High dose BCNU chemotherapy with autologous bone marrow transplantation and full dose radiotherapy for grade IV astrocytoma

Abstract

Summary In a series of 22 patients, high dose BCNU (800-1,000 mgm-2) with autologous bone marrow transplantation was given as the first post-surgical treatment for grade IV astrocytoma and followed by full dose radiotherapy. When compared to historical experience and matched to control patients in national studies, there appeared to be a small prolongation of survival but no increase in the proportion of long survivors. Acute myelosuppression was mild but toxicity to lung and liver was substantial and limited further dose escalation. Late bone marrow failure was seen in 4 patients. Pharmacokinetic studies were performed and suggested that the late marrow failure was due to persistence of BCNU at the time of marrow return.Despite the suggestion of a prolongation of survival this approach is not routinely recommended and a randomised trial is probably not justified.The management of high grade glioma is unsatisfactory (Bloom, 1982). Radiotherapy following surgery will prolong survival by several months but long term survivors from grade IV astrocytoma (glioblastoma multiforme) are rare. Conventional chemotherapy has little to offer. These tumours share the relatively poor cellular chemosensitivity of most solid human cancers. In addition penetration of drugs into high grade gliomas is poor. They often have poor vascularisation and probably also a partially intact bloodbrain barrier in parts of the tumour (Workman, 1986).has been tested in conventional doses following surgery and radiotherapy for the treatment of high grade glioma. It gives a small, statistically significant, prolongation of survival but overall results are still poor with a median survival of only 12 months (Walker et al., 1980;Green et al., 1983). The dose of BCNU that can be given is limited by myelosuppression which is characteristically later in onset than that seen with most cytotoxic drugs (Phillips et al., 1986). The dose of BCNU can be increased when it is given with autologous bone marrow transplantation (ABMT) and such high doses of BCNU can produce useful palliative effects in patients whose grade gliomas recur after surgery and radiotherapy. Two recent studies have reported a small number of long term survivors with this approach (Fingert & Hochberg et al., 1984;Phillips et al., 1986). The late onset of myelosuppression (usually after 10 days) when coupled with the prompt recovery produced by autologous bone marrow transplantation (usually before 20 days) would be expected to result in a relatively short period of myelosuppression even for high dose BCNU. We have explored the use of high dose BCNU (HDBCNU), 800-1,000 mg m -2 with autologous bone marrow transplantation as the primary post-surgical treatment of grade IV astrocytoma followed by full dose radiotherapy. Our hypothesis was that the high dose of the drug when given to tumours before irradiation might be expected to result in improved penetration into the tumour and an enhanced anti-tumour effect which could then be supplemented by full dose radiotherapy. Tumour volume reducti...

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