Cisplatin is a chemotherapy drug belonging to the class of alkylating agents . It is considered a powerful antitumor agent, so much so that it is included in the list of essential drugs compiled by the World Health Organization;
Therapeutic indications
Cisplatin can be used alone, or in combination with other anticancer drugs, to treat various types of tumors, including:
- Ovarian cancer, advanced or metastatic;
- Bladder cancer, advanced or metastatic;
- Testicular cancer, advanced or metastatic;
- Small cell and non-small cell lung cancer, advanced or metastatic;
- Advanced and metastatic squamous cell cancer of the head and neck.
Cisplatin is particularly effective in the treatment of testicular cancer: if used in combination with bleomycin (a cytotoxic antibiotic) or vinblastine (an antimitotic), the chances of recovery increase considerably.
Cisplatin can also be used in combination with Auger therapy, a particular type of radiotherapy that uses low-energy electron beams to irradiate the malignant cells that make up the tumor.
Studies carried out and clinical efficacy
1. Combination therapy with cisplatin in the treatment of advanced non-small cell lung cancer
Cisplatin is often used in combination with other anticancer drugs.
This study was conducted to establish the efficacy and safety of combined therapies with pemetrexed, docetaxel and cisplatin.
It was performed on 97 patients with advanced non-small cell lung cancer. The patients were divided into two groups; one group was given cisplatin in combination with pemetrexed (an antimetabolite agent), while the other group was given cisplatin in combination with docetaxel (an antimitotic agent).
The study showed that the two therapeutic strategies have the same efficacy. However, pemetrexed and cisplatin therapy showed a significantly lower incidence rate of side effects - such as leukopenia, anemia, thrombocytopenia, nausea and vomiting - compared to docetaxel therapy.
2. Combination therapy with cisplatin, fluorouracil and elemi emulsion in the treatment of advanced gastric cancer
Elemi is an oleoresin that is obtained by carving the trunk of plants belonging to the Burseraceae family .
In this study, 64 patients - suffering from advanced gastric cancer - underwent a combination therapy based on cisplatin and fluorouracil to which oral administration of an elemi emulsion was added. The study showed that the drug-emulsion combination can significantly improve the curative efficacy of the therapy without increasing adverse reactions. In fact, with cisplatin and fluorouracil therapy, the one-year survival rate was 45%; by adding the emulsion, however, the survival rate seems to increase to 56%.
3. Mitigation of the side effects given by cisplatin after taking Vetiver oil
The use of cisplatin, despite its effectiveness, is limited due to the heavy side effects it causes.
The purpose of this study was to investigate the protective effects of Vetiver Java oil . The evaluation was carried out on Swiss albino mice which were administered Vetiver oil orally, for seven days, before the administration of cisplatin. After this period the drug was administered. The study demonstrated significant attenuation of renal toxicity and cisplatin-induced myelosuppression. This study therefore highlights interesting protective capabilities of Vetiver oil against the side effects induced by cisplatin therapy.
Warnings
Cisplatin should be administered under close supervision by a physician who specializes in the administration of anticancer chemotherapy agents.
The drug is packaged in dark bottles as photosensitive; it must therefore be kept away from light.
Cisplatin is able to react with metallic aluminum to form a black platinum precipitate. Therefore, the drug should be administered without the use of needles, syringes and catheters containing aluminum.
Before, during and after the entire period of therapy, renal, hepatic, hematopoietic (amount of blood cells) and serum electrolytes (calcium, magnesium, sodium, potassium) functions should be monitored .
Interactions
The administration of cisplatin in conjunction with other nephrotoxic substances (ie toxic to the kidneys) - such as, for example, cephalosporins, aminoglycosides or contrast media - enhances the toxic effect on the kidneys.
During and after treatment with cisplatin it is recommended to use cautiously other drugs excreted mainly via the kidneys.
The concomitant administration of ototoxic drugs (toxic to the ear) - such as aminoglycosides and loop diuretics - may intensify the toxicity of cisplatin to the ear.
Ifosfamide (an anticancer alkylating agent ) may increase the risk of hearing loss due to cisplatin treatment.
Concomitant use of myelosuppressive agents or radiotherapy may increase the myelosuppressive activity of cisplatin.
If cisplatin is given in combination with vinblastine or bleomycin it can cause Raynaud's phenomenon.
Concomitant administration of cisplatin and docetaxel may induce neurotoxic effects (toxic to the nervous system) that are more severe than those induced by single use of the two drugs.
The effectiveness of cisplatin can be reduced by taking some chelating agents, such as, for example, penicillamine .
Side effects
The side effects due to the administration of cisplatin may vary according to the dose administered and depending on whether the drug is used alone or in combination chemotherapy. Moreover, there is a great variability of response even between one individual and another.
The following are some of the side effects of cisplatin treatment.
Nephrotoxicity
Cisplatin is extremely nephrotoxic (toxic to the kidney), especially in those patients with pre-existing renal dysfunction. The nephrotoxicity of cisplatin is a dose-limiting side effect : it means that this type of toxicity reduces the dose of drug that can be given to the patient.
Neurotoxicity
The neurotoxicity caused by cisplatin is dose-dependent, ie it increases with increasing drug intake. It can manifest itself with the onset of paresthesia (loss of sensitivity to limbs or other areas of the body), areflexia (total loss of reflexes) and loss of proprioception, ie loss of the ability to perceive and recognize the position of one's body in the space.
Regular neurological checks should be performed during and after cisplatin treatment.
ototoxicity
It usually occurs in the form of tinnitus (whistling, buzzing, rustling or pulsing in the ear) and / or with hearing loss . Hearing loss can be unilateral or bilateral and tends to become more severe with repeated doses. There are no effective treatments to prevent this side effect, which may be more pronounced in children than in adults.
A careful audiometric check should be performed before starting cisplatin therapy and between one administration and another.
Myelosuppression
Cisplatin can induce myelosuppression, which is to promote the suppression of bone marrow . This suppression results in reduced hematopoiesis (reduced synthesis of blood cells).
The decreased synthesis of blood cells can lead to:
- anemia (reduced amount of hemoglobin in the blood);
- leukopenia (reduced number of white blood cells) with consequent increased susceptibility to infection contraction ;
- thrombocytopenia (reduced number of platelets) with increased risk of bleeding.
Myelosuppression is a dose-dependent side effect.
Nausea and vomit
Cisplatin is a powerful emetogen (induces vomiting) and - unless antiemetic drugs (antivomito) are given - this side effect almost always appears.
Generally, to prevent this effect, antiemetics (such as, for example, ondansentron ) are used in combination with corticosteroids (such as, for example, dexamethasone ).
Electrolytic disorders
Cisplatin can cause hypomagnesemia, hypokalemia and hypocalcemia, or - respectively - a decrease in magnesium, potassium and calcium levels in the blood.
Cardiac disorders
Cisplatin therapy can cause cardiac arrhythmias, including bradycardia and tachycardia . In particular, these effects have been observed when cisplatin is used in combination with other cytotoxic drugs.
Hypertension can occur and, in some cases, myocardial infarction may occur even a few years after the end of therapy.
Vascular pathologies
It is very common that phlebitis may occur in the area where cisplatin is injected.
Cerebral or myocardial ischemia may also occur.
Respiratory disorders
Dyspnoea, respiratory failure and, in some cases, pneumonia may occur following treatment with cisplatin.
Hepato-biliary disorders
Cisplatin can cause an alteration in liver function and an increase in blood levels of transaminases (enzymes used as indicators to detect possible liver damage) and bilirubin (a yellow pigment contained in bile, produced by the catabolism of hemoglobin).
Skin and subcutaneous tissue disorders
Erythema, ulcers and rashes may occur in the area where cisplatin was injected. In addition, alopecia may occur.
Action mechanism
Cisplatin - like all alkylating agents - is able to form bonds with the two strands that make up DNA.
DNA consists of two strands joined together to form a double helix.
DNA is made up of many monomers, called nucleotides. There are 4 types of nucleotides: adenine (A), guanine (G), cytosine (C) and thymine (T), which combine with exclusive pairs of AT (adenine-thymine) and CG (cytosine-guanine) held together by hydrogen bonds .
The sequence of bases present along the DNA molecule carries the genetic information.
The double strand of DNA consists of four fundamental units called nitrogenous bases : these molecules are cytosine, thymine, adenine and guanine. Cisplatin performs its cytotoxic action by binding to a nitrogen atom present in the guanine structure, but is also able to form bonds with adenine. The binding of cisplatin to DNA strands prevents it from being transcribed and replicated, condemning the cells to meet the mechanism of programmed cell death ( apoptosis ).
Mode of Use - Posology
Cisplatin is a clear, light yellow liquid. Administration is usually done by intravenous infusion over 6-8 hours.
The dose of cisplatin administered depends on the type of cancer that is intended to be treated and whether the drug is used alone or in combination with other drugs.
Monotherapy
Cisplatin monotherapy can be administered in two different ways:
- Single dose, in a quantity ranging from 50 to 120 mg / m2 of body surface every 3-4 weeks;
- Doses divided into a quantity ranging from 15 to 20 mg / m2 per day, for five consecutive days, every 3-4 weeks.
These doses can be given to both adults and children.
Association chemotherapy
If cisplatin is used in combination chemotherapy, the administered dose should be reduced. Typically, the usual dose is 20 mg / m2 or more, given as a single dose, every 3-4 weeks.
In the case of treatment of cervical cancer, cisplatin is usually used in combination with radiotherapy. In this case, the usual dose administered is 40 mg / m2 per week, for six weeks.
Due to the renal toxicity of cisplatin, the dose administered should be decreased in patients with renal dysfunction.
To avoid, or at least contain, kidney damage caused by cisplatin, patients should be hydrated with solutions containing chlorides. Saline or mannitol diuretics can be given to promote continued drug excretion during and after therapy.
Pregnancy and breastfeeding
There are insufficient data on the use of cisplatin by pregnant women, but it is suspected that it may cause serious birth defects.
Animal studies have however shown reproductive toxicity and transplacental carcinogenicity . Cisplatin can therefore be toxic to the fetus when administered to a pregnant woman, so it is strongly advisable to avoid its use.
Precautions should be taken by both sexes to avoid pregnancies during cisplatin therapy and for at least six months after the end of it.
Since cisplatin is also excreted via breast milk, it is not recommended for breast-feeding.
Contraindications
The use of cisplatin is contraindicated in patients allergic to the drug itself or to other platinum-containing compounds.
Cisplatin is contraindicated in patients with myelosuppression, in patients with renal dysfunction and in dehydrated patients. It is also contraindicated in patients with impaired hearing.
Discovery of cisplatin
Like many of the discoveries that revolutionized the world of chemistry and medicine, the discovery of the cytotoxic action of cisplatin also occurred by chance.
Originally, cisplatin was first described in 1845 by the Italian chemist Michele Peyrone and for a long time was known as "Peyrone chloride".
The experiment was carried out on bacterial cultures of Escherichia coli incubated in a culture medium containing ammonium chloride (necessary for bacterial growth) inside a chamber containing two platinum electrodes.
Scientists noted that when the electric field was applied, bacterial replication stopped. The growth of the bacteria was not interrupted, but these did not grow more normally, but rather abnormally. Scientists deduced that by applying the electric field, chemical species were generated that could alter bacterial growth and block replication. Rosenberg's studies continued until he came to understand that the cytotoxic action was due to the formation of an organometallic complex: cisplatin .
Subsequently, numerous studies were carried out to assess the potential of cisplatin in the treatment of tumors.
In December 1978, the United States Food and Drug Administration approved the use of cisplatin for the treatment of testicular and ovarian cancer and the following year it was approved in other European countries.
