Sun K. Yi

Validating the RTOG-endorsed brachial plexus contouring atlas: An evaluation of reproducibility among patients treated by intensity-modulated radiotherapy for head-and-neck cancer

PURPOSE To evaluate interobserver variability for contouring the brachial plexus as an organ-at-risk (OAR) and to analyze its potential dosimetric consequences in patients treated with intensity-modulated radiotherapy (IMRT) for head-and-neck cancer. METHODS AND MATERIALS Using the Radiation Therapy Oncology Group (RTOG)-endorsed brachial plexus contouring atlas, three radiation oncologists independently delineated the OAR on treatment planning computed-tomography (CT) axial scans from 5 representative patients undergoing IMRT to a prescribed dose of 70 Gy for head-and-neck cancer. Dose-volume histograms for the brachial plexus were calculated, and interobserver differences were quantified by comparing various dosimetric statistics. Qualitative analysis was performed by visually assessing the overlapping contours on a single beams eye view. RESULTS Brachial plexus volumes for the 5 patients across observers were 26 cc (18-35 cc), 25 cc (21-30 cc), 29 cc (28-32 cc), 29 cc (23-38 cc), and 29 cc (23-34 cc). On qualitative analysis, minimal variability existed except at the inferolateral portion of the OAR, where slight discrepancies were noted among the physicians. Maximum doses to the brachial plexus ranged from 71.6 to 72.6 Gy, 75.2 to 75.8 Gy, 69.1 to 71.0 Gy, 76.4 to 76.9 Gy, and 70.6 to 71.4 Gy. Respective volumes receiving doses greater than 60 Gy (V60) were 8.6 to 10.9 cc, 6.2 to 8.1 cc, 8.2 to 11.6 cc, 8.3 to 10.5 cc, and 5.6 to 9.8 cc. CONCLUSION The RTOG-endorsed brachial plexus atlas provides a consistent set of guidelines for contouring this OAR with essentially no learning curve. Adoption of these contouring guidelines in the clinical setting is encouraged.

Development of a standardized method for contouring the lumbosacral plexus: A preliminary dosimetric analysis of this organ at risk among 15 patients treated with intensity-modulated radiotherapy for lower gastrointestinal cancers and the incidence of radiation-induced lumbosacral plexopathy

PURPOSE To generate a reproducible step-wise guideline for the delineation of the lumbosacral plexus (LSP) on axial computed tomography (CT) planning images and to provide a preliminary dosimetric analysis on 15 representative patients with rectal or anal cancers treated with an intensity-modulated radiotherapy (IMRT) technique. METHODS AND MATERIALS A standardized method for contouring the LSP on axial CT images was devised. The LSP was referenced to identifiable anatomic structures from the L4-5 interspace to the level of the sciatic nerve. It was then contoured retrospectively on 15 patients treated with IMRT for rectal or anal cancer. No dose limitations were placed on this organ at risk during initial treatment planning. Dosimetric parameters were evaluated. The incidence of radiation-induced lumbosacral plexopathy (RILSP) was calculated. RESULTS Total prescribed dose to 95% of the planned target volume ranged from 50.4 to 59.4 Gy (median 54 Gy). The mean (± standard deviation [SD]) LSP volume for the 15 patients was 100 ± 22 cm(3) (range, 71-138 cm(3)). The mean maximal dose to the LSP was 52.6 ± 3.9 Gy (range, 44.5-58.6 Gy). The mean irradiated volumes of the LSP were V40Gy = 58% ± 19%, V50Gy = 22% ± 23%, and V55Gy = 0.5% ± 0.9%. One patient (7%) was found to have developed RILSP at 13 months after treatment. CONCLUSIONS The true incidence of RILSP in the literature is likely underreported and is not a toxicity commonly assessed by radiation oncologists. In our analysis the LSP commonly received doses approaching the prescribed target dose, and 1 patient developed RILSP. Identification of the LSP during IMRT planning may reduce RILSP. We have provided a reproducible method for delineation of the LSP on CT images and a preliminary dosimetric analysis for potential future dose constraints.

Controlling the diameter, monodispersity, and solubility of ApoA1 nanolipoprotein particles using telodendrimer chemistry

Nanolipoprotein particles (NLPs) are nanometer‐scale discoidal particles that feature a phospholipid bilayer confined within an apolipoprotein “scaffold,” which are useful for solubilizing hydrophobic molecules such as drugs and membrane proteins. NLPs are synthesized either by mixing the purified apolipoprotein with phospholipids and other cofactors or by cell‐free protein synthesis followed by self‐assembly of the nanoparticles in the reaction mixture. Either method can be problematic regarding the production of homogeneous and monodispersed populations of NLPs, which also currently requires multiple synthesis and purification steps. Telodendrimers (TD) are branched polymers made up of a dendritic oligo‐lysine core that is conjugated to linear polyethylene glycol (PEG) on one end, and the lysine “branches” are terminated with cholic acid moieties that enable the formation of nanomicelles in aqueous solution. We report herein that the addition of TD during cell‐free synthesis of NLPs produces unique hybrid nanoparticles that have drastically reduced polydispersity as compared to NLPs made in the absence of TD. This finding was supported by dynamic light scattering, fluorescence correlation spectroscopy, and cryo transmission electron microscopy (Cryo‐EM). These techniques demonstrate the ability of TDs to modulate both the NLP size (6–30 nm) and polydispersity. The telodendrimer NLPs (TD‐NLPs) also showed 80% less aggregation as compared to NLPs alone. Furthermore, the versatility of these novel nanoparticles was shown through direct conjugation of small molecules such as fluorescent dyes directly to the TD as well as the insertion of a functional membrane protein.

Image guided volumetric response during chemoradiotherapy for head and neck squamous cell carcinoma as a predictor of disease outcomes

PURPOSE The goal of this study was to correlate volumetric image guided disease response to clinical outcomes in patients receiving chemoradiation therapy (CRT) for locally advanced head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS Thirty four patients completing definitive CRT for locally advanced HNSCC with megavoltage computed tomography (MVCT) guided tomotherapy IMRT were retrospectively reviewed for volumetric response. Grossly identifiable primary tumor (PT) and nodal disease (ND) response was evaluated by weekly MVCT regression. Percent end-of-treatment (EOT) residual volumes and regression rates were correlated with risk of local failure (LF), progression free survival (PFS), and overall survival (OS). RESULTS A total of 7 LFs were identified in 6 patients at a median follow-up of 8months. The mean percent EOT residual volumes for PT and ND in patients with and without LF were 20% vs. 5% (p=0.005) and 47% vs. 6% (p=0.0001), respectively. The PT and ND volume regression rates for patients with and without LF were 12.7% per week vs. 15.9% per week (p=0.04) and 3.4% per week vs. 10.5% per week (p<0.001), respectively. Utilizing an EOT cut-off value of 25% residual volume, the relative risks of LF for PT and ND were 14.7 (p=0.03) and 25 (p=0.001), respectively. Patients found with PT and/or ND residual volumes <25% at EOT had longer 2year OS of 100% vs. 67% (p=0.0023) and PFS of 87% vs. 17% (p<0.001) compared with patients with residual volumes >/= 25% at EOT. CONCLUSION Patients with locally advanced HNSCC who have significant MVCT volume reduction over the course of definitive CRT tend to have favorable clinical outcomes.

Dose delivered to the lumbosacral plexus from high-dose-rate brachytherapy for cervical cancer

Objective To calculate dose delivered to the lumbosacral plexus (LSP) with cervical brachytherapy using 3-dimensional imaging, and to compare this with the position of the tandem in the pelvis using bony landmarks. We also report long-term LSP toxicity outcomes. Methods and Materials Treatment planning images from 55 patients treated with tandem and ring brachytherapy from October 2009 through November 2012 were reviewed. The LSP was contoured on planning computed tomographic scans to calculate dose received. Lumbosacral plexus dose was studied as a function of tandem distance from the sacrum and pubic symphysis (STratio) measured on digitally reconstructed radiographs. Patient and implant characteristics were included as covariates on LSP dose. Clinical follow up on LSP toxicity was recorded. Results Patients were prescribed 550 to 700 cGy using computed tomography–based imaged-guided brachytherapy for 4 to 5 fractions. The maximum dose to 2 cc (D2cc) of LSP ranged from 44 to 287 cGy per implant. The median D2cc was 118 cGy, corresponding to 18% of prescription dose. Patients with an STratio less than 0.33 (closer to the sacrum) and at least 0.33 had median LSP doses of 138 and 98 cGy, respectively. Lumbosacral plexus dose did not change significantly with body mass index, uterus position, or tumor stage. Two patients reported symptoms of peripheral neuropathy, with a median follow-up of 14.7 months. Conclusions The mean D2cc per fraction to the LSP is roughly 20% of the prescribed high dose-rate and varies with the position of the tandem from the sacrum. The dose threshold for radiation-induced neuropathy of the LSP remains undefined.

Role of Concurrent Systemic Therapy with Adjuvant Radiation Therapy for Locally Advanced Cutaneous Head and Neck Squamous Cell Carcinoma

Objective To evaluate the role of concurrent systemic therapy to postoperative radiation therapy (RT) for locally advanced cutaneous head and neck squamous cell carcinoma (LA-cHNSCC). Materials and methods A retrospective study of 32 patients with LA-cHNSCC receiving postoperative RT with and without systemic therapy was conducted. Patients with LA-cHNSCC after surgical resection with one or more high risk features were evaluated. Local regional control (LRC), distant control (DC), and acute and late toxicities were evaluated with Fisher exact tests. Progression-free survival (PFS) and overall survival (OS) were evaluated utilizing Kaplan Meier and log-rank analyses. Univariate Cox proportional hazard analyses were used to examine patient, disease, and treatment-related factors with OS and PFS. Results While comparing patients receiving RT with systemic therapy (n = 14) vs RT alone (n = 18), LRC was 92.9% vs 72.2% (p = 0.20), DC 92.9% vs 94.4% (p = 1.0), median PFS 17.7 months vs 34.4 months (p = 0.48), and median OS 20.9 months vs 34.4 months (p = 0.03), respectively. On univariate analyses, use of concurrent systemic therapy was associated with an increased risk of death with an HR of 3.5 [95% confidence interval (CI): 1.04 - 11.6] (p = 0.04), while patients treated for recurrent disease who had previously treated superficial primaries had improved OS with an HR of 0.10 [95% CI: 0.01-0.80] (p = 0.03). There were no significant differences in acute or chronic toxicities between groups. Conclusions Patients receiving postoperative RT alone for LA-cHNSCC had better OS than patients receiving concurrent systemic therapy. There were no differences in any other endpoints evaluated.

Abstract LB-12: Building a novel multifaceted nano-carrier: In vivo and in vitro applications of multifunctional nanolipoprotein particles

We have developed a novel process of production and assembly of nanolipoprotein particles (NLPs) as a multifaceted reagent for cancer imaging, drug delivery, immunomodulation and stabilizing membrane protein complexes for in vitro studies. Nanolipoproteins are components of the human HDL lipoprotein complexes that could be isolated and reconstituted to form NLPs. NLPs are discoidal nanoparticles of 10∼20 nm that self-assemble around a phospholipid bilayer. This bilayer mimics closely the cell membrane can support molecules such as dyes and proteins. NLPs present distinct advantages in terms of particle size, monodispersity and consistency: the circular protein belt constrains the dimensions of the bilayer and ensures NLP particle size distributions can be monodispersed and consistent between preparations. We have demonstrated when targeting agents and imaging agents are attached to the NLPs, they were able to accumulate at the tumor region and can be used for tumor imaging; We also managed to conjugate recombinant IL2 to NLPs. Our data showed that IL2-NLP conjugates were able to stimulate immunomodulation in mice both in vivo and in vitro. NLPs also have shown great promise for solubilizing and characterizing membrane proteins and may make many more membrane protein related complexes accessible for biophysical and biochemical study. Our approach represents a unique solution to the challenge of generating soluble and functional polytopic membrane proteins, facilitating the structural and functional characterization, providing a platform for high-throughput drug screening, and potentially a new type of carrier for tumor imaging and drug delivery. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-12. doi:1538-7445.AM2012-LB-12