Safety of endoscopy in patients undergoing treatments with antiangiogenic agents:A 5-year retrospective review

lNTRODUCTlON

Angiogenesis is a complex process of forming vascular network by endothelial cells proliferation mediated by growth factors like vascular endothelial growth factors (VEGF),insulin like growth factors,fibroblast growth factors and hypoxia inducible factors.It is first initiated during embryogenesis from mesodermal precursor cells,later repeated during process of healing.Similarly,when tumor cells are subjected to hypoxia,they produce growth factor leading to angiogenesis.This not only provide a source of nutrition but also a means for metastasis.

Folkman postulated the idea of antiangiogenic agents (AAs) as an effective cancer therapy in early 1970[1].Currently,AAs are widely used in the treatment of malignant tumors owing to their effectiveness in increasing survival.Monoclonal antibodies,VEGF decoy receptor,and small molecule tyrosine kinase inhibitors are three major classes of anti-angiogenics currently in clinical practice[2].However,VEGF also play a crucial role in wound healing and the use of AAs may potentially lead to complications such as bleeding and impaired wound healing[1,3].

Post-procedure adverse events were higher among patients receiving AAs[4].The potential for increased occurrence of complications such as bleeding among cancer patients on AAs after procedures have led to the postponement of elective surgical procedures and endoscopies for at least 28 d after AA treatment.The mechanism of gastrointestinal (GI) perforation is attributed to splanchnic or mesenteric thrombi,impaired healing and proliferation,decreased blood supply to intestinal wall,and decreased stability secondary to tumor destruction have been postulated[5].There is limited and inconsistent data in the literature regarding the rate of adverse events during endoscopy among patients on AAs.Imbulgoda

[6] reported two complications of perforation (2/80 patients) in patient receiving bevacizumab while undergoing placement of self-expanding metal stent.More recently Kachaamy

[7] revealed a low adverse event of 1.6% (7/455) in patients receiving AA.The cautious approach of delaying even low risk endoscopic procedures among patients receiving AAs may have resulted from the extrapolation of findings from studies of surgical procedures where increased adverse events like bleeding and impaired wound healing were observed[4].It is important to note that endoscopic procedures are not as invasive as other surgical procedures and recommendations should not be solely based on data from surgical procedures.

Naturally a great scramble70 ensued, and at last the laughter and shouting awoke the Queen, who rang for her maids to ask the reason of such an unwonted hurry-burly

In this single centered study,we reviewed medical records of the patients who underwent GI endoscopy after receiving anti-angiogenics therapy within the past 28 d.Here we aim to investigate 30 d adverse events in patients receiving AA undergoing an endoscopic procedure.

MATERlALS AND METHODS

Study design and patient population

This is a single center retrospective study conducted at a non-National Cancer Institute (NCI)designated hospital specializing in treatment of cancers in the state of Georgia,United States.Inclusion criteria for the study were: (1) Patients receiving treatment with AAs including vascular endothelial growth factor (VEGF),VEGF receptor inhibitors,epidermal growth factor receptor inhibitors,multitargeted tyrosine kinase inhibitors,and mammalian target of rapamycin inhibitor;and (2) Patients undergoing endoscopic procedures within 28 d of AA administration between from January 1,2015 -March 31,2020.Exclusion criteria included: Age less than 18 years old.All patients undergoing endoscopic procedures within 28 d after administration of AAs were included in the study analysis.The Augusta University Investigation Review Boards approved this study.

Patients who met the inclusion and exclusion criteria were identified using I2B2 software,and details regarding the endoscopic procedures and the timing of AA administration were obtained from the electronic medical records.Endoscopic procedures were categorized as either high risk or low risk based on existing literature regarding endoscopic procedural risks associated with antithrombotic agents[8].Low risk procedures included diagnostic endoscopies or with biopsy.In contrast,high risk procedures consisted of stent placements,gastrostomy tube placements,snare polypectomy,endoscopic retrograde cholangiopancreatography,and endoscopic ultrasound with fine needle aspiration.

Statistical analysis

Statistical analyses were performed utilizing simple descriptive statistics including percentages and frequencies.The demographic data,the mortality rate and the endoscopic adverse events were analyzed using descriptive statistics.The primary outcome measure was mortality rate within 30 d of endoscopy whereas the secondary outcome measures were procedure-related adverse events such as bleeding and perforation within 30 d of endoscopy.The adverse events were labeled according to the common terminology criteria for adverse events version (have version 5.0 now) which defines adverse events(AEs) as an unintended and unfavorable outcome associated with a medical treatment or procedure that may or may not be associated to the medical treatment or procedure.Classification of the severity of AEs were based on a grading system from 1 to 5 wherein 1 is mild,2 is moderate,3 is severe,4 is lifethreatening and 5 is death.The mortality rate and incident rate of AEs were determined using the total number of study participants as the denominator.

RESULTS

Patient characteristics

Use of AAs have also been associated with an increased bleeding risk.This was demonstrated in a meta-analysis of 38 randomized controlled trials evaluating safety and efficacy of bevacizumab,which revealed a dose-dependent increased risk of bleeding (RR: 1.36

2.87)[17].Another meta-analysis evaluating 22 studies identified an incidence of high-risk bleeding of 2.8% (95%CI 2.1%-3.8%) among patients receiving bevacizumab[18].In comparison to the findings of the previously mentioned metaanalysis,our study did not identify any patients with post-procedure bleeding.However,one patient had persistent variceal hemorrhage despite attempts for endoscopic control with variceal ligation.

“Yes, listen,” replied the crow, “but it is so difficult to speak your language. If you understand the crows’ language then I can explain it better. Do you?”

Procedures

A total of 85 endoscopic procedures were performed with 24 (28.2%) categorized as high-risk and 61(71.8%) procedures as low-risk.High risk procedures included variceal bleeding control,percutaneous gastrostomy tube placement,pneumatic balloon dilation,and stent placement while low-risk included diagnostic procedures along with mucosal biopsies.The average duration between administration of AAs and the performance of endoscopic procedures was 9.9 d (Table 3).

We performed a retrospective analysis of patients,on antiangiogenic agents,who were admitted to the hospital at our institute.We used simple descriptive statistics to primarily assess mortality within 30 d of the procedure along with the incidence of bleeding and perforation.

Adverse events and mortality

Among the eighty-five endoscopic procedures that were performed,there were no procedure related adverse events that were documented.One patient on lenvatinib therapy for metastatic hepatocellular carcinoma had persistent bleeding despite esophageal variceal banding and died 4 d later from hemorrhagic shock.Another patient on sorafenib therapy for AML died 24 d after an esophagogastroduodenoscopy with biopsy while on hospice care (Table 4).

DlSCUSSlON

We found no procedure-related adverse events in our small population study among the patients receiving antiangiogenic agents.These results need to be further confirmed in a multicentric larger population group.

The first AA to be approved for use was bevacizumab for treatment of breast cancer and since then,AAs have played an integral role in the treatment of many oncological conditions[9].Various AAs have shown a survival benefit for patients undergoing treatment of colorectal,liver,renal-cell,ovarian,endometrial,cervical,breast,and gliomas[10-14].Bevacizumab and other AAs have been associated with poor wound-healing and increases the risk of complications if undergoing surgical and endoscopic procedures.Current literature suggest that the use of bevacizumab and other VEGF inhibitors can impair wound healing and potentially lead to severe wound healing complications[3].It is therefore recommended to delay elective surgeries for at least 28 d from the time of AA administration[15,16].At present,there is no recommendation regarding the timing of endoscopic procedures among patients on AAs.Our study indicates that there were no procedure related AEs when AAs were administered within 28 d of an endoscopic procedure including high-risk ones.

Fifty-nine patients (M/F = 25/34) were included in this study who underwent a total of 85 endoscopic procedures.The mean age of the study population was 64.9 years at the time of endoscopy.Majority of the patients were Caucasians (54.2%) or African Americans (40.7%).The most common malignancy types were colorectal cancer (20.7%),liver (11.9%),ovarian (10.2%) and lung (10.2%);and the majority(59.3%) had stage IV metastatic disease at the time of endoscopy (refer to Table 1).Thirty patients (50%)were on bevacizumab whereas other patients were on imatinib (11.7%),lenvatinib (6.7%),ramucirumab(5%) as detailed on Table 2.One of the patients with the diagnosis of acute myeloid leukemia (AML)who was being treated with two anti-angiogenic agents bevacizumab and sorafenib.

AAs have also been linked with increased gastrointestinal perforation especially if endoscopic interventions like colonic self-expanding stents (SEMS) are attempted.The rate of perforation ranges between 2%-12% among patients undergoing SEMS placement[19,20].A meta-analyses evaluating effectiveness and safety of monoclonal antibodies including bevacizumab,cetuximab and panitumumab concluded that the use of these agents have serious adverse events including gastrointestinal perforation[20].This risk of gastrointestinal perforation,even with the performance of high-risk endoscopic procedures,was not seen in our study which supports the findings of the multicenter outcome study by Kachaamy

[7] regarding the safety of endoscopy among patients on AAs.

Several years later, young Tom was rummaging1 around in the garage as only a five- or six-year-old can rummage2 when he came across the all-leather, NFL regulation, 1963 Chicago Bears-inscribed football. He asked if he could play with it. With as much logic3 as I felt he could understand, I explained to him that he was still a bit too young to play carefully with such a special ball. We had the same conversation several more times in the next few months, and soon the requests faded away.

Strengths of our study include the removal of any potential selection bias with the inclusion of all patients who underwent endoscopic procedures while on AAs.Given that our facility is not an NCIdesignated cancer center,the findings of our study are generalizable and applicable to the general practice.Nonetheless,this study is limited by its retrospective nature and small sample size.

CONCLUSlON

With the increased survival rate of cancer patients with newer chemotherapy,more patients would require endoscopic procedures for further surveillance and screening.It is important to assess the safety of endoscopic procedures among patients receiving therapy such as antiangiogenic agents who are at higher risk for bleeding and perforation.

ARTlCLE HlGHLlGHTS

Research background

High-grade bleeding and perforation are some of the side effects of antiangiogenic agents.The safety of endoscopy in patients receiving this therapy is unknown.Here we attempt to explore the incidence of bleeding,perforation,and mortality in our single centered study.

Research motivation

In this single center retrospective study,the rate of endoscopic procedure-related adverse events and death within 28 d of AA administration are low.Our study results further support the findings of Kachaamy

[7] on the safety of endoscopy among patients on AAs.While it is recommended to hold AAs 28 d prior to the performance of an elective endoscopic procedure,this should not delay the performance of an emergent or urgent endoscopic procedure given its good safety profile.Our study reiterates the safety data of low-risk endoscopic procedures in this sub-group of patients.This also raises further questions about whether there is a need to hold anti-angiogenics in patients on antiangiogenics prior to high-risk endoscopic procedures.Awareness of newer medication and its implication on our current practice of gastroenterology are crucial for delivering optimal patient care.Future prospective studies should be evaluated in a multicentric larger population groups while keeping in mind that the GI cancers have an inherent increased risk of bleeding and perforation.

Research objectives

14. Carroty: Redheads have a long history of symbolism attached to their hair color, most generally in the category of demonic associations (Tresidder, p. 220).Return to place in story.

Research methods

My mind was subdued10 as my heart overflowed11 with the magic of gratitude12 and wonder. I slipped my ring onto my trembling hand, and a smile filled my soul as I whispered, Thanks Mom.

8. Alone in the wood: Julius Heusher states that the woods represent the loss of security and previous values (Heuscher 1974).Return to place in story.

Research results

There is limited data on the safety of endoscopy in patients undergoing treatment with AA for oncological malignancies.Most recently,in a retrospective multi-center study by Kachaamy

[7],the safety of endoscopy was investigated to identify adverse events and mortality in cancer patients being treated with AAs and undergoing endoscopy within 31 d of administration of AAs.It was concluded that endoscopy is well tolerated in patients on AAs and the incidence of adverse events was 0.7%,while the 30 d mortality was estimated at 6.5[7].In our study,no procedural adverse events were observed,and the mortality rate was 2.35%.One of the two patient succumbed to persistent variceal bleeding,and the other patient died after transition to comfort care.

Research conclusions

Our study reveals that endoscopic procedures are safe in patients receiving antiangiogenic agents.It affirms to not delay emergent or urgent endoscopic procedures among this population.

He very soon found out that in addition to her natural indolence, she was being as much indulged and spoilt day by day as if the Fairy had been her grandmother, and was obliged to remonstrate17 very seriously upon the subject

Research perspectives

Future research should be carried out in a multicentric and larger group of the population than the one in this study to further assess the safety of the endoscopic procedure among this population group.

1872FAIRY TALES OF HANS CHRISTIAN ANDERSENA STORY FROM THE SAND-HILLSby Hans Christian AndersenTHIS story is from the sand-dunes or sand-hills of Jutland, but itdoes not begin there in the North, but far away in the South, in Spain. The wide sea is the highroad from nation to nation; journey in thought; then, to sunny Spain. It is warm and beautiful there;the fiery pomegranate flowers peep from among dark laurels; a coolrefreshing breeze from the mountains blows over the orange gardens,over the Moorish halls with their golden cupolas and coloured walls.

Azam MU and Hudgi AR performed the research,collected the data,wrote the paper,contributed to analysis and reviewed the article;Uy P collected the data and reviewed the article;Makhija J performed the formal analysis;Yap JE conceptualized,supervised the report and approved the final draft submitted.

This study was reviewed and approved by the Ethics Committee of the Augusta University Medical Centre.

To understand the risk of endoscopy in patients on antiangiogenic agents.

Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.

All authors declare that they have no conflict of interest.

The technical appendix,statistical code,and dataset are available from the corresponding author at jyap@augusta.edu.Consent was not obtained as this was a retrospective study.No additional data are available.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution Noncommercial (CC BYNC 4.0) license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

United States

Mohammad Azam 0000-0002-3847-5285;Amit Hudgi 0000-0002-3062-7694;Pearl Princess Uy 0000-0002-0884-3104;Jinal Makhija 0000-0002-6931-5188;John Erikson L Yap 0000-0002-0441-3211.

“Little maiden,” said the lord-in-waiting, “I will obtain for you constant employment in the kitchen, and you shall have permission to see the emperor dine, if you will lead us to the nightingale; for she is invited for this evening to the palace.” So she went into the wood where the nightingale sang, and half the court followed her. As they went along, a cow began lowing.

Wang LL

A

Wang LL

1 Folkman J.Role of angiogenesis in tumor growth and metastasis.

2002;29: 15-18 [PMID: 12516034 DOI:10.1053/sonc.2002.37263]

2 Al-Husein B,Abdalla M,Trepte M,Deremer DL,Somanath PR.Antiangiogenic therapy for cancer: an update.

2012;32: 1095-1111 [PMID: 23208836 DOI: 10.1002/phar.1147]

3 Sharma K,Marcus JR.Bevacizumab and wound-healing complications: mechanisms of action,clinical evidence,and management recommendations for the plastic surgeon.

2013;71: 434-440 [PMID: 22868316 DOI:10.1097/SAP.0b013e31824e5e57]

4 Tol J,Cats A,Mol L,Koopman M,Bos MM,van der Hoeven JJ,Antonini NF,van Krieken JH,Punt CJ.Gastrointestinal ulceration as a possible side effect of bevacizumab which may herald perforation.

2008;26: 393-397[PMID: 18335169 DOI: 10.1007/s10637-008-9125-4]

5 Sliesoraitis S,Tawfik B.Bevacizumab-induced bowel perforation.

2011;111: 437-441 [PMID:21803880]

6 Imbulgoda A,MacLean A,Heine J,Drolet S,Vickers MM.Colonic perforation with intraluminal stents and bevacizumab in advanced colorectal cancer: retrospective case series and literature review.

2015;58: 167-171 [PMID:25799132 DOI: 10.1503/cjs.013014]

7 Kachaamy T,Gupta D,Edwin P,Vashi P.Safety of endoscopy in cancer patients on antiangiogenic agents: A retrospective multicenter outcomes study.

2017;12: e0176899 [PMID: 28472195 DOI:10.1371/journal.pone.0176899]

8 ASGE Standards of Practice Committee,Acosta RD,Abraham NS,Chandrasekhara V,Chathadi KV,Early DS,Eloubeidi MA,Evans JA,Faulx AL,Fisher DA,Fonkalsrud L,Hwang JH,Khashab MA,Lightdale JR,Muthusamy VR,Pasha SF,Saltzman JR,Shaukat A,Shergill AK,Wang A,Cash BD,DeWitt JM.The management of antithrombotic agents for patients undergoing GI endoscopy.

2016;83: 3-16 [PMID: 26621548 DOI:10.1016/j.gie.2015.09.035]

9 Gerriets V,Kasi A.Bevacizumab.In: StatPearls [Internet].Treasure Island (FL): StatPearls Publishing,2022 [PMID:29489161]

10 Shojaei F,Ferrara N.Antiangiogenic therapy for cancer: an update.

2007;13: 345-348 [PMID: 18032969 DOI:10.1097/PPO.0b013e31815a7b69]

11 Rini BI,Halabi S,Rosenberg JE,Stadler WM,Vaena DA,Archer L,Atkins JN,Picus J,Czaykowski P,Dutcher J,Small EJ.Phase III trial of bevacizumab plus interferon alfa

interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206.

2010;28: 2137-2143 [PMID: 20368558 DOI:10.1200/JCO.2009.26.5561]

12 Pal SK,McDermott DF,Atkins MB,Escudier B,Rini BI,Motzer RJ,Fong L,Joseph RW,Oudard S,Ravaud A,Bracarda S,Suárez C,Lam ET,Choueiri TK,Ding B,Quach C,Hashimoto K,Schiff C,Piault-Louis E,Powles T.Patient-reported outcomes in a phase 2 study comparing atezolizumab alone or with bevacizumab

sunitinib in previously untreated metastatic renal cell carcinoma.

2020;126: 73-82 [PMID: 32233107 DOI: 10.1038/s41591-018-0053-3]

13 Chellappan DK,Leng KH,Jia LJ,Aziz NABA,Hoong WC,Qian YC,Ling FY,Wei GS,Ying T,Chellian J,Gupta G,Dua K.The role of bevacizumab on tumour angiogenesis and in the management of gynaecological cancers: A review.

2018;102: 1127-1144 [PMID: 29710531 DOI: 10.1016/j.biopha.2018.03.061]

14 Bose D,Meric-Bernstam F,Hofstetter W,Reardon DA,Flaherty KT,Ellis LM.Vascular endothelial growth factor targeted therapy in the perioperative setting: implications for patient care.

2010;11: 373-382 [PMID: 20171141 DOI:10.1016/S1470-2045(09)70341-9]

15 Gordon CR,Rojavin Y,Patel M,Zins JE,Grana G,Kann B,Simons R,Atabek U.A review on bevacizumab and surgical wound healing: an important warning to all surgeons.

2009;62: 707-709 [PMID: 19461291 DOI:10.1097/SAP.0b013e3181828141]

16 Ahmadizar F,Onland-Moret NC,de Boer A,Liu G,Maitland-van der Zee AH.Efficacy and Safety Assessment of the Addition of Bevacizumab to Adjuvant Therapy Agents in Cancer Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

2015;10: e0136324 [PMID: 26331473 DOI: 10.1371/journal.pone.0136324]

17 Hang XF,Xu WS,Wang JX,Wang L,Xin HG,Zhang RQ,Ni W.Risk of high-grade bleeding in patients with cancer treated with bevacizumab: a meta-analysis of randomized controlled trials.

2011;67: 613-623[PMID: 21243343 DOI: 10.1007/s00228-010-0988-x]

18 Yan FH,Zhang Y,Bian CL,Liu XS,Chen BC,Wang Z,Wang H,Ji-Fu E,Yu ED.Self-expanding metal stent insertion by colorectal surgeons using a two-person approach colonoscopy without fluoroscopic monitoring in the management of acute colorectal obstruction: a 14-year experience.

2021;19: 194 [PMID: 34215276 DOI:10.1016/j.clcc.2019.05.009]

19 Lee JH,Emelogu I,Kukreja K,Ali FS,Nogueras-Gonzalez G,Lum P,Coronel E,Ross W,Raju GS,Lynch P,Thirumurthi S,Stroehlein J,Wang Y,You YN,Weston B.Safety and efficacy of metal stents for malignant colonic obstruction in patients treated with bevacizumab.

2019;90: 116-124 [PMID: 30797835 DOI:10.1016/j.gie.2019.02.016]

20 da Silva WC,de Araujo VE,Lima EMEA,Dos Santos JBR,Silva MRRD,Almeida PHRF,de Assis Acurcio F,Godman B,Kurdi A,Cherchiglia ML,Andrade EIG.Comparative Effectiveness and Safety of Monoclonal Antibodies(Bevacizumab,Cetuximab,and Panitumumab) in Combination with Chemotherapy for Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.

2018;32: 585-606 [PMID: 30499082 DOI:10.1007/s40259-018-0322-1]