Avani D. Rao

Patient-reported outcomes of a multicenter phase 2 study investigating gemcitabine and stereotactic body radiation therapy in locally advanced pancreatic cancer

PURPOSEnWe previously reported clinical outcomes and physician-reported toxicity of gemcitabine and hypofractionated stereotactic body radiation therapy (SBRT) in locally advanced pancreatic cancer (LAPC). Here we prospectively investigate the impact of gemcitabine and SBRT on patient-reported quality of life (QoL).nnnMETHODS AND MATERIALSnForty-nine LAPC patients received 33 Gy SBRT (6.6 Gy daily fractions) upfront or after ≤3 doses of gemcitabine (1000 mg/m2) followed by gemcitabine until progression. European Organization for Research and Treatment of Cancer QoL core cancer (QLQ-C30) and pancreatic cancer-specific (European Organization for Research and Treatment of Cancer QLQ-PAN26) questionnaires were administered to patients pre-SBRT and at 4 to 6 weeks (first follow-up [1FUP]) and 4 months (2FUP) post-SBRT. Changes in QoL scores were deemed clinically relevant if median changes were at least 5 points in magnitude.nnnRESULTSnForty-three (88%) patients completed pre-SBRT questionnaires. Of these, 88% and 51% completed questionnaires at 1FUP and 2FUP, respectively. There was no change in global QoL from pre-SBRT to 1FUP (P = .17) or 2FUP (P > .99). Statistical and clinical improvements in pancreatic pain (P = .001) and body image (P = .007) were observed from pre-SBRT to 1FUP. Patients with 1FUP and 2FUP questionnaires reported statistically and clinically improved body image (P = .016) by 4 months. Although pancreatic pain initially demonstrated statistical and clinical improvement (P = .020), scores returned to enrollment levels by 2FUP (P = .486). A statistical and clinical decline in role functioning (P = .002) was observed in patients at 2FUP.nnnCONCLUSIONSnGlobal QoL scores are not reduced with gemcitabine and SBRT. In this exploratory analysis, patients experience clinically relevant short-term improvements in pancreatic cancer-specific symptoms. Previously demonstrated acceptable clinical outcomes combined with these favorable QoL data indicate that SBRT can be easily integrated with other systemic therapies and may be a potential standard of care option in patients with LAPC.

Reirradiation for Recurrent Pediatric Central Nervous System Malignancies: A Multi-institutional Review

PURPOSEnReirradiation has been proposed as an effective modality for recurrent central nervous system (CNS) malignancies in adults. We evaluated the toxicity and outcomes of CNS reirradiation in pediatric patients.nnnMETHODS AND MATERIALSnThe data from pediatric patients <21xa0years of age at the initial diagnosis who developed a recurrent CNS malignancy that received repeat radiation therapy (RT) across 5 facilities in an international pediatric research consortium were retrospectively reviewed.nnnRESULTSnSixty-seven pediatric patients underwent CNS reirradiation. The primary diagnoses included medulloblastoma/primitive neuroectodermal tumor (n=20; 30%), ependymoma (n=19; 28%), germ cell tumor (n=8; 12%), high-grade glioma (n=9; 13%), low-grade glioma (n=5; 7%), and other (n=6; 9%). The median age at the first course of RT was 8.5xa0years (range 0.5-19.5) and was 12.3xa0years (range 3.3-30.2) at reirradiation. The median interval between RT courses was 2.0xa0years (range 0.3-16.5). The median radiation dose and fractionation in equivalent 2-Gy fractions was 63.7xa0Gy (range 27.6-74.8) for initial RT and 53.1xa0Gy (range 18.6-70.1) for repeat RT. The relapse location was infield in 52 patients (78%) and surrounding the initial RT field in 15 patients (22%). Thirty-seven patients (58%) underwent gross or subtotal resection at recurrence. The techniques used for reirradiation were intensity modulated RT (n=46), 3-dimensional conformal RT (n=9), stereotactic radiosurgery (n=4; 12-13xa0Gyxa0×xa01 or 5xa0Gyxa0×xa05), protons (n=4), combined modality (n=3), 2-dimensional RT (n=1), and brachytherapy (n=1). Radiation necrosis was detected in 2 patients after the first RT course and 1 additional patient after reirradiation. Six patients (9%) developed secondary neoplasms after initial RT (1 hematologic, 5 intracranial). One patient developed a secondary neoplasm identified shortly after repeat RT. The median overall survival after completion of repeat RT was 12.8xa0months for the entire cohort and 20.5 and 8.4xa0months for patients with recurrent ependymoma and medulloblastoma after reirradiation, respectively.nnnCONCLUSIONSnCNS reirradiation in pediatric patients could be a reasonable treatment option, with moderate survival noted after repeat RT. However, prospective data characterizing the rates of local control and toxicity are needed.

A Novel Absorbable Radiopaque Hydrogel Spacer to Separate the Head of the Pancreas and Duodenum in Radiation Therapy for Pancreatic Cancer

PURPOSEnWe assessed the feasibility and theoretical dosimetric advantages of an injectable hydrogel to increase the space between the head of the pancreas (HOP) and duodenum in a human cadaveric model.nnnMETHODS AND MATERIALSnUsing 3 human cadaveric specimens, an absorbable radiopaque hydrogel was injected between the HOP and duodenum by way of open laparotomy in 1 case and endoscopic ultrasound (EUS) guidance in 2 cases. The cadavers were subsequently imaged using computed tomography and dissected for histologic confirmation of hydrogel placement. The duodenal dose reduction and planning target volume (PTV) coverage were characterized using pre- and postspacer injection stereotactic body radiation therapy (SBRT) plans for the 2 cadavers with EUS-guided placement, the delivery method that appeared the most clinically desirable. Modeling studies were performed using 60 SBRT plans consisting of 10 previously treated patients with unresectable pancreatic cancer, each with 6 different HOP-duodenum separation distances. The duodenal volume receiving 15xa0Gy (V15), 20xa0Gy (V20), and 33xa0Gy (V33) was assessed for each iteration.nnnRESULTSnIn the 3 cadaveric studies, an average of 0.9xa0cm, 1.1xa0cm, and 0.9xa0cm HOP-duodenum separation was achieved. In the 2 EUS cases, the V20 decreased from 3.86xa0cm3 to 0.36xa0cm3 and 3.75xa0cm3 to 1.08xa0cm3 (treatment constraint <3xa0cm3), and the V15 decreased from 7.07xa0cm3 to 2.02xa0cm3 and 9.12xa0cm3 to 3.91xa0cm3 (treatment constraint <9xa0cm3). The PTV coverage improved or was comparable between the pre- and postinjection studies. Modeling studies demonstrated that a separation of 8xa0mm was sufficient to consistently reduce the V15, V20, and V33 to acceptable clinical constraints.nnnCONCLUSIONSnCurrently, dose escalation has been limited owing to radiosensitive structures adjacent to the pancreas. We demonstrated the feasibility of hydrogel separation of the HOP and duodenum. Future studies will evaluate the safety and efficacy of this technique with the potential for more effective dose escalation using SBRT or intensity-modulated radiation therapy to improve the outcomes in patients with unresectable pancreatic cancer.

Practice patterns of palliative radiation therapy in pediatric oncology patients in an international pediatric research consortium

The practice of palliative radiation therapy (RT) is based on extrapolation from adult literature. We evaluated patterns of pediatric palliative RT to describe regimens used to identify opportunity for future pediatric‐specific clinical trials.

Multiplex Proximity Ligation Assay to Identify Potential Prognostic Biomarkers for Improved Survival in Locally Advanced Pancreatic Cancer Patients Treated With Stereotactic Body Radiation Therapy

PURPOSEnTo explore seromarker levels for associations with outcomes in locally advanced pancreatic cancer (LAPC) patients who received chemotherapy and stereotactic body radiation therapy (SBRT).nnnMETHODS AND MATERIALSnSerum from LAPC patients in 2 prospective trials of hypofractionated SBRT (5-6.6xa0Gyxa0×xa05) was collected before SBRT. Proximity ligation assay quantified the expression levels of 36 pancreatic cancer-specific candidate seromarkers: Axl, BMP2, CA 125, CA 19-9, CEA, CXCL-1/6/9/10, EGFR, Gas6, Her2, IGF-2, IGFBP-2/3/7, IL-6/6Ra/7/8/12, mesothelin, MMP-1/2/3/7, osteopontin, PDGFRa, PDK1, PF4, RegIV, SPARC, TGF-β, VEGF-A/D, and YKL40. Seromarker values were log transformed owing to log-normal distribution of the values, and Cox regression analysis was performed to assess for any association with overall survival. The Benjamini-Hochberg method was used to control for a false discovery rate (FDR) of only 10%.nnnRESULTSnSixty-four patients with LAPC were included. No clinical factors (including surgical resection, receipt of pre-SBRT chemotherapy, receipt of post-SBRT chemotherapy, performance status, and age) or potential biomarkers in the panel were associated with improved survival in this cohort after application of the FDR correction. Potential prognostic factors for improved survival for future investigation included surgical resection (P=.007, adjusted P=.153) and the serum expression of IL-8 (P=.006, adjusted P=.153), CA 19-9 (P=.031, adjusted P=.377), and MMP-1 (P=.036, adjusted P=.377).nnnCONCLUSIONSnThese data explore the expression of a panel of proteins in pre-SBRT serum of LAPC patients in the context of a conservative FDR correction. None of the clinical factors or expression levels of the serum proteins were found to be associated with survival; however, IL-8, CA 19-9, and MMP-1 were highlighted as possible candidates warranting inclusion in future seromarker studies in the ongoing efforts to identify tools for risk stratification and treatment allocation in LAPC.

Demonstration of Safety and Feasibility of Hydrogel Marking of the Pancreas–Duodenum Interface for Image Guided Radiation Therapy (IGRT) in a Porcine Model: Implications in IGRT for Pancreatic Cancer Patients

Purpose: To test the feasibility and safety of injecting a high-contrast hydrogel marker at the head of the pancreas (HOP) and duodenum interface and assesses the marker visibility on cone beam computed tomography (CBCT) to localize this important boundary during image guided radiation therapy in a porcine model. Methods and Materials: This was a 2-stage study. The feasibility/visibility stage evaluated the ability to place the hydrogel using endoscopic ultrasound guidance on 8 swine (4 euthanized at post-injection day 8, 4 euthanized at post-injection day 22) and assessed the quality of visibility of the marked location on CBCT in the longer-surviving group. The risk assessment stage evaluated the toxicity of targeted intrapancreatic injections (3 swine) and intramural duodenal wall injections (3 swine) to assess toxicity of a misplaced hydrogel injection. All swine underwent postmortem examination and histopathologic studies. Results: The HOP—duodenum interface was successfully marked using hydrogel in 6 of the 8 swine. Histopathologic examination of the 6 successful hydrogel injections showed mild/minimal (4 cases) or moderate (2 cases) reactive inflammation isolated to the injection site. Of the 4 swine survived to 22 days, 3 demonstrated successful hydrogel placement at the HOP—duodenum interface, and this marked location was clearly visible for positional guidance on CBCT. There was no evidence of pancreatitis or duodenal toxicity in the swine undergoing targeted intrapancreatic or intramural duodenum injections for the risk assessment stage. Conclusions We demonstrate the feasibility and safety of injecting a hydrogel marker to highlight the HOP—duodenum interface that has acceptable visibility on CBCT. This technique, translated to humans, enables on-board visualization of this important boundary between the radiation target and dose-limiting, radiosensitive duodenum, facilitating efforts to safely deliver dose-escalated radiation therapy.

Dose Prediction Model for Duodenum Sparing With a Biodegradable Hydrogel Spacer for Pancreatic Cancer Radiation Therapy

PURPOSEnWe previously have shown the feasibility of duodenum sparing using a biodegradable hydrogel spacer in pancreatic cancer radiation therapy. In this study, we propose an overlap volume histogram (OVH) prediction model to select patients who might benefit from hydrogel placement and to predict the hydrogel spacing required to achieve clinical constraints.nnnMETHODS AND MATERIALSnOVH metrics for the duodenum were collected from the stereotactic body radiation therapy plans of 232 patients with unresectable pancreatic cancer (33xa0Gy in 5 fractions). OVH metrics L9cc and L3cc were defined as the tumor volume expansion distance at which 9xa0cm3 and 3xa0cm3 volumes of the duodenum overlap with tumor. D9cc and D3cc of the duodenum were defined as the dose-volume histogram dose to 9xa0cm3 and 3xa0cm3, respectively, of the duodenum. Prediction models were established by linear regression between Lx and Dx, where xxa0=xa03xa0cm3 and 9xa0cm3. OVH thresholds were obtained for predicting the target spacer thickness. The accuracy of the prediction model was then evaluated using treatment plans on pre-and post-hydrogel injection computed tomography scans from 2 cadaver specimens and 6 patients with previously treated locally advanced pancreatic cancer with simulated spacer.nnnRESULTSnLinear regression analysis showed a significant correlation between Lx and Dx (r2xa0=xa00.51 and 0.51 for L3cc-D3cc and L9cc-D9cc, respectively; both Pxa0<xa0.01). The OVH thresholds were Lˆ3ccxa0=xa07xa0mm and Lˆ9ccxa0=xa013xa0mm. The observed planning doses D3cc and D9cc of duodenum from pre-and post-hydrogel injection computed tomography scans of cadaver specimens and clinical patients with simulated spacer using predicted target spacer thickness were within the OVH model prediction range.nnnCONCLUSIONnOur model may predict which patients require placement of a hydrogel spacer before stereotactic body radiation therapy to meet predefined dose constraints. Furthermore, by predicting the required target hydrogel thickness, the spacer injection can be better guided to improve efficacy.

Impact of race, ethnicity, and socioeconomic factors on receipt of radiation after breast conservation surgery: analysis of the national cancer database

IntroductionMany eligible women with invasive breast cancer do not receive recommended adjuvant radiation (RT), despite its role in local control and overall survival. We examined trends in RT use over 10xa0years, and the impact of sociodemographic factors on the receipt of standard-of-care RT, using the National Cancer Database (NCDB).Materials/methodsWomen under age 70 with invasive breast cancer who underwent BCS from 2004 to 2014 were analyzed. Receipt of RT was evaluated in the whole cohort and by time period to identify temporal trends. Multiple logistic regression models were used to assess associations between factors such as race, insurance status, ethnicity, and receipt of RT.ResultsA total of 501,733 patients met eligibility criteria. The percentage of patients undergoing adjuvant RT increased from 86.7% in 2004 to 92.4% in 2012, and then decreased in 2013 and 2014 to 88.9%. On univariate analysis, patients of white race were significantly more likely to receive RT compared with patients of black race (90.4% vs 86.9%, pu2009<u20090.0001), as were non-Hispanic women compared to Hispanic patients (90.2% vs. 85.3%, pu2009<u20090.0001). On multivariate analysis, race, ethnicity, insurance status, education level, and age remained significantly associated with receipt of RT. On temporal analysis, gaps remained stable, with no significant improvements over time.ConclusionsThis analysis suggests a recent decline in guideline-concordant receipt of RT in women under 70, and persistent disparities in the use of RT after BCS by race, ethnicity, and socioeconomic factors. These findings raise concern for a recent detrimental change in patterns of care delivery.

Effects of biodegradable hydrogel spacer injection on contralateral submandibular gland sparing in radiotherapy for head and neck cancers

Xerostomia is the most common late toxicity after head and neck radiation. We demonstrate injection of a hydrogel spacer anteriorly displacing the submandibular gland. This procedure enables reduced dose to the displaced submandibular gland in cadaveric models of oropharynx cancer treated with IMRT, with potential implications in reducing xerostomia risk.