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MISONIDAZOLE NEUROPATHY - A PROSPECTIVE STUDY:

B. Melgaard, 0. KGhler, H. Sand Hansen, J. Overgaard, J. Munck- Hansen, O.B. Paulson. Neurology Service and Department of Head- and Neck-Oncology, Finseninstituttet, Copenhagen, Department of Oncology, Radiumstationen, Arhus and Department of Neurology, Rigshospitalet, Copenhagen, Denmark.

The first clinical trials of the radio-sensitizing drug misonida- zole in the treatment of solid tumours resulted in the develop- ment of peripheral neuropathy in 30 - 508 of the patients. This led to a reduction of the maximum dose of misonidazole to less than 11 g pr. m2 over 4 weeks. In order to evaluate the frequency of peripheral neuropathy in patients receiving misonidazole up to a maximum dose of 11 g, we carried out a prospective study in patients who participated in a double blind study of misonidazole versus placebo combined with radio-therapy treatment for cancer of the pharynx or larynx.

MATERIAL This consisted of 79 patients of which nine patients were exclu- ded from different causes. The remaining 70 patients consisted of 5 2 males and 18 females with a median age of 61 and 60 years re- spectively. All patients were referred to radiotherapy treatment of carcinoma of the pharynx or larynx and in addition were given either placebo or misonidazole during the first' four weeks of ra- diotherapy. Misonidazole/placebo were given in two or five weekly fractions during the four week period up to a total dose of 11 g .

All patients were examined neurologically before start of treat- ment and three and eight weeks after. Vibration perception tres- hold (VPT) of the'big toes and indices were measured in all pa- tients at each examination.

RESULTS Sixteen patients developed symptoms and signs of peripheral neu- ropathy during or shortly after termination of treatment. Symp- toms consisted of painful paraesthesiaes in the feet and someti- mes in the hands accompanied in some patients by loss of sensa- tion in the feet resulting in difficulties in walking. Signs ranged from loss of touch-and-pain sense in the toes to severe impairment of all sensory modalities in the feet and lower legs.

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Achillestendon reflexes were preserved in all patients. In all patients hut one VPT increased with more than 50% from the first to the second examination. 14 patients out of 3 6 receiving miso- nidazole (38%) developed neuropathy while this occurred in two patients in the placebo group of 3 4 patients. (P<o,005). The one patient without increase in VPT received placebo. In the groupre- ceiving misonidazole treatment no differences were found between those who developed peripheral neuropathy and those who did not in average daily alcohol intake, fractioning of misonidazole or VPT levels preceeding therapy. Initial levels of VPT in patients without symptoms and sings of neuropathy increased more than 50% in the feet in lo patients from the first to the second or the third examination. In 2 more patients an increase between 2 0 and 50% were found while in the remaining levels were unchanged. It turned out that 7 of those patients exhibiting VPT increases had received placebo while 5 had received misonidazole.

DISCUSSION The occurence of peripheral neuropathy in this double-blind study was as frequent as that reported in previous report where higher doses of misonidazole were employed. There was however a tendency towards milder and in some cases transient symptoms in the pre- sent material. Misonidazole neuropathy is a striking clinical en- tity completely dominated by sensory symptoms which are often ve- ry painful and at clinical examination preserved achillestendon reflexes are consistently found. It was surprisingly found that neither initial VPT levels nor reported alcohol intake could predict the development of periphe- ral neuropathy. Thus high alcohol intake and high VPT levels were equally prevalent in the non-neuropathy and neuropathy groups re- ceiving misonidazole. Furthermore subclinical evaluation of the development of periphe- ral neuropathy by means of VPT measurement proved none-useful as those patients in whom an increase was found turned out to be e- venly divided between placebo and misonidazole groups. Thus we have been unable to define patients at risk with regard to the development of peripheral neuropathy. This study was supported by a grant 5/80 from The Danish Cancer Society.