Flashcards in Principles of anti-cancer drug therapy Deck (69)
cytotoxic drugs used in cancer treatment
When is chemotherapy indicated? 6
1.) Primary treatment for disseminated disease (lymphoma and other haematopoietic tumours)
2.) Adjuvant therapy following surgery for highly metastatic tumours
3.) In certain tumours following incomplete resection (microscopic residual disease) Also consider radiation
4.) Neo-adjuvant chemotherapy
5.) Treatment of chemosensitive tumours not amenable to surgery or radiation
6.) Primary treatment for TVT (vincristine)
Give some examples of tumours where adjuvant chemotherapy following surgery for highly metastatic tumours may be used.
High grade STS
Grade 3 MCTs
Grade 2 MCT with high mitotic index
When is chemo contraindicated?
when surgery or radiation treatment is a more effective alternative
How can chemo be administered?
COMMONLY - IV, PO, SC (drug-dependent)
OTHER: intracavitary (mesothelioma and caicnomatosis with 5-FU or carboplatin) or intralesional (rarely)
Where multiple carcinomas develop simultaneously, usually after dissemination from a primary source. It implies more than spread to regional nodes and even more than just metastatic disease. The term is usually taken to mean that there are multiple secondaries in multiple sites.
cancer of cells that develop from the mesothelium which is the protective lining that covers the internal organs of the body.
How do chemo drugs work?
Interfere with cell growth or division
Can affect different stages of the cell cycle
Some drugs are cell cycle specific, others aren't and can theoretically affect cells even in the resting (G0 phase)
How do vinca alkaloids work?
inhibit microtubule formation and interfere with the G2/M phase and anti-metabolites act in the S phase
How do alkylating agents work?
not cell cycle specific (also anti-tumour antibiotics and platinum drugs)
When is chemo most likely to be effective?
when the disease burden is low (less effective for bulky disease)
When do you apply adjuvant chemotherapy?
following surgery, let the surgical wound heal (requires cell division) but then start chemo asap.
What does the cell kill hypothesis state?
that tumour cell kill follows first order kinetics (a given dose of cytotoxic drug will kill a fixed percentage of the tumour population as opposed to a set number of tumour cells. Will not completely eradicate the tumour)
Outline cytotoxic drug therapy
Use at the MTD (--> highest fractional kill)
Pulse doses (often used with carefully selected inter-dose intervals)
Is combination of single agent chemo usually more effective?
Combination (exceptions are vincristine in TVC and doxorubicin or carboplatin in OSA). Repeated use of a single agent is likely to select for resistant cells, whereas alternating drugs is less likely to cause selection pressure.
What are the principles of combination chemo?
USE DRUGS THAT ARE:
1.) are effective against the tumour individually
2.) different modes of action and don't interfere with each other's action
3.) act on different stages of the cell cycle
4.) don't have overlapping toxicities
What combination chemotherapy protocols are commonly used to treat lymphoma in dogs and cats?
1.) COP-based (cyclophosphamide, vincristine, prednisolone)
2.) Doxorubicin-containing protocols (CHOP) e.g. Wisconsin-Madison protocol
3.) Modified LOPP protocol for TC lymphoma (lomustine, vincristine, procarbazine, prednisolone)
How are cytotoxic chemotherapy drugs dosed?
MTD tends to correlate better with body surface area than body weight (and relates to metabolism). Most drugs are used on a mg/m2 basis.
BSA conversion charts
Obese animals - dose according to estimated lean body weight
Small dogs/cats - show increased toxicities when based on a mg/m2 basis - so dogs <10kg and cats are sometimes dosed on a mg/kg basis
What are the stages of chemotherapy?
Name 2 alternatives to conventional cytotoxic chemotherpay
1.) Metronomic chemotherapy/ continuous low dose chemotherapy
2.) Receptor tyrosine kinase inhibitors (RTKIs)
Outline metronomic chemotherapy/continuous low dose chemotherapy
usually cytotoxic drug given alongside an NSAID
AIM = to slow growth by inhibiting angiongenesis via immunomodulatory effects, decreasing circulating Tregs and promoting anti-tumour immunity
No dramatic shrinkage, but stable disease/lack of progression.
Low dose cyclophosphamide most commonly
Similar survival times (canine HSA)
Can be used to delay time to recurrence in incompletely resected canine STS.
Interfere with aberrant signalling through cell surface receptors in cancer cells and have effects inhibiting angiogenesis, reducing proliferation and promoting apoptosis.
Dosed daily or EOD or MWF
Tumours may not shrink dramatically, but stable disease/lack of progression may be achieved
Toceranib and mastinib licensed for treatment of canine MCT.
List what factors affect the success of anti-cancer drug therapy?
Penetration of drug into tumour
Development of drug resistance
What drugs are resistant/sensitive to anti-cancer drugs?
Highly sensitive - lymphoma
Relatively resistant - pancreatic and renal carcinomas
What does drug penetration into tumour depend on? 2
tumour blood supply and natural barriers
How does tumour drug resistance develop?
decreased drug uptake
increased drug removal from cell
decreased drug activation
increased drug inactication
increased/altered drug targets
use of alternative pathways
increased DNA repair
When does multi-drug resistance occur?
when tumour cells become cross-resistant to unrelated compounds
What is multi-drug resistance associated with?
increased expression of multi-drug resistance gene (MDR1), leading to increased p-glycoprotein (Pgp) expression, which pumps cytotoxic drugs such as vinca alkaloids and doxorubicin out of the cell. MDR1 gene can be activated by glucocorticoids and these drugs can induce resistance to vinca alkaloids/doxorubicin.
What should you do if resistance occurs?
switch to drugs that the tumour has not been exposed to before - preferably combinations of drugs with different mechanisms of action (rescue therapy)