisms: increased secretion of electrolytes caused by luminal secretagogues or reduced absorptive capacity (due to surgery or epithelial damage), called secretory diarrhea; increased intraluminal osmotic substances leading to osmotic diarrhea; or altered gastrointestinal (GI) motility. Direct ischemic mucosal damage is reported in patients treated with agents targeting the vascular endothelial growth factor (VEGF), while an immune-mediated colitis is responsible for diarrhea with immune checkpoint inhibitors.

●Secretory diarrhea – Both FU and irinotecan cause acute damage to the intestinal mucosa, leading to loss of epithelium [2,3]. FU induces mitotic arrest of crypt cells, leading to an increase in the ratio of immature secretory crypt cells to mature villous enterocytes [2]. The increased volume of fluid that leaves the small bowel exceeds the absorptive capacity of the colon, leading to clinically significant diarrhea. Irinotecan produces mucosal changes associated with apoptosis, such as epithelial vacuolization and goblet cell hyperplasia, suggestive of mucin hypersecretion [3-5]. These changes appear related to the accumulation of the active metabolite of irinotecan, SN-38, in the intestinal mucosa [6].

Up to 50 percent of patients treated with TKIs experience diarrhea [7]. It is thought that the diarrhea occurs through multiple mechanisms. Increased chloride secretion caused by dysregulation of the epidermal growth factor receptor (EGFR) signaling pathway [8,9], colonic crypt damage, gut dysmotility, and alteration in gut microbiota have been proposed. Many cytotoxic chemotherapeutic agents and other classes of antineoplastic drugs cause diarrhea due to damage to the intestinal mucosa, leading to a loss of absorptive surfaces.

●Osmotic diarrhea – Damage to the brush border enzyme system within the epithelium can cause osmotic diarrhea due to inadequate digestion. Approximately 10 percent of patients being treated with FU have decreased expression of the enzyme lactase in their intestinal brush border, leading to lactose intolerance [10,11]. The D-xylose absorption test has been reported to be abnormal in several patients undergoing chemotherapy [12,13], suggesting the presence of carbohydrate malabsorption (such as sucrose, fructose, or even complex polysaccharides). In one study, consumption of a diet high in lactose was associated with increased diarrhea in the setting of adjuvant FU, especially when consumption of fermentable oligo-, di- and monosaccharides and polyols (FODMAP) foods was also high [14].

●Altered intestinal motility – Early-onset diarrhea with irinotecan occurs during or within several hours of drug infusion in 45 to 50 percent of patients and is cholinergically mediated [15]. By contrast, late irinotecan-associated diarrhea is not cholinergically mediated and, instead, appears to be multifactorial, with contributions from dysmotility and secretory factors, as well as a direct toxic effect on the intestinal mucosa. (See 'Irinotecan' below.)

●Drugs that target angiogenesis – Therapies that target angiogenesis, including monoclonal antibodies against vascular endothelial growth factor (VEGF) and its receptor, and antiangiogenic TKIs are associated with GI tract perforation [16,17]. The mechanism by which this happens has not been proven, but proposed mechanisms include intestinal wall disruption (ulceration) in areas of tumor necrosis, disturbed platelet-endothelial cell homeostasis causing submucosal inflammation and subsequent ulcer formation, impaired healing of pathologic, chemotherapy-induced or surgical bowel injury, and mesenteric ischemia from thrombosis and/or vasoconstriction; all of these may result in diarrhea as well. Randomized trials of bevacizumab added to chemotherapy for colorectal cancer have resulted in small increases in severe diarrhea, but this has not been observed in other tumor types, suggesting that bevacizumab may not be causing diarrhea directly but, instead, diarrhea may be caused by one of the indirect mechanisms mentioned above [18,19].

In a study of patients who developed diarrhea in the setting of antiangiogenic therapy with concomitant chemotherapy, normal endoscopic findings were more common in patients with diarrhea alone than in those with diarrhea plus symptoms of enterocolitis such as blood or mucus in stool, pain, fever, or abdominal distension [20]. Endoscopic abnormalities included ulcerations and nonulcerative inflammation. Patients with abnormal endoscopic findings were more likely to have active inflammation on histology. (See 'Intestinal perforation' below.)

●Checkpoint inhibitor immunotherapy – Ipilimumab is a monoclonal antibody directed against CTLA-4, an immune checkpoint molecule on the T-cell surface. Pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, and cemiplimab are monoclonal antibodies directed against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1). These drugs are approved for multiple indications, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, Hodgkin lymphoma, and many others. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic therapy of advanced clear cell renal carcinoma" and "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Ipilimumab' and "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Nivolumab plus ipilimumab, with or without chemotherapy'.)

The presumed mechanism of action for checkpoint inhibitor immunotherapy is to reduce tolerance to tumor-associated antigens, leading to increased antitumor immune cell activity. At the same time, this may result in decreased tolerance to self-antigens. A wide range of immune-mediated adverse events have been observed, including enterocolitis, which can be serious or life-threatening. It is critical to recognize that treatment of diarrhea caused by immune checkpoint inhibitors may require systemic glucocorticoids. The manifestations and management of checkpoint inhibitor immunotherapy-induced enterocolitis are discussed separately. (See "Immune checkpoint inhibitor colitis".)

Clinical manifestations — Typical CRD typically begins with an increasing frequency of bowel movements and/or a loosening of stool consistency. Excessive gas and/or intestinal cramping commonly accompanies CRD. As the CRD progresses, it can become severe, with frequent watery stools. With some drugs (eg, duvelisib), the stool may contain mucus or blood. Even mild CRD can have a profound impact on quality of life, as many chemotherapies are administered for several months to years, and thus CRD should be managed aggressively in the outpatient setting.

CRD can be debilitating and, in some cases, life-threatening. Findings in such patients include volume depletion, acute kidney injury, and electrolyte disorders, such as hypokalemia, metabolic acidosis, and depending upon water intake, hyponatremia (increased water intake that cannot be excreted because of the hypovolemic stimulus to release of antidiuretic hormone) or hypernatremia (insufficient water intake to replace losses). Infection, including life-threatening sepsis, can result due to a breach of the intestinal mucosa, which is worsened in the setting of chemotherapy-induced immunosuppression.

Given the risk for dehydration and infection, severe CRD frequently requires hospital admission for adequate supportive care. Other sequelae of CRD include increased cost of care, reduced quality of life, treatment delays, and diminished compliance with treatment regimens, which may compromise long-term outcomes if the chemotherapy is being administered with curative intent [21].

The severity of CRD is often described using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grades; the latest version is outlined in the table (table 1). Severity is determined by an increase in the number of stools per day or ostomy output compared with baseline, the need for hospitalization, and the effect on activities of self-care. It is critical to ascertain the patient's baseline bowel pattern when grading the severity of diarrhea.

Assessment of patients with acute CRD is addressed in detail elsewhere. (See "Management of acute chemotherapy-related diarrhea", section on 'Clinical assessment'.)

Colitis syndromes that may arise in patients treated with chemotherapy — Patients undergoing chemotherapy may develop several types of colitis. (See "Management of acute chemotherapy-related diarrhea", section on 'Differential diagnosis'.)

●Neutropenic enterocolitis – Neutropenic enterocolitis (a form of necrotizing enterocolitis or typhlitis) is one of the most common GI complications in leukemia patients who are undergoing induction therapy and can occur in other malignancies or following stem-cell-supported high-dose chemotherapy [22,23].

Neutropenic enterocolitis should be considered in any severely neutropenic patient (particularly absolute neutrophil count <500 cells/microL) who presents with fever and abdominal pain. The location of abdominal pain is often in the right lower quadrant, and constitutional symptoms such as fever frequently appear during the third week (median 17 days) after receiving cytotoxic chemotherapy, at a time when neutropenia is most profound. Additional symptoms may include abdominal distension, cramping, tenderness, nausea, vomiting, watery or bloody diarrhea, and frank hematochezia. The appearance on computed tomography (CT) is characteristic (picture 1).

The pathogenesis, risk factors, diagnosis, and management of patients with neutropenic enterocolitis are discussed separately. (See "Neutropenic enterocolitis (typhlitis)".)

●Ischemic colitis – A small number of cases of ischemic colitis have been reported with docetaxel-containing regimens in patients with metastatic breast cancer, including 3 of 14 patients in a phase I study of docetaxel plus vinorelbine [24,25]. The typical onset is 4 to 10 days following administration. Patients with acute colonic ischemia usually present with rapid onset of mild abdominal pain and tenderness over the affected bowel, commonly on the left side of the abdomen. Mild to moderate amounts of rectal bleeding or bloody diarrhea typically develop within 24 hours of the onset of abdominal pain. (See "Overview of intestinal ischemia in adults".)

●Clostridioides difficile-associated colitis – Clostridioides difficile colitis is a common problem in patients with cancer, mostly due to the high rate of oral antibiotic use and hospitalization. However, several reports have described this complication in patients without any prior antibiotic use following chemotherapy [26-28]. The proposed mechanism is chemotherapy-induced intestinal damage that facilitates the proliferation of C. difficile. Frequent occurrence of C. difficile-related diarrheal episodes has been reported in patients treated with paclitaxel-containing regimens, especially with the use of "dose-dense" regimens [29].

Watery diarrhea is the cardinal symptom of C. difficile-associated diarrhea with colitis (≥3 loose stools in 24 hours). Other manifestations include lower abdominal pain and cramping, low-grade fever, nausea, anorexia, and leukocytosis. Ileus can occur in severe cases. The spectrum of illness varies from mild to fulminant; management is discussed in detail elsewhere. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis" and "Clostridioides difficile infection in adults: Treatment and prevention".)

●Lymphocytic colitis – Patients receiving treatment with aflibercept may develop lymphocytic colitis (microscopic colitis), for which specific treatment with budesonide may be beneficial [30]. (See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management", section on 'Glucocorticoids for active disease'.)

Differential diagnosis — Patients who develop acute diarrhea during chemotherapy may also suffer from organic causes of diarrhea, such as bacterial overgrowth, fat or bile acid malabsorption, intake of excess quantities of sorbitol or lactose intolerance, and inflammatory and infectious causes, which should not be overlooked.

Clinical manifestations, differential diagnosis, and management of acute chemotherapy-related diarrhea are discussed elsewhere. (See "Management of acute chemotherapy-related diarrhea".)

Risk with conventional cytotoxic agents

Fluorouracil — One of the main dose-limiting side effects of fluoropyrimidines such as FU (and its oral prodrugs capecitabine and ftorafur-uracil [UFT]) is diarrhea. Both the therapeutic efficacy and frequency of diarrhea associated with FU are increased when given concurrently with leucovorin (LV), a folic acid derivative. Diarrhea is also schedule-dependent. The highest frequency of diarrhea occurs with bolus rather than continuous 24-hour infusion of FU/LV for up to five days, particularly with weekly bolus administration, but it can occur with all schedules of administration [31-36]. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Less fit patients or a contraindication to oxaliplatin' and "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status", section on 'Fluoropyrimidine monotherapy'.)

In multiple reports of weekly FU/LV, diarrhea was seen in up to 50 percent of patients, half of whom required hospitalization for intravenous (IV) fluids [31,32,35]. In one series, 11 of 221 patients (5 percent) died of treatment-related toxicity, most of them older adult patients with concomitant leukopenia and sepsis [35]. Based upon these observations, treatment is routinely withheld for grade 2 or worse (table 1) diarrhea and not restarted until diarrhea resolves, an approach that has led to a significant reduction in severe enterotoxicity with these regimens. (See "Management of acute chemotherapy-related diarrhea", section on 'Restarting chemotherapy'.)

No risk factor can reliably predict the development of diarrhea with FU therapy, but the risk is increased in the presence of an unresected primary tumor, shortened bowel resulting from previous surgery, previous episodes of CRD, treatment during the summer season [37,38], and when bolus FU and LV are combined with oxaliplatin [39] or irinotecan. (See 'IFL' below.)

Women appear to suffer more toxicity from FU than men for unclear reasons [40,41]. In a meta-analysis of over 2400 patients enrolled in five trials (three for advanced disease, two in the adjuvant setting), significantly more women experienced ≥grade 3 toxicity during therapy than did men (50 versus 40 percent) [40]. All of these trials used a five-day bolus schedule of FU and LV. These data suggest that women may be better served by less toxic administration schedules of FU, including short-term infusional regimens. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer" and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Not candidates for intensive therapy'.)

Predictive markers — Early detection of patients who are at risk of developing life-threatening toxicity from fluoropyrimidines based upon predictive markers might allow dose reduction or selection of an alternative treatment regimen. The two most-studied predictive factors are enzymatic activity of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthetase (table 2).

DPD deficiency — Dihydropyrimidine dehydrogenase (DPD), the first of three enzymes in the fluoropyrimidine metabolic pathway, is the rate-limiting enzyme in FU catabolism. Enzyme activity varies widely, with most of the variability arising from genetic polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD). Patients who are partially or totally deficient in DPD activity cannot adequately degrade fluoropyrimidines, leading to an increased risk of severe, sometimes fatal, toxicity. In patients with even partial DPD deficiency, administration of a fluoropyrimidine can lead to life-threatening complications, including severe diarrhea, mucositis, and pancytopenia [42-50]. Nausea, vomiting, rectal bleeding, volume depletion, skin changes, neurologic abnormalities (cerebellar ataxia, cognitive dysfunction, altered level of consciousness), and cardiotoxicity may also occur. (See "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management", section on 'DPYD polymorphisms'.)

Molecular analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene that may result in partial or total loss of DPD activity [51-53]. Only four have been consistently associated with a marked decrease in DPD activity and enhanced fluoropyrimidine toxicity, including DPYD*2A single-nucleotide polymorphism (SNP) [51,54-63], DPYD*13 SNP [51,53,64], DPYD*9B SNP [51,53,63], and a collection of SNPs termed HapB3 [65-67]:

●DPYD*2A is a single-nucleotide polymorphism (SNP); splice site variant IVS14+1G>A with the nucleotide change 1905+1G>A, resulting in an exon 14 deletion [del]

●DPYD*13 SNP, has a nucleotide change 1679T>G, with resultant amino acid substitution I560S

●DPYD*9B SNP, has a nucleotide change c.2846A>T, with resultant amino acid substitution D949V

●HapB3 is composed of three intronic variants (c.483+18G>A, c.680+139G>A, and c.959-51T>C), and one synonymous variant (c.1236G>A); there is another deep intronic variant in the DPYD gene (c.1129-5923C>G) in tight linkage with HapB3, and this polymorphism (c.1129-5923C>G/HapB3) may contribute to fluoropyrimidine toxicity. In Europeans, c.1129-5923C>G/HapB3 is the most common DPYD variant, with carrier frequencies of approximately 5 percent [68]. However, the effects of this variant are modest [69], which probably explains the disparate reports on its influence on FU toxicity [64-67,70].

Although complete DPD deficiency is rare (and usually associated with homozygosity for one of the alleles associated with reduced enzyme activity), partial deficiencies due to the inheritance of one high-risk allele are more common, particularly in Black women. These demographic differences can be illustrated by an analysis of enzyme levels from 258 normal volunteers [71]. No person had complete DPD deficiency, while partial DPD deficiency was present in 12.3, 4.0, 3.5, and 1.9 percent of Black women and men, and White women and men, respectively. Only four (1.6 percent) volunteers (three Black women and one Black man) had profound DPD deficiency.

Despite the association of one of these high-risk alleles with severe CRD, we do not routinely test DPYD genotype for all patients initiating fluoropyrimidine therapy. In the United States, one of the three high-risk alleles, DPYD*2A, *13, and *9B, is present in fewer than 10 percent of patients in most populations, and inheritance of a high-risk allele is not always associated with life-threatening toxicity (ie, the positive predictive value of having one of these alleles on the risk of severe toxicity is variable). Inheritance of one of these high-risk alleles does not account for the majority of FU-associated severe toxicity, which is estimated to occur in 15 to 30 percent of treated patients (ie, sensitivity is limited). Finally, even if preemptive pharmacogenomics testing is done and these high-risk alleles are not detected, patients can still have life-threatening toxicity (ie, the specificity is limited). These issues can be illustrated by the following data:

●In one series, one of the three high-risk DPYD variants was found in only 30 percent of FU-treated patients (13 of 44) who developed grade 3 or 4 toxicity [51]. Similarly, a systematic review by the Clinical Pharmacogenetics Implementation Consortium (CPIC) concluded that between 23 and 38 percent of severe fluoropyrimidine toxicity could be attributed to DPYD variants (clinical sensitivity approximately 31 percent) [72].

●In a prospective study of 683 patients receiving FU monotherapy, grade 3 or 4 toxicity occurred in 16 percent, and genotyping revealed the DPYD*2A allele in only 5 percent of those with treatment-related toxicity [56]. Furthermore, fewer than half of those who had the DPYD*2A allele developed grade 3 or 4 toxicity (positive predictive value 46 percent). Of interest, there was a gene-sex interaction, resulting in an odds ratio (OR) of 41.8 for male patients but only 1.33 for female patients.

●In another series of 430 patients initiating therapy with FU or capecitabine for any tumor type, 24 of the 104 patients experiencing grade 3 or 4 toxicity in the first four cycles of therapy (23 percent) were found to have one of four high-risk variant alleles (DPYD*2A, *13, *9B, and one other high-risk allele, 1601G>A) [61]. Only 6 percent of the entire cohort had one of these four variants. In contrast to the prior series, the positive predictive value of having inherited any of these four high-risk alleles for severe (grade 3 or 4) diarrhea, mucositis, or myelosuppression during the first four cycles of therapy in this study was >99 percent.

Some of the inconsistency in study results may be attributable to variations in the treatment regimens across studies. The DPYD*2A allele has been associated with toxicity more frequently when FU was administered in combination with other chemotherapeutic agents rather than as monotherapy [72]. Furthermore, there appears to be significant interethnic differences in frequency and genetic constitution of DPD deficiency [73].

A major issue is that inheritance of one of these high-risk alleles does not account for all cases of DPD deficiency. Impaired DPD activity has been detected in some patients with normal wild-type DPYD alleles, presumably due to epigenetic mechanisms, including microRNAs, that regulate enzyme activity [74,75].

Despite these difficulties, the potential benefits of identifying patients who have inherited one of these three high-risk alleles in terms of reducing treatment-related toxicity and improving the cost-effectiveness of care can be illustrated by the following reports:

●In a report of data from a large cohort of patients with stage III colon cancer who were enrolled on the adjuvant NCCTG N0147 trial, the frequency of finding one of the three high-risk DPYD alleles was low overall; of the 2886 patients who were genotyped, 27 (0.9 percent), 4 (0.1 percent), and 32 (1.1 percent) carried the DPYD*2A, *13, and *9B variants, respectively [76]. However, of the 2594 patients with complete adverse event data, grade 3 or 4 adverse events developed in 22 of the 25 patients with the *2A variant (88 percent positive predictive value), in two of four *13 carriers (50 percent), and in 22 of 27 *9B carriers (82 percent). The *2A variant was significantly associated with nausea and vomiting and neutropenia but not diarrhea, while the *9B variant was significantly associated with dehydration, diarrhea, neutropenia, and thrombocytopenia.

●In a more recent series, 1181 patients initiating fluoropyrimidine therapy were prospectively screened for the four most common DPYD variants found in the Netherlands (DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A) prior to initiating therapy; 85 patients (8 percent of total) were heterozygous DPYD variant allele carriers and were treated with a reduced dose of fluoropyrimidine [77]. The risk of grade 3 or worse adverse events was 39 percent in patients with DPYD variant alleles compared with 23 percent in DPYD wild-type patients. In pharmacokinetic analyses, mean drug and therapeutic metabolite exposure was similar between DPYD variant allele carriers treated with a reduced dose and wild-type patients. Interestingly, there was no correlation between DPD enzyme activity and the occurrence of severe fluoropyrimidine-related toxicity in DPYD variant allele-carrying patients.

●In a cost-effectiveness analysis of screening patients intended to receive fluoropyrimidine-based chemotherapy for the four most common DPYD variants found in the Netherlands (DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A), the expected total costs for the screening strategy were 2599 euros per patient compared with 2650 euros per patient for the non-screening strategy [78]. The study also found that the total costs of hospitalization for five DPYD variant allele carriers that experienced severe toxicity were much higher than prospectively screening the whole study population (232,061 versus 23,718 euros).

As noted above, the DPYD*2A, DPYD*13, DPYD*9B, and HapB3 variants are the most commonly reported high-risk DPYD variants. Other alleles with equivocal effects on the likelihood of fluoropyrimidine-related toxicity include polymorphisms in the DPYD*4 allele and the DPYD*5 allele [54,62,65,77].

If a high-risk DPYD variant is identified prior to treatment, guidelines for fluoropyrimidine dosing are available from the CPIC (table 3) [79,80]. However, they do not provide recommendations on whether and when to perform pharmacogenomics testing. Given the low frequency of finding a predictive allele and the low sensitivity (ie, patients who lack one of these high-risk DPYD variants may still suffer grade 3 or 4 fluoropyrimidine-related toxicity), preemptive genetic testing of all patients due to receive a fluoropyrimidine in order to identify those with DPD deficiency is controversial and not widely practiced [81]. The US Food and Drug Administration (FDA) does not currently require pharmacogenetic testing before fluoropyrimidine administration. In the United States, testing is usually reserved for patients who develop unusually early, severe, treatment-related toxicity (diarrhea, mucositis, myelosuppression, neurotoxicity, cardiotoxicity) in the first cycle of fluoropyrimidine therapy.

On the other hand, in March 2020, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recommended all patients planned to receive any fluoropyrimidine therapy undergo pharmacogenomics testing prior to starting therapy [82], and this approach has been adopted in updated guidelines for management of localized colon cancer from the European Society for Medical Oncology (ESMO) [83]. This subject is discussed in detail below. (See 'Testing for DPYD and TYMS variants' below.)

TYMS gene variations — In addition to DPYD, high-risk polymorphisms in the thymidylate synthetase gene (TYMS) may be associated with a 1.4- to 2.4-fold increase in the risk of severe toxicity from FU-based chemotherapy; however, the data are less certain than with the high-risk DPYD genotypes.

Thymidylate synthetase (TS), a critical enzyme for thymidine production, is potently inhibited by FU. The important polymorphisms that might influence fluoropyrimidine toxicity are outlined in the table (table 2) and are described in detail in the following sections:

●Expression of TYMS is regulated by transcription factors that bind to the promoter region. The 5' untranslated region (UTR) contains a variable number of 28 bp tandem repeats (VNTRs), which can stimulate transcriptional activity. The vast majority of individuals carry TYMS alleles that contain two or three repeats in this promoter region, designated 2R and 3R [84,85]. Patients who are homozygous for the triple repeat (3R/3R) have a greater number of binding sites for transcription factor and higher TS levels compared with those who are 2R/2R or 3R/2R; conversely, 2R/2R homozygotes have low TS levels in normal tissues and may be at a greater risk of FU cytotoxicity. Notably, patients who overexpress TS have relative resistance to fluoropyrimidines.

●An SNP has been described in the 12^th nucleotide of the second repeat of the 3R allele, which abolishes a promoter binding site in the 3R allele (designated the 3RC allele) and leads to markedly reduced TS activity [84,86-89]. Others describe greater toxicity with a similar substitution of cytosine for guanine at the 12^th nucleotide in two 28 bp repeats in the 5' UTR (designated 2RC) [88,90].

The available data linking these polymorphisms to increased fluoropyrimidine toxicity are conflicting, as evidenced by the following reports:

●The 2R/2R genotype has been associated with greater toxicity in many [85,91-93], but not all [61,93,94], studies. Even in positive studies, the sensitivity and positive predictive value appear to be limited. As an example, in three studies totaling 200 unselected patients who received FU, 44 (22 percent) developed grade 3 or 4 toxicity [85,91,92]. Only 13 of the 44 had the high-risk 2R/2R genotype (sensitivity 30 percent), while of the 25 patients who inherited the 2R/2R high-risk genotype, only 13 developed grade 3 or 4 toxicity (positive predictive value 52 percent).

●Inheritance of a high-risk 2RC allele has been associated with an increase in toxicity [88,90]. In a series of 1613 patients, 28 had the 2RC variant allele (1.7 percent), and 20 had a high-risk genotype (2RG/2RC, 3RC/2RC, and 2RC/2RC) [90]. Both early severe toxicity and toxicity-related hospitalization were more frequent in risk-associated genotype carriers (OR 3.0 [95% CI 1.04-8.93] and 3.8 [95% CI 1.19-11.9], respectively).

Other predictive markers — The contribution of other genetic and nongenetic factors has not been well studied [95,96]. At least some data suggest marked regional differences in tolerability of fluoropyrimidines, with the highest toxicity rates in the United States and the lowest in East Asia [97]. This may be due, in part, to differences in dietary folic acid intake [97,98]. Reduced folates (such as LV) stabilize the binding of the FU metabolite fluorodeoxyuridine monophosphate to thymidylate synthetase, enhancing the response to fluoropyrimidine therapy [99] but also increasing toxicity. Higher pretreatment serum folate levels have also been linked to greater toxicity from capecitabine, an orally active prodrug of FU [100]. (See 'Capecitabine' below.)

Testing for DPYD and TYMS variants — We do not routinely implement testing for DPYD and/or TYMS genotype for all patients initiating fluoropyrimidine therapy, but test for the panel of DPD alleles (rather than just DPYD*2A) in patients who have had severe and unexpected toxicity from fluoropyrimidines. TYMS genotyping could be included along with DPYD testing, where available, for patients who have had severe reactions to fluoropyrimidine therapy (table 2).

Pharmacogenetic profiling has the potential to identify patients who may experience severe adverse effects with fluoropyrimidines, but the clinical utility of preemptive testing remains controversial (reviewed in [101]). Some authors suggest genotype testing prior to initiating fluoropyrimidine therapy in all patients, and some institutions have adopted this approach [102-106]. Clinical guidelines are disparate:

●Preemptive testing for DPYD variants is now recommended by the EMA [82] but not the FDA.

●Preemptive testing has been endorsed (at least prior to administration of adjuvant fluoropyrimidine-containing chemotherapy for localized colon cancer) by ESMO [83], but not by the National Comprehensive Cancer Network (NCCN).

Given these issues, not surprisingly, clinical adoption of pretreatment DPYD testing has been extremely limited in the United States [107].

Although fatal toxicity from fluoropyrimidine therapy is quite rare, preemptive testing for the presence of these four DPD alleles (DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A) may prevent severe toxicity and appears to be at least cost-neutral in a European population [78]. An important point is that there are no prospective randomized trials that demonstrate improved toxicity without compromise of efficacy in patients who are preemptively screened versus not screened using any assay for DPD activity, including pharmacogenetic testing for high-risk DPYD and TYMS variants.

Preemptive genotyping may not be covered by insurance in the United States, and the turn-around time for various laboratories is listed as up to 10 days.

At many institutions, including those of several of the authors and editors associated with this review, genotyping is reserved for those patients who have unexpected toxicity (myelosuppression, mucositis, diarrhea, neurotoxicity, cardiotoxicity) during the first few cycles of fluoropyrimidine therapy. These patients should be suspected of having an at-risk DPYD or TYMS mutation, for which testing for at-risk mutations in DPYD and TYMS is reasonable, as dosing recommendations for DPYD mutation carriers are available from CPIC, and because identification of at-risk mutations may be of use if family members are to be treated in the future with fluoropyrimidines. Any patient who experiences severe toxicity following treatment with a fluoropyrimidine, regardless of whether they have an identified at-risk variant in DPYD or TYMS will require a significant dose reduction if continued treatment is planned.

●Phenotypic testing as an alternative to genotyping – As an alternative to genotyping, phenotypic testing may be used to assess DPD functionality; DPD deficiency is reflected by a reduced ratio of dihydrouracil: uracil in plasma, or higher levels of uracil [108-110]:

•One prospective study of 59 patients with GI malignancies assessed DPD function in all patients prior to their initial FU dose by measuring the ratio of dihydrouracil to uracil in blood as a surrogate test. Patients with reduced DPD activity (a dihydrouracil:uracil ratio <4, 23 percent of the total) were treated with a preemptive reduction in FU dose, and this strategy was associated with reduced rates of FU toxicity, and no difference in response rate or other cancer outcomes [108].

•In another report of 243 patients initiating fluoropyrimidine therapy, elevated plasma uracil levels >16 ng/mL was associated with a 20-fold higher risk to develop grade 4 toxicity, and had a higher sensitivity than assessment for three common DPYD variants, but the combined use of genotyping plus phenotyping did not improve toxicity prediction [109].

Although potentially more rapid than genotyping, these assays are not widely available, at least in the United States.

Management of DPD-deficient patients — If a DPYD variant is identified prior to treatment, guidelines for management are available from CPIC (table 3) [65]. The authors note that not all patients who harbor reduced- or no-function variants of DPYD manifest toxicity, and, therefore, they recommend increasing the fluoropyrimidine dose in the absence of toxicity or in patients who have subtherapeutic plasma levels. This dose increase is of particular importance for patients being treated with curative intent.

Alternative agents are needed for patients who are homozygous (ie, carrying two nonfunctional alleles). The quinazoline folate analog raltitrexed, which is a thymidylate synthetase inhibitor, may be a useful substitute for FU in patients with DPD deficiency [111], but it is not available in the United States. UFT is not a safe substitute for FU in this situation [112] as it is a combination of ftorafur (tegafur), an FU prodrug, plus uracil, which competes with FU for DPD.

Where available, another option is close monitoring of FU levels and pharmacokinetically guided dosing. (See "Dosing of anticancer agents in adults", section on 'Therapeutic drug monitoring'.)

Guidelines are not available from the CPIC or any other group for management of patients who are identified as having high-risk TYMS variants.

Most cases of DPD deficiency are diagnosed only after a severe reaction to FU. Management of these patients should include aggressive hemodynamic support, parenteral nutrition, antibiotics, hematopoietic colony stimulating factors, and, where available, uridine triacetate (see 'Uridine triacetate' below). Dialysis is of no benefit if renal function is normal, since even with complete DPD deficiency, FU is rapidly cleared through the urine [42]. Patients diagnosed with DPD deficiency should be advised to inform family members in case they will be treated with fluoropyrimidine chemotherapy in future.

Uridine triacetate — Uridine triacetate (originally called vistonuridine) is an orally administered prodrug of uridine, a specific pharmacologic antidote to fluoropyrimidines, including FU and capecitabine. It is a safe and potentially life-saving treatment for overdoses of these agents. Uridine triacetate was studied in 173 adult and pediatric patients who were treated in two separate trials and had either received an overdose of FU or capecitabine (n = 147) or had early-onset, unusually severe, or rapid-onset life-threatening toxicities within 96 hours after receiving FU (n = 26, the fraction who had DPD deficiency as the cause for severe early toxicity could not be determined) [113]. Overall, 137 of 142 assessable overdose patients treated with uridine triacetate (96 percent) survived to 30 days, had rapid reversal of acute neurotoxicity or cardiotoxicity (affecting 12 patients), and either prevention of or recovery from severe mucositis or leucopenia. Among the 26 patients treated for early-onset toxicity following fluoropyrimidine therapy (some of whom presumably had DPD deficiency), 21 survived to 30 days (81 percent); all five deaths were in patients who initiated uridine triacetate beyond 96 hours after the last dose of the fluoropyrimidine. Adverse events attributable to uridine triacetate were mild and infrequent, and included diarrhea, nausea, and vomiting.

There are few data on the specific use of uridine triacetate in patients who develop severe fluoropyrimidine toxicity because of DPD deficiency [114]. However, the drug has been shown to prevent fatalities in mice who are treated with FU after receiving an inhibitor of DPD [115]. Thus, DPD-deficient patients who develop early severe toxicity after receiving the first dose of a fluoropyrimidine could also benefit from treatment with uridine triacetate, if the deficiency is identified soon enough after the fluoropyrimidine is administered and the drug can be obtained within 96 hours of the last dose. Uridine triacetate should not be administered for nonemergent toxicities as it may interfere with the efficacy of fluoropyrimidine treatment.

Uridine triacetate was approved by the FDA in December 2015 for emergency use following an FU or capecitabine overdose, regardless of the presence of symptoms, for patients who exhibit early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (eg, GI toxicity and/or neutropenia) within 96 hours following the end of FU or capecitabine administration [116]. The dose and schedule for adults is 10 g orally every six hours for 20 doses. The dose and schedule for pediatric patients is 6.2 g/m² of body surface area orally every six hours for 20 doses. Despite its approval, uridine triacetate is not available commercially in any country. Ordering information for emergency use of uridine triacetate is available from vistogard.com.

Capecitabine — Capecitabine is a rationally designed oral fluoropyrimidine prodrug that is converted to FU in three sequential enzymatic reactions. The dose-limiting toxicities are diarrhea, palmar-plantar erythrodysesthesia, and neutropenia. Capecitabine is associated with higher rates of diarrhea compared with infusional FU regimens [117-119].

Like FU, capecitabine is catabolized by DPD, and there is a risk for early and severe toxicity in those who are DPD deficient. However, the specific genetic markers of capecitabine-related toxicity are less well studied than with other fluoropyrimidines, such as FU.

As with FU, routine testing for high-risk DPYD or TYMS alleles is not widely practiced prior to initiation of capecitabine because of the low frequency of finding a high-risk allele and the fact that patients who lack a high-risk variant may still suffer grade 3 or 4 FU-related toxicity. Nevertheless, testing is appropriate for patients who develop early severe toxicity (neutropenia, mucositis, diarrhea, neurotoxicity, and/or cardiotoxicity). (See 'DPD deficiency' above.)

To avoid the risk of severe and potentially fatal reactions, the United States prescribing information for capecitabine recommends to withhold or permanently discontinue the drug in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate a near-complete or total absence of DPD activity [120]. Furthermore, it states that no capecitabine dose has been proven safe for patients with complete absence of DPD activity and that there are insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test. However, it stops short of recommending preemptive testing for all patients prior to initiating therapy.

Uridine triacetate is approved for emergency use in cases of capecitabine overdose or early-onset, severe, or life-threatening toxicity, such as might occur in a DPD-deficient patient. (See 'Uridine triacetate' above.)

Dosing — There appear to be large regional differences in the tolerance to capecitabine and other fluoropyrimidines [97]. These differences might, in part, be based on population-specific pharmacogenomic variability (eg, Asian patients seem to tolerate fluoropyrimidines better than non-Asian patients, and although not studied according to ethnicity, genetic factors that are associated with capecitabine sensitivity, such as SNPs, have been identified [121]). However, differences in lifestyle and diet (eg, dietary folate intake) could also contribute.

Because of these issues, the optimal dose of capecitabine, particularly for American patients, remains undefined. The initially approved dose for treatment of metastatic breast and colorectal cancer was 2500 mg/m² per day for 14 of every 21 days, but later studies suggest that this dose is too high, particularly in American patients. Lower doses (beginning at 2000 mg per day for 14 of every 21 days) may improve the therapeutic index without compromising efficacy. An alternative capecitabine dosing schedule as has been used in women with breast cancer (2000 mg total dose in two divided doses for seven days on, seven days off) may be associated with less diarrhea [122,123]. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Capecitabine' and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Oral fluoropyrimidines'.)

Ftorafur — Two oral formulations of ftorafur (tegafur), a FU prodrug, have been developed and are in use in Japan; neither drug is available in the United States.

●UFT is a combination of ftorafur with uracil, which has been in widespread use in Japan for over 20 years. UFT is currently not available in the United States. Uracil competitively inhibits the enzyme DPD, leading to higher intratumoral concentrations of FU.

Grade 3 or 4 diarrhea is seen in up to 12 percent of patients treated with single-agent UFT and in 8 to 20 percent of those in whom UFT was given with LV [124,125]. Prompt discontinuation of UFT at the onset of diarrhea usually prevents severe GI toxicity.

●S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur, gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of DPD), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea).

In animal models, potassium oxonate is protective against FU-induced diarrhea [126,127]. In a randomized phase III trial of surgery followed by one year of S-1 versus surgery alone in gastric cancer, the incidence of grade 3 or 4 diarrhea was only 3.1 percent with S-1 [128]. However, in a randomized trial of S-1 versus capecitabine as adjuvant therapy for colon cancer, grade 3 or 4 diarrhea occurred more commonly with S-1 than capecitabine (8 versus 2 percent) [129]. Randomized controlled trials of S-1 with oxaliplatin compared with FOLFOX or CAPOX have found a higher incidence of severe diarrhea in the S-1 arm compared with standard therapy [130,131].

Irinotecan — There are two types of diarrhea associated with irinotecan:

●Early-onset diarrhea with irinotecan occurs during or within several hours of drug infusion in 45 to 50 percent of patients and is cholinergically mediated (ie, related to increased motility) [15]. It is often accompanied by other symptoms of cholinergic excess, including abdominal cramping, rhinitis, lacrimation, and salivation. The mean duration of symptoms is 30 minutes; it is usually well controlled by subcutaneous or IV atropine. (See 'Pathogenesis/mechanisms' above.)

●By contrast, late irinotecan-associated diarrhea is not cholinergically mediated. The pathophysiology of late diarrhea appears to be multifactorial, with contributions from dysmotility and secretory factors, as well as a direct toxic effect on the intestinal mucosa [132,133].

Late diarrhea from irinotecan is unpredictable, noncumulative, and occurs at all dose levels. In early clinical trials of irinotecan, late diarrhea and neutropenia were the main dose-limiting toxicities [134,135]. Diarrhea of any grade was seen in 50 to 88 percent of patients, and it was severe in 9 to 31 percent. Diarrhea has been less common in later studies because of the stricter adherence to management guidelines (including routine early institution of high-dose loperamide) and the use of infusional rather than bolus FU in combination with irinotecan. (See "Management of acute chemotherapy-related diarrhea", section on 'Loperamide and diphenoxylate-atropine'.)

The median time to onset is approximately six days with the 350 mg/m² every-three-week schedule and 11 days with the weekly schedule (125 mg/m²) [133,136]. Late diarrhea is less common with the every-three-week schedule. In a randomized trial comparing the two administration schedules of single-agent irinotecan, the incidence of severe diarrhea was significantly less with the every-three-week schedule (19 versus 36 percent for weekly therapy) [137]. However, the incidence of cholinergic symptoms was significantly lower with weekly therapy (31 versus 61 percent). In some studies, older age, low performance status, and prior pelvic radiation were found to be predisposing factors [133]. For unclear reasons, diarrhea is more common in White patients than in Black patients receiving irinotecan-based therapy [138].

Irinotecan produces mucosal changes associated with apoptosis, such as epithelial vacuolization, and goblet cell hyperplasia, suggestive of mucin hypersecretion [3]. These changes appear related to the accumulation of the active metabolite of irinotecan, SN-38, in the intestinal mucosa [6].

SN-38 is glucuronidated in the liver and is then excreted in the bile. The conjugated metabolite SN-38G does not appear to cause diarrhea. However, SN-38G can be deconjugated in the intestine by beta-glucuronidase present in intestinal bacteria. A direct correlation has been noted between mucosal damage and either low glucuronidation rates or increased intestinal beta-glucuronidase activity [139-141]. Severe toxicity has been described with irinotecan in patients with Gilbert syndrome who have defective hepatic glucuronidation [140]. (See "Gilbert syndrome" and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Treatment-related toxicity'.)

Common genetic polymorphisms of the UDP-glucuronyltransferase (UGT) gene can affect the metabolism of irinotecan. The possible impact of genetic variability on the toxicity of irinotecan is discussed below. (See 'Irinotecan plus FU' below.)

UGT1A1 polymorphisms — Preemptive testing for the uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) genotypes that are associated with a poor metabolizer phenotype prior to initiating irinotecan is a controversial and evolving area, and experts differ. Although many institutions do not routinely screen patients, at our institution preemptive testing is recommended for all individuals initiating irinotecan, and we reduce initial starting doses by approximately 30 percent if a high-risk genotype is identified.

SN-38 is further metabolized by the polymorphic enzyme UGT1A1. Individuals who inherit certain polymorphisms in the UGT1A1 gene or its promoter have reduced enzymatic activity and they are referred to as having a "poor metabolizer" phenotype because of decreased clearance of SN-38, which increases the risk for severe irinotecan-related neutropenia and, to a lesser degree, diarrhea. Most of the reported data describing the excess toxicity experienced by these individuals are in those carrying one or more *28 alleles, which is the most frequent alteration in European and African ancestries [142]. The *6 polymorphism is also associated with irinotecan toxicity and is more common in East Asian ancestry than in European or African ancestry. The *93 polymorphism is associated with increased SN-38 exposure and irinotecan toxicity and is common in African and European ancestries but less common in East Asian ancestry (table 4) [142,143]. In general, patients carrying two alleles (eg, homozygotes with *28/*28, *6/*6, or *6/*28) conferring decreased expression of function are at a higher risk for severe toxicity, compared with those carrying one allele (eg, *1/*28).

Some poor metabolizers may be identified because they have Gilbert's syndrome, an inherited deficiency in UGT1A1 enzyme activity caused by polymorphisms in the UGT1A1 gene (typically the *28 allele), and characterized by increased unconjugated bilirubin in the blood, which is usually asymptomatic. Otherwise, the identification of individuals who have a poor metabolizer phenotype requires genetic testing for high-risk alleles. In one study of 1500 patients undergoing routine genotyping at a single institution, 17 percent were found to have a UGT1A1 genotype that would result in a poor metabolizer phenotype (*6/*6, *28/*28, *6/*28) [106].

The United States Prescribing Information for irinotecan specifies that individuals who are homozygous for the UGT1A1 *28 or *6 allele and compound heterozygotes (*6/*28) are at risk for severe irinotecan toxicity (mainly neutropenia) and both pre-emptive testing for these UGT1A1 high-risk genotypes and a reduced initial dose of irinotecan in poor metabolizers should be "considered" [120]. However, whether preemptive testing for UGT1A1 genotype should be carried out in all individuals prior to receiving irinotecan is a controversial, evolving area, and experts differ. Some, including our institution, screen all patients. However, others do not. Preemptive testing is not widely recommended in various oncology guidelines.

This subject is addressed in detail elsewhere. (See "Dosing of anticancer agents in adults", section on 'UGT1A1 polymorphisms and irinotecan'.)

Irinotecan plus FU — A standard regimen for treatment of metastatic colorectal cancer is the combination of irinotecan, FU, and LV [144,145]. Both irinotecan and FU have overlapping toxicity profiles; a major concern with early studies of this triplet regimen was the potential for enhanced GI toxicity. The spectrum of GI toxicity with combined irinotecan plus FU and LV is schedule dependent:

IFL — In two early trials of bolus irinotecan plus weekly FU and LV (the IFL regimen), unacceptably high rates of early treatment-related mortality were noted [146-148]. In both trials, patients receiving irinotecan plus bolus FU and LV (either daily or weekly) had a threefold higher rate of treatment-related death than those enrolled on other arms [146]. Most of the early deaths appeared to be due to a cluster of mainly GI symptoms that included diarrhea, nausea, vomiting, and abdominal cramping, which was typically accompanied by dehydration, neutropenia, fever, and electrolyte abnormalities [147].

Use of this regimen is no longer recommended, largely because of the risk of diarrhea and neutropenia.

FOLFIRI — GI toxicity is less severe with other irinotecan-containing regimens that utilize irinotecan plus LV and short-term infusional FU (eg, FOLFIRI). In at least four trials, rates of grade 3 or 4 diarrhea with FOLFIRI (every-other-week irinotecan plus short-term infusional FU and LV) were between 10 and 14 percent [117,145,149,150].

The better tolerability of regimens in which irinotecan is combined with infusional rather than bolus FU [117] has led to the widespread use of FOLFIRI rather than IFL. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Irinotecan regimens'.)

Liposomal irinotecan plus fluorouracil and leucovorin — Liposomal irinotecan is a nanoliposomal encapsulated preparation that allows irinotecan to remain in circulation for a longer duration compared with standard irinotecan; this increases drug uptake within tumor cells and conversion of irinotecan to its active form, SN-38 [151]. Liposomal irinotecan is approved in combination with FU/LV for second-line treatment of gemcitabine-refractory metastatic pancreatic cancer based on results from the international phase III NAPOLI-1 trial [152]. Severe diarrhea, which can be of early-onset or late-onset type, occurred in 13 percent of those receiving combination therapy in this trial.

As with nonencapsulated irinotecan, the manufacturer of liposomal irinotecan recommends that the starting dose be lowered (from 70 to 50 mg/m² every two weeks) in patients homozygous for UGT1A1*28 [120]. However, it does not specifically recommend testing for the UGT1A1*28 variant prior to starting therapy. (See "Second-line systemic therapy for advanced exocrine pancreatic cancer", section on 'Liposomal irinotecan'.)

Irinotecan plus capecitabine — Several studies of irinotecan plus capecitabine compared with FOLFIRI as treatment of metastatic colorectal cancer have demonstrated high rates GI toxicity [117,153]. The irinotecan doses were 240-250 mg/m² every 21 days. A more favorable toxicity profile was noted in a phase III randomized trial of XELIRI versus FOLFIRI used a lower irinotecan dose of 200 mg/m² every 21 days and lower capecitabine dose of 800 mg/m² twice daily on days 1 through 14, every 21 days [154].

Oxaliplatin combinations — Combinations of oxaliplatin plus FU and LV have become the most widely chosen first-line chemotherapy regimens for metastatic colorectal cancer, at least in North America. In addition, oxaliplatin-containing regimens have also been shown to provide a survival benefit over non-oxaliplatin-containing regimens for adjuvant therapy of stage III colon cancer. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'FOLFOX versus FOLFIRI' and "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Oxaliplatin-based therapy'.)

Enterotoxicity with combined oxaliplatin and FU-containing chemotherapy is dependent on the schedule of FU administration. With oxaliplatin combined with short-term infusional FU (a regimen referred to as FOLFOX), rates of grade 3 or 4 diarrhea are less than 20 percent [155-158]. On the other hand, enterotoxicity is much more frequent and severe with regimens that combine oxaliplatin with weekly bolus FU and LV (eg, FLOX) [39], especially those that include daily bolus FU and LV [148].

This was shown in the NSABP C-07 trial, a comparison of the Roswell park regimen without or with (ie, FLOX) oxaliplatin as adjuvant therapy for stage II or III colon cancer [39]. During therapy, 79 of 1857 patients (4.3 percent) developed a syndrome of bowel wall injury characterized by hospitalization for management of severe diarrhea or dehydration and radiographic or endoscopic evidence of bowel wall thickening or ulceration, and the incidence was significantly higher in patients assigned to FLOX as compared with FU/LV (5.5 versus 3 percent). The incidence of bowel wall injury during chemotherapy was particularly high with FLOX as compared with FU and LV in patients aged 60 or older (6.7 versus 2.9 percent) and in females (9.1 versus 3.9 percent).

Enteric sepsis, characterized by grade 3 or worse diarrhea and grade 4 neutropenia (with or without bacteremia), occurred in 22 patients on FLOX and 8 patients on FU/LV. There were five deaths due to enteropathy, all in patients with enteric sepsis, with or without bowel wall injury. These results underscore the need to closely monitor patients treated with adjuvant FU/LV chemotherapy for diarrhea and provide aggressive management of this symptom complex, particularly if oxaliplatin has been added.

Capecitabine plus oxaliplatin — The combination of oxaliplatin and capecitabine (XELOX, also called CAPOX) has also been intensely investigated given its convenience. A phase III comparison of XELOX (capecitabine at 1000 mg/m² twice a day for 14 days plus oxaliplatin 130 mg/m² on day 1 every three weeks) versus FOLFOX (continuous infusion of FU at 2250 mg/m² over 48 hours on days 1, 8, 15, 22, 29, and 36 plus oxaliplatin 85 mg/m² on days 1, 15, and 29 every six weeks) in patients with metastatic colorectal cancer reported a significantly lower rate of grade 3 or 4 diarrhea with XELOX (14 versus 24 percent) but a significantly higher rate of grade 1 or 2 hyperbilirubinemia (37 versus 21 percent) [159].

The largest amount of safety data for XELOX comes from the IDEA collaboration, an international study that compared three versus six months of adjuvant chemotherapy [160]. The six trials included in the IDEA collaboration included 5071 patients who received XELOX, 2554 for three months and 2517 for six months. As expected, rates of grade 3 or worse diarrhea were higher in patients receiving six months of XELOX versus three months (21.5 versus 17.2 percent), but rates of diarrhea were similar for patients receiving XELOX versus oxaliplatin plus short-term infusional FU (FOLFOX). (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Duration of therapy'.)

Fluoropyrimidine, irinotecan and oxaliplatin combinations — Combinations of leucovorin-modulated FU, plus irinotecan, and oxaliplatin (FOLFIRINOX, FOLFOXIRI) have increased rates of diarrhea compared with two-drug chemotherapy regimens such as FOLFOX or FOLFIRI, but they have become the standard of care for many patients with pancreatic cancer and select patients with colorectal cancer due to their superior efficacy and survival data.

●The ACCORD 11 trial, a randomized comparison of the FOLFIRINOX regimen (table 5) against gemcitabine in metastatic pancreatic cancer, showed that 21 of 165 patients (12.7 percent) experienced grade 3 or worse diarrhea compared with 3 of 169 patients (1.8 percent) receiving gemcitabine alone [161]. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'FOLFOX and FOLFIRINOX'.)

●Similarly, in a study of modified FOLFIRINOX (table 6) as adjuvant therapy for pancreatic cancer, 47 of 238 patients (20 percent) experienced grade 3 or higher diarrhea, and 200 of 238 patients (84.4 percent) experienced diarrhea of any grade [162].

●A related regimen, FOLFOXIRI in combination with bevacizumab (table 7) has been compared with both FOLFOX/bevacizumab and FOLFIRI/bevacizumab in metastatic colorectal cancer (see "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Three- versus two-drug combinations'):

•The TRIBE study showed that 47 of 250 patients (18.8 percent) who received FOLFOXIRI/bevacizumab experienced grade 3 or higher diarrhea, which was significantly higher than 27 of 254 patients (10.6 percent) who received FOLFIRI/bevacizumab [163].

•The TRIBE 2 study comparing FOLFOXIRI/bevacizumab with FOLFOX/bevacizumab also showed higher rates of grade 1 or 2 diarrhea (50.3 versus 35.1 percent) and grade 3 or higher diarrhea (17.0 versus 5.4 percent) with the four-drug regimen [164].

Pemetrexed — Pemetrexed is an antifolate with activity in NSCLC and mesothelioma. In phase II and III trials of pemetrexed monotherapy, diarrhea (typically grade 1 or 2) has been reported in approximately 10 to 15 percent of patients [165-167]. Pemetrexed in combination with platinum chemotherapy is widely used as treatment for NSCLC. Severe diarrhea is rare with pemetrexed/platinum regimens [168-170]. (See "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation" and "Systemic treatment for unresectable malignant pleural mesothelioma".)

Cabazitaxel — Cabazitaxel is a semisynthetic taxane that is approved for the treatment of advanced prostate cancer. Diarrhea is a frequent problem, developing in 15 to 50 percent of treated patients, but it is severe (grade 3 or 4) in only 1 to 6 percent [171-174]. Nevertheless, in a pivotal phase III trial conducted in men with advanced prostate cancer, some deaths occurred in men treated with cabazitaxel that were attributed to diarrhea and electrolyte imbalance [173]. A later study that established the noninferiority of a 20 mg/m² dose compared with the standard 25 mg/m² dose showed that diarrhea rates and severity may be dose dependent. While the greatest improvement was in rates of neutropenia (41.8 versus 73.3 percent) and febrile neutropenia (2.1 versus 9.2 percent, the rates of diarrhea of any grade (30.7 versus 39.8 percent) and of grade 3 or higher diarrhea (1.4 versus 4.0 percent) were also modestly improved [175]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Men who have received prior docetaxel'.)

Other taxanes — Diarrhea is commonly reported in studies of the other taxanes such as docetaxel, paclitaxel and nanoparticle albumin-bound (nab)-paclitaxel. In studies of docetaxel used for castration-resistant prostate cancer, diarrhea occurred in approximately 35 percent of patients but was grade 3 or higher in less than 3 percent [176,177]. Rates and severity of diarrhea are similar with paclitaxel and nabpaclitaxel compared with docetaxel [178,179]. For example, in the Impassion130 trial comparing nabpaclitaxel plus atezolizumab versus nabpaclitaxel alone, approximately 33 percent of patients experienced diarrhea of any grade, and less than 3 percent experienced grade 3 or higher diarrhea in both study arms [178].

Predictably, combining taxanes with other chemotherapeutic agents can increase both the frequency and severity of diarrhea. For example, in a study of perioperative chemotherapy for gastric cancer, the regimen of FU/LV, oxaliplatin and docetaxel (FLOT) caused significantly more diarrhea than the epirubicin-containing regimens (52 versus 29 percent for grade 1 or 2 and 10 percent versus 4 percent for grade 3 or 4, p = 0.0016) [180].

Bortezomib and other proteasome inhibitors — Diarrhea is commonly seen with bortezomib, a proteasome inhibitor used in the treatment of multiple myeloma [181]. In the pivotal studies with this agent, diarrhea occurred in 51 percent of patients, with 8 percent of the events being grade 3 or 4. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors' and "Multiple myeloma: Treatment of first or second relapse", section on 'Daratumumab, bortezomib, dexamethasone (DVd)'.)

Diarrhea is less common and less severe with carfilzomib [182] and the orally active agent ixazomib [183].

Vorinostat and belinostat — Vorinostat, a histone deacetylase inhibitor, was approved by the FDA in 2006 for the management of cutaneous T-cell lymphoma. In the pivotal studies of this agent, diarrhea was observed in 52 percent of the patients, with the great majority of these episodes being grade 1 or 2 events controllable by oral agents [184].

Belinostat is another histone deacetylase inhibitor that is approved for treatment of peripheral T-cell lymphoma. In an initial study, diarrhea was reported in 23 percent of treated patients but was severe in only 2 percent [185].

Lenalidomide and other immunomodulatory imide (IMiD) drugs — Lenalidomide can cause constipation or diarrhea. Pomalidomide can also cause both constipation or diarrhea in up to one-third of patients. Among patients with diarrhea, bile salt malabsorption may be one potential etiology that responds to treatment including reduced fat intake and bile acid sequestrants [186].

Risk with molecularly targeted agents — Diarrhea is a common side effect of several molecularly targeted agents.

Small molecule EGFR inhibitors — Diarrhea is common in patients receiving small molecule epidermal growth factor receptor (EGFR) TKIs, such as erlotinib, gefitinib, afatinib, dacomitinib, osimertinib, and mobocertinib [169,187-190]. For patients treated with gefitinib and erlotinib, diarrhea is most likely to occur within the first four weeks of treatment initiation; with afatinib, diarrhea is most likely to occur within the first seven days. Although diarrhea is reported in up to 90 percent of patients treated with any of these agents (especially those treated with afatinib [191] and mobocertinib [192]), it is severe in fewer than 20 percent and typically can be easily managed by the use of loperamide. Uncommonly, diarrhea necessitates dose reduction or treatment interruptions. Although diarrhea can have a profound effect on patients, the available evidence suggests that diarrhea may be a surrogate indicator of antitumor efficacy [193,194].

Synergistic toxicity may be a problem when these agents are combined with chemotherapy. Diarrhea has been a significant dose-limiting toxicity in a number of studies combining EGFR inhibitors with concurrent radiation and chemotherapy [195,196].

Anti-EGFR monoclonal antibodies — Cetuximab is a chimeric immunoglobulin G subclass 1 (IgG1) monoclonal antibody that binds to the extracellular domain of the epidermal growth factor receptor (EGFR), competitively inhibiting ligand binding. In contrast with small-molecule EGFR inhibitors, cetuximab-related diarrhea is generally not severe:

●A phase II study of cetuximab as monotherapy for 346 patients with metastatic colorectal cancer reported diarrhea of any grade in 12.7 percent [197].

●When toxicities were reported, regardless of attribution to treatment, in a phase II study of patients with lung cancer treated with cetuximab alone, 22.7 percent had diarrhea of any grade [198].

●Rates of grade 3 or 4 diarrhea in studies of single-agent cetuximab are only 1.5 to 2 percent [197-201].

Panitumumab is a fully human IgG2 monoclonal antibody directed against the EGFR. A phase III comparison of best supportive care (BSC) with or without panitumumab reported diarrhea of any grade in 21 percent of patients receiving panitumumab (grade 3, 1 percent), compared with 11 percent with BSC alone (none grade 3) [202]. Similar results are reported by others with panitumumab monotherapy [203].

PI3K inhibitors — Phosphoinositide 3-kinase (PI3K) inhibitors (eg, idelalisib, duvelisib, and alpelisib) are all associated with diarrhea, which can be severe.

●Idelalisib – Idelalisib is an oral inhibitor of PI3K delta; it is approved for treatment of relapsed chronic lymphocytic leukemia, follicular lymphoma, and small lymphocytic lymphoma. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Idelalisib'.)

Across clinical trials, approximately 14 percent of treated patients have developed severe diarrhea or colitis (grade 3 or worse) [204-206]. Diarrhea can occur at any time during treatment, and it responds poorly to antimotility agents. Following interruption of therapy and, in some cases, the use of glucocorticoids or budesonide [205], the median time to resolution is between one and four weeks. Some patients with moderate to severe diarrhea have developed serious and fatal intestinal perforation. (See 'Idelalisib' below.)

●Duvelisib – Duvelisib is an oral dual inhibitor of PI3K delta and gamma that is approved for treatment of chronic lymphocytic leukemia. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

Serious (grade ≥3), including fatal, diarrhea or colitis has been reported in 11 to 23 percent of patients treated with duvelisib [207-209]. The United States Prescribing Information recommends withholding the drug for moderate (grade 1 or 2) diarrhea that is unresponsive to antidiarrheal agents and for those with abdominal pain, stool with mucus or blood, peritoneal signs, or grade 3 diarrhea [120]. Supportive therapy should be initiated with enteric-acting glucocorticoids (eg, budesonide), or systemic glucocorticoids if there is abdominal pain, peritoneal signs, stool with mucous or blood, or grade 3 diarrhea.

Both idelalisib and duvelisib carry boxed warnings from the FDA for diarrhea and colitis.

●Alpelisib – Alpelisib is another inhibitor of PI3K alpha that is approved, in combination with fulvestrant, for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers that have a mutation in the catalytic alpha subunit of PI3K.

Diarrhea is common and occurs in approximately 60 percent of treated patients; it is severe (grade 3) in approximately 7 percent [210]. Specific recommendations for treatment interruption/dose reduction in the event of diarrhea are outlined in the table (table 8).

Small molecule inhibitors of VEGFR — Sorafenib, sunitinib, axitinib, regorafenib, pazopanib, cabozantinib, lenvatinib, and vandetanib are orally active inhibitors of multiple tyrosine kinases including the vascular endothelial growth factor receptor (VEGFR). Diarrhea is a prominent side effect of all VEGFR inhibitors. In clinical trials, diarrhea of any grade has been reported in 30 to 79 percent of patients (highest rates with vandetanib), with severe diarrhea (grade 3 or 4) in 3 to 17 percent [211-217]. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Gastrointestinal toxicities'.)

BCR-ABL1 and KIT tyrosine kinase inhibitors — Imatinib, an inhibitor of BCR-ABL1 and other tyrosine kinases, such as KIT, causes diarrhea in approximately 30 percent of patients, but severe diarrhea is rare [218]. Similarly, dasatinib, which targets BCR-ABL1, KIT, and the Src family of tyrosine kinases (among others), causes diarrhea in approximately 30 percent, which is severe in <5 percent. Hemorrhagic colitis is also reported in patients treated with dasatinib, although the frequency with which this occurs is not established [219]. Nilotinib, an inhibitor of BCR-ABL1, KIT, and PDGFR is also associated with diarrhea in 19 to 28 percent of patients, which is usually not severe [220].

Similarly, diarrhea is reported in 28 percent of patients treated with the KIT/PDGFRA inhibitor ripretinib, but it is severe in only 1 percent [221].

On the other hand, bosutinib, an inhibitor of BCR-ABL1 and the Src family of kinases, causes diarrhea in a higher proportion of patients (76 to 84 percent) and is severe in approximately 9 percent [222]. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy", section on 'Bosutinib'.)

Ponatinib is a pan-BCR-ABL inhibitor; in contrast with other agents, diarrhea is uncommon with this drug [223,224].

Lapatinib, pertuzumab, neratinib, and tucatinib — These are all drugs that target HER2 (EGFR2) and other EGFRs. The use of these agents to treat advanced HER2-positive breast cancer and metastatic HER2-positive colorectal cancer is discussed separately. (See "Systemic treatment for HER2-positive metastatic breast cancer" and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, HER2 overexpressors'.)

●Lapatinib – Lapatinib, an orally active TKI that affects both the HER2 (also called erbB-2) and EGFR (also called erbB-1), causes diarrhea in approximately 80 percent of patients; it is severe (grade 3 or 4) in 20 to 30 percent of patients [225]. Patients are typically managed with antidiarrheal agents such as loperamide. Severe diarrhea may require hydration, electrolyte repletion, and/or interruption of therapy (recommended for grade 3 toxicity) (table 1), and grade 1 or 2 toxicity that is complicated by moderate to severe abdominal cramping, grade 2 or worse nausea or vomiting (table 9), decreased performance status, sepsis, fever, neutropenia, bleeding, or dehydration). Treatment can be reintroduced at a lower dose when diarrhea resolves to grade 1 or less.

●Pertuzumab – Pertuzumab is a recombinant monoclonal antibody directed against HER2, but it does not require HER2 overexpression for activity. Treatment-related diarrhea is frequent, but not commonly severe [226,227]. In a study of pertuzumab monotherapy in patients with metastatic breast cancer, diarrhea of any grade developed in 48 percent, but it was severe (grade 3 or 4) in only 3 percent [226].

●Neratinib – Neratinib is an orally active, irreversible TKI of HER1, HER2, and HER4, as well as EGFR; it is approved for extended adjuvant therapy in early stage HER2-positive breast cancer, and in combination with capecitabine for advanced HER2-positive breast cancer. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Dual anti-HER2 therapy in high-risk disease'.)

With conventional dosing (240 mg daily starting immediately), treatment-related diarrhea occurs in almost all patients, and it is severe (grade 3 or 4) in approximately 40 percent in the absence of routine antidiarrheal prophylaxis [228]. The United States Prescribing information for neratinib recommends antidiarrheal prophylaxis with loperamide during the first two cycles (56 days) of treatment, initiated with the first dose, which improves tolerability [229]. Dose modifications for grade 2 to 4 diarrhea are also included in the prescribing information.

Tolerability is improved with a gradually escalated initial dosing schedule (120 mg daily for one week, 160 mg daily for one week, followed by 240 mg daily thereafter, with only "as needed" loperamide), which was approved in 2021.

●Tucatinib – Tucatinib targets HER2 and HER3. Tucatinib can cause severe diarrhea with dehydration, hypotension, acute kidney injury, and death. The United States Prescribing Information for tucatinib does not recommend prophylactic antidiarrheal therapy, but has specific recommendations for dose interruption, reduction, and drug discontinuation for treatment-related diarrhea, depending on the severity [230].

In the HER2Climb trial, over 80 percent of patients developed diarrhea during treatment with combined trastuzumab, capecitabine, and tucatinib, including 12 percent with grade 3 diarrhea and 0.5 percent with grade 4 diarrhea (both of whom died with diarrhea as a contributing cause) [231].

Cyclin-dependent kinase inhibitors — Palbociclib, ribociclib, and abemaciclib are oral inhibitors of cyclin-dependent kinases (CDK) 4 and 6; they are approved for treatment of hormone receptor-positive metastatic breast cancer. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'AIs plus CDK 4/6 inhibitors'.)

Diarrhea is a frequent adverse reaction with the CDK 4/6 inhibitors, especially with abemaciclib. Abemaciclib is more selective for CDK 4 compared with palbociclib and ribociclib and, as a result, causes more diarrhea and fatigue but fewer hematologic adverse events. Diarrhea occurs in 81 to 86 percent of treated patients, but it is typically low grade (severe in 10 to 13 percent) [232,233].

Ribociclib has a much lower rate of diarrhea regardless of combination with tamoxifen, an aromatase inhibitor, or with fulvestrant; approximately 33 percent of patients experience diarrhea of any grade and only 1 percent experience grade 3 or higher diarrhea [234,235]. Palbociclib may have the lowest rates of diarrhea with 26 percent of patients experiencing diarrhea of any grade and only 1.4 percent experiencing grade 3 diarrhea in the PALOMA-2 study of palbociclib combined with letrozole [236]. Diarrhea typically responds to antidiarrheal therapy, and treatment discontinuation is rarely needed.

Trastuzumab antibody-drug conjugates — Ado-trastuzumab-emtansine (T-DM1) is an antibody drug conjugate that consists of the HER2-targeting properties of trastuzumab linked to the microtubule inhibitory agent DM1. As a treatment for advanced HER2-positive breast cancer, trastuzumab emtansine resulted in diarrhea in 23 percent of patients, but severe diarrhea occurred in fewer than 2 percent of patients [237]. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Second-line treatment'.)

Fam-trastuzumab deruxtecan links the anti-HER2 antibody with a cytotoxic topoisomerase 1 inhibitor [238]. As a treatment for patients with advanced HER2-positive breast cancer previously treated with ado-trastuzumab emtansine, fam-trastuzumab deruxtecan was associated with diarrhea in 29 percent of patients and severe diarrhea in only 3 percent. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Second-line treatment' and "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Fam-trastuzumab deruxtecan'.)

Sacituzumab govitecan — Sacituzumab govitecan is an antibody-drug conjugate that combines a humanized monoclonal antibody, which targets the human trophoblast cell-surface antigen 2 (Trop-2), with SN-38, a metabolite of irinotecan, which is conjugated to the antibody by a cleavable linker. It is approved for triple-negative breast cancer. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Sacituzumab govitecan'.)

Severe diarrhea may occur with this agent, including cases of neutropenic colitis. In the IMMU-132-01 study, diarrhea occurred in 63 percent and was severe in 9 percent [239]. For patients who develop diarrhea, after infectious causes have been ruled out, loperamide should be initiated promptly, with additional supportive measures (fluids, electrolyte repletion) as clinically indicated. Grade 3 or 4 diarrhea that is not controlled with antidiarrheal agents should prompt dose reduction [240].

As with irinotecan, patients who inherit an UGT1A1*28 allele who receive sacituzumab govitecan are mainly at risk for excess neutropenia and not diarrhea. The United States Prescribing Information for sacituzumab govitecan does not provide any recommendation for lower initial doses of sacituzumab in patients known to be homozygous or heterozygous for the *28 allele [120]. (See 'UGT1A1 polymorphisms' above.)

Sotorasib — Sotorasib is an inhibitor of RAS GTPase family; it's approved for advanced non-small cell lung cancer with a RAS G12C mutation. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Sotorasib'.)

Diarrhea is reported in approximately 40 percent of treated patients, but it is severe in only 5 percent. The United States Prescribing Information provides guidance for dose management in patients with severe diarrhea despite appropriate supportive care (including antidiarrheal therapy) [120].

Temsirolimus and everolimus — Temsirolimus and everolimus, which are inhibitors of the mammalian target of rapamycin (mTOR), can cause diarrhea, but severe gastrointestinal toxicity is rare [241,242]. Diarrhea occurred in 27 percent of patients with renal cell carcinoma treated with temsirolimus but severe diarrhea occurred in only 1 percent [242]. In a placebo-controlled trial for treatment of advanced renal cell carcinoma, the incidence of diarrhea in the everolimus arm was 17 percent (1 percent grade 3) compared with 3 percent in the placebo arm (0 percent severe) [241]. In patients with advanced breast cancer, everolimus was associated with a 33 percent risk of diarrhea, but severe diarrhea was rare [243].

ALK inhibitors — Crizotinib, ceritinib, alectinib, and brigatinib are orally active inhibitors of the anaplastic lymphoma kinase (ALK); all are approved for treatment of advanced or metastatic NSCLC if the tumor contains a characteristic EML4-ALK fusion oncogene. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Ceritinib' and "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Crizotinib'.)

Diarrhea is a common side effect, particularly with ceritinib, but rarely severe [120]:

●In a review of over 250 treated patients, the incidence of all-grade diarrhea with ceritinib was 86 percent; it was severe (≥grade 3) in 6 percent.

●In a review of 397 patients treated with crizotinib, 49 percent developed diarrhea of any grade, and it was severe in <1 percent.

Diarrhea seems to be significantly less frequent with alectinib, a newer agent with more potent ALK inhibitory activity and better central nervous system penetration. In the randomized phase III ALEX study comparing alectinib with crizotinib, diarrhea was significantly less common with alectinib (12 versus 45 percent), and there were no patients with grade 3 or higher diarrhea [244].

MEK inhibitors — Cobimetinib, trametinib, and binimetinib are orally active inhibitors of the mitogen-activated protein kinase enzymes MEK1/MEK2; they are approved for treatment of metastatic melanoma with the BRAF V600 mutation in combination with their respective BRAF inhibitor partners, vemurafenib, dabrafenib, and encorafenib. The combination of dabrafenib and trametinib is FDA approved for treatment of metastatic NSCLC with a BRAF V600 mutation. Encorafenib is FDA approved in combination with the EGFR inhibitor cetuximab for treatment of metastatic colon cancer with the BRAF V600E mutation. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)

Diarrhea is a frequent complication of these drugs. In clinical trials, approximately one-half of patients develop diarrhea, but it is severe (grade 3 or worse) in fewer than 5 percent of cases [245-247]. The United States Prescribing Information for these drugs recommends withholding the drug for grade 2 or worse adverse reactions, including diarrhea (table 1), and permanent discontinuation if toxicity does not improve to grade 0-1 within three or four weeks or for any recurrent grade 4 toxicity.

BTK inhibitors — Ibrutinib, acalabrutinib, and zanubrutinib are orally active inhibitors of Bruton’s tyrosine kinase (BTK), a nonreceptor kinase that is critical for proliferation and survival of the malignant cells in many B-cell malignancies. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Ibrutinib' and "Treatment of relapsed or refractory mantle cell lymphoma", section on 'Bruton tyrosine kinase inhibitors'.)

In a phase III trial, the incidence of treatment-related diarrhea with ibrutinib was 42 percent; only 4 percent of patients had severe (grade 3 or 4) diarrhea (table 1) [248]. The United States Prescribing Information provides specific guidelines for dose reduction in response to adverse events, including diarrhea [120].

The risk of diarrhea was slightly less (all-grade 34.1 percent, 0.6 percent grade 3 or worse) in the monotherapy arm of the phase III ELEVATE TN trial of acalabrutinib [249,250]. The United States Prescribing Information provides specific guidelines for dose reduction in the setting of grade 3 or higher nonhematologic toxicity [120].

FGFR inhibitors — Three oral tyrosine kinase inhibitors of the fibroblast growth factor receptor (FGFR) are approved for cancer treatment: erdafitinib, infigratinib, and pemigatinib. All three drugs have been associated with diarrhea in approximately one-half of treated patients that is severe in less than 5 percent.

PARP inhibitors — The poly(ADP-ribose) polymerase (PARP) inhibitors, which include olaparib, rucaparib, and niraparib, are a novel class of drugs targeting DNA repair mechanisms that are best studied in ovarian cancer, but olaparib also has approvals in breast, pancreatic, and prostate cancer. Both diarrhea and constipation are frequently reported in trials of these drugs, but they were also common in the placebo arms of these studies. This is likely because bowel dysfunction is common in ovarian cancer due to high rates of peritoneal involvement.

For olaparib and rucaparib, both constipation and diarrhea are reported in approximately 30 percent of patients [251-253]. Niraparib on the other hand is more frequently associated with constipation (40 percent of patients) but causes diarrhea less often (19 percent) [254].

Rituximab — Rituximab, an anti-CD20 monoclonal antibody used to treat B-cell lymphoma, can cause new-onset ulcerative colitis or exacerbation of preexisting colitis [255].

Risk with immune checkpoint inhibitors — A wide range of immune-mediated adverse events have been observed in patients treated with immune checkpoint inhibitors, including enterocolitis, which can be serious or life-threatening. It is critical to recognize that treatment of diarrhea caused by immune checkpoint inhibitors may require systemic glucocorticoids. The manifestations and management of checkpoint inhibitor immunotherapy-induced enterocolitis are discussed separately. (See "Immune checkpoint inhibitor colitis".)

Treatment — Management of acute chemotherapy-related diarrhea is discussed elsewhere. (See "Management of acute chemotherapy-related diarrhea".)

CONSTIPATION — Constipation can be defined as a decreased frequency of defecation (usually less than three bowel movements per week) accompanied by discomfort or difficulty with evacuating the bowels. It is a common problem in patients with cancer, with a reported prevalence of 40 to 90 percent in patients with advanced cancer [256]. Constipation in patients with cancer is usually due to a combination of poor oral intake and drugs, such as opioid analgesics or antiemetic agents that slow intestinal transit time. As an example, 5HT3 receptors are present on enteric neurons, and ondansetron was shown to slow colonic transit time in healthy subjects [257]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Opioid bowel dysfunction'.)

Constipation can have a significant detrimental impact on quality of life and can lead to nausea, vomiting, hemorrhoids, anal fissures, bowel obstruction, and urinary retention [256]. Overflow diarrhea can occur from fecal leakage around impacted stool [258].

Specific cancer drugs associated with constipation

Vinca alkaloids — Constipation is rarely a dose-limiting toxicity for chemotherapeutic agents, except for the vinca alkaloids (eg, vincristine, vinblastine, and vinorelbine), especially vincristine. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Vincristine'.)

These drugs have pronounced neuropathic effects and increase gastrointestinal (GI) transit time [259]. The constipating effect of vinca alkaloid therapy is usually apparent after the first dose and is typically not cumulative. It is most prominent 3 to 10 days after chemotherapy and then resolves, in most cases, after a few days [260].

Constipation occurs in one-quarter to one-third of patients treated with vincristine [261,262] and is severe (table 10) in 2 to 3 percent [261,263]. In one series of 392 patients, 2.8 percent required hospitalization for adynamic ileus [261].

Vincristine-induced constipation is more severe at higher doses (above 2 mg). This was illustrated in a report of 104 patients with Hodgkin or non-Hodgkin lymphoma [264]. Vincristine was given in a non-capped dose of 1.4 mg/m², and 90 percent of patients received more than 2 mg in the first dose. Severe constipation occurred in 10 percent. Rapid improvement usually occurred within a few weeks after the cessation of therapy.

Immunomodulatory imide (IMiD) drugs — Thalidomide and its analogs lenalidomide and pomalidomide are immunomodulatory imide drugs (IMiDs) that are approved for the treatment of multiple myeloma. Lenalidomide is also approved for treatment of certain types of lymphoma and myelodysplastic syndrome. Thalidomide is also approved for treatment of erythema nodosum leprosum. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Immunomodulatory drugs'.)

The most common toxicity with thalidomide, besides sedation, is constipation. In a major myeloma trial, constipation developed in 35 percent of patients at 200 mg/day and in 59 percent at 800 mg/day [265]. These rates seem higher than those observed in a phase II trial of thalidomide (starting dose 800 mg daily) in patients with recurrent high-grade glioma, in which constipation was the most common toxicity but only occurred in 19 percent of patients; no severe episodes were noted [266].

Thalidomide-induced constipation is dose dependent, appears early after the initiation of therapy (within two to four days) in most patients, and is more severe in older adults and in those receiving opioid analgesics [267]. The mechanism might be neuromuscular inertia with resultant hypotonia. Thalidomide-induced hypothyroidism should be considered in patients with persistent constipation or if it appears late in the disease course.

Lenalidomide, an immunomodulatory agent derived from thalidomide, is used more frequently than thalidomide for treatment of multiple myeloma due to its efficacy and reduced toxicity, including constipation. When added to dexamethasone, the incidence of constipation was 30 percent, but severe constipation occurred in less than 3 percent of patients [268,269]. Lenalidomide maintenance therapy after autologous stem cell transplantation has not been associated with frequent constipation [270].

In clinical trials, pomalidomide has been associated with diarrhea or constipation in approximately one-third of treated patients, none of which were severe [271].

Vandetanib — Vandetanib is a multitargeted inhibitor of several tyrosine kinases. In clinical trials involving patients with medullary thyroid cancer and lung cancer, vandetanib was associated with constipation in 9 to 37 percent of patients, with 0 to 3 percent severe [272-274]. Vandetanib is more often associated with diarrhea. (See 'Small molecule inhibitors of VEGFR' above.)

Belinostat — Belinostat is a histone deacetylase inhibitor that is approved for treatment of peripheral T-cell lymphoma. In an initial clinical trial involving 129 patients, belinostat was associated with constipation in 23 percent of patients, with 2 percent severe [185]. Diarrhea was equally common. (See 'Vorinostat and belinostat' above.)

Treatment — The treatment of chemotherapy-induced constipation begins with anticipation and prevention:

●We encourage increased fluid intake.

●Laxatives should be started at the first sign of constipation or, for patients treated with agents that are known to be associated with constipation (eg, vinca alkaloids), given routinely to prevent constipation.

●The most frequently used laxatives in patients with advanced cancer are osmotic agents (such as polyethylene glycol and lactulose) and stimulant laxatives (eg, senna and bisacodyl) [256]. The Multinational Association for Supportive Care in Cancer (MASCC) recommended polyethylene glycol as the initial laxative of choice for patients with advanced cancer based on evidence in the general population, expert opinion, and clinical experience [258].

●Patients should be frequently reassessed for response to treatment with changes or additions made to the treatment regimen [258].

●Nonabsorbable soluble dietary fiber or bulk agents should be avoided in patients with low fluid intake due to increased risk of mechanical bowel obstruction [256].

●We do not routinely prescribe docusate sodium for constipation. A randomized trial of sennosides with docusate sodium or placebo found no improvement in constipation in hospice patients [275].

A summary of dose, onset of action, and side effects for a variety of agents for chronic constipation is provided in the table (table 11). (See "Management of chronic constipation in adults".)

Management of opioid-induced constipation is addressed in detail elsewhere. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Opioid bowel dysfunction'.)

INTESTINAL PERFORATION — Bowel perforation is an uncommonly encountered complication that seems to be associated with antiangiogenic agents, particularly bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor (VEGF).

This complication is not unique to agents that target angiogenesis. Bowel perforation has also been seen (albeit rarely) with other tumors involving the gastrointestinal (GI) tract that respond rapidly to conventional cytotoxic chemotherapy (eg, GI tract lymphomas). (See "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)".)

Angiogenesis inhibitors — All VEGF-targeted therapies, including bevacizumab, ramucirumab, aflibercept, and the orally active antiangiogenic tyrosine kinase inhibitors (TKIs), can cause GI perforation (GIP), although this complication is best described in patients receiving bevacizumab [18,276-278]. GIP has been reported in patients treated with bevacizumab for a variety of malignancies but is most often described in the setting of metastatic colorectal cancer and epithelial ovarian cancer. GIP can occur anywhere along the GI tract, often away from tumor sites or prior surgical anastomoses. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Intestinal perforation/fistula formation'.)

Although several risk factors have been described for GIP during bevacizumab treatment, bowel perforation may occur even in the absence of predisposing risk factors, and it remains difficult to predict which patients will develop this complication. Many cases involve perforation of an in situ bowel primary. However, GIP can also occur at previously resected primary sites, often in the setting of previous irradiation or a prior anastomotic leak. GIP can also occur during bevacizumab treatment of malignancies that lack disease within the peritoneal cavity (eg, primary malignant brain tumors) [279]. In a community-based observational study of patients with metastatic colorectal cancer treated with bevacizumab, 1.9 percent experienced GIP [280]. Most GIP occurred ≤6 months after starting bevacizumab (median, 3.35 months). There was no cumulative risk of GIP with bevacizumab exposure. The US Food and Drug Administration (FDA) label for bevacizumab states that the majority of cases occurred within the first 50 days of initiation of bevacizumab.

In order to minimize the risk of GIP and fistula formation, at least 28 days (preferably six to eight weeks) should elapse between surgery and the last dose of bevacizumab, except in emergency situations. Clinicians should maintain a high index of suspicion for GIP in patients who develop acute abdominal pain while receiving bevacizumab, even if they have no apparent risk factors.

Perforation may be asymptomatic, or it can present with abdominal pain from peritoneal contamination, free air, hemoperitoneum, or an intra-abdominal abscess. Patients with confirmed or highly suspected GIP whose overall condition is unstable secondary to the GIP should be considered for immediate surgical repair or diversion. Those who are more stable can be considered for less invasive management strategies such as bowel rest and broad-spectrum antibiotics with or without percutaneous drainage of concurrent abscesses. The timing of the presentation, the patient's overall condition, their goals and wishes, and overall prognosis are important factors in the decision to explore these patients surgically. This subject is addressed in detail elsewhere. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Intestinal perforation/fistula formation'.)

Thalidomide in multiple myeloma — At least one case report describes four cases of bowel perforation in patients receiving thalidomide for multiple myeloma [281]. The true incidence is unknown.

EGFR inhibitors — Cases of GIP (some fatal) have also been reported in patients receiving the small-molecule epidermal growth factor receptor (EGFR) inhibitor erlotinib and gefitinib [282]. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'EGFR TKI toxicity'.)

Idelalisib — Fatal and serious intestinal perforation has occurred in patients treated with idelalisib, an oral inhibitor of phosphoinositide 3-kinase (PI3K) delta that is approved for treatment of relapsed chronic lymphocytic leukemia, follicular lymphoma, and small lymphocytic lymphoma. At the time of perforation, some patients have had moderate to severe diarrhea. Idelalisib should be discontinued permanently in patients who experience intestinal perforation. (See 'PI3K inhibitors' above.)

Trametinib — The MEK inhibitor trametinib has been associated with GIP. Across clinical trials of trametinib administered as a single agent or in combination with dabrafenib, the risk of GIP was less than 1 percent [283].

SUMMARY AND RECOMMENDATIONS

●Chemotherapy-related diarrhea

•Acute chemotherapy-related diarrhea (CRD) is most commonly described with fluoropyrimidines (particularly fluorouracil [FU] and capecitabine), irinotecan, pemetrexed, and cabazitaxel. (See 'Risk with conventional cytotoxic agents' above.)

•Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in fluoropyrimidine catabolism, and enzyme activity varies widely mostly due to genetic polymorphisms in the DPD gene (DPYD). (See 'Fluorouracil' above and 'Capecitabine' above.)

Testing is commercially available that might identify patients who are at risk for severe toxicity from fluoropyrimidines based upon DPYD and TYMS genotype. However, we do not routinely test DPYD and/or TYMS genotype for all patients initiating fluoropyrimidine therapy. We advocate testing for a panel of relevant DPD alleles (rather than just DPYD*2A) plus TYMS genotyping in patients who have had severe and unexpected toxicity from fluoropyrimidines (table 2). (See 'Testing for DPYD and TYMS variants' above.)

•Late diarrhea from irinotecan is unpredictable, noncumulative, and not dose-dependent. Strict adherence to management guidelines (including early institution of high-dose loperamide) and the use of infusional rather than bolus FU in combination with irinotecan has reduced the incidence. Preemptive testing for UGT1A1 genotypes that are associated with a poor metabolizer phenotype prior to initiating irinotecan is a controversial and evolving area, and experts differ. At our institution preemptive testing is recommended for all such individuals, and we reduce initial starting doses by approximately 30 percent if a high-risk genotype is identified. (See 'Irinotecan' above.)

•Acute chemotherapy-related diarrhea is also common with bortezomib and vorinostat. (See 'Bortezomib and other proteasome inhibitors' above and 'Vorinostat and belinostat' above.)

•The most common molecularly targeted agents associated with CRD are small-molecule tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), especially afatinib and neratinib; anaplastic lymphoma kinase (ALK) inhibitors such as ceritinib; the CDK4/6 inhibitor abemaciclib; combinations of MEK and BRAF inhibitors such as trametinib/dabrafenib and binimetinib/encorafenib; the Bruton tyrosine kinase (BTK) inhibitor ibrutinib; and the phosphoinositide 3-kinase (PI3K) inhibitors idelalisib, duvelisib, and alpelisib. (See 'Risk with molecularly targeted agents' above.)

●Constipation

•Constipation is rarely dose-limiting for chemotherapeutic agents, except for vincristine, lenalidomide, thalidomide, and pomalidomide. (See 'Vinca alkaloids' above.)

•Treatment should focus on anticipation and prevention. Laxatives should be started at the first sign of constipation or should be given routinely to prevent constipation. (See 'Constipation' above.)

●Bowel perforation

•Bowel perforation is an uncommonly encountered complication that seems to be associated with antiangiogenic agents, particularly bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF). (See 'Intestinal perforation' above.)

•Bowel perforation is rarely reported with EGFR inhibitors, MEK inhibitors, PI3K delta inhibitors, thalidomide, and immunotherapy.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Smitha S Krishnamurthi, MD, who contributed to earlier versions of this topic review.