Currently in veterinary oncology all chemotherapeutic agents are used on an off-label basis, however, this is about to change. The conditionally approved Paccal Vet® is a member of the taxane family and in human oncology, taxanes have been shown to have activity against many cancer histologies including mammary cancer, head and neck squamous cell carcinoma, ovarian cancer, lung cancer, Kaposi sarcoma, gastric cancer, prostate cancer, soft tissue sarcoma, and bladder cancer. Taxanes were first derived from natural sources, however, others have been synthesized artificially (Paclitaxel was originally derived from the Pacific yew). The primary mechanism of action involves disruption of microtubule function which is essential for cell division. Taxanes stabilize tubulin in the microtubule, thereby inhibiting the process of cell division. This leads to a “frozen mitosis” and is in stark contrast to the vinca alkaloids, which destroy mitotic spindles.
As a class, taxanes have poor water solubility and need to to be dissolved before administration. Cremophor® is composed of polyoxyethylated castor oil and dehydrated alcohol and was the first method used to dissolve taxanes for infusion. Since the ratio of Taxane: Cremaphor® in Paclitaxel (Taxol) is 1:88, this means that each ml of solution is composed mostly of solvent, not the active drug. This leads to prolonged infusion volume and infusion times (3 to 6 hours). Taxanes often cause an allergic reaction in humans necessitating the use of antihistamines and steroids before injection. Even with pre-treatments, allergic reactions to Taxol occur in ~41% of people treated. In humans, Cremaphor® hypersensitivity has been overcome by using nab-paclitaxel (Abraxane®). This solution cannot be used in dogs because it uses human albumin, thus limiting its use in veterinary oncology. Taxol has been evaluated in one study of dogs (n=25) against a variety of histologies and although a number of response were noted, 64% (16/25) experienced allergic reactions despite receiving antihistamines and corticosteroids. It was also noted that 56% (14/25) needed to receive a second dose of premedication. The general infusion times lasted between 3 to 6 hours.
Paccal Vet®-CA1 (paclitaxel for injection) differs from human generic paclitaxel as it eliminates the need for Cremophor® through the use of a patented combination of water-soluble retinoid derivatives (of vitamin A) called XR-17. This novel formulation has been evaluated in dogs. In 2 pilot studies, collectively 60% (6 out of 10 dogs) with mammary carcinoma treated with paclitaxel or Paccal Vet®-CA1 (paclitaxel for injection) were accessed as responders (complete or partial). Responders had progression-free survivals (PFS) ranging from 56 days – 1 year and overall survivals ranging from 56 to 498 days vs. non-responders that had PFS ranging from 20 to 56 days and overall survivals ranging from 40 to 56 days. In separate studies evaluating squamous cell carcinoma, 24% (4/17) patients responded to therapy. Responders (2/17) had PFS ranging from 260 to 388 days. Dogs with stable disease (2 /17) had PFS ranging from 91 to 144 days. Non-responders (13/17) had PFS ranging from 21 to 63 days. In a randomized trial investigating the efficacy and safety of this formulation in non-resectable Grade 2 or 3 mast cell tumors in dogs, the overall response rate at 14 weeks was 7%. Similar to all chemotherapy agents, most side effects were transient and clinically manageable (alopecia, neutropenia, vomiting, anorexia and lethargy). A dose delay was required in < 10% of dogs and in a large-scale study, only 1% (2/168) of dogs experienced allergic reactions.
Based upon data from these studies, Paccal Vet®‑CA1 has been granted conditional approval by the FDA for the treatment of:
- Non-resectable stage III, IV or V mammary carcinoma in dogs that have not received previous chemotherapy, or radiotherapy.
- Resectable and non-resectable squamous cell carcinoma in dogs that have not received previous chemotherapy, or radiotherapy.
Full approval will be based upon data from several current prospective studies. The dose (150 mg/m2) is administered intravenously over 15 to 30 minutes every 3 weeks for up to 4 doses. It is important to note, however, that a conditionally approved drug CANNOT be used in a “off label” manner per the FDA.
Paccal Vet®‑CA1 represents the first conditionally approved taxane in veterinary medicine and preliminary data suggests it is not only safe but has efficacy against mammary cancer and squamous cell carcinoma. Once fully approved, we will have the opportunity to test this agent against a wide variety of histologies and potentially incorporate its use into existing chemotherapy protocols.
Dr. Craig A Clifford DVM, MS, DACVIM (Oncology)
Hope Veterinary Specialists
Cremophor® is a registered trademark of BASF.
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Vail et al. JVIM 2012;26:598-607
Paccal Vet®-CA1 package insert