Carboplatin: Action, Use and Notes in Cancer Therapy

Carboplatin is a second-generation platinum-containing cytostatic agent used in oncology for the treatment of various cancers. It belongs to the class of platinum compounds and is an analogue of the older active ingredient cisplatin. Compared to cisplatin, carboplatin has a more favourable tolerability profile, particularly with regard to nephrotoxicity and nausea, while myelotoxicity is more pronounced.

Carboplatin is administered exclusively in oncology centres and hospitals under strict medical supervision. As a component of combination chemotherapy regimens, it has established itself in numerous tumour indications and is an indispensable part of modern oncology.

Mechanism of Action

Carboplatin belongs to the alkylating agents and exerts its cytotoxic effect through covalent binding to the DNA of tumour cells. In the aqueous environment of the body, reactive aqua complexes form from the platinum centre, which then react with nucleophiles in the DNA. The preferred attack sites are the N7 positions of guanine bases.

The cross-linking of adjacent guanine bases on the same DNA strand (intrastrand) or on opposite strands (interstrand) disrupts normal DNA replication and transcription. The affected cells can no longer repair the damage and die by apoptosis. Since tumour cells divide more frequently than most normal body cells, they are particularly sensitive to this form of DNA damage.

Carboplatin does not act in a cell cycle-specific manner, meaning it can attack tumour cells in various phases of the cell cycle. This distinguishes platinum compounds from other cytostatics such as taxanes or vinca alkaloids, which are only effective in certain cell cycle phases. The broader activity makes carboplatin a valuable combination partner in polychemotherapy.

Indications

Carboplatin is approved for several oncological indications and is also used in numerous other tumour entities. The most important areas of application include:

• Ovarian carcinoma: carboplatin in combination with paclitaxel is one of the standard therapies for advanced and relapsed ovarian carcinoma
• Non-small cell lung carcinoma (NSCLC): in combination with various partners, also in conjunction with immunotherapy agents
• Small cell lung carcinoma (SCLC): frequently in combination with etoposide
• Head and neck tumours: as a radiosensitiser in combination with radiotherapy
• Bladder carcinoma, testicular carcinoma, cervical carcinoma: use in selected therapy protocols
• High-dose therapy before stem cell transplantation: carboplatin is used as a conditioning regimen

The decision on the use of carboplatin is made by a specialised oncological team on the basis of tumour entity, stage, prior treatments and individual health status of the patient. Current therapy protocols and guidelines are regularly updated and may vary depending on medical progress.

Dosage and Administration

Carboplatin is administered exclusively by specialised oncologists in clinics or oncological day clinics. Self-medication is not possible.

Unlike other cytostatics, carboplatin is not dosed by body surface area in mg/m2, but according to a special calculation, the so-called Calvert formula. This takes into account the patient's individual renal function (glomerular filtration rate, GFR) and a target dose expressed as AUC (area under the curve, in mg/ml x min). The formula is:

Total dose (mg) = AUC x (GFR + 25)

Typical AUC values range between 4 and 6 mg/ml x min depending on indication and therapy protocol. Carboplatin is administered as an intravenous infusion over 15 to 60 minutes. Cycle intervals are generally 21 to 28 days, adjusted to recovery of bone marrow.

In patients with impaired renal function, the dose must be carefully adjusted, as carboplatin is almost completely eliminated renally. GFR is redetermined before each cycle.

Side Effects

Carboplatin has a characteristic side effect profile that differs from that of cisplatin. The dose-limiting toxicity is myelosuppression.

Common and clinically relevant side effects:

Myelosuppression (bone marrow failure): This is the most serious side effect. Thrombocytopenia (platelet deficiency), anaemia and leukopenia (white blood cell deficiency) occur regularly. Blood count checks before each cycle are mandatory. Blood transfusions, platelet concentrates or growth-stimulating factors (G-CSF) can be used as needed.

Nausea and vomiting: Significantly milder than with cisplatin, but still relevant. Modern antiemetic prophylaxis (e.g. 5-HT3 antagonists, dexamethasone, NK1 antagonists) makes treatment tolerable for most patients.

Nephrotoxicity: Significantly lower than cisplatin, but careful monitoring of renal function is still necessary.

Neurotoxicity: Peripheral polyneuropathy with tingling, numbness or pain in the hands and feet can occur, particularly with combination therapies with taxanes or after several cycles.

Hepatotoxicity: Transient elevations of liver enzymes occur and usually resolve after completion of therapy.

Ototoxicity: Hearing loss, particularly in the high-frequency range, is less common than with cisplatin but can occur, particularly in children.

Allergic reactions: Hypersensitivity reactions including anaphylaxis occur in approximately 2 percent of patients, more frequently after several cycles. Premedication strategies and desensitisation protocols are available.

Drug Interactions

The combination of carboplatin with other nephrotoxic substances (e.g. aminoglycoside antibiotics, NSAIDs, vancomycin) increases the risk of kidney damage and should be avoided if possible or closely monitored.

Concurrent use with other cytostatics can cause additive or synergistic toxicities, particularly with regard to myelosuppression. Combination with taxanes, anthracyclines or topoisomerase inhibitors requires careful dose adjustment and close blood count monitoring.

Live vaccines should generally not be administered during chemotherapy, as the immune system is weakened by myelosuppression. Inactivated vaccines can be administered but may be less effective.

Carboplatin can affect phenytoin plasma levels through altered absorption or altered metabolism. Close monitoring of phenytoin levels is advisable.

Special Notes

Preparation and handling: As a cytostatic, carboplatin must be prepared and administered under special protective measures. Preparation takes place exclusively by trained personnel in clean room pharmacies in compliance with statutory regulations for the manufacture of cytostatic preparations.

Renal function: Creatinine and clearance must be determined before each therapy cycle. Inadequate dose calculation in the presence of impaired renal function can lead to severe, life-threatening myelosuppression. The Calvert formula requires an accurate and current measurement of GFR.

Fertility: Carboplatin is gonadotoxic and can lead to permanent infertility in both men and women. Reproductive medicine options (e.g. cryopreservation of sperm or eggs) should be discussed with the patient before starting therapy.

Pregnancy and breastfeeding: Carboplatin is teratogenic and embryotoxic. It is contraindicated during pregnancy, particularly in the first trimester. Women of childbearing age must use reliable contraception during and after therapy. Breastfeeding must be discontinued during therapy.

Frequently Asked Questions

How does carboplatin differ from cisplatin?

Both belong to platinum compounds and have similar mechanisms of action. Carboplatin is better tolerated with regard to nausea, vomiting and nephrotoxicity. However, myelosuppression is more pronounced with carboplatin. Dosing is performed using the Calvert formula rather than by body surface area.

How is carboplatin administered?

Carboplatin is administered exclusively intravenously as an infusion, generally over 15 to 60 minutes. Oral intake is not possible. Treatment takes place in clinics or oncological day clinics.

Can an allergy to carboplatin develop?

Yes, hypersensitivity reactions occur, often after the sixth or subsequent cycles. Symptoms range from rash and itching to severe anaphylactic reactions. Desensitisation protocols allow continuation of therapy in many cases.

References

• European Medicines Agency (EMA): Carboplatin Summary of Product Characteristics (current version)
• Calvert AH et al.: Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7(11):1748-1756
• Guideline Programme Oncology: S3 Guideline Ovarian Carcinoma (current version)
• Onkopedia: Carboplatin (German Society for Haematology and Medical Oncology)
• Skeel RT, Khleif SN (eds.): Handbook of Cancer Chemotherapy. Lippincott Williams and Wilkins, 2011