Various protocols are described in the literature. Three examples are provided below.

Note that oral cytotoxic drugs cannot be split or divided. It is also important that patients are not overdosed with cytotoxic medications. Ideally, for these reasons a reformulating pharmacy should be used to match patient requirements exactly. If this is not possible, then patients should be underdosed rather than overdosed based on the available tablet sizes, Extended dosing frequency can occasionally be used to enable a larger tablet size to be administered. Refer to specialist texts or seek advice from a veterinary oncologist for further information regarding protocols.

Protocol 1: Combination cytotoxic therapy COP (low dose)

Induction

Cyclophosphamide: 50 mg/m2 p.o. on alternate days or 50 mg/m2 p.o. for the first 4 days of each week

Vincristine: 0.5 mg/m2 i.v. q7d

Prednisolone: 40 mg/m2 p.o. q24h for first 7 days then 20 mg/m2 p.o. on alternate days and given with cyclophosphamide.

Maintenance after a minimum of 2 months

Cyclophosphamide: 50 mg/m2 p.o. on alternate days or 50 mg/m2 p.o. for the first 4 days of each second week (alternate-week therapy)

Vincristine: 0.5 mg/m2 i.v. q14d

Prednisolone: 20 mg/m2 p.o. on alternate days of each second week and given with cyclophosphamide.

Maintenance after 6 months (if disease in remission)

Cyclophosphamide: 50 mg/m2 p.o. q48h (one week in three) or 50 mg/m2 p.o. for the first 4 days of each third week (one week in three)

Vincristine: 0.5 mg/m2 i.v. q21d

Prednisolone: 20 mg/m2 p.o. on alternate days of each third week and given with cyclophosphamide

Maintenance after 12 months

Cyclophosphamide: 50 mg/m2 p.o. q48h (one week in four) or 50 mg/m2 p.o. for the first 4 days of each fourth week (one week in four)

Vincristine: 0.5 mg/m2 i.v. q28d

Prednisolone: 20 mg/m2 p.o. on alternate days of each fourth week and given with cyclophosphamide.

General notes

• GI protectants: ranitidine 2 mg/kg q12h p.o., sucralfate 500 mg/dog p.o. q8h (dogs up to 20 kg), 1–2 g/dog p.o. q8h (dogs >20 kg) are recommended for first 14 days. Cimetidine is avoided due to its effect on the hepatic cytochrome P450 enzyme pathway and the potential for altering metabolism of chemotherapeutics.
• Melphalan (5 mg/m2 p.o.) may be administered as an alternative to cyclophosphamide after 6 months in order to reduce the risk of haemorrhagic cystitis.
• Chlorambucil (5 mg/m2 p.o. on alternate days) or melphalan may be given as alternatives for cyclophosphamide if haemorrhagic cystitis develops.
• Doxorubicin (30 mg/m2 i.v. q3wk) or asparaginase/L-asparginase (400 IU/kg s.c., i.m. q7d or as necessary) may be used to manage relapsing or recurrent disease. (Refer to specialist texts or advice regarding protocols for treating relapsed lymphoma.)

Recommended monitoring:

• Haematology every 1–2 weeks initially, followed by every 4 weeks if the patient is tolerating chemotherapy well
• Biochemistry at regular intervals depending on other illnesses.
• Urine – dipstick every 1–2 weeks in the first 2 months. Full urinalysis prior to first dose, then as required.

Contraindications and adverse effects

Myelosuppression, haemorrhagic cystitis (cyclophosphamide only) or GI effects may occur. Peripheral neuropathies, although reported, are rare. Discontinue cyclophosphamide therapy if the neutrophil count decreases to <2 × 109/l; check count weekly and do not resume treatment until neutrophil count is >3 × 109/l. If neutropenia recurs following reinstitution of therapy, decrease dose by 10–25%.

Protocol 2: Combination cytotoxic therapy COP (high dose)

Induction

Cyclophosphamide: 250 mg/m2 p.o. q21d

Vincristine: 0.75 mg/m2 i.v. q7d for 4 weeks then 0.75 mg/m2 i.v. q21d administered with cyclophosphamide

Prednisolone: 1 mg/kg p.o. q24h for 4 weeks then 1 mg/kg p.o. on alternate days.

Maintenance after 6 months

Cyclophosphamide: 250 mg/m2 p.o. q28d

Vincristine: 0.75 mg/m2 i.v. q28d with cyclophosphamide

Prednisolone: 1 mg/kg p.o. on alternate days.

Maintenance after 12 months

Cyclophosphamide: 250 mg/m2 p.o. q28d

Vincristine: 0.75 mg/m2 i.v. q5wk

Prednisolone: 1 mg/kg p.o. on alternate days.

Maintenance after 18 months

Cyclophosphamide: 250 mg/m2 p.o. q28d

Vincristine: 0.75 mg/m2 i.v. q6wk

Prednisolone: 1 mg/kg p.o. on alternate days.

Maintenance after 24 months

Stop if in remission

General notes

• GI protectants: ranitidine 2 mg/kg q12h p.o., sucralfate 500 mg/dog p.o. q8h (dogs up to 20 kg), 1–2 g/dog p.o. q8h (dogs >20 kg) are recommended for first 14 days. Cimetidine is avoided due to its effect on the hepatic cytochrome P450 enzyme pathway and the potential for altering metabolism of chemotherapeutics.
• Melphalan (5 mg/m2 p.o.) may be administered as an alternative to cyclophosphamide after 6 months in order to reduce the risk of haemorrhagic cystitis.
• Chlorambucil (5 mg/m2 p.o. on alternate days) or melphalan may be given as alternatives for cyclophosphamide if haemorrhagic cystitis develops.
• Doxorubicin (30 mg/m2 i.v. q3wk) or asparaginase/L-asparginase (400 IU/kg i.m. q7d or as necessary) may be used to manage relapsing or recurrent disease. (Refer to specialist texts or advice regarding protocols for treating relapsed lymphoma.)

Recommended monitoring:

• Haematology every 1–2 weeks initially, followed by every 4 weeks if the patient is tolerating chemotherapy well
• Biochemistry at regular intervals
• Urine – dipstick weekly and full urinalysis every 4 weeks.

Contraindications and adverse effects

Myelosuppression, haemorrhagic cystitis (cyclophosphamide only) or GI effects may occur. Peripheral neuropathies, although reported, are rare. Discontinue cyclophosphamide therapy if the neutrophil count decreases to <2 × 109/l; check count weekly and do not resume treatment until neutrophil count is >3 × 109/l. If neutropenia recurs following reinstitution of therapy, decrease dose by 10–25%.

Protocol 3: Combination cytotoxic therapy Madison–Wisconsin

Week 1

Vincristine: 0.7 mg/m2 i.v. once

Prednisolone: 2 mg/kg p.o. q24h

Asparaginase: 400 IU/kg s.c., i.m. once

(NB: Many oncologists now use the CHOP protocol, which is based on this protocol but with the omission of asparaginase in weeks 1 and 2)

Week 2

Cyclophosphamide: 250 mg/m2 p.o. once

Prednisolone: 1.5 mg/kg p.o. q24h

Furosemide: 2.0–2.2 mg/kg s.c., i.v.

Asparaginase: 400 IU/kg s.c., i.m. once can be administered if remission is not achieved

Week 3

Vincristine: 0.7 mg/m2 i.v. once

Prednisolone: 1 mg/kg p.o. q24h

Week 4

Doxorubicin: 30 mg/m2 i.v. once (in 0.9% NaCl) given over 20 minutes (Chlorphenamine 2–10 mg/dog i.m. once and maropitant 1 mg/kg s.c. once are given before doxorubicin)

Prednisolone: 0.5 mg/kg p.o. q24h for one week

Week 5

No medication (prednisolone is stopped)

Week 6

Vincristine: 0.7 mg/m2 i.v. once

Week 7

Cyclophosphamide: 250 mg/m2 p.o., i.v.

Furosemide: 2.0–2.2 mg/kg s.c., i.v.

Week 8

Vincristine: 0.7 mg/m2 i.v. once

Week 9

Doxorubicin: 30 mg/m2 i.v. once (in 0.9% NaCl) given over 20 minutes. (Chlorphenamine 2–10 mg/dog i.m. once and maropitant 1 mg/kg s.c. once are given before doxorubicin)

Week 10

No medication

Week 11

Vincristine: 0.7 mg/m2 i.v. once

Week 12

No medication

Week 13

Cyclophosphamide: 250 mg/m2 p.o., i.v. once

Furosemide: 2.0–2.2 mg/kg s.c., i.v.

Week 14

No medication

Week 15

Vincristine: 0.7 mg/m2 i.v. once

Week 16

No medication

Week 17

Doxorubicin: 30 mg/m2 i.v. (in 0.9% NaCl) given over 20 minutes. (Chlorphenamine 2–10 mg/dog i.m. once and maropitant 1 mg/kg s.c. once are given before doxorubicin)

Week 18

No medication

Week 19

Vincristine: 0.7 mg/m2 i.v. once

Week 20

No medication

Week 21

Cyclophosphamide: 250 mg/m2 p.o., i.v. once

Furosemide: 2.0–2.2 mg/kg s.c., i.v.

Week 22

No medication

Week 23

Vincristine: 0.7 mg/m2 i.v. once

Week 24

No medication

Week 25

Doxorubicin: 30 mg/m2 i.v. once (in 0.9% NaCl) given over 20 minutes. (Chlorphenamine 2–10 mg/dog i.m. once and maropitant 1 mg/kg s.c. once are given before doxorubicin)

Restaging (which may include haematology and biochemistry blood tests, thoracic radiography and abdominal ultrasonography) can be scheduled for 1, 3 and 6 months post cessation of chemotherapy. In the case of multicentric lymphoma, peripheral lymph node assessment, by physical examination, is scheduled monthly post cessation of chemotherapy. A post-doxorubicin echocardiogram is usually scheduled for one month post chemotherapy cessation. Some veterinarians use the canine lymphoma blood test, as an additional test, to ascertain response and remission status.

General notes

• In dogs <10 kg, use doxorubicin at a dose of 1 mg/kg i.v. once.
• If reduced cardiac contractility, doxorubicin can be substituted by epirubicin 30 mg/m2 or mitoxantrone 5.5 mg/m2 (both i.v. in 0.9% NaCl).
• If sterile haemorrhagic cystitis occurs on cyclophosphamide, discontinue and substitute chlorambucil (1.4 mg/kg p.o.) for subsequently scheduled doses.
• Asparaginase (400 IU/kg i.m., s.c.) can be given with each vincristine injection until clinical remission is achieved. Chlorphenamine (2–10 mg/dog i.m. once) should be given before the asparaginase.
• GI protectants: ranitidine 2 mg/kg q12h p.o., sucralfate
• 500 mg/dog p.o. q8h (dogs up to 20 kg), 1–2 g/dog p.o. q8h (dogs >20 kg) are recommended for first 14 days. Cimetidine is avoided due to its effect on the hepatic cytochrome P450 enzyme pathway and the potential for altering metabolism of chemotherapeutics.
• After initial 6 months all medication is stopped until a relapse occurs.

Suggested monitoring:

• Haematology is done every week with treatment
• Urinalysis is done on weeks 0, 3, 8, 15 and 23
• (Biochemistry may be done on week 8)
• Baseline echocardiography – should be done before giving doxorubicin.

Contraindications and adverse effects

Myelosuppression, haemorrhagic cystitis (cyclophosphamide only), cardiotoxicity (doxorubicin only) or GI effects may occur. Peripheral neuropathies, although reported, are rare. Discontinue chemotherapy therapy if the neutrophil count decreases to <2 × 109/l; check count weekly and do not resume treatment until neutrophil count is >3 × 109/l. Patients may require hospitalization or antibiosis if the neutrophil count is <2, or if they have clinical signs of infection/sepsis – consult a specialist text or oncologist for advice as required. If neutropenia recurs following reinstitution of therapy, decrease dosage by 10–25%.