Download 1. Introduction to cancer therapeutics - WHO archives

Chapter 6.5: Cancer and Cancer Therapeutics
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Background Paper
Cancer and Cancer Therapeutics:
Opportunities to Address Pharmaceutical Gaps
By Warren Kaplan, Ph.D., JD, MPH
7 October 2004
6.5-1
Chapter 6.5: Cancer and Cancer Therapeutics
Table of Contents
EXECUTIVE SUMMARY .....................................................................................................4
Burden of Disease ...................................................................................................................... 4
Treatment Options..................................................................................................................... 4
Pipeline of Potential Products .................................................................................................. 5
Public and Private Funding...................................................................................................... 5
1.
INTRODUCTION TO CANCER THERAPEUTICS ....................................................5
2.
WHAT ARE THE EPIDEMIOLOGICAL TRENDS FOR EUROPE AND THE
WORLD? ..............................................................................................................................6
2.1
Global Perspective ........................................................................................................ 6
2.2
Cancer in Europe .......................................................................................................... 7
2.3
Specific cancers ........................................................................................................... 14
2.4
Cancer Survival Rates ................................................................................................ 15
2.5
Trends in Cancer in the United States ..................................................................... 15
3.
WHAT IS THE CONTROL STRATEGY? IS THERE AN EFFECTIVE PACKAGE OF
CONTROL METHODS ASSEMBLED INTO A “CONTROL STRATEGY” FOR MOST
EPIDEMIOLOGICAL SETTINGS?....................................................................................16
3.1
Prevention.................................................................................................................... 17
3.2
Early Detection and Screening .................................................................................. 17
3.3
Diagnosis and Treatment........................................................................................... 17
3.4
Support and Rehabilitation ....................................................................................... 17
3.5
Palliative Care ............................................................................................................. 18
4.
WHAT IS KNOWN OF THE AFFORDABILITY, FEASIBILITY, AND
SUSTAINABILITY OF THE CONTROL STRATEGY? .....................................................18
Economic Burden..................................................................................................................... 18
5.
WHY DOES THE DISEASE BURDEN PERSIST? .....................................................18
6. WHAT CAN BE LEARNT FROM PAST/CURRENT RESEARCH INTO
PHARMACEUTICAL INTERVENTIONS FOR THIS CONDITION? ..............................19
6.1
Chemoprevention and Biomarkers .......................................................................... 19
6.2
Targeted Therapy: Cancer as a “Chronic” Disease ................................................ 19
6.3
Tumor Vaccines .......................................................................................................... 20
6.4
The role of “Outcomes Research: ............................................................................. 20
7. WHAT IS THE CURRENT “PIPELINE” OF PRODUCTS THAT ARE TO BE USED FOR
THIS PARTICULAR CONDITION? .................................................................................21
7.1
Summary of European Trial Protocols .................................................................... 21
7.2
Summary of U.S. Trial Protocols .............................................................................. 22
7.3
Comparative Trials ..................................................................................................... 23
7.4
Analysis of Cancer Therapeutics: U.S. Pharmaceutical Industry ........................ 23
7.5
Analysis of Cancer Therapeutics by EORTC .......................................................... 24
7.6
Summary of Investigational New Drugs (U.S.)...................................................... 24
7.7
Does Market Size Drive the Cancer pipeline? ........................................................ 25
6.5-2
Chapter 6.5: Cancer and Cancer Therapeutics
8.
PUBLIC FUNDING FOR CANCER R&D .................................................................30
8.1
Europe .......................................................................................................................... 30
8.2
United States ............................................................................................................... 32
9. WAYS FORWARD FROM A PUBLIC HEALTH VIEWPOINT WITH REGARD TO
PUBLIC FUNDING ............................................................................................................33
9.1
Gaps Between Current Research and Potential Research Issues which Could
Make a Difference. ................................................................................................................... 33
10. CONCLUSION ..........................................................................................................34
REFERENCES.....................................................................................................................35
6.5-3
Chapter 6.5: Cancer and Cancer Therapeutics
Executive Summary
Burden of Disease

In the year 2000, malignant tumors were responsible for 12 per cent of the nearly 56
million deaths worldwide from all causes. In many countries, more than a quarter of
deaths are attributable to cancer.

In 2000, 5.3 million men and 4.7 million women developed a malignant tumor and
altogether 6.2 million died from the disease.

Cancer has emerged as a major public health problem in developing countries,
matching its effect in industrialized nations.

Over one-quarter of the global burden of cancer incidence occurs in Europe, despite
the fact that persons living in Europe comprise only approximately one-eighth of the
world’s population.

In 1997, there were over 1.6 million new cases of cancer (excluding non-melanoma
skin cancer) in the European Union of which, slightly more than half (53%) occurred
in men . Approximately, one million persons died from cancer in the same year, of
which 56% were males. Age-adjusted rates indicate that overall risk of disease tends
to be higher in Northern and Western countries of the EU relative to those in the
South, in part reflecting the distribution of the most common cancers, particularly
lung cancer incidence in men and breast cancer in women.

In the EU, lung cancer is the principal cause of death in men (25% of all male cancer
deaths) followed by colorectal and prostate cancers. In women, the three major causes
of death are breast cancer (16% of all female deaths), colorectal (12%) and lung cancer
(9%) Stomach cancer is the fourth most common cause of cancer death in both sexes,
comprising more than 5% of total cancer deaths in both men and women.
Treatment Options
The wide range of cancer treatments and associated services reflects the biological diversity
of cancer. For most solid tumors if the cancer is at a relatively early stage of development,
surgery is the most standard and effective form of initial cancer treatment. As cancers
progress, treatments typically include radiation, chemotherapy, and in hormone-regulated
tumors, hormone ablation therapy. The stage of cancer at diagnosis, the rate of progression,
and the treatment options vary significantly with the type of cancer a patient presents with.

It is difficult to generalize on how many of the over 100 cancers are particularly
refractory to treatment, although of the major cancers, lung cancer is problematic and
bladder cancer is the most expensive cancer to treat.
6.5-4
Chapter 6.5: Cancer and Cancer Therapeutics
Pipeline of Potential Products

There is a large and dynamic pipeline of early stage and stage III products.

The distribution of therapeutics in clinical trials across cancer types seems to correlate
with the incidence of those cancer types reasonably well-suggesting that the
pharmaceutical industry is appropriately matching its resources to the size of the
market.
Public and Private Funding
The European Union does not match the private or public funding levels of the United States
with regard to cancer therapeutic research and development. However, based upon what we
understand to be the epidemiology of cancer in expanded Europe and the rest of the world,
and the current states of private and public sector institutions in this regard, we believe the
European Union can, from a public health viewpoint, fill treatment gaps in the following
areas:
1.

Expand capacity (infrastructure and human resources) and strengthen coordination
to conduct comparative Phase II/III clinical trials.

Continue to invest in basic research into cancer biology
Introduction to cancer therapeutics
'Cancer' is a generic term used to describe a group of over a hundred diseases that occur
when malignant forms of abnormal cell growth develop in one or more body organs. Cancer
arises after a series of genetic mutations remove the normal checks on cell growth. These
cancer cells continue to divide and grow to produce tumours. Cancer cells can invade
adjacent structures and spread via the lymph or blood to distant organs. Some of the
biological mechanisms that change a normal cell into a cancer cell are known; others are not.
Cancer differs from most other diseases in that it can develop at any stage in life and in any
body organ. No two cancers behave exactly alike. Some may follow an aggressive course,
with the cancer growing rapidly. Other types grow slowly or may remain dormant for years.
Very high cure rates can be achieved for some types of cancers, but for others the cure rates
are disappointingly low and await improved methods of detection and treatment. The wide
range of cancer treatments and associated services reflects the biological diversity of cancer.
It is estimated that about 80 percent of cancers are due to environment or lifestyle, and
therefore are potentially preventable.1 The risk factors for some cancers have been clearly
identified, but for others further research is needed. Based on current evidence, at least 30
percent of future cancer cases are preventable by comprehensive and carefully considered
action, taken now.2
The cancer treatment that a patient receives is determined by the stage of cancer at diagnosis,
the type and location of the cancer, the standard medical practices in the patient’s country,
and the ability of the patient to pay for treatment (through national or private insurance or
otherwise). For most solid tumors if the cancer is at a relatively early stage of development,
surgery is the most standard and effective form of initial cancer treatment. As cancers
6.5-5
Chapter 6.5: Cancer and Cancer Therapeutics
progress, treatments typically include radiation, chemotherapy, and in hormone-regulated
tumors, hormone ablation therapy.
The stage of cancer at diagnosis, the rate of progression, and the treatment options vary
significantly with the type of cancer a patient presents with.
Multiple metastases (in various locations) ultimately limit surgical removal and the
effectiveness of anti-cancer drugs. When cancers recur and spread beyond the initial site or
region, systemic treatment is most often used. Chemotherapy is the most prevalent form of
systemic treatment, because it can reach and destroy cancer cells throughout the body.
Chemotherapy may be used alone or in combination with other forms of treatment.
Hormone-regulated tumors, such as certain breast and prostate cancers use the body’s
natural hormones to grow, and they can become resistant to standard treatments including
chemotherapy. Certain cancers (such as lung, pancreatic and kidney cancers) are largely
resistant at the time of diagnosis, owing to the aggressiveness of progression of these cancer
types, and/or to the stage at which such cancers are typically diagnosed. Other cancers
become resistant over a period of months or years. Overall, thirty to eighty percent of cancers
can become refractory.3 4 5
2.
What are the Epidemiological Trends for Europe and the World?
2.1
Global Perspective
The most recent comprehensive global examination of cancer to date is the World Cancer
Report (REF). 6 Cancer rates could further increase by 50% to 15 million new cases in the
year 2020. 6 Nonethless, from a global perspective, there is strong justification for focusing
cancer prevention activities particularly on two main cancer-causing factors - tobacco and
diet. Efforts should also continue to curb infections such has human papilloma virus which
can cause cancer and hepatitis, which is a significant risk factor for cancer.
In the year 2000, malignant tumors were responsible for 12 per cent of the nearly 56 million
deaths worldwide from all causes.6 In many countries, more than a quarter of deaths are
attributable to cancer. In 2000, 5.3 million men and 4.7 million women developed a
malignant tumor and altogether 6.2 million died from the disease. The report also reveals
that cancer has emerged as a major public health problem in developing countries, matching
its effect in industrialized nations. Major findings of the World Cancer Report are as follows:

Tobacco consumption remains the most important avoidable cancer risk. In the 20th
century, approximately 100 million people died world-wide from tobacco-associated
diseases (cancer, chronic lung disease, cardiovascular disease and stroke). Half of
regular smokers are killed by the habit.

The lung cancer risk for regular smokers as compared to non-smokers (relative risk,
RR) is between 20 and 30 fold. In countries with a high smoking prevalence and
where many women have smoked cigarettes throughout adult life, roughly 90 per
cent of lung cancers in both men and women are attributable to cigarette smoking.

For smokers, the RR for cancers of the oral cavity, pharynx, larynx and squamous cell
carcinoma of the esophagus is greater than six, and three to four for carcinomas of the
pancreas. These risk estimates are higher than previously estimated and additional
6.5-6
Chapter 6.5: Cancer and Cancer Therapeutics
cancer sites have been identified as being associated with tobacco smoking, including
cancers of the stomach, liver, uterine cervix, kidney (renal cell carcinoma) nasal
cavities and sinuses, and myeloid leukemia.
2.2

Involuntary (passive) tobacco smoke is carcinogenic and may increase the lung
cancer risk by 20 per cent. There is currently no evidence that smoking causes breast,
prostate or endometrial cancer of the uterus.

In developing countries, up to 23 per cent of malignancies are caused by infectious
agents, including hepatitis B and C virus (liver cancer), human papillomaviruses
(cervical and ano-genital cancers), and Helicobacter pylori (stomach cancer). In
developed countries, cancers caused by chronic infections only amount to
approximately 8 per cent of all malignancies. This discrepancy is particularly evident
for cervical cancer. In developed countries with an excellent public health
infrastructure and a high compliance of women, early cytological detection of cervical
cancer (PAP smear) has led to an impressive reduction of mortality while in other
world regions, including Central America, South East Africa and India, incidence and
mortality rates are still very high. Today, more than 80 per cent of all cervical cancer
deaths occur in developing countries.

More than 50 per cent of the world’s cancer burden, in terms of both numbers of cases
and deaths, already occurs in developing countries.

The Western lifestyle is characterized by a highly caloric diet, rich in fat, refined
carbohydrates and animal protein, combined with low physical activity, resulting in
an overall energy imbalance. It is associated with a multitude of disease conditions,
including obesity, diabetes, cardiovascular disease, arterial hypertension and cancer.
Malignancies typical for affluent societies are cancers of the breast, colon/rectum,
uterus (endometrial carcinoma), gallbladder, kidney and esophagus. Prostate cancer
is also strongly related to the Western lifestyle, but there is an additional ethnic
component; black people appear to be at a greater risk than whites and the latter at
higher risk than Asian populations. Since they have a common cause, these
neoplasms typically go together. There is no region in the world that has a high
incidence of breast cancer without a concurrent colon cancer burden.

Lung cancer is the most common cancer worldwide, accounting for about 1.2 million
new cases annually; followed by breast cancer,at just over 1 million cases, and
colorectal cancer with just under 1 million cases. The three leading cancer killers are
different than the three most common forms, with lung, stomach, and liver having
the highest mortality burden.

Industrial nations with the highest overall cancer rates include: U.S.A, Italy,
Australia, Germany, The Netherlands, Canada and France. Developing countries
with the lowest cancer incidences were in Northern Africa Southern and Eastern
Asia.7

New drugs will not necessarily eradicate tumors, but when used in combination with
other agents, may turn many cases of rapidly fatal cancer into ‘manageable’ chronic
illness.
Cancer in Europe
6.5-7
Chapter 6.5: Cancer and Cancer Therapeutics
It has been estimated that over one-quarter of the global burden of cancer incidence occurs
in Europe, despite the fact that persons living in Europe comprise only approximately oneeighth of the world’s population.8
2.2.1
WHO Subregion Euro (A)
The WHO subregion (Euro A) consists of Andorra, Austria, Belgium, Croatia, the
Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel,
Italy, Luxembourg, Malta, Monaco, the Netherlands, Norway, Portugal, San Marino,
Slovenia, Spain, Sweden, Switzerland and the United Kingdom. For EuroA, Tables
1A and 1B are ranked order list of the top 16 cancers in terms of mortality
(Table 1A: both sexes; Table 1B: women) and their individual proportions of
their total mortality. Tables 1C and 1D are ranked order lists of the top 15-16
cancers in terms of incidence (new cases) and their individual proportions of
their total incidence (Table 1C: both sexes; Table 1D: women).9
6.5-8
Chapter 6.5: Cancer and Cancer Therapeutics
Table 1A: Both sexes: mortality
Euro (A )
Number of deaths (000s)
Proportion of total (%)
Trachea, bronchus, and lung
207.2
19.5
Colon and rectum
141.8
13.3
Breast
92.7
8.7
Prostate
70.2
6.6
Stomach
66.8
6.3
Lymphomas and multiple myeloma
55.0
5.2
Pancreas
53.6
5.0
Liver
38.6
3.6
Bladder
37.6
3.5
Leukaemia
37.3
3.5
Oesophagus
29.2
2.7
Ovary
25.7
2.4
Mouth and oropharynx
24.9
2.3
Corpus uteri
16.0
1.5
Melanoma of the skin
15.5
1.5
Cervix uteri
8.3
0.8
Table 1 B:
Euro(A) Females Mortality, Percentage of total Female Mortality
Breast
91.8
19.6
Colon and rectum
69.7
14.9
Trachea, bronchus, and lung
49.2
10.5
Stomach
27.9
6.0
Lymphomas and multiple myeloma
27.4
5.9
Pancreas
26.9
5.8
Ovary
25.7
5.5
Leukaemia
17.2
3.7
Corpus uteri
16.0
3.4
Liver
13.3
2.8
Bladder
10.5
2.2
Cervix uteri
8.3
1.8
Oesophagus
7.8
1.7
Melanoma of the skin
7.2
1.5
Mouth and oropharynx
5.7
1.2
6.5-9
Chapter 6.5: Cancer and Cancer Therapeutics
Table 1C: Both sexes: Number of new cases, percentage of total (Euro(A)
Colon and rectum
264.7
15.4
Trachea, bronchus and lung
227.3
13.2
Breast
221.8
12.9
Prostate
139.1
8.1
Bladder
86.5
5.0
Lymphomas and multiple myeloma
80.2
4.7
Stomach
79.6
4.6
Corpus uteri
68.3
4.0
Pancreas
55.5
3.2
Melanoma of the skin
49.1
2.8
Leukaemia
48.6
2.8
Liver
40.1
2.3
Ovary
39.4
2.3
Mouth and oropharynx
38.6
2.2
Oesophagus
31.2
1.8
Cervix uteri
18.8
1.1
Table 1D: Female new cases, Euro(A), Percentage of total female new cases
Breast
221.8
26.2
Colon and rectum
131.0
15.4
Corpus uteri
68.3
8.1
Trachea, bronchus and lung
55.3
6.5
Lymphomas and multiple myeloma
40.9
4.8
Ovary
39.4
4.6
Stomach
33.9
4.0
Pancreas
28.1
3.3
Melanoma of the skin
26.5
3.1
Leukaemia
23.0
2.7
Bladder
21.4
2.5
Cervix uteri
18.8
2.2
Liver
14.0
1.7
Mouth and oropharynx
9.9
1.2
Oesophagus
8.4
1.0
6.5-10
Chapter 6.5: Cancer and Cancer Therapeutics
2.2.2
European Union (15 Member States)
The EUCAN database holds information on pre-2004 cancer incidence, mortality,
prevalence and survival in the EU15. 10
In 1997, there were over 1.6 million new cases of cancer (excluding non-melanoma
skin cancer) in the European Union of which, slightly more than half (53%) occurred
in men. Approximately, one million persons died from cancer in the same year, of
which 56% were males. Age-adjusted rates indicate that overall risk of disease tends
to be higher in Northern and Western countries of the EU relative to those in the
South, in part reflecting the distribution of the most common cancers, particularly
lung cancer incidence in men and breast cancer in women. The three most common
cancers that develop in men (lung, colorectal and prostate) and in women (breast,
colorectal, and lung) comprise almost half of the total cancer incidence experienced in
the EU. Lung cancer is the principal cause of death in men (25% of all male cancer
deaths) followed by colorectal and prostate cancers. In women, the three major causes
of death are breast cancer (16% of all female deaths), colorectal (12%) and lung cancer
(9%) Note the comparison to Table 1B (19.6, 14.5 and 10.5%, respectively). Stomach
cancer is the fourth most common cause of cancer death in both sexes, comprising
more than 5% of total cancer deaths in both men and women.
According to prevalence figures, there are over 4.5 million people living with cancer
in the European Union, who were diagnosed with cancer during the previous five
years.10
Prevalence reflects both incidence and fatality of the disease, and breast cancer (one
in five prevalent cases), colorectal cancer (one in seven prevalent cases) and prostate
cancer (one in ten prevalent cases) comprise 46% of the cancers in men and women in
the EU. Lung cancer, although the second most common tumor overall, is associated
with a very poor prognosis, thus the number of prevalent cases is relatively small,
with about one in 20 persons alive with this neoplasm in the EU.
2.2.3 Further details
In Austria, Germany, The Netherlands, Poland, Slovakia, Slovenia and Switzerland
the prevalence of stomach, colon, rectum, lung, breast, cervix uteri, corpus uteri and
prostate cancer, as well as skin melanoma, Hodgkin's disease, leukaemia and all
malignant neoplasms combined was estimated in the EUROPREVAL study.11
A large heterogeneity was observed within central European countries. Overall
cancer prevalence was the highest in Germany and Switzerland, and the lowest in
Poland and Slovenia. As shown by incidence data, breast cancer was the most
frequent malignancy among women in all countries, and this is still the case in 2000
(See Table 1B and Table 1D). Among men, prostate cancer was the leading
malignancy in Germany, Austria and Switzerland, and lung cancer was the major
cancer in Slovenia, Slovakia and Poland. The Netherlands had a high prevalence of
both prostate and lung cancer. This burden of cancer could be interpreted as a
6.5-11
Chapter 6.5: Cancer and Cancer Therapeutics
paradoxical effect of better treatments and thereby improved survival. It could also
be taken as being indicative of poor advances in treatment.
2.2.4 Temporal trends
Cancer is a major health problem in Europe. The number of cases diagnosed annually
(incidence) has been growing steadily for at least the last 20 years.12 This increase
reflects increasing life expectancy at birth with a consequent shift in the agedistribution of the population toward the elderly, the latter a common demographic
phenomenon in developed countries.13 On the other hand, in most of these countries
the age-adjusted incidence and mortality rates for some major cancers such as the
tobacco-related cancers and stomach cancer are no longer increasing. Over the same
period, the prognosis (survival probability) for all cancers combined has been
improving throughout Europe. 14, 15
Figure 1 (in two parts) shows the standardized mortality rates (per 100000 persons)
for all cancers and all ages for various EU15 countries. Mortality rates have been
steady or slightly decreasing over the past 20 years. Figure 2 shows the standardized
mortality rates (per 100000 persons) for all cancers and all ages for various EU10
countries. Mortality rates have been steadily increasing over the past 20 years, with
recent encouraging reductions in mortality in some countries (Hungary, Malta,
Czech Republic).
Standardized death rate (all causes)
Greece
Death rate (all ages) per 100000
Ireland
280
Italy
260
240
Luxembourg
220
Netherlands
200
Norway
180
160
Portugal
140
Spain
120
100
Sweden
1
4
7 10 13 16 19 22 25 28
Year (1=1970)
6.5-12
United Kingdom
Chapter 6.5: Cancer and Cancer Therapeutics
Death rate (all ages) per
100000
Standardized death rate (all causes)
280
260
240
220
200
180
160
140
120
100
Austria
Belgium
Denmark
Finland
France
1
4
7 10 13 16 19 22 25 28
Year (1= 1970)
Figure 2: Standardized death rate for all cancers in EU10 countries.
Standardized death rate (all causes)
280
Death rate (all ages) per 100000
260
240
Czech Republic
Estonia
Hungary
Latvia
Lithuania
Malta
Poland
Slovakia
Slovenia
220
200
180
160
140
120
100
1
4
7 10 13 16 19 22 25 28 31
Year (1=1970)
Notwithstanding the above, although overall cancer mortality in Europe has been
steadily decreasing since the early 1990s, cancer in the central-eastern European
countries is still substantial, and mortality has actually continued to increase.16 In
contrast with the European Union and Nordic countries, Central and Eastern Europe
present higher current levels and an increasing trend of cancer mortality. Age6.5-13
Chapter 6.5: Cancer and Cancer Therapeutics
standardized rates for overall cancer mortality increased at an annual average of
2.43% in Central and Eastern European countries during the period from 1980 to
2001, while the European Union, Nordic countries and Switzerland underwent an
average decrease of 7.27% per year. 17 Differences in lifestyle and environmental
exposure are the most likely causes for this Western /Central and Eastern Europe
disparity and these are inevitably linked to political, social, and economic
inequalities. Even if attempts at cancer prevention are eventually realized, a major
cancer burden will likely persist for many decades to come in Central and Eastern
Europe.
2.3
Specific cancers
2.3.1 Lung cancer
Data on lung cancer mortality patterns throughout Europe were collected up to
1998.18 Lung cancer mortality rates up to age 75 years portray a general trend of
decreasing lung cancer death rates among men and increasing lung cancer death
rates among women. Exceptions to this decrease among men include Hungary where
not only are current mortality rates much higher than previously observed in any
other country (at 76.7 out of 100,000 in 1998) but they are projected to increase further
in the short term. Rates among adults aged <55 years have recently peaked,
indicating that overall rates are likely to peak in the next decade. Among women,
rapid increases in lung cancer have been observed in Denmark, Netherlands,
Hungary, Ireland and UK. Whereas Ireland and UK rates have started to decrease
and are projected to continue falling, rates in the other three countries are projected to
increase further. Trends in women aged <55 years indicate that rates in Danish
women will peak in the next decade, whereas lung cancer rates among Dutch women
are likely to continue increasing. Rates in Hungarian women are likely to increase
and will surpass the current high rate observed in Denmark.18
2.3.2 Breast cancer
Trends in the incidence of and mortality from breast cancer result from a variety of
influences including screening programs, such as those introduced in several
European countries in the late 1980s. Incidence and mortality rates for 16 European
countries were recently analysed.19 New cases (Incidence) of breast cancer increased
in all countries. The estimated annual percent change (EAPC) in breast cancer
incidence varied from 0.8 to 3.0% . Earlier mortality trends were maintained in the
most recent decade in Estonia (EAPC= +1.8%) and Sweden (-1.2%). In other countries,
previously increasing mortality changed as mortality flattened or declined in Finland,
Denmark, France, Italy and Norway (EAPC 0.0 to -0.3%), England and Wales (-3.1%),
Scotland (-2.0%), and The Netherlands (-1.0%) (all five of which have national
screening programs) and in Slovakia (-1.1%), Spain (-0.7%), and Switzerland (-1.1%).
In some countries with screening programs, declines in mortality started before
screening was introduced, and declines also occurred in non-screened age groups
and in some countries without national screening programs at all. This suggests that
the major determinants of the observed trends vary among the countries and may
include earlier detection through screening in countries where this has been
introduced, but also improvements in therapy, in countries with or without
screening.19
6.5-14
Chapter 6.5: Cancer and Cancer Therapeutics
2.4
Cancer Survival Rates
The EUROCARE project analysed cancer survival data from 45 population-based
cancer registries in 17 European countries, revealing wide differences in cancer
survival.20 Five-year relative survival for 1,836,287 patients diagnosed with one of 13
cancers during the period 1978-1989. The data, from 20 cancer registries in 13
countries, were grouped into four regions: Finland, Sweden, Iceland (Northern
Europe); Denmark, England and Scotland (UK and Denmark); France, The
Netherlands, Germany, Italy and Switzerland (Western Europe); Estonia and Poland
(Eastern Europe), and broken down into four periods (1978-1980, 1981-1983, 19841986, 1987-1989). Survival increased with time for all tumors, particularly for cancers
of testis (12% increase, i.e. from 79.9 to 91.9%), breast, large bowel, skin melanoma
(approximately 9-10%), and lymphomas (approximately 7%). For most solid tumors,
survival was highest in Northern Europe and lowest in Eastern Europe, and also low
in the UK and Denmark. Regional variation was less marked for the lymphomas.
Survival improved more in Western than Northern Europe. For potentially curable
malignancies such as Hodgkin's disease, large bowel, breast and testicular cancers,
there were substantial increases in survival, suggesting an earlier diagnosis and more
effective treatment. The persisting regional differences suggest there are
corresponding differences in the availability of diagnostic and therapeutic facilities,
and in the effectiveness of healthcare systems.20
2.5
Trends in Cancer in the United States
Each year, the American Cancer Society estimates the number of new cancer cases
and deaths expected in the United States in the current year and compiles the most
recent data on cancer incidence, mortality, and survival rates based on incidence data
from the National Cancer Institute and mortality data from the National Center for
Health Statistics.21 A total of 1,368,030 new cancer cases and 563,700 deaths are
expected in the United States in 2004. Incidence rates stabilized among men from
1995 through 2000 but continued to increase among females by 0.4% per year from
1987 through 2000. Mortality rates have decreased by 1.5% per year since 1992 among
men, but have stabilized from 1998 through 2000 among women. Cancer death rates
continued to decrease from the three major cancer sites in men (lung and bronchus,
colon and rectum, and prostate) and from female breast and colorectal cancers in
women. 21 In analyses by race and ethnicity, African-American men and women have
40% and 20% higher death rates from all cancers combined compared with white
men and women, respectively. Cancer incidence and mortality rates are lower in
other racial and ethnic groups than in Whites and African Americans for all sites
combined and for the four major cancer sites. 21 However, these groups generally
have higher rates for stomach, liver, and cervical cancers than do Whites.
Furthermore, minority populations are more likely to be diagnosed with advanced
stage disease than are Whites.
6.5-15
Chapter 6.5: Cancer and Cancer Therapeutics
3.
What is the Control Strategy? Is There an Effective Package of
Control Methods Assembled Into a “Control Strategy” for most
Epidemiological Settings?
The aim of cancer control is a reduction in both the incidence of the disease and the
associated morbidity and mortality, as well as improved life for cancer patients and their
families. Significant advances in cancer therapy have been made for many years. For
example, a significant advance in colorectal cancer treatment was the introduction of 5fluorouracil-based adjuvant chemotherapy for patients with surgically resected late stage
colon cancer, which reduced mortality by as much as 30%.22 The steady decline in female
breast cancer mortality in the U.S. since 1990 has been partly attributed to increased use of
adjuvant chemotherapy.23 For large cell lymphoma, chemotherapy in the 1970s was shown
to achieve disease remission and improve survival.24
Advances continue to be made. For example the development of immunotherapy
(interleukin-2 ) for melanomna25 and survival improvements in patients with chronic
myelocytic leukemia using imatinab mesylate (Gleevec ®).26
At the national level, however, most countries have yet to establish comprehensive national
cancer control programs. In developing countries in particular, where a large proportion of
cancers are detected late in the course of the disease, efforts to achieve earlier diagnosis and
delivery of adequate palliative care and pain relief deserve urgent attention.27
A comprehensive national cancer control strategy would be required for any country for the
following reasons:

people are going to continue to develop cancer and die from it

cancer control is unique in its complexity, involving a range of diseases and a
diversity of service providers – it cannot be achieved by any single organization or by
government alone

effective and efficient use of limited resources is crucial

establishing an alliance of organizations and health professionals, both government
and non-government, is critical if action is to be cost-effective

it is important to act now, before the full impact of the ageing population is felt by the
health care system.28
There are many activities within the continuum of cancer control.
6.5-16
Chapter 6.5: Cancer and Cancer Therapeutics
3.1
Prevention
According to the World Health Organization27 cancer prevention should be a key element in
all cancer control programs. Cancer prevention focuses not only on factors that increase a
person's chances of developing cancer (such as smoking), but also on protective factors such
as a healthy diet and physical activity. Exposure to risk factors is generally the result of a
complex range of behavioral, social, economic, environmental and cultural factors that are
not easy to change so that efforts to reduce the incidence of lifestyle-related cancers require a
comprehensive approach.
3.2
Early Detection and Screening
Early detection means detecting cancer prior to the development of symptoms or as soon as
is practicable after the development of symptoms. Its aim is to detect the cancer when it is
localized to the body organ of origin, before it has time to spread to other parts of the body.
Early detection is only part of a wider strategy including diagnosis, treatment and follow-up
27 which can involve strategies to promote early presentation, including education about
signs and symptoms and improved access to primary care. Early detection of cancer prior to
the development of symptoms occurs through screening. Although a number of cancer
screening tests have been developed, only a few have been proven effective and therefore
recommended for defined populations. 27
3.3
Diagnosis and Treatment
Diagnosis involves clinical assessment and a range of investigations, such as endoscopy,
imaging, histopathology, cytology and laboratory studies. Diagnostic tests are also important
in identifying the extent to which the cancer may have spread (known as 'staging'). Cancer
staging is necessary for determining options for treatment and assessing likely prognosis.
The cancer treatment that a patient receives is determined in large part by the stage of cancer
at diagnosis. For most solid tumors, surgery is the most standard and effective form of
initial cancer treatment. As cancers progress, treatments typically include radiation,
chemotherapy, and in hormone-regulated tumors, hormone ablation therapy.
3.4
Support and Rehabilitation
The impact of cancer extends beyond the physical effects of the disease to include
psychological, social, economic, sexual and other consequences. Coping with the disease and
its treatment involves a range of issues.29 These needs may occur during diagnosis,
treatment or follow-up after treatment, and include issues of survivorship, recurrence of the
disease and, in some cases, death. There is growing evidence that supportive care and
rehabilitation can buffer cancer patients and their caregivers from psychiatric, psychological
and social morbidity.29
6.5-17
Chapter 6.5: Cancer and Cancer Therapeutics
3.5
Palliative Care
Palliative care is intended to improve the quality of life of patients and their families facing
the problems associated with life-threatening illness, through the prevention and relief of
suffering by means of early identification and assessment and treatment of pain and other
problems.27
In the mid-1980s, targets for cancer control were set by the European Union in a program
known as Europe Against Cancer. This program has been recently reviewed.30 Alhough the
overall burden of cancer has been decreasing, the target of a 15% reduction in the expected
numbers of cancer deaths in the EU was not met. Only Austria and Finland achieved the
15% reductions in deaths in both men and women. The UK and Luxembourg (where the
small population and annual number of deaths make interpretation difficult) came close to
meeting these targets, as did Italy. These countries can be considered to have effective overall
programs to reduce cancer mortality, whether directly or indirectly associated with the
Europe Against Cancer program. Portugal, Spain and Greece had the poorest performance.
4.
What is Known of the Affordability, Feasibility, and
Sustainability of the Control Strategy?
Economic Burden
Many attempts have been made to estimate the significant economic and humanistic burden
on patients and society. Investigators estimated inpatient costs alone incurred in the US in
1994 to be around dollars US 5.14 billion (about €4 billion).31 Therefore, the economic burden
of colorectal cancer in the US could be projected to be somewhere in the range of dollars US
5.5-6.5 billion by considering that inpatient costs approximate 80% of total direct costs. No
worldwide data have been published, but assuming that the US represents 25-40% of total
expenditures in oncology, as seen for breast and lung cancers, a rough estimate for the global
economic burden of colorectal cancer alone would be in the range of dollars US 14-22 billion
(about €11-18 billion) .31
Because of long- term survival and the need for lifelong routine monitoring and treatment,
the cost per patient of bladder cancer from diagnosis to death is the highest of all cancers,
ranging from 96,000-187,000 US dollars (2001 values) in the US.32
5.
Why Does the Disease Burden Persist?
In short, cancer persists because there is no cure or unequivocal preventative measures. It
seems unlikely in the near future that either will be achieved. Cancer is a multidimensional
condition, and its causes are both genetic and environmental. Since many cancers are due to
environment or lifestyle, they are potentially preventable. Increases in certain cancer types
(primarily lung, oral, and pharyngeal cancers) can be anticipated in countries, such as China,
where smoking has not been controlled.
A serious challenge for the future is the aging of the population, with dramatic increases in
the number of people over the age of 65 as well as increases in the number over 80, a
population that has received little attention. Due to the increase in the total population, as
well as the increased cancer risk associated with aging, we would expect the number of
6.5-18
Chapter 6.5: Cancer and Cancer Therapeutics
cancer diagnoses in Europe to continue to increase, while there will be concomitant declines
in cancer mortality rates. Heightened efforts in screening, diagnosis, education, basic
research, tobacco control (especially among women), and other public health interventions
will be required
6. What can be Learnt from Past/Current Research into Pharmaceutical
Interventions for this Condition?
The advances in cancer therapeutics has been rapid and impressive so that we can only
highlight a few lessons of relevance to the public health viewpoint of the present report.
6.1
Chemoprevention and Biomarkers
Cancers in organs containing epithelial sites such as breast, colon, prostate and lung
represent major preventable causes of mortality.33 There is strong epidemiological and
laboratory evidence, albeit largely circumstantial,
that naturally occurring dietary
components may exert protective effects against cancers in these organs in humans.34 These
include vitamins and minerals (such as folate, vitamin E, vitamin D, calcium, and selenium);
naturally occurring phytochemicals (such as curcumin, genistein, indole-3-carbinol, and
l-perillyl alcohol). Many synthetic compounds (such as retinoids, selective oestrogen
receptor modulators, and cyclooxygenase-2 inhibitors) are also implicated.35 However,
clinically relevant preventive efficacy for such dietary phytochemicals depends on clinical
trials. Before such trials, novel preventative agents can be evaluated using human tissue
derived preclinical models, and on identification of mechanism-based genetic, molecular,
endocrine and cellular biomarkers specific for pre malignant lesions.36, 37, 38, 39 Promising
agents identified through these preclinical studies can then be rapidly tested via
conventional clinical trials.
Cancer is a comparatively infrequent event, and clinically overt cancer usually takes many
years to develop. Clinical trials to test the effectiveness of chemopreventive agents therefore
require large study populations and a long term commitment of resources. The availability of
biomarkers as surrogate end points for clinical disease would allow smaller trials of shorter
duration, facilitating clinical research into chemoprevention.
6.2
Targeted Therapy: Cancer as a “Chronic” Disease
Cancer biology and medicine have made remarkable and rapid progress because of advances
in molecular biology and genetics. Currently,there are therapies that target the genes that
cause specific diseases. Mainstream cancer therapies of the late 20th century (e.g.
chemotherapy) indiscriminately kill all cells in their path. Thus, one reason why targeted
therapies are promising is that chemotherapy has limits. Lung, colon, breast and prostate
cancers, once they have metastasized to other body parts, are essentially incurable using
standard chemotherapy. Today’s emerging targeted therapies are designed to destroy
specific cancerous cells and leave healthy cells intact. One of the more recent examples
includes the “small molecule” imanitib mesylate (Gleevec® in the US, Glivec tm outside the
US), which is a specific inhibitor for tyrosine kinase in Philadelphia chromosome positive
chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). 40 41 In the
coming years, many candidate drugs will be tested and used with this similar concept and
technology.
6.5-19
Chapter 6.5: Cancer and Cancer Therapeutics
In principle, targeted therapies can be tailored to the genetic mechanisms responsible for a
particular patient's tumor. Therefore, one could control a particular cancer’s runaway growth
properties, thus controlling the growth of the malignancy in the body and causing the cancer
to exist chronically within the body.42 There are, however, tremendous hurdles to overcome.
Tumors grow by multiple mechanisms so that preventing one such mechanism might not be
enough and since cancer cells mutate rapidly, tumors can evolve resistance and neighboring
cells in a tumor might be different and not susceptible to the same drug. Just targeting, for
instance, a receptor on a tumor surface is quite different than targeting something that causes
the tumor.
6.3
Tumor Vaccines
Since the 1990s, tumor immunology has developed into a distinct discipline with a
metamorphosis from clinical observations in oncology to understanding its scientific
underpinnings. This has been particularly relevant to the development of active
immunotherapies (vaccines) for cancer. Traditionally, vaccines have been effective in the
induction of protective immunity to bacteria and viruses based on recognition of foreign, or
non-self, antigens on these pathogens.43 However, cancer cells arise from one's own tissue
(self) and this poses a challenge in the development of effective active immunotherapies for
cancer. The question becomes whether the immune system mount an effective response to
reject “itself” (i.e., a tumors) The vast majority of antigens on cancers characterized to date
are unaltered “self” antigens.44 These are antigens encoded by genes expressed by both
tumor cells as well as their normal cell counterparts. That cancer immunity exists, is
observed clinically in the form of spontaneous regressions in melanoma, GI tumors, lung and
breast cancers.44, 45 The immune repertoire therefore contains auto-reactive immune cells that
may reject tumors, when activated appropriately.44 These auto-reactive cells, upon
recognizing target molecules on normal cells have the potential to induce tissue destruction
leading to toxic autoimmunity.
6.4
The role of “Outcomes Research:
We have seen that cancer is one of the main healthcare problems in Europe. Workers in the
field have noted the need to create and sustain coordinated interaction between technology,
biology, clinical research, clinical practice and health policy.46 Outcome Research (OR),
defined as the discipline that describes, interprets, and predicts the impact of various
influences, especially interventions, on final endpoints (from survival to satisfaction with
care) that matter to decision makers (from patients to society at large), with special emphasis
on the use of patient-reported outcomes (PRO). The research includes end points such as
survival, health-related quality of life, satisfaction and patient experience, and economic
burden.46 Outcomes research has the unique opportunity to help understand the value of
drugs that have received accelerated approval. In the UK specific interdisciplinary projects
have been launched by the NCRI.47
The correct placement of Outcomes Research in the anti-cancer drug development process
may better integrate both translational and outcome research in the mainstream of clinical
research into anti-cancerdrugs, thus speeding up the introduction of the results of patientoriented clinical research into clinical practice.
6.5-20
Chapter 6.5: Cancer and Cancer Therapeutics
7. What is the Current “Pipeline” of Products that Are to Be Used for
this Particular Condition?
7.1
Summary of European Trial Protocols
We also looked at the database of the European Organization for Research and Treatment of
Cancer (EORTC: www.eortc.be.org). The following Table 7.1 is taken directly from the
database which summarized the number of protocols for different tumor sites, although we
then calculated the data in columns (3) and (4).
Table 7.1
Tumor site
Lung
Breast
Head and Neck
Soft Tissue and Bone Sarcoma
Ovarian
Bladder
Melanoma
Colon
Prostate
Non Hodgkins Lymphoma
Brain
Kidney
Acute Myelogenous Leukemia
Rectal
Testicular
Myelodysplastic Syndromes
Gastric
Pancreatic
Acute Lymphocytic Leukemia
Cervical
Endometrial
Esophageal
Liver
Hodgkins Disease
Mesothelioma
AIDS
Osteosarcoma
Chronic Myelogenous Leukemia
Chronic Lymphocytic Leukemia
Multiple Myeloma
Biliary Tract
Solid Tumors, Unspecified
Refractory Lymphoid Neoplasms
Uterine
Colorectal
Vulvar
Fallopian Tube
Anal
Thyroid
Number of protocols
68
60
40
37
31
28
28
27
25
24
23
21
19
18
16
14
13
12
12
10
9
8
7
7
7
5
5
5
5
4
3
3
2
2
2
2
1
1
1
6.5-21
(3)
Percentage of total
(4)
Cumulative percent
10.9%
9.6%
6.4%
5.9%
5.0%
4.5%
4.5%
4.3%
4.0%
3.9%
3.7%
3.4%
3.1%
2.9%
2.6%
2.3%
2.1%
1.9%
1.9%
1.6%
1.4%
1.3%
1.1%
1.1%
1.1%
0.8%
0.8%
0.8%
0.8%
0.6%
0.5%
0.5%
0.3%
0.3%
0.3%
0.3%
0.2%
0.2%
0.2%
10.9%
20.6%
27.0%
33.0%
37.9%
42.4%
46.9%
51.3%
55.3%
59.2%
62.9%
66.2%
69.3%
72.2%
74.8%
77.0%
79.1%
83.1%
85.0%
86.7%
88.1%
89.4%
90.5%
91.6%
92.8%
93.6%
94.4%
95.2%
96.0%
96.6%
97.1%
97.6%
97.9%
98.2%
98.6%
98.9%
99.0%
99.4%
99.5%
Chapter 6.5: Cancer and Cancer Therapeutics
Tumor site
Number of protocols
Primary Cutaneous Lymphomas
Neuroendocrine
Uveal
7.2
1
1
1
(3)
Percentage of total
(4)
Cumulative percent
0.2%
0.2%
0.2%
99.7%
99.8%
100.0%
Summary of U.S. Trial Protocols
We searched the U.S. clinical trials database (http:www.clinicaltrials.gov) for the number of
trials (total trials 4973) corresponding to the following cancers (list taken from Tables 1A
through 1D).
Table 7.2
Total number
Percent of total cancer trials
Leukemias
Lymphoma and multiple
myeloma
804
16.2%
769
15.5%
Breast
Tracheal Bronchus Lung
Prostate
606
584
336
12.2%
11.7%
6.8%
Ovarian
Oral, pharynx
Colon and rectal
Melanoma
Liver
Uterine
Stomach (gastric)
Bladder
Pancreas
Cervical
Oesophagus
324
263
261
211
188
152
113
104
100
89
69
6.5%
5.3%
5.2%
4.2%
3.8%
3.1%
2.3%
2.1%
2.0%
1.8%
1.4%
6.5-22
Chapter 6.5: Cancer and Cancer Therapeutics
7.3
Comparative Trials
The vast majority of clinical trials are randomized, placebo-controlled trials but to gain
information about real world clinical effectiveness of medicines on the market intended for
human use, head-to-head comparative trials are needed. We reviewed the above-referenced
NIH database in a preliminary way using various search terms to find clinical trial protocols
comparing one drug to another. We obtained a total of 206 entries- about 5% of total cancer
trials using this search strategy. However, these clinical trials include trials that compare
non pharmacological interventions. We actually found only 58 drug to drug cancer trials.
Four of these comparative (4/58 = 6.9%) are in Phase I, fourteen (14/58= 24%) are in phase II
and forty (40/58= 69%) are in phase III.
7.4
Analysis of Cancer Therapeutics: U.S. Pharmaceutical Industry
We looked at the U.S. pharmaceutical industry association (PhRMA) website
(http:www.phrma.org) and tallied the total number of therapeutics for all types of cancer.
We found 317 drugs based on this “data mining” exercise. The breakdown of these 317
medicines is tabulated below in Table 7.4.
Table 7.4
Cancer
Number of medicinesi
Breast
Tracheal Bronchus
Lung
Prostate
Ovarian
Melanoma
Pancreas
Colon and rectal
Cervical
Lymphoma and
multiple myeloma
Liver
Leukemias
Bladder
Stomach (gastric)
Oesophagus
Uterine
Oral, pharynx
63
51
44
42
23
22
21
11
9
7
6
6
5
4
3
0
The number of medicines for each cancer is the number of different medicines for that cancer type,
but there are 317 total medicines, but not 317 DIFFERENT medicines since many of the same
interventions will be used for different cancers.
i
6.5-23
Chapter 6.5: Cancer and Cancer Therapeutics
7.5
Analysis of Cancer Therapeutics by EORTC
We performed a similar analysis for the medicines used in clinical protocols found on the
EORTC database). See Section 8.12.
Table 7.5
Cancer
7.6
Number of medicines
Breast
Melanoma
29
28
Lung
Leukemias
27
23
Ovarian
19
Lymphomas, multiple myeloma
Colorectal
19
17
Prostate
Renal
14
13
Gastric
Pancreatic
11
10
Uterine
8
Cervical
Bladder
7
7
Liver
Oral, pharynx
5
5
Esophageal
3
Summary of Investigational New Drugs (U.S.)
These 317 medicines in the PhRMA database include investigational new drugs (INDs) as
well as older, established medicines being used in new indications. We separately searched
the NIH clinical trials database for all trials involving “investigational new drugs”. This term
has a specific legal meaning according to the U.S. FDA and essentially is a new therapeutic
product that has been approved for clinical development. The data generated in lab and
animal tests suggest its effectiveness in treating a human disease. We analyzed data for
investigational new drugs from the set of major cancer types found in Table 1A . We found
57 INDs, consisting of 41 different molecular entities.ii Of these 57 INDs, 11 are in phase I
(19.2%), 39 in phase II (68%), and 7 in phase III (12%). Results are in Table 7.6. From our
information developed on the 317 medicines in clinical trials in Section 7.3, we infer that a
majority of “drugs trials” involve already marketed drugs tested in combination or in new
indications or with a different schedule.
We made one assumption, namely that if the IND chemical was labeled “unknown” and this
appeared in trials for different cancers, then the respective molecular entities were different.
ii
6.5-24
Chapter 6.5: Cancer and Cancer Therapeutics
Table 7.6
Type of cancer
Number of INDs
11
10
6
6
5
5
4
3
3
1
1
1
1
Breast
Lung
Prostate
Renal
Lymphs and myelomas
Leukemias
Brain
Colorectal
Ovarian
Melanoma
Uterine
Pancreas
Gastric
7.7
Does Market Size Drive the Cancer pipeline?
Do these myriad of cancer medicines and numbers of cancer trials bear any relationship to
the size of the cancer market? One could a priori expect that, regardless of whether supported
by the public or private sectors, the number of therapeutics in clinical trials are ultimately
driven by the size of the cancer market.
For a given cancer type, we predicted the number of INDs in clinical trials by scaling the
number of INDs for that cancer in clinical cancer trials to some measure of the incidence of
the given cancer type.iii We scaled the number of INDs in clinical trials for a given cancer by
the following factor: incidence of cancer type/total incidence of all cancers. Thus, if the total
number of INDs for all cancers in clinical trials is 100, and breast cancer incidence is 10% of
the total incidence of all cancers, we predict there should be 10 INDs for breast cancer (100 *
(0.10)) if cancer R&D is driven entirely by the “market” (i.e., the number of new cases of
breast cancer each year). Incidence of all cancers in the U.S. is derived from reference [21].
We only have data for incidence of the most common cancers for Euro(A)iv as opposed to the
25 countries of the European Union, so we performed this same analysis for information on
medicines in clinical trials in the EORTC using Euro(A) incidence data.
Figure 7.7A shows the relationship between the actual number of medicines in the EORTC
trials for cancers (shown on the X axis) and the predicted number of medicines (based on
Euro(A) incidence data for females) for these cancers.v
It may well be that, given the chronic and often insidious (i.e., asymptomatic) nature of some cancers, we
should use prevalence as a better estimator of the cancer burden. Total prevalence is the number of persons in a
defined population alive at a given time who have had cancer diagnosed at some time in the past. [reference 8]
The incentives for R&D with regard to treating newly diagnosed patients may be very different from those for
supporting long-term survivors. We have used incidence data, however, because it was more readily available
and this analysis should be repeated using prevalence.
iv WHO Global burden of disease database: Euro (A) = Andorra, Austria, Belgium, Croatia, Czech Republic,
Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, Malta, Monaco,
Netherlands, Norway, Portugal, San Marino, Slovenia, Spain, Sweden, Switzerland, United Kingdom.
v These figures show the data as a continuous function but they are not, as the data are discrete and could also
be shown as a series of vertical bar graphs. The connected points are, however, easier to visualize.
iii
6.5-25
Chapter 6.5: Cancer and Cancer Therapeutics
6.5-26
Chapter 6.5: Cancer and Cancer Therapeutics
Figure 7.7B shows the relationship between the actual number of medicines in the EORTC
trials for cancers (shown on the X axis) and the predicted number of medicines (based on
Euro(A) incidence data for both sexes) for these cancers.
6.5-27
Chapter 6.5: Cancer and Cancer Therapeutics
Figure 7.7C shows the relationship between the actual number of INDs in the U.S. (2003) for
cancers shown on the X axis and the predicted INDs (based on incidence data for both sexes)
for these cancers.
Figure 7.7D
Figure 7.7D (above) shows the relationship between the actual number of INDs in clinical
trials in the U.S. (2003) for the cancers shown on the X axis and the predicted number of
INDs (based on incidence data for females) for these cancers.
6.5-28
Chapter 6.5: Cancer and Cancer Therapeutics
Figure 7.7E (above) shows the relationship between the actual number of cancer therapeutics
in clinical trials in the U.S. (2003) for the cancers shown on the X axis and the predicted
number of therapeutics (based on incidence data for both sexes) for these cancers.
Figure 7.7F (below) shows the relationship between the actual number of cancer
therapeutics in clinical trials in the U.S. (2003) for the cancers shown on the X axis and the
predicted number of cancer therapeutics (based on incidence data for females only) for these
cancers.
The above data probably does not warrant a statistical analysis. The principal, and
rebuttable, assumption is that incidence is a proxy for “market size” and Figure 7.6F in
6.5-29
Chapter 6.5: Cancer and Cancer Therapeutics
particular shows a remarkably consistent relationship between the number of medicines in
clinical trials for a given cancer and incidence (e.g., size of the market) of that cancer- a
proposition that makes intuitive sense. It appears from this crude analysis that the
pharmaceutical industry is correctly judging their efforts and that overall drug development
for most cancers in the public and private sectors is roughly congruent with the
incidence/market for that cancer. This should be not a surprise to anyone. Various cancers
might be underrepresented or overrepresented (melanoma, pancreas) based on “market” but
the limits of the data cannot suggest a more nuanced statement.
8.
Public Funding for Cancer R&D
8.1
Europe
It is difficult to obtain information on how much money is being spent on cancer research in
Europe on a yearly basis. The presence of Framework Programs provide “top down”
funding but there is less information regarding “bottom up” support from the EU for
contracts and grants to researchers based on peer-reviewed merit.
8.1.1
United Kingdom
In 2003/4, the National Health Service (NHS) received from the government £68.7
billion (nearly $140 billion USD) - an increase of nearly 40%, or £19.4 billion more,
than the £49.3 billion budget of 2000. An estimated £335 million (US $517 million) is
spent each year on basic research, treatment and prevention for all cancers. A recent
report by the National Cancer Research Institute (NCRI) provided the first detailed
analysis of cancer research spending by the UK government and charities.47 There are
some mismatches between actual research funding and cancer burden. Although
lung, stomach and pancreatic cancers are among the most fatal, less money is spent
on research into their causes and treatments than on other types of cancer.
Specifically, although lung cancer accounted for about 22% of cancer deaths in Britain
in 2000, it receives only 3% of the research budget, while leukemia, which causes 3%
of deaths, gets 18% of the money. For other cancers, the relative proportion of
funding is in line with the number of cases of the disease and death rates. Breast
cancer accounts for 18% of funding, colon and rectal cancer have about 12% of the
funds, and prostate cancer accounts for 9% of the money. 48
8.1.2
France
In early 2003, the French government announced a new "Cancer Plan" covering all
aspects of treatment and prevention, and costed at €640m over five years. 49 The
cancer plan also aims to give a new impetus to cancer research, with a planned
additional investment in research over the next five years of around €100m (~£70m).
An overall research strategy will be developed by a new National Cancer Institute
(INCa), established in April 2004. Three priority areas for research have been
identified:
Epidemiology and social sciences: Social science research will focus on public health
education, quality of life for the patient, health economics and cost/benefit of different
treatments. Epidemiological studies will address environmental risk factors,
nutrition, and exposure to carcinogens in the workplace.
6.5-30
Chapter 6.5: Cancer and Cancer Therapeutics
Functional genomics: Research will use proteomic and genomic analysis and tumor
genotyping to identify new target molecules for therapeutic and diagnostic purposes.
Clinical research: The long-term aim is for 10% of patients in larger regional
hospitals and 5% of other patients to be included in clinical trials.49
The institute will have an annual budget of €90m (€11m has already been made
available). Funding will also come from private sources and donations. Eighty five
percent of the annual budget will be devoted to research funding. The remainder of
funds will be devoted to information and prevention campaigns and evaluation of
care and policy. It is anticipated that cancer research programs will be launched in
childhood cancers, cancers of the elderly and rare cancers. Clinical research will also
be an important priority, with INCa coordinating large scale national clinical trials.
INCa will fund cancer research in part through acting as a funding agency similiar to
the UK's research councils, issuing calls for proposals open to all French public
research and universities.49 This part of INCa's work is modeled on the US National
Cancer Institute.
A recent report has been openly critical of Europe’s failure to follow through on a
policy of boosting research spending to 3% of gross domestic product (GDP) by 2010.
50
That ambitious policy was proposed in 2002 during the European Council’s
Barcelona round.The European Commission has made proposals suggesting an
increase in the portion of funds allocated to research. That would see a rise from the
current level of about €5 billion up to €12 billion in the next funding period (the
Seventh Framework from 2007–2013) or roughly €2 billion per year for all basic
research.51
8.1.3
Sixth framework program
Several programs in the Sixth EU Framework are related to cancer therapeutics,
although their funding is presently under negotiation.52
 Understanding the role of hypoxia and factors regulating it, in tumor
development.

Characterizing a subset of mutations in the p53 gene that bring about a gain of
function. This information might be used to predict responses to conventional
chemotherapy, as well as in prognosis.

Developing a rational basis for developing inhibitors of specific proteases in
selected cancers.

Using isolated human stem cells form different sources including bone
marrow / blood and epithelial tissues to repair normal tissue damaged during
radiation treatment.

Identifying novel cancer-related genes expected to play an important role in
the diagnosis and treatment of cancer.

Generating an array of kinase substrates that play a crucial role in mitosis and
that might be disregulated in cancers.
6.5-31
Chapter 6.5: Cancer and Cancer Therapeutics

Creating a network of clinical trials in the fields of leukemia and breast cancer.

Building a tumor tissue collection and analysis network to conduct pilot
studies for addressing the question, whether or not adjuvant therapies can be
omitted from patients whose probability of developing metastatic disease is
low.

Setting up of a network of excellence that makes sample banks and
population registries available for population-based molecular epidemiology
projects.

Developing a network of European molecular imaging laboratories for early
stage diagnosis as well as therapeutic and prognosis assessment of cancer.
8.1.4
The European Organisation for Research and Treatment of Cancer (EORTC)
The EORTC was established in 1962 in Belgium under the initial title ‘Groupe
Européen de Chimothérapie Anticancéreuse and became the EORTC in 1968. It is an
international non-profit research organisation operating as an association under
Belgian law. It is designed set up a research organisation in Europe that would
promote and co-ordinate high-quality laboratory research and clinical trials and
provides a base of scientific expertise and administrative support for a network of
scientists and clinical investigators. EORTC currently links a network of more than
2,500 pre-clinical scientists and oncologists from 32 countries. It encompasses all
aspects of cancer research, from basic laboratory research and new drug development
to large phase III clinical trials and meta-analyses. Around 100 protocols are
permanently open to recruitment and every year about 7,000 new patients - over 85%
within the EU – are treated in EORTC trials.
The EORTC Data Center in Brussels has received continuous support for 30 years
from the US National Cancer Institute (NCI). The ultimate goal of the EORTC is to
improve the standard of cancer treatment in Europe by developing new drugs and
other innovative approaches or modalities, and to test more effective treatment
strategies using commercial available drugs, or surgery and radiotherapy. Within
Phase III trials the EORTC conducts parallel quality of life studies and health
economics evaluations. The EORTC website is: http://:www.eortc.be.org.
8.2
United States
8.2.1
The National Cancer Institute (NCI)
The National Cancer Institute (NCI), established under the National Cancer Act of
1937, is the USA’s Federal Government's principal agency for cancer research and
training. The NCI is a component of the National Institutes of Health (NIH), one of
eight agencies that compose the Public Health Service (PHS) in the Department of
Health and Human Services (DHHS). Funding for the National Institutes of Health
for 2005 is set at $28.757 billion, an increase of 2.6 percent. Of that amount, NCI by
itself would receive $4.87 billion. We note that the French cancer plan (Section 8.1.2)
is funded at about $120 million a year for 5 years and the NHS budget is about $500
million per year (Section 8.1.1).
6.5-32
Chapter 6.5: Cancer and Cancer Therapeutics
The National Cancer Institute supports and co-ordinates research projects conducted
by universities, hospitals, research foundations, and businesses throughout this
country and abroad through research grants and co-operative agreements. It
conducts research in its own laboratories and clinics and, among other things,
supports a national network of cancer centers. The NCI’s website is:
http://www.cancer.gov.
9. Ways Forward from a Public Health Viewpoint with Regard to
Public Funding
9.1
Gaps Between Current Research and Potential Research Issues which Could
Make a Difference.
The therapeutic pipeline is dynamic and significant private sector funding is being put into
the cancer R&D system. There remain gaps between current and potential issues that could
make a difference.

Basic knowledge of cancer and resistance to therapy
There are still many unmet medical needs in cancer treatment and these should be
well known to those with the relevant expertise. Progress in the treatment of lung
cancer has been very limited53 as the majority of cases are diagnosed at a late stage.
The benefit of adjuvant chemotherapy for kidney cancer is considered unproven. 54
Survival rates for some childhood cancers such as acute myeloid leukemia are still
low. As no cure is yet available, a strong unmet medical need exists for innovative
new therapies for chronic lymphocytic leukemia.55 The existing literature only
contributes marginally to our knowledge concerning the burden of bladder cancer
and new and innovative pharmaceutical and other technologies are badly needed.32

Getting promising drug candidates for rare cancers “off of the shelf”
Notwithstanding the looming importance of pharmacogenomics, large
pharmaceutical firms still face significant pressures to produce drugs targeted at
large patient populations. This business strategy often deters investments in
treatments for rare, life-threatening diseases. More significantly for the present
review, this business strategy often allows drug candidates to remain untested for
these rare conditions.

Comparative trials
Placebo controlled clinical trials provide important information but do not answer
questions about the drug’s benefit relative to other drugs in the same class or relative
to other treatment types. This type of information is often important to health
planners at all levels of government. Although indirect comparisons of two drugs
based on separate placebo controlled trials may suggest one is better than the other,
such comparisons are often not conclusive.56 There are many reasons why head-tohead comparisons are rare (See Background Document in Final Report). Some are
related to financing, regulation and business aspects. Head-to-head studies provide
critical information about efficacy and safety and therefore they should be considered
and either funded entirely by the public sector or co-funded by the public sector.
6.5-33
Chapter 6.5: Cancer and Cancer Therapeutics
10.
Conclusion
There is momentum building within the EU for a EU-wide program to support funding in
the basic sciences. Cancer research will presumably be a beneficiary. A recent meeting
sponsored by the Irish government, the current holder of the EU presidency- with support of
the European Commission (REF) attempted to draw a consensus about the state of European
basic science and whether new EU action was needed.57 Representatives of 27 countries
(current EU states, accession states, allied countries) unanimously agreed on a set of
conclusions regarding the state of EU basic science. Some of these conclusions are
summarized below and are specifically relevant to cancer research as well:

There is a need to create a more attractive basic research environment, supported by
high quality education, appropriate research funding, research infrastructure, and
science-innovation links, where top quality researchers can be recognized and can
excel.

Industry also needs high-quality research including implementation of the
knowledge generated through basic research, as a basis for competitiveness.

A European initiative is required to promote excellence in basic research by
promoting international competition among individual research teams. The sole
selection criterion should be excellence, identified by international peer review.

There is a need to provide specific funding for basic research of high quality, in the
next Framework Program (7th.

The European Commission should bring forward to the Competitiveness Council
proposals for the governance, management and accountability of a European
initiative to be funded in large part via awarding of individual grants on a
competitive basis.
The European Commission should make proposals regarding financial perspectives of
research, suggesting an increase in funding allocated to research. The research agenda
should be set by scientific excellence alone.
The EU should continue to pursue excellence in cancer research within the existing financing
structures. Cancer R&D is proceeding but it still is extremely challenging. Many cancers are
still refractory to treatment and survival is low. The following quote with regard to the U.S.
in our view reasonably sums up the situation:
If the government`s role in reducing AIDS mortality represents a great victory for the
idea that directed research campaigns can substantially affect the history of an epidemic, the
war on cancer is an entirely different matter. For more than half a century, all the weapons of
directed medical research-extramural grants to academic researchers, intramural programs of
research and drug development, public-private partnerships, and outright support of
industry- have been deployed against cancer with far less satisfactory results.58
Research in basic cancer biology in the EU as well as drug development should
continue as presently supported, bearing in mind that substantial resources are already
being devoted to this by the United States.
6.5-34
Chapter 6.5: Cancer and Cancer Therapeutics
References
1 Doll R and Peto R. 1981 The causes of cancer. Journal of the National Cancer Institute 66: 1191–308.
2 World Health Organization 1995. National Cancer Control Programmes: Policies and management
guidelines. Geneva: World Health Organization.).
3 Textbook of Therapeutics: Drug and Disease Management Seventh Edition edited by Eric T.
Herfindal and Dick R. Gourley
4 Wiley Textbook of Uncommon Cancer, 2nd Edition D. Raghavan (Editor), M. L. Brecher (Editor), D.
H. Johnson (Editor), N. J. Meropol (Editor), P. L. Moots (Editor), J. T. Thigpen (Editor) ISBN: 0-47192921-2, 776 pages
5 E. van der Schueren,, K. Kesteloot, I. Cleemput, Federation of European Cancer Societies. Full
Report.
2000. Economic evaluation in cancer care: questions and answers on how to alleviate conflicts between
rising needs and expectations and tightening budgets European Journal of Cancer 36 : 13-36.
6 World Cancer Report, 2003, World Health Organization, International Agency for Research on
Cancer, at http://www.iarc.fr/WCR
7 GLOBOCAN 2000 available GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence
Worldwide, Version 1.0. IARC CancerBase No. 5. Lyon, IARCPress, 2001.http://wwwdep.iarc.fr/globocan/globocan.html
8 Bray F, Sankila R, Ferlay J, Parkin DM. Estimates of cancer incidence and mortality in Europe in
1995. 2002. Eur J Cancer 38:99-166.
9 Shibuya, K, Mathers CD, Boschi-Pinto C, Lopez AD, & Murray CJL. 2003. Correction: Global and
regional estimates of cancer mortality and incidence by site: II. results for the global burden of disease
BMC Cancer. 3 (1): 20
10 Bray F, Guerra M, Guerra YI, & Parkin DM. 2003. The Comprehensive Cancer Monitoring
Programme in Europe, European Journal of Public Health, 13 (3 Supplement): 61-66.
11 Lutz JM, Francisci S, Mugno E, Usel M, Pompe-Kirn V, Coebergh JW, Bieslka-Lasota M; 2003.
EUROPREVAL Working Group, Cancer prevalence in Central Europe: the EUROPREVAL Study.
Ann Oncol. 14:313-322.
12 Coleman MP, Estève J, Damiecki P, Arslan A, Renard H. 1993. Trends in cancer incidence and
mortality. Lyon: International Agency for Research on Cancer, IARC Scientific Publications No.121.)
13 Micheli A, Yancik R, Krogh V, et al. 2002. Contrasts in cancer prevalence in Connecticut, Iowa, and
Utah. Cancer 95:430-439.
14 . Estève J, De Angelis G, Verdecchia A. Trends in cancer survival probability over the period 197889. In: Berrino F, Capocaccia R, Estève J, et al. Survival of Cancer Patients in Europe: the EUROCARE2 Study. Lyon: International Agency for Research
6.5-35
Chapter 6.5: Cancer and Cancer Therapeutics
15 Coebergh JWW, Sant M, Berrino F, Verdecchia A, editors. Survival of adult Cancer Patient in
Europe Diagnosed from 1978-1989: The EUROCARE II Study. European Journal of Cancer
1998;34:2137-271.
16 Dobrossi L. 2002. Cancer Mortality in central-Eastern Europe: facts behind the figures. Lancet
Oncology, 3:374-81.
17 Antunes JL, Toporcov TN, de Andrade FP . 2003. Trends and patterns of cancer mortality in
European countries. Eur. J. Cancer Prev. 12: 367-372,.
18 Brennan P, I. Bray. 2002. Recent trends and future directions for lung cancer mortality in Europe.Br
J Cancer.87:43-48.
19 Botha JL, Bray F, Sankila R, Parkin DM. 2003. Breast cancer incidence and mortality trends in 16
European countries. Eur J Cancer. 39(12):1718-29.
20 Sant M, Capocaccia R, Coleman MP, Berrino F, Gatta G, Micheli A, Verdecchia A, Faivre J,
Hakulinen T, Coebergh JW, Martinez-Garcia C, Forman D, Zappone A. 2001. Cancer survival
increases in Europe, but international differences remain wide. EUROCARE Working Group. Eur J
Cancer. 37:1659-67.
21 Jemal A, Tiwari, RC; Murray T; Ghafoor A; Samuels A, Ward E, Feuer EJ, & Thun MJ, 2004.
Cancer Statistics, CA Cancer J Clin 54:8–29.
22 Moertel CG, Fleming TR, Macdonald JS et al. 1990. Levamisole and fluorouracil for adjuvant
therapy of resected colon carcinoma, NEJM 322: 353-358.
23 Mariotto A, Feuer EJ, Harlan LC, Wun LM, Johnson KA, Abrams J. 2002. Trends in use of adjuvant
multi-agent chemotherapy and tamoxifen for breast cancer in the United States: 1975-1999, JNCI 94:
1626-1634.
24 DeVita VT Jr, Canellos GP, Chagner B, Schein P, Hubbard SP, Young RC. 1975. Advanced diffuse
histiocytic lymphoma, a potentially curable disease. Lancet 1: 248-250.
25 Agarwala S. 2003. , Improving survival in patients with high-risk and metatstatic melanoma:
immunotherapy leads the way. Am. J. Clin. Dermatol. 4:333-346.
26 Nadal E., Olavarria E. 2004. Imatinib mesylate (Gleevec/Glivec) a molecular-targeted therapoy for
chronic myeloid leukemia and other malignancies. Int. J. Clin. Pract. 58: 511-516.
27 World Health Organization, National Cancer Control Programmes, Policies and Managerial
Guidelines, 2nd edition, (ISBN 92 4 154557 7), WHO Geneva 2002.
28 Bennett, JA, Brewer C. Beyko S., Bennett SAL. 1999 Cancer Control Strategies in Eleven OECD
Countries at aix1.uottawa.ca/~sbennet/OECDStrategy.pdf, last accessed 4 August 2004.
29 Canadian Strategy for Cancer Control 2002 Canadian Strategy for Cancer Control. 2002.
Supportive Care/Cancer Rehabilitation Workgroup Final Report. URL: at
http://209.217.127.72/cscc/pdf/finalsupportiveJan2002.pdf., last accessed 2 August 2004.
30 P. Boyle, A. d’Onofrio, P. Maisonneuve, G. Severi, C. Robertson, M. Tubiana & U. Veronesi. 2003.
6.5-36
Chapter 6.5: Cancer and Cancer Therapeutics
Measuring progress against cancer in Europe: has the 15% decline targeted for 2000 come about?
Annals of Oncology 14: 1312–1325.
31 Redaelli A, Cranor CW, Okano GJ, Reese PR.. 2003. Screening, prevention and socioeconomic costs
associated with the treatment of colorectal cancer. Pharmacoeconomics. 2003;21:1213-38.
32 Botteman MF, Pashos CL, Redaelli A, Laskin B, Hauser R. 2003. The health economics of bladder
cancer: a comprehensive review of the published literature. Pharmacoeconomics. 21:1315-30.
33 Jemal A, Thomas A, Murray T and Thun M Cancer Statistics –2002. CA Cancer J Clin. 52:23-47
34 Armstrong B and Doll R . 1975. Environmental factors and cancer incidence and mortality in
different countries, with special reference to dietary practices. Int J Cancer 15:617-631.
35 Greenwald P. 2002. Science, medicine, and the future: Cancer chemoprevention
BMJ, 324:714-718.
36 Hursting SD, Slaga TJ, Fischer SM, DiGiovanni J, Phang JM. 1999. Mechanism-based cancer
prevention approaches: targets, examples, and the use of transgenic mice. J Natl Cancer Inst.91:215-25.
37 Chemoprevention Working Group. 1999. Prevention of cancer in the next millennium: report of the
Chemoprevention Working Group to the American Association for Cancer Research. Cancer Res.
59:4743-58.
38 Smith-Warner SA, Giovannucci E. Fruit and vegetable intake and cancer. In: Heber D, Blackburn
GL, Go VLW, eds. Nutritional oncology. San Diego: Academic Press, 1999:153-83.
39 Huang M-T, Asawa T,Ho C-T, Rosen RT, eds. Food phytochemicals for cancer prevention I—fruits
and vegetables. Washington, DC: American Chemical Society, 1994.
40 Kurzrock R, Kantarjian H and Talpaz M. 2001. Chronic myelogenous leukemia in chronic phase.
Curr Treat Options Oncol 8:245-252.
41 Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich
MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B,
Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD and Joensuu H. 2002. Efficacy and safety of
imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 347:472-48
42 NYTIMES Drugs May Turn Cancer Into Manageable Disease ANDREW POLLACK, June 6, 2004,
www.newyorktimes.com
43 Srinivasan*R and Wolchok JD. 2004. Tumor antigens for cancer immunotherapy: therapeutic
potential of xenogeneic DNA vaccines . Journal of Translational Medicine 2:12 , at
http://www.translational-medicine.com/content/2/1/12, last accessed 1 August 2004.
44 Challis GB, Stam HJ. 1990. The spontaneous regression of cancer. A review of cases from 1900 to
1987. Acta Oncol. 29:545-550.
45 Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A,
Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G. 2003. Intratumoral T cells, recurrence, and
survival in epithelial ovarian cancer. N Engl J Med 348:203-213.
6.5-37
Chapter 6.5: Cancer and Cancer Therapeutics
46 Apolone G., 2003. Clinical and Outcome Research in oncology The need for integration Health and
Quality of Life Outcomes 2003, 1:3 available from: http://www.hqlo.com/content/1/1/3
47 National Cancer Research Institute, at http://www.ncri.org.uk/home/index.cfm, last accessed 11
July 2004.
48 BBC News, press release, at http://news.bbc.co.uk/1/hi/health/3520068.stm, last accessed 4 July
2004.
49 British Embassy Paris, 17 July 2003, at http://www.britishembassy.gov.uk, last accessed 9 July 2004.
50 European Commisstion, at http://europa.eu.int/comm/research/era/pdf/com3percent_en.pdf.
Brussels, 11.9.2002 COM(2002) 499 final COMMUNICATION FROM THE COMMISSION
51 Bosch, X. November 25,2003 Call to raise EU science funds Parliamentary support for a report
urging lots more cash | By Xavier Bosch], available at
http://www.biomedcentral.com/news/20031125/06/, last accessed 3 August 2004.
52 European Commission-Research 6th framework at http://europa.eu.int/comm/research/fp6.
53 Spira, A, Ettinger DS, Multidisciplinary management of lung cancer, NEJM 2004, 350: 379-392
54 Jemal A , Clegg LX, Ward E, Ries LAG, Wu X, Jamison PM et al., 2004. Annual Report to the Nation
on the Status of Cancer, 1975-2001, with a Special Feature regarding survival, Cancer 101: 3-27
55 Redaelli A., Laskin BL., Stephens JM., Botteman MF. & Pashos CL. 2004 The clinical and
epidemiological burden of chronic lymphocytic leukaemia. European Journal of Cancer Care 13 : 279–
287
56 McAlister FA, Laupacis A, Wells GA and Sackett DL. 1999. User’s guide to the Medical Literature:
XIX: Applying clinical trial results. B. Guidelines for determining whether a drug is exerting (more
than) a class effect. JAMA 282:1371-1377.
57 CORDIS press release, Signs of change in EU science "Europe's Search for Excellence in Basic
Research"
High Level Symposium on Excellence in Basic Research in Europe Brussels, 12. February 2004, at
http://www.cordis.lu/press-service/20040213.htm.
58 Goozner M. 2004. The $800 Million Pill. , page 164. University of California Press
6.5-38