Cyclophosphamide

Mechanism of Action

Cyclophosphamide is a type of nitrogen mustard drug which exerts its effects through the alkylation of DNA. The drug is not cell-cycle phase-specific and metabolizes to an active form capable of inhibiting protein synthesis through DNA and RNA crosslinking. [1][2]

The majority of the antineoplastic effects of cyclophosphamide are due to the phosphoramide mustard formed from the metabolism of the drug by liver enzymes like cytochrome P-450. Hepatic enzymes first convert cyclophosphamide to hydroxycyclophosphamide and then subsequently metabolized to aldophosphamide. Aldophosphamide is cleaved to the active alkylating agent phosphoramide mustard and acrolein. The phosphoramide metabolite forms cross-linkages within and between adjacent DNA strands at the guanine N-7 position. These modifications are permanent and eventually lead to programmed cell death.[4] Acrolein has no antitumor activity but is the principal-agent responsible for the manifestation of hemorrhagic cystitis.

In addition to antimitotic and antineoplastic effects, cyclophosphamide has immunosuppressive effects and selectivity for T cells. High-dose cyclophosphamide is used in eradication therapy of malignant hematopoietic cells, while lower dosages have shown merit for use in selective immunomodulation of regulatory T cells. The drug decreases the secretion of interferon-gamma and IL-12 while increasing the secretion of Th2 cytokines like IL-4 and IL-10 in the CSF and peripheral blood.[5][6] Due to these effects, cyclophosphamide is considered as a valuable addition to tumor vaccination protocols, post-transplant alloreactivity management, and the treatment of immune-mediated conditions and some forms of vasculitis.[7][1][2]While the precise mechanism with which cyclophosphamide exerts its immunomodulatory effects are not completely clear, several studies have suggested a few probable modes of action. These include the elimination of regulatory T cells in naïve or malignant host cells, the induction of T cell growth factors like type I interferons, and preconditioning host cells for donor T cells, thus reducing alloreactivity.[5][7][6]

Administration

In the treatment of a variety of malignancies, clinicians use cyclophosphamide in combination with other chemotherapeutic agents. It is often included in standard treatment regimens for Hodgkin and non-Hodgkin lymphoma as a component of CHOP along with hydroxydaunorubicin, oncovin, and prednisone. If the malignancy has B-cell involvement, rituximab, and an anti-CD-20 monoclonal antibody, it is added to the CHOP regimen (called R-CHOP).[5][8][9]Cyclophosphamide has also been used in combination with corticosteroids in the treatment of multiple myeloma, chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, neuroblastoma, retinoblastoma, small cell lung cancer, and various types of sarcoma. As cyclophosphamide exerts immunosuppressive properties in addition to its anti-neoplastic effects, it is indicated in the management of other immune conditions such as severe multiple sclerosis and nephrotic syndrome.[10][11]

Cyclophosphamide is often orally administered, and the length of treatment and dosage depends upon individual factors such as metabolism, drug interactions, body mass, and age of the patient. There are standard guidelines available for the appropriate dosage and indications depending upon the goal of treatment. The general recommendation for patients without hematological deficiencies is an induction dose of IV cyclophosphamide of 40 to 50 mg/kg divided into dosages over 2 to 5 days. The maintenance dosage is dependent upon individual tolerance but is generally 1 to 5 mg/kg taken orally every day. A daily oral dose of 2 to 3 mg/kg is recommended for pediatric patients. It should not be taken for more than 90 days to avoid hemorrhagic cystitis and sterility risk in males. The recommendation for the oral formulation is that it be taken at the same time every day, usually in the morning, with liquid. If GI irritation is noted, the tablet can be taken with food.[10][4]While taking cyclophosphamide, an adequate intake of fluids is necessary to precipitate diuresis to reduce the risk of urinary tract side effects. To avoid the side effect of hemorrhagic cystitis, maintain a minimum urinary output of 100 mL/hr during therapy.[9]

Mesna is a prophylactic cytoprotective drug administered orally or by IV to reduce the effects of hemorrhagic cystitis in patients treated with high-dose cyclophosphamide or ifosfamide. The recommended dosage of Mesna is generally as a fractionated dosing schedule of three IV bolus injections of 240 mg per meter cubed every 4 hours.[3][4]

Adverse Effects

The main areas of concern regarding the adverse side effects of cyclophosphamide are associated with bladder and gonadal toxicity. Common adverse side effects reported in several studies and clinical trials involving the use of cyclophosphamide include hemorrhagic cystitis, amenorrhea, myelosuppression, alopecia, and spells of nausea and vomiting. [12][13][2]Chronic or recurrent hemorrhagic cystitis is a side effect of particular clinical significance and may arise from the use of cyclophosphamide without adequate hydration or concurrent administration of mesna. The limiting factor in cyclophosphamide dosage in the treatment of neoplasms and immune-inflammatory conditions is urinary tract toxicity.  The severity of hemorrhagic cystitis may vary from light pinkish to exsanguinating hemorrhage. Other urinary tract symptoms include increased urinary frequency and urgency due to urinary clot retention, nocturia, and dysuria.[12][7][3]As previously outlined, acrolein is the principal-agent involved in the precipitation of hemorrhagic cystitis. The metabolite causes heightened vascular fragility and dilatation, irritation of the bladder mucosa, the release of pro-inflammatory mediators like tumor necrosis factor-alpha, IL-1 beta, and endogenous nitric oxide leading to hemorrhage. Prolonged exposure to acrolein may increase the severity of hemorrhagic cystitis. Due to the dose and time-dependent nature of the severity of this symptom, th recommendation is that the patient intake adequate fluids to force diuresis and reduce exposure of urothelium to acrolein. Continuous bladder irrigation and mesna use are also helpful in the management of drug-induced hemorrhagic cystitis.[5][12][6]

Cyclophosphamide can cause myelosuppression leading to the development of sepsis and septic shock. Antibiotic therapy and additional surveillance may be warranted at the discretion of the treatment team.There are also reports of cardiotoxicity, pulmonary toxicity, veno-occlusive liver disease, and secondary malignancies in some cases of cyclophosphamide use. Myocarditis, pericardial effusion with cardiac tamponade, pneumonitis, and respiratory failure are possible risks. Higher dosages of cyclophosphamide are associated with a greater incidence of these side effects and increased mortality.[13][10][2]

The alkylating effects of cyclophosphamide may also affect the processes of oogenesis and spermatogenesis, leading to sterility in both sexes. The risk of sterility of time and dose-dependent and is irreversible in some patients. Sterility may manifest as amenorrhea in women and testicular atrophy in men. Patients should receive adequate education on the risks of infertility before initiation of cyclophosphamide therapy.[12][7]

Contraindications

As with any drug, the use of cyclophosphamide is not recommended in patients with allergies or hypersensitivity reactions to the drug or any of its metabolites. Deaths from anaphylactic reactions, as well as adverse interactions with other chemotherapy drugs like busulfan or chlorambucil, have been reported.Patients with urinary flow obstructive conditions should not take cyclophosphamide due to an increased risk of developing hemorrhagic clot retention.[12][10][2][14]

Pregnant or nursing women should not take cyclophosphamide as the use of the drug has been associated with embryo-fetal toxicity. Cyclophosphamide is present in breast milk, and exposure may cause congenital disabilities, delayed development, and fetal death. It is a strong recommendation that female patients receiving treatment with cyclophosphamide avoid pregnancy during treatment and use contraceptive measures during treatment and up to a full year following completion of treatment.[12][7][13]

Monitoring

The monitoring of complete blood counts in patients is an essential part of the management of cyclophosphamide toxicity. As cyclophosphamide can cause myelosuppression, it should not be used in patients with lab values of neutrophils of 1500/mm^3 or less and platelets less than 50000/mm^3. CBC values should be monitored in addition to the administration of G-CSF to reduce the effects of neutropenia and infection risk.[4][15][16]Before the induction of cyclophosphamide treatment, any urinary obstructions should be corrected or excluded. Urinalysis is also a recommendation to evaluate for the presence of hematuria, proteinuria, or bacterial infections. Patients also require monitoring for signs and symptoms of cardiotoxicity, pulmonary toxicity, and history of pre-existing cardiac disease. These tests may include tests for cholesterol, lipids, and triglycerides. The gold-standard test is generally considered to be an angiogram taken during cardiac catheterization or non-invasively via computed tomography.[5][12][13][17][14]

Patients experiencing severe symptoms of cyclophosphamide toxicity may be taken off the medication or have their dose reduced by their physician.[12][18][3][16]

Toxicity

Clinicians need to consider possible side effects, interactions, and associated toxicities should before administering cyclophosphamide. As an immunosuppressive agent, cyclophosphamide toxicity correlates with the development of leukopenia, thrombocytopenia, and anemia. These conditions may lead to the occurrence of recurrent infections and may interfere with wound healing. Other symptoms of cyclophosphamide toxicity include GI disturbances, alopecia, hemorrhagic cystitis, renal tubular necrosis, infertility, pulmonary fibrosis, and cardiotoxicity. The manifestation of cyclophosphamide toxicity becomes aggravated by concurrent use of phenobarbital, other myelosuppressives, radiation, and succinylcholine.[19][20]

To minimize the negative effects of cyclophosphamide toxicity, recommendations include monitoring the patient’s hematologic profile and modification of treatment as needed. Patients should maintain adequate hydration, and mesna can be prescribed as prophylaxis against the development of hemorrhagic cystitis. If overdose is suspected, the patient or caregiver must seek emergency medical attention immediately.[20]

Enhancing Healthcare Team Outcomes

In the development of professional health care delivery, the ability of interprofessional health care providers to work as a cohesive unit has been proven to increase the quality of patient care and increase positive prognostic outcomes. This paradigm is achieved through integrated patient-centered care, sharing of values, communication, and a clear definition of interprofessional responsibilities.[21][22]

In the modern health care environment, patients rely on effective teamwork within a team of health professionals. This methodology should include primary care providers, oncologists, specialty care nurses, and oncologic pharmacists. Effective communication minimizes errors and potential adverse events. Various studies on effective leadership and team development have supported Tuckman’s stages of group development. In this model, a team undergoes four stages: forming, storming, norming, and performing. Passing through all of these stages is both necessary and inevitable for an effective team to form. Following this process, the members of the team are better able to assess their roles and the roles of others on the team. Each member possesses specialized skills and knowledge complementary to the others, allowing for heightened patient care.[23]

This coordination is key in the appropriate use of cyclophosphamide. Adhering to the Team-Based Competencies set forth by the Interprofessional Education Collaborative, including honesty, discipline, and mutual goals, the healthcare team, is better able to assess the appropriate management of cyclophosphamide use. On an organizational level, enhanced teamwork can lead to reduced time and costs associated with hospitalizations, reduced unexpected admissions, and increased ease of access to services. From a patient’s perspective, effective teamwork means increased satisfaction with care, improved prognosis, and a reduction in medical error.[22] [Level 1]

Interprofessional team dynamics in using cyclophosphamide include the prescriber deciding it is the appropriate agent for the patient, but that is only the beginning. A board-certified oncology pharmacist should be consulted regarding potential drug interactions, appropriate dosing, and have involvement in the ongoing monitoring of the patient. Once on the drug, oncology specialty nurses should have involvement in monitoring the patient for treatment progress as well as adverse drug reactions and can reach out to the oncology pharmacist and/or the oncologist as appropriate. These interprofessional examples will result in better outcomes with cyclophosphamide. [Level 5]