Page 207 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

186 PART 3 Therapeutic Modalities for the Cancer Patient

are expressed in canine mammary tumors as well. 49,51 The normal a continuing dialog as needs may change throughout treatment,
tissue distribution of the ABC transporters is also beginning to be cannot be underestimated.
Dosing conventions have been developed from formal phase
investigated in dogs, with initial studies showing relatively similar
VetBooks.ir tissue distributions and presumed function. 52,53 Feline ABCG2 I studies for an increasing number of agents investigated spe-
cifically in companion animals. Nonetheless, suggested starting
has specific amino acid changes that lead to transporter dysfunc-
tion with regard to a number of substrates, suggesting that cats doses represent an estimate of the MTD from a small popu-
may have altered pharmacokinetic disposition for drugs that are lation of animals, and safe individual patient dosing may vary
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ABCG2 substrates. substantially. There are numerous reasons for pharmacokinetic
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variability in cancer drugs among a population of patients.
Combination Therapies Concurrent illness or organ dysfunction, extreme tumor burden,
specific breed sensitivities (e.g., Collies with ABCB1 mut/mut),
The success of combination chemotherapy compared with single- or idiosyncratic considerations (anticipated drug–drug interac-
agent treatment is attributed to providing maximal cell kill within tions or drug allergies) will mandate modifications of the pro-
the range of tolerable host toxicity, providing a broader range tocol and dosing. Concurrent illness and organ dysfunction can
of interactions between the drugs and the heterogeneous tumor have profound effects on selection of anticancer agents and dos-
cell population, and slowing the development of cellular drug ing. In general, predictable dose adjustments for pets with renal
resistance. However, certain guidelines should be followed when or hepatic disease have not been developed and treatment should
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designing a combination protocol. Only drugs with known be approached conservatively. Interestingly, in cats, the glomer-
efficacy as single agents against the cancer of interest should be ular filtration rate (GFR) can be used to define an individual
included, with preference for drugs that can induce a complete dose for carboplatin that will permit some patients with renal
remission in at least some patients. Whenever possible, drugs disease to be safely dosed that would not have been safe if dosed
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with nonoverlapping toxicities should be used. This potentially by conventional methods. Chemotherapeutic dosing in obese
will result in a wider range of AEs, but a lower risk of a severe or patients often raises questions about drug partitioning in lipid
life-threatening episode. Lastly, drugs should be used at their opti- storage sites around the body. Distribution of many pharma-
mal dose and schedule, and drug combinations should be given at ceutical agents may be affected in obese patients; however, there
consistent intervals. is no accepted scale for empiric dose adjustments in humans.
The success of combination therapies as opposed to single- Individual factors such as the specific drug, degree of obesity,
agent therapy is best illustrated in veterinary oncology by treat- and other comorbidities may convince a clinician to dose reduce
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ment protocols for canine lymphoma. DOX is the most active or cap the dose of a chemotherapeutic agent. Some reviews
single-agent therapy tested, and the addition of DOX to other suggest that dose reductions based on body mass may ultimately
active protocols (i.e., cyclophosphamide [CP], vincristine, and be detrimental to outcomes in obese patients. It is the ini-
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prednisone) empirically increases median remission duration and tial chemotherapeutic intervention that is expected to result in
median survival time compared with either DOX alone or combi- the greatest opportunity to benefit the patient and, therefore,
nations without DOX (see Chapter 33, Table 33.4). 56–72 In con- thoroughly assessing the patient’s specific medical limitations
trast, in dogs with appendicular osteosarcoma (OSA), adjuvant and then proceeding with thoughtfully designing, administer-
treatment with combinations of platinum and DOX empirically ing, and completing a therapeutically robust protocol is highly
does not show any improvement in disease-free interval or survival desirable.
over those treated with single-agent DOX or platinum protocols As individual patient tolerance and response to each compound
(see Chapter 25, Table 25.2). 73 in a multiagent protocol is observed, future modifications may be
The concept of summation dose-intensity (SDI) can be used anticipated more accurately. The greatest benefit achievable with
to compare different combination chemotherapy protocols. 74,75 anticancer cytotoxic therapy requires a commitment to dose inten-
The contribution of each drug is based on its fractional dose- sity. Optimal dose intensity demands therapeutic monitoring to
intensity (DI) (relative to maximum DI when the drug is used either reduce or increase the dose based on the patient’s capacity to
as a single agent) and its relative antitumor potency compared maintain an acceptable quality of life during effective therapy. The
with the other drugs included in the protocol. The individual decision to increase the dose of an agent is conceptually challeng-
contributions of each drug are then added together. SDI > 1 ing but important. To make a recommendation to increase dosing
implies a benefit over monotherapy using the single-most active of a cytotoxic compound, owner understanding and monitoring of
drug at its MTD and optimum dosing schedule. SDI = 1 implies the patient’s hematologic values and clinical events during the first
equality, and SDI < 1 implies diminished efficacy. treatment cycle are critical. A dose of a cytotoxic agent that does not
result in any change in the target normal tissue (e.g., blood neutro-
Toxicities Associated with Drug Therapy of phil count) is likely ineffective and could potentially be increased at
the next infusion with continued follow-up to determine adequacy
Cancer of dose adjustments (Fig. 12.3). Dose reductions are deleterious to
Chemotherapy may fail to produce a positive clinical benefit for the optimum delivery of chemotherapy but are to be anticipated.
the reasons described earlier but may also fail because of unaccept- Specific guidelines for dose adjustments of antineoplastic agents
able toxicity. Anticipating and managing AEs requires a thorough are not standardized and are done empirically with a 10% to 25%
understanding of drug activity profiles and clinical experience reduction in dose generally considered for patients experiencing
modifying chemotherapeutic administration. The first step in the severe or unacceptable hematologic or gastrointestinal AEs. Close
process of successfully managing cancer in companion animals is monitoring and preemptive management of signs may permit suc-
always a clear and frank discussion with the owner regarding the cessful management of any potential future clinical signs, and clini-
potential for benefit, toxicity, cost, and time commitment. A com- cal management is based on the extent and severity of the resulting
mon understanding about the goals of therapy, and committing to signs as described in Table 12.2.