This document discusses Dr. Paul Cornes and his presentation on affordable cancer treatment in Malaysia. It notes that Dr. Cornes has received salary from the UK National Health Service and honoraria from several pharmaceutical companies. The document then discusses evidence that the radiosensitivity of normal tissues may change during the day, with studies finding less toxicity for head and neck cancer patients receiving morning radiation. It advocates researching existing cheaper drugs and educating patients and doctors about value in cancer care.

1. Dr Paul Cornes
Conflict of interest
 Salary received:
• United Kingdom National Health Service
 Honoraria received:
• Roche
• Janssen
• Sandoz
• Lilly
• European Generics Association
• Teva
• Hospira

2. The affordable way forward for
cancer treatment in Malaysia
Dr Paul Cornes,
Consultant Oncologist,
Bristol Haematology & Oncology Centre
Comparative Outcomes Group
 Strive not to be a success,
ESO Task Force Advisory Board on
Access to Innovative Treatment in
Europe
but rather to be of value
European School of Oncology
Piazza Indipendenza, 2
6500 Bellinzona - Switzerland
paul.cornes@yahoo.co.uk

3. The affordable way forward for
cancer treatment in Malaysia
 Strive not to be a success,
but rather to be of value

4. The affordable way forward for
cancer treatment in Malaysia
 Strive not to be a success,
but rather to be of value

5. Question
 Would you recommend
your partner have radical
radiotherapy treatments….
1. In the morning 8-10am ?
2. In the evening 4-6pm ?
3. Whenever it’s convenient?

6. Does the radiosensitivity (a/b) of normal OAR
tissues change during the day?
 216 patients with head & Neck cancer randomised to morning (8-
10 AM) vs. afternoon (4-6 PM) RT
 stratified by radiation dose, smoking status, and centre
– Bjarnason GA. Comparison of toxicity associated with early morning versus late
afternoon radiotherapy in patients with head-and-neck cancer: a prospective
randomized trial of the National Cancer Institute of Canada Clinical Trials Group
(HN3). Int J Radiat Oncol Biol Phys. 2009 Jan 1;73(1):166-72. doi:
10.1016/j.ijrobp.2008.07.009.

7. Does the radiosensitivity of normal tissues
change during the day?
 Morning RT was associated with
• Less mucositis G3 or greater
– 52.9% vs. 62.4% p=0.17
• Significantly less weight loss after 5 months (p = 0.024)
 High risk subgroup of 111 patients treated to 66-70 Gy
• Significantly less mucositis, >20% absolute difference
– 44.6% vs. 67.3%, p = 0.022
• a longer interval to the development of Grade 3 or greater
mucositis
– median, >7.9 vs. 5.6 weeks, p = 0.033
 High risk subgroup of 53 patients, who smoked during therapy,
• Significantly less mucositis with morning RT >30% absolute
difference
– 42.9% vs. 76%, p = 0.025

8. Does the radiosensitivity of normal tissues
change during the day?
 A circadian rhythm is seen
in the human oral mucosa
cell cycle, with most cells
in the G(1) phase in the
morning and M phase at
night
Conclusion - The alpha/beta
radiation sensitivity of some
tissues changes with the time
of day

9. Does the radiosensitivity of normal tissues
change during the day?
 A circadian rhythm is seen in the Gut
– Polidarová L. Temporal gradient in the clock gene and cell-cycle checkpoint
kinase Wee1 expression along the gut.Chronobiol Int. 2009 May;26(4):607-20.
doi: 10.1080/07420520902924889.
 individual circadian clocks may control the timing of cell cycle
within different regions of the gut.
 the circadian clocks within each part of the gut are mutually
synchronized with a phase delay in the cranio-caudal axis
Conclusion - The alpha/beta
radiation sensitivity of some
tissues changes with the time
of day

10. Does the radiosensitivity of tumour tissues
change during the day?
 A radiation response circadian rhythm is seen in xenograft
tumours
– Mullins D. Chronomodulation of topotecan or X-radiation treatment increases
treatment efficacy without enhancing acute toxicity. Int J Radiat Oncol Biol Phys.
2005 May 1;62(1):230-7.
• Xenografts are most sensitive at 3am
Conclusion - The alpha/beta
radiation sensitivity of some
tissues changes with the time
of day

11. Question – take 2
 Would you now
recommend your partner
have radical radiotherapy
treatment for head & neck
cancer….
1. In the morning 8-10am ?
2. In the evening 4-6pm ?
3. Whenever it’s convenient?

12. How much data do we need to reduce
uncertainty?
 Tells us just how much clinical radiotherapy research still
remains to be done!
Were your opinions
changed by a 216
patient randomised
trial?
Consider – if a drug,
or IMRT reduced
complications by
20-35% absolute –
would you be
advocating for it?
Rearranging patient
RT bookings in your
centre may be more
cost-effective than
IMRT
If you didn’t know of
this trial – why
wasn’t it “promoted”
to you?

13. Question
 Would you recommend
your partner have radical
radiotherapy with
1. Step-and-shoot IMRT?
2. Arc IMRT?
3. Whichever is available?

14.  Adversity is the mother of invention
 In 1939-1945, while its cities burned and its people starved from
a submarine blockade of the Atlantic Ocean, the British Invented
• Radar
• Computers
• Antibiotics
• Jet airplanes
• And established the World Bank at Bretton Woods to finance
the rebuilding of the world after the war had ended

15. Malaysia to lead
Cancer research?

16. Global Cancer: ESMO symposium 2014
10% of the GDP of
the world is
allocated to health
Today's available knowledge
about cancer only applies to
10% of the world population
E Cancer TV Interview. Prof Eduardo Cazap - SLACOM, Buenos Aires, Argentina. http://ecancer.org/video/3140/cancer-care-
as-a-human-right-in-low-income-countries.php. Accessed Sept 29, 2014.

17. Malaysia to lead
value based
research?

18. Value based research
 Metastatic relapsed,
or inoperable
squamous cell
carcinoma of head
and neck (HNSCC)
 Options
• Supportive care
• +/- chemotherapy
• +/- Cetuximab
£121,367 GBP per
quality-adjusted life-year
(QALY): Manufacturers
estimate of benefit
Head and Neck Cancers Treatment Regimens. http://www.cancertherapyadvisor.com/head-and-neck-cancers-treatment-regimens/article/218124/?DCMP=OTC-cta_
regasset. Accessed Sept 8, 2014. Greenhalgh J et al. Cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck.
Health Technol Assess. 2009 Oct;13 Suppl 3:49-54. doi: 10.3310/hta13suppl3/08.

19. Value based research
 Metastatic relapsed, or
inoperable squamous cell
carcinoma of head and neck
(HNSCC)
 Options
• Supportive care
• +/- platinum based
chemotherapy
• +/-
Cetuximab/chemotherapy
 Tata Memorial India,
– 2014 ASCO Annual
• 110 patients, Randomised
phase 2
Patil VM, Noronha V, Banaval SD, et al. A phase II study comparing metronomic chemotherapy with chemotherapy (single-agent cisplatin), in
patients with metastatic, relapsed, or inoperable squamous cell carcinoma of head and neck. J Clin Oncol 32:5s, 2014 (suppl; abstr 6017)

20. Value based research
 Oral metronomic (MC) cyclophosphamide and MTX (10
USD/Month cost) vs single-agent cisplatin
• PFS median 101 vs 66 days (P=0.014)
• OS: 249 vs 142 days (p=0.02 log rank)
 MC experienced longer progression-free survival
Patil VM, Noronha V, Banaval SD, et al. A phase II study comparing metronomic chemotherapy with chemotherapy (single-agent cisplatin), in
patients with metastatic, relapsed, or inoperable squamous cell carcinoma of head and neck. J Clin Oncol 32:5s, 2014 (suppl; abstr 6017)

21. Value based research
 Bevacizumab improves DFS in breast cancer, but does not
appear to impact on OS
 Vitamin D during adjuvant breast cancer therapy
• Vitamin D has pleiotropic effects that extend beyond their
impact on bone health, including the disruption of
downstream VD receptor signaling, and HER2 signaling via the
ErbB2/AKT/ERK pathway.
 retrospective review of all patients (n = 308) given trastuzumab-based
chemotherapy; 2006 – 2012 - University of Miami/Sylvester
Comprehensive Cancer Center (UM/SCCC).
• 33.3% having a Vit D deficiency at the start of therapy
• 54.5% prescribed Vit D
• final multivariate model, Vitamin D use was associated with
improved DFS [HR 0.36; 95% CI 0.15-0.88; p = 0.026].
– OS no difference
Zeichner SB. Improved Clinical Outcomes Associated With Vitamin D Supplementation During Adjuvant Chemotherapy In Patients With HER2+
Non-metastatic Breast Cancer. Clin Breast Cancer. Published Online: August 15, 2014
DOI: http://dx.doi.org/10.1016/j.clbc.2014.08.001. Accessed Sept 9, 2014

22. Drug development: a crisis in innovation?
 Since the 1950’s, the cost to develop a new drug doubled each 9
years.
• Now has risen 80-fold in inflation-adjusted terms
– Scannell JW et al Diagnosing the decline in pharmaceutical R&D efficiency. Nat
Rev Drug Discov. 2012 Mar 1;11(3):191-200. doi: 10.1038/nrd3681.

23. Drug development: a crisis in innovation?
 One option is to research trials with pre-existing cheaper drugs
 Example:
 Cimetidine in colorectal cancer
• 6 RCTs published from 1995 to 2007, including 1229 patients.
• 5 trials cimetidine, 1 ranitidine.
• Analysis of the five cimetidine trials (n = 421) revealed a
statistically significant improvement in overall survival (HR
0.53; 95% CI 0.32 to 0.87).
Deva S and Jameson M (2012) Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal
cancer. Cochrane Database Syst Rev. 2012 Aug 15;8:CD007814. doi: 10.1002/14651858.CD007814.pub2.

24. Drug development: a crisis in innovation?
Cost = $2-4
per month
of treatment
Current Standard Adjuvant
is Outpatient FOLFOX
regimen - costs $34,000/6
months
Shiroiwa, Takeru et al. Cost-Effectiveness of
Adjuvant FOLFOX Therapy for Stage III Colon
Cancer in Japan Based on the MOSAIC Trial
Value in Health , 2012;15(2):255 - 260
Deva S and Jameson M (2012) Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal
cancer. Cochrane Database Syst Rev. 2012 Aug 15;8:CD007814. doi: 10.1002/14651858.CD007814.pub2.

25. Drug development: a crisis in innovation?
 One option is to research trials with pre-existing cheaper drugs
 Example:
 Cimetidine in colorectal cancer
Current Standard Adjuvant
• 6 RCTs published from 1995 to 2007, including 1229 patients.
• 5 trials cimetidine, 1 ranitidine.
• Analysis of the five cimetidine trials (n = 421) revealed a
statistically significant improvement in overall survival (HR
0.53; 95% CI 0.32 to 0.87).
http://www.goodrx.com/cimetidine. Accessed Sept 29, 2014
Cost = $2-4
per month
of treatment
is Outpatient FOLFOX
regimen - costs $34,000/6
months
Shiroiwa, Takeru et al. Cost-Effectiveness of
Adjuvant FOLFOX Therapy for Stage III Colon
Cancer in Japan Based on the MOSAIC Trial
Value in Health , 2012;15(2):255 - 260

26. the ReDO project
http://www.redo-project.org/
 The Repurposing Drugs in Oncology (ReDO) Project seeks to
repurpose well-known and well-characterised non-cancer drugs
for new uses in oncology.
 Screens old drugs for activity in cancer, and proposes
• clinical trials – phase 2/3
• Observational case by case studies
 First 6 studies
Pan Pantziarka. The Repurposing Drugs in Oncology (ReDO) Project. ecancer 8 442 / DOI: 10.3332/ecancer.2014.442. the
ReDO project. http://ecancer.org/journal/8/full/442-the-repurposing-drugs-in-oncology-redo-project.php#ref7

27. Malaysia to lead
cancer education?

28. Middle income countries face a challenge
 More cancer
• by 2030 cancer incidence in the low to medium human
development index (HDI) countries will represent 52% of the
global total, or 10.6 million cases
– Bray F et al (2012) Global cancer transitions according to the human
development index (2008–2030): a population-based study. Lancet Oncol. 2012
Aug;13(8):790-801.
10% of the GDP of
the world is
allocated to health
Today's available knowledge
about cancer only applies to
10% of the world population
Bray F et al (2012) Global cancer transitions according to the human development index (2008–2030): a population-based
study. Lancet Oncol. 2012 Aug;13(8):790-801.

29. Middle income countries face a challenge
 Less drugs
low and middle
income countries
account for 61%
of the world’s
burden of cancer,
yet only account
for 5% of anti-cancer
drug sales.
The International Network For Cancer Treatment and Research Statistics> http://www.inctr.org/about-inctr/statistics/.
Accessed Sept 29, 2014

30. Middle income countries face a challenge
 Less trained staff
• There is a mis-match between the distribution of health care
workers by level of health expenditure and burden of disease
in regions of the world as defined by WHO
The International Network For Cancer Treatment and Research Statistics> http://www.inctr.org/about-inctr/statistics/.
Accessed Sept 29, 2014

31.  ASCO strategic value initiative:
• 3 Goals
 Oncologists will have the skills and tools
needed to assess relative value of
interventions and use these in discussing
treatment options with their patients.
 Patients will have ready access to information
that assists them in selecting high value
treatment that meets their unique needs.
 Those responsible for covering the costs of
cancer care will have a useful algorithm with
which to define and assess value of cancer
treatment options.
ASCO in Action Brief: Value in Cancer Care
Posted January 21, 2014. URL = http://www.asco.org/advocacy/asco-action-brief-value-cancer-care. Accessed October 6, 2014

32. Malaysia to lead
patient education?

33. Affordability of health care
 Income inequality is associated with health inequality
 Unless measures are put in place to counteract it.
Ref: Income Gini index map according to The World Bank (various 1994-2011), data from Income Gini index map according to
The World Bank (various 1994-2011). URL: http://en.wikipedia.org/wiki/Gini_coefficient. Accessed Nov 17, 2014

34. Affordability of health care
 Kondo 2009: BMJ Meta-analysis
systematically examined 9 cohort and 19
cross-sectional studies involving a total of
more than 61 million subjects to describe
the association between the Gini
coefficient of financial inequality and
mortality and self-reported health status
 Health falls once inequality exceeds 0.3
 Current World Bank Rating
• 0.43 in Malaysia
• 0.31 in Rep. of Korea
• 0.34 in Japan
Suggests
improving health
education and
increasing access
to health care by
the socially and
economically
disadvantaged
will have a greater
impact in
Malaysia than in
her neighbours
Ref: World Bank - Malaysia Overview (Updated on February 28, 2014). URL: http://www.worldbank.org/en/country/malaysia/overview. Accessed Nov 17, 2014. Kondo,
N., et al. (2009). Income inequality, mortality, and self rated health: meta-analysis of multilevel studies BMJ, 339 (nov10 2) DOI: 10.1136/bmj.b4471

35. Malaysia – partner
with industry?

36. When will new cancer drug costs fall?
Memorial Sloan Kettering Cancer Center - centre for health policy & outcomes. URL http://www.mskcc.org/research/health-policy-outcomes/cost-drugs
Cost of Cancer Drugs. Accessed October 7, 2014

37. When will new cancer drug costs fall?
Costs are rising
exponentially
Median costs of a new cancer
drug $ 100,000 USD per
patient per month in 2035
Economic recessions have
little impact on prices
Log
Cost
Memorial Sloan Kettering Cancer Center - centre for health policy & outcomes. URL http://www.mskcc.org/research/health-policy-outcomes/cost-drugs
Cost of Cancer Drugs. Accessed October 7, 2014

38. When will new cancer drug costs fall?
All the advances in
the understanding
of cancer biology
and new
technology have
failed to reduce the
rising price of
commercial drug
development
Costs are rising
exponentially
Median costs of a new cancer
drug $ 100,000 USD per
patient per month in 2035
Memorial Sloan Kettering Cancer Center - centre for health policy & outcomes. URL http://www.mskcc.org/research/health-policy-outcomes/cost-drugs
Cost of Cancer Drugs. Accessed October 7, 2014

39. DOI: http://dx.doi.org/10.1007/s11523-011-0196-3
Albert Einstein
Strive not to be a success,
but rather to be of value