Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer.

Kemp, George M.; Rose, Peter G.; Lurain, John R.; Berman, Michael L.; Manetta, Alberto; Roullet, Bernard; Homesley, Howard D.; Belpomme, D.; Glick, John H.

doi:10.1200/jco.1996.14.7.2101

Cited by 415 publications

(201 citation statements)

References 54 publications

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“…Pre-existing hearing loss or chronic noise exposure clearly increases the risk for persisting auditory symptoms at least threefold, raising the question of clinical implications. Trials focusing on the ability of chemical substances, such as amifostine, to protect normal tissue from cisplatin toxicity are becoming increasingly important (Kemp et al, 1996). Future studies should prospectively evaluate the risk factors identified and use them as stratification criteria for clinical trials aiming at the prevention of cisplatin induced ototoxicity.…”

Section: Discussionmentioning

confidence: 99%

Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer

Bokemeyer

Berger²,

Hartmann³

et al. 1998

Br J Cancer

291

179

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Summary This study evaluates the degree and relevance of persisting ototoxicity after cisplatin-based standard-dose chemotherapy for testicular cancer, with emphasis on identification of potential factors for an increased risk of this late sequel. Hearing thresholds of 86 patients with a median age of 31 years (range 21-53 years) and a median follow-up time of 58 months (range 15-159 months) were assessed by conventional pure-tone audiometry. Interviews were conducted evaluating the patients' history with special regard to audiological risk factors, as well as circumstances of ototoxic symptoms. Details concerning treatment and patient variables were extracted retrospectively from the patients' charts. An additional screening programme assessed current body functions, blood parameters and other late toxicities. Symptomatic ototoxicity persisted in 20% of patients (59% tinnitus, 18% hearing loss, 23% both), while 10% had experienced completely reversible ototoxic symptoms for a duration of 1-18 months after treatment. Symptoms were bilateral in 81 % of patients. Hearing thresholds were compatible with cisplatin-induced hearing loss in 42% of audiograms performed. Subjective (history) and objective (audiogram) findings were not always consistent. The following statistically significant risk factors for ototoxicity were established: high cumulative dose of cisplatin (P < 0.0001); history of noise exposure (P = 0.006). Additionally, high doses of vincristine (P = 0.001) seemed to result in reversible ototoxic symptoms. No other independent risk factors were identified. In conclusion, persisting ototoxicity represents a clinical sequel for approximately 20% of testicular cancer patients treated at standard dose but may affect more than 50% of patients receiving cumulative doses of cisplatin > 400 mg m-2. Previous noise exposure may also result in a threefold increased risk for cisplatin ototoxicity. Future studies should use these risk factors as important stratification criteria for trials aiming at the evaluation and prevention of cisplatin-induced ototoxicity.Keywords: chemotherapy; ototoxicity; long-term toxicity; testicular cancerThe ototoxic potential of the chemotherapeutic agent cisplatin was recognized 2 decades ago (Piel et al, 1974). Despite the widespread use of cisplatin in standard treatment protocols for testicular, ovarian, head and neck, lung and other types of cancers, data on the frequencies of ototoxicity are not consistent, and risk factors have not been clearly identified so far. The measurement of the auditory function is limited because of the different diagnostic methods used for objective assessment and the subjective perception of symptoms; patients' characteristics, such as age or noise exposure, may additionally influence the hearing ability and different definitions of 'normal' and 'abnormal' hearing thresholds may also cause further discrepancies in reported results.In the current study the auditory function was evaluated in a homogeneous group of young men receiving cisplatin-based com...

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Section: Discussionmentioning

confidence: 99%

Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer

Bokemeyer

Berger²,

Hartmann³

et al. 1998

Br J Cancer

291

179

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“…Large comparative clinical trials of amifostine in patients with advanced ovarian cancer (Kemp et al, 1996), rectal cancer (Liu et al, 1992), and head and neck cancer (Brizel et al, 2000) have been completed. These trials have shown that amifostine protects against the cytotoxic effects of cisplatin, cyclophosphamide, and radiation therapy.…”

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confidence: 99%

p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

et al. 2003

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To determine the role of p53 protein on the cellular effects of amifostine, we used molecularly engineered HCT116 colon cancer cells in which the p53 gene was inactivated by targeted homologous recombination or p53 protein was degraded by high-level expression of papillomavirus E6 protein. Amifostine induced a G1 arrest and protected against paclitaxel toxicity in p53-proficient but not in p53-deficient cells. In the absence of p53 protein, amifostine enhanced the cytotoxicity of paclitaxel. In addition, treatment of HCT116 cells with amifostine alone resulted in apoptotic cell death. Compared with p53-deficient cells, p53-proficient cells exhibited low-level resistance to amifostine-induced apoptosis. Amifostine induced the expression of p53 protein in p53-proficient cells and the expression of p21 protein in both p53-proficient and -deficient cells. These findings indicate that amifostine-induced G1 arrest and cytoprotection are mediated via a pathway that is dependent on p53 protein and that amifostine-induced expression of p21 protein is not sufficient to sustain a G1 arrest or to mediate cytoprotection. In addition, these findings identify p53 protein as a mechanism of resistance to amifostine-induced apoptosis.

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“…, and the evidence of its broad spectrum cytoprotective properties resulting in a reduction of both haematologic and organ toxicities without tumour protection (Kemp et al, 1996;Elias et al, 2000;Hartmann et al, 2000aHartmann et al, , 2000b. Preservation of renal function using the combination of cisplatin, ifosfamide and etoposide plus amifostine had been previously demonstrated (Hartmann et al, 1999b).…”

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confidence: 99%

A randomized trial of amifostine in patients with high-dose VIC chemotherapy plus autologous blood stem cell transplanation*

et al. 2001

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This pilot study evaluates the degree of side effects during high-dose chemotherapy (HD-VIC) plus autologous bone marrow transplant (HDCT) and its possible prevention by the cytoprotective thiol-derivate amifostine. Additionally, the in-patient medical costs of both treatment arms were compared. 40 patients with solid tumours were randomized to receive HD-VIC chemotherapy with or without amifostine (910 mg/m 2 at day 1–3) given as a short infusion prior to carboplatin and ifosfamide. Patients were stratified according to pretreatment. HDCT consisted of an 18 h infusion of carboplatin (500 mg/m 2/ d over 18 h), ifosfamide (4 g/m 2 /d over 4 h) and etoposide (500 mg/m 2 /d) all given for 3 consecutive days. All patients received prophylactic application of G-CSF (5 μg kg −1 subcutaneously) to ameliorate neutropenia after treatment. Patients were monitored for nephrotoxicity, gastrointestinal side effects, haematopoietic recovery, as well as frequency of fever and infections. The median fall of the glomerular filtration rate (GFR) was 10% from baseline in the amifostine group (105 to 95 ml min −1 ) and 37% in the control patient group (107 to 67 ml min −1 ) ( P < 0.01). Amifostine-treated patients revealed a less pronounced increase in albumine and low molecular weight protein urinary excretion. Stomatitis grade III/IV occurred in 25% without versus 0% of patients with amifostine ( P = 0.01). Acute nausea/vomiting was frequently observed immediately during or after the application of amifostine despite intensive antiemetic prophylaxis consisting of 5-HT 3 -receptor antagonists/dexamethasone/trifluorpromazine. However, delayed emesis occurred more often in the control patients. Engraftment of neutrophil (> 500 μl −1 ) and thrombocytes (> 25 000 μl −1 )were observed at days 9 versus 10 and 10 versus 12, respectively, both slightly in favour of the amifostine arm. In addition, a lower number of days with fever and a shortened duration of hospital stay were observed in the amifostine arm. The reduction of acute toxicity observed in the amifostine arm resulted in 30% savings in costs for supportive care (Euro 4396 versus Euro 3153 per patient). Taking into account the drug costs of amifostine, calculation of in-patient treatment costs from the start of chemotherapy to discharge revealed additional costs of Euro 540 per patient in the amifostine arm. This randomized pilot study indicates that both organ and haematotoxicity of HD-VIC chemotherapy can be ameliorated by the use of amifostine. Additionally, a nearly complete preservation of GFR was observed in amifostine-treated patients which may be advantageous if repetitive cycles of HDCT are planned. Larger randomized trials evaluating amifostine cytoprotection during high-dose chemotherapy are ...

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Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer.

Abstract: Pretreatment with amifostine reduces the cumulative hematologic, renal, and neurologic toxicities associated with the CP regimen, with no reduction in antitumor efficacy.

Cited by 415 publications

References 54 publications

Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer

Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer

p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

A randomized trial of amifostine in patients with high-dose VIC chemotherapy plus autologous blood stem cell transplanation*

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