Management of regorafenib-related toxicities: a review

Abstract

Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany) is an oral multikinase inhibitor that targets the angiogenic tumor microenvironment and oncogenic kinases including vascular endothelial growth factor receptor 2 (VEGFR2), VEGFR1, VEGFR3, fibroblast growth factor receptor 1 (FGFR1), RAF, KIT, RET and BRAF. Its antiangiogenic effect is greater than that of its related drug, sorafenib. Regorafenib has been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer (mCRC) in patients who have failed treatment with fluoropyrimidine, oxaliplatin and irinotecan based chemotherapy, an anti-VEGF therapy and, if KRAS wild type, an anti-EGFR therapy. The FDA based this approval on data from the CORRECT trial, which showed the efficacy of regorafenib compared with placebo. The most common grade 3–4 adverse reactions with the drug are hand foot skin reactions (HFSR), diarrhea, hypertension and fatigue. This review discusses the efficacy data, and the incidence and management of regorafenib’s toxicities.

Introduction

Angiogenesis is vital to tumor cell proliferation by facilitating the development of distant metastasis [Ellis, 2004] and an increased risk of recurrence [Maeda et al. 1995]. In colon cancer, the rate of angiogenesis in node negative, resected tumors is associated with a lower rate of 5-year survival rate and early relapse [Frank et al. 1995].

Vascular endothelial growth factor (VEGF) is a protein that binds and activates the type 1 and 2 vascular endothelial growth factor receptors (VEGFR1, VEGFR2) on the vascular endothelium [Maeda et al. 1995]. The VEGF family consists of five glycoproteins: VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-E. Ligand binding stimulates downstream signaling leading to the inhibition of apoptosis as well as stimulation of mitosis and cytoskleletal changes associated with motility [Frank et al. 1995]. The family of VEGF proteins binds to several different VEGFRs. VEGFR1, VEGFR2, and VEGFR3 have similar structural features. VEGFR1 interacts with placental growth factor (PlGF), VEGF-B and VEGF-A. VEGF has a higher affinity for VEGFR1, but VEGFR1 has weaker tyrosine kinase activity. VEGFR2 interacts with the processed forms of VEGF-C and VEGF-D in addition to VEGF. This receptor is the primary mediator of the mitogenic and angiogenic effects of VEGF. VEGFR3 only interacts with VEGF-C and D and is important in lymphangiogenesis. [Maeda et al. 1995; Wilhem et al. 2011, 2006].

Hypoxia is thought to play a major role in the overall process of angiogenesis and has been shown to stimulate VEGF. VEGF is overexpressed in gastrointestinal tumors and has been associated with increased tumor vascularity, proliferation, progression, invasion and metastatic disease [Waddell and Cunningham, 2013; Wehler et al. 2013]. Additionally, VEGF levels are elevated in patients with metastatic colorectal cancer (mCRC), suggesting that VEGF induced vascular permeability may contribute to malignant ascites [Zopf et al. 2010]. It has been shown that VEGF antagonists increase the intratumoral delivery of cytotoxic chemotherapeutic agents thereby improving their antitumor efficacy without increasing toxicity [Cyran et al. 2013].

Bevacizumab, an immunoglobulin G₁ (IgG₁) antibody that binds to VEGF, interferes with VEGF binding to VEGFR1 and VEGFR2. Hurwitz and colleagues demonstrated a benefit of adding bevacizumab to standard chemotherapy in a phase III trial of mCRC [Hurwitz et al. 2004]. Ziv-Aflibercept (Ziv) is a fusion protein consisting of human VEGF receptor extracellular domains fused to the F_c portion of human IgG₁. Ziv complexes with VEGF and prevents it from interacting with its receptors on endothelial cells. This VEGF trap is thought to effective because of its high affinity to VEGF and binding to proangiogenic factors such as VEGF-B and placental growth factor 1 (PIGF1) and PIG2. A phase III, randomized study evaluated Ziv in combination with fluorouracil, leucovorin and irnotecan (FOLFIRI) in mCRC [Tabernero et al. 2014]. A total of 612 patients were randomized to Ziv or placebo in combination with FOLFIRI with the primary endpoint of overall survival (OS). The addition of Ziv to FOLFIRI significantly improved OS and progression-free survival (PFS) compared with placebo. The main side effects were anti-VEGF related effects.

Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany) has a structure similar to sorafenib (Nexavar, Bayer) differing only in the fluorine on the phenyl ring. This difference results in a greater inhibitory effect on angiogenesis related receptors, including VEGFR2 and fibroblast growth factor receptor 1 (FGFR1) [Wilhem et al. 2011, 2006] (Figure 1). Regorafenib also inhibits VEGFR1, VEGFR3, RAF, TIE2 (epidermal growth factor homology domain 2), KIT, RET and BRAF [Waddell et al. 2013]. Therefore, regorafenib targets a wide range of angiogenic factors, the tumor microenvironment and oncogenic kinases [Bayer Healthcare Pharmaceutical, 2012].

Figure 1.

Mode of action of Regorafenib.

FGFR1, fibroblast growth factor receptor 1; VEGFR1, vascular endothelial growth factor receptor 1.

Clinical efficacy of regorafenib in colon cancer

Preclinical

While sorafenib did not show a benefit in mCRC in preclinical models [Wehler et al. 2013], regorafenib has shown positive results in mCRC. Using colorectal tumor (CRC) xenografts, preclinical studies have shown a dose dependent decrease in tumor vascularity and tumor growth [Zopf et al. 2010]. In another preclinical study, xenografts injected into rats had decreased imaging markers of vascularity that correlated with immunohistological markers of tumor vascularity [Cyran et al. 2013]. An aggressive murine CT26 metastatic colon cancer model was used to show that regorafenib reduced tumor vascularity. This was done by using an imaging biomarker and the data were confirmed on immunohistochemical analysis [Abou-Elkam et al. 2013]. In this study, liver metastases were also prevented.

Phase I

Several phase I studies have been performed with regorafenib. Mross and colleagues enrolled 53 subjects (16 with colorectal cancer) in an open label, nonrandomized, dose escalating phase I study using oral doses of 10–220 mg daily [Mross et al. 2012]. The dose limiting toxicities were found to be hand foot skin reaction, rash, abdominal pain and asthma seen at the dose of 220 mg dose level.

Another phase I dose escalation trial enrolled 38 subjects with advanced solid tumors (colorectal 16%) and used doses of 20–140 mg [Shimizu et al. 2010]. The maximum tolerated dose (MTD) in this study was 100 mg orally daily every 21 days, continuously.

Strumberg and colleagues also studied 38 subjects with refractory mCRC in a phase I dose escalation study. Patients enrolled on the dose escalation portion trial received doses of 60–220 mg per day of regorafenib. Based on the positive results of the dose escalation portion of this trial, additional mCRC patients were enrolled in an extension of the trial. These patients received 160 mg orally daily for 21 out of 28 days [Strumberg et al. 2012]. The most common toxicities seen were hand foot skin reactions (HFSR), fatigue, voice change and rash. A total of 27 patients were evaluable for response; of these 74% showed some disease control with regorafenib treatment.

Awada and colleagues investigated a different schedule of administration of regorafenib in their phase I trial [Awada et al. 2005]. Patients received treatment in a 28 day cycle with 21 days of regorafenib treatment followed by 7 days off. Patients received oral doses of 10–120 mg daily. Pharmacokinetic (PK) and pharmacodynamic (PD) parameters as well as tumor response was evaluated in 44 patients with solid tumors (CRC 34%). PK parameters showed a linear association with dose and PD parameters correlated with dose exposure. Partial response (PR) and stable disease (SD) were achieved in two and four patients, respectively. The dose limiting toxicity was reported in patients receiving the 120 mg dose. Adverse events included gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%) and hepatic (61%).

To evaluate the benefit of adding regorafenib to the standard line chemotherapy, Schultheis and colleagues conducted a phase IB study evaluating the PK parameters and safety of sequentially administered regorafenib in combination with mFOLFOX6 (5-FU, leucovorin and oxaliplatin) or FOLFIRI every 2 weeks as first- or second-line treatment for CRC [Schultheis et al. 2013]. Regorafenib 160 mg was given once daily on days 4–10 and 18–24 of every 4 week cycle. Regorafenib increased exposure of SN-38, the active metabolite of irinotecan, by 32%. Regorafenib had similar toxicity profile of the chemotherapy combination. Despite the increase in irinotecan metabolite exposure, there was no decrease in tolerability. It was found that 15 and 11 subjects had SD in the mFOLFOX6 and FOLFIRI arms, respectively.

Phase III

Based on the phase I data, regorafenib has been studied in multiple phase III clinical trials. In the international, phase III CORRECT trial [Grothy et al. 2013], 753 patients with mCRC, who were refractory to all locally approved therapies for mCRC, were enrolled. Patients were randomized in a 2:1 ratio to regorafenib or placebo. A total of 500 patients received oral regorafenib 160 mg daily for 3 weeks on and 1 week off, while a total of 253 patients received placebo on the same time schedule. The PFS of patients on the regorafenib arm was 1.9 months versus 1.7 months in the placebo arm. The median OS was 6.4 months versus 5 months in the regorafenib and placebo arms, respectively. Both of these differences were statistically significant. The most common grade 3 or higher toxicity were HFSR (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), hypertension (7%) and rash/skin desquamation (6%).

The GRID trial, a double blind, placebo-controlled study, enrolled 199 subjects with refractory gastrointestinal stomal tumors (GIST) [Demetri et al. 2013]. Patients received regorafenib 160 mg by mouth (PO) or placebo daily for 3 out of 4 weeks each cycle. The primary endpoint of the trial was PFS. The median PFS was 4.8 months for regorafenib versus 0.9 months for placebo. Adverse events were reported in 98% of the patients taking regorafenib versus 68% of patients taking placebo. The most common adverse reactions reported were HFSR (56%), hypertension (48.5%), diarrhea (40%) and fatigue (38.6%). Of these toxicities less than half were grade 3 or higher. Grade 3 toxicities were seen in 19.7% of HFSR adverse events, 22.7% of hypertension adverse events, 5.3% of diarrhea adverse events and 2.3% of fatigue adverse events. The only grade 4 toxicity was reported in patients with hypertension with only 0.8% of patients reporting this toxicity.

Bugano and colleagues reviewed the experience at their institution after the approval of regorafenib by the US Food and Drug Administration (FDA) [Gomes et al. 2014]. They found 61 patients who were treated with the drug, of whom 57 had mCRC. The initial starting dose of regorafenib was 160 mg in the majority of patients (66.7%). Dose reductions or interruption of therapy were required in 43.8% of patients, while 24% of patients discontinued therapy due to toxicity. The most common grade 3 toxicity seen was HFSR. The median time that patients remained on regorafenib was 2.2 months and the median OS was 9.1 months.

A phase IIIb study is currently underway to assess the efficacy of regorafenib in patients with mCRC who have progressed after standard chemotherapy. The CONSIGN [ClinicalTrials.gov identifier: NCT01538680] trial is a prospective, interventional, open-label, single-arm, multicenter study for patients in whom no alternate therapy exists. This trial will give patients access to regorafenib while FDA approval for the drug is sought. Patients will receive regorafenib 160 mg PO daily every 3 out of 4 weeks until progression of disease or unacceptable toxicity.

Regorafenib-related toxicities and their management

The development of oral agents for the treatment of malignancies has become increasingly common and represents a step forward in terms of convenience for patients. However, these agents are not without adverse reactions and toxicities. In early phase studies, regorafenib has been associated with a number of adverse reactions which should be manageable if identified promptly and treated correctly. The most common adverse effects seen with regorafenib, as defined by the US National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, are listed in Table 1 and include HFSR, rash, fatigue, diarrhea and hypertension. It is important that, once therapy is initiated, there continue to be frequent communication between the patients and the healthcare providers to reduce the risk of morbidity with this agent.

Table 1.

Selected grade 3/4^* adverse events (%) with the CORRECT and GRID studies.

Adverse event	CORRECT	CORRECT	GRID	GRID
	Grade 3 (%)	Grade 4 (%)	Grade 3 (%)	Grade 4 (%)
Any	51	17	58	2
Diarrhea	7	< 1	5	0
Fatigue	9	< 1	2	0
Hypertension	7	0	23	1
HFSR	17	0	20	0
Anemia	2	< 1
Thrombocytopenia	3	< 1

^*National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.

HFSR, hand foot skin reaction.

Dermatologic adverse reactions

Dermatologic reactions are very common with the multikinase inhibitors, and in particular regorafenib has been associated with these types of reaction. In general, the dermatologic adverse reactions are not fatal but can cause both physical and emotional discomfort. Prompt recognition and treatment may alleviate symptoms and increase quality of life (QoL). It is essential that the oncologist is familiar with the basic principles of management of skin diseases.

Some general concepts that should be communicated to patients starting treatment with regorafenib include patient education with regard to good skin care, the importance of proper hydration and lifestyle modifications. In general, all patients should be instructed to avoid the use of alcohol-based lotions, avoid activities that lead to drying of the skin (i.e. long hot baths), avoid skin irritants such as benzoyl peroxide, perfumes, etc. and limit sun exposure through the use of sunscreen and protective clothing.

One specific type of dermatologic adverse reaction that may develop in patients taking regorafenib is HFSR. Patients with HFSR present with a prodrome of dysesthesias in the palms and soles, which then progresses to a burning pain with well-demarcated erythema and callus-like thickening in the affected areas. Figure 2 shows the typical localized hyperkeratotic skin lesions with surrounding erythema. HFSR commonly presents in regions of the hands and feet where there is constant pressure or flexure, such as the palms, fingertips, finger creases and webs, soles of the feet, and toes. Blisters may develop in areas of pallor and eventually desquamation occurs [Nagore et al. 2000]. HFSR most typically occurs within the first 4 weeks after initiating therapy and therefore weekly monitoring during the first 2 cycles of regorafenib followed by assessment every 4 weeks is critical. Early detection and treatment can reduce the severity and time course of the reaction. With proper management symptoms should resolve completely.

Figure 2.

The typical localized hyperkeratotic skin lesions with surrounding erythema.

One important measure that can be taken to aid early recognition of HSFR includes performing a full skin exam prior to initiation of therapy so that any changes can be noted. Areas with callouses should be softened. Patients should be counseled to avoid skin trauma, pressure and friction. Other preventative measures such as the use of padded socks and shoes should be discussed. Patients should also be instructed to maintain skin moisture with the use of emollients. The avoidance of behaviors that may lead to dry skin such as the use of alcohol-containing lotions and the use of hot water should also be reinforced.

If patients do develop HFSR, the painful skin regions can be treated with oral or topical analgesics and skin cooling packs. Patients experiencing grade 2/3 HFSR can have their symptoms alleviated with the use of topical steroids such as Clobetasol 0.05% ointment twice daily or topical anesthetic/analgesic preparations such as lidocaine cream or topical salicylic acid (6%). Oral analgesics can be prescribed for more painful lesions not amenable to topical preparations.

For patients who experience grade 2 or greater HFSR, the dose of regorafenib should be modified as follows: after the occurrence of grade 2 HFSR of any duration, the dose should be reduced to 120 mg. The dose should be reduced to 80 mg if there is a re-occurrence of grade 2 HFSR while on the 120 mg dose or for any grade 3 or 4 HSFR. Treatment with regorafenib should be held for at least 7 days in patients with grade 2 HFSR that is recurrent, in patients with grade 3 or greater HFSR or in patients with recurrent grade 2 HFSR that does not improve within 7 days of dose reduction [Bayer Healthcare Pharmaceutical, 2012].

Rash or desquamation

In addition to the localized reactions seen in patients with HFSR, patients on regorafenib can also present with rash or desquamation in all areas of the body. Rash is a general term used to describe many skin eruptions; further classification is based on the morphological appearance of the reaction. The rash can occur anywhere on the body and typically presents with a maculopapular appearance, the macules being flat areas of the skin that may be discolored and the papules being raised, solid areas. Erythema, pruritus, photosensitivity, dry peeling skin and/or blistering have also been associated with this type of skin reaction. NCI CTCAE grading of rash is based on the percentage of body surface area involved: grade 1 is <10%; grade 2 is 10–30%; and grade 3 is >30%. Rash of any grade was reported in 26% of patients in the CORRECT trial; grade 3 or greater was reported in 6% of patients. In the GRID trial 18% of patients reported rash of any grade, with only 2% reporting grade 3 or greater rash. In the CORRECT and GRID studies [Grothey et al. 2013; Demetri et al. 2013], this toxicity developed most often during the first cycle of therapy. Although not fatal, timely identification and treatment lead to improved QoL for patients. Specific treatments will vary based on the degree and intensity of the affected area. For grade 1 rashes, no changes in the dosing of the regorafenib is suggested; topical moisturizing creams, cold compresses, mid potency corticosteroid creams (2.5% hydrocortisone) and topical antibiotics may be used to alleviate symptoms. For grade 2 or higher rash, along with the previously listed treatments, oral antihistamines and/or oral antibiotics may be added [Belum et al. 2013].

Hypertension

Regorafenib has been associated with the development of hypertension mainly due to its effects as a VEGF inhibitor. Although the exact mechanism for the development of hypertension has not been well defined, multiple mechanisms have been proposed: impaired angiogenesis leading to a decrease in the density of microvessels; endothelial dysfunction with associated decrease in nitrous oxide leading to increased oxidative stress; or changes in neurohormonal factors and/or in the renin-angiotensin–aldosterone system [Wang et al. 2014]. Regardless of the underlying mechanism of regorafenib-induced hypertension, its development can lead to delays/interruptions of treatment.

CTCAE version 4.03 defines the five grades of hypertension as described elsewhere [Demetri et al. 2013; Grothey et al. 2013]. A meta-analysis of regorafenib treatment in solid tumors showed an overall incidence of hypertension to be 44% [95% confidence interval (CI) 30.8–59.0%] and of high-grade hypertension to be 13% (95% CI: 5.2–27.0%). The changes to the cardiovascular system that regorafenib induces are thought to be reversible; hypertension typically resolves after cessation of the drug [Ewer and Ewer, 2011]. There are no evidence-based guidelines for the treatment of regorafenib-induced hypertension; no single antihypertensive agent is preferred compared with the others. For grade 2 hypertension, single agents such as angiotensin converting enzyme (ACE) inhibitors can be started. With grade 3 hypertension, an additional agent such as a beta-blocker may be added. If a two-drug regimen is inadequate, calcium channel blockers may be added as a third agent. The one class of antihypertensives that should be avoided are diuretics; these agents may contribute to dehydration if the patient also experiences regorafenib-induced diarrhea. If refractory grade 3 hypertension occurs, regorafenib dose reductions, at 40 mg dose intervals, should be instituted. If grade 4 hypertension occurs, regorafenib therapy should be held until blood pressure returns to grade 2 or less. If regorafenib dosing is resumed, the dose should be 40 mg below original dose. Table 2 provides details of dose adjustments for regorafenib based on the degree of hypertension as outlined in the regorafenib trials.

Table 2.

General guidelines for dosing and schedule modification due to adverse events per NCI CTCAE v4.03.

Event	Action to be taken
Hypertension
Grade 3	If not controlled with medication, discontinue regorafenib.
Grade 4	Discontinue regorafenib.
Proteinuria
>2 g protein / 24 hours	Hold regorafenib until proteinuria improves to ⩽2 g of protein / 24 hours. Discontinue regorafenib in a patient with >2 g proteinuria / 24 hours that does not resolve in 3 months’ time after holding regorafenib. Work up for proteinuria such as renal biopsy should be considered.
Grade 4 proteinuria (nephrotic syndrome)	Discontinue regorafenib treatment.
Gastrointestinal perforation
Gastrointestinal perforation or dehiscence	Discontinue regorafenib
Thromboembolic events
Grade 3 venous thromboembolic event or Incidentally discovered pulmonary embolus first occurrence	• Hold regorafenib treatment. • If the planned duration of therapeutic-dose anticoagulant therapy is ⩽2 weeks, regorafenib should be held until the period of therapeutic dose anticoagulant therapy is over. • If the planned duration of therapeutic dose anticoagulant therapy is >2 weeks, regorafenib should be held for 2 weeks and then may be resumed during the period of therapeutic dose anticoagulant therapy as soon as all of the following criteria are met:  ▪ The patient must be on a stable dose of anticoagulant and, if on warfarin, have an International Normalized Ratio (INR) within the target range (usually between 2 and 3) prior to restarting study drug treatment.  ▪ The patient has no history of grade 3 or 4 hemorrhagic events before starting regorafenib.  ▪ The patient has no evidence of tumor invading or abutting major blood vessels on any prior computerized tomography scan.
Any grade arterial thromboembolic event or symptomatic grade 4 venous thromboembolic event first occurrence	Discontinue regorafenib.
Hemorrhage
Grade 1 and 2 Grade 3 or 4 (first occurrence)	No dose modification. Discontinue study treatment.

NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.

The most important preventative step is to identify and treat hypertension before initiation of regorafenib therapy. Upon initiation of treatment with regorafenib, weekly blood pressure monitoring by a healthcare provider is needed. Weekly monitoring should continue for the first two cycles of therapy. Thereafter patients should be encouraged to measure their blood pressure at home on a daily basis.

Stomatitis

Stomatitis is a frequent complication of chemotherapy and may represent a significant risk factor for the development of sepsis. Until recently, stomatitis has been viewed as the result of a direct toxic effect to the epithelial cells of the mucosa. New data have emerged showing this side effect to be a more complicated process. Briefly, chemotherapy and targeted agents, such as regorafenib, may cause stomatitis by causing direct DNA damage to the mucosal surface through the generation of oxygen-free radicals or through the initiation of transcription factor activation. These reactive species may also stimulate secondary mediators of injury such as nuclear factor-κb (NF-κb) tumor necrosis factor (TNF) or interleukins which cause further damage and tissue injury [Sonis et al. 2004]. The end result of these pathways may lead to ulceration, erythema, edema and pain within the oropharynx. Patients may develop functional difficulties such as the inability to take in nutrients, to swallow and may have difficulties with speech.

There are five grades of stomatitis defined by CTCAE v4.03. This toxicity is frequently encountered with regorafenib and typically occurs during the second week after initiation of therapy. Preventative measures that may be taken to reduce the risk of development of stomatitis include the practice of good oral hygiene, with the use of a soft toothbrush or swab after each meal and before going to sleep. Use of an alcohol-free, saline mouthwash at regular, frequent intervals may be helpful in ameliorating stomatitis. For patients with dentures, daily cleaning should be implemented. The avoidance of substances that may be irritating such as foods that are heavily spiced, hot foods and acidic drinks should be avoided.

If stomatitis does occur treatment is largely supportive. Frequent rinsing, every 1–2 hours, with a saline mouthwash can help. Alternatives to saline mouthwashes include solutions of 1 g bicarbonate mixed with water, hexetidine, nystatin 100,000 IU/ml, or mepivacaine hydrochloride (10 mg/ml). Oral lidocaine use prior to the use of oral rinses may help reduce pain. If an oral fungal infection is suspected, treatment with nystatin (5 ml), swish and swallow, 4 times daily for 10 days is recommended.

In patients who develop grade 3 or 4 stomatitis, the mouthwash protocol can be increased to 8–12 rinses per day or more frequently. If there is no improvement after 7 days, then regorafenib should be stopped until the stomatitis reduces back to grade 1. At that time, retrial with the same dose regorafenib can be initiated.

Diarrhea

Diarrhea occurred in 34% of patients enrolled in the CORRECT trial, with 7% of patients experiencing grade 3 or 4. Diarrhea can be defined as the occurrence of greater than three loose/watery stools per day or an increase in baseline number of stools per day [Sastre et al. 2014]. The five grades of diarrhea severity are defined in CTCAE v4.03. Severe diarrhea, such as grade 3 or 4, could result in fluid and electrolyte depletion. The sequelae of these fluid and electrolyte depletions may result in dehydration, renal failure and potentially cardiovascular compromise.

Education and communication are the keys to addressing this toxicity. Chronic grade 2 diarrhea can be more debilitating than a short course of grade 3 diarrhea. Assessment of the symptoms associated with the diarrhea should be made. Questions regarding the frequency of the stool, its consistency, color and any associated pain should be investigated. Education about variability of stool and types of stool will help subjects to understand when to contact someone. A stool chart, such as the one described by Heaton and colleagues, may be a helpful tool for patients [Lewis and Heaton, 1997]. If the number of daily stools increases by more than three, the patient should notify a healthcare provider. Unfortunately, relatively few preventative measures are available; however, patients can be educated as to the importance of a low fiber/low fat diet in preventing diarrhea.

If diarrhea does occur, it can be treated at home with the anti-diarrheal, loperamide, for a maximum of 48 hours. Patients should also be instructed to rehydrate with liquids that contain electrolytes and water. If after 48 hours of loperamide treatment the diarrhea is greater than grade 3, hospitalization of the patient should be considered to meet demands for fluid and electrolytes.

Liver function

Abnormalities in liver function, as assessed by the measurement of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin levels, is a common occurrence with many chemotherapeutic agents as well as with regorafenib. CTCAE v4.03 defines four grades of severity. In the CORRECT trial, increases in AST (7%) and ALT (5.4%) were reported in patients while increases of bilirubin were found in 20% [Grothey et al. 2013]. The majority of these increases were grade 1 or 2. The GRID trial reported one fatality related to liver dysfunction.

Symptoms and exam findings include scleral icterus, jaundice of the skin, dark urine, alternations of sleep and nausea/vomiting. As with other toxicities associated with regorafenib, the appearance of these lab abnormalities tended to occur early in the course of treatment, typically within the first two cycles. Based on this timing, it is important to monitor these patients closely at the initiation of treatment. Recommendations include obtaining baseline lab values and monitoring every 2 weeks during the first 2 cycles of therapy, and monthly thereafter or as clinically necessary. Table 3 outlines the dose modifications based on liver dysfunction as described in the GRID and CORRECT studies.

Table 3.

Dose modifications based on liver dysfunction.

NCI CTCAE v4.03	First occurrence	Restart	Reoccurrence
Baseline	Give on time.		Give on time
Grade 0 →1	Check AST, ALT, bilirubin twice weekly for 2 weeks then weekly for at least 4 weeks		Check AST, ALT, bilirubin twice weekly for 2 weeks then weekly for at least 4 weeks
Grade 1 →2
Baseline	Delay drug until ⩽ grade 1	Reduce drug by 1 dose level*	Discontinue treatment
Grade 0 →2	Check AST, ALT and bilirubin twice weekly	Check AST, ALT, bilirubin twice weekly for 2 weeks then weekly for at least 4 weeks
Baseline Any grade → 3	Delay drug until ⩽ grade 1 if baseline grade was 0 or 1	Reduce drug by 1 dose level	Discontinue treatment
	Delay drug until ⩽ grade 2 if baseline grade was 2 Check AST, ALT and bilirubin twice weekly If AST or ALT > 8× upper limit of normal (ULN) with any rise in bilirubin, consider permanent discontinuation	Check AST, ALT, bilirubin twice weekly for 2 weeks then weekly for at least 4 weeks
Baseline	Discontinue treatment
Any grade → 4

^*Dose levels 160 mg, 120 mg, 80 mg.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.

Fatigue

Fatigue is defined by CTCAE v4.03 as ‘a disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities’. Fatigue is common toxicity associated with cancer treatment and can have a major adverse impact on QoL for patients. It may be associated with other symptoms such as sleep disturbances, pain and/or depression [Carroll et al. 2007]. CTCAE v4.03 details three grades of fatigue. In the CORRECT study, 47% of subjects suffered from fatigue [Bennion and Molassiotis, 2013; Petersen et al. 2013] and 39% of patients in the GRID study reported this symptom [Grothey et al. 2013]. Early reporting of symptoms of fatigue by patients to their healthcare providers may facilitate treatment. Patients should be educated as to the symptoms they may experience – tired eyes or legs, whole body tiredness, stiff shoulders, decreased or a lack of energy, inability to concentrate, weakness or malaise, boredom or lack of motivation, sleepiness, increased irritability, nervousness, anxiety or impatience. During the first 2 cycles of regorafenib, fatigue should be assessed weekly; subsequent assessments can be performed every 2 weeks.

There are both pharmacological and nonpharmacological treatments for fatigue. Any underlying disorders such as anemia should first be corrected in patients complaining of fatigue. Nonpharmacologic treatments such as exercise, nutritional support, improved sleep hygiene, stress management and exercise should be discussed with the patient [Gagnon et al. 2013; Carroll et al. 2007]. Pharmacologic therapy with psychostimulants and central nervous system (CNS) stimulants may be useful in a select group of patients, although their use is not universally recommended [Ruddy et al. 2014]. For patients experiencing grade 1 or 2 fatigue while on regorafenib, the aforementioned therapies should be initiated. If patients experience grade 3 fatigue with regorafenib, dose modification should be considered.

Proteinuria

In the CORRECT study, 7% experienced proteinuria [Grothey et al. 2013]. Patients should be evaluated for proteinuria before starting regorafenib and monitored regularly throughout treatment [Grothey et al. 2014]. If the degree of proteinuria is ⩽ grade 1, regorafenib can be given. If proteinuria is ⩾ grade 2, the urinary protein creatinine ratio should be obtained. If protein creatinine ratio is >1, a 24-hour urine collection should be sent to quantify protein content. In a patient with urine protein >2g/24 hours, we recommend holding regorafenib until proteinuria reduces to <2 g/24 hours. If the 24-hour urine does not improve within 3 months, we recommend discontinuing regorafenib permanently. If proteinuria recurs, regorafenib should be held till it improves to <2 g/24 hours and consideration should be given to reducing regorafenib by 40 mg. In subjects with grade 4 proteinuria (nephrotic syndrome) or thrombotic microangiopathy, regorafenib should be permanently discontinued.

Cardiovascular

The rate of thromboembolism during regorafenib treatment does not appear to be elevated compared with other agents in this class of drugs. Abel-Rahman and Fouad conducted a meta-analysis and did not find increased rates of thromboembolism with regorafenib [Abel-Rahman and Fouad, 2014]. In the CORRECT study, the rate of thromboembolism was 12% in both the regorafenib and placebo arms [Grothey et al. 2013]. If grade 3 thrombosis does occur, regorafenib should be held. For grade 4 thrombosis, regorafenib should be stopped. We recommend that patients with a severe arterial thromboembolic event during regorafenib treatment should discontinue treatment permanently. Many patients with a history of arterial thromboembolic event are routinely treated with low dose aspirin. In such patients, regorafenib can be continued. Regorafenib also inhibits CYP2C9, the enzyme responsible for metabolizing warfarin. Inhibition of warfarin’s metabolism could lead to an increased risk of bleeding. Therefore patients receiving warfarin treatment during regorafenib therapy should be followed closely with serial INR tests.

Hemorrhage was also reported in the CORRECT study [Grothey et al. 2013]. Two patients experienced gastrointestinal bleeding and one pulmonary hemorrhage. With grade 3 hemorrhage, in the absence of any coagulation disorder that could increase the risk of bleeding, regorafenib should be held until the bleeding resolves. In patients with grade 3 hemorrhage on full-dose anticoagulation, regorafenib should be discontinued. If there is a repeat episode of grade 3 hemorrhage or a new grade 4 hemorrhage, regorafenib should be permanently stopped. Patients with brain metastases pose a potential high risk for death with bleeding and may exclude treatment with regorafenib.

Hematologic

Thrombocytopenia of all grades was reported to be 15% for patients participating in the CORRECT trial. Grade 3 or 4 thrombocytopenia was reported in 3.4% and 0.4% of patients, respectively. Neither the GRID trial or CORRECT trial listed thrombocytopenia as a major toxicity, defined as occurring in >10% of patients enrolled, in their trials [Grothey et al. 2013; Demetri et al. 2013]. Neutropenia was also not listed in either the GRID or CORRECT trial as being a major toxicity. Anemia of all grades was listed as occurring in 14% of patients in the CORRECT trial; grade 3 or 4 anemia was seen in 5.4% and 0.4% of patients, respectively.

Although hematologic toxicities were not that prevalent in the two major regorafenib studies, it is recommended that complete blood counts be monitored at baseline and prior to each cycle of therapy. Refer to Table 4 for dose modifications based on hematologic toxicity.

Table 4.

Dose modifications for toxicities (excluding HFSR, hypertension, liver dysfunction).

Grade of event	Dose interruption	Dose modification	Dose for subsequent cycles
Grade 0–2	Treat on time	No change	No change
Grade 3	Delay until ⩽ grade 2	Reduce by 1 dose level	If toxicity remains ⩽ grade 2, dose re-escalation can be considered. If dose is re-escalated and ⩾ grade 3 toxicity recurs, institute permanent dose reduction.
Grade 4	Delay until ⩽ grade 2	Reduce by 1 dose level; Permanent discontinuation per physician’s discretion

HFSR, hand foot skin reaction.

Wound healing complications

Due to regorafenib’s ability to target multiple cell signaling pathways, including those associated with VEGF, wound healing may be impaired. Therefore, we recommend holding regorafenib for at least 4 weeks prior to and after the elective surgery. Full wound healing is recommended before the re-initiation of regorafenib therapy. For minor surgeries and procedures such as tooth extraction, biopsy or port placement, regorafenib should be held until the wound has healed. If there is failure of wound healing, regorafenib should be discontinued.

Drug interactions

Many drugs, including regorafenib, are metabolized in the liver through the CYP isoenzyme system. Regorafenib is metabolized by CYP3A4 and UGT1A9 enzymes to two active metabolites M-2 (N-oxide) and M-5 (demethylated N-oxide). The activity of both metabolites is similar to that of the parent drug [Strumberg et al. 2012]. The CYP enzymes can be either inhibited or induced through co-administration of drugs that also affect the same enzyme. Co-administration of a strong inhibitor of CYP3A4 with regorafenib would result in an increase in serum area under the curve (AUC) levels of regorafenib. This could lead to increased toxicity of the drug. Conversely the co-administration of a strong inducer of CYP3A4 with regorafenib would result in lower serum AUC of regorafenib and potentially reduced efficacy. The M-2 and M-5 metabolites of regorafenib also affect the CYP isoenzymes. They have been found to be inhibitors of the CYP2C9, CYP2B6, CYP3A4 and CYP2C8 enzymes [van Leeuwen et al. 2014]. Table 5 lists drugs that may interact with regorafenib and the result of that interaction. Given the potential for drug interactions, medication reconciliation should be done on all patients prior to initiating treatment with regorafenib.

Table 5.

Major drug interactions with regorafenib.

Inducers of CYP3A4*	Inhibitors of CYP3A4$	CYP2C9 inhibition‡	UGT1A1 inhibitor§
Carbamazepine	Conivaptan	Warfarin	Irinotecan
Phenobarbital	Boceprevir
Rifampin	Clarithromycin
Phenytoin/fosphenytoin	Grapefruit juice
Isoniazid	Indinavir
St John’s wort	Itraconazole
	Ketoconazole
	Nefazodone
	Nelfinavir
	Posaconazole
	Voriconazole
	Ritonavir
	Saquinavir
	Telaprevir
	Telithromycin

^*Inducers of CYP3A4 may decrease exposure to regorafenib and exposure to M-2 and M-5 metabolites may increase.

^$Inhibitors of CYP3A4 may increase exposure to regorafenib and exposure to M-2 and M-5 metabolites may decrease.

^‡Regorafenib inhibits CYP2C9; concomitant administration of drugs that are CYP2C9 substrates may result in increased exposure of that drug.

^§Regorafenib is a UGT1A1 inhibitor. Concomitant use with irinotecan may result in increased irinotecan exposure.

Discussion

It is important to acknowledge that the management of adverse events associated with regorafenib and similar agents such as sorafenib is based on clinical experience rather than prospectively tested, randomized strategies. No national or international guidelines are present at the moment. Therefore, physicians treating these cancer patients must use their own clinical judgment and individualize dose and treatment based on particular patient.

Regorafenib is structurally related to sorafenib and differs from the latter by the presence of a fluorine atom in the center phenyl ring [Fabian et al. 2005]. The slight structural difference resulted in higher inhibitory potency against various pro-angiogenic receptors than sorafenib including VEGFR2, FGFR1 and similar for platelet-derived growth factor receptor-β (PDGFRβ). Other receptor kinases inhibited by regorafenib include VEGFR1, VEGFR-3, RAF, TIE2 and mutant oncogenic kinases KIT, RET and BRAF [Wilhelm et al. 2011]. In addition, sorafenib was not able to show significant antitumor activity in CRC both in preclinical and clinical studies.

Regorafenib has been shown to be an active therapy that provides a survival advantage in patients with mCRC and GIST who have failed other therapies. Overall, this multikinase inhibitor has been well tolerated with manageable side effects. The adverse event profile associated with regorafenib appears to be quite similar to sorafenib as the major toxicities seen in clinical trials with both these agents were HFSR, diarrhea, hypertension and fatigue. Moreover, the side effects of regorafenib seem quite predictable across tumor types and patient populations, and symptoms can be effectively managed as long as healthcare professionals are familiar with recognizing them early (starting within 3–4 days of treatment initiation) and assess patients regularly to interact at the inset

We strongly suggest that all patients planned to receive regorafenib should receive written information about the drug and its related side effects, including interaction with prescription and over-the- counter medications since cancer patients tend to use many drugs. Moreover, written information on dosing instructions can enhance adherence to treatment regimen as well as minimize toxicities. Nothing can be more helpful than a clear and open communication between patients and physicians to overcome any barriers. Frequent patient visits and encouraging patients to express their concerns and issues can help establish a sense of collaboration that may improve adherence and facilitate toxicity management.

To date, the efficacy and toxicity of regorafenib has been evaluated in patients with advanced disease and the side effects of long-term therapy with regorafenib in patients with less advanced tumor types are still unclear. As the trial data matures, we will have more clarity on the safety of regorafenib.

As more data become available, specific guidelines for the management of regorafenib-related toxicities will become more detailed as well. This will be vital, as anti-angiogenic agents become a more integral part of the standard care of patients with colorectal and other malignancies. Overall, however, the clear benefits of anti-angiogenic therapy vastly outweigh the small risks in the majority of patients. The key to administering treatment safely will be through education of patients, nurses and other healthcare providers.