Madeline Carroll

Prospective Trial of Synchronous Bevacizumab, Erlotinib, and Concurrent Chemoradiation in Locally Advanced Head and Neck Cancer

Purpose: We assessed the safety and efficacy of synchronous VEGF and epidermal growth factor receptor (EGFR) blockade with concurrent chemoradiation (CRT) in locally advanced head and neck cancer (HNC). Experimental Design: Newly diagnosed patients with stage III/IV HNC received a 2-week lead-in of bevacizumab and/or erlotinib, followed by both agents with concurrent cisplatin and twice daily radiotherapy. Safety was assessed using Common Toxicity Criteria version 3.0. The primary efficacy endpoint was clinical complete response (CR) rate after CRT. Results: Twenty-nine patients enrolled on study, with 27 completing therapy. Common grade III toxicities were mucositis (n = 14), dysphagia (n = 8), dehydration (n = 7), osteoradionecrosis (n = 3), and soft tissue necrosis (n = 2). Feeding tube placement was required in 79% but no patient remained dependent at 12-month posttreatment. Clinical CR after CRT was 96% [95% confidence interval (CI), 82%–100%]. Median follow-up was 46 months in survivors, with 3-year locoregional control and distant metastasis-free survival rates of 85% and 93%. Three-year estimated progression-free survival, disease-specific survival, and overall survival rates were 82%, 89%, and 86%, respectively. Dynamic contrast enhanced MRI (DCE-MRI) analysis showed that patients who had failed had lower baseline pretreatment median Ktrans values, with subsequent increases after lead-in therapy and 1 week of CRT. Patients who did not fail had higher median Ktrans values that decreased during therapy. Conclusions: Dual VEGF/EGFR inhibition can be integrated with CRT in locally advanced HNC, with efficacy that compares favorably with historical controls albeit with an increased risk of osteoradionecrosis. Pretreatment and early DCE-MRI may prospectively identify patients at high risk of failure. Clin Cancer Res; 18(5); 1404–14. ©2012 AACR.

A Safety and Survival Analysis of Neoadjuvant Bevacizumab with Standard Chemoradiation in a Phase I/II Study Compared with Standard Chemoradiation in Locally Advanced Rectal Cancer

INTRODUCTION Bevacizumab is increasingly being tested with neoadjuvant regimens in patients with localized cancer, but its effects on metastasis and survival remain unknown. This study examines the long-term outcome of clinical stage II/III rectal cancer patients treated in a prospective phase II study of bevacizumab with chemoradiation and surgery. As a benchmark, we used data from an analysis of 42 patients with locally advanced rectal cancer treated with a contemporary approach of preoperative fluoropyrimidine-based radiation therapy. MATERIALS AND METHODS Outcome analyses were performed on 32 patients treated prospectively with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery as well as 42 patients treated with standard fluoropyrimidine-based chemoradiation. RESULTS Overall survival, disease-free survival, and local control showed favorable trends in patients treated with bevacizumab with chemoradiation followed by surgery. Acute and postoperative toxicity appeared acceptable. CONCLUSIONS Neoadjuvant bevacizumab with standard chemoradiation and surgery shows promising long-term efficacy and safety profiles in locally advanced rectal cancer patients.

Dynamic Contrast-Enhanced MRI in Head-and-Neck Cancer: The Impact of Region of Interest Selection on the Intra- and Interpatient Variability of Pharmacokinetic Parameters

PURPOSE Dynamic contrast-enhanced (DCE) MRI-extracted parameters measure tumor microvascular physiology and are usually calculated from an intratumor region of interest (ROI). Optimal ROI delineation is not established. The valid clinical use of DCE-MRI requires that the variation for any given parameter measured within a tumor be less than that observed between tumors in different patients. This work evaluates the impact of tumor ROI selection on the assessment of intra- and interpatient variability. METHOD AND MATERIALS Head and neck cancer patients received initial targeted therapy (TT) treatment with erlotinib and/or bevacizumab, followed by radiotherapy and concurrent cisplatin with synchronous TT. DCE-MRI data from Baseline and the end of the TT regimen (Lead-In) were analyzed to generate the vascular transfer function (K(trans)), the extracellular volume fraction (v(e)), and the initial area under the concentration time curve (iAUC(1 min)). Four ROI sampling strategies were used: whole tumor or lymph node (Whole), the slice containing the most enhancing voxels (SliceMax), three slices centered in SliceMax (Partial), and the 5% most enhancing contiguous voxels within SliceMax (95Max). The average coefficient of variation (aCV) was calculated to establish intrapatient variability among ROI sets and interpatient variability for each ROI type. The average ratio between each intrapatient CV and the interpatient CV was calculated (aRCV). RESULTS Baseline primary/nodes aRCVs for different ROIs not including 95Max were, for all three MR parameters, in the range of 0.14-0.24, with Lead-In values between 0.09 and 0.2, meaning a low intrapatient vs. interpatient variation. For 95Max, intrapatient CVs approximated interpatient CVs, meaning similar data dispersion and higher aRCVs (0.6-1.27 for baseline) and 0.54-0.95 for Lead-In. CONCLUSION Distinction between different patients primary tumors and/or nodes cannot be made using 95Max ROIs. The other three strategies are viable and equivalent for using DCE-MRI to measure head and neck cancer physiology.

SU‐E‐T‐363: Investigation of PRESAGE® Dosimeters for Proton Therapy

Purpose: To evaluate a formulation of PRESAGE® intended for proton therapy and to use it to compare measurements with calculations for a spot scanning pencil proton beam and a passively scattered proton beam.Methods: Two 7.5 cm high by 9.5 cm diameter cylindrical PRESAGE® dosimeters were used. CTimages were used to design two treatment plans with an Eclipse treatment planning system (TPS). The first plan used a single pencil beam of energy 153.2 MeV to provide a range of 16 cm in water. Four regions of the dosimeter were irradiated delivering doses in the peak of approximately 6, 10, 13 and 19 Gy(RBE) by rotating the dosimeter between spot deliveries. The second plan used a single passively scattered field with a spread out Bragg peak (SOBP) of 4 cm. This plan delivered approximately 10 Gy(RBE). The dosimeters were analyzed using an optical CT scanner. The measured optical densities were converted to dose via a calibration curve, exported to the CERR environment and fused to the treatment plan. Dose distributions were scaled to the SOBP plan. Dose profiles were taken along the axis of each spot and the SOBP and perpendicularly across the SOBP.Results: The dose measured in the peak of single spot irradiations increased proportionally to the MU setting. The distal falloff was steeper than predicted by the TPS. The cross profiles for the SOBP plan matched within 2 mm with the TPS. The depth profile was noisy within the modulated area. Noise decreased as dose increased for both dosimeters Conclusions: This formulation of PRESAGE® shows promise as a 3D dosimeter for proton therapy. A dose calibration specific to protons will facilitate further analysis and enable measurement of complex distributions. Work supported by PHS CA010953 and CA081647, awarded by NCI, DHHS.

SU‐E‐T‐73: Investigation of 3D Dosimetry for Proton Therapy Using PRESAGE

PURPOSE This investigation studies the feasibility of PRESAGE, a 3D polyurethane dosimeter, for relative dosimetry measurements of clinically relevant proton treatments using an anthropomorphic head phantom developed by the Radiological Physics Center (RPC). Performance of a low-LET dependent PRESAGE was evaluated by comparison to the traditionally used radiochromic film, EBT2, and thermoluminescent dosimeters (TLDs). METHODS The head phantom consists of a human skeleton with synthetic isocyanate rubber having similar tissue-equivalent radiological properties to high-energy protons cast around it to mimic natural heterogeneous anatomical structures. The phantom has a cutout that admits either a film and TLD insert or a PRESAGE dosimeter. A treatment plan was developed and delivered twice: once with the film/TLD insert and again with the PRESAGE dosimeter. The 3D dose distribution from the PRESAGE was read out using the Duke medium-field-of-view optical-CT scanner (DMOS). The measured dose distributions were compared to the treatment plan and the distance to agreement (DTA) within the high dose regions was calculated in the sagittal and coronal planes as measured by the EBT2 film. RESULTS PRESAGE dose profiles showed agreement within 3mm and 4mm in the coronal and sagittal planes respectively. Film data showed agreement to 2mm in both planes. A 2D gamma comparison between the PRESAGE and planning data gave 95% agreement with 5%/3mm and 5%/4mm in those respective fields. CONCLUSION PRESAGE dosimeters show great potential for measuring dose distributions from proton fields within heterogeneous volumes, with the opportunity to measure volumetric dose data. Data within the high dose regions of the treatment showed comparable DTAs from two dosimetry systems. With film measurements confirming PRESAGE readings, dose data in low dose regions in clinically sensitive regions can now be better determined. Additional work will include organs at risk (OAR) considerations allowing for detailed DVH comparisons, as well as 3D gamma analysis. NIH grant 5R01CA100835.

SU‐E‐T‐132: Investigation of Photon and Proton Overlapping Fields in PRESAGE‐ Dosimeters

PURPOSE To evaluate the effects of overlapping dose volumes for varying field arrangements in two formulations of PRESAGE®: one intended for, and irradiated with, proton beams and the other photon beams. METHODS For each treatment modality (photon, proton), three overlapping field setups were performed. These included a stationary dosimeter irradiated over six fractions, a dosimeter shifted laterally to the field to deliver a dose plateau in two fractions, and a dosimeter rotated on its axis to deliver a two-field (for protons) and four-field (for photons) box treatment overlapping in the center of the dosimeter. All subsequent fractions were given within ten minutes and never less than one minute apart. Two cylindrical PRESAGE® dosimeters approximately 7.5 cm in length by 7.5 cm in diameter were irradiated for each setup. The dosimeters were paired, with one dosimeter given total dose by a single fraction while the other followed one of the overlapping field setups. The dosimeters were analyzed using an optical CT scanner and exported to the CERR environment where the doses were compared between paired dosimeters. RESULTS Dose profile comparisons showed relative dose agreement between paired dosimeters within 5% along the SOBP region of the proton formulation. In the case of the fractionated proton irradiation, there was an over-response while other setups resulted in under-responses. Dose agreement between the photon dosimeter treated with six fractions showed a dose under-response within 11% and never less than 5%. Future measurements will include the remaining field setups. CONCLUSIONS The proton formulation of PRESAGE® showed good dose agreement between single and multiple field irradiations. While the photon formulation had slightly less agreement, additional field setup comparisons may show improved results. These results will aid future measurements of overlapping field treatment plans delivered to PRESAGE® for treatment verification for proton and photon 3D dosimetry.

Abstract LB-213: Plasma soluble VEGFR1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer

We explored plasma and urinary concentration of four members of the vascular endothelial growth factor (VEGF) family as potential response and toxicity biomarker of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The levels of VEGF, placental growth factor (PlGF) and soluble VEGF receptors 1 and −2 (sVEGFR1 and sVEGFR2) were measured by multiplex array in plasma and urine at baseline and during treatment. Pre-treatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment (evaluated histologically using ypT, Mandard and N scoring at surgery) as well as for all acute toxicities in patients with locally advanced rectal cancer treated prospectively from 2002 to 2008 with bevacizumab, 5-fluorouracil and radiation therapy prior to surgery in a phase I/II trial (N=32 patients). Of all biomarkers, the pretreatment plasma sVEGFR1 - an endogenous blocker of VEGF and a factor linked with “vascular normalization” - was strikingly associated with both tumor regression and with the number of adverse events after preoperative (neoadjuvant) bevacizumab and chemoradiation. Thus, plasma sVEGFR1 is a strong candidate as the first biomarker to stratify patients for bevacizumab therapy. Therefore, future studies of bevacizumab and/or cytotoxics should be further explore sVEGFR1 as biomarker in neoadjuvant setting as well as in metastatic disease. This study was partially supported by NIH grants R21-CA99237, P01-CA80124, R01-CA115767, R01-CA85140, R01-CA126642 and Federal Share/NCI Proton Beam Program Income grants, and by the National Foundation for Cancer Research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-213.

Abstract LB-76: A study of neoadjuvant bevacizumab with standard chemoradiation versus chemoradiation alone in locally advanced rectal cancer

The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is increasingly being tested with pre-operative (neoadjuvant) regimens in patients with localized cancer, but its effects on metastasis and survival remain unknown. This study examined the outcome of clinical stage II/III rectal cancer patients treated on a prospective phase II study of bevacizumab based chemoradiation and surgery to a contemporarily treated group of patients with standard chemoradiation and surgery at the same institution (Duke University Medical Center). Outcome analyses were performed on: 1. thirty-two patients treated prospectively from 2002 to 2008 with neoadjuvant bevacizumab, 5-fluorouracil and radiation therapy and surgery; versus 2. forty-two patients treated from 2004 to 2008 with capecitabine, radiation therapy and surgery. The current median follow-up is 3 years. While local control was 100% in both groups (i.e., there was no local recurrence), the patients treated with bevacizumab-based chemoradiation and surgery showed statistically significantly higher overall survival rates and a trend higher disease-free survival rates than patients treated with chemoradiation alone and surgery. No statistically significant differences were observed in local control or toxicity between the two groups. These data indicate that adding bevacizumab to neoadjuvant chemoradiation compares favorably to chemoradiation alone in a contemporary population of rectal cancer patients. The efficacy of neoadjuvant bevacizumab will have to be established prospectively in randomized studies, but bevacizumab with standard chemoradiation and surgery shows promising safety profiles and does not appear to increase metastasis after three years in locally advanced rectal cancer patients. This study was partially supported by NIH grants R21-CA99237, P01-CA80124, R01-CA115767, R01-CA85140, R01-CA126642 and Federal Share/NCI Proton Beam Program Income grants, and by the National Foundation for Cancer Research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-76.

WE‐C‐BRC‐02: Combined Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE‐MRI) and Magnetic Resonance Thermal Imaging (MRTI) for Optimal Hyperthermia Treatment of Advanced Extremity Sarcomas: Fifteen Patients Update

Purpose: To deliver optimal hyperthermia (HT) treatments for patients with advanced extremity sarcomas using DCE‐MRI and MRTI Method and Materials: Patients were treated on a protocol using radiotherapy consisting of 45 Gy and once a week HT for 5 weeks in a setting that allows the use of a 1.5 T GE magnet for imaging. Pre‐ and post first HT treatment DCE‐MR images were acquired and analyzed with software from iCAD Inc. (Nashua, NH) based on a full time point pharmacokinetics (PK) analysis that measures tumors permeability (Ktrans) and extracellular volume fraction (Ve). Multi‐slice temperature rise images were obtained using the proton resonance frequency shift technique during heating in a 140 MHz phased array HT applicator and compared to invasive temperature measurements. Thermal dose metrics were calculated and correlated with response and with the PK parameters. Results: Fifteen patients were enrolled on this protocol; ten patients were heated. Permeability maps derived from DCE‐MR images were used to guide the placement of the invasive catheter to span regions varying from high to low perfusion. The MRTI images were used to steer the power, with the intent of heating the tumor uniformly while maintaining surrounding normal tissue at lower temperatures. From the evaluable HT treatments, we achieved excellent correlation (ΔT<1°C) between the MRTI and invasive measurements. As a trend, patients that were either pathological complete or partial responders had a decrease in Ktrans. The Ve parameter showed no clear trend with pathological response or % necrosis. As expected, tumors that were more vascularized (higher Ktrans) heated less than tumors with a high degree of necrosis or fluid pockets. Conclusion: DCE‐MRI coupled with MRTI provides information on tumor environment that can improve planning, delivery, and evaluation of HT treatments. Supported by a grant from the NCI CA42745.