Advances In Radiation Oncology Research Articles

Comparative Dosimetric Analysis of conventional 3DCRT and VMAT for Head and Neck Cancer

Introduction: Advancements in radiation oncology improve the outlook for patients with head and neck cancer which allowed to escalate the dose of radiation to tumours while minimizing the dose to surrounding healthy tissues. This study aims comparison of radiotherapy treatment planning of 3 DCRT and VMAT for head and neck cancer.Methods: Prospective study conducted on fifty patients of head and neck cancer in which 25 patients were treated with 3 DCRT and 25 patients treated with VMAT. Both plans were evaluated to compare the efficiency of VMAT and 3 DCRT dosimetrically in terms of PTV volume, homogeneity index, conformity index and doses to organs at risk. Results: Dose D98% for PTV66 was 59.39 Gy and 51.82 for VMAT and 3DCRT respectively. Conformity index was 1.0816 and 1.4472 for VMAT and 3DCRT plans respectively and the difference was statistically significant. Homogeneity index was 0.1473 for VMAT and 0.2997 for 3DCRT which proves that VMAT was more homogeneous. OARs sparing was also better with VMAT compared to 3DCRT especially the OARs which were very close to target volume especially parotid glands, Brainstem and optic nerve. Conclusion: Compared to 3DCRT plans, VMAT plan produced significantly better target coverage, homogeneous as well as dose conformity. Doses to organs at risk such as spinal cord and parotid glands were also reduced. Besides, the delivery of VMAT treatment was more efficient.

MR-LINAC, a New Partner in Radiation Oncology: Current Landscape.

Technological advances in radiation oncology are oriented towards improving treatment precision and tumor control. Among these advances, magnetic-resonance-image-guided radiation therapy (MRgRT) stands out, with technological advances to deliver targeted treatments adapted to a tumor's anatomy on the day while minimizing incidental exposure to organs at risk, offering an unprecedented therapeutic advantage compared to X-ray-based IGRT delivery systems. This new technology changes the traditional workflow in radiation oncology and requires an evolution in team coordination to administer more precise treatments. Once implemented, it paves the way for newer indication for radiation therapy to safely deliver higher doses than ever before, with better preservation of healthy tissues to optimize patient outcomes. In this narrative review, we assess the technical aspects of the novel linear accelerators that can deliver MRgRT and summarize the available published experience to date, focusing on oncological results and future challenges.

Radiation Treatment Plan Evaluation Education in Residency: A Needs Assessment

Advances in radiation oncology have steadily increased the complexity of radiation treatment plan (RTP) development and evaluation. We hypothesized that radiation oncology attendings and residents would hold different attitudes regarding resident knowledge and comfort with RTP review. A web-based survey was distributed to residents (38-item) and attendings (32-item) at 14 ACGME-accredited residency programs. The survey consisted of a combination of multiple-choice questions and free text responses. A total of 169 residents and 71 faculty received the survey. The response rate was 38%. Resident respondents (n = 71) were PGY-2 (21%), -3 (30%), -4 (21%), and -5 (28%), and faculty respondents (n = 20) had 1-4 years (30%), 5-9 (35%), 10-15 (25%), >15 (10%) years in practice. 34% of residents report reviewing ≤2 plans and spending ≤20 minutes on plan review each week. 47% of residents report reviewing less than half of all new treatment plans for their patients. While 20% of residents report "often" or "always" reviewing treatment plans with an attending, 31% report they "rarely" or "never" do. More than half (56%) of residents felt that they have inadequate exposure to RTP review and 47% felt they are receiving inadequate education in this area. 83% cited "difficulty aligning resident and attending schedules" as a reason for inadequate exposure and education. 32% of residents report "rarely" or "never" making suggestions to optimize a plan and 21% report they do so "often" or "always". 54% of residents do not feel confident independently evaluating treatment plans, 31% do not feel confident identifying major planning errors, and 42% do not feel confident optimizing or suggesting minor improvements to plans. In contrast, attendings report that on average, they review 70% of all new treatment plans alongside residents. 40% report they do not have enough time to review RTPs with residents, with 75% citing "difficulty aligning resident and attending schedules" as a main reason. 50% of attendings report that residents "rarely" or "never" suggest optimizations for treatment plans that require them, but 90% of attendings "agree" or "strongly agree" that residents are competent at RTP evaluation by the end of a rotation. Both residents and attendings (90% each) believe that residents would benefit from a dedicated resource on RTP review. Across respondents, 96% were familiar with a systematic RTP review approach and 97% "agree" or "strongly agree" that systematic RTP review improves their ability to evaluate a plan. A large percentage of residents feel they have inadequate RTP education in residency and lack confidence when evaluating RTPs. There is discordance between resident and faculty perceptions of RTP review education and resident competence, but a vast majority agree that systematic RTP review is valuable. Future work should focus on development of learning tools for RTP evaluation using a systematic review process.

ACVR and ECVDI consensus statement: Reporting elements for toxicity criteria of the veterinary radiation therapy oncology group v2.0.

The toxicity criteria of the veterinary radiation therapy oncology group (VRTOG) version 2 guidelines are a substantial update to reflect significant advances in radiation oncology over the last three decades. Radiation therapy techniques provide precise and spatially accurate radiation delivery, which facilitates treating tumors in more anatomic locations and incorporating hypofractionated protocols. The purpose of this update is to aid radiation oncology teams in capturing and grading clinically relevant data that impacts the decision-making process in everyday practice and the assessment of clinical trials involving radiation therapy. A dedicated committee initially updated the criteria to include more anatomical sites and grades to characterize a broad spectrum of possible radiation-induced acute and late tissue changes. Through the revision process, which solicited and incorporated feedback from all radiation oncologists within the American College of Veterinary Radiology (ACVR) and specialists outside the ACVR, the authors endeavored to create a grading structure reflective of clinical decision-making in daily radiation oncology. The updated VRTOG v2 toxicity criteria guideline complements the updated Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) guidelines. Because radiation oncology continues to progress rapidly, the VRTOG toxicity criteria should be regularly updated as adverse event data that will be collected following this update further informs the practice of radiation oncology.

Assessment of Medical Student Research Mentorship in Radiation Oncology

Mentored medical student (MS) research opportunities in radiation oncology (RO) provide in-depth exposure to the specialty and may promote greater interest in a career in RO. Many radiation oncologists conduct research; however, the extent to which they directly engage MSs in their research is unknown. The purpose of this study was to characterize MS authorship in American Society for Radiation Oncology (ASTRO) journals. The byline and abstract of all scientific articles (ie, clinical, basic science, training/education) and case reports published from 2019 to 2021 in the International Journal of Radiation Oncology, Biology, and Physics; Practical Radiation Oncology; and Advances in Radiation Oncology were reviewed. Characteristics of MSs and senior authors are reported. A total of 105 of 1785 articles (5.8%) included an MS author, among which 72 (68.6%) were clinical, 13 training/education (12.4%), 12 case reports (11.4%), and 8 basic science (7.6%). MS authors were more common for publications in Advances in Radiation Oncology (9.0%) than Practical Radiation Oncology (6.4%) or the International Journal of Radiation Oncology, Biology, and Physics (4.2%; P=.002). There were 125 unique MS authors from 72 institutions, among which 40 were first author (32.0%), 28 second author (22.4%), and 57 third (or higher) author (45.6%). There were 88 unique senior authors from 55 institutions, among which 10 (11.3%) were on 2 or more MS publications, and 57 (64.7%) shared the same institution as the MS. The median number of articles per mentor institution was 1 (interquartile range, 1-2), and the mentor institutions in the upper quartile in terms of number of MS publications accounted for 53 (50.5%) of all MS publications. Few publications in American Society for Radiation Oncology journals include MS authors with mentorship disproportionately from a small number of academic faculty at select institutions. These findings suggest that there is great potential for radiation oncologists to proactively engage more students in their work.

Advances in Radiation Oncology for Pancreatic Cancer: An Updated Review

This review aims to summarize the recent advances in radiation oncology for pancreatic cancer. A systematic search of the MEDLINE/PubMed database and Clinicaltrials.gov was performed, focusing on studies published within the last 10 years. Our search queried "locally advanced pancreatic cancer [AND] stereotactic body radiation therapy (SBRT) [OR] hypofractionation [OR] magnetic resonance guidance radiation therapy (MRgRT) [OR] proton" and "borderline resectable pancreatic cancer [AND] neoadjuvant radiation" and was limited only to prospective and retrospective studies and metanalyses. For locally advanced pancreatic cancers (LAPC), retrospective evidence supports the notion of radiation dose escalation to improve overall survival (OS). Novel methods for increasing the dose to high risk areas while avoiding dose to organs at risk (OARs) include SBRT or ablative hypofractionation using a simultaneous integrated boost (SIB) technique, MRgRT, or charged particle therapy. The use of molecularly targeted agents with radiation to improve radiosensitization has also shown promise in several prospective studies. For resectable and borderline resectable pancreatic cancers (RPC and BRPC), several randomized trials are currently underway to study whether current neoadjuvant regimens using radiation may be improved with the use of the multi-drug regimen FOLFIRINOX or immune checkpoint inhibitors.

Current landscape of radiation oncology in esophageal cancer: a narrative review.

Esophageal cancer is an aggressive disease that is the sixth leading cause of cancer-related death worldwide. The overall treatment paradigm for esophageal cancer has changed considerably over the past decade. This narrative review aims to summarize the current landscape of radiation oncology for esophageal cancer. A systematic search of the MEDLINE/PubMed database and Clinicaltrials.gov was performed, focusing on studies published within the last 10 years. Our search queried "esophageal cancer [AND] neoadjuvant radiation" as well as "locally advanced esophageal cancer [AND] definitive radiation". Our search resulted in 298 total references. These were manually reviewed, and only 58 references were within our scope of interest ranging from 2012-2022. For resectable esophageal cancer, neoadjuvant chemoradiation followed by surgery has been defined as the standard of care over the past decade. In patients with incomplete response to neoadjuvant chemoradiation, the benefit of immunotherapy in the adjuvant setting has recently been established. Ongoing studies are examining whether perioperative chemotherapy may be equivalent to neoadjuvant chemoradiation in resectable esophageal adenocarcinoma. For locally advanced esophageal cancer, recent studies have failed to show a benefit with radiation dose escalation in an unselected population, although the use of early positron emission tomography (PET) response to guide dose escalation is currently being studied. Other ongoing studies aiming to improve outcomes in locally advanced esophageal cancer involve using proton beam therapy to reduce toxicity and combining immunotherapy or targeted therapies with chemoradiation to amplify response. Recent advances in radiation oncology may continue to improve outcomes for patients with esophageal cancer.

Assessment of Medical Student Research Mentorship Based on Publications in ASTRO Journals

<h3>Purpose/Objective(s)</h3> Mentored research opportunities often stimulate medical student (MS) interest in a particular field and help them to be competitive residency applicants. Many MSs pursue at least one research project during medical school. According to the Association of American Medical Colleges faculty roster there are approximately 1,800 radiation oncology (RO) faculty at US MD-granting medical schools; however, little is known about whether radiation oncologists are providing adequate research opportunities to MSs who are potentially interested in the specialty. We hypothesize that relatively few academic RO faculty mentor MSs in research, and the minority of publications in American Society for Radiation Oncology (ASTRO) journals will have MS co-authors. <h3>Materials/Methods</h3> Data for this study derived from a review of the byline and abstract of all 1,785 scientific articles (i.e., clinical, basic science, training/education) and case reports published from 2019-2021 in The International Journal of Radiation Oncology, Biology, and Physics (IJROBP), Practical Radiation Oncology (PRO), and Advances in Radiation Oncology (ARO). Review, editorial, and correspondence article types were excluded. MS authors were defined as individuals affiliated with a medical school but lacking an MD, DO, or PhD degree. The primary faculty mentor was defined as the senior (last) author. Information related to article type, methods, institution, and author position was recorded. Descriptive statistics and Chi square test were used where appropriate. <h3>Results</h3> A total of 105 of 1,785 articles (6%) included a MS author, among which 72 (69%) were clinical, 13 (11%) training/education, 12 (11%) case reports, and 8 (8%) basic science. MS authors were more common for publications in ARO (9%) than PRO (6%) or IJROBP (4%, <i>p</i> = 0.002). Thirty-eight (32%) MSs were first author, 26 (22%) second author, and 55 (46%) third author or beyond. There were 88 unique faculty mentors for these articles, with 10 mentors (11%) on 2 or more MS publications, and 57 mentors (64.7%) sharing the same institution as the MS. The median number of articles per mentor institution was 1 (interquartile range 1-2), and the mentor institutions in the upper quartile in terms of number of MS publications accounted for 53 (50.5%) of all MS publications. <h3>Conclusion</h3> Over the past 3 years, a small fraction of publications in ASTRO journals included MS authors, with mentorship disproportionately from a small number of academic faculty at select institutions. Though RO faculty may mentor MSs on projects published in other journals, efforts to more broadly encourage academic RO faculty to offer MSs research opportunities on RO-related projects may help stimulate more interest in RO, and reverse the recent trend of fewer residency applicants.

WITHDRAWN: ASTRO's Advances in Radiation Oncology in 2022

This Fall marks ASTRO's Advances in Radiation Oncology's seventh year of publishing. The last year has been our most successful to date with our Cite Score rising to 4.3 (see Figure #1), placing Advances in the top third of comparable journals. A conventional impact factor is expected to granted in 2023.

Advances in Radiation Oncology: Current Status and Future Directions in India.

Radiation therapy is one of the core components of the comprehensive cancer care. Several new advancements in the radiation physics, radiation biology, and technical upgradation have led us in to a new era of radiation oncology. The access to quality radiation therapy treatment however remains a concern, and this mini-review emphasizes on these issues and also focuses on the future directions for radiation oncology in India.

Advances in Radiation Oncology for the Treatment of Cervical Cancer.

Background: Over the past two decades, there has been significant advancement in the management of cervical cancer, particularly in the domain of definitive chemoradiotherapy for locally advanced cervical cancer (LACC). Indeed, radiation treatment paradigms have shifted from a two-dimensional (2D) approach solely based on anatomical bony landmarks, to an image-guided three-dimensional (3D) approach, with the goal of delivering doses more precisely to clinical targets with an increased sparing of organs-at-risk. Methods: This is a narrative review on the advances in radiation technologies for the treatment of cervical cancer. Using the PubMed database, we identified articles published in English up until November 18, 2021 on the treatment of LACC with external beam radiotherapy (EBRT) and brachytherapy. A search of the Clinicaltrials.gov and Clinicaltrialsregister.eu retrieved information on ongoing clinical trials on the topic of combined immunotherapy and radiotherapy in cervical cancer. Results: We highlight the historical evolution from the use of 2D radiotherapy to 3D-conformal radiotherapy, and then intensity modulated radiotherapy (IMRT) for the delivery of EBRT. We also discuss advances in brachytherapy, notably the transition to 3D image-guided adaptive brachytherapy (3D-IGABT). In this context, we highlight large cohort studies that were recently constructed and have shown significant improvement in local control and treatment-related toxicities with 3D-IGABT. Finally, we discuss other advances in the field, notably the use of stereotactic body radiotherapy (SBRT) as a substitute to brachytherapy, and the addition of immunotherapy to chemoradiation. Conclusions: The use of IG-IMRT and 3D-IGABT have considerably improved treatment outcomes and toxicity profiles for patients with LACC, and are now considered the gold standard in many countries. The use of SBRT boost as a replacement for brachytherapy has been associated with increased toxicity and decreased efficacy and should be used with caution in the context of clinical trials. New experimental approaches include the addition of immunotherapy to chemoradiation regimens.

The Effect of Radiation and Chemoradiation Therapy on the Head and Neck Mucosal Microbiome: A Review.

Radiation (RT) and chemoradiation therapy (CRT) play an essential role in head and neck cancer treatment. However, both cause numerous side effects in the oral cavity, paranasal sinuses, and pharynx, having deleterious consequences on patients’ quality of life. Concomitant with significant advances in radiation oncology, much attention has turned to understanding the role of the microbiome in the pathogenesis of treatment-induced tissue toxicity, to ultimately explore microbiome manipulation as a therapeutic intervention. This review sought to discuss current publications investigating the impact of RT and CRT-induced changes on the head and neck microbiome, using culture-independent molecular methods, and propose opportunities for future directions. Based on 13 studies derived from a MEDLINE, EMBASE, and Web of Science search on November 7, 2021, use of molecular methods has uncovered various phyla and genera in the head and neck microbiome, particularly the oral microbiome, not previously known using culture-based methods. However, limited research has investigated the impact of RT/CRT on subsites other than the oral cavity and none of the studies aimed to examine the relationship between the head and neck microbiome and treatment effectiveness. Findings from this review provide helpful insights on our current understanding of treatment-induced oral mucositis, dental plaque, and caries formation and highlight the need for future research to examine the effect of RT/CRT on the sinonasal and oropharyngeal microbiome. In addition, future research should use larger cohorts, examine the impact of the microbiome on treatment response, and study the effect of manipulating the microbiome to overcome therapy resistance.

Trends in Fractionation in Radiation Oncology Over the Past Decade

Advances in radiation oncology have allowed for more accurate targeting of treatment areas allowing for safer hypofractionation. Additionally, many trials have been published supporting the use of hypofractionation as an alternative to longer courses of radiation. In the United States most reimbursement models are currently based on a fee for service model which increases payment based on the number of treatments delivered. Our goal was to analyze available Medicare billing data in order to evaluate trends in fractionation in the United States.Medicare Provider Utilization and Payment Data was accessed from the CMS.gov website for years 2012 - 2018. Radiation Oncology specific providers (ROP) and only data corresponding to the billing code for status checks (77427), were extracted. Status checks (SC) were used as a surrogate for length of fractionation. Only ROP's that were practicing every year between 2012 through 2018 were included and those with less than 100 status checks in a year at any single practice setting were excluded. Providers were classified as hospital-based practices versus independent clinics and academic versus private practice. ROP's were separated into four regions based on Census classifications: Northeast, Midwest, South, and West.Amongst ROP's with at least 100 SC per year, there was an overall decrease in average number of SC per patient from 2012 to 2018 (3.96 to 3.64, respectively) or an overall 8% decrease in fractions delivered per patient. This holds true for those based in hospitals (3.85 to 3.45) and independent clinic (4.07 to 3.73) locations from 2012 to 2018, respectively. The number of patients per year each provider treated has decreased from 172 (2012) to 163 (2018). The total number of providers seeing at least 100 SC/year has decreased from 2012 to 2018 (2,353 to 2,011). A decrease in fractionation was experienced in all regions of the country with the largest overall decrease in the Northeast (13% vs 8.8% in the South). Large practices (greater than 10 ROP's) treated less fractions per patient than smaller practices. A larger decrease in fractions per patient was seen in academic practices with a 14% drop in status checks per patient vs 9.9% in private practices from 2012-2018. In 2018, academic physicians treated each patient with 15% less fractions than private practice.Trends in fractionation confirm that as a specialty, we are moving more towards hypofractionation with an overall decrease in fractions per patient over the past decade. This is seen in all settings regardless of practice setting, location, and size of practice. Academic ROP's have decreased the rate of fractions per patient at a slightly higher rate than private practice ROP's. Given the reduced number of visits for the patient, this is a positive for improving the cost-effectiveness of medicine as well as reducing the financial and logistical burden for the patient.

Emerging Cybersecurity Threats in Radiation Oncology

PurposeModern image guided radiation therapy is dependent on information technology and data storage applications that, like any other digital technology, are at risk from cyberattacks. Owing to a recent escalation in cyberattacks affecting radiation therapy treatments, the American Society for Radiation Oncology's Advances in Radiation Oncology is inaugurating a new special manuscript category devoted to cybersecurity issues. Methods and MaterialsWe conducted a review of emerging cybersecurity threats and a literature review of cyberattacks that affected radiation oncology practices. ResultsIn the last 10 years, numerous attacks have led to an interruption of radiation therapy for thousands of patients, and some of these catastrophic incidents have been described as being worse than the coronavirus disease of 2019 impact on centers in New Zealand. ConclusionsCybersecurity threats continue to evolve, making combatting these attacks more difficult for health care organizations and requiring a change in strategies, tactics, and culture around cyber security in health and radiation oncology. We recommend an assume breach mentality (threat-informed defense posture) and adopting a cloud-first and zero-trust security strategy. A reliance on computer-driven technology makes radiation oncology practices more vulnerable to cyberattacks. Health care providers should increase their resilience and cyber security maturity. The increase in the diversity of these attacks demands improved preparedness and collaboration between oncologic treatment centers both nationwide and internationally to protect patients.

ACTIVE INVOLVEMENT OF RADIOLOGIST IN RADIATION ONCOLOGY PRACTICE

Advancements in Radiation Oncology from conventional to 3D conformal radiotherapy treatment demands expertise in many steps of radiation planning, the horizon of radiologist is now expanded by many folds and made radiologist as a integral part of the Radiation Oncology Department. A critical aspect of radiotherapy treatment planning (RTP) is determining how to deliver the required radiation dosage to cancer cells while minimising the exposure to normal tissue for which the prerequisite is identification and accurate delineation of tumour volume as well as normal structure resulted in an increase in the therapeutic ratio by reducing complication associated with normal tissue and allowing for higher target dosage and better local control. In modern radiotherapy CT images are the standard set of imaging modality required for the radiotherapy planning along with it many other modalities like MRI, PET or DSA are used by superimposing on original CT images in order to contour or delineate the structures defined by International Commission on Radiation Units and Measurements in Reports 50, 62 and 71 (ICRU) for radiotherapy planning which comprise of Gross tumour volume, clinical target volume, planning target volume, irradiated volume, Internal target volume and the normal structures as Organ at risk. It is self-evident that the contribution of a radiologist with a thorough knowledge of the development of these new modalities is critical for optimising the potential of these novel modes of radiation treatment delivery.

A Mixed-Methods Analysis of a Single-Institution Radiation Oncology Virtual Medical Student Rotation

The COVID-19 pandemic prompted the widespread development of virtual rotations, replacing traditional in-person experiences. 1 Friedman CP. The virtual clinical campus. Academic Medicine. 1996; Crossref Scopus (17) Google Scholar ,2 Kahn JM Fields EC Pollom E et al. Increasing Medical Student Engagement Through Virtual Rotations in Radiation Oncology. Advances in Radiation Oncology. 2021; 6 Abstract Full Text Full Text PDF Scopus (11) Google Scholar These rotations introduce the role of radiation in cancer care and recruit students to residency programs. The Department of Radiation Oncology at the University of California, San Francisco developed a comprehensive 2-week virtual rotation that aimed to maintain broad clinical exposure for medical students. However, effective strategies for incorporating students into clinical interactions, modeling interdisciplinary practice, assessing students' growth, and facilitating interpersonal interactions between students, residents, and faculty using the virtual platform remain unclear.

Adjuvant radiation therapy in breast cancer: Recent advances & Indian data.

Breast cancer is the most common cancer among women in India, and adjuvant radiotherapy is an integral part of curative treatment in most patients. The recent decades have witnessed several advances in radiation therapy delivery. Several advances in radiation oncology have been identified which include technological advances, change in fractionation used, use of cardiac-sparing radiotherapy as well as efforts to personalize radiotherapy using accelerated partial breast irradiation or avoidance of radiotherapy in certain subpopulations. Indian data are available in most areas which have been summarized. However, increasing emphasis on research in these areas is needed so that effectiveness and safety in our setting can be established. Advances in breast cancer radiotherapy have resulted in improved outcomes. Data published from India suggest that these improved outcomes can be replicated in patients when appropriate treatment protocols are followed.

G2/M Checkpoint Abrogation With Selective Inhibitors Results in Increased Chromatid Breaks and Radiosensitization of 82-6 hTERT and RPE Human Cells.

While technological advances in radiation oncology have led to a more precise delivery of radiation dose and a decreased risk of side effects, there is still a need to better understand the mechanisms underlying DNA damage response (DDR) at the DNA and cytogenetic levels, and to overcome tumor resistance. To maintain genomic stability, cells have developed sophisticated signaling pathways enabling cell cycle arrest to facilitate DNA repair via the DDR-related kinases and their downstream targets, so that DNA damage or DNA replication stress induced by genotoxic therapies can be resolved. ATM, ATR, and Chk1 kinases are key mediators in DDR activation and crucial factors in treatment resistance. It is of importance, therefore, as an alternative to the conventional clonogenic assay, to establish a cytogenetic assay enabling reliable and time-efficient results in evaluating the potency of DDR inhibitors for radiosensitization. Toward this goal, the present study aims at the development and optimization of a chromosomal radiosensitivity assay using the DDR and G2-checkpoint inhibitors as a novel modification compared to the classical G2-assay. Also, it aims at investigating the strengths of this assay for rapid radiosensitivity assessments in cultured cells, and potentially, in tumor cells obtained from biopsies. Specifically, exponentially growing RPE and 82-6 hTERT human cells are irradiated during the G2/M-phase transition in the presence or absence of Caffeine, VE-821, and UCN-1 inhibitors of ATM/ATR, ATR, and Chk1, respectively, and the induced chromatid breaks are used to evaluate cell radiosensitivity and their potency for radiosensitization. The increased yield of chromatid breaks in the presence of DDR inhibitors, which underpins radiosensitization, is similar to that observed in cells from highly radiosensitive AT-patients, and is considered here as 100% radiosensitive internal control. The results highlight the potential of our modified G2-assay using VE-821 to evaluate cell radiosensitivity, the efficacy of DDR inhibitors in radiosensitization, and reinforce the concept that ATM, ATR, and Chk1 represent attractive anticancer drug targets in radiation oncology.

GRECO-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with GC4711 in the treatment of unresectable or borderline resectable nonmetastatic pancreatic cancer (PC).

TPS4175 Background: While systemic treatment of PC has improved, rates of surgical resection - considered optimum treatment - remain low. Patients with un-resectable or borderline PC still have poor outcomes, with both toxicity and disease progression during induction chemotherapy limiting the number eligible for surgery. SBRT practice to enhance margin negative resection or to provide local control, if inoperable after neoadjuvant therapy, has shifted to higher dose delivery (Mellon 2015, Colbert 2018), but timing and appropriate patient selection are under constant debate. SBRT delivery over 50Gy exhibits superior cell killing compared to conventionally fractionated RT but carries potential GI toxicity risk (Zhong 2017). GC4711 is a selective superoxide dismutase mimetic that converts superoxide to hydrogen peroxide. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control without compromising radiation safety (Sishc, AACR 2019). GC4711 consistently augmented tumor control by SBRT in PC experimental xenograft mouse models. In a pilot phase 1/2 trial (GC4419-101), subjects with locally advanced PC were randomized to receive SBRT plus either the selective dismutase mimetic GC4419 or placebo. This pilot trial has demonstrated acceptable safety with SBRT (5 × 10-11Gy), as well as apparent improvements in survival, surgical resection, locoregional control, and time to distant metastases. Altogether, these data support the hypothesis that GC4711 may improve tumor outcomes and the benefit-risk ratio of 5-fraction SBRT delivering 50Gy by improving efficacy without increasing GI-toxicity. Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study to determine the effect on overall survival of adding GC4711 to SBRT following 4 months of chemotherapy in subjects with un-resectable or borderline non-metastatic PC. Approximately 160 subjects will be enrolled at over 20 sites to receive GC4711 100 mg or placebo IV given as IV infusion over 15 min, prior to each of 5 SBRT fractions of 10Gy). Subjects judged operable will be explored within 8 weeks after SBRT. All subjects will complete 2 additional months of adjuvant chemotherapy. Primary end point is overall survival and secondary endpoints address resection rates, local and distant disease progression, and safety, while exploratory studies include ctDNA, tumor exome/transcriptome sequencing, and immune profiling, patient-reported symptoms (PRO-CTCAE), CA19.9 normalization, and radiomics. Colbert L, Rebueno N, Moningi S et al Advances in Radiation Oncology (2018) 3, 693-700 Mellon EA, Hoffe SE, Springett GM, et al Acta Oncologica, 2015;54:7 Zhong J, Patel K, Switchenko J, et al. Cancer. 2017 Sep 15;123(18):3486-3493. Sishc BJ, Saha D, Story MD. AACR PADC 2019 C52. Clinical trial information: NCT04698915.

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.