Page 728 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

706 PART IV Specific Malignancies in the Small Animal Patient

tapering oral prednisone regimen (same prednisone regimen in author does not dose-modify for heterozygous MDR1 gene muta-
Box 33.3) as a less aggressive, less time-consuming, and less costly tions as little documented clinically significant chemosensitivity
approach. The expected CR rate for the single-agent DOX proto-
exists in these animals.
VetBooks.ir col will range from 50% to 75%, with an anticipated MST of 6 The Case for Treating T-Cell Lymphoma Differently
246,250,273,274
The addition of oral cyclophosphamide
to 8 months.
(50 mg/m daily for 3 days starting on the same day as DOX) With some exceptions (e.g., TZL), multicentric T-cell lymphoma,
2
to single-agent DOX resulted in a numerically, but not statisti- compared with multicentric B-cell lymphoma, is associated with
cally, improved outcome in a randomized trial comparing DOX/ similar initial response rates, but significantly lower response
prednisone with DOX/cyclophosphamide/prednisone (PFS of 5.6 durations (e.g., PFS) after chemotherapy (including CHOP-
months vs 8.2 months, respectively). 274 This trial was powered based protocols). 68,112,113,116,123,226,242,244,277,281–283 In addition,
only to detect a three-fold difference in PFS; therefore larger trials the effectiveness of a single treatment of DOX in the treatment
should be undertaken to confirm any benefit. Alternatively, a less of naïve lymphoma in one retrospective case series suggested a
time-intense protocol with treatments every 3 weeks involves the lower initial response rate for T-cell, compared with B-cell, immu-
previously mentioned rabacfosadine/DOX protocol. 230 nophenotypes; however, this study performed only a single day
If clients are reticent to include IV medications, the author 7 evaluation. 281 Many question whether dogs diagnosed with
often recommends a protocol of either oral lomustine (CCNU; T-cell lymphoma should be treated with standard CHOP-based
70 mg/m by mouth [PO] every 3 weeks for five treatments) and protocols or with alternative protocols. This is a valid question;
2
2
prednisone or oral cyclophosphamide (250 mg/m [PO] every however, the answer remains elusive because adequately powered
2–3 weeks) with prednisone. The CCNU protocol has been asso- randomized controlled trials do not currently exist to demonstrate
ciated with short median remissions (40 days) in one small case if an alternate protocol is better for this immunophenotype. Sev-
series 275 ; however, in the author’s experience, a subset of dogs have eral alternative protocols (MOPP, LOPP, VELCAP-TSC) have
remained in remission for several months on this protocol when been reported and reviewed for induction therapy in dogs with
clients decline IV medication. multicentric T-cell lymphoma. 110,284–286 These alternative pro-
If financial or other client concerns preclude the use of systemic tocols tend to add or substitute alkylating agents (e.g., nitrogen
chemotherapy, prednisone alone (2 mg/kg PO, daily) will often mustard, lomustine, procarbazine) for DOX. Although reports
result in short-lived remissions of approximately 1 to 2 months; have suggested improvements in remission durations in dogs with
however, an occasional durable remission will result. In these either confirmed T-cell lymphoma or lymphoma with hypercal-
cases, it is important to educate clients that, should they decide to cemia and no immunophenotypic classification, the confidence
pursue more aggressive therapy at a later date, dogs receiving sin- intervals of the medians all overlap with data from CHOP-based
gle-agent prednisone therapy are more likely to develop multidrug protocols, and differences in determining PFS, response evalua-
resistance (MDR) and experience shorter remission and survival tion, and study population (in particular, some do not adequately
durations with subsequent combination protocols. 258,276–278 This distinguish indolent multicentric lymphoma) in these reports
is especially true after long-term prednisone use or in dogs that preclude confident comparisons. As yet, no controlled, random-
have experienced a relapse while receiving prednisone. Therefore ized trials have documented improvement with this approach.
the earlier that clients opt for more aggressive therapy, the more Ultimately, the development of better protocols for treating T-cell
likely a durable response will result. lymphoma awaits careful, randomized, prospective trial assess-
A CBC should be performed before each chemotherapy treat- ment. Until such time, the author prefers to initiate CHOP-based
ment. Dogs should have a minimum of 1500 neutrophils/μL induction and switch to lomustine-based rescue at the first sign of
(some oncologists use a cut-off of 2000 neutrophils/μL) and progression or to enter dogs into clinical trials with novel agents.
50,000 platelets/μL before the administration of myelosuppressive Although species differences may exist, in people with aggressive
chemotherapy. 279 If the neutrophil count is lower than 1500/μL, T-cell NHL, alternative protocols rich in alkylating agents have
it is recommended to wait 5 to 7 days and repeat the CBC; if the not shown superiority over CHOP-based protocols, and the
neutrophil count has increased to more than 1500 cells/μL, the National Comprehensive Cancer Network recommend human
drug can be safely administered. A caveat to these restrictions is patient participation in clinical trials as the “gold standard” for
that for dogs presenting before initiation of chemotherapy with aggressive nonindolent T-cell lymphomas.
low neutrophil and platelet counts due to bone marrow effacement
(myelophthisis), myelosuppressive chemotherapy is instituted in Evaluation of Treatment Response
the face of cytopenias to clear the bone marrow of neoplastic cells VCOG has published criteria for evaluation of treatment response
and allow hematopoiesis to normalize. (v1.0) to standardize reporting of outcome results and compari-
In those breeds likely to have homozygous MDR1 gene muta- sons among protocols for peripheral nodal disease using criteria
tions (e.g., collies; see Chapter 12), and therefore to be at risk for readily available in the practice setting. 253 The most important of
serious chemotherapy toxicity, 280 the author [DMV] will initiate these outcome measures and the preferred temporal outcome cri-
a CHOP protocol out of sequence, beginning with non-MDR1– terion for assessing protocol activity is now considered to be PFS,
substrate drugs, such as cyclophosphamide. This ensures treat- which is defined as being the time from treatment initiation to
ment of the lymphoma while allowing sufficient time for analysis tumor progression or death from any cause. This brings veterinary
of MDR1 gene mutations before initiating MDR1 substrate drugs. outcome reporting more in line with human standards. Because
No specific protocols have been scrutinized for treating dogs that the majority of dogs with lymphoma eventually experience relapse
are double-mutant for MDR1; however, if using MDR1-substrate after chemotherapy-induced remissions and because methodol-
drugs, the author initiates treatment using a 40% to 50% dose ogy for differentiating complete and partial responses is analysis
reduction. Subsequent dose modifications (increased or decreased dependent on how responses are determined, PFS removes many
dosage) can be implemented, depending on the level of adverse sources of bias. Further, overall survival in published reports
events observed, particularly low neutrophil counts at nadir. The invariably includes patients who go on to receive varied rescue