Page 729 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 33 Hematopoietic Tumors 707

protocols that bias the overall result, making it a less comparable relapse after chemotherapy include inadequate dosing and/or fre-
outcome. Widespread application of these standardized criteria quency of administration of chemotherapy, failure to achieve high
concentrations of chemotherapeutic drugs in certain sites such as
should permit more suitable comparisons in the future. True iCR
VetBooks.ir rarely occur in dogs with lymphoma; documenting iCRs is lim- the CNS, and initial treatment with prednisone alone.
At the first recurrence of lymphoma, it is recommended that
ited to investigative trials striving to achieve them because we lack
meaningful therapeutic options. reinduction be attempted first by reintroducing the induction pro-
Improved methods of detecting minimal residual disease (MRD) tocol that was initially successful, provided the recurrence occurred
or early recurrence have been investigated in dogs with lymphoma temporally far enough from the conclusion of the initial protocol
and include advanced imaging and detection of molecular and bio- (e.g., ≥2 months) to make reinduction likely. The cumulative dose
logic markers of MRD. Advanced functional and anatomic imag- of DOX that will result from reinduction, baseline cardiac assess-
ing techniques (i.e., PET/CT) are the current standard for assessing ment, the use of cardioprotectants, alternative drug choices, and
treatment response and early relapse of lymphoma in humans and client education should all be considered. In general, the dura-
have also been investigated in dogs (see Fig. 33.10). 221,223–226 As tion of reinduction remission will be half that encountered in the
these techniques become available to a broader veterinary popu- initial therapy; however, a subset of animals will enjoy long-term
lation, their clinical application will surely increase. Molecular reinductions, especially if the dog completed the initial induction
detection of MRD applies clonality and PCR techniques. Beyond treatment protocol and was currently not receiving chemotherapy
diagnostic applications, these techniques have been applied to deter- for several months when relapse occurred. Reinduction rates of
mine cytoreductive efficacy of various chemotherapeutic drugs and nearly 80% to 90% can be expected in dogs that have completed
to document and predict early relapse in patients before more con- CHOP-based protocols and then relapse while not receiving ther-
ventional methods. 123,217,246,287–293 Regarding biomarkers of MRD, apy. 232,300 The duration of a second CHOP-based remission in
preliminary investigations have suggested serum lactate dehydroge- one report was predicted by the duration of the interval between
nase activity, thymidine kinase 1 activity, haptoglobin, and serum protocols and the duration of the first remission. 123,300
C-reactive protein may be candidates in the dog. 202–206,294 If reinduction fails or the dog does not respond to the initial
As we become more proficient at defining MRD, the pressing induction, the use of so-called “rescue” agents or “rescue” protocols
clinical question becomes how we use this information. Theoreti- may be attempted. These are single drugs or drug combinations
cally, such information could suggest when more aggressive ther- that are typically not found in standard CHOP protocols and are
apy or alternative therapy should be instituted in patients who withheld for use in the drug-resistant setting. The most common
have not achieved a “molecular remission” or who are undergoing rescue protocols used in dogs include single-agent use or a combi-
early relapse; however, until we determine what these interven- nation of rabacfosadine, actinomycin D, mitoxantrone, DOX (if
tions should be based on prospective trial assessment, the clinical DOX was not part of the original induction protocol), dacarba-
utility of MRD analytics remain theoretical. zine (DTIC), temozolomide, lomustine (CCNU), l-asparaginase,
mechlorethamine, vincristine, vinblastine, procarbazine, predni-
Reinduction and Rescue Chemotherapy sone, and etoposide. Some rescue protocols are relatively simple
and convenient single-agent treatments, whereas others are more
Eventually, the vast majority of dogs that achieve a remission will complicated (and expensive) multiagent protocols, such as MOPP.
relapse or experience recrudescence of lymphoma. This usually Overall rescue response rates of 40% to 90% are reported; however,
represents the emergence of tumor clones or tumor stem cells responses are usually not durable with median response durations
(see Chapter 2) that are inherently more resistant to chemo- of 1.5 to 2.5 months being typical regardless of the complexity of
therapy than the original tumor, the so-called MDR clones that the protocol. A small (<20%) subset of animals will enjoy longer
either were initially drug resistant or became so after exposure to rescue durations. Table 33.5 provides a summary of canine res-
selected chemotherapy agents. 295 Evidence suggests that in dogs cue protocols and published results. 270,301–320 Current published
with relapsed lymphoma, tumor cells are more likely to express data from rescue protocols do not include sufficient numbers for
genes (e.g., MDR1) that encode ABC-transporter protein trans- adequate statistical power, nor do they compare protocols in a
membrane drug pumps often associated with MDR. 196,197,296–299 controlled, randomized prospective fashion. Therefore compara-
MDR1 represents only one of the plethora of mechanisms that tive evaluations of efficacy among various protocols are subject
lead to drug-resistant disease (see Chapter 12). Other causes of to substantial bias, making direct comparisons difficult. Choice

TABLE 33.5 Summary of Response for Rescue Protocols a
Median
Number of Overall Response Complete Response Median Duration of
PRIVATE Protocol Animals (%) Response (%) Duration c Complete Response References
Actinomycin-D 25 0 0 0 days 0 days 316
Actinomycin-D 49 b 41 41 129 days 129 days 310
Dacarbazine 40 35 3 43 days 144 days 313
Dacarbazine or 63 71 55 45 days NR 311
temozolomide-
anthracycline
Continued