Ifosfamide


Article Author:
Mounika Gangireddy


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Vinod Nookala


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Updated:
5/10/2019 12:01:14 PM

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
  • Ewings sarcoma
  • Cervical cancers 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 tumor of the testis. The indications for the use of ifosfamide include: 

1. Germline tumor of the testis[2][3][2]:

The FDA approved regimen is ifosfamide along with mesna at a dose of 1200g/m^2/day for five days and is repeated every three weeks or following count recovery. When ifosfamide is used along with other chemotherapeutic drugs mainly cisplatin, paclitaxel or etoposide, there has been complete remission in about 21 to 26% of the population. Aggressive hydration (at least 2 liters oral or IV) is necessary during administration.

2. Soft tissue sarcomas (off label use)[4]

Non-comparative studies have shown that the combination therapies with ifosfamide/mesna, when used as induction therapy, have shown objective response rates around 40%.

3. Ewings 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. 

4. Cervical cancer, recurrent or metastatic (off label use)[6][2][6]:

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

5. Bladder Carcinoma: mainly advanced carcinoma (off label use)[7]:

6. Non-Hodgkins Lymphoma (off label Use)[8]:

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

7. Hodgkins Lymphoma (off-label use)[8]:

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

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

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

9. Osteosarcoma (off label use)[10]

10. Ovarian Cancer[11][2][11]

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

11.Thymic cancer[12]:

Ifosfamide has off label use in the advanced stage 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 (pro-drug). It gets metabolized in the liver by CYP450 enzymes to active metabolites. These active metabolites (phosphoramide mustard derivatives and acrolein) bind to the DNA and inhibit DNA synthesis.[13] The two mechanisms by which this metabolite acts are as follows. First, it causes cell damage by forming interstrand or intrastrand crosslinks, and second, it leads to apoptosis of the damaged cell.[14] These active metabolites upregulate the reactive oxygen species (ROS) which results in irreparable DNA damage and cease the protein formation. When 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.[14] Filtration primarily occurs through the kidney, and the doses require adjustment according to renal function. 

Administration

The primary mode of administration of the drug is through the intravenous (IV) route.[2] The oral form had a bioavailability close to 100 percent but resulted in severe neurotoxicity, and since then the administration has switched to the intravenous form.[15] 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 was used more commonly to treat a wide range of malignancies. For this reason, the administration is almost always along with mesna[2]. Mesna converts to dimesna in the plasma gets filtered at the level of kidneys where it switches back to mesna. At the urothelium, mesna combines with the active metabolites like acrolein (urotoxic) and forms a non-toxic compound which then gets eliminated in the urine.[2] Mesna administration can be either orally 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.

Adverse Effects

Adverse effects are mainly dose-related. They can be described based on the systems.[16] These include gastrointestinal, dermatological, central nervous system, hematological, renal, endocrine, and cardiac[17][18]:

  1. Gastrointestinal: nausea and vomiting (over 50%); abdominal cramps; anorexia - usually patients are advised to stay hydrated and are encouraged to drinks lots of water while on this therapy.[17]Antiemetics are generally given along with the drug. 
  2. Dermatological: alopecia - it is a universal side effect noted with ifosfamide. (90%)
  3. Central nervous system: encephalopathy. (15%)
  4. Hematological: leukopenia, anemia, thrombocytopenia. (30 to 50%)
  5. Renal: hematuria (90%) - when used alone.
  6. Endocrine and metabolic: metabolic acidosis. (30%)
  7. Cardiac: Arrhythmias. (under 10%)

Contraindications

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

  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.[19]
  3. Severe thrombocytopenia and leukopenia - due to the known toxic effect hematologically, the drug is avoided in case of severe thrombocytopenia and leukopenia. 
  4. Severe renal/hepatic impairment - drug metabolism occurs in the liver, and it gets excreted through the kidneys; prohibits its usage in severe renal and hepatic impairment.[20]

Monitoring

To understand the therapeutic index of the drug, one needs to know the pharmacokinetics and pharmacodynamics of the drug. Regarding the 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 as well with 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. Total clearance of the drug is 3.6L/h. Usually fractionation of the drug results in faster rates of elimination.

The most common dose administered is 1.2 gm/m/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 hematological recovery. Drug levels can be measured in the urine by gas chromatography-mass spectrometry.[21] The 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 as the drug undergoes renal elimination.[22] Dose reduction is to 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.[23]

The dose also needs to be adjusted according to the toxicity profile. Instances of severe leukopenia or thrombocytopenia require dosage reduction. In case more severe toxicity such as encephalopathy probably requires termination of therapy.

Toxicity

Most of the toxicities of ifosfamide are from its active metabolites. Acrolein plays a significant role in causing major renal and bladder related toxicities. As the kidneys filter these metabolites, they generate reactive oxygen species and nitrogen compounds which results in damage to the renal as well as 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 the bone marrow. Specific case reports have shown an association between ifosfamide and Fanconi syndrome. It results in cardiac toxicity and can cause pneumonitis. These toxicities include:  

1. Hemorrhagic cystitis

The main adverse effects for years has been hemorrhagic cystitis. The theory behind it was during its hepatic metabolism, a product named acrolein was produced which was excreted by the kidneys and accumulates in the bladder.[19] Through its apoptotic properties and production of multiple ROS as well as nitric oxide, it results in the release of numerous cytokines which cause ulceration of the bladder epithelium. As a result, it causes 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 urothelium and results in a non-toxic product for excretion in the urine. It is always important to prevent the development of cystitis rather than treating it. The current treatment options available are continuous bladder irrigation, intravesicular infusion of ammonium potassium sulfate and formalin, and in some instances cystectomy.[19] Mesna should be administered before, during and after ifosfamide along with aggressive hydration (at least 2 liters oral of IV form) per day to prevent urotoxicity.

2. Neurotoxicity

 Central nervous system toxicity appears as encephalopathy with varying severity (confusion, hallucinations, drowsiness, coma). It presents in about 30% of the cases.[24] The mechanism is unknown, and the symptoms occur with administration of high doses of the drug either orally or intravenously but more with oral administration.[24] Usually, the symptoms present within 2 to 96 hours after drug administration and are reversible within 48 to 72 hours after discontinuation of the drug.[15] The mechanism of neurotoxicity is still unknown. Risk factors associated for development of neurotoxicity include oral administration, previous chemotherapy with cisplatin, impaired renal and hepatic function, low albumin and brain metastasis. Recent studies showed the utilization of methylene blue for both treatment and prophylaxis of ifosfamide-induced encephalopathy.[25] Methylene blue helps in the reversal of symptoms within 24 hours of its administration. As prophylaxis, the severity of symptoms has reduced when compared to previous cycles and can restore the therapy with ifosfamide. The dosage of methylene blue is 50 mg orally in 5% glucose solution every four hours till recovery.[15] 

3. Hematological toxicity 

A dose-limiting toxicity is myelosuppression. 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; this allows starting the next cycle in around three weeks after the first treatment. This effect is dose-related. Incidence of myelosuppression is low when fractionated doses are used rather than higher doses.[26] At a dose of 1.2gm/m^2/day for five days, the white cell count is below 3 x 109/L, and platelet count below 20000 occurs in 30% of cases.[26]

4. 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. Clinically manifested as metabolic acidosis, polyuria, and renal phosphate wasting. Seen in about 5% of cases.[27] Supplementation with vitamin D and phosphate is essential in the pediatric population affected. Etiology remains unclear.

4. Miscellaneous toxicities: There are reports of arrhythmias, heart failure and pulmonary toxicity in the form of pneumonitis.[28]

5. Malignancy of ureter and bladder: There have been case reports which demonstrated a 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, but even more so with a chemotherapeutic agent like ifosfamide. Nursing is helpful in closely watching the patient during and after drug administration, identifying the adverse reactions and reporting them immediately. Oncology nurses are specially trained to administer chemotherapy. The role of pharmacists is crucial as they help formulate the dosing as well as monitor them for potential toxicity. For better outcomes, plan needs to be discussed in detail among all the members involved in patient care like nurses, pharmacists, physicians as well as family to lower the mortality and morbidity. [Level V]


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Ifosfamide - Questions

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A 16 year old was recently diagnosed with germ cell tumor of the testis. He was started on a chemotherapy combinations containing ifosfamide. The patient developed gross hematuria a week after completion of chemotherapy and was subsequently diagnosed with hemorrhagic cystitis. Which of the following steps would have prevented the above mentioned complication?



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Ifosfamide - References

References

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