Removing Mesna From Cyclophosphamide Cycles in VAdriaC-IE for Ewing Sarcoma

Précis

This retrospective cohort study provides preliminary evidence for safe removal of mesna from VAdriaC cycles, as the incidence of hemorrhagic cystitis did not increase in patients with Ewing sarcoma who received cyclophosphamide without prophylactic mesna.

Abstract

Objectives

The primary objective was to compare the incidence of hemorrhagic cystitis (HC) in patients who did vs did not receive prophylactic sodium 2-mercaptoethanesulfonate (mesna) with cyclophosphamide-containing cycles of VAdriaC-IE (vincristine, doxorubicin [Adriamycin], and cyclophosphamide, followed by ifosfamide and etoposide). The secondary objective was to quantify the cost savings and opportunity cost of this change.

Study Design

This was a single-center, retrospective cohort study of adults with Ewing sarcoma who were treated between June 2017 and June 2023.

Methods

Patients were eligible for inclusion if they were older than 18 years and had received at least 1 cycle of VAdriaC-IE at Vanderbilt University Medical Center. Patients (N = 34) were separated into 2 cohorts: those who received prophylactic mesna with cyclophosphamide (n = 22) and those who did not (n = 12).

Results

The incidence of HC was zero in both the nonmesna cohort and mesna cohort, with no statistically significant differences in the rates of gross hematuria (8% vs 9%, respectively; P = .941), irritative voiding (17% vs 9%; P = .512), or urinary incontinence (0% in both). Not administering prophylactic mesna with cyclophosphamide-containing cycles of VAdriaC-IE resulted in an estimated institutional pharmacy cost savings of $9259.32 per year and an estimated opportunity cost of $270,816 per year for the infusion center.

Conclusion

Removal of prophylactic mesna from VAdriaC did not increase the incidence of HC or associated urinary symptoms in patients with Ewing sarcoma. This study’s findings do not support the use of prophylactic mesna with VAdriaC and provide preliminary evidence that mesna can be safely removed from these cycles. Potential benefits of not administering mesna with VAdriaC include reduced patient and institutional pharmacy costs, increased opportunity cost for the infusion center, and improved patient quality of life due to less time spent in the health care system and reduced financial toxicity.

Introduction

The alkylating agents cyclophosphamide and ifosfamide are structurally related oxazaphosphorines that are widely used in the treatment of pediatric and adult malignancies and for certain nonmalignant conditions. These agents are associated with numerous toxicities, most notably hemorrhagic cystitis (HC), which is a diffuse inflammatory condition of the urinary bladder that results in bleeding from the bladder mucosa and gross hematuria.1 Cyclophosphamide- and ifosfamide-induced HC are secondary to the urotoxic metabolite acrolein that concentrates in the bladder and leads to sloughing of the bladder mucosa.^1,2

The overall reported incidence of HC with cyclophosphamide and ifosfamide varies widely from 0% to 50% among studies due to poorly defined diagnostic criteria and presence of confounding variables; however, the incidence of HC is lower with cyclophosphamide than with ifosfamide.³ The risk of HC following cyclophosphamide administration is dose dependent because the incidence of HC increases with higher doses of cyclophosphamide, specifically doses greater than or equal to 50 mg/kg or 2 g/m2 used in stem cell transplant conditioning regimens.^3-6 Other risk factors for HC following cyclophosphamide administration include radiation to the pelvic region; history of stem cell transplantation; viral infection with BK virus, adenovirus, or cytomegalovirus; and genetic polymorphisms in genes involved with cyclophosphamide metabolism.^5-7

Sodium 2-mercaptoethanesulfonate (mesna) is a synthetic sulfhydryl, or thiol, compound that inactivates the urotoxic metabolite acrolein to reduce the risk of bladder irritation (Figure). The free thiol groups of mesna bond directly to acrolein via a double bond, causing a conjugation reaction that creates a nontoxic thioether that is excreted in the urine.⁸ Concomitant use of mesna with ifosfamide has been shown to reduce the risk of macroscopic and microscopic hematuria^9-12; however, using mesna with cyclophosphamide vs saline diuresis has produced mixed results.^13-16 According to historical guidance from the American Society of Clinical Oncology (ASCO), the use of mesna is recommended with all dose levels of ifosfamide to reduce the risk of urothelial toxicity but is recommended only with high doses of cyclophosphamide used in the setting of stem cell transplantation.¹⁷

Ewing sarcoma is a rare, aggressive bone cancer that most often occurs in adolescents and young adults.18 The prognosis for localized Ewing sarcoma has significantly improved with the addition of intensive, multiagent chemotherapy for local control.¹⁸ Incorporating ifosfamide and etoposide (IE) into the chemotherapy regimen VAdriaC (vincristine, doxorubicin [Adriamycin], and cyclophosphamide) was first studied in 1996 by Wexler et al and demonstrated a significant improvement in outcomes in patients with localized, high-risk Ewing sarcoma.¹⁹ Based on results from Wexler et al19 and additional studies,^20,21 VAdriaC-IE is the preferred regimen for first-line treatment of Ewing sarcoma per National Comprehensive Cancer Network Guidelines.²² In these studies of VAdriaC-IE for Ewing sarcoma, prophylactic mesna was used with all doses of ifosfamide and cyclophosphamide, despite dosing cyclophosphamide at only 1200 mg/m².^19-21

Because VAdriaC-IE has continued to be a standard-of-care primary treatment for Ewing sarcoma, our institution included prophylactic mesna with all ifosfamide and cyclophosphamide doses to align with published protocols but removed it from VAdriaC cycles of adult sarcoma VAdriaC-IE treatment plans based on ASCO recommendations¹⁷ in February 2021. The objective of this study was to compare the incidence of HC in patients who received prophylactic mesna with cyclophosphamide vs those who did not and to quantify the economic impact of this change.

Study Design

This was a single-center, retrospective cohort study of adults with Ewing sarcoma who were treated at Vanderbilt University Medical Center (VUMC) between June 2017 and June 2023. Patients were eligible for inclusion if they were older than 18 years and had received at least 1 cycle of VAdriaC-IE at VUMC. Upon study inclusion, patients were separated into 2 cohorts: those who received prophylactic mesna with cyclophosphamide and those who did not. The primary outcome of this study was the incidence of HC. Secondary outcomes were rates of irritative voiding and urinary incontinence as well as the quantification of the cost savings and opportunity cost of removing prophylactic mesna from cyclophosphamide-containing cycles of VAdriaC. This study was approved by the institutional review board at our institution with waiver of informed consent.

Methods

Patients were identified via a pharmacy informatics database query of the electronic medical record and were included if they had an active treatment plan at VUMC for VAdriaC-IE between June 2017 and June 2023. After the patient query was generated, the primary investigator performed manual chart review of the electronic medical record for every patient to determine eligibility for study inclusion and to collect pertinent points for analysis. The primary investigator deidentified all patient data for patients included in the study and stored the data in a secure REDCap database. Patient demographic data and disease characteristics, such as the primary location of disease, were collected. Data were also collected on treatment regimen characteristics for each patient, including dosing body weight, dosing body surface area, dosing intensity, number of total cycles completed, total amount of cyclophosphamide received, number of treatment delays, and dose reductions. Preexisting risk factors for HC that were collected included urinary issues, pelvic involvement of disease, previous chemotherapy or radiation therapy, history of BK virus infection, previous stem cell transplant, history of graft-vs-host disease, and concomitant immunosuppressive medication and/or steroid use during treatment. Lastly, data were collected on symptoms of HC, including gross hematuria, irritative voiding, and urinary incontinence.

Identification of urinary symptoms and diagnosis of HC were determined from progress-note documentation in the electronic medical record. Diagnosis of HC required confirmation through cystoscopy and biopsy of the bladder epithelium. Grading of HC severity was based on Common Terminology Criteria for Adverse Events version 5.0 for noninfective cystitis (Supplementary Appendix).²³

Infusion chair time was defined as the amount of time the patient occupies a room in the infusion center for the purpose of receiving cancer treatment. The estimated value of infusion chair time in our infusion center ($2015 per patient) was divided by the average length of infusion for all patients (2.5 hours), resulting in an estimated chair time value of $806 per hour for this study. For the basis of the pharmacy cost-savings calculations, we used average wholesale pricing (AWP) for 1-g mesna vials ($7.96/vial) and 400-mg mesna tablets ($94.31/tablet).

VAdriaC-IE regimen components

VAdriaC-IE was given as 14 cycles of alternating VAdriaC and IE, with VAdriaC administered on odd-numbered cycles and IE administered on even-numbered cycles. The length of each cycle was 14 days or 21 days (physician discretion). Routine monitoring for hematuria was performed via urinalysis on day 1 of every VAdriaC cycle and every day of each IE cycle.

VAdriaC cycles consisted of the following:

• intravenous (IV) vincristine 1.5 mg/m2 given over 10 minutes;
• IV doxorubicin 75 mg/m2 given over 5 to 15 minutes;
• and IV cyclophosphamide 1200 mg/m2 given over 60 minutes.

For the mesna-containing protocol, IV mesna 240 mg/m² was given over 15 minutes at hour 0 and hour 4 following cyclophosphamide administration, and mesna 480 mg/m² orally was given at hour 6 following cyclophosphamide administration.

All agents in VAdriaC were given on day 1 of each cycle. Hydration with normal saline 0.9% 1000 mL given over 120 minutes began 60 minutes prior to cyclophosphamide administration. Antiemetic premedications were given 30 minutes prior to beginning the vincristine infusion and consisted of dexamethasone 12 mg orally, ondansetron 16 mg orally, and aprepitant 130 mg intravenously.

Based on the assumption that only 2 doses of IV mesna would be given in the infusion center, the total time spent in the infusion center at VUMC per patient was approximately 5 hours per VAdriaC cycle.

IE cycles consisted of the following:

• IV etoposide 100 mg/m2 given over 60 minutes;
• IV ifosfamide 1800 mg/m2 given over 60 minutes;
• IV mesna 360 mg/m2 given over 15 minutes at hour 0 and hour 4 following ifosfamide cyclophosphamide administration;
• and oral mesna 720 mg/m2 at hour 6 following ifosfamide administration.

All agents in IE were given on days 1 through 5 of each cycle. Hydration with normal saline 0.9% 2000 mL given over 120 minutes began 30 minutes prior to ifosfamide administration. Antiemetic premedications were given 30 minutes prior to beginning the ifosfamide infusion and consisted of dexamethasone 12 mg orally and ondansetron 16 mg orally. Based on the assumption that only 2 doses of IV mesna would be given in the infusion center, the total time spent in the infusion center per patient was approximately 5 hours per day for each IE cycle.

Statistical Analysis

Because of the retrospective nature of this study, we used descriptive statistics to analyze our findings. A Pearson test was used to explore the differences in rates of HC as well as potentially confounding factors for HC development such as preexisting urinary problems, pelvic involvement of disease, history of BK virus, and previous chemotherapy and/or radiation therapy.^5-7 We used a Wilcoxon test to explore potentially confounding factors for HC development such as patient weight used for cyclophosphamide dosing, total number of VAdriaCIE cycles received, and total amount of cyclophosphamide received. Categorical variables were summarized with percentages and frequencies, and continuous variables were summarized with medians and IQRs. The threshold to detect a significant difference between the 2 groups was a P value less than .05.

Results

Forty-one patients were screened for inclusion in the study, and 34 patients were included and put into 2 cohorts: those who received mesna with cyclophosphamide cycles (n = 22) and those who did not (n = 12). Baseline characteristics of study participants are summarized in Table 1. Overall, median age was 29 years (range, 19-70), 17 (50%) patients were female, and 30 (88%) patients were White. The most common HC risk factor in both groups was pelvic involvement of disease, which was present in 7 (58%) patients in the nonmesna group and 5 (23%) patients in the mesna group. No significant differences were identified in demographic data, baseline HC risk factors, or treatment regimen characteristics between the 2 groups; however, there were notable numerical—though not statistically significant—differences in certain treatment regimen characteristics between the 2 groups. More patients in the mesna group completed all planned cycles of treatment (64% vs 50% in the nonmesna group), received more total cycles of treatment (14 cycles vs 9 cycles, respectively), and received more total cyclophosphamide.

The primary outcome of incidence of HC was zero in both groups, and there were no statistically significant differences in the rates of gross hematuria (8% vs 9%; P = .941), irritative voiding (17% vs 9%; P = .512), or urinary incontinence (0% in both groups) (Table 2). The calculations to quantify the cost savings and opportunity cost of removing prophylactic mesna from cyclophosphamide are detailed in the Supplementary Appendix. Operating under the assumption (based on historical trends) of treating 12 patients per year with VAdriaC-IE, with VAdriaC administered on the 7 odd-numbered cycles, the total estimated annual cost savings for the pharmacy department was $9259.32 based on AWP of IV and oral mesna and the estimated opportunity cost for the infusion center of removing prophylactic mesna from cyclophosphamide cycles was $270,816 per year.

Discussion

The removal of prophylactic mesna from cyclophosphamide-containing cycles in VAdriaC-IE did not increase the incidence of HC, gross hematuria, irritative voiding, or urinary incontinence in patients with Ewing sarcoma. The annual pharmacy cost savings of this change was $9259.32, and the annual opportunity cost for the infusion center associated with this change was approximately $270,816 based on treating 12 patients per year with VAdriaC-IE.

Multiple studies have demonstrated that mesna is not more effective than saline diuresis for preventing cyclophosphamide-induced HC. Shepherd et al and Bedi et al randomly assigned patients undergoing conditioning regimens for bone marrow transplant to receive mesna or forced saline diuresis for uroprotection against cyclophosphamide-induced HC and found no difference in the incidence of HC.^14,24 Similarly, Gonella et al retrospectively studied bone marrow transplant patients who received cyclophosphamide and found no correlation between mesna use and HC development.²⁵ Additionally, Tsuboi et al conducted a retrospective multivariate analysis of risk factors for HC following hematopoietic stem cell transplantation and found that prophylactic mesna administration anecdotally increased the risk of early-onset HC.²⁶ In the largest trial to date comparing mesna vs no mesna with cyclophosphamide, Yilmaz et al retrospectively studied 1018 patients receiving cyclophosphamide for rheumatologic conditions and found no difference in the incidence of HC, regardless of mesna use.²⁷ Our study similarly demonstrated no difference in the incidence of HC between patients who received mesna and those who did not, which supports the existing literature that mesna is no more effective than supportive hydration when given with cyclophosphamide.

Zero patients experienced HC in our study, regardless of the receipt of mesna. The absence of HC could be explained by the requirements needed to satisfy an HC diagnosis in our study; however, only 9% of all patients in our study experienced gross hematuria. Also, numerically more patients in the mesna group completed planned treatment, received more cycles of treatment, and received more total cyclophosphamide, although none of these differences were statistically significant. These numerical differences are most likely due to more patients in the nonmesna group transferring their care to a local oncologist, having a change in diagnosis that prompted a treatment change, or still being on active treatment at the time of data collection. Additionally, the dose of cyclophosphamide used in VAdriaC-IE at our institution is 1200 mg/m², so our study findings support the existing literature that cyclophosphamide doses less than those used in stem cell transplantation (< 50 mg/kg or 2000 mg/m²) are associated with low overall rates of HC. Our findings also support the ASCO recommendation that prophylactic mesna is not needed with cyclophosphamide doses that are less than those used in stem cell transplantation.¹⁷

The impact of removing prophylactic mesna from cyclophosphamide doses in VAdriaC-IE extends beyond clinical outcomes. The removal of mesna from cyclophosphamide cycles resulted in patients spending at least 4 fewer hours in the infusion center per VAdriaC cycle—and 56 fewer hours in infusion overall. This could positively impact quality of life by allowing patients to spend less time in the health care system and more time doing activities they value. Additionally, removing mesna from cyclophosphamide doses in VAdriaC-IE eliminates the need to coordinate outpatient prescriptions for oral mesna, which may result in even less time spent in the health care system as well as a reduction in financial toxicity.

In contrast, there are potential risks of removing mesna from cyclophosphamide-containing cycles in VAdriaC-IE, such as hemorrhagic cystitis and its sequelae, which include gross hematuria, irritative voiding, renal function impairment, potential need for hospitalization, and potential delay in receiving curative treatment. Although these risks exist, the incidence of HC in the cohort who did not receive mesna with cyclophosphamide was zero.

To our knowledge, this is the first study analyzing the effect of removing mesna from cyclophosphamide cycles for Ewing sarcoma treatment. Most existing data are focused on bone marrow transplant patients or on those with nonmalignant diseases; therefore, our study addresses mesna utility in a unique patient population. A major strength of our study is that the baseline characteristics and presence of confounding variables that would potentially increase the risk of HC were similar between the 2 study groups. Another strength is that 35% of patients had pelvic involvement of disease, representing a population at higher risk of HC. Lastly, this is the first study to our knowledge to report the potential financial impact of removing prophylactic mesna from cyclophosphamide doses.

Limitations

Our study had limitations. The retrospective nature of this study may limit the external validity of our findings by not being able to control for all confounding variables and being able to collect only data in the electronic medical record. We also were not able to assess the impact on quality of life between cohorts. In addition, our study was a single-center analysis, which may limit the applicability of our findings to only high-volume sarcoma centers such as ours. The single-center nature of our study also limits the applicability of our findings to institutions that use a similar regimen for mesna administration. Institutions that administer only 1 dose of mesna in the infusion center and the last 2 doses in the outpatient setting would not have as substantial of an opportunity cost or cost savings as seen in our findings. Also, the use of AWP to evaluate cost savings may overestimate the true savings realized by the pharmacy because pharmacy reimbursement is not incorporated in AWP. We used AWP to describe cost savings to provide the most universal estimate because patient-specific insurance and reimbursement will be heterogenous based on the specific plan and patient.

Conclusion

This study provides preliminary evidence for safe removal of mesna from VAdriaC cycles during Ewing sarcoma treatment. Removal of prophylactic mesna did not increase the incidence of HC, hematuria, irritative voiding, or urinary incontinence. Potential benefits of removing mesna from cyclophosphamide cycles include an improvement in patient quality of life due to less time spent in the health care system and the potential for reduced financial toxicity, patient and institutional pharmacy cost savings, and an increase in opportunity cost for the infusion center. Future studies should explore these findings in a larger population.

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The authors have nothing to disclose.