LOPP chemotherapy as a first-line treatment for dogs with T-cell lymphoma

Transcription

1 Received: 3 February 2017 Revised: 31 March 2017 Accepted: 3 April 2017 DOI: /vco ORIGINAL ARTICLE LOPP chemotherapy as a first-line treatment for dogs with T-cell lymphoma P. M. Brown S. Tzannes S. Nguyen J. White V. Langova Department of Oncology, Small Animal Specialist Hospital (SASH), North Ryde, Australia Correspondence P. M. Brown, Department of Oncology, Small Animal Specialist Hospital (SASH), 1/1 Richardson Place, North Ryde, NSW 2113, Australia. pbrown@sashvets.com Background: The aim of this study was to describe the use of a lomustine (CCNU), vincristine, procarbazine and prednisolone (LOPP) protocol used for treatment of chemotherapy naive T- cell lymphoma patients and to describe the response rate, toxicity and disease-free interval compared historically to CHOP chemotherapy. Materials and Methods: Retrospective case study of 31 dogs with naïve T-cell lymphoma treated with a lomustine (CCNU), vincristine, procarbazine and prednisolone (LOPP) protocol. Results: Thirty-one dogs with T cell lymphoma were treated. The overall response rate was 97%. Of the 30 dogs that had a response to LOPP chemotherapy, the median disease free interval was 176 days (range days). The median overall survival time for this study group was 323 days (range days). All deaths in this study were attributable to lymphoma. Conclusion: LOPP chemotherapy for T cell lymphoma is well tolerated with a low toxicity profile and an excellent overall response rate. This protocol showed minimal toxicity and comparable disease free interval and survival times for canine high grade T cell lymphoma treated with CHOP. KEYWORDS canine, chemotherapy, LOPP, lymphoma, T-cell 1 INTRODUCTION Successful treatment of canine lymphoma involves multi-agent chemotherapy protocols. A commonly used protocol consisting of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) has a reported response rate approaching 90%. T-cell phenotype for lymphoma has been shown to be a poor prognostic indicator in a number of studies. 1 9 Dogs with T-cell lymphoma have had decreased response rates to chemotherapy, with reduced remission times and overall survival times (OSTs), when compared with dogs with B-cell phenotype. 1,4 13 Duration of first remission for dogs with T-cell lymphoma has been previously reported as being between 1.7 and 6.3 months and overall survival of 4 to 9 months, which is greatly reduced compared to the 5 to 11 months and 11 to 13 months respectively, reported for dogs with B-cell lymphoma. 3,5,6,9,12 Alternative protocols for both naive and refractory large cell lymphoma have been investigated in dogs. Mechlorethamine, vincristine, prednisolone and procarbazine (MOPP) protocol has been used in the treatment of humans with both Hodgkin s and non-hodgkin s lymphoma. 14 A MOPP protocol has also been investigated for dogs with relapsed/refractory lymphoma as well as a first-line treatment in combination with l-asparaginase. 9,15 This combination chemotherapy protocol showed a high overall response rate as a first-line treatment but concurrently, a high rate of toxicity. Mechlorethamine is unavailable for veterinary use in some countries and so alternatives to this alkylating agent have also been investigated. Carmustine has been used as a substitute for mechlorethamine (BOPP protocol) for relapsed lymphoma with a reported 50% response rate and a concurrently high rate of toxicity. 15 Lomustine, vincristine, procarbazine and prednisolone combination protocol (LOPP) has been previously evaluated as an alternative to MOPP as a rescue protocol for canine lymphoma. 15,16 These studies report overall response rates of between 52% and 61% in a relapse setting for both B and T phenotypes, but with high rates of toxicity. 15,16 The purpose of this retrospective study was to evaluate the response rate and toxicity of a modified LOPP chemotherapy protocol as first-line therapy for the treatment of T-cell lymphoma in dogs. 2 MATERIALS AND METHODS 2.1 Study population Dogs with lymphoma treated with a LOPP chemotherapy protocol at the author s institution between January 2011 and June 2016 were John Wiley & Sons Ltd wileyonlinelibrary.com/journal/vco Vet Comp Oncol. 2018;16:

2 BROWN ET AL. 109 retrospectively identified. Inclusion criteria were a cytological or histopathological diagnosis of intermediate- or high-grade lymphoma, confirmed T-cell immunophenotype, intent to treat with LOPP chemotherapy and staging that included a complete blood count, serum biochemistry panel, thoracic radiography and abdominal ultrasound. Dogs with stage I or II lymphoma, epitheliotrophic lymphoma and low-grade lymphoma were excluded. Dogs with a history of prior chemotherapy or corticosteroid treatment were also excluded. 2.2 Diagnosis and staging The diagnosis of intermediate or large cell lymphoma was made on cytopathological or histopathological evaluation of a lymph node or extra-nodal site in all cases. Immunoreactivity with CD3 antibody and lack of reactivity with CD79a constituted a diagnosis of T-cell lymphoma. Clinical stage was based on the World Health Organization (WHO) criteria for canine lymphoma. 17 Two or three view thoracic radiographs were reviewed for evidence of enlargement of intrathoracic lymph nodes (sternal, mediastinal and tracheobronchial lymph nodes), changes of the lung pattern, or any other abnormalities. An abdominal sonogram was collected before initiation of treatment and again at the completion of the protocol to confirm remission. Bone marrow examination was not routinely performed in this cohort of patients; with patients being classified as stage V disease if central nervous system, ocular, blood or gastrointestinal involvement was documented. 2.3 Treatment Dogs treated in this study received injectable chemotherapy treatment only at the author s institution and so were evaluated with physical examination and haematology and biochemistry every 14 days. This LOPP protocol differed to protocol previously described and used for relapsed disease, the timing of the lomustine compared to the administration of vincristine was on consecutive days instead of the same day and the dose interval between vincristine doses was increased from 7 days to 14 days. 15 Lomustine, procarbazine and prednisolone was dispensed to the owners and its administration was performed in the patients home. Both FDA-approved and compounded formulations of lomustine and procarbazine were used during the study, this was determined by drug availability and patient size. 2.4 Response All responses were classified according to the VCOG consensus statement for lymphoma. 18 A complete remission (CR) was considered a resolution of all clinically detectable disease. A designation of no response (NR) or partial response (PR) was determined based on the clinician s measurements and assessment in the medical record. 2.5 Toxicity Toxicity was determined through evaluation of clinical records and haematology and biochemical analysis performed at each patient visit. Owners were provided a questionnaire at the time of each visit and were asked to report any observed side effects noted since the previous visit. The severity, duration and necessity for treatment for these side effects was determined by the clinician assessing the patient for that visit and toxicity was graded and recorded in the clinical record. Haematologic and biochemical parameters were assessed prior to the start of each cycle and a complete blood count was performed 7 days after the first lomustine administration, or at any time side effects were noted. 2.6 Statistical analysis Complete and PR rates were defined as the number of dogs experiencing respective remissions compared to the total number of dogs treated. Disease-free interval (DFI) was defined as the time from first documented remission until relapse, dogs were censored if they did not relapse or received autologous bone marrow transplantation after completion of chemotherapy. OST was defined as the time between first treatment and death. Dogs were censored from overall survival if they were still in remission and alive at the time of analysis. Kaplan Meier calculations were performed for both DFI and OST. Dogs lost to follow-up were censored at the last date of contact. Kaplan Meier curves were created for categorical variables and for continuous variables categorized by median values (eg, age < 7.5 years and 7.5 years). Separate Cox proportional hazard analyses were performed to assess the effect of the body weight, hypercalcaemia, administration of l-asparaginase, thrombocytopenia, stage and substage on DFI and OST while accounting for the potential confounding variables of age and sex. Variables significant at.5 on bivariate analyses were entered into a multivariate model followed by a backwards stepwise protocol. The significance of each explanatory variable was tested using the Wald test. Explanatory variables that were not statistically significant were removed from the model one at a time, beginning with the least significant. A P-value.05 was considered statistically significant. 3 RESULTS 3.1 Treatment Thirty-one dogs were included in this study. All dogs were treated with a modified LOPP protocol (Table 1), which included l-asparaginase as part of induction in 13 of 31 dogs. Dogs in this study received an average of 6 cycles (range 2-16) with the intended protocol consisting of 6 cycles over a total of 24 weeks. Twentythree dogs (74%) completed the intended LOPP protocol. 3.2 Patient characteristics Median age was 7 years (range 3-13 years). Breeds represented were cross breed (6) Boxer (2), Rhodesian ridgeback (2), Rottweiler (2), Golden retriever (2), Kelpie (2), Labrador (2), Jack Russell Terrier (1), Beagle (1), Sheltie (1), Japanese Spitz (1), Douge de Bordeaux (1), Dalmation (1), Gordon Setter (1), British Bulldog (1), Shih Tzu (1), Weimerana (1), Bullmastiff (1), Cocker Spaniel (1) and Bullterrier (1). Fifteen dogs were neutered males, 13 dogs were neutered females and 3 were intact males. The majority of dogs in this study were

3 110 BROWN ET AL. TABLE 1 A LOPP cycle Day Drug = 0 Vincristine (0.5 mg/m 2 ) Lomustine (60 mg/m 2 ) Procarbazine (50 mg/m 2 ) Prednisolone (1 mg/kg) Abbreviations: LOPP, lomustine, vincristine, procarbazine and prednisolone. medium to large sized with the median weight being 26 kg (range 5-65 kg). All dogs in this study were diagnosed as having lymphoma based on histologic or cytologic evaluation of lymph node or extranodal structures. T-cell lymphoma was diagnosed by immunocytochemistry in 28 dogs and by immunohistochemistry in the remaining 3 dogs. Twenty-five dogs were diagnosed with multicentric T-cell lymphoma, 4 dogs were diagnosed with cranial mediastinal T-cell lymphoma and the remaining 2 dogs were diagnosed with hepatic T-cell lymphoma. Of the 25 multicentric lymphoma dogs, 17 were classified as stage III (or higher) and 14 as having definitive stage V disease. There were 14 dogs classified as having substage-b disease and the remaining 17 dogs were considered substage-a. In total, 10 dogs (32%) were hypercalaemic on presentation with the remaining 21 having both normal total and ionized calcium. 3.3 Treatment response/toxicity, survival and prognostic factors The overall response rate in this population of dogs was 97%. Twenty-eight out of 31 (90%) of dogs were assessed to have had a CR to LOPP chemotherapy. Two dogs (7%) were assessed as having a PR, while 1 dog had NR (3%). Of the 30 dogs that had a response to the LOPP protocol, the median DFI was 176 days (range ). Nine dogs (29%) remained in remission and 1 dog (3%) had received an autologous bone marrow transplant after obtaining a CR at the time of writing of this study. Their data was censored from DFI calculations, the range for DFI for these dogs was 102 to 1635 days. Response, remission and survival times for all dogs in this study are summarized in Table 2. A Kaplan Meier curve for DFI, including 95% confidence intervals, is depicted in Figure 1. Dogs with mediastinal and hepatic lymphoma were analysed separately and their data TABLE 2 Response, remission and survival information for dogs treated with LOPP chemotherapy LOPP chemotherapy Response CR 28 (90%) PR 2 (7%) SD 0 (0%) PD 1 (3%) Median disease-free interval (days) 176 ( ) Median survival time (days) Overall (CR + PR + SD + PD) Responders (CR + PR) 323 ( ) 328 ( ) Abbreviations: CR, complete remission; LOPP, lomustine, vincristine, procarbazine and prednisolone; PD, progressive disease; PR, partial response; SD, stable disease. FIGURE 1 Kaplan Meier graph for disease-free interval (DFI) compared to dogs with multicentric lymphoma, this data are presented in Table 3. There were 3 dogs with mediastinal lymphoma and 1 dog with hepatic lymphoma that remained in remission at the time of writing and so their data was also not included in DFI analysis (at a follow-up time of range-range days). The OST for all dogs in this study was 323 days (range ). Twenty-one dogs relapsed during the study period and 12 of these dogs (57%) received rescue chemotherapy. Rescue agents included a repeated LOPP protocol (6), l-asparaginase and doxorubicin (3), epirubicin and chlorambucil (1), epirubicin alone (1) and doxorubicin alone (1). Ten dogs were alive at the end of the study period, with the longest survivor being at 1696 days since diagnosis. The 1- and 2-year survival rates for dogs treated with LOPP chemotherapy were 39% and 25%, respectively. No deaths in the study population of dogs were confirmed to be because of causes unrelated to their lymphoma. A Kaplan Meier curve for OST, including 95% confidence intervals, is depicted in Figure 2. Thirteen dogs (42%) experienced side effects during their chemotherapy protocol. The most frequently reported side effects involved TABLE 3 Comparative analysis of multicentric, mediastinal and hepatic lymphoma CR PR DFI (d) OS (d) Multicentric (25) Mediastinal (4) Hepatic (2) Abbreviations: CR, complete remission; DFI, disease-free interval; PR, partial response; OS, overall survival.

4 BROWN ET AL. 111 FIGURE 2 the gastrointestinal tract; nausea, vomiting and diarrhoea; in 6 of 31 dogs and evidence of myelosuppression (neutropenia and a cumulative thrombocytopenia) in 7 of 31 dogs. These side effects necessitated a dose reduction of vincristine in 5 of 13 dogs and a swap from procarbazine to chlorambucil in 1 dog. Unique to the use of lomustine, evidence of hepatotoxicity was reported in 8 of 31 dogs and lead to the addition of s-adenlymethionine (denosyl) in all 8 dogs and a dose reduction of lomustine (CCNU) (6 dogs) or substitution for cyclophosphamide (2 dogs). Four dogs required hospitalization for treatment of chemotherapy-induced side effects. The incidence and severity of side effects has been summarized in Table No grade V toxicities were reported in any dogs during this study. Statistical analysis using Cox regression analysis testing failed to identify variables that were significantly associated with DFI or OST (Tables 5 and 6). 4 DISCUSSION Kaplan Meier graph for overall survival time (OST) The purpose of the study was to evaluate the use of LOPP chemotherapy in dogs with T-cell lymphoma. A secondary goal was to identify any prognostic factors for these dogs that were associated with DFI and OST. For dogs with T-cell lymphoma, we found that there was a high response rate (97%) but that the response was of limited duration (DFI 176 days) compared historically to that of B-cell lymphoma. OSTs were modestly improved compared to other reported TABLE 4 Incidence and severity of side effects to LOPP (VCOG CTCAE) 18 Grade I Grade II Grade III Grade IV GIT Haematologic Hepatotoxicity Abbreviations: CTCAE, common terminology criteria for adverse events; GIT, gastrointestinal; LOPP, lomustine, vincristine, procarbazine and prednisolone; VCOG, veterinary cooperative oncology group. protocols, with a lower reported overall toxicity rate (Table 4). Increased OSTs were seen when patients were treated with rescue chemotherapy of varying protocols. The use of rescue chemotherapy is dictated primarily by owner preference as well as financial constraints and so not all dogs routinely receive rescue chemotherapy. No prognostic factors were significantly associated with DFI or OST in this study. Hypercalcaemia and substage were negative prognostic factors in previous studies on B- and T-cell lymphoma and may prove to be significant if a larger number of patients are studied. In normal cells and tumour cells, one of the many mechanisms for cellular DNA repair includes the proteins O6-alkyltransferase (AGT) and O6-methylguanine-DNA methyltransferase (MGMT). These proteins mediate a reaction with the O6-position of guanine in DNA, removing the lesion and leaving the guanine intact. Lomustine is a classic alkylating agent that acts by covalent binding of alkyl groups of DNA molecules, which results in reactive intermediates and DNA damage because of double-strand breaks. Procarbazine is a non-classic alkylating agent that requires metabolic activation and results in methylation of nucleic acids. Neoplastic T lymphocytes have been found to contain very low levels of the AGT and MGMT proteins, which make alkylating agents a good choice for treatment as these cells are often unable to effectively repair DNA damaged caused by alkylation or methylation. 20,21 The hypothesis behind using a chemotherapy protocol that was alkylating agent rich was that T lymphocytes would have a higher response rate to these drugs due to inefficient DNA repair, and this was demonstrated by the high ORR of 97% in this study group. The comparable DFI and OST to other multi-agent protocols could be due to the acquisition of cellular resistance, likely influenced by an increased capacity to repair alkylated lesions through an upregulation of AGT or MGMT repair protein production and efficacy. The LOPP protocol used in this study differed to the previously described protocol used in relapsed disease. 15 The dose interval between vincristine injections was increased from 7 days to 14 days. The administration of lomustine occurred 1 day after vincristine administration instead of on the same day. These changes were instituted to minimize the haematologic and gastrointestinal toxicity to patients that resulted in only 9% of patients being able to receive the full doses of chemotherapy in the previous study. 15 This change to the dosing schedule for the LOPP protocol effectively reduced the overall toxicity rate of this protocol and 82% of patients received full doses of all the drugs in this modified LOPP protocol. This demonstrates a significant improvement to toxicity and patient tolerability compared to the original protocol. Previously, three studies have reported on the response rates, DFI and OST for dogs with non-indolent T-cell lymphoma treated with multi-agent chemotherapy protocols. The median DFI of 178 days (95% CI, ) and the median OST of 323days (95% CI, ) in this study were similar to those previously reported in three studies of canine T-cell lymphoma: (1) median DFI of 189 days and OST of 270 days 9 ; (2) median DFI of 175 days and OST of 237 days 22 ; and (3) median DFI of 104 days and OST of 235 days. 12 In this study, CR and ORR were 88% and 95%, respectively; higher than the CR of 64% and ORR of 73% reported for the VELCAP-TSE study 22 and similar to the previously reported CR of 78% and ORR of

5 112 BROWN ET AL. TABLE 5 Factors affecting disease-free interval in dogs with T-cell lymphoma treated with LOPP; results of bivariate Cox regression analysis Variable Coefficient Exponentiated coefficient Standard error (coefficient) P value Age (years) Sex (male) Weight (kg) Hypercalcemia (present) L 0 asparaginase administered Stage 3b Stage 5a Stage 5b Substage b Side effects (present) Abbreviation: LOPP, lomustine, vincristine, procarbazine and prednisolone. TABLE 6 Factors affecting overall survival (OST) in dogs with T-cell lymphoma treated with LOPP; results of bivariate Cox regression analysis Variable Coefficient Exponentiated coefficient Standard error (coefficient) P value Age (years) Sex (male) Weight (kg) Hypercalcemia (present) L 0 asparaginase administered Stage 3b Stage 5a Stage 5b Substage b Side effects (present) Abbreviation: LOPP, lomustine, vincristine, procarbazine and prednisolone. 98% in the L-MOPP study, 9 and the CR of 88% and ORR of 96% of the L-CHOP study. 12 When compared to previous studies, this LOPP protocol had significantly lower reported toxicity, with side effects reported in only 42% of dogs with no stage V toxicities. The L- MOPP 9 and VELCAP-TSE 22 protocols had reported toxicity rates of 67% and 90% respectively, so it appears this is a better tolerated protocol. These comparisons have been summarized in Table 7. Limitations of this study include the retrospective nature and small sample size. Clinical stage is an inconsistent predictor of remission and survival and was not shown to have an impact on either outcome in this study. This may reflect inconsistent staging; cytologic evaluation of the liver, spleen and bone marrow were not routinely performed, so the recorded stage of an individual reflected only their minimum stage. This may explain why there were more stage III dogs in this study compared to stage IV/V dogs when compared to other T-cell lymphoma studies. 9,12 TABLE 7 Comparison of L-CHOP, 12 L-MOPP, 9 VELCAP-TSE 21 and LOPP protocols L-CHOP L-MOPP VELCAP-TSE LOPP ORR (%) DFI (days) OST (days) Toxicity (%) Not reported Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine and prednisolone; DFI, disease-free interval; MOPP, mechlorethamine, vincristine, prednisolone and procarbazine; ORR, overall response rate; OST, overall survival time; VELCAP-TSE, vincristine, l-asparaginase, cyclophosphamide, doxorubicin, lomusine, actinomycin, procarbazine and prednisolone. 5 CONCLUSIONS The modified LOPP chemotherapy protocol shows a high overall response rate and comparable DFI and OST for patients with T-cell lymphoma. This protocol exhibits an acceptable level of toxicity and high degree of owner compliance. The LOPP chemotherapy protocol is a viable treatment option for dogs with high-grade T-cell lymphoma. ACKNOWLEDGEMENTS The contribution of referring veterinarians to patient care and the provision of follow-up data from owners was greatly appreciated. Portions of this work were presented as an Abstract at the 2016 Australian College of Veterinary Scientists Annual Science week conference on the Gold Coast as well as in poster form at the Annual Veterinary Cancer Society conference in Florida REFERENCES 1. Fournel-Fleury C, Ponce F, Felman P, et al. Canine T-cell lymphomas: a morphological, immunological, and clinical study of 46 new cases. Vet Pathol. 2002;39: Fournel-Fleury CM, Magnol JP, Bricaire P, et al. Cytohistological and Immunological classification of canine malignant lymphomas: comparison with human non-hodgkin s lymphomas. J Comp Pathol. 1997;117: Ruslander DA, Gebhard DH, Tompkins MB, Grindem CB, Page RL. Immunophenotypic characterization of canine lymphoproliferative disorders. In vivo. 1997;11:

6 BROWN ET AL Sueiro FA, Alessi AC, Vassallo J. Canine lymphomas: a morphological and immunohistochemical study of 55 cases, with observations on p53 immunoexpression. J Comp Pathol. 2004;131: Valli VE, Kass PH, San Myint M, Scott F. Canine lymphomas: association of classification type, disease stage, tumor subtype, mitotic rate, and treatment with survival. Vet Pathol. 2013;50: Modiano JFB, Breen M, Burnett RC, et al. Distinct B-cell and T-cell lymphoproliferative disease prevalence among dog breeds indicates heritable risk. Cancer Res. 2005;65: Ponce F, Magnol JP, Ledieu D, et al. Prognostic significance of morphological subtypes in canine malignant lymphomas during chemotherapy. Vet J. 2004;167: Wilkerson MJ, Dolce K, Koopman T, et al. Lineage differentiation of canine lymphoma/leukemias and aberrant expression of CD molecules. Vet Immunol Immunopathol. 2005;106: Brodsky EMM, Maudlin GN, Lachowicz JL, Post GS. Asparaginase and MOPP treatment of dogs with lymphoma. J Vet Intern Med. 2009;23: Hosoya KK, Kisseberth WC, Lord LK, et al. Comparison of COAP and UW-19 protocols for dogs with multicentric lymphoma. J Vet Intern Med. 2007;21: Legendre AM. Treatment of dogs with lymphoma: a work in progress. J Vet Intern Med. 2007;21: Rebhun RB, Kent MS, Borrofka SA, et al. CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma. Vet Comp Oncol. 2011;9: Regan RC, Kaplan MS, Bailey DB. Diagnostic evaluation and treatment recommendations for dogs with substage-a high-grade multicentric lymphoma: results of a survey of veterinarians. Vet Comp Oncol. 2013;11: Hancock BW, Vaughan Hudson G, Vaughan Hudson B, et al. British National Lymphoma Investigation randomised study of MOPP (mustine, Oncovin, procarbazine, prednisolone) against LOPP (Leukeran substituted for mustine) in advanced Hodgkin s disease long term results. Br J Cancer. 1991;63: LeBlanc AK, Mauldin GE, Milner RJ, et al. Efficacy and toxicity of BOPP and LOPP chemotherapy for the treatment of relapsed canine lymphoma. Vet Comp Oncol. 2006;4: Fahey CE, Milner RJ, Barabas K, et al. Evaluation of the University of Florida lomustine, vincristine, procarbazine, and prednisone chemotherapy protocol for the treatment of relapsed lymphoma in dogs: 33 cases ( ). J Am Vet Med Assoc. 2011;239: Valli VE, San Myint M, Barthel A, et al. Classification of canine malignant lymphomas according to the World Health Organization criteria. Vet Pathol. 2011;48: Vail DM, Michels GM, Khanna C, et al. Response evaluation criteria for peripheral nodal lymphoma in dogs (v1.0) a Veterinary Cooperative Oncology Group (VCOG) consensus document. Vet Comp Oncol. 2010;8: VCOG-CTCAE. Veterinary cooperative oncology group common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.0. Vet Comp Oncol. 2004;2: Dolan MEM, McBae BL, Ferries-Rowe E, et al. O6-alkylguanine-DNA alkyltransferase in cutaneous T-cell lymphoma: implications for treatment with alkylating agents. Clin Cancer Res. 1999;5: Hansen RJ, Nagasubramanian R, Delaney SM, Samson LD, Dolan ME. Role of O6-methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice. Carcinogenesis. 2007;28: Goodman IH, Moore AS, Frimberger AE. Treatment of canine nonindolent T cell lymphoma using the VELCAP-TSC protocol: a retrospective evaluation of 70 dogs ( ). Vet J. 2016;211: How to cite this article: Brown PM, Tzannes S, Nguyen S, White J, Langova V. LOPP chemotherapy as a first-line treatment for dogs with T-cell lymphoma. Vet Comp Oncol. 2018;16: