mesna and Hematuria

Mesna can be given orally to simplify outpatient ifosfamide therapy. Oral administration of mesna solution or tablets has been approved in Canada, Denmark, Germany, Italy, The Netherlands, and the United Kingdom, and programs for registration are ongoing in other European countries and in the United States. This review summarizes dosing schedules and the incidence of hematuria in 47 clinical studies, in which oral mesna was given to at least 1,986 patients who received more than 6,475 courses of ifosfamide. Various doses and schedules of oral mesna, usually in combination with intravenously injected mesna, provided effective uroprotection for a wide range of ifosfamide regimens.

Topics: Administration, Oral; Ambulatory Care; Antineoplastic Agents, Alkylating; Cystitis; Drug Administration Schedule; Europe; Hematuria; Hemorrhage; Humans; Ifosfamide; Injections, Intravenous; Mesna; Tablets; United States

Haemorrhagic cystitis (HC) is an uncommon but potentially devastating complication of chemotherapy and bone marrow transplantation in children. We aimed to test the hypothesis that early recognition, sodium pentosan polysulfate (SPP), and avoidance of urethral catheterisation improve outcomes in children with HC.. A retrospective case note review was performed of all patients treated for HC in our hospital from 2002 to 2010. A protocol for the management of HC was introduced in 2007 advocating early detection, use of SPP, and avoidance of urethral catheterisation. Data collected on each patient included primary condition, medications at onset, blood transfusions, duration of symptoms, catheter usage, and outcome. Statistical analysis was performed using the Mann-Whitney U test, and Fisher's Exact test as appropriate, P < .05 being significant.. Five patients were treated using protocol with 5 historical controls. There was no significant difference between the ages of the group, diagnosis, and treatment at onset of HC. In the historical group, 4 of 5 died with HC, but all recovered in the protocol group (P < .05). Blood transfusion requirements were also significantly reduced after protocol introduction (P < .05).. Early identification, avoidance of urethral catheterisation, and use of SPP significantly reduces blood transfusion requirements and mortality from HC.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; BK Virus; Child; Combined Modality Therapy; Cyclophosphamide; Cystitis; Fanconi Anemia; Female; Hematopoietic Stem Cell Transplantation; Hematuria; Herpesviridae Infections; Humans; Immunocompromised Host; Leukemia; Male; Mesna; Pentosan Sulfuric Polyester; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Ultrasonography; Urinary Catheterization

In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients.. Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration.. Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels.. Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Breast Neoplasms; Cyclophosphamide; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Hypersensitivity; Equipment Failure; Erythrocyte Transfusion; Female; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Hematuria; Home Infusion Therapy; Humans; Mesna; Middle Aged; Neoplasm Metastasis; Paclitaxel

This two-arm, double-blind, randomized trial was conducted to determine the effects of lenograstim, a glycosylated recombinant human granulocyte colony-stimulating factor (rHu-G-CSF), on the hematologic tolerance of patients with sarcoma treated with mesna, doxorubicin, ifosfamide, and doxorubicin (MAID) chemotherapy.. Forty-eight patients with metastatic or locally advanced soft tissue sarcoma were, following the first cycle of a combination with doxorubicin 60 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2 given on days 1 to 3, randomized to receive either lenograstim 5 micrograms/kg/d by once-daily injection from day 4 to day 13, or its vehicle. For subsequent cycles, 28 patients continued on the same chemotherapy and lenograstim was systematically given as prophylactic treatment in an open manner.. Following the first cycle of MAID, the duration of neutropenia was reduced in patients who received lenograstim as compared with those who received placebo, with a median duration of neutropenia ( < 0.5 x 10(9)/L neutrophils) of 0 days (range, 0 to 3) and 5 days (range, 0 to 10), respectively (P < .001). All patients who received lenograstim had recovered at least 1 x 10(9)/L neutrophils (polymorphonuclear lymphocytes [PMN]) on day 14, compared with only one of 26 in the placebo group (P < .001). The median time to recover this neutrophil level was 12 days (range, 10 to 13) and 17 days (range, 14 to 21), respectively (P < .001). Neutropenic fever occurred in five (23%) and 15 (58%) patients respectively (P = .02). Twenty-eight patients received at least two cycles (median, four) of MAID at the same dose. Toxicity remained constant across all treatment cycles. A progressive increase in thrombocytopenia was noted, with median platelet nadirs of 102 x 10(9)/L at cycle 2 and 19.5 x 10(9)/L at cycle 6, but did not result in significant treatment modifications. Consequently, median relative dose-intensities remained greater than 0.95 for up to six consecutive MAID cycles.. Lenograstim significantly improved hematologic tolerance in patients treated with the MAID chemotherapy regimen and, therefore, allowed optimal adhesion to the theoretic doses planned for up to six cycles. Whether such an optimization in relative dose-intensity will result in an improvement of treatment efficacy remains to be determined.

Topics: Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Double-Blind Method; Doxorubicin; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematuria; Hemoglobins; Humans; Ifosfamide; Injections, Subcutaneous; Length of Stay; Lenograstim; Leukocyte Count; Male; Mesna; Middle Aged; Nausea; Neutropenia; Platelet Count; Recombinant Proteins; Regression Analysis; Sarcoma; Soft Tissue Neoplasms; Stomatitis

To compare the use of intravenous (IV) hydration plus either continuous bladder irrigation or mesna for the prevention of hemorrhagic cystitis in the bone marrow transplant setting.. Two hundred patients were prospectively randomized to receive either continuous bladder irrigation with 200 mL/h of normal saline, or continuous infusion mesna at 100% of the cyclophosphamide dose.. The overall incidence of hematuria of any grade was significantly higher in the bladder-irrigation group (76%) compared with the mesna group (53%) (P = .007). However, the incidence of grade III and IV hematuria was the same in both groups (18%; P = NS). Moderate or severe discomfort or bladder spasms were reported in 84% of the patients who received bladder irrigation, compared with 2% of the patients who received mesna prophylaxis (P < .0001). Urinary tract infections (UTIs) were documented in 27% of the patients in the bladder-irrigation group, compared with 14% of the patients in the mesna group (P = .03).. Both continuous bladder irrigation and mesna were equally effective in preventing severe hemorrhagic cystitis associated with high-dose cyclophosphamide and bone marrow transplantation. However, the use of mesna was associated with significantly less discomfort and a lower incidence of UTIs.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Cystitis; Female; Hematuria; Humans; Male; Mesna; Middle Aged; Neoplasms; Prospective Studies; Therapeutic Irrigation; Urinary Bladder

Twenty patients received 27 courses of ifosfamide administered as a 24-hour continuous infusion for 14 days without Mesna. The goal of the study was to deliver a dose rate and total cumulative dose of ifosfamide that would be comparable to standard bolus or short-term infusions administered with Mesna. Dose escalations proceeded from 200 to 300, 400, 450, 500, and 550 mg/m2/d. Four patients developed transient microscopic hematuria at 400, 450, and 500 mg/m2/d. There were no instances of macroscopic hematuria. At 550 mg/m2/d, three patients experienced nonurologic toxicity; confusion (1), nausea (1), and Grade 2 leukopenia (1). The recommended dose of 500 mg/m2/d delivers a total dose of 7 g/m2 per cycle, which is comparable to that delivered in clinical practice for bolus or short-term infusion. Because few patients received multiple courses over time, the cumulative effects are indeterminate in the present trial. The frequency and predictability of hematuria are not precise, and at least daily monitoring by urine Hematest is essential, adding Mesna to the infusate in patients with persistent hematuria. The protracted infusion schedule for ifosfamide permits convenient outpatient administration without Mesna and reduces the drug cost of clinical usage of this agent by up to $890 per cycle. Clinical activity was demonstrated in a single patient, but a comparative trial of standard bolus schedules with the protracted infusion schedule will be necessary to determine if the clinical effectiveness of the drug is maintained.

Topics: Adult; Aged; Drug Administration Schedule; Drug Evaluation; Female; Hematuria; Humans; Ifosfamide; Infusions, Intravenous; Leukopenia; Male; Mesna; Middle Aged; Nausea

In order to evaluate the preventive efficacy, safety and usefulness of mesna (Sodium 2-mercaptoethane sulfonate) against ifosfamide-induced urinary disorders, a placebo-controlled double-blind comparative study was performed. Ifosfamide was administered by intravenous drip infusion at a daily dose of 2 g/m2 for 5 consecutive days, and mesna was intravenously administered at 20% of the ifosfamide dose, three times daily for 5 consecutive days. The results obtained are as follows. (a) Of 101 accrued patients, 91 patients were evaluated consisting of 45 for the mesna group and 46 for the placebo group. There was no intergroup difference in the number of the evaluated cases and patient characteristics. (b) Micturition pain and feeling of residual urine graded as moderate or severe were not observed for the mesna group, but were observed for the placebo group with incidences of 19.6% (9/46) for micturition pain and 15.2% (7/46) for feeling of residual urine; the intergroup differences in the appearance of these urinary symptoms were statistically significant (P = 0.0003 for micturition pain; P = 0.0009 for feeling of residual urine). The incidence of hematuria graded as moderate or severe was 6.7% (3/45) in the mesna group, which was significantly lower than the 32.6% (15/46) in the placebo group (P = 0.0008). (c) No side-effect attributable to mesna was observed. (d) A judgment of "useful" was obtained in 80.0% (36/45) of the patients treated with mesna, which was significantly higher than the 34.8% (16/46) of the patients treated with placebo (P = near 0). On the basis of the above results, we conclude that the preventive efficacy, safety and usefulness of mesna against ifosfamide-induced urinary disorders have been well demonstrated in this study.

Topics: Adult; Aged; Double-Blind Method; Female; Hematuria; Humans; Ifosfamide; Lung Neoplasms; Male; Mesna; Middle Aged; Pain; Urination Disorders; Urologic Diseases

European and American investigators have reported response rates of 38% to 83% for ifosfamide alone in pretreated sarcomas. In a phase II trial of ifosfamide 2.0g/m2 days 1 to 4 with mesna uroprotection in 124 patients with previously failed sarcomas, four (3%) responded completely (95% exact confidence interval, 1% to 8%) and 26 (21%) had a complete or partial response (95% exact confidence interval, 14% to 29%). The median time to progression was 5 and 9 months for partial and complete responders, respectively. In the subset of soft tissue sarcomas, the response rate for the patients receiving bolus administration was 26%, compared with 9% for the patients receiving a continuous infusion schedule (P = .03). The response rates among patients with soft tissue and bony sarcomas with a performance score of 0-2 and 0-1 prior to chemotherapy administration were 20% and 40%, respectively. Somnolence or confusion developed in 19%. Neurotoxicity was significantly associated with poor performance status (P less than .01), elevated creatinine (P less than .01), and low bicarbonate levels (P = .05). A serum bicarbonate less than 20 developed in 31% of the patients and was significantly associated with older age (P = .01), elevated creatinine (P = .02), and female sex (P = .06). Hematuria was significantly associated with no uroprotection (the first four patients did not receive mesna because it was unavailable), but was not associated with prior cyclophosphamide, pelvic radiotherapy, age, or bolus v continuation infusion schedule. Thus, ifosfamide is active in failed sarcomas and warrants further study in previously untreated patients with sarcoma.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Clinical Trials as Topic; Female; Hematuria; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms

A prospective randomised study was carried out to compare the effect of mesna (2-mercaptoethane sulphonate sodium) with that of forced diuresis in preventing cyclophosphamide induced haemorrhagic cystitis in marrow transplant recipients. Sixty-one consecutive BMT recipients were randomised for treatment with forced diuresis or mesna. The incidence of macroscopic haematuria was significantly lower in the mesna treated group (chi 2 = 4.03, P less than 0.05). No specific side effects of mesna were detected. The lymphopenia induced by cyclophosphamide in the aplastic recipients was similar in the mesna and forced diuresis groups suggesting that mesna has no effect on the lymphocytotoxic activity of cyclophosphamide, although 6 out of 7 episodes of graft failure documented in the study occurred in mesna treated patients. As a result of this study our present policy is to use mesna in all BMT recipients but to continue careful documentation of the incidence of graft failure.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Child, Preschool; Colony-Forming Units Assay; Cyclophosphamide; Cystitis; Diuresis; Graft Rejection; Hematuria; Hemorrhage; Humans; Leukocyte Count; Mercaptoethanol; Mesna; Postoperative Complications; Prospective Studies

Mesna is superior to standard prophylaxis in inhibiting the urotoxicity of oxazaphosphorines. Mesna does not interfere with the antitumour effect of oxazaphosphorines and other cytostatics. Mesna is well tolerated. Mesna can be given orally. Mesna should be administered with each ifosfamide treatment and with high dose cyclophosphamide. It should also be given to any patient who may be at risk of developing cystitis following oxazaphosphorine treatment.

Topics: Clinical Trials as Topic; Cyclophosphamide; Drug Interactions; Hematuria; Humans; Ifosfamide; Mercaptoethanol; Mesna; Neoplasms

A multicentre, randomised, clinical study was performed by sequential analysis to quantify the uroprotective efficacy of sodium 2-mercaptoethane sulfonate (mesna, Asta D 7093, Uromitexan) during high-dosed chemotherapy with oxazaphosphorines. Patients were entered as matched pairs serially according to time of admission, trial centre, cytostatic therapy (cyclophosphamide, Endoxan; ifosfamide, Holoxan) and tumor diagnosis, and were given uroprotection at random either with mesna or standard prophylactic measures. The maximum number of erythrocytes in the urine (n/microliter) was chosen as effect variable in a qualitative manner: effective protection delta less than or equal to 15 erythrocytes/microliter urine ineffective protection delta greater than 15 erythrocytes/microliter urine. The scheme of sequential analysis was based on 1. a uroprotective efficacy of 70% of the standard prophylaxis, 2. an assumed efficacy of 95% of mesna treatment and 3. an alpha-error and beta-error of 0.05 and 0.10 respectively. The admission of the twentieth patient completed the eighth matched pair of patients. This pair proved to be the sixth discordant pair with regard to uroprotective efficacy. The significant uroprotective superiority (p less than 0.05) of mesna was proven in view of clear decisions in favour of the test compound.

Topics: Hematuria; Humans; Mercaptoethanol; Mesna; Phosphoramide Mustards; Urologic Diseases

Topics: Clinical Trials as Topic; Cyclophosphamide; Cystitis; Hematuria; Humans; Ifosfamide; Mercaptoethanol; Mesna; Neoplasms

In 8 patients receiving intravenous isophosphamide 2 g/m2 at 2-week intervals for advanced bronchogenic carcinoma the protective effect of 2-mercaptoethane sulphonate sodium (mesnum) against isophosphamide-induced urothelial toxicity was tested in a single-blind crossover trial. With isophosphamide alone, 7 of the 8 patients developed either haematuria or symptoms of bladder irritation; when mesnum was given in addition, only 1 patient had microhaematuria and frequency, and this was in association with a urinary-tract infection. 5 patients then received fifteen courses of isophosphamide in increasing doses of 4 to 8 g/m2 i.v. with mesnum. In contrast to previous experience with isophosphamide at this high dosage, frank haematuria was never seen, microhaematuria was seen after only three courses, and mild dysuria after only one course. Pharmacokinetic studies showed that mesnum did not interfere with the metabolism of isophosphoramide or its active anti-tumour metabolite, isophosphoramide mustard. Mesnum therefore enhances the therapeutic ratio of isophosphamide and may thereby increase its clinical efficacy.

Topics: Acrolein; Carcinoma, Bronchogenic; Clinical Trials as Topic; Cyclophosphamide; Female; Hematuria; Humans; Ifosfamide; Kinetics; Lung Neoplasms; Male; Mercaptoethanol; Mesna; Phosphoramide Mustards; Urinary Bladder

A randomized study in 20 patients with cancer was carried out to test the clinical efficacy of sodium-2-mercaptoethane sulfonate (ASTA D-7093; mesnum) as an agent to prevent urotoxic side effects (in particular, hemorrhagic cystitis) during cytostatic therapy with the oxazaphosphorines cyclophosphamide and ifosfamide. Eleven patients received mesnum iv and nine patients received a standard prophylaxis. The frequency of microhematuria was significantly lower in the patients receiving mesnum. A slight microhematuria was observed in one patient. With the standard prophylaxis, all nine patients receiving single-agent therapy with ifosfamide or cyclophosphamide had hematuria and three of these had macrohematuria. According to the available results, a daily mesnum dose of 60% (wt/wt) of the ifosfamide or cyclophosphamide dose is recommended. This dose should be divided into three equal fractions. The first administration should be given concurrently with the cytostatic agent and the subsequent two administrations at 4 and 8 hours after administration of the cytostatic agent. Significantly higher doses of mesnum (eg, 133% of the cyclophosphamide or ifosfamide doses) lead to gastrointestinal disorders, which are easily reversible.

Topics: Clinical Trials as Topic; Cystitis; Drug Therapy, Combination; Hematuria; Humans; Male; Mercaptoethanol; Mesna; Neoplasms; Phosphoramide Mustards; Urologic Diseases

The protective roles of lipoic acid (LA)/vitamin C (VC) and mesna on preventing cyclophosphamide (CYP)-induced haemorrhagic cystitis (HC) were investigated. Swiss mice were divided into five groups randomly. HC was induced by a single dose of CYP injection (150-mg kg(-1) bodyweight). Group I was injected with saline (four times in total) throughout as control group. Group II received CYP and three equal doses of saline. Group III received CYP and three doses of mesna, whereas Group IV (or Group V) received CYP, mesna + two doses of VC (or LA). All injections were performed intraperitoneally. After 24 h of cystitis induction, the bladders were collected for all the experiments. Histological characterization showed that CYP injection resulted in severe HC. Reactive oxygen species (ROS) and thiobarbituric acid reactive substances' levels were increased in CYP group. The activities of antioxidant enzymes, e.g. superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase, were inhibited significantly in CYP groups, respectively. In addition, activation of c-jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinase (MAPK) may be involved in the mechanism of CYP-induced HC but not extracellular signal regulated kinases (ERK). Significant suppression of p38 phosphorylation on Group V suggests that LA and mesna may have synergistic beneficial effect. In Groups III-V, all the parameters of HC and oxidative stress were inhibited significantly. Taking together, we found that these results illustrated that ROS play an important role on CYP-induced HC and the administration of LA/VC with mesna may have therapeutic potential against CYP-induced bladder HC.

Topics: Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Cyclophosphamide; Cystitis; Drug Synergism; Hematuria; MAP Kinase Signaling System; Mesna; Mice; Organ Size; Phosphorylation; Protective Agents; Random Allocation; Reactive Oxygen Species; Thioctic Acid; Urinary Bladder

Cyclophosphamide (CP) is widely used, alone or in combination with other chemotherapeutic agents, for treatment of neoplastic diseases. Its urotoxicity may cause dose-limiting side-effects, for example hemorrhagic cystitis. The agent most often used to prevent this side-effect is mesna (2-mercaptoethane sulfonate). Overproduction of reactive oxygen species during inflammation is one reason for possible urothelial injury. The aim of this study was to evaluate whether combinations of quercetin and epigallocatechin 3-gallate (EGCG), flavonoid antioxidants and mesna could prevent cystitis induced by cyclophosphamide, better than mesna alone. A total of 38 male Sprague-Dawley rats were divided into five groups. Four groups received single dose of CP (100 mg kg(-1)) intraperitoneally at the same time. Group 2 received CP only, group 3 received mesna (3 x 21.5 mg kg(-1)), group 4 received a single dose of mesna+EGCG (2 x 20 mg kg(-1)), and group 5 received a single dose of mesna+quercetin (2 x 20 mg kg(-1)), before and after CP injection. Group 1 (not treated) served as control. CP injection alone resulted in severe cystitis. Mesna resulted in some, but not full, protection against CP toxicity. Quercetin and catechine, together with mesna, resulted in full protection against CP toxicity, on the basis of histopathology of the urinary bladder. It was concluded that oxidants might be important in the pathogenesis of CP-induced cystitis, and that flavonoid antioxidants, used in addition to mesna, may help to ameliorate bladder damage.

Topics: Animals; Antineoplastic Agents, Alkylating; Antioxidants; Catechin; Cyclophosphamide; Cystitis; Drug Therapy, Combination; Flavonoids; Hematuria; Injections, Intraperitoneal; Male; Malondialdehyde; Mesna; Organ Size; Protective Agents; Quercetin; Rats; Rats, Sprague-Dawley; Urinary Bladder

The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: Gleevec (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Benzamides; Bone Neoplasms; Cystitis; Diphosphonates; Drug Approval; Gastrointestinal Neoplasms; Hematuria; Hemorrhage; Humans; Ifosfamide; Imatinib Mesylate; Imidazoles; Mesna; Multiple Myeloma; Orphan Drug Production; Piperazines; Protective Agents; Pyrimidines; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration; Zoledronic Acid

Hemorrhagic cystitis (HC) is the syndrome of hematuria combined with symptoms of lower urinary tract irritation in the absence of bacterial infection or generalized hemorrhagic diathesis. HC often occurs as a difficult complication after autologous as well as allogeneic hematopoietic cell transplantation (HCT). It may be secondary to pretransplant preparative regimen (chemotherapy and/or radiation therapy) or viral infection by adenovirus, JC and BK viruses. The most effective treatment for HC has not been established yet. We report a case of a 17-year-old male with common acute lymphoblastic leukemia (cALL) in second CR, who was treated with high-dose chemotherapy (BuCy conditioning regimen) followed by autologous bone marrow transplantation (ABMT), complicated by hemorrhagic cystitis on day 0 (several hours after infusion of transplant material). The immediate use of increased dose of 2-mercaptoethane sulfonate sodium (mesna), bladder irrigation and intensive hydration with forced diuresis resulted in resolution of macroscopic hematuria on day +3 after the transplant and urinary tract recovery with normalization of urine analysis parameters on day +7.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Hematuria; Humans; Leukemia, Lymphoid; Male; Mesna; Premedication

Chemotherapy with oxazaphosphorines, such as cyclophosphamide (CYP), is often limited by unacceptable urotoxicity. Without uroprotection, hemorrhagic cystitis (HC) becomes dose-limiting. To compare the uroprotective efficacy of classical 2-mercaptoethanesulfonic acid (Mesna) treatment with dexamethasone in CYP-induced HC, male Wistar rats (150-200 g; N = 6 in each group) were treated with saline or Mesna (40 mg/kg, ip) immediately and 4 and 8 h after ip administration of CYP (200 mg/kg). One, 2 or 3 doses of Mesna were replaced with dexamethasone (1 mg/kg, ip). The animals were sacrificed 24 h later. Cystitis was evaluated by determining the changes in bladder wet weight (BWW) and by macroscopic and microscopic analysis. CYP treatment induced a marked increased in BWW (162%, P<0.05), which was significantly inhibited by treatment with 3 doses of Mesna (P<0.05; 80%). The replacement of 1 or 2 doses of Mesna with dexamethasone reduced the increase in BWW by 83.3 and 95%, respectively. Macroscopic analysis of the bladder of rats with CYP-induced HC showed severe edema and hemorrhage, confirmed by microscopic analysis, that also showed mucosal erosion, inflammatory cell infiltration and ulcerations. The replacement of 1 or 2 doses of Mesna with dexamethasone inhibited the CYP-induced increase in BWW and almost abolished the macroscopic and microscopic alterations, with no significant difference between the effects of Mesna and dexamethasone, indicating that both drugs were efficient in blocking HC. However, although the replacement of all Mesna doses with dexamethasone reduced the edema, it did not prevent HC, suggesting that Mesna is necessary for the initial uroprotection.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Cyclophosphamide; Cystitis; Dexamethasone; Hematuria; Hemorrhage; Male; Mesna; Protective Agents; Rats; Rats, Wistar

Twenty-one consecutive patients with refractory or relapsed non-Hodgkin's lymphomas were treated with a novel combination chemotherapy (MINE-BOP), comprising myelosuppressive (ifosfamide, mitoxantrone, etoposide) and non-myelosuppressive (bleomycin, vincristine and prednisone) drugs. Median age of the patients was 42 years and all had intermediate or high-grade lymphoma. Fifteen patients had refractory disease. All patients had previously been treated with one or two regimens, containing anthracyclines. In all cases the duration between the last chemotherapy and the MINE-BOP regimen was shorter than 12 months. Response rate was 57% with 33% complete remission (CR). Median disease-free and overall survivals were 7 and 10 months respectively. The serum LDH level was the only significant prognostic factor in this study. The toxicity of this regimen was moderate with 24% of febrile neutropenia and 9% of microscopic hematuria. Toxic death due to febrile neutropenia was observed in one patient who had bone marrow involvement. To conclude, the addition of non-myelosuppressive drugs to the chemotherapy regimen and shortening the interval between the application of cytotoxic drugs as used in the present study did not show any improvement of response and survival in this group of patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Cytarabine; Disease-Free Survival; Etoposide; Female; Hematuria; Humans; Ifosfamide; Lymphoma, Non-Hodgkin; Male; Mesna; Middle Aged; Mitoxantrone; Neutropenia; Prednisone; Prospective Studies; Recurrence; Survival Rate; Vincristine

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Small Cell; Etoposide; Hematuria; Humans; Ifosfamide; Male; Mesna; Quadriplegia; Urinary Bladder Neoplasms

From January 1983 through August 1988, 318 consecutive patients with refractory germ cell neoplasms were treated with ifosfamide-containing combination chemotherapy. The patients received ifosfamide at 1.2 gm/m2/day with cis-platin 20 mg/m2/day for 5 days and etoposide 75 mg/m2/day for 5 days or vinblastine 0.11 mg/kg on days 1 and 2 for each cycle. Of 277 evaluable patients, NAC was used as an uroprotector in the initial 86 patients while the latter 191 consecutive patients received mesna to reduce urothelial toxicity. Dosages of NAC was 2.0 gm po q 6 hr and for mesna 120 mg/m2 IV push prior to ifosfamide and then 1200 mg/m2/day as continuous infusion of 5 consecutive days. All patients received 3.0 liters of normal saline per day. The number of courses of chemotherapy given in the two groups were similar. Twenty-four of the 86 patients (27.9%) receiving NAC developed hematuria (13 patients - grade 1, 4 patients - grade 2, and 7 patients - grade 3 toxicity). While 8 out of 191 (4.2%) mesna patients developed hematuria (6 - grade 1 and 2 - grade 3) (p < 0.0001). The incidence of severity of renal toxicity was similar in the two groups. Ifosfamide dosage was reduced solely for urothelial toxicity in 11 patients receiving NAC compared with none of the patients receiving mesna (p < 0.0001). Chemotherapy response was similar in the two groups. In conclusion, mesna provides better urothelial protection from ifosfamide-induced toxicity than NAC and allows better maintenance of the drug dosage.

Topics: Acetylcysteine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dysgerminoma; Etoposide; Hematuria; Humans; Ifosfamide; Male; Mesna; Severity of Illness Index; Vinblastine

Topics: Bone Marrow Transplantation; Cyclophosphamide; Cystitis; Hematuria; Humans; Mesna

We studied the efficacy of mesna as a protectant for urotoxicity in pediatric patients receiving chemotherapy including oxazaphosphorines. Nineteen patients with malignant diseases (5 neuroblastoma, 3 acute lymphocytic leukemia, 4 acute non-lymphocytic leukemia, 2 non-Hodgkin lymphoma, 3 osteosarcoma and 2 rhabdomyosarcoma) were treated with a total of 106 courses of therapy between June of 1986 and May of 1989. Of these, no gross hematuria were seen. Microhematuria transiently occurred only in 2 courses (5%) of 1 patient (2%). These data indicated that mesna was highly effective for urotoxicity of oxazaphosphorines without any side effects, especially in pediatric patients.

Topics: Bone Neoplasms; Child; Cyclophosphamide; Cystitis; Female; Hematuria; Humans; Ifosfamide; Leukemia; Lymphoma, Non-Hodgkin; Male; Mercaptoethanol; Mesna; Neuroblastoma; Osteosarcoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rhabdomyosarcoma

Topics: Acetylcysteine; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Hematuria; Humans; Ifosfamide; Mercaptoethanol; Mesna; Urogenital Neoplasms

The Gastrointestinal Tumor Study Group (GITSG) investigated the efficacy of ifosfamide with mesna uroprotection in 30 patients with advanced inoperable pancreatic carcinoma that was confirmed histologically. All patients were required to have at least one bidimensional measurable lesion that could be followed by palpation or radiologic examination. Genitourinary toxicity presenting as hematuria occurred in five patients, but was not severe enough to curtail treatment in any of these patients. The major toxicity was neurologic, with 12 patients (41%) reporting at least one episode; four of which were graded as severe and two as fatal. Three partial tumor responses to treatment were reported (10%) and the median survival time was just 11 weeks. In our experience, ifosfamide with mesna uroprotection does not appear to be active in pancreatic carcinoma.

Topics: Adult; Aged; Carcinoma; Drug Evaluation; Female; Hematuria; Humans; Ifosfamide; Male; Mesna; Nervous System Diseases; Pancreatic Neoplasms

Ifosfamide (1.25 g/m2 intravenously/day x 5) with mesna (20% of the ifosfamide dose x six doses on each day of ifosfamide therapy) was administered to 46 previously treated patients with non-Hodgkin's lymphoma of which 31 were eligible and evaluable. A 29% response rate (9/31) was observed (2 CR and 7 PR) with a median duration of response of 2.5 months. Myelosuppression was dose-limiting. Hemorrhagic cystitis was observed in three patients (10%). Nausea and vomiting was generally mild or moderate. One patient developed transient neurotoxic symptoms with confusion and disorientation. An additional patient developed an anaphylactic-type reaction with shortness of breath and respiratory strider during the fourth course of therapy. Ifosfamide, as a single agent, produces remissions of limited duration in non-Hodgkin's lymphoma in patients in second or third relapse.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Drug Evaluation; Hematologic Diseases; Hematuria; Humans; Ifosfamide; Lymphoma, Non-Hodgkin; Mercaptoethanol; Mesna; Middle Aged

Topics: Adult; Aged; Carcinoma, Bronchogenic; Female; Hematuria; Humans; Ifosfamide; Lung Neoplasms; Lymphoma, Non-Hodgkin; Male; Mercaptoethanol; Mesna; Middle Aged; Neoplasms; Ovarian Neoplasms; Testicular Neoplasms

Mesna is a sulfhydryl compound that reacts with the metabolites of cyclophosphamide that are excreted in the urine and may produce bladder wall irritation. Mesna is converted in the blood to a biochemically inactive compound that is reduced back to mesna in the kidneys. In this way it has the potential to protect the bladder mucosa without interfering with the antineoplastic effect of cyclophosphamide. Twenty-two patients who had developed hemorrhagic cystitis from cyclophosphamide were treated again with cyclophosphamide and mesna prophylaxis. A total of 68 cycles of cyclophosphamide were given with mesna, with a median of three cycles per patient. A recurrence of cystitis was prevented in all but one patient. Thus, mesna is effective in preventing recurrent cystitis in patients receiving further cyclophosphamide.

Topics: Adolescent; Adult; Child; Cyclophosphamide; Cystitis; Cystoscopy; Female; Hematuria; Humans; Male; Mercaptoethanol; Mesna; Prospective Studies; Rhabdomyosarcoma; Sarcoma

We examined the possibility of continuing oxazaphosphorine therapy in patients with previously documented cyclophosphamide- or ifosfamide-induced hematuria by concomitant use of the uroprotective agent, mesna. Twenty-six patients with oxazaphosphorine-induced hematuria received additional cyclophosphamide or ifosfamide with mesna. Twelve, who had previously experienced hematuria with ifosfamide, received a median of 3.5 more cycles of ifosfamide/mesna. One patient developed further hematuria (grade 1). Of seven patients who experienced acute hematuria with cyclophosphamide, one experienced further hematuria after an additional course of cyclophosphamide with mesna, but none of the other six patients developed further hematuria when administered either cyclophosphamide/mesna (two) or ifosfamide/mesna (four). Seven patients who had chronic cyclophosphamide-induced hematuria had further oxazaphosphorine with mesna without worsening of their hematuria. Mesna is an effective uroprotective agent that prevents recurrent acute hemorrhagic cystitis, or worsening of chronic hemorrhagic cystitis, in patients receiving further oxazaphosphorine after previous ifosfamide- or cyclophosphamide-induced hematuria.

Topics: Adolescent; Adult; Child; Child, Preschool; Cyclophosphamide; Cystitis; Female; Hematuria; Hemorrhage; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Neoplasms

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Hematuria; Humans; Ifosfamide; Infant; Mercaptoethanol; Mesna

Following bone marrow transplantation employing conditioning including 'high-dose' cyclophosphamide, 65 patients were studied for the subsequent development of symptomatic haemorrhagic cystitis. There was no protection from the urothelial toxicity of cyclophosphamide metabolites afforded by the concurrent administration of 2-mercaptoethane sodium sulphonate (mesna) if timing errors in administration were made. Other factors which might increase the risk of haemorrhagic cystitis due to cyclophosphamide administration include the prior administration of busulphan to patients with chronic granulocytic leukaemia, in whom the incidence of haemorrhagic cystitis was 36% compared with 4% in all other patients. We have also investigated the use of intravesical prostaglandin E2 as a treatment for haemorrhagic cystitis in eight patients, two of whom appeared to obtain major benefit.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Cyclophosphamide; Cystitis; Female; Hematuria; Hemorrhage; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mesna; Middle Aged; Risk Factors

In an open multicenter phase III trial, prophylaxis of the urinary tract with sodium 2-mercaptoethanesulfonate (Mesnum) was carried out in 242 patients treated with oxazaphosphorines for various malignant tumors. Under the protection of Mesnum 29 patients were treated with cyclophosphamide (Endoxan), 195 with ifosfamide (Holoxan) and 8 with trofosfamide (Ixoten). Other cytostatics were also used (polychemotherapy) in 92 cases. On administration of Mesnum, 7 macrohematurias reappeared, only 3 of them however with correct application, and 22 microhematurias, 12 of them with correct application. Cylindrurias were re-established in 3 patients. In Mesnum we have a compound which can control the urotoxicity ("uroprotector") of oxazaphosphorines which limits their therapeutic use.

Topics: Adolescent; Adult; Aged; Bronchial Neoplasms; Child; Cyclophosphamide; Female; Gastrointestinal Diseases; Hematuria; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Middle Aged; Ovarian Neoplasms; Phosphoramide Mustards; Testicular Neoplasms

Ifosfamid is an alkylating cytostatic agent which appears to differ in its clinical spectrum from the chemically similar cyclophosphamid. So far, however, its pronounced urotoxicity has limited dosage. In spite of prophylactic measures such as forced diuresis and alkalinization of the urine, the treatment has frequently has to be broken off because of macrohematuria and hemorrhagic cystitis. By repeated intravenous administration of sodium-mercapto-ethan-sulfonate (NNI: Mesnum) the urotoxic side effects of ifosfamid can largely be prevented. During 26 cycles of treatment in 18 patients, asymptomatic microhematuria was observed 6 times and macrohematuria only once in a patient with vesico-vaginal fistula. In another case where therapy had had to be discontinued because of hemorrhagic cystitis in spite of conventional prophylaxis, the treatment could be continued without change in the urine sediment under prophylaxis with Mesnum. Mesnum does not affect the antitumoral activity of ifosfamid.

Topics: Adult; Cyclophosphamide; Cystitis; Hematuria; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Osteosarcoma