Drug‐eluting bead chemoembolization for the treatment of nonresectable hepatic carcinoma in dogs: A prospective clinical trial

Abstract Background Effective treatment options for nonresectable hepatic carcinoma (HC) in dogs are limited. Hypothesis/Objective Objectives were to report outcomes, complications, and tumor responses via computed tomography (CT) assessment after drug‐eluting bead transarterial chemoembolization (DEB‐TACE) for nonresectable HC in dogs. The authors hypothesized that major complications would be uncommon and short‐term CT assessment would demonstrate stable disease or partial response. Animals Client‐owned dogs (n = 16) with nonresectable HC. Methods Prospective, single‐arm clinical trial. Drug‐eluting bead transarterial chemoembolization was performed to varying levels of blood flow stasis. Computed tomography imaging was compared before and approximately 12 weeks after initial treatment. Results Drug‐eluting bead transarterial chemoembolization was successfully administered in all attempts. Based on percent change in elliptical tumor volume response (mL), stable disease (8/13; 62%) was the most common outcome followed by partial response (3/13; 23%) and progressive disease (2/13; 15%) with a median of 74 days (range, 39‐125) after initial treatment. Median tumor volume (mL) after DEB‐TACE decreased in volume by 13% (range, 56% decrease to 77% increase). Mild complications consistent with postembolization syndrome occurred after 7/27 (26%) treatments. Major complications occurred after 3/27 (11%) treatments: hepatic abscess/septicemia (2) and cholecystitis/death (1), resulting in treatment‐induced death after 2/27 (7%) treatments. Median survival time after treatment was 337 days (range, 22‐1061). Dogs with a presenting complaint of weight loss (P = .02) had a significantly shorter median survival time (126 days; range, 46‐337) than those dogs without prior history of weight loss (582 days; range, 22‐1061). Conclusions Drug‐eluting bead transarterial chemoembolization for nonresectable HC is a feasible procedure, which promoted stable disease or partial response in 85% of dogs in this study sample.

Conclusions: Drug-eluting bead transarterial chemoembolization for nonresectable HC is a feasible procedure, which promoted stable disease or partial response in 85% of dogs in this study sample.
The objectives of this study were to report outcomes, complications, and computed tomography (CT) elliptical tumor volume response rates associated with administration of 100 to 300 μm doxorubicin DEB-TACE to dogs with nonresectable HC. The authors hypothesized that major 31 complications associated with DEB-TACE treatment would be uncommon and that diagnostic imaging would demonstrate short-term stable disease (SD) or partial response after DEB-TACE. Dogs were included if a cytologic or histologic diagnosis of HC was obtained and if the mass was determined by a surgeon to be nonresectable without substantial risk when assessed by either preoperative computed tomography angiography (CTA) or during exploratory laparotomy. Dogs were excluded if they were treated with chemotherapy, radiation therapy, or surgical intervention other than surgical biopsy within the previous 3 months.

| Case selection
Dogs were staged with standard techniques including physical examination, 3-view thoracic radiography or thoracic CT scan, abdominal CTA, complete blood cell count, serum biochemistry profile, resting bile acids, and urinalysis. The first treatment was performed within 30 days of staging.

| Medical records review
Medical records review was performed, and data recorded included signalment (age, breed, and sex), weight, presenting clinical signs at diagnosis of HC, prior surgeries, biopsy and cytologic findings, history of abdominal effusion, diagnostic imaging findings and tumor volume measurements, DEB-TACE procedural information and schedule, duration of procedure, procedural complications, postprocedural complications, survival times (STs), and necropsy results.

| Treatment protocol
Dogs were to receive 2 DEB-TACE procedures 6 weeks apart. The goal of the initial DEB-TACE procedure was prolonged chemotherapeutic drug-delivery through administration of drug-eluting beads within the tumor while preserving blood flow through the lobar and first-order hepatic arteries, enabling subsequent treatments. The goal of the second treatment was to repeat chemotherapeutic drugdelivery and then additionally provide embolization to vascular stasis, defined as no evidence of continued hepatic arterial flow to the tumor or lack of tumor blush. 32   Response to treatment was generated by the system in tumor volume (in mL). 36,37 Elliptical tumor response was categorized as complete response: complete resolution of all disease; partial response: ≥30% decrease size; SD: percent difference in size between −30% and 20%; and progressive disease ≥ 20% increase in size. [38][39][40]

| Complications
At each visit, a detailed history was obtained from the owner. Complications attributable to the procedure were considered mild if able to be managed by either outpatient or inpatient interventions that did not require anesthesia, or major if requiring urgent intervention under anesthesia for resolution or resulting in death. 31   The median total procedural duration was 91 minutes (range, 70-125). See Table 2 for tumor volume measurements before and after embolization.

| Chemotherapy administered IV
All 16 dogs were discharged from the hospital 1 to 2 days after each DEB-TACE treatment.   There was no association between the date of the first treatment and death as a result of the treatment, implying the absence of a substantial learning curve (P = .28).

| Long-term outcomes
There was no association between whether the first embolization was taken to stasis (P = .88) or whether there were complications after the first embolization (P = .62) and survival. There was no association between whether the second embolization was taken to stasis (P = .99) or whether there were complications after the second embolization (P = .6) and survival.
There was no association between tumor volume (mL) on pretreatment CT and survival (P = .13). There was a statistically significant association between larger tumor volume/body weight (mL/kg) on pretreatment CT and shorter survival (P = .03). There was no association between post-treatment CT tumor volume (mL) and survival (P = .15); however, there was again a statistically significant association between post-treatment CT larger tumor volume/body weight (mL/kg) and shorter survival (P = .02). CT tumor response criteria which were not significantly associated with survival included percent change in tumor volume, or percent change in tumor volume adjusted for bodyweight before or after treatment (P = .39, P = .39). There was no association between a history of weight loss and tumor size as volume (mL) or volume/body weight (mL/kg) (P = .44, P = .18).

| Necropsy
Six out of 16 dogs (38%) had full (4/6; 67%) or partial (2/6; 33%) necropsy reports available; 2 out of 6 necropsy reports were limited in scope with the necropsy report of 1 dog was limited to the hepatic mass and the necropsy report of another dog was limited to the liver and gallbladder. Five out of 6 necropsy reports (83%) confirmed regrowth of HCC; the final necropsy report was consistent with HC. One dog had incompletely resected HCC with vascular invasion diagnosed via excisional biopsy 1608 days before DEB-TACE with suspected HCC regrowth on CT; however, necropsy results were consistent with focal and metastatic HC, suspected to be of

| DISCUSSION
There are currently no established therapeutic recommendations for dogs with metastatic, nonresectable, or incompletely excised HC. 42 The results of this study showed that DEB-TACE treatment for nonresectable HC could be performed successfully, resulted in few major complications, and resulted in 77% of tumors displaying a reduction in volume on follow-up CTA. Drug-eluting bead transarterial chemoembolization could emerge as a viable treatment alternative for dogs with nonresectable HC.
In DEB-TACE in people, the most common complications after embolization are minor and include PES, a syndrome mediated by an inflammatory response to the embolization/chemotherapeutic agent, manifesting in self-limiting abdominal pain, nausea, fever, and fatigue within 14 days of treatment. 19,43,44 In people, PES is associated with a 2-fold increased risk of death. 43 The current study failed to demonstrate an association between PES in dogs and reduced STs; however, the study population was small and the lack of significance could be attributed to a type II statistical error. In people, diarrhea is a less common complication after DEB-TACE, occurring about in~1.6% of humans. 45 46 Larger tumors and increased quantities of embolics are linked to hepatic abscessation in people. 44 The relatively larger tumors treated in dogs might contribute to the higher risk of subsequent abscessation.
Hemoabdomen after TACE is a rare complication with in people with a risk of 0.2% to 0.4% per procedure and more common in larger, heterogeneous, subcapsular, exophytic tumors; these are common characteristics of nonresectable HC in dogs. [48][49][50]  A Nord Grant provided financial support this work. Biocompatibles provided the DEBs for this study. None of the remaining authors had any personal or financial relationships that could inappropriately influence or bias the contents of the paper.

OFF-LABEL ANTIMICROBIAL DECLARATION
Authors declare no off-label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION
Approved by The Animal Medical Center. Each client provided consent and was counseled for participation in the study for each animal.

HUMAN ETHICS APPROVAL DECLARATION
Authors declare human ethics approval was not needed for this study.