Optimum combination of targeted 131I and total body irradiation for treatment of disseminated cancer.

PURPOSE

Radiobiological modeling was used to explore optimum combination strategies for treatment of disseminated malignancies of differing radiosensitivity and differing patterns of metastatic spread. The purpose of the study was to derive robust conclusions about the design of combination strategies that incorporate a targeting component. Preliminary clinical experience of a neuroblastoma treatment strategy, which is based upon general principles obtained from modelling, is briefly described.

METHODS AND MATERIALS

The radiobiological analysis was based on an extended (dose-rate dependent) formulation of the linear quadratic model. Radiation dose and dose rate for targeted irradiation of tumors of differing size was in part based on microdosimetric considerations. The analysis was applied to several tumor types with postulated differences in the pattern of metastatic spread, represented by the steepness of the slope of the relationship between numbers of tumors present and tumor diameter. The clinical pilot study entailed the treatment of five children with advanced neuroblastoma using a combination of 131I metaiodobenzylguanidine (mIBG) and total body irradiation followed by bone marrow rescue.

RESULTS

The theoretical analysis shows that both intrinsic radiosensitivity and pattern of metastatic spread can influence the composition of the ideal optimum combination strategy. High intrinsic radiosensitivity generally favors a high proportion of targeting component in the combination treatment, while a strong tendency to micrometastatic spread favors a major contribution by total body irradiation. The neuroblastoma patients were treated using a combination regimen with an initially low targeting component (2 Gy whole body dose from targeting component plus 12 Gy from total body irradiation). The treatment was tolerable and resulted in remissions in excess of 9 months in each of these advanced neuroblastoma patients.

CONCLUSIONS

Radiobiological analysis, which incorporates simple models of metastatic spread, emphasizes the importance of the total body irradiation component in a targeting/total body irradiation combination strategy. However, the analysis favors a larger targeting component than is used in clinical practice at present. A cautious escalation of the 131I mIBG component in the combination treatment of advanced neuroblastoma appears justified.