Introduction
Targeted therapies are a category of drugs that inhibit cancer by interfering with specific molecules involved in the growth, progression, and spread of malignant cells. Targeted therapies act on specific molecular targets, whereas most standard chemotherapies act on many rapidly dividing normal and cancer cells. Many different targeted therapies have been approved by the US Food and Drug Administration (FDA) to treat specific types of cancer. Targeted therapies are generally less toxic than standard chemotherapy drugs because just as they are sometimes more efficacious because they are designed to act on specific molecular targets, they have less effects on other cells. Some therapies, however, do have substantial side effects. The most common gastrointestinal side effects seen with targeted therapies are discussed in this chapter and include diarrhea, nausea, vomiting, hepatotoxicity, and gastrointestinal perforation.
Diarrhea
Targeted therapy-induced diarrhea: Targeted therapy-induced diarrhea is a challenge in daily clinical practice. The frequency, severity, and causes of symptoms differ based on the agent used and is common in patients receiving tyrosine kinase inhibitors (TKIs). Targeted therapies that are commonly associated with diarrhea include—endothelial growth factor receptor (EGFR)–targeted TKIs (e.g., erlotinib, gefitinib, afatinib, osimertinib), EGFR-targeted monoclonal antibodies (mAbs) (e.g., cetuximab, panitumumab), c-Kit TKIs (e.g., imatinib, sunitinib, regorafenib), multi-TKIs (e.g., sorafenib, sunitinib, axitinib), and mitogen-activated protein kinase (MEK) inhibitors (e.g., trametinib, selumetinib). The most commonly used method for assessing the severity of diarrhea is National Cancer Institute Common Toxicity Criteria (NCI CTC) ( Table 13.1 ).
| Grade | Severity of Diarrhea |
|---|---|
| 1 | Increase of <4 stools per day over baseline; mild increase in ostomy output compared with baseline |
| 2 | Increase of 4–6 stools per day over baseline; IV fluids indicated <24 h; moderate increase in ostomy output compared with baseline |
| 3 | Increase of ≥7 stools per day over baseline; incontinence; IV fluids >24 h; hospitalization indicated; severe increase in ostomy output compared with baseline; limiting self-care ADL |
| 4 | Life-threatening consequences; urgent intervention indicated |
| 5 | Death |
EGFR–Targeting Agents
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Diarrhea and the EGFR pathway: EGFR-TKIs increase chloride secretion and induce secretory diarrhea. This is thought to be mediated by inhibition of wild-type EGFR in the gut. The incidence and severity of diarrhea are higher with EGFR-TKIs than with EGFR-mAbs. The occurrence of diarrhea is up to 60% for all grades, with grade 3 diarrhea developing in 6% to 9% of cases with EGFR-TKIs. EGFR-mAbs cause grade 2 diarrhea in 21% of cases and grade 3 diarrhea in about 1% to 2% of cases.
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Mechanism of action: The EGFR, also known as Erb1 or HER1, works via activation of intercellular signaling pathways, particularly RAS/MAPK (mitogen-activating protein kinase) and PI3K (phosphoinositide-3 kinase)/AKT pathways, , and results in the upregulation of mitogenic, anti-apoptotic, angiogenic, and pro-invasive cellular mechanisms. EGFR is overexpressed in many cancers such as breast, colorectal, head and neck, non–small-cell lung, ovarian, and pancreatic cancers, making it a useful target for cancer-directed therapy.
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Anti-EGFR TKIs: Anti-EGFR TKIs compete with adenosine triphosphate (ATP) and inhibit EGFR tyrosine kinase activity. FDA-approved TKIs include gefitinib, erlotinib, afatinib, and osimertinib. Gefitinib and erlotinib are reversible TKIs used for metastatic non–small-cell lung cancer (NSCLC) with EGFR exon 19 deletions or the exon 21-substitution mutation L858R. Erlotinib is also used in pancreatic cancer. Afatinib is an irreversible HER2, EGFR, and HER4 directed TKI used in metastatic NSCLC. Osimertinib is an irreversible TKI approved for metastatic NSCLC with T790M mutation on progression on or after EGFR TKI therapy ; it is also approved as first line treatment of NSCLC with sensitizing EGFR mutations. Gefitinib causes diarrhea in 39% to 49.7% of cases, erlotinib in 48%, and afatinib in 22%.
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Anti-EGFR mAbs: Cetuximab and panitumumab are FDA-approved anti-EGFR mAbs. The FDA first approved cetuximab in 2004 for the treatment of advanced colorectal cancer. More recently, cetuximab has also been approved in combination with radiation for head and neck squamous cell carcinoma. , Panitumumab was approved for the treatment of metastatic colorectal cancer in 2006. Cetuximab is a mouse–human chimeric monoclonal immunoglobulin G1 (IgG1) that binds to the extracellular ligand-binding domain of EGFR and prevents tyrosine kinase activation and downstream EGFR signaling, promoting EGFR internalization and antibody-dependent cell-mediated cytotoxicity (ADCC). Diarrhea occurs more often with cetuximab or panitumumab given in combination with chemotherapy than with monotherapy. , The overall incidence of diarrhea is about 80% in patients treated with cetuximab and chemotherapy and 70% in patients treated with panitumumab and chemotherapy.
c-KIT–Targeting Agents
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Diarrhea and the c-KIT pathway: Diarrhea is one of the most common adverse effects observed during treatment with imatinib. Approximately 20% to 26% of patients experience diarrhea during therapy. Sunitinib and regorafenib cause diarrhea in 44%, and 34% to 40% of patients, respectively. The high expression of KIT in the intestinal cells of Cajal might be a potential mechanism for diarrhea by imatinib or sunitinib.
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Mechanism of action: Stem cell growth factor receptor, c-KIT, or CD117, regulates cell proliferation and differentiation. Stem cell factor dimers interact with KIT, inducing receptor dimerization, leading to auto-inhibition and transphosphorylation of intercellular proteins and activation of intercellular signaling pathways. Normally this pathway plays an important role in mast cell survival and function, pigmentation, gametogenesis, differentiation of hematopoietic stem cells, and development of gastric pacemaker cells. c-KIT deregulation in cancer occurs mainly through c-KIT overexpression and genetic mutation. c-KIT mutations occur in gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), germ cell tumors, , melanoma, mastocytosis, and sinonasal NK/T cell lymphoma.
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c-KIT TKIs: FDA-approved agents are imatinib, sunitinib, and regorafenib. Imatinib inhibits BCR-ABL kinase in CML, and also inhibits other receptor tyrosine kinases including c-KIT and PDGF, and is currently approved for c-KIT–positive GIST tumors. , Sunitinib is a second-generation multi-TKI used for GIST upon disease progression. Regorafenib is also a multikinase inhibitor approved for patients with GIST refractory to both imatinib and sunitinib.
VEGF–Targeting Agents
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Diarrhea and the vascular endothelial growth factor (VEGF) pathway: VEGF–targeting TKIs that cause diarrhea include sorafenib, sunitinib (44%), pazopanib (52%, grade 3 diarrhea), axitinib (11%), vandetanib (52% any grade diarrhea, 5.6% high-grade diarrhea), regorafenib (34%–40%), lenvatinib, and cabozatinib (64%).
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Mechanism of action: The VEGF family includes 5 glycoproteins: VEGFA, VEGFB, VEGFC, VEGFD, and placental growth factor (PGF), which interact with and activate receptors belonging to the tyrosine kinase family: VEGFR1, VEGFR2, and VEGFR3. Upon interaction with their ligands, VEGFRs activate downstream signaling pathways, leading to endothelial cell effects including proliferation, survival, migration, vasodilation, and increased permeability. VEGFRs are expressed on tumor cells and endothelial cells in NSCLC, gastric cancer, breast cancer, leukemia, prostate cancer, and hepatocellular carcinoma. VEGF signaling also has important effects that promote tumor angiogenesis and distant metastasis.
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VEGF–targeted therapy: Inhibitors of the VEGF pathway include TKIs, mAbs against VEGF or VEGFRs, and soluble VEGF receptors. FDA-approved TKIs are sorafenib, sunitinib, pazopanib, axitinib, vandetanib, regorafenib, lenvatinib, cabozantinib, and ponatinib. Sorafenib is approved for the treatment of advanced renal cell carcinoma and is in late stage clinical trials for hepatocellular carcinoma, metastatic melanoma, and NSCLC. Bevacizumab is an mAb against VEGF, and is approved for colorectal cancer, breast cancer, cervical cancer, ovarian cancer, renal cell carcinoma, glioblastoma, and NSCLC.
CDK4/6 Inhibitors
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Diarrhea and CDK4/6 inhibitors: Palbociclib and ribociclib often cause low-grade (grades 1 and 2) diarrhea, whereas abemaciclib commonly causes grade 3 diarrhea. Abemaciclib monotherapy for patients with hormone receptor (HR) positive, HER2 negative metastatic breast cancer typically causes diarrhea within 1 week of therapy initiation. Most cases of diarrhea resolve quickly, with a median duration of 7.5 days (grade 2) and 4.5 days (grade 3).
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Mechanism of action: The cyclin D-cyclin–dependent kinase 4/6-Rb (CDK4/6) pathway controls the transition from the G1 (first growth phase) to the S phase (DNA replication phase). Mitogenic growth factor signaling activates the RAS/MAPK and PI3K pathways, leading to the upregulation of D-type cyclins (D1, D2 and D3) by increased transcription and decreased proteasomal degradation. D cyclin binds to CDK4 and CDK6 to form a complex required for DNA replication. Cyclin D1 overexpression occurs in breast cancer, head and neck squamous cell carcinoma (HNSCC), NSCLC, colorectal cancer, endometrial cancer, pancreatic cancer, melanoma, and neuroblastoma. ,
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CDK4/6 targeted–therapy : CDK4 and CDK6 have been targeted in HR positive, HER2 negative breast cancer. FDA-approved CDK4/6 inhibitors are palbociclib, ribociclib, and abemaciclib.
Mitogen-Activated Protein Kinase Inhibitors
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Diarrhea and mitogen-activated protein kinase (MEK) inhibitors : Trametinib and selumetinib are selective inhibitors of MEK1 and MEK2. Approximately 45% to 50% of patients treated with these drugs experience diarrhea of any grade.
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Mechanism of action: MEK is a family of protein kinases consisting of seven genes: MEK1–2 and MKK3–7. The MAPK signaling pathway includes the enzymes RAS, RAF, MEK, and extracellular signal-regulated kinase (ERK) and is an important pathway in cellular proliferation. MEK1 and MEK2 have the ability to phosphorylate both tyrosine and serine/threonine residues, and their substrates ERK1 and ERK2, phosphorylate nuclear and cytosolic targets leading to cellular responses.
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MEK inhibitors: Trametinib is a selective MEK1 and MEK2 inhibitor, approved as a single agent treatment of patients with advanced melanoma with serine/threonine kinase (BRAF) V600E or V600K mutations.
Management of Diarrhea
There are no specific guidelines available on the management of different grades of targeted therapy-induced diarrhea. Patients must be rehydrated orally or by parenteral infusion based on severity, to prevent diarrhea-related complication such as dehydration, electrolyte imbalances, and hypovolemic shock in extreme scenarios ( Table 13.2 ).
| Grade | Management |
|---|---|
| 1 | •Continue kinase inhibitors; prescribe loperamide or codeine |
| •Rule out infective cause | |
| •Dietary modification | |
| 2 | •Withhold kinase inhibitors until symptoms have resolved to grade 1 or baseline; restart at a lower dose |
| •Continue loperamide or codeine | |
| •Rule out infectious causes | |
| •Dietary modification | |
| 3 | •Stop kinase inhibitors; scheduled use of loperamide or codeine |
| •Hospitalization for intravenous rehydration and electrolyte replacement | |
| •Rule out infectious causes | |
| •Give antibiotics including a fluroquinolone if diarrhea persists for over 24 h, patient develops fever, or has grade 3/4 neutropenia | |
| •Hold kinase inhibitors until < grade 1 then restart with a lower dose | |
| 4 | •Permanent discontinuation of kinase inhibitors |
| •Hospitalization for intravenous hydration and electrolyte replacement | |
| •Consider colonoscopy to assess for colitis and to exclude infectious causes | |
| •Cover with antibiotics if no improvement in 24 h, patient develops fever, or has grade 3/4 neutropenia |
Pharmacological Management of Diarrhea
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Opioids : Loperamide is the opioid of choice for the management of diarrhea because it has local activity in the gut. It reduces stool weight, frequency of bowel movements, urgency, and fecal incontinence. Other opioids that are also used include tincture of opium, morphine, and codeine. Loperamide can be started at an initial dose of 4 mg followed by 2 mg every 2 to 4 hours (with a maximum daily dosage of 16 mg). If diarrhea persists over 48 hours, other agents such as diphenoxylate/atropine, octreotide, or tincture of opium should be introduced. Diphenoxylate/atropine, 2.5 mg/0.025 mg tablet, should be started at one to two tablets as needed and the maximum daily dose should not exceed 20 mg/0.2 mg. The recommended dose of tincture of opium is 10 to 15 drops every 3 to 4 hours.
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Octreotide : Octreotide is a somatostatin analog that decreases the secretion of a number of hormones. It suppresses the release of insulin, glucagon, vasoactive intestinal peptide (VIP), and gastric acid. Octreotide also prolongs intestinal transit time, reducing secretion and increasing absorption of fluid and electrolytes. It can be started at an initial dose of 100 to 150 µg every 8 hours intravenously or subcutaneously; the dose can be titrated up to 500 µg every 8 hours.
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Steroids: Treatment with corticosteroids alone or in combination with loperamide is controversial and thus is not currently recommended.
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Over the counter: Over the counter bismuth-containing medications can provide diarrhea and cramping relief.
Nonpharmacological Management of Diarrhea
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Avoidance of dairy
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Encouragement of low-fiber diet
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Encouragement of foods high in potassium
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Avoidance of spicy foods, high-fat foods, and high-fiber foods
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Avoidance of caffeine and alcohol
Targeted Therapy-Related Nausea and Vomiting
Nausea and vomiting are common adverse effects of targeted therapy. Incidence rates depend on the type of drug used, dose of the drug, and route of administration of the drug (intravenous drugs cause nausea and vomiting more rapidly than drugs given orally). Some other risk factors include female gender, age younger than 50 years, and history of anxiety or motion sickness. Targeted therapies that are well known to cause nausea and vomiting are anaplastic lymphoma kinase (ALK) inhibitors (e.g., crizotinib, alectinib), mesenchymal epithelial transition factor (c-MET) kinase inhibitors (e.g., cabozantinib), CDK4/6 inhibitors (e.g., palbociclib, ribociclib, abemaciclib), and poly ADP-ribose polymerase (PARP) inhibitors (e.g., olaparib).
ALK Targeted–Therapy and Nausea and Vomiting
Grade 1 and 2 nausea or vomiting are commonly seen with crizotinib (39%–56%) and alectinib use. Taking crizotinib with food is a helpful strategy for alleviating nausea. Nausea and vomiting can be prevented using antiemetics such as ondansetron, metoclopramide, or dimenhydrinate. Ondansetron should be avoided in patients with risk of QT prolongation.
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Mechanism of action: ALK is a receptor tyrosine kinase that belongs to the insulin receptor superfamily. The ALK protein, also known as CD246, was first identified in anaplastic large cell lymphoma as a constitutively active fusion gene product. ALK is normally expressed in brain, small intestine, colon, prostate, and testicular cells. The ALK protein is encoded by the ALK gene located on chromosome 2 (2p23 segment). Chromosomal rearrangement resulting in an oncogenic fusion gene is the most common alteration of ALK in human cancer. Multiple fusion partners for ALK have been identified such as nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), an oncogenic protein found in ALK-positive anaplastic large cell lymphoma (ALCL). TPM3-ALK and TPM4-ALK translocations have been found in renal cell cancer , and esophageal cancer, respectively. EML4-ALK translocations have been found in NSCLC, breast, and colorectal cancers. Patients with ALK rearrangements tend to be younger at diagnosis (median age 50 years) and are typically nonsmokers. Amplification of the ALK gene has been observed in neuroblastoma, NSCLC, and inflammatory breast cancer. ALK gene mutations have been observed in familial neuroblastoma, anaplastic thyroid cancer, and NSCLC.
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ALK–targeted therapy: The first clinically approved ALK inhibitor was crizotinib, approved by the FDA for use in ALK-positive NSCLC. Crizotinib is an oral TKI that was initially developed as a c-MET inhibitor but was later found to inhibit ALK. It also inhibits Hepatocyte Growth Factor Receptor (HGFR), ROS1 (c-ros), and Recepteur d’Origine Nantais (RON). The therapeutic efficacy of crizotinib is limited by secondary resistance, so more potent second-generation ALK inhibitors were developed. Other FDA-approved ALK inhibitors are ceritinib, , alectinib, , and brigatinib.
c-MET Targeted–Therapy and Gastrointestinal Side Effects
The most common gastrointestinal side effects of cabozantinib are nausea and vomiting. Cabozantinib is a substrate of CYP3A4. Clinicians should be aware that drugs that inhibit this enzyme may potentially increase the adverse effects of cabozantinib. Grapefruit should be avoided because it may increase the concentration of drug in the blood.
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c-MET: c-MET is also known as hepatocyte growth factor receptor (HGFR). c-MET is a receptor tyrosine kinase encoded by c-MET proto-oncogene. It has a high affinity for hepatocyte growth factor (also known as scatter factor). The precursor protein undergoes proteolytic cleavage to yield a heterodimer, ligand binding then induces receptor dimerization and subsequent activation of intercellular signaling pathways such as RAS/MAPK, PI3k/AKT, SRC, and JAK/STAT pathways. This activation leads to cellular responses, including cellular proliferation, migration, invasion, angiogenesis, protection from apoptosis, and metastasis. , The c-MET receptor tyrosine kinase can be activated via gene mutation, amplification, protein overexpression, and/or ligand-dependent autocrine/paracrine activation. Overexpression of c-MET has been found in head and neck, lung, gastric, colorectal, breast, and brain cancers. Gene mutations have been observed in NSCLC, gastric, hepatocellular, and papillary renal carcinomas. Coexpression of c-MET and HGF has been reported in breast cancer and glioma. There is an interaction between c-MET and EGFR pathways, where EGFR signaling leads to ligand-dependent c-MET activation.
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c-MET – targeted therapy : Several strategies have been developed to inhibit the c-MET signaling pathway; these include selective c-MET kinase inhibitor such as tivantinib, nonselective c-MET kinase inhibitors such as cabozantinib, anti-c-MET monoclonal antibody, and anti-HGF monoclonal antibodies. Cabozantinib is a multikinase inhibitor used in advanced renal cell carcinoma and medullary thyroid cancer.
Pharmacological Management
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Serotonin (5-HT3) antagonists block the effects of serotonin in the central nervous system (CNS). Serotonin is important in triggering nausea and vomiting in the brain. Examples: ondansetron, granisetron, dolasetron, palonosetron.
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NK-1 antagonists are usually used in combination with other antiemetics to delay nausea and vomiting. Examples: aprepitant (oral formulation), rolapitant (IV formulation).
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Dopamine antagonists prevent dopamine from binding to the areas in the brain that trigger nausea and vomiting. Examples: prochlorperazine, metoclopramide.
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Antianxiety drugs also reduce nausea and vomiting. Examples: lorazepam, alprazolam, olanzapine.
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Steroids have potent antinausea effects. Examples: dexamethasone, methylprednisone.
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Cannabinoids, although not universally accepted, have shown promise in the treatment of nausea and vomiting.
Nonpharmacological Treatment
There are several nonpharmacological treatment options that may be used alone for mild nausea or can be used in conjunction with antiemetics. Studies are limited and include:
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Frequent, small meals
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Clear liquid diet
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Hard candy
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Bland foods
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Avoidance of fatty, fried, or spicy foods
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Encouragement to sit upright for at least 1 hour after each meal
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Cognitive behavioral therapy including biofeedback techniques, guided imagery, and self-hypnosis
Hepatotoxicity
Targeted therapy and hepatotoxicity : Liver damage is a clinically significant adverse effect of targeted therapy. Liver damage can occur in the form of necrosis of hepatocytes, cholestatic liver damage, and in severe cases, cirrhosis. The types of targeted therapies that have been known to cause hepatotoxicity include TKIs such as c-KIT TKIs (sunitinib, regorafenib), multi-TKIs (pazopanib), MEK inhibitors (trametinib), anti-HER-2 therapy (lapatinib), and anti-EGFR targeting agents (gefitinib, erlotinib). TKIs are also associated with increased risk of drug-induced liver injury (DILI).
Assessment of Liver Toxicity
Table 13.3 delineates the grading system most commonly used when assessing for liver toxicity caused by cancer-directed therapies.
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Sunitinib: Sunitinib is orally available multikinase inhibitor. Its targets include VEGFR-1, VEGFR-2, platelet-derived growth factor receptors (PDGFRs) alpha and beta, c-KIT, and FMS–like tyrosine kinase-3 ligand (FLT3L). Sunitinib is also metabolized by CYP3A4. As a result, sunitinib can cause hepatotoxicity.
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Regorafenib: Regorafenib is a diphenylurea-based multikinase inhibitor of VEGFR1, VEGFR2, VEGFR2, TIE2, KIT, RET, RAF1, BRAF, PDGFR, and fibroblast growth factor receptor (FGFR). Similar to sunitinib, regorafenib is metabolized by CYP3A4 and is associated with hepatotoxicity.
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Pazopanib : Pazopanib is an angiogenesis inhibitor. It works by targeting PDGFR, VEGFR, and c-KIT. Pazopanib has been associated with increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at least three times higher than the upper limit of normal in 18% of cases. Furthermore, grade 4 toxicity has been reported in up to 25% of patients. An increase in the serum bilirubin level is seen in 36% of patients who are treated with pazotinib.
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Lapatinib : Lapatinib is a TKI that inhibits ERBB1 (Her1/EGFR) and ERRB2 (Her2/EGFR2). It is associated with ALT and AST increases at least three times higher than the upper limit of normal and bilirubin increases of more than twice the upper limit of normal. It is also metabolized by CYP3A4 and is associated with hepatotoxicity.
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Trametinib : Trametinib is a selective MEK1 and MEK2 inhibitor. When used in combination with dabrafenib, it is associated with elevated alkaline phosphatase levels in 60% of patients.
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