Four chemotherapy protocols for lymphoma are provided below. The CHOP and high- and low-dose COP protocols are first-line chemotherapy protocols. LPP, an all-oral protocol for dogs, is generally considered a rescue protocol but may be used for first-line treatment of T cell lymphoma or when injectable chemotherapy cannot be given. Many other chemotherapy protocols for lymphoma are available.

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

Health and safety considerations

See Appendix I for Safety and handling of chemotherapeutic agents.

Dosing considerations

The therapeutic index (the gap between the therapeutic and the toxic dose of a drug) is narrow for chemotherapy agents. Consequently, careful calculation of treatment dose is required. Companies such as ChemoPet will prepare single per patient doses of injectable chemotherapy to allow accurate dosing (see Appendix I for Useful websites). For oral medications, a compounding/reformulating pharmacy should ideally be used to match requirements as closely as possible. These services have the additional benefit of reducing waste caused by bulk purchase of compounded medicines. If the ideal dose cannot be formulated, it is safer to slightly underdose rather than overdose using the available tablet sizes. For drugs given on an ongoing basis, extending the dosing interval or alternating the administered dose on different days can be used to average out to the required dose across a treatment period. Under no circumstances should oral chemotherapy treatments be crushed, broken or opened to try to create a more accurate dose because of the high risk of aerosolization of chemotherapy during this process. Please 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 individual variation in chemotherapy tolerance. Certain individuals may be very sensitive to vincristine, doxorubicin and epirubicin due to a mutation of the ABCB1 gene. Collie type dogs are generally at higher risk of carrying this mutation (see Sedation protocols for dogs with the ABCB1 gene in this appendix for further information).

Pre-chemotherapy checks

• Haematology – treatment can be given if the neutrophil count is >3×109/l and the platelet count is >100×109/l. If the neutrophil count is <3×109/l then withhold treatment and recheck in 3–5 days.
• Biochemistry – significant organ dysfunction (especially liver) can reduce tolerance to chemotherapy. A biochemistry profile should be checked prior to commencing chemotherapy and then approximately every 6 months during treatment.
• Urinalysis – dipstick test a free-catch urine sample prior to each cyclophosphamide administration. If blood is noted, suspend cyclophosphamide. Chlorambucil can be substituted where sterile haemorrhagic cystitis is suspected.
• If the patient is too lively or anxious to give i.v. chemotherapy safely, consider pre-treatment sedation or anxiolytic therapy.
• 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 chemotherapy agents included in the protocols below can induce myelosuppression (usually 7–10 days after treatment) or GI problems (vomiting, diarrhoea and inappetence usually within four days of treatment). These signs are transient and will typically resolve in a few days with appropriate supportive management. It may be helpful to prescribe maropitant in case of problems. GI disturbance can be reduced by fasting prior to treatment.
• Some cats suffer prolonged anorexia after vincristine treatment especially if they are in poor clinical condition (e.g. at the start of treatment). Consider using the low end of the dose range of vincristine for the first treatment (0.5 mg/m2). For cats who suffer this adverse effect, some authors substitute vinblastine (at 1.5 mg/m2) for vincristine on an ongoing basis.
• In breeds prone to the MDR1 mutation (see ‘Dosing considerations’, above), pending return of genetic test results, commencing chemotherapy for lymphoma with cyclophosphamide is a helpful amendment to standard protocols.
• 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 q12h) is often used. Cimetidine is avoided due to its effect on the hepatic cytochrome P450 enzyme pathway and the potential for altering metabolism of chemotherapeutics. Famotidine may be considered 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/vinblastine are vesicants and doxorubicin/epirubicin are severe vesicants. Should extravasation occur, contact an oncologist immediately.
• Rapid administration of doxorubicin or epirubicin can induce arrythmia and consequent hypotension. These drugs should be administered as a slow infusion over 20 minutes.
• Doxorubicin and epirubicin can cause systolic dysfunction at high cumulative doses (>180 mg/m2). Baseline echocardiography can be considered in all patients especially those with pre-existing heart disease prior to administration. Diagnostic yield of echocardiography in patients with no evidence of heart disease is low. Repeat echocardiography is indicated when cumulative doses reach 180 mg/m2. In case of cardiac dysfunction, mitoxantrone (5.0–5.5 mg/m2 over 10 minutes) can be considered as an alternative to doxorubicin/epirubicin.

CHEMOTHERAPY PROTOCOLS FOR LYMPHOMA

Protocol 1: 25-week CHOP/CEOP protocol

Week 26 and thereafter: Stop chemotherapy and monitor for relapse monthly for 6 months and then every other month (see ‘Disease monitoring and relapse’, below).

Notes specific to CHOP/CEOP protocol:

• Check haematology prior to each treatment.
• 0.9% NaCl rather than calcium-containing fluids should be used to dilute doxorubicin/epirubicin.
• Give maropitant (1 mg/kg i.v. or p.o.) alongside epirubicin/doxorubicin.
• Chlorambucil (20 mg/m2 p.o.) may be given as an alternative for cyclophosphamide if haemorrhagic cystitis develops.
• Assess nadir neutrophil count 7 days after the first doxorubicin/epirubicin treatment. If the neutrophil count is <0.75×109/l, prescribe prophylactic antibiotics (until neutrophil count is >1×109/l). 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. If the neutrophil count is <1×109/l, decrease the dose of the causative chemotherapy drug by 10%, if recurrent contact an oncologist for advice.

Protocol 2: COP (high dose)

Most oncologists prefer a CHOP type protocol, but high-dose COP is a useful and relatively straightforward alternative.

Induction:

After 12 months: Stop and monitor for relapse monthly for 6 months and then every other month (see ‘Disease monitoring and relapse’, below).

Notes specific to high-dose COP protocol:

• Check haematology prior to each vincristine treatment.
• If the post-treatment neutrophil count is <0.75×109/l, prescribe prophylactic antibiotics (until neutrophil count is >1×109/l). 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. If the neutrophil count is <1×109/l, decrease the dose of the causative chemotherapy drug by 10%, if recurrent 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 frequency of GI adverse events (especially in cats).

Protocol 3: COP (low dose)

The description of this protocol is misleading since the summated dose per unit of time 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) versus high-dose COP, especially in cats. Most oncologists prefer a CHOP or high-dose COP protocol.

Induction:

Maintenance:

Maintenance after 6 months (if disease in remission):

After 12 months: Stop and monitor for relapse monthly for 6 months and then every other month (see ‘Disease monitoring and relapse’, below).

Notes specific to low-dose COP protocol: See ‘Notes specific to high-dose COP protocol’, above.

Protocol 4: LPP

Notes specific to LPP protocol:

• Check haematology prior to each lomustine treatment.
• Check alanine aminotransferase (ALT) prior to each lomustine treatment. An increase 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.
• Assess nadir neutrophil 8–10 days after the first lomustine. If the neutrophil count is <0.75×109/l, prescribe prophylactic antibiotics (until neutrophil count is >1×109/l). 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. If the neutrophil count is <1×109/l, decrease future doses of lomustine by 10%, if recurrent contact an oncologist for advice.

Disease monitoring and relapse

Restaging: Restaging should ideally 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 (e.g. 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 2–4 months. Many patients (around 80% of canine patients) that relapse after completion of 6 months of treatment in remission can reattain remission by reintroduction of the original chemotherapy protocol. For patients who relapse during treatment or fail to respond to reintroduction of treatment, rescue therapy is indicated. Commonly used rescue protocols in dogs include ʟ-asparaginase (single agent), LOPP (lomustine, vincristine, procarbazine, prednisolone) and DMAC (dexamethasone, melphalan, actinomycin D, cytosine arabinoside), or single agent doxorubicin if COP was 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 antimetastatic treatment in tumours that have metastasized or high-risk tumours (high grade and/or high miotic index). Conventional chemotherapy is not recommended for the prevention of recurrence of incompletely resected MCTs as further surgery, radiation or electrochemotherapy are considered more effective; if a medical option is required in this context, a tyrosine kinase inhibitor (toceranib or masitinib) should be used prior to conventional chemotherapy.

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

12-week vinblastine and prednisolone protocol

Notes specific to vinblastine and prednisolone protocol:

• Check haematology prior to each treatment.
• If the post-treatment neutrophil count is <0.75×109/l, prescribe prophylactic antibiotics (until neutrophil count is >1×109/l). 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. If the neutrophil count is <1x109/l, decrease dose of vinblastine by 10%, if recurrent contact an oncologist for advice.

Disease monitoring and relapse

Restaging: Restaging should ideally 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).