Literature review Flashcards by Bushra Zaidi

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)

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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

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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

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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)

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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

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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

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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

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Rancilio et al. 2012. Use of 3-dimensioanl conformal RT for treatment of a heart base chemodectoma in a dog

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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

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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)

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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?

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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

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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

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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

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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)

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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***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