Veterinary Chemotherapy: Past Paper 2024 PDF

Cancer and chemotherapy in veterinary medicine How to give chemotherapy without harming your patient Nick Bacon MA VetMB CertVR CertSAS DiplECVS DACVS FRCVS ACVS Founding Fellow, Surgical Oncology RCVS Specialist (Surgical Oncology) Clinical Director...

Cancer and chemotherapy in veterinary medicine How to give chemotherapy without harming your patient Nick Bacon MA VetMB CertVR CertSAS DiplECVS DACVS FRCVS ACVS Founding Fellow, Surgical Oncology RCVS Specialist (Surgical Oncology) Clinical Director, AURA Veterinary Professor, Surgical Oncology, University of Surrey www.auravet.com What is chemotherapy (cytotoxic drug therapy) and when is it indicated? Rationale behind drug doses and administration schedules Factors affecting success of therapy Adverse effects Mechanism of action / indications for specific drugs  2003 ECVIM – 1987 ACVIM – Oncology Oncology specialty specialty Veterinary vs human chemotherapy Similar but not the same! Same drugs but smaller doses Less intense schedules Palliation /control rather than cure Lack of intensive facilities for management of complications Aim to prolong life, but QoL is paramount Discuss all options/ factors at outset….  Quality of life + Disease Tx Reaching this objective is our responsibility as clinicians Establish a tailored treatment plan for the patient – There is no single size in cancer treatment! Good communication with owners is vital ❑ WHAT IS CHEMOTHERAPY AND WHEN IS IT INDICATED? The treatment of disease by the use of chemical substances, especially the treatment of cancer by Efficacy cytotoxic and other drugs Toxicity Cytotoxic Cytostatic Many cancer drugs aim to kill cancer cells. The word cytotoxic means toxic to cells, or cell killing. So MTD chemotherapy is cytotoxic therapy. Other treatments do not aim to kill cancer cells. They work by stopping the cancer cells from multiplying. So they stop the cancer growing. This is cytostatic therapy. Cytostatic means 'cell stopping‘ (e.g. Metronomic chemotherapy)  How do cytotoxic drugs work?? Cytotoxic drugs interfere with cell growth or division Some act at specific stages of the cell cycle Some are cell cycle non-specific Mitosis Differentiation 2% M G0 Most drugs work best on Resting actively dividing cells… Synthesis of Tumours with a high components G2 G1 Synthesis of for mitosis cellular mitotic index are more 19% components for DNA likely to be sensitive synthesis 40% S Cells in G0 (resting) are Replication of relatively resistant DNA genome 39% Chemotherapy targets rapidly dividing cells Cancer cells are not the Not all cells in a only replicating cells tumour are replicating BM suppression Lack of effectiveness GI adverse effects Mechanism of action Affects tissues with high mitotic rates Tumoral response to CMTX Adverse effects in normal tissue > mitosis > chemosensitivity Myelosupression GI Toxicity We should combine drugs that act on different phases of the cell cycle Rationale behind timing of treatment, drug dosing and treatment regimes Timing of Treatment - Tumour growth Best time to treat with chemotherapy Cell Plateau phase of growth no. 109 Limit of clinical detection 106 103 Log phase of growth Time Timing of treatment… Treat as early as possible in the disease course! (Unlikely to be effective in bulky, end stage disease…) Following surgery…(Micrometastatic disease / microscopic residual disease) Start treatment as soon as the surgical wound has healed! The case for neoadjuvant (primary) chemotherapy Neoadjuvant = prior to de nitive surgery Often the standard of care in people with STS Conversion of tumour pseudocapsule into a thick, collagenised capsule with no viable tumour cells (documented in people) A better de ned tumour which is more amenable to complete histologic excision Complicated by retrospective data and the use of non- randomised historical controls fi fi Pseudocapsule Reactive zone Muscle Tumour Satellite tumour Skip metastasis Can the “pseudocapsule” be sterilised? Successful Treatment of High Grade Soft Tissue Sarcoma with Induction Chemotherapy: Clinicopathological Analysis of Thick Capsule Formation Allowing Less Extensive SECTION 111 "Marginal" Surgical Resection. BASIC SCIENCE AND PATHOLOGY Sub-category: Sarcoma Characterization of the Pseudocapsule Category: Sarcoma of Soft-Tissue Sarcomas Meeting: An Experimental Study in Rats 2001 ASCO Annual Meeting STEVEN M.D.,* RICHARD GITELIS, THOMAS, M.D.,** ALEXANDERTEMPLETON, M.D.,* Abstract No: A N D FRITZ M.D.*,t SCHAJOWICZ, 2912 Citation: The irradiated animals showed marked thickening of the capsular structure Proc Am Soc The surrounding Clineffect Oncol the ofsarcoma. preoperative radiation 20: 2001 (abstr therapy on the 2912) The nonirradiated tissue sarcoma^.^.^ animals showedMore specifically, a minimalcom- pseudocapsular pseudocapsule of experimental rat soft-tissue sar- bining radiation and surgery with limb pres- structurecomas with a characteristic tumor has not been histologically evaluated in a penetration. Irradiation produced distinct Author(s): histologic changes controlled study.in The the pseudocapsule. irradiated animal showed ervation is a popular treatment pro- Felasfa M. Wodajo, marked James thickeningWittig, of the Dhruv capsularKumar, structureDennis sur- gram.2,6,8-10. Priebat, Robert 5 sHenshaw, 12.14. IM. everal authors Martinhave M. Malawer, Washington rounding the sarcoma. Everywhere morphologi- advocated the use of preoperative Cancer Institute, Washington Hospital Center, Washington, DC; Department Pathology, Washington Hospital Center,radiation cally distinct from the tumor, there was no evi- Washington, DC. and have suggested that the pseudocapsule A bit less A bit more this…. this…  Dosing of cytotoxic drugs... Use at the maximum tolerated dose highest fractional kill with each Normal treatment tissue (But avoid adverse effects!) Multiple doses are required Pulse dosing at intervals Allow normal tissues to recover between doses But don’t allow tumour to regrow Tumour cell no. Time   Combination chemotherapy More likely to be effective than single agent – less selection pressure Use drugs which: Are known to be effective as single agent Have different modes of action and don’t interfere with each other Act at different stages of the cell cycle Don’t have overlapping toxicities  Stages of Chemotherapy Induction Initial treatment protocol, fairly intense Aim to induce remission (i.e. state where tumour is not clinically detectable) Maintenance – only in some protocols Follows induction, less intense Aim to maintain remission Re-induction When tumour relapses Return to initial protocol - Aim to re-induce remission Rescue When tumour becomes resistant to current therapy Use different drugs that tumour has not been exposed to before with different mechanism of action Dosing Dog or cat? (m2 vs. mg/kg) Size and body score – Small dogs Doxorubicin mg/kg – Obesity: over dosage risk!!! Breed – MDR1 mutation: Doxo and vincristine – Collies, Shelties, border collies, Australian shepherds, long hair whippet – Mutation Test: Giessen University (blood) Factors affecting the success of chemotherapy Tumour cell type Intrinsic resistance e.g. many carcinomas, melanoma Drug distribution Blood supply Barriers to diffusion Development of resistance Tumours are genetically unstable Drugs selection of resistant cell types  Development of resistance Many mechanisms… Multi-drug resistance MDR1 upregulation Pgp efflux pump Doxorubicin and vinca alkaloids are pumped out Glucocorticoids cause MDR1 upregulation  How do we chose the chemotherapeutic protocol Drug combination Specific anticancer activity Different mechanism of action No overlapping toxicities Dose intensity (mg/m2/week) “maximum tolerated dose without significant toxicity” How do we chose the chemotherapeutic protocol Disease – Disease extension (stage) CURATIVE – Presentation INTENT Patient PALLIATIVE – Clinical status INTENT – Concurrent diseases – Individual characteristics Owner – Expectations and feelings – Understanding of disease and treatment – Economic factors – Time availability – Others Chemotherapy - Indications Systemic neoplasms or highly chemosensitive (e.g. lymphoma, TVT) TVT o TVT CURATIVE INTENT Chemotherapy - Indications Adjuvant chemotherapy – Delay/eliminate microscopic metastasis – Delay/avoid recurrence after incomplete surgical margins – Examples: OSA, HSA, high grade STS or CARCINOMAS, grade III MCT or grade II MCT with high mitotic index.  Osteosarcoma Treatment of micrometastatic disease Haemangiosarcoma – To treat micrometastatic disease In some tumours, following incomplete resection (but also consider radiation) CURATIVE INTENT Chemotherapy - Indications Neoadjuvant chemotherapy – Volume reduction that allows surgical resection (chemosensitive neoplasms) – Should NOT be used when surgery or radiation is a more effective alternative!! CURATIVE INTENT PALLIATIVE INTENT Day 1 Day 90 Day 120 Chemotherapy - Indications Palliative Not indicated when: There is an alternative more effective Tx Neoplasms not sensitive to CMTX Metabolic systems are impaired Routes of administration Oral IV SC Intra-cavitary Intra-lesional IA Oral chemotherapy >>>>>> Tissue damage!! Drug Volume Days-weeks Pruritus, erythema, dermatitis, ulceration, necrosis Clinical signs: Symptomatic Tx Immediate Tx – Corticosteroids+ topical AI – Vincristine: hot packing hyaluronidase – Doxorubicin: cold packing DMSO dexrazoxane  Intra-arterial chemotherapy Standard chemotherapy is delivered via a peripheral vein Cytotoxic agent circulates via heart and lungs before reaching the arterial supply of the tumour Why not deliver chemotherapy to the arterial supply of the tumour ? Increases efficacy by delivering high concentrations at target site Reduces exposure of healthy tissue to the chemotherapy Reduced side effects such as nausea and vomiting Courtesy Gerard McLachlan, AURA  Access via carotid or femoral artery Fluoroscopic guidance allows super-selection of the artery supplying the tumour Intracavitary chemotherapy Indications – Malignant effusions – Mesotheliomas, carcinomatosis Drugs – 5-Fluoruracil, carboplatin, mitoxantrone Management – Permanent pleural/abdominal catheters Advantages – Improvement quality of life – Less toxicity and complications – Effusion drainage and QMTX administration Adverse effects: Prevention and management Drug Dosage/Doses Individual Factors: MDR1 Renal/hepatic systems Clinical condition  75 – 120 days Haematologic toxicity 7 – 10 days Hours to 2 days Neutropenia / thrombocytopenia Neutrophil nadir 7d (5-10d) carboplatin 10-14d! Nadir PLT 10-14d Melphalan, lomustine cumulative toxicity CBC at nadir Very important especially first Tx’s when dosage decrease is performed after neutropenia Neutropaenia Neutrophil count usually is back to normal in 2-3 d Consider dosage reduction –if neutrophil count frequency @ high doses Tx: metoclopramide CRI ranitidine, cisapride, erythromycin Plan Dose change Discontinuation Vinblastine Nausea/Vomiting Plan ?? Prophylactic administration of anti-emetic drugs –Actinomycin, cisplatin, doxorubicin Prophylaxis post administration Management and preventive plan before next Tx AntiemeticTherapy Ondansetron Metoclopramide Maropitant Anorexia Aetiology: nausea, abdominal pain Appetite stimulants –cyproheptadine Cardiotoxicity Doxorubicin Cardiac myocytes more sensitive to free radical damage Decrease contractibility DCM >180mg/m2 in healthy hearts –That is 6 doxo doses! Toxicity dependent of concentration peak in blood –Infusion administration 20-30 min Cardiotoxicity Monitoring cardiac toxicity: Echocardiography…when? Arrhythmias / cardiac murmurs Breed DCM predisposition If more than 5-6 doses If shortening fraction is sub-optimal? Alternative drugs Cardioprotectors? Discontinue Tx? Urinary system toxicity Sterile cystitis Prevalence 10%: cyclophosphamide – High doses in one time – Long term oral treatment at lower doses – Small dogs?? Prevention – High doses: split dose in 2 to 4 parts (am/pm/48hr) – Furosemide – Do not continue long term oral Tx (except if 15mg/m2 PO EOD) Urinary system toxicity Sterile cystitis Prognosis Clinical signs persist weeks to months Irreversible if mark fibrosis occurs Treatment Discontinue cyclophosphamide!! Rule out urinary tract infection Symptomatic Tx: –AINEs –Oxybutynin –DMSO (severe) –Formalin Urinary system toxicity Nephrotoxicity Cisplatin Alternative: Carboplatin – Reduce dose with CRF Lomustine (cats) Hepatotoxicity Lomustine 7% prevalence liver failure in dogs Approx 50% have high ALT; 29% 5 fold upper ref limit Monitoring liver enzymes pre-treatment needed –Might change dose / frequency Unpredictable Chose dose and interval according with case scenario Hypersensitivity Asparaginase Skin reaction, facial oedema, hyperthermia Prevention (when more than one dose given) –Antihistamines –Corticosteroids Don’t give it again! Symptomatic Tx –IV Fluids, corticoids, cooling down patient Doxorubicin Mast cell degranulation –Slow infusion –Prophylactic antihistamines Alopecia/hyperpigmentation Doxorubicin Hyperpigmentation and facial alopecia =racoon’s face! Breeds Poodles, Terriers, Old English sheepdogs Cats: whisker loss Reversible after Tx discontinuation Drug extravasation Prevention d catheter Cleanly-placen Firmly taped iline Flush with sa Treatment Try aspiration of drug Vincristine – hot compresses, hyaluronidase Doxorubicin – ice, dexrazoxane Feline Toxicity Cisplatin Fatal pulmonary edema Carboplatin 5-Flurouracil Fatal Neurotoxicity (even if topical) Handling cytotoxic drugs Safety for veterinary staff Staff training!!!! Disposable gown Disposable gloves for chemotherapy Mask/visor – absence of closed system Treatment area Quiet, isolated, low traffic Identify patients treated with chemotherapy Protocol for handling patient’s waste Handling cytotoxic drugs Instructions for owners/ vet staff Special risk for pregnant women Carcinogenic Mutagenic Teratogenic Handling waste –48 hrs –Use gloves (hope you always do anyway!) Disposal of chemotherapy contaminated material  Any questions? www.auravet.com