Results for “THERAPY” — Page 16

DOE OSTI2016

A Roadmap and Cost Implications of Establishing Comprehensive Cancer Care Using a Teleradiotherapy Network in a Group of Sub-Saharan African Countries With No Access to Radiation Therapy

Purpose: To propose a roadmap and explore the cost implications of establishing a teleradiotherapy network to provide comprehensive cancer care and capacity building in countries without access to radiation therapy. Methods and Materials: Ten low-income sub-Saharan countries with no current radiation therapy facilities were evaluated. A basic/secondary radiation therapy center (SRTC) with 2 teletherapy, 1 brachytherapy, 1 simulator, and a treatment planning facility was envisaged at a cost of 5 million US dollars (USD 5M). This could be networked with 1 to 4 primary radiation therapy centers (PRTC) with 1 teletherapy unit, each costing USD 2M. The numbers of PRTCs and SRTCs for each country were computed on the basis of cancer incidence, assuming that a PRTC and SRTC could respectively treat 450 and 900 patients annually. Results: An estimated 71,215 patients in these countries will need radiation therapy in 2020. Stepwise establishment of a network with 99 PRTCs and 28 SRTCs would result in 155 teletherapy units and 96% access to radiation therapy. A total of 310 radiation oncologists, 155 medical physicists, and 465 radiation therapy technologists would be needed. Capacity building could be undertaken through telementoring by networking to various international institutions and professional societies. Total infrastructure costs would be approximately USD 860.88M, only 0.94% of the average annual gross domestic product of these 10 countries. A total of 1.04 million patients could receive radiation therapy during the 15-year lifespan of a teletherapy unit for an investment of USD 826.69 per patient. For the entire population of 218.32 million, this equates to USD 4.11 per inhabitant. Conclusion: A teleradiotherapy network could be a cost-contained innovative health care strategy to provide effective comprehensive cancer care through resource sharing and capacity building. The network could also be expanded to include other allied specialties. The proposal calls for active coordination between all national and international organizations backed up by strong geopolitical commitment and action from all stakeholders.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2016

Oxygen and Perfusion Kinetics in Response to Fractionated Radiation Therapy in FaDu Head and Neck Cancer Xenografts Are Related to Treatment Outcome

Purpose: To test whether oxygenation kinetics correlate with the likelihood for local tumor control after fractionated radiation therapy. Methods and Materials: We used diffuse reflectance spectroscopy to noninvasively measure tumor vascular oxygenation and total hemoglobin concentration associated with radiation therapy of 5 daily fractions (7.5, 9, or 13.5 Gy/d) in FaDu xenografts. Spectroscopy measurements were obtained immediately before each daily radiation fraction and during the week after radiation therapy. Oxygen saturation and total hemoglobin concentration were computed using an inverse Monte Carlo model. Results: First, oxygenation kinetics during and after radiation therapy, but before tumor volumes changed, were associated with local tumor control. Locally controlled tumors exhibited significantly faster increases in oxygenation after radiation therapy (days 12-15) compared with tumors that recurred locally. Second, within the group of tumors that recurred, faster increases in oxygenation during radiation therapy (day 3-5 interval) were correlated with earlier recurrence times. An area of 0.74 under the receiver operating characteristic curve was achieved when classifying the local control tumors from all irradiated tumors using the oxygen kinetics with a logistic regression model. Third, the rate of increase in oxygenation was radiation dose dependent. Radiation doses ≤9.5 Gy/d did not initiate an increase in oxygenation, whereas 13.5 Gy/d triggered significant increases in oxygenation during and after radiation therapy. Conclusions: Additional confirmation is required in other tumor models, but these results suggest that monitoring tumor oxygenation kinetics could aid in the prediction of local tumor control after radiation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2017

Clinical Outcomes of Image Guided Adaptive Hypofractionated Weekly Radiation Therapy for Bladder Cancer in Patients Unsuitable for Radical Treatment

Purpose and Objectives: We report on the clinical outcomes of a phase 2 study assessing image guided hypofractionated weekly radiation therapy in bladder cancer patients unsuitable for radical treatment. Methods and Materials: Fifty-five patients with T2-T4aNx-2M0-1 bladder cancer not suitable for cystectomy or daily radiation therapy treatment were recruited. A “plan of the day” radiation therapy approach was used, treating the whole (empty) bladder to 36 Gy in 6 weekly fractions. Acute toxicity was assessed weekly during radiation therapy, at 6 and 12 weeks using the Common Terminology Criteria for Adverse Events version 3.0. Late toxicity was assessed at 6 months and 12 months using Radiation Therapy Oncology Group grading. Cystoscopy was used to assess local control at 3 months. Cumulative incidence function was used to determine local progression at 1 at 2 years. Death without local progression was treated as a competing risk. Overall survival was estimated using the Kaplan-Meier method. Results: Median age was 86 years (range, 68-97 years). Eighty-seven percent of patients completed their prescribed course of radiation therapy. Genitourinary and gastrointestinal grade 3 acute toxicity was seen in 18% (10/55) and 4% (2/55) of patients, respectively. No grade 4 genitourinary or gastrointestinal toxicity was seen. Grade ≥3 late toxicity (any) at 6 and 12 months was seen in 6.5% (2/31) and 4.3% (1/23) of patients, respectively. Local control after radiation therapy was 92% of assessed patients (60% total population). Cumulative incidence of local progression at 1 year and 2 years for all patients was 7% (95% confidence interval [CI] 2%-17%) and 17% (95% CI 8%-29%), respectively. Overall survival at 1 year was 63% (95% CI 48%-74%). Conclusion: Hypofractionated radiation therapy delivered weekly with a plan of the day approach offers good local control with acceptable toxicity in a patient population not suitable for radical bladder treatment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2017

Renal Function Outcomes of High-risk Neuroblastoma Patients Undergoing Radiation Therapy

Purpose: To analyze the renal function outcomes in patients undergoing radiation therapy for neuroblastoma. Methods and Materials: The clinical metrics of renal function were analyzed in patients undergoing radiation therapy for high-risk neuroblastoma from 2000 to 2015. The blood urea nitrogen (BUN) and creatinine values before radiation therapy were compared with last available follow-up values and analyzed with the clinical circumstances, including follow-up length, age at primary irradiation, nephrectomy, and radiation technique. The creatinine clearance was estimated using the Shull method. Results: With a median follow-up period of 3.5 years, none of the 266 patients studied developed a chronic renal insufficiency. For all patients, the creatinine level increased from 0.44 to 0.51 mg/dL and the BUN increased from 10.53 to 15.52 mg/dL. Three patients required antihypertensive medication. The patients who underwent intensity modulated radiation therapy did not experience increased creatinine levels during the follow-up period; however, they had a reduced median follow-up length compared with patients treated with anteroposterior/posteroanterior beams (4.7 vs 3.3 years). A longer follow-up length was associated with an increased creatinine level. The preradiation therapy creatinine level increased with patient age, similar to that of the last follow-up creatinine level, suggesting that the changes in creatinine could likely be explained by physiologic increases associated with aging rather than radiation-induced renal damage. The creatinine clearance did not decrease in any circumstance. Conclusions: The present cohort had excellent renal outcomes after radiation therapy for neuroblastoma. No patient developed chronic renal insufficiency, and the small increases in BUN and creatinine we observed correlated, as expected, with increases in patient age. The results of the present study revealed a possible advantage for intensity modulated radiation therapy in preserving renal function; however, the follow-up length is a recognized confounding variable. The kidneys are vital structures to consider when planning radiation therapy for neuroblastoma patients, and we have found encouraging evidence that modern techniques to spare them in the setting of multiple treatment-related insults have been successful.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2017

Empowering Intensity Modulated Proton Therapy Through Physics and Technology: An Overview

Considering the clinical potential of protons attributable to their physical characteristics, interest in proton therapy has increased greatly in this century, as has the number of proton therapy installations. Until recently, passively scattered proton therapy was used almost entirely. Notably, the overall clinical results to date have not shown a convincing benefit of protons over photons. A rapid transition is now occurring with the implementation of the most advanced form of proton therapy, intensity modulated proton therapy (IMPT). IMPT is superior to passively scattered proton therapy and intensity modulated radiation therapy (IMRT) dosimetrically. However, numerous limitations exist in the present IMPT methods. In particular, compared with IMRT, IMPT is highly vulnerable to various uncertainties. In this overview we identify three major areas of current limitations of IMPT: treatment planning, treatment delivery, and motion management, and discuss current and future efforts for improvement. For treatment planning, we need to reduce uncertainties in proton range and in computed dose distributions, improve robust planning and optimization, enhance adaptive treatment planning and delivery, and consider how to exploit the variability in the relative biological effectiveness of protons for clinical benefit. The quality of proton therapy also depends on the characteristics of the IMPT delivery systems and image guidance. Efforts are needed to optimize the beamlet spot size for both improved dose conformality and faster delivery. For the latter, faster energy switching time and increased dose rate are also needed. Real-time in-room volumetric imaging for guiding IMPT is in its early stages with cone beam computed tomography (CT) and CT-on-rails, and continued improvements are anticipated. In addition, imaging of the proton beams themselves, using, for instance, prompt γ emissions, is being developed to determine the proton range and to reduce range uncertainty. With the realization of the advances described above, we posit that IMPT, thus empowered, will lead to substantially improved clinical results.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2018

Dose-limiting Urinary Toxicity With Pembrolizumab Combined With Weekly Hypofractionated Radiation Therapy in Bladder Cancer

There is currently significant interest in the potential benefits of combining radiation and immune checkpoint blockade (ICB) to stimulate both regional and distant abscopal immune responses. In melanoma and lung cancer, patients who have received radiation therapy during ICB appear to have prolonged survival. The PLUMMB trial (Pembrolizumab in Muscle-invasive/Metastatic Bladder cancer) (NCT02560636) is a phase I study to test the tolerability of a combination of weekly radiation therapy with pembrolizumab in patients with metastatic or locally advanced urothelial cancer of the bladder. In the first dose-cohort, patients received pembrolizumab 100 mg 3-weekly, starting 2 weeks before commencing weekly adaptive bladder radiation therapy to a dose of 36 Gy in 6 fractions. The first dose-cohort was stopped after 5 patients, having met the predefined definition of dose-limiting toxicity. Three patients experienced grade 3 urinary toxicities, 2 of which were attributable to therapy. One patient experienced a grade 4 rectal perforation. In view of these findings, the trial has been paused and the protocol will be amended to reduce radiation therapy dose per fraction. The authors advise caution to those combining radiation therapy and ICB, particularly when radiation therapy is given at high dose per fraction for pelvic tumours. The PLUMMB trial met the protocol-defined definition of dose-limiting toxicity and will be amended to reduce radiation therapy dose.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2013

The host immunological response to cancer therapy: An emerging concept in tumor biology

Almost any type of anti-cancer treatment including chemotherapy, radiation, surgery and targeted drugs can induce host molecular and cellular immunological effects which, in turn, can lead to tumor outgrowth and relapse despite an initial successful therapy outcome. Tumor relapse due to host immunological effects is attributed to angiogenesis, tumor cell dissemination from the primary tumors and seeding at metastatic sites. This short review will describe the types of host cells that participate in this process, the types of factors secreted from the host following therapy that can promote tumor re-growth, and the possible implications of this unique and yet only partially-known process. It is postulated that blocking these specific immunological effects in the reactive host in response to cancer therapy may aid in identifying new host-dependent targets for cancer, which in combination with conventional treatments can prolong therapy efficacy and extend survival. Additional studies investigating this specific research direction—both in preclinical models and in the clinical setting are essential in order to advance our understanding of how tumors relapse and evade therapy. -- Highlights: • Cancer therapy induces host molecular and cellular pro-tumorigenic effects. • Host effects in response to therapy may promote tumor relapse and metastasis. • The reactive host consists of immunological mediators promoting tumor re-growth. • Blocking therapy-induced host mediators may improve outcome.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

EUD-based biological optimization for carbon ion therapy

Purpose: Treatment planning for carbon ion therapy requires an accurate modeling of the biological response of each tissue to estimate the clinical outcome of a treatment. The relative biological effectiveness (RBE) accounts for this biological response on a cellular level but does not refer to the actual impact on the organ as a whole. For photon therapy, the concept of equivalent uniform dose (EUD) represents a simple model to take the organ response into account, yet so far no formulation of EUD has been reported that is suitable to carbon ion therapy. The authors introduce the concept of an equivalent uniform effect (EUE) that is directly applicable to both ion and photon therapies and exemplarily implemented it as a basis for biological treatment plan optimization for carbon ion therapy. Methods: In addition to a classical EUD concept, which calculates a generalized mean over the RBE-weighted dose distribution, the authors propose the EUE to simplify the optimization process of carbon ion therapy plans. The EUE is defined as the biologically equivalent uniform effect that yields the same probability of injury as the inhomogeneous effect distribution in an organ. Its mathematical formulation is based on the generalized mean effect using an effect-volume parameter to account for different organ architectures and is thus independent of a reference radiation. For both EUD concepts, quadratic and logistic objective functions are implemented into a research treatment planning system. A flexible implementation allows choosing for each structure between biological effect constraints per voxel and EUD constraints per structure. Exemplary treatment plans are calculated for a head-and-neck patient for multiple combinations of objective functions and optimization parameters. Results: Treatment plans optimized using an EUE-based objective function were comparable to those optimized with an RBE-weighted EUD-based approach. In agreement with previous results from photon therapy, the optimization by biological objective functions resulted in slightly superior treatment plans in terms of final EUD for the organs at risk (OARs) compared to voxel-based optimization approaches. This observation was made independent of the underlying objective function metric. An absolute gain in OAR sparing was observed for quadratic objective functions, whereas intersecting DVHs were found for logistic approaches. Even for considerable under- or overestimations of the used effect- or dose–volume parameters during the optimization, treatment plans were obtained that were of similar quality as the results of a voxel-based optimization. Conclusions: EUD-based optimization with either of the presented concepts can successfully be applied to treatment plan optimization. This makes EUE-based optimization for carbon ion therapy a useful tool to optimize more specifically in the sense of biological outcome while voxel-to-voxel variations of the biological effectiveness are still properly accounted for. This may be advantageous in terms of computational cost during treatment plan optimization but also enables a straight forward comparison of different fractionation schemes or treatment modalities.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

WE-FG-BRB-03: Challenges and Opportunities for Implementing Biological Optimization in Particle Therapy

The physical pattern of energy deposition and the enhanced relative biological effectiveness (RBE) of protons and carbon ions compared to photons offer unique and not fully understood or exploited opportunities to improve the efficacy of radiation therapy. Variations in RBE within a pristine or spread out Bragg peak and between particle types may be exploited to enhance cell killing in target regions without a corresponding increase in damage to normal tissue structures. In addition, the decreased sensitivity of hypoxic tumors to photon-based therapies may be partially overcome through the use of more densely ionizing radiations. These and other differences between particle and photon beams may be used to generate biologically optimized treatments that reduce normal tissue complications. In this symposium, speakers will examine the impact of the RBE of charged particles on measurable biological endpoints, treatment plan optimization, and the prediction or retrospective assessment of treatment outcomes. In particular, an AAPM task group was formed to critically examine the evidence for a spatially-variant RBE in proton therapy. Current knowledge of proton RBE variation with respect to dose, biological endpoint, and physics parameters will be reviewed. Further, the clinical relevance of these variations will be discussed. Recent work focused on improving simulations of radiation physics and biological response in proton and carbon ion therapy will also be presented. Finally, relevant biology research and areas of research needs will be highlighted, including the dependence of RBE on genetic factors including status of DNA repair pathways, the sensitivity of cancer stem-like cells to charged particles, the role of charged particles in hypoxic tumors, and the importance of fractionation effects. In addition to the physical advantages of protons and more massive ions over photons, the future application of biologically optimized treatment plans and their potential to provide higher levels of local tumor control and improved normal tissue sparing will be discussed. Learning Objectives: To assess whether the current practice of a constant RBE of 1.1 should be revised or maintained in proton therapy and to evaluate the potential clinical consequences of delivering RBE-weighted dose distributions based on variable RBE To review current research on biological models used to predict the increased biological effectiveness of proton and carbon ions to help move towards a practical understanding and implementation of biological optimization in particle therapy To discuss potential differences in biological mechanisms between photons and charged particles (light and heavy ions) that could impact clinical cancer therapy H. Paganetti, NCI U19 CA21239D. Grosshans, Our research is supported by the NCIK. Held, Funding Support: National Cancer Institute of the National Institutes of Health, USA, under Award Number R21CA182259 and Federal Share of Program Income Earned by Massachusetts General Hospital on C06CA059267, Proton Therapy Research and Treatment Center.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

WE-FG-BRB-04: RBEs for Human Lung Cancer Cells Exposed to Protons and Heavier Ions: Implications for Clinical Use of Charged Particles in Cancer Therapy

The physical pattern of energy deposition and the enhanced relative biological effectiveness (RBE) of protons and carbon ions compared to photons offer unique and not fully understood or exploited opportunities to improve the efficacy of radiation therapy. Variations in RBE within a pristine or spread out Bragg peak and between particle types may be exploited to enhance cell killing in target regions without a corresponding increase in damage to normal tissue structures. In addition, the decreased sensitivity of hypoxic tumors to photon-based therapies may be partially overcome through the use of more densely ionizing radiations. These and other differences between particle and photon beams may be used to generate biologically optimized treatments that reduce normal tissue complications. In this symposium, speakers will examine the impact of the RBE of charged particles on measurable biological endpoints, treatment plan optimization, and the prediction or retrospective assessment of treatment outcomes. In particular, an AAPM task group was formed to critically examine the evidence for a spatially-variant RBE in proton therapy. Current knowledge of proton RBE variation with respect to dose, biological endpoint, and physics parameters will be reviewed. Further, the clinical relevance of these variations will be discussed. Recent work focused on improving simulations of radiation physics and biological response in proton and carbon ion therapy will also be presented. Finally, relevant biology research and areas of research needs will be highlighted, including the dependence of RBE on genetic factors including status of DNA repair pathways, the sensitivity of cancer stem-like cells to charged particles, the role of charged particles in hypoxic tumors, and the importance of fractionation effects. In addition to the physical advantages of protons and more massive ions over photons, the future application of biologically optimized treatment plans and their potential to provide higher levels of local tumor control and improved normal tissue sparing will be discussed. Learning Objectives: To assess whether the current practice of a constant RBE of 1.1 should be revised or maintained in proton therapy and to evaluate the potential clinical consequences of delivering RBE-weighted dose distributions based on variable RBE To review current research on biological models used to predict the increased biological effectiveness of proton and carbon ions to help move towards a practical understanding and implementation of biological optimization in particle therapy To discuss potential differences in biological mechanisms between photons and charged particles (light and heavy ions) that could impact clinical cancer therapy H. Paganetti, NCI U19 CA21239D. Grosshans, Our research is supported by the NCIK. Held, Funding Support: National Cancer Institute of the National Institutes of Health, USA, under Award Number R21CA182259 and Federal Share of Program Income Earned by Massachusetts General Hospital on C06CA059267, Proton Therapy Research and Treatment Center.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

WE-FG-BRB-01: Clinical Significance of RBE Variations in Proton Therapy

The physical pattern of energy deposition and the enhanced relative biological effectiveness (RBE) of protons and carbon ions compared to photons offer unique and not fully understood or exploited opportunities to improve the efficacy of radiation therapy. Variations in RBE within a pristine or spread out Bragg peak and between particle types may be exploited to enhance cell killing in target regions without a corresponding increase in damage to normal tissue structures. In addition, the decreased sensitivity of hypoxic tumors to photon-based therapies may be partially overcome through the use of more densely ionizing radiations. These and other differences between particle and photon beams may be used to generate biologically optimized treatments that reduce normal tissue complications. In this symposium, speakers will examine the impact of the RBE of charged particles on measurable biological endpoints, treatment plan optimization, and the prediction or retrospective assessment of treatment outcomes. In particular, an AAPM task group was formed to critically examine the evidence for a spatially-variant RBE in proton therapy. Current knowledge of proton RBE variation with respect to dose, biological endpoint, and physics parameters will be reviewed. Further, the clinical relevance of these variations will be discussed. Recent work focused on improving simulations of radiation physics and biological response in proton and carbon ion therapy will also be presented. Finally, relevant biology research and areas of research needs will be highlighted, including the dependence of RBE on genetic factors including status of DNA repair pathways, the sensitivity of cancer stem-like cells to charged particles, the role of charged particles in hypoxic tumors, and the importance of fractionation effects. In addition to the physical advantages of protons and more massive ions over photons, the future application of biologically optimized treatment plans and their potential to provide higher levels of local tumor control and improved normal tissue sparing will be discussed. Learning Objectives: To assess whether the current practice of a constant RBE of 1.1 should be revised or maintained in proton therapy and to evaluate the potential clinical consequences of delivering RBE-weighted dose distributions based on variable RBE To review current research on biological models used to predict the increased biological effectiveness of proton and carbon ions to help move towards a practical understanding and implementation of biological optimization in particle therapy To discuss potential differences in biological mechanisms between photons and charged particles (light and heavy ions) that could impact clinical cancer therapy H. Paganetti, NCI U19 CA21239D. Grosshans, Our research is supported by the NCIK. Held, Funding Support: National Cancer Institute of the National Institutes of Health, USA, under Award Number R21CA182259 and Federal Share of Program Income Earned by Massachusetts General Hospital on C06CA059267, Proton Therapy Research and Treatment Center.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2019

A Prospective, Open-Label, Multicenter Phase 2 Trial of Neoadjuvant Therapy Using Full-Dose Gemcitabine and S-1 Concurrent with Radiation for Resectable Pancreatic Ductal Adenocarcinoma

Background: Neoadjuvant therapy reportedly shows only marginal clinical benefit in pancreatic ductal adenocarcinoma (PDAC), especially in resectable cases. However, with more effective regimens, neoadjuvant therapy may become a standard of care for resectable cases. A prospective, open-label, multicenter phases 1 and 2 trial of neoadjuvant therapy was conducted using full-dose gemcitabine and S-1 concurrently with 50.4 Gy of radiation therapy (GSRT) for resectable PDAC. This report describes the phase 2 results. Methods: The phase 2 part of this study enrolled 57 patients with cytologically or histologically proven PDAC deemed resectable based on imaging before neoadjuvant therapy. These patients received GSRT. After reevaluation by computed tomography scan, surgical exploration was performed, followed by adjuvant therapy. According to the prescribed protocol of the clinical trial, statistical analyses included 57 phase 2 patients and 6 phase 1 patients who received the same dosage as in phase 2. Results: This trial enrolled 63 patients (42 men and 21 women) with a median age of 70 years. Leukopenia or neutropenia of grade 3 or higher occurred for 79% of the patients, but no other severe adverse events were observed. Among the 63 patients, 54 underwent surgical resection. Intention-to-treat analysis of the 63 patients showed an excellent median survival time lasting as long as 55.3 months. The patients who completed neoadjuvant therapy, surgery, and adjuvant therapy had a 5-year survival rate of 56.6%. Conclusions: This regimen showed outstanding clinical efficacy with acceptable tolerability for patients with resectable PDAC.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2018

Sono-photodynamic modality for cancer treatment using bio-degradable bio-conjugated sonnelux nanocomposite in tumor-bearing mice: Activated cancer therapy using light and ultrasound

Highlights: • An up-to-date cancer therapy: Sono-photodynamic therapy (SPDT) in combination with sonnelux (SLux) as a sono-photosensitizer loaded on folic acid conjugated nanographene oxide nanoparticles (FA-NGO- SLux). • A novel nanomaterial with great potential as effective drug delivery system in targeting sono-photo-dynamic-therapy (SPDT). The underlying work was conducted aiming at cancer targeted therapy using the sono-photodynamic therapy (SPDT) in combination with sonnelux (SLux) as a sono-photosensitizer loaded on folic acid conjugated nanographene oxide nanoparticles (FA-NGO-SLux) as an up-to-date treating cancer modality. Study was conducted on A total of 130 male Swiss albino mice with age 60–65 day, weighing 20 ± 25 g, inoculated with Ehrlich ascites carcinoma (EAC) subdivided into 13 group. Two sources of energy were used; namely infrared laser and Ultrasound (pulsed and continuous wave mode). Results revealed that Nano-SLux is a potential photosensitizer and sonosensitizer for photodynamic or sonodynamic treatment of Ehrlich ascites tumor tissue. Nano-SLux can play important roles in inhibiting tumor growth and even inducing cell death, which might be attributed to Photo and/or sono-chemical activation mechanism. Infra-red laser in combination with ultrasound in the presence of Nano- SLux has a potential antitumor effect. Sonocation followed by light photon irradiation proves its excellent efficiency as an anticancer therapy. The results suggest that folic acid-conjugated nano-graphene oxide loaded with sono-photo-sensitizers (FA–NGO–SPSs) could be used as a novel nanomaterial with great potential as effective drug delivery system in targeting sono-photo-dynamic-therapy (SPDT).

60 APPLIED LIFE SCIENCES↗

DOE OSTI2013

Interval to Biochemical Failure Predicts Clinical Outcomes in Patients With High-Risk Prostate Cancer Treated by Combined-Modality Radiation Therapy

Purpose: To validate the prognostic value of interval to biochemical failure (IBF) in patients with high-risk prostate cancer (HiRPCa) treated with combined-modality radiation therapy (CMRT) with or without androgen deprivation therapy (ADT). Methods and Materials: We conducted a retrospective review of HiRPCa (prostate-specific antigen >20 ng/mL, Gleason score [GS] 8-10, or clinical T stage T3-T4) treated with either dose-escalated external beam radiation therapy (EBRT) or CMRT. Interval to biochemical failure was classified as ≤18 or >18 months from the end of all therapy to the date of biochemical failure (BF). Kaplan-Meier methods and Cox proportional hazards regression were used to evaluate the prognostic value of IBF ≤18 months for distant metastasis (DM) and prostate cancer-specific mortality (PCSM). Results: Of 958 patients with a median follow-up of 63.2 months, 175 patients experienced BF. In those with BF, there were no differences in pretreatment clinical characteristics between the EBRT and CMRT groups, except for a higher proportion of patients with GS 8-10 in the CMRT group (70% vs 52%, P=.02). Median IBF after all therapy was 24.0 months (interquartile range 9.6-46.0) in the EBRT group and 18.9 months (interquartile range 9.2-34.5) in the CMRT group (P=.055). On univariate analysis, IBF ≤18 months was associated with increased risk of DM and PCSM in the entire cohort and the individual EBRT and CMRT groups. On multivariate analysis, only GS 9-10 and IBF ≤18 months, but not the radiation therapy regimen or ADT use, predicted DM (hazard ratio [HR] 3.7, P<.01, 95% confidence interval [CI] 1.4-10.3 for GS 9-10; HR 3.9, P<.0001, 95% CI 2.4-6.5 for IBF ≤18 months) and PCSM (HR 14.8, P<.009, 95% CI 2.0-110 for GS 9-10; HR 4.4, P<.0001, 95% CI 2.4-8.1 for IBF ≤18 months). Conclusions: Short IBF was highly prognostic for higher DM and PCSM in patients with HiRPCa. The prognostic value of IBF for DM and PCSM was not affected by the radiation therapy regimen or ADT use.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2015

Phase 1 Trial of Bevacizumab With Concurrent Chemoradiation Therapy for Squamous Cell Carcinoma of the Head and Neck With Exploratory Functional Imaging of Tumor Hypoxia, Proliferation, and Perfusion

Purpose: A phase 1 trial was completed to examine the safety and feasibility of combining bevacizumab with radiation and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) treated with curative intent. Additionally, we assessed the capacity of bevacizumab to induce an early tumor response as measured by a series of biological imaging studies. Methods and Materials: All patients received a single induction dose of bevacizumab (15 mg/kg) delivered 3 weeks (±3 days) before the initiation of chemoradiation therapy. After the initial dose of bevacizumab, comprehensive head and neck chemoradiation therapy was delivered with curative intent to 70 Gy in 33 fractions with concurrent weekly cisplatin at 30 mg/m{sup 2} and bevacizumab every 3 weeks (weeks 1, 4, 7) with dose escalation from 5 to 10 to 15 mg/kg. All patients underwent experimental imaging with [{sup 18}F]fluorothymidine positron emission tomography (FLT-PET) (proliferation), [{sup 61}Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) PET (Cu-ATSM-PET) (hypoxia), and dynamic contrast-enhanced computed tomography (DCE-CT) (perfusion) at 3 time points: before bevacizumab monotherapy, after bevacizumab monotherapy, and during the combined therapy course. Results: Ten patients were enrolled. All had stage IV HNSCC, all achieved a complete response to treatment, and 9 of 10 remain alive, with a mean survival time of 61.3 months. All patients experienced grade 3 toxicity, but no dose-limiting toxicities or significant bleeding episodes were observed. Significant reductions were noted in tumor proliferation (FLT-PET), tumor hypoxia (Cu-ATSM-PET), and DCE-CT contrast enhancement after bevacizumab monotherapy, with further decreases in FLT-PET and Cu-ATSM-PET during the combined therapy course. Conclusions: The incorporation of bevacizumab into comprehensive chemoradiation therapy regimens for patients with HNSCC appears safe and feasible. Experimental imaging demonstrates measureable changes in tumor proliferation, hypoxia, and perfusion after bevacizumab monotherapy and during chemoradiation therapy. These findings suggest opportunities to preview the clinical outcomes for individual patients and thereby design personalized therapy approaches in future trials.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2016

Stochastic Predictions of Cell Kill During Stereotactic Ablative Radiation Therapy: Do Hypoxia and Reoxygenation Really Matter?

Purpose: To simulate stereotactic ablative radiation therapy on hypoxic and well-oxygenated in silico tumors, incorporating probabilistic parameter distributions and linear-quadratic versus linear-quadratic-cubic methodology and the evaluation of optimal fractionation schemes using biological effective dose (BED{sub α/β=10} {sub or} {sub 3}) comparisons. Methods and Materials: A temporal tumor growth and radiation therapy algorithm simulated high-dose external beam radiation therapy using stochastic methods. Realistic biological proliferative cellular hierarchy and pO{sub 2} histograms were incorporated into the 10{sup 8}-cell tumor model, with randomized radiation therapy applied during continual cell proliferation and volume-based gradual tumor reoxygenation. Dose fractions ranged from 6-35 Gy, with predictive outcomes presented in terms of the total doses (converted to BED) required to eliminate all cells that could potentially regenerate the tumor. Results: Well-oxygenated tumor control BED{sub 10} outcomes were not significantly different for high-dose versus conventional radiation therapy (BED{sub 10}: 79-84 Gy; Equivalent Dose in 2 Gy fractions with α/β of 10: 66-70 Gy); however, total treatment times decreased from 7 down to 1-3 weeks. For hypoxic tumors, an additional 28 Gy (51 Gy BED{sub 10}) was required, with BED{sub 10} increasing with dose per fraction due to wasted dose in the final fraction. Fractions of 9 Gy compromised well for total treatment time and BED, with BED{sub 10}:BED{sub 3} of 84:176 Gy for oxic and 132:278 Gy for non-reoxygenating hypoxic tumors. Initial doses of 12 Gy followed by 6 Gy further increased the therapeutic ratio. When delivering ≥9 Gy per fraction, applying reoxygenation and/or linear-quadratic-cubic cell survival both affected tumor control doses by a significant 1-2 fractions. Conclusions: The complex temporal dynamics of tumor oxygenation combined with probabilistic cell kinetics in the modeling of radiation therapy requires sophisticated stochastic modeling to predict tumor cell kill. For stereotactic ablative radiation therapy, high doses in the first week followed by doses that are more moderate may be beneficial because a high percentage of hypoxic cells could be eradicated early while keeping the required BED{sub 10} relatively low and BED{sub 3} toxicity to tolerable levels.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2018

External beam planning module of Eclipse for external beam radiation therapy

Eclipse is a 3-dimensional (3D) treatment planning system for radiation therapy offered by Varian Medical Systems, Inc. The system has the network connectivity for the electronic transfer of image datasets and digital data communication among different equipment. The scope of this project for this special issue of Medical Dosimetry on 3D treatment planning systems is the assessment of planning tools in the external beam planning module of Eclipse to generate optimized treatment plans for patients undergoing external beam radiation therapy. This treatment planning system is relatively mature to be able to generate (1) simple treatment plans, (2) conformal radiation therapy plans, (3) static intensity-modulated radiation therapy (IMRT) plans, (4) volumetric-modulated arc therapy (VMAT) plans, and (5) treatment plans for electron beam therapy. The treatment planning tools are relatively plentiful to assist in the radiation therapy treatment planning. Some new features have been incorporated in the latest version and are helpful for making high-quality treatment plans. However, the location of the tools is not intuitive, and hence, familiarity with the user interface is essential to the efficient use of the treatment planning system. In addition, there are a number of dose algorithms available for the computation of dose distributions. The understanding of each dose computation algorithm is essential for the optimal use of this treatment planning system.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2016

Novel technologies and theoretical models in radiation therapy of cancer patients using 6.3 MeV fast neutrons produced by U-120 cyclotron

The analysis of clinical use of neutron therapy with 6 MeV fast neutrons compared to conventional radiation therapy was carried out. The experience of using neutron and mixed neutron and photon therapy in patients with different radio-resistant malignant tumors shows the necessity of further studies and development of the novel approaches to densely-ionizing radiation. The results of dosimetry and radiobiological studies have been the basis for planning clinical programs for neutron therapy. Clinical trials over the past 30 years have shown that neutron therapy successfully destroys radio-resistant cancers, including salivary gland tumors, adenoidcystic carcinoma, inoperable sarcomas, locally advanced head and neck tumors, and locally advanced prostate cancer. Radiation therapy with 6.3 MeV fast neutrons used alone and in combination with photon therapy resulted in improved long-term treatment outcomes in patients with radio-resistant malignant tumors.

62 RADIOLOGY AND NUCLEAR MEDICINE↗