Bohomolets Oncology Lecture year 5

CancerCancer

is the term used to describe is the term used to describe uncontrolled cell growth which uncontrolled cell growth which can lead to tumour formationcan lead to tumour formation

may be either may be either benign benign (noninvasive growth, no (noninvasive growth, no

metastases) metastases) malignant malignant (invasive growth, (invasive growth,

metastases).metastases).

Cancer will have a direct Cancer will have a direct effect on 1 in 3 people during effect on 1 in 3 people during their lifetime. Our increased their lifetime. Our increased life expectancy and modern life expectancy and modern lifestyles (diet, smoking, lifestyles (diet, smoking, alcohol and stress) all act as alcohol and stress) all act as contributory factors. The contributory factors. The most common cancers most common cancers amongst men are prostate, amongst men are prostate, colorectal and lung with the colorectal and lung with the incidence of these cancers incidence of these cancers expected to increase by 57% expected to increase by 57% by 2020(Irish Cancer by 2020(Irish Cancer society). The most common society). The most common cancers amongst women are cancers amongst women are breast, lung and bowel breast, lung and bowel cancers and over the last 20 cancers and over the last 20 years the incidence of breast years the incidence of breast cancer has increased by 50% cancer has increased by 50% (CRUK). 350 000 new cases (CRUK). 350 000 new cases of colorectal cancer are of colorectal cancer are reported in the western world reported in the western world per year while in Europe per year while in Europe there are approximately 430 there are approximately 430 000 new cases of breast 000 new cases of breast

cancer diagnosed every year.cancer diagnosed every year.

Cancer rates could further increase by 50% to 15 Cancer rates could further increase by 50% to 15 million new cases in the year 2020, according to the million new cases in the year 2020, according to the World Cancer Report, the most comprehensive World Cancer Report, the most comprehensive global examination of the disease to date. However, global examination of the disease to date. However, the report also provides clear evidence that healthy the report also provides clear evidence that healthy lifestyles and public health action by governments lifestyles and public health action by governments and health practitioners could stem this trend, and and health practitioners could stem this trend, and prevent as many as one third of cancers worldwide.prevent as many as one third of cancers worldwide.

In the year 2000, malignant tumours were In the year 2000, malignant tumours were responsible for 12 per cent of the nearly 56 million responsible for 12 per cent of the nearly 56 million deaths worldwide from all causes. In many deaths worldwide from all causes. In many countries, more than a quarter of deaths are countries, more than a quarter of deaths are attributable to cancer. In 2000, 5.3 million men and attributable to cancer. In 2000, 5.3 million men and 4.7 million women developed a malignant tumour 4.7 million women developed a malignant tumour and altogether 6.2 million died from the disease. The and altogether 6.2 million died from the disease. The report also reveals that cancer has emerged as a report also reveals that cancer has emerged as a major public health problem in developing countries, major public health problem in developing countries, matching its effect in industrialized nations.matching its effect in industrialized nations.

TypesTypes

Carcinomas Carcinomas are malignancies that are malignancies that arise from epithelium.arise from epithelium.

Adenocarcinomas Adenocarcinomas are malignancies are malignancies that arise from epithelium and have a that arise from epithelium and have a glandular component.glandular component.

Sarcomas Sarcomas are malignancies that are malignancies that arise from mesodermal tissues.arise from mesodermal tissues.

Neoplastic transformation.Neoplastic transformation.

Neoplastic cells have "escaped" from Neoplastic cells have "escaped" from the normal homeostatic inhibition (or the normal homeostatic inhibition (or regulation) of cell proliferation. regulation) of cell proliferation.

Causes of neoplastic transformation Causes of neoplastic transformation are listed below with illustrative are listed below with illustrative examples of human tumors. Because no examples of human tumors. Because no single etiology is known for most human single etiology is known for most human cancer, it is assumed that multiple cancer, it is assumed that multiple factors lead to neoplastic trans factors lead to neoplastic trans formation.formation.

CarcinogensCarcinogens

ChemicalChemical Physical Physical Hereditary factors Hereditary factors Geographic factors Geographic factors Oncogenic virusesOncogenic viruses

Examples of human Examples of human oncogenesoncogenes

Primary prevention is the Primary prevention is the priority in cancer priority in cancer

fighting.fighting. Smoking control Smoking control Dietary factor Dietary factor

an increase in consumption of fresh fruit and an increase in consumption of fresh fruit and vegetables, low-calory products, intensification of vegetables, low-calory products, intensification of physical activity and lowering of body mass produce a physical activity and lowering of body mass produce a reduction in the incidence of cancer of the stomach, reduction in the incidence of cancer of the stomach, large bowel, breast, corpus uteri, prostate. large bowel, breast, corpus uteri, prostate.

Prevention of infection including vaccination is the Prevention of infection including vaccination is the most efficient method for prevention of cancer of most efficient method for prevention of cancer of the liver, cervix uteri, some leukemias and the liver, cervix uteri, some leukemias and lymphomas, H. pylori associated stomach cancer. lymphomas, H. pylori associated stomach cancer.

Control of environmental hazards such as intensive Control of environmental hazards such as intensive ultraviolet radiation, ionizing radiation, air and soil ultraviolet radiation, ionizing radiation, air and soil pollution decrease the rate of skin cancer, pollution decrease the rate of skin cancer, melanoma, etc. melanoma, etc.

The main adaptive mechanisms involved in the carcinogenic process. As a The main adaptive mechanisms involved in the carcinogenic process. As a result of the action of carcinogenic agents, and in relation to the functional result of the action of carcinogenic agents, and in relation to the functional status of the affected cells, a number of systems are triggered off: status of the affected cells, a number of systems are triggered off: detoxification and conjugation systems, the metabolisation of the said agents, detoxification and conjugation systems, the metabolisation of the said agents, DNA repairing enzymes, increased shock proteins (HSP), the induction of DNA repairing enzymes, increased shock proteins (HSP), the induction of clonal proliferation. All these systems are valuable to the survival of the body clonal proliferation. All these systems are valuable to the survival of the body and the species and culminate in the apoptosis of damaged cells as the last and the species and culminate in the apoptosis of damaged cells as the last attempt at adaptation of a social kind for the good of the body. When these attempt at adaptation of a social kind for the good of the body. When these compensation mechanisms prove ineffective, imprecise or are exceeded by compensation mechanisms prove ineffective, imprecise or are exceeded by cell adaptive capacity, the resulting structural and functional alterations cell adaptive capacity, the resulting structural and functional alterations trigger off (induction) a very long process which often lasts between one and trigger off (induction) a very long process which often lasts between one and two thirds of the body's life, in various stages, multistep and multifactorial: two thirds of the body's life, in various stages, multistep and multifactorial: this neoplastic transformation leads to a purposeless, egoistic, anarchic this neoplastic transformation leads to a purposeless, egoistic, anarchic proliferation of cells which wish to survive at all costs, even to the detriment proliferation of cells which wish to survive at all costs, even to the detriment of the body of which they form part. Following the exhaustion of cell adaptive of the body of which they form part. Following the exhaustion of cell adaptive defences, there is an accumulation of additional genetic alterations defences, there is an accumulation of additional genetic alterations (promotion and progression), the cells become manifestly neoplastic and (promotion and progression), the cells become manifestly neoplastic and continue their egoistic adaptation, according to the laws of natural selection: continue their egoistic adaptation, according to the laws of natural selection: the cells which survive are those which adapt best to the hostile environment the cells which survive are those which adapt best to the hostile environment of the host's body, which are unaffected by proliferation control mechanisms of the host's body, which are unaffected by proliferation control mechanisms (contact inhibition, differentiation factors, apoptosis, etc.), which make the (contact inhibition, differentiation factors, apoptosis, etc.), which make the best of the growth factors present in their microenvironment, which best of the growth factors present in their microenvironment, which accomplish the so-called decathlon of the metastatization process, namely accomplish the so-called decathlon of the metastatization process, namely acquiring new capacities which can overcome the basal membrane, invade acquiring new capacities which can overcome the basal membrane, invade tissues to which they are attracted and continue to proliferate. Manifestly tissues to which they are attracted and continue to proliferate. Manifestly neoplastic cells become not self at a later stage, managing to escape the neoplastic cells become not self at a later stage, managing to escape the immune system using various adaptive mechanisms which induce immune immune system using various adaptive mechanisms which induce immune tolerance/anergy. From this point of view, cancer may be regarded as an tolerance/anergy. From this point of view, cancer may be regarded as an incidental factor in the host's cell adaptation processes; the latter are much incidental factor in the host's cell adaptation processes; the latter are much more important from a biological point of view and their absence is more important from a biological point of view and their absence is incompatible with life: cancer might therefore be regarded as a cell incompatible with life: cancer might therefore be regarded as a cell adaptation pathology.adaptation pathology.

Stages of cancerogenesisStages of cancerogenesis

structural and functional alterations structural and functional alterations trigger off - induction trigger off - induction

accumulation of additional genetic accumulation of additional genetic alterations - promotionalterations - promotion

unaffected by proliferation control unaffected by proliferation control mechanisms (contact inhibition, mechanisms (contact inhibition, differentiation factors, apoptosis) - differentiation factors, apoptosis) - progressionprogression

Genetic systems implicated Genetic systems implicated in carcinogenesisin carcinogenesis

There are two main categories of genes involved in There are two main categories of genes involved in cancer: protoconcogenes and tumor suppressor genes. cancer: protoconcogenes and tumor suppressor genes. The development of cancer can require the production of The development of cancer can require the production of several successive gene accidents within a given cell. several successive gene accidents within a given cell. Most of these alterations appear to be somatic changes. Most of these alterations appear to be somatic changes. Only one of these two steps would involve germinal Only one of these two steps would involve germinal processes and only in hereditary tumors. When altered, processes and only in hereditary tumors. When altered, these genes, implicated in cell proliferation, these genes, implicated in cell proliferation, differentiation and normal cell death, contribute to the differentiation and normal cell death, contribute to the initiation and/or the progression of tumors. Other genes initiation and/or the progression of tumors. Other genes have an indirect effect on the malignant transformation have an indirect effect on the malignant transformation and thus complete the action of oncogenes and and thus complete the action of oncogenes and suppressor genes at certain stages of cancerogenesis. suppressor genes at certain stages of cancerogenesis. The genes implicated in individual susceptibility to The genes implicated in individual susceptibility to cancer is an example (genes coding for DNA repair cancer is an example (genes coding for DNA repair enzymes and for proteins which inactivate exogenous enzymes and for proteins which inactivate exogenous cancerogenenic agents. Others are genes coding for cancerogenenic agents. Others are genes coding for growth factors and angiogenic factors, genes involved in growth factors and angiogenic factors, genes involved in metastatic dissemination including those which code for metastatic dissemination including those which code for proteases and adherence proteins, and finally genes proteases and adherence proteins, and finally genes affecting chemoresistance.affecting chemoresistance.

Metastatic progressionMetastatic progression

Acquisition of tumorigenic Acquisition of tumorigenic phenotype and clonalityphenotype and clonality

The Vogelstein model of The Vogelstein model of multistep carcinogenesismultistep carcinogenesis

Intervention period for Intervention period for carcinogenesiscarcinogenesis

Pathogenesis of Pathogenesis of metastasismetastasis

Frequency of metastatic Frequency of metastatic sites sites

Interation between tumour Interation between tumour cells, endothelial cells and cells, endothelial cells and

macrophagesmacrophages

Tumour GradingTumour Grading

well differentiatedwell differentiated middle differentiatedmiddle differentiated poorly differentiatedpoorly differentiated undifferentiatedundifferentiated

Depends on:Depends on: degree of cellular anaplasiadegree of cellular anaplasia mitotic activitymitotic activity

Tumor staging (AJCC, IUAC)Tumor staging (AJCC, IUAC)T describes the primary tumor – the size of the tumour at its T describes the primary tumor – the size of the tumour at its

primary site and/or the involvement of local structures primary site and/or the involvement of local structures describe the tumour topography.describe the tumour topography.

TO: no evidence of primary tumorTO: no evidence of primary tumor TIS (in situ): tumor limited to mucosaTIS (in situ): tumor limited to mucosa T1: tumor limited to mucosa or submucosaT1: tumor limited to mucosa or submucosa TT2: 2: tumor to but not through the serosatumor to but not through the serosa T3: tumor through the serosa but not into adjacent organsT3: tumor through the serosa but not into adjacent organs T4: tumor into adjacent organs (direct extension)T4: tumor into adjacent organs (direct extension)N describes the involvement of regional lymph nodes with N describes the involvement of regional lymph nodes with

metastatic spread.metastatic spread. NO: no metastases to lymph nodesNO: no metastases to lymph nodes N1: only perigastric lymph nodes within 3 cm of the primary N1: only perigastric lymph nodes within 3 cm of the primary

tumortumor N2: only regional lymph nodes more than 3 cm from tumor N2: only regional lymph nodes more than 3 cm from tumor

but removeable at operationbut removeable at operation N3: other intra-abdominal lymph nodes involvedN3: other intra-abdominal lymph nodes involvedM describes documented evidence of distant metastases.M describes documented evidence of distant metastases. M0: no distant metastasesM0: no distant metastases Ml: distant metastasesMl: distant metastases

Stage grouping.Stage grouping. Staging is necessary to choose the Staging is necessary to choose the

appropriate therapy and to assess the appropriate therapy and to assess the prognosis. It also allows investigators to prognosis. It also allows investigators to report their results in a standardized way report their results in a standardized way so that conclusions regarding treatments so that conclusions regarding treatments and their outcomes are interpretable.and their outcomes are interpretable.

Stage 0: TIS, NO, M0Stage 0: TIS, NO, M0 Stage 1: T1, NO, M0Stage 1: T1, NO, M0 Stage 2: T2 or T3, NO, M0Stage 2: T2 or T3, NO, M0 Stage 3: T1-3, N1 or N2, M0Stage 3: T1-3, N1 or N2, M0 Stage 4: any T4, any T3, any N3, any MlStage 4: any T4, any T3, any N3, any Ml

Clinical manifestations of Clinical manifestations of cancercancer

Seven classic symptoms of cancer are:Seven classic symptoms of cancer are: Change in bowel or bladder habitsChange in bowel or bladder habits A sore that does not healA sore that does not heal Unusual bleeding or dischargeUnusual bleeding or discharge Thickening or lump in the breast or Thickening or lump in the breast or

elsewhereelsewhere Indigestion or difficulty swallowingIndigestion or difficulty swallowing Obvious change in a wart or moleObvious change in a wart or mole Nagging cough or hoarsenessNagging cough or hoarseness

Other manifestationsOther manifestations Growth, causing a mass, obstruction, or Growth, causing a mass, obstruction, or

neurologic deficitneurologic deficit Growth into neighboring tissues, causing Growth into neighboring tissues, causing

pain, paralysis, fixation, or immobility of a pain, paralysis, fixation, or immobility of a palpable masspalpable mass

Tumor necrosis, causing bleeding or feverTumor necrosis, causing bleeding or fever Systemic manifestation, such as Systemic manifestation, such as

thrombophlebitis, endocrine symptoms due thrombophlebitis, endocrine symptoms due to hormones secreted by the tumor, and to hormones secreted by the tumor, and cachexiacachexia

Metastatic spread as the first symptom, such Metastatic spread as the first symptom, such as enlarged lymph nodes, neurologic as enlarged lymph nodes, neurologic symptoms, or pathologic bone fracturessymptoms, or pathologic bone fractures

Screening tests for cancer Screening tests for cancer detection.detection.

Mammography (annually after age Mammography (annually after age 40-50)40-50)

Stool for occult blood and digital Stool for occult blood and digital rectal examination (annually after rectal examination (annually after age 50)age 50)

Pap smear of the cervix (every 3 Pap smear of the cervix (every 3 years after two negative tests 1 year years after two negative tests 1 year apart)apart)

Diagnostic proceduresDiagnostic procedures

Types of biopsyTypes of biopsy Aspiration biopsyAspiration biopsy Needle biopsyNeedle biopsy Incisional biopsy Incisional biopsy Excisional biopsy Excisional biopsy Staging laparotomyStaging laparotomy

Imaging studiesImaging studies X-ray images computed tomography (CT scan) ultrasound endoscopic examinations magnetic resonance imaging (MRI) positron emission tomography (PET) radioisotope scanning

bone scanning lymphoscintigraphy

Multimodality cancer Multimodality cancer therapy.therapy.

Basic methodsBasic methods Surgery Surgery RadiationRadiation ChemotherapyChemotherapy Immunotherapy Immunotherapy

Surgery and radiation therapy Surgery and radiation therapy Chemotherapy and immunotherapy Chemotherapy and immunotherapy Neoadjuvant therapyNeoadjuvant therapy Adjuvant therapyAdjuvant therapy

Cancer surgery.Cancer surgery. Curative resection. Curative resection.

Wide local resection. Wide local resection. Radical local resection. Radical local resection. Radical resection with en bloc excision of Radical resection with en bloc excision of

lymphatic drainage lymphatic drainage Super radical resectionsSuper radical resections

Other surgical resectionsOther surgical resections Resection of recurrent cancer Resection of recurrent cancer Resection of metastases Resection of metastases Palliative surgery Palliative surgery DebulkingDebulking

Cytotoxic Cytotoxic chemotherapieschemotherapieshave formed the cornerstone of frontline cancer therapy have formed the cornerstone of frontline cancer therapy

for the last 30 years.for the last 30 years.While effective in some patients this group of drugs has While effective in some patients this group of drugs has been hampered by their toxic side effects, high relapse been hampered by their toxic side effects, high relapse rates and an increasing incidence of drug specific rates and an increasing incidence of drug specific resistance. In recent years the introduction of antibody resistance. In recent years the introduction of antibody targeted therapies has led to major improvements in targeted therapies has led to major improvements in cancer care. The development of antibodies to different cancer care. The development of antibodies to different targets can overcome the resistance observed with targets can overcome the resistance observed with conventional chemotherapies by targeting different conventional chemotherapies by targeting different pathways. The success of several antibody based pathways. The success of several antibody based therapies in the clinic, such as Avastin and Herceptin therapies in the clinic, such as Avastin and Herceptin has increased demand for monoclonal antibody has increased demand for monoclonal antibody therapies with the market expected to reach $26 billion therapies with the market expected to reach $26 billion by 2010. Antibody based therapies are now recognized by 2010. Antibody based therapies are now recognized as key components of modern frontline cancer as key components of modern frontline cancer therapies. Fusion Antibodies oncology research is therapies. Fusion Antibodies oncology research is focused on the discovery, validation and development of focused on the discovery, validation and development of novel therapeutic antibodies for the treatment of cancer.novel therapeutic antibodies for the treatment of cancer.