14- Treatment of cancer (radiotherapy, immunotherapy and surgery) Flashcards
Radiotherapy
Aim:
to deliver carefully calculated doses of radiation to cancer cell, whilst minimising the radiation exposure to surrounding tissues -> overall aim to achieve a high rate of local tumour control with a low risk of complications
how radiotherapy is used in treatment of cancer
As a primary treatment
- i.e. sole radical treatment
- e.g. prostate cancer
In conjunction with surgery
- Neoadjuvant – prior to surgery -shrink a tumour before surgical resection
- Intraoperative- during surgery
- Adjunction- post surgery
Can also be administer alongside systemic therapies
Palliative treatment
- Radiotherapy to a tumour causing spinal cord compression -> reducing neuropathic symptoms
- Radiotherapy to bony mets to reduce pain
40% of all patients cured/ 50% of all cancer patients will benefits from receiving radiotherapy
how radiotherapy works
- Used high energy radiation to eliminate cancer cells
- Radiation used is ionising, meaning it forms ions which then deposit energy into the cells of the tissues they pass through
Causes cell death in one of 2 ways - Apoptosis by causing DNA damage
- Preventing cancer cell proliferation, by causing single and dsDNA breaks (mitotic cell death)
*Cancer cells have a reduced capacity to repair DNA in comparison to healthy cells
*
Dosage of radiotherapy
- Delivered in fractions (sessions) until the total prescribed cumulative disease has been delivered
- Amount of energy absorbed in measured in Grays (Gy)
- Fractions help reduce the risk of acute tissue reactions and minimises damage to normal cells (which are able to undergo repair between fractions)
radiotherapy involves
planning and simulation
Planning
- Involves using imaging to determine where the radiation is to be aimed
- Aim to maximise radiation dose to anormal cells and monimise exposure to normal cells
- Margins are placed around the gross tumour volume to encompass microscopic disease spread
- Aim is to delivered higher dosing to the tumour volumes and comparably lower dosing to vulnerable anatomical structures such as the bladder, small bowel, rectum and femoral head
Simulation
- A custom radiation planning appointment- places patient in a reproducible position for the radiotherapy
- Ct allows relevant anatomy to be viewed from the direction of the radiation beam
- Once all info obtained, small tattoos may be placed on the patient to line up with laser beams in the treatment room
- Immobilises and moulds are also used to maintain patient in the same position so that the exact position can be recreated in each session
2 primary methods of delivering radiation
External beam radiation - most common
Systemic
others: Internal radiation/ brachytherapy
External beam radiation- most common
Delivered form outside the body by aiming high energy rays (e.g. protons, photons, particle radiation) towards the cancers location
Systemic
Radioactive substance injected/swallowed e.g. iodine radiation for thyroid cancer
Internal radiation/ brachytherapy
- Uses radioactive sources inc catheter or seeds to delivered radiation from inside the body directly to the tumour site
- Boosts treatment or primary treatment
- Benefits: since radiation delivered directly to the tumour, surrounding healthy tissues is exposed to a relatively small dose
- E.g. cervical and prostate cancer
Side effects of radiotherapy
Can significantly impact patients quality of life and limit doses of radiation able to be delivered.
- Usually localised side effects compared to systemic therapies like chemo and immunotherapy
Early side effects (within 3 months) of radiotherapy
That manifest within a few weeks of completing course- tend to resolve within a few weeks (reversible)
- Skin reactions
o Erythema, desquamation
- Fatigue
- Mucositis
- Diarrhoea
- Nausea
Late side effects of radiotherapy
Occurs months to years after course of radiation- tend to be irreversible
Excessive extracellular matrix, deposition of collagen and fibrinogenesis play a key role in aetiology
- Radiation induced fibrosis
- Atrophy
- Neural or vascular damage
- Range of endocrine effects (diabetes, hypothyroidism)
Small risk of inducing secondary malignancy due to associated DNA damage
Radiotherapy prescription
- Dose in Gray (the unit of absorbed dose, joule/kg)
- Divided into fractions (no of sessions) to minimize side effects
- Typical prescriptions:
- 50 Gy / 25 fractions
- 8 Gy / single fraction
- Target to GTV (gross tumour volume) or CTV (clinical target volume)
- Side effects local to site treated
- Aim to avoid interruptions – need a good reason to miss treatment
Radiosensitisers
- Temozolamide
–>Oral chemo for GBM - Capecitabine
–> Oral chemo for Colorectal Cancer - Cisplatin
–>Wide range of uses (Lung, teratoma, gynae, H&N) - Cetuximab –Monoclonal antibody
–>Given if prior Cisplatin or cannot tolerate Cisplatin - 5FU
–> GI tract tumours
Immunotherapy
- Aim it to boost natural immune defences so it can recognise, target and destroy cancer cells
- Most commonly refers to checkpoint inhibitors
Categorisation of immunotherapy
- Checkpoint inhibitors
- Adoptive cell therapy
- Cancer vaccine
- Cytokines
- Oncolytic virus therapy
- Monoclonal antibodies
–> May stop a cancer cell from growing but also trigger immune system to attack and kill cancer cells
Checkpoint inhibitors
Background
Checkpoints are receptors on the surface of T cell. They suppress T cell immune response to prevent T cells from attacking normal cells
- Can be used as single agents or in combination
- Types
o PDL1 receptor inhibitors
o PD1 rector inhibitors
o CTLA-4 receptor inhibitors
PD-1/PD-L1 immune checkpoint
e.g. Nivolumab, Pembrolizumab
Used in melanoma, lung, renal cancers
- Inhibitors of PD-1 and PD-L1 disrupt the PD-1/PD-L1 interaction and allow T effector cells to become activated and kill tumour cells. From this we have developed PD-1 inhibitors Nivolumab and Pembrolizumab and PD-L1 inhibitors which are just unpronouncable!
- PD-1 is a negative regulator of T-cell activity that inhibits T-cell activity at multiple stages of the immune system. Binding of the T-cell’s PD-1 to PD-L1 or PD-L2 on the cancer cell leads to inactivation of the T-cell so it can not kill the tumour cells.
CTLA4 inhibitors
- Ipilimumab
- Used in melanoma
Adoptive cell therapy
- T cells are isolated from the patients.
- Modification and multiplication of those cells in the laboratory and then re-injection back to the patient circulation
**- CAR-T – **chimeric antigen receptor T-cell – therapy - Very expensive! One session = £280000
- Licensed in the UK for B cell CLL and lymphoma (DLBCL)
Cancer vaccines
- Sipuleucel-T is the first human cancer treatment vaccine to receive FDA approval. The treatment is personalised , using a patient’s own dendritic to create an immunostimulatory vaccine.
- Licensed for metastatic prostate cancer.
Cytokines
- They are small proteins naturally produced and secreted by several immune system cells. They are crucial in signaling between immune cells, as well as between immune cells and several other cell types in the body
- Interleukin 2 (IL-2) is the only cytokine licenced to treat cancer (Kidney and melanoma)
Oncolytic virus therapy
- Viruses target particular cancer . The virus will infect the cancer cell and replicate itself. This results in destruction of the cancer cell, releasing the tumour antigens and activating antibodies. T-cells will be activated and generates antitumor response causing the cancer cell to die
- T-VEC is an intra-lesionally delivered vaccine, contains a genetically engineered herpes simplex virus type 1 (HSV-1) that selectively replicates in tumour, lyses tumour cells, while promoting antitumor immunity. It is licenced in melanoma.
Targeted cancer drugs/ Biologics
Background
- Work by targeting those differences that help cancer cells to survive and grow. They are one of the main treatments for some cancers:
o Advanced melanoma
o Leukaemia - Also known as biologics
Categorisation of targeted cancer drugs based on how they work
- Monoclonal antibodies
o Sort of immunotherapies too - Cancer growth blockers
- Drugs that block cancer blood vessel growth
- PARP inhibitors
However not a simple way of grouping targeted drugs. Some drugs belong to. More than one group because they work in more than one ways e.g. a drugs ghat works by blocking cancer cell growth may also be a monoclonal antibody. Some monoclonal antibodies trigger the immune system to attack and kill cancer cells-> therefore also a type of immunotherapy.
how targeted cancer drugs work
How they work
* stop cancer cells from dividing and growing
* seek out cancer cells and kill them
* encourage the immune system to attack cancer cells
* stop cancers from growing blood vessels
* help carry other treatments such as chemotherapy, directly to the cancer cells
Monoclonal antibodies/ targeted therapy
Background
Bind to a certain antigen/proteins on cancer cell surface, blocking specific downstream signalling pathways and arresting cell proliferation
- A targeted therapy and an immunotherapy
Herceptin (HER-2) and breast cancer
Indication
- Immunotherapy may be used in patients whose cancers express specific growth factor receptors.
- It can be used either as adjuvant therapy or as a monotherapy in patients who have received at least two chemotherapy regimens for metastatic breast cancer*.
MOA - One of the most common targets is the human epidermal growth factor receptor(HER-2 positive malignancies) for which Herceptin (Trastuzumab) is a monoclonal antibody that targets its activity.
*A common side-effect of treatment is cardiotoxicity, hence cardiac function must be monitored before and during treatment
monoclonal antibody examples
Examples
- HER2 inhibitor e.g. Trastuzumab in breast and gastric cancers
- VEGFR (vascular endothelial growth factor receptor) inhibitors e.g. Bevacizumab in ovarian & bowel cancer
- EGFR inhibitor (epithelial growth factor receptor) e.g. Cetuximab/Panitumumab in bowel cancer
Side effects of targeted therapy
- Skin toxicity
– Acneiform rash
– Dry skin - Hair growth disorders
- Pruritus
- Nail changes
- Fatigue
- Myelosuppression
- Diarrhoea
- Nausea
- Hypertension
- Proteinuria
- GI perforation
- Delayed wound healing
- Arterial thromboembolic events
- Cardiac ischaemia
- Flu-like symptoms
- Abnormal LFTs
- Allergic reaction
Hormone therapy
Background
- A medication used to block or lower the amount of hormones in the body to slow down or stop growth of cancer
How hormone therapies work
- Some cancer use hormones to grow or develop- hormone sensitive
o Breast cancer
o Prostate cancer
o Ovarian cancer
o Uterine cancer - Hormone therapy for cancer uses medicines to block or lower the amount of hormone in the body to stop or slow down the growth of cancer
hormone therapies for breast cancer
Tamoxifen (pre-meno)
Anastrozole (post-meno)
tamoxifen
Indication
- Pre-menopausal women
MOA
- SERM- selective oestrogen receptor modulator
o converse effects in breast and endometrial tissue
in endometrium = ER agonist
in breast = ER antagonist
* cell cycle arrest
- Blockage of oestrogen receptor in breast tissue
ADR
- Risk of thromboembolism during and after surgery or during periods of immobility
- Uterine carcinoma (due to pro-oestrogenic effect on the uterus)
Aromatase Inhibitors (post-menopausal)
e.g such as Anastrozole, Letrozole, or Exemestane
Indication
- Post-menopausal patients as adjuvant therapy, shown to be superior in this patient subgroup to Tamoxifen, however are more expensive.
MOA
- Act through binding to oestrogen receptors to inhibit further malignant growth and preventing further oestrogen production, as well as blocking the conversion of androgens to oestrogen in peripheral tissues.
womb cancer and hormone therapy
Progesterone treatment is used to shrink larger uterine cancers to treatment cancers that have come back
e.g.
Medroxyprogesterone acetate (Provera)
Megestrol (Megace)
Hormone therapy for prostate cancer
Prostate cancers depend on testosterone to grow. Hormone therapy lowers the amount of testosterone in the body.
- Can lower the risk of early prostate cancer from coming back when you have it with other treatments
- Can also be used to shrink advanced prostate cancer or slow growth
Luteinising hormone releasing hormone (LHRH) agonists
- Stop the testicles creating testosterone by blocking LH (released by the pituitary)
- Examples: Goserelin (Zoladex), Triptorelin (decapetyl)
Gonadotrophin releasing hormone (GnRH) blocker
Stop GnRH from the hypothalmus from triggering the pitituiary to secrete LH -> therefore testicles do not produce testosterone
e.g. Degarelix (Firmagon)
Side effects of hormone therapy
Women
- Fatigue
- Digestive problems e.g. nausea, vomiting or diarrhoea
- Menopausal symptoms
o Periods stop
o Hot flushes
o Night sweat
o Vaginal dryness
o Weight gain - Bone pain
o Aromatase inhibitors
o Tamoxifen
Causes bone thinning in in pre-menopasual but not post-menopausal women - Mood swings and depression
- Blood clots
o Tamoxifen - Malignancy
o Tamoxifen increases risk of uterine cancers
Side effects of hormone therapy
Men
Men
- Tiredness
- Impotence
- Hot flushes and sweating
- Gynaecomastia
- Pain from tumour flare
- Weight gain
- Bone changes
- Mood swings and depression
- CVD
diagnosis of cancer summary
1) Screening –> Asymptomatic
2) Primary care consultation –>Symptomatic
- History and examination e.g. weight loss, rectal bleeding, anaemia, night sweats
- Investigations
3) Secondary care consultation
- Specialist blood tests e.g. tumour markers
- Imaging
–> CT with contrast
–> Endoscopy
Staging process
- Staging CT CAP
- Biopsy e.g. of tumour and lymph node biopsy
- MRI
- PET for mets
- MDT discussion
surgery in cancer
Depends upon accurate staging of the cancer and patient assessment
–> Preoperative imaging and TNM staging
-
Curative
+- adjuvant chemotherapy/ radiotherapy -
Palliative
Stent
Bypass
Defunctioning stoma
Palliative resection
Adjuvant approach
When a tumour is locally advanced, chemo, radio or targeted therapies may be important to:
o Control growth of tumour
o Down-stage tumour to render it operable
o Because impact of systemic disease risk may outweigh local control
MDT approach
The pre-operative multidisciplinary team including anaesthetists, cardiologists, dieticians, psychologists and social workers, and tumour-specific specialist nurses often assesses fitness for cancer surgery and the psychosocial impact of surgery.
Staging aim
- Assessment of local disease
- Assessment of distant disease
- Therefore: determines operability and choice of treatment
Method of staging
- Pre-operative imaging
o Tumour size
o Invasion into surrounding structures
o operability
o nodal involvement and distant metastases - Histopathological biopsy
o (adrenal tumours and paraaortic masses not suitable)
Different staging systems e.g. TNM, Dukes (bowel cancer)
TNM
* T1: Tumour invades submucosa
* T2: Tumour invades muscularis propria
* T3: Tumour invades through muscularis propria into subserosa
* T4: Tumour perforates the visceral peritoneum or
invades other structures.
* N1: 1-3 nodes
* N2: 4 or more nodes
* M: metastasis
Surgery of the primary tumour
Aim: to remove cancer with an adequate margin of normal tissue with minimal morbidity. Clear margins increase local control (margin requirements differ according to the origin of the tumour and functional impact)
- Often balancing margins with cosmetic appearance
Surgery of the lymph node basin
Many solid tumours require removal of draining lymph nodes for the purpose of staging and/or to achieve local control. Often prophylactic removal based on type of tumour.
- Sentinel node biopsy-> when lymph node metastases are not evidence pre-op
o Used in breast cancer, penile cancer and melanoma
o Aim: provide an assessment as a staging tool to predict prognosis and influence of adjuvant therapies
Surgery in metastatic disease and emergencies
- Management of emergencies e.g. bowel obstruction, oesophageal obstruction
- In some tumour types such as breast cancer, colorectal cancer or liver metastases, removal of primary who has stable metastatic disease may improve prognosis and survival
Prophylactic surgery
- BRCA1 or 2
- Lynch syndrome
Side effects surgery
- Bleeding, infection and pain
- Damage to nerves, bladder, ureter or bowel
- Post-operative ileus
- Anaesthetic risks
- Laparoscopic surgery converted during the operation to open surgery (laparotomy)
- Leakage or failure of the anastomosis
- Requirement for a stoma
- Failure to remove the tumour
- Change in bowel habit
- Venous thromboembolism (DVT and PE)
- Incisional hernias
- Intra-abdominal adhesions
how is radiation damage during radiotherapy limited
-radiation given at many angles to reduce burden on surrounding tissue, but concentrate radiation at the cancer
- give breaks between radiation to limit exposure to radiotherapy
- brachtheryapy- radiation injected into cancer directly- preventing harm to healthy tissue
