Continuing Education Activity

Ifosfamide is a cytotoxic, antineoplastic drug used to manage and treat various cancers such as lymphoma, sarcoma, and lung cancer. This activity describes the indications, administration, and contraindications for ifosfamide as a valuable agent in treating various cancers. Furthermore, this activity will highlight the mechanism of action, adverse event profile, and other vital factors, e.g., pharmacodynamics, pharmacokinetics, monitoring, relevant interactions pertinent for interprofessional team members in the management of patients with malignancies and related conditions.

Objectives:

• Outline the typical mechanism of action of ifosfamide.
• Identify the most common adverse effects associated with ifosfamide.
• Summarize the toxicology of ifosfamide.
• Describe the importance of collaboration and communication among the interprofessional team to optimize patient care receiving ifosfamide therapy.

Indications

Ifosfamide is an alkylating agent and an analog of cyclophosphamide, used as a single agent or in combination with other agents to treat a wide variety of malignancies. These malignancies include[1]:

• Germline tumor of the testis
• Soft tissue sarcomas
• Ewing sarcoma
• Cervical cancer, either recurrent or metastatic
• Advanced bladder carcinoma
• Non-Hodgkin lymphoma
• Hodgkin lymphoma
• Small and nonsmall cell lung carcinoma
• Osteosarcoma
• Ovarian cancer
• Thymic cancer

Among all these cancers, the Food and Drug Administration (FDA) has approved the drug only for germline tumors of the testis. The indications for the use of ifosfamide include: 

Germline Tumor of the Testis[2][3]

The FDA-approved regimen is ifosfamide and mesna at a 1.2 g/m²/day dose for five days, repeated every three weeks or following count recovery. When using ifosfamide and other chemotherapeutic drugs, mainly cisplatin, paclitaxel, or etoposide, there has been complete remission in about 21 to 26% of the treated population. Aggressive hydration (at least 2 liters oral or IV) is necessary during administration.

Soft Tissue Sarcomas (off label use)[4]

Noncomparative studies have shown that combination therapy with ifosfamide/mesna has demonstrated objective response rates of around 40% when used as induction therapy.

Ewing Sarcoma (off label use)[5]

Doses of ifosfamide vary based on the age group. Used alongside vincristine, etoposide, doxorubicin along with mesna in different regimens. Overall, survival is better with combination therapies. 

Cervical Cancer, Recurrent, or Metastatic (off label use)[6]

Ifosfamide is dosed along with mesna at 1500 g/m2/day every three weeks. When used along with paclitaxel and cisplatin, the response rate was 18 to 45%.

Bladder Carcinoma: Mainly Advanced Carcinoma (off label use)[7]

Non-Hodgkin Lymphoma (off label use)

Used in Burkitt lymphoma and diffuse large B cell lymphoma (DLBCL) as salvage therapy.

Hodgkin Lymphoma (off-label use)[8]

Used in relapsed or refractory cases in the RICE regimen (rituximab, ifosfamide, carboplatin, and etoposide) along with mesna.

Small and Non-small-cell cancer[9]:

When used as maintenance or consolidation has been shown to have more benefit than standard regimens.

9. Osteosarcoma (off label use)[10]

Ovarian Cancer[11]

Used in advanced stages that are platinum-resistant. Many additional trials are underway. Response rates have been more than 40% when used as a combination.

Thymic Cancer[12]

Used in advanced stages of thymic cancer.

Mechanism of Action

• Ifosfamide belongs to the class of the oxazaphosphorine alkylating agents. It is an inactive compound in its parent form (prodrug). It is metabolized in the liver by CYP450 enzymes to active metabolites. These active metabolites (phosphoramide mustard derivatives and acrolein) bind to DNA and inhibit DNA synthesis.[13]

• There are two mechanisms by which these metabolites act. First, they cause cell damage by forming interstrand or intrastrand crosslinks, leading to apoptosis of the damaged cell. Second, the active metabolites also upregulate the reactive oxygen species (ROS), resulting in irreparable DNA damage and the cessation of protein formation.

• Compared to other alkylating compounds, cyclophosphamide and ifosfamide have more anti-tumor activity as their derivatives. Mainly, phosphoramide mustard derivatives and acrolein are cytotoxic rather than cytostatic. Filtration primarily occurs through the kidney, and dosing requires adjustment according to renal function.[14]

Administration

The primary route of administration is intravenous (IV).[2] The oral form had a bioavailability close to 100% but resulted in severe neurotoxicity, and since then, the administration route has switched to IV.[15] 

For germ-cell testicular cancer, the dosing regimen is 1.2 g/m²/day IV for the initial five days of a 21-day cycle. IV infusion is typically for a period of 30 minutes along with IV hydration and mesna to prevent bladder toxicity. Ifosfamide is emetogenic; hence, antiemetics are routinely prescribed to prevent chemotherapy-induced nausea and vomiting. Precipitation of ifosfamide-induced encephalopathy (IIE) by aprepitant has been reported in the literature. [16][17]

Researchers discovered ifosfamide over two decades ago, but it was subject to dose limitations due to the development of hemorrhagic cystitis. Only after the availability of the thiol neuroprotective compound mesna was the drug used more commonly to treat a wide range of malignancies. For this reason, the administration is almost always along with mesna. Mesna converts to dimesna in the plasma, which is filtered at the level of kidneys, where it is converted back to mesna.

At the urothelium, mesna combines with active metabolites like acrolein (urotoxic) and forms a non-toxic compound, which is eliminated in the urine. Mesna administration can be either oral or IV. The half-life of mesna is around 0.4 hours. It is completely excreted in four hours if given IV and in eight hours if given orally.[2]

Adverse Effects

Adverse effects are mainly dose-related and can be described based on the system affected.[18] These include the gastrointestinal, dermatologic, central nervous system, hematologic, renal, endocrine, and cardiac[19][20]:

1. Gastrointestinal: nausea and vomiting (over 50%); abdominal cramps; anorexia - usually, patients are advised to stay hydrated and drink plenty of water while on this therapy.[19] Antiemetics are generally given along with the drug. 
2. Dermatologic: alopecia - it is a universal side effect noted with ifosfamide (90%).
3. Central nervous system: encephalopathy (15%).
4. Hematologic: leukopenia, anemia, thrombocytopenia (30 to 50%).
5. Renal: hematuria - when used alone (90%).
6. Endocrine and metabolic: metabolic acidosis (30%).
7. Cardiac: arrhythmia (under 10%).
8. Hepatic: The severity of liver injury ranges from mild elevations in liver enzymes to massive, fatal hepatic necrosis due to hepatic veno-occlusive disease.[21]

Contraindications

There are very few known contraindications for the use of ifosfamide. The absolute contraindications are known hypersensitivity to the drug or its components and urinary tract outflow obstruction. Relative contraindications include myelosuppression and severe renal or hepatic impairment.

1. Known hypersensitivity to the drug and/or its components - can result in anaphylaxis with drug administration.[15]
2. Urinary outflow obstruction - there is a high chance of developing cystitis when there is urinary tract obstruction due to an accumulation of toxic compounds.[22]
3. Severe thrombocytopenia and leukopenia - due to the known toxic effect hematologically, the drug is avoided in severe thrombocytopenia and leukopenia.
4. Severe renal or hepatic impairment - drug metabolism occurs in the liver, and the drug is excreted by the kidneys, prohibiting its use in severe renal and hepatic impairment.[23]

Monitoring

To understand the drug's therapeutic index, one needs to know the pharmacokinetics and pharmacodynamics of the drug. Regarding pharmacokinetics, the volume of distribution (Vd) of the drug is almost equal to the total body water when administered in the IV form. Vd varies with weight and age (elderly and pediatric).[15] Vd increases with age and in obese individuals.[2] The half-life of the drug after a single administration is four to seven hours. The total clearance of the drug is 3.6L/h. Usually, fractionation of the drug results in faster elimination rates.

The most common dose administered is 1.2 g/m²/day, given very slowly over 30 minutes for five consecutive days.[2] Complete blood count with differential, renal function, liver function, urine output, and urinalysis are necessary before each dose. Dosing repeats every three weeks or after hematologic recovery. Drug levels can be measured in the urine by gas chromatography-mass spectrometry.[24] Therapeutic drug monitoring takes place after assessing the pharmacokinetics of the first course of the drug, followed by subsequent alterations in the dose as there is wide variability in the pharmacokinetics of ifosfamide.

Dosing needs to be adjusted in renal impairment because the drug undergoes renal elimination.[25] Dose reduction is 80% of the dose if creatinine clearance (CrCl) is 46 to 60 mL/minute. However, if CrCl is 31 to 45 mL/minute, administer 75% of the dose and with CrCl under 30 mL/minute, reduce to 70% of the regular dose. There is no requirement for dose adjustment with hepatic impairment, but caution is advised. The drug requires adjustment according to weight.[26]

The dose also needs to be adjusted according to the toxicity profile. Instances of severe leukopenia or thrombocytopenia require dosage reduction. More severe toxicity, such as encephalopathy, typically requires termination of therapy.

Toxicity

Most of the ifosfamide toxicity is due to its active metabolites. Acrolein plays a significant role in causing major renal and bladder-related toxicity. As the kidneys filter these metabolites, they generate ROS and nitrogen compounds, damaging the renal and urothelial cells. The etiology behind neurotoxicity is similar to that of renal toxicity but is not fully understood. As with other anti-neoplastic drugs, ifosfamide is toxic to bone marrow. Other toxicities include the following:

Hemorrhagic Cystitis

Before the availability of mesna, the main adverse effect was hemorrhagic cystitis. This is due to hepatic metabolism producing acrolein, which is excreted by the kidneys and accumulates in the bladder.[22] Its apoptotic properties and production of multiple ROS and nitric oxide result in the release of numerous cytokines that cause ulceration of the bladder epithelium and hemorrhagic cystitis. Mesna is a drug developed in 1983 to help with this adverse effect of ifosfamide. As described earlier, mesna combines with the urotoxic metabolites at the level of the urothelium, leading to a non-toxic product for excretion in the urine. It is always important to attempt to prevent the development of cystitis rather than to treat it. The current treatment options are continuous bladder irrigation, intravesicular infusion of ammonium potassium sulfate and formalin, and in some instances, cystectomy.[22] Mesna should be administered before, during, and after ifosfamide along with aggressive hydration (at least 2 liters oral or IV) to prevent urotoxicity.

Neurotoxicity

Central nervous system toxicity appears as encephalopathy with varying severity (confusion, hallucinations, drowsiness, coma). It presents in about 30% of the cases, and the symptoms occur when administering high doses of the drug either orally or intravenously but more with oral administration.[27] Usually, the symptoms present within 2 to 96 hours after drug administration and are reversible within 48 to 72 hours following discontinuation of the drug.[15] Risk factors associated with the development of neurotoxicity include oral administration, previous chemotherapy with cisplatin, impaired renal and hepatic function, low albumin, and brain metastasis. Methylene blue can be used for both treatment and prophylaxis of ifosfamide-induced encephalopathy due to the drug's ability to prevent the formation of neurotoxic metabolites that cause encephalopathy.[28] Methylene blue helps in the reversal of symptoms within 24 hours of its administration. The dosage of methylene blue is 50 mg orally in 5% glucose solution every four hours until recovery.[15] As prophylaxis, the severity of symptoms is reduced compared to previous cycles and can restore therapy with ifosfamide. The prophylactic dose is 50 mg IV every 6 to 8 hours during ifosfamide administration.

Hematologic Toxicity

Myelosuppression is a dose-limiting toxicity. The blood counts reach a nadir in about 8 to 13 days of the treatment cycle. Recovery generally occurs around day 17 of the treatment cycle, starting the next cycle in around three weeks after the first treatment. This effect is dose-related. The incidence of myelosuppression is low when fractionated doses are used rather than higher doses.[29] At a dose of 1.2 g/m²/day for five days, a white cell count below 3 x 10^9/L and a platelet count below 20000/microL occurs in 30% of cases.[29]

Nephrotoxicity

Most commonly noted in children and is seen when co-administered with cisplatin. It can lead to Fanconi syndrome, in which there is impairment of proximal tubule function resulting in irreversible damage. This manifests clinically as metabolic acidosis, polyuria, and renal phosphate wasting and is seen in about 5% of cases.[30] Supplementation with vitamin D and phosphate is essential in the affected pediatric population. Etiology remains unclear.

Miscellaneous Toxicities

There are reports of arrhythmias, heart failure, and pulmonary toxicity in the form of pneumonitis.[31]

Malignancy of Ureter and Bladder

There has been a reported case of multifocal urothelial carcinoma in a patient treated with ifosfamide many years ago.[13]

Enhancing Healthcare Team Outcomes

For chemotherapy drug administration and monitoring, the role of nursing and pharmacy is very crucial. All healthcare providers need to collaborate as an interprofessional team to ensure optimal care and minimal adverse effects with any drug therapy, even more so with a chemotherapeutic agent like ifosfamide. Nursing is helpful in closely monitoring the patient during and after drug administration, identifying adverse reactions, and reporting them immediately. Oncology nurses have specialized training in the administration of chemotherapy. The role of pharmacists is crucial as they help formulate the dosing and monitor them for potential toxicity. Nursing and pharmacists can provide patient counseling about the drug, including what to expect following administration and as the cycles progress. For better outcomes, the plan requires detailed discussion among all the members involved in patient care like nurses, pharmacists, physicians, and family to lower mortality and morbidity. [Level 5]