Oncology

Page created on April 29, 2020. Last updated on July 14, 2020 at 16:22

Summary of cancer treatments

• Treatment of head and neck cancers
  • Cancer of oral cavity -> surgery, adjuvant RT or RCT if high-risk features
  • Cancer of pharynx
    • Nasopharynx -> RCT
    • Oropharynx -> RCT/surgery
    • Hypopharynx -> surgery
  • Cancer of larynx
    • Early cancer -> RT/surgery
    • Locally advanced cancer -> RCT/total laryngectomy
    • Advanced cancer -> total laryngectomy + adjuvant RT
  • Stage III and IV head and neck cancers -> RCT/radiobiotherapy
• Treatment of NSCLC
  • Stage I – IIIa -> surgery ± adjuvant CT
  • Stage IIIb -> RCT
  • Stage IIIc – IV
    • Squamous cell carcinoma -> polychemotherapy ± immunotherapy
    • Adenocarcinoma -> targeted therapy against EGFR, ALK, ROS
• Treatment of SCLC
  • Limited disease -> RCT + prophylactic cranial irradiation if remission is achieved
  • Extensive disease -> CT + prophylactic cranial irradiation in most cases
• Treatment of breast cancer
  • Early breast cancer
    • Without BRCA mutation -> breast-conserving surgery + adjuvant RT
    • With BRCA mutation -> Mastectomy + prophylactic contralateral mastectomy + prophylactic bilateral salpingo-oopherectomy
  • For locally advanced breast cancer -> neoadjuvant systemic therapy + surgery + adjuvant systemic therapy
  • For metastatic breast cancer -> neoadjuvant systemic therapy + surgery and/or RT
    • With BRCA mutation -> PARP inhibitors
• Treatment of oesophageal cancer
  • Localized disease -> neoadjuvant CT/RCT + surgery + adjuvant CT
  • Advanced disease -> RCT/targeted/immunotherapy
• Treatment of gastric cancer
  • Localized disease -> neoadjuvant CT/RCT + surgery + adjuvant CT/RCT
  • Advanced disease -> neoadjuvant CT + surgery + adjuvant CT ± targeted/immunotherapy
• Treatment of pancreatic cancer
  • Resectable disease -> surgery + adjuvant CT/RCT
  • Non-resectable disease -> CT ± palliative surgery
• Treatment of HCC
  • Very early or early stage -> Surgery
  • Early stage -> Liver transplant
  • Intermediate stage -> TACE
  • Advanced stage -> Sorafenib
  • Terminal stage -> Palliative
• Treatment of CRC
  • Stage I -> Surgery
  • Stage II, III -> Surgery + adjuvant CT
  • Stage IV -> Palliative
• Treatment of non-melanoma skin cc (BCC, SCC) -> surgery
• Treatment of melanoma
  • Localized disease -> surgery
  • Regional and metastatic disease -> surgery + adjuvant targeted/immuno
• Treatment of CNS tumours
  • Low-grade glioma -> surgery
  • High-grade glioma -> surgery + RCT (temozolomide)
  • Multiple brain mets -> whole brain radiotherapy
  • Primary CNS lymphoma -> CT (methotrexate)
• Treatment of ovarian cancer
  • Stage I, II -> surgery + adjuvant CT
  • Stage III, IV -> cytoreduction + adjuvant CT
• Treatment of cervical cancer
  • Early cervical disease -> surgery/RT ± adjuvant RCT
  • Locally advanced disease -> RCT
  • Metastatic disease -> Palliative
• Treatment of endometrial cancer
  • Stage I, II -> Surgery + adjuvant RT
  • Stage III, IV -> Cytoreduction + adjuvant CT/RT/hormonal
• Treatment of prostate cancer
  • Low and intermediate risk localized disease -> Observation/surgery/RT
  • High-risk localized and locally advanced disease -> [ADT + ERBT] or surgery
  • Hormone-naive metastatic disease -> ADT + antiandrogens
  • Castration-resistant metastatic disease -> ADT + antiandrogens + CT/immunotherapy
• Treatment of bladder cancer
  • Non-muscle-invasive disease -> TUR-B + intravesical BCG or chemo
  • Muscle-invasive disease -> surgery or [TUR-B + RCT]
  • Metastatic disease -> palliative
• Treatment of RCC
  • Localized disease -> surgery
  • Metastatic disease -> targeted/immunotherapy
• Treatment of testicular cancer
  • Localized disease -> observation or [orchidectomy + adjuvant CT]
  • Locally advanced disease -> orchidectomy + adjuvant RT/CT/RPLND
  • Metastatic disease -> orchidectomy + adjuvant CT

Introduction to oncology

• https://www.cancer.org/ is a surprisingly good source for information on the specific malignancies. They explain specific procedures, staging, diagnosis and treatment of all cancers. If there’s something which you don’t understand, I recommend you check there
• Epidemiology
  • Most frequent cancers (USA)
    • (Except skin cancer, which is the most common)
    • Prostate/breast
    • Lung and bronchus
    • Colorectal
  • Cancers causing the most deaths (USA)
    • Lung and bronchus
    • Prostate/breast
    • Colorectal
• The clinical courses of cancer patients
  • The absolute cure rate is 60%
  • 30% survive several years
  • 10% experience no real effect of treatment
• CAUTION – cancer’s seven warning signs
  • Change in bowel or bladder habits
  • A sore that does not heal
  • Unusual bleeding or discharge
  • Thickening of lump in breast or elsewhere
  • Indigestion or difficulty in swallowing
  • Obvious change in wart or mole
  • Nagging cough or hoarseness
• Grading
  • Grading is based on how differentiated the tumor is on histology, compared to healthy tissue
  • From G1 (well differentiated) to G4 (very poorly differentiated)
  • Special grading systems
    • Gleason score – for prostate cancer
  • Grading also takes into account:
    • The degree of vessel penetration
    • Presence of hormonal receptors or growth factor receptors
    • Presence of certain gene mutations
• Staging
  • TNM staging system is often used
    • Brain tumours and haematological malignancies use other systems
  • Clinical staging (cTNM) – staging based on the clinical information (obtained before surgery)
    • Including physical examination, blood tests, imaging, biopsy, endoscopy, etc.
    • Histopathological examination of biopsy is performed for most cancers
  • Pathological staging (pTNM) – staging based on the clinical information + information from the pathologist after surgical resection
    • Some cancers are not treated surgically, so there will be no pTNM stage, only cTNM stage
    • Many tumours are examined histopathologically twice – once of the biopsy taken before surgery, and once of the tumour which was removed during surgery
  • Treatment-associated staging (yTNM) – staging after chemotherapy and/or radiation therapy
  • Generally:
    • Stages I and II are referred to as “early” or “non-invasive” disease
    • Stage III is referred to as “locally” or “regionally” “advanced” or “invasive” disease
    • Stage IV is referred to as “advanced” or “metastatic” disease
• Prognostic factors
  • Those factors which determine the patient’s prognosis
  • Most important factors
    • Grading
    • Staging
    • Performance status
      • Different performance status scales exist
      • Eastern Cooperative Oncology Group performance status (ECOG PS)
        • Grade 0 – Fully active, no restriction on daily activity
        • Grade 4 – Completely disabled, not capable of self-care, totally confined to bed or chair
        • Grade 5 – dead
      • Karnofsky performance scale (KPS)
        • 100 – normal
        • 0 – dead
  • Other factors
    • Age
    • The excess of weight loss
    • The localization of the disease
• Predictive factors
  • Those factors which are associated with response or lack of response to a particular therapy
    • For example, the presence of oestrogen receptors in breast cancer is a predictive factor, as it predicts the patient’s response to antioestrogens
  • Many predictive factors are also prognostic factors
• Oncological teams
  • Cancers patients are treated by oncological teams rather than individual oncologists
  • This:
    • Optimizes treatments
    • Allows learning from each other
    • Allows teamwork across multiple modalities (pathology, radiology, etc.)
    • Allows responsibility to be shared
    • Allows members of the team to support each other
  • Includes
    • Oncologists
    • Pathologists
    • Radiologists
    • Nurses
    • Etc.
• Treatment
  • Cancer treatment doesn’t begin until the staging is complete, unless
    • The cancer is causing urgent, life-threatening complications
    • Complete staging is impossible or too dangerous (certain brain tumours)
  • Important factors in treatment decision
    • Performance status
    • Renal function
    • Liver function
    • Bone marrow function
  • Types of therapy
    • Curative therapy – therapy with the intent of curing the cancer
    • Palliative therapy – therapy with the intent of relieving symptoms and improving quality of life
    • Neoadjuvant therapy – chemo and/or radiation before surgery
      • Neoadjuvant therapy can reduce the tumour size, making surgery more likely to be curative
    • Adjuvant therapy – chemo and/or radiation after surgery
  • Modalities
    • Surgery – in 60% of cases
    • Radiotherapy – in 30% of cases
    • Medical therapy – in 10% of cases
    • Modalities are generally combined
      • Radiochemotherapy refers to simultaneous use of radio and chemo, as opposed to radio first and then chemo after
  • Treatment response
    • Complete response/regression (CR) – no evidence of tumour after a certain amount of time
    • Partial response/regression (PR) – decrease in tumour volume
    • Stable disease (SD) – minimal decrease or increase in tumour volume
    • Progressive disease (PD) – increase in tumour volume

1. The basic principles of tumor biology

• Etiological factors contributing to cancer development
  • Environmental exposure
    • Asbestos -> mesothelioma, RCC
    • Formaldehyde -> nose and nasopharyngeal cc
  • Radiation
    • Those with childhood leukaemia often develop solid tumours 10 – 20 years after the radiotherapy
  • Lifestyle problems
    • Smoking -> lung cancer, head and neck cancer
    • Alcohol -> head and neck cancer, oesophageal cancer
  • Alimentary factors
    • Obesity, diabetes -> CRC
  • Hygienic problems
    • -> cancer of glans penis
  • Infections
    • HPV -> cervical cc
    • EBV -> nasopharyngeal carcinoma
    • Aflatoxin -> HCC
  • Hormonal effects
    • Oestrogen -> breast cc, endometrial cc
    • Testosterone -> prostate cc
  • Genetic background
    • BCL/ABL => CML
    • APC => CRC
• Biological factors contributing to cancer development
  • Trouble in communication between cells
  • Absence of contact inhibition
  • Uncontrolled growth and cell dividing
  • Omitting the integrity of neighbouring cells, tissues and organs
  • Neo-vascularization and aberrant blood vessels
  • The possibility of penetrating blood vessels
  • Disturbing the metabolic activity of the organ
  • Evolving paraneoplastic symptoms

2. Principles of surgical oncology

• Debulking and cytoreduction
  • Debulking or cytoreduction = surgically removing as much of a tumour as possible, in cases where the whole tumour cannot be removed
  • Debulking can be performed palliatively, to increase survival, or with curative intent, by increasing the penetration of adjuvant radiation and/or chemo into the tumour
  • Performed in ovarian cc, endometrial cc, etc.
• En-bloc resection
  • The entire tumour and a continous layer of healthy tissue around it is removed together
• Surgical margin
  • During surgery, the margin of the removed tissue is marked with ink
  • While the surgeons wait the pathologist will make frozen slides of the removed tissue and examine it histologically
  • By using the ink as a reference, the pathologist can determine whether the surgery removed all of the tumour or not
  • If the surgical margin is clear/negative/clean, there are no tumour cells at the margin, so further treatment is usually not needed
  • If the surgical margin is positive, more surgery or other adjuvant treatment is needed to ensure that no tumour cells remain
  • R0 resection – complete resection of the tumour
    • No macroscopic evidence of tumour, with negative margins
  • R1 resection – microscopic remnants of tumour remain
    • No macroscopic evidence of tumour, but positive margins
  • R2 resection – macroscopic remnants of tumour remain
• Preoperative (neoadjuvant) and postoperative (adjuvant) therapy
  • For some cancers clinical studies have established that neoadjuvant and/or adjuvant therapy is beneficial
  • In some cases, postoperative therapy is only indicated if certain features of the tumour are discovered during surgery (during pathological staging), like
    • Incomplete (R1, R2) surgical resection
    • Spread to lymph nodes
    • Certain mutations
    • Very deep invasion
    • Etc.
    • These are features which are associated with high risk of recurrence or poor prognosis
  • Postoperative therapy can be chemo, radio, radiochemotherapy, etc.

3. Radiation physics

• Types of radiation used
  • Natural radiation (due to radioactive decay)
    • Alpha radiation (two protons and two neutrons)
    • Beta radiation (high-energy electrons)
      • Electrons (beta radiation) has low penetration power, so beta radiation is only suitable for treating tumours near the skin surface
  • Gamma radiation (high-energy photons)
    • Photon radiation (gamma and X-ray radiation) has high penetration power, so it is suitable for treating deep tumours
  • Artificial radiation
    • X-rays (gamma radiation which is artificially made)
    • Heavy ion radiation
      • Heavy ions, like carbon ions, are accelerated to high speeds
      • Proton radiation (alpha radiation) and heavy-ion radiation don’t penetrate tissues deeper than a certain point
        • This makes these types of radiation suitable for treating tumours where radiation-sensitive tissue is very close, for example inside the skull
        • They’re also suitable for treating tumours close to the skin
        • This effect is due to the so-called “Bragg peak” on the percentage depth dose distribution
• Particle therapy
  • Accelerated protons or heavy ions are sent into the tumour
  • Very expensive
• Compton-scattering is the most important radiation effect on tissues in radiotherapy
  • The photoelectric effect, pair production and coherent scattering are less important
• The inverse square law
  • The law states that the intensity of radiation decreases in an inverse square ratio with the distance from the source of the radiation
  • For example
    • If the distance from the source is doubled, the radiation intensity is reduced to one fourth
    • If the distance from the source is increased three-fold, the radiation intensity is reduced to one ninth
  • The inverse square law is important in treatment planning in brachytherapy
• Percentage depth dose (PDD)
  • The PDD is the percentage of the maximum dose which is deposited in tissue (or something, it’s confusing)
  • PDD is important in treatment planning in teletherapy
• Squamous cell cancers are generally very radiosensitive
  • Adenocarcinomas on the other hand, are not
• Radiation biology
  • Radiation induces double-stranded breaks in DNA
  • The cell is most sensitive to radiation in the M and G2 phases of the cell cycle
  • The oxygen effect
    • According to the oxygen effect, normoxic tissues and cells are more radiosenstive than hypoxic ones
    • The oxygen effect occurs because oxygen “stabilizes” or “makes permanent” the DNA damage produced by reactive oxygen species
    • In hypoxic tissues, the DNA damage is not made permanent and can therefore be repaired by the cell

4. The equipment used in radiation oncology

• Types of radiotherapy
  • External beam radiation therapy (EBRT)/teletherapy
    • The radiation source is outside the patient
    • The source can be rotated around the patient, allowing the radiation beam to target the tumour from a variety of directions
    • Types
      • Conventional external beam therapy
      • Three-dimensional conformal radiotherapy (3DCRT)
      • Intensity modulated radiation therapy (IMRT)
      • Stereotactic radiosurgery/radiotherapy
  • A multileaf collimator (MLC) is used to shape the radiation beam
    • Especially used in IMRT and 3DCRT
  • Internal radiation therapy/brachytherapy
    • The radiation source is inside or very close to the patient, as close to the tumour as possible, or even inside the tumour
    • Can be temporary or permanent
      • Temporary brachytherapy – the radiation source is placed and then removed after some time
        • Most common
      • Permanent brachytherapy – a small radiation source is permanently placed into the patient
        • Also called “seed implantation”
        • The radioactive “seed” loses its radioactivity after some months, but won’t be removed
    • Can be high dose-rate (HDR), low dose-rate (LDR) or pulsed dose-rate (PDR)
      • HDR reduces the treatment time, and is most commonly used
      • HDR = dose rate of more than 12 Gy per hour
        • Treatment typically lasts a few minutes
      • LDR = dose rate of less than 2 Gy per hour
        • Treatment typically lasts 24 hours
      • PDR = short pulses of radiation are given
        • Treatment typically lasts 24 hours
    • Types
      • Intracavital brachytherapy
        • Into the cervix, bronchi, etc.
      • Interstitial brachytherapy
        • Into the breast, prostate, etc.
  • Systematic radiation therapy
    • An isotope is injected into the patient, by itself or attached to a specific molecule
    • The isotope will travel to the tumour and irradiate it from inside
    • The isotope often gives off alpha or beta-waves, as these waves don’t travel far in the body
      • Alpha waves only travel 100 µm
    • Examples
      • Radioactive iodine given for thyroid cancer
      • Radium-223 given for bone metastases
• Equipment used in brachytherapy
  • Afterloading
    • The technique where a machine (an afterloader) is used to deliver the radiation source into the patient during brachytherapy
    • This eliminates the need for a person to deliver the radiation source, eliminating radiation exposure for that person
      • Manual delivery of brachytherapy is seldom used for this reason
    • Often used with HDR, sometimes called HDR Afterloading
    • ¹⁹²Iridium is often used as radiation source
• Equipment used in teletherapy
  • Cobalt unit
    • Older type of teletherapy
    • The external beam is generated using ⁶⁰Cobalt
  • Linear accelerator (LINAC)
    • More modern than cobalt unit
    • Most commonly used device for external beam radiation therapy
    • The external beam is generated using linear acceleration
    • A multileaf collimator allows precise modification of the radiation field
    • Used for stereotactic surgery, intensity modulated radiotherapy, particle therapy etc.
  • Gamma knife
    • Used for stereotactic radiosurgery in the brain
  • Tomotherapy
  • CyberKnife

5. Treatment planning, radiation protection

• Treatment planning
  • Imaging is used to form a virtual model of the patient, including the tumour
    • Native CT is almost always used, because the physical interactions between the radiation and the tissue is the same in native CT as in radiotherapy
      • This means that a native CT contains the dose-absorbing properties of the tissues of the patient
    • By using image registration and image fusion, multiple imaging modelities may be combined, if needed
      • Image registration refers to “matching” multiple imaging modalities by mapping the coordinates of anatomical structures on the different modalities, so that they “match” on top of each other
      • Image fusion refers to displaying multiple modalities on top of each other after image registration
      • MRI provides good differentiation between different soft tissues
      • PET provides good information of functionality and metastases
      • Ultrasound cannot be used for treatment planning
  • Computer systems allow for simulation and calculation of how different radiotherapy approaches would deliver radiation to the tumour and the surrounding tissues
  • Modern techniques allow for even more precise radiation planning
    • Intensity-modulated radiation therapy (IMRT)
    • 3D conformal radiation therapy (3DCRT)
    • Intensity-modulated arc therapy (IMAT)
    • Image-guided radiation therapy (IGRT)
  • Volumes in radiotheapy planning
    • Gross tumour volume (GTV) = the volume of the macroscopic tumour
    • Clinical target volume (CTV) = the GTV + microscopic, un-imageable tumour spread
    • Planning target volume (PTV) = the CTV + uncertainties in planning or delivery
• Fractionation of radiation therapy
  • Most cancers respond based on the total (cumulative) amount of radiation, not the size of the individual doses
    • However, side effects are mostly related to the sizes of the individual doses
  • As such, the sizes of the doses can be increased or decreased
  • Hypofractionated radiation therapy
    • When the total dose of radiation is divided into larger but fewer doses
    • Used for cancers which are sensitive to large individual radiation doses
    • Treatment course is completed quicker
    • Often used in breast cancer and prostate cancer
  • Hyperfractionated radiation therapy
    • When the total dose of radiation is divided into smaller but more doses, often given more than once a day
    • May produce fewer side effects
    • Used for cancers with high turnover, like SCLC

6. Basic concepts of chemotherapy

• Polychemotherapy = simultaneous use of multiple chemo drugs
  • The term is not consistently used, even by me
  • Recently, we have moved from preferring to use multiple chemo drugs, so the term is kind of reduntant
• Mode of actions
  • Induce DNA damage
  • Inhibit DNA repair mechanisms
  • Inhibit metabolism
    • For example nucleotide synthesis
  • Inhibit mitosis
  • Inhibit neo-vascularization
• Commonly used drugs
  • Platinum-based drugs
    • Cisplatin
      • Very nephrotoxic – renal function must be measured before use
    • Carboplatin
      • Less nephrotoxic – sometimes used as an alternative to cisplatin in case of poor kidney function
  • 5-FU
  • Taxanes
    • Paclitaxel
    • Docetaxel
• Commonly used regimens
  • FLOT
    • 5-FU
    • Leucovorin
    • Oxaliplatin
    • DoceTaxel
  • FOLFOX
    • FOLinic acid (leucovorin)
    • 5-FU
    • Oxaliplatin
  • FOLFIRI
    • FOLinic acid
    • 5-FU
    • IRInotecan
  • ECX
    • Epirubicin
    • Cisplatin
    • Capecitabine
  • Gem/cis
    • Gemcitabine + cisplatin
  • XELOX
    • Capecitabine + oxaliplatin

7. Basic concepts of hormone therapy

8. Biological therapy, targeted therapy and immunotherapy

• Targeted therapy
  • Targeted therapy refers to using drugs which are not cytotoxic but rather specifically target certain molecules
  • Targeted therapy often prolongs survival, sometimes for years, and the patient remains on the targeted therapy during this time
  • Biological therapy
    • = refers to biological drugs, most commonly monoclonal antibodies
    • Bevacizumab – anti-VEGF
      • Inhibits vascular proliferation and therefore neovascularization
    • Cetuximab – anti-EGFR
  • Small molecules
    • = refers to small molecule drugs, which enter the cells and inhibit certain intracellular proteins
    • Gefitinib, erlotinib – EGFR inhibitors
    • Alectinib – ALK inhibitor
    • Vemurafenib – BRAF inhibitor
      • Only works on a certain type of BRAF mutation in melanoma
      • Actually stimulates wildtype BRAF
    • Sorafenib – Multi protein kinase inhibitor
      • Inhibits VEGFR, PDGFR, RAF, etc.
  • Common side effects
    • Anti-EGFR and EGFR inhibitors
      • Acneiform dermatitis
    • Anti-BRAF and BRAF inhibitors
      • Photosensitivity
      • Squamous cell carcinoma
    • Sorafenib
      • Alopecia
      • Hand-foot syndrome
• Immunotherapy
  • Immune checkpoint inhibitors
    • Most commonly used immunotherapy
    • These drugs are monoclonal antibodies and therefore also technically biological drugs
    • These drugs inhibit the mechanism by which cancer cells inhibit the immune system
    • Anti-PD-1 – nivolumab, pembrolizumab
    • Anti-CTLA-4 – ipilimumab
  • Vaccines
  • Cytokines

9. Cancer pain management

• Pain -> opioids
• Nausea -> ondansetron
• Diarrhoea -> loperamide
• Phlebitis -> local anti-inflammatory cream

10. Psycho-oncology

11. Oncologic emergencies

• In case of oncological emergencies oncotherapy can be initiated without knowing the histology of the cancer
• Increased intracranial pressure
  • Due to brain metastases or primary brain tumor
  • Urgent MRI should be made
  • ASAP treatment includes dexamethasone, forced diuresis (fluid + loop diuretics) and mannitol to reduce oedema
  • Then treat tumor
• Spinal cord compression
  • Due to enlarging vertebral metastasis or pathologic vertebral fracture due to metastasis
  • Often from breast, lung, prostate, etc.
  • Most often involves thoracic spine
  • X-ray will show blastic or lytic lesions
  • MRi will show localization of spinal cord compression
  • ASAP treatment includes dexamethasone and spinal decompression surgery
  • Then treat tumor
• Superior vena cava syndrome
  • Can be due to lung cancer, lymphoma etc, but also due to non-cancer conditions (see surgery 1)
  • X-ray will show mediastinal widening
  • CT with contrast will give more detailed picture
  • Hyperfractionated radiation therapy given to provide rapid tumor reduction and symptom relief
• Malignant pleural effusion
  • Exudate, not transudate
  • Due to tumor cell implants on pleura
  • Due to metastatic breast, lung or lymphoma
  • Chest x-ray shows effusion
  • Thoracentesis shows exudate, also drains fluid
  • Chest tube can be inserted to continually drain fluid
  • Pleurodesis – procedure where the visceral and parietal pleurae are adhered together to prevent fluid accumulation
    • A sclerosing agent like doxycycline, bleomycin or talc is added to the pleural cavity
    • These agents cause the pleurae to adhere to each other
• Airway obstruction
• Ileus
• Hypercalcaemia of malignancy
  • In breast, lung, or multiple myeloma
  • Due to osteolytic metastases, or due to PTH-related peptide secretion
  • Symptoms include fatigue, vomiting, altered mental status
  • Treatment involves hydration and furosemide + bisphosphonates
• Hyponatraemia
  • Due to syndrome of inappropriate ADH, due to SCLC or other neuroendocrine tumor
  • ASAP slow infusion of hypertonic saline
• Tumor lysis syndrome
  • Due to chemo of chemosensitive, high cell-turnover tumours, especially leukaemias, lymphomas
  • Massive cell death release causes hyperkalaemia, hyperuricaemia, hyperphosphataemia, secondary hypocalcaemia
  • Prevention is essential, by hydrating patients, possibly giving allopurinol
  • Manifest tumor lysis syndrome may require dialysis
• Febrile neutropaenia
  • Defined as a single measurement of > 38,3°C oral or a sustained temperature of 38,0°C for 1 hour + neutropaenia (< 500/µL)
  • Take two sets of blood culture ASAP, then immediately start empiric broad-spectrum AB therapy
  • Aminoglycoside + antipseudomonal beta-lactam
• Disseminated intravascular coagulation
  • Due to acute promyelocytic leukaemia (APML)
  • Signs of haemorrhage and thrombosis
  • All-trans retinoic acid treats APML
  • Replacement of platelets and coagulation factors may be necessary
• Hyperviscosity syndrome
  • Due to myeloproliferative disease or ALL
  • Hyperviscous blood causes symptoms of impaired microcirculation
  • Treatment includes phlebotomy

12. Palliative care

Specific malignancies template

• The next topics about specific malignancies will follow this template
• Epidemiology
• Etiology
  • Causes, risk factors
• Pathology
  • Relevant pathological aspects
• Clinical features
  • Signs and symptoms
• Stages
  • The clinical and pathological stages. Often based on TNM
  • Sometimes the stages are classified like this
  • Early stage/localized disease
    • The tumour is localized to the primary organ
  • Locally/regionally advanced disease
    • The tumour has spread locally or to local lymph nodes
  • Metastatic/disseminated disease
    • The tumour has spread distally (M1)
• Risk groups
  • Factors which determine the risk of metastases and poor outcomes
  • Often, these include stage, grade, certain lab markers, certain histological features, etc.
  • The treatment is often based on the risk group
  • Cancers are often divided into low, intermediate and high-risk groups depending on the presence of these factors
  • Age and performance status are important factors for all cancers
• Diagnosis
  • The process of establishing the diagnosis of cancer
• Work-up after diagnosis
  • As soon as the diagnosis is established the staging work-up must begin for the clinical staging of the cancer
  • Often includes imaging modalities to evaluate spread and lymph node metastases
  • Can also include tests for biomarkers, biopsy of lymph nodes, etc.
  • NB! It’s common to do MRI of the brain if metastases are present on imaging
  • NB! It’s common to do bone scans if skeletal symptoms are present
• Treatment
  • Surgery
    • Explains the surgical modalities used, etc.
  • Systemic therapy
    • Chemotherapy
    • Targeted therapy
    • Hormonal therapy
    • Immunotherapy
  • Radiotherapy
  • Treatment according to stage:
  • Early stage/localized disease
  • Locally/regionally advanced disease
  • Metastatic/disseminated disease

13. Tumors of head and neck

• Tumours of the head and neck include
  • Eye and orbital tumours
  • Oral cavity tumours
  • Pharyngeal tumours
    • Nasopharynx
    • Oropharynx
    • Hypopharynx
  • Laryngeal tumours
    • Supraglottic
    • Glottic
    • Subglottic
  • Tumours of the nasal cavity and paranasal sinuses
  • Tumours of the salivary gland
  • Tumours of the thyroid gland
• Epidemiology
  • Head and neck cancer is the 6^th most common cancer worldwide
• Etiology
  • Smoking
  • Alcohol
  • Poor oral hygiene
  • EBV – for nasopharyngeal carcinoma
  • HPV – for oropharyngeal and laryngeal cancer
• Pathology
  • 80% are squamous cell
  • 20% are adenocarcinoma, lymphoma, sarcoma, etc.
  • Precancerous lesions
    • Leukoplakia
    • Erythroplakia
    • Lichen planus
  • Metastasizes most often to lung
• Clinical features
  • Ulceration of mucosa
  • Exophytic growth of mucosa
  • Neck mass
  • Sore throat
  • Hoarseness
  • Pain radiating into the ear
    • Due to cranial nerve affection
  • Dysphagia
• Diagnosis
  • FNAB or direct excision biopsy
• Work-up after diagnosis
  • CT with contrast or MRI of head and neck
  • Laryngoscopy
  • Neck US
  • PET scan
• Treatment
  • Majority of cases are treated with multiple modalities
  • Surgery
    • Only used if R0 resection with acceptable functional results is expected
      • This means that surgery is not performed unless the surgeon believes that he can completely resect the tumour
    • If early stage cancer -> transoral surgery (TORS)
    • If cancer has spread to lymph nodes, neck dissection must be performed
      • Modified radical neck dissection
      • Selective neck dissection
    • Surgery, especially of pharynx and larynx, impairs quality of life, which must be taken into account when deciding treatment modality
  • Radiotherapy
    • External beam radiotherapy or brachytherapy
    • Can be given with curative or palliative intention
    • Can be given postoperatively or primarily
    • Primary radiotherapy alone is usually sufficient in
      • Cancer of the lip
      • Cancer of the nose
      • Cancer of the floor of the mouth (brachytherapy)
      • Cutaneous lymphoma
  • Chemotherapy
    • Cisplatin
    • Taxanes
    • 5-FU
  • Biological and immunotherapy
    • Cetuximab (anti-EGFR)
    • Nivolumab (anti-PD-1)
    • Pembrolizumab (anti-PD-1)
  • Cancer of oral cavity
    • Surgery
    • Postoperative radiotherapy or radiochemotherapy is indicated if high-risk features are present
      • R1 or R2 resection
      • T3 or T4 tumours
      • Lymph node spread
      • Etc.
    • Before radiotherapy of the oral cavity, dental care is essential
      • Bad teeth etc. can act as a source of inflammation after radiotherapy
  • Cancer of pharynx
    • Nasopharynx is the most radiosensitive, hypopharynx is the least radiosensitive
    • Nasopharyngeal cancer – radiochemotherapy
    • Oropharyngeal cancer – radiochemotherapy is preferred, surgery is option
    • Hypopharyngeal cancer – surgery is preferred, radiochemotherapy is option
  • Cancer of larynx
    • Early cancer – radio or surgery alone
    • Locally advanced cancer – radiochemotherapy or total laryngectomy
    • Advanced cancer – total laryngectomy with adjuvant radiotherapy
  • Stage III and IV
    • Radiochemotherapy or radiobiotherapy
    • With cisplatin or cetuximab, respectively

14. Lung cancer

• Epidemiology
  • Cancer with the highest mortality rate worldwide
• Etiology
  • Smoking
    • 80% of lung cancer deaths are due to tobacco use
  • Air pollution
  • Asbestos
• Clinical features
  • Cough
  • Haemoptysis
  • Dyspnoea
  • Chest pain
  • Extrapulmonary symptoms
    • Superior vena cava syndrome
    • Weight loss
    • etc.
• Diagnosis
  • If lesions suspicious of tumor is found, biopsy must be taken
  • Acquiring tissue specimens is better than acquiring cytologic specimens
    • As only tissue specimens yield enough material for immunohistochemistry and genetical testing
    • This is important for prognosis and treatment
    • However, cytologic specimen is usually sufficient to determine the histological subtype and to confirm the cancer diagnosis
  • Procedures which yield tissue specimens
    • Endobronchial biopsy or resection
    • Transbronchial biopsy or resection
    • Mediastinoscopy (to biopsy mediastinal nodes or masses)
  • Procedures which yield cytologic specimens
    • Sputum analysis
    • Bronchoalveolar lavage
    • Transthoracic fine needle aspiration biopsy
    • Transbronchial fine needle aspiration biopsy
• Work-up after diagnosis
  • Contrast CT imaging of chest, liver and adrenal glands
  • PET scan
  • If CT finds metastases (advanced disease), then perform MRI for brain metastases and x-ray/bone scintigraphy for skeletal metastases
  • Lung function test
• Non-small cell lung cancer (NSCLC)
  • Accounts for 85% of cases
  • Types
    • Adenocarcinoma
      • 40% of cases
      • Idiopathic
      • Peripheral
    • SCC
      • 20% of cases
      • Smoking, etc.
      • Central
    • Large cell carcinoma
      • 10% of cases
      • Peripheral
  • Staging
    • Stage I, II
      • Tumor size < 7 cm
      • No mediastinal invasion
      • No lymph node involvement beyond ipsilateral hilar nodes
      • No distant metastasis (M0)
    • Stage IIIA
      • Tumor size > 7 cm
      • No mediastinal invasion
      • Mediastinal lymph node involvement
      • No distant metastasis (M0)
    • Stage IIIB
      • Any tumor size
      • Mediastinal invasion
      • Distant lymph node spread, but no distant metastasis (M0)
    • Stage IV
      • Any tumour size
      • Any lymph node status
      • Distant metastasis M1
  • Treatment
    • Generally, any tumor stage I – IIIb is potentially curable, while any other stage is palliative
    • Surgery
      • Lobectomy
      • Wedge resection
      • Pneumonectomy
    • Chemotherapy
      • Cisplatin
      • Taxanes (paclitaxel)
    • Radiotherapy
      • External beam therapy and brachytherapy
      • Stereotactic radiotherapy can be used for peripherally located inoperable tumors
      • Emergency indications for radiation
        • Superior vena cava syndrome
        • Malignant spinal cord compression
        • Brain metastasis
    • Targeted therapy
      • EGFR tyrosine kinase inhibitors – erlotinib, gefitinib
      • ALK and ROS inhibitor – crizotinib
      • ALK inhibitor – alectinib
      • Anti-VEGF – bevacizumab
    • Immunotherapy
      • PD-1 inhibitors – pembrolizumab, nivolumab
      • PD-L1 inhibitors – avelumab, atezolizumab, durvalumab
    • Stage I – IIIa
      • Surgery
      • Postoperative chemotherapy in some cases
    • Stage IIIb
      • Radiochemotherapy
    • Stage IIIc – IV
      • Palliative
      • Any combination of chemo, immune and targeted therapy, depending on histological type and molecular testing
      • Squamous cell carcinoma
        • Polychemotherapy
        • Check for presence of PD-L1, if yes -> pembrolizumab
      • Adenocarcinoma
        • Check for KRAS, EGFR, ROS mutation and ALK/EML4 inversion
        • If KRAS mutation -> chemotherapy
          • KRAS mutation indicates poor prognosis
        • If EGFR mutation -> EGFR inhibitor
        • If ALK/EML4 inversion -> ALK inhibitor
        • If ROS mutation -> ROS inhibitor
• Small cell lung cancer (SCLC)
  • Accounts for 15% of cases
  • Is a neuroendocrine tumor
  • Has worse prognosis than NSCLC, but is very radio-and-chemosensitive
  • Has a much higher turnover than NSCLC (tumor doubling every 50 days vs 200 days)
  • Associated with paraneoplastic syndromes, like SIADH, Cushing syndrome, etc.
  • Staging
    • Because SCLC is radiosensitive its staging system is based on whether radiotherapy of the tumor is feasible
    • “Limited disease” (corresponds to stages I – IIIB)
      • 20% of cases at diagnosis
      • Cancer spread confined to one hemithorax, and radiotherapy is therefore feasible
    • “Extensive disease”
      • 75% of cases at diagnosis
      • Cancer spread beyond one hemithorax, and radiotherapy is therefore not feasible
  • Treatment
    • Chemotherapy
      • Cisplatin + etoposide
    • Prophylactic cranial irradiation
      • Improves survival by killing brain metastases which are often already present but not visible on scans
    • Limited disease – curative
      • Radiochemotherapy
      • Prophylactic cranial irradiation if remission is achieved
    • Extensive disease – palliative
      • Chemotherapy
      • Prophylactic cranial irradiation in most cases

15. Breast Cancer (BC)

• Epidemiology
  • Most common cancer in women worldwide
  • 2/3 of cases occur in women 55 or older
• Etiology
  • Female gender
    • Obviously the biggest risk factor
  • Old age
  • Family history
    • 5 – 10% of cases are hereditary
    • BRCA1 or BRCA2
    • Women with 2 or more first-degree relatives with breast or ovarian cancer have more than 50% risk of developing BC
  • Personal history (women who already have had breast cancer)
  • Certain benign breast conditions
  • Not breastfeeding
    • Breastfeeding lowers BC risk
  • Drinking alcohol
  • Being overweight
  • Physical inactivity
  • Smoking
  • Risk factors which cause increased oestrogen exposure
    • Not having children
    • Early menarche
    • Late menopause
    • Using hormone replacement therapy
• Genetic testing for hereditary breast cancer is indicated in:
  • Women diagnosed with early stage breast cancer
    • Genetic result will determine the treatment
  • Women with metastatic breast cancer
    • Genetic result will determine the treatment
  • Healthy women who are suspected to have BRCA1 or BRCA2 mutation
    • For example, healthy women with close relatives with breast or ovarian cancer
• Pathology
  • Histological subtypes
    • Invasive ductal carcinoma – 80% of cases
      • Originates from a milk duct of the breast
    • Invasive lobular carcinoma – 10% of cases
      • Originates from a breast lobule
    • Other – 10% of cases
  • Molecular subtypes
    • Hormone receptor positive or negative
      • Oestrogen receptor and/or progesterone receptor
      • 60% are hormone receptor positive
      • Hormone receptor positivity indicates better prognosis
    • HER2 positive or negative
      • HER2 positivity is due to amplification of the HER2 gene
      • 20 % are HER2 positive
      • HER2 positivity indicates a more aggressive cancer, but because we have targeted therapy against HER2 the prognosis of HER2 positive cancers is the same as HER2 negative
      • Presence of HER2 can be detected by FISH (most accurate) or IHC
    • If all three are negative the cancer is known as “triple negative”
      • 15% are triple negative
      • Triple negativity indicates poorer prognosis
• Clinical features
  • Many are asymptomatic – screening is important
  • Lump in the breast
• Stages
  • Early breast cancer
    • Stage 0 – non-invasive
      • Survival 100%
    • Stage 1 – tumour is < 2 cm, no spread
      • Survival 98%
    • Stage 2 – tumour is > 2 cm, may have spread to nearby lymph nodes
      • Survival 93%
    • 30% of early BC relapse into metastatic BC
  • Advanced breast cancer
    • Stage 3 (locally advanced BC) – cancer spread beyond nearby lymph nodes but not to other organs
      • Survival 72%
    • Stage 4 (metastatic BC) – cancer spread to other organs
      • Survival 22%
      • Metastases to bone, brain, liver or lung
• Diagnosis
  • Mammography
  • Ultrasound of breast and nearby lymph nodes
  • MRI
    • For women with dense breasts, silicone implant or BRCA mutation
  • Biopsy
    • Core needle biopsy, FNAB, or excisional
    • Mandatory for diagnosis
• Work-up after diagnosis
  • Determination of histological and molecular subtypes
  • Biopsy of suspicious lymph nodes
  • CT chest, abdomen, pelvis
• Treatment
  • Multidisciplinary teams (oncological teams) are used in the treatment of breast cancer
  • Surgical treatment
    • Some form of surgery is performed in all cases which are operable
    • Mastectomy
      • Radical or modified mastectomy
      • Breast reconstruction can be performed in the same surgery as the mastectomy or at a later point
      • Breast reconstruction can be achieved by implants, by autologous tissue implantation, or both
    • Breast-conserving surgery
      • Sometimes called lumpectomy
      • Must always be followed up by radiotherapy
    • Staging of axillary lymph nodes
      • Must be performed during all surgeries
      • By biopsy or lymph node dissection
  • Radiotherapy
    • Treatment planning is always based on CT to minimize heart and lung radiation
    • The standard is to deliver whole-breast radiation
  • Systemic therapy
    • The molecular subtype determines the systemic therapy
    • Chemotherapy
      • Anthracycline
      • Taxanes
    • Hormonal therapy
      • Hormonal therapy is indicated in most hormone positive patients
      • Selective oestrogen receptor modulators
        • Tamoxifen
      • Aromatase inhibitors
      • Fulvestrant
    • Targeted therapy
      • Anti-HER2
        • For most HER2+ patients
        • Trastuzumab
      • PARP inhibitors
        • For BRCA-positive advanced BC
    • Immune therapy
      • Atezolizumab (PD-L1 inhibitor)
      • For triple-negative breast cancer
  • For early breast cancer (stage 0 – 2)
    • Without BRCA mutation
      • Breast-conserving surgery + adjuvant radiotherapy
    • With BRCA mutation
      • Mastectomy
      • Prophylactic contralateral mastectomy
      • Prophylactic bilateral salpingo-oopherectomy
  • For locally advanced breast cancer (stage 3)
    • Neoadjuvant systemic therapy + surgical resection + adjuvant systemic therapy
  • For metastatic breast cancer (stage 4)
    • The cancer is generally not curable, but it is treatable
    • Neoadjuvant systemic therapy + surgical resection and/or radiotherapy
    • With BRCA mutation – PARP inhibitors

16. Cancer of the oesophagus and the stomach

• Oesophageal cancer
  • Epidemiology
  • Etiology
    • GERD
    • Smoking
    • Poor diet
    • Obesity
    • Alcohol
  • Pathology
    • Adenocarcinoma
      • Develops from Barrett’s oesophagus
      • Rising incidence
    • Squamous cell carcinoma
      • The most common type, but incidence is declining
    • The absence of tunica serosa in parts of the oesophagus causes oesophageal cancer to metastasize early
  • Clinical features
    • Asymptomatic early
    • Dysphagia
    • Retrosternal pain
  • Diagnosis
    • Oesophageal endoscopy (oesophagogastroduodenoscopy)
      • Best initial and confirmatory test
      • Biopsy can be performed
  • Work-up after diagnosis
    • Endoscopic ultrasound
      • To assess T and N stage
    • CT chest, abdomen
      • To assess M stage
  • Treatment
    • Surgery
      • Endoscopic submucosal resection
        • For very early localized disease
      • Subtotal or total oesophagectomy
        • Most commonly performed surgery
    • Systemic therapy
      • Chemotherapy
        • Commonly used in oesophageal cancer
        • FLOT
      • Targeted therapy
        • Trastuzumab – anti-HER2
      • Immunotherapy
        • Pembrolizumab
    • Radiotherapy
      • Often used with chemotherapy
    • Localized disease
      • Surgery
        • May be sufficient in early localized disease
      • Neoadjuvant chemotherapy or radiochemotherapy
      • Adjuvant chemotherapy
    • Advanced disease
      • Palliative
      • Radiochemotherapy
      • Targeted or immunotherapy
      • Oesophageal stent placement
• Gastric cancer
  • Epidemiology
    • Male > female
    • Old age
    • High incidence in Korea, Japan
    • Declining incidence in the west
  • Etiology
    • Foods rich in nitrates
    • Salty food
    • Nicotine use
    • Atrophic gastritis
    • H. pylori
    • Gastric ulcers
  • Pathology
    • According to histological cell type
      • Adenocarcinoma (90%)
      • Signet ring cell carcinoma
    • According to the Lauren classification
      • Intestinal type
      • Diffuse type
    • At diagnosis 75% already have metastases
  • Clinical features
    • Often asymptomatic in early stages
    • General signs
      • Iron deficiency anaemia
        • Due to chronic blood loss
      • Weakness
    • Abdominal pain
    • Nausea, vomiting
    • Painful, movable mass in epigastric region
  • Diagnosis
    • Faecal blood test
      • Positive in some cases
    • Gastroscopy (= upper endoscopy) with biopsy
      • Biopsy confirms diagnosis
  • Work-up after diagnosis
    • Endoscopic ultrasound
    • Chest, abdominal and pelvic CT
    • Bone scintigraphy
      • If suspected bone metastasis
    • Laparoscopy
      • If suspected peritoneal carcinosis
  • Treatment
    • Surgery
      • Radical gastrectomy and lymphadenectomy
    • Systemic therapy
      • Chemotherapy
        • FLOT
        • ECX
      • Targeted therapy
        • Trastuzumab – anti-HER2
        • Ramucirumab – anti-VEGF
      • Immunotherapy
        • Pembrolizumab – anti-PD-1
    • Localized disease
      • Surgery
      • Both neoadjuvant and adjuvant chemotherapy or radiochemotherapy are often used
    • Advanced disease
      • Palliative
      • Perioperative chemotherapy + surgery
      • Targeted therapy and immunotherapy are options

17. Cancer of the pancreas and the liver

• Pancreatic cancer
  • Epidemiology
    • The 10^th most frequent cancer, but the fourth leading cause of cancer-related death
  • Etiology
    • Smoking
    • Chronic hepatitis
    • Diabetes
    • Obesity
  • Pathology
    • Responds poorly to chemotherapy
    • Aggressive growth
    • 2/3 in head
    • 1/3 in tail
    • 95% are adenocarcinomas
  • Clinical features
    • Asymptomatic early
    • Belt-like epigastric pain
    • Jaundice
    • Weight loss
    • Trousseau syndrome
      • A paraneoplastic syndrome
      • Causes superficial thrombophlebitis
    • Courvoisier sign
      • Enlarged gallbladder + painless jaundice
  • Stages
    • Resectable disease
      • 15% present in this stage
      • Median survival of 20 – 24 months
    • Locally advanced (unresectable) disease
      • 25% present in this stage
      • Median survival of 8 – 12 months
    • Metastatic disease
      • 50% present in this stage
      • Median survival of 6 – 12 months
    • Overall 5-year survival for all patients is < 5%
  • Diagnosis
    • Abdominal US
      • If positive -> CT with contrast
    • CT with contrast or MRI
      • Sufficient for diagnosis
      • Also provides information for staging
    • Biopsy is required to establish diagnosis
      • However, if there is high clinical suspicion, a biopsy is not necessary
  • Work-up after diagnosis
    • CT chest
    • PET
  • Treatment
    • Surgery
      • Surgery is the only potentially curative treatment
      • “Whipple procedure” (= pancreaticoduodenectomy)
        • If pancreatic head tumour
      • Distal resection
        • If pancreatic body or tail tumour
    • Systemic therapy
      • Chemotherapy
        • Gemcitabine
        • 5-FU
        • Albumin-bound paclitaxel
      • Targeted therapy
        • Erlotinib
    • Radiotherapy
      • Not so frequently used
    • Resectable disease
      • Surgery + adjuvant chemotherapy or chemoradiotherapy
      • If the tumour is borderline resectable -> neoadjuvant chemotherapy
    • Non-resectable disease
      • Palliative treatment
      • Surgery to relieve bile tract obstruction, ileus, etc.
      • Chemotherapy
      • Enrolment into clinical trials
• Hepatocellular carcinoma
  • Epidemiology
    • Men > women
    • Old age
    • Most common in southeast Asia and Africa
  • Etiology
    • Cirrhosis
      • 80% of HCC cases are preceded by cirrhosis
    • Risk factors independent of cirrhosis
      • Hep B, C
      • Alcohol liver disease
      • Non-alcoholic steatohepatitis
      • Haemochromatosis
      • Aflatoxin
  • Clinical features
    • Usually asymptomatic
      • Patient may have symptoms from underlying disease (cirrhosis, hepatitis)
    • General symptoms
      • Weight loss
      • Weakness
      • Abdominal pain
  • Diagnosis
    • AFP
    • Abdominal US
      • Initial test
      • Focal lesions in a cirrhotic liver are primary liver cancer until proven otherwise
    • Abdominal CT
      • Confirmatory test
    • Liver biopsy
      • Not necessary if definitive diagnosis is established with above tests
      • Carries risk of bleeding and tumor spread
  • Stages
    • Many staging systems for HCC exist, and none are universally accepted
    • It appears that POTE uses the Barcelona Clinic Liver Cancer (BCLC) staging
    • This system stages the cancer based on liver function (Child-Pugh score), patient performance status (ECOG PS) and tumor morphology
    • Liver function is scored according to Child-Pugh score
      • This score checks multiple parameters that reflect liver function and gives points and a final score
        • Child-Pugh A – good liver function
        • Child-Pugh B
        • Child-Pugh C – poor liver function
      • Bilirubin
      • Albumin
      • Prothrombin time
      • INR
      • Presence of ascites
      • Presence of hepatic encephalopathy
    • Very early stage (stage 0)
      • Solitary lesion < 2 cm
      • ECOG PS 0
      • Child-Pugh A
    • Early stage (stage A)
      • Solitary lesion < 2 cm or 3 nodules < 3 cm
      • ECOG PS 0
      • Child-Pugh A or B
    • Intermediate stage (stage B)
      • Multifocal disease
      • ECOG PS 0
      • Child-Pugh A or B
    • Advanced stage (stage C)
      • Portal invasion or extrahepatic spread
      • ECOG PS 1 – 2
      • Child-Pugh A or B
    • Terminal stage (stage D)
      • ECOG PS 3 – 4
      • Child-Pugh C
  • Treatment
    • Targeted therapy
      • Sorafenib
        • Multi protein kinase inhibitor
        • Inhibits VEGFR, PDGFR, RAF, etc.
    • Very early or early stage tumor
      • Surgical resection
    • Early stage tumor
      • Liver transplantation
    • Intermediate stage tumor
      • TACE (transarterial chemoembolization)
    • Advanced stage tumor
      • Sorafenib
    • Terminal stage tumor
      • Palliative care
  • Prevention
    • Patients with high risk for HCC (cirrhosis, hep B or C) should be regularly screening with AFP

18. Colorectal cancer

• Epidemiology
  • 3^rd most common malignancy
  • 2^nd most common cause of cancer-related death
  • Average age – 60s
  • 90% of CRC are sporadic, 10% are hereditary
• Etiology
  • Old age
  • Positive family history
  • IBD
  • Lifestyle factors
    • Smoking
    • Alcohol
    • Obesity
    • Diets high in meat, fat and low in fibre
    • Low level of physical activity
  • Hereditary CRC
    • Familial adenomatous polyposis
      • 100% risk of CRC
      • Germline APC mutation
    • Hereditary nonpolyposis colorectal cancer (Lynch syndrome)
      • 80% risk of CRC
      • DNA mismatch repair gene germline mutation
• Pathology
  • Most CRC arise from adenomatous polyp
    • Normal epithelium -> hyperproliferation -> adenomatous polyp -> invasive carcinoma
  • Adenocarcinoma accounts for 95% of all CRC
  • RAS, APC, p53 are all involved in carcinogenesis
  • Incidence according to location
    • Right-side colon – 1/4 of cases
    • Left-side colon – 1/3 of cases
    • Rectum – 40% of cases
  • Metastases
    • Colon cancer
      • Mesenteric, paraaortic, retroperitoneal lymph nodes
      • Liver
      • Ovary (Krukenberg tumour)
      • Lung
      • Bone
    • Rectal cancer
      • Pararectal lymph nodes
      • Liver
      • Lung
      • Bone
• Clinical features
  • Often asymptomatic until late stages
  • General symptoms
    • Weight loss
    • Fatigue
    • Abdominal discomfort
  • Right-sided carcinomas
    • Iron deficiency anaemia
      • Is very suspicious for CRC in elderly and postmenopausal women
    • Melena
  • Left-sided carcinomas
    • Changes in bowel habits
  • Rectum and sigmoid
    • Haematochezia
    • Thin stools
    • Rectal pain
• Stages
  • Stage I
    • T1 or T2, N0, M0
    • Only invasion of submucosa
  • Stage II
    • T3 or T4, N0, M0
    • Invasion of muscularis propria but N0, M0
  • Stage III
    • Any T, N1 or N2, M0
    • Invasion of subserosa or beyond but M0
  • Stage IV
    • Any T, any N, M1
    • Invasion or visceral peritoneum or adjacent organs
• Diagnosis
  • Colonoscopy with biopsy
    • Gold standard for diagnosis
    • It is mandatory to survey the whole colon, as multiple cancers may be present simultaneously
  • (Barium enema)
    • May show a filling defect reminiscent of an apple-core
  • (Digital rectal examination)
    • Can only detect 10% of cancers
• Work-up after diagnosis
  • Transrectal ultrasound – for T and N stage
  • Chest, abdominal and pelvic CT
    • For staging
  • Lab
    • Elevated CA19-9, CEA
  • Histological evaluation
    • Tumour grading
    • Mismatch repair gene mutations
    • HER2 mutation
• Treatment of colon cancer
  • Surgical therapies
    • Depends on exact localization of tumor
      • Segment resection with intraabdominal anastomosis
      • Rectal extirpation with colostomy
      • Left or right hemicolectomy
    • Lymphadenectomy
      • Always performed, for pathologic staging
    • Resection of metastases in the liver and/or lung
      • One of the few cancers in which it is benificial to resect metastases
  • Chemotherapeutical regimens
    • Chemotherapy
      • FOLFOX
      • FOLFIRI
    • Biological therapy
      • Usually added in stage IV tumors
      • Anti-VEGF – bevacizumab
      • Anti-EGFR – cetuximab/panitumumab
    • Targeted therapy
      • Multi-tyrosine kinase inhibitors like regorafenib
  • Radiation therapies
    • Radiation is not used for colon cancer (or any intraabdominal cancer) because the small bowel is very sensitive to radiation
    • Radiation can be used for rectal cancer, as it lies in the pelvic region
  • Stage I
    • Curative treatment
    • Surgical resection
  • Stage II and III
    • Curative treatment
    • Surgical resection + adjuvant (6 months postoperative) chemotherapy
    • 5-FU or FOLFOX
  • Stage IV
    • Palliative treatment
    • Indicated in bleeding or bowel obstruction
    • Surgical therapy
    • Chemotherapy
    • Biological therapy
• Treatment of rectal cancer
  • Radiation therapies
    • Radiation can be used for rectal cancer, as it lies in the pelvic region
  • Stage I
    • Curative treatment
    • Surgical resection
  • Stage II and III
    • Curative treatment
    • Neoadjuvant radio-chemotherapy + surgical resection + adjuvant chemotherapy
    • 5-FU
  • Stage IV
    • Palliative treatment
    • Surgical treatment if bleeding or bowel obstruction

19. Non-melanoma skin cancer

• Etiology
  • UVA and UVB
    • Cumulative, i.e. total sun exposure
• Pathology
  • UVA causes reactive oxygen species formation
  • UVB
    • Causes direct DNA damage
    • Is more carcinogenic, but most of it is absorbed by the stratosphere
• Basal cell carcinoma
  • Epidemiology
    • Technically the most common cancer, but it is often excluded from data due to its low mortality and morbidity
    • BCC accounts for 75% of all skin cancer
  • Pathology
    • Hedgehog pathway is often mutated
    • Types
      • Nodular BCC
      • Superficial BCC
      • Morpheaform BCC
      • Naevoid basal cell carcinoma syndrome
        • Autosomal dominant disease
        • Multiple BCC in young age
        • Bone and neurological malformations
      • Etc.
  • Treatment
    • Surgery
      • Surgical excision
      • Primary treatment is almost all cases
    • Radiotherapy
      • If surgery is not an option
    • Chemotherapy
      • Only topical (5-FU)
    • Alternatives for superficial and small BCCs
      • Cryosurgery
      • Photodynamic therapy
      • Laser ablation
      • Topical chemotherapy
      • Topical imiquimod
    • Targeted therapy
      • Vismodegib or sonidegib
        • Hedgehog pathway inhibitors
      • For metastatic BCC or BCC which recurs after surgery
• Squamous cell carcinoma
  • Epidemiology
    • SCC accounts for 18% of all skin cancer
  • Etiology
    • UV
    • Immunosuppression
      • SCC is the most common cause of death in transplant patients
    • HPV
    • Precursor lesion
      • Actinic keratosis
  • Treatment
    • Surgery
      • Surgical excision
      • Primary treatment is almost all cases
    • Radiotherapy
      • If surgery is not an option
      • As adjuvant therapy if high-risk features are discovered during pathological staging
    • Immune therapy
      • For advanced SCC
      • Cemiplimab – anti-PD-1
    • Alternatives for superficial and small SCCs
      • Cryosurgery
• Merkel cell carcinoma
  • Cancer development related to immune system dysfunction
    • Higher incidence and worse prognosis in immunocompromised
    • Merkel cell polyomavirus
  • Pinkish nodule on sun-exposed areas
  • Treatment is surgical excision
• Dermatofibrosarcoma protuberans
  • Rare tumour, but the most common cutaneous sarcoma
  • Translocation between chromosome 17 and 22
  • Treatment is surgical excision
• Kaposi sarcoma (KS)
  • Etiology
    • Immunosuppression
    • HHV8
  • Types
    • Classic
    • Endemic (in Africa)
    • Associated with non-HIV immunosuppression
    • HIV related
    • Nonepidemic variant
  • Treatment
    • Classic KS -> surgery or radiotherapy
    • HIV-related KS -> treatment of AIDS alone may cause cancer regression
    • KS associated with non-HIV immunosuppression -> changing immunosuppressing drug alone may cause regression

20. Melanoma

• Epidemiology
  • Melanoma accounts for 5% of all skin cancer
• Etiology
  • UVA and UVB
    • Especially high doses over short period, in contrast to non-melanoma skin cancer
  • Skin type I and II
  • Sunburns in childhood
  • Precursor lesions
    • Giant (> 20 cm) congenital nevi
    • Lentigo maligna
    • Dysplastic nevi
• Pathology
  • BRAF mutation is found in 50%
  • Breslow depth, mitotic rate and presence of ulceration on histology are important prognostic factors
  • Types
    • Superficial spreading melanoma
      • 57% of cases
      • Long horizontal spreading phase
    • Nodular melanoma
      • 21% of cases
      • No horizontal spreading phase, just vertical spreading phase
      • Poor prognosis
    • Lentigo maligna melanoma
      • Best prognosis
    • Acral lentiginous melanoma
• Stages
  • Localized disease – cancer confined to primary site
    • 84% of cases
    • 98% 5-year survival
  • Regional disease – cancer spread to regional lymph nodes
    • 9% of cases
    • 63% 5-year survival
  • Metastatic disease – cancer has metastasized
    • 4% of cases
    • 22% 5-year survival
• Diagnosis
  • Dermoscope
  • Full-thickness excisional biopsy
    • Removes the entire tumour with a small margin of healthy skin around
    • This is both diagnostic and therapeutic
  • Check for BRAF mutation
• Treatment
  • Surgery
    • Immediate complete excision is the gold standard
    • A sufficiently large safety margin (1 – 2 cm, depending on Breslow stage) must be used
  • Chemotherapy
    • Not used in melanoma
  • Immunotherapy
    • Checkpoint inhibitors are commonly used in advanced disease
    • Ipilimumab – anti-CTLA-4
    • Nivolumab, pembrolizumab – anti-PD-1
    • Atezolizumab – anti-PD-L1
  • Targeted therapy
    • Vemurafenib – BRAF inhibitor
      • MEK inhibitor (trametinib) is given simultaneously to prevent resistance
  • Localized disease
    • Surgery is often enough
    • Sentinel lymph node biopsy may be performed. If positive -> lymph node dissection and adjuvant immunotherapy or targeted therapy
  • Regional and metastatic disease
    • Surgery + adjuvant immunotherapy and/or targeted therapy

21. Soft tissue sarcomas and bone tumors

22. Nervous system tumors

• Epidemiology
  • CNS malignancies account for 2% of adult malignancies, but 30% of childhood malignancies
  • CNS metastases occur in 10% of cancer patients
  • Secondary CNS tumours (metastases) are more common than primary
    • Often from lung, breast, melanoma, etc.
  • Most common CNS tumours
    • Meningiomas
    • Glioblastoma
  • Most common in children – medulloblastoma
• Etiology
  • HIV
  • Nitrosoureas
  • Head irradiation
  • Hippel-Lindau syndrome
  • Recklinghausen syndrome
• Pathology
  • Location
    • In adults – most tumours are supratentorial
    • In children – most tumours are infratentorial
  • Classification of primary CNS tumours
    • Neuroepithelial tumours
      • Gliomas (most common)
        • Astrocytoma
        • Ependymoma
        • Oligodendroglioma
        • Glioblastoma (grade IV)
      • Embryonal tumours
        • Primitive neuroectodermal tumor (PNET)
        • Medulloblastoma
      • Pinealomas
      • Schwannoma
      • etc.
    • Non-neuroepithelial tumours
      • Meningiomas
      • Tumours of the choroid plexus
      • Germinomas
      • Primary CNS lymphomas
      • Pituitary adenomas
      • etc.
• Clinical features
  • Seizures
    • Most typical symptom of CNS tumour
  • Focal neurological disturbances
  • Personality changes
  • Headache
  • Vomiting
  • Hypertension (Cushing reflex)
• Risk factors
  • Grade
    • Most important prognostic factor in CNS tumours
  • Age
  • Performance state
• Diagnosis
  • Imaging
    • MRI with contrast (best)
    • CT
• Treatment
  • Neurosurgical intervention
    • Very important in neurooncology because the tumour may have to be removed urgently to reduce symptoms
    • Surgical resection is performed in nearly all CNS tumours
  • Radiotherapy
    • Most brain tumour patients receive some form of radiotherapy, often after surgery as adjuvant therapy
    • External beam radiotherapy is much more common than brachytherapy
    • Advanced techniques like 3DCRT, IMRT and radiosurgery are used to minimize damage to the brain
    • Radiosurgery/stereotactic radiotherapy/gamma knife/Cyber knife therapy
      • Used for lesions smaller than 3 cm
      • Results similar to neurosurgery
    • Craniospinal irradiation
      • For tumours which often spread to CSF, like medulloblastoma
      • The brain and spinal cord are simultaneously irradiated
    • Whole brain radiotherapy (WBRT)
      • Radiation to the whole brain
      • Used for multiple CNS metastases
    • Radiotherapy cause oedema -> increased ICP
      • Prophylactic anti-oedema drugs like steroids, diuretics
  • Chemotherapy
    • Drugs has to penetrate BBB to be eligible for use against CNS tumours
    • Temozolomide
      • Most important drug for CNS tumours
    • BCNU (carmustine)
    • Methotrexate
      • For CNS lymphomas
  • For low-grade (I, II) glioma
    • Neurosurgery alone
  • For high-grade (III, IV) gliomas
    • Neurosurgery (tumour debulking, as complete resection is rarely possible) + radiotherapy + chemotherapy (temozolomide)
  • For primary CNS lymphoma
    • Chemotherapy (methotrexate)
    • Neurosurgery is not used as CNS lymphoma is diffuse rather than localized
  • For meningiomas, mesenchymal tumours, etc.
    • Neurosurgery
    • Radiotherapy in case of unresectable or malignant tumours
  • For secondary brain tumours
    • Solitary tumour – surgery
    • Few metastases – radiosurgery
    • Multiple lesions – whole brain radiotherapy
  • For spinal cord tumours
    • Surgery, sometimes radiotherapy

23. Gynaecologic tumors

• Ovarian tumors
  • Epidemiology
    • Second most common gynaecological cancer
    • Highest mortality of all gynaecological cancers
    • Primarily a disease of postmenopausal women
  • Etiology
    • Family history
    • BRCA mutation
    • Risk factors which increase oestrogen exposure
      • Early menarche
      • Late menopause
      • Obesity
      • Nulliparity
  • Pathology
    • 90% are epithelial
    • 10% are stromal or germ-cell
  • Clinical features
    • Often produces symptoms late
    • Abdominal pains
    • Ascites
    • Symptoms of metastases into bladder, rectum, etc.
  • Screening
    • No effective screening for general population
    • Screening is only for high-risk women
      • Family history
      • BRCA mutation
    • Pelvic examination twice early
    • Ultrasound
  • Stages
    • Stage I – cancer confined to ovary
      • Rare
    • Stage II – cancer has extended into pelvis
    • Stage III – metastases outside pelvis
      • Most patients are discovered at this stage
      • 20 – 30% 5-year survival
    • Stage IV – distant metastases
    • The staging is pathological, meaning that the findings during exploratory surgery are what determine the stage
    • 70% of cases are discovered in stage III or IV
  • Diagnosis
    • Transvaginal US
      • Gold standard for suspected ovarian cancer
      • Can show the presence of a mass, but cannot distinguish benign from malignant
    • FNAB is never performed as it may cause spreading
    • Diagnosis is generally made during exploratory surgery
    • CA-125 serum marker
  • Work-up after diagnosis
    • CT abdomen and pelvis
    • Vaginal and abdominal US
  • Treatment
    • Surgery
      • Exploratory surgery plays the biggest role in the treatment of ovarian cc and is both diagnostic and therapeutic
      • Surgery always involves:
        • Total extrafascial hysterectomy
        • Bilateral salpingo-oophorectomy
        • Pelvic and para-aortic lymphadenectomy
        • Omentectomy
      • Cytoreduction
        • Performed in stage III, IV, when complete resection of the tumour is impossible
        • Debulking of any lesions suspicious for metastases
      • During the surgery visual assessment of the upper abdomen, peritoneal surfaces, mesentery and other abdominal organs is performed
        • Any abnormal findings are biopsied and intraoperatively examined by a pathologist – if they are metastases, they are debulked
        • This is part of the surgical staging
      • Young, fertile, early-stage patients may receive fertility-preserving surgery instead
        • This involves unilateral salpingo-oophorectomy instead of bilateral, and no hysterectomy
    • Chemotherapy
      • Ovarian cc is chemosensitive
      • Chemo is always used after surgery as adjuvant therapy
        • Except in stage Ia (rare)
      • Paclitaxel + cisplatin/carboplatin
    • Targeted therapy
      • Bevacizumab
    • Radiotherapy
      • Rarely used due to low radiosensitivity
      • Sometimes as palliative treatment
    • Stage I – II
      • Complete resection during exploratory surgery + adjuvant chemotherapy
    • Stage III – IV
      • Cytoreduction during exploratory surgery + adjuvant chemotherapy
  • Follow-up
    • Tumor marker CA-125 is used for follow-up
  • Prognosis
    • High incidence, high mortality
    • High rate of recurrence
    • Prognosis in stage III, IV depends on the degree of cytoreduction which is achieved
• Cervical cancer
  • Etiology
    • HPV 16, 18, 31, 33
    • Smoking
    • HIV
  • Pathology
    • Originates from the squamocolumnar junction
    • 90% squamous cell
      • Originate from the surface of the cervix (ectocervix)
    • 10% adenocarcinoma
      • Originate from the endocervix
      • Worse prognosis than squamous
    • Very rare
      • Clear cell
      • Small cell
  • Clinical features
    • Asymptomatic in early stages
    • Abnormal vaginal discharge or bleeding
  • Stages
    • FIGO staging system
    • Early cervical cancer
      • Cancer which has not invaded the parametrium
      • Includes stages Ia, Ib, IIa
    • Locally advanced cancer
      • Cancer which has invaded the parametrium
      • Includes stages IIb and III
    • Metastatic cancer
      • M1
      • Stage IV
    • CT or MRI for staging
  • Screening
    • With pap smear
    • Annually after sexually active age
    • Low risk patients who has had two successive negative smears can perform it less frequently
  • Diagnosis
    • Pap smear
      • High specificity but moderate sensitivity
      • Scraping of ectocervix and endocervix with spatula or brush
      • Also used for screening
    • Colposcopy with biopsy
      • Excisional biopsy (conization)
  • Work-up after diagnosis
    • Imaging
      • CT, MRI, PET
    • Bimanual examination
      • One finger in vagina and one finger in anus
      • Used to palpate for spreading to parametrium
    • Creatinine and urea
      • Cervical cc can invade the ureters, causing kidney injury
      • Cisplatin is nephrotoxic, so knowing the status of the kidney before therapy is important
    • CT chest, abdomen, pelvis
    • MRI pelvis
  • Treatment
    • Surgical
      • Conservative surgery
        • Extrafascial hysterectomy without pelvic adenectomy
      • Wertheim operation
        • Modified radical hysterectomy + pelvic lymphadenectomy
        • Total removal of uterus and its ligaments
        • Removal of pelvic lymph nodes on both sides
    • Radiation
      • Radiation is very effective in all stages of cervical cc
      • External beam radiation therapy (EBRT)
        • The bladder is sensitive to radiation, so external radiation for cervical cancer should be limited to 50 Gy
        • After 50 Gy has been delivered by ERBT, we switch to brachytherapy
      • HDR brachytherapy with afterloading
    • Chemotherapy
      • Not often used in early cervical cancer
      • Often used in combination with radiotherapy
      • Cisplatin
        • Most commonly used chemotherapy in cervical cc
      • 5-FU sometimes added
    • Microinvasive cervical cancer
      • Corresponds to stage Ia1
      • Conservative surgery
    • Early cervical cancer
      • No invasion of parametrium
      • Wertheim operation or radiation
      • Both surgery and radiation have equal probability of cure but different morbidity
      • Postoperative radiochemotherapy, if features that signify high risk for recurrence are discovered during the surgery, like
        • Lymph node spread
        • Positive surgical margins
        • Invasion into parametrium
        • Other high-risk features
    • Locally advanced cervical cancer
      • Invasion of parametrium
      • Radiochemotherapy
      • Surgery is not used
    • Stage IVb or recurrent cc
      • Palliative treatment, if there are symptoms like pelvic pain, bleeding
      • Radiotherapy or systemic therapy
• Endometrial cancer
  • Epidemiology
    • Most common gynaecological cancer
    • Primarily occurs in postmenopausal women
  • Etiology
    • Unopposed oestrogen
      • Obesity
      • Nulliparity
      • Infertility
    • Diet
    • Diabetes
    • Hypertension
    • Tamoxifen treatment
  • Pathology
    • Type I – endometrioid type
      • In 80% of cases
      • Grows slowly
      • Hormone-sensitive
      • Good prognosis
    • Type II – other types
      • Not hormone sensitive
      • Not from endometrium
      • Poor prognosis
  • Clinical features
    • Early signs and symptoms
      • Screening is not needed
    • Vaginal discharge
    • Abnormal vaginal bleeding
  • Stages
    • Stage I – cancer confined to the uterus
      • 72% are diagnosed at this stage
    • Stage II – cancer has spread to cervix
    • Stage III – cancer has spread beyond uterus but still only in the pelvis
    • Stage IV – distant metastases
      • 3% are diagnosed at this stage
  • Diagnosis
    • Fractional dilatation and curettage -> histology
      • Gold standard for any abnormal bleeding
  • Work-up after diagnosis
    • MRI abdomen, pelvis
    • Chest X-ray
  • Treatment
    • Surgery
      • Total abdominal hysterectomy (TAH) with bilateral salpingo-oopherectomy
        • Pelvic and para-aortic lymphadenectomy may also be performed
      • Performed in all cases where possible
      • The majority of patients with endometrial cancer present with early stage cancer, which is curable with surgery alone
      • During the pathological staging, the cancer will be staged as low, intermediate or high-risk for persistence or recurrence, based on factors like
        • High tumour grade
        • Deep myometrial invasion
        • Lymph node involvement
        • etc.
      • Low-risk disease does not require adjuvant therapy
        • Surgery alone is curative in most low-risk patients
      • Intermediate-risk disease will be treated by postoperative (adjuvant) radiotherapy
      • High-risk disease will be treated by postoperative (adjuvant) chemotherapy
    • Radiotherapy
      • Compared to cervical cancer, endometrial cancer is not so sensitive to radiotherapy
      • Primary radiotherapy (without surgery) is reserved for inoperable or palliative patients
      • Both external beam radiotherapy and intravaginal brachytherapy are used
    • Chemotherapy
      • Not commonly used in endometrial cancer
      • Platinum-based drugs
    • Hormonal therapy
      • Progestins are the most commonly used hormonal agents
    • Stage I and II
      • Surgery (+ postoperative radiotherapy)
      • Some patients with stage I may be candidates for hormonal therapy only, which preserves fertility
        • Hormonal therapy is less effective than surgery, however
    • Stage III and IV
      • Treatment is often palliative
      • Cytoreductive surgery when feasible
        • Cytoreductive surgery increases survival
      • Any combination of chemo, radio or hormonal therapy

24. Urologic and male genital cancers

• Prostate cancer
  • Epidemiology
    • The lifetime risk of prostate cancer is 1 in 8
    • 64% of men between 60 and 70 have it
  • Metastases
    • Bone
    • Liver
    • Bladder
  • Risk groups
    • The risk for progression to metastatic disease is based on the following factors:
    • TNM Stage
    • Gleason score
    • PSA level
  • Diagnosis
    • PSA
      • New ways to measure PSA may increase the specificity of PSA for prostate cancer
        • Free to total PSA radio
        • Complexed PSA
        • [-2]proPSA percent
        • PSA velocity
        • PSA density
      • PSA is also used for follow-up
    • Biopsy
      • For definitive diagnosis
      • Transurethral, transrectal or transperineal
  • Work-up of diagnosed prostate cancer
    • Histopathological examination of biopsy
      • Grading according to the Gleason score
        • Gleason 2 – 6 = low grade
        • Gleason 7 = intermediate grade
        • Gleason 8 – 10 = high grade
    • MRI
    • Bone scan
      • If high grade
  • Progression of localized prostate cancer
    • If cancer is not completely cured during the primary treatment, it will relapse
    • Relapsed cancer is often treated with hormone therapy
    • Hormone therapy initially helps, as the cancer at this stage is hormone-naïve or castrate-sensitive prostate cancer (CSPC)
    • After some time, however, hormone therapy loses its efficacy. The cancer has become castration-resistant prostate cancer (CRPC)
      • At this point the testosterone levels are still at castration levels, but the tumour has grown independent of testosterone
      • This doesn’t mean that hormone therapy is useless
      • CRPC is often metastatic
  • Treatment
    • Observational strategies
      • Many cases of prostate cancer are better left untreated
      • Watchful waiting
      • Active surveillance
    • Surgery
      • Radical prostatectomy
      • Pelvic lymphadenectomy may be performed
    • Radiotherapy
      • Prostate cancer requires a very high load of radiation for local control, up to 100 Gy total
        • For this reason, EBRT and brachytherapy are often combined
      • External beam radiation therapy
      • Brachytherapy
        • HDR or seeding
    • Systemic therapy
      • Hormonal therapy
        • Androgen deprivation therapy (ADT)
          • Orchiectomy (surgical castration)
          • GnRH agonists or antagonists (chemical or pharmacological castration)
        • Antiandrogens
          • Never given alone – always combined with castration
          • Abiraterone – testosterone synthesis inhibitor
          • Enzalutamide – androgen receptor antagonist
        • Side effects of hormonal therapy
          • Erectile dysfunction
          • Osteoporosis
          • Metabolic syndrome
          • Cognitive loss
      • Chemotherapy
        • Docetaxel or other taxanes
        • Used only in castrate-resistant metastatic disease
      • Immunotherapy
        • Sipuleucel-T (a cancer vaccine)
      • Bone-targeting therapy
        • In cases of bone metastases
        • Bisphosphonates
        • Denosumab
        • Radium-223
          • This isotope mimics calcium and so is incorporated into areas of bone where bone metastases are forming
    • Low-risk and intermediate-risk localized disease
      • Observational strategies
      • Surgery or radiotherapy
    • High-risk localized and locally advanced disease
      • ADT + ERBT or surgery
    • Metastatic disease
      • Hormone-naive
        • ADT + antiandrogens
      • Castration-resistant
        • ADT + antiandrogens + chemo/immunotherapy
        • Radium-223 is often used due to bone metastases
• Bladder cancer
  • Epidemiology
    • Most common cancer of the urinary system
  • Etiology
    • Smoking
  • Pathology
    • Urothelial carcinoma
      • Most common
    • Squamous cell carcinoma
      • Associated with schistosomiasis, chronic UTI and indwelling catheters
  • Clinical features
    • Painless gross haematuria
      • Most common
    • Irritative voiding symptoms
      • Dysuria
      • Increased frequency
      • Urinary urgency
  • Stages
    • Non-muscle invasive bladder cancer (NMIBC) = stage I
      • Ta, T1 or Tis
    • Muscle-invasive bladder cancer (MIBC) = stage II, III
      • T2, T3, T4
    • Metastatic bladder cancer = stage IV
      • M1
  • Diagnosis
    • Urine cytology
    • Cystoscopy
      • Often combined with photodynamic diagnostics (PDD), which causes tumour cells to fluoresce
      • Simple biopsies can be taken
    • Transurethral resection of bladder tumour (TUR-B)
      • Both diagnostic and therapeutic
      • In all (non-metastatic) bladder cancers it’s important to know whether the cancer has invaded the muscular layer or not, which only TUR-B can tell
  • Work-up after diagnosis
    • If the cancer isn’t muscle-invasive, no further work-up is necessary
    • CT urography
      • These cancers are often multifocal, so the entire urinary tract must be examined
    • CT abdomen and pelvis
  • Treatment
    • Surgery
      • Transurethral resection of bladder tumour (TUR-B)
        • The tumour and some surrounding bladder tissue are removed with a transurethral resectoscope
        • This is both diagnostic and therapeutic
        • After the resection, chemotherapeutical drugs or BCG are instilled into the bladder to reduce any residual cancer cells
      • Radical cystectomy
      • Bladder preservation therapy
        • (Extensive) TUR-B followed by radiochemotherapy
        • An alternative to radical cystectomy which preserves the bladder
    • Radiotherapy
      • Inoperable tumours
      • As part of bladder preservation therapy
    • Systemic therapy
      • Chemotherapy
        • Gem/cis
      • Immunotherapy
        • Atezolizumab (anti-PD-L1)
        • Pembrolizumab (anti-PD-1)
      • BCG vaccine
        • Intravesical BCG helps the immune system kill urothelial cancer
    • Non-muscle-invasive bladder cancer
      • TUR-B alone is often enough
      • Intravesical BCG or chemo is instilled after TUR-B
    • Muscle-invasive bladder cancer
      • Radical cystectomy or bladder preservation therapy
    • Metastatic bladder cancer
      • TUR-B is not performed
      • Palliative
      • Chemotherapy or immunotherapy
• Renal cell carcinoma (RCC)
  • Etiology
    • Smoking
    • Obesity
    • Family history
  • Pathology
    • These are adenocarcinomas which arise from tubular epithelium
      • Urothelial cancers of the renal pelvis (etc.) don’t count as RCC
    • 80 – 90% are clear cell carcinoma
    • 10 – 15% are papillary carcinoma
  • Clinical features
    • Mostly asymptomatic
      • 50% are incidental findings on imaging
    • Haematuria
    • Anaemia
    • Palpable flank mass
    • Paraneoplastic syndromes
  • Stages
    • T1 – tumour < 7 cm
    • T2 – tumour > 7 cm
    • T3 – Tumour extends into renal vein or perinephric tissues
    • T4 – Tumour extends beyond Gerota fascia
  • Risk groups
    • The risk for progression to metastatic disease is based on the following factors:
    • TNM stage
    • Tumour size
    • Presence of histological necrosis
    • Tumour grade
    • Abnormal labs (LDH, Hb, Plt, etc.)
  • Diagnosis
    • CT abdomen with contrast
  • Work-up after diagnosis
    • CT/MRI thorax
  • Treatment
    • Surgery
      • Nephron-sparing surgery (= partial nephrectomy)
        • Preferred, when feasible
      • Radical nephrectomy
    • Radiotherapy
      • Stereotactic radiotherapy
      • For inoperable patients
    • Systemic therapy
      • Targeted therapy
        • Anti-VEGF
          • Bevacizumab
        • mTOR inhibitors
          • Everolimus
        • Tyrosine kinase inhibitors
          • Sunitinib, sorafenib, etc.
          • Cabozantinib
          • Pazopanib
      • Immunotherapy
        • Nivolumab (anti-PD-1)
        • Ipilimumab (anti-CTLA-4)
    • Localized disease
      • Surgery
    • Metastatic disease
      • Low or intermediate risk -> targeted therapy
      • High risk -> immunotherapy
• Testicular cancer
  • Epidemiology
    • Most common cancers in men 15 – 35
    • Surprisingly rare in women
  • Etiology
    • Cryptorchidism
    • Klinefelter syndrome
  • Pathology
    • Seminomas (50%)
      • Very radiosensitive
    • Non-seminomas (50%)
      • Often a combination of embryonal carcinoma, yolk sac, choriocarcinoma, etc.
      • Moderately radiosensitive
  • Clinical features
    • Mostly asymptomatic
    • Testicular lump
  • Stages
    • Limited disease – cancer limited to testicles
    • Locally advanced disease – retroperitoneal lymph node involvement
    • Metastatic disease – M1
  • Diagnosis
    • Testicular ultrasound
      • Often enough to establish the presence of malignant tumour
    • Tumor markers
      • LDH
      • hCG
      • AFP
    • Orchidectomy
      • Both diagnostic and therapeutic
  • Work-up after diagnosis
    • CT chest, abdomen, pelvis
  • Treatment
    • Surgery
      • Radical (inguinal) orchidectomy
        • Performed in all cases
      • Retroperitoneal lymph node dissection (RPLND)
        • Para-aortic lymph nodes are most commonly affected
    • Radiotherapy
      • External beam radiotherapy
      • Generally only used in seminomas, not non-seminomas
      • Radiotherapy is less and less used, chemo is more and more preferred instead
    • Chemotherapy
      • Cisplatin
      • Etoposide
      • Bleomycin
    • Localized disease (stage I)
      • Orchidectomy
      • Active surveillance
        • In low-risk localized disease
      • Adjuvant chemotherapy
        • In intermediate and high-risk localized disease
    • Locally advanced disease (stage II)
      • Orchidectomy + adjuvant radio (targeting retroperitoneal lymph nodes) or polychemotherapy or RPLND
    • Metastatic disease (stage III)
      • Orchidectomy + polychemotherapy