34th Annual Scientific Meeting proceedings

Non-resectable and metastatic tumors of the hepatobiliary system present a difficult challenge for veterinarians and pet owners.  The relatively limited efficacy of intravenous chemotherapy for macroscopic disease, and the limitations of radiation therapy have stimulated the search for additional therapeutic options.  Similar difficulties in human oncology have inspired various creative, image-guided, regional tumor therapies in the continuously developing subspecialty of interventional radiology (IR).  IR involves the use of contemporary imaging techniques such as fluoroscopy and ultrasonography to selectively access vessels and other structures in order to deliver different materials for therapeutic reasons.  In the past two decades, IR techniques have expanded considerably with both hepatobiliary vascular and non-vascular procedures being performed routinely in humans.  Specifically, IR techniques are being increasingly utilized to help palliate humans with cancer in which traditional therapies have failed or have been demonstrated to provide little benefit.  These techniques are particularly useful in cases of regional disease in order to maximize local therapy and minimize systemic toxicity.  While results have been variable, regional techniques such as percutaneous tumor ablation, intra-arterial chemotherapy, transcatheter arterial embolization/chemoembolization, and/or palliative stenting have been demonstrated to improve survival times, disease-free intervals, recurrence rates, or completeness of tumor necrosis.

Traditional Therapies

Traditional treatment modalities still remain an important part of managing patients with metastatic or non-resectable cancers.  Systemic chemotherapy typically demonstrates poor response rates for most bulky tumors or metastatic disease, however can occasionally shrink excessively large tumors enabling subsequent resection.  Radiation therapy is just starting to be investigated further for non-resectable liver tumors.  Surgery can still play a major role in animals with advanced malignancies, even when tumor excision is not possible.  De-bulking non-resectable tumors may occasionally be indicated, but is typically avoided as the patient’s quality of life is often not substantially improved in these situations, and surgical complications are not uncommon.

Palliative Stenting for Malignant Obstructions

Animals are routinely euthanized for local effects of a tumor rather than the systemic effects associated with a large cancer burden.  For example, malignant obstructions of the biliary tract or hepatic/portal venous system can result in life-threatening signs.  IR techniques involving the placement of intra-luminal stents to palliate similar malignant obstructions in humans have been described.  Palliative stenting procedures in the liver include vascular stenting as well as biliary stenting for benign or malignant obstructions.  These IR techniques were rapid, safe, minimally-invasive, and effective, and complications were often minor and uncommon.

Intra-Arterial Chemotherapy Delivery

Current therapies for bulky tumors not amenable to complete surgical include chemotherapy, radiation therapy, and surgical debulking, but none are able to consistently produce durable remissions.  Research suggests that some of these tumors can respond more favorably to higher concentrations of chemotherapy, however significant deleterious side effects often result when dose escalations are attempted.  Recent advancements in interventional radiology techniques now enable veterinarians to administer different drugs into the arteries feeding the actual tumors via minimally-invasive approaches in order to achieve very high regional drug concentrations within the tumor without the systemic side effects that would occur had these levels been administered intravenously.  This basically provides a local dose escalation without the increased systemic toxicities.  Studies confirm both higher achieved levels of chemotherapy within the targeted tissues as well as improved tumor remissions in laboratory animals.  It is possible that we can demonstrate similar effects in our canine patients with naturally occurring tumors not amenable to currently available standard-of-care treatments.

Arterial Embolization / Chemoembolization / Dearterialization                        

“Embolotherapy” involves the use of fluoroscopy to selectively access specific vascular structures in order to deliver particulate material to control hemorrhage, occlude vascular malformations, or reduce tumor growth.  Arterial embolization techniques using polyvinyl alcohol particles or other materials have been performed in veterinary patients to control intractable epistaxis associated with nasal tumors, to reduce hemorrhage associated with non-resectable tumors, or to control pain and slow tumor growth of metastatic cancer.  In some cases, subsequent surgical resection was possible following the embolization-induced tumor shrinkage. 

Chemoembolization involves super-selective intra-arterial chemotherapy delivery in conjunction with subsequent particle embolization.  Intra-arterial chemotherapy has been shown to result in a 10- to 50-fold increase in intra-tumoral drug concentrations when compared to systemic intravenous chemotherapy administration. Subsequent particle embolization results in tumor cell necrosis and paralyzes tumor cell excretion of chemotherapy resulting in minimized systemic toxicity.  This procedure is most commonly used in the treatment of diffuse hepatocellular carcinoma or metastatic liver disease in humans.  Most hepatic tumors depend upon hepatic arterial blood supply (up to 95%) for growth in contrast to the normal liver parenchyma that receives the majority of its blood supply via the portal vein (only ~20% from the hepatic artery). Hepatic artery embolization should theoretically cause more ischemia to the liver tumor while the remaining normal hepatic parenchyma obtains sufficient oxygenation from the portal venous system.  In addition, when used within the liver, the chemotherapy is often typically mixed with a carrier agent, Ethiodol.  This oily substance supplies radiographic contrast to the chemotherapy as well as acting as a tumor localizer and embolic agent.  Hepatic tumors lack Kupfer cells which are important for metabolizing oily substances (lipid) in normal hepatic parenchyma.  Therefore, the Ethiodol and accompanying chemotherapy are concentrated within the liver tumor rather than the surrounding healthy hepatic parenchyma.  Recently, chemotherapy-eluting beads have been evaluated in veterinary patients with nonresectable liver tumors and current research is being conducted with the use of an ethanol:lipiodol emulsion.

Reported complications in the human literature include hemorrhage at the vascular access site, non-target embolization complications (skin necrosis, damage to normal parenchyma), hepatic infarction/abscessation, acute renal failure (for liver tumors), and post-embolization syndrome, a collection of clinical signs characterized by malaise, fever, and pain.

Tumor Ablation

Percutaneous tumor ablation techniques (radiofrequency ablation as well as microwave ablation, laser thermal ablation, cryoablation, and percutaneous ethanol injection) tend to be most effective with a few (<3), small (<4cm diameter) lesions.  These circumstances are fairly uncommon in the author’s clinical experience, however with the routine use of more advanced imaging techniques in veterinary medicine, lesions of this size and number may become increasingly apparent during tumor re-staging procedures, making tumor ablation techniques a reasonable option in the future.  More recently, advances in local ablation technology has provided the ability to more closely monitor the areas of ablation as well as to provide larger ablation areas. 

Biliary Interventions

Biliary interventions can be performed for benign or malignant biliary obstructions.  These techniques can be performed in both cats and dogs but the smaller the patient the more difficult these techniques are to perform.  ERCP (endoscopic retrograde cholangiopancreatography) or EBS (endoscopic biliary stenting) is technical very challenging and an experience MD practitioner is required when learning these procedures.  There are adult (but more commonly pediatric) side-view endoscopes which are required for these procedures.  A combination of endoscopy and fluoroscopy is used to identify the obstruction and either place a removeable/retrievable stent or a permanent stent to relive the obstruction.  As these procedures are technically challenging and access to a skilled MD is not always available, we have been working on developing hybrid surgical/fluoroscopic techniques to relive biliary obstructions using a modified “rendezvous technique” described in people.  This technique may be more accessible to veterinarians and can result in successful decompression of biliary obstructions. 

References available upon request