Irinotecan

Irinotecan (or irinotecan) is an anticancer drug belonging to the camptothecin family.

To this family belong all those drugs that derive from camptothecin, a natural molecule able to inhibit the proliferation of cancer cells.

Irinotecan - Chemical Structure

Camptothecin was extracted for the first time from the bark of Camptotheca acuminata (a tree originating in China).

Indications

For what it uses

Irinotecan can be used alone, or in combination with other anticancer drugs, to treat:

Advanced colorectal cancer;
Ovarian cancer;
Non-small cell lung cancer.

Warnings

Irinotecan must be administered under the close supervision of a doctor who specializes in the administration of anticancer drugs and only in specialized facilities.

Due to the toxicity of irinotecan, it is important to monitor patients' liver and kidney function during the entire treatment period with the drug.

Patients who present a risk factor for developing respiratory and / or cardiac conditions should be carefully monitored.

Although irinotecan is not a blistering agent, extravasation from the infusion site must not occur; for this - during the administration - the patients must be kept under close observation.

Interactions

The concomitant administration of irinotecan and drugs that are enzyme inducers - such as, for example, phenobarbital (a barbiturate) and carbamazepine (a drug used for epilepsy) - can cause a reduction in the therapeutic efficacy of irinotecan itself.

Irinotecan can decrease the intestinal absorption of phenytoin (a drug used for epilepsy) thus intensifying epileptic seizures.

The concomitant intake of irinotecan and ketoconazole (an antifungal drug) may decrease the plasma concentration of irinotecan, thereby reducing its therapeutic efficacy. The same thing can happen if St. John's Wort (or St. John's wort ), an officinal plant having antiviral and antidepressant properties, is administered concurrently with irinotecan.

Irinotecan can interact with the activity of oral anticoagulants .

Irinotecan and vaccines

Vaccination of patients receiving irinotecan with live attenuated virus vaccines is not recommended. Irinotecan causes reduced white blood cell production; in this way, it seriously compromises the immune system by preventing the patient from responding to the vaccine adequately.

In immunocompromised patients, in fact, the administration of live virus vaccines can cause infections and increase the side effects of the vaccine itself, due to an increase in viral replication.

In some cases, the developing infection can be fatal.

Side effects

Irinotecan can induce various side effects, which depend on the amount of drug administered and the patient's condition. Furthermore, it is not said that all adverse effects occur with the same intensity in each individual, as each patient responds differently to chemotherapy.

The following are the main side effects induced by the drug.

Myelosuppression (bone marrow suppression)

Irinotecan can cause bone marrow suppression. This suppression leads to reduced haematopoiesis, ie a reduced synthesis of blood cells. The decrease in blood cell production 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 ;
Plateletopenia (reduced number of platelets) leading to bruising and abnormal bleeding with an increased risk of bleeding .

Gastrointestinal disorders

Irinotecan therapy may cause disorders such as nausea, vomiting and diarrhea .

Vomiting usually occurs a few hours after taking the drug and may last a few days. Generally, this symptom is kept under control with the use of anti-emetic (ie antivomito) drugs. If, however, the vomiting is in severe form and if it persists despite the use of drugs, it is necessary to inform the doctor.

Diarrhea can be early or late.

In the case of early diarrhea, this occurs - generally - 24 hours after taking the drug and is due to the cholinergic activation induced by irinotecan; it can be treated using drugs with a cholinergic antagonist action.

Late diarrhea, on the other hand, can occur from three to ten days after taking the drug. Normally, diarrhea is controlled with the use of antidiarrheal drugs, but - if it is severe - it may be necessary to reduce the dose of medication administered or even to stop treatment.

Following dehydration associated with diarrhea and / or vomiting, renal failure, hypotension or heart failure may occur. Therefore, it is essential to drink a lot to replenish lost fluids.

Fall of hair, eyelashes and hair

Treatment with irinotecan can lead to loss of hair, eyelashes and hair in general . These can thin out or fall completely. Generally, this symptom occurs a few weeks after taking the drug. It is however a reversible side effect, hair and hair should grow back after stopping therapy.

Oral cavity disorders

Irinotecan can cause pain and dryness in the oral cavity and the appearance of small ulcers . This side effect can be prevented by drinking plenty of fluids and performing regular tooth cleaning with a soft toothbrush. Furthermore, a temporary alteration of the sense of taste may occur, which returns to normal at the end of the therapy.

Muscle cramps

Irinotecan therapy can cause muscle cramps . Usually, they occur in mild form, but - if they occur in a severe form - anti-inflammatory drugs may be required.

Hepatic impairment

Irinotecan may cause a temporary reduction in liver function, which usually occurs with an increase in blood transaminase values. The function of the liver, however, should return to normal at the end of the therapy.

Skin disorders

Treatment with irinotecan can cause acne-like rashes that can be itchy . It is therefore recommended to use neutral detergents and possibly - if the doctor considers it necessary - the use of antihistamine creams.

Allergic reactions

Irinotecan - like all medicines - can trigger allergic reactions in sensitive individuals. Allergic reactions can manifest as rashes accompanied by itching, localized redness in the face, chills, fever, dizziness, headache, shortness of breath and / or increased urination. Symptoms can occur both mild and severe. If it occurs in severe form, appropriate drug treatment may be necessary.

Acute cholinergic syndrome

Irinotecan can cause an acute cholinergic syndrome that manifests itself as early diarrhea associated with other symptoms such as sweating, abdominal cramps, miosis and increased salivation. If this adverse effect occurs, atropine sulfate should be administered, unless clinical contraindications are present. In this regard, caution should be used in asthmatic patients.

Cardiac disorders

Although it is not a common side effect, myocardial ischemia events may occur following irinotecan treatment. However, these events occurred mainly in patients suffering from pre-existing cardiac pathologies.

Respiratory disorders

Irinotecan therapy can cause dyspnea and - although rarely - can cause the onset of interstitial lung disease manifesting as a pulmonary infiltrate .

Infertility

Irinotecan can induce infertility in both female and male patients.

Other side effects

Other side effects that may be caused by irinotecan are:

colitis;
Intestinal perforation;
Anorexia;
Abdominal pain;
Muscle cramps;
paresthesia;
Fever in the absence of infections;
Systemic disorders related to the administration site;
Hypokalaemia (or hypopotassemia), that is, lack of potassium in the blood;
Transient increases in alkaline phosphatase, bilirubin and / or creatinine levels in the bloodstream.

Action mechanism

Irinotecan - before carrying out its cytotoxic action (toxic to cells) - must be activated through an enzymatic hydrolysis reaction that takes place at the liver level. The drug is thus transformed into an active compound that is able to inhibit one of the fundamental enzymes in the DNA replication process: type I topoisomerases .

This inhibition causes genomic aberrations that send the cell to apoptosis (a mechanism of programmed cell death).

Mode of Use - Posology

Irinotecan is available for intravenous administration; looks like a clear liquid.

It can be administered through three different routes:

Through a cannula (a thin tube) that is inserted into a vein of an arm or hand;
Through a central venous catheter that is inserted subcutaneously into a vein near the clavicle;
Through the PICC line ( Peripherally Inserted Central Catheter ), in this case, the catheter is inserted into a peripheral vein, usually of an arm. This technique is used for the administration of anticancer drugs for a prolonged time.

Monotherapy

When the drug is used on its own, the dose of irinotecan usually used is 350 mg / m2 of body surface area, given by intravenous infusion over a period of 30 to 90 minutes.

Doses are given at three-week intervals.

Association therapy

Irinotecan can also be given in combination with other anticancer drugs. In particular, it is often administered in combination with 5-fluorouracil and folinic acid. When used in combination with these drugs, the dose of irinotecan administered is usually reduced to 180 mg / m2 of body surface area, administered by intravenous infusion over a period of 30 to 90 minutes. In this case, the doses are generally administered every two weeks.

The dosage, however, must be established by the oncologist according to the type of pathology to be treated and the clinical picture of each individual patient.

In patients with pre-existing liver and / or renal dysfunction a dose reduction of irinotecan may be required.

Even in elderly patients - due to the increased frequency of loss of vital functions - an adjustment in the dose of drug to be administered may be necessary.

Pregnancy and breastfeeding

Since irinotecan was found to be embryotoxic and teratogenic in animal studies, its use during pregnancy (especially during the first trimester) should be avoided, except in cases of necessity where the oncologist considers it necessary to take the drug.

Precautions must be taken by both sexes to avoid pregnancy during all irinotecan treatment. Precautions must also be taken at the end of chemotherapy for a minimum period of three months.

Due to potential side effects that irinotecan can cause in infants, its use is contraindicated in women who are breast-feeding.