This is the context of the topic chemotherapeutic drugs series. Today is part 3. Topic of discussion for today is combination chemotherapy, various types of chemotherapy, Pharmacokinetic Terms, area under the curve, toxicities of chemotherapy drugs etc.
Here is a quick link to previous topics.
Principles of combination chemotherapy
Combination chemotherapy accomplishes three important objectives not possible with single-agent therapy:
(1) It provides maximum cell kill within the range of toxicity tolerated by the host for each drug;
(2) It offers a broader range of coverage of resistant cell lines in a heterogeneous tumor population; and
(3) It prevents or slows the development of new drug-resistant cell lines.
Why combination chemotherapy:
- Achieve complete remission
- Prolong the duration of their remissions
- Overcome drug resistance to individual agents
- Prevent or delay the development of acquired resistance.
- Additive or synergistic mechanisms of action
- Drugs with nonoverlapping toxicity profiles
Selection of Chemotherapy drugs for combination regimens
The following principles have been established to guide drug selection in combination regimens:
- Drugs known to be active as single agents should be selected for combinations. Preferentially, drugs that induce complete remissions should be included. Use drugs active as a single agent
- Drugs with different mechanisms of action should be combined in order to allow for additive or synergistic effects on the tumor.
- Drugs with differing dose-limiting toxicities should be combined to allow each drug to be given at full or nearly full therapeutic doses. Use drugs with different side effects
- Drugs should be used in their optimal dose and schedule.
- Drugs should be given at consistent intervals. The treatment-free interval between cycles should be the shortest possible time for recovery of the most sensitive normal tissue.
Drugs with different mechanisms of resistance should be combined to minimize cross-resistance.
The above picture shows the site of action of various chemotherapeutic drugs.
Dose intensity:
Most cytotoxic anticancer drugs have a steep dose-response curve, and a small increment in the dose can significantly enhance the therapeutic effect of a drug in preclinical studies. A reduction in dose is associated with a decrease in cure rate before a significant reduction in the complete remission rate occurs. A dose reduction of about 20% can lead to a loss of up to 50% of the cure rate.
Rationale Of Systemic Chemotherapy
Neoadjuvant chemotherapy [preoperatively]
- To make non-operable tumors operable
- To achieve organ preservation
- To select sensitivity for specific treatment (biomarkers)
Adjuvant chemotherapy [postoperatively]
- To kill micro-metastatic disease
- To increase disease-free survival
Palliative chemotherapy
Chemotherapy is given to control symptoms or prolong life in a patient in whom cure is unlikely. Know more about palliative chemotherapy.
Salvage chemotherapy
A potentially curative, high-dose regimen given to a patient who has failed or recurred following a prior curative regimen.
*Induction chemotherapy
The intent is to induce complete remission when initiating a curative regimen (usually applied to hematologic malignancies)
*Consolidation chemotherapy
Repetition of the induction regimen in a patient who has achieved a complete remission after induction, with the intent of increasing cure rate or prolonging remission.
*Maintenance chemotherapy
Long-term, low-dose, single- or combination chemotherapy in a patient who has achieved a complete remission, with the intent of delaying the regrowth of residual tumor cells.
Pharmacokinetic Terms
Clearance (Cl) Vol/time (mL/min): Used to quantify the rate of drug elimination;
expressed in terms of volume of plasma cleared of drug per unit of time.
Total clearance is the sum of renal, metabolic, spontaneous chemical degradation, and biliary (fecal) elimination.
Half-life (t 1/2): Time required to reduce the drug concentration by 50%
Area under the curve: A measure of how much drug reaches a person’s bloodstream in a given period of time after a dose is given. The area under the plot of plasma concentration of a drug versus time after dosage (called “area under the curve” or AUC) gives insight into the extent of exposure to a drug and its clearance rate from the body.
Bioavailability generally refers to the fraction of a drug that is absorbed systemically and is thus available to produce a biological effect.
Here is a quick YouTube video to understand the area under the curve better.
Volume of distribution: volume required to dissolve the total amount of drug to give the final conc. found in plasma); a property of the drug rather than a real volume or physiologic compartment.
Trough concentration: the concentration of drug in the blood immediately before the next dose is administered, although this does not necessarily represent the lowest concentration during a dosing interval.
Minimum concentration (C-min): the lowest concentration of drug in the blood following the administered dose. The lowest drug concentration frequently occurs immediately before the next dose is administered; for these drugs, the minimum concentration and the trough concentration are identical.
Treatment Strategies to Circumvent the Blood-Brain Barrier:
- High-dose systemic chemotherapy: High-dose methotrexate, cytarabine
- Identifying drugs that penetrate the blood-brain barrier (cross into CSF): Thiotepa, topotecan
- Disruption of the blood-brain barrier: Osmotic disruption with mannitol
- Regional drug administration: IT
Intrathecal injection:
Advantage of IT: delivering very high drug concentrations to the CSF and meninges with low doses and therefore with minimal systemic toxicity.
Disadvantages: painful, inconvenient, and may be technically challenging. In 10% of intralumbar injections, the drug is not delivered into the subarachnoid space but is instead injected or leaks into the subdural or epidural space. Because of the slow circulation of the CSF, the distribution of drugs within the subarachnoid space, specifically to the ventricles, is not uniform. The distribution of drug from the lumbar sac to the ventricles can be improved by positioning the patient prone for 60 minutes after intralumbar injection.
Toxicity of chemotherapeutic Drugs
Acute toxicities common to many anticancer drugs include myelosuppression, nausea and vomiting, alopecia, orointestinal mucositis, liver function abnormalities, allergic or cutaneous reactions, and local ulceration from subcutaneous drug extravasation.
Unique toxicities include:
- cardiotoxicity associated with the anthracyclines;
- hemorrhagic cystitis associated with cyclophosphamide and ifosfamide;
- peripheral neuropathy from vincristine, cisplatin, and paclitaxel;
- nephrotoxicity from cisplatin and ifosfamide;
- ototoxicity from cisplatin; and
- coagulopathy from L-asparaginase.
How can we prevent these toxicities? Rescue Approach:
- HSCT to rescue patients from myeloablative doses of anticancer drugs
- leucovorin or glucarpidase to counteract the toxicities of HDMTX,
- antiemetics to block nausea and vomiting
- mesna to prevent the hemorrhagic cystitis
- the use of colony-stimulating factors (e.g., filgrastim, peg-filgrastim) to alleviate myelosuppression
- dexrazoxane to prevent anthracycline cardiotoxicity.
Role of chemotherapeutic agents in other diseases:
These chemotheraputic drugs are also used in other pediatric diseases. Here are some lists.
- Ankylosing Spondylitis
- Multiple Sclerosis
- Crohn’s disease
- Psoriasis, Psoriatic Arthritis
- Systemic Lupus Erythematosus
- JIA
- Scleroderma.
