Targeted Therapies

Report
Dr G Srinivasan
Locum Cons Oncologist
Broomfield Hospital
Chelmsford
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 (1871-1960)
Paul Ehrlich
1854-1915
Nobel Prize 1908, Medicine &
Physiology
Father of Chemotherapy
Chemical warfare - World War I
2nd December 1943
105 German bombers – attacked 27 Allied ships in Bari Harbour
‘John Harvey’ - 2000 shells of mustard gas
Louis Goodman & Alfred Gilman – injected Nitrogen mustard
into patient with Hodgkin’s Lymphoma- 1942
Serendipity
Serendipity
Adapted from History of Cancer Chemotherapy, Cancer Research Nov 1 2008, 68, 8643
Adapted from History of Cancer Chemotherapy, Cancer Research Nov 1 2008, 68, 8643
Radiotherapy
Chemotherapy
Surgery
Cancer treatment
Targeted therapy
Gene therapy
Hormonal therapy
Vaccine/ Immune therapy
Purpose of Chemotherapy treatment
Cure cancers - Testicular cancers, Lymphomas, choriocarcinoma
Improve chances of cure
- Adjuvant
- Neoadjuvant
Palliation
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
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)
‘ Reversible Toxicity ‘
Affect rapidly dividing cells
Bone marrrow
GI Tract
Germinal epithelium
Lymphoid tissue
Hair follicles
‘ Irreversible Toxicity’
Target slow growing cells
cumulative
kidneys
heart
lungs
Therapeutic Index
Toxic Dose ₅₀
Effective Dose ₅₀
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
Management
Prevention
Quick recognition – stop infusion
Cold packs
Dexrazoxane (Savene) – originally used to prevent cardiotoxicity of
anthracyclines
Fe + anthracyclines → Oxygen free radicals
To be given within 6 hours – day 1, 2 and 3 ( £7000)
Hyaluronidase infiltration - Vinca alkaloids, taxanes
Dimethyl sulfoxide (DMSO) – topical solvent
Assessment of Veins
Recognise need for central lines – PICC, Hickman, Portacath
National Extravasation Information Service, St Chad’s Unit, City Hospital, Birmingham
www.extravasation.org.uk
Goolsby TV, Lombardo EA (2006) Extravasation of chemotherapeutic agents:
Prevention and treatment. Semin.Oncol. 33, 139-43
Over compliance
Chemotherapy Induced Nausea & Vomiting
CINV
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
Acute emesis - < 24 hours
Delayed emesis - > 24 hours
Anticipatory emesis – before chemotherapy
CINV
Emetogenic potential
High
Moderate
> 90 %
30 – 90 %
Alkylating agents
cisplatin
cyclophosphamide
Procarbazine
Oxaliplatin
Carboplatin
Ifosfamide
anthracycline
Temozolamide
Imatinib
Low
10-30%
Gemcitabine
Taxanes
5 FU
Capecitabine
Antifolates
Minimal
< 10%
Vinca alkaloids
Monoclonal Ab
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
CINV
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
Beware of other causes of emesis
Bowel obstruction
Constipation
Radiotherapy
Hypersenstivity to Chemotherapy
Not uncommon
Oxaliplatin/ Carboplatin - Type 1 reaction
Severe anaphylaxis rare
Taxanes - 1st dose hypersensitivity
Paclitaxel – cremaphore ethanol
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
Tumour Lysis Syndrome
Uncommon
Bulky tumour
High sensitivity to chemotherapy
Escape of large amount of cellular components into circulation
↑ urea, ↑K, ↑ PO4, ↓ Ca
Biochemical vs Clinical
Renal failure, arrythmias, hypotension, seizures, death
Beware – adequate hydration/ urine output, steroids, allopurinol,
Uric acid
Urate oxidase
Rasburicase
Allantoin
Flu like syndrome
Fever, malaise, headaches, chills, myalgia, arthralgia
Interferons, interleukins
Monoclonal Ab
Colony stimulating factor
chemotherapy
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,
3rd space collections
Neutropenia
< 1.5 x 10⁹/ L
Febrile (Temp > 37.5 C) + neutropenia
Neutropenic Sepsis – vasodilation, hypotension, end organ failure
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,
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 48-72 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 42 -72 hrs
Consider Teicoplanin, antifungals
Follow local protocols, microbiology advice
Serum lactate
Blood culture peripheral + central line
Neutropenic Sepsis – consider ITU/ HDU – fluids, O₂ , monitoring
G-CSF
Profound (< 0.1 x 10⁹/ L), prolonged (>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
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
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
Alopecia
Scalp hair loss
Scalp cooling, wigs
Skin toxicity
Palmar- plantar erythrodysaesthesia (PPE)
Capecitabine, Caelyx
All Tyrosine kinase inhibitors – acneiform rash
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
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,
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
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
Cancer patient vs Cancer Survivor
58% of long term survivors of childhood cancer suffer one ongoing medical
problem; 32% have two or more
41%
26%
17%
15%
14%
13%
10%
Endocrine disorder
organ toxicity
impaired mobility
Neuropsychological
infertility
Sensory deficits
Cosmetic problems
Second cancers
Gonadal dysfunction
(Stevens et al, Eur J Cancer, 1998)
Hormonal Therapies
Breast cancer
Tamoxifen – (SERM) - hot flushes, thrombosis, ↑endometrial cancers,
visual problems
Fulvestrant (ER antagonist)
Anastrazole (Non steroidal aromatase inhibitor) - arthralgia, osteoporosis
Letrozole
Exemestane (steroidal AI)
LHRH agonist implants
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
Nephro toxcity
Cisplatin
(also Ototoxcity)
Assess Renal function including GFR
Carboplatin- less nephrotoxic
EDTA, 24 hour Creatinine clearance
Cockcroft- Gault formula
F x (140- age in yrs) x weight (kg)
Crcl =
(GFR)
Serum Creatinine (mmol/L)
F = 1.04 (females); 1.23 (males)
Calvert’s formula
Dose (mg) = desired AUC x (GFR + 25)
AUC – Area under the curve
AUC 8 for adjuvant Germ cell tumours
Usually 5 or 6
Antibodies
Small molecules
Cytokines
Vaccines
Targeted Therapies
Hormonal therapy
Gene therapy
Blood cell growth factors
Monoclonal Antibodies
Type
Origin
Nomenclature
Example
Murine
Mouse
- omab
Tositumomab (Bexxar)
- ximab
Cetuximab, Rituximab, infliximab
Chimeric
Humanised
Human
65-90% human
Rest murine
95% human
5% murine
Human
- zumab
Trastuzumab, bevacizumab
- umab
Denosumab, Panitumumab
Tyrosine Kinase Inhibitors (TKI’s)
Axitinib (Inlyta)
Sunitinib (Sutent)
Crizotinib (Xalkori)
Ruxolitinib (Jakafi™)
Sorafenib (Nexavar)
Dasatinib (Sprycel)
Nilotinib (Tasigna)
Erlotinib (Tarceva)
Lapatinib (Tykerb)
Imatinib (Gleevec)
Gefitinib (Iressa)
Pazopanib (Votrient™)
Vandetanib (Caprelsa)
Adapted from Annals of Oncology
mTOR Inhibitors
Mammalian Target of Rapamaycin
Rapamycin and Rapalogues
Temsirolimus
Everolimus
Hyperglycemia – due to ↑ gluconeogenesis ↓ peripheral gluc uptake
Dyslipidemia
Lung injury, mucositis, rash
£££
Cetuximab – 8 wks - £20,000
Ipilimumab for melanoma - £ 20,000 per dose x 4
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.
Cancer waiting times
Also, patients or their families may demand chemotherapy regardless
of the patient's prognosis,
70 yr man
Cancer ascending colon – R hemicolectomy - 2010
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?
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?
Summary
Cancer incidence and people diagnosed with it is increasing
More patients and elderly patients are being treated
Cancer treatment is advancing rapidly
Long term survival seen in some tumour types
More and more combination treatments
More and unique side effects
Long term consequences of cancer therapy
Thank you

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