Radiotherapy Fractionation Research Articles

Impact of the COVID-19 Pandemic on Radiotherapy Patients by Age and Residence

Background/Aim: This epidemiology study aimed to investigate how the COVID-19 pandemic affected the weekly number of external beam radiotherapy (EBRT) fractions concerning patient age and residence distance from our radiotherapy center (RTC). Methods: Twenty-two-month intervals before and after the onset of the COVID-19 pandemic were compared. Results: The average weekly number of fractions from May 2018 to February 2020 was 692.8 (SD 67.6), and from March 2020 to December 2021 was 639.3. (SD 84.7). The weekly number of fractions decreased by 42.4 % in March 2021 and by 67.9 % in April 2020 compared to the same period in 2019. When comparing patients under 70 years of age to those over 70, the decrease was 28.0 % vs. 6.9 %, respectively. According to the Wilcoxon signed-rank test (Z = - 5.2, p = 0.001), the outbreak of the COVID-19 pandemic had a statistically significant impact on the decrease in the weekly number of fractions. The distance between the city of residence and the RTC was not a significant factor but years of life (more than 70) was. Conclusion: During the "waves" of the pandemic, radiation therapy (RT) was not administered to specific groups of cancer patients eligible for it because other medical departments for oncology patients were closed.

What did COVID-19 pandemics teach us about single-fraction radiotherapy for painful bone metastases-State of the art or undertreatment?

Choosing the optimal treatment approach for patients with painful bone metastases during the COVID-19 pandemic became challenging. A simple technique, single fraction radiotherapy was recommended for these patients usually referring to bone metastases as a single entity, although it is a very heterogeneous group of patients. This study aimed to analyze the response to palliative single fraction radiotherapy in relation to age, performance status, primary tumor, histopathology, and bone localization in the group of patients with painful bone metastases. A clinical, prospective, non-randomized study was conducted at the Institute for Oncology and Radiology of Serbia, which included 64 patients with noncomplicated, painful bone metastases who underwent palliative, pain-relieving radiation therapy with a single tumor dose of 8Gy in a single hospital visit. Response to treatment was patient reported via telephone interview using visual analog scale. The response assessment was based on the international consensus panel of radiation oncologists. In the entire group of patients, 83% responded to radiotherapy. No statistically significant difference was observed in response to therapy, time to reach the maximum response, degree of pain reduction, nor in response duration depending on the patient's age, performance status, the primary origin of the tumor, histopathology, or location of the metastasis (bone) that was irradiated. Regardless of clinical parameters, palliative radiotherapy with a single dose of 8Gy can be considered very effective in quick pain relief in patients with noncomplicated painful bone metastases. Single fraction radiotherapy in a single hospital visit, as well as patient-reported outcome for these patients may be considered favorable beyond Covid pandemics.

A phase II randomized clinical trial to assess toxicity and quality of life of breast cancer patients with hypofractionated versus conventional fractionation radiotherapy with regional nodal irradiation in the context of COVID-19 crisis.

This study, conducted during the COVID-19 crisis, primarily aimed to compare the acute toxicity between conventional fractionated radiation therapy (CF-RT) with hypofractionated radiation therapy (HF-RT) among patients who underwent breast-conserving surgery or mastectomy in whom breast or chest wall and regional nodal irradiation (RNI) were indicated. The secondary endpoints were both acute and subacute toxicity, cosmesis, quality of life, and lymphedema features. In this open and non-inferiority randomized trial, patients (n = 86) were randomly allocated 2:1 in the CF-RT arm (n = 33; 50 Gy/25 fractions ± sequential boost [10 Gy/5 fractions]) versus the HF-RT arm (n = 53; 40 Gy/15 fractions ± concomitant boost [8 Gy/15 fractions]). Toxic effects and cosmesis evaluation used the Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE) and the Harvard/National Surgical Adjuvant Breast and Bowel Project (NSABP)/Radiation Therapy Oncology Group (RTOG) scale. For the patient-reported quality of life (QoL), the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) and the breast cancer-specific supplementary questionnaire (QLQ-BR23) were used. Lymphedema was assessed by comparing volume differences between the affected and contralateral arms using the Casley-Smith formula. Grade 2 and grade 3 dermatitis were lower with HF-RT than with CF-RT (28% vs. 52%, and 0% vs. 6%, respectively; p = 0.022). HF-RT had a lower rate of grade 2 hyperpigmentation (23% vs. 55%; p = 0.005), compared to CF-RT. No other differences in overall rates of physician-assessed grade 2 or higher and grade 3 or higher acute toxicity between HF-RT and CF-RT were registered. There was no statistical difference between groups regarding cosmesis, lymphedema rate (13% vs. 12% HF-RT vs. CF-RT; p = 1.000), and functional and symptom scales, during both the irradiation period and after 6 months of the end of treatment. The results revealed that the subset of patients up to 65 years or older did not show a statistical difference between both arm fractionation schedules (p > 0.05) regarding skin rash, fibrosis, and lymphedema. HF-RT was non-inferior to CF-RT, and moderate hypofractionation showed lower rates of acute toxicity, with no changes in quality-of-life outcomes. ClinicalTrials.gov, identifier NCT40155531.

Radiation fractionation effect on IDO1 through NF-kB/COX2 axis in non-small cell lung cancer.

e20613 Background: Lung cancer is the leading cancer mortality worldwide. Radiotherapy(RT) plays an important role in lung cancer treatment. Different does fractionation of RT has different effects on the prognosis of lung cancer. For example, stereotactic body radiotherapy can significantly improve the prognosis compared with conventionally Fractionated Radiotherapy. In non-small cell lung cancer, we have previously shown that Indoleamine 2,3-dioxygenase 1 (IDO1) metabolites and radiation induced changes had significant effects on long-term survival in patients treated with either Stereotactic body Radiation Therapy of 10Gy fraction size or conventional fractionated radiotherapy of 2Gy fraction size. However, the underlining molecular mechanism is unknown. In this study, we aimed to elaborate the molecular mechanism of such clinical differential effects in the laboratory. Methods: This study applied two dose/fractionation regimens with a similar BED10: 10Gyx1 and 2Gyx8. 10Gyx1 and 2Gyx8 were tested in cell lines of A549, H1299, Calu-1, TC-1 of human and murine NSCLC as well as normal rat cardiomyocyte cell line H9c2, and in vivo (TC-1 implanted C57Bl/6 mice). The mRNA and protein levels of IDO1, p-NF-kB, COX2 from cells and tumor tissues were determined by using qPCR, western blot and immunohistochemistry. Survival outcome was tested by colony formation assay in vitro and tumor growth curve in vivo. Results: In vitro, 10Gyx1 and 2Gyx8 induced IDO1 expression in all tested cell lines and the level of IDO1 expression induced by 10Gyx1 was lower than 2Gyx8. Both 10Gyx1 and 2Gyx8 increased p-NF-kB and COX2 expression and the level induced by 10Gyx1 was lower than 2Gyx8. In tumor bearing mice, two dose/fractionation regimens also induced intratumor IDO1 expression and increased the levels of p-NF-kB and COX2. Interestingly, the increased levels of IDO1, p-NF-kB, COX2 after 10Gyx1 were also significantly lower than 2Gyx8 in vivo. IDO inhibitor synergized with RT and enhanced cell killing efficacy of RT. Conclusions: The findings of this study suggest different does fractionation of RT induced up-regulation of IDO1 through NF-kB/COX2 axis in NSCLC and non-cancerous cell lines, what’s more, hypofractionated radiotherapy 10Gyx1 had less upregulation that of conventionally fractionated radiotherapy 2Gy x8 on IDO1 immune inhibitory pathway. The finding of hypofractionated radiotherapy less immune suppression differ from the traditional belief of more immune stimulation. Our current study provides a rationale in using IDO1 as a biomarker to design RT dose fractionation and/or immunotherapy in combination and possibilities for clinical trials to design IDO1 inhibitors in combination with radiotherapy.

Tolerability and response of palliative radiotherapy in patients receiving tumor-infiltrating lymphocyte therapy.

e14527 Background: Tumor-infiltrating lymphocyte (TIL) therapy is an emerging therapeutic option for patients with metastatic tumors having progressed on multiple lines of systemic therapy. It is unknown how TIL therapy impacts the tolerability and effectiveness of palliative radiotherapy (RT). We herein present a case series of patients having received both TIL therapy and palliative RT along with the associated local responses and toxicity profiles. Methods: A single institution retrospective database review identified patients treated with TIL therapy following progression on ≥2 standard treatment(s) for metastatic disease. Patients were eligible for inclusion if they received palliative radiotherapy treatment within 1 year of TIL delivery as pre- or post-TIL therapy. Patient demographic data was collected and descriptive statistics reported. Radiographic imaging response was assigned in accordance with Response Evaluation Criteria in Solid Tumors (RECIST). Toxicities were graded in accordance with Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Results: Between 2017–2021, a total of 10 patients receiving TIL therapy treated across 12 courses of palliative RT were included for analysis. 8 of 10 patients (80%) had a primary diagnosis of malignant melanoma and 2 (20%) had non-small cell lung cancer. RT was administered to 7 patients pre- and 3 patients post-TIL therapy. Within the pre-TIL cohort, 2 patients received RT between TIL harvest and infusion. Patients received an average total dose of 26 Gy (range, 8-45 Gy). Median patient follow-up after RT was 6 months. Of the patients who received RT prior to TIL therapy, 6 of 9 sites demonstrated at-least stable disease at the site of RT versus 1 of 3 sites receiving post-TIL RT. Across the cohort, 2 patients experienced Grade 1 toxicities associated with RT treatment. No Grade 2+ events were reported. Conclusions: Palliative RT appears to be safe and tolerable when delivered both prior to and post-TIL therapy. RT may be an option for bridging therapy between TIL harvest and infusion. Local response rates to RT were greater in patients receiving RT prior to TIL infusion. Further investigations are warranted to determine the optimal dose, fractionation, and timing of RT when integrating it into future TIL therapy protocols. [Table: see text]

Impact of Cochlear Dose on Hearing Preservation Following Stereotactic Radiosurgery in Treatment of Vestibular Schwannomas: A Multi-Center Study

Stereotactic radiosurgery (SRS) is a well-established treatment for vestibular schwannomas (VS). Hearing loss remains a main morbidity of VS and its treatments, including SRS. The effects of radiation parameters of SRS on hearing remain unknown. The goal of this study is to determine the effect of tumor volume, patient demographics, pretreatment hearing status, cochlear radiation dose, total tumor radiation dose, fractionation, and other radiotherapy parameters on hearing deterioration. Multicenter retrospective analysis of 611 patients who underwent SRS for VS from 1990-2020 and had pre- and post-treatment audiograms. Pure tone averages (PTAs) increased and word recognition scores (WRSs) decreased in treated ears at 12-60 months while remaining stable in untreated ears. Higher baseline PTA, higher tumor radiation dose, higher maximum cochlear dose, and usage of single fraction resulted in higher post radiation PTA; WRS was only predicted by baseline WRS and age. Higher baseline PTA, single fraction treatment, higher tumor radiation dose, and higher maximum cochlear dose resulted in a faster deterioration in PTA. Below a maximum cochlear dose of 3 Gy, there were no statistically significant changes in PTA or WRS. Decline of hearing at one year in VS patients after SRS is directly related to maximum cochlear dose, single versus 3-fraction treatment, total tumor radiation dose, and baseline hearing level. The maximum safe cochlear dose for hearingtbrowd preservation at one year is 3 Gy, and the use of 3 fractions instead of one fraction was better at preserving hearing.

A phase II randomized clinical trial to assess toxicity and quality of life of patients with breast cancer with hypofractionated versus conventional fractionation radiotherapy with regional nodal irradiation.

588 Background: The primary aim was comparing acute toxicity between conventional fractionated radiation therapy (CF-RT) and hypofractionated radiation therapy (HF-RT) for patients undergoing breast-conserving surgery or mastectomy with breast or chest wall and regional nodal irradiation (RNI). The secondary endpoints were acute and subacute toxicity, cosmesis, quality of life, and lymphedema features. Methods: Unblinded randomized trial with total of 86 patients treated with CF-RT (n = 33; 50 Gy/25 fractions ± sequential boost [10 Gy/5 fractions]) versus HF-RT (n = 53; 40 Gy/15 fractions ± concomitant boost [8 Gy/15 fractions]). Toxic effects and cosmesis evaluation used the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE) and the Harvard/NSABP/RTOG scale. Patients-reported QoL was determined using European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) and the breast cancer-specific supplementary questionnaire (QLQ-BR23). Lymphedema determination compared volume differences between the affected and contralateral arms using the Casley-Smith volume formula. Results: Grade 2 and grade 3 skin rash dermatitis were lower with HF-RT than with CF-RT (28% vs. 52%, 0% vs. 6%; p = 0.022, respectively). HF-RT vs. CF-RT had lower rate of grade 2 hyperpigmentation (23% vs. 55%; p = 0.005). No differences in overall rates of any physician-assessed grade 2 or higher and grade 3 or higher acute toxicity between HF-RT vs. CF-RT were registered. There was no statistical difference between the CF-RT and the HF-RT regarding cosmesis, lymphedema rate (13% vs. 12% HF-RT vs. CF-RT; p = 1.000, respectively), and functional and symptom scales during irradiation and after six months of treatment. Conclusions: HF-RT showed lower rates of acute toxicity, with no changes in quality-of-life outcomes. Clinical trial information: NCT04015531 .

Randomised phase III trial of the hypoxia modifier nimorazole added to radiotherapy with benefit assessed in hypoxic head and neck cancers determined using a gene signature (NIMRAD).

6006 Background: Tumour hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the addition of nimorazole to definitive radiotherapy (RT). Methods: NIMRAD was a phase III, multi-centre, placebo-controlled, double-blind trial in patients with HNSCC unsuitable for concurrent platinum chemotherapy or cetuximab with definitive RT (NCT01950689). Patients were randomized 1:1 to receive nimorazole (1.2 g/m2 daily, prior to RT) + RT (65 Gy in 30 fractions over 6 weeks) or placebo (taken via the same schedule) + RT. The primary endpoint was loco-regional control (freedom from loco-regional progression, FFLRP) in patients with hypoxic tumours, defined as greater than or equal to the median hypoxia score of the first 50 patients analysed (≥0.079), using a validated 26-gene signature. The planned sample size was 340 patients allowing for signature generation in 85%, assumed HR 0.50 for nimorazole effectiveness in the hypoxic group, and requiring 66 loco-regional failures to have 80% power in a two-tail log-rank test at the 5% significance level. Results: 338 patients were randomised by 19 UK centres from May 2014 to May 2019, with a median follow-up of 3.1 years (95%CI 2.9-3.4). Hypoxia scores were available for 286 (85%). The median patient age was 73 years (range 44-88); and clinical factors were balanced between the arms, both for the whole population and hypoxic group (Table). There were 36 (25.9%) loco-regional failures in the hypoxic group, where nimorazole + RT did not improve FFLRP (adjusted HR 0.72; 95% CI 0.36-1.44; p=0.35), or overall survival (adjusted HR 0.96; 0.53-1.72; p=0.88) compared with placebo + RT. Similarly, nimorazole + RT did not improve FFLRP or OS in the whole population. In total (n=338), 73% of patients allocated nimorazole adhered to the drug for ≥50% of RT fractions. Nimorazole + RT caused more acute nausea compared with placebo + RT (CTCAE v4.0 G1+2: 56.6% vs 42.4%, G3: 10.1% vs 5.3%, respectively; p=0.003), with no differences in other early or late toxicities. Conclusions: Addition of the hypoxia modifier nimorazole to RT for locally advanced HNSCC in older and less fit patients did not improve loco-regional control or survival. Clinical trial information: NCT01950689 . [Table: see text]

Clinical Outcomes of Patients with Metastatic Breast Cancer Treated with Hypo-Fractionated Liver Radiotherapy.

To retrospectively review the clinical outcomes of patients with metastatic breast cancer (MBCa) following liver directed ablative intent radiotherapy (RT). Demographics, disease and treatment characteristics of patients with MBCa who received liver metastasis (LM) directed ablative RT between 2004-2020 were analysed. The primary outcome was local control (LC), secondary outcomes included overall survival (OS) and progression-free survival (PFS) analyzed by univariate (UVA) and multi-variable analysis (MVA). Thirty MBCa patients with 50 LM treated with 5-10 fraction RT were identified. Median follow-up was 14.6 (range 0.9-156.2) months. Class of metastatic disease was described as induced (12 patients, 40%), repeat (15 patients, 50%) and de novo (three patients, 10%). Median size of treated LM was 3.1 cm (range 1-8.8 cm) and median biologically effective dose delivered was 122 (Q1-Q3; 98-174) Gy3. One-year LC rate was 100%. One year and two-year survival was 89% and 63%, respectively, with size of treated LM predictive of OS (HR 1.35, p = 0.023) on UVA. Patients with induced OMD had a significantly higher rate of progression (HR 4.77, p = 0.01) on UVA, trending to significance on MVA (HR 3.23, p = 0.051). Hypo-fractionated ablative liver RT in patients with MBCa provides safe, tolerable treatment with excellent LC.

A comparative study of the treatment outcome of moderately accelerated radiation fractionation (with concurrent chemotherapy in daily dosing) to conventional chemo-radiotherapy in locally advanced head and neck cancers: Supportive in a resource constrained environment.

In our country, head and neck cancers account for about a third of all cancers. Moreover, the patients typically present in advanced stages, which entails intensive multimodality therapy; but there is not much scope for improved survival outcomes. In view of this, a study was conducted to know the effects of treatment intensification, wherein moderately accelerated fractionation radiotherapy was given to patients presenting with advanced cancer of head and neck. This treatment was further intensified by accompanying radiation with concurrent cisplatin chemotherapy in daily doses. The control arm received the current standard therapy of conventional fractionation radiotherapy with weekly cisplatin chemotherapy. The primary objective of the study was to determine the prospect of tumor control (TC), disease-free survival (DFS), and overall survival (OS). The secondary objective was to study acute toxicity and late toxicity of the highest grade in both treatment groups. The study was conducted on a total of 60 patients who presented with locally advanced squamous cell carcinoma of the head and neck. The 30 patients in the control group received conventional fractionated radiotherapy (five fractions per week) with weekly cisplatin chemotherapy (40 mg/m 2 ), whereas the remaining 30 in the study group received moderately accelerated radiotherapy (six fractions per week with same treatment field) along with daily cisplatin chemotherapy (6 mg/m 2 ) with a reduction in treatment time by 1 week. The overall response to therapy assessed as TC, DFS, and OS was compared, and no statistically significant difference between the two treatment arms was observed. However, the mean overall treatment time was reduced in the study group to 45 days as compared with 49 days in the control group ( P = 0.001). The acute toxicities of xerostomia ( P = 0.057) and skin ( P = 0.052) and late toxicity of aspiration/laryngeal toxicity ( P = 0.002) were higher in grade and number in the study group with accelerated fractionation. Hence, the study results suggest that it is a feasible option to combine the therapeutic benefits of accelerated fractionation radiotherapy with concurrent chemotherapy in patients with locally advanced head and neck carcinomas. There is a significant decrease in the overall treatment time and a considerable reduction in the load on the resource-constrained healthcare system. It would be equitable to point out that higher grade of few toxicities in the acceleration arm are likely due to doses to organs at risk being intensified with accelerated fractionation, which can now be delivered in a controlled manner with the latest high precision techniques, resulting in improved toxicity profile and quality of life which is the way forward for future studies.

Acute Toxicity of Hypofractionated and Conventionally Fractionated (Chemo)Radiotherapy Regimens for Bladder Cancer: An Exploratory Analysis from the RAIDER Trial

AimsAdding concurrent (chemo)therapy to radiotherapy improves outcomes for muscle-invasive bladder cancer patients. A recent meta-analysis showed superior invasive locoregional disease control for a hypofractionated 55 Gy in 20 fractions schedule compared with 64 Gy in 32 fractions. In the RAIDER clinical trial, patients undergoing 20 or 32 fractions of radical radiotherapy were randomised (1:1:2) to standard radiotherapy or to standard-dose or escalated-dose adaptive radiotherapy. Neoadjuvant chemotherapy and concomitant therapy were permitted. We report exploratory analyses of acute toxicity by concomitant therapy-fractionation schedule combination. Materials and methodsParticipants had unifocal bladder urothelial carcinoma staged T2-T4a N0 M0. Acute toxicity was assessed (Common Terminology Criteria for Adverse Events) weekly during radiotherapy and at 10 weeks after the start of treatment. Within each fractionation cohort, non-randomised comparisons of the proportion of patients reporting treatment emergent grade 2 or worse genitourinary, gastrointestinal or other adverse events at any point in the acute period were carried out using Fisher's exact tests. ResultsBetween September 2015 and April 2020, 345 (163 receiving 20 fractions; 182 receiving 32 fractions) patients were recruited from 46 centres. The median age was 73 years; 49% received neoadjuvant chemotherapy; 71% received concomitant therapy, with 5-fluorouracil/mitomycin C most commonly used: 44/114 (39%) receiving 20 fractions; 94/130 (72%) receiving 32 fractions. The acute grade 2+ gastrointestinal toxicity rate was higher in those receiving concomitant therapy compared with radiotherapy alone in the 20-fraction cohort [54/111 (49%) versus 7/49 (14%), P < 0.001] but not in the 32-fraction cohort (P = 0.355). Grade 2+ gastrointestinal toxicity was highest for gemcitabine, with evidence of significant differences across therapies in the 32-fraction cohort (P = 0.006), with a similar pattern but no significant differences in the 20-fraction cohort (P = 0.099). There was no evidence of differences in grade 2+ genitourinary toxicity between concomitant therapies in either the 20- or 32-fraction cohorts. ConclusionGrade 2+ acute adverse events are common. The toxicity profile varied by type of concomitant therapy; the gastrointestinal toxicity rate seemed to be higher in patients receiving gemcitabine.

Development and characterization of a versatile mini-beam collimator for pre-clinical photon beam irradiation.

Interest in spatial fractionation radiotherapy has exponentially increased over the last decade as a significant reduction of healthy tissue toxicity was observed by mini-beam irradiation. Published studies, however, mostly use rigid mini-beam collimators dedicated to their exact experimental arrangement such that changing the setup or testing new mini-beam collimator configurations becomes challenging andexpensive. In this work, a versatile, low-cost mini-beam collimator was designed and manufactured for pre-clinical applications with X-ray beams. The mini-beam collimator enables variability of the full width at half maximum (FWHM), the center-to-center distance (ctc), the peak-to-valley dose ratio (PVDR), and the source-to-collimator distance (SCD). The mini-beam collimator is an in-house development, which was constructed of 10× 40mm2 tungsten or brass plates. These metal plates were combined with 3D-printed plastic plates that can be stacked together in the desired order. A standard X-ray source was used for the dosimetric characterization of four different configurations of the collimator, including a combination of plastic plates of 0.5, 1, or 2mm width, assembled with 1 or 2mm thick metal plates. Irradiations were done at three different SCDs for characterizing the performance of the collimator. For the SCDs closer to the radiation source, the plastic plates were 3D-printed with a dedicated angle to compensate for the X-ray beam divergence, making it possible to study ultra-high dose rates of around 40Gy/s. All dosimetric quantifications were performed using EBT-XD films. Additionally, in vitro studies with H460 cells were carriedout. Characteristic mini-beam dose distributions were obtained with the developed collimator using a conventional X-ray source. With the exchangeable 3D-printed plates, FWHM and ctc from 0.52 to 2.11mm, and from 1.77 to 4.61mm were achieved, with uncertainties ranging from 0.01% to 8.98%, respectively. The FWHM and ctc obtained with the EBT-XD films are in agreement with the design of each mini-beam collimator configuration. For dose rates in the order of several Gy/min, the highest PVDR of 10.09 ± 1.08 was achieved with a collimator configuration of 0.5mm thick plastic plates and 2mm thick metal plates. Exchanging the tungsten plates with the lower-density metal brass reduced the PVDR by approximately 50%. Also, increasing the dose rate to ultra-high dose rates was feasible with the mini-beam collimator, where a PVDR of 24.26 ± 2.10 was achieved. Finally, it was possible to deliver and quantify mini-beam dose distribution patterns in vitro. With the developed collimator, we achieved various mini-beam dose distributions that can be adjusted according to the needs of the user in regards to FWHM, ctc, PVDR and SCD, while accounting for beam divergence. Therefore, the designed mini-beam collimator may enable low-cost and versatile pre-clinical research on mini-beamirradiation.

Abstract #1393024: A Rare Case of ACTH-Producing Pituitary Carcinoma in Nelson’s Syndrome

A 55-year-old male with Nelson's Syndrome was originally diagnosed with Cushing’s disease 5 years prior after the identification of a 15 x 13 mm pituitary adenoma and ACTH 174 pg/mL. He had typical symptoms including proximal weakness, easy bruising, abdominal striae, weight gain, and atraumatic vertebral fractures. Pathology following TSRPT at that time showed an ACTH-producing tumor with MIB1 index 20%. He had initial improvement of his Cushing's stigmata but one year later developed proximal muscle weakness, hypokalemia requiring replacement, worsening diabetes, and weight gain. Repeat MRI was negative for new/recurring lesion. One and a half years after initial TSRPT, he started on ketoconazole 400 mg three times daily and cabergoline 1 mg TID as a repeat MRI showed a recurring pituitary lesion measuring 13 x 14 x 9 mm with corresponding ACTH level 159 pg/mL. He underwent radiotherapy with 20 Gy in one fraction and two months later underwent bilateral adrenalectomy with cessation of ketoconazole and cabergoline. Two years later, his ACTH level increased to 1,342 pg/mL and he underwent another fraction of radiotherapy of 20 Gy. A repeat MRI showed a decrease in the size of pituitary lesion. However, eight months later, his ACTH levels peaked at 45,510 pg/mL and he underwent a second TSRPT and a stereotactic radiosurgery series of 54 Gy in 30 fractions over three months. Surgical pathology showed a low-grade neuroendocrine neoplasm without any mitotic figures and an MIB-1 index 15% Two months following the SRS series, his ACTH levels peaked at 188,567 pg/mL. He presented to the ED for abdominal pain and CT Abdomen showed possible metastatic lesions in the liver, one of which was subsequently biopsied and positive for pituitary carcinoma. He is currently undergoing capecitabine chemotherapy and an SRS series to the liver with plans to add temozolomide upon completion of the SRS. A key learning point is to suspect metastatic disease with drastic ACTH increases. PET scan imaging is recommended in a patient with rapid or significant increase in ACTH level with or without progression of a lesion centrally. Additionally, although the original histology did not show carcinoma, the elevated MIB-1 index should raise the suspicion for malignant possibility and therefore, increased surveillance. Functional pituitary carcinoma has the twofold task of treating the excess hormone production and controlling the spread of metastatic disease. Given the rarity of this type of cancer, a multi-disciplinary approach best serves the patient including endocrinology, oncology, (neurological) surgery, and radiation oncology. More data and studies are needed to definitively assess efficacy of chemotherapeutics including capecitabine and temozolomide for these types of tumors.

Outcomes of hypofractionation for early-stage glottic carcinoma.

Our goal is to evaluate hypofractionation in early-stage glottic carcinoma of a single center in line with randomized trials. Between June 2016 and January 2021, 33 early glottic carcinoma patients treated with IMRT (intensity-modulated radiotherapy) in the Radiation Oncology Department were analyzed. Descriptive statistics and survival analysis were applied. Survival analysis and curves were done via the Kaplan-Meier method. Survival curves were analyzed due to the T stage. Log-rank test was used for the analysis of T stage survival curves. Twenty (60.1%) patients were T1 whereas six (18.2%) and seven (21.2%) were Tis. 56.25 Gy, 63 Gy, and 65.25 Gy were delivered to the patients with Tis, T1, and T2, respectively. All groups were treated with 2.25 Gy per fraction. T2 stage had lesser DFS (disease-free survival) compared to Tis and T1 stage and it was statistically significant (P = 0.035). Hypofractionation with 2.25 Gy per fraction may be standard for early glottic carcinoma with similar results compared to microsurgery and conventional fractionation radiotherapy.

Fibrous dysplasia mimicking skeletal involvement in Lymphoma.

We present the case of a 19-year-old male with nodular sclerosing classical Hodgkin lymphoma, who had an incidental finding of fibrous dysplasia of the bone. This caused 18-F-fluorodeoxyglucose (18-F-FDG) avidity on positron emission tomography-computed tomography (PET-CT) scan leading to incorrect initial staging. This patient presented with a 4-month history of enlarging cervical lymph nodes, without B symptoms. He had no prior medical history. His initial diagnostic 18-F-FDG PET-CT demonstrated moderately avid left cervical and superior mediastinal lymphadenopathy and two partially sclerotic, partially lytic bone lesions. These were moderately avid, one in the proximal right humerus (SUV 6.1) and the second in the posterior distal humerus (SUV 8.1). There was no other avid lymphadenopathy (see Figure 1). He had a magnetic resonance imaging (MRI) scan and an orthopaedic opinion was sought; the lesions were felt likely to be skeletal involvement of his Hodgkin lymphoma. Therefore, his staging was 4A, with an international prognostic score of 2, and treatment was commenced following a RATHL approach starting with ABVD chemotherapy. The interim PET-CT scan following cycle 2 of ABVD demonstrated a complete metabolic response within the cervical and mediastinal lymphadenopathy, but persistent avidity within the right humeral shaft lesions which were essentially unchanged in size with a mild reduction in 18-F-FDG avidity (see Figure 2). He did report some aching in the right arm. This discrepant radiological response prompted further investigation. The bone lesions were evaluated with a CT and MRI scan, and his case was discussed again with the orthopaedic team who at that point felt the radiological appearances were suggestive of fibrous dysplasia. He had a biopsy of the bone lesion and histological examination confirmed the diagnosis of fibrous dysplasia with no evidence of Hodgkin lymphoma or other primary bone malignancy. The patient's staging was therefore amended to stage 2A early favourable (ESR 4 mm/h at diagnosis), and treatment was changed to combined modality chemo-radiotherapy. He had already completed 2 cycles of ABVD and so proceeded to receive 20 Gy in 10 fractions of consolidation radiotherapy. His end-of-treatment PET-CT scan is awaited but clinically he remains in complete remission. He will require surveillance imaging of the bony lesions. Fibrous dysplasia of the bone (FD) is an uncommon genetic disorder causing benign fibroosseous bone lesions. It is diagnosed predominantly in children and young adults. It has a wide spectrum of presentations but is often asymptomatic and can be found incidentally. Malignant transformation can rarely occur. Radiological features can vary from classical ground glass lesions to cystic or sclerotic lesions. FD lesions can show a large variability in 18-F-FDG uptake on PET-CT, and avidity in FD may change over time. There are several other case reports of FD mimicking skeletal involvement in lymphoma. In conclusion, discrepant responses to treatment should be further investigated. Careful interpretation of 18-F-FDG avid bone lesions is required to avoid misdiagnosis or overtreatment. FD should be considered within the differential diagnosis, especially in younger patients. Orla Gildea: conception, literature review and writing—original draft preparation Claire Burney: supervision and writing—review and editing Julian Kabala: resources, visualisation The authors declare no conflict of interest. Self. N/A. Uploaded. N/A. Not applicable to this article as no new data were created or analysed.

Prospective Evaluation of Limited-Stage Small Cell Lung Cancer Radiotherapy Fractionation Regimen Usage and Acute Toxicity in a Large Statewide Quality Collaborative

National guidelines on limited stage small cell lung cancer (LS-SCLC) treatment give preference to a hyperfractionated regimen of 45 Gy/30 fractions delivered twice-daily, however use of this regimen is uncommon compared to once-daily regimens. The purpose of this study was to characterize the LS-SCLC fractionation regimens used throughout a statewide collaborative, analyze patient and treatment factors associated with these regimens, and describe real-world acute toxicity profiles of once- and twice-daily RT regimens. Demographic, clinical, and treatment data along with physician toxicity and patient-reported outcomes were prospectively collected by 29 institutions within the [quality consortium] between 2012 and 2021 for patients with LS-SCLC. We modeled the influence of RT fractionation and other patient-level variables clustered by treatment site on the odds of a treatment break specifically due to toxicity with multilevel logistic regression. Common Terminology Criteria for Adverse Events, version 4.0, incident Grade 2 or worse toxicity was longitudinally compared between regimens. There were 78 patients (15.6% overall) treated with twice-daily RT and 421 patients treated with once-daily RT. Patients receiving twice-daily RT were more likely to be married/living with someone (65% vs 51%, p=0.019) and to have no major comorbidities (24% vs 10%, p=0.017). Once-daily RT fractionation toxicity peaked during RT and twice-daily toxicity peaked within 1 month after RT. After stratifying by treatment site and adjusting for patient-level variables, once-daily treated patients had a 4.11 (95% confidence interval 1.31-12.87) higher odds of treatment break specifically due to toxicity than twice-daily treated patients. Hyperfractionation for LS-SCLC remains infrequently prescribed despite the lack of evidence demonstrating superior efficacy or lower toxicity of once-daily RT. With peak acute toxicity after RT and lower likelihood of a treatment break with twice-daily fractionation in real-word practice, providers may start utilizing hyperfractionated RT more frequently.

30 Gy in 4 Stereotactic Body Radiotherapy Fractions for Complex Spinal Metastases: Mature Outcomes Supporting This Novel Regimen.

We designed a 30 Gy in 4 fractions stereotactic body radiotherapy protocol, as an alternative option to our standard 2-fraction approach, for primarily large volume, multilevel, or previously radiated spinal metastases. We report imaging-based outcomes of this novel fractionation scheme. The institutional database was reviewed to identify all patients who underwent 30 Gy/4 fractions from 2010 to 2021. Primary outcomes were magnetic resonance-based vertebral compression fracture (VCF) and local failure per treated vertebral segment. We reviewed 245 treated segments in 116 patients. The median age was 64 years (range, 24-90). The median number of consecutive segments within the treatment volume was 2 (range, 1-6), and the clinical target volume (CTV) was 126.2 cc (range, 10.4-863.5). Fifty-four percent had received at least 1 previous course of radiotherapy, and 31% had previous spine surgery at the treated segment. The baseline Spinal Instability Neoplastic Score was stable, potentially unstable, and unstable for 41.6%, 51.8%, and 6.5% of segments, respectively. The cumulative incidence of local failure was 10.7% (95% CI 7.1-15.2) at 1 year and 16% (95% CI 11.5-21.2) at 2 years. The cumulative incidence of VCF was 7.3% (95% CI 4.4-11.2) at 1 year and 11.2% (95% CI 7.5-15.8) at 2 years. On multivariate analysis, age ≥68 years ( P = .038), CTV volume ≥72 cc ( P = .021), and no previous surgery ( P = .021) predicted an increased risk of VCF. The risk of VCF for CTV volumes <72 cc/≥72 cc was 1.8%/14.6% at 2 years. No case of radiation-induced myelopathy was observed. Five percent of patients developed plexopathy. 30 Gy in 4 fractions was safe and efficacious despite the population being at increased risk of toxicity. The lower risk of VCF in previously stabilized segments highlights the potential for a multimodal treatment approach for complex metastases, especially for those with a CTV volume of ≥72 cc.

Anti-PD-1 immunotherapy with dose-adjusted ultra-hypofractionated re-irradiation in patients with locoregionally recurrent head and neck cancer

IntroductionPatients with recurrent inoperable squamous-cell head-neck cancer (HNSCC) after chemo-radiotherapy have an ominous prognosis. Re-irradiation can be applied with some efficacy and high toxicity rates. Anti-PD-1 immunotherapy is effective in 25% of patients. Immunogenic death produced by large radiotherapy (RT) fractions may enhance immune response.Materials and methodsWe evaluated the efficacy and tolerance of ultra-hypofractionated immuno-radiotherapy (uhypo-IRT) in 17 patients with recurrent HNSCC and 1 with melanoma. Four of HNSCC patients also had oligometastatic disease. Using a dose/time/toxicity-based algorithm, 7, 7 and 4 patients received 1, 2 and 3 fractions of 8 Gy to the tumor, respectively. Nivolumab anti-PD-1 immunotherapy was administered concurrently with RT and continued for 24 cycles, or until disease progression or manifestation of immune-related adverse events (irAEs).ResultsEarly and late RT toxicities were minimal. Three patients developed irAEs (16%). After the 12th cycle, 7/17 (41.2%) and 5/17 (29.4%) patients with HNSCC showed complete (CR) and partial response (PR), respectively. CR was also achieved in the melanoma patient. The objective response rates in HNSCC patients were 57%, 86% and 66%, after 1, 2 and 3 fractions, respectively (overall response rate 70.6%). Most responders experienced an increase in peripheral lymphocyte counts. The median time to progression was 10 months. The 3-year projected locoregional progression-free survival was 35%, while the 3-year disease-specific overall survival was 50%.ConclusionsAnti-PD1 uhypo-IRT is safe and effective in patients with recurrent HNSCC. The high objective response rates and the long survival without evidence of disease support further trials on uhypo-IRT.

Oral Sequelae after Head and Neck Radiotherapy: RCT Comparing 3D-Printed Tissue Retraction Devices with Conventional Dental Splints.

To evaluate oral sequelae after head and neck radiotherapy (RT) when using two different types of intraoral appliances. Thermoplastic dental splints (active control) protect against backscattered radiation from dental structures. Semi-individualized, 3D-printed tissue retraction devices (TRDs, study group) additionally spare healthy tissue from irradiation. A total of 29 patients with head and neck cancer were enrolled in a randomized controlled pilot trial and allocated to receive TRDs (n = 15) or conventional splints (n = 14). Saliva quality and quantity (Saliva-Check, GC), taste perception (Taste strips, Burghart-Messtechnik), and oral disability (JFLS-8, OHIP-14, maximum mouth opening) were recorded before and 3 months after RT start. Radiotherapy target volume, modality, total dose, fractionation, and imaging guidance were case-dependent. To evaluate intra-group developments between baseline and follow-up, nonparametric Wilcoxon tests were performed. Mann-Whitney-U tests were applied for inter-group comparisons. At follow-up, taste perception was unimpaired (median difference in the total score; TRDs: 0, control: 0). No significant changes were found regarding oral disability. Saliva quantity (stimulated flow) was significantly reduced with conventional splints (median -4 mL, p = 0.016), while it decreased insignificantly with TRDs (median -2 mL, p = 0.07). Follow-up was attended by 9/15 study group participants (control 13/14). Inter-group comparisons showed no significant differences but a tendency towards a better outcome for disability and saliva quality in the intervention group. Due to the small cohort size and the heterogeneity of the sample, the results must be interpreted with reservation. Further research must confirm the positive trends of TRD application. Negative side-effects of TRD application seem improbable.

Effect of Stereotactic Body Radiation Therapy on Diverse Organ Lesions in Advanced Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

The combination of stereotactic body radiation therapy (SBRT) and immune checkpoint inhibitors (ICIs) is actively being explored in advanced non-small-cell lung cancer (NSCLC) patients. However, little is known about the optimal fractionation and radiotherapy target lesions in this scenario. This study investigated the effect of SBRT on diverse organ lesions and radiotherapy dose fractionation regimens on the prognosis of advanced NSCLC patients receiving ICIs. The medical records of advanced NSCLC patients consecutively treated with ICIs and SBRT were retrospectively reviewed at our institution from Dec. 2015 to Sep. 2021. Patients were grouped according to radiation sites. Progression-free survival (PFS) and overall survival (OS) were recorded using the Kaplan-Meier method and compared between different treatment groups using the log-rank (Mantel-Cox) test. A total of 124 advanced NSCLC patients receiving ICIs combined with SBRT were identified in this study. Radiation sites included lung lesions (lung group, n=43), bone metastases (bone group, n=24), and brain metastases (brain group, n=57). Compared with the brain group, the mean PFS (mPFS) in the lung group was significantly prolonged by 13.3 months (8.5 months vs. 21.8 months, HR=0.51, 95%CI: 0.28-0.92, P=0.0195), and that in the bone group prolonged by 9.5 months with a 43% reduction in the risk of disease progression (8.5 months vs. 18.0 months, HR=0.57, 95%CI: 0.29-1.13, P=0.1095). The mPFS in the lung group was prolonged by 3.8 months as compared with that in the bone group. The mean OS (mOS) in the lung and bone groups was longer than that of the brain group, and the risk of death decreased by up to 60% in the lung and bone groups as compared with that of the brain group. When SBRT was concurrently given with ICIs, the mPFS in the lung and brain groups were significantly longer than that of the bone group (29.6 months vs. 16.5 months vs. 12.1 months). When SBRT with 8-12 Gy per fraction was combined with ICIs, the mPFS in the lung group was significantly prolonged as compared with that of the bone and brain groups (25.4 months vs. 15.2 months vs. 12.0 months). Among patients receiving SBRT on lung lesions and brain metastases, the mPFS in the concurrent group was longer than that of the SBRT→ICIs group (29.6 months vs. 11.4 months, P=0.0003 and 12.1 months vs. 8.9 months, P=0.2559). Among patients receiving SBRT with <8 Gy and 8-12 Gy per fraction, the mPFS in the concurrent group was also longer than that of the SBRT→ICIs group (20.1 months vs. 5.3 months, P=0.0033 and 24.0 months vs. 13.4 months, P=0.1311). The disease control rates of the lung, bone, and brain groups were 90.7%, 83.3%, and 70.1%, respectively. The study demonstrated that the addition of SBRT on lung lesions versus bone and brain metastases to ICIs improved the prognosis in advanced NSCLC patients. This improvement was related to the sequence of radiotherapy combined with ICIs and the radiotherapy fractionation regimens. Dose fractionation regimens of 8-12 Gy per fraction and lung lesions as radiotherapy targets might be the appropriate choice for advanced NSCLC patients receiving ICIs combined with SBRT.