Cytotoxic chemotherapy, radiotherapy and drug resistance I Flashcards
What are the current cancer treatments?
- surgery - highly successful for localised primary disease
- radiotherapy - external beam, intracavity, radioimmunotherapy (zevalin)
- chemotherapy - applicable to systemic metastasised disease
- immunotherapy (inc. vaccines, eg. cervarix)
- gene therapy (eg. GDEPT)
List some stats on 5 yr survival of non small cell lung cancer (NSCLC) by stage
- stage I/II localised disease - surgery 45-70%
- stage III localised advanced - XRT/chemo= 10-25%
- stage IV metastatic - chemo <5%
What is adjuvant therapy?
- chemotherapy following primary surgery
What is neoadjuvant therapy?
- chemotherapy to reduce the bulk of primary tumours prior to surgery or radiotherapy
What is the fractional cell kill hypothesis for chemotherapy?
- a given drug concentration applied for a defined time period will kill a constant fraction of the cell population, independent of the absolute number of cells
- survival is inversely related to tumour burden: a single leukaemic cell is capable of multiplying to kill the host
- implications : tumour best treated whet they are small and treatment should continue until last cell is dead
What are the classes of anticancer drugs?
- DNA interactive (alkylating mustards, cyclophosphamide, chlorambucil, cisplatin)
- block DNA synthesis (antimetabolites, 5FU, methotrexate)
- affect DNA processing (doxorubicin, etoposide)
- block mitosis (tubulin, vinca alkaloids)
- hormone based (anti-oestrogen)
- molecularly targeted therapy - monoclonal antibodies (rituximab, trastuzumab)
- signal transduction inhibitors (RTKIs)
What phase-dependent drugs affect the S-phase?
- ara C
- hydroxyurea
- methotrexate
What drugs are phase dependent that affect G2/mitosis?
- etoposide
- vincas
- taxanes
What are some phase-independent drugs?
- alkylating agents
- nitrosoureas
- mitomycin C
What drugs cause haematological toxicity?
- myelosuppresion - risk of infection
- thrombocytopenia - risk of haemorrhage - may be delayed with some drugs
What drugs cause gastrointestinal toxicitiy?
- cisplatin - nausea and vomiting
- irinotecan - diarrhoea
What other toxicities are caused by drugs?
- alopecia - cyclophosphamide
- pulmonary - bleomycin
- cardiac toxicity - doxorubicin
- renal - cisplatin
- bladder toxicity - ifosfamide
What is the tumour response to drugs?
- CR - complete response = complete resolution of all measurable disease for at least one month
- PR - partial response = 50% reduction in the product of two perpendicular diameters for one month or more
- SD - stable disease = ‘o change in size of measurable tumour over a period of one month or more’
What are the steps involved in finding new cancer drugs?
- target identification (cell growth and molecular biology)
- hit identification (screening design)
- lead optimisation (chemistry, pharmacology)
- preclinical development (manufacture, formulation
- clinical trials (regulatory approval)
Describe phase I of clinical trials for anticancer drugs
- regulatory filling, IND
- generally performed in cancer patients rather than healthy volunteers - bc low TI
- 20-30 patients
- what is maximum dose tolerated in patients?
- what is the dose limiting toxicity?
- anti-tumour activity NOT primary aim
- increasing emphasis on pharmacodynamics
What is dose escalation in phase I trials?
- fundamental conflict
- too fast = may get sudden jump from no toxicity to life-threatening
- too slow - large numbers of patients treated at ineffective doses, slower entry into phase II
- modified fibonacci scheme used
Describe phase II of clinical trials for anticancer drugs
‘learning’
- goal to assess probability of positive risk to benefit ratio in phase III
- generally single agent, single tumour type
- single arm vs historical control
- randomised control trial (RCT)
Describe phase II of clinical trials for anticancer drugs
‘learning’
- goal to assess probability of positive risk to benefit ratio in phase III
- generally single agent, single tumour type
- single arm vs historical control
- randomised control trial (RCT)
Describe phase II of clinical trials for anticancer drugs
‘confirming’
- is the drug more effective than established therapy
- randomised clinical trials
What are the future directions?
- individualisation of chemotherapy - based on tumour genotype or microarrays
- better detection (imaging, blood markers, susceptibility genes BRCA1/2)
- better prevention - diet
What drugs are used in metastatic colorectal cancer?
- 5FU
- irinotecan, oxaliplatin
- capecitabine (oral 5FU + DPD inhibitor)
