Improving plan quality in cervical brachytherapy using a simple knowledge-based prediction tool for OAR dose (D2cm3).

PURPOSE: Toxicity from cervical brachytherapy has been demonstrated to correlate with the D2cm3 of the bladder, rectum, and bowel. This suggests a simplified version of knowledge-based planning investigating the relationship of the overlap distance for 2cm3 and the D2cm3 from planning may be possible. This work demonstrates the feasibility of simple knowledge-based planning to predict the D2cm3, detect suboptimal plans, and improve plan quality. METHODS AND MATERIALS: The overlap volume histogram (OVH) method was used to determine the distance for 2cm3 of overlap between the OAR and CTV_HR. Linear plots modeled the OAR D2cm3 and 2cm3 overlap distance. Two datasets of 20 patients (plans from 43 insertions in each dataset) were used to create two independent models, and the performance of each model was compared using cross-validation. Doses were scaled to ensure consistent CTV_HR D90 values. The predicted D2cm3 is entered as the maximum constraint in the inverse planning algorithm. RESULTS: Mean bladder D2cm3 decreased by 2.9% for the models from each dataset, mean rectal D2cm3 decreased 14.9% for the model from dataset 1 and 6.0% for the model from dataset 2, mean sigmoid D2cm3 decreased 10.7% for the model from dataset 1 and 6.1% for the model from dataset 2, mean bowel D2cm3 decreased 4.1% for the model from dataset 1 but no statistically significant difference was observed for the model from dataset 2. CONCLUSIONS: A simplified knowledge-based planning method was used to predict D2cm3 and was able to automate optimization of brachytherapy plans for locally advanced cervical cancer.

An International Expert Delphi Consensus to Develop Dedicated Geriatric Radiation Oncology Curriculum Learning Outcomes.

PURPOSE: The management of older adults with cancer is rapidly becoming a significant challenge in radiation oncology (RO) practice. The education of future radiation oncologists in geriatric oncology is fundamental to ensuring that older adults receive high-quality care. Currently RO trainees receive little training and education in geriatric oncology. The objective of this study was to define core geriatric RO curriculum learning outcomes relevant to RO trainees worldwide. METHODS AND MATERIALS: A 2-stage modified Delphi consensus was conducted. Stage 1 involved the formation of an expert reference panel (ERP) of multiprofessional experts in geriatric oncology and/or RO and the compilation of a potential geriatric RO learning outcomes set. Stage 2 involved 3 iterative rounds: round 1 and round 2 (both online surveys), and an intervening ERP round. These aimed at identifying and refining ideal geriatric RO learning outcomes. Invited participants for round 1 and 2 included oncology health care professionals with expertise across RO, geriatric oncology, and/or education and consumers. Predefined Delphi consensus definitions were applied to the results of rounds 1 and 2. RESULTS: An ERP of 11 experts in geriatric oncology and/or RO was formed. Seventy potential knowledge- and skill-based learning outcomes were identified. In round 1, 103 of 179 invited eligible Delphi participants completed the survey (58% response rate). The ERP round was conducted, resulting in the exclusion of 28 learning outcomes. In round 2, 54 of 103 completed the survey (52% response rate). This identified a final total of 33 geriatric RO learning outcomes. CONCLUSIONS: The geriatric RO learning outcomes described in this study form an international consensus that can inform RO training bodies worldwide. This represents the first fundamental step in developing a global educational framework aimed at improving RO trainee knowledge and skills in geriatric oncology.

Improving the Education of Radiation Oncology Professionals in Geriatric Oncology: Where Are We and Where Should We Be?

As the global population ages, the care of older adults with cancer is increasingly recognised as a growing challenge in oncology practice worldwide. At present, outcomes for older adults with cancer are worse than younger counterparts. The need for improved clinician education around geriatric oncology is internationally recognised as being fundamental to addressing this problem. Radiation therapy represents an excellent localised treatment modality for older adults due to its limited systemic toxicity, especially in circumstances in which surgery and chemotherapy are deemed inappropriate. Thus, the education of future radiation oncologists and other radiation oncology professionals (including radiation therapists, nurses, and physicists) in geriatric oncology is crucial to ensuring the complex needs of this patient population are met. However, evidence shows that within the specialty of radiation oncology, knowledge levels around key concepts in geriatric oncology are low and there is limited educational focus on the specific issues important for the care of older adults. An evidence-based, global approach to improving radiation oncology professionals' knowledge and clinical practice in geriatric oncology is needed to provide optimal care for older adults undergoing radiation therapy. This article provides an overview of the current status of geriatric oncology training and education in the specialty of radiation oncology and future directions to improve the knowledge and skills of radiation oncology professionals in caring for older adults.

Repurposing FDA approved drugs as radiosensitizers for treating hypoxic prostate cancer.

BACKGROUND: The presence of hypoxia is a poor prognostic factor in prostate cancer and the hypoxic tumor microenvironment promotes radioresistance. There is potential for drug radiotherapy combinations to improve the therapeutic ratio. We aimed to investigate whether hypoxia-associated genes could be used to identify FDA approved drugs for repurposing for the treatment of hypoxic prostate cancer. METHODS: Hypoxia associated genes were identified and used in the connectivity mapping software QUADrATIC to identify FDA approved drugs as candidates for repurposing. Drugs identified were tested in vitro in prostate cancer cell lines (DU145, PC3, LNCAP). Cytotoxicity was investigated using the sulforhodamine B assay and radiosensitization using a clonogenic assay in normoxia and hypoxia. RESULTS: Menadione and gemcitabine had similar cytotoxicity in normoxia and hypoxia in all three cell lines. In DU145 cells, the radiation sensitizer enhancement ratio (SER) of menadione was 1.02 in normoxia and 1.15 in hypoxia. The SER of gemcitabine was 1.27 in normoxia and 1.09 in hypoxia. No radiosensitization was seen in PC3 cells. CONCLUSION: Connectivity mapping can identify FDA approved drugs for potential repurposing that are linked to a radiobiologically relevant phenotype. Gemcitabine and menadione could be further investigated as potential radiosensitizers in prostate cancer.

Lost in application: Measuring hypoxia for radiotherapy optimisation.

The history of radiotherapy is intertwined with research on hypoxia. There is level 1a evidence that giving hypoxia-targeting treatments with radiotherapy improves locoregional control and survival without compromising late side-effects. Despite coming in and out of vogue over decades, there is now an established role for hypoxia in driving molecular alterations promoting tumour progression and metastases. While tumour genomic complexity and immune profiling offer promise, there is a stronger evidence base for personalising radiotherapy based on hypoxia status. Despite this, there is only one phase III trial targeting hypoxia modification with full transcriptomic data available. There are no biomarkers in routine use for patients undergoing radiotherapy to aid management decisions, and a roadmap is needed to ensure consistency and provide a benchmark for progression to application. Gene expression signatures address past limitations of hypoxia biomarkers and could progress biologically optimised radiotherapy. Here, we review recent developments in generating hypoxia gene expression signatures and highlight progress addressing the challenges that must be overcome to pave the way for their clinical application.

Does magnetic resonance imaging improve soft tissue sarcoma contouring for radiotherapy?

OBJECTIVE: Soft tissue sarcomas (STS) are a rare, heterogeneous tumour group. Radiotherapy improves local control. CT is used to plan radiotherapy, but has poor soft tissue definition. MRI has superior soft tissue definition. Contour variation amongst oncologists is an important factor in treatment failure. This study is the first to directly compare STS tumour contouring using CT vs MRI. METHODS: Planning CT and T 2 weighted MR images of eight patients with STS were distributed to four oncologists. Gross tumour volume was contoured on both imaging modalities using in-house software. Images were recontoured 6 weeks later. The mean distance to agreement (DTA), standard deviation of the DTA, dice similarity coefficient (DSC) and contour volume were calculated for each oncologist and compared to a median contour volume. Results for CT and MRI were compared using a pairwise Student's t-test. RESULTS: When comparing MRI to CT, tumour volumes were significantly smaller, with a difference of 21.4 cm3 across all patients (p = 0.008). There was not a statistically significant difference in the mean distance to agreement or dice similarity coefficient, but the standard deviation of the DTA showed a statistically significant improvement ( p = 0.04). For intraobserver variation, there was no statistically significant improvement using MRI vs CT. CONCLUSION: Oncologists contour smaller tumour volumes using MRI, with reduced interobserver variation. Improving the reliability and consistency of contouring is needed for improved quality assurance. ADVANCES IN KNOWLEDGE: With further experience, the use of MRI in STS radiotherapy planning may reduce variation between oncologists and contribute to improved local control and reduced treatment toxicities.

Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer.

BACKGROUND: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer. METHOD: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). RESULTS: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P < .05), with borderline significances achieved in the other two (P < .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours. CONCLUSION: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.

Focal boost to residual gross tumor volume in brachytherapy for cervical cancer-A feasibility study.

PURPOSE: Image-guided plan optimization with MRI and CT for interstitial and intracavitary brachytherapy is an established technique in treating cervical cancer. The purpose of this study was to assess the feasibility of boosting the dose to the residual gross tumor volume (GTV-Tres) to 140% of the high-risk clinical target volume (HR-CTV) prescription. METHODS AND MATERIALS: Brachytherapy plans from 50 consecutive patients were analyzed in this study. All received external beam radiotherapy followed by brachytherapy (6 Gy × 4 fraction or 7 Gy × 4 fraction to HR-CTV). The original treatment plans were reoptimized escalating the GTV-Tres dose 140% of the original HR-CTV prescription dose to 8.4 Gy and 9.8 Gy/ per fraction, respectively, with the aim of achieving GTV-TresV140 ≥ 90% and D98 ≥ 100 Gy. The HR-CTV coverage and organ at risk (OAR) dose-volume histogram values were kept within the tolerance, which had been accepted for the original clinical plans. RESULTS: A total of 24 patients (48%) achieved the planning goal after reoptimization. There was no significant difference between the D2cc of the OARs of the clinical plan and the study boost plan. The factors having greatest impact on the delivered dose to the GTV-Tres are proximity of the OAR, intrauterine positioned outside the GTV-Tres, and suboptimal interstitial placement for boosting GTV-Tres. CONCLUSIONS: It is possible to boost the prescription dose to the GTV-Tres achieving 140% increase, which equates to an EQD2α/ß=10 > 100 Gy. Plans without both interstitial catheters and/or intrauterine within the GTV-Tres are most likely to be suboptimal. This planning study demonstrates that dose escalation to the GTV-Tres is feasible and further work into clinical application should be considered.

Are Future Radiation Oncologists Equipped With the Knowledge to Manage Elderly Patients With Cancer?

PURPOSE: To assess radiation oncology (RO) trainee knowledge, attitudes, and clinical practice relating to geriatric oncology. METHODS AND MATERIALS: A custom online survey was anonymously administered to RO trainees across Australia, New Zealand, and Singapore. The survey assessed 3 domains: (1) trainee demographics and prior training in geriatric medicine; (2) current clinical practice and attitudes regarding elderly cancer patients and radiation therapy; and (3) opinions regarding educational opportunities around geriatric oncology. The survey was developed and reviewed by radiation oncologists with expertise in education and training. RESULTS: A total of 61 trainees (52%) responded to the survey. More than half had not undertaken a geriatric medicine term before RO speciality training. A total of 91.8% of respondents had not received teaching during RO training specifically regarding geriatric oncology. The use of geriatric assessment (GA) tools for determining suitability for radiation therapy was uncommon, with 80.3% of respondents rarely or never using them. More than two-thirds of respondents reported not seeking or rarely seeking multidisciplinary input from a geriatrician when assessing suitability for treatment. Trainees had low confidence levels in managing complex issues commonly observed in the elderly. Only 39.3% felt they had the confidence to manage these issues, with 31.2% not confident/not at all confident. Respondents reported functional status, assessment of comorbidity, physiologic age, and cognition as the major factors applied to treatment decisions. Input from a geriatrician was lowest ranked. Of factors influencing choice of dose/fractionation schedule, physiologic age ranked highest, whereas use of GA tool ranked the lowest. The majority of trainees (85.3%) agreed or strongly agreed they would benefit from more training around RO in elderly patients, and 65.6% felt the addition of learning objectives to RO curriculum around geriatric oncology would be valuable. CONCLUSIONS: Radiation oncology trainees report inadequate training and experience in geriatric oncology and geriatric medicine. Radiation oncology trainees rarely use and poorly understand the rationale for GA tools and geriatrician input in clinical practice. Trainees strongly support improved education in geriatric oncology.

The dosimetric impact of air in vaginal vault brachytherapy.

PURPOSE: Vaginal vault brachytherapy is an adjuvant treatment to reduce risk of local recurrence in endometrial cancer. Axial imaging has demonstrated the presence of air gaps between the surface of a cylindrical applicator and mucosal wall. The impact of these on dosimetry and applicability of the TG-43 formalism in the presence of air has been assessed. METHODS AND MATERIALS: The planning CT scans for a retrospective sample of 82 patients were examined for the presence of air gaps. These were quantified in terms of the radial and longitudinal aspect with reference to the applicator, frequency per patient, and location along the applicator. Monte Carlo calculations and ionization chamber measurements were made in a phantom to estimate the uncertainty of the TG-43 algorithm. RESULTS: The overall incidence of air gaps was 91.4%. The most common radial size was between 2 and 3 mm (43.0%) that resulted in an average dose reduction of 14.8%. There is a strong correlation between radial dimension and TG-43 calculated dose reduction. Monte Carlo simulations and phantom measurements indicated that the inhomogeneity resulted in a maximum of 2.4% deviation from doses calculated using TG-43. CONCLUSIONS: Air gaps are common. TG-43 formalism is not significantly compromised by the presence of air. However, the presence of the air does produce a displacement of the mucosal surface away from the applicator and this causes a significant dose reduction.