LT28-32. 104 good questions, nicely answered!

What kind of treatment for tumors do you have?

Patient specific therapeutic plan:
- type of tumor
- growth velocity
- metastases

Palliative treatment
- pain management
- supportive care

Pharmacological therapy
- cytostatics
- hormones
- immunomodulators
- target therapy

What is the difference in growth in normal cells and in tumor cells?

Normal cells: growth in balance.
Tumor cells: growth out of control, transcription of proteins that stimulate cell division is high, transcription of proteins that inhibit cell division is low

What are cytostatic drugs?

They interfere in different phase of the cel cycle.

Alkalyting cytostatics.
Antimetabolites
Antimitotics
Topo-isomerase inhibotrs

What are general principles of cytostatic drugs?

Affect only one characteristic aspect of cancer cell biology , namely cell division
No specific inhibitory effects on invasiveness, loss of differentiation or tendency to metastases
Induce damage to DNA synthesis and initiate apoptosis
Main target is cell division, they affect all rapidly dividing normal tissues.
They have toxic effects.

What are general toxic effects of chemotherapy?

Bone marrow toxicity (myelosuppression)
Impaired wound healing
Loss of hair
Damage to gastro-intestinal epithelium -> is also a rapid dividing cell
Depression of growth in children
Sterility
Teratogenicity
Nausea and vomiting

What patient characteristics are imporant in cancer?

Age, comorbidity, personality, social circumstances, performance score, treatment preferences of the patient

What treatment is often given in women with breast cancer ER or PR positive?

Treatment targeted on the ER and PR.
In elder women the treatment is often tolerated, because they hae less estrogen.
Most of those patients have a very long stabilised disease with this therapy.
No surgery and radiation given.

What is the performance scale?

0: fully active
1: restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature
2: ambulatory and capable of all self-care but unable to carry out any work activites. Up and about more than 50% of waking hours.
3: capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4: completely disables, cannot carry on any self-care. totally confined to bed or chair
5: death

What is the natural course of sarcoma?

Usually no lymphogenic spread

What is the natural course of pancreatic cancer?

high risk of liver metastases early on

What is the natural course of small cell lung cancer?

High chance of brain metastases

How is cancer diagnosis and staging done?

Always histology: tissue, immunochemistry for more detailed differentiation
Supported by imaging (staging): X-rays, ultrasound, endoscopies, MRI, CT, PETscan
Sometimes laboratory investgations.

What is a PET scan?

Distant metastases, radiolabeled sugar will go to tumor cells, because they need a lot of sugars to perform their activity
The radiolabeled sugars you see in the PET scan.
But some cancers don't take those sugars, those are pre-malignant tumors, or tumors who don't have a great potency

What ways does cancer have to spread?

locally (T stage)
lymphogenic (Nstage)
hematogenic (m stage)

Why do we stage cancer?

Helps planning treatment
Helps estimating prognosis
Helps identifiying eligibility for clinical trials/studies
Makes comparison possible between institutes
Communication

When do you do cancer staging?

If there exists a high likelihood of finding metastatic disease
- in cancer types with known high prevalence of early metastatic disease (eg lung cancer)
- in cancer that is advanced at presentation N++ breastcancer

If finding metastatic disease has large clinical consequecenes
- refraining from surgery if metastses are found
- adding chemotherapy

NOt every patient with a cancer diagnosis is fully staged
- T1N0 breast cancer: only mammography and ultrasound of axilla, not other imaging

What additional information do you want apart from tissue type and grade?

Hormone receptor expression
Growth factors
Gene expression profile: mamaprint
mutations
Lymphovascular space invsasion

Which primary treatment options are there in cancer?

Dependent on organ of origin, function of affected organ, sensitivity to treatment
Dependent on stage of disease
Surgery, chemotherapy, radiotherapy, combination

What do you ask yourself when you're considering adjuvant treatment?

How large is the risk of local recurrence? supplementary local treatment, systemic?
how large is the risk for development of metastases? systemic therapy

Why should you give someon with breast cancer adjuvant chemotherapy?

To attack possibly present micrometastases

Why should you vie someone with oesophageal cancer adjuvant treatment?

No gain in survival of adjuvant treatment documented. Most patients die of the metastatic disease.
Adjuvnt chemotherapy only treats micrometastatic disease

What questions with: expected disease course after primary treatment?

Should you expect a local or locoregional recurrence? if so, treatment options?
Should you expect metastases? if so, treatment options?
Should you expect treatment complications?
Does this patient need help or extra guidance?
How are you going to organize the follow-up

Why do we do a follow-up in breast cancer?

Management of expectations.
After primary treatment the patient can develop distant metastases or recurrens

What differences are there in cancer?

Within a patient with several disesae locations: metastases in lung and liver, mixed respons on systemic therapy

Between types of cancer: breast cancer vs lung cancer, colon cancer vs rectal cancer, SCLC vs NSCLC

What is radiation oncology?

separate discipline in oncology
using ionizing radiation to treat cancer
curative intent in many patients
netherlands worldswide leader in research

What is the difference between radiologist and radiotherapist?

A radiotherapist is not the same as radiology.
As much vs as little radiation as possible
Not the same as nuclear medicine
But with soluble radionucleitides vs linear accellators and fixed sourcess

What is the contribution of radiotherapy to cancer care?

100.000 new patients with cancer in 2011
Increase 3% per year due to aging and population increase
50% iraadiated: curative intent/palliative intent
Increasing numbers of long survivors
More awareness of side effects

What is the mechanism of action in radiation/

Radiation causes DNA strand breaks
Repair processes before cell division: suspension of division
Normal cells recognize and repair most of the damge
Cancer cells have less regenerative capacity and die at cell division
Side effects determined by slow down of cell division in surrounding healthy tissue (acute vs late)
Acute side effects: fast growing tissues

Radiotherapy in historical perspective?

1895: röntgenfoto
1910: radioactivity
1950: cobalt-60
1970: linear accelerators
now: planning treatment, 3DCT, intesnity modulated Rt, image guided RT, brachytherapy, stereotactic RT
2018: proton therapy

With what in the electromagnetic spectrum do we treat patients?

Gamma rays and photons, they have a high energy, so can ionize a lot of targets.

How is external delivery of radiation, how is internal delivery of radiation?

External: linear accelerators
Internal: brachytherapy

Tell the differences between alpha, beta and gamma particles.

Alpha particle: high energy but cannot penetrate far
Beta particle: high energy stopped later
Gamma: high penetration, only thick layer of concrete could stop it

What kind of radiation could we use for superficial tumors?

Electron radiation, an electron goes a couple of mm below the skin and is than stopped.

What is photon radiation?

Photon penetrates more in the body, givse a lot of energy.

What is external beam radiotherapy?

Local treatment
Linear accelerator: on- off
The patient is not radioactive after the treatmetn

What is the mechanism of action of ionizing radiation?

Direct photon DNA interaction: dNA damage
and indirect action: via oxygen radicals

causes double strand DNA damage, single strand DNA damage, losing of peptides

What is the aim of radiotherapy?

To kill the tumor
higher dose does not always give more tumor control.
Local recurrence free survival, overall survival is comparable

What is the therapeutic window?

Spaces between the graph of the toxicity and the effect
Depends on the normal tissue whether you're going to accept the toxicity or not

How can you increase the tumor control?

Space between normal and tumor cell is the therapeutic window.
You have to incresae the cose. But the dose in the normal tissue has to be at the same level, so you get an increased therapeutic window.
So you take measures to change the tolerance boundary.
Daardoor vergroot je je therapeutic window.

How can you increase the therapeutic window?

Besides you could also decrease the dose in normal tissue to increase your therapeutic window. The curve of toxicity will move to the right. (decreased toxicity)

You can increase the dose, the curve will go to the left

Lower the dose to normal tissue (decreased toxicity)
- shield healthy tissue
- irradiate from multiple directions (treatment planning)
- image guided therapy

Fractination of the total dose: normal tissue can have more dose.
Enhancement sensitivity

What are early side effects of radiotherapy?

mucositis
swallowing problems, passage problems, nausea, diarrhea, dermatitis, pneumonitis, alopecia

What are late side effects of radiotherapy?

proctitis -> ontsteking van anus en rectum
myelopathy
secundary tumors, mutation in normal cell and normall needs to develop to a tumor cells, this takes some years, mostly you find it in the low dose of the radiation field

What are chronic side effects of radiotherapy?

Fibrosis -> there is also inflammation during the process

What damage is done in the bone marrow with dose of 1-5% harm (Gy)?

2-3 Gy, damage: aplasia

What damage is done in the lung with dose of 1-5% harm (Gy)?

20 Gy, damage: pneumonitis

What damage is done in the spinal cord with dose of 1-5% harm (Gy)?

50 Gy, damage: necorsis

How do you choose fractination schedules?

Some tumors are really sensitive, other tumors are resistant for radiotherapy. And you give a higher dose.
The fraction of dose varies
The total dose varies
Not all tumor cells are similar in radiation sensitivty

What technical options are there to lower the dose to normal tissue?

More directions of radiation dose
Decrease the dose if you give it from 4 fields.
Shielding with led, you can reduce the dose in normal tissue.

Brachtherapy: dose is more locally

What is delineation of treatment volume?

In the CT you are going to dilineate the tumor. In every coupe you deliniate the tumor so you know where tumor is.
Because you know where the organs are, you know better how to avoid them.

You make daily aligment on tattoos, so that the patientw ill always be in the same positiion

What is clinical target volume? What is planning target volume?

Clinical target volume: area around the tumor for the microscopic infiltration
Planning target volume: volume we take into account for movement during therapy.
Lung tumors: you have to get a larger planning target volume than a tumor in the arm which is fixated

What are sollution to account for movements?

- Wider margins, larger target volume -> side effects
- Smaller margings: regional misses?
- image guided radiotherapy IGRT

How can you enhance the sensitivity of tumor cells to radiation?

This would give an increased tumor control.
- chemoradiotherapy
- biological agents (cetuximab in head and neck cancer)
- oxygen to tumor -> better tumor control in radiation
- hyperthermia -> rise of the body temperature to 40 degrees, most of the proteins will be degraded, radiotherapy there is an ehancement of the effect

What is the mechanism of action of chemoradiation?

DNA damage to tumor cells more often fatal than with irradiation alone.
Different modes of action for radiation and chemotherapy
Normal cells ahve greater variety of escape mechanism and repair the damage
Chemotherapy as radiosensitizer enhances the effect of radiotherapy
Compraed to radiotherapy more toxicity

- synergy in damage inflicted: cisplating adducts to DNA in combination with radiation induces a single strand break, which is more difficult to repair.

- inhibition of post-irradiation repair: cheotherapy can inhibit metabolism

- effects of radiation and chemotherapy in different phases of the cell cycle

- chemotherapy treats hypoxic cells (less radiosensitive)

What are the effects of chemoradiation?

seen as local treatment to increase local control and thereby cure.
systemic effect chemotherapy, not in all tumors. Sometimes higher dose of chemotherapy and than there is a systemic effect, but no in all tumor types

What are examples of chemoradiation in primary treatment?

anal cancer, larynx cnacer

What are examples of chemoradiation in adjuvant treatment?

stomach cnacer
lung cancer

What are examples of chemoradiation in neoadjuvant treatment

oesofagal cancer
rectal cancer

What toxicities in chemoradiation? Acute/Late

Acute: skin, mucosa, pain, infections
Late: function loss (incontinence, swallowing), fibrosis/stenosis, oedema, infertility

In what cancer is curative ressection not possible?

head and neck tumors
cervical carcinoma
vulvar cancer
esophageal cancer
lung cance rstage III disease, lymph nodes involved in mediastinum, you have to give chemoradiation

What kind of chemotherapy do you have in chemoradiation therapy (CRT)

5FU
cisplating/carboplatin -> squamous cell carcinoma
paclitaxel
mitomycin
temozolmide
capecitabine -> rectal cancer

What kind of adenocarcinomas are treated with chemoradiation therapy?

lung cancer
esophageal cancer
cervical cancer

What is the cross effect on distant metastases of chemoradiation thearpy?

- fewer locoregional recurrences, less dissemination from these recurrens
- effective treatment of primary tumor helps, mechanism unknown
- direct systemic effect of chemotherapy
- tumor regression predicts survival
- active tumor the prognosis is low, if there was a low tumor response and no tumor could be found, tahn there is a good survivl
- You only find it after surgery
- has become the standard treatment, neo-adjuvant: radiation

What is proton therapy?

H+ geven hun energie af aan het lichaam.
One proton enters the body and gives its energy in a certain moment Bragg peak.
After bragg pek no radiation any more int he tissue.
If you give a lot of Bragg peaks you can cover the tumor

What are advantages of proton therapy?

increasing dose to the tumor: improving local control
rather spring normal tissue: less side effects, induction of secondary tumor is lower

What are disadvantges of proton therapy?

Expensive treatment --> difficult to generate those proteins, you need a special machine
REstricted in radiation possibilities, you can irradiate photons from every angle, but with protons there is a limit

What are indiciations for proton therapy?

Children: barin tumor which dessiminates in the CSF.
If you give photon therapy , the organs in front will be targeted as well.
Skull base chordoma/chondrosarcoma

Genomically targeted therapy
Chemotherapy
Immune checkpoint therapy
Combination with genoically targeted agent and immune checkpoint therapy.
Which gives the best percent survival?

Combination with genomically targeted agent and immune checkpoint therapy
Immune checkpoint therapy
Genomically targeted therapy
Chemotherapy

But patients will still develop resistance or recurrence.

What is the pahtway of genomics in personalized medicine?

History physical
Imaging
Pathology
Clinical chemistry
Genomics

What is DNA next generation sequencing? (NGS)

Probes get out the properotion of DNA that is relevant for the diagnosis and treatment of a certain cancer. It is cheaper and faster.
You use probes, you only sequence the exon regions.
In whole genome seuqncing you sequence 3 billion base pairs and do that several times.
In target sequencing you only sequence the genes.
Probes that are homologous for your genes, these probes can be RNA, that have some markers.

When they bind your target of interset, you digest your probes away and you only sequence the DNA you capture.

What are the steps of next generation sequencing?

1) collect blood
2) extract and fragment DNA
3) capture exome DNA with primers
4) recover only exome DNA fragments
5) sequence on next-generation platform

What is SNP testing?

Genomic tests.
Some polymorphisms are important, see the differences

What are investigational tests?

Whole genome sequencing (WGS)
RNA sequencing
Methylome

What are established tests?

Familial mutations (gene panels)
Somatic mutations analyses (targeted gene panel ampliseq cancer hotspot panel V2)
SNPs in genes involved in drug metabolism (pharmacogenomics)
Gene expression panels (oncotype DX/mammaprint for breast cancer)

What is class comparison?

Two groups of patients, good and bad responders.
Interregate the genes that are differnetially exprssed between these two groups.
So you compare the classes

What is class prediction?

You have already established the differences.
Results in a test with diagnostic relevance.
If some genes are highly expressed, these patients will respond well to certain therapies.
When you get a patient, you analyze the patient and check whether its profile matches a responder or non-responder.
You predit where this profile fits.

What is class discovery?

no information about the patient.
You pick heterogenous group of tumors.
You look to the expression profiles and cluster it based on affinity of expression of different genes. You make clusters and try to extract biolgoical or clincial sginificance.

What are challenges in precision medicine?

Patient selection
Result interpretation and explanation: increased complexity of the results that are obtaining is difficult to deal with
Data that you get of patients is very complex.
omputationally intensive: data storage capacity, cloud computing, data transfer speeds
Privacy concers: data security is essential (separate servers for outside facing apps and databases)

What is precision medicine?

Step towards personalized medicine, in that it uses more variables to stratify patients but not completely individualized (group of patients with clinical relevance, eg KRAS mutant patients and you define the treatment you are going to give)

What medicine if you have a ER positive tumor

tamoxifen

What drug f you have a HER2 receptor?

trastuzumab

Which FDA-approved genomic tests are now routine for breast cancer?

Oncotype-DX examines the expression of 21 genes (including 5 controls) to determine the risk of recurrence in node-negative luminal breast cancer.

Patients falling within the low recurrence score group do NOT need chemotherapy

What are umbrella trials?

Organized per organ, but they're futher subdivided.
Umbrella trial on colorectal cancer and there will be a group with MMR-D, MMR-P, KRAS mutant, KRAS wildtype

1 type of cancer
different genetic mutations

What are basket trials?

Doesn't know where your tumor is. They're based on characteristics of the tumor.

multiple types of cancer
1 common genetic mutation

What is cisplatin? And what are the side effects?

Alkylating cytostatics
Central platinum atom surrounded by two chlorine atoms and ammonia groups
After entering the cell --> reactive comlex

Common side effects:
- severe vomiting and nasea
- myelosuppression is relatively low
- nephrotoxic

Hyperhydration and dialysis prevent nephrotoxicity

In which phase anti-microtubule drugs?

Mitose, spindle defects

What are deficiencies in growth conditions in G1 phase?

Lack of growth factors
Anti-proliferative factors
DNA damage
Ionising radition
UV

What drugs in replication faults?

Anti-metabolites
DNA damage
Phase s

What drugs in topoII inhibitors?

Chromosome catenation. gives DNA damage

Phase G2

What is the mechanism of action in antimetabolites?

- Structural similarity with vitamins, nucleosides or amino acids
- Compete with natrural substrate for thea ctive site of an enzyme
- Mimic action of normal metabolites in folic acid cycle and the metabolic pathway of purine and pyrimidine synthesis
- Act during S-phase

What is 5 fluorouracil (5FU)

Anti-metabolite.
Common side effects:
Mucositis
Myelosuppresion
Diarrhea

What do mitosis inhibitors?

Microtubule and spindles for division of DNA over two daughter cells.
Mechanism of action:
- binding to microtubules
- stabilize the microtubules by inhibiting their polymerization
- induce cell shape changes
this inhibits cell division

What are topoisomerase inhibitors?

Interfere in the G2 phase, the phase where cell is preparing for mitosis.
Topoisomerase enzymes: unwind, cut and ligate DNA, crucial role in competition of mitosis + DNA replication.
Topoisomerase inhibitors block tese enzymes and prevent the cell from replication.

- inhibition of topo-isomerase
- inhibition of unwindg, cutting and ligation of DNA
- inhibition of DNA replication and RNA transcription

What are limitations of cytostatic drugs?

Problems with safety profile of cheotherapeutic agents
Problems with efficacy of chemotherapeutic agents -> resitance to cytostatics
Cytostatics predominantly affect rapidly dividing cells
Do not specificially target cancer cells
They only influence a cells ability to divide and have little effect on other aspect of tumor progression
Cytostatics are associated with high incidence of adverse side effects: bone marrow suppression, alopedcia, mucositis, nausea, vomiting

What kind of resistance to cytostatics can occur?

Primary: present when the drug is first given
Requierd: developing during treatment (adaptation or mutation of tumor cells)

What are possible explanation of development of resistance to cytostatics?

-Insufficient activation of the drug (eg fluorouracil to FDUMP) metabolism of the drug has changed, drugs that are used a s a pro-drug that needs to be activated, that activation could be reduced -Increased inactivation
-Increased concentration of the target enzyme due to a compensation mechanism (eg methotrexate), could first be very effective, but due to an increase it can be less effective
-Rapid repair of drug-induced lesions (eg alkylating agents)
-Altered activity of target such as topoisoerase II (eg doxorubicin)
-Mutation of various genes

What are side effects of cytotoxic drugs?

Emesis (vomting and nasea)

Acute emesis: 1-2 h after onset of chemotherapy and can last for 8-24 h
Delayed emesis: usually 24-72 h or later after the onset of chemotherapy

What are examples of 5-HT3 receptor antagonists?

odansetron
granisetron

What are examples of D2-antagonist

metoclopraide

What is target cell therapy?

Monoclonal antibodies can mark tumor cells on the outside by binding to specific proteins (receptors)

Make the tumor cell recognizable for immune cell attack.

If you're able to block the receptor, you're able to reduce the cell growth, so you reduce the expression of grow stimulating proteins

What is the function of the HER2 receptor?

Growth factors bind to HER 2
this gives growth factor production and proliferation

What are tyrosine kinase inhibitors, name an example.

Protein kinase inhibitors, interfere in the intraclelular signaling pathway.

Imatinib: inhibitor of protein tyorisine kinase, inhibition of cell proliferation, induces apoptosis

What is palliative treatment?

Reduces the severity of disease symptoms, eg nausea/vomiting pain, quality of life
Improves quality of life

What are palliative beneftis of radiotherapy?

pain relief
reduction of headache and vomiting in raised intracranial presure from CNS metastases
relief of obstruction of bronchus, oesphagus, ureter and lyphatic
preservation of skeletal integrity from metastases in weight-bearing bones
reversal of neurological impairment from spinal cord or optic nerve compression by metastases

What are acute side effects of radiotherapy?

anorexia, nausea, malaise
mcuositis, oesophagitis, diarrhoa
alopecia
myelosuppresion

late side effects

secondary malignancies

LT28-32

104 important questions on LT28-32