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