oesophageal cancer
TRANSCRIPT
Oesophageal CancerAsma, Bhumi, Faith, Gold, Kunal and Rebecca
Group D1 and H1
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
Poster TitleNames of Authors
Addresses
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
Oesophageal cancer is a cancer of the oesophagus which carries ingested food to the stomach. 13th most common cancer in the UK.
Main risk factors are Smoking and consumption of AlcoholThere are two main types of oesophageal cancer:
Prevalence
1 Year Prevalence 5 Year Prevalence 10 Year Prevalence
Male2,864 5,727 6,978
Female 1,418 2,868 3,674
Persons 4,282 8,595 10,652
Squamous Cell Carcinoma (SCC)
Present in the upper region of the oesophagusOccurs due to rapid, uncontrolled proliferation of squamous cells lining the
upper region of the oesophagus.Incidence
Symptoms
Persistent Indigestion
Difficulty Swallowing
Bleeding into the oesophagus
Hoarseness, or persistent
cough Chest pain Weight loss
Adenocarcinoma Present in the lower region of the oesophagus.Occurs when glandular cells which secrete mucus into the oesophagus
proliferate rapidly and uncontrollably.
[2]Cancer Research UK Pie Chart
stating statistics about oesophageal
cancer
[1] Cancer Research UK - Incidence of
Oesophageal cancer in males and females
between different age ranges
[3] Graph from Medscape showing
incidence of Adenocarcinoma and SCC
[4] Figures released by Cancer Research UK of people still alive
at the end of 2006
Introduction
Poster TitleNames of Authors
Addresses
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
StagingThere are 2 main ways of staging oesophageal cancer known as the:
TNM System
• Stage T (subdivided into T1-T4b) stands for ‘Tumour’ and it describes its’ progression.
• Same principle applies for Stage N (subdivided into NO-N3) which stands for ‘Nodes’.
• Stage M (subdivided into MO-M1) stands for “Metastasis”. It refers to whether the cancer has spread to another part of the body or not.
Number System
Stage TNM Equivalent Description
T N M
0 - Abnormal cells present in oesophagus lining
1A 1 0 0 Cancer only in oesophagus lining
1B 2 0 0 Cancer spreads into muscle layer
2A 3 0 0 Cancer spreads through oesophagus wall
2B 1 1 0 Cancer spreads into top 2 layers of oesophagus
3A 1/2 2 0 Same as 2B as well as spreading to 3-6 lymph nodes
3B 3 2 0 Cancer spreads to outer layer of oesophagus and 3-6 nodes
3C 4b Any 0 Cancer spreads to nearby structures (e.g. spine) and nodes
4 Any Any 1 Cancer spreads to nearby nodes and other parts of the body (e.g. liver)
[5] T and N stages of oesophageal cancer
[6]Visual representation of different stages of
oesophageal cancer using the number system
Poster TitleNames of Authors
An anthracycline that intercalates into DNA and inhibits topoisomerase II.
[7]– Epirubicin
mechanism of action
[8]– Epirubicin free radical
production
Cisplatin works by binding to DNA and non-DNA targets which subsequently, induces cell death through necrosis, apoptosis or both.
A pyrimidine analogue antimetabolite that inhibits the action of the enzyme thymidylate synthase.
[11]- 5-fluorouracil mechanism
of action
ECF Drug Mechanisms
CisplatinEpirubicin 5-Fluorouracil (5-FU)
ECF Combination therapy
Why combination therapy?• Combining drugs that act
in different phases of the cell cycle increases the number of cells exposed to cytotoxic effects, leading to a more complete kill
• To reduce resistance
ECF effect on cell cycle
5-FU
Epirubicin
Cisplatin is non cell cycle specific [12]
Regimen Details
Drug Dose Administration DurationEpirubicin 50mg/m2 IV D1Cisplatin 60mg/m2 IV D15-FU 200mg/m2/24hrs IV Continous infusion D1-21
You have ECF in 3 week cycles. You may have 6 to 8 cycles lasting up to 6 months in total.
[13]
[10] -DNA
distortions caused
by cisplatin binding
[9] - Mechanism of
cisplatin induced cell
death
Administration
• Epirubicin as an injection directly into central line or cannula with a drip (infusion) of fluids to flush it through
• Cisplatin, in 1 litre Sodium Chloride 0.9% IV over 2 hours 1litre Sodium Chloride 0.9% + 40mmol KCl + 1g MgSO4 IV infusion over 2 hours
• Then 500ml Sodium Chloride 0.9% IV infusion over 60 minutes
• 5-FU infusion, via central venous catheter and ambulatory infusion
device [14]
Complete disappearance of the oseophageal tumour
Partial response
No improvement
0% 10% 20% 30% 40%
Treatment Outcome, determined endoscopically
Study
Conclusion: “This regimen appeared particularly useful in inducing response in the primary tumour and in liver and lymph node metastases. This brief period of response may allow a window for re-assessment with view to surgery” [15]
Side Effects and Dose-limiting toxicityDelayed Late
Alopecia Cardiotoxicity (Dose limiting) Ototoxicity Amenorrhoea Skin changes e.g rashes and
flare Loss of fertility Nephrotoxicity
Immediate
Acute Emesis Allergy Burning sensation at site (due
to extravasation) Urine Discoloration
Delayed Emesis Fatigue Diarrhoea (Dose limiting) Myelosupression (Dose
limiting) Reduced appetite Metallic taste Peripheral neuropathy Numbness/Tingling of fingers Mucositosis
[17]- Supportive therapy regimes to be given when side-
effects or toxicity do occur.
• Study showing that oeseopahageal cancer can be downgraded using ECF, allowing possibility of surgery, carried out at the Royal Marsden Hospital
• The patients in this study had irresectable, locally advanced or metastatic squamous oesophageal carcinomas
• After ECF treatment, 5 patients were able to undergo treatment
[16]Graph
showing
people’s
response to
ECF
treatment
Addresses
Supportive therapy
Resistance
• ABC Efflux transporters increased
• Decreased topoisomerase II inhibition
• Increases levels of glutathione or glutathione peroxidase activity
• Overcome resistance by treatment with verapamil and BSO
Epirubicin
• Increased thymidylate synthase• Decreased affinity of enzyme for
active drug• Reduced availability due to reduced
folate cofactor (FH4)• Increased drug inactivation• Decreased conversion to active
form• Altered amount of target enzyme or
receptor• LEUCOVORIN to overcome
resistance
5-Fluorouracil
• Up regulation of metabolizing enzymes
• Increased capacity to repair intrastrand adducts
• Methallothionein induction
• P-glycoprotein (Efflux transporter)• Thymidylate synthase• Cellular thiols
• Glutathione S transferase• Mellathionein
• Inhibiting the above to overcome MDR
• Less likely because combination therapy used
Multidrug Resistance MDR (Biomarkers)
Cisplatin
[18]-Diagram showing different resistance
mechanisms
The goal of supportive care is to prevent,
control, or relieve
complications and adverse
effects associated with the treatment
Cardiac monitoring,
Dexrazoxane
Blood transfusion
Antiemetics – 5-HT3 receptor antagonist,
dexamethasone, NK -1 receptor
antagonist
Antimicrobial prophylaxis,
G-CSF
Laxatives and Antimotility
drugs
Nephrotoxicity: Hydration with
saline + administration
of Mannitol
Analgesics and anaesthetics e.g. xylocaine
and saline mouthwash
Poster TitleNames of Authors
Addresses
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
Conclusion
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2014.
[3] Medscape (2014). http://www.medscape.com/viewarticle/557839 . Last accessed 23rd November 2014.
[4] Cancer Research UK. (2014). Oesophageal Cancer Statistics. Available: http://www.cancerresearchuk.org/cancer-info/cancerstats/types/oesophagus/. Last accessed 23 Nov
2014.
[5] University Hospitals. (2014). Barrett's Esophagus. Available: http://www.uhhospitals.org/health-and-wellness/health-library/a-c/barretts-esophagus#prettyPhoto . Last accessed
23 Nov.
[6 ] UCSF Medical Center. (2014). Esophageal Cancer. Available: http://top.ucsf.edu/conditions--procedures/esophageal-cancer.aspx . Last accessed 23 Nov 2014.
[7] Allan J. Coukell and Diana Faulds. (1997). Epirubicin: An Update. AOls Drug Evaluation. 53 (3), 453-482.
[8] Dr Varun Goel. (2012). Anthracyclines. Available: http://www.slideshare.net/goelvarundoc/anthracyclinesfinal. Last accessed 26/11/2014.
[9] Dong Wang & Stephen J. Lippard. (2005). Cellular processing of platinum anticancer drugs. Nature Reviews: Drug Discovery. 4 (1), 307-320.
[10] Eastman, A. (1999) The Mechanism of Action of Cisplatin: From Adducts to Apoptosis, in Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug (ed B. Lippert),
Verlag Helvetica Chimica Acta, Zürich.
[11] Schwarzenbach H. (2010). Predictive diagnostics in colorectal cancer: impact of genetic polymorphisms on individual outcomes and treatment with fluoropyrimidine-based
chemotherapy. Available: http://openi.nlm.nih.gov/detailedresult.php?img=3405340_13167_2010_22_Fig1_HTML&req=4 . Last accessed 25 Nov 2014.
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2014.
[13] Multimed Inc. (2011). Capecitabine or infusional 5-fluorouracil for gastroesophageal cancer: a cost–consequence analysis. Available:
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[14] T.Pacheca Palomar . (2009). ECF: Epirubicin / Cisplatin / PVI 5-Fluorouracil for Oesophageal or Gastric Cancer. South East London Cancer Network
[15] [16] H. J.N. Andreyev, A.R. Norman, D. Cunningham, A.R. Padhani, A.S. Hill, P. J. Ross and A. Webb. (1995). Squamous Venous Oesophageal Cancer can be Downstaged Using
Protracted Infusion of 5Fluorouracil with Epirubicin and Cisplatin (ECF) . European journal of cancer . 31 (13), 2209 -2214
[17] A.M. Horgan, J.J. Knox, G. Liu , C. Sahi, P.A. Bradbury, N.B. Leighl. (2014).Capecitabine or infusional 5-fluorouracil for gastroesophageal cancer: a cost–consequence
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[18] Hanane Akhdar, Claire Legendre, Caroline Aninat and Fabrice More (2012). Anticancer Drug Metabolism: Chemotherapy Resistance and New Therapeutic Approaches, Topics
on Drug Metabolism, Dr. James Paxton (Ed.), ISBN: 978-953-51-0099-7, InTech, DOI: 10.5772/30015. Available from:
http://www.intechopen.com/books/topics-on-drug-metabolism/anticancer-drug-metabolism-chemotherapy-resistance-and-new-therapeutic-approaches
[19] Cunningham D, Allum W, Stenning S, et al. Perioperative Chemotherapy Versus Surgery Alone for Resectable Gastroesohpageal Cancer. New England Journal of
Medicine. 2006 ; 355:11-20.
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Macmillan Cancer UK. (2014). ECF chemotherapy. Available: http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Treatmenttypes/Chemotherapy/
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ECF Therapy is recommended for treatment of Adenocarcinomas, especially prior to or following surgery.European Trial on ECF therapy concludes:• Both progression-free survival and overall survival were significantly improved with the use of ECF.• Rates of complications during surgery were nearly identical: 46% for those treated with ECF and 45%
for the group who underwent surgery only.• At 5 years, overall survival was 36% for those treated with ECF compared with only 23% for those
treated with surgery only.• Progression-free survival was reduced by 34% among patients treated with chemotherapy compared
to those treated with surgery only.• Treatment with ECF was generally well tolerated. [19]