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© 1999 American Society for Clinical Oncology
American Society of Clinical Oncology Clinical Practice Guidelines for the Use of Chemotherapy and Radiotherapy ProtectantsFrom the American Society of Clinical Oncology Address reprint requests to American Society of Clinical Oncology, Health Services Research Department, 225 Reinekers Lane, Suite 650, Alexandria, VA 22314; email guideline{at}asco.org ABSTRACT PURPOSE: Because toxicities associated with chemotherapy and radiotherapy can adversely affect short- and long-term patient quality of life, can limit the dose and duration of treatment, and may be life-threatening, specific agents designed to ameliorate or eliminate certain chemotherapy and radiotherapy toxicities have been developed. Variability in interpretation of the available data pertaining to the efficacy of the three United States Food and Drug Administration–approved agents that have potential chemotherapy- and radiotherapy-protectant activity—dexrazoxane, mesna, and amifostine—and questions about the role of these protectant agents in cancer care led to concern about the appropriate use of these agents. The American Society of Clinical Oncology sought to establish evidence-based, clinical practice guidelines for the use of dexrazoxane, mesna, and amifostine in patients who are not enrolled on clinical treatment trials. METHODS: A multidisciplinary Expert Panel reviewed the clinical data regarding the activity of dexrazoxane, mesna, and amifostine. A computerized literature search was performed using MEDLINE. In addition to reports collected by individual Panel members, all articles published in the English-speaking literature from June 1997 through December 1998 were collected for review by the Panel chairpersons, and appropriate articles were distributed to the entire Panel for review. Guidelines for use, levels of evidence, and grades of recommendation were reviewed and approved by the Panel. Outcomes considered in evaluating the benefit of a chemotherapy- or radiotherapy-protectant agent included amelioration of short- and long-term chemotherapy- or radiotherapy-related toxicities, risk of tumor protection by the agent, toxicity of the protectant agent itself, quality of life, and economic impact. To the extent that these data were available, the Panel placed the greatest value on lesser toxicity that did not carry a concomitant risk of tumor protection. RESULTS AND CONCLUSION: Mesna: (1) Mesna, dosed as detailed in these guidelines, is recommended to decrease the incidence of standard-dose ifosfamide-associated urothelial toxicity. (2) There is insufficient evidence on which to base a guideline for the use of mesna to prevent urothelial toxicity with ifosfamide doses that exceed 2.5 g/m2/d. (3) Either mesna or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide use in the stem-cell transplanta-tion setting. Dexrazoxane: (1) The use of dexrazoxane is not routinely recommended for patients with metastatic breast cancer who receive initial doxorubicin-based chemotherapy. (2) The use of dexrazoxane may be considered for patients with metastatic breast cancer who have received a cumulative dosage of 300 mg/m2 or greater of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy. (3) The use of dexrazoxane in the adjuvant setting is not recommended outside of a clinical trial. (4) The use of dexrazoxane can be considered in adult patients who have received more than 300 mg/m2 of doxorubicin-based therapy for tumors other than breast cancer, although caution should be used in settings in which doxorubicin-based therapy has been shown to improve survival because of concerns of tumor protection by dexrazoxane. (5) There is insufficient evidence to make a guideline for the use of dexrazoxane in the treatment of pediatric malignancies, with epirubicin-based regimens, or with high-dose anthracycline-containing regimens. Similarly, there is insufficient evidence on which to base a guideline for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease. (6) Patients receiving dexrazoxane should continue to be monitored for cardiac toxicity. Amifostine: (1) Amifostine may be considered for the reduction of nephrotoxicity in patients receiving cisplatin-based chemotherapy. (2) Although amifostine may be considered for the reduction of neutropenia in patients receiving alkylating agents, chemotherapy dose reduction or growth factor use should be considered as an alternative to the use of amifostine. (3) Present data are insufficient to recommend the use of amifostine for protection against thrombocytopenia or the routine use of amifostine to prevent cisplatin-associated neurotoxicity or ototoxicity. Similarly, present data are insufficient to support the use of amifostine for the prevention of paclitaxel-associated neurotoxicity. (4) Use of amifostine may be considered to decrease the incidence of acute and late xerostomia in certain patients undergoing fractionated radiation therapy in the head and neck region, although present data are insufficient to recommend the use of amifostine to prevent radiation therapy–associated mucositis. Details regarding dose and management of amifostine side effects, including hypotension, are included in the guidelines. Further research is warranted to further define the role of these chemotherapy- and radiotherapy-protectant agents in the care of cancer patients. THE TOXICITIES OF chemotherapy and radiotherapy can adversely affect short and long-term patient quality of life, can limit the dose and duration of treatment, can be life-threatening, and may contribute to both the medical and nonmedical costs of cancer care. These adverse consequences of cancer treatment have led to the development of specific agents designed to ameliorate or eliminate certain chemotherapy- and radiotherapy toxicities. The ideal chemotherapy- and radiotherapy-protectant agent would prevent all toxicities, from non–life-threatening side effects (alopecia) to irreversible morbidities (hearing loss, neurotoxicity) to potentially fatal events (severe cardiomyopathy, severe thrombocytopenia), without adversely affecting the antitumor efficacy of the cancer therapy, and would be easy to administer and relatively nontoxic in its own right. However, most agents developed to date have a much more narrow spectrum of toxicity protection. For example, the development of serotonin receptor antagonists has led to dramatic improvement in the ability to control chemotherapy-related nausea and vomiting. Because their mechanism of action and cellular targets made it highly unlikely that their use would interfere with the antitumor activity of concomitant chemotherapy, and because the toxicity end point—acute nausea and vomiting—is relatively easy to measure, the design of randomized, controlled trials to assess the clinical efficacy of the serotonin receptor antagonists was straightforward. Evidence-based guidelines have already been developed for their use. Similarly, the development of myeloid and, more recently, thrombopoietic growth factors made it possible to ameliorate myelosuppression. Again, tumor protection, at least in nonhematologic malignancies, has not been a major concern because of the narrow cellular target of these agents. The American Society of Clinical Oncology (ASCO) has published and updated guidelines for the use hematopoietic colony-stimulating factors,1,2 thus the use of these agents will not be readdressed here. Variability in interpretation of the available data regarding the efficacy of the three United States Food and Drug Administration (FDA)–approved agents that have potential chemotherapy- and radiotherapy-protectant activity—dexrazoxane, mesna, and amifostine—and questions about the role of these protectant agents in cancer care led ASCO to convene an Expert Panel under the auspices of its Health Services Research Committee to develop recommendations regarding the use of dexrazoxane, mesna, and amifostine (Table 1).4,5
LITERATURE REVIEW AND DATA COLLECTION Pertinent information from the literature published during the time period of 1966 through May 1999 was retrieved and reviewed for the creation of these guidelines. Searches were conducted of MEDLINE and Cancer Lit (National Library of Medicine, Bethesda, MD) to obtain pertinent articles. Search words included amifostine, mesna, and dexrazoxane. Directed searches of the primary articles were performed. In addition, certain authors/investigators were contacted to obtain more recent and, in some cases, unpublished information. CONSENSUS DEVELOPMENT BASED ON EVIDENCE The entire Panel met twice. The purpose of the first meeting was to identify topics to be addressed by the guidelines, to develop a strategy for completion of the guidelines, and to do a preliminary review of the initial literature search. The purpose of the second meeting was to review the developed guidelines and evaluate more critically the recommendations and supporting evidence. The guidelines were circulated in draft form, and all members of the Panel had an opportunity to comment on the levels of evidence as well as the systematic grading of the data supporting each recommendation. Subsequently, the guidelines in draft form were submitted to independent reviewers (see Acknowledgment). Final text editing was performed by Martee L. Hensley, MD, MSc, and Lynn M. Schuchter, MD. GUIDELINES AND CONFLICT OF INTEREST The content of the guidelines and the manuscript was reviewed and approved by the Health Services Research Committee and by the ASCO Board of Directors before dissemination. All members of the Expert Panel complied with ASCO policy on conflict of interest, which requires disclosure of any financial or other interest that might be construed as constituting an actual, potential, or apparent conflict. Members of the Expert Panel completed ASCO's disclosure form and were asked to reveal ties to companies developing products that might potentially be affected by promulgation of the guidelines. Information was requested regarding employment, consultancies, stock ownership, honoraria, research funding, expert testimony, and membership on company advisory committees. The Panel made decisions on a case-by-case basis as to whether an individual's role should be limited as a result of a conflict. REVISION DATES At annual intervals, the Panel chairpersons and two Panel members designated by the chairpersons will determine the need for revisions to the guidelines based on an examination of current literature. The entire Panel will be reconvened every 3 years to discuss potential changes, or more frequently if new information suggests that more timely modifications may be warranted. When appropriate, the Panel will recommend revised guidelines to the Health Services Research Committee and the ASCO Board of Directors for review and approval. DEFINITION OF TERMS Chemotherapy and radiotherapy protectants were defined as those agents with potential ability to protect nontumor tissues from the cytotoxic effects of chemotherapy and/or radiotherapy. In this definition, the Panel did not include those agents that may ameliorate known chemotherapy side effects (nausea/vomiting, myelosuppression) but that do not specifically offer nontumor cells protection from the effects of chemotherapy and/or radiotherapy. These guidelines address only those chemotherapy and radiotherapy protectants that are FDA-approved for use in humans. SUMMARY OF OUTCOMES ASSESSED The most important outcomes in the care of cancer patients are overall survival, disease-free survival, quality of life, toxicity, and cost-effectiveness of the interventions used to improve survival and quality of life.6 The technologies assessed for these guidelines, chemotherapy and radiotherapy protectants, are interventions that aim to decrease toxicities that are associated with cancer therapy. Although it is possible that interventions that decrease toxicity may improve quality of life, this relationship cannot be assumed without formal measurements of quality of life. Similarly, although the ability to make chemotherapy more tolerable, as manifested by a reduction in laboratory abnormalities, may make it possible to deliver more chemotherapy without dose delay or dose reduction for many tumors, it has not been shown that dose delays or reductions decrease survival outcomes. Most data regarding chemotherapy- and radiotherapy-protectant agent efficacy come from trials that have been designed to assess toxicity without prospective assessment of quality of life and without sufficient power to assess impact on survival. Given this rather limited focus of the available data, the Panel weighed the evidence with particular attention to the seriousness of the toxicity the agent was designed to prevent, the efficacy of the agent in preventing such toxicity, the potential additional toxicities associated with the use of the chemotherapy- or radiotherapy-protectant agent, and best available evidence for impact on tumor response rates and survival. It is the opinion of the Panel that further research is needed to determine the impact of protectant use on quality of life and on the cost-effectiveness of using protectants where the benefits of use are modest. As noted in a prior ASCO publication on outcome assessment of cancer treatment, there is no minimum benefit above which treatments are justified; rather, benefits should be balanced against toxicity and cost.6
MESNA
DEFINITION OF PROBLEM High, single ifosfamide doses (3.8 to 5 g/m2/d) demonstrate biphasic plasma elimination with a terminal half-life of 15 hours.20,21 In contrast, multiple-day, lower-dose ifosfamide (1.6 to 2.4 g/m2/d for 3 days) shows monoexponential decay with a half-life of 6.9 hours.20 Both cyclophosphamide and ifosfamide have been reported to demonstrate time-dependent increases in metabolism when administered in fractionated doses over several days.21-24 Increased clearance of the parent compound is accompanied by increases in systemic and urinary tract exposure to active metabolites. The significance of this greater exposure of the urinary tract to oxazaphosphorine active metabolites with respect to mesna dose requirements has not been fully evaluated. However, in one study of 11 patients receiving a 5-day fractionated course of ifosfamide (1.5 g/m2/d) plus mesna (0.3 g/m2 at hours 0, 4, and 8), the mean molar excess of urinary mesna over the 4-hydroxy metabolite of ifosfamide (the ratio of mesna to 4-hydoxy-ifosfamide in the urine) ranged from 11 to 72 on day 1 and 6 to 40 on day 5.24 Thus, although urinary excretion of ifosfamide metabolites rises with fractionated doses administered over several days, mesna in standard doses seems to sufficiently inactivate the urotoxic ifosfamide metabolites.
MESNA PHARMACOLOGY Only a small portion of a dose remains in the circulation as the physiologically active compound. Both mesna and dimesna are very hydrophilic and, therefore, remain in the intravascular compartment, where they are rapidly cleared by the kidneys. The free sulfhydryl (thiol) groups of mesna combine directly with a double bond of acrolein and with other urotoxic 4-hydroxy-oxazaphosphorine metabolites to form stable nontoxic compounds. Because urinary mesna concentration greatly exceeds plasma mesna concentrations, regional detoxification of urotoxic oxazaphosphorine metabolites occurs in the urinary system. This restriction of mesna to the urinary system implies that mesna neither protects against nonurologic toxicities of oxazaphosphorines nor interferes with their cytotoxic activity.25,26 Mesna, in doses of up to 70 to 100 mg/kg IV, was shown to produce no toxic effect on bone marrow, hepatic, renal, or CNS functions in a phase I/II study.27 Vomiting and diarrhea occurred only after doses of more than 80 mg/kg.28 Bioavailability and systemic and urinary pharmacokinetics of mesna influence its efficacy as a urothelial protectant. After oral administration, mesna has a bioavailability of 50% to 75% and urinary mesna concentrations are approximately one half of those observed after IV infusion. The mean terminal half-life of mesna is 0.4 hours, and the half-life of dimesna is 1.2 hours. Urinary excretion of mesna is almost complete in the first 2 to 4 hours after IV administration but is increased to approximately 8 hours after oral dosing, largely because of delayed onset while the drug is absorbed from the gastrointestinal tract.29,30
GUIDELINES FOR THE USE OF MESNA AS A UROTHELIAL PROTECTANT Level of Evidence: I Grade of Recommendation: A Early studies compared the risks of hematuria in patients receiving uroprotection with mesna (17% to 66% of total oxazaphosphorine dose administered IV at hours 0, 4, and 8) or standard prophylaxis (approximately 4 L/d IV fluids, furosemide, alkalinization of the urine) after administration of ifosfamide (50 mg/kg/d for 5 days) or cyclophosphamide (50 mg/kg for 1 day).31,32 Fluid intake was limited to a maximum of 2 L/d in the mesna group. In the standard prophylaxis group, nine of nine patients developed microhematuria, and three of nine subsequently developed macrohematuria. In the mesna group, two of 11 patients had microhematuria. There were no differences in tumor response rates in this small study. More recently, the efficacy of mesna against ifosfamide-induced urotoxicity was assessed in a double-blind, randomized, placebo-controlled study involving 91 assessable patients. Forty-five patients received mesna (20% of the ifosfamide dose administered IV at hours 0, 4, and 8) and 46 patients received placebo. Both groups received 2 L/d of IV fluid.33 The incidence of moderate to severe hematuria was 6.7% in the mesna group and 32.6% in the placebo group (P = .0008). Micturition pain and a feeling of residual urine were not observed in any of the patients who received mesna, whereas 19.6% of patients in the placebo group had micturition pain (P = .0003) and 15.2% had a feeling of residual urine (P = .0009). In a retrospective review of 748 nonrandomized patients, all of whom received ifosfamide 50 mg/kg/d for 5 days, 399 patients were treated with mesna and 409 patients received standard prophylaxis. The incidence of any urotoxicity was 3.5% among patients receiving mesna and 38% among patients receiving standard prophylaxis (IV hydration, administration of diuretics, and alkalinization). Grade 2 (defined as macroscopic hematuria and fibrinous deposits/severe reddening at cystoscopic examination) or grade 3 (defined as macrohematuria, reduced bladder capacity, and ulcerous or necrotic findings on cystoscopic examination) urothelial toxicity was seen in 0.5% of mesna-treated patients and 18.5% of patients who received standard prophylaxis.34 Additional phase II and observational studies corroborate the results of these studies, consistently showing a decreased incidence of urotoxicity when mesna is used concomitantly with oxazaphosphorines.35-41 Of note, urothelial protection is not absolute, as even among patients who received mesna, the incidence of urotoxicity in these studies ranged from 1% to 10%. Mesna Dosing With Standard-Dose Ifosfamide Guideline: It is suggested that the daily dose of mesna be calculated to equal 60% of the total daily dose of ifosfamide and be administered as three bolus doses given 15 minutes before and 4 and 8 hours after administration of each dose of ifosfamide when the ifosfamide dose is less than 2.5 g/m2/d administered as a short infusion. For use with continuous infusion ifosfamide, mesna may be administered as a bolus dose equal to 20% of the total ifosfamide dose followed by a continuous infusion of mesna equal to 40% of the ifosfamide dose, continuing for 12 to 24 hours after completion of the ifosfamide infusion. Level of Evidence: III Grade of Recommendation: B The dose and schedule of administration of mesna used in clinical trials has varied. However, the most common dose and schedule consists of mesna administered at 20% of the total daily ifosfamide dose (20% weight/weight) given 15 minutes before and 4 and 8 hours after ifosfamide infusion for a total of 60% weight/weight dose of ifosfamide. The most common ifosfamide doses and schedule used in these trials were 1.2 to 2.0 g/m2/d for 5 days with ifosfamide typically administered as a 60-minute infusion. The FDA-approved dosing schedule of mesna is 20% weight/weight of ifosfamide administered IV before and 4 and 8 hours after ifosfamide administration. Mesna has also been administered as a continuous infusion at a dose equal to 60% to 160% weight/weight of the ifosfamide dose. There are no experimental or clinical data to support the use of mesna at doses greater than 60% weight/weight ifosfamide for standard doses of ifosfamide. Mesna doses greater than 120% of the ifosfamide dose may be associated with increased gastrointestinal toxicity.31 Continuous mensa infusion has been most commonly used in protocols where ifosfamide was administered as a 24- to 72-hour infusion. Generally, a mesna loading dose of 20% of the oxazaphosphorine dose is administered, and the mesna infusion equal to 40% of the total daily ifosfamide dose is administered concomitantly with the ifosfamide and continued for 12 to 24 hours after the termination of the ifosfamide infusion. Continuous infusion of mensa provides constant delivery of free thiols to the urinary system and thus has the theoretical advantage of avoiding periods of low levels of protection that are associated with the IV bolus dose schedule of mensa. Use of diuretics that alkalinize the urine or IV hydration in excess of 2 L/d is unnecessary in patients receiving mesna in the non–stem-cell transplantation setting. Urinary alkalinization may be counterproductive in the prophylaxis of oxazaphosphorine-related hemorrhagic cystitis.7,42 In rats, diuretics that acidify the urine, such as ammonium chloride and furosemide, prevent cyclophosphamide-associated bladder toxicity, whereas a diuretic that alkalinizes the urine (acetazolamide) does not. It is possible that high urine flow rates may limit the usefulness of mesna by decreasing the bladder concentration of mesna. Mesna Dosing With High-Dose Ifosfamide Guideline: There is insufficient evidence on which to base a recommendation for the use of mesna with ifosfamide doses in excess of 2.5 g/m2/d. The efficacy of mesna for urothelial protection with very high-dose ifosfamide has not been established. Based on the longer half-life of ifosfamide in these dosages, more frequent and prolonged mesna dosage regimens may be necessary for maximum protection against urotoxicity. Level of Evidence: IV Grade of Recommendation: D It is unclear whether standard doses of mesna (20% of total daily ifosfamide dose [20% weight/weight] at hours 0, 4, and 8) are sufficient to provide neutralization of the higher amounts of urotoxic metabolites that are generated by larger ifosfamide doses. The dose-dependent elimination has significant implications for designing appropriate mesna dosing schedules, as the duration of mesna uroprotection may need to be prolonged to provide adequate protection against ifosfamide bladder toxicity when high, single-day doses are administered. The efficacy of mesna as a urothelial protectant when used with high-dose ifosfamide was assessed in a randomized, cross-over trial involving 13 patients with non–small-cell lung cancer.43 All patients received ifosfamide 6 g/m2 as a single dose on day 1 with or without mesna, with cross-over to the other treatment regimen in cycle 2. Mesna 1.2 g/m2 (20% of total ifosfamide dose) was administered intravenously at hours 0, 4, and 8 on days 1 through 3. Macrohematuria was observed in one of 10 patients who received mesna and in seven of 10 patients who received ifosfamide without mesna (P < .025). Two studies using ifosfamide doses of 4 to 16 g/m2/d plus mesna have been reported. In both studies, ifosfamide and mesna were administered by continuous infusion over 3 to 4 days, with the mesna infusion continuing for 12 to 24 hours after completion of ifosfamide.44,45 In the study of Le Cesne et al,45 acute renal failure was observed in 10% of patients (four of 40) who received 4 g/m2/d of ifosfamide for 3 days with mesna. All cases of acute renal failure were irreversible, and all had a clinical presentation consistent with acute tubular necrosis. Hematuria was observed in 27% of patients on this regimen. In the study of Elias et al,44 six of 29 patients (21%) developed renal insufficiency. Mesna Administration by the Oral Route Guideline: IV administration of the first dose of mesna at a dose equal to 20% of the total daily ifosfamide dose, followed at 2 and 8 hours by 40% weight/weight of the ifosfamide dose administered orally, may be considered an acceptable alternative to the three-dose IV mesna regimen when the total ifosfamide daily dose is less than 2.0 g/m2. Level of Evidence: II Grade of Recommendation: B In a recent study by Goren et al,30 12 patients receiving ifosfamide (1.2 g/m2/d for 5 days) were randomized to receive either the IV mesna at hours 0, 4, and 8 or IV mesna administered at hour 0 followed by oral mesna (40% weight/weight of the ifosfamide dose) at hours 2 and 8 on the first day of the 5-day course. Patients were subsequently crossed over to the alternative regimen on days 2 through 5. The profile of urinary excretion rates in the amount of mesna excreted during their first 12 hours after the ifosfamide dose was similar for the two regimens; however, the IV-oral profile showed less fluctuation in the excretion rate and higher trough values. During hours 12 to 24, approximately eight-fold more mesna was excreted by patients who were given the IV-oral regimen compared with those who were given the IV regimen. These data suggest that the IV-oral regimen results in sufficient urinary excretion of mesna to be uroprotective. No ifosfamide-induced hematuria was detected. The IV-oral regimen was well tolerated despite the inclusion of patients receiving highly emetogenic chemotherapy. However, it should be noted that for this study, mesna tablets (300 mg each) were developed to mask the unpleasant taste of the mesna solution, and this may have made compliance with the oral regimen more likely. Without the availability of a tablet form of mesna, the IV formulation has been administered by the oral route in two prospective studies. In one study, all mesna doses (400 mg/m2) were administered by mouth four times daily, beginning 1 hour before ifosfamide administration (1.5 g/m2/d). Only one of 25 patients required hospital admission for vomiting in order to receive IV mesna. In this phase II study, nine of 25 patients developed microscopic hematuria. There were no episodes of macroscopic hematuria.46 A three-armed prospective study47 randomized patients to receive either (1) IV mesna at 33% of the total daily ifosfamide dose at hours 0, 4, and 8, (2) IV mesna at 33% of the total daily ifosfamide dose at hours 0 and 4 followed by oral mesna at 66% of the total ifosfamide dose at hour 8, or (3) IV mesna at 50% of total daily ifosfamide dose at hours 0 and 4. In this study involving 122 patients, the incidence of urotoxicity was 0% for the three-dose all-IV mesna regimen, 1.36% for the IV followed by oral mesna regimen, and 2.7% for the two-dose IV regimen. An oral dosage formulation of mesna is not currently available. The IV solution is often diluted with juice or a carbonated beverage to mask its disagreeable taste. Compliance may be a concern. A better oral formulation might lead to the more routine use of oral mesna. Oral mesna dosage and schedule for patients who receive high-dose ifosfamide regimens require further investigation. Mesna Use With Cyclophosphamide Guideline: Mesna plus saline diuresis or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide in the setting of stem-cell transplantation. Level of Evidence: II Grade of Recommendation: C
The data are inconsistent regarding the benefit for mesna compared with saline diuresis in patients receiving high-dose cyclophosphamide. Shepard et al14 studied 100 patients undergoing allogeneic (70 patients) or autologous (30 patients) bone marrow transplantation. Patients randomized to IV hydration received IV fluid Hows et al16 studied 61 patients undergoing allogeneic bone marrow transplantation conditioned with cyclophosphamide 50 mg/kg/d for 4 days or 60 mg/kg/d for 2 days plus total-body irradiation. Patients were randomized to receive either 6 L of saline per day plus furosemide and acetazolamide or 3 to 4 L of saline per day plus mesna at 40% weight/weight cyclophosphamide given at 0, 3, 6, and 9 hours after cyclophosphamide administration. The incidence of macroscopic hematuria in the group of patients who received hydration alone was 44%, compared with 11% in the mesna group. However, one patient in the mesna group and one in the saline hydration group required nephrostomy tube drainage and multiple blood transfusions.16
Randomized trials show that saline diuresis or mesna plus saline diuresis are superior to continuous bladder irrigation (CBI) for the prevention of hemorrhagic cystitis. Atkinson et al13 studied 34 patients receiving allogeneic bone marrow transplantation conditioned with cyclophosphamide 60 mg/kg/d for 2 days plus busulfan or total-body irradiation. Patients were randomized to receive 6 L/d IV hydration plus continuous bladder irrigation with sterile normal saline. No patients received mesna. The incidence of macroscopic hematuria was 29% in the group randomized to hydration alone versus 48% in the group randomized to CBI (P, nonsignificant). Vose et al48 prospectively studied 200 patients undergoing allogeneic (30 patients) or autologous (170 patients) bone marrow transplantation who were conditioned with a variety of regimens, all including cyclophosphamide Surveillance of Patients Receiving Ifosfamide and/or Cyclophosphamide and Mesna Guideline: There are insufficient data to make a recommendation regarding specific monitoring for hemorrhagic cystitis in patients who receive mesna to ameliorate ifosfamide- or high-dose cyclophosphamide–associated urothelial toxicity. Recommendations for monitoring reflect the design of clinical trials involving mesna use and the opinion of the Panel. Level of Evidence: V Grade of Recommendation: D Based on the design of trials involving mesna as a urothelial protectant, a baseline pretreatment urinalysis should be obtained. While patients are receiving ifosfamide or high-dose cyclophosphamide, monitoring for the development of hematuria and monitoring of urine output are prudent. DEXRAZOXANE
DEFINITION OF PROBLEM In a retrospective review of 3,941 patients receiving doxorubicin-containing chemotherapy, the cumulative risk of CHF was correlated with patient age, total anthracycline dose, and dose schedule.53 Older patients who received the drug every third week had the greatest risk of developing CHF at a given cumulative drug dose, compared either with younger patients or with those treated with a weekly schedule. Neither a previous history of mediastinal irradiation nor the concurrent administration of other potentially cardiotoxic agents was shown to influence the risk of developing CHF once the effects of age, schedule, and cumulative dose were considered.53 Children had a decreased risk of cardiomyopathy compared with adults at any given cumulative doxorubicin dose.53 However, other reported data suggest that the risk of cardiomyopathy may be increased in children,54,55 particularly in those who received mediastinal irradiation56 or irradiation that included the lower part of the heart.57,58 Studies conducted in adult59 and pediatric60 patient populations have not reliably correlated changes in serially obtained pre-ejection period/left ventricular ejection time (LVET) ratios or ECGs with the development of CHF. Several reports suggest that changes in quantitative radionuclide angiocardiography studies allow identification of patients whose anthracycline therapy should be discontinued.61-63 In one study, cardiomyopathic effects were present in endomyocardial biopsies from patients who had received as little as 45 mg/m2 of doxorubicin. Significant histologic changes were observed at cumulative doxorubicin doses that did not cause an increase in the pre-ejection period/LVET ratio.64 The degree of endomyocardial injury was statistically correlated with the dose and schedule of doxorubicin administration. Less severe injury was associated with a lower cumulative doxorubicin dose, administration using a weekly schedule, and administration using a continuous infusion, compared with patients who received doxorubicin using a high-dose schedule that was administered every third week.65,66 In addition, the frequency of severe morphologic changes in endomyocardial biopsy specimens was lower in patients who received a continuous infusion of doxorubicin compared with patients who received the drug using a high-dose rate administered every third week.66 Patients with one or more of the following risk factors were shown to benefit from careful prospective, monitoring of cardiac function: previous mediastinal irradiation; history of coronary, valvular, or myocardial heart disease; long-standing history of hypertension (diastolic blood pressure of > 100 mmHg obtained at least 5 years before the initiation of doxorubicin), age more than 70 years; and previous treatment with more than 550 mg/m2 of doxorubicin. Patients without these risk factors had a negligible risk of anthracycline-related cardiomyopathy and did not benefit from serial noninvasive monitoring of cardiac function.67 Long-term follow-up studies of pediatric patients who received anthracyclines for various cancers have demonstrated impaired left ventricular function in 20% to 40% of survivors68-72 The frequency of cardiac toxicity was increased in female patients,73,74 those who received a higher cumulative anthracycline dose,68,73-75 and those who had longer follow-up since diagnosis.72,74,75
DEXRAZOXANE PHARMACOLOGY
GUIDELINES FOR THE USE OF DEXRAZOXANE Level of Evidence: II Grade of Recommendation: C Three randomized, placebo-controlled trials of dexrazoxane in patients with advanced breast cancer have been conducted. In all studies, women with prior anthracycline-based therapy were excluded, as were women with preexisting cardiac disease. In a study involving 92 patients, Speyer et al76 demonstrated a cardioprotective benefit with dexrazoxane use when the end point was defined as the percent decrease in the left ventricular ejection fraction (LVEF) or clinical CHF. Women with advanced or metastatic breast cancer were treated with fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 (FAC) in conjunction with either dexrazoxane or placebo. For the subset of patients with a cumulative doxorubicin dose of 400 to 499 mg/m2, the mean decrease in LVEF was 16% in patients receiving placebo and 1% in patients receiving dexrazoxane (P = .001). Clinical CHF developed in 11 patients in the placebo arm versus two patients in the dexrazoxane arm (P = .02). In this small study, there were no statistically significant differences detected in response rates or progression-free survival. Myelosuppression was slightly greater in patients receiving dexrazoxane. Two additional placebo-controlled trials reported by Swain et al80,81 involving a combined total of 534 patients address the potential cardioprotective benefit of dexrazoxane use in advanced breast cancer patients who receive doxorubicin-based therapy. Cardiac events were defined as a decline in LVEF to at least 5% below the institution's lower limit of normal, a decline in LVEF of at least 20% from the patient's baseline, or the development of clinical CHF. Cardiac events were observed in 14% of patients who received dexrazoxane versus 31% of patients receiving placebo. The hazard ratio for development of cardiac toxicity of placebo to dexrazoxane for the larger of these two studies (n = 349) was 2.63 (95% confidence interval [CI], 1.61 to 4.27); this value seemed to reach statistical significance. The smaller study (n = 185) demonstrated a similar clinical and statistically significant hazard ratio of 2.00. In the larger of these two trials, which was the only reported trial sufficiently powered to detect a difference in response rates, there was a statistically significant difference in response rates: the overall response rate (complete responses plus partial responses) was 47% in patients receiving dexrazoxane versus 61% in patients receiving placebo (P = .019). Overall survival rates were not statistically different between the two arms in either of the studies. As in the study conducted by Speyer et al,76 myelosuppression in the studies of Swain et al80,81 was greater in patients receiving dexrazoxane. Grade 4 granulocytopenia was documented in 75% of patients in the dexrazoxane arm compared with 64% of patients receiving placebo (P = .009). In addition, nausea and vomiting were significantly more frequent in patients receiving dexrazoxane in the Swain studies. Current evidence demonstrates that although dexrazoxane use has a measurable cardioprotective benefit in patients with advanced breast cancer who receive doxorubicin-based chemotherapy, its use (1) has not been shown to increase overall or disease-free survival, (2) may cause increased hematologic toxicity, and (3) may decrease tumor response rates. In addition, the cardioprotective benefit can be seen with delayed initiation of dexrazoxane therapy (vide infra). Thus the use of dexrazoxane with initial doxorubicin-based therapy is not recommended.
Delayed Use in Patients With Metastatic Breast Cancer Who Have Received Level of Evidence: III Grade of Recommendation: B
A single, nonrandomized study involving 201 women addressed the issue of beginning dexrazoxane therapy in women with metastatic breast cancer who had received a cumulative dose
Although there was no statistically significant difference in time to progression, there was a significant difference in overall survival. The hazard ratio for death for continued placebo versus dexrazoxane was 2.2 (95% CI, 1.4 to 3.3; P < .001); ie, the risk of dying was twice as great in patients who continued on placebo after receiving
No trial reported to date addresses the issue of whether patients who received Use in Patients Receiving Adjuvant Chemotherapy for Breast Cancer Guideline: The use of dexrazoxane in the adjuvant setting is not suggested outside of a clinical trial. Level of Evidence: V Grade of Recommendation: Panel Consensus There are no randomized, controlled clinical trials using dexrazoxane in the adjuvant breast cancer setting. The Panel is concerned that the decreased response rates seen in the metastatic setting could potentially diminish the benefit of adjuvant chemotherapy, and thus the use of dexrazoxane is not recommended in this setting unless patients are participating in a clinical trial that addresses this question.
Other Malignancies
Use in Adult Patients With Other Malignancies
Guideline: The use of dexrazoxane can be considered in adult patients who have received Level of Evidence: III to V Grade of Recommendation: Panel Consensus
There are limited data addressing the use of dexrazoxane in patients receiving anthracycline-based chemotherapy in other disease settings.82,83 No large study addressing the issues of tumor protection has been published. However, because the pathophysiology of cardiotoxicity is not expected to differ from that of the metastatic breast cancer setting, the use of dexrazoxane can be considered in patients who have received Use in Pediatric Malignancies Guideline: There is insufficient evidence to make a recommendation for use of dexrazoxane in the treatment of pediatric malignancies. A single randomized, open-label trial involving 38 patients demonstrated a cardioprotective benefit in pediatric sarcoma patients who received doxorubicin-based therapy,84 but the trial is insufficiently powered to rule out tumor protection. This randomized, prospective, non–placebo controlled trial evaluated the effect of treatment with dexrazoxane (ICRF-187) on cardiac function in patients 4 to 24 years of age with Ewing's sarcoma, peripheral neuroectodermal tumor, rhabdomyosarcoma, or nonrhabdomyosarcoma soft tissue sarcoma. Eighteen patients were randomized to treatment with combination chemotherapy that included doxorubicin (50 to 70 mg/m2/cycle). Twenty patients were randomized to therapy with the same combination chemotherapy in addition to dexrazoxane (1,000 to 1,400 mg/m2/cycle) given 15 minutes before doxorubicin. Multigated radionuclide angiography scans were obtained before therapy and after cumulative doxorubicin doses of 210, 310, 360, and 410 mg/m2. The nuclear medicine physicians who interpreted the multigated radionuclide angiography scans were blinded to the patients' randomization group, but the treating physicians were not blinded to the randomization status. Dose-limiting toxicity was defined as a reduction in LVEF to less than 45%, a decrease in LVEF of greater than 20% from baseline, or evidence of clinical CHF. The cumulative doxorubicin dose at which dose-limiting cardiac toxicity occurred was significantly lower for the control patients than for the dexrazoxane treated patients (310 mg/m2 v 410 mg/m2; P < .05). The proportion of patients who ever experienced dose-limiting cardiac toxicity was significantly higher among patients in the controls group than among the dexrazoxane-treated patients (10 of 15 patients v four of 18; P < .01). The objective response rates were 81% (13 of 16; three complete responses and 10 partial responses) for the control patients and 80% (16 of 20; four complete responses and 12 partial responses) for the dexrazoxane-treated patients (including three nonrandomized patients). Within the limited power of this small study to detect such differences, this study showed no significant differences between dexrazoxane-treated patients and controls in terms of event-free survival time at 24 months (43% v 39%), median survival time (43 v 24 months), or overall survival (61% v 44%). Grade 3 thrombocytopenia occurred significantly more frequently in patients who were treated with dexrazoxane. There are ongoing trials addressing the role of dexrazoxane in pediatric patients with acute lymphoblastic leukemia, T-cell non-Hodgkin's lymphoma, and Hodgkin's disease. Other Anthracycline Doses and Schedules Use in Patients Receiving Other Anthracyclines or Other Anthracycline Dose Schedules Guideline: The current data regarding the use of dexrazoxane in patients who receive epirubicin-based therapy are insufficient to make a recommendation. There is currently no evidence regarding the use dexrazoxane with other potentially cardiotoxic agents (liposomal doxorubicin, mitoxantrone) or with other dosing schedules (prolonged infusion doxorubicin); thus no guideline can be made for the use of dexrazoxane with other anthracyclines and other anthracycline dose schedules. Two nonblinded, randomized, controlled trials using variable drug regimens demonstrated the cardioprotective effect of dexrazoxane when used with initial epirubicin-based therapy for metastatic breast cancer85 or soft tissue sarcoma,83 but the trials were underpowered to detect differences in response rates. In the study by Venturini et al,85 162 women with metastatic breast cancer were randomized to epirubicin-based chemotherapy ± dexrazoxane. There was no placebo control. Patients with a baseline LVEF of less than 50% were excluded; however, patients may have received prior anthracycline-based therapy in the adjuvant setting. Patients who had received a prior anthracycline were treated with cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2 ± dexrazoxane. Patients without prior anthracycline exposure received single-agent, high-dose epirubicin (120 mg/m2) (HDepi) ± dexrazoxane. All cardiotoxic events occurred in patients receiving HDepi. There were no cardiac events in any patients receiving standard-dose cyclophosphamide, epirubicin, and fluorouracil. The incidence of cardiac toxicity for all patients on study was 7.3% for patients receiving dexrazoxane and 23.1% for patients on the control arm. The odds ratio for developing cardiac toxicity in patients treated with dexrazoxane versus control patients was 0.29 (95% CI, 0.09 to 0.78; P = .006). Lopez et al83 reported a study involving 95 patients with metastatic breast cancer who were randomized to receive single-agent HDepi 160 mg/m2 ± dexrazoxane. These 95 breast cancer patients were combined with 34 patients treated with HDepi 160 mg/m2 ± dexrazoxane for soft tissue sarcoma. Using this combined population, a cardioprotective benefit (measured as a smaller decline in LVEF) was reported for patients who received dexrazoxane therapy. The response rate for the soft tissue sarcoma patients was 37.5% in the control group and 11% in the dexrazoxane group (P = .11). The response rate was 69% for the breast cancer patients who did not receive dexrazoxane (95% CI, 56% to 82%) and 67% for the dexrazoxane-treated breast cancer patients (95% CI, 53% to 81%). Both the Venturini et al85 and the Lopez et al83 studies used sample sizes based on cardiac events as the primary end point. Although both studies report no significant difference in response rate or survival rates, both have limited power to detect differences in these important outcomes. Use in Patients Receiving High-Dose Anthracycline Therapy Guideline: There is insufficient evidence on which to base a recommendation for the use of dexrazoxane in patients who receive high-dose anthracycline therapy. The doses of doxorubicin that were used in the randomized trials demonstrating cardioprotective efficacy for dexrazoxane have ranged from 50 to 60 mg/m2 doxorubicin (adults) to 70 mg/m2 doxorubicin (pediatric patients). Epirubicin doses used in randomized trials range from 60 to160 mg/m2. The impact of dexrazoxane on cardiotoxicity for doses outside of these ranges is unknown. Patients With Cardiac Risks Use in Patients With Cardiac Risk Factors Guideline: There is insufficient evidence on which to base a recommendation for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease. There are no studies addressing the use of dexrazoxane in patients with established CHF or with a resting LVEF of less than 45%. In the randomized, placebo-controlled trials, approximately 7% of patients treated with dexrazoxane had cardiac events, despite the fact that all patients had normal baseline LVEFs at time of enrollment. Because the cardioprotective effect of dexrazoxane is not absolute, the use of a doxorubicin-based regimen in patients with established CHF should be carefully individualized. Advanced breast cancer patients with a baseline normal LVEF and a history of hypertension, age older than 65 years, history of a myocardial infarction more than 6 months before beginning doxorubicin therapy, history of mediastinal radiation therapy, or a history of angina were included in the clinical trials of doxorubicin-based therapy ± dexrazoxane. The subset analyses of these patients with cardiac risk factors, but without existing CHF, demonstrated cardioprotection with dexrazoxane use. Monitoring Therapy Termination of Anthracycline Therapy for Patients Receiving Dexrazoxane Guideline: Patients who receive dexrazoxane should continue to undergo cardiac monitoring. After cumulative doxorubicin doses of 400 mg/m2, cardiac monitoring should be frequent. The Panel suggests repeating the monitoring study after a cumulative dose of 500 mg/m2 is reached and subsequently after every 50 mg/m2 of doxorubicin. The Panel suggests that the termination of dexrazoxane/doxorubicin therapy be strongly considered in patients who develop a decline in LVEF to below institutional normal limits or who develop clinical CHF. Level of Evidence: V Grade of Recommendation: Panel Consensus There are no data regarding the continued use of dexrazoxane/doxorubicin therapy in patients with declining LVEFs. The recommendations for cardiac monitoring and for termination of therapy are based on the design of the randomized, placebo-controlled trials. Dose of Dexrazoxane Guideline: It is suggested that patients who are being treated with dexrazoxane receive dexrazoxane at a ratio of 10:1 with the doxorubicin dose, administered via slow IV push or short IV infusion 15 to 30 minutes before doxorubicin administration. Level of Evidence: III Grade of Recommendation: B AMIFOSTINE Amifostine, formerly known as WR-2721, is a naturally occurring thiol that can protect cells from damage by scavenging oxygen-derived free radicals. This drug arose from a classified nuclear warfare project sponsored by the United States Army and was ultimately selected from a group of more than 4,400 chemicals screened because of its superior radioprotective properties and safety profile.86 Subsequently, amifostine was evaluated for its potential role in reducing the toxicity of radiation therapy as well as chemotherapeutic agents that alter the structure and function of DNA, such as alkylating agents and platinum agents. Unlike dexrazoxane and mesna, for which the protective effects are directed against specific organs, amifostine has been evaluated as a broad-spectrum cytoprotective agent. A profile emerged from preclinical studies that demonstrated the ability of amifostine to selectively protect almost all normal tissues except the CNS, but not neoplastic tissues, from the cytotoxic effects of some chemotherapeutic agents and radiation therapy.86,87
MECHANISM OF ACTION OF AMIFOSTINE The mechanism by which amifostine exerts its selective protection of normal tissue is based on the ability of free thiol to be taken up in higher concentration in normal organs than in tumor tissue. The differential uptake of WR-1065 is due to differences in the microenvironment at the tissue level resulting in the slow entry of the free thiol into tumor masses.86,88 Tumors are relatively hypovascular, thus resulting in tissue hypoxia, anaerobic metabolism, and a low interstitial pH. The combined hypovascularity and low pH results in low rates of prodrug activation by alkaline phosphatase. In addition, the distribution of alkaline phosphatase in normal and malignant tissue differs, with higher concentrations of this enzyme found in capillaries and arterioles of normal cells and lower levels of alkaline phosphatase found in tumor tissue. Thus selective protection is afforded normal tissues by reduced metabolism of amifostine to the active protector WR-1065 and low uptake by tumors of WR-1065.89 The end result is as much as a 100-fold greater steady concentration of the free thiol into normal organs such as bone marrow, kidney, salivary glands, and heart, compared with tumor tissue. Once the free thiol WR-1,065 has entered a normal cell, it is available to bind directly to, and thus detoxify, the active species of alkylating agents, platinum agents, or ionizing radiation.
CLINICAL USE OF AMIFOSTINE
PREPARATION AND HANDLING AND ADMINISTRATION OF AMIFOSTINE
QUESTION OF TUMOR PROTECTION WITH AMIFOSTINE
GUIDELINES FOR THE USE OF AMIFOSTINE Guideline: Amifostine may be considered for the prevention of nephrotoxicity in patients who receive cisplatin-based chemotherapy. Level of Evidence: I Grade of Recommendation: A
Several studies have evaluated the role of amifostine in protecting against nephrotoxicity associated with cisplatin chemotherapy. The only randomized clinical study is a phase III study designed to evaluate the protective effects of amifostine in patients receiving cyclophosphamide and cisplatin.93 Two hundred forty-two patients with advanced ovarian cancer were randomized to receive six cycles of cyclophosphamide at 1,000 mg/m2 and cisplatin at 100 mg/m2 alone or the same regimen preceded by amifostine at a dose of 910 mg/m2. The two groups of patients received comparable doses of cisplatin (median cumulative doses, 555 mg/m2 and 500 mg/m2 for the amifostine and control groups, respectively). The clinical end points of the trial included assessment of hematologic and renal function, peripheral neuropathy, and ototoxicity. In terms of nephrotoxicity, by cycles 5 and 6, a significantly greater proportion of patients in the control arm compared with patients on the amifostine arm could not receive cisplatin as scheduled because of elevated serum creatinine level. Thirty-three percent of patients treated with chemotherapy alone had Neutropenia and Thrombocytopenia The magnitude and duration of neutropenia is dependent on the specific chemotherapeutic agents used as well as the intensity of chemotherapy. The studies of amifostine for protection from neutropenia have focused on cyclophosphamide, which is useful in treating many cancer types. Neutropenia, consisting primarily of leukopenia, is the principal dose-limiting toxic effect of cyclophosphamide.96 Although this drug is relatively platelet sparing, significant thrombocytopenia can occur, especially after high doses. Amifostine has also been evaluated in preventing thrombocytopenia associated with carboplatin. Carboplatin toxicity differs significantly from that of cisplatin. The usual dose-limiting toxic effect of carboplatin is bone marrow suppression, particularly thrombocytopenia. The platelet nadir occurs 3 weeks after an IV bolus injection. The degree of thrombocytopenia is based on renal function. A formula for quantifying exposure to carboplatin based on renal function has been proposed by Calvert et al,100 which allows for the individualization of carboplatin dosing and reduction of toxicity. Neutropenia Guideline: The Panel recommends that amifostine be considered for the reduction of neutropenia-associated events in patients who receive alkylating-agent chemotherapy. However, in the absence of clinical data supporting maintenance of the chemotherapy dose-intensity, physicians should consider chemotherapy dose reduction as an alternative to the use of amifostine. Level of Evidence: I Grade of Recommendation: A Thrombocytopenia Guideline: Present data are insufficient to recommend the use of amifostine for protection against thrombocytopenia in patients who receive alkylating-agent chemotherapy or carboplatin. Level of Evidence: II Grade of Recommendation: B Numerous phase I and II studies have been conducted that were designed to evaluate the myeloprotective effects of amifostine against alkylating agents or platinum-based chemotherapy. In these early studies, the results consistently demonstrated a modest reduction in the depth of neutrophil nadir counts.101,102 These preliminary results led to the randomized clinical trial described above93 in which 242 patients with ovarian cancer received cyclophosphamide (1,000 mg/m2) and cisplatin (100 mg/m2) with or without amifostine. One of the end points of this study was the cumulative incidence of neutropenic events through the six cycles of therapy. A neutropenic event was defined as grade 4 neutropenia associated with fever and/or infection that required antibiotic therapy. The percentage of patients who experienced neutropenia-associated events was reduced by 53% in the amifostine arm (P = .019), with a 10% incidence in the amifostine arm and 21% incidence in the chemotherapy-alone arm. There was also a significant reduction in the length of hospital stay (89 v 226 days; P = .019) as well as days on antibiotics (111 v 284 days; P = .031). In this study, complete blood counts were not taken frequently enough to ensure a valid assessment of the impact of amifostine on neutrophil nadirs. There was no difference between the two groups in the number of platelet units or RBC units transfused, although there was a trend in favor of the amifostine group. In a study conducted by the Cancer and Leukemia Group B, the prophylactic use of amifostine with granulocyte-macrophage colony-stimulating factor (GM-CSF) was compared with GM-CSF alone in 50 patients with solid tumors who received high-dose cyclophosphamide therapy (3 g/m2 every 2 weeks).103 The amifostine dose was 740 mg/m2 for the majority of patients and was given before the cyclophosphamide and again 2 hours after completion of the cyclophosphamide. There was no statistically significant difference between the two arms with respect to WBC or granulocyte nadir, platelet nadir, or duration of low blood counts. In a small randomized clinical trial, patients with advanced cancer received carboplatin with or without amifostine.104 The dose of carboplatin administered was 500 mg/m2, and amifostine was given 15 minutes before the carboplatin and repeated 2 hours later because of the long half-life of carboplatin. A total of 55 patients were entered onto the study. There was no difference in the median platelet count after cycle 1, and overall, the platelet nadir was 88 x 109/L in those patients receiving carboplatin alone versus 127 x 109/L in those patients who received amifostine (P = .023). There was no difference in transfusion requirements and no difference in neutropenia between the two arms. In another small randomized phase II study of amifostine with carboplatin (600 mg/m2), there was no difference in platelet nadir or neutrophil nadir, nor was there any difference between the incidence of grade 3/4 thrombocytopenia or neutropenia between those patients who received carboplatin and those who received carboplatin plus three doses of amifostine. Alternative approaches to the administration of amifostine to protect against neutropenia include chemotherapy dose reduction, particularly in the absence of a reason to maintain dose-intensity, or the use of specific hematopoietic growth factors, such as granulocyte colony-stimulating factor or GM-CSF. In addition, close monitoring of temperature and absolute neutrophil count, initiation of empiric antibiotics if a fever develops, and hospitalization until satisfactory resolution of infection and neutropenia are alternative approaches to therapeutic intervention with amifostine or growth factors or dose reduction of chemotherapy. Neurotoxicity and Ototoxicity With prolonged administration of cisplatin, especially in combination with taxane, peripheral neuropathy is becoming a more significant side effect. The peripheral neuropathy is distal, symmetric, and predominantly involves large-fiber sensory, polyneuropathy-producing parathesias, which is dose-related and cumulative (total dose usually more than 300 to 600 mg/m2) and may be irreversible. Ototoxicity secondary to cisplatin manifests as high-frequency hearing loss above the frequency of normal speech and may occur in as many as 30% of treated patients. Rarely, complete hearing loss and disabling tinnitus occur. Dose-limiting side effects of paclitaxel include neutropenia, neurotoxicity, and myalgias. With hematopoietic growth factors, severe cumulative neurotoxicity has emerged as a limitation to dose escalation, prolonged therapy, and combining paclitaxel with other active agents, such as cisplatin. Guideline: Present data are insufficient to support the routine use of amifostine for the prevention of cisplatin-associated neurotoxicity or ototoxicity. Level of Evidence: II Grade of Recommendation: B There are limited data on the role of amifostine in protecting against neurotoxicity and ototoxicity associated with cisplatin-based chemotherapy. Several phase I and II trials, as well as retrospective analyses, have been conducted, but each has significant limitations, which makes it difficult to draw conclusions. From these studies, there is a suggestion that amifostine may protect against cisplatin-associated neurotoxicity. The only randomized study that carefully addressed the issue of neuroprotection is the phase III randomized controlled trial in 242 patients with ovarian cancer who were treated with six cycles of cisplatin (100 mg/m2) and cyclophosphamide (1,000 mg/m2), with or without amifostine, which was described previously.93 After six cycles of therapy, nine patients pretreated with amifostine had grade 3 neuropathy compared with 15 patients treated with chemotherapy alone (P = .029). There was no statistically significant difference between the two arms in terms of ototoxicity, which was defined as clinical hearing loss or tinnitus requiring dose modification or discontinuation of cisplatin (16% in the chemotherapy arm v 9% in the amifostine plus chemotherapy arm; P = .108). The data from additional phase III randomized controlled clinical trials are necessary before amifostine can be recommended to protect against neurotoxicity. Additional studies are needed to determine the role of amifostine in protecting against neurotoxicity associated with chemotherapy. An important part of these studies should be an objective, quantitative measurement of neurotoxicity, such as nerve conduction studies or measurement of vibratory threshold, rather than relying on the often subjective assessment by a clinical examination. Paclitaxel-Associated Neurotoxicity The neuropathy associated with paclitaxel is a peripheral sensory neuropathy. Symptoms of numbness and tingling, pain, impairment of fine motor skills, and difficulty ambulating with loss of deep tendon reflexes have been dose limiting.96 The most common complaint is a burning pain in the feet. The neuropathy is typically reversible when the agent is discontinued.105 Guideline: Present data are insufficient to support the use of amifostine for the prevention of paclitaxel-associated neurotoxicity. Level of Evidence: III Grade of Recommendation: B Recent preclinical studies have demonstrated that amifostine can reduce the toxicities associated with paclitaxel.106 Although paclitaxel toxicity was previously attributed to microtubule stabilization, recent data also show direct effects on DNA.107 There are no data from phase II or III studies to evaluate whether amifostine protects against paclitaxel neurotoxicity. The available clinical data are derived from a phase I dose-escalation study of paclitaxel and amifostine.108 In that study, 22 patients with advanced malignancies were treated with 910 mg/m2 of amifostine and escalating doses of paclitaxel starting at 135 mg/m2 up to 310 mg/m2. Only two patients developed grade 3 neuropathy, which is less than expected compared with other trials of paclitaxel at these doses. Further studies are now ongoing to assess the ability of amifostine to protect against paclitaxel- |
3 L/m2/d plus IV furosemide after each dose of cyclophosphamide to maintain urine output at greater than 100 mL/h. Patients randomized to mesna received mesna (40% weight/weight of cyclophosphamide dose given at hours 0, 3, 6, and 9) plus IV fluids 1.5 L/m2/d. In the group of patients who received hydration alone, 20% of patients developed consistent or severe hemorrhagic cystitis, compared with 33% of patients in the mesna group (P = .31). Among patients in the hydration group, 7.5% of patients developed severe hemorrhagic cystitis, compared with 12.5% in the mesna group (P = .71). Stem-cell engraftment rates did not differ between the two groups.