Diarrhea treatment recommendations

March 2018

Assessment and management of diarrhea following VEGF

receptor TKI treatment in patients with ovarian cancer

Joyce Liu,a Shibani Nicum,b Peter Reichardt,c Kenneth Croitoru,d Beate Illek,e

Manuela Schmidinger,f Catherine Rogers,g Christin Whalen,a Gordon C Jaysong

aDana-Farber Cancer Institute, Boston, MA, USA; bDepartment of Oncology,

University of Oxford, Oxford, UK; cSarkomzentrum Berlin-Brandenburg, HELIOS

Klinikum Berlin-Buch, Berlin, Germany; dZane Cohen Centre for Digestive Diseases,

Division of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto,

Canada; eChildren’s Hospital Oakland Research Institute, Oakland, CA, USA;

fDepartment of Medicine I, Clinical Division of Oncology, Medical University of Vienna,

Vienna, Austria; gChristie Hospital and Institute of Cancer Studies, University of

Manchester, Manchester, UK

Corresponding author: Gordon C Jayson

Christie Hospital and Institute of Cancer Studies, University of Manchester,

Manchester, M20 4BX, UK

Email: gordon.jayson2@christie.nhs.uk

Tel: +44 161 3060808

Fax: +44 161 446 8027

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Co-authors:

Shibani Nicum: Department of Oncology, University of Oxford, Churchill Hospital, Old

Road, Headington, Oxford, OX3 7LE, UK. snicum@nhs.net

Peter Reichardt: Sarkomzentrum Berlin-Brandenburg, HELIOS Klinikum Berlin-Buch,

Schwanebecker Chaussee 50, 13125 Berlin, Germany. peter.reichardt@helios-

kliniken.de

Kenneth Croitoru: Zane Cohen Centre for Digestive Diseases, Division of

Gastroenterology, University of Toronto, Mount Sinai Hospital, Room 437, 600

University Avenue, Toronto, Ontario, M5G 1X5, Canada.

Ken.Croitoru@sinaihealthsystem.ca

Beate Illek: Children’s Hospital Oakland Research Institute, 5700 Martin Luther King Jr

Way, Oakland, CA 94609, USA. billek@chori.org

Manuela Schmidinger: Department of Medicine I, Clinical Division of Oncology, Medical

University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria.

manuela.schmidinger@meduniwien.ac.at

Catherine Rogers: Christie Hospital and Institute of Cancer Studies, University of

Manchester, 550 Wilmslow Road, Manchester, M20 4BX, UK.

catherine.rogers@christie.nhs.uk

Christin Whalen: Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA

02215, USA. christin_whalen@dfci.harvard.edu

Gordon C Jayson: Christie Hospital and Institute of Cancer Studies, University of

Manchester, 550 Wilmslow Road, Manchester, M20 4BX, UK.

gordon.jayson2@christie.nhs.uk

Running title: VEGFR-TKI-induced diarrhea in ovarian cancer

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Target journal: Gynecologic Oncology

Manuscript type: Review

Word count: 3213 (max 5500)

Tables/figures: 2 (max 6)

References: 37 (max 70)

Funding: AstraZeneca funded the meeting at which the content of this manuscript

was conceived. The funder had no input into the topics included, the development of

the recommendations, or the writing of the manuscript.

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Abstract

Angiogenesis is a proven clinical target for the treatment of advanced epithelial

ovarian cancer. Vascular endothelial growth factor receptor tyrosine kinase inhibitors

(VEGFR-TKIs) offer patients potential new treatment regimens as they can be given

as monotherapy, in combination with poly(ADP-ribose) polymerase (PARP)

inhibitors, or with and following cytotoxic chemotherapy.

If VEGFR-TKIs are licensed for use in ovarian cancer, patients will require prompt

and effective management of adverse events, including diarrhea, to optimize

compliance and benefit. As diarrhea is one of the most prevalent toxicities of this

class of drug, it is important to consider the potential causes, be they disease related

(bowel obstruction), treatment related (VEGFR-TKI-related or infective/neutropenic

septic diarrhea when patients are receiving cytotoxic chemotherapy combined with

VEGFR inhibitor treatment), or incurred through diet.

Here, we provide an overview of the possible mechanisms responsible for VEGFR-

TKI-induced diarrhea. We review potential interventions that can help in the

management of diarrhea induced by VEGFR-TKIs, when used in combination or as

single agents, and we provide a diarrhea treatment algorithm to serve as a clinical

reference point for the management of diarrhea in patients with ovarian cancer

treated with a VEGFR-TKI in combination with chemotherapy or PARP inhibitors, or

as monotherapy.

Word count: 199 (max 300)

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Keywords: Ovarian cancer, diarrhea, VEGF receptor tyrosine kinase inhibitor,

VEGF, VEGFR, TKI

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Introduction

Ovarian cancer occurs in 239,000 women annually worldwide and is the leading

cause of gynecologic cancer deaths in the UK and USA [1]. Angiogenesis, the

formation of new blood vessels from pre-existing vessels, is a validated target for

treating several tumor types through the use of inhibitors of the vascular endothelial

growth factor (VEGF) pathway [2]. In ovarian cancer, angiogenesis is a proven

clinical target, as demonstrated in Phase III trials of the humanized anti-VEGF

antibody bevacizumab [3]. In addition to bevacizumab, inhibitors of angiogenesis

include VEGF receptor tyrosine kinase inhibitors (VEGFR-TKIs) such as cediranib,

pazopanib and nintedanib (Supplementary Table 1). These VEGFR-TKIs have the

potential to offer additional therapeutic options for patients with ovarian cancer.

In ovarian cancer, recent studies have shown that when inhibitors of angiogenesis

are combined with cytotoxic chemotherapy followed by maintenance monotherapy,

response rate and progression-free survival (PFS) significantly improved, thus

delaying the need for further cytotoxic chemotherapy [3-5]. Interestingly, when

combined with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, the

VEGFR-TKI cediranib significantly improved PFS compared with PARP inhibitor

treatment alone [6].

A known side effect of chemotherapy, VEGFR-TKIs (as monotherapy and in

combination) and PARP inhibitors is an increase in the severity and incidence of

diarrhea [6-9]. Diarrhea can be a debilitating and potentially life-threatening toxicity

(Figure 1, inset table) that can adversely affect a patient’s health-related quality of

life (HRQoL). Loss of fluids and electrolytes associated with persistent or severe

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diarrhea can result in life-threatening dehydration, renal insufficiency and electrolyte

imbalances and may contribute to cardiovascular morbidity. Furthermore, reduced

compliance because of adverse events (AEs) such as diarrhea may compromise

clinical outcomes [10]. In the ICON6 trial of cediranib in combination with

chemotherapy followed by cediranib maintenance treatment, AEs, particularly

diarrhea, fatigue and hypertension, were problematic in some patients, and up to

39% of patients in the intervention arm, compared with 12% in the reference group,

stopped the trial early because of toxic side effects [11].

VEGFR-TKIs are widely used in other cancers, including gastrointestinal stromal

tumors (GIST) and renal cell carcinoma (RCC) [12,13]. Experience gained from the

effective management of VEGFR-TKI-induced diarrhea in these tumor types may

help to provide guidance for the successful management of diarrhea experienced by

patients with VEGFR-TKI-treated ovarian cancer. Here, we provide an overview of

the possible mechanisms responsible for VEGFR-TKI-induced diarrhea and the

effects that such agents have had on patients who have participated in clinical trials.

We also review potential interventions that can help in the management of VEGFR-

TKI-induced diarrhea, when used either in combination or as single agents.

Mechanisms of VEGFR-TKI-induced diarrhea are unknown

The incidence of chemotherapy-induced diarrhea (CID) has been reported to be as

high as 50–80% of patients (≥30% Common Terminology Criteria for Adverse Events

[CTCAE] grade 3–5) [7], with most chemotherapeutic agents inducing diarrhea [14].

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Similarly, VEGFR-TKI-induced diarrhea has been reported to be a common AE

(Supplementary Table 1).

Understanding the pathophysiological mechanisms of diarrhea following anticancer

therapies would lead to the development of effective treatments. The mechanisms

for CID are becoming clearer and include severe intestinal damage caused by

mucositis, carbohydrate or fat malabsorption, and/or indirect biological signaling, all

of which have been outlined and discussed in detail previously [15-17]. Other

potential causes of CID include overuse of antibiotics, underuse of antidiarrheal

agents, malabsorption syndromes, concurrent radiotherapy and infection [18]. The

involvement of intestinal chloride secretion has been recently considered as a

mechanistic hypothesis [17]. However, the gastrointestinal tract has complex

secretory, absorptive and propulsive functions that involve multifaceted neurologic,

hormonal, muscular, immune and enzyme systems, along with multiple specialized

cell types, which make it a difficult organ system to study. Mechanisms by which

VEGFR-TKI-induced diarrhea occur are yet to be elucidated and may be distinct or

overlap with those for CID.

In contrast to bevacizumab, which inhibits angiogenesis by binding to VEGF-A,

multikinase inhibitors may affect more than VEGF-A signaling, and diarrhea is a

more frequently observed side effect with this class of drugs. For example, VEGFR-

TKI-induced diarrhea could be caused by inhibition of the receptor tyrosine kinases

associated with VEGF-B or -C (VEGFR-1, -2 or -3) or by off-target inhibition of

receptor tyrosine kinases, such as platelet-derived growth factor (PDGF), c-KIT,

FLT3, etc [8]. Other proposed mechanisms that could cause diarrhea relate to the

widespread expression of VEGFRs in the intestine [19]. Indeed, the addition of

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VEGFR inhibitors significantly reduces the capillary network in pancreatic islets and

intestinal villi, decreasing zymogen granules in the pancreas and pancreatic islet

capillaries [8]. Consequently, patients treated with strong VEGFR inhibitors report

watery, fatty stools (grade 3; >7 stools/day) [20].

VEGFR inhibitors may also cause changes to the bowel mucosa, leading to diarrhea.

In the intestinal mucosa, small perturbations of blood flow can result in metabolic

changes that resemble ischemia and hypoxia, which may cause diarrhea and

ischemic colitis [21]. Inhibition of c-KIT by VEGFR inhibitors may result in altered

bowel function by changing the regulation of interstitial cells of Cajal, the pacemaker

cells of the intestine, potentially leading to bacterial overgrowth and diarrhea [22].

Together, these data suggest that a mixture of pancreatic, neurologic and vascular

bowel function with potential bacterial overgrowth may account for VEGFR-TKI-

associated diarrhea. However, the increased prevalence of diarrhea in patients

receiving this class of drug compared with bevacizumab suggests that the

mechanism is not solely related to VEGF-A, and further research is required.

Impact of diarrhea – clinical trial experience of diarrhea in

ovarian cancer patients treated with VEGFR-TKIs

There are currently three VEGFR-TKIs, cediranib, nintedanib and pazopanib, which

have been evaluated for the treatment of ovarian cancer in different disease settings.

Supplementary Table 1 details the key safety and efficacy data in ovarian cancer for

these VEGFR-TKIs, demonstrating that diarrhea is a common toxicity.

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Diarrhea can cause discomfort, fatigue and sleep disturbance and can affect social

functioning because patients are reluctant to leave the house [23]. There is little

information on the impact of treatment with VEGFR inhibitors on diarrhea-related

HRQoL of patients with ovarian cancer. In ICON6, the global HRQoL outcome at 12

months, measured using the QLQ-C30 questionnaire, showed that cediranib

treatment had neither a clinically nor a statistically significant impact on overall

HRQoL [24]. Although the inclusion of clinical management guidelines in ICON6

resulted in prompt management of AEs to restrict the number of patients requiring a

dose reduction or discontinuation, exploratory analyses showed that diarrhea was

more common in patients receiving cediranib both concurrently with chemotherapy

and as maintenance monotherapy [24].

To address the current lack of HRQoL data, we interviewed a small number of

patients who received cediranib in two ovarian cancer trials (Supplementary Table

2): the UK Medical Research Council ICON6 study (NCT00532194) and the US

National Cancer Institute (NCI) study (NCT01116648). Although definite conclusions

could not be made because of the small number of patients questioned, consistent

features of treatment-related diarrhea and its impact on HRQoL were reported

(Supplementary Table 2).

Assessment of VEGFR-TKI-induced diarrhea in ovarian cancer

Based on the evidence reported here and extensive discussions at a 1-day meeting,

the authors have developed an algorithm for the assessment and management of

VEGFR-TKI-induced diarrhea when given in combination with cytotoxic

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chemotherapy or other anticancer treatments, or as monotherapy, in patients with

ovarian cancer (Figure 1).

To reduce the occurrence of VEGFR-TKI-induced diarrhea and enable treatment to

be provided at its onset, patient education is of paramount importance. At the time of

initiating monotherapy with VEGFR-TKIs, patients should be informed of the

potential side effects of this treatment, provided with self-assessment tools to assess

bowel function, and given preventative dietary recommendations and antidiarrheal

tablets (eg loperamide) with appropriate dosing recommendations as outlined in

Figure 2, inset table. Potential risk factors to determine if a patient is at an increased

risk of developing diarrhea have been identified and should be discussed with the

patient. Examples include the concomitant stomatitis, emesis, anorexia, anemia,

cramps, or a combination of these features. However, the relative risk of developing

diarrhea associated with these symptoms has not been quantified and their

contribution is not specific for ovarian cancer patients [25,26].

Patients receiving cytotoxic chemotherapy are at risk of developing diarrhea, which

can be a serious and life-threatening complication and can also lead to treatment

delays, dose reductions or treatment discontinuation [7]. Mucositis and neutropenia

from chemotherapy treatment can significantly increase complications associated

with CID. Thus, it is important that patients who are prescribed VEGFR-TKIs with

cytotoxic chemotherapy and who experience diarrhea consult their oncology team for

evaluation to distinguish between infective diarrhea, neutropenic septic diarrhea,

cytotoxic-chemotherapy-associated diarrhea and VEGFR-TKI-induced diarrhea.

VEGFR inhibitors can also cause bowel perforation in patients with bowel

obstruction, a complication that can occur during ovarian cancer disease

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progression. Therefore, VEGFR inhibitor treatment should not be initiated in patients

with ovarian cancer until symptoms of bowel obstruction have abated following

treatment with cytotoxic chemotherapy.

VEGFR-TKIs – assessment of the seriousness of diarrhea and warning signs

The seriousness of diarrhea is graded according to CTCAE (Figure 1, inset table)

[27]. Clinical assessment and grading of diarrhea are important factors in

establishing whether a patient can be managed without hospital admission. The

severity and duration of diarrhea should be determined, and the evaluation should

include questions concerning foods or concurrent and recent drugs that might play a

contributory role, for example, recent antibiotics that may have contributed to

Clostridium difficile diarrhea. Specific warning signs to be initially assessed and

excluded as the cause of diarrhea are bowel obstruction, neutropenic sepsis (due to

chemotherapy treatment), gram-negative sepsis and infective diarrhea (Figure 1). If

any of these causes are suspected, or if the patient presents with diarrhea of CTCAE

grade ≥3, or grade 1 or 2 with one or more of the signs or symptoms outlined in

Figure 1, inset table, the patient would require medical attention [28].

Management of VEGFR-TKI-induced diarrhea through alternative

dose scheduling – experience from patients with GIST and RCC

Patients with GIST or RCC are often treated with VEGFR-TKIs as monotherapy,

such as sunitinib (VEGFR- and PDGF-receptor [PDGFR]-TKI). In the real-world

setting, sunitinib is often taken in alternative dosing schedules (ADS) or with

individualized dosing to increase tolerability to the drug [12,13]. ADS are used to

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balance toxicity and efficacy; they involve varying the set number of days on/off

treatment, offering a treatment holiday, reducing the dose, or a combination of these

factors. Several studies have shown that switching to an alternative schedule with

more frequent dose interruptions over a 6-week cycle is associated with improved

outcomes and increased tolerability [12].

A large study of over 1000 patients with GIST who received sunitinib assessed the

benefits of ADS [13], reporting that patients who used ADS had better PFS and

overall survival (OS) than those who adhered to the initial dosing schedule (IDS).

The ADS patients took treatment over a longer interval and the median total dose

was greater. The overall rate of treatment-related AEs was greater in patients

receiving ADS compared with IDS; however, the proportion of patients who

permanently discontinued treatment was lower. When adjusted for duration of

treatment, overall incidence and incidence of the most common AEs (including

diarrhea but with the exception of hypothyroidism) were decreased in the ADS group

compared with the IDS group [13].

A retrospective review of alternative, shorter schedules of sunitinib (2 weeks on, 1

week off treatment [2/1 schedule]; 1 week on, 1 week off treatment [1/1 schedule])

rather than the standard treatment schedule (4 weeks on, 2 weeks off treatment [4/2

schedule]) in RCC found that patients who started or switched to alternative sunitinib

schedules experienced the same clinical efficacy but with reduced toxicities (grade

≥3, lower incidence of dose reduction) compared with the 4/2 schedule [12].

A retrospective evaluation of 185 RCC patients treated with first-line sunitinib using

the conventional 4/2 schedule or ADS (2/1 schedule or other alternative schedules)

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reported that 53% of patients continued with the 4/2 schedule, while 47%

transitioned to ADS following development of fatigue (64%), hand–foot syndrome

(38%) and diarrhea (32%). Median OS was 17.7 months (95% confidence interval

[CI] 10.8–22.2 months) on the 4/2 schedule, compared with 33.0 months (95% CI

29.3 to not estimable) on ADS (P<0.0001). Comparison of toxicity prevalence before

and after schedule adjustment demonstrated a clear reduction in toxicity rates [29].

Another retrospective review of 172 patients utilized an individualized treatment

strategy whereby all patients were started on standard dosing of sunitinib, with dose

and schedule modifications considered to keep patients’ toxicity to grade ≤2. Of

three groups (group 1, sunitinib 50 mg, 4/2 schedule; group 2, sunitinib 50 mg, 2/1 or

1/1 schedule; group 3, sunitinib 37.5 or 25 mg, 1/1 schedule), median PFS was 5.3,

10.9, and 11.9 months, respectively (P<0.0001; 8.9 months overall), and median OS

was 15.4, 23.4, and 24.5 months, respectively (group 2 vs group 1, P=0.03; group 3

vs group 1, P=0.003). Dynamic microbubble ultrasound evaluation in patients

receiving sunitinib demonstrated that maximum anti-angiogenic activity was

achieved after 14 days, with no further reduction in blood flow from day 14 to 28,

suggesting that the putative antitumor mechanism of sunitinib (ie reduction in tumor-

associated blood flow) is optimized after 14 days and day 15–28 dosing may

increase toxicity without meaningful contribution to efficacy [30].

A reduction in the dose of sunitinib (37.5 mg) given continuously compared with the

standard 4/2 (50 mg) schedule was investigated in a randomized phase II trial in

RCC patients. This demonstrated no differences in drug tolerance or patient-reported

symptoms, with a trend towards superiority of the 4/2 schedule over continuous

dosing [31]. Based on this study, the 4/2 schedule remained the standard of care for

RCC [12].

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Data from the GIST and the RCC studies described here, along with personal

experience from the authors (PR, MS), suggest that active management of VEGFR-

TKI dosing with close follow-up and prompt dose modification allows patients to

avoid toxicities and receive prolonged treatment, resulting in greater clinical benefit.

Management of VEGFR-TKI-induced diarrhea in ovarian cancer

when given as monotherapy or combined with chemotherapy or

other anticancer therapies

Diarrhea associated with VEGFR-TKIs is predominantly mild (grade 1, defined as an

increase of <4 bowel movements per day in addition to number before treatment,

mild increase in stoma output) or moderate (grade 2, defined as an increase of 4–6

bowel movements per day in addition to number before treatment, moderate

increase in stoma output) in intensity. However, to avoid escalation of symptoms and

to prevent dose reduction or discontinuation, it is important to manage symptoms as

early as possible and prevent further incidences.

Patients receiving VEGFR-TKIs who present with grade 2 diarrhea with

accompanying worrying clinical features or test results (Figure 1, inset table), or

grade ≥3 diarrhea (defined as an increase of ≥7 bowel movements per day in

addition to the number before treatment, incontinence, severe increase in stoma

output, limiting of self-care activities of daily living, life-threatening consequences,

hospitalization/urgent intervention indicated), may need to be considered for

evaluation and/or hospital admission unless clinical review suggests that the patient

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is well hydrated, has not yet had any antidiarrheal medication and can be reviewed

daily [16,23,32]. If patients experience grade ≥3 diarrhea following treatment with a

VEGFR-TKI, treatment should be withheld until symptoms are controlled.

Patients with grade 1 or 2 diarrhea with no accompanying features (Figure 1, inset

table) may be managed conservatively in the outpatient setting. Patients should stop

all lactose-containing products, alcohol and highly concentrated supplements, drink

8–10 large glasses of clear liquid a day, eat small meals frequently (eg bananas,

rice, air-oxidized apple and toast [BRAT] diet) [23,32,33], initiate loperamide

treatment (unless the patient is at imminent risk of bowel obstruction from ovarian

cancer), record the number of bowel movements, and report symptoms that might be

of further clinical significance, such as fever or dizziness upon standing (see Figure

2, inset table for ‘Diarrhea symptom management for patients’ for specific dietary,

rehydration and antidiarrheal details) [23,32]. After 24 hours of symptom

management, patients should be contacted to determine if their symptoms have

improved. If diarrhea is resolving, patients should continue their dietary

modifications, gradually re-introduce solid foods into their diet and discontinue

loperamide treatment after 12 hours without diarrhea. If diarrhea persists at a low

grade (grade 1 or 2), loperamide dosage can be adjusted. If symptoms do not

improve following 24 hours of antidiarrheal medications and the patient continues to

experience diarrhea, with no indication of underlying cause, the VEGFR-TKI should

be stopped until the patient’s symptoms have been controlled and loperamide

dosage should be increased. If diarrhea of a low grade is unresolved after 48 hours

of treatment and there are no associated symptoms of concern, patients should be

referred for further investigations, including stool sampling, abdominal examination

and electrolyte evaluations. Such patients should have fluids and electrolytes

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replaced if needed and antibiotics prescribed if there is a suspicion of an infective

cause.

Evidence from GIST and RCC patients suggests that ADS with VEGFR-TKIs should

be considered to allow patients to continue with treatment [13]. Figure 2 outlines the

ADS evaluation steps for ovarian cancer patients receiving VEGFR-TKIs. ADS

should be individualized to each patient to find the optimum dose and schedule. It is

important that patients are regularly assessed and their VEGFR-TKI dosage and

schedule reviewed to enable them to continue treatment. When the patient is no

longer experiencing diarrhea, and if both the patient and physician agree, dose re-

escalation of the VEGFR-TKI could be considered. For patients who have been

receiving VEGFR-TKIs together with chemotherapy and who are to receive

maintenance treatment with VEGFR-TKIs following completion of their

chemotherapy and their diarrhea has stabilized, dose re-escalation of the VEGFR-

TKI can be considered when entering the maintenance phase of treatment.

Following treatment with VEGFR-TKIs in combination with chemotherapy or other

anticancer therapies, specific risks and management should be considered when

diarrhea occurs. Particular care must be given to patients who present with grade 2

diarrhea with accompanying worrying clinical features or abnormal test results

(outlined in Figure 1, inset tables ‘Specific warning signs to be assessed to evaluate

the severity of a patient’s VEGFR-TKI-induced diarrhea’, ‘Non-treatment-related

secondary causes’ and ‘Treatment-related secondary causes’), and consideration

must be given as to whether these patients may require hospitalization and

evaluation [23,32]. Patients with grade ≥3 diarrhea require aggressive management

[28]. If neutropenic sepsis is suspected, patients should be managed according to

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local guidelines with empirical antibiotic therapy, and if bowel obstruction is

suspected, patients should be managed according to local guidelines.

Conclusions

VEGFR-TKIs are an alternative therapeutic strategy for the treatment of ovarian

cancer. If VEGFR-TKIs are licensed for use in ovarian cancer, patients will only

attain optimum benefit if prompt and effective management of AEs such as diarrhea

is implemented. Treatment interruptions and prompt dose reductions have proven to

be a successful strategy for improving compliance when VEGFR-TKIs are used to

treat other malignancies, and similar strategies could be utilized for ovarian cancer

patients [8]. Further research is required to elucidate the mechanisms by which

VEGFR-TKI-induced diarrhea occurs and investigators should develop predictive

models that identify the ovarian cancer patients who are most at risk of developing

diarrhea following treatment with a VEGFR-TKI. Here, we have presented a diarrhea

treatment algorithm that should serve as a clinical reference point for the

management of diarrhea in patients with ovarian cancer treated with a VEGFR-TKI in

combination with chemotherapy or other anticancer therapies, or as monotherapy.

Contributors

All authors were present at a 1-day meeting during which the need for

recommendations on VEGFR-TKI-induced diarrhea in patients with ovarian cancer

was established and an outline for this review was agreed. All authors contributed to

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the writing of the manuscript by allocation of topics. All authors critically reviewed the

manuscript in its entirety and approved the final content.

Acknowledgments

The authors would like to thank the patients who participated in the HRQoL

interviews. Medical writing assistance was provided by Claire Routley, PhD of

Mudskipper Business Ltd, funded by AstraZeneca. Role of the funding source:

AstraZeneca funded the meeting at which the content of this manuscript was

conceived. The funder had no input into the topics included, the development of the

recommendations, or the writing of the manuscript.

Conflicts of interest

Joyce Liu has served as a consultant for AstraZeneca and Tesaro. Gordon Jayson

has received research funding from AstraZeneca and Roche. Peter Reichardt has

served as consultant for Novartis, Pfizer, Bayer, PharmaMar, Amgen,

GlaxoSmithKline, AstraZeneca, Clinigen and Lilly and has received honoraria from

Novartis, Pfizer, Bayer, PharmaMar, Amgen, GlaxoSmithKline and Lilly. Ken Croitoru

has served as a consultant for AstraZeneca and Boehringer Ingelheim. Shibani

Nicum has received research funding from AstraZeneca and has served as a

consultant for AstraZeneca, Roche, Tesaro and Clovis. Beate Illek has received

research funding from GlaxoSmithKline. Manuela Schmidinger has served as a

consultant for AstraZeneca, Pfizer, Roche, Novartis, BMS, Astellas, Eisai, Ipsen and

Exelixis. Catherine Rogers and Christin Whelan have no conflicts to declare.

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References

1. Ferlay J, Soerjomataram I, Ervik M et al. GLOBOCAN 2012 v1.1, Cancer

Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon,

France: International Agency for Research on Cancer. 2014. Available at:

http://globocan.iarc.fr.

2. Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology:

current status and future directions. Lancet 2016;388:518-29.

3. Rossi L, Verrico M, Zaccarelli E, Papa A, Colonna M, Strudel M, et al.

Bevacizumab in ovarian cancer: a critical review of phase III studies. Oncotarget

2017;8:12389-405.

4. Ledermann JA, Perren TJ, Raja FA, Embleton A, Rustin GJS, Jayson G, et al.

Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed

platinum sensitive ovarian cancer: results of the ICON6 trial. Eur J Cancer

2013;49(Suppl 3):abst LBA 10.

5. Hou MM, Wang Z, Janku F, Piha-Paul S, Naing A, Hong D, et al. Continuous anti-

angiogenic therapy after tumor progression in patients with recurrent high-grade

epithelial ovarian cancer: phase I trial experience. Oncotarget 2016;7:35132-43.

6. Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, et al.

Combination cediranib and olaparib versus olaparib alone for women with recurrent

platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol

2014;15:1207-14.

21

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

7. Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology,

frequency and guideline-based management. Ther Adv Med Oncol 2010;2:51-63.

8. Schmidinger M. Understanding and managing toxicities of vascular endothelial

growth factor (VEGF) inhibitors. EJC Suppl 2013;11:172-91.

9. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al.

Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous

ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status

in a randomised phase 2 trial. Lancet Oncol 2014;15:852-61.

10. Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral

anticancer treatment. CA Cancer J Clin 2009;59:56-66.

11. Ledermann JA, Embleton AC, Raja F, Perren TJ, Jayson GC, Rustin GJS, et al.

Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a

randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2016;387:1066-

74.

12. Kalra S, Rini BI, Jonasch E. Alternate sunitinib schedules in patients with

metastatic renal cell carcinoma. Ann Oncol 2015;26:1300-4.

13. Reichardt P, Kang YK, Rutkowski P, Schuette J, Rosen LS, Seddon B, et al.

Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety

and efficacy in a worldwide treatment-use trial of sunitinib. Cancer 2015;121:1405-

13.

22

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

14. Boussios S, Pentheroudakis G, Katsanos K, Pavlidis N. Systemic treatment-

induced gastrointestinal toxicity: incidence, clinical presentation and management.

Ann Gastroenterol 2012;25:106-18.

15. Gibson RJ, Stringer AM. Chemotherapy-induced diarrhoea. Curr Opin Support

Palliat Care 2009;3:31-5.

16. Andreyev J, Ross P, Donnellan C, Lennan E, Leonard P, Waters C, et al.

Guidance on the management of diarrhoea during cancer chemotherapy. Lancet

Oncol 2014;15:e447-e460.

17. Van Sebille YZ, Gibson RJ, Wardill HR, Bowen JM. ErbB small molecule tyrosine

kinase inhibitor (TKI) induced diarrhoea: chloride secretion as a mechanistic

hypothesis. Cancer Treat Rev 2015;41:646-52.

18. Kornblau S, Benson AB, Catalano R, Champlin RE, Engelking C, Field M, et al.

Management of cancer treatment-related diarrhea. Issues and therapeutic

strategies. J Pain Symptom Manage 2000;19:118-29.

19. Fan L, Iseki S. Immunohistochemical localization of vascular endothelial growth

factor in the endocrine glands of the rat. Arch Histol Cytol 1998;61:17-28.

20. Schmidinger M. Mechanisms and management of diarrhoea from anti-VEGFR-

TKIs. 2013. Available at: http://www.euikcs.com/kca/docs/f-05-SCHMIDINGER.pdf.

23

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

21. Lordick F, Geinitz H, Theisen J, Sendler A, Sarbia M. Increased risk of ischemic

bowel complications during treatment with bevacizumab after pelvic irradiation:

report of three cases. Int J Radiat Oncol Biol Phys 2006;64:1295-8.

22. Sanders KM, Koh SD, Ward SM. Interstitial cells of Cajal as pacemakers in the

gastrointestinal tract. Annu Rev Physiol 2006;68:307-43.

23. Hirsh V. Managing treatment-related adverse events associated with EGFR

tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr Oncol

2011;18:126-38.

24. Stark DP, Cook A, Brown JM, Brundage MD, Embleton AC, Kaplan RS, et al.

Quality of life with cediranib in relapsed ovarian cancer: the ICON6 phase 3

randomized clinical trial. Cancer 2017;123:2752-61.

25. Dranitsaris G, Lacouture ME. Development of prediction tools for diarrhea and rash

in breast cancer patients receiving lapatinib in combination with capecitabine.

Breast Cancer Res Treat 2014;147:631-8.

26. Maroun JA, Anthony LB, Blais N, Burkes R, Dowden SD, Dranitsaris G, et al.

Prevention and management of chemotherapy-induced diarrhea in patients with

colorectal cancer: a consensus statement by the Canadian Working Group on

Chemotherapy-Induced Diarrhea. Curr Oncol 2007;14:13-20.

27. National Cancer Institute. Common Terminology Criteria for Adverse Events,

Version 4.03. 2010. Available at: http://ctep.cancer.gov.

24

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

28. Cancer Research UK. Symptoms of diarrhoea. 2016. Available at:

http://www.cancerresearchuk.org/about-cancer/coping-with-cancer/coping-

physically/bowel/types/diarrhoea/symptoms-of-diarrhoea.

29. Atkinson BJ, Kalra S, Wang X, Bathala T, Corn P, Tannir NM, et al. Clinical

outcomes for patients with metastatic renal cell carcinoma treated with alternative

sunitinib schedules. J Urol 2014;191:611-8.

30. Bjarnason GA, Khalil B, Hudson JM, Williams R, Milot LM, Atri M, et al. Outcomes

in patients with metastatic renal cell cancer treated with individualized sunitinib

therapy: correlation with dynamic microbubble ultrasound data and review of the

literature. Urol Oncol 2014;32:480-7.

31. Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, et al.

Randomized Phase II trial of sunitinib on an intermittent versus continuous dosing

schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol

2012;30:1371-7.

32. Hirsh V, Blais N, Burkes R, Verma S, Croitoru K. Management of diarrhea induced

by epidermal growth factor receptor tyrosine kinase inhibitors. Curr Oncol

2014;21:329-36.

33. U.S. National Library of Medicine. Diarrhea. 2017. Available at:

https://medlineplus.gov/diarrhea.html.

25

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

34. Benson AB, III, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA,

Jr., et al. Recommended guidelines for the treatment of cancer treatment-induced

diarrhea. J Clin Oncol 2004;22:2918-26.

35. Saltz LB. Understanding and managing chemotherapy-induced diarrhea. J Support

Oncol 2003;1:35-46.

36. Rabbani GH, Teka T, Zaman B, Majid N, Khatun M, Fuchs GJ. Clinical studies in

persistent diarrhea: dietary management with green banana or pectin in

Bangladeshi children. Gastroenterology 2001;121:554-60.

37. Rabbani GH, Larson CP, Islam R, Saha UR, Kabir A. Green banana-supplemented

diet in the home management of acute and prolonged diarrhoea in children: a

community-based trial in rural Bangladesh. Trop Med Int Health 2010;15:1132-9.

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Figure legends

Figure 1. Algorithm for the assessment and management of VEGFR-TKI-

induced diarrhea for patients with ovarian cancer [27,28,34]

*Specific warning signs (inset table), †potential secondary causes (inset table), ‡symptom

management (Figure 2, inset table) and §dose optimization (Figure 2) are detailed as indicated

Figure 2. Alternative dose schedule recommendations for VEGFR-TKIs in

women receiving treatment who develop persistent grade 1–2 uncomplicated

diarrhea resistant to loperamide: diarrhea symptom management [23,26,32,34-

37] and symptom management and treatment recording for patients

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