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CHOP Chemotherapy for the Treatment of Canine Multicentric Tcell Lymphoma

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CHOP Chemotherapy for the Treatment of Canine Multicentric Tcell Lymphoma Original Article DOI: 10.1111/j.1476-5829.2010.00230.x CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma R. B. Rebhun1,M.S.Kent1,S.A.E.B.Borrofka1∗,S.Frazier1,K.Skorupski1 andC.O.Rodriguez1 1Department of Surgical and Radiological Sciences and The Comparative Cancer Center, One Shields Avenue, University of California, Davis, CA, USA Abstract Dogs with multicentric T-cell lymphoma are commonly treated with CHOP chemotherapy protocols that include cyclophosphamide, doxorubicin, vincristine and prednisone. The purpose of this study was to evaluate the use of CHOP chemotherapy for dogs with multicentric T-cell lymphoma. Identification of prognostic factors in this specific subset of dogs was of secondary interest. Twenty-three out of 24 dogs responded to CHOP chemotherapy and these dogs remained on the protocol for a median of 146 days. No variable was associated with progression free survival (PFS) including stage, substage, hypercalcemia or radiographic evidence of a cranial mediastinal mass. The Keywords canine, chemotherapy, median overall survival time (OST) for all dogs was 235 days. Dogs that were thrombocytopenic at CHOP, lymphoma, T cell presentation experienced a significantly longer OST (323 versus 212 days, P = 0.01). Introduction (stage III–V) disease, inclusion of canine patients with stage I–II, low-grade, or extranodal lymphoma Doxorubicin-based chemotherapy protocols con- may further confound the results of therapeutic taining cyclophosphamide, vincristine and pred- efficacy studies.1 nisone (CHOP), with or without L-asparaginase, are Combination chemotherapy with mechloretha- often recommended as first-line therapy for canine mine, vincristine, procarbazine and prednisone non-Hodgkin’s lymphoma (NHL) patients regard- (MOPP) for the treatment of dogs with T-cell less of immunophenotype. Whereas the B-cell (or hypercalcemic) NHL was recently reported.7 immunophenotype is the most common form of Treatment with MOPP resulted in a 78% com- canine NHL, approximately 10–38% of cases are plete response (CR) rate with median progression of T-cell origin.1 Although several morphological free (PFS) and overall survival time (OST) of subtypes of canine T-cell lymphomas have been 189 and 270 days, respectively.12 The PFS and described, overall, the T-cell phenotype is associ- OST of dogs that received MOPP therapy were ated with a poor prognosis when compared to B-cell numerically superior to most prior reports of NHL.2–7 Correspondence address: dogs with confirmed T-cell lymphoma that were R. B. Rebhun Repeated studies have defined both clinical treated solely with CHOP-based chemotherapy Department of Surgical and and molecular distinctions between B- and T- Radiological Sciences (PFS 94–200 days and OST 120–239 days).3,5–7 cell canine NHL; however, historical studies have and The Comparative However, these historical studies were based on rel- Cancer Center not always separated analyses of B- and T-cell atively few T-cell NHL dogs with unreported sites 2112 Tupper Hall NHL patients.2–5,7–11 While approximately 85% of One Shields Avenue of involvement. canine NHL patients will present with multicentric University of California The purpose of this retrospective study was to Davis, CA 95616 evaluate the use of CHOP-based chemotherapy USA ∗Current address: University Clinic for Companion Animals, e-mail: Division of Diagnostic Imaging, Yalelaan108, 3584 CM for first-line therapy of dogs with multicentric [email protected] Utrecht, The Netherlands. (stages III–V) T-cell NHL that were routinely 38 © 2010 Blackwell Publishing Ltd CHOP chemotherapy for canine T-cell lymphoma 39 staged. Evaluation of possible prognostic factors in partial response was determined based on the clin- this specific subset of dogs with generalized T-cell ician’s comments in the medical record, as lymph lymphoma was of secondary interest. node measurements were not recorded in all cases. Materials and methods Statistical analyses Study population Complete and partial response rates were defined as the number of dogs experiencing respective remis- Twenty-four dogs with T-cell lymphoma that were sions compared to the total number of dogs treated. treated with a CHOP chemotherapy protocol at the PFS was defined as the time of first treatment until University of California-Davis Veterinary Medical relapse. OST was defined as the time between first Teaching Hospital (UCD-VMTH) between Jan- treatment and death. PFS and OST analyses were uary 2000 and January 2008 were retrospectively performed using the Kaplan-Meier product limit identified. Inclusion criteria were a cytological or method. Dogs were censored if they were still in histological diagnosis of intermediate- or high- remission and alive at the time of analysis. Dogs lost grade lymphoma, confirmed T-cell immunophe- to follow-up were censored at the last date of con- notype, intent to treat with CHOP chemotherapy, tact. Dogs were censored from analysis if the cause of and pre-treatment staging that included a complete death was confirmed to be unrelated to lymphoma blood count, serum chemistry panel, thoracic radio- on necropsy exam. The following variables were graphs, abdominal ultrasound and a bone marrow tested for their effect on PFS and OST by a log-rank aspirate. Dogs with stage I or stage II lymphoma, test: stage V, bone marrow involvement, circulating dogs with gastrointestinal or skin involvement and blasts, substage, radiographic evidence of a cranial dogs with suspected low-grade lymphoma were mediastinal mass, hypercalcemia, thrombocytope- excluded. Dogs with a history of prior chemother- nia, leucopenia, weight, and use of vinblastine. A apy or steroid treatment were also excluded. P-value ≤0.05 was considered statistically signifi- cant. A commercially available software program Diagnosis and staging (Stata version 10.0, StataCorp LP, College Station, The diagnosis of NHL was made on cytopathologi- TX, USA) was used to perform statistical analyses. cal or histopathological evaluation of a lymph node in all cases. Immunoreactivity with CD3 antibody Results and lack of reactivity with CD79a constituted a Treatment diagnosis of T-cell NHL. Clinical stage was based on the World Health Organization (WHO) crite- Twenty-four dogs were included in this study. All ria for canine NHL1; however, splenic and liver dogs were treated with a 26-week CHOP chemo- aspirates were not routinely performed and there- therapy protocol that included L-asparaginase fore it was not possible to definitively differentiate (Table 1). Two of these 24 dogs were treated with stage III from stage IV disease in this population maintenance therapy consisting of dactinomycin of patients. Two or three view thoracic radio- and leukeran after completion of the 26-week graphs were reviewed by a single board certified protocol. It is routine practice at the UCD-VMTH radiologist (SB). Thoracic radiographs were evalu- to substitute vinblastine for vincristine in patients ated for enlargement of intrathoracic lymph nodes that do not tolerate vincristine. In this regard, 8 (sternal, mediastinal and tracheobronchial lymph out of 24 dogs (33%) received at least one dose of nodes), changes of the lung pattern, or any other vinblastine during their CHOP protocol. abnormalities. Patient characteristics Response Median age was 7 years (range 4–13 years). Breeds A CR was considered as resolution of all clinically represented were mixed (6), Boxer (5), Golden detectable diseases. A designation of no response or Retriever (5), Labrador Retriever (1), Bulldog (1), © 2010 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, 9, 1, 38–44 40 R. B. Rebhun et al. Table 1. CHOP-based chemotherapy treatment protocol Week Protocol 0123456789101214161820222426 −1 L-asparaginase (400 IU kg ) • Vincristine (0.5-0.7 mg m−2 IV) •• •• • • • • Cyclophosphamide (200–250 mg m−2 IV or PO) •• • • Doxorubicin (30 mg m−2 IV) •• • • Prednisone (tapering dose) ••••• Weimeraner (2), Australian Cattle dog (1), Springer Treatment response, survival and prognostic Spaniel (1), German Shepherd (1) and Cocker factors Spaniel (1). Thirteen dogs were neutered males, The overall response rate in this population of eight were spayed females and three were intact dogs was 96%. Twenty-one out of 24 (88%) dogs males. Nineteen dogs were diagnosed as having had a CR to CHOP chemotherapy. Two dogs NHL based on cytological evaluation of lymph (8%) were designated as having a partial response, node aspirates, and the remaining five dogs were while one dog had no response (4%). Of the diagnosed based on histopathological evaluation of 23 dogs that experienced a response, the median lymph node biopsies. T-cell NHL was diagnosed by time that they received CHOP-based chemother- immunocytochemistry in 21 dogs and immunohis- apy was 146 days (95% CI 105–236 days). The tochemistry in the remaining three dogs. median duration of CR was 104 days (95% CI Fourteen dogs were categorized as having stage 84–126 days). The two dogs with designated partial V disease. Eleven of these 14 dogs had evidence responses remained progression free on CHOP for of bone marrow involvement, whereas 1 dog was 118 days and 133 days. None of the tested variables classified as stage V based on ocular involvement. significantly affected PFS. The additional two dogs classified as stage V disease The OST for all dogs was 235 days (95% CI were found to have circulating blasts on routine 167–244 days). Twenty-three of 24 dogs received evaluation of their CBC, without demonstrable non-standardized (non-CHOP) rescue chemother- bone marrow involvement. In total, seven dogs apy protocols according to the clinician’s and were found to have circulating tumor cells on rou- owner’s preference. Rescue agents included CCNU tine evaluation of the CBC. Thirteen dogs were of (21 dogs), MOPP (5 dogs), DTIC (5 dogs), mitox- substage b and the remaining 11 dogs were consid- antrone (1 dog), cytosar (2 dogs) and toceranib ered substage a. Nine dogs were hypercalcemic on (1 dog). Three dogs also underwent some form of presentation.
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