Chapter 6.5: Cancer and Cancer Therapeutics

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 October2004

Table of Contents

Executive Summary

Burden of Disease

Treatment Options

Pipeline of Potential Products

Public and Private Funding

1.Introduction to cancer therapeutics

2. What are the Epidemiological Trends for Europe and the World?

2.1 Global Perspective

2.2 Cancer in Europe

2.3 Specific cancers

2.4 Cancer Survival Rates

2.5 Trends in Cancer in the United States

3. What is the Control Strategy? Is There an Effective Package of Control Methods Assembled Into a “Control Strategy” for most Epidemiological Settings?

3.1 Prevention

3.2 Early Detection and Screening

3.3 Diagnosis and Treatment

3.4Support and Rehabilitation

3.5 Palliative Care

4. What is Known of the Affordability, Feasibility, and Sustainability of the Control Strategy?

Economic Burden

5. Why Does the Disease Burden Persist?

6. What can be Learnt from Past/Current Research into Pharmaceutical Interventions for this Condition?

6.1Chemoprevention and Biomarkers

6.2Targeted Therapy: Cancer as a “Chronic” Disease

6.3Tumor Vaccines

6.4 The role of “Outcomes Research:

7. What is the Current “Pipeline” of Products that Are to Be Used for this Particular Condition?

7.1Summary of European Trial Protocols

7.2Summary of U.S. Trial Protocols

7.3Comparative Trials

7.4 Analysis of Cancer Therapeutics: U.S. Pharmaceutical Industry

7.5 Analysis of Cancer Therapeutics by EORTC

7.6Summary of Investigational New Drugs (U.S.)

7.7Does Market Size Drive the Cancer pipeline?

8. Public Funding for Cancer R&D

8.1Europe

8.2United States

9. Ways Forward from a Public Health Viewpoint with Regard to Public Funding

9.1Gaps Between Current Research and Potential Research Issues which Could Make a Difference.

10. Conclusion

References

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.

Pipeline ofPotential 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:

• 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

1.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 cancerat 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 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 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.
• 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.

2.2 Cancer in Europe

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 one-eighth 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]

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

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

2.2.2 European Union (15 Member States)

The EUCAN databaseholds 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 Switzerlandthe 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]