Cytotoxic Chemotherapy: New Players, New Tactics
Veterinary clients often seek the same new and innovative cancer treatment options for their companion animals that they read about in the press or on the Internet. It is, therefore, necessary for the practitioner to have an understanding of the development of new and innovative cytotoxic drugs and delivery techniques. This article describes the drug development process and how a new product eventually finds its way into clinical use. Some of the newer drugs and delivery techniques applied to small animals are reviewed.
Introduction
Of all the treatment modalities available in veterinary clinical oncology, surgery remains the most commonly applied and the most likely to effect a cure. Local recurrence and/or distant metastasis cause most of the tumor-related morbidity and mortality that develop after surgery. The utility and general use of adjunctive (i.e., preceding or following surgery) and primary chemotherapy in systemic hematopoietic disorders (e.g., lymphoma, myeloma) have greatly increased in the last decade. Several well-designed clinical trials have been completed or are presently underway at various institutions, addressing the efficacy of novel cytotoxic agents and delivery methods for dogs and cats with malignancies. It is important for veterinary practitioners to be aware of the expanding knowledge base pertaining to chemotherapeutic options, whether they plan to apply this knowledge in their practices or use it for referring clients to oncological centers. Additionally, with the increasing availability of veterinary clinical trials aimed at evaluating new therapies, and as veterinary clients become more savvy about Internet search mechanisms, it is equally important to be knowledgeable about where and how to refer cancer cases to reputable and relevant clinical trial centers.
The purposes of this paper are to discuss new or novel chemotherapeutic agents, innovative applications of chemotherapeutic drugs, and new delivery methods that may be used for some of the more established drugs. The discussion is limited to more traditional “cytotoxic” chemotherapeutic agents and does not elaborate on immune modulators, antiangiogenic drugs, or molecular-based, targeted “static” drugs. Because of the broad range of this topic, this paper is not designed as an in-depth study, but the authors provide more complete sources of information whenever possible.
Evaluation of New Agents
It is important to have a working knowledge of how a new drug or compound is brought into general clinical use. When evaluating new cytotoxic agents in animals, the first clinical step is normally to determine the maximally tolerated dose (MTD). The MTD is the dose that can be used routinely in the majority of animals and results in an “acceptable” level of toxicity. In the opinion of most veterinary oncologists, an acceptable level of toxicity is defined as the dose that results in any toxicity requiring hospitalization in <5% of the treated population.
The MTD is usually determined in the context of a phase I trial. A phase I trial is, by definition, a dose-determining toxicity trial. It normally involves extrapolating a safe starting dose from rodent or human dosage recommendations and using that dose in a small subset (usually three) of tumor-bearing pet animals while observing them for significant toxicity. Pets involved in phase I trials have all types of cancer and are typically individuals that have not responded to traditional therapy. Additionally, the cancers may be the type where no traditional therapy exists. If no significant toxicity is observed in the first subset of animals, another subset is then treated at a higher dose and observed for significant toxicity. This dose escalation is continued until a predetermined, unacceptable percentage of animals in a particular dosage group develops significant toxicity. The MTD is set at the dosage used safely in the previous treatment group.
Only a relatively safe general dose is determined in a phase I trial. The anticancer effect of the drug under investigation is not determined in a phase I trial; however, some information is usually gained on efficacy. The greatest limitation of phase I trials is that only short-term toxicities (e.g., bone marrow, gastrointestinal) are generally evaluated, and long-term or less common toxicities may only be found in subsequent, larger efficacy trials.
After an MTD is established, the next usual step is to determine efficacy in the context of a phase II trial. A phase II trial treats a series of animals with a particular tumor type at the MTD and determines antitumor responses. Responses may be defined by one or more parameters, such as shrinkage of measurable tumor, stabilization of disease, improvement in quality of life, or prolongation of remission or survival. The purposes of the phase II trial are to determine which tumor types are responsive to the new agent and to gain a more thorough understanding of the toxicity profile.
Once responsive tumor types are determined, the next questions to be answered are whether the agent is more effective, less toxic, or less expensive than the “standard-of-care” treatment available for that tumor type and/or whether the widespread application of this new agent results in even more effective therapy. These questions are generally answered in the context of phase III trials. Phase III trials are generally randomized, prospective trials evaluating a new chemotherapeutic agent against the standard treatment, or trials of the standard treatment plus the new agent versus the standard treatment alone. Most of the information in this article represents data from phases I and II trials. Phase III trials are currently less common in veterinary medicine. Several such trials have been performed or are ongoing in animals, however, and are discussed where relevant.
New Players
Several of the “new” chemotherapeutic agents actually have been around for several years; however, their use has been anecdotal, and only recently has information on safety and efficacy been subjected to the rigors of scientific review in refereed publications [see Table].
Vinorelbine
Vinorelbinea (Navelbine; generics also exist) is a semisynthetic derivative of the vinca alkaloid class of drugs. As such, its mechanism of action is similar to other members of the group, in that microtubules are disrupted—especially those comprising the mitotic spindle apparatus, which ultimately induces metaphase arrest in dividing cells.1 In a recent phase I study of dogs, vinorelbine had a well-tolerated toxicity profile and significant efficacy against certain tumor types.1 Vinorelbine was given once weekly, intravenously (IV), at dosages ranging from 10 to 20 mg/m2 in this trial.1 The MTD was between 15 and 18 mg/m2 once weekly. It was recommended that treatment in dogs be initiated at 15 mg/m2, and if toxicity is acceptable, then increasing the dosage to 18 mg/m2 may be considered. Neutropenia was the dose-limiting toxicity. Anorexia, vomiting, diarrhea, and one case of a cutaneous rash were also observed, but these side effects were generally self-limiting and did not require hospitalization.1 While a phase II trial has not yet been reported for vinorelbine, the phase I trial suggested significant activity in dogs with primary lung tumors. Now that an MTD has been established, efficacy data will surely be generated in the future. At present, no published data exist for vinorelbine in cats.
Paclitaxel
Paclitaxelb (Taxol; generics also exist), originally extracted from the bark of the Pacific Yew tree, is a mitotic spindle poison.2 It has significant efficacy in people with several types of epithelial cancers and has recently been evaluated in animals.2 The most difficult aspect of using paclitaxel is associated with the carrier, cremophor EL, which is used to solubilize the drug. Cremophor EL is highly allergenic in most species, and dogs and cats are no exception. In the dog, use of paclitaxel requires treatment with antihistamines and corticosteroids both before and during drug delivery.
A starting dose of 165 mg/m2 based on a previous abstract was found to cause unacceptable toxicity.2 The current recommended dose in dogs is 132 mg/m2 by slow IV infusion once q 3 weeks.2 The treatment protocol begins with oral prednisone (1 mg/kg) given the evening before treatment. On the day of treatment, 30 to 60 minutes before paclitaxel infusion, dogs are premedicated with diphenhydramine (4 mg/kg intramuscularly [IM]) and dexamethasone sodium phosphate (2 mg/kg IV). Paclitaxel (6 mg/mL) is diluted in 10 times its volume of 5% dextrose/water, and an IV infusion is initiated at 30 mL per hour for 10 minutes. If no significant allergic reactions are noted after 10 minutes, the infusion rate is doubled to 60 mL per hour IV for 10 minutes. If no reaction is noted at this rate, the infusion rate is increased to 90 mL per hour IV for the rest of the infusion. If significant allergic reactions are noted (e.g., hives, pruritus, agitation, head-shaking, vomiting), the infusion is discontinued. The dog is again pretreated with diphenhydramine and dexamethasone, and after 15 minutes, the infusion is reinitiated at a lower infusion rate.
Other than side effects related to the infusion, the dose-limiting toxicity in dogs with paclitaxel was neutropenia. Hair loss, vomiting, and diarrhea (usually self-limiting) were also observed. Antitumor responses occurred in dogs with metastatic osteosarcoma, mammary adenocarcinoma, and malignant histiocytosis.2 Stabilization of disease was also observed with metastatic pilomatrix carcinoma (n=1), anal sac adenocarcinoma (n=1), and lung carcinoma (n=1).2 Further evaluations of larger study populations are currently underway. Although paclitaxel can be difficult to administer, a subset of dogs will likely benefit from its use. In the authors’ experience, paclitaxel-induced allergic reactions are usually too severe in cats to allow delivery of the drug at a therapeutic dosage.
A related drug, docetaxelc (Taxotere), is currently being evaluated in small animals. The incidence of severe anaphylactoid reactions with this product may be less than with paclitaxel; however, generic forms are not yet available, and the cost may be prohibitive for some owners.
Gemcitabine
Gemcitabined (Gemzar) is an antimetabolite nucleoside (pyrimidine) analog that has been used in animals, both as a direct cytotoxic agent and as a radiation sensitizer.3–5 As with other pyrimidine analogs, gemcitabine’s method of action is attributed to its incorporation into deoxyribonucleic acid (DNA) and ultimate inhibition of DNA replication.3 While several anecdotal dosing regimens have been suggested, a biweekly (q 2 weeks) administration of 675 mg/m2 IV appears to be well tolerated in dogs.4 The drug is diluted in 10 mL/kg of normal saline (0.9% sodium chloride [NaCl]) immediately prior to delivery. A safe dose in the cat has not been published. Anecdotally, 250 mg/m2 IV has been used.3
Although this drug has not been extensively studied in small animals, only limited efficacy has been reported in tumor-bearing dogs, and results have been disappointing in most cases. Positive responses have been observed in a small number of dogs with lymphoma, oral malignant melanoma, and perianal squamous cell carcinoma (SCC).4 Stabilization of disease for short periods of time (i.e., 2 to 5 months) was also observed for some other tumor types. Short-lived stabilization of disease was observed in a small number of cats with oral SCC.3
At the suggested dosage, hematological and gastrointestinal toxicity in dogs was mild and self-limiting in most cases. One case of retinal detachment in a dog receiving gemcitabine has also been reported. Twice-weekly radiosensitization doses of 50 mg/m2 IV in the dog and 25 mg/m2 IV in the cat induced unacceptable hematological and local tissue toxicity in one study.5
Lomustine
Although it is an older drug, there has been a recent resurgence of interest in the use of lomustinee (CCNU). Lomustine belongs to the alkylating agent class of chemotherapeutics.3,6–10 It is now used extensively in dogs and is also being evaluated in cats. The dose most commonly used in dogs is 70 to 80 mg/m2 per os (PO) q 3 weeks. It is available in 10- and 40-mg capsules, and pharmacies will often formulate other dosage types. In the cat, dosages of 50 to 60 mg/m2 PO have been utilized at intervals ranging from 3 to 6 weeks.8,9 In the authors’ experience, most cats tolerate q 3-week dosing intervals; however, hematological parameters may require that some cats receive the drug at 4- to 6-week dosing intervals.
The acute dose-limiting toxicity for lomustine in both dogs and cats is primarily a neutropenia that is most prominent 7 days after therapy. It is recommended that complete blood counts be monitored 1 week after each dose of lomustine and just prior to subsequent administrations. Acute gastrointestinal toxicity may occur; however, it is usually mild and self-limiting. Potentially more serious, delayed toxicities may be associated with higher cumulative doses of lomustine. These delayed side effects include hepatotoxicity and thrombocytopenia. Such adverse effects usually develop several weeks to months after initiation of lomustine chemotherapy and warrant measuring a pretreatment serum alanine transaminase (ALT) and platelet count, as well as periodically (e.g., q 2 months) reassessing their values. If sustained elevations in ALT or a downward trend in platelet counts are observed, discontinuance of lomustine is indicated.
Lomustine is currently used as a first-line chemotherapeutic agent for dogs with cutaneous lymphoma and mast cell tumors.6,7,10 Lomustine has additionally been used as a second-line rescue agent in dogs with lymphoma that has failed to respond to more traditional multidrug protocols. Anecdotal evidence suggests that lomustine is also effective in dogs with systemic and malignant histiocytosis and histiocytic sarcoma. In cats, positive responses have occurred in the treatment of lymphoma, mast cell tumors, multiple myeloma, and fibrosarcomas.8,9
Ifosfamide
Ifosfamidef is an alkylating agent that has been evaluated in tumor-bearing dogs and cats (to a lesser extent).3,11 It must be given concurrently with saline diuresis and a thiol compound, mesna, in order to prevent sterile hemorrhagic cystitis secondary to a metabolite that is toxic to the bladder. Mesna and ifosfamide are sold and packaged together. The recommended dosage and delivery schedule for dogs is to give mesna (reconstituted in 0.9% NaCl to a concentration of 20 mg/mL) at 20% of the calculated ifosfamide dose. The mesna is given as an IV bolus, and then the dog is diuresed with 0.9% NaCl at 18.3 mg/kg per hour IV for 30 minutes. Ifosfamide (375 mg/m2 reconstituted in 0.9% NaCl to a volume of 9.15 mL/kg) is then given IV over 30 minutes, followed by an additional 5 hours of IV saline diuresis (18.3 mL/kg per hour). Two additional mesna doses are given at 2 and 5 hours during the diuresis period. Ifosfamide may be given at 2- or 3-week intervals in dogs. Only anecdotal reports exist of ifosfamide’s use in the cat, and it appears that higher doses are tolerated. More thorough investigations on the use of ifosfamide in cats are required, however.
When given with mesna, the dose-limiting toxicity of ifosfamide is myelosuppression, manifested primarily as neutropenia. Mild, self-limiting, gastrointestinal toxicity (i.e., inappetence, vomiting, diarrhea) may also be seen. In one study of 72 tumor-bearing dogs, a disappointing overall response rate of 6% was reported.11 Positive responses mostly occurred in dogs with sarcomas, including cutaneous hemangiosarcoma and leiomyosarcoma. Only one of 40 dogs with lymphoma responded favorably to ifosfamide.11
New Tactics
New methods of delivery, formulation, or timing of cytotoxic drugs have also been evaluated in small animals. Some tactics are available to practitioners, while others are still in development.
Liposomal Formulations
Liposomes are closed vesicular structures that consist of one or more lipid bilayers. Several different kinds of liposomes can be engineered with different physical properties that dramatically alter drug pharmacokinetics and/or pharmacodynamics. Liposomes can be loaded with drugs or other compounds, either as part of the bilayer itself or packaged within the center of the vesicle. Most liposomal formulations are designed to enhance antitumor efficacy, decrease normal tissue toxicity, or induce a combination of the two effects. Several cytotoxic drugs are now available in liposomal formulations.
Doxil,g a liposomal formulation of doxorubicin, has been used effectively in dogs and cats.12,13 Unlike with the original form of doxorubicin, myelosuppression and cardiotoxicity are not dose-limiting with Doxil. This makes Doxil a suitable drug for use in dogs with preexisting cardiac disease or in dogs that have received cumulative doses of unencapsulated doxorubicin that are approaching cardiotoxic levels. In dogs, the dose-limiting toxicity of liposomal doxorubicin is a cutaneous toxicity called palmar-plantar erythrodysesthesia. Palmer-plantar erythrodysesthesia is characterized by lesions ranging from mild erythema and alopecia to severe crusting and ulceration, primarily in the axillae, inguinal region, and the skin surrounding the footpads. The severity of these cutaneous lesions may be lessened with the administration of vitamin B6 (i.e., pyridoxine at 25 to 50 mg PO q 8 hours) throughout the course of treatment.14 The dose-limiting toxicity of Doxil in cats is a delayed nephrotoxicity; therefore, adequate renal function is imperative in cats receiving the drug. The recommended dose of Doxil in both dogs and cats is 1 mg/kg IV q 3 weeks.13
Tumor types in dogs with reported positive responses to liposomal doxorubicin include lymphoma, malignant histiocytosis, neurofibrosarcoma, fibrosarcoma, mammary adenocarcinoma, anal sac adenocarcinoma, and SCC.12,15 Additionally, dogs with doxorubicin-resistant lymphoma have responded positively to Doxil, which implies the presence of some mechanism of abrogating drug resistance. Feline vaccine-associated sarcomas have responded favorably to Doxil; however, unencapsulated doxorubicin appears to be just as effective.13
Another liposomal formulation of doxorubicin, Myocet,h has also been used successfully in a dog with melphalan and doxorubicin-resistant multiple myeloma.15 This formulation was given at a dose of 35 mg/m2 IV and resulted in a durable remission.15 The formulation also allowed a cumulative dose of doxorubicin >500 mg/m2 to be given without the development of cardiotoxicity.
Liposomal formulations of cisplatin have also been used in dogs and cats. While they have been shown to be safe and abrogate the renal toxicity (in dogs) and the respiratory toxicity (in cats) associated with unencapsulated cisplatin, they have not demonstrated superior therapeutic efficacy.16–19
Inhalational Chemotherapy
Inhalational chemotherapy has been successfully used to treat dogs with pulmonary cancers. In theory and in practice, significantly higher drug levels can be achieved at the level of the tumor with inhalational chemotherapy, while less systemic toxicity is observed because whole-body drug levels are kept low. Inhalational chemotherapy is not routinely available, however, and the reader is referred to a recent review article for a more complete discussion of the topic.20
Intralesional Chemotherapy
Injecting chemotherapeutic drugs directly into a tumor should result in significant intratumoral drug levels and less systemic toxicity. In animals, intralesional chemotherapy has usually involved the injection of platinum agents (e.g., carboplatin) into cutaneous tumors (e.g., solar-induced SCCs in cats and horses) and sarcoids in horses. The intralesional injection of carboplatin (100 mg/m2) in purified sesame oil at 10- to 14-day intervals demonstrated good efficacy for SCC of the nasal planum in cats.21 Significant improvement was also observed when intralesional carboplatin (1.5 mg/cm3 q 7 days) was used in conjunction with radiotherapy in cats with advanced nasal planum SCC.22
Intralesional injection of 5-fluorouracil is used for the treatment of some human cutaneous malignancies, and there is anecdotal evidence of its efficacy in certain equine tumors. Preliminary evidence shows that intralesional injection of bleomycin may be associated with antitumor activity in equine and feline SCCs and in canine acanthomatous epulis.23,24
Metronomic Chemotherapy
Recently, the concept of low-dose, continuous delivery of cytotoxic agents, sometimes called “metronomic” chemotherapy, has been introduced.25 With this delivery method, treatments are spaced such that the normal tissues have sufficient time to recover, rather than administering the cytotoxic agent at the MTD. With metronomic delivery, a more frequent (e.g., daily) low dose (well below the MTD) of the drug is given continuously. There is significant in vitro and in vivo (in rodent tumor models) evidence to suggest that cytotoxic agents applied in this fashion affect the endothelium of growing tumor vasculature and exert their effects through an antiangiogenic mechanism rather than through tumor cell cytotoxicity.25 The theorized outcome of metronomic chemotherapy is stabilization rather than regression of disease. Administration of chemotherapeutics in this fashion also has the possible advantage of being less toxic, because doses well below the MTD are used.
It appears that combining metronomic chemotherapy with drugs known to possess some inherent antiangiogenic activity (e.g., doxycycline) and cyclooxygenase-2 inhibitors (e.g., piroxicam) may increase the likelihood of an antitumor response. At present, several trials of metronomic therapy are underway in humans and animals. It must be stressed that these studies have not been subjected to rigorous evaluation, and, therefore, the use of metronomic chemotherapy awaits validation through appropriate clinical trials.
Conclusion
Every year, several new antineoplastic drugs or treatment approaches become available. Ultimately, the goal is to develop less-toxic, more efficacious therapies that maintain and prolong the quality of life for companion animals. Evaluation of such drugs through phase I trials is first necessary to determine an appropriate dose for each animal species. Once a dose has been established, then further evaluations of efficacy can begin. As less-toxic, more targeted approaches become available, their widespread use should result in more efficacious and better tolerated therapeutic protocols. Because of the increasing number of veterinary clinical trials being conducted regionally and nationally, it is recommended that practitioners keep abreast of their availability by visiting veterinary informational Web sites, including that of the Veterinary Cancer Society (www.vetcancersociety.org).
Navelbine; Glaxo Smith Kline, Research Triangle Park, NC 27709
Taxol; Bristol-Myers Squibb, Princeton, NJ 08543
Taxotere; Aventis Pharmaceuticals, Bridgewater, NJ 08807
Gemzar; Eli Lilly & Co., Indianapolis, IN 46285
CCNU; Bristol-Myers Squibb, Princeton, NJ 08543
Ifex; Bristol-Myers Squibb, Princeton, NJ 08543
Doxil; Ortho Biotech Products, Bridgewater, NJ 08807
Myocet; The Liposome Company, Princeton, NJ 08540
