A phase I/II dose-escalation/efficacy study of palliative stereotactic body radiosurgery, including bioanatomic imaging to assess response

Abstract

Stereotactic Body Radiotherapy (SBRT) is a treatment methodology used to treat small tumor volumes to high doses of radiation while minimizing dose to surrounding organs at risk. This abstract describes the results of an ongoing Phase I/II study evaluating palliative single-dose body radiosurgery. Eligibility criteria included: a well-circumscribed tumor (primary or metastatic) on contrast-enhanced CT scan diameter ≤6 cm; age ≤18 years; life expectancy ≥3 months. No chemotherapy or immunotherapy were allowed ≤3 weeks prior to ≤4 weeks after treatment. Patients were stratified to dose levels by tumor volume (Fig. 1) For treatment planning, the GTV was represented by the contrast enhancing-lesion. The CTV = GTV. The PTV consisted of the CTV with ≤7 mm margin added in all directions to account for errors, systematic or random. It was recommended that ≥95% of the CTV be encompassed within the 65% (±15%) isodose cloud volume. The Primary Endpoints were acute toxicity (Phase I) and local control (Phase II). For the Phase I arm, 3 patients were enrolled per cohort. DLT was defined as any treatment-related grade 4 or 5 acute toxicity within the treated regions (chest/abdomen/pelvis) using NCI CTC 3.0. The continuous reassessment method (CRM) was used to determine the next dose level. The maximum tolerated dose (MTD) was defined as the dose at which 2/6 patients had a treatment-related dose-limiting toxicity (DLT) within 3 months after treatment. For the Phase II arm, the dose at which LC at 3 months was ≥80% was the desired endpoint. LC was defined by RECIST criteria. A minimum of 5 patients were enrolled per cohort. After 5 patients had been followed for three months, the CRM could be invoked to modify dose. For small tumors (median pre-treatment diameter 2.3 cm) treated on the second dose tier, both the Phase I and Phase II arm have completed 3-month follow-up. All lesions received 22.5 Gy prescribed at the 80% IDL. The median follow-up time was 140 days with a 100% survival rate. The 3-month incidence of any DLT was zero percent. The 3-month LC rate was 80%, but failures beyond this time point are beginning to be seen. In patients who had stable disease or partial response (as defined by RECIST) at three months, the median decrease in quantitative PET uptake was 21%. 22.5 Gy given stereotactically in a single fraction to small tumors was not associated with significant toxicity, and dose for small tumors will now be escalated. When three successive CRM iterations predict the same dose, the MTD will have been defined. For medium and large tumors, the Phase I arm has not yet completed accrual(table 1).