High Incidence of Secondary Brain Tumours After Radiotherapy and Antimetabolites

Authors: Relling MV, et al.
Source: Lancet 1999; Volume 354: pages 34 - 39

Background

St. Jude Children's Research Hospital has published an early report of their data from Total XII protocol regarding secondary brain tumors in patients treated with acute lymphoblastic leukemia (ALL). One hundred and eighty-eight patients were enrolled with 182 obtaining a complete response (CR) with induction chemotherapy. Maintenance chemotherapy consisted of daily oral 6-mercaptopurine (6-MP) and weekly intravenous methotrexate (MTX). Those patients at high risk (WBC over 25000 or presence of the Philadelphia chromosome) and/or with overt CNS disease received cranial irradiation. Dose of radiation was based on whether treatment was for prophylaxis (18 Gy) or for actual CNS disease (24 Gy). The results reveal that 6 of 52 patients who received cranial irradiation developed a brain tumor, while there were none found thus far in the 101 patients who did not receive cranial irradiation. The factors associated with a higher rate of disease include high erythrocyte concentrations of thioguanine nucleotide metabolites (metabolites of 6-MP) and defective thiopurine methyltransferase (enzyme that helps metabolize 6-MP) phenotype.

Summary/Discussion/Conclusion

St. Jude Children's Research Hospital (SJCRH) has been one of the pioneers in pediatric cancer care internationally. Being that acute leukemia is the most common childhood malignancy, SJCRH has extensively researched its treatment and accumulated a great deal of data on survival and late complications. A recently published trial in the JCO has documented their rate of secondary brain tumors from ALL treatment prior to 1988. They demonstrated less than a 2% incidence (21 patients out of over 1600) at 20 years.1 A great majority of the patients reviewed had received cranial irradiation (over 1200 patients). This manuscript was published to warn of findings that were discovered with patients treated from 1988 to 1991 in regards to secondary brain tumors.

The rate of secondary brain tumors was an alarming 12.8% in patients receiving cranial irradiation. The abstract is cautious against the routine use of cranial irradiation. However, careful attention to the paper reveals the significant differences in the systemic chemotherapy that may have been a factor in increasing the rate of secondary brain malignancy. The cranial irradiation doses were entirely similar to patients treated in the past at SJCRH. The major difference was that systemic MTX was given intravenously during the radiation therapy (RT), which had not been done previously. Also, the 6-MP oral daily dose concurrent with RT was also significantly higher than prior concurrent doses. This, coupled with the information that patients with a defective enzyme in breaking down 6-MP had a higher propensity in developing secondary brain tumors (43% versus 8% at 8 years), leads one to believe that the intensification of antimetabolite therapy plays a very large role in the adverse outcomes described in this paper.

These data do support that cranial irradiation is associated with secondary brain tumors from ALL treatment. However, one must incorporate antimetabolite systemic therapy into the picture. Judicious use of cranial irradiation is still warranted, as the standard of care remains that cranial irradiation in high-risk patients. It would appear prudent to avoid systemic MTX and even 6-MP during RT.