IMPROVING CHEMOTHERAPY AND ITS PROTOCOLS TUMOUR TYPES

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1 Vet Times The website for the veterinary profession IMPROVING CHEMOTHERAPY AND ITS PROTOCOLS TUMOUR TYPES Author : Frances Taylor Categories : Vets Date : August 29, 2011 Frances Taylor discusses, in the second of a two-part article, different presentations and monitoring methods THE first part of this article (VT41.25) covered general recommendations regarding chemotherapy administration in small animal practice, including patient selection, drug administration and managing patient toxicity. Part two provides a brief overview of individual tumour types commonly treated using chemotherapy, including drug protocols and patient monitoring. Mast cell tumours Mast cell tumours come in different guises, and choosing which patients are appropriate for therapy is as important as which therapy is appropriate. Fine-needle aspiration of masses allows a diagnosis to be made prior to excision ( Figure 1 ). Tumour staging, including palpation and aspiration of the local lymph node and abdominal imaging, is preferable for patients with intermediate or high-grade tumours, before deciding on a therapeutic plan. Wherever feasible, a mast cell tumour is a surgical disease, using wide excision of the primary tumour. Where a single local lymph node is affected with metastatic disease, it can also be excised. 1 / 8

2 Dogs with extensive primary tumours or distant or extensive metastatic disease are more likely to be candidates for medical management. Each case requires assessing on its own merits, and you may wish to consult an oncologist. However, the following guidelines can help. Low-grade mast cell tumours. Full surgical excision is curative in almost all cases. Intermediate-grade mast cell tumours. According to early pathology papers (Patnaik, 1984), around half of intermediate-grade mast cell tumours go on to recur and/or metastasise, but in more recent papers, this proportion is somewhat lower (Seguin et al, 2001; Weisse, 2002). Following complete excision, the author would not normally recommend adjunctive chemotherapy for intermediate grade mast cell tumours unless there are negative prognostic indicators, such as a high mitotic rate (more than 5/10 high power field [hpf]), a high Ki-67 count (more than 1.8 per cent), lymph node metastasis or an ulcerated or invasive primary tumour. High-grade mast cell tumours. Where wide excision is possible, this should be carried out following tumour staging. The author would normally recommend adjunctive chemotherapy for all high-grade mast cell tumours. Chemotherapy for mast cell tumours In the minimal disease setting following excision, a vinblastine and prednisolone protocol is normally used. Where non-resectable disease or metastatic disease is present, starting with a vinblastine and prednisolone or chlorambucil and prednisolone protocol is an option, as these are relatively inexpensive and normally very well tolerated. If these protocols are unsuccessful, I would try a tyrosine kinase inhibitor (TKI) such as toceranib or mastinib. Even though TKIs are not classical cytotoxic agents, they still require diligent clinical, haematological and biochemical monitoring, with appropriate dose delays and reductions in the case of toxicities. Where a large tumour burden is present, an attempt to downsize it using prednisolone or a course of conventional chemotherapy should be made before starting TKI therapy, to prevent excessive tumour degranulation on treatment induction. Lomustine can also be used for mast cell tumours, and can sometimes be successful where other agents have failed. Regardless of the therapy, dogs with a significant disease burden often benefit from antacids (H2 blockers or omeprazole) and gastroprotectants to offset the effects of hyperhistaminaemia caused by the tumour. Lymphoma 2 / 8

3 The main induction chemotherapy options for canine and feline lymphomas are cyclophosphamide, vincristine and prednisone (COP) and cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) protocols ( Table 1 ). A reasonable amount of published evidence suggests that a CHOP protocol for canine lymphoma affords a higher remission rate and longer remission periods than COP, but this must be balanced against the often-greater financial costs and potential for drug toxicity. In cats, little published evidence supports the use of CHOP over COP for lymphoma, although many oncologists will extrapolate the evidence from other species where a more aggressive protocol will give better results. Cats do not tend to tolerate the higher dose of vincristine as well as dogs do, and the author would normally use the 0.5mg/m 2 dose in this species. Rescue protocols can include single-agent doxorubicin, lomustine and various combination protocols (such as mechlorethamine, oncovin, procarbazine and prednisone [MOPP], dexamethasone, melphalan, actinomycin D and cytosine arabinoside [DMAC] and so on), with or without the use of L-asparaginase. Low-grade lymphocytic lymphomas and chronic lymphoid leukaemias can be treated using a chlorambucil and prednisolone protocol. Multiple myeloma The therapy mainstay for multiple myeloma in dogs is oral melphalan and prednisolone, with good response rates and survival times reported (Matus, 1986). This protocol is generally very welltolerated in terms of toxicity, but it is important to support patients with paraneoplastic hypercalcaemia, hyperproteinaemia and related renal and coagulopathic issues as appropriate. In cats, therapy is not wellestablished, and a full 2mg tablet dose of melphalan can cause a profound neutropaenia. Therefore, the author has tablets reformulated into lower dose capsules by a pharmaceutical laboratory for feline myeloma patients. Osteosarcoma The priority in treating dogs with appendicular osteosarcoma is providing analgesia for what is invariably a very painful tumour. Analgesia is achieved by either amputation, limb-spare surgery or palliative radiotherapy ( Figure 2 ). Chemotherapy inhibits the onset of clinical metastatic disease and extends survival from around three to six months without chemotherapy, to nine to 12 months with chemotherapy. Various chemotherapy protocols have been described probably the most commonly provided is four cycles of carboplatin at threeweekly intervals (Bergman et al, 1996). Osteosarcoma in cats has a much lower metastatic rate than in dogs, so adjunctive chemotherapy is not routinely used. 3 / 8

4 Transitional cell carcinoma Canine transitional cell carcinoma (TCC) can be a challenging disease to treat, as the vast majority of cases are non-surgical and the published response rates to medical therapy are low (around 30 per cent). In general, the author would tend to try piroxicam or meloxicam as firstline therapy, as a proportion of patients will show a good clinical response to these drugs alone. Piroxicam has published evidence supporting its use (Knapp et al, 1994), but meloxicam has a lower risk of gastrointestinal toxicity and, anecdotally, can also be beneficial. If this therapy fails, chemotherapy can be added in for refractory cases of which mitoxantrone has a reasonable response rate (Henry et al, 2003). For patients with urinary obstruction, the option of using palliative stenting techniques is available. Histiocytic sarcoma Canine histiocytic sarcoma can present as a localised peripheral tumour with or without metastatic spread. Alternatively, it can primarily affect single or multiple internal organs. Only patients with localised disease are treated using surgery or radiotherapy, with lomustine chemotherapy as an adjunct to this (Skorupski, 2009). For patients with disseminated disease, chemotherapy using lomustine may provide palliation. The use of doxorubicin has also been described for this tumour (Fidel, 2006). Haematological aberrations (particularly thrombocytopaenia) are common in dogs with disseminated disease, and patients need careful evaluation before a therapeutic plan is decided upon. Histiocytic sarcoma in cats is a rare tumour, and reported responses to chemotherapy have unfortunately been poor. Pulmonary carcinoma In the absence of negative prognostic indicators (multiple tumours, lymph node metastasis, presence of effusion and/ or primary tumour more than 5cm diameter), the prognosis following surgical resection for pulmonary carcinoma in dogs can be very good (McNeil et al, 1997; Polton et al, 2008). If the patient is not a surgical candidate and is stable, the tendency is to offer palliative vinorelbine chemotherapy (Poirer et al, 2002), which tends to be tolerated extremely well. In cats, this disease frequently metastasises to the digits; the role of chemotherapy is not well-established and it is not commonly used. Vaccine-associated sarcoma A compartmental resection at the first surgery provides the best chance of a good outcome for 4 / 8

5 vaccine-associated sarcoma in cats ( Figure 3. Although there is little published evidence for the adjunctive use of chemotherapy, the author uses epirubicin chemotherapy pre and postoperatively, and survival times have been very good. For cases where the tumour is too extensive for resection, anthracycline chemotherapy can be used palliatively (Poirer, 2002). Anal sac adenocarcinoma Anal sac adenocarcinoma (ASA) is primarily a surgical disease, and resection of the primary tumour and lymph node metastases (if present) can achieve worthwhile survival times in suitable candidates (Polton et al, 2007). For cases where primary or lymph node disease is too extensive to be surgical, carboplatin chemotherapy can be used in a palliative setting to extend survival. When used in this way, significant tumour shrinkage is not commonly seen, but stable disease can often be maintained for several months (unpublished observations). The author would offer adjunctive chemotherapy following metastatic lymph node resection, with the intention of extending the disease-free interval. Where distant metastases are present at diagnosis, chemotherapy is likely to hold little benefit (Polton and Brearley, 2007). Drug protocols Vinblastine and prednisolone Vinblastine: 2mg/m 2 IV weekly for four doses then fortnightly for four doses. Prednisolone: 40mg/m 2 PO daily for seven days and then taper. Monitoring: haematology profile prior to each vinblastine injection. Toxicities: myelosuppression (uncommon) and occasional gastrointestinal toxicity. Chlorambucil and prednisolone Chlorambucil: 4mg/m 2 to 6mg/m 2 PO q 48 hours ongoing. Prednisolone: 40mg/m 2 PO daily for seven days, then taper. Monitoring: haematological profile fortnightly initially, then monthly if no evidence of myelosuppression. Toxicities: myelosuppression (this is rare). 5 / 8

6 Lomustine Lomustine: 60mg/m 2 to 90mg/m 2 PO q three weeks. Monitoring: haematological profile and liver parameters before each dose. Toxicities: myelosuppression (potentially severe), gastrointestinal toxicity and hepatic toxicity (uncommon, but irreversible and potentially fatal). Carboplatin Carboplatin: 300mg/m 2 IV q three weeks. Monitoring: haematology profile prior to each dose. Toxicities: myelosuppression, gastrointestinal toxicity and potentially nephrotoxic. Doxorubicin (single agent) Doxorubicin: 30mg/m 2 IV q three weeks. Monitoring: haematology profile prior to each dose. Cardiac monitoring where appropriate. Renal parameters prior to each dose in cats. Toxicities: myelosuppression, gastrointestinal toxicity, extravasation injury, cardiotoxicity and renal toxicity in cats. COP protocol for lymphoma Vincristine: 0.7mg/m 2 IV weekly for four weeks, then 0.7mg/m 2 IV every two weeks for four weeks, then 0.7mg/m 2 IV every four weeks ongoing. Or vincristine: 0.5mg/m 2 IV weekly for eight weeks, then 0.5mg/m 2 IV every two weeks for four weeks, then 0.5mg/m 2 IV every four weeks ongoing. Cyclophosphamide: equivalent to 50mg/m 2 PO q 48 hours while on weekly vincristine, then 50mg/m2 PO q 48 hours during the weeks that vincristine is administered. Prednisolone: 40mg/m 2 PO q 24 hours for seven days, then 20mg/m 2 PO q 48 hours ongoing; reduce dose to 10mg/m 2 q 48 hours in patients that have undue steroid side effects. Monitoring: haematology prior to every vincristine injection and regular urinalysis to monitor for cyclophosphamideinduced cystitis. 6 / 8

7 Toxicity. Vincristine: vomiting in a small number of animals and myelosuppression rarely. Cyclophosphamide: myelosuppression and cyclophosphamide-induced chemical cystitis. Prednisolone: polyuria, polydipsia, increased appetite, excessive panting (dogs), lethargy, thromboembolism and gastrointestinal tract toxicity. CHOP protocol Monitoring: haematology profile prior to each injectable drug and cardiac monitoring as appropriate. Toxicities. As for COP plus doxorubicin. Masitinib Masitinib: 12.5mg/kg bodyweight daily. Monitoring: haematological, biochemical (hepatic parameters) and urinalysis (proteinuria) at the clinician s discretion (suggestion: every two weeks for the first two months, then every four weeks thereafter). Toxicities. Gastrointestinal, renal (protein loss syndrome), hepatic, haemolytic anaemia and neutropaenia. Toceranib Toceranib: 3.25mg/kg bodyweight q 48 hours. Monitoring: haematological, biochemical and urinalysis (proteinuria) at four weeks post-starting, then every six weeks following this. Toxicities. Gastrointestinal, renal, haematological, cutaneous or musculoskeletal. References Bergman P J et al (1996). Amputation and carboplatin for treatment of dogs with osteosarcoma: 48 cases ( ), J Vet Intern Med 10: Fidel J et al (2006). Histiocytic sarcomas in flat-coated retrievers: a summary of 37 cases (November 1998 to March 2005), Vet Comp Oncol 4: Henry C J, McCaw D L, Turnquist S E et al (2003). Clinical evaluation of mitoxantrone and piroxicam in a canine model of human invasive bladder carcinoma, Clin Cancer Res 9: Knapp D W et al (1994). Piroxicam therapy in 34 dogs with transitional cell carcinoma of the 7 / 8

8 Powered by TCPDF ( urinary bladder, J Vet Intern Med 8: Matus R E et al (1986). Prognostic factors for multiple myeloma in the dog, J Am Vet Med Assoc 188: 1,288-1,292. McNeil E A et al (1997). Evaluation of prognostic factors for dogs with primary lung tumors 67 cases ( ), J Am Vet Med Assoc 211: 1,422-1,427. Patnaik A et al (1984). Canine cutaneous mast cell tumour; morphologic grading and survival time in 83 dogs, Veterinary Pathology 21: Poirier V J, Thamm D H et al (2002). Liposome-encapsulated doxorubicin (Doxil) and doxorubicin in the treatment of vaccine-associated sarcoma in cats, J Vet Intern Med 16(6): Poirier V J, Burgess K E, Adams W M and Vail D M (2004). Toxicity, dosage, and efficacy of vinorelbine (Navelbine) in dogs with spontaneous neoplasia, J Vet Intern Med 18(4): Polton G A and Brearley M J (2007). Clinical stage, therapy, and prognosis in canine anal sac gland carcinoma, J Vet Intern Med 21(2): Polton G A, Brearley M J, Powell S M and Burton C A (2008). Impact of primary tumour stage on survival in dogs with solitary lung tumours, J Small Anim Prac 49(2): Séguin B et al (2006). Recurrence rate, clinical outcome, and cellular proliferation indices as prognostic indicators after incomplete surgical excision of cutaneous grade II mast cell tumors: 28 dogs ( ), J Vet Intern Med 20(4): Skorupski K A et al (2009). Long-term survival in dogs with localized histiocytic sarcoma treated with CCNU as an adjuvant to local therapy, Vet Comp Oncol 7: Weisse C et al (2002). Recurrence rates and sites for grade II canine cutaneous mast cell tumors following complete surgical excision, J Am Anim Hosp Assoc 38(1): / 8