Neurophysiological study of peripheral neuropathy after high-dose Paclitaxel: lack of neuroprotective effect of amifostine.
OBJECTIVE
To determine if there is a beneficial effect of amifostine in preventing or reducing the neuropathy induced by high-dose paclitaxel.


METHODS
Breast cancer patients receiving high-dose infusional paclitaxel (725 mg/m(2)/24 h) in combination with doxorubicin (165 mg/m(2)/96 h) and cyclophosphamide (100 mg/kg/2 h; ACT) were studied on two autologous peripheral blood stem cell transplant protocols, one with and one without amifostine (740 mg/m(2) administered over 10 min before and 12 h after initiation of the paclitaxel infusion). Patients were evaluated before ACT and 20-40 days later with neurological examination, a composite peripheral neuropathy score, peroneal and sural nerve conduction studies, and quantitative sensory testing.


RESULTS
There was no significant difference in paclitaxel maximum concentration, systemic clearance, or area under the curve determinations. Narcotic requirement as well as recovery of hematopoietic counts were also similar in subjects with or without amifostine. After ACT was administered, there was a decrease in peroneal nerve compound muscle action potential amplitude and sural nerve sensory action potential amplitude, as well as an increase in vibratory and cold detection thresholds. Clinical composite peripheral neuropathy scores were similar despite amifostine treatment; and logarithm to the base 2 ratios post/pre ACT showed no significant effect of amifostine on peroneal nerve compound muscle action potential, sural nerve sensory action potential, vibratory detection thresholds, or cold detection thresholds. All subjects had acroparesthesias and lost their ankle deep-tendon reflexes after administration of ACT.


CONCLUSIONS
Single high-dose paclitaxel produces predictable clinical and neurophysiological changes so that patients receiving high-dose therapy are ideal subjects to test the effectiveness of neuroprotective agents. Amifostine was ineffective in preventing or reducing the neurotoxicity of high-dose paclitaxel.
Openshaw
Harry
H
Department of Neurology, City of Hope National Medical Center, Duarte, California 91010, USA. hopenshaw@coh.org
Beamon
Karen
K
Synold
Timothy W
TW
Longmate
Jeff
J
Slatkin
Neal E
NE
Doroshow
James H
JH
Forman
Stephen
S
Margolin
Kim
K
Morgan
Robert
R
Shibata
Stephen
S
Somlo
George
G
D000328:Adult; D004999:Amifostine / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy; D003520:Cyclophosphamide / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009294:Narcotics / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000009:adverse effects* / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D009294:Narcotics; D011837:Radiation-Protective Agents; D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D004999:Amifostine; D017239:Paclitaxel