Daily Fractions Research Articles

Association between RT-PCR Ct values and COVID-19 new daily cases: a multicenter cross-sectional study.

Proactive prediction of the epidemiologic dynamics of viral diseases and outbreaks of the type of COVID-19 has remained a difficult pursuit for scientists, public health researchers, and policymakers. It is unclear whether RT-PCR Cycle Threshold (Ct) values of COVID-19 - or any other virus - as indicator of viral load, could represent a possible predictor for underlying epidemiologic changes on a population level. The study objective is thus to investigate whether population-wide changes in SARS-CoV-2 RT-PCR Ct values over time are associated with the daily fraction of positive COVID-19 tests. In addition, this study analyses the factors that could influence RT-PCR Ct values. A retrospective cross-sectional study was conducted on 63,879 patients from May 4, 2020 to September 30, 2020, in all COVID-19 facilities in the Kingdom of Bahrain. Data collected included number of tests and newly diagnosed cases, as well as Ct values, age, sex nationality, and symptomatic status. Ct values were found to be negatively and very weakly correlated with the fraction of daily positive tests in the population r = -0.06 (CI 95%: -0.06; -0.05; p=0.001). The R-squared for the regression model (adjusting for age and number of daily tests) showed an accuracy of 45.3%. Ct Values showed an association with nationality (p=0.012). After the stratification, the association between Ct values and the fraction of daily positive cases was only maintained for the female sex and Bahraini-nationality. Symptomatic presentation was significantly associated with lower Ct values (higher viral loads). Ct values do not show any correlation with age (p=0.333) or sex (p=0.522). We report one of the first and largest studies to investigate the epidemiologic associations of Ct values with COVID-19. Although changes in Ct values showed a moderate association with daily cases, our results indicate that it may not be as predictive within a simple model. More population studies and models from global cohorts are necessary.

Smarter Medicine in Radiation Oncology - current and proven treatment concepts offering the greatest possible benefit to cancer patients in clinical practice

Smarter Medicine in Radiation Oncology - current and proven treatment concepts offering the greatest possible benefit to cancer patients in clinical practice Abstract. Modern procedures in radiation therapy with respect to indication, therapy planning and implementation of shorter treatment regimens result in high local tumor control and excellent quality of life in frequent and clinically relevant disease entities including breast and prostate cancer as well as bone metastases. In the adjuvant therapy for early breast cancer, a careful comparative analysis of the use of endocrine adjuvant treatment over five years versus postoperative radiation therapy over less than four weeks may result in omission of radiation treatment in a selected patient population. Partial breast irradiation, while treating the tumor bed only in low risk situations, and hypofractionated whole breast radiotherapy for patients with a higher risk profile for local recurrence, halved treatment time compared to 10 years ago, making adjuvant radiotherapy for patients with breast cancer more convenient. In patients with localized prostate cancer, the introduction of hypofractionated treatment regimens halved the number of daily fractions and current developments point towards a one-week outpatient therapy for locally limited disease using high precision stereotactic techniques and accurate therapy planning based on multifunctional imaging. Patients with bone metastases are more and more treated with a single fraction, high precision stereotactic radiotherapy (radiosurgery) with high analgesic potential and achieving long lasting local tumor control. These modern, often significantly shorter, radiotherapy treatment regimens not only result in an excellent treatment response and better quality of life for patients, but also include a better utilization of radiotherapy resources needing less treatment machines and thus helping to reduce costs in the Swiss healthcare system.

Deep Reinforcement Learning for Fractionated Radiotherapy in Non-Small Cell Lung Carcinoma

Lung cancer is by far the leading cause of cancer death among both men and women. Radiation therapy is one of the main approaches to lung cancer treatment, and its planning is crucial for the therapy outcome. However, the current practice that uniformly delivers the dose does not take into account the patient-specific tumour features that may affect treatment success. Since radiation therapy is by its very nature a sequential procedure, Deep Reinforcement Learning (DRL) is a well-suited methodology to overcome this limitation. In this respect, in this work we present a DRL controller optimizing the daily dose fraction delivered to the patient on the basis of CT scans collected over time during the therapy, offering a personalized treatment not only for volume adaptation, as currently intended, but also for daily fractionation. Furthermore, this contribution introduces a virtual radiotherapy environment based on a set of ordinary differential equations modelling the tissue radiosensitivity by combining both the effect of the radiotherapy treatment and cell growth. Their parameters are estimated from CT scans routinely collected using the Particle Swarm Optimization algorithm. This permits the DRL to learn the optimal behaviour through an iterative trial and error process with the environment. We performed several experiments considering three rewards functions modelling treatment strategies with different tissue aggressiveness and two exploration strategies for the exploration-exploitation dilemma. The results show that our DRL approach can adapt to radiation therapy treatment, optimizing its behaviour according to the different reward functions and outperforming the current clinical practice.

Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR) in Preclinical Models Enhances Single-Agent Immune Checkpoint Blockade.

Harnessing the immune-stimulatory effects of radiation by combining it with immunotherapy is a promising new treatment strategy. However, more studies characterizing immunotherapy and radiation dose scheduling for the optimal therapeutic effect is essential for designing clinical trials. A new ablative radiation dosing scheme, personalized ultrafractionated stereotactic adaptive radiation therapy (PULSAR), was tested in combination with α-PD-L1 therapy in immune-activated and resistant syngeneic immunocompetent mouse models of cancer. Specifically, tumor growth curves comparing immunotherapy and radiation therapy dose sequencing were evaluated in immunologically cold and hot tumor models. The response relative to cytotoxic killer T cells was evaluated using an α-CD8 depleting antibody, and immunologic memory was tested by tumor rechallenge of cured mice. We report that both radiation and immunotherapy sequencing, as well as radiation therapy fraction spacing, affect the combination treatment response. Better tumor control was achieved by giving α-PD-L1 therapy during or after radiation, and spacing fractions 10 days apart (PULSAR) achieved better tumor control than traditional daily fractions. We showed that CD8+ depleting antibody abrogated tumor control in the PULSAR combination treatment, and certain treatment schedules induced immunologic memory. These results illustrate that radiation therapy dosing and scheduling affect tumor control, in combination with checkpoint blockade therapies. PULSAR-style radiation dosing is more complementary in combination with single-agent immunotherapy than traditional daily fractions in this preclinical model. Preclinical investigation could prove helpful in designing clinical trials investigating combination therapy.

A COMPARATIVE STUDY ASSESSING THE DIFFERENT PATTERNS OF RADIATION REACTIONS IN HEAD AND NECKCANCER PATIENTS UNDERGOING RADIATION THERAPY AT DIFFERENT TIMES OF THE DAY-IN THE MORNING VERSUS EVENING

Background: Human oral mucosa, is a prime target for radiation induced toxicity in patients undergoing radiotherapy for head and neck cancer. The oral cavity is highly susceptible to direct and indirect toxic effects of cancer chemotherapy and ionizing radiation. In our study we investigated the role of chronotherapy with respect to radiation induced mucositis occurring in the normal oral mucosa and treatment response in tumor tissue in cancer patients undergoing radiation therapy to head and neck region. Materials and Methods: This non-randomized clinical study was done to compare the two different timing schedules in the management of head and neck cancer by external beam radiation therapy by cobalt-60 (Theratron780C). In morning arm (arm A), Patients received external beam radiotherapy (EBRT) by cobalt-60 with SSD of 80cm with daily fractions, five days a week, between 8AM–10 AM whereas in evening arm (arm B), patients received EBRT by cobalt-60 with daily fractions, five days a week, between 3PM–5 PM. Both the arms received same radiation regimen. Results: The study concluded that in the morning arm the onset of oral mucositis was observed to be significantly delayed and the duration of mucositis was also significantly shorter as compared to the evening arm. Statistically significant difference in severity of mucositis was found between the two arms. Conclusion: Since there is no active measure to minimize normal tissue toxicity, chronomodulated radiotherapy would be a feasible and cost effective treatment strategy that can be put into clinical practice.

In vivo assessment of the safety of standard fractionation Temporally Feathered Radiation Therapy (TFRT) for head and neck squamous cell carcinoma: An R-IDEAL Stage 1/2a first-in-humans/feasibility demonstration of new technology implementation

IntroductionPrior in silico simulations of studies of Temporally Feathered Radiation Therapy (TFRT) have demonstrated potential reduction in normal tissue toxicity. This R-IDEAL Stage 1/2A study seeks to demonstrate the first-in-human implementation of TFRT in treating patients with head and neck squamous cell carcinoma (HNSCC). Materials and methodsPatients with HNSCC treated with definitive radiation therapy were eligible (70 Gy in 35 fractions) were eligible. The primary endpoint was feasibility of TFRT planning as defined by radiation start within 15 business days of CT simulation. Secondary endpoints included estimates of acute grade 3–5 toxicity. ResultsThe study met its accrual goal of 5 patients. TFRT plans were generated in four of the five patients within 15 business days of CT simulation, therefore meeting the primary endpoint. One patient was not treated with TFRT at the physician’s discretion, though the TFRT plan had been generated within sufficient time from the CT simulation. For patients who received TFRT, the median time from CT simulation to radiation start was 10 business days (range 8–15). The average time required for radiation planning was 6 business days. In all patients receiving TFRT, each subplan and every daily fraction was delivered in the correct sequence without error. The OARs feathered included: oral cavity, each submandibular gland, each parotid gland, supraglottis, and posterior pharyngeal wall (OAR pharynx). Prescription dose PTV coverage (>95%) was ensured in each TFRT subplan and the composite TFRT plan. One of five patients developed an acute grade 3 toxicity. ConclusionsThis study demonstrates the first-in-human implementation of TFRT (R-IDEAL Stage 1), proving its feasibility in the modern clinical workflow. Additionally, assessments of acute toxicities and dosimetric comparisons to a standard radiotherapy plan were described (R-IDEAL Stage 2a).

Metformin with neoadjuvant chemoradiation to improve pathologic response in rectal cancer: A pilot phase I/II trial

PurposeNeoadjuvant radiotherapy with or without chemotherapy decreases the risk of local recurrence after surgery for rectal cancer. Emerging data suggest that diabetic patients on metformin may have improved cancer outcome after radiotherapy. A single institutional pilot study was performed to determine if metformin given concurrently with long course chemoradiation (CRT) may improve pathologic complete response (pCR) in non-diabetic rectal cancer patients. The study was designed to construct a confidence interval (CI) for the pCR rate to determine the sample size for a phase 2 trial. MethodsNon-diabetic patients with biopsy confirmed rectal cancer deemed candidates for long course neoadjuvant CRT were invited to participate. Radiation consisted of 50.4 Gy in 28 daily fractions with concurrent daily capecitabine (825 mg/m2 twice daily). Participants self-administered metformin (500 mg of twice daily) 2 weeks prior to, during and for 4 weeks after CRT. ResultsA total of 16 patients were accrued. One patient withdrew from the study. Only grade 1 or 2 adverse events were observed. Three patients had a clinical complete response (cCR) and did not undergo surgery. Of the 12 patients who underwent surgery, there were two pCRs. For the combined pCR/cCR rate of 33% (95% CI 19–47%), a total of 85 patients will be required to yield a 95% CI with a 10% margin of error. ConclusionsAdding metformin to neoadjuvant CRT for rectal cancer does not appear to enhance toxicities. These results will be used to refine the design and conduct of a future phase 2 trial to determine whether adding metformin to CRT improves pCR/cCR rates.

Investigation of the usage potential of the evacuated tube and the flat plate collectors to assist an absorption chiller

In this study, the usage potential of the evacuated tube collectors (ETCs) and the flat plate collectors (FPCs) for assisting an absorption chiller (AC) are comparatively investigated by using TRNSYS software. ETC and FPC are examined under different load conditions and scenarios to see if the collectors satisfy the required source temperature for an absorption chiller system (ACS) with LiBr – H2O pair. Daily and seasonal analyses are carried out. Daily analyses consist of three scenarios: both the auxiliary heater and the load are turned off in the first scenario while only the load is turned on in the second; both the auxiliary heater and the load are turned on in the third scenario that is also performed for summer season as a fourth scenario. The working fluid in all scenarios is a heat transfer fluid (HTF). In the third scenario at 250 kg/h load, the maximum collector outlet temperature is 113 °C and 99 °C, the daily solar fraction (SF) is 83% and 57%, the temperature to load is 106 °C and 86 °C for ETC and FPC, respectively. In the seasonal analysis, the seasonal SF is 81% and 20.19% at 250 kg/h load for ETC and FPC, respectively. Higher temperature and SF are obtained when HTF is used instead of water. It has been observed that the required source temperature for ACS can be provided with ETC.

MRI-based radiomics: promise for locally advanced cervical cancer treated with a tailored integrated therapeutic approach

To assess prognostic factors by analyzing clinical and radiomic data of patients with locally advanced cervical cancer (LACC) treated with definitive concurrent cisplatin-based chemoradiotherapy (CCRT) using magnetic resonance imaging (MRI). We analyzed radiomic features from MRI in 60 women with FIGO (International Federation of Gynecology and Obstetrics) stage IB2-IVA cervical cancer who underwent definitive CCRT 45-50.4 Gy (in 25-28 fractions). Thirty-nine (65.0%) received EBRT sequential boost (4-20 Gy) on primary tumor site and 56 (93.3%) received high-dose-rate brachytherapy boost (6-28 Gy) (daily fractions of 5-7 Gy). Moreover, 71.7% of patients received dose-dense neoadjuvant chemotherapy for 6 cycles. The gross tumor volume was defined on T2-weighted sequences and 29 features were extracted from each MRI performed before and after CCRT, using dedicated software, and their prognostic value was correlated with clinical information. In univariate analysis, age ⩾60 years and FIGO stage IB2-IIB had significantly better progression-free survival (PFS) (p = 0.022 and p = 0.009, respectively). There was a trend for significance for worse overall survival (OS) in patients with positive nodes (p = 0.062). In multivariate analysis, only age ⩾60 years and FIGO stage IB2-IIB reached significantly better PFS (p = 0.020 and p = 0.053, respectively). In radiomic dataset, in multivariate analysis, pregray level p75 was significantly associated with PFS (p = 0.047), pre-D3D value with OS (p = 0.049), and preinformation measure of correlation value with local control (p = 0.031). The combination of clinical and radiomics features can provide information to predict behavior and prognosis of LACC and to make more accurate treatment decisions.

Chemotherapy of GEP Regimen(Gemcitabine,etoposide and Pegaspargase) for the Patients with Newly Diagnosed Extranodal Natural Killer/T Cell Lymphoma: a Phase II Clinical Trial

Introduction: Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive form of non-Hodgkin's lymphoma,which is relatively more common in Asia and Latin America.Radiation therapy(RT) is widely administered for patients with localized nasal disease. However, local and systemic failures are observed frequently in patients who receive RT alone.Therefore, chemotherapy is needed in combination with RT to reduce the risk of recurrence. The patients with newly diagnosed stage III/IV ENKTL were rare and their prognosis was poorer.Chemotherapy was the major therapeutic tool for them.However,the optimal chemotherapy regimen for this disease has not been fully defined. Therefore, the purpose of this study is to prospectively evaluate efficacy and safety of GEP Regimen (Gemcitabine, Etopie and Pegaspargase ) in patients with newly diagnosed ENKTL(ClinicalTrials.gov number, NCT02705508).Methods: Enrolment began in March 2016 for a Phase II single-center clinical trial.Treatment GEP dosages were as follows: days 1 and 8,30min intravenous infusion of 1000mg/m2 gemcitabine;day1-3,4h intravenous infusion of 100mg/m2 etoposide;day1,deep intramuscular injection of 2500unit/m2 PEG-ASP at three different sites.The regimen was repeated every 3 weeks.Stage IE/IIE patients underwent four cycles induction chemotherapy, followed by involved-field radiotherapy after got complete remission,partial regression or stable disease.Three-dimensional conformal radiotherapy was done by linear accelerator at 2.0 grays (Gy) per daily fraction with 5-6 weeks. The involved-field radiation (IFRT) dose was 50-56Gy.Stage IIIE/IVE patients were given for six cycles unless there was disease progression or unacceptable side effects, or withdrawal of patient consent.Results: Until August 2, 2017, we have completed the enrolment of 20 patients with newly-diagnosed untreated ENKTL.The main clinical characteristics of the 20 patients are presented in Table 1.The median age was 50 years andranged from 20 to 70 years. The majority of patients initially presented withlocalized disease (stagesI and II; n = 17, 85%).All patients(n=20)have begun treatment and are evaluable for response. Of the 20 patients, complete remission (CR) rates is 100% to chemotherapy alone.Fifteen patients with localized disease(stage IE/IIE) achieved a CR after two cycles of GEP regimen. CR was achieved after 2 courses of chemotherapy in two stage IIIE/IVE patients and after 4 courses in one patient.Toxicities are recorded as the number of patients experiencing a certain adverse event.The most common grade 1-2 non-haematological (non-heme) adverse effects (AEs) are fatigue (n=12), nausea (n=10),oral mucositis (n=4).Fourteen(n=15) patients were confirmed to have decreased fibrinogen. Most of these were grade 1/2 and no bleeding or other adverse events were observed.Grade 3 non-heme AEs included fatigue (n=3), oral nausea (n=2), mucositis (n=1).There was no grade 4 non-heme toxicities during chemotherapy.Grade 1-2 hematological (heme) AEs included neutropenia (n=9), anemia (n=12) and thrombocytopenia(n=3). Common grade 3-4 haematological AEs was neutropenia (n=11), anemia (n=4) and thrombocytopenia(n=10).No patients interrupted treatment for severe adverse events and no treatment-related deaths occurred.Conclusions: Preliminary data indicate that the GEP regimen chemotherapy in newly diagnosedENKTL patients was efficacious and well-tolerated, while the long-term outcome is required to be followed up. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-Term Follow-Up after Radiotherapy of Hidradenitis Suppurativa

Background: Patients with hidradenitis suppurativa (HS) are still often disappointed with the current treatments offered and there is a clear demand for more effective options. Since the late 1990s there has been a revival in the use of radiotherapy (RT) for different benign diseases, including HS. During the past 20 years one case series and some scattered case reports have described promising results of RT. Objectives: To evaluate the long-term efficacy of RT in early-stage HS. Methods: A postal survey-based long-term follow-up with simple factual questions of partly retrospective and partly contemporary characteristics was performed. Sixty-four patients (96 axillae), diagnosed with mild to moderate HS were irradiated with a orthovoltage unit with 100 kV, 3 mm Al or 200 kV, 0.5 Cu filtering, respectively. Four to six biweekly fractional doses ranging from 0.75 to 1 Gy up to a total dose of 6 Gy in one series, and in chronic cases followed by four daily fractions of 2 Gy up to a total dose of 14 Gy, were given. Late treatment toxicity and the rate of remission of the disease were evaluated. Results: The overall response rate of the survey was 64.1% with 40.6% (26/64) valid, complete questionnaires. In total, 40 axillae were irradiated in these 26 patients. After a median follow-up of 40 years (range 32–52) complete remission of the lesions occurred in 34 of the 40 sites (85%). None of the 26 patients with 40 irradiated sites reported adverse effects at the time of the survey. Conclusions: RT appears to be an effective treatment for early and mild HS in the majority of patients. In this case series, no side effects were reported after a median follow-up period of 40 years.

Prognostic significance of inflammatory response markers for locally advanced squamous cell carcinoma of the external auditory canal and middle ear.

We investigated the prognostic significance and treatment outcomes of pretreatment inflammatory response markers for locally advanced squamous cell carcinoma (SCC) of the external auditory canal (EAC) and middle ear (ME). Between July 2003 and July 2019, 21 patients with SCC of the EAC (n = 18) or ME (n = 3) who received radiotherapy with or without surgery or systemic therapy (radiotherapy alone [n = 2], radiotherapy + systemic therapy [n = 6], radiotherapy + surgery [n = 7], radiotherapy + surgery + systemic therapy [n = 6]) were retrospectively examined. The median radiation dose was 66.0 (range, 50.4–70.0) Gy, with daily fractions of 1.8–2.0 Gy. The median follow-up period was 25 months (range, 6–137). The two-year overall survival (OS), progression-free survival (PFS), and locoregional control (LC) rates were 61%, 48%, and 55%, respectively. OS, PFS, and LC did not differ significantly according to patient- (age, sex), tumor- (Pittsburgh stage, pretreatment neurological findings), and treatment-related (surgery or systemic therapy, radiation dose, prophylactic neck irradiation) factors. Conversely, there were significant differences in OS, PFS, and LC between patients with high and low pretreatment C-reactive protein-to-albumin ratios (p = 0.002, 0.003, and 0.004, respectively). OS also differed significantly between patients with high and low pretreatment neutrophil-to-lymphocyte ratios (NLR; p = 0.037). Other inflammatory response markers, including platelet-to-lymphocyte ratio (PLR) and albumin-to-globulin ratio (AGR), did not influence OS, PFS, or LC. Our findings suggest that pretreatment C-reactive protein-to-albumin ratio and NLRs have a significant impact on treatment outcomes in patients with locally advanced SCC of the EAC and ME.

Forecasting Individual Patient Response to Radiation Therapy in Head and Neck Cancer With a Dynamic Carrying Capacity Model

Purpose:To model and predict individual patient responses to radiation therapy.Methods and Materials:We modeled tumor dynamics as logistic growth and the effect of radiation as a reduction in the tumor carrying capacity, motivated by the effect of radiation on the tumor microenvironment. The model was assessed on weekly tumor volume data collected for 2 independent cohorts of patients with head and neck cancer from the H. Lee Moffitt Cancer Center (MCC) and the MD Anderson Cancer Center (MDACC) who received 66 to 70 Gy in standard daily fractions or with accelerated fractionation. To predict response to radiation therapy for individual patients, we developed a new forecasting framework that combined the learned tumor growth rate and carrying capacity reduction fraction (δ) distribution with weekly measurements of tumor volume reduction for a given test patient to estimate δ, which was used to predict patient-specific outcomes.Results:The model fit data from MCC with high accuracy with patient-specific δ and a fixed tumor growth rate across all patients. The model fit data from an independent cohort from MDACC with comparable accuracy using the tumor growth rate learned from the MCC cohort, showing transferability of the growth rate. The forecasting framework predicted patient-specific outcomes with 76% sensitivity and 83% specificity for locoregional control and 68% sensitivity and 85% specificity for disease-free survival with the inclusion of 4 on-treatment tumor volume measurements.Conclusions:These results demonstrate that our simple mathematical model can describe a variety of tumor volume dynamics. Furthermore, combining historically observed patient responses with a few patient-specific tumor volume measurements allowed for the accurate prediction of patient outcomes, which may inform treatment adaptation and personalization.

HGG-16. DISSECTING THE EFFECT OF ATM DELETION ON RADIOSENSITIVITY IN DIFFUSE MIDLINE GLIOMAS WITH H3K27M MUTATION

Abstract Diffuse midline gliomas (DMGs) are responsible for a large proportion of childhood brain tumor deaths. Currently, radiation therapy is thought to be one of the most effective treatment options, but more than 90% of children still die within 2 years of diagnosis. DMGs are defined by somatic histone 3 K27M (H3K27M) mutations that have been shown to promote the G0/G1 to S cell cycle transition. The majority of DMGs also contain loss-of-function mutations in TP53. Prior research demonstrated that orthotopic xenograft and primary mouse models of non-H3K27M-mutated gliomas with inactivation of p53 are preferentially radiosensitized by inactivation of Ataxia Telangiectasia Mutated (ATM), a kinase that mediates DNA repair in response to DNA damage caused by radiation. The high frequency of mutations that deregulate p53 in DMGs raises the possibility that H3K27M-mutant DMGs may also be radiosensitized by ATM inhibition, representing a unique therapeutic opportunity. Here, we hypothesize that H3K27M-mutant DMGs that have loss of function of p53 will be radiosensitized by loss of ATM. To test this hypothesis, we used the RCAS-TVA viral gene delivery system to generate genetically-faithful primary mouse models of H3K27M-mutant DMG with p53 deletion, and we used Cre recombinase to delete Atm in the tumor cells of these mice and generated littermate controls that retained Atm. Mice were imaged weekly via luciferase-based bioluminescence to track tumor development and irradiated with three daily fractions of 10 Gy after tumor detection. We subsequently quantified the survival of mice without neurological decline following irradiation. In separate cohorts, we collected primary tumors after irradiation to verify H3K27M expression and to assess cell cycle arrest and mechanisms of cell death. These studies will elucidate mechanisms by which ATM inactivation can radiosensitize H3K27M-mutant DMGs with nonfunctioning p53, which will guide the design of clinical trials testing ATM inhibitors in DMG patients.

EPEN-04. SIOP EPENDYMOMA I: FINAL RESULTS, LONG TERM FOLLOW-UP AND MOLECULAR ANALYSIS OF THE TRIAL COHORT: A BIOMECA CONSORTIUM STUDY

IntroductionSurgery and radiotherapy are established childhood ependymoma treatments. The efficacy of chemotherapy has been debated. We report final results of the SIOP Ependymoma I trial, with 12-year follow-up, in the context of a post-hoc analysis of more recently described biomarkers. Aims and MethodsThe trial assessed event free (EFS) and overall survival (OS) of patients aged three to 21 years with non-metastatic intracranial ependymoma, treated with a staged management strategy targeting maximum local control. The study also assessed: the response rate (RR) of subtotally resected (STR) disease to vincristine, etoposide and cyclophosphamide (VEC); and surgical operability. Children with gross total resection (GTR) received radiotherapy of 54 Gy in 30 daily fractions over six weeks, whilst those with STR received VEC before radiotherapy. We retrospectively assessed methylation and 1q status alongside hTERT, RELA, Tenascin C, H3K27me3 and pAKT expression. ResultsBetween 1999 and 2007, 89 participants were enrolled, 15 were excluded with metastatic (n=4) or non-ependymoma tumours (n=11) leaving a final cohort of 74. Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. 1q gain was associated with poorer EFS (p=0.002, HR=3.00, 95%CI 1.49–6.10). hTERT expression was associated with worse five-year EFS (20.0% Vs 83.3%, p=0.014, HR=5.8). GTR was achieved in 33/74 (44.6%) and associated with improved EFS (p=0.006, HR=2.81, 95% confidence interval 1.35–5.84). There was an improvement in GTR rates in the latter half of the trial (1999-2002 32.4% versus 2003-2007 56.8%). Despite the protocol, 12 participants with STR did not receive chemotherapy. However, chemotherapy RR was 65.5% (19/29, 95%CI 45.7–82.1). ConclusionsVEC exceeded the pre-specified RR of 45% in children over three years with STR intracranial ependymoma. However, cases of inaccurate stratification at treating centres highlights the need for rapid central review. We also confirmed associations between 1q gain, hTERT expression and outcome.

Phase Ib, international, dose-escalation study to evaluate the safety, pharmacokinetics (PK) and efficacy of ST-617 for the attenuation of oral mucositis (OM) in patients receiving chemoradiation (CRT) for head and neck (H&N) cancer.

6075 Background: OM is a common, painful, and costly toxicity associated with cytotoxic regimens used to treat H&N cancers, which may result in radiotherapy treatment interruptions to negatively impact tumor control. There are currently no approved interventions to successfully prevent or delay OM onset among patients being treated with radiation therapy, with or without concomitant chemotherapy (CRT). Oxidative stress is a critical event in OM’s pathogenesis. Through its effect on Nrf2, ST-617 has marked anti-oxidative activity/properties. Supportive Therapeutics is developing ST-617, a dithioethione, for the attenuation of OM onset, duration and severity. The objective of this trial was to assess the safety, tolerability, PK, PD and efficacy of ST-617 in patients at high risk of severe OM (SOM). Methods: A dose escalation trial in which ST-617 administered as an oral suspension, 1-2 hours before the administration of daily RT fractions was performed at 9 study sites in South Africa and Australia. Eighteen patients with diagnoses of oral or oropharyngeal CA were enrolled (up to 6 pts/dose). Patients received concomitant cisplatin either weekly or tri-weekly. ST-617 was administered 3 days prior to CRT, and then continuing daily until the end of treatment. Safety outcomes, using CTCAE criteria (v 4.03) were used. Dose escalation occurred in the absence of toxicity. OM occurrence and severity were assessed by trained and validated evaluators using WHO, NCI-CTC and RTOG criteria; scores were centrally assigned. The primary efficacy endpoints included the incidence and duration of SOM (WHO grades 3 or 4) vs historical controls. PD tracking measured total ROS/RNS, GSH/GSSG, regulation in plasma and buccal epithelial cells. Results: 17 pts completed the 50, 100 and 150mg/day with no safety issues. No early dose limiting toxicity (DLT) or serious Adverse Event linked to ST-617 were observed. AEs observed were mainly nausea which is usually associated with CRT as expected. The 100 mg/day dose has been well tolerated with no grade 4 OM. No CRT dose interruptions or delays due to OM has been observed. Total ROS/RNS levels in plasma and buccal samples show significant decrease with increased ST-617 dosing from 50 to 100 mg/day. Conclusions: ST-617 administration was safe at all doses tested. The course and severity of patients treated with ST-617 compared favorably with historical controls. Mechanistic correlation between ROS/RNS levels was seen. A randomized, controlled, double blind trial is planned with the recommended dose of 100mg/day. Clinical trial information: 20180138.

Influence of preoperative chemoradiation on tumor-infiltrating lymphocytes in locally advanced rectal cancer: The STAR-01 cohort.

3611 Background: Preoperative chemoradiotherapy may increase antitumor immunity through enhancing T-cell activation and tumor infiltration. These effects could possibly sensitize tumors to immunotherapies, including checkpoint inhibitors. We explored whether preoperative chemoradiation for locally advanced rectal cancer induces immunologic changes and if the post-operative biological parameters are associated with tumor regression grade (TRG sec. Ryan –AJCC Eight ed.). Methods: The multicenter STAR-01 study compared a standard preoperative chemoradiotherapy regimen (50.4 Gy in 28 daily fractions with concomitant infused fluorouracil at the dose of 225 mg/m2/d) with the same regimen plus oxaliplatin given weekly at the dose of 60 mg/m2 in patients with locally advanced rectal cancers. Paired pre- and post-operative specimens were available for 58 patients from this trial and were analyzed by immunohistochemistry. The immunoistochemical analysis was performed with a panel of immune cells and associated factors as CD3, CD20, CD4/CD8, PD1. The pattern of tumor infiltrating lymphocytes (TILs) and related infiltrating lymphocytes (RILs) was also evaluated. Response to pre-operative chemoradiotherapy was assessed according to TRG. Results: After therapy we observed a decreased CD4/CD8 ratio (p < 0.001) and reduced expression level of CD20 (p < 0.001). The expression level of CD3+ and PD-1+ cells after therapy did not change significantly. The relative increase of lymphocytes CD8+ inside CD4/CD8 ratio evaluated on post-operative samples was significantly associated with TRG 0 (p < 0.001). Conclusions: Our data suggest that chemoradiation may induce an enrichment of CD8+ T lymphocytes and this translates in better response to chemoradiation. The new frontier of best treatment could be the use of specific immune cells (T lymphocytes) to trigger the system's immune response against disease.

Is it advantageous to use deep inspiration breath hold (DIBH) over free breathing for FAST-Forward dose fractionation scheme in treating carcinoma of left-sided breast? A dosimetric study

Abstract Aim: To study the effect of deep inspiration breath hold (DIBH) on Fast-Forward trial for left-sided breast radiotherapy dosimetrically using tangential field-in-field (FiF), flattening filtered volumetric-modulated arc therapy (FF-VMAT) and flattening filter free volumetric-modulated arc therapy (FFF-VMAT) in comparison with free breathing (FB). Methods: Computed tomography images were acquired on 15 patients with carcinoma of left breast in FB and DIBH. Planning target volume (PTV) and organs at risk were contoured on both image sets. Dose of 26 Gy in five daily fractions was prescribed to PTV. FiF, FF-VMAT and FFF-VMAT plans were created in treatment planning system on both FB and DIBH. PTV V95%, V107%, D0·1 cc, CI and HI, heart V1·5 Gy, V7 Gy, lung left V8 Gy, monitor units (MU) and beam ON time were used for evaluation. Different technique analysis in same breathing condition and FB versus DIBH for same planning technique were performed. Results: Mean of all 15 patients was reported as mean ± 1 standard deviation. PTV V95% was 97·55 ± 0·10 (FiF), 95·75 ± 0·66 (FF-VMAT) and 96·15 ± 0·46 (FFF-VMAT) in FB while 97·34 ± 0·50 (FiF), 96·03 ± 0·71 (FF-VMAT) and 95·86 ± 0·63 (FFF-VMAT) in DIBH. Heart V7 Gy was 8·53 ± 4·26 (FiF), 8·86 ± 2·20 (FF-VMAT) and 9·27 ± 2·46 (FFF-VMAT) in FB while 6·30 ± 2·98 (FiF), 5·23 ± 2·20 (FF-VMAT) and 4·68 ± 2·01 (FFF-VMAT) in DIBH. p-value of heart V7 Gy between FB and DIBH was 0·278 (FiF), 0·009 (FF-VMAT) and 0·003 (FFF-VMAT). Beam ON time for FFF-VMAT was reduced by 65% (FF-VMAT) and 11% (FiF). Conclusion: Conformal dose to PTV was achieved better with VMAT plans. FFF-VMAT was delivered in less time compared to FF-VMAT and FiF for 26 Gy in five fractions. Heart dose can be significantly minimised with DIBH for VMAT plans.

PO-0189 The second planning-CT in a two daily fractions implant can be omitted in cervical cancer IGABT

PO-0189 The second planning-CT in a two daily fractions implant can be omitted in cervical cancer IGABT

The prognostic impact of daytime and seasonality of radiotherapy on head and neck cancer

BackgroundThe potential impact of daytime and season of radiotherapy application on prognosis is unclear. This was analyzed in a retrospective cohort of patients who were diagnosed with non-metastatic head and neck squamous cell carcinoma (HNSCC) and treated with definitive radiotherapy with or without chemotherapy. Materials and methodsPatient and tumor characteristics, treatment parameters and outcome until last follow-up or death were obtained. Median radiotherapy delivery daytime of each patient was categorized as morning (AM) and afternoon (PM). Treatment season was defined by median date of treatment course. Each year was divided into DARK and LIGHT according to equinoxes. Time-to-event endpoints were defined by first biopsy confirming the HNSCC. ResultsSix hundred fifty-five cases were identified who were treated with (chemo)radiotherapy between 2002 and 2015. Median follow-up was 47 months. No significant heterogeneity in patient, tumor and treatment characteristics were observed between DARK and LIGHT or regarding median daily fraction time (X2 p > 0.05). Five-year loco-regional control (73% vs. 61%; p = 0.0108) and progression-free survival (51% vs. 43%; p = 0.0374) were superior when radiotherapy was administered in DARK. Neither the daytime nor any other treatment time-related parameter affected prognosis. ConclusionThis is the first study investigating and presenting the prognostic impact of seasonality regarding the treatment course on loco-regional control and progression-free survival (DARK > LIGHT). The biological mechanism of action is unclear. These results should be interpreted with caution and our findings have to be validated externally.