Chemotherapy Flashcards
chemotherapy mechanism of action
- Most agents target DNA either directly or indirectly.
- Chemotherapeutic agents are preferentially toxic towards actively proliferating calls. Tumours which divide rapidly, with short doubling times, usually respond best to chemotherapy.
There are other factors that determine a tumour’s chemosensitvity. For example, although cytotoxic drugs consistently cause DNA damage, tumour cells differ with regard to their response (death or recovery) to that damage.
chemotherapy indications list
- neoadjuvant
- primary
- adjuvant
- palliative
- curative
- prophylactic
definition and aims of neoadjuvant chemotherapy
- Pre-operative treatment of an operable tumour before definitive surgical intervention.
- aims of this are to make the tumour smaller, to allow less radical surgery, while at the same time treating occult micro metastases.
This approach is established for osteosarcoma and is being tested in clinical trials for other malignancies, such as breast cancer. This is therefore treatment which aims to increase cure rates.
definition and aims of primary chemotherapy
Initial chemotherapy for a tumour that is inoperable or of uncertain operability, where a reduction in the tumour bulk in a pre-defined manner may make surgery with curative intent feasible. This is therefore treatment which may increase cure rates.
adjuvant chemotherapy definition and aims
The use of chemotherapy following a complete macroscopic clearance at surgery. Chemotherapy in this setting treats the occult microscopic metastases which we know usually lead to relapse after surgery for lymph-node positive disease (e.g. breast cancer and colorectal cancer). This is therefore treatment which increases cure rates.
palliative chemotherapy definition and aims
This is treatment to alleviate symptoms and in some cases prolong life in patients who cannot be cured.
Chemotherapy given in the palliative setting has to be a carefully balanced decision so that the patient’s quality of life is not made worse by the treatment.
It may be justified to give second or third line chemotherapy if the disease remains chemo-sensitive (e.g. breast cancer, ovarian cancer, colorectal cancer).
curative chemotherapy aims
In some malignancies there is still a real chance of a cure even if there is metastatic disease at presentation (e.g. germ cell tumours, Hodgkin’s disease, Non-Hodgkin’s lymphoma and many childhood cancers). This justifies the use of more intensive treatment associated with greater toxicity.
prophylactic chemotherapy definition and example
Hormonal treatments may be given before overt malignancy appears. For instance tamoxifen may be used for in-situ breast cancer before invasive carcinoma is recognised
Cytotoxic chemotherapy is most commonly given as a combination of different drugs. This is because:
- Different classes of drugs have different actions and may kill more cancer cells together by imparting several sub-lethal cell injuries than the sum of the cells they can kill when given individually (‘synergism’).
- There is less chance of drug-resistant malignant cells emerging.
- When drugs with different sites of toxicity are combined, dose can be maintained for each drug.
Single-agent chemotherapy may also be appropriate, especially in the palliative setting.
Most chemotherapy is given cyclically to allow normal cells to recover from the toxicity of treatment. The cells usually affected by chemotherapy at standard doses are haematopoietic stem cells and the lining of the GI tract, producing low blood counts (‘myelosuppression’) and mucositis. Giving the treatment every 3-4 weeks allows these cells to recover.
Theoretically any cycle of chemotherapy will only kill a proportion of the tumour cells. Therefore repeated cycles are required to get tumour clearance. However, there is no advantage in giving endless cycles of chemotherapy, as this does not prevent resistance emerging and increases toxicity; many treatments are maximally effective after a 6-month course.
which treatment can be given as outpatients and which treatments require inpatient
Conventional doses of drugs are those known to be effective against the particular malignancy and which, in the majority of patients, cause tolerable side effects. Many of these treatments can be given in an out-patient setting.
“High dose” treatments produce toxicity that is much greater. Such treatments require particularly specialized supportive care or they are lethal; including bone marrow support with growth factors, or often ‘rescue’ of the bone marrow using the infusion of previously harvested blood stem cells or bone marrow. The toxicity of this treatment is justified only when longterm survival or cure are possible, which is only the case in relatively few cancers, such as Hodgkins disease and Ewings Sarcoma.
in which cases is prolonged chemotherapy to maintain remission appropriate? when is it inappropriate?
The use of prolonged chemotherapy to maintain a remission has little demonstrated advantage in solid tumours, as resistant clones soon develop and toxicity increases.
In childhood leukaemia 18 months maintenance chemotherapy following the induction of a complete remission is central to modern treatment.
Advantages and disadvantages of giving chemotherapy orally? Which drugs are available orally?
- freeing the patient from lengthy hospital visits and invasive procedures.
- It doesn’t necessarily reduce toxicity however as the drug is still cytotoxic and regular review is almost always still required.
- Only a minority of drugs including cyclophosphamide, etoposide, capecitabine and tamoxifen are available orally.
- Variations in the levels of drug circulating based upon whether and when the drug is taken can be problematic.
how is the majority of chemotherapy delivered?
Systemic delivery:
Most chemotherapy is given intravenously as bolus injection or short infusion.
Some chemotherapy may be given as a continuous infusion via a central venous line, either peripherally placed or tunneled under the skin to reduce the chances of infection.
what are the different options for delivering chemotherapy regionally?
- Intravesical. Chemotherapy is routinely given this way in the management of superficial bladder cancer. This has the advantage of producing high doses at the site of the tumour, with negligible systemic absorption and hence minimal systemic toxicity.
- Intraperitoneal : Chemotherapy may be administered directly into the peritoneal cavity in the context of tumours that spread trans-coelomically (e.g. ovarian cancer).
- Intra-arterial : Any tumour that has a well-defined blood supply is potentially suitable for intra-arterial chemotherapy (e.g. hepatic artery infusion for liver metastases). This allows higher doses to be delivered to the involved site and reduces systemic toxicity.
how are chemotherapy doses calculated?
- Body surface area (BSA): Routine cytotoxic chemotherapy doses are calculated according to the patient’s body surface area. The most commonly used formula is that of DuBois and DuBois, which dates from 1916.
- Carboplatin, a commonly used chemotherapy drug, is the only one to have its dose calculated directly according to the renal function.
- Some of the newer drugs, such as the monoclonal antibody trastuzumab, are calculated on body weight alone.
List of principles of delivery of chemotherapy
- administer drugs in combination
- schedule treatments in cycles of a few weeks
- administer the optimal dose
- use maintenance treatment only where eveidence supports it
- use the most effective route of administration
- calculation of doses
list of immediate complications of chemotherapy
- nausea and vomiting
- myelosuppression
- gastrointestinal side effects: oral mucositis, diarrhea and constipation
- alopecia
- neurological:Peripheral neuropathies, Autonomic neuropathy, CNS toxicity, ototoxicity
- genitourinary: nephotoxicity, bladder toxicity
- cardiac: acute arrhythmias and cardiac ischaemia
- hepatic: hepatic failure
- skin and soft tissue: Extravasation,Palmar plantar erythema (Hand-foot syndrome), Photosensitivity, Pigmentation
- others: Myalgia and arthralgia, Allergic reactions, lethargy
chemo SE: nausea and vomiting causes and treatment
The nausea arises from a combination of direct stimulation of the vomiting centre, peripheral stimulation and anticipatory causes
5-HT antagonist drugs like Ondansetron
- Chemotherapy causes bone marrow suppression by.. ?
- at which point in the cycle is myelosupression at its worst?
- Haematopoietic recovery usually occurs after…
Chemotherapy causes bone marrow suppression by killing haematopoietic progenitor cells. This leads to a leucopenia and thrombocytopenia generally after 10 -14 days from the beginning of each cycle. The lowest point of this drop is known as the nadir. As progenitors recover the peripheral counts return.
A neutrophil count greater than 1 x 109/1 is rarely associated with a clinical infection. However, the risk of infection with a count less than 0.5 x 109/1 is significant.
Haematopoietic recovery usually occurs after 3-4 weeks, enabling further cycles of chemotherapy to be given.
GI side effects in chemotherapy and its causes
- Oral mucositis may reflect more general damage to the whole gastrointestinal epithelium, a rapidly dividing cell population susceptible to cytotoxic chemotherapy.
- Diarrhoea occurs frequently due to colitis or small bowel mucosal inflammation.
- Constipation is usually due to dehydration with reduced oral intake due to nausea, and to adverse effects of other medications being taken such as opiate analgesics or 5-HT antagonists.
- Rarely a paralytic ileus can develop due to autonomic neuropathy after platinum agents or vinca alkaloids.
Alopecia as a side effect of chemo and how it can be minimised
- Alopecia results from the effects of the cytotoxic drugs on the rapidly dividing cell population at the hair follicle.
- The effect is reversible, with hair returning when chemotherapy is discontinued.
- In some cases alopecia can be controlled by the use of a cold cap which reduces the blood flow to the scalp.
- Although alopecia has no inherent medical risk it is a significant toxicity because of its effects on psychological well-being.
- Interestingly, not all chemotherapy drugs cause significant alopecia
neurological side effects of chemotherapy
- Peripheral neuropathies. These occur with the platinum drugs (particularly cisplatin), taxanes, and vinca alkaloids. The neuropathy, principally affecting sensory nerves, may recover partially over a period of months, but patients are usually left with a residual deficit.
- Autonomic neuropathy. The same pathogenic process that affects peripheral nerves may also lead to autonomic dysfunction.
- Central neurological toxicity. Although rare, certain drugs are associated with toxicity to the CNS, for example ifosfamide-induced encephalopathy and 5-FU induced cerebellar toxicity.
- Ototoxicity. Cochlear damage rather than auditory nerve damage is believed to be responsible for the high tone hearing loss associated with cisplatin. The effect is permanent. Pre-existing high-tone hearing damage precludes the use of cisplatin.
