Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseasesA data-driven review.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 62, No. 1, January 2010, pp 9–21 DOI 10.1002/art.25061 © 2010, American College of Rheumatology REVIEW Incidence and Prevention of Bladder Toxicity From Cyclophosphamide in the Treatment of Rheumatic Diseases A Data-Driven Review Paul A. Monach, Lindsay M. Arnold, and Peter A. Merkel agents in carrying an increased risk of both common and opportunistic infections, teratogenicity, sterility, and secondary hematologic malignancy. Cyclophosphamide, and the related agent ifosfamide, can also cause toxicity to the urinary bladder, including hemorrhagic cystitis and bladder cancer (10,11). The prospect of preventing these serious bladder toxicities with mesna (2mercaptoethanesulfonic acid) has led to the common use of this agent, which is considered safe and is frequently recommended in textbooks and clinical guidelines for routine use (5,12–14). Thus, it is relevant and timely to review the data on the bladder toxicity of cyclophosphamide, with a focus on the rheumatic diseases, in order to review the rationale and evidence for prescribing mesna to prevent such bladder toxicity and to outline practical recommendations for the use of mesna in the rheumatology setting. Introduction Cyclophosphamide has been used since the 1960s to treat severe manifestations of autoimmune inflammatory diseases such as systemic lupus erythematosus, systemic vasculitis, and systemic sclerosis (scleroderma) (1–4). This alkylating agent, which is considered to be the “strongest” medication commonly used by rheumatologists, has well-established efficacy in lupus nephritis and systemic necrotizing vasculitis, conditions for which it became regarded as the standard of care by the 1980s (1,2,5). Cyclophosphamide continues to be used regularly, in clinical practice and in clinical trials, to treat other severe manifestations of lupus, lung disease in scleroderma, many types of vasculitis, and other systemic inflammatory diseases (4,6–9). Despite the development of and interest in other agents to treat severe inflammatory disease, cyclophosphamide is unlikely to be consigned to the status “of historic interest only” any time soon. Although the doses of cyclophosphamide prescribed in autoimmune diseases are lower than the doses typically prescribed for cancer chemotherapy, in rheumatic diseases the drug is often used for extended periods of time and, due to a high rate of clinical relapse, treatment often requires repeated courses. Cyclophosphamide resembles many other chemotherapeutic Medical literature search strategy Articles related to the association of cyclophosphamide with hemorrhagic cystitis and bladder cancer were initially identified using the following search parameters in PubMed (www.ncbi.nlm.nih.gov): [cyclophosphamide AND (cystitis OR bladder cancer) AND (vasculitis OR arteritis OR granulomatosis OR rheumatoid OR lupus OR scleroderma OR non-Hodgkin’s)]. This search yielded 157 articles, the abstracts of which were reviewed, yielding 19 articles that either contained primary data on more than a few patients or reviewed older literature. A review of the references in these 19 articles revealed only 2 other studies containing additional primary data. Articles related to the use of mesna to prevent cystitis were initially identified using the following search parameters in PubMed: [(cyclophosphamide OR Dr. Monach’s work was supported in part by an Arthritis Investigator Award from the Arthritis Foundation. Paul A. Monach, MD, PhD, Lindsay M. Arnold, PharmD, BCPS, Peter A. Merkel, MD, MPH: Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts. Address correspondence and reprint requests to Paul A. Monach, MD, PhD, Vasculitis Center, E5, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118. E-mail: firstname.lastname@example.org. Submitted for publication February 24, 2009; accepted in revised form September 25, 2009. 9 10 MONACH ET AL ifosfamide) AND cystitis AND mesna]. This search yielded 164 articles, the abstracts of which were reviewed, yielding 15 articles that included primary data or reviewed the data (much of it unpublished) related to US Food and Drug Administration (FDA) approval of oral mesna (15). An evaluation of the articles referenced in this latter review as well as in a clinical practice guideline for the use of chemotherapy and radiotherapy protectants (16) yielded only 2 articles containing additional primary data. A search of the Cochrane Database of Systematic Reviews using “mesna” as a key word yielded 4 articles, none of which was related to cyclophosphamide or ifosfamide and bladder toxicity. A search using “cyclophosphamide” as a key word yielded 101 articles, only 1 of which focused on adverse events (secondary malignancies); a review of this article did not identify additional studies relevant to the present topic. Information pertaining to the pharmacology of cyclophosphamide, its metabolites, and mesna was obtained from textbooks and reviews and from references obtained from these sources. Cyclophosphamide pharmacology Cyclophosphamide is an oxazophosphorine alkylating agent that causes crosslinking of DNA strands, thereby preventing cell division and causing cell death. Cyclophosphamide has major activity against rapidly proliferating cells that is not cell cycle specific, and its mechanism in treating autoimmune disease is not well understood. Mechanisms postulated include apoptosis induction, decreased IgG production due to B cell suppression, and decreased production of adhesion molecules and cytokines (17). Cyclophosphamide is a prodrug metabolized via the hepatic P450 enzymatic system to both active and inactive metabolites, as outlined in Figure 1. Among these, the inactive (nonalkylating) metabolite acrolein (18) is presumed to be the cause of cystitis, based on its subsequent excretion into and concentration in the urine and on direct evidence of acute bladder toxicity in animals (19–21). Acrolein is considered likely to be the cause of bladder cancer as well, although there is no direct evidence to support this. The great majority of bladder cancers that arise following cyclophosphamide treatment, as with idiopathic bladder cancers, are transitional cell carcinomas, but rare cases of sarcomas and other types of bladder carcinoma have been reported (22–24). Oral and intravenous (IV) administration of cyclophosphamide have been reported to produce similar Figure 1. Chemical structures, metabolism, and interactions of cyclophosphamide and mesna. Phosphoramide mustard is the main active (alkylating) metabolite of cyclophosphamide, and acrolein is the inactive metabolite thought to be responsible for bladder toxicity. Conversion of aldophosphamide to phosphoramide mustard and acrolein occurs in the plasma. Acrolein is then excreted into the urine, and phosphoramide mustard undergoes spontaneous degradation. Both mesna and dimesna are excreted in the urine, and one-third of excreted dimesna is converted back to mesna in the renal tubule. The periods of time listed with mesna and dimesna indicate the length of time after administration that these agents appear in the bladder. peak concentrations (25), with oral bioavailability of 75–100%. Cyclophosphamide is primarily cleared through the liver, with only 10–15% of the drug excreted unchanged in the urine, although urine is the site of excretion of numerous inactive metabolites (17,18). Tubular reabsorption is high given its nonionized nature, resulting in significant elimination via hepatic metabolism. No change in the rate of toxicity among patients with liver disease has been reported (17). A low level of alkylating activity from unbound metabolites is typically observed in the plasma for at least 24 hours, but this may be significantly prolonged in patients with severe renal failure. However, the necessity for dose adjustments in CYCLOPHOSPHAMIDE AND MESNA 11 Table 1. Incidence of hemorrhagic cystitis following treatment with daily oral cyclophosphamide (CYC)* No. of patients Total CYC dose, gm‡ CYC duration, months‡ Author, year (ref.) Disease(s) CYC dose Mesna Total Cystitis† Mean Range Mean Range Aptekar et al, 1973 (37) Townes et al, 1976 (39) Plotz et al, 1979 (35)§ Austin et al/Carette et al, 1986/1983 (1/36) Stillwell et al, 1988 (32) Pederson-Bjergaard et al, 1988 (10) Silver et al, 1993 (31) Radis et al, 1995 (38)§ Talar-Williams et al, 1996 (33) Reinhold-Keller et al, 2000 (34) SLE, WG, RA RA SLE, RA SLE 1.3–1.5 mg/kg 2 mg/kg 1–4 mg/kg 1–4 mg/kg No No No No 46 24 54 40 10 4 7 6 28 26 48 ND 6–74 19–34 2–152 ND 15 7 28 ND 3–41 5–9 1–91 ND WG NHL SSc RA WG WG 1–2 mg/kg 100 mg/m2 1–2 mg/kg 50–150 mg 2 mg/kg 2 mg/kg No No No No No Yes 111 471 14 119 145 142 17/45¶ 33# 2 14 42/51** 17†† 101 ND ND 53 124 129 5–531 ND ND ND ND 42–350 38 ND 9 32 37 29 4–144 ND 6–12 ND ND 9–77 * There was some overlap of patients in the studies by Plotz et al, Austin et al, and Carette et al. SLE ⫽ systemic lupus erythematosus; WG ⫽ Wegener’s granulomatosis; RA ⫽ rheumatoid arthritis; ND ⫽ no data; NHL ⫽ non-Hodgkin’s lymphoma; SSc ⫽ systemic sclerosis. † The definition of cystitis differed between studies; cystoscopy was not required for the diagnosis, except as noted otherwise. ‡ Among the subset of patients with cystitis, unless noted otherwise. § Data for CYC dose and duration were based on all patients in the study; no data were available for the subset of patients with cystitis. ¶ In the smaller number of patients (n ⫽ 17), cystitis was defined by gross hematuria or was confirmed by cystoscopy; the larger number of patients (n ⫽ 45) was calculated based on the percent of patients with hematuria in whom cystitis was confirmed by cystoscopy (65%). # Defined by gross hematuria or confirmed by cystoscopy. ** In the smaller number of patients (n ⫽ 42), cystitis was confirmed by cystoscopy; the larger number of patients (n ⫽ 51) was calculated based on the percent of patients with hematuria in whom cystitis was confirmed by cystoscopy (70%). †† Confirmed by cystoscopy. patients with renal dysfunction is not well documented but is commonly advised (5,17,18,26). For the treatment of autoimmune diseases, cyclophosphamide dosing is typically 1.5–2 mg/kg/day when it is provided orally or 500–1,000 mg/m2 IV in monthly or biweekly pulse-dose regimens (3,5,7,8,27–30). For comparison, treatment of malignancies often involves doses ⬎1,000 mg/m2 administered on weekly or biweekly schedules in combination with other drugs or radiation therapy. It is thus difficult to extrapolate outcomes and toxicities from the oncology literature to patients given cyclophosphamide for the treatment of autoimmune diseases. Association between treatment with daily oral cyclophosphamide and hemorrhagic cystitis The mode of cyclophosphamide administration that has generated the most concern with regard to bladder toxicity is daily oral dosing, because the duration of treatment and the total cumulative exposure are generally higher compared with intermittent IV dosing, and hydration and bladder evacuation cannot be assured. The development of hemorrhagic cystitis during treatment with oral cyclophosphamide has been evaluated in 3 large cohorts of patients with Wegener’s granulomatosis (WG) and in additional cohorts of patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or non-Hodgkin’s lymphoma (NHL) (1,10,31–39) (Table 1). The strategy of encouraging patients to drink large volumes of fluids was specifically mentioned in a few studies (32,35,37), but compliance with these directions was not assessed. The methods of diagnosing hemorrhagic cystitis differed somewhat among these studies, but in all cases the initial screening involved routine urinalyses during the period of treatment. In the studies in which the diagnosis was usually (32,33) or always (34) confirmed by cystoscopy, the incidence of hemorrhagic cystitis ranged from 12% to 41%. The mean cyclophosphamide exposure of patients who had hemorrhagic cystitis was ⬎100 gm over a mean of ⬎30 months, with a wide range of both the total dose and the duration of treatment (Table 1). Few studies provide any information about the severity of hemorrhagic cystitis, in terms of either the degree or duration of discomfort or the need for transfusion. From these limited data, cystitis severe enough to require transfusion appears to be uncommon (occurring in 3 of 69 patients in 3 studies) (32,33,37). Although many patients with WG or SLE had renal involvement, no data relating the risk of cystitis to renal dysfunction were reported in any study. 12 MONACH ET AL Table 2. Incidence of bladder cancer following treatment with daily oral cyclophosphamide (CYC)* No. of patients CYC treatment Bladder cancer Latency, years 46 54 40 0 2 1 NA 6–7 4 NA 100 ND 1–2 mg/kg 100 mg/m2 111 471 3 7 1–14 5–12 ND 6.8 RA WG 50–150 mg 2 mg/kg 119 145 9 7 4–23 0.6–15 WG, MPA WG 2 mg/kg 2 mg/kg 123 142 3 1 WG ND 1,065 WG 1–2 mg/kg 293 Author, year (ref.) Disease(s) CYC dose Aptekar et al, 1973 (37) Plotz et al, 1979 (35) Austin et al/Carette et al, 1983/1986 (1/36) Stillwell et al, 1988 (32) Pederson-Bjergaard et al, 1988 (10) Radis et al, 1995 (38) Talar-Williams et al, 1996 (33) Westman et al, 1998 (40) Reinhold-Keller et al, 2000 (34) Knight et al, 2004/2002 (42,43) Faurschou et al, 2008 (41) SLE, WG, RA SLE, RA SLE 1.3–1.5 mg/kg 1–4 mg/kg 1–4 mg/kg WG NHL Total Duration, years Total dose, gm† Followup, years‡ NA 2–4 4 NA ND ND ND 4.5 7.1 3.2–14.2 1–12 2.8–4.2 56–531 83–129 6.0 3.8 22 31 8.8–56 13–65 5§ 0.6–5.1 120 ⫾ 56 19–251 13.1 8.5 ⬎5 7 4.8 ND 1.0–13.9 ⬎1 6 ND 350 4.6 7.0 11 4–15 4.8 2.6–8.1 7.2¶ 0–234 ND 5 7–18 3.6 1.2–8.3 ⬎1# ⬎36# 6.0 OR 95% CI ND * There is some overlap of patients in the studies by Plotz et al, Austin et al, and Carette et al. Latency is defined as the time between beginning cyclophosphamide treatment and the diagnosis of bladder cancer. In the study by Reinhold-Keller et al, oral mesna was also given routinely. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for the development of bladder cancer represent the comparison of CYC-treated patients with control subjects. SLE ⫽ systemic lupus erythematosus; WG ⫽ Wegener’s granulomatosis; RA ⫽ rheumatoid arthritis; NA ⫽ not applicable; ND ⫽ no data; NHL ⫽ non-Hodgkin’s lymphoma; MPA ⫽ microscopic polyangiitis. † Values are the range or mean ⫾ SD, for patients in whom bladder cancer developed. ‡ For the studies by Aptekar et al, Plotz et al, Austin et al, Carette et al, Stillwell et al, Pederson-Bjergaard et al, and Radis et al, values are the means; for all other studies, values are the medians. § Value is the mean. ¶ Value is the median. # Values are for 4 of 5 patients with bladder cancer. Association of daily oral cyclophosphamide with an increased risk of bladder cancer The incidence of bladder cancer following treatment with daily oral cyclophosphamide has been reported for many of the same cohorts used to investigate hemorrhagic cystitis (1,10,32–38) and for several separate cohorts that were used to measure the incidence of multiple types of cancer (40–43) (Table 2). Most of the analyses were based on single-center cohorts, with odds ratios (ORs) for the development of bladder cancer usually calculated in comparison with registry data. Although the number of cases of cancer observed in each cohort was small (range 0–11), resulting in large confidence intervals (CIs) for the ORs for cancer risk, a substantially elevated risk of bladder cancer associated with cyclophosphamide treatment was observed in all studies (OR range 3.6–100). The total cumulative doses of cyclophosphamide given to patients in whom bladder cancer subsequently developed varied widely but were ⬎100 gm in the majority of cases and ⬎30 gm in the great majority (missing data preclude the calculation of percentages) (Table 2). An elevated risk of bladder cancer in association with cyclophosphamide treatment for WG, RA, and NHL was clearly observed; an analogous risk was not identified with certainty among patients with SLE, but a smaller number of patients with SLE was studied (Table 2). In 3 studies, 2 of which involved WG (31,40) and 1 of which involved NHL (10), time-dependent analyses demonstrated that the prevalence of bladder cancer reached 10% between 11 years and 16 years after the beginning of treatment with cyclophosphamide. The largest study of bladder cancer following cyclophosphamide treatment described 31 cases among 6,171 patients with NHL (5.0%) (44). Results of this study are more difficult to compare with those of the other studies (and thus are not included in Table 2) due to the variety of cyclophosphamide regimens used and the frequent concomitant use of radiation therapy (an independent risk factor for bladder cancer). The yearly incidence of bladder cancer among white persons in the US has been estimated at 40 per 100,000 men and 10 per 100,000 women (45). This incidence rises with age; therefore, the baseline risk for patients with WG, as used to calculate ORs as described above (10,40,41), is somewhat higher: 58–67 per CYCLOPHOSPHAMIDE AND MESNA 13 Table 3. Association of bladder cancer with a prior diagnosis of hemorrhagic cystitis in patients treated with daily oral cyclophosphamide* Bladder cancer Author, year (ref.)/ cystitis definition Stillwell et al, 1988 (32) Cystoscopy Pedersen-Bjergaard et al, 1988 (10) No data Radis et al, 1995 (38) Nonglomerular hematuria Cystoscopy Talar-Williams et al, 1996 (33) Nonglomerular hematuria Cystoscopy Reinhold-Keller et al, 2000 (34) Cystoscopy Total Nonglomerular hematuria Cystoscopy Disease No bladder cancer Cystitis No cystitis Cystitis No cystitis P† 3 0 14 94 0.003 2 5 31 433 0.08 5 3 4 6 13 11 97 99 0.004 0.07 6 5 1 2 45 46 93 92 0.008 0.10 1 0 16 125 0.12 17 14 10 13 119 118 842 843 ⬍0.0001 ⬍0.0001 WG NHL RA WG WG * In the study by Reinhold-Keller et al, oral mesna was also given routinely. Cystitis was defined by the presence of nonglomerular hematuria or was proven by cystoscopy. Both definitions were used separately to calculate statistics, and 2 separate totals were calculated and analyzed due to the use of both definitions in 2 of the studies. WG ⫽ Wegener’s granulomatosis; NHL ⫽ non-Hodgkin’s lymphoma; RA ⫽ rheumatoid arthritis. † For the association of cystitis with bladder cancer, using Fisher’s exact test for each study individually and the Mantel-Haenszel test for the total, stratified by study. 100,000. Smoking is the best-documented environmental risk factor for bladder cancer and increases the risk ⬃3-fold (46). Among the studies referenced above in which tobacco use was reported, more than half of the patients in whom bladder cancer developed were smokers or former smokers (10,32,33,35,38). Thus, treatment with oral cyclophosphamide confers an independent, substantial, and probably doserelated increased risk of bladder cancer, with an effect that may be delayed for many years after the medication has been discontinued. Probable association of hemorrhagic cystitis with increased future risk of bladder cancer In most studies examining the risk of bladder cancer following treatment with daily oral cyclophosphamide, bladder cancer was associated with previous hematuria during cyclophosphamide treatment and/or with documented cystitis (32–34) (Table 3). Similarly, the available data appear to confirm a strong association between prior cystitis and the subsequent risk of developing bladder cancer, with an OR of 7.2 (95% CI 1.9–27) obtained using the Mantel-Haenszel estimator. However, because both cystitis and bladder cancer are associated with the cumulative dose of cyclophosphamide and the duration of treatment, a causeand-effect relationship between cystitis and cancer cannot be firmly established. There are 2 caveats to this apparent association. First, it is possible that selection bias influenced these studies: patients in whom hematuria develops early in the course of treatment are much more likely to be evaluated later—by history, urinalysis, urine cytology, and/or screening cystoscopy—than are patients who never had such abnormalities. Second, a registry-based case–control study does not support the conclusion that bladder cancer is associated with a history of cystitis. Knight et al (42) reported that only 1 of 11 patients with bladder cancer (all of whom had been treated for WG with oral cyclophosphamide) had a history of cystitis documented by cystoscopy, and that hematuria in the other 10 patients was first noted shortly before the diagnosis of cancer. In contrast, 18 of 25 control subjects had a history of microscopic hematuria (42). However, it is unclear whether a uniform screening strategy was used, or whether a distinction between glomerular (i.e., associated with red blood cell casts or declining renal function) and nonglomerular hematuria could be made. 14 MONACH ET AL Table 4. Incidence of hemorrhagic cystitis following treatment with intermittent IV cyclophosphamide (CYC) for rheumatic diseases* No. of patients Author, year (ref.) Disease(s) CYC dose 2 Mesna No Austin et al, 1986 (1) SLE 0.5–1.0 gm/m every 3 mos Hoffman et al, 1990 (48) WG 1.0 gm/m2 every 1–3 mos No 2 Gourley et al, 1996 (3) SLE 0.75 gm/m every 1–3 mos Yes Martin et al, 1997 (50) SLE, vasc 0.5–1.0 gm/m2 every mo No Guillevin et al, 1997 (53) WG 0.7–1.0 gm/m2 every 3–6 wks No Adu et al, 1997 (54) WG, MPA, PAN 15 mg/kg every 2–6 wks Yes Martin-Suarez et al, 1997 (55) SLE, vasc, myo 0.5 gm every 1–4 wks Yes/no Koldingsnes et al, 1998 (51) WG 15 mg/kg every 2–8 wks No Haubitz et al, 1998 (52) WG, MPA 0.75 gm/m2 every mo ⫻ 12 No 2 Ginzler et al, 2005 (6) SLE 0.5–1.0 gm/m every mo ⫻ 6 No Hoyles et al, 2006 (8) SSc 0.6 gm/m2 every mo ⫻ 6 No Goransson et al, 2008 (49) SLE, WG, myo 15 mg/kg every mo No Total Cystitis 20 14 55 75 27 24 90 11 22 69 22 42 0 1† 0 0 1 0 1‡ 0 0 0 0 0 Total CYC dose, gm Mean Range ND ND ND 5 28 ND 3 ND 16 ND 6 10 ND ND ⬍15 ND ND ⬍30 1–25 12–88 ⬍20 ⬍9 ND 1–52 CYC duration, years Mean Range 4 0.8 ND 0.5 ND ND 0.3 3.3 ND ND ND 1.2 ND 0.1–1.8 ⬍3 ND ND ⬍1.5 0.0–3.7 1.0–8.2 ⬍1 0.1–0.5 0.1–0.5 0.0–8.8 * The total cyclophosphamide dose and the duration of therapy were based on all patients in the study. IV ⫽ intravenous; SLE ⫽ systemic lupus erythematosus; ND ⫽ no data; WG ⫽ Wegener’s granulomatosis; vasc ⫽ vasculitis; MPA ⫽ microscopic polyangiitis; PAN ⫽ polyarteritis nodosa; myo ⫽ myositis; SSc ⫽ systemic sclerosis. † Patient also had a history of cystitis with oral cyclophosphamide. ‡ Patient was 1 of 8% of patients in this case series who were not treated with mesna. In summary, the available data indicate, with some caveats, that antecedent hemorrhagic cystitis is associated with a future increased risk of bladder cancer. Lack of evidence for a strong association of periodic IV cyclophosphamide with hemorrhagic cystitis or bladder cancer Periodic, usually IV, dosing of cyclophosphamide has been the standard of care for lupus nephritis for ⬎20 years (1,3,6), and similar regimens have been used for other severe rheumatic diseases (8,28,47). Mesna is used more frequently in this setting than is daily oral therapy, likely due to convenience or by the adoption of a practice that is common in oncology. However, even when mesna has not been routinely used, few cases of hemorrhagic cystitis have been reported in clinical trials or additional case series of patients treated with periodic IV cyclophosphamide for rheumatic diseases. Three cases were identified among 471 treated patients in the studies listed in Table 4, and the great majority of these patients did not receive mesna (1,3,6,8,48–55). The development of bladder cancer after pulse regimens has been described in only a few case reports (56–58). It is important to note that cystitis and bladder cancer were not the primary topics of investigation in these studies; thus, there are no descriptions of strategies for systematic screening for hematuria or subsequent cystoscopy, and the duration of followup was likely too short (median ⬍5 years) to detect many bladder cancers. Even if one assumes that the reported difference in bladder toxicity between daily oral and periodic IV cyclophosphamide regimens is real, it is possible that this finding simply reflects the total dose of cyclophosphamide rather than the timing or route of administration. Few patients in studies of periodic IV cyclophosphamide have received more than 30 gm, in marked contrast to studies of bladder toxicity in patients given daily oral cyclophosphamide (compare the total doses in Tables 1, 2, and 4). Regardless of the reason, however, it is clear that the risk of hemorrhagic cystitis with periodic IV dosing of cyclophosphamide as used in rheumatology is quite low, in contrast to the experience with high-dose IV cyclophosphamide and ifosfamide as used in oncology (see discussion below). Additional, although indirect, support for a low risk of bladder cancer with periodic IV cyclophosphamide comes from observational studies. Unselected patients with lupus do not appear to be at elevated risk of bladder cancer (OR 1.23, 95% CI 0.66–2.11), based on a multicenter cohort study of 9,547 patients followed up for an average of 8 years (59). Exposure to cyclophosphamide was not reported in this study; however, based on the frequency of severe nephritis in SLE and the near-universal use of this treatment during the period of study (59), one can expect that at least 30% of the patients received periodic IV cyclophosphamide for at least 6 months. Several smaller studies have also consistently failed to document an excess risk of bladder cancer in patients with lupus (60–65). CYCLOPHOSPHAMIDE AND MESNA Mesna pharmacology Mesna is a thiol compound, completely lacking in antineoplastic activity, that is used in conjunction with oxazophosphorine alkylating agents as a uroprotective agent. Mesna is thought to decrease the incidence of cystitis and bladder cancer by counteracting the toxic effects of acrolein (16,66,67). The administration of mesna with cyclophosphamide for the prevention of bladder toxicity is a practice derived primarily from investigations with ifosfamide, a structural analog of cyclophosphamide. Following either oral or IV administration, mesna undergoes rapid dimerization within plasma to the inactive disulfide compounds dimesna, mesnacysteine, mesna-glutathione, and others (67). Both mesna and dimesna are cleared quickly by the kidneys. Dimesna undergoes filtration by the glomerulus, and roughly one-third is then converted back to mesna in the renal tubules by glutathione reductase (66). Mesna then binds to acrolein within the urine. The free sulfhydryl group found in mesna combines directly with the double bond of acrolein as well as other urotoxic 4-hydroxyoxazaphosphorine metabolites (16,66) (Figure 1). The conversion of 4-hydroxycyclophosphamide to acrolein may also be inhibited by mesna (68). Both of these factors contribute to the inhibition of acrolein binding to cell-surface proteins in the bladder, thereby potentially limiting cyclophosphamide-associated toxicities. Urinary mesna concentrations greatly exceed plasma concentrations, allowing for rapid clearance of acrolein from the urinary system. However, mesna does not protect against nonurologic toxicities associated with the oxazaphosphorines. Mesna has 50–75% bioavailability after oral administration and is not affected by food intake (16,66). Urinary thiol concentrations following oral administration are approximately one-half those observed after IV administration. Oral administration is associated with delayed peak urinary concentrations (3 hours after dosing compared with 1 hour following IV administration ) and prolonged excretion. When oral doses of mesna are doubled, peak urinary thiol concentrations are unchanged but are maintained for longer periods of time (67). The recommended dosing of IV mesna is a total dose equal to 20% (weight/weight) of the total cyclophosphamide dose, in the form of 3 equal doses of mesna, with the first dose administered 15–30 minutes prior to cyclophosphamide and the others administered 4 hours and 8 hours following cyclophosphamide (67). 15 When mesna is given orally, the dose should be equal to 40% of the cyclophosphamide dose (oral or IV), based on the 50% oral bioavailability of mesna. For convenience, a combination of IV and oral doses can be given: an initial IV dose (equal to 6.8% of the cyclophosphamide dose) followed by 2 oral doses (each equal to 13.3% of the cyclophosphamide dose). If the first dose of mesna is administered orally, it should be given 2 hours before cyclophosphamide (oral or IV), but the second and third oral doses can still be given 4 hours and 8 hours after cyclophosphamide, as with IV mesna dosing. Two forms of mesna are available for oral use. The IV solution, at a concentration of 10 mg/ml, can be ordered by outpatient pharmacies in the US, at a wholesale cost of approximately $0.55 per typical daily dose of 60 mg. A tablet is available but at a cost of approximately $4.50 per 60 mg, and the only strength sold is 400 mg, making dosing for patients with rheumatic diseases both expensive and technically challenging. The principal disadvantage of using the IV solution orally is the strong sulfurous odor and taste; mixing with a carbonated beverage or juice drink is recommended. Beyond the issues of taste and inconvenience, mesna is generally well tolerated, with mild gastrointestinal toxicity being the most common side effect. Allergic reactions to mesna have been reported but are considered rare (69). Although renal dysfunction might theoretically increase the risk of systemic cyclophosphamide toxicity due to a decreased rate of elimination of the drug and its metabolites, renal insufficiency seems unlikely to lead to an increased rate of bladder toxicity, because the delivery of acrolein to the bladder is also reduced. Similarly, because mesna requires active glomerular filtration and tubular secretion in order to reach the urine, use of mesna in patients with significant renal dysfunction is unlikely to be beneficial. However, the relative urinary concentrations of mesna and acrolein have never been measured in the setting of renal insufficiency, and oliguria could lead to prolonged exposure of the bladder to whatever amount of acrolein arrives there; thus, one cannot regard use of mesna in patients with renal insufficiency as having been addressed conclusively. Efficacy of mesna for the prevention of hemorrhagic cystitis Data for the use of mesna to prevent hemorrhagic cystitis caused by cyclophosphamide in the treatment of rheumatic diseases are not conclusive. This 16 topic is best approached in a broader context that includes strategies for hydration, data on the use of mesna in patients with cancer, and insights from animal models. These data were obtained with the use of periodic high-dose IV cyclophosphamide or ifosfamide, both of which are associated with high risks of cystitis. It is unclear whether these results are more applicable, in rheumatic diseases, to periodic IV dosing (in which the route and schedule of administration are similar but the baseline risk is much lower) or to daily oral dosing (in which the route and schedule are very different, but the baseline risk is similarly high). Hydration. Hydration with IV fluids immediately prior to and for several hours after IV administration of cyclophosphamide, as well as oral hydration for 72 hours following the cyclophosphamide dose, is typically recommended to aid in the prevention of hemorrhagic cystitis. When oral cyclophosphamide is given, patients are instructed to drink fluids at the time of dosing and for several hours thereafter and to take cyclophosphamide in the morning to limit retention of metabolites in the urine overnight. It should be noted that since the time when bladder toxicities of oxazophosphorines were first recognized, the effectiveness of hydration per se has never been formally evaluated, having been regarded as the standard of care against which all other strategies for bladder protection are to be compared. Mesna in animal models of cystitis. Studies in rodents support the effectiveness of mesna in preventing acute bladder toxicity from cyclophosphamide or acrolein (21,70–74). These studies typically involved the brief use of high doses of cyclophosphamide and thus provide better support for the use of mesna in patients with malignancies than in patients with rheumatic disease. Mesna and cystitis in rheumatic diseases. The prospect of preventing cystitis and/or bladder cancer by coadministering mesna to patients receiving daily oral cyclophosphamide has never been addressed in a systematic manner. Among the studies of patients with WG, the incidence of cystitis may have been lower in the single cohort that routinely received oral mesna (12%) (34) than in the 2 others that did not receive oral mesna (35–41%) (30,31) (Table 1). However, the possibility of important differences in the dosing schedules, total cumulative doses, and clinical characteristics, particularly renal dysfunction, makes a direct comparison problematic. Similarly, differing approaches to screening for and the diagnosis of cystitis among these 3 studies introduce another source of uncertainty. However, because these studies provide the only data relevant to the question of whether mesna prevents cystitis in patients MONACH ET AL receiving daily oral cyclophosphamide, and interpretation and comparison of these studies are the subject of debate (34,75), a detailed review of the controversy is warranted. Reinhold-Keller et al (34) diagnosed all cases of cystitis by cystoscopy, and all cases of nonglomerular hematuria were investigated in this way; therefore, their report of a 12% incidence appears accurate. TalarWilliams et al (33) reported nonglomerular hematuria in 73 of 145 patients (50%). Cystoscopy was performed in only 60 of these 73 patients, with confirmation of cystitis in 42 (i.e., 70% of those undergoing cystoscopy), giving a minimum prevalence of cystitis in the cohort of 29%. Both “50%” and “29%” have been used to describe the incidence of cystitis in this study (34,75). However, the most appropriate estimate is probably neither of these figures but instead is the percent of confirmed cases (42 of 60 [70%]) multiplied by the percent with hematuria (50%), resulting in an incidence of 35% (Table 1). Stillwell et al (32) diagnosed cystitis either on the basis of gross hematuria (11 patients) or by cystoscopy performed for the followup of new microscopic hematuria. However, only a minority of patients with microscopic hematuria were investigated by cystoscopy (20 of 52), and because the percent of patients in whom cystitis was confirmed by cystoscopy was 65% (which notably is similar to the incidence of 70% reported by TalarWilliams), one could reasonably extrapolate that the true incidence of cystitis in the study by Stillwell et al is 41% (11 ⫹ [0.65 ⫻ 52] ⫽ 45 of 111 patients). Despite the difficulty of directly comparing these 3 studies, it is worth noting that the study showing the lowest incidence of cystitis (in the setting of routine mesna therapy) used the most thorough screening strategy (34), which should have biased toward a higher rather than lower incidence. Although routine treatment with mesna has recently been incorporated into some protocols that have used periodic IV dosing of cyclophosphamide (28), data on the efficacy of mesna in preventing cystitis are lacking, because the baseline risk of cystitis with such regimens appears to be quite low (Table 4). Mesna and cystitis with high-dose cyclophosphamide or ifosfamide. Mesna as prophylactic therapy against bladder toxicity has been tested only in a randomized, controlled manner among patients receiving high-dose IV cyclophosphamide or ifosfamide as part of bone marrow transplantation (BMT) protocols or as chemotherapy for solid malignancies. Mesna treatment (with maintenance hydration of 1.5–3 liters/day) has been compared with IV hyperhydration (either 6 liters/day with a diuretic or 3 liters/m2/day), with similar CYCLOPHOSPHAMIDE AND MESNA but incomplete effectiveness in preventing short-term bladder toxicity caused by high-dose IV cyclophosphamide in BMT (76,77). By pooling the results from these 2 studies, hematuria of any degree was observed in 41 (57%) of 72 patients receiving mesna and in 44 (67%) of 66 patients receiving hyperhydration; macroscopic hematuria was observed in 17 (24%) of 72 patients receiving mesna and in 17 (26%) of 66 patients receiving hyperhydration. In patients also receiving hydration during high-dose IV cyclophosphamide treatment, the addition of mesna was more effective than the addition of continuous bladder irrigation in preventing acute bladder toxicity (78). Mesna is routinely used (and is FDA-approved in both IV and oral forms) as prophylaxis against cystitis in ifosfamide-containing regimens (16), based on 4 small controlled trials of IV mesna (79–82), 3 subsequent trials showing equivalent rates of cystitis comparing IV with oral mesna (15,83), and additional uncontrolled but often larger series (84–90) that made comparisons with the high rate of hemorrhagic cystitis (⬃50%) noted in early studies of ifosfamide (11). Even with mesna prophylaxis, however, the rates of acute urotoxicity ranged from 1% to 10% in these studies (16). In addition, among 15 patients without clinical evidence of bladder toxicity 24 hours after receiving ifosfamide and mesna, the bladder mucosa was macroscopically (10 of 15 patients) and microscopically (100%) abnormal, with mucosal alterations including edema, exocytosis, and hemorrhage (91). Summary. Direct evidence for the effectiveness of mesna in preventing cystitis comes only from its use with ifosfamide in patients with cancer and on data from animal models, both of which are of uncertain relevance to the use of cyclophosphamide in patients with rheumatic diseases. The data from rheumatology series are consistent with a protective effect but are inadequate to draw a firm conclusion. Paucity of data on the efficacy of mesna for the prevention of bladder cancer in patients treated with cyclophosphamide or ifosfamide No study has compared the incidences of bladder cancer resulting from the use of cyclophosphamide with or without mesna. Among studies describing long-term followup after treatment with daily oral cyclophosphamide (10,32–34,38,40–42), the only study in which mesna was routinely used revealed a low rate of bladder cancer (1 of 142 treated patients) despite one of the longest average followup times (see Table 2) and 17 perhaps the most comprehensive (or at least the bestdocumented) screening strategy (34). However, with such small numbers of events, a comparison among studies or pooling of these data is even more problematic than it is for comparing the incidences of cystitis. There are no published data regarding the effect of mesna on the rate of secondary bladder cancer in patients treated for malignancies with high-dose IV cyclophosphamide or ifosfamide; the prospect and need for such studies have been noted (92). A single study in rodents supports the effectiveness of mesna in preventing bladder cancer induced by prolonged exposure to cyclophosphamide. Cyclophosphamide administered orally at a dosage of 2.5 mg/kg/day for 5 days per week produced bladder tumors in 24 of 80 treated rats (30%); the incidence of tumors was reduced to 22% (8 of 36) in rats given low-dose mesna (5 mg/kg/day) and to 7% (3 of 41) in rats given high-dose mesna (15 mg/kg/day) (93). Evidence-based consensus guidelines on the use of mesna Evidence-based consensus guidelines on the use of mesna have not addressed its value in patients with rheumatic diseases. Given the low reported incidence of hemorrhagic cystitis with standard doses of IV cyclophosphamide in patients with cancer, the American Society of Clinical Oncology does not recommend the routine use of mesna for patients receiving cyclophosphamide and states that mesna should be used only in conjunction with the administration of high-dose cyclophosphamide, typically defined as 50 mg/kg or 2 gm/m2 (16,94). In the rheumatology literature, guidelines for the use of mesna vary and are not detailed. Guidelines from the British Society for Rheumatology for the management of antineutrophil cytoplasmic antibody–associated vasculitis have recommended that mesna be “considered for patients on IV cyclophosphamide therapy” (95). Similarly, guidelines on vasculitis from the European League Against Rheumatism recommend that “patients receiving pulse cyclophosphamide should also be given oral or IV mesna” and add that “mesna may also be beneficial in patients receiving continuous oral cyclophosphamide” (5). In contrast, consensus guidelines for management of lupus have made no mention of mesna (30,96). Rheumatology textbooks and other resources regularly recommend use of mesna for patients receiving IV cyclophosphamide, with little or no comment on the use of mesna with oral cyclophosphamide (12–14). 18 MONACH ET AL Overall, the paucity of evidence supporting the use of mesna is striking in light of recommendations for its use and the common adoption of such guidelines in rheumatology practice. However, there is also no evidence against the effectiveness of mesna and little prospect of the issue being definitively addressed in a trial. With uncertain and unquantifiable risks and benefits, patient and physician preference can and should play important roles, and thus, recommendations to “consider” use of mesna are fully consistent with the evidence. However, the conclusions of this review diverge from most recommendations in one important respect: on the basis of the much clearer risks of bladder toxicity with daily oral cyclophosphamide, the inclination to use mesna should be much stronger with daily oral dosing compared with periodic IV dosing. Summary and recommendations The conclusions of this literature review are as follows: 1) daily oral cyclophosphamide is associated with an increased risk of both hemorrhagic cystitis and bladder cancer, in a dose-dependent and/or durationdependent manner; 2) hemorrhagic cystitis that occurs during cyclophosphamide treatment is associated with an increased risk of bladder cancer years later; 3) IV cyclophosphamide therapy, as prescribed for rheumatic diseases, carries a low risk of cystitis and probably also of bladder cancer; 4) evidence for the effectiveness of mesna in preventing cystitis is based largely on its use with ifosfamide in patients with cancer and on data from animal models, both of which are of uncertain relevance to the use of cyclophosphamide in patients with rheumatic diseases; 5) there is no direct evidence for the effectiveness of mesna in preventing bladder cancer in humans. On the basis of the current evidence, the following recommendations for use of mesna in the rheumatology setting are proposed: 1. Explain to patients that the evidence for the benefit of mesna in rheumatologic diseases is not strong. 2. Upon starting a first course of oral or IV cyclophosphamide, discuss the issues with the patient; if the patient expresses no strong preference, do not use mesna. 3. Additional factors to consider when deciding on the use of mesna are as follows: a. the expense of mesna, especially oral tablet form; b. the inconvenience of the relatively complex dos- ing regimen for mesna, particularly for daily dosing; c. the ability to tolerate hydration during either daily oral or pulse IV therapy with cyclophosphamide; d. the total cumulative dose of cyclophosphamide for patients requiring a repeat course. 4. Upon starting a second course of cyclophosphamide (i.e., more than 4–6 months of total treatment), particularly with oral dosing, consider recommending mesna. 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