E. Duffy

Defining the Optimal Planning Target Volume in Image-Guided Stereotactic Radiosurgery of Brain Metastases: Results of a Randomized Trial

PURPOSE To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence. METHODS AND MATERIALS Adult patients with 1 to 3 brain metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board-approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator-based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS). RESULTS Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non-small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in neurocognition or quality of life was observed. CONCLUSIONS SRS was well tolerated, with low rates of LR and RN in both cohorts. However, given the higher potential risk of RN with a 3-mm margin, a 1-mm GTV expansion is more appropriate.

Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers.

PURPOSE Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. METHODS AND MATERIALS Women aged ≥55 years with clinically node-negative, estrogen receptor-positive, and/or progesterone receptor-positive HER2-, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed. RESULTS No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. CONCLUSIONS Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers.

A phase 1 trial of preoperative partial breast radiation therapy: Patient selection, target delineation, and dose delivery.

Purpose Diffusion of accelerated partial breast irradiation (APBI) into clinical practice is limited by the need for specialized equipment and training. The accessible external beam technique yields unacceptable complication rates, likely due to large post-operative target volumes. We designed a phase I trial evaluating preoperative radiotherapy to the intact tumor utilizing widely available technology. Methods Patients received 15, 18, or 21Gy in a single fraction to the breast tumor plus margin. Magnetic resonance imaging (MRI) was used in conjunction with standard computed tomography (CT)-based planning to identify contrast enhancing tumor. Skin markers and an intra-tumor biopsy marker were utilized for verification during treatment. Results MRI imaging was critical for target delineation as not all breast tumors were reliably identified on CT scan. Breast shape differences were consistently seen between CT and MRI but did not impede image registration or tumor identification. Target volumes were markedly smaller than historical post-operative volumes and normal tissue constraints were easily met. A biopsy marker within the breast proved sufficient for set up localization. Conclusions This single fraction linear-accelerator based ABPI approach can be easily incorporated at most treatment centers. In vivo targeting may improve accuracy and can reduce the dose to normal tissues.

Abstract P5-14-04: Preoperative single-fraction partial breast radiotherapy – Initial results from a novel phase I dose-escalation protocol with exploration of radiation response biomarkers

Purpose/Objectives(s) : Women with biologically favorable early stage breast cancer are increasingly treated with accelerated partial breast techniques. However, many alternative techniques require costly specialized equipment not routinely available in most radiation oncology facilities. In addition, suboptimal cosmetic outcomes have been reported with the external beam technique, possibly related to large post-operative treatment volumes. To address these issues, we designed a phase I dose-escalation protocol to determine the maximally tolerated dose (MTD) of a single radiosurgery treatment delivered preoperatively to the intact tumor plus a small margin. Materials/Methods: Women aged 55 or older with clinically node negative, ER and/or PR+, HER2-, T1 invasive carcinomas were enrolled (n = 26). Patients with low/intermediate grade in situ disease Tumor tissue was obtained from diagnostic and lumpectomy specimens. Immunohistochemistry (IHC) for Fas was performed on paraffin-embedded samples before and after radiation. A histoscore was created using the average membrane and cytoplasmic staining intensity multiplied by the percentage of positive cells. Results: Thirty-two women were treated, 8 each at the 15, 18, and 21Gy dose levels with an additional expansion cohort at the final 21Gy dose level. The maximally tolerated dose was not reached. Three patients required post-operative conventional radiation due to high-risk tumor features (ex. larger primary, nodal involvement). At a median follow-up of 6.8 months, primarily mild toxicities (grade 1-2 dermatitis, fibrosis, and pain) were noted. At 6 months (n = 20), all reported cosmetic outcomes are excellent or good. At 12 months (n = 10), 80% are excellent or good. Both patients with a fair/poor cosmetic outcome received radiosurgery plus post-operative conventional treatment; one experienced grade 3 breast atrophy. There have been no local or distant recurrences to date. Post-treatment MRIs were obtained in 20/32 patients, with early indicators of decreased cell density and increased vascular permeability. Sixteen patients had evaluable paired IHC and six demonstrated significant Fas up-regulation after radiation. The mean combined post-treatment histoscore was about twice as high as the mean pre-treatment score. Conclusion: Preoperative stereotactic radiotherapy to the intact breast tumor can be delivered with widely available clinical tools in a convenient single fraction, and provides a unique opportunity to study breast cancer radiation response. 21Gy did not yield dose-limiting toxicity and will be utilized for future studies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-04.