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Lymphoma: chemotherapy protocols

ISSN 2398-2950


Synonym(s): Immediate to high grade lymphoma chemotherapy protocols

Introduction

  • The following chemotherapy protocols for lymphoma will be covered:
    • Induction protocols:
      • Modified UW-Madison (UW 25) (CHOP-based).
      • Combination cytotoxic therapy COP.
    • Rescue protocols:
      • CCNU + prednisolone.
      • Doxorubicin + prednisolone.
Do not use without consulting specialist oncologist.Refer to chemotherapy safety administration Chemotherapy: safe handling.

Induction protocols

Protocol 1: Modified UW-Madison (UW 25) (CHOP-based)

Induction

Print table as supplied below for completion by veterinarian Chemotherapy protocol: modified UW-Madison (UW 25).

Week 1 

CBC
Vincristine 0.5-0.7 mg/m2 IV 
+/- L-asparaginase 400 IU/kg SQ or IM 
Prednisolone 2 mg/kg PO SID 

Week 2 

CBC
Cyclophosphamide 200-250 mg/m2 IV or PO 
Prednisolone 1.5 mg/kg PO SID 

Week 3 

CBC
Vincristine 0.5-0.7 mg/m2 IV 
Prednisolone 1 mg/kg PO SID 

Week 4 

CBC and renal values
Doxorubicin 30 mg/m2 IV 
Prednisolone 0.5 mg/kg PO SID 

Week 5 

CBC only 
No chemotherapy 
Discontinue prednisolone 

Week 6 

Vincristine 0.5-0.7 mg/m2 IV 

Week 7 

CBC
Cyclophosphamide 200-250 mg/m2 IV or PO 

Week 8 

Vincristine 0.5-0.7 mg/m2 IV 

Week 9 

CBC and renal values
Doxorubicin 1mg/kg IV 

Week 10 

No chemotherapy 
If patient is in complete remission,
continue with treatments at 2 week intervals on week 11

Maintenance

Week 11 

CBC
Vincristine 0.5-0.7 mg/m2 IV 

Week 13 

CBC
Cyclophosphamide 200-250 mg/m2 IV or PO    

Week 15 

CBC
Vincristine 0.5-0.7 mg/m2 IV  

Week 17 

CBC and renal values
Doxorubicin 1 mg/kg IV 

Week 19 

CBC
Vincristine 0.5-0.7 mg/m2 IV  

Week 21 

CBC
Cyclophosphamide 200-250 mg/m2 IV or PO 

Week 23 

CBC
Vincristine 0.5-0.7 mg/m2 IV 

Week 25 

CBC and renal values
Doxorubicin 1 mg/kg  IV 

Important considerations

  • Myelosuppression and gastrointestinal toxicity (eg inappetence, vomiting, and/or diarrhea) are possible toxicities of vincristine Vincristine, cyclophosphamide Cyclophosphamide, and doxorubicin Doxorubicin.
  • Additional toxicities of vincristine include:
    • Severe tissue necrosis and extravasation injury Chemotherapy: extravasation if given outside of the vein.
    • Peripheral neuropathies, most commonly manifested as paralytic ileus in cats.
  • Additional toxicities of doxorubicin include:
    • Severe tissue necrosis and extravasation injury if given outside of the vein. Doxorubicin should be administered through a "clean stick" catheter.
Careful monitoring of the patient is advised during administration to ensure the catheter remains in place.
  • Hemorrhagic colitis.
  • Anaphylactoid reactions secondary to mast cell degranulation. Premedication with 1-2 mg/kg of diphenhydramine Diphenhydramine IM approximately 30 mins prior to treatment is recommended by some oncologists to prevent this toxicity.
  • Acute cardiac toxicity manifested as arrhythmias.
  • Nephrotoxicity in cats (check renal values prior to administration).
  • Acute toxicities may be minimized by administering the drug slowly (over 10 minutes in cats).
  • A complete blood count (CBC Hematology: complete blood count (CBC)) must be performed within 48 h prior to chemotherapy administration. Ideally this should be done the day of chemotherapy administration. Delay chemotherapy by 3-7 days and then recheck CBC if:
    • Neutrophil count < 2500 cells/µl.
    • Platelet count < 75,000 cells/µl.
    • Patient is exhibiting GI signs secondary to previous chemotherapy.
  • Reduce chemotherapy dose by 20% in patients experiencing significant myelosuppression, GI toxicity and/or those requiring treatment delays during weekly administration.
  • Only continue with the CHOP protocol if complete remission has been achieved by week 6.
  • If patient is in complete remission at week 25, discontinue all therapy and re-evaluate monthly with a thorough physical examination.

Print out owner factsheet on Cancer treatment - lymphoma chemotherapy Cancer treatment - lymphoma chemotherapy to give to your client.

Protocol 2: Combination cytotoxic therapy COP

Induction

Cyclophosphamide

50 mg/m2 PO on alternate days or 50 mg/m2 PO for the first 4 days
of each week

Vincristine 

0.5 mg/m2 IV q7d

Prednisolone

40 mg/m2 PO q24h for first 7 days then 20 mg/m2 PO on alternate days
and given with cyclophosphamide

Maintenance after minimum of 2 months

Cyclophosphamide

50 mg/m2 PO on alternate days or 50 mg/m2 PO for the first 4 days
of each second week (alternate week therapy)

Vincristine

0.5 mg/m2 IV q14d

Prednisolone

20 mg/m2 PO on alternate days of each second week and
given with cyclophosphamide

Maintenance after 6 months (if disease in remission)

Cyclophosphamide

50 mg/m2 PO q48h on alternate days
or 50 mg/m2 PO for the first 4 days of each third week (1 week in 3)

Vincristine

0.5 mg/m2 IV q21d

Prednisolone

20 mg/m2 PO on alternate days of each third week and
given with cyclophosphamide

Maintenance after 12 months

Cyclophosphamide

50 mg/m2 PO q48h on alternate days
or 50 mg/m2 PO for the first 4 days of each fourth week (1 week in 4)

Vincristine

0.5 mg/m2 IV q21d

Prednisolone

20 mg/m2 PO on alternate days of each fourth week and
given with cyclophosphamide

Important considerations

  • Myelosuppression and/or GI effects may occur.
  • Perform a complete blood count (CBC) with platelet count Hematology: platelet count weekly during the induction course and then prior to every dose of chemotherapy. Delay chemotherapy by 3-7 days and recheck CBC if neutrophils <2000 cells/µl or if platelets <75,000 cells/µl.
  • Peripheral neuropathies (mostly paralytic intestinal ileus in cats), although reported, are rare.
  • Vincristine can be replaced by vinblastine Vinblastine in cases who suffer severe gastrointestinal toxicity from vincristine.  
  • Reduce vincristine and cyclophosphamide dose by 20% if significant myelosuppression or GI effects are seen. Alternatively, the vincristine and cyclophosphamide doses can be separated by one week to help ameliorate toxicities.
  • Various rescue protocols may be used to manage relapsing disease (see below). 

Rescue protocols

Protocol 1: CCNU + prednisolone

Week 1 

CBC + biochemical profile 
CCNU 40-50 mg/m2 PO 
Prednisolone 2 mg/kg PO SID 

Week 2 

No chemotherapy. Recheck CBC 
Prednisolone 1.5 mg/kg PO SID 

Week 3 

No chemotherapy
Prednisolone 1.5 mg/kg PO SID 

Week 4 

CBC + biochemical profile 
CCNU 40-50 mg/m2 PO 
Prednisolone 0.5-1.0 mg/kg PO SID 

Week 5 

No chemotherapy 
Continue prednisolone 0.5-1.0 mg/kg PO SID 

Week 6 

No chemotherapy 
Continue prednisolone 0.5-1.0 mg/kg PO SID 

Week 7 

CBC + biochemical profile 
CCNU 40-50 mg/m2 PO 
Continue prednisolone 0.5-1.0 mg/kg PO SID 

Important considerations

  • In cats, 40-50 mg/m2 of CCNU (lomustine) Lomustine is recommended. Lomustine comes as 10, 40 and 100 mg capsules. Consider using a compounding pharmacy rather than rounding dose to nearest 10 mg. Lomustine is a carcinogen and should be handled with caution.
  • Myelosuppression and gastrointestinal toxicity (eg inappetence, vomiting, and/or diarrhea) are possible toxicities of lomustine. Myelosuppresion can be severe with lomustine, especially in cats. Therefore, use with extreme caution in this species. Additionally, prolonged (weeks) myelosuppression has been noted in some cats even at this dosing range, so treatment intervals may need to be extended to every 4-6 weeks in those cases. Alternatively, consider dose reduction in sensitive cats.
  • Hepatotoxicity (rare in cats), cumulative and permanent bone marrow injury (specifically thrombocytopenia), and rarely nephrotoxicity are possible toxicities of lomustine. Perform a baseline biochemical profile prior to the first dose of lomustine. If evidence of organ or permanent bone marrow toxicity occurs, discontinue lomustine. A CBC must be performed within 48 h prior to chemotherapy administration. Ideally this should be done the day of chemotherapy administration. Delay chemotherapy by 3-7 days and then recheck CBC if:
    • Neutrophil count <2000 cells/µl.
    • Platelet count <100,000 cells/µl.
    • Patient is exhibiting GI signs secondary to previous chemotherapy.
  • Perform a CBC with platelet count 7 days after the first dose of lomustine to assess degree of myelosuppression. Consider prophylactic antibiotics in afebrile, apparently healthy patients with neutrophil counts <1000 cells/µl. Consider hospitalization and treatment for sepsis (IV fluids and broad spectrum antibiotics) in febrile and/or sick patients with neutropenias. Once the nadirs have been established, post-chemotherapy CBCs are unnecessary unless the patient becomes ill and/or if dose reductions are required (see below).
  • Reduce lomustine doses by 20% in patients experiencing significant myelosuppression, GI toxicity, and/or in those requiring hospitalization due to toxicity. Following dose reduction, recheck CBC with platelet count 7 days after treatment.
  • Continue lomustine treatments every 3 weeks with prednisolone for 6 lomustine treatments if a response has been achieved after 2 doses.

Protocol 2: Doxorubicin + prednisolone 

Week 1 CBC + biochemical profile (at least renal values)
Doxorubicin 1 mg/kg IV
Prednisolone 2 mg/kg PO SID
Week 2 No chemotherapy
Recheck CBC
Prednisolone 1.5 mg/kg PO SID
Week 3 No chemotherapy
Prednisolone 1.0 mg/kg PO SID
Week 4 CBC + biochemical profile (at least renal values)
Doxorubicin 1 mg/kg IV
Prednisolone 0.5-1 mg/kg PO SID
Week 5 No chemotherapy
Continue prednisolone 0.5-1.0 mg/kg PO SID
Week 6 No chemotherapy
Continue prednisolone 0.5-1.0 mg/kg PO SID
Week 7 CBC + biochemical profile (at least renal values)
Doxorubicin 1 mg/kg IV
Prednisolone 0.5-1 mg/kg PO SID

Important considerations 

  • Myelosuppression and gastrointestinal toxicity (eg inappetence, vomiting, and/or diarrhea) are possible toxicities  
  • Additional toxicities of doxorubicin include: Severe tissue necrosis and extravasation injury if given outside of the vein. Doxorubicin should be administered through a "clean stick" catheter. 
Careful monitoring of the patient is advised during administration to ensure the catheter remains in place. 
  • Hemorrhagic colitis. 
  • Anaphylactoid reactions secondary to mast cell degranulation. Premedication with 1-2 mg/kg of diphenhydramine Diphenhydramine IM approximately 30 mins prior to treatment is recommended by some oncologists to prevent this toxicity. 
  • Acute cardiac toxicity manifested as arrhythmias. 
  • Nephrotoxicity in cats.  
  • Acute toxicities may be minimized by administering the drug slowly (over 10 minutes in cats). 
  • A complete blood count (Hematology: complete blood count (CBC)) must be performed within 48 h prior to chemotherapy administration. Ideally this should be done the day of chemotherapy administration. Delay chemotherapy by 3-7 days and then recheck CBS if: 
    • Neutrophil count < 2500 cells/µl. 
    • Platelet count < 75,000 cells/µl. 
    • Patient is exhibiting GI signs secondary to previous chemotherapy. 
  • Reduce chemotherapy dose by 20% in patients experiencing significant myelosuppression, GI toxicity and/or those requiring treatment delays during weekly administration. 
  • Only continue with the protocol (5 doses in total) if remission has been achieved after 2 doses. 
  • Other rescue protocol to be handled by specialists: 

Legal and safety precautions

Legal

  • Employers have a legal duty to protect employees and the public from any consequences of their work, including exposure to cytotoxic drugs (In the UK this is covered by the Healthand Safety at Work Act 1974 and Management of Health and Safety at Work Regulations 1999). It is their legal obligation to have a health and safety policy and to consult with their employees and safety representatives on the risks identified within the workplace and the measures needed to prevent or control these risks. Cytotoxic drugs are considered as hazardous (as defined in the UK by the Control of Substances Hazardous to Health Regulations 2002 (CoSHH)).
  • In the UK carcinogenic substances are subject to Appendix 1 of the CoSHH Approved Code of Practice (ACOP) which provides additional guidance. Under CoSHH, employers have a legal duty to assess the risks from handling cytotoxic drugs for employees and anyone else affected by this type of work, and to take suitable precautions to protect their health.
  • Employers need to ensure that employees handling cytotoxic drugs are given suitable and sufficient information, instruction and training.
  • Employees also have a duty to take care of their own health and safety at work and those around them that may be affected by their actions.

Hazardous

  • Based upon animal studies, cytotoxic agents are considered to be mutagenic, teratogenic, abortigenic and carcinogenic. These are just four of the reasons why these agents should be treated with caution and only prescribed in appropriate circumstances. Handling requires special equipment.
  • Chemotherapy-induced adverse effects require experience in their prevention and management and this requires familiarity with the drug or drugs in use.

Experience

  • Practitioners using chemotherapy are strenuously advised to seek advice of a veterinary oncologist or to refer cases for management when optimal treatment requires use of a chemotherapeutic agent with which the practitioner and their colleagues lack confidence and experience.

Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Elliott J, Finotello R (2018) A dexamethasone, melphalan, actinomycin‐D and cytarabine chemotherapy protocol as a rescue treatment for feline lymphoma. Vet Comp Oncol 16 (1), E144-E151 PubMed.
  • Martin O A, Price J (2018) Mechlorethamine, vincristine, melphalan and prednisolone rescue chemotherapy protocol for resistant feline lymphoma. J Feline Med Surg 20(10), 934-939 PubMed.
  • Collette S A, Allstadt S D, Chon E M, Vernau W, Smith A N, Garrett L D, Choy K, Rebhun R B, Rodriguez C O, Skorupski K A (2016) Treatment of feline intermediate‐ to high‐grade lymphoma with a modified university of Wisconsin–Madison protocol: 119 cases (2004–2012). Vet Comp Oncol 14 (1), 136-146 PubMed.
  • Krick E L, Cohen R B, Gregor T P, Salah P C, Sorenmo K U (2013) Prospective Clinical Trial to Compare Vincristine and Vinblastine in a COP ‐Based Protocol for Lymphoma in Cats. J Vet Intern Med 27(1), 134-140 PubMed.
  • Waite A H K, Jackson K, Gregor T P, Krick E L (2013) Lymphoma in cats treated with a weekly cyclophosphamide-, vincristine-, and prednisone-based protocol: 114 cases (1998–2008). J Am Vet Med Assoc 242(8), 1104-1109 PubMed.  
  • Dutelle A L, Bulman-Fleming J C, Lewis C A, Rosenberg M P (2012) Evaluation of lomustine as a rescue agent for cats with resistant lymphoma. J Feline Med Surg 14 (10), 694-700 PubMed.
  • Oberthaler K T, Mauldin E, McManus P M, Shofer S, Sorenmo K U (2009) Rescue therapy with doxorubicin-based chemotherapy for relapsing or refractory feline lymphoma: A retrospective study of 23 cases. J Feline Med Surg 11(4), 259-265 PubMed.
  • Milner R J, Peyton J, Cooke K et al (2005) Response rates and survival times for cats with lymphoma treated with the University of Wisconsin-Madison chemotherapy protocol: 38 cases (1996-2003). JAVMA 227 (7), 1118-1122 PubMed.
  • Brønden L B, Rutteman G R, Flagstad A et al (2003) Study of dog and cat owners' perceptions of medical treatment for cancer. Vet Rec 152 (3), 77-80 PubMed.
  • Fan T M, Kitchell B E, Dhaliwal R S et al (2002) Hematological toxicity and therapeutic efficacy of lomustine in 20 tumor-bearing cats: critical assessment of a practical dosing regimen. JAAHA 38 (4), 357-363 PubMed.
  • Teske E, van Straten G, van Noort R et al (2002) Chemotherapy with cyclophoshamide, vincristine, and prednisolone (COP) in cats with malignant lymphoma: new results with an old protocol. J Vet Intern Med 16 (2), 179-86 PubMed.
  • Guillermo Couto C (2001) What is new on feline lymphoma? J Feline Med Surg (4), 171-176 PubMed.
  • Kristal O, Lana S E, Ogilvie G K, Rand W M, Cotter S M, Moore A S (2001) Single Agent Chemotherapy with Doxorubicin for Feline Lymphoma: A Retrospective Study of 19 Cases (1994–1997). J Vet Intern Med 15 (2), 125-130 PubMed.
  • Malik R, Gabor L J, Foster S F et al (2001) Therapy for Australian cats with lymphosarcoma. Aust Vet J 79 (12), 808-817 PubMed.
  • Rassnick K M, Gieger T L, Williams L E et al (2001) Phase 1 evaluation of CCNU (lomustine) in tumor-bearing cats. J Vet Intern Med 15 (3), 196-199 PubMed.
  • Zwahlen C H, Lucroy M D, Kraegel S A et al (1998) Results of chemotherapy for cats with alimentary malignant lymphoma: 21 cases (1993-1997). JAVMA 213 (8), 1144-1149 PubMed.
  • Moore A S, Cotter S M, Frimberger A E et al (1996) A comparison of doxorubicin and COP for maintenance of remission in cats with lymphoma. J Vet Intern Med 10 (6), 372-375 PubMed.

Other sources of information

  • Vail D M, Pinkerton M E (2020) Feline lymphoma and leukemias. In: Small Animal Clinical Oncology. 6th edn. Eds Withrow & MacEwen’s. Elsevier Saunders, St. Louis. pp 715-729. 
  • Morrison W B (2002) Cancer in Dogs and Cats. 2nd edition, p 662.
  • Tennant B (2002) BSAVA Small Animal Formulary, 4th edn. pp 280-281.