Literature review Flashcards
Hallman et al 2018, Incidence and risk factors associated with development of clinical cardiooxicity in dogs receiving doxorubicin
How may developed cardiotoxicity?
List the 4 risk factors?
What was not associated with cardiotoxicity?
Incidence in high risk and low risk breeds?
4% (20/494 dogs)
Higher cumulative dose, high body weight, decreased in fractional shortening after 5 doses, and ventricular premature contractions
duration of DOX infusion
15.4% (high), 3% (low risk breeed)
Abma et al. 2018, A single dose of IV combretastatin A4-phosphate is reasonably well tolerated and significantly reduces tumor vascularization in canine spontaneous cancers
What is C4AP?
8 dogs with solid tumors were enrolled? Dose given?
Toxicity?
Cardiovascular changes noted?
Result?
Anti-tumor vascular agent that blocks tumor blood flow
single dose of 75 mg/m2
1 developed tetraparesis
Confined to HR and cTnI levels
Epperly et al. Dogs with acute myeloid leukemia or lymphoid neoplasms (large cell lymphoma or acute lymphoblastic leukemia) may have indistinguisable mediastinal masses on radiographs
Medistinal mass was detected on radiographs in what % in lymphoid group and myeloid group?
What was the median size ratio of mediastinal mass to cardiac solhoutte in the 2 groups?
Normal thoracic radiorgaphs?
Conclusion?
73/218 (33%) lymphoid group and 9/20 (45%) in myeloid group
0.20 lyphoid group and 0.23 in myeloid group
111/218 (51%) in lymphoid and 9/20 (45%) in myeloid group
Consider acute myeloid leukemia if there is a mediastinal mass but size does not differentiate between lymphoud or myeloid neoplasm
Magestro et al. 2017, Stereotactic body radiation therapy for heart-base tumors in 6 dogs
Dogs had presumed chemodectomas
How much did the tumor volume decrease?
Treatment related complications?
Major complication?
MST for dogs alive?
30-76% in 4 dogs
Cough, tachyarrythmias, CHF
2 dogs experienced sudden death at 150 and 295 days after SBRT
3 dogs alive 408-751 days (1-2 yr) and 1 dog 1228 days (3.4 yr)
Rohrer et al. 2018, Dosimetric benefit of adaptive radiotherapy in the neoadjuvant management of canine and feline thymoma - An exploratory case series
What is adaptive RT?
Rapid tumor shrinkage was observed when? Mean shrinkage? Tumor regression?
What was the OAR (organs at risk) to the heart and lungs?
Treatment plan is altered throughout the treatment course
1 week of therapy with mean shrinkage of 31% +/- 15.2% or tumor regression of 5.2% per day
After midtherapy planning, -18.2% in mean heart dose and -27.9% in V20 lung dose
Mullin et al. Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs
64 dogs treated with singl-agent DOX for presumptive cHSA
What was the objective response rate (CR + PR)?
Biological response rate (CR + PR+ SD) or clinical benefit?
MST compated to control dogs?
What was associated with improved PFS and OS?
What was negatively associated with PFS in univariate analysis?
41%
68%
116 days (4 mo) compared to 12 days for control dogs
Biologic response
Large tumor size
Ployart et al. 2013, Thoracoscopic resection of right auricular masses in dogs: 9 cases (2003-2011)
What were the clinical signs?
Diagnosis?
Results?
8 dogs had clinical signs or cardiac tamponade and R-CHF
8 HSA and 1 pyogranulomatous lesion
8 lesions were removed and 1 dog died during surgery - Masses close to the base of the right atrial appendage may not be amenable to resection. Masses at the tip of the right auricular appendage can be removed by thoracospically
Rancilio et al. 2012. Use of 3-dimensioanl conformal RT for treatment of a heart base chemodectoma in a dog
Case et al. Outcome evaluation of a thoracoscopic pericardial window procedure or subtotal pericardectomy via thoracotomy for the treatment of pericardial effusion in dogs
58 dogs with pericardial effusion
Clinical signs?
DFI and MST for dogs with idiopathic pericardial effusion and neoplastic effusion
Similar except lethargy between gods treated wtih subtotal peri vis thoracotomy or the pericardial window procedure
Dogs with idiopathic pericardial effusion treated with thorascopic pericardial windown had shorter DFI and MST than those treated with thoracotomy - due to inaccuracy of initial diagnosis or ineffectiveness of peircardial window
No difference in DFI or MST in dogs with neoplastic pericardial effusion treated with either technique
Atencia et al. Thoracoscopic pericardial windown for management of pericardial effusion in 15 dogs
Idiopathic pericardial effusion (n=10), cardiac mass (n=4) and mesothelioma (n=1)
Median thoracoscopic surgery time?
Complications? Median time to discharge?
MST for dogs with idiopathic pericardial effusion vs. neoplasia?
52.5 mins (45-80)
26% in 4 cases, 1 (1-6 days)
635 days or 1.7 yr (70-1165) vs. 30 days (1-107)
Cote et al. 2013. Thoracic radiographic findings for dogs with cardiac tamponade atributable to pericardial effusion
50 dogs with cardiac tamponade (CT) and 23 control dogs (10 healthy and 13 with cardiac disease other than CT)
Sensitivity and specificity of enlargment of cardiac silhoutte with CT attributable to PE?
Sensitivity and specificity of globoid appearance for dogs with CT?
Sensitivity and specificity of a convex appearance?
- 6% and 47.8%
- 9% and 40%
- 1% and 35%
Thoracic radiographs should not be considered reliable for identification of dogs with CT?
Nolan et al. 2017. Pilot study to determine feasability of RT for dogs with right atrial masses and hemorrhagic pericardial effusion?
6 dogs with right atrial/auricular mass
Treatment related complications?
Pericardiocentesis performed before and after RT?
Pre- and post-treated plasma VEGF concentrations?
Cardiac troponin?
Median OST?
None
0.91x per weel before RT and 0.21x per week after RT
No different
Siginificant increases 4hr after irradiation
79 days
Kelsey et al. 2017. Neuromuscular blocakge and inspiratory breath hold during stereotactic body radiation therapy for treatment of heart base tumors in 4 dogs
Neuromuscular blocake used?
Mean treatment delivery time? Mean anesthesia time?
Atracurium or vecuronium
26 minutes, 89 minutes
No hemoglobin destauration or hypercapnia
No complications noted
Guglielmini et al. 2016. Sensitivity, specificity, and interobserver variability of survery thoracic radiography for the detection of heart base masses in dogs
30 dogs with HBM and 120 control dogs
Sensitivity of STR for diagnosis of HBM?
Specificity?
Results?
40% and 56.7% for observer A and 63% and 80% for observer B
96.7% for A and 99.2% and 92.5% for observer B
Survery thoracic radiographs (STR) are highly specific but not highly sensitive predictor for HBM in dogs
Pedro et al. 2016. Cytological diagnosis of cardiac masses with ultrasound guided fine needle aspirates
6 cases identified
Ultrasound guided transthoracic FNAs performed
Complications noted?
Was a diagnosis obtained?
Mild self-limiting pericardial effusion (1) and ventricular ectopic complex (1)
Diagnosis confirmed in all cases: inflammation (1), HSA (2), sarcoma (1), and chemodectoma (1)
Vognoli et al. 2013. Whole body CT characteristics of skeletal and cardiac muscular metastatic neoplasia in dogs and cats
Noted varying enhacement patterns, which was most common?
In 20 cases 2 or more lesions were observed
Location of muscular metastasis?
Ring enhancing (16), heterogeneously enhancing (8), homogeneously enhancing (5)
epaxial muscles of cervical, thoracic, and lumbar spine (18), superfical muscles of thoracic wall (13), scapular/shoulder area (3), hindlimbs (3), abdominal wall muscles (1)
Ghaffari et al. 2014. A retropsective evaluation of doxorubicin-based chemotherapy for dogs with right atrial masses and pericardial effusion
MST for dogs that received doxorubicin?
Side effects?
139.5 days or 4.65 mo (2-302 days)
Frequent but mild
Rajagopalan et al. 2013. Comparison of presumptive echocardiographic and definitive diagnosis of cardiac tumors in dogs
A total of 24 client owned dogs
Presumptive diagnosis of chemodectoma, ectopic thyroid CA, or LSA was correct in?
Presumptive diagnosis of HSA was correct in?
Pericardial effusion?
ECG abnormalities?
Survival?
7/9 cases (78%)
4/8 cases (50%)
10/24 cases (42%)
8/24 (33%)
<1 to >150 days
Amati et al. 2014. Pericardial lymphoma in 7 cats
Clinical findings at presentation?
Thoracic imaging findings?
Immunophenotyping of 6 cats?
4 cats no tx, 1 prednisone, and 2 chemo - survival?
poor BCS, dehydration, dyspnea
pleural effusion, difffuse thickening of pericardium
3 were T cell and 3 B cell
6 cats 7-11 days, 1 cat that got chemo 750 days
Lew eat al. 2019. Retrospective evaluation of canine heart base tumors treated with toceranib phosphate: 2011-2018
28 dogs with HBT
What was the overall response rate?
Overall MST?
Overall response rate for presenting with metastasis and MST?
How may had improvement in CS?
Toxicity?
10%
823 days (2.2 yr)
28.5% and 532 days (1.5 y)
90% had improvement and 81% had complete resolution
54% and mostly GI
Saba et al. Indirect assessment of dihydropyrimidine dehydrogenase activiy in cats
Determinined uracil:dihydrouracil (U:UH2) in plasma using HPLC in 73 cats
What was the mean U:UH2?
How may had >2 - assocaited with decreased DPD activity in humans?
Who had lower levels?
1.66
23%
SF cats had lower compared to FI and age was weakly but significantly correlated
Wypij et al. Pamidronate disodium for palliative therapy for feline bone-invasive tumors
8 cats treated with IV pamidronate - 1 cat in combination with chemo and 2 cats as single agent, what was the median PFI?
Side effects noted?
What was median overall survival? for cats with SCC?
What was median PFS for all cats? SCC?
81 days
3 cats developed azotemia (37.5%)
116.5 days, 170 days
55 days, 71 days
Hafeman et al. Bisphosphanates significantly increase the activity of doxorubicin or vincristine against canine malignant histiocytosis cells
The combination of what 2 drugs was associated with synergistic killing and increase in cell cycle arrest?
What other combination increased cell killing? What was the mechanism?
Clodronate and vincristine
Zoledronate and doxorubicin, zoledronate increased uptake of doxorubicin by MH cells
Pan et al. Safety evaluation of combination CCNU and continuous toceranib in tumor bearing dogs: a phase I dose-finding study
What was the DLT for the combination? What the MTD for CCNU?
What was the objective response rate? Biologic response rate?
neutropenia, 50 mg/m2 q3wk
38.4% and 53.8%
Combination was well tolerated
Musser et al. Low apparent risk of CCNU-associated clinical hepatotoxicity in cats
CCNU given as single agent 31-60 mg/m2 once every 4-8 weeks
How may cats developed elevation in ALT after treatment?
How many cats developed hepatotoxicity?
Any association between dosing frquency, cumulative dose, initial starting dose, or concurrent medications and increase in ALT?
2 cats (6.8%) 1 month after tx with CCNU
1 cat without elevation in ALT
None were found.
Hepatic injury is uncommon in cats with CCNU
Best et al. 2013. Incidence of sterile hemorrhagic cystitis in dogs receiving cyclophosphamide orally for 3 days without concurrrent furosemide as part of a chemotherapeutic treatment for lymphoma: 57 cases (2007-2012)
How many developed SHC?
How may developed myelosuppression? GI efffects?
None
None, 5 had mild
Gaeta et al. Risk factors for development of steril hemorrhagic cystitis in canine LSA patients receiving oral cyclophosphamide: a case-control study
22 dogs with SHC and 66 control dgos were identified
On univariable analysis, what were the risk factors for SHC?
On multivariable analysis? Decreased risk?
SHC is a delayed toxicity associated with high cumulative doses
Age, induction protocol, and cumulative dose were associated with increased risk.
Increasing cumulative dose was associated with increased risk. Short induction protocol
Marrington et al. Toxicity associated with epirubicin treatments in a large case series of dogs
Epirubicin is a stereoisomer of?
What were the most common toxicity?
What reduced dose toxicity?
Did prophylactic anti-emetics, gaatroproectants, and antibiotics reduce the frequency of GI toxicity?
Doxorubicin
lethargy (50), diarrhea (49), vomiting (42), anorexia (40), hypersensitivity (2), extravasation (2)
Dose reductions
They did not.
Venable et al. Dexrazoxane treatment of doxorubicin extravasation injury in four dogs?
Signs noted at extravasation site in dogs treated within 2 hrs? Treated in 48 hours?
Outcome for the 3 dogs and 1 dog?
Mild erythema and edema developed within 1 hours to 6 days in 3 dogs that received zinecard within 2 hrs after extravasation. Extensive tissue necrosis
Surgical intervention for dog with tissue necrosis and the other 3 dogs lesions resolved on medical management.
Treat with dexrazoxane within 6 hours of extravasation.
Ratteree et al. 2012. Value of echocardiography and electrocardiography as screening tools prior to doxorubicin administration
Of the 101 dogs, how many were excluded from doxorubicin administration?
What were the most common arrythmias?
What was the incidence of cardiotoxicity in treated dogs?
6 dogs (6%) were exluded
Ventricual premature contractions
8%
Wittenburg et al. Development of a limited sampling model for prediction of doxorubicin exposure in dogs.
3 blood samples are obtained over 1 hours post-treatment that accurately predict patient exposure
Rasmussen et al. Phase I lead-in and subsequent randomized trial assessing safety and modulation of regulatory T cell numbers following maximally tolerated dose doxorubicin and metronomic dose cyclophosphamide combination chemotherapy protocol on tumor-bearing dogs
What happened to circulating lymphocytes in dogs receiving combination DOX/mCTX and single agent DOX?
How were the depletions between the 2 groups?
Significant depletion of circulating lymphocytes without selectivity for Tregs
Depletion were similar between dogs in dogs reciving DOX or DOX/mCTX
Tater et al. Assessment of cardian troponin I and tissue velocity imaging in 14 dogs with malignant lymphoma undergoing chemotherapy treatment with doxorubicin
Echocardiographsic measurement and cTn1 levels were obstained before and after doxorubicin in 14 dogs
What was concluded about echocardiographic parameters, tissue Doppler indices, and cTnI concerntrations?
Did not differ at any point in a 12-week protocol
Doxorubicin may not be associated with significant myocardial damage
Marconato et al. An Open-label Phase 1 dose escalation clinical trial of a single intravenous administration of gemcitabine in dogs with advanced solid tumors
22 client owned dogs. Treated at 4 dose levels ranging from 800-950 mg/m2 (escalation of 50 mg/m2).
What was the DLT? What was MTD?
At 900mg/m2 what responses were observed?
What is the recommended dose for future Phase 2 studies?
Neutropenia. 900 mg/m2
2 CR and 5 PR
900 mg/m2 once weekly
Leach et al. Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occuring cancer
36 dogs given chlorambucil at 4mg/m2
What was the overall remission rate? CR and PR?
What was the median PFI? MST?
11% (3 CRs with MCT, STS, and thyroid carcinoma) that lasted 35 weeks
PR in 1 dog with histiocytic sarcoma (39 weeks survival)
61 days (2 mo), 153 days (5 mo)
Leo et al. Evaluation of low-dose metronomic cyclophosphamide toxicity in cats with malignant neoplasia
24 cats with variety of neoplasms (13 sarcomas, 12 carcinomas, 1 melanoma, 1 neuroendocrine tumor)
What was noted in the 1st month of treatment? Other toxicites noted?
Toxicities noted at 2 months?
GI toxicity. 2/24 (8%) grade I hematological toxicity and 1/24 (4%) grade I renal toxicity
2 grade III and 1 grade I renal azotemia
Larson et al. 2015. PK of orally administered low-dose rapamycin in healthy dogs
5 healthy dogs
Oral administration of low-dose (0.1 mg/kg) rapamycin achieved blood concentrations in ____ per mililiter?
nanograms per milliliter
Frazier et al. Phase I clinical trial of oral rosiglitazone in combination with IV carboplatin in cancer bearing dogs
What is rosiglitazone?
What was the DLT and dose (6-8 mg/m2)?
Changes in liver values?
Peroxisome proliferator-activated receptor gamma (PPARg) agonist and antidiabetic agent - reduce tumor cell growth
Hepatic and 8 mg/m2
Mild to moderate elevations in ALT, no changes with ALP, tbili, or GGT
Waite et al. 2011. Phase II study of oral docataxel and cyclosporine in canine epithelial cancer
51 dogs enrolled.
What was the overall response rate? Highest response rate was seen in who?
Main toxicity noted?
17%. 50% response rate in dogs with oral SCC
GI
Vail et al. 2012. A randomized trial investigating the efficacy and safety of water soluble Paclitaxel (Paccal Vet) for treatment if nonresectable grade 2 or 3 MCT in Dogs
250 dogs with nonresectable grade 2 or 3 MCT
What was the overall CORR (confimred overall response rate) and BORR compared to lomustine?
Paclitaxel treated dogs were __x more likely to have responsd and __x more like to experience bologic observed response?
Toxicities?
7% vs 1% and 23% vs. 10%
6.5x, 3.1x
33% receiving lomustine were d/c due to hepatopathy and 2% receiving paclitaxel
H. von Euler. A dose finding study with novel water soluble formulation of paclitaxel for the treatment of malignant high-grade solid tumors in dogs
What was the ORR, median time to response, and median PFS?
What was the associated AE?
86%, 14 days, and 131 days
Myelosuppression
Kim et al. 2015. Exploration of paclitaxel as treatment for malignant tumors in cats: a descriptive case series
9 cats treated at 80 mg/m2 IV every 21 days upto 2 doses
AEs?
Response rate?
Median TTP
thrombocytopenia, GI signs, hypersensitivity (5)
SD and PR in 56%
28 days
Gagnon et al. 2015. Treatment-related toxicites in tumor bearing cats treated with temozolomide alone or in combination with doxorubicin: a pilot assessment
TMZ orally once for 5 days every 3 weeks at 20mg/cat with various malignancies in 10 cats
Response noted in 8 cats?
Toxicity noted in cats?
2 CR, 1 SD, 5 PR
Effusion with higher cumulative dose of TMZ
Mitchell et al. 2012. Clinical and Immunomodulatory effects if Toceranib Combined with Low-dose cyclophosphamide in dogs with cancer
15 client owned dogs with advanced tumors
What happened to Tregs and IFN-g?
Toceranib decreased percentage of Tregs in peripheral blood.
Dogs receiving toceranib and cytoxan had increase in IFN-g whihc was inversely correlated with Treg after 6 weeks of combination treatment
London et al. 2012 Preliminary evidence for biologic activity of toceranib phosphate in solid tumors
Clinical benefit was noted in how many dogs?
AGASACA?
OSA?
Thyroid carcinoma?
Head and neck carcinoma?
Nasal carcinoma?
74%
28/32 = 87% AGASACA
11/23 = 23% OSA
12/15= 80% Thyroid
7/8 = 87.5%
5/7 = 71% nasal carcinoma
Chon et al. Safety evaluation of combination toceranib phosphate and piroxicam in tumor-bearing dogs (exclusing MCTs): a phase I dose finding study
Dosage recommendations for both drugs?
Standard dosage of both drugs (3.25 mg/kg EOD and piroxicam 0.3 mg/kg/day) was safe
Robat et al. Safety evaluation of combination vinblastine and toceranib phosphate in dogs: a phase I dose-finding study
DLT for combination?
MTD for vinblastine?
What was the observed objective response?
Neutropenia
1.6 mg/m2 every other week with toceranib 3.25 mg/kg EOD
50% dose reduction with vinblastine does not support combination
71% objective response
Achanta et al. Reaction phenotyping of vinblastine metabolism in dogs
What is the major cytochrome P450 isoform for the metabolism in dogs?
CYP3A12
Lind et al. 2013. Evaluation of vincristine associated myelosuppression (VAM) in Border Collies
How may developed VAM of the 5 Border Collies?
What was identified in these border collies?
3/5 (60%) border collies with ABCB1 wildtype developed VAM.
8 single nucleotide polymorphisms in ABCB1 were detected
Pierro et al. 2013. Phase I clinical trial of vinorelbine in tumor bearing cats
19 cats enrolled in study
What was the MTD in cats?
Acute DLT?
11.5 mg/m2 once weekly- maximum dosage administered was 15.5 mg/m2
Neutropenia, vomiting, nephrotoxicity
Wouda et al. 2015. Clinical effects of vinorelbine administration in the management of various malignant tumor types in dogs: 58 cases (1997-2012)
CR?
PR?
SD?
PD?
Median time to tumor progression?
2% for 162 days
11% for 91 days
43% 68 days
43% for 21 days
103 days
Heyden et al. 2012. Influence of P-glycoprotein modulation on plasma concentrations and PK or orally administered prednisolone in dogs
What does Rifampin and ketoconazole do to P-gp?
What did Rifampin tx do?
What did ketoconazole do?
Rifampin is an inducer of P-gp and ketoconazole in an inhibitor of P-gp
Upregulated duodenal P-gp and reduced the AUC of prednisolone
Downreulated duodenal P-gp and increased the AUC of prednisolone
Silver et al. 2012. Evaluation of oral antimitotic agent (ABT-751) in dogs with lymphoma
What is ABT-751?
31 dogs with naive (19) or relapsed non-Hodgkin’s LSA (11)
What was the MTD?
DLT?
What was the objective response and response of duration?
antimitotic agent that targets MT polymerization
350mg/m2 PO Q24hr
vomiting, diarrhea - improved if given 48hr
20% and 21 to 111 days
Vail et al. 2012: Phase I study to determine MTD and DLT of orally administered Idarubicin in Dogs with LSA
What was the MTD in dogs > 15 kg?
DLT?
22 mg/m2
Neutropenia and thrombocytopenia
Meier et al. 2013. Use of Epothilone B (Ptupilone) in refractory lymphoma and advanced solid tumors in dogs
What are epothilone?
20 dogs with various malignancies
Canine HSA and lymphoma cell lines, what was noted?
Main AEs?
MTD in dogs?
Mictorubule stabilizing agent
50% decrease in proliferative activity
diarrhea, anorexia, vomiting, nausea
2.76 mg/m2 IV once weekly
Cora et al. 2013. Comparison of automated versus manual neutrophil counts for the detection of cellular abnormaltiies in dogs receiving chemotherapy: 50 cases
What was the correlation coefficient of the neutrophil count?
0.96
LeBlanc et al. Serial evaluation of neutrophil function in tumor bearing dogs undergoing chemotherapy
Flow cytometry used to asses neutrophil oxidative burst and phagocytic activites at baseline, 7 and 21 days after induction chemotherapy in 20 dogs with LSA
Dogs had ___ percentage of neutrophils exhibiting oxidative burst after stimulation with E. coli and PMA at 7 days
Induction chemotherapy suppresses percentage of neutrophils oxidative burst with improvement over time
lower
Janssens et al. Inductively coupled plasma mass-spectrometric determination of platinum in excretion products of client-owned pet dogs
What is the major route of elimination of Pt in dogs?
How else does excretion occur and for how long?
Pt excretion can be found for how long?
Urine
Feces and saliva with highest amount during the first 5 days
Upto 21 days
Kidd et al. Development of ELISA to detect circulating anti-asparaginase antibiodies in dogs with lymphoid neoplasia treated with E. coli L-asparaginase
How many dogs developed titers after single injection in 10 dogs?
With repeated exposires in 7 dogs?
3/10 (30%)
4/7 (57%)
Britton et al. Evaluation of factors associayed with prolonged hospital stay and outcome of febrile neutropenic patients reciving chemotherapy: 70 cases (1997-2010)
Majority of patients recieved what chemo?
What factors were associated with long hospital stay?
What were associated with death in hospital?
70% got vincristine or doxorubicin prior to FN
Tachycardia at admission, complicating medical issues, G-CSF
Hypotension and G-CSF
Mason et al. Gastrointestinal toxicity after vincrsitine or cyclophosphamide administered with or without maropitant in dogs: a prospective randomised controlled study
Was there a difference in vomiting, diarrhea, appetite loss, or lethargy between dogs that got cerenia or did not?
Cerenia did not reduce the frequency of AEs and should only be given as required
Genoni et al. Safety of intrathecal administration of cytosine arabinoside and methotrexate in dogs and cats
How many developed side effects?
Is it safe?
1 dog developed tonic-clonic seizure after cytosar and methotrexate administration and responsed to diazepam
Very safe :)
Kicenuik et al. Treatment time, ease of use and cost associated with use of Equashiled, Phaseal, or no closed system transfer device for administration of cancer chemotherapy to a dog model
Administration was fastest with?
Which was easier to use?
Which cost less?
Equashiled
Equashiled was easier to use than Phaseal or CSTD (closed system trasnfer device)
Equashiled cost less but sold in bulk
Fulkerson et al. PK and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs
What is zebularine?
Cmax?
Mean half-life?
Which dose resulted in AEs?
Oral cytidine analog wuth demethylating activity
23 and 8.6 with 8 and 4 mg/kg dose
5.7 and 7.1 with 8 and 4 mg/kg dose
Single 8 mg/kg dose was well tolerated. Daily 4 mg/kg caused neutropenia, anorexia, dermatologic changes
Finlay et al. Evaluation of the risks of chemotherapy in dogs with thrombocytopenia
Was there any difference in AEs in dogs with thrombotyoepnia?
No statistically significant difference in incidence of GI AEs or hemorrhage between thrombocytopenic and control dogs
Moretti et al. Nucleated erythrocytes in blood smears of dogs undergoing chemotherapy
Sthanasiadi et a. Safety, tolerability and PK properties of the novel triazene Trin 2755 in tumor bearing dogs
Lewis et al. Comparison of chemotherapeutic drug resistance in cells transfected with canine ABCG2 or feline ABCG2
Goal to compare canine ABCG2-mediated drug resistance to feline ABCG2
HEK293 cells were transfected with canine, feline, or no ABCG2 and exposed to carbo, DOX, mitox, toceranib, or vincristine
Canine conferred more resistance than feline to what drug?
Neither conferred resistance to what drug?
Canine conferred resistance but not feline to?
Mitoxantrone
DOX, Vinc, toceranib
Carbo - drug not a substrate for ABCG2
Guth et al. Liposomal clodronate treatment for tumor macrophage depletion in dogs with STS
Tumor related macrophages correlate with tumor growth.
13 dogs with STS
5/13 dogs density of _____ macrophages were decreased after LC treatment
Circulating concentrations of ____ were also decreased
CD11b+, IL-8
Bavcar et al. 2017. Combination toceranib and lomustine shows freqeunt high grade toxicities when used for treatment of non-resectable or recurrent MCT in dogs
10 dogs with advanced MCT and treated with toceraniv 2.7 mg/kg EOD, lomustine 60 mg/m2 q3wk, prednisolone 1 mg/kg EOD alternating with toceranib
Objective RR?
AEs?
50%
All dogs had AEs, 3 dogs died and trial was stopped :(
Laprais et al. 2017. Is CCNU valuable for treatment of cutaneous epitheliotropic LSA in dogs?
Which drugs have the highest rate of CR?
MST w/o tx?
MST with CCNU protocol?
MST with retinoids, PEG ELSPAR, prednisolone monotherapy?
CCNU and pegylated liposomal DOX in 1/3 of dogs
3 to 5 months
6 months
11 months, 9 months, 4 months
Pierro et al. 2017. Febrile neutropenia in cats treated with chemotherapy.
22 FN events in 20 cats
Most common diagnosis?
Most common agents?
CS?
Median # of days betweem chemo and FN?
LSA
Vinca alkaloids and lomustine
Anorexia, lethargy, vomiting, diarrhea
5 days, tx with IV fluids and antibiotics
Burton et al. 2016. Frequency and severity of neutropenia associatyed with FDA approved and compounded formulation of lomustine in dogs with cancer.
37 dogs treated with FDA approved or compounded lomustine
21 dogs recived FDA approved and 16 dogs from compounding pharmacy
Neutropenia in FDA approved?
Neutropenia in compounded lomustine?
All dogs were neutropenic. 71% had grade 3 or higher neutropenia
25% were neutropenic with 12.5% grade 3 neeutropenia
Potency of lomustine from 5 pharmacies ranged from 50-115% with 1 sample within +/- 10%
Chakkath et al. 2015. Alkylation and Carbamylation Effects of Lomustine and its major metabolites and MGMT expression in canine cells
Low MGMT expression in canine lymphoiud cell line 17-71 while GL-1 cells dont
Halsey et al. 2014. Development of an in vitro model of acquired resistance to toceranib phosphate in canine MCT
Rassnick et al. 2014. Tolerability of lomustine in combination with cyclophosphamide in dogs with LSA
CCNU given 60 mg/m2 on day 0, CTX given 250 mg/m2 divided over day 0-4, antibiotics
Main toxic effect? Frequency of grade 4 neutropenia
Neutropenia, 30%
Mean body weight of dogs that developed grade 4 neutropenia was less (20kg) than those that did not develop grade 4 neutropenia (32kg)
Dose of CCNU combined with CTX every 4 weeks is tolerable
Meervenne et al. 2014. Comparison between symptomatic treatment and lomustine supplementation in 71 dogs with intracranial, space occupying lesions
15 dogs tx with steroids and anti-epileptics, 56 dogs recived addition al tx with lomustine
MST b/w the 2 groups?
What affected survival time?
No difference, 60 and 93 days
Female dogs survived longer than male dogs
Dutelle et al. 2012. Evaluation of lomustine as a rescue agents for cats with resistant LSA
39 cats with resistant LSA
What were the significant prognostic factors for PFI?
Overall PFI?
MPFI for large versus small and intermediate cell LSA
MPFI for GI versus non-GI LSA
Cell size, # of previous chemotherapy drugs, # of previous chemo protocols, and anatomic location of LSA
39 days
21 vs. 169 days
180 vs. 25 days
Saba et al. 2012. Phase II clinical evaluation of lomustine chemotherapy for feline vaccine-associated sarcoma
28 cats with measurable VAS
Overall RR?
Median PFS and median duration of response?
Common toxicity?
25%
60.5 and 82.5 days
Neutropenia
Bergman et al. 2016. Evaluation of local toxic effects and outcomes for dogs undergoing marginal tumor excision with intralesional cisplatin-impregnated bead placement for treatment of STS: 62 cases (2009-2012)
How many had toxicosis at bead placement?
Median DFI in grade 1, 2 and 3
Disease free survival rates with grade 1, 2, and 3?
71% (24/51)
Not reached for grade 1 and 2, 148 days with grade 3
88%, 75%, and 64%
Kenward et al. Anti-nausea effects and PK of ondansetron, maropitamt. amd metoclopramide in a low-dose cisplatin model of nausea and vomiting in dog: a bling crossover study
Placebo treated group vomited?
Ondansetron or maropitant group?
Metoclopramide?
AVP (arginine vasopression) and cortisol were prevented by?
The drug with greated anti-emetic and anti-nausea efficacy?
7 times
Did not vomit
No effect on vomiting or nausea
Ondansetron and partially by maropitant (NK1 antagonist), metoclopramide (D2 antagonist) had no effect
Ondansetron (5-HT3 antagonist)
Michalowsska et al. 2014. Phase I/II clinical trial of encapsulated, cytochrome P450 expressing cells as local activators of cyclophosphamide to treate spontaneous canine tumors
Encapsulated cells overexpressing cytochrome P450 enzyme isoform 2B1 were implanted around malignant mammary tumors. Dogs were given cyclophosphamide.
Reduction in tumors?
Tumors that received cyclophosphamide alone?
Take home?
50% (6/11)
SD
Encapsulated c ytochrome P450 combined with chemo may be useful in treatment of mammary tumors
Denies et al. Immunological and angiogenic markers during metronomic temozolomide and cyclophosphamide in canine cancer patients
10 healthy dogs and 30 canine cancer patients
Percentage of Tregs in cancer patent and healthy dogs?
Treatment with temozolomide and Tregs?
TSP-1 and VEGF levels?
Decrease in Tegs in patients with metronomic cyclophposphamide and combination.
No effect of Tregs
Lower in cancer patients and higher in healhty dogs but not influence by metronomic regimens
Robat et al. 2017. Potency and stability of compounded cyclophosphamide: a pilot study
Obtained 15mg cyclophosphamide capsules from 5 pharmacies and did potency analysis at 2 timepoints.
Potency results?
Stability?
Inadequate
Adequte at 60 days except for 1 sample
Chan et al. 2016, Incidence of sterile hemorrhagic cystitis in tumoe bearing dogs concurrently treated with an oral metronomic cyclophosphamide chemotherapy and furosemide: 55 cases (2009-2015)
SHC was how common?
Identified in 2/55 (3.6%)
Low inicidence of SHC, furosemide may protect against SHC
Matsuyama et al. 2017. Evaluation of toxicity of a chronic alternate day metronomic cyclophosphamode chemotherapy protocol in dogs with naturally occuring cancer
50 dogs with median lenght of treatment of 90 days
Treatment was discontinued in how many?
How many developed SHC? Median time?
What was associated with higher risk of SHC?
22/50 - 44% due to AEs
16 dogs (32%), 130 days
higher cumulative dose
Burton et al. 2017. Potency and stability of compounded formulations of chlorambucil, melphalan, and cyclophosphamide
Compounded 1 mg CHB, CTX 5mg, melphalan 1 mg
Potency of CHB?
Melphalan?
At 6 weeks?
Cyclophosphamide?
71-104%
58-109%
<90% strenght at baseline and 6 weeks
92-107%
Variability of compounded chemotherary products, need to consider potency and stability
Harper et al. Toxicity of metronomic cyclophosphamide chemotherapy in UK population of cancer bearing dogs: a retropsective study
Included 65 dogs
cyclophosphamide between 5-15 mg/m2/day or EOD
How frequent was toxicity? What were the 2 common toxicities?
Median time to development of SHC?
49%. SHC (25%, 16) and GI (18%, 12)
110 days
Setyo et al. 2017. Furosemide for prevention of cyclophosphamide-associated strile hemorrhagic cystitis in dogs receiving metronomic low-dose oral cyclophosphamide
115 dogs treated with metronomic cyclophosphamide
Incidence of SHC?
Incidence of SHC with and w/o furosemide?
Other risk factors associated with SHC?
21.7% (25 dogs)
10% and 30%
None
Furosemide is effective in preventing SHC
Stroda et al. 2017. PK of cyclophosphamide and 4-hydroxycyclophosphamide in cats after oral, IV, and IP administration
6 healthy cats - 200 mg/m2 via each route (oral, IV, IP)
PK for the 3 routes?
AUC?
Toxicity?
Similar regardless of route
Lower for oral route
Well tolerated
Pellin et al. 2017. Safety evaluation of combination doxorubicin and toceranib phosphate in tumor bearing dogs? a phase I finding study
DLT?
MTD for both drugs?
AEs?
Neutropenia
25 mg/m2 IV q21 days and 2.75 mg/kg EOD
None
Warrants further investigation in phase II/III trials
Thornton et al. 2017. Owner perceptions of their cats quality of life when treated with a modified University of Wisconsin-Madison protocol for LSA
Postal questionare sent to owners of 33 cats
Median quality of life score before and after diagnosis? During chemotherapy
Quality of life scores correlated with?
10, 3, 7
Appetite
Most owenrs were happy their cat was treated (75%)
Garnett et al. 2016. Fixed-dose rate administration of gemcitabine in cancer bearing cats: A pilot study
Cats treated with <2.5 mg/m2?
10 mg/m2?
Best dose?
Failed to achieve target plasma concentration (TPC)
Exceeded TPC
2-5 mg/m2
Batchinski et al. 2014. Evaluation of ifosfamide salvage therapy for metastatic canine OSA
19 included and 17 evaluated for response
Overall response?
Median survival duration?
11.8% (1/17 CR, 1/17 PR, 2/17 SD, 13/17 PD)
95 days
Custead et al. 2017. Retrospective comparison of three doses of metronomic chlormabucil for tolerability and efficacy in dogs with spontaneous cancer
88 dogs comparing 3 doses of CHB at 4, 6, 8 mg/m2
Toxicity at 6 mg/m2?
8 mg/m2?
Severity of GI signs was worse and development of GI was shorter compared to 4 mg/m2
Thrombocytopenia ocurred earlier at 8 than 4 mg/m2
Higher doses did not provide improved responses and were associated with more AEs
Rivera et al. 2013. Clinical efficay and safty of water-soluble micellar paclitaxel in canine mastocytomas
Paccal Vet administred at 145 mg/m2 IV q21 days for 3 cycles to 29 dogs
CR and PR?
Median time to progression?
Side effects?
59%
247 days (8.2 mo)
grade 3/4 neutropenia and garde 1/2 leukopenia in majority of dogs
Lyles et al. 2012. In vitro effects of tyrosine kinase inhibitor, masitinib mesylate, on canine HSA cell linces
Masnitib causes dose-dependent HSA cell death with activation of caspase 3/7
Increase in VEGF in proximity to IC50 (50% inhibitory concentration)
Smrkovski et al. 2015. Masitinib mesylate for metastatic and non-resectable canine cutaneous MCT
26 dogs included in study
Overal RR?
MST for responders and non-responders?
Toxicity?
Most significant prognostic factor?
50%
630 days (1.7 yr) vs. 137 days (4.6 mo)
61.5% which were mild and self-limiting
Response to masitnib and not tumor grade, stage or location
Holtermann et al. 2016. Masitinib monotherapy in canine epitheliotrophic LSA
CR noted in how may dogs?
KIT expression? SCF? PDGF
2/10
Negative, 6/8 positive, 2/8
Effective in treating LSA but effects not mediated through KIT receptor
Grant et al. 2016. Clinical response of masitinib mesylate in the treatment of canine macroscopic MCT
39 dogs treated with masitinib for macroscopic MCT
Clinical response rate? CR and PR?
Median time to progression?
AEs?
MST?
82%, 15 CR (38.5%) and 17 PR (44%)
80 days
64% with serum ALT elevation (23%) and vomiting (15%)
159 days
Leblanc et al., 2012. Preliminary evaluation of serial (18) FDG-PET?CT to assess response to toceranib phosphate therapy in canine canine
6 dogs
Bernabe et al. 2013. Evaluation of the AE profile and PD of toceranib phosphate administered to dogs with solid tumors at doses below the maximum tolerated dose
Toceranib given at 2.5-2.75 mg/kg EOD and measured plasma toceranib and VEGF concentrations on days 0, 7, 14, 30
Resulted in 6-8 hr plasma concentration of 100-200 ng/ml, aboe the 40 ng/ml concentration needed for target inhibition
VEGF concentration increased significantly ovet the 30 day treatment period indicating VEGFR2 inhibition
Associated with lower AEs compared to the 3.35 mg/kg EOD labeled dose
Merrick et al. 2017. Retrospective evaluation of toceranib phosphate toxicity in cats.
55 cats and 55% had carcinoma
Median dose of 2.7 mg/kg given M,W,F
Common hematological toxicity?
Common biochemical alteration?
GI toxicity?
Thrombocytopenia (16%) and neutropenia (9%)
Azotemia (14%) and ALT elevation (7%)
21.8% - much lower than dogs
Harper et al. 2017. Toxicity and response in cats with neoplasia treated with toceranib phosphate
14 cats and were previously treated (surgery, RT, chemo) with epithelial tumors or MCTs
Toxicity?
Biological response?
Median duration of response?
10/14 cats - myelosuppression and GI, 2 developed severe hepatotoxicity
57.1%
90 days - no response in cats with SCC
Tjostheim et al. 2016. Effects of toceranib phosphate on systolic blood pressure and proteinuria in dogs
26 control dogs and 30 dogs with cancer
Systolic blood pressure?
Prevalence of systemic hypertension and proteinuria in treatment dogs?
Higher after initiation of treatment
37% and 21% comapred to 15% and 0% in healthy dogs
Wouda et al. 2018. Safety evaluation of combination carboplatin and toceranib phosphate in tumor bearing dogs: a phase I dose finding study
Toceranib 2.7 mg/kg EOD and carboplatin 200 mg/me IV q 21 days in 11 dogs
MTD for both drugs?
DLT?
Response?
Toceranib 2.7 mg/kg EOD and carboplatin 200 mg/me IV q 21 days
Neutropenia
2 PR, 6 SD
Hume et al. 2018. Effects of toecranib phosphate on hypothalmic-pituitary-thyroid axis in tumor bearing dogs
Thyroid dysfunction is assocaited with use in people
43 dogs
Toceranib can disrupt the thyoid axis in dogs and TT4, fT4, TT3, TSH should be monitored
Teske et al. 2014. Intraperitoneal antineoplastic drug delivery: experience with a cyclophosphamide, vincristine, and prednisolone protocol in cats with malignant LSA
26 cats with malignant lymphoma received IP-COP
CR rate?
Median duration of first remission? 1- and 2- year survival?
77% (n=20)
420 days, 67% and 48%
Young cats more favourable prognosis and achieving CR was essential for long term survival
No IP AEs
Collicutt et al. 2013. Erythrocyte dysplasia in peripheral blood smears from 6 thrombocytopenic dogs treated with vincristine sulfate
19 dogs got vinc for IMT
2/5 had evidence of erythrodysplasia
Clincially insignificant
Cai et al. 2017. Phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate in dogs with naturally occurring malignant tumors
18 rats, 9 mice, and 16 dogs with cancer
Plasma cytokeratin-18 concentrations as nonivasive biomarkers of early GI toxicosis in dogs receiving toceranib
20 healthy dogs and 25 dogs with surgically excised MCT
Toceranib 2.75 mg/kg EOD
Mean plasma CK18 concentration on day 0?
No different than healthy dogs
Decreased by 98pg/mL from day 0 to 28 days
Not a clinically useful biomarker for GI toxicosis
Henry et al. 2018. Clinical evaluation of Tavocept to decrease diuresis time and volume in dogs with bladder cancer receiving cisplatin
Tavocept is a chemoprotectant that has mitigated cisplatin toxicity and decreased diuresis in humans
14 dogs with TCC
Frequency of toxicity?
Diuresis time?
Response rate?
MST?
3 dogs (21%) had increase in creatinine and BUN and 2 of these were isisthenuric
Less
Less, from >6 hours to 90 minutes
27% which was inferioir to historical group
253 days vs. 246 days comparable to historical control
Hess et al. 2018 Analysis of platinum content in biodegradable carboplatin-impregnated beads and retrospective assessment of tolerability for intralesional use of the beads in dogs following excision of SQ sarcomas: 29 cases
Mild to moderate local adverse events for 11/29 tumors (38%)
No systemic toxicosis
Local disease free rate 1-, 2-, 3-year - 70%, 70%, and 58%
Miller et al. 2018. Suspected carboplatin extravasation reactions in 7 dogs
Wounds noted 7 days later
Healed with medical and surgical debridement median 25 days
Extravasation injury should be considered as possible local complication with carboplatin
Richardson et al. 2018. Correlation between body weight and mitoxantrone-associated neutropenia in dogs
Mitoxantrone 5 mg/m2 IV
Grade 3 neutropenia and grade 4?
Dogs <10kg?
Dogs <15kg?
21% and 14%
More likely to develop grade 3 and 4 neutropenia
More likely to develop grade 3 and 4 neutropenia
Dose reduction should be considered in <10 kg dogs and increased risk of neutropenia in 10.1-15kg dogs
Selting et al. 2018. Evaluation of intravenous and SQ administration of a novel, excipient free, nanoparticle formulation of paclitaxel in dogs with spontaneously occuring neoplasia
Menard et al. 2018. Concurrent 5-FU and carboplatin for the treatment of canine carcinomas
24 dogs treated with 180-25 mg/m2 IV carbo and 5-FU 150 mg/m2
Common toxicity?
Response rate
14 dogs had myelosuppressoon - thrombocytopenia more common than neutropenia
GI signs were uncommon
43%
Glutathione-S-transeferase theta genotypes and the risk of cyclophosphamide toxicity in dogs
Borrensen et al. Liposomal encapsulated chemotherapy: Current evidence for its use in companinon animals
Hwang et al. 2018. Oncolytic reovirus therapy: Pilot study in dogs with spontaneously occuring tumors
