Subscribe to RSS
DOI: 10.1055/a-1481-7066
Maintenance treatment in relapsed canine lymphoma after a short L-CHOP protocol
Erhaltungstherapie für das rezidivierte Lymphom des Hundes nach einem kurzen L-CHOP-Protokoll![](https://www.thieme-connect.de/media/10.1055-s-00034911/202103/lookinside/thumbnails/10-1055-a-1481-7066-1.jpg)
Abstract
Objective A number of different rescue protocols for relapsed canine multicentric large-cell lymphoma have been described. The aim of this pilot study was to evaluate the efficacy of a maintenance treatment in dogs that experienced a second complete remission after a short L-CHOP-rescue protocol.
Material and methods Included in the study were dogs experiencing the first lymphoma relapse during a treatment-free period which were treated with a short L-CHOP protocol, achieved a complete remission and were afterwards treated with a continuous maintenance phase (MP) protocol. The L-CHOP protocol consisted of weekly treatments, with at least 3 additional treatments following complete remission. Thereafter the MP protocol with 2-week treatment intervals was conducted. It consisted of alternating oral home administration of different alkylating agents and one intravenously administered cytotoxic agent of a different mechanism of action. The dogs were presented either every 4 or 6 weeks for intravenous treatment and at this time a complete blood count was performed. The durations of the first remission, disease-free interval and overall survival time were evaluated.
Results A total of 20 dogs were included in the study. A median of 7 weekly applications were given before the treatment was switched to the MP protocol. During MP, 14 dogs were treated intravenously every 6 weeks and 6 dogs every 4 weeks. Haematological adverse events were mainly mild. During the L-CHOP-protocol, one septic event occurred, and 2 dogs were hospitalized due to gastrointestinal adverse events. No patient required hospitalization during the MP. Fifteen dogs completed at least one cycle in the MP and a median of 8.5 chemotherapeutic treatments were administered. The median disease-free interval was 264 days and the median overall survival time was 737 days.
Conclusion and clinical relevance The protocol was generally well tolerated. Since 5 patients showed disease progression during the first cycle of the MP, dogs should ideally be evaluated for minimal residual disease before being switched to the MP. The case number in the presented study was low and the treatment relatively heterogeneous. Therefore, more dogs have to be treated with the proposed protocol before general recommendations can be made.
Zusammenfassung
Gegenstand und Ziel Für das rezidivierte kanine multizentrische Lymphom sind viele verschiedene Therapieprotokolle beschrieben. Ziel dieser Pilotstudie war, die Effektivität einer Erhaltungstherapie bei Hunden mit einer zweiten kompletten Remission nach einem kurzen L-CHOP-Protokoll zu evaluieren.
Material und Methoden Eingeschlossen wurden Hunde, die zum Zeitpunkt des ersten Rezidivs nach einer therapiefreien Zeit mit einem kurzen L-CHOP-Protokoll und nach Erreichen einer kompletten Remission mit einem Erhaltungsprotokoll behandelt wurden. Das L-CHOP-Protokoll umfasste wöchentliche Behandlungen mit mindestens 3 Gaben über die komplette Remission hinaus, danach erfolgte die Umstellung auf das Erhaltungsprotokoll mit Therapieintervallen von 2 Wochen. Dieses beinhaltete verschiedene vom Tierbesitzer oral verabreichte Alkylanzien sowie ein intravenös appliziertes Chemotherapeutikum mit einem anderen Wirkmechanismus. Zum Zeitpunkt der alle 4 oder 6 Wochen vorgenommenen intravenösen Behandlung wurde ein Blutbild erstellt. Evaluiert wurden die erste Remissionsdauer, das krankheitsfreie Intervall und die Gesamtüberlebenszeit.
Ergebnisse Bei den 20 in die Studie eingeschlossenen Hunden erfolgten median 7 wöchentliche Behandlungen mit dem L-CHOP-Protokoll, bevor das Protokoll auf die Erhaltungsphase umgestellt wurde. In dieser erhielten 14 Hunde die intravenöse Medikation alle 6 Wochen und 6 Hunde alle 4 Wochen. Hämatologische Nebenwirkungen waren grundsätzlich mild. Ein Hund entwickelte während des L-CHOP-Protokolls eine Sepsis und 2 Tiere mussten wegen gastrointestinaler Nebenwirkungen stationär aufgenommen werden. In der Erhaltungsphase war keine stationäre Aufnahme erforderlich. Bei 15 Hunden fand in der Erhaltungsphase mindestens ein Zyklus statt und median wurden 8,5 Behandlungen durchgeführt. Das mediane krankheitsfreie Intervall betrug 264 Tage, die mediane Gesamtüberlebenszeit 737 Tagen. Bei 6 Hunden gab es keine Verlaufskontrolle.
Schlussfolgerung und klinische Relevanz Das Therapie nach dem Erhaltungsprotokoll wurde im Allgemeinen gut vertragen. Da 5 Hunde im ersten Zyklus eine Progression der Erkrankung zeigten, sollte vor der Umstellung auf das Protokoll der Erhaltungsphase idealerweise eine Untersuchung auf eine nur mikroskopisch nachweisbare Erkrankung stattfinden. Aufgrund der geringen Anzahl an Hunden, die eine relativ heterogene Therapie erhielten, muss das vorgeschlagene Protokoll bei einer größeren Anzahl Hunden Anwendung finden, bevor allgemeine Empfehlungen ausgesprochen werden können.
Key words
Chemotherapy - dog - large-cell lymphoma - multicentric lymphoma - recurrence - rescue therapySchlüsselwörter
Chemotherapie - großzelliges Lymphom - Hund - multizentrisches Lymphom - Rezidiv - RettungstherapieSupplementary material
- Supplementary material is available under https://dx.doi.org/10.1055/a-1481-7066
- Supplementary material
Publication History
Received: 17 May 2020
Accepted: 05 January 2021
Article published online:
22 June 2021
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Marconato L, Gelain ME, Comazzi S. The dog as a possible animal model for human non-Hodgkin lymphoma: a review. Hematol Oncol 2013; 31: 1-9 DOI: 10.1002/hon.2017.
- 2 Chun R, Garrett LD, Vail DM. Evaluation of a high-dose chemotherapy protocol with no maintenance therapy for dogs with lymphoma. J Vet Intern Med 2000; 14: 120-124
- 3 Curran K, Thamm DH. Retrospective analysis for treatment of naive canine multicentric lymphoma with a 15-week, maintenance-free CHOP protocol. Vet Comp Oncol 2016; 14 (Suppl. 01) 147-155 DOI: 10.1111/vco.12163.
- 4 Garrett LD, Thamm DH, Chun R. et al. Evaluation of a 6-month chemotherapy protocol with no maintenance therapy for dogs with lymphoma. J Vet Intern Med 2002; 16: 704-709
- 5 Moore AS, Cotter SM, Rand WM. et al. Evaluation of a discontinuous treatment protocol (VELCAP-S) for canine lymphoma. J Vet Intern Med 2001; 15: 348-354
- 6 Rassnick KM, Bailey DB, Malone EK. et al. Comparison between L-CHOP and an L-CHOP protocol with interposed treatments of CCNU and MOPP (L-CHOP-CCNU-MOPP) for lymphoma in dogs. Vet Comp Oncol 2010; 8: 243-253 DOI: 10.1111/j.1476-5829.2010.00224.x.
- 7 Rebhun RB, Kent MS, Borrofka SA. et al. CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma. Vet Comp Oncol 2011; 9: 38-44 DOI: 10.1111/j.1476-5829.2010.00230.x.
- 8 Simon D, Nolte I, Eberle N. et al. Treatment of dogs with lymphoma using a 12-week, maintenance-free combination chemotherapy protocol. J Vet Intern Med 2006; 20: 948-954
- 9 Zenker I, Meichner K, Steinle K. et al. Thirteen-week dose-intensifying simultaneous combination chemotherapy protocol for malignant lymphoma in dogs. Vet Rec 2010; 167: 744-748 DOI: 10.1136/vr.c5081.
- 10 Wang SL, Lee JJ, Liao AT. Comparison of efficacy and toxicity of doxorubicin and mitoxantrone in combination chemotherapy for canine lymphoma. Can Vet J 2016; 57: 271-276
- 11 Elliott JW, Cripps P, Marrington AM. et al. Epirubicin as part of a multi-agent chemotherapy protocol for canine lymphoma. Vet Comp Oncol 2013; 11: 185-198 DOI: 10.1111/j.1476-5829.2011.00311.x.
- 12 Hosoya K, Kisseberth WC, Lord LK. et al. Comparison of COAP and UW-19 protocols for dogs with multicentric lymphoma. J Vet Intern Med 2007; 21: 1355-1363
- 13 Morrison-Collister KE, Rassnick KM, Northrup NC. et al. A combination chemotherapy protocol with MOPP and CCNU consolidation (Tufts VELCAP-SC) for the treatment of canine lymphoma. Vet Comp Oncol 2003; 1: 180-190 DOI: 10.1111/j.1476-5810.2003.00027.x.
- 14 Flory AB, Rassnick KM, Erb HN. et al. Evaluation of factors associated with second remission in dogs with lymphoma undergoing retreatment with a cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy protocol: 95 cases (2000–2007). J Am Vet Med Assoc 2011; 238: 501-506 DOI: 10.2460/javma.238.4.501.
- 15 Rassnick KM, McEntee MC, Erb HN. et al. Comparison of 3 protocols for treatment after induction of remission in dogs with lymphoma. J Vet Intern Med 2007; 21: 1364-1373
- 16 Lautscham EM, Kessler M, Ernst T. et al. Comparison of a CHOP-LAsp-based protocol with and without maintenance for canine multicentric lymphoma. Vet Rec 2017; 180: 303 DOI: 10.1136/vr.104077.
- 17 Simon D, Moreno SN, Hirschberger J. et al. Efficacy of a continuous, multiagent chemotherapeutic protocol versus a short-term single-agent protocol in dogs with lymphoma. J Am Vet Med Assoc 2008; 232: 879-885 DOI: 10.2460/javma.232.6.879.
- 18 Saba CF, Thamm DH, Vail DM. Combination chemotherapy with L-asparaginase, lomustine, and prednisone for relapsed or refractory canine lymphoma. J Vet Intern Med 2007; 21: 127-132
- 19 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: 28-37 DOI: 10.1111/j.1476-5829.2009.00200.x.
- 20 [Anonym]. Veterinary cooperative oncology group – common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.1. Vet Comp Oncol 2016; 14: 417-446 DOI: 10.1111/vco.283.
- 21 Bergman PJ, Ogilvie GK, Powers BE. Monoclonal antibody C219 immunohistochemistry against P-glycoprotein: sequential analysis and predictive ability in dogs with lymphoma. J Vet Intern Med 1996; 10: 354-359
- 22 Lee JJ, Hughes CS, Fine RL. et al. P-glycoprotein expression in canine lymphoma: a relevant, intermediate model of multidrug resistance. Cancer 1996; 77: 1892-1898 DOI: 10.1002/(sici)1097–0142(19960501)77:9<1892::aidL42:DASHcncr20>3.0.co;2.
- 23 Ammersbach MA, Kruth SA, Sears W. et al. The effect of glucocorticoids on canine lymphocyte marker expression and apoptosis. J Vet Intern Med 2006; 20: 1166-1171 DOI: 10.1892/0891-6640(2006)20[1166:teogoc]2.0.co;2.
- 24 Gustafson D, Bailey DB. Cancer Chemotherapy. In: Vail DM, Thamm D, Liptak J. ed. Withrow and MacEwen’s Small Animal Clinical Oncology. St. Louis: Elsevier; 2019: 182-208
- 25 Ganzina F. 4’-epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data. Cancer Treat Rev 1983; 10: 1-22
- 26 Ganzina F, Di Pietro N, Magni O. Clinical toxicity of 4’-epi-doxorubicin (epirubicin). Tumori 1985; 71: 233-240
- 27 Tham P, Dougherty W, Iatropoulos MJ. et al. The effect of mitoxantrone treatment in beagle dogs previously treated with minimally cardiotoxic doses of doxorubicin. Am J Pathol 1987; 128: 121-130
- 28 Daters AT, Mauldin GE, Mauldin GN. et al. Evaluation of a multidrug chemotherapy protocol with mitoxantrone based maintenance (CHOP-MA) for the treatment of canine lymphoma. Vet Comp Oncol 2010; 8: 11-22 DOI: 10.1111/j.1476-5829.2009.00199.x.
- 29 Marquardt TM, Lindley SES, Smith AN. et al. Substitution of mitoxantrone for doxorubicin in a multidrug chemotherapeutic protocol for first-line treatment of dogs with multicentric intermediate-to large-cell lymphoma. J Am Vet Med Assoc 2019; 254: 236-242 DOI: 10.2460/javma.254.2.236.
- 30 Gramer I, Kessler M, Geyer J. Determination of MDR1 gene expression for prediction of chemotherapy tolerance and treatment outcome in dogs with lymphoma. Vet Comp Oncol 2015; 13: 363-372 DOI: 10.1111/vco.12051.
- 31 Warry E, Hansen RJ, Gustafson DL. et al. Pharmacokinetics of cyclophosphamide after oral and intravenous administration to dogs with lymphoma. J Vet Intern Med 2011; 25: 903-908 DOI: 10.1111/j.1939-1676.2011.0730.x.
- 32 Furner RL, Brown RK, Duncan G. Pharmacokinetics of the absorption, distribution, and elimination of melphalan in the dog. Cancer Treat Rep 1977; 61: 1637-1646
- 33 Harding K, Bergman N, Smith A. et al. Response rate to a single dose of vinblastine administered to dogs with treatment-naive multicentric lymphoma. Vet Comp Oncol 2018; 16: 636-641 DOI: 10.1111/vco.12433.
- 34 Lenz JA, Robat CS, Stein TJ. Vinblastine as a second rescue for the treatment of canine multicentric lymphoma in 39 cases (2005 to 2014). J Small Anim Pract 2016; 57: 429-434 DOI: 10.1111/jsap.12500.
- 35 Chu EDVJ. Principles of medical oncology. In: DeVita Jr VTHS, Rosenberg SA. eds. Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins; 2005
- 36 Fournier Q, Serra JC, Handel I. et al. Impact of Pretreatment Neutrophil Count on Chemotherapy Administration and Toxicity in Dogs with Lymphoma Treated with CHOP Chemotherapy. J Vet Intern Med 2018; 32: 384-393 DOI: 10.1111/jvim.14895.
- 37 Gaeta R, Brown D, Cohen R. et al. Risk factors for development of sterile haemorrhagic cystitis in canine lymphoma patients receiving oral cyclophosphamide: a case-control study. Vet Comp Oncol 2014; 12: 277-286 DOI: 10.1111/vco.12009.
- 38 Chan CM, Frimberger AE, Moore AS. Incidence of sterile hemorrhagic cystitis in tumor-bearing dogs concurrently treated with oral metronomic cyclophosphamide chemotherapy and furosemide: 55 cases (2009–2015). J Am Vet Med Assoc 2016; 249: 1408-1414 DOI: 10.2460/javma.249.12.1408.
- 39 Setyo L, Ma M, Bunn T. et al. Furosemide for prevention of cyclophosphamide-associated sterile haemorrhagic cystitis in dogs receiving metronomic low-dose oral cyclophosphamide. Vet Comp Oncol 2017; 15: 1468-1478 DOI: 10.1111/vco.12292.
- 40 Serra M, Papakonstantinou S, Adamcova M. et al. Veterinary and toxicological applications for the detection of cardiac injury using cardiac troponin. Vet J 2010; 185: 50-57 DOI: 10.1016/j.tvjl.2010.04.013.
- 41 Aresu L, Martini V, Rossi F. et al. Canine indolent and aggressive lymphoma: clinical spectrum with histologic correlation. Vet Comp Oncol 2015; 13: 348-362 DOI: 10.1111/vco.12048.
- 42 Cozzi M, Marconato L, Martini V. et al. Canine nodal marginal zone lymphoma: Descriptive insight into the biological behaviour. Vet Comp Oncol 2018; 16: 246-252 DOI: 10.1111/vco.12374.
- 43 Comazzi S, Aresu L, Marconato L. Transformation of Canine Lymphoma/Leukemia to More Aggressive Diseases: Anecdotes or Reality?. Front Vet Sci 2015; 2: 42 DOI: 10.3389/fvets.2015.00042.
- 44 Chalfon C, Martini V, Comazzi S. et al. Minimal residual disease in lymph nodes after achievement of complete remission predicts time to relapse in dogs with large B-cell lymphoma. Vet Comp Oncol 2019; 17: 139-146 DOI: 10.1111/vco.12453.
- 45 Aresu L, Arico A, Ferraresso S. et al. Minimal residual disease detection by flow cytometry and PARR in lymph node, peripheral blood and bone marrow, following treatment of dogs with diffuse large B-cell lymphoma. Vet J 2014; 200: 318-324 DOI: 10.1016/j.tvjl.2014.03.006.
- 46 Marconato L, Stefanello D, Valenti P. et al. Predictors of long-term survival in dogs with high-grade multicentric lymphoma. J Am Vet Med Assoc 2011; 238: 480-485 DOI: 10.2460/javma.238.4.480.