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Combination Therapies Studies have shown that combination therapies offer improved efficacy
1. Vinblastine and prednisone, Thamm 1999: Pred
@ 2 mg/kg/d, tapered and discontinued over 12-26 weeks; VBL @ 2mg/m2 every 1 to 2 weeks. Efficacy (gross disease) ORR 47%. Adverse effects (AE): 8/41 (20%), typically after 1st VBL, 15% mild, 5% severe and treatment discontinued
2. VBL, CTX and prednisone, Camps-Palau 2007: Pred @ 1 mg/kg/d, tapered and discontinued over 24-32 weeks; VBL @ 2-2.2 mg/m2 every 3 weeks; CTX @ 200-250 mg/m2 IV or PO every 3 weeks. Efficacy (gross disease, n=11), ORR 64% AE: Well-tolerated, Grade 1 neutropenia & grade 2 GI toxicity
3. Vinblastine, CCNU and prednisone, Rassnick 2010: Pred @ 2 mg/kg/d, tapered and discontinued over 24-28 weeks; CCNU @ 70 mg/m every 4 weeks, wk 1, 5, 9, then q 6 wk; VBL @ 3.5 mg/m2 every 4 weeks, wk 3, 7, 11, then q 6 wk, Prophylactic TMS for 1st treatments, Efficacy (gross disease) ORR 65%, Overall PFS for adjuvant 489 d (16 months), AE: febrile neutropenia, Persistent ALT 9%
4. Leukeran and prednisone Taylor 2009: ORR 38% Median response duration 533 d
Tyrosine kinase inhibitors (TKI) are drugs that inhibit RTK, and most block kinase binding to ATP
competitive inhibitor of ATP binding which prevents phosphorylation of intracellular kinase domain of associated RTK and subsequent signal transduction. The drugs may also inhibit other RTK in split kinase family including VEGF and PDGFR.
Palladia (toceranib phosphate) is an oral TKI that blocks activity of multiple receptors and selectively target split kinase family of RTKs. It exerts antiangiogenic and antiproliferative effects. The oral bioavailability is 77%. Palladia is labeled for dogs with grade 2 or 3, recurrent cutaneous MCT, + regional LN involvement, and was FDA approved in June 2009. Palladia is 1st anti-cancer drug FDA approved for dogs.
In the clinical field study of single agent Palladia (London 2009, Clin Cancer Research), this was a multi-center placebo-controlled, double-blinded study looking at the objective response (PR or CR) to single-agent Palladia @ 3.25mg/kg EOD. The biologic response rate was 59.5% for all dogs (blinded + open): CR 16%, PR 31.3%, and SD 12.2%. The odds ratio of OR was 6.5x higher in Palladia-treated patients vs. placebo. Grade 2 MCT had better outcomes than grade 3, and had a significantly longer time to progression (TTP) and significantly longer response duration. Palladia was effective with or without c-Kit mutation (positive: 69% response; negative: 37% response)
An Urban Experience
formalin-fixed parameters do not reflect margin size at surgery. Tissue shrinkage of up to 30% for cutaneous tissues occurs.
Radiation therapy (RT) is recommended when wide surgical excision not feasible. Monotherapy has varying control rates 40 to 45 Gy 1 year control rates of 50, but surgery to achieve clinical stage 0 (microscopic disease) followed by full course RT, (typically 15 treatments over 3 weeks) has high control rates of 85-95% 2-year control rates for grade 1 and 2. Should do prophylactic nodal irradiation (PNI)? It is probably unwarranted in low to intermediate grade MCT.
Chemotherapy: Single-Agent
• Vincristine McCaw 1997: NOT effective for measurable disease
• Vinorelbine: Grant 2008: Overall Response rate (ORR) 8%
• Single-Agent Vinblastine
• Henry 2007: ORR 12%
• Rassnick 2008L Higher dose higher RR (27 vs 12%)
• Greater GI toxicities and grade 3 or 4 neutropenias
• Single-Agent Lomustine: Rassnick 1999: ORR 42%, Neutropenia was dose limiting toxicity
• Single-Agent Hyroxyurea: Rassnick 2010: ORR 28%, overall remission duration 60 d., Neutropenia was dose limiting toxicity
Steroids As a single agent in grade 2-3 (McCaw 1994), ORR was 20% (5 of 25). But prior to RT for non- resectable grade 1-3 (Dobson 2004), RR was higher at 75% (18/24). When given prior to surgery (neoadjuvant) for grade 1-3 pre-op (Stanclift, 2008), ORR was 70%.
Single agent summary Response rates (CR &PR) are variable
Vincristine 7% Lomustine 42% Steroids 20-75%

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