Three studies have combined intraarterial chemotherapy with radiation therapy in the treatment of canine osteosarcoma (Heidner et al. 1991; Powers et al. 1991; Withrow et al. 1993). In an appendicular osteosarcoma study, client‐owned dogs were treated with intraarterial cisplatin (2 doses, 21 days apart), and the majority also underwent radiation therapy (Withrow et al. 1993). This group of dogs experienced no significant renal or bone marrow toxicity that affected their long‐term outcome, and radiation side effects were rare. Median survival time in these dogs was 9.3 months. The authors noted that the survival time for these dogs was longer than would be expected for amputation alone, suggesting that there was a survival benefit to the intraarterial chemotherapy. Additionally, the metastasis‐free interval was better than what had been reported previously with radiation therapy alone. Dogs with > 75% tumor necrosis had significantly lower recurrence rates at one year (15%) vs. dogs with < 75% tumor necrosis (65%) (Withrow et al. 1993). In a separate study comparing different treatments for canine osteosarcoma, including intraarterial chemotherapy alone and intraarterial chemotherapy with radiation therapy, the percentage of tumor necrosis was 49.1 and 83.7%, respectively, for those treatment categories (Powers et al. 1991). That study demonstrated that a radiation dose of 28.1 Gy when combined with intraarterial chemotherapy resulted in 80% tumor necrosis (Powers et al. 1991). Another study documented a median survival time of 6.7 months in dogs receiving intraarterial cisplatin chemotherapy in conjunction with radiation therapy as an alternative to amputation or limb‐sparing surgery (Heidner et al. 1991).
There are a vast number of applications for intraarterial chemotherapy that should be investigated in veterinary patients. In humans, the combination of intraarterial chemotherapy and radiation therapy has been successful in treating head and neck malignancies (Wilson et al. 2001; Bertino et al. 2007). These experiences should be used as a scaffolding to develop new treatment strategies for our veterinary patients.
Transarterial Embolization and Chemoembolization
Transarterial embolization (TAE) and transarterial chemoembolization (TACE) are well‐established treatment modalities in human medicine. TAE and TACE are generally not considered first‐line therapies when other standard treatments such as surgery remain as a viable option (Stuart 2003). These procedures are often performed with reversible interruption, meaning that a temporary vascular occlusion agent should be used to allow for future treatments and to prevent collateral formation of blood vessels to the tumor (Greenfield 1980; Gunvén 2008).
TACE has been promoted for several reasons. Eliminating the blood flow to an area that has received chemotherapy will reduce the washout of that drug (Gunvén 2008). Additionally, vessels that are exposed to chemotherapy will also become ischemic (secondary to the embolization), making them more susceptible to the toxic effects of the drug. The embolization may also cause the drug to be retained in the tumor for an extended period of time (Gunvén 2008). As the chemotherapy is given directly into an artery that is feeding the tumor, the systemic side effects may be less, and the tumor may see a higher concentration of drug (Gunvén 2008). TAE may be used as the definitive treatment of neoplastic disease but can also be used preoperatively to decrease blood loss during surgical removal of a tumor (Greenfield 1980; Kadir et al. 1983).
The effects of TAE and TACE have been most studied in the treatment of liver pathologies. There are several factors that make the liver particularly suitable for these techniques. First, the liver has a unique dual blood supply that allows for embolization, while still maintaining an adequate blood supply to healthy tissue. The portal vein provides the majority of the liver’s blood supply (75–85%) with the hepatic artery providing the rest (Zhou et al. 2009). Second, the hepatic artery is the major blood supply to most primary hepatic tumors (85–100%) and tumors that metastasize to the liver (80–100%) (Breedis and Young 1954). This unique arterial blood supply allows the interventional radiologist to occlude blood supply to the tumor without causing significant ischemia to normal liver tissue (Stuart 2003). Third, many drugs have an increased ability to concentrate in the liver, and this limits the systemic toxicity that can be seen with conventional chemotherapy (Stuart 2003). Lastly, the arterial vascular supply to the liver is easily accessible with selective and superselective catheterization (Pentecost 2006).
Lipiodol is an iodized poppy seed oil that has been used as a vehicle for chemotherapy delivery during hepatic TACE (Bhattacharya et al. 1994). Lipiodol has several unique properties as it is radiopaque and is preferentially retained in hepatocellular carcinoma cells (Bhattacharya et al. 1994). These properties make Lipiodol a useful agent to have available during hepatic embolization procedures.
Some studies have identified TACE as the gold standard for the treatment of nonresectable hepatocellular carcinoma in humans (Maleux et al. 2009). Several studies have shown that the administration of TACE in humans with hepatocellular carcinoma improves survival (Camma et al. 2002; Llovet et al. 2002; Lo et al. 2002; Maleux et al. 2009); however, TACE may not provide a survival benefit over TAE (Camma et al. 2002; Gunvén 2008). The use of TACE in the neoadjuvant setting or in a combined preoperative and postoperative protocol has also been evaluated (Liu and Yang 2009; Zhou et al. 2009).
A technique for embolization of hepatic neoplasia was recently described in veterinary patients (Weisse 2009). Clinical veterinary literature documenting both TAE and TACE therapies is limited, and those available have demonstrated mixed results. The embolization of hepatocellular carcinoma, hepatocellular adenoma, fibrosarcoma, nasal adenocarcinoma, and metastatic osteosarcoma has been attempted (Sun et al. 2002; Weisse et al. 2002; Cave et al. 2003; Marioni‐Henry et al. 2007). In the report evaluating two cases of hepatocellular carcinoma, one dog received TAE and the other dog received TACE (Weisse et al. 2002). In those cases, the survival times after embolization were approximately 4 months and 28 days, respectively; however, subjective decrease in the size of the tumor in the dog undergoing TAE was noted and blood flow to the embolized region was decreased (Weisse et al. 2002).
Investigation into the use of TAE and TACE in the treatment of other tumor types has also been performed in humans (Al‐Badr and Faught 2001; Stuart 2003; Nagino et al. 2006; Liapi and Geschwind 2007; Ginat et al. 2009). The potential applications of TAE and TACE have not been well investigated in veterinary patients. Further research into this arena may reveal other tumor types that might respond to these treatments, potentially improving outcomes for companion animals with neoplasia.
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