Cisplatin

Primary Uses

Cisplatin is primarily used to treat several types of advanced or metastatic cancers. It is often prescribed when the cancer has spread to other parts of the body or cannot be managed by surgery or radiation alone. Common uses include:

• Testicular Cancer: It is used to treat metastatic testicular tumors, typically in combination with other chemotherapy medications after surgery or radiation.
• Ovarian Cancer: It is used for metastatic ovarian tumors. It may be used as a first-line treatment alongside other drugs or as a secondary treatment if the cancer does not respond to other therapies.
• Bladder Cancer: It is used as a single-agent treatment for advanced bladder cancer that is no longer localized.

Combination Therapy

In many cases, cisplatin is not used alone. It is frequently part of a combination chemotherapy regimen, where multiple drugs work together to target cancer cells. For example, it may be used with other medications to treat advanced urothelial carcinoma (a type of bladder cancer) that has spread or cannot be removed by surgery.

Mechanism of Action

Cisplatin belongs to a group of medicines known as platinum-containing compounds. It is used to treat various types of cancer by slowing or stopping the growth of malignant cells.

The medication works through the following process:

• DNA Binding: Once cisplatin enters the body, it targets the DNA inside cells. It attaches itself to the DNA strands, creating cross-links.
• Preventing Replication: These cross-links act as a physical barrier that prevents the cell from copying its genetic material. Without the ability to replicate DNA, the cell cannot divide to create new cancer cells.
• Cell Death: When a cell's DNA is damaged and cannot be repaired or replicated, the cell eventually dies.

Because cancer cells generally divide more rapidly than healthy cells, they are more susceptible to the effects of cisplatin. However, the drug can also affect some healthy cells that divide quickly, which contributes to its side effects.

Common Side Effects

Many people receiving cisplatin experience digestive symptoms. These may include:

• Severe nausea and vomiting, which may last for several days
• Diarrhea
• Loss of appetite
• Changes in the way food tastes
• Temporary hair loss

Serious Side Effects

Some side effects require immediate medical attention. Contact your healthcare provider right away if you experience:

• Kidney problems: Decreased urination, swelling in the feet or lower legs, or blood in the urine.
• Hearing changes: Ringing in the ears (tinnitus) or loss of hearing, which may be permanent in some cases.
• Nerve damage: Numbness, tingling, burning pain, or weakness in the hands or feet.
• Signs of infection: Fever, chills, sore throat, or other persistent signs of illness.
• Allergic reactions: Rash, hives, itching, swelling of the face or throat, or difficulty breathing.
• Vision changes: Blurred vision or changes in how you see colors.
• Electrolyte imbalances: Muscle cramps, bone pain, or an irregular heartbeat.
• Unusual bleeding: Easy bruising, nosebleeds, or bleeding gums.

Boxed Warnings

Cisplatin has several boxed warnings due to the potential for severe side effects. These include:

• Kidney Damage: Severe kidney toxicity is a major risk. This effect is cumulative, meaning the risk increases with more doses.
• Hearing Loss: Significant hearing loss, especially of high-pitched sounds, and ringing in the ears (tinnitus) can occur. This is more common and may be more severe in children.
• Bone Marrow Suppression: The drug can lower the number of blood cells, increasing the risk of infection, bleeding, and anemia.
• Severe Nausea and Vomiting: These symptoms can be intense and may require specialized medication for prevention and management.

Other Major Precautions

Nerve Damage: Peripheral neuropathy, which causes numbness, tingling, or pain in the hands and feet, may occur. This risk increases with the total amount of drug received.

Allergic Reactions: Some individuals may experience severe allergic reactions, including swelling, wheezing, or low blood pressure, usually within minutes of receiving the medication.

Electrolyte Imbalances: Cisplatin can cause low levels of magnesium, calcium, and potassium in the blood.

Pregnancy and Breastfeeding: This medication can cause fetal harm. Effective contraception is typically recommended during treatment. Breastfeeding is generally advised against while using this drug.

Monitoring

Healthcare providers typically monitor kidney function, hearing, and blood cell counts before and during each course of treatment. Intensive hydration is often used before and after the dose to help prevent kidney damage.

Pregnancy

Cisplatin can cause harm to a developing fetus. Research suggests that exposure to this medication during pregnancy may result in birth defects or other serious complications. Because of these risks, healthcare providers generally advise the following:

• Pregnancy Prevention: Patients who can become pregnant are typically advised to use effective birth control during treatment.
• Notification: If pregnancy is suspected or occurs during treatment, it is important to inform a healthcare professional immediately to evaluate the risks.
• Fertility Considerations: Cisplatin may also affect fertility in both men and women. Men are often advised to use contraception to avoid fathering a child while receiving this medication.

Breastfeeding

There is limited information regarding whether cisplatin is present in human breast milk. Due to the potential for severe side effects in a nursing infant, breastfeeding is generally not recommended while undergoing treatment with cisplatin. Patients are encouraged to discuss alternative feeding methods with their healthcare team.

Available Forms

Cisplatin is supplied in forms intended for administration by a healthcare professional in a medical setting. It is not available for self-administration.

• Intravenous Injection: This medication is commonly provided as a sterile aqueous solution in vials.
• Powder for Injection: It may also be available as a lyophilized powder that must be reconstituted into a liquid solution before use.

Cisplatin is administered as an infusion into a vein. It is not available in oral forms such as tablets or capsules.

FDA Approval and Indications

Cisplatin was initially approved by the FDA in 1978. It is currently indicated for the treatment of the following conditions:

• Metastatic testicular tumors, often in combination with other approved chemotherapeutic agents.
• Metastatic ovarian tumors, typically as combination therapy with other agents in patients who have already received surgery or radiotherapy.
• Advanced bladder cancer that is no longer responsive to local treatments like surgery or radiotherapy.

In March 2024, the FDA also approved cisplatin for use in combination with nivolumab and gemcitabine as a first-line treatment for adults with unresectable or metastatic urothelial carcinoma.

Boxed Warnings

The FDA requires a boxed warning for cisplatin due to the potential for severe adverse reactions. These include:

• Nephrotoxicity: Dose-related and cumulative kidney damage is a major concern. Renal function must be monitored closely, and hydration is required before and after administration.
• Ototoxicity: Hearing loss and tinnitus may occur, particularly with high doses or frequent cycles. This effect may be more severe in pediatric patients.
• Nausea and Vomiting: Severe gastrointestinal distress is common and may require the use of antiemetic medications.
• Myelosuppression: The drug can suppress bone marrow activity, leading to low levels of white blood cells, red blood cells, and platelets.
• Peripheral Neuropathy: Nerve damage causing tingling or numbness in the extremities may occur, sometimes after prolonged treatment.

Regulatory Requirements

Because of its toxicity profile, cisplatin must be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Regular laboratory testing, including kidney function tests and hearing evaluations, is mandated during the course of therapy.

FDA-Approved Indications

Cisplatin is indicated for the treatment of several specific types of metastatic or advanced cancers:

• Metastatic Testicular Tumors: It is used in combination with other approved chemotherapeutic agents for patients who have already received appropriate surgical or radiotherapeutic procedures.
• Metastatic Ovarian Tumors: It is used as a primary treatment for advanced disease in combination with other agents, or as a secondary therapy for patients who have not responded to standard treatments.
• Advanced Bladder Cancer: It is used as a single agent for patients with transitional cell bladder cancer that is no longer manageable by local treatments such as surgery or radiation.

Recent FDA Approvals

In March 2024, the FDA approved the use of nivolumab in combination with cisplatin and gemcitabine for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma, a type of bladder cancer.

FDA Boxed Warnings

The FDA has issued boxed warnings for cisplatin due to the risk of severe and potentially cumulative toxicities:

• Nephrotoxicity: Dose-related kidney damage is a major risk. Patients must be adequately hydrated before and after administration to reduce this risk.
• Ototoxicity: Significant hearing loss or tinnitus may occur, and this effect may be more pronounced in children.
• Myelosuppression: The drug can cause severe suppression of bone marrow function, leading to low levels of white blood cells, red blood cells, and platelets.
• Nausea and Vomiting: Severe gastrointestinal distress is common and typically requires the use of antiemetic medications.

The FDA also highlights the risk of medication errors, specifically the potential for cisplatin to be confused with carboplatin, which has a different dosing schedule and toxicity profile.