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ACCEPTED MANUSCRIPT. 1. Gastrointestinal perforation and fistula formation in five cases with colorectal cancer during treatment with regorafenib. Authors.
Accepted Manuscript Gastrointestinal perforation and fistula formation in five cases with colorectal cancer during treatment with regorafenib Ayako Doi, Yasutoshi Kuboki, Kohei Shitara, Shota Fukuoka, Hideaki Bando, Wataru Okamoto, Takashi Kojima, Toshihiko Doi, Atsushi Ohtsu, Takayuki Yoshino PII:

S1533-0028(16)30257-2

DOI:

10.1016/j.clcc.2016.11.003

Reference:

CLCC 340

To appear in:

Clinical Colorectal Cancer

Received Date: 25 July 2016 Revised Date:

2 October 2016

Accepted Date: 14 November 2016

Please cite this article as: Doi A, Kuboki Y, Shitara K, Fukuoka S, Bando H, Okamoto W, Kojima T, Doi T, Ohtsu A, Yoshino T, Gastrointestinal perforation and fistula formation in five cases with colorectal cancer during treatment with regorafenib, Clinical Colorectal Cancer (2017), doi: 10.1016/ j.clcc.2016.11.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Gastrointestinal perforation and fistula formation in five cases with colorectal cancer during treatment with regorafenib Authors

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Ayako DOI1, Yasutoshi KUBOKI1, Kohei SHITARA1, Shota FUKUOKA1, Hideaki BANDO1, Wataru OKAMOTO1, Takashi KOJIMA1, Toshihiko DOI1, Atsushi OHTSU1, Takayuki YOSHINO1 Affiliations

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1-Department of gastrointestinal oncology, National cancer center hospital east, Kashiwa, Japan Kashiwa, Japan Corresponding author: Yasutoshi KUBOKI, M.D.

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5-Department of experimental therapeutics, National cancer center hospital east,

Department of gastrointestinal oncology, National cancer center hospital east, Kashiwa, Kashiwanoha6-5-1, Kashiwa, Chiba, 277-8577, Japan

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Tel: +81-471-33-1111; Fax: +81-471-31-9960: [email protected]

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Abstract Regorafenib is an oral multi-kinase inhibitor that targets multiple pathways, including vascular endothelial growth factor receptor (VEGFR), and improves survival in cases with metastatic colorectal cancer (mCRC). Gastrointestinal (GI)

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perforation and fistula are well-recognized adverse events associated with agents that target the VEGF pathway including bevacizumab. Herein, we report five cases with GI perforation or fistula formation during treatment with regorafenib. We identified one case with GI perforation (0.6%) and four cases

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with fistula formation (2.4%) among 170 mCRC cases administered regorafenib in our hospital. In all five cases, GI perforation or fistula involved the residual tumor, and they were successfully treated with antibiotic therapy or surgery and

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recovered from these adverse events. It is important to recognize that GI

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perforation and fistula may occur in cases being treated with regorafenib.

Keywords colorectal cancer, regorafenib, gastrointestinal perforation, fistula,

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chemotherapy

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Clinical Practice Points

Regorafenib is an oral multi-kinase inhibitor including VEGF pathway for metastatic colorectal cancer. Gastrointestinal (GI) perforation and fistula formation related to regorafenib were also reported as well as bevacizumab or other tyrosine kinase inhibitors. GI perforation and fistula during or after regorafenib therapy involved the residual tumor, and all cases with GI perforation and fistula complained of a fever and/or a pain. If patients have a fever or pain, we should pay careful attention to these adverse events.

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Introduction Angiogenesis plays an important role in the growth, proliferation, and metastasis of solid tumors. One of the main angiogenic factors is vascular endothelial growth factor (VEGF). VEGF and its receptor are involved in new blood vessel may be promising anti-cancer agents. 1,2,3)

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formation and tumor progression. Therefore, inhibitors of the VEGF pathway

Several agents that target the angiogenic signal pathway that includes VEGF

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have been developed. Bevacizumab is a monoclonal antibody, targeting VEGF-A, which was approved for the treatment of multiple solid tumors, including metastatic colorectal cancer (mCRC), non-small cell lung cancer,

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ovarian cancer, renal cell cancer, and recurrent glioblastoma. 4) Bevacizumab as well as other tyrosine kinase inhibitors (TKIs) that target VEGF pathway, such as sunitinib or sorafenib, cause gastrointestinal (GI) perforation and fistula 5-18)

formation (Table 1).

Regorafenib, an oral multi-kinase inhibitor targets

multiple pathways, including those involving VEGFR1-3, tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2), KIT,

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platelet derived growth factor receptor (PDGFR), and rearranged during transfection (RET) tyrosine kinase, and the inhibition of VEGF pathway may increase the risk of serious adverse events such as GI perforation and fistula 19,20)

Only a few cases of GI perforation or fistula have been reported

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formation.

among patients taking regorafenib.

21)

Fistula occurred in four of 500 cases

(0.8%) in the phase III CORRECT trial for mCRC, GI perforation did in one of

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136 cases (0.7%) in the phase III CONCUR trial for mCRC and two of 188 cases (1.1%) in the phase III GRID trial for advanced GIST. 15,16,22,23) A description of the trials of agents that target the VEGF pathway and reports of GI perforation and fistula is in Table1. However, we are still not sufficiently aware of these events during regorafenib treatment in a routine clinical practice setting. Herein, we report five cases of GI perforation or fistula formation during regorafenib treatment to clarify the characteristics and the clinical course of patients who developed these adverse events during treatment or within 30 days of the last administration of regorafenib.

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Case Report and Discussion We retrospectively analyzed data from 170 cases with mCRC who received regorafenib between May 2013 and March 2016 at the National Cancer Center Hospital East. We identified one case with GI perforation (0.6%) and four cases

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with fistula formation (2.4%) (Table 2). There were three male and two female, and the median age was 59 years (range, 44–78 years). All cases had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. The primary tumor was previously resected in three cases, and the location of the

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residual primary tumor or local recurrence was the rectum in three cases and the colon in two cases. There were three cases with peritoneum metastases. All cases had previously received two or more lines of chemotherapy including

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bevacizumab. One case had received previous abdominal irradiation. In all five cases, GI perforation or fistula involved the residual tumor, including three at the site of the primary tumor or local recurrence in rectum, and two cases at the site of the primary tumor in the transverse colon or jejunum which was involved in peritoneal metastases. An abscess and Fournier’s gangrene due

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to the fistula were observed between the tumor and perineum in three cases with rectal cancer. Figure 1 presents a representative fistula formation case. A computed tomography (CT) scan in case of jejunum perforation showed tumor

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shrinkage in the peritoneal metastasis by regorafenib treatment and, in addition, free air in the abdominal cavity (Figure 2). According to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, all cases had radiological stable

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disease by regorafenib treatment. The median time between onset of GI perforation or fistula formation and the initiation of regorafenib was 20 days (range 5–84 days). These events occurred during regorafenib treatment in four cases and eight days after termination of regorafenib in one case. The median time between the last administration of bevacizumab as prior treatment and onset of GI perforation or fistula was 71 days (range 29-107 days) and all events occurred more than 34 weeks after the initiation of bevacizumab treatment. The main symptoms for these events were fever and pain. Three cases underwent emergency surgery with debridement. 4

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The other two cases received antibiotic treatment, and one of them required additional surgery, so a total of four cases required surgery. All cases recovered from these adverse events, median time from the onset to recovery was 13 days, and there were no deaths related to the GI perforation or fistula. Two cases

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received subsequent chemotherapy. One case was alive more than 1 year later and the other four cases died from disease progression with a median survival of 6 months after GI perforation and fistula formation (range 3-20 months).

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We reported the clinical characteristics of four cases of GI fistula and one of perforation that were treated for mCRC with regorafenib. The incidence of these adverse events was similar to the incidence in previous reports related to

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administration of bevacizumab or other TKIs. Although all cases had received bevacizumab before treatment with regorafenib, we speculate that these adverse events were related to regorafenib rather than bevacizumab. As the reason for this, it was reported that GI perforation and fistula related to bevacizumab occurred within 15 weeks after the initiation of bevacizumab treatment, while our cases occurred more than 34 weeks after the initiation of 24)

In addition, the estimated half-life of bevacizumab

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bevacizumab treatment.

was approximately 20 days, although our cases occurred more than 29 days after the last dose of bevacizumab. Therefore, we considered that there was the

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reasonable casual relationship between these adverse events and regorafenib. Several mechanism for GI perforation as a result of VEGF inhibition have been

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proposed, including: 1) decreased capillary density in the intestinal mucosa and regeneration of the normal mucosa depending on nitric oxide and prostacyclin involving VEGF, 2) shrinkage and necrosis of the tumor infiltrating the intestinal mucosa in response to treatment, 3) bowel ischemia by thrombosis or cholesterol embolism syndrome of the mesenteric vessels, and 4) the regression of normal blood vessels.

24)

Other risk factors for GI perforation are bowel

surgery, abdominal irradiation, colonoscopy within 1 month, peptic ulcer disease, administration of nonsteroidal anti-inflammatory drugs or steroids, intact primary tumor, abdominal carcinomatosis, bowel obstruction, diverticulosis, and chemotherapy induced colitis.

19,24)

A recent study reported that, contrary to 5

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previous reports, only a residual primary tumor, abdominal irradiation, or age younger than 65 years were associated with GI perforation.

25,26)

Similarly, two

cases in our study had residual primary tumor, one case had been previously treated with abdominal irradiation, and four cases younger than 65 years old. Of

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note, the stenosis and accumulation of feces due to residual tumor resulting in increased inner pressure of bowel itself, may be associated with fistula formation in three cases with rectal tumors. Therefore, we supposed that perforation and fistula tended to occur in the rectum when the tumor remained during treatment

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with regorafenib. It was reported that GI perforation might occur in response to treatment. 20) We actually found shrinkage of the peritoneal metastasis in one case with GI perforation. The precise analyses of the value of peritoneal

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metastasis and residual primary tumor as a risk factor for GI perforation or fistula warrant further evaluation. Conclusion

It is still unclear whether VEGFR-TKIs, including regorafenib, increase the risk of GI perforation, because, unlikely to bevacizumab, a meta-analysis of

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VEGFR-TKIs indicated that there was no difference in frequency of GI perforation between the TKIs and the control arm.

27)

However, the

meta-analysis might have been influenced by the fact that there were fewer cases with abdominal primary tumors in the analysis of TKIs (58%) than there

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were in the analysis of bevacizumab (74%). 5,27) In addition, because regorafenib inhibits some mechanisms of tumor vascularization that differ from bevacizumab,

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there may be some differences in characteristics of perforation. Further analysis using a large sample size is necessary to clarify the role of VEGFR-TKIs as risk factors for GI perforation or fistula and the clinical characteristics because we had a small sample enrolled from a single institution. Finally, all cases in this study complained of a fever and/or a pain, which were adequately

treated

by

antibiotic

treatment

or

surgery.

There

were

treatment-related deaths from these adverse events in some case reports of regorafenib and other TKIs. 21,28) If patients have a fever or pain during or after regorafenib therapy, then we should pay careful attention to these adverse events. 6

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6. Van Cutsem E, Rivera F, Berry S et al: Safety and efficacy of first-line bevacizumab with FOLFOX. XELOX, FOLFIRI and fluoropyrimidines in

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24. Sliesoraitis S, Tawfik B: Bevacizumab-induced bowel perforation. J Am 25. Staif MIW, Elfiky A, Salem RR et al: Gastrointestinal perforation due to

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28. Inoue T, Kinoshita H, Komai Y et al: Two cases or gastrointestinal perforation after radiotherapy in patients receiving tyrosine kinase inhibitor for advanced

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renal cell carcinoma. World J Surg Oncol 2012 Aug 20; 10: 167.

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Figure legends Figure 1. This is a representative fistula formation case: a 62 year old male with local

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recurrence of rectal cancer who developed rectum-perineum fistula formation. Computed tomography (CT) image of the case before regorafenib treatment by CT scan (a, b, c). Rectal local recurrence is seen at anastomosis. CT image of the case after 57 days of regorafenib treatment (d, e, f). In Figure (d) and (e), the

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abscess around the anastomosis is indicated by an arrow. In Figure (f), the rectum-perineum fistula in the left gluteal is indicated by arrows.

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Figure 2.

This is the GI perforation case: a 78 year old female with ascending colon cancer with synchronous peritoneal metastases who developed a jejunum perforation. CT image of the case before regorafenib treatment (a, b). Peritoneal metastases (arrow head) are seen at the periumbilical and intrapelvic sites. CT image of the case after 10 days of regorafenib treatment (c, d). The periumbilical peritoneal

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metastasis (arrow head) shrank (c). Free air and fluid (arrow) were seen in the abdominal cavity, showing the existence of jejunum perforation involved in

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peritoneal metastasis (arrow head) (d).

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Table1. GI perforation or fistula during angiogenesis inhibitors for colorectal cancer

Perforation

1.5

[7]

Phase III

1914

Perforation

1.9

[8]

Phase III

694

Perforation

0.6

[9]

Fistula

0.9

Phase III

521

Perforation

1.2

[10]

Observational

1953

Perforation

1.9

[11]

Perforation

0.7

[12]

Fistula

1.5

Perforation

1.4

Fistula

1.4

Perforation

1.7

Fistula

0.8

Phase III

611 74

529

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Phase III

[13]

[14]

500

Fistula

0.8

[15]

Phase III

136

Fistula

0.7

[16]

Sunitinib

Phase II

74

Perforation

1.4

[17]

Sorafenib

Phase I

18

Fistula

5.6

[18]

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Phase III

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Regorafenib

(%)

393

Phase II Ramucirumab

patients*

Reference

Phase III

cohort study Aflibercept

Incidence

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Bevacizumab

Number of Events

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Study setting

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Agent

*; Safety population which included all patients receiving at least one dose of the agents

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Case

Age

Sex

PS

Event

Primary

Focus

tumor 62

M

0

Fistula

Rectum

Previous

Symptom

treatment Rectum

Onset

Treatment

Outcome

51

Surgery

Improved

20

Surgery

Improved

84

Surgery

Improved

Fever

5

Antibiotics

Improved

Pain

10

Surgery

Improved

(days)*

Operation

Fever

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1

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Table2. Characteristics of GI perforation or fistula cases

FOLFOX/BV

Pain

2

59

M

0

Fistula

Rectum

Rectum

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FOLFIRI/BV

Fever

FOLFOX/BV

Fever

FOLFIRI/

Pain

Operation

Radiation

Pain

FOLFOX

FOLFIRI/BV

44

M

0

Fistula

Rectum

Rectum

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3

5

52 78

F F

0 1

Fistula Perforation

T/C

T/C

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4

EP

Aflibercept (P2)

A/C

Jejunum

TAS102/BV (P2) FOLFOX/BV FOLFIRI/BV Operation FOLFOX/BV FOLFIRI/BV

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T/C; Transverse colon, A/C; Ascending colon, BV; Bevacizumab, P2; Phase 2 trial, *; Onset of GI perforation or fistula

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formation from regorafenib intiaion

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b

d

e

c

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a

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Figure1 CT scans

f

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b

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a

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Figure2 CT scans

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d

c