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Dr G Srinivasan Locum Cons Oncologist Broomfield Hospital Chelmsford.

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Presentation on theme: "Dr G Srinivasan Locum Cons Oncologist Broomfield Hospital Chelmsford."— Presentation transcript:

1 Dr G Srinivasan Locum Cons Oncologist Broomfield Hospital Chelmsford

2 From inability to let well alone; from too much zeal for the new and contempt for what is old; from putting knowledge before wisdom, science before art, and cleverness before common sense; from treating patients as cases; and from making the cure of the disease more grievous than the endurance of the same, Good Lord, deliver us. Sir Robert Hutchison MD FRCP ( )

3 Paul Ehrlich Nobel Prize 1908, Medicine & Physiology Father of Chemotherapy

4 Serendipity Chemical warfare - World War I 2 nd December German bombers – attacked 27 Allied ships in Bari Harbour ‘John Harvey’ shells of mustard gas Louis Goodman & Alfred Gilman – injected Nitrogen mustard into patient with Hodgkin’s Lymphoma Serendipity

5 Adapted from History of Cancer Chemotherapy, Cancer Research Nov , 68, 8643

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7 Cancer treatment Surgery Radiotherapy Chemotherapy Targeted therapy Gene therapy Vaccine/ Immune therapy Hormonal therapy

8 Purpose of Chemotherapy treatment Cure cancers - Testicular cancers, Lymphomas, choriocarcinoma Improve chances of cure - Adjuvant - Neoadjuvant Palliation

9 Chemotherapeutic agents Alkylating agents – cross-linking of DNA strands Polyfunctional – cyclophosphamide, melphalan, chlorambucil, Busulphan, Thiotepa, Busulfan, Nitrosoureas Others – Cisplatin, Carboplatin, Oxaliplatin, Procarbazine, Darcarbazine, Temozolomide, Ifosfamide Anti-metabolites Purine antagonists – 6 MP, 6 TG, Fludarabine Pyrimidine antagonists – 5 FU, Cytarabine, Gemcitabine, Capecitabine, methotrexate, pemetrexed

10 Antibiotics Anthracyclines – Doxorubicin, Epirubicin, Daunorubicin, Idarubicin Plicamycin, Mithramycin, Bleomycin Taxanes – Paclitaxel, Docetaxel, Abraxane Vinca alkaloids – Vincristine, Vinblastine, Vinorelbine, Vindesine, Vinflunine Topoisomerase inhibitors Type 1 – Irinotecan, Topotecan Type 2 – Etoposide (derived from podophyllin)

11 ‘ Reversible Toxicity ‘ Affect rapidly dividing cells Bone marrrow GI Tract Germinal epithelium Lymphoid tissue Hair follicles

12 ‘ Irreversible Toxicity’ Target slow growing cells cumulative kidneys heart lungs

13 Therapeutic Index Toxic Dose ₅₀ Effective Dose ₅₀

14 Acute/ Sub acute complications Administration Extravasation Vesicant - Pain, burning, erythema, blistering, necrosis, ulceration/ plastic surgery Anthracyclines, Vinca alkaloids, alkylating agents, Taxanes Irritants – pain, hyperpigmentation, phlebitis Carboplatin, Gemcitabine, Melphalan, Irinotecan, Bleomycin

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16 Management Prevention To be given within 6 hours – day 1, 2 and 3 ( £7000) Quick recognition – stop infusion Dexrazoxane (Savene) – originally used to prevent cardiotoxicity of anthracyclines Fe + anthracyclines → Oxygen free radicals Cold packs Hyaluronidase infiltration - Vinca alkaloids, taxanes Dimethyl sulfoxide (DMSO) – topical solvent

17 Assessment of Veins Recognise need for central lines – PICC, Hickman, Portacath National Extravasation Information Service, St Chad’s Unit, City Hospital, Birmingham Goolsby TV, Lombardo EA (2006) Extravasation of chemotherapeutic agents: Prevention and treatment. Semin.Oncol. 33, Over compliance

18 Chemotherapy Induced Nausea & Vomiting Vomiting Centre Chemoreceptor Trigger Zone (CTZ) / Area Postrema (base of IV ventricle) Outside blood brain barrier Receptors – Dopamine D2, serotonin 5 HT-3, opioid, acetylcholine, Subst P CINV Acute emesis - < 24 hours Delayed emesis - > 24 hours Anticipatory emesis – before chemotherapy

19 Emetogenic potential High ModerateLowMinimal cisplatin cyclophosphamide Procarbazine Alkylating agents Oxaliplatin Carboplatin Ifosfamide anthracycline Temozolamide Imatinib Gemcitabine Taxanes 5 FU Capecitabine Antifolates Vinca alkaloids Monoclonal Ab CINV > 90 %30 – 90 %10-30% < 10%

20 Management of CINV Anti emetics 5 HT3 antagonists – Ondansetron, granisetron, Palanosetron Dopamine antagonists – Metaclopramide, Domperidone, Haloperidol, chlorpromazine Prochlorperazine – Buccastem, Stemetil, Cyclizine Anti histamines – H1 receptor blockers - Cyclizine NK1 antagonists - Aprepitant Benzodiazepines – Lorazepam (anticipatory emesis) Corticosteroids Ginger, alternate therapies

21 High emetogenic - Steroids + 5 HT3 antogonists + Aprepitant Moderate - 5 HT3 antagonists + steroids Low - Steorids As and when required – Dopamine antagonists Refractory vomiting - s/c infusion via syringe drivers, hydration CINV

22 Beware of other causes of emesis Bowel obstruction Constipation Radiotherapy

23 Hypersenstivity to Chemotherapy Not uncommon Oxaliplatin/ Carboplatin - Type 1 reaction Severe anaphylaxis rare Taxanes - 1 st dose hypersensitivity Facilities for treatment of anaphylaxis Pretreatment with corticosteroids, antihistamine – standard protocol ? rechallenge Monoclonal Ab - Murine, Chimeric vs Humanised Cholinergic Syndrome – Irinotecan – flushes, sweating, diarrhoea Atropine as pre-medication Oesophageal- pharyngeal synd – Oxaliplatin – avoid cold drinks Paclitaxel – cremaphore ethanol

24 Tumour Lysis Syndrome Uncommon Bulky tumour High sensitivity to chemotherapy Escape of large amount of cellular components into circulation ↑ urea, ↑K, ↑ PO4, ↓ Ca Renal failure, arrythmias, hypotension, seizures, death Beware – adequate hydration/ urine output, steroids, allopurinol, Uric acid Urate oxidase Rasburicase Allantoin Biochemical vs Clinical

25 Flu like syndrome Fever, malaise, headaches, chills, myalgia, arthralgia Interferons, interleukins Monoclonal Ab Colony stimulating factor chemotherapy

26 Haematological toxicity Marrow suppression - cytotoxic Depends on Drugs – single agent / combination Dose Schedule - eg., 14 day CHOP vs 21 day CHOP Patient factor – bone mets, radiation, age, previous chemotherapy, 3 rd space collections

27 Neutropenia Febrile (Temp > 37.5 C) + neutropenia Neutropenic Sepsis – vasodilation, hypotension, end organ failure < 1.5 x 10⁹/ L Low risk Fit patient, no extremes of age Regime not very marrow suppressive Neutropenia not expected to be prolonged No systemic symptoms Someone at home, access to telephone, hospital High risk Myelotoxic regimes – eg., lymphoma, leukaemia Immunosuppression – HIV,

28 Awareness and Access Patient / staff education 24/7 access to specialist care, Acute Oncology Service Oral antibiotics – Ciprofloxacin 750 mg bd + Co-amoxiclav 625 mg tds x 7 days Clarithromycin if allergic to Penicillin Admission – do not wait for investigation result Piperacillin IV 4.5 g tds + Gentamicin 6mg/Kg loading dose hrs, if afebrile 24 hrs more followed by oral AntiBx for 5 days Teicoplanin if allergic to Penicillin Consider removing central line if fever does not subside in hrs Consider Teicoplanin, antifungals Follow local protocols, microbiology advice

29 Serum lactate Blood culture peripheral + central line Neutropenic Sepsis – consider ITU/ HDU – fluids, O₂, monitoring G-CSF Profound ( 10 days) neutropenia Sepsis, organ failure Fungal infection Elderly, frail Post neutropenic scenario Dose reduction – palliative chemTx GCSF secondary prophylaxis in curative, adjuvant regime Primary GCSF prophylaxis Lenogastrim, filgastrim, Pegylated GCSF –long acting

30 Role for Prophylactic AntiBx Significant Trial - Quniolone AntiBx vs Placebo – small but definite role Prophylactic Septrin – for lymphomas Anaemia Red cell transfusions – to improve quality of life Erythropoietin – not routinely recommended, under NICE review Thrombocytopaenia – Platinum compounds, bone marrow infiltration

31 Mucositis Stomatitis Could be isolated or part of neutropenia Head & Neck radiotherapy Meticulous oral hygeine, rinses, anti thrush, analgesics Diarrhoea Flouropyrimidines, Irinotecan, small molecule targeted agents Sunitinib, Sorefanib, Erlotinib, Gefitinib Hydration, loperamide, severe cases Octreotide infusion Dihydropyrimidine dehyrdrogenase (DPD) deficiency ~ 5 % of Caucasians

32 Alopecia Scalp hair loss Scalp cooling, wigs Skin toxicity Palmar- plantar erythrodysaesthesia (PPE) Capecitabine, Caelyx All Tyrosine kinase inhibitors – acneiform rash

33 Cardiac Toxicity Anthracyclines Doxorubicin – breast, lymphomas, small cell lung ca, sarcomas Congestive cardiomyopathy – few months to few years Cumulative dose Upto 450 mg/m² - rare 550 mg/ m² - 7% 600 mg/ m² - 15% 700 mg / m² - 30% Prior heart disease, chest radiation, age extremes, young women, HT Pre chemo cardiac evaluation – Echo, MUGA Counsel/ consent Dexrazoxane Liposomal anthracyclines

34 Endothelial damage with Cisplatin – Testicular cancers HT – increased risk for CVS related mortality Trastuzumab (Herceptin) Know cardiac toxicity Avoid using with anthracyclines Monitor 3 monthly Echo/ MUGA Reversible Long term effects unknown Sunitinib, Bevacizumab (VEGF inhibitors) HT, vascular thromboses,

35 Pulmonary Toxicity Acute pneumonitis Pulmonary fibrosis Hypersensitivity pneumonitis Non-cardiogenic pulmonary oedema Bleomycin, Busulphan, methotrexate, gemcitabine Lung function tests CXR Diff Dx – bacterial infections, PE, pneumocystis carinii Role of corticosteroids Influence of RadioTx

36 Neurological toxicity Peripheral neuropathy Cisplatin, Oxaliplatin, Taxanes, Vinca alkaloids Cerebellar syndrome 5- FU Acute encephalopathy (ifosphamide) cranial nerve palsies, autonomic disturbance ? Increase in Strokes – VEGF inhibitors and HT

37 Cancer patient vs Cancer Survivor 58% of long term survivors of childhood cancer suffer one ongoing medical problem; 32% have two or more 41% Endocrine disorder 26% organ toxicity 17% impaired mobility 15% Neuropsychological 14% infertility 13% Sensory deficits 10% Cosmetic problems ( Stevens et al, Eur J Cancer, 1998 ) Second cancers Gonadal dysfunction

38 Hormonal Therapies Breast cancer Tamoxifen – (SERM) - hot flushes, thrombosis, ↑endometrial cancers, visual problems Fulvestrant (ER antagonist) Anastrazole Letrozole (Non steroidal aromatase inhibitor) - arthralgia, osteoporosis Exemestane (steroidal AI) LHRH agonist implants

39 Prostate cancer LHRH agonist - Goserelin, Leuprorelin, Triptorelin - hot flushes, sweating, mood swings, fatigue, osteoporosis Bicalutamide - Non steroidal anti androgens - Gynaecomastia, liver dysfn Flutamide Cyproterone acetate – Steroidal antiandrogen Diethylstilboesterol - fluid retention, heart problems, thrombosis Corticosteroids Abiraterone (CYP 17 inhibitor) LHRH antagonists – Degrelix, abarelix Bisphosphonates – Gastritis, atrial fi

40 Nephro toxcity Cisplatin Assess Renal function including GFR Carboplatin- less nephrotoxic EDTA, 24 hour Creatinine clearance Cockcroft- Gault formula Crcl = F x (140- age in yrs) x weight (kg) Serum Creatinine (mmol/L) F = 1.04 (females); 1.23 (males) (GFR) Calvert’s formulaDose (mg) = desired AUC x (GFR + 25) AUC – Area under the curve AUC 8 for adjuvant Germ cell tumours Usually 5 or 6 (also Ototoxcity)

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42 Small molecules Antibodies Vaccines Targeted Therapies Gene therapy Hormonal therapy Blood cell growth factors Cytokines

43 Type Monoclonal Antibodies MurineMouse - omab Chimeric 65-90% human Rest murine - ximab Humanised 95% human 5% murine - zumab Human - umab Cetuximab, Rituximab, infliximab Tositumomab (Bexxar) Trastuzumab, bevacizumab Denosumab, Panitumumab OriginNomenclatureExample

44 Tyrosine Kinase Inhibitors (TKI’s) Vandetanib (Caprelsa) Axitinib (Inlyta) Crizotinib (Xalkori) Dasatinib (Sprycel) Erlotinib (Tarceva) Gefitinib (Iressa) Imatinib (Gleevec) Lapatinib (Tykerb) Nilotinib (Tasigna) Pazopanib (Votrient™) Ruxolitinib (Jakafi™) Sorafenib (Nexavar) Sunitinib (Sutent)

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46 Adapted from Annals of Oncology

47 mTOR Inhibitors Mammalian Target of Rapamaycin Rapamycin and Rapalogues Temsirolimus Everolimus Hyperglycemia – due to ↑ gluconeogenesis ↓ peripheral gluc uptake Dyslipidemia Lung injury, mucositis, rash

48 Big side effect £££ Cetuximab – 8 wks - £20,000 Ipilimumab for melanoma - £ 20,000 per dose x 4 Cancer Drug Fund NICE

49 Chemotherapy | National Cancer Action Team The National Cancer Action Team are leading a number of work streams to ensure that the recommendations of the NCAG report and the Cancer Reform... Doctors 'rely on chemo too much' BBC News Doctors are being urged to re-think their approach to giving chemotherapy during care at the end of life. A review of 600 cancer patients who died within 30 days of treatment found that in more than a quarter of cases it actually hastened or caused death. The report by the National Confidential Enquiry into Patient Outcome and Death said doctors should consider reducing doses or not using chemotherapy at all. Some 80,000 patients undergo chemotherapy each year This report provides very disturbing information about the safety of treatment for incurable cancer Professor Jane Maher, of Macmillan Cancer Support This report provides very disturbing information about the safety of treatment for incurable cancer Professor Jane Maher, of Macmillan Cancer Support This report provides very disturbing information about the safety of treatment for incurable cancer Professor Jane Maher, of Macmillan Cancer Support Professor Jane Maher, chief medical officer at Macmillan Cancer Support, said: "This report provides very disturbing information about the safety of treatment for incurable cancer.

50 Chemotherapy units 'stretched to the limit' Cancer patients face the prospect of longer waits for chemotherapy because units are being “stretched to the limit” by ever-increasing demand, say specialists. Daily Telegraph, 7 th July 2013 Cancer waiting times Breach Patient / relatives demands Targets Also, patients or their families may demand chemotherapy regardless of the patient's prognosis,

51 Oncologist

52 70 yr man Cancer ascending colon – R hemicolectomy Multiple liver metastases – Mar 2013 Current Rx – Palliative Oxaliplatin/ Capecitabine/ Bevacizumab Name the main side effect from Oxaliplatin The man complains of profuse diarrhoea – what could be responsible? Which agent is the targeted RX? What does it target? What will you monitor? He develops a massive PE – what could be responsible?

53 This man’s liver metastases progresses. He is KRAS wild type You commence him on a combination of Irinotecan/ infusional 5 FU/ Cetuximab What drug would you give as pre treatment before Irinotecan? Patient seeks advice for extensive skin rash/ acne – which agent is responsible?

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55 Summary Cancer treatment is advancing rapidly More patients and elderly patients are being treated Cancer incidence and people diagnosed with it is increasing Long term survival seen in some tumour types More and more combination treatments More and unique side effects Long term consequences of cancer therapy

56 Thank you


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