**Abstract**

This chapter discusses effective diagnostics and treatment of canine hepatic carcinoma (CHC), where state-of-the-art global technologies are complemented by traditional Chinese veterinary medicine (TCVM). The biokinetic Ga-67 model of CHC is proposed to clarify the Ga-67 metabolic mechanism among various organs. It is aimed at identifying the best routine for detecting the metastatic or primary CHC and substantiating the optimal further treatment. The routine examination of CHC can be performed via Ga-67 nuclear examination or MRI, biological index, X-ray, and abdominal ultrasound. The available methods of animal cancer treatment imply separate or combined application of surgery, radiation therapy, and chemotherapy targeted at the particular cancer cells. However, there is also a general concern on the quality of life of pets/canine patients. This leaves enough space to the TCVM (including acupuncture and famous herbal drugs) with a long application history in Asia and growing usage as alternative treatment in other regions. However, its current applications to domestic animals/pets suffering from carcinomas are based on individual expert opinions, while there are no outlined veterinary treatment strategies and guidelines for clinical practice in this field. A comprehensive combination of state-of-the-art global technologies and TCVM is considered instrumental in curing canine hepatic carcinoma.

**Keywords:** canine hepatic carcinoma, nuclear examination, Ga-67 biokinetic model, traditional Chinese veterinary medicine, acupuncture

### **1. Introduction**

#### **1.1 Motivation and purpose**

Dog owners are aware of the sad fact that their pets are vulnerable to various tumors that may occur at any age/location and cause severe complications. In particular, canine hepatic tumors correspond to 0.6 to 1.3% of canine neoplasms, while about 7–36% of dogs are metastasized from other organs [1–9]. The canine patients, which usually suffer from systemic metabolic stress and cachexia, require a surgery or chemotherapy based on the veterinarians' recommendations and life expectations. Noteworthy is that different tumor types of primary carcinoma can arise from different cell types listed in **Table 1** [2]. The major types of primary liver cancer are hepatocellular carcinoma (HCC), bile duct carcinoma, neuroendocrine (carcinoid) tumor, and mesenchymal tumor (sarcoma). Hepatocellular carcinoma (HCC) is generally found in dogs, especially elder ones. Compared with the modular or diffuse forms, the majority of HCC has a lower rate of metastasis. A single massive HCC tumor can usually be removed by surgical treatment. However, the most difficult clinical treatment is the diffuse HCC involving in the entire liver. Dogs with multiple liver lobes' HCC are not recommended to undergo surgical resection, have a poor prognosis and very limited treatment options [2–4, 10–13]. Bile duct carcinomas are the second common malignant liver tumor in dogs. Neuroendocrine tumors are quite rare and mostly nodular or diffuse, while primary liver sarcomas, including hemangiosarcoma, fibrosarcoma, and hepatocellular carcinoma, are unusual clinically. Dogs with liver tumors can be either asymptomatic or exhibit nausea, vomiting, weight loss, loss of appetite, diarrhea, lethargy, or PU/PD. Occasionally, yellowing of the skin and eyes like jaundice, or neurological signs (hepatic encephalopathy), such as seizures, disorientation, and weakness, are observed. Liver carcinoma grows slowly and manifests itself too late [2–6, 14–16]. This study attempts to set up the Ga-67 nuclear examination protocol for liver carcinoma canine patients, which would guide the veterinary expert and dog owner on the further optimal treatment: intensive surgery/chemotherapy or/and traditional Chinese veterinary medicine.

## **1.2 Definition of critical terminology**

In this study, the global state-of-the-art approach to the above problem implies the conventional medicine based on modern science and advanced evaluation methods of canine physical and biochemical conditions. The respective treatment methods include chemotherapy, drugs, radiology, and surgery. Local tumor ablation and radiotherapy have been applied in veterinary medicine for decades. Chemotherapy is related to the use of several anti-cancer drugs administered intravenously, orally, or subcutaneously, which circulate in the patient's body and attack cancer cells. The most common chemotherapy drugs for treating liver cancer are listed in **Table 2**. Alkylating agents react with DNA strands and change the DNA structure. The commonly utilized


**157**

*Canine Hepatic Carcinoma: Diagnoses and Treatments Via Global State-of-the-Art Approach…*

**Drug Indications Toxicity Dosage and Route of** 

Sterile hemorrhagic

cystitis BM\* , Gl#

BM\*

Melphalan MM<sup>Ψ</sup>, Plasma cell tumors BM\* 0.1 mg/kg/day PO x 10 days,

BM\* , Gl# , hypersensitivity reaction, perivascular damage with extravasation, cumulative myocardial toxicity

(dogs), nephrotoxicity (cats)

BM\* , Gl# , perivascular damage with extravasation

, Nephrotoxicity, Fatal pulmonary edema (cats)

**Administration**

IV or PO

(mild) Variable PO

, liver Dogs: 60–90 mg/m2

q3wk

Cats: 50 to 60 mg/m2

10 mg/cat PO q3 to 4wk

then 0.05 mg/kg QOD; 0.2 pulse dose at 7 mg/m2 daily for five days q3wk

Dogs:≧15 kg: 30 mg/m2

Dogs: < 15 kg: 1 mg/kg IV

Cats: 1 mg/kg or 25 mg/m2

Dogs: 5 to 6 mg/m2

Cats: 6 to 6.5 mg/m2

Cats: 240 to 260 mg/m2

(saline Do not use in cats emesis, diuresis)

q2 to 3wk

q2 to 3wk

q3wk

q3wk

q3 to 4wk

(mild), Gl# 0.8 mg/kg IV once weekly

(mild), Gl# Variable; SQ, IM. IV.

BM\* Limited studies Dogs: 100

to 1000 mg/m2

50 mg/m2 twice/wk. with RT<sup>ω</sup>

25 mg/m2

with RT<sup>ω</sup>

IV;

twice/wk.

Cats:

Dogs: 70 mg/m2

, Gl# Dogs: 300 mg/m2

Typically 200–250 mg/m2

PO

PO or

IV

IV q3wk

IV

IV q3wk

IV q3wk

IV

*DOI: http://dx.doi.org/10.5772/intechopen.96077*

Cyclophosphamide Lymphoma, Sarcoma,

Chlorambucil Lymphoma

Carcinoma

(lymphocytic) CLL§

hemorrhagic cystitis

sterile

occurs

Doxorubicin Lymphoma, Sarcoma,

Mitoxantrone Lymphoma

CCNU (Lomustine) Lymphoma, MCT※ BM\*

Carcinoma

Carcinoma

Carboplatin Sarcoma, Carcinoma BM\*

Cisplatin Sarcoma, Carcinoma BM\*

Methotrexate Lymphoma BM\*

Gemcitabine Lymphoma, MM<sup>Ψ</sup>,

Lymphoma BM\*

Carcinoma. feline SCC¶

, MCT※, to replace Cyclophosphamide if

Alkylating Agents

Anthracyclines

Platinum Drugs

Antimetabolites

Cytosine arabinoside

**Table 1.** *Primary hepatobiliary tumor types.*


*Canine Hepatic Carcinoma: Diagnoses and Treatments Via Global State-of-the-Art Approach… DOI: http://dx.doi.org/10.5772/intechopen.96077*

*Canine Genetics, Health and Medicine*

**1.2 Definition of critical terminology**

**Classification Types**

*Source: DOI: 10.1016/j.cvsm.2016.11.016.*

*Primary hepatobiliary tumor types.*

1. Hepatocellular a. Hepatic adenoma

4. Mesenchymal a. Hemangiosarcoma

2. Biliary a. Biliary adenoma (or cystadenoma)

b. Biliary carcinoma 3. Neuroendocrine a. Neuroendocrine carcinoma or carcinoid

> b. Leiomyosarcoma c. Fibrosarcoma d. Osteosarcoma

e. Malignant mesenchymoma f. Chondrosarcoma

b. Hepatocellular carcinoma c. Hepatoblastoma

about 7–36% of dogs are metastasized from other organs [1–9]. The canine patients, which usually suffer from systemic metabolic stress and cachexia, require a surgery or chemotherapy based on the veterinarians' recommendations and life expectations. Noteworthy is that different tumor types of primary carcinoma can arise from different cell types listed in **Table 1** [2]. The major types of primary liver cancer are hepatocellular carcinoma (HCC), bile duct carcinoma, neuroendocrine (carcinoid) tumor, and mesenchymal tumor (sarcoma). Hepatocellular carcinoma (HCC) is generally found in dogs, especially elder ones. Compared with the modular or diffuse forms, the majority of HCC has a lower rate of metastasis. A single massive HCC tumor can usually be removed by surgical treatment. However, the most difficult clinical treatment is the diffuse HCC involving in the entire liver. Dogs with multiple liver lobes' HCC are not recommended to undergo surgical resection, have a poor prognosis and very limited treatment options [2–4, 10–13]. Bile duct carcinomas are the second common malignant liver tumor in dogs. Neuroendocrine tumors are quite rare and mostly nodular or diffuse, while primary liver sarcomas, including hemangiosarcoma, fibrosarcoma, and hepatocellular carcinoma, are unusual clinically. Dogs with liver tumors can be either asymptomatic or exhibit nausea, vomiting, weight loss, loss of appetite, diarrhea, lethargy, or PU/PD. Occasionally, yellowing of the skin and eyes like jaundice, or neurological signs (hepatic encephalopathy), such as seizures, disorientation, and weakness, are observed. Liver carcinoma grows slowly and manifests itself too late [2–6, 14–16]. This study attempts to set up the Ga-67 nuclear examination protocol for liver carcinoma canine patients, which would guide the veterinary expert and dog owner on the further optimal treatment: intensive surgery/chemotherapy or/and traditional Chinese veterinary medicine.

In this study, the global state-of-the-art approach to the above problem implies the conventional medicine based on modern science and advanced evaluation methods of canine physical and biochemical conditions. The respective treatment methods include chemotherapy, drugs, radiology, and surgery. Local tumor ablation and radiotherapy have been applied in veterinary medicine for decades. Chemotherapy is related to the use of several anti-cancer drugs administered intravenously, orally, or subcutaneously, which circulate in the patient's body and attack cancer cells. The most common chemotherapy drugs for treating liver cancer are listed in **Table 2**. Alkylating agents react with DNA strands and change the DNA structure. The commonly utilized

**156**

**Table 1.**


*\*: BM; bone marrow, #: Gl; gastrointestinal, §: CLL; chronic lymphocytic leukemia,* ※*: MCT; mast cell tumor,*  Ψ*: MM; multiple myeloma,* ω*: RT: radiation therapy, ¶: SCC; squamous cell carcinoma.*

*Source: https://veteriankey.com/chemotherapy/, chapter 44: Chemotherapy.*

*Alkylating agents react with DNA strands and changing the DNA structure. Anthracycline antibiotics exert their cytotoxic effect through different mechanisms, including free radical formation, DNA intercalation, and protein synthesis inhibition. Platinum drugs act at the N7 position of guanine and adenine residues, suggesting DNA as the primary target of the drug. Antimetabolites are drugs that interfere with enzymes or affect DNA synthesis. Antimicrotubule Agents interfere with the mitotic spindle, which inhibits cellular division and proliferation.*

#### **Table 2.**

*Classification of chemotherapy drugs for treatment.*

alkylating agents in veterinary oncology are chlorambucil, cyclophosphamide, melphalan, and lomustine. The common toxicity of cyclophosphamide is related to sterile hemorrhagic cystitis. Anthracycline antibiotics exert their cytotoxic effect through different mechanisms, including free radical formation, DNA intercalation, and protein synthesis inhibition. An example of such medicine is Mitoxantrone, which is metabolized in the liver and eliminated via feces and urine. Platinum drugs act at the N7 position of guanine and adenine residues, having DNA as their primary target and being eliminated via kidneys [6]. Antimetabolites are drugs that interfere with enzymes or affect DNA synthesis. Their chemo group, methotrexate, is primarily eliminated via renal excretion. Finally, there are antimicrotubule agents, which interfere with the mitotic division process, inhibiting cell division and proliferation.

Quite a recent treatment introduced to veterinary oncology is radiology or radiation therapy. It rapidly became one of the most common procedures of cancer treatment, insofar as it could be clinically performed when surgical resection of the tumor remaining after chemotherapy would be problematic or too dangerous. Radiotherapy can make cells unable to replicate and eliminate the cell division and proliferation. However, radiation therapy can damage normal cells, rather than only malignant ones. A well-designed radiotherapy program is intended and designed to maximize tumor effect and minimize normal

**159**

**Figure 1.**

*Preast, TCVM fundamental principles, 2nd edition).*

*Canine Hepatic Carcinoma: Diagnoses and Treatments Via Global State-of-the-Art Approach…*

tissue effect. The benefit of radiotherapy is a cure for tumors and a split course

*Etiology of neoplasia in TCVM. The factors contributing to form phlegm, qi and blood stagnation, blood stasis, and eventually, neoplasia, are summarized. It is shown that qi deficiency is the root of cancer and phlegm, qi/blood stagnation, and blood stasis are one part of the branches. (cited from Huisheng Xie, Vanessa* 

The alternative approach to the above "targeted instrumental and drug invasion into the injured body part" is the overall improvement of the whole body and emotional well-being of a patient. In case of canine patients, this approach is reduced to the Traditional Chinese Veterinary Medicine (TCVM), which has been introduced several thousand years ago as a system of health care and is being implemented globally nowadays as alternative medicine [12]. Briefly, the TCVM has accumulated a vast list of robust diagnoses of canine diseases based on basic symptoms and appearances (tongue color, skin conditions, iris, pulse, etc.). A veterinarian analyzes these symptoms and the related overall system problems. The proposed cure is TCVM-based herbal medicine aimed to fine-tune the immune system and prevent a reoccurrence of an illness or future problem as illustrated in **Figure 1** [18, 19].

*DOI: http://dx.doi.org/10.5772/intechopen.96077*

treatment before surgery or chemotherapy [17].

*Canine Hepatic Carcinoma: Diagnoses and Treatments Via Global State-of-the-Art Approach… DOI: http://dx.doi.org/10.5772/intechopen.96077*

tissue effect. The benefit of radiotherapy is a cure for tumors and a split course treatment before surgery or chemotherapy [17].

The alternative approach to the above "targeted instrumental and drug invasion into the injured body part" is the overall improvement of the whole body and emotional well-being of a patient. In case of canine patients, this approach is reduced to the Traditional Chinese Veterinary Medicine (TCVM), which has been introduced several thousand years ago as a system of health care and is being implemented globally nowadays as alternative medicine [12]. Briefly, the TCVM has accumulated a vast list of robust diagnoses of canine diseases based on basic symptoms and appearances (tongue color, skin conditions, iris, pulse, etc.). A veterinarian analyzes these symptoms and the related overall system problems. The proposed cure is TCVM-based herbal medicine aimed to fine-tune the immune system and prevent a reoccurrence of an illness or future problem as illustrated in **Figure 1** [18, 19].

#### **Figure 1.**

*Canine Genetics, Health and Medicine*

Antimicrotubule Agents

Miscellaneous

**Table 2.**

5FU Sarcoma, carcinoma BM\*

Vincristine Lymphoproliferative

cancer, Sarcoma

Vinblastine Lymphoma, MCT※ BM\*

Procarbazine Lymphoma BM\*

*Source: https://veteriankey.com/chemotherapy/, chapter 44: Chemotherapy.*

*Classification of chemotherapy drugs for treatment.*

L-Asparaginase Lymphoma Hypersensitivity

Ψ*: MM; multiple myeloma,* ω*: RT: radiation therapy, ¶: SCC; squamous cell carcinoma.*

alkylating agents in veterinary oncology are chlorambucil, cyclophosphamide, melphalan, and lomustine. The common toxicity of cyclophosphamide is related to sterile hemorrhagic cystitis. Anthracycline antibiotics exert their cytotoxic effect through different mechanisms, including free radical formation, DNA intercalation, and protein synthesis inhibition. An example of such medicine is Mitoxantrone, which is metabolized in the liver and eliminated via feces and urine. Platinum drugs act at the N7 position of guanine and adenine residues, having DNA as their primary target and being eliminated via kidneys [6]. Antimetabolites are drugs that interfere with enzymes or affect DNA synthesis. Their chemo group, methotrexate, is primarily eliminated via renal excretion. Finally, there are antimicrotubule agents, which interfere with the mitotic division process, inhibiting cell division and proliferation. Quite a recent treatment introduced to veterinary oncology is radiology or radiation therapy. It rapidly became one of the most common procedures of cancer treatment, insofar as it could be clinically performed when surgical resection of the tumor remaining after chemotherapy would be problematic or too dangerous. Radiotherapy can make cells unable to replicate and eliminate the cell division and proliferation. However, radiation therapy can damage normal cells, rather than only malignant ones. A well-designed radiotherapy program is intended and designed to maximize tumor effect and minimize normal

*\*: BM; bone marrow, #: Gl; gastrointestinal, §: CLL; chronic lymphocytic leukemia,* ※*: MCT; mast cell tumor,* 

*Alkylating agents react with DNA strands and changing the DNA structure. Anthracycline antibiotics exert their cytotoxic effect through different mechanisms, including free radical formation, DNA intercalation, and protein synthesis inhibition. Platinum drugs act at the N7 position of guanine and adenine residues, suggesting DNA as the primary target of the drug. Antimetabolites are drugs that interfere with enzymes or affect DNA synthesis. Antimicrotubule Agents interfere with the mitotic spindle, which inhibits cellular division and proliferation.*

**Drug Indications Toxicity Dosage and Route of** 

, Gl# , Neurotoxicity, Fatal neurotoxicity

in cats

BM\* , Gl# , Constipation (ileus), Peripheral neuropathy, Perivascular tissue reaction

, Gl# , Perivascular tissue reaction

reaction

**Administration**

Dogs: 150 mg/m2

0.5 to 0.75 mg/m2

2 to 2.2 mg/m2

m2

, Gl# Variable; dogs: 50 mg/ m2 /day

400 lU/kg or 10.000 IU/

 SQ or IM (10,000 IU maximum) weekly

in cats

wk. IV, topically Do not use

weekly or every other week

once/

IV

IV weekly

**158**

*Etiology of neoplasia in TCVM. The factors contributing to form phlegm, qi and blood stagnation, blood stasis, and eventually, neoplasia, are summarized. It is shown that qi deficiency is the root of cancer and phlegm, qi/blood stagnation, and blood stasis are one part of the branches. (cited from Huisheng Xie, Vanessa Preast, TCVM fundamental principles, 2nd edition).*

### **1.3 Background review and rationale study with reference**

Liver carcinoma can be diagnosed or detected by using multiple methods. Histological findings are considered the most robust for canine patients. The TNM staging system for canine hepatocellular carcinoma (HCC) is summarized in **Table 3** [20]. Veterinary surgeons may perform additional blood examinations to look for signs of liver dysfunction. Surgery is one of the treatments for all liver tumors. However, right-sided tumors are more challenging to resect because the resection lesion is related to the vena cava [2]. For massive hepatic carcinoma, surgical resection via lobectomy is the treatment when complete resection is accepted [10, 11]. The mass ligation for complete lobectomy is not recommended for large dogs, or central or right divisional liver tumors, because this method will increase the risk of complications, such as bleeding or bile leakage. Surgical stapling devices are recommended to perform liver lobectomy; in these devices, overlapping rows of staples are quickly placed to attenuate vascular and biliary structures within the liver lobe's hilus. If stages T3, N1, or M1 in **Table 3** are confirmed by clinicalstage evaluations, no surgical resection is recommended [20] because it would not remove some malignant liver tumors. Therefore, chemotherapy becomes an alternative treatment. Unfortunately, according to many clinical practices and references, chemotherapy is not very effective liver carcinoma treatment. Thus, HCC treatment with intravenous gemcitabine or carboplatin is no longer performed. Instead, in the last decade, the Metronomic chemotherapy and Sorafenib treatment (5 mg/kg, twice daily) became widely used due to lower-dose usage and administration ease [6, 7].

Alternatively, radiotherapy is sometimes used to make the liver tumor smaller or incapsulate it. However, it is not applicable to most liver tumor cases because of its side-effects. The major complication is a radiation heat-induced damage to the adjacent unaffected liver tissue. A 3D-CRT (three-dimensional conformal radiation therapy) is introduced as a new viable treatment option for canine patients with an inoperable massive liver carcinoma. From 6 to 10 Gy per fraction are prescribed on the planning target volume, and the total dose is 18–42 Gy with 1 to 2 fractions per week [17].

#### **1.4 The innovative features of this study**

This study is the first attempt to apply the biokinetic Ga-67 model to canine liver carcinoma. The aim is to identify the best routine for detecting the metastatic or primary hepatic carcinoma and substantiating the optimal further treatment.


**161**

**Figure 2.**

**2.1 Biological index**

*Canine Hepatic Carcinoma: Diagnoses and Treatments Via Global State-of-the-Art Approach…*

The biokinetic model of Ga-67 evolution was elaborated in this study for the case–control group of canine liver carcinoma via in-vivo gamma camera/8-slice CT technique. The circulation of time-dependent concentrations of Ga-67 among organs was monitored and simulated. The obtained quantitative data for organs and branching ratios among organs were incorporated into the biokinetic model of

Due to the absence of nerves in the liver, the early liver neoplasia is painless. Therefore, when canine patients are clinically examined, their liver disease if any is

The clinical symptoms include depression, lack of appetite, vomiting, weight loss, diarrhea, PU/PD, abdominal distention, lethargy, icterus, and ascites. The neurological disorder is mainly caused by hypoglycemia, hepatic encephalopathy, or

Hematologic features, including mild non-regenerative anemia, inflamed leukocytosis, and thrombocytosis, are common in canine liver tumors [1, 15, 16].

*A 12-year-old female Maltese had distention of the abdomen, was diagnosed with a liver tumor via ultrasound.*

metastasis of the central nervous system as shown in **Figure 2** [9, 21–24].

*DOI: http://dx.doi.org/10.5772/intechopen.96077*

**1.5 The specific rationale study with a solid description**

Ga-67 radionuclide administered during the hepatic survey.

**2. Diagnosis of canine hepatic carcinoma**

diagnosed as moderate or severe.

**Table 3.**

*The TNM staging system for canine hepatocellular carcinoma.*

*Canine Hepatic Carcinoma: Diagnoses and Treatments Via Global State-of-the-Art Approach… DOI: http://dx.doi.org/10.5772/intechopen.96077*
