Palliative care
Veronika Langova MVDr, MANZCVS (Med) FANZCVS (Onc)
• Pet palliative care focuses on alleviating patient discomfort and controlling clinical signs while addressing the client's emotional needs. • Fundamental concerns are pain management, hygiene, nutrition, mobility and safety in the home. • The next tier of care focuses on the pet's mental state and engagement with human family Palliative care members as well as interactions with other household pets.
• Cancer is the Leading Cause of Pet Animal Death • 45% of 10 to 16 year old dogs • 23% overall
American Journal of Veterinary Research 1982 Increasing Prevalence Due to Increasing Age
• Preventive medicine better management of diseases • Vaccinations • Nutrition • Human-animal bond Psychological Implication to the Owner
• 1 in 4 get cancer • Experience of cancer • Negative attitude detrimental Cancer treatment
• 1/3 we can cure • 1/3 we can manage for prolonged period of time ‘remission’ • 1/3 we palliate • Using chemotherapy • Radiation • Pain management • Nutritional support
Palliative care • USING CHEMOTHERAPY Ben Ten
• 10 yo MN LabxKelpie • Owner noticed snoring and occasional sneezing 6 months ago • Recently developed epistaxis Ben Ten
CT scan Histopathology immunohistochemistry Ben Ten CD3 (Tcell) CD79 (Bcell) Spike
• 14 yo MN Cattle dog • Presented with large mass on the left mandible, left submandibular lymph node enlargement • Histopathology: T cell lymphoma ROXY Roxy • cytology • What about muzzle MCT? • Geiger et al JVIM 2003 • 24 dogs with muzzle MCT ROXY • 2 Grade I, 15 Grade II, 7 Grade III • Median survival 30 months • Grade was prognostic for local control of disease and survival Ellis Imaging • Histopathology soft tissue sarcoma METRONOMIC CHEMOTHERAPY
• Administration of large boluses of chemotherapy with a period of ‘recovery’ between doses describes traditional maximum tolerable dose (MTD) chemotherapy
Researchgate 17 METRONOMIC CHEMOTHERAPY
• Low dose daily chemotherapy administration without the need for a recovery period describes metronomic chemotherapy
Researchgate 18 METRONOMIC CHEMOTHERAPY
Mechanisms of action of metronomic chemotherapy: 1. Effects on neovascularisation 2. Effects on the immune system 3. Effects on cancer cells and cancer stem cells 4. Induction of tumour dormancy
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• Angiogenesis is the formation of new blood vessels and is a Hallmark of Cancer • Numerous pro-angiogenic factors involved • Inhibition of angiogenesis can prevent tumour growth and potentially cause tumour regression
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• Angiogenesis inhibitors are an emerging field in cancer therapy • Metronomic chemotherapy utilising anti-neoplastic drugs • Monoclonal antibodies • Tyrosine kinase inhibitors • Thalidomide
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• Effects on the immune system – “immune escape’ is now considered a Hallmark of Cancer • T-regulatory cells (Tregs) are important immunosuppressive cells that can prevent immune detection of tumour cells by the rest of the immune system • Increased numbers of Tregs have been detected in tumours and circulating in cancer patients
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• Reductions in circulating Treg numbers have been shown to occur with metronomic chemotherapy treatment • Most frequently used drug is Cyclophosphamide • Alkylating agent used in both MTD and metronomic protocols
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• Cancer stem cells have many unique properties • Metronomic chemotherapy can disrupt the CSC niche through anti-angiogenic effects • Direct cytotoxicity (minor)
IntechOpen 24 First work showing evidence for metronomic chemotherapy published in 2002 for human breast cancer Metronomic • First published studies in canine cancer chemotherapy (haemangiosarcoma and STS) published 2007
“The use of low-dose metronomic chemotherapy in dogs – an insight into a modern cancer field” Gaspar et al, VCO2017 Ellis
7 months on metronomic chemotherapy before having signs of PD effecting her quality of life • Using chemotherapy • Radiation • Pain management • Nutritional support
Palliative care • Radiation • Cure or shrink early stage cancer
• Stop cancer from reoccurring somewhere else ( lymph nodes, other organs such as lung brain) What are the • Treat symptoms caused by advanced cancer goals of RT? (pain, trouble swallowing or breathing, bowel blockage)
• Treat recurrent cancer • Internal Radiation Therapy (Brachytherapy) • Placement of a radioactive implant inside the body in or near the tumor. • Nasal tumors cutaneous SCC
Types of RT • Systemic Radiation Therapy • Radioactive are used to treat certain types of cancer systemically. • radioactive iodine, strontium, samarium, and radium. • Definitive therapy • Objective is long term local control • Higher total doses of radiation given over multiple (daily) fractions in smaller individual doses • More acute side effects while sparing late responding tissues Intention of • Goal is to limit late toxicity to critical structures • Radiation E.g. 2.5 Gy x 20 fractions = 50 Gy total • Mast cell tumors Therapy • Soft tissue sarcomas • Brain tumors • Spinal tumors • Thyroid tumors • Variety of carcinomas • Palliative therapy • Objective is to alleviate clinical signs associated with the tumor • Improve quality of life rather than long-term tumor control Intention of • Less intense treatment schedule – once weekly or daily for low total dose Radiation • Less acute side effects but higher risk of late effects Therapy • E.g. 8 Gy x 4 fractions = 32 Gy total • Osteosarcoma • Metastatic ASAC • Thyroid tumors • melanoma Mefodiy
• 6 yo Irish wolfhound cross male • Hx of lameness for 3 weeks • Swelling of the carpus Mefodiy
• Examination • Fairly unremarkable • Firm immobile mass left carpus moderate soft tissue swelling
• Diagnostics • CBC and Biochemistry – unremarkable- PF?? • Thoracic and abdominal CT Mefodiy Stereotactic radiosurgery for Tx of osteosarcomas in distal limb Farese JAVMA2004
11 dogs dose 20-30 Gy MST 363 days 4/11 pathological fracture 5.8 months after SRS
Outcome and complications in dogs with appendicular OSA Tx with SRT and concurrent stabilization Boston VS2017 18 dogs with SRT (1x30Gy or 3x12 Gy) had their tumor surgically stabilised complications in 16/17, 15 being major infections and fractures most common 9 dogs amputated at 152 days MST for all dogs 345 days Mefodiy
• Treatment
• Pamidronate 1 mg/kg IV once a month • Stereotactic radiation 3x • Carboplatin 300 mg/m2 IV Q 3weeks • Using chemotherapy • Radiation • Pain management • Nutritional support
Palliative care • Pain management Multimodal analgesia • Aims to block the pain pathways at multiple sites, using agents with different modes of action • More effective pain control ALPHA2 • Reduced prevalence of side effects AGONISTS OPIOIDS OPIOIDS KETAMINE ALPHA2
LOCAL ANAESTHETICS ALPHA 2 NSAIDS OPIOIDS • NSAIDs • Paracetamol • Opioids • Alpha 2 agonists • +/- Ketamine • Loco-regional block Severe acute pain Paracetamol
• Weak inhibitor of PGs synthesis (weak anti-inflammatory properties) • Analgesic and anti-pyretic effects • May act on cannabinoid receptors • Activates TRPV1 rec – responsible for central and peripheral pain transmission • Activates serotoninergic pathway • Inhibits nitric coxide and tumour necrosis factor ⍺ • Contraindicated in cats • Minimal side effects • No good evidence of effective dose, duration or analgesic effects Opioids • Oral, injectable, transdermal, transmucosal • Drugs availability • Methadone, morphine, fentanyl - full µ agonists • Buprenorphine - partial µ agonist • Butorphanol - µ antagonist and κ agonist • Methadone vs fentanyl • Duration of action (fentanyl < methadone) • Potency (fentanyl > methadone)
• Methadone vs morphine • Decreased incidence of vomiting • Decreased incidence of histamine release • Methadone 0.3 mg/kg IV or IM • NSAIDs • Paracetamol • Ketamine • Gabapentin • Amantadine • Codeine versus Tramadol
Chronic pain Gabapentin
• Neuronal Calcium channel inhibitor • Decrease release of excitatory neurotransmitters • 5-10 (10-20) mg/kg PO BID or TID • Neuropathic pain • Safely combined with other drugs • Main adverse effects are sedation and ataxia • Tend to improve over time Amantadine
• Dopamine agonist and NMDA receptor antagonist • Originally used as an antiviral agent • Chronic pain in particular with central sensitization • 3-5 mg/kg SID (may go up to BID) – may take up to 2 weeks to have an effect • Rare side effects • CNS stimulation at high doses (Avoid co-administration with serotonin reuptake inhibitors) • Vomiting and diarrhea Tramadol
Tramadol
•Noradrenaline reuptake inhibition •Serotonin reuptake inhibition •µ opioid receptor agonism (low affinity)
M1 metabolite (little production in dogs)
•µ opioid receptor agonism
Variability in efficacy (no good evidence of effect)
2-5 mg/kg PO BID
Side effects
•Sedation •Vomiting ad diarrhea • µ opioid agonist • In dogs: 4% oral bioavailability • negligent amount of morphine metabolite • Codeine 6 glucuronide may provide some analgesic effects • 1-2 mg/kg PO q 8-12 h Codeine
Oral/Skull SCC
• Monthly bisphosphonates infusion 1 mg/kg IV over 2 hours • Oral toceranib as metronomic chemotherapy • Oral NSAIDs Oral tablets (aledronate), IV infusions (pamidronate, zoledronate)
Used in humans to treat bone loss and osteoporosis Adjunctive • Inhibit ingestion of bone by osteoclasts therapies - Bisphosphonates Useful for bone metastasis – pain relief, strengthen bone • Not actual chemotherapy
Idiopathic hypercalcaemia in cats Certain tumour types have been shown to over-express COX receptors and so these tumours may be better treated with NSAIDs Palliation - Oral SCC, OSA , nasal carcinomas Pred vs. NSAIDs Endothelial cells Use of NSAIDs undergoing angiogenesis in metronomic often utilise COX pathways chemotherapy Prednisolone has some useful ‘side effects’ for cancer patients • Polyphagia Palliation - Useful for lymphoma and for diseases causing Pred vs. hypercalcaemia NSAIDs Useful for pulmonary metastatic disease that causes coughing à reduces clinical signs
Useful for peri-tumoural swelling of brain tumours Highly selective Receptor involved in mediation of pain caused antagonist of the EP4 by inflammation grapiprant receptor (PGE2) (specifically OA)
Does not affect other PGs receptors
Excellent safety profile
2 mg/kg PO SID • Use IV infusions (lidocaine, ketamine, dexmedetomidine, bisphosphonates) to treat Nonopiate neuropathic and cancer pain • The effects of the infusions outlast their Intravenous duration, often by weeks to months. Infusions • Lidocaine and ketamine have been studied most extensively in humans, with several randomized, placebo-controlled studies demonstrating superiority to placebo. • Lidocaine dose and duration of infusion typically HUMAN range from 1 to 5 mg/kg or higher, given over a MEDICINE period of time from 30 minutes to several hours. • A bolus of ketamine of 0.5 mg/kg or less is usually administered over less than an hour and may be followed by an infusion; however, ketamine may be administered daily for over a week in some cases. • Infusions of lidocaine, ketamine, and dexmedetomidine are commonly used in veterinary medicine for relief of acute pain.
• However, minimal data exist to support their use for relief of chronic pain, and they are used far less commonly for this purpose.
• Bisphosphonates like pamidronate are used in dogs with bone malignancies to Veterinary decrease pain by inhibiting osteoclast activity • ketamine and lidocaine infusions at doses similar to those used in humans. applications Patients are typically admitted as day cases. An IV catheter is placed, and the patient receives the infusion throughout the.
• Empirically, these infusions appear to be most effective against pain from primary bone tumors (eg, of the skull or mandible, appendicular skeleton, ribs, or vertebral bodies, which likely has both inflammatory and neuropathic components), although patients with extensive soft tissue tumors and other neuropathic pain generators also seem to respond. Blinded, randomized, placebo-controlled clinical trials are sorely needed. These infusions are relatively inexpensive and could be administered easily in a general practice setting. • A wide variety of toxins produced by animals or other organisms selectively modulate ion channels and receptors in pain pathways • Research into these substances has generated novel drugs used in humans to treat chronic pain • ziconotide (Prialt drug administered by Toxins intrathecal infusion for severe chronic pain, is the synthetic form of the conotoxin MVIIA, a peptide produced by a marine cone snail that selectively antagonizes the voltage-gated calcium channel, CaV2.2. • Botulinum toxin is also used to treat a wide variety of pain syndromes . • In 2 recent studies, intrathecal injection of resiniferatoxin (an agonist of the nonselective cation channel transient receptor potential vanilloid 1 found in the plant Euphorbia resinifera) and substance P-saporin (a conjugate Veterinary of the neurotransmitter, substance P, and the neurotoxin saporin) produced positive outcomes applications in dogs with naturally occurring pain from bone malignancy. • Intra-articular (IA) resiniferatoxin has also been shown to relieve osteoarthritis (OA) pain in dogs. • Theoretically, toxins could be used to relieve pain from a wide variety of other pain generators too, from other types of neoplasia • Using chemotherapy • Radiation • Pain management • Nutritional support
Palliative care • Nutrition • WEIGHT LOSS • Cats – most common oral tumour • Environmental factors •• Metastasis is rare - < 10% • Sublingual, mandible, maxilla • Local control difficult
Feline oral SCC • Surgery Complete margins are challenge Less tolerant mandibulectomy
• Radiation therapy • Palliative only • Multiple protocols e.g. 8 Gy x 4 weekly, 4.8 Gy x 10 daily
• Oral chemotherapy Toceranib phosphate • Enteral support Feline oral SCC • Feline SCC Enteral support Feline SCC • Enteral support Feline SCC • Enteral support • Mitazepine: ‘Happy • various appetite Palliative care drug’ Oral tablets stimulants— - appetite • Atypical anti-depressant megestrol, dronabinol ( with serotonergic activity Marinol), cyproheptadine Mirtazepine • Serotonin syndrome? (Periactin), thalidomide (Thalomid), • We use it as an appetite pentoxifylline stimulant (Pentoxil/Trental), • Dosage varies (empirical) nandrolone decanoate • Once daily for 3 days (DecaDurabolin), in dogs • oxandrolone (Oxandrin • Once every 2 days in and corticosteroids cats
66 • Cancer-related or chemotherapy- related (can we tell the difference?) nausea and vomiting 67 • Drooling/hypersalivation • Excessive swallowing • Inappetance • Vomiting vs. regurgitation (prodromal signs) • Approximately 10-20% of veterinary oncology patients suffer from nausea
Palliative care - appetite • • • ABSTRACT • In palliative care, drugs are considered futile if they do not have a short-term benefit in symptom control or quality of life. The authors examined pharmacotherapy prescribed for patients referred to palliative care to identify futile drugs. This was a retrospective analysis of patients referred over 6 months, focusing on the prescription of gastric protectants, antidiabetic agents, bisphosphonates, anticoagulants, antidementia drugs, statins, and antihypertensive agents. The sample consisted of 448 patients. Gastric protectants were Palliative care prescribed futilely in 50% of cases (125/248), statins in 97% (69/71), antihypertensive agents in 27% (42/155), antidiabetic drugs in 1% (1/70), bisphosphonates in 27% (4/15), and antidementia drugs in 100% (9/9). This study reveals that many patients with advanced cancer continue to be treated with inappropriate drugs and points to the need for medical training in palliative care, drawing attention to the need for therapeutic review at each medical visit. Oral tablets and injectable (SC/IV) Approved for dogs and cats Once daily treatment (by either route) Neurokinin (NK1) receptor antagonist à •Works in the brain Blocks substance P Dosages: 1mg/kg SC/IV or 2-4mg/kg PO Higher if used for travel sickness New studies show no need to give a ‘break’ Maropitant Oral tablets/wafers and injectable (IV/IM) Human medication: Dogs and cats Created specifically for chemo/RT induced nausea in people Serotonin (5-HT) receptor antagonist Drug interactions? Dosages: 0.1-1mg/kg PO/IV/IM BID• Really variable reported range and only 2 oral sizes
Ondansentron Oral tablets and injectable (IV) • Human medication: Dogs, cats, horses Proton pump inhibitor Decreases gastric acid secretion Ulcers Dosage: 0.5-1mg/kg PO/IV Do not split tablets Round up Omeprazole- GI protectant Oral tablets Creates a physical barrier by binding to exposed gastric/oesophageal mucosa Oesophagitis – given as a slurry Gastric ulcers – given as a tablet Dosage – 250mg-1000mg (¼-1 tablet) Sucralfate- GI protectant BID/TID
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