Four chemotherapy protocols for lymphoma are provided below. The CHOP and COP protocols are first-line chemotherapy protocols. LPP is an all-oral protocol, suitable for dogs, that is generally considered a rescue protocol, but may be considered first-line for treatment of T-cell lymphoma or when injectable chemotherapy cannot be given. There is a vast array of other chemotherapy protocols for lymphoma available in the literature.

The vinblastine and prednisolone protocol is a standard protocol for treatment of mast cell tumour (MCT) in the adjuvant or neoadjuvant setting.

Health and safety considerations

Chemotherapeutic agents are mutagenic, teratogenic and carcinogenic; therefore, great care must be taken to ensure safe use of these agents. The ACVIM small animal consensus statement on safe use of cytotoxic chemotherapeutics in veterinary practice (Smith et al., 2018) is a useful resource when developing safe chemotherapy preparation and administration protocols.

Some general considerations are:

• Chemotherapeutic agents should be stored in secure, clearly labelled containers.
• Chemotherapy should be given in a calm and quiet environment.
• People who are or may become pregnant should not be involved in handling or administering chemotherapeutics or handling treated animals (or their excreta).
• When administering chemotherapy, appropriate personal protective equipment must be worn.
• Oral cytotoxic drugs must not be split or divided and should not be crushed.
• Closed administration systems are recommended.

Dosing considerations

The therapeutic index (the gap between the therapeutic and the toxic dose of a drug) is narrow for chemotherapeutic agents. Consequently, careful calculation of treatment dose is required. Ideally, a compounding/reformulating pharmacy should be used to match patient requirements as closely as possible for oral medications. Veterinary specials manufacturers (e.g. ChemoPet) will prepare single, per patient, doses of chemotherapy to allow accurate dosing. These services have the additional benefit of reducing wastage caused by bulk purchase of medicines. If the ideal dose cannot be formulated, then it is safer to slightly underdose than to overdose. For drugs given on an ongoing basis, extending the dosing frequency or alternating administered dose on different days can average out the required dose over a period of time. Refer to specialist texts or seek advice from a veterinary oncologist for support with individual cases.

In addition to factors under the clinician’s control, there is marked variation in chemotherapy tolerance between individual animals. Whilst it can be difficult to predict chemotherapy tolerance, certain breeds (generally collie type) are very sensitive to vinblastine, vincristine, doxorubicin and epirubicin due to the ABCB1 mutation (a commercial test is available, see Useful websites).

Pre-chemotherapy checks

• Haematology. Treatment can be given if the neutrophil count is >3 × 109/l and platelet count >100 × 109/l. If the neutrophil count is <3 × 109/l, withhold treatment and recheck in 3–5 days.
• Biochemistry. Significant organ dysfunction (especially liver) can reduce tolerance to chemotherapy; therefore, biochemistry should be checked prior to commencing chemotherapy and then approximately every 6 months during treatment.
• Urinalysis. Test a free-catch urine sample with a dipstick prior to each cyclophosphamide administration. If blood is noted, suspend cyclophosphamide and culture urine. Chlorambucil can be substituted pending culture result or if the urine culture is negative and therefore consistent with sterile haemorrhagic cystitis.
• Consider pre-treatment sedation or anxiolytic therapy if the patient is too lively or anxious for i.v. chemotherapy to be given safely.
• Catheters should be placed in all cases and only catheters placed by ‘first-stick’ should be used for chemotherapy. Catheters should be flushed thoroughly with 0.9% NaCl prior to use.

Common adverse events associated with chemotherapy

• All of the chemotherapeutic agents included in the protocols below can induce myelosuppression (usually 7–10 days after treatment) or GI problems (vomiting, diarrhoea and inappetence usually within 4 days of treatment). These are transient and will typically resolve in a few days with appropriate supportive management. It is helpful to prescribe some maropitant for owners to have to hand in case of problems. GI problems can be reduced by fasting the patient prior to treatment.
• Certain breeds (generally collie type, although infrequently Border Collies) are more sensitive to vinblastine, vincristine, doxorubicin and epirubicin due to the ABCB1 mutation (a commercial test is available, see Useful websites). Pending return of genetic test results, commencing chemotherapy for lymphoma with cyclophosphamide is a helpful amendment to standard protocol
• High doses of prednisolone may induce low-grade GI haemorrhage. GI protectants should be considered when prednisolone doses are 20 mg/m2 q24h or greater. Omeprazole (1 mg/kg q24h or q12h) is often used by oncologists. Ranitidine with sucralfate is an alternative approach. Cimetidine is avoided due to its effect on the hepatic cytochrome P450 enzyme pathway and the potential for altering metabolism of chemotherapeutics. Famotidine is a good option in cats.
• Cyclophosphamide may induce haemorrhagic cystitis. This risk can be reduced by co-administration of furosemide, enabling free access to water and allowing opportunities for dogs to urinate frequently in the 48 hours after treatment.
• Vincristine and vinblastine are vesicants, and doxorubicin and epirubicin are severe vesicants. Should extravasation occur, contact an oncologist immediately.

Chemotherapy protocols for lymphoma:

PROTOCOL 1: 25-week CHOP/CEOP protocol

Week 26 and thereafter: Stop chemotherapy and monitor for relapse (see below for options at recurrence/relapse).

Notes:

• The Pre-chemotherapy checks and Common adverse events associated with chemotherapy sections above should be reviewed.
• Haematology should be checked prior to each treatment.
• Doxorubicin and epirubicin can cause systolic dysfunction at high cumulative doses (>180 mg/m2). Baseline echocardiography should be considered in all patients, especially those with pre-existing heart disease. Diagnostic yield of echocardiography in patients with no evidence of heart disease is low. Repeat echocardiography is indicated when the cumulative dose reaches 180 mg/m2. In cases of cardiac dysfunction, mitoxantrone (5.5 mg/m2 i.v. over 10 minutes) can be considered as an alternative to doxorubicin or epirubicin.
• 0.9% NaCl, rather than calcium-containing fluids, should be used to dilute doxorubicin or epirubicin.
• Maropitant (1 mg/kg i.v. or p.o.) should be given alongside epirubicin or doxorubicin. 
• Rapid administration of doxorubicin or epirubicin can induce arrythmia and consequent hypotension. Therefore, these drugs should be administered as a slow infusion over 15–20 minutes.
• Chlorambucil (20 mg/m2 p.o.) may be given as an alternative to cyclophosphamide if haemorrhagic cystitis develops.
• A nadir neutrophil count should be assessed 7 days after the first doxorubicin or epirubicin treatment. If the neutrophil count is <1 × 109/l, decrease dose of the causative chemotherapeutic drug by 10% and prescribe prophylactic antibiotics until the neutrophil count is >1 × 109/l. If recurrent, contact an oncologist for advice. If the neutrophil count is <1 × 109/l and the patient is pyrexic or unwell, administer i.v. antibiotics and contact an oncologist for advice.

PROTOCOL 2: COP (high dose)

Most oncologists prefer a CHOP protocol, but high-dose COP is a useful and relatively straightforward protocol often used in a general practice setting.

After 12 months: Stop chemotherapy and monitor for relapse (see below for options at recurrence/relapse).

Notes:

• The Pre-chemotherapy checks and Common adverse events associated with chemotherapy sections above should be reviewed.
• Haematology should be checked prior to each vincristine treatment. 
• If the post-treatment neutrophil count is <1 × 109/l, decrease dose of the causative chemotherapeutic drug by 10% and prescribe prophylactic antibiotics until the neutrophil count is >1 × 109/l. If recurrent, contact an oncologist for advice. If the neutrophil count is <1 × 109/l and the patient is pyrexic or unwell, administer i.v. antibiotics and contact an oncologist for advice.
• Chlorambucil (20 mg/m2 p.o.) may be given as an alternative for cyclophosphamide if haemorrhagic cystitis develops.
• Delaying cyclophosphamide until 3 days after vincristine may reduce the frequency of adverse GI events (especially in cats).

PROTOCOL 3: COP (low dose)

The description of this protocol is somewhat misleading in that the summated dose intensity is higher for ‘low-dose’ COP than for ‘high-dose’ COP in the induction and early maintenance phases. Anecdotally, there may be a higher risk of adverse events (during these phases) than with high-dose COP, especially in cats. Most oncologists prefer a CHOP type or the high-dose COP protocol.

Induction:

Maintenance:

Maintenance after 6 months (if disease in remission):

After 12 months: Stop chemotherapy and monitor for relapse (see below for options at recurrence/relapse).

Notes:

• The Pre-chemotherapy checks and Common adverse events associated with chemotherapy sections above should be reviewed.
• Haematology should be checked prior to each vincristine treatment. 
• If the post-treatment neutrophil count is <1 × 109/l, decrease dose of the causative chemotherapeutic drug by 10% and prescribe prophylactic antibiotics until the neutrophil count is >1 × 109/l. If recurrent, contact an oncologist for advice. If the neutrophil count is <1 × 109/l and the patient is pyrexic or unwell, administer i.v. antibiotics and contact an oncologist for advice.
• Chlorambucil (5 mg/m2 p.o. on alternate days) may be given as an alternative for cyclophosphamide if haemorrhagic cystitis develops.

PROTOCOL 4: LPP

LPP is an all-oral protocol suitable for dogs, which is generally considered a rescue protocol but may be considered first-line for treatment of T-cell lymphoma or when injectable chemotherapy cannot be given.

• Day 1: Lomustine 70 mg/m2 p.o.
• Days 1–14: Procarbazine 50 mg/m2 p.o. q24h.
• Days 1–21: Prednisolone 30 mg/m2 p.o. q24h.
• Repeat on a 21-day cycle.

Notes:

• The Pre-chemotherapy checks and Common adverse events associated with chemotherapy sections above should be reviewed.
• Haematology should be checked prior to each lomustine treatment.
• Alanine aminotransferase (ALT) should be checked prior to each lomustine treatment. An elevation of ALT to >250 IU/l is an indication to stop treatment. Co-administration of S-adenosylmethionine has been shown to reduce the frequency of severe hepatopathies related to lomustine.
• A nadir neutrophil count should be assessed 8–10 days after the first lomustine administration. If the neutrophil count is <1 × 109/l, decrease dose of lomustine by 10% and prescribe prophylactic antibiotics until the neutrophil count is >1 × 109/l. If recurrent, contact an oncologist for advice. If the neutrophil count is <1 × 109/l and the patient is pyrexic or unwell, administer i.v. antibiotics and contact an oncologist for advice.

Disease monitoring and relapse

• Restaging – ideally, restaging should be performed at the end of the induction phase (prior to week 6/7 of treatment) and at treatment cessation.
• Remission – attaining complete remission is an important prognostic indicator (especially in cats). Complete remission is defined as the lack of identifiable disease (for example, the lymph nodes should be normal on palpation and a cytological assessment should not yield evidence of tumour cells).
• Relapse – if a patient completes treatment in remission, they should be monitored monthly for at least 6 months. Most canine multi-centric lymphoma patients relapse after 1–3 months. Many patients that relapse after cessation of treatment can re-attain remission by reintroduction of the original chemotherapy protocol. For patients who relapse during treatment or fail to respond to the reintroduction of treatment, rescue therapy is indicated; commonly used rescue protocols in dogs include asparaginase as a single agent, LOPP and DMAC (or doxorubicin if COP used originally). Rescue therapy in cats is less successful than in dogs.

Chemotherapy protocols for mast cell tumour

Chemotherapy is used in the neoadjuvant setting (to shrink tumours and make excision possible) or as an anti-metastatic treatment for tumours that have metastasized or high-risk tumours (high grade and/or elevated miotic index). Conventional chemotherapy is not recommended for the prevention of recurrence of incompletely resected MCTs as further surgery and radiation are considered more effective; if a medical option is required in this context, a tyrosine kinase inhibitor (toceranib or masitinib) should be used first prior to conventional chemotherapy.

Several protocols have been reported. The most used protocol includes vinblastine and prednisolone as below.

12-week vinblastine and prednisolone protocol

Notes:

• The Pre-chemotherapy checks and Common adverse events associated with chemotherapy sections above should be reviewed.
• Haematology should be checked prior to each treatment.
• If the post-treatment neutrophil count is <1 × 109/l, decrease dose of vinblastine by 10% and prescribe prophylactic antibiotics until the neutrophil count is >1 × 109/l. If recurrent, contact an oncologist for advice. If the neutrophil count is <1 × 109/l and the patient is pyrexic or unwell, administer i.v. antibiotics and contact an oncologist for advice.

Disease monitoring and relapse

• Restaging – Ideally, restaging should be performed at week 12 for high-risk tumours without known metastasis and after week 4 and at week 12 for tumours with known metastasis. If restaging is clear, further restaging is recommended every 3 months (for a year) for high-risk tumours.
• Relapse – If additional metastatic lesions are identified (liver, spleen or lymph nodes) or treatment fails to yield remission, further treatment with lomustine or a tyrosine kinase inhibitor is indicated (contact an oncologist).

References

Smith AN, Klahn S, Phillips B et al.(2018) ACVIM small animal consensus statement on safe use of cytotoxic chemotherapeutics in veterinary practice.Journal of Veterinary Internal Medicine 32, 904–913