INTRODUCTION IN CLINICAL ONCOLOGY

Important aspects, challenges, new treatments

Cancer: death sentence or chronic disease?

Of all the common medical diagnoses, cancer probably carries the greatest stigma and is associated with the most fear.

Causes: no signs for early detection, connected with pain, treatment with side effects

Why is threatening

AGRESSIVE DISEASE

Six steps to become a cancer

1. Grow without a trigger (selfsufficiency in growth stimuli).

2. Don ’ t stop growing (insensitivity to inhibitory stimuli)..

3. Don ’ t die (evasion of apoptosis).

4. Don ’ t age (immortalization).

5. Feed themselves (neoangiogenesis).

6. Spread (invasion and metastasis)

STATISTIC DATA

WHO information concerning EU states

2000-2010: mortality rates

– Cardiovascular disease 9,7% ↓

– Respiratory disease 5,8% ↓

– Malignant disease 7,2% ↑

2008-2010 incidency:

EU28 average 273,6

Hu 1. place 375,4

Cancer death in Europe 2011-2012

The incidency of malignant disease in Hungary 2009-2011

Increasing tendency in 2012-2013

Number of death in Hungary

The direction of cancer research What’s new?

• Development of molecular biology, new data from mechanism of carcinogenesis

• Explanation concerning tumor growth, proliferation..

• Analysis of total genom, experimental gene surgery, gene manipulation

• The role of apoptosis , immuno-oncology

Etiology : DNA level

• Cancer : genetic disease,caused by the accumulation over time of changes to the normal DNA sequence

• alterations, loss, or amplification

• nearly all cancers are clonal in origin;

– they originate from a single progenitor cell rather than a group of cells.

Supposed steps of tumorgenesis

• Intrinsic instability of genes

– Hereditary or aquired

• More and more alterations

• Stem cell theory

Most important gene groups

• Oncogenes

– Protooncogen oncogen

• Tumorsuppressor genes

– Mutations, inactivation result in loss of activity

• DNA repair genes altered by environment agents

Etiology (???)

• RNA viruses • Human T - cell leukaemia virus Leukaemia • HIV (and Epstein – Barr virus) Non - Hodgkin ’ s lymphoma • HIV (and human herpesvirus 8) Kaposi ’ s sarcoma • Hepatitis C virus Hepatocellular cancer • DNA viruses • Human papillomavirus Cervical cancer • Hepatitis B virus Hepatocellular cancer • Epstein – Barr virus Burkitt lymphoma, • Hodgkin ’ s disease, • nasopharyngeal cancer • Bacteria • Helicobacter pylori Gastric cancer, gastric lymphoma • Helminths • Schistosoma haematobium Bladder cancer

• Liver flukes Cholangiocarcinoma

Etiology : radiation

• Ionazing

– Sources: natural, arteficial, radioizotops, X-ray machine...

• Non-ionazing

Etiology: hereditary genetic predisposition

Statistics :1,0-1,5 x higher risk

BUT

-only an indication of risk level

-cannot accurately predict for an individual absolutely if, when and where cancer will develop.

Known genetic alteration

Cowden sy PTEN,SDH Breasr, endometrium, Melanoma Colorectal cc

FAP APC Colon gastric Small gut Thyroid gland

Hereditary breast and ovarium cancer

BRCA1, BRCA2 Breast ovary pancreas

Li- Fraumeni p53 breast adrenocorticoid brain sarcoma

Von Hippel- Lindau VHL Clear cell carcinoma Pheocromocytoma Neuroendocrin tumor

MEN RET Medullary thyroid cc

When should we think at hereditary disease

– Several organs effected

– In body doublets both organs effected

– Young patient

– Tumor not used in that gender (ex.breast cancer in men)

Screening: only for early detection

Organ Test Positiv level of

evidence

recommended

Breast

over age 50

Mammography Strong yes

age 40-50 Mammography Fairly strong yes

Colorectal

over 50

Occult blood test Strong yes

Sigmoidoscopy Strong yes

Colonoscopy Fairly strong

yes

Cervix Papanicolau Strong yes

Lung Chest radiogram None No

Melanoma Skin examination moderate yes

Screening

Organ site Precursors Methode of

detection

Oropharynx Leucoplakia Visual

Skin Actinic keratoses Visual

Esophagus Barett’s Endoscopy

Colon Adenoma (polyp) Colonoscopy

Breast LCIS, DCIS Mammography

Cervix Intraepithelial

neoplasia

Colposcopy

Diagnostic procedures

• Data of family members

• Anamnestic data

• Physical examination

• Imaging/laboratory/hystology

• Staging

• Decision making / therapeutic strategy

Difficulty at the beginning

• Symptoms are not always relevants

• Tumor not available for biopsy

• Paraneoplastic syndromes can imitate other illnesses

• Right evaluation of all results

Physical examination

• Skin: pale, icteric, livid….

• Palpable tumor: abdomen, lymph nodes, breast…

• RDE

• …………………

Paraneoplasy

• Skin

• Neurological symptomes

• Disorder of ion balance

• Thrombo-embolism

• Vasculitis

Neurological symptoms

• PEM/PSN

– SCLC

• Myastenia

– Thymoma

• Retinopathia

– Melanoma,SCLC

• Limbic encephalitis

– Thymoma, SCLC, breast,M. Hodgkin

Decision making

• Stage of the disease : operable or not

• Systemic disease or not

• Chemoterapy or radiotherapy or both

• Together or sequevential

• Curative or palliative

• Risk/benefit ratio

Prognostic factors

• Stage

• Histology

• Operability

• Age

• Comorbidity

Operability

• Depends of localization

• Presence of metastasis

– not a strict contraindication anymore

• Age

• Commorbidity

• Compliance

Principles of chemotherapy

1. Only agents that have been proven effective should be used. 2. Each agent used should have a different mechanism of action. 3. Each drug should have a different spectrum of toxicity and (ideally) of resistance. 4. Each drug should be used at maximum dose.(???) 5. Agents with similar dose-limiting toxicities can be combined safely only

by reducing doses, resulting in decreased effects.

Citotoxic agents

• Drugs acting in different cell-cycles

– Antimetabolite (pemetrexet,5 –FU, gemcitabine..)

– Vinca-alkaloid (vincristine, vinblastin,vinorelbin..)

– Taxanes ( docetaxel, paclitaxel)

– Camptotecine (topotecan, irinotecan)

• Drugs acting not depending on cell cycle

– Alkilating agents (carboplatin, oxaliplatin,cis-platin..)

– Antibiotics (epirubicin,, mitomycin-C, doxorubicin )

• Others

– Topo-izomerase inhibitors I, II ( irinotecan, topotecan,etoposid)

– Antifolates (methotrexat)

Chemosensitivity of tumours

• Sensitive and curable

Leukaemias, Lymphomas Germ cell tumours Childhood tumours

• Sensitive and normally incurable (radical palliation)

Small cell lung cancer Myeloma

• Moderately sensitive (palliation or adjuvant treatments)

Breast cancer, Colorectal cancer, Ovarian cancer, Bladder cancer

• Low sensitivity (chemotherapy of limited use)

Kidney cancer ,Melanoma, Adult brain tumours, Prostate cancer

Effect of chemotherapy

• Complete remission

• Partial remission ( RECIST criteria) – More than 50% decrease in volume

– Minimal change :less than 50% more than 25%

• Stable disease

• Progressive disease – More than 25% increase in volume, new lesion

Clinical Uses of Chemotherapy

• Adjuvant chemotherapy : in patients who remain at high risk of recurrence after all clinically detectable disease has been eradicated

• Neoadjuvant therapy: the application of chemotherapy prior to any other anticancer therapy can provide improved survival and/or organ sparing and preservation of function.

• Palliative therapy: management of advanced and metastatic disease- can be curative too

Neoadjuvant chemotherapy

• Goal:

– to make a tumor resectable

– to achieve a downstaging

– organ preservation ( sectorresection of breast after chemotherapy)

– in vivo prove of drug effectiveness

• Which organs can be treated?

– Breast, head and neck, gastric , lung, rectum

Adjuvant treatment

● High grade tumors after surgical intervention

● To prevent local recurrence

● To prevent dissemination

Palliative treatment

• Metastatic disease

• Different agents in different lines

• Quality of life has importance

• Dose adjusted

How long do we treat?

• Adjuvant

– Per protocol-

• chemotherapy 6 month

• endocrin therapy for breast cancer 5 or 7 years

• Palliative

– Untill progression or intolerable side effects

Side effects of chemotherapy

• General side effects – Fatigue, chills, fever, alopetia

• Side effects by organs – Myelon-depression

– Gastrointestinal

– Respiratory system

– Cardiovascular system

– Urogenital system

– Gonads

– Neurologic system

Molecullary targeted treatment: new options

• MTOR pathway signaling

• Non thyrosin kinase signaling

(ex. bcr-abl)

• Thyrosin kinase signaling

• Intracellular signaling

Receptors with therapeutic importance

• EGFR :( colorectal, headand neck, lung)

• Ras: k, n ( colorectal,NSCLC )

• ALK : lung

• Oestrogen: breast, endometrium

• Progesteron: breast, endometrium

• Her2neu: breast, gastric cc

• cKit : GIST

• Somatostatin: neuroendocrin tumor

Side effects

• Vomiting: setrons, metoclopramid

• Mucositis: rinsing, Kabiglutamin

• Anaemia: erythropoetin ( EPO )

• Neutropenia: coloniastimulating agents

• Diarrhea: lopedium

• Hand-food syndrome:hydrating unguent

• Folliculitis due to egfr inhibitors: antibiotics

• Hypertension: monitoring

challenge: breaking bad news

• First shock for the patient

• How to be empathic enough, without crying with the patient

• Subconcious present- patient doesn’t hear the reality: need for a relative around if it’s possible

Challenge: treatment

• Find the right treatment option

• Good patient-doctor relation

• To be up-to-date

• To use the new drugs in their places

Challenge:elderly patients

• What age is considered old

• Importance of commorbidity

• Consider biological age

• Consider patients decision

• Importance of dose modification

Challenge: when to stop

• Wait and see

• Treatment holiday

• Progressive disease

• Best supportive care

Oncology: failure or success ???

• One can hear only the grave cases

• Tabu

• Stigma

• Supportive/palliative therapy is not used widely enough

• Psychological support missing

• A lot of information from complementer medicine makes people confused (role of immune system, the disease can be cured by concentration and change of lifestyle…. )

Take home message

• Working in team

• Give all chance to the patient to live with cancer

• Supportive agents make chemotherapy bearable

• Communication with patient in case of every new decision about treatment change

• Have the power to stop treatment when it results more harm than benefit