the affordable way forward for cancer treatment in malaysia

Dr Paul Cornes

Conflict of interest

Salary received:

• United Kingdom National Health Service

Honoraria received:

• Roche

• Janssen

• Sandoz

• Lilly

• European Generics Association

• Teva

• Hospira

Strive not to be a success,

but rather to be of value

The affordable way forward for

cancer treatment in Malaysia

Comparative Outcomes Group

ESO Task Force Advisory Board on

Access to Innovative Treatment in

Europe

European School of Oncology

Piazza Indipendenza, 2

6500 Bellinzona - Switzerland

Dr Paul Cornes,

Consultant Oncologist,

Bristol Haematology & Oncology Centre

[email protected]



The affordable way forward for

cancer treatment in Malaysia

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?

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.

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



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



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




of day

Does the radiosensitivity of tumour tissues


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




of day

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?

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?

Question

Would you recommend

your partner have radical

radiotherapy with

1. Step-and-shoot IMRT?

2. Arc IMRT?

3. Whichever is available?

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

Malaysia to lead

Cancer research?

Global Cancer: ESMO symposium 2014

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.

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

Malaysia to lead

value based

research?

Value based research

Metastatic relapsed,

or inoperable

squamous cell

carcinoma of head

and neck (HNSCC)

Options

• Supportive care

• +/- chemotherapy

• +/- Cetuximab

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.

£121,367 GBP per

quality-adjusted life-year

(QALY): Manufacturers

estimate of benefit


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)


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)


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

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.


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.


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.

Cost = $2-4

per month

of treatment

Current Standard Adjuvant

is Outpatient FOLFOX

regimen - costs $34,000/6

monthsShiroiwa, 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


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).

http://www.goodrx.com/cimetidine. Accessed Sept 29, 2014

Cost = $2-4

per month

of treatment

Current Standard Adjuvant

is Outpatient FOLFOX

regimen - costs $34,000/6

monthsShiroiwa, 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

the ReDO project

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

http://www.redo-project.org/

Malaysia to lead

cancer education?

Middle income countries face a challenge

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

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.


The International Network For Cancer Treatment and Research Statistics> http://www.inctr.org/about-inctr/statistics/.

Accessed Sept 29, 2014

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

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

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

Malaysia to lead

patient education?

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

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

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

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

Malaysia – partner

with industry?

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




Median costs of a new cancer

drug $ 100,000 USD per

patient per month in 2035

Costs are rising

exponentially

Economic recessions have

little impact on prices

Log

Cost




Median costs of a new cancer

drug $ 100,000 USD per

patient per month in 2035

Costs are rising

exponentially

All the advances in

the understanding

of cancer biology

and new

technology have

failed to reduce the

rising price of

commercial drug

development

DOI: http://dx.doi.org/10.1007/s11523-011-0196-3

Albert Einstein



the affordable way forward for cancer treatment in malaysia

Health & Medicine

timeof day

morning rt

xradiation treatment

early morning

months p

individual circadian

gut polidarov

head neck cancer