Gy Fractions Research Articles

Near-maximum rib dose is the most relevant risk factor for ipsilateral spontaneous rib fracture: adosimetric analysis of breast cancer patients after radiotherapy.

Spontaneous rib fracture (SRF) is acommon late complication in treated breast cancer patients. This study evaluated the incidence and risk factors of ipsilateral SRF after radiotherapy (RT) in breast cancer patients. In addition, we identified dosimetric parameters that were significantly associated with ipsilateral SRF. We retrospectively reviewed 2204patients with breast cancer who underwent RT between 2014 and 2016, and were followed up with bone scans. We evaluated clinical risk factors for ipsilateral SRF. Dose-volume histogram analysis was also performed for patients (n = 538) whose dosimetric data were available. All ipsilateral ribs were manually delineated, and dosimetric parameters of the ribs were converted into the equivalent dose in 2 Gy fractions (EQD2). Most of the patients with SRF (87.3%) were asymptomatic, and the remaining symptomatic patients complained of mild tenderness or chest wall discomfort; these symptoms all resolved within 6months without any treatment. Ipsilateral SRF occurred in 14.5% of patients 3years after RT. The median time to develop ipsilateral SRF was 15months. In dosimetric analysis, near-maximum rib dose (D2cc) best predicted ipsilateral SRF. The cut-off value of D2cc was EQD2 52 Gy, as determined by receiver operating characteristic analysis. In multivariate analysis including dosimetric variables, D2cc EQD2 ≥ 52 Gy was the only significant risk factor for ipsilateral SRF. Our data demonstrated that near-maximum rib dose was the best dosimetric parameter to predict ipsilateral SRF in RT-treated breast cancer patients. In addition, our results suggest that patients who received RT with exceeding rib dose cut-off value and had ipsilateral SRF on bone scan be recommended routine follow-up without additional imaging tests.

Tumor size before image-guided brachytherapy is an important factor of local control after radiotherapy for cervical squamous cell carcinoma: analysis in cases using central shielding.

We analyzed the local control (LC) of cervical squamous cell carcinoma treated by computed tomography (CT)-based image-guided brachytherapy (IGBT) using central shielding (CS). We also examined the value of tumor diameter before brachytherapy (BT) as a factor of LC. In total, 97 patients were analyzed between April 2016 and March 2020. Whole-pelvic (WP) radiotherapy (RT) with CS was performed, and the total pelvic sidewall dose was 50 or 50.4 Gy; IGBT was delivered in 3–4 fractions. The total dose was calculated as the biologically equivalent dose in 2 Gy fractions, and distribution was modified manually by graphical optimization. The median follow-up period was 31.8 months (6.3–63.2 months). The 1- and 2-year LC rates were 89% and 87%, respectively. The hazard ratio was 10.11 (95% confidence interval: 1.48–68.99) for local recurrence in those with a horizontal tumor diameter ≥ 4 cm compared to those with < 4 cm before BT. In CT-based IGBT for squamous cell carcinoma, favorable LC can be obtained in patients with a tumor diameter < 4 cm before BT. However, if the tumor diameter is ≥ 4 cm, different treatment strategies such as employing interstitial-BT for dose escalation may be necessary.

Radiation Therapy for Relapsed or Refractory Diffuse Large B-Cell Lymphoma: What Is the Right Regimen for Palliation?

PurposeTo report objective response rates (ORR), time to local failure (TTLF), and overall survival (OS) among patients with relapsed or refractory diffuse large B-cell lymphoma after salvage- or palliative-intent radiation therapy (RT) and to investigate whether outcomes differed with conventional versus hypofractionated (≥2.5 Gy/fraction) RT. Methods and MaterialsA single-institution observational cohort study was performed for patients who completed a course of RT for relapsed or refractory diffuse large B-cell lymphoma between January 1, 2008, and April 1, 2020. Predictors of ORR, TTLF, and OS were calculated using univariable and multivariable regression models. The Kaplan-Meier method was used to estimate TTLF and OS, and log-rank analysis was used to compare outcomes. Equivalent dose in 2 Gy fractions (EQD2) was calculated using an α/β of 10. ResultsOne-hundred and sixty-nine patients were treated with 205 RT courses (73 [36%] salvage, 132 [64%] palliative), and hypofractionated RT was used in 100 RT courses (49%). Median RT dose was 30 Gy (range, 8-60 Gy). ORR was 60% for the total cohort (53% and 69% for palliative and salvage cohorts, respectively). Over a median follow-up time of 4 months, median OS in all patients was 5 months (3 and 22 months for palliative and salvage cohorts, respectively). No statistically significant differences in ORR, TTLF, and OS were observed with hypofractionation compared with conventional fractionation. EQD2 ≥35 Gy was associated with improved ORR (odds ratio, 3.79 [1.19-12.03]; P = .024) and prolonged TTLF (0.39 [0.18-0.87]; P = .022), while double-hit receptor status (8.18 [1.08-62.05]; P = .042), cell of origin (3.87 [1.17-8.74]; P = .0012), and bulky disease (≥7.5 cm; 2.12 [1.18-3.81]; P = .012) were associated with inferior TTLF. In the palliative-only cohort, a low-dose regimen of 8 Gy in 2 fractions was associated with similar ORR compared with other fractionation schema but trended towards inferior TTLF (P = .36). ConclusionsHypofractionation is not associated with differences in disease outcomes for patients with relapsed or refractory diffuse large B-cell lymphoma, while higher RT dose (EQD2 ≥35 Gy) may improve ORR and TTLF. Future work is warranted to elucidate the ideal dose and fractionation schema for such patients who will likely also undergo novel systemic agents and cellular therapies.

Trastuzumab emtansine increases the risk of stereotactic radiosurgery-induced radionecrosis in HER2 + breast cancer.

In this study, we investigate factors associated with radionecrosis (RN) in HER2 + (human epidermal growth factor receptor 2) patients with brain metastases (BrM) treated with stereotactic radiosurgery (SRS). Patients with HER2 + breast cancer BrM treated with SRS (2010-2020) were identified from an institutional database. The incidence of RN was determined per treated BrM according to serial imaging and/or histology. Factors associated with RN such as age, RT dose, BrM volume, and initiation of Trastuzumab Emtansine (T-DM1) were investigated with univariate and multivariable analyses (MVA). 67 HER2 + patients with 223 BrM were identified. 21 patients (31.3%) were treated with T-DM1 post-SRS, including 14 patients (20.9%) who received T-DM1 within 12months of SRS. The median follow-up was 15.6 (interquartile range (IQR) 5.4-35.3) months. The overall probability of RN post-SRS was 21.6% (95% confidence interval (CI) 2.7-10.7), and the 1 and 2year risk was 6.7% (95% CI 2.7-10.7) and 15.2% (95% CI 9.2-21.3). MVA identified T-DM1 treatment post-SRS (hazard ratio (HR) 2.5, 95% CI 1.2-5.3, p = 0.02) and equivalent dose in 2Gy fractions (EQD2) > 90 Gy2 (HR 2.4, 95% CI 1.1-5.1, p = 0.02) as predictors of RN. Patients treated with T-DM1 and SRS had a 29.9% (95% CI 15.3-44.6%) probability of RN, with a 25.2% (95% CI 12.8-37.6%) risk at 1- and 2years post-T-DM1. The majority of RN were symptomatic (71%), with a median time to RN of 4.8months. T-DM1 exposure post-SRS was associated with a higher risk of RN among patients with HER2 + BrM.

The association of vagina equivalent dose in 2Gy fraction (EQD2) to late vagina toxicity in patients of cervical cancer treated with WPRT plus IGABT

To evaluate the associations of vaginal dose parameters and incidence of vaginal stenosis in patients with cervical cancer treated with image-guided brachytherapy (IGBT). Fifty-four patients with cervical cancer treated with IGBT were included. The vagina contouring was done on previously treated CT images and the vaginal dose points were marked. The cumulative dose in EQD2 from EBRT and IGBT was calculated for both aspects and the vaginal toxicity was evaluated. At median follow-up time of 18.5 months, grade 2 or higher vaginal stenosis was observed in 24% of patients. On univariate analysis, parameters that were associated with ≥ grade 2 vaginal stenosis were age, mean dose of lateral 5 mm vagina, dose at PIBS-2 cm, mid vaginal D0 .03cc, mid vagina D1cc, lower vagina D0.03cc, lower vagina D0.1cc, lower vagina D1cc and lower vagina D2cc. On multivariate analysis, the significant parameters were age > 68.5 years old (P = 0.038), mean dose of lateral 5-mm (P = 0.034), and dose at PIBS-2 cm (P = 0.042). Age > 68.5 years old, mean dose of lateral 5 mm vagina and dose at PIBS-2 cm were associated with grade 2 or higher vaginal stenosis.

Abstract 3152: IFN-gamma stimulated cryopreserved mesenchymal stromal cells for treatment of radiation induced xerostomia

Abstract Purpose/Objectives: There is a critical need for a treatment that will safely and effectively alleviate radiation-induced xerostomia (RIX). Head and neck radiation results in hyposalivation and altered sialochemistry which patients experience as xerostomia. We performed a preclinical and a pilot clinical study to determine if IFN-ɣ stimulated marrow-derived mesenchymal stromal cells (MSC(M)) from HNC patients could function as a source of autologous cells for the treatment of RIX and as a tool in preclinical murine studies of RIX. Materials/Methods: Bone marrow aspirates from HNC patients previously treated with chemoradiation were obtained (IRB #2019-0497, NCT 04007081). MSC(M)s were isolated from bone marrow. MSC(M) were expanded in culture, surface marker expression was confirmed via flow cytometry, stimulated with IFN-ɣ, and cryopreserved. Thawed MSC(M)s were profiled to evaluate their functionality after cryorecovery. Cells were tested for their ability to stimulate salivary production in a murine model of RIX by injecting 1x106 cells into the submandibular gland (SMG) one week after a single 15 Gy fraction of radiation. Efficacy was evaluated by saliva production and histology. Results: MSC(M)s from six patients were expanded to &amp;gt;20x106 cells (median 15.5, range of 8-20 days). Post-thaw cultures demonstrated robust growth, with a median doubling time of 3.1 days. Cultured cells showed an MSC(M) phenotype, positive for CD73, CD90, and CD105 and negative for CD14, CD20, CD34, or CD45. IFN-ɣ stimulated MSC(M)s had immunomodulatory potential based on increased expression of IDO, ICAM-1, PD-L1, MHC I and MHC II expression compared with non-stimulated MSC(M)s (391%, 263%, 114%, 70% and 196% percent increase respectively). In a murine model of RIX, radiation resulted in structural changes to the gland as evidenced by increased fibrosis, decreased acinar size, and immune cell infiltration. Injection of MSC(M)s to the SMG following radiation resulted in improved saliva production, a reduction in fibrosis, and an increase in the size and density of acini within the tissue compared to control. Conclusions: These data strongly support the feasibility of a first-in-human clinical trial of autologous IFN-ɣ stimulated MSC(M)s to treat RIX and the potential of using human-derived MSC(M)s in future murine studies of RIX. Citation Format: Cristina Paz, Grace Blitzer, Annemarie Glassey, Kwangok P. Nickel, Jayeeta Giri, Andrea Pennati, Daniel Robbins, Tadeas Lunga, Susan Thibeault, Jacques Galipeau, Randall Kimple. IFN-gamma stimulated cryopreserved mesenchymal stromal cells for treatment of radiation induced xerostomia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3152.

Results of a prospective randomized trial on long-term effectiveness of protons and carbon ions in prostate cancer: LEM I and α/β = 2 Gy overestimates the RBE

AimTo analyze the long-term effectiveness of carbon ions relative to protons in the prospective randomized controlled ion prostate irradiation (IPI) trial. MethodsEffectiveness via PSA assessment in a randomized study on prostate irradiation with 20x3.3 Gy(RBE) protons versus carbon ions was analyzed in 92 patients. Proton RBE was based on a fixed RBE of 1.1 while the local effect model (LEM) I and an α/β = 2 Gy was used for carbon ions. The dose in the prostate was recalculated based on the delivered treatment plan using LEM I and LEM IV and different α/β values. ResultsFive-year overall and progression free survival was 98% and 85% with protons and 91% and 50% with carbon ions, respectively, with the latter being unexpectedly low compared to Japanese carbon ion data and rather corresponding to a photon dose <72 Gy in 2 Gy fractions. According to LEM I and the applied α/β-value of 2 Gy, the applied carbon ion dose in 2 Gy(RBE) fractions (EQD2) was 87.46 Gy(RBE). Recalculations confirmed a strong dependence of RBE-weighted dose on the α/β ratio as well as on the RBE-model. ConclusionThe data demonstrate a significant lower effectiveness of the calculated RBE-weighted dose in the carbon ion as compared to the proton arm. LEM I and an α/β = 2 Gy overestimates the RBE for carbon ions in prostate cancer treatment. Adjusting the biological dose calculation by using LEM I with α/β = 4 Gy could be a pragmatic way to safely escalate dose in carbon ion radiotherapy for prostate cancer.

DIPG-33. Treating Pediatric Diffuse Intrinsic Pontine Glioma with Brain Radiation and Temozolomide: A Case Report

Abstract Diffuse Intrinsic Pontine Gliomas (DIPG) is a rare and highly aggressive central nervous system tumour arising from glial cells which occur mostly in children. It remains a potentially deadly cancer despite treatment, with the highest mortality rate, in which most children die within 1-year of diagnosis. Radiation therapy might improve the clinical symptoms, but the results are temporary, with tumor progression typically occurring months post radiation, whereas chemotherapy remains controversial. Here we present a case report of a patient with DIPG Indonesia and how we diagnose and currently treat it. An eight years-old boy presented with decrease level of consciousness with headache, limb weakness, slurred speech, double vision, hemifacial weakness, paraplegia, and disequilibrium which worsened two weeks prior to admission. He was initially noted to have a medially inverted left eye two months prior to admission. On physical examination, there was a N.VI and N.VII palsy, hyperreflexia, paraplegia, and nystagmus. Head MRI demonstrated a solid with minimal enhancement after contrast administration in the left pons region extending into mesencephalon with cystic component and flat floor of fourth ventricle sign, causing hydrocephalus, suggestive diffuse intrinsic pontine glioma. He was given fractionated focal intensity modulated radiation therapy (IMRT) to the tumor along with 5 mm margins with a total dose of 54 Gy. 1.8 Gy fractions, given once daily for 5 days per week over a period of 6 weeks. Supportive care in the form of corticosteroids is used to treat the peri-tumoral edema. There was a short period of motoric improvement. But then the disease progressed with the latest head CT showed hydrocephalus formation with increased size of mass. He is treated with chemotherapy using Temozolomide, and currently alive after 3 months post diagnosis. Keywords: childhood brain tumour, Diffuse Intrinsic Pontine Glioma, radiation therapy

External beam and stereotactic radiation in the treatment of fibrolamellar carcinoma.

e16137 Background: Fibrolamellar Carcinoma (FLC) is an extremely rare (&lt; 50 cases/year US), distinct type of primary liver cancer, unrelated to hepatocellular carcinoma (HCC), affecting healthy children and young adults that often presents at an advanced stage. Surgery is the only known cure, but is only possible in half of patients, and, even with surgery, there is an 80% relapse rate. Loco-regional therapies can make surgery possible or replace surgery, allow systemic therapy time to work, and prolong life. However because of the paucity of data and the common misunderstanding of treating FLC as a “variant of hepatocellular carcinoma (HCC)” it is often assumed to be radio-resistant. For example, the 2021 NCCN Guidelines give no specific recommendations for radiation in FLC but classifying FLC as a “variant of HCC'' recommend 25 1.8Gy fractions (45Gy) with a boost to 50-60 Gy for external beam radiation(EBRT) and 3-5 10Gy fractions for stereotactic body radiation (SBRT). In their HCC reviews, the New England Journal of Medicine (2020), ASCO (2019), and the Fibrolamellar Cancer Summit (2017) do not discuss radiation. This is the largest collection of FLC patients treated with radiation in the literature to date and will hopefully inform clinicians of the option to use radiotherapy in this difficult to treat cancer. Methods: We reviewed the literature for cases of FLC treated with radiation after 2000. With IRB approval, (ORA#19071603), we collected data on all Rush FLC patients treated with radiation. Descriptive statistics were used to characterize this group of patients. Results: We found 29 instances of EBRT or SBRT treating FLC: 3 case reports, 21 of our patients (two had multiple (2 and 4) distinct treatments). Of these 24 (13F/10M/1 Unknown), median age at diagnosis/start of treatment 17(11-40)/23(13-45) underwent radiation with a median dose of 36 Gy (20-50). Ten of 27 were considered “palliative” treatments. High fraction therapy (&gt; 10 fractions) was used 9 times while low fraction therapy (≤ 10 fractions) 16. Biological Equivalent Dose median was 0.36108(0.2008-0.505). Six patients were treated concurrently with nivolumab. Mean prior systemic therapies was 2.6 (0-10) and 5 patients received prior radiation. Fourteen patients underwent SBRT, 10 conventional, 2 IMRT, and 2 unknown. Best response by RECIST 1.1 of the 27 instances with outcome data, was 21 CR, 2 PR, 2 PD, and 2 SD, for a objective response rate (CR + PR) of 85% and a cancer control rate (CR + PR + SD) of 93% at a median follow up of 13 months. In 18 out of 29 instances (62%), surgery was avoided after radiation. Late recurrence was noted in 2 out of 26 instances (8%). Conclusions: FLC is a rare disease lacking radiation guidelines. Our data strongly suggest radiotherapy can be effective with a variety of doses and strategies. We hope our report will encourage clinicians to consider EMRT/SBRT as part of a multi-modal approach to this difficult to treat cancer.

Anlotinib plus radiotherapy-temozolomide for newly diagnosed glioblastoma: A prospective, multicenter phase II study.

e14020 Background: Concurrent radiotherapy and temozolomide (TMZ) followed by adjuvant TMZ (STUPP regimen) is the standard therapy for newly diagnosed glioblastoma after resection, however, the progression-free survival (PFS) was only about 7 months (m) and the overall survival (OS) was less than 17m. This study aims to assess the efficacy and safety of adding anlotinib, a multitarget tyrosine kinase inhibitor, to the STUPP regimen for newly diagnosed glioblastoma. Methods: This was a prospective, sing-arm, multicenter, phase II study (NCT04119674). Eligible patients (pts) were diagnosed with newly diagnosed GBM and had undergone surgery within 6 weeks before enrollment. Previous exposure to other therapies was not permitted. Other key inclusion criteria included 18 to 75 years old, Karnofsky performance status ≥ 60 %, had at least one measurable lesion according to RANO criteria, and adequate bone marrow, hepatic, and renal functions. All pts received radiotherapy (54̃60 Gy administered as 1.8-2.0 Gy fractions, 5 days per week) for 6 weeks, with concurrent oral TMZ (75 mg/m2 QD) and anlotinib (8 mg QD, d1̃d14 per 3 weeks). After a 28-day treatment break, adjuvant therapy was started with six cycles of TMZ (150–200mg/m2, d1–5/4wks) and eight cycles of anlotinib (10 mg QD, d1–14/3wks) ，and followed by anlotinib monotherapy until disease progression or intolerable toxicities. The primary endpoint was progression-free survival (PFS). The adverse events (AEs) were recorded according to CTCAE 5.0. Results: From January 2019 to February 2021, 33 pts (17 males and 16 females) were enrolled from 7 hospitals in China. The median age was 52 (range: 32, 69). At the data cutoff date on January 25th, 2022, all pts had completed the concurrent treatment and 30 pts (90.0%) completed the 6 cycles of adjuvant treatment. The median treatment duration of anlotinib was 16 cycles. At the data cutoff date, 21 patients experienced disease progression and 17 pts were dead. The median PFS was 10.9m (95% CI, 6.6-15.2) and the median OS reached 18.7m (95% CI, 15.0-22.4). The PFS at 1 year was 45.5% and OS at 1 year was 72.7%. No grade 3 or worse AEs were observed during the concurrent phase and anlotinb maintenance phase. Three pts (9.1%) had grade 3 or 4 thrombocytopenia and 1 pts (3.0%) had grade 3 vomiting during the course of adjuvant therapy. Conclusions: This is the first study to explore the feasibility of adding anlotinib to the standard treatment for newly diagnosed GBM. The efficacy was impressive in that the median OS had exceeded 18m and the safety profile was favorable. The positive-controlled study was ongoing. Clinical trial information: NCT04119674.

Interim analysis of neoadjuvant chemoradiotherapy with sequential ipilimumab and nivolumab in rectal cancer (CHINOREC): A prospective randomized, open-label, multicenter, phase II clinical trial.

e15604 Background: Immune checkpoint inhibitors (ICI) do not seem to be effective in solid cancers, which lack an immunogenic priming. Radiotherapy (RT) can induce an immunogenic cell death (ICD) and thereby restore the susceptibility to ICI, especially in microsatellite stable (MSS) cancers. This study evaluates safety, tolerability and feasibility of neoadjuvant chemoradiotherapy (CRT) with concomitant ipilimumab (IPI) and nivolumab (NIVO) in locally advanced rectal cancer (LARC). Here we present the first requisite interim analysis. Methods: This is a prospective, randomized, open-label, multicenter, phase II investigator- initiated trial (IIT). Key eligibility criteria are patients with LARC and the medical need for a neoadjuvant CRT, without metastatic disease that is considered incurable by local therapies. In total 80 patients will be randomized (ratio 30:50) to receive either neoadjuvant CRT alone (50 Gy in 2 Gy fractions over 25 working days + concurrent capecitabine 1650 mg/m2/d PO) or in combination with a single dose of IPI 1 mg/kg IV at day 7, following 3 cycles of NIVO 3 mg/kg IV Q2W, starting on day 14. Patients undergo surgery within 10-12 weeks post CRT. The primary endpoint is safety of neoadjuvant CRT with sequential IPI and NIVO following surgical resection. Surgical complications are graded by the “Clavien-Dindo Classification” v2.0 and treatment-related adverse events (TRAEs) by the Common Terminology Criteria of Adverse Events (CTCAE) v5.0. Interim analyses for the surgical complication “reoperation” will be assessed after every 10th patient in the IPI/NIVO treatment arm. Reoperation numbers are compared to historically known and published ratios. If the observed case numbers are above the calculated upper 95% confidence interval (95% CIup), the study will be terminated. Results: From 06/2020-02/2022, 36 patients have been accrued, of whom 23 were randomized to the CRT+IPI/NIVO arm. Of these, the first 10 patients who underwent successful surgery were used for the present interim analysis. No patient experienced a surgical complication with the need for a reoperation (3Grade IIIb). Any surgical complication occurred in 8 (80%) patients, with the most common being Grade I (70%) and Grade II (50%) events. Conclusions: The addition of sequentially applied IPI and NIVO to neoadjuvant CRT does not increase the number of surgical reoperation rates. The study meets it’s interim analysis criteria to be safe to continue accrual. Clinical trial information: NCT04124601.

Non-injection-site soft tissue sarcoma in cats: outcome following adjuvant radiotherapy.

Biological behaviour and treatment options of non-injection-site soft tissue sarcomas (nFISS) in cats are less well understood than in dogs. The aim of this retrospective study was to assess the outcomes of cats with nFISS following treatment with adjuvant radiotherapy. The medical records of cats with soft tissue sarcomas in locations not associated with, and histology reports not suggestive of, injection-site sarcomas were reviewed. All cats underwent adjuvant radiotherapy, either hypofractionated (32-36 Gy delivered in weekly 8-9 Gy fractions) or conventionally fractionated (48-54 Gy delivered in 16-18 3 Gy fractions) to microscopic disease. In total, 18 cats were included in the study, 17 with extremity nFISS and one with facial nFISS. Nine received radiotherapy after a single surgery and nine after multiple surgeries for recurrent nFISS. Eight cats were treated with a hypofractionated protocol and 10 with a conventionally fractionated protocol. The median follow-up time was 540 days (range 51-3317 days). The tumour recurred in eight (44.4%) cats following adjuvant radiotherapy; it recurred in three (37.5%) cats following a hypofractionated protocol and in five (50%) cats following a conventionally fractionated protocol. The overall median progression-free interval (PFI) for 17/18 cats was 2748 days, while the median PFI for the 7/8 cats with recurrence was 164 days. The recurrence for one cat was reported, but the date was unknown and it was therefore censored from these data. When stratifying based on the protocol, the median PFI for hypofractionated and conventionally fractionated protocols was 164 days and 2748 days, respectively. Statistically, there was no significant difference between the two protocols (P = 0.636). Adjuvant radiotherapy resulted in good long-term tumour control in 12/18 cats with nFISS. Further studies in larger populations are required to assess the significance of radiation dose and fractionation on tumour control and the effect of multiple surgeries prior to initiation of radiotherapy on outcome.

ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children

Background and purposeMyeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children with high-risk acute lymphoblastic leukemia (ALL). TBI practices are heterogeneous and institution-specific. Since TBI is associated with multiple late adverse effects, recommendations may help to standardize practices and improve the outcome versus toxicity ratio for children. Material and methodsThe European Society for Paediatric Oncology (SIOPE) Radiotherapy TBI Working Group together with ESTRO experts conducted a literature search and evaluation regarding myeloablative TBI techniques and toxicities in children. Findings were discussed in bimonthly virtual meetings and consensus recommendations were established. ResultsMyeloablative TBI in HSCT conditioning is mostly performed for high-risk ALL patients or patients with recurring hematologic malignancies. TBI is discouraged in children <3–4 years old because of increased toxicity risk. Publications regarding TBI are mostly retrospective studies with level III–IV evidence. Preferential TBI dose in children is 12–14.4 Gy in 1.6–2 Gy fractions b.i.d. Dose reduction should be considered for the lungs to <8 Gy, for the kidneys to ≤10 Gy, and for the lenses to <12 Gy, for dose rates ≥6 cGy/min. Highly conformal techniques i.e. TomoTherapy and VMAT TBI or Total Marrow (and/or Lymphoid) Irradiation as implemented in several centers, improve dose homogeneity and organ sparing, and should be evaluated in studies. ConclusionsThese ESTRO ACROP SIOPE recommendations provide expert consensus for conventional and highly conformal myeloablative TBI in children, as well as a supporting literature overview of TBI techniques and toxicities.

Cellular Damage in the Target and Out-Of-Field Peripheral Organs during VMAT SBRT Prostate Radiotherapy: An In Vitro Phantom-Based Study.

Simple SummaryNew developments show that patients with prostate cancer can benefit from radiotherapy delivered with a hypo-fractionated regimen. The aim of our study was to investigate the effect of hypo-fractionated stereotactic body radiation therapy (SBRT) of prostate cancer on out-of-field organs. We used a humanoid phantom to irradiate prostate cells in conditions similar to patient therapy, using SBRT planning. Our results show that radiation doses in the location of the intestine and lung resulted in significantly higher radiation doses than the further locations. We observed a high radiotoxic effect in the cells irradiated in the prostate, and a small increase in DNA damage and cell killing in the intestine location. Gene expression analysis revealed significant enrichment of the biological processes related to the radiation response in the prostate. In the lung and thyroid, the enrichment of several gene groups was revealed, however the processes were not clearly related to the response to radiation. Our study provides extensive data on out-of-field safety of prostate SBRT.Hypo-fractionated stereotactic body radiation therapy (SBRT) is an effective treatment for prostate cancer (PCa). Although many studies have investigated the effects of SBRT on the prostate and adjacent organs, little is known about the effects further out-of-field. The aim of this study was to investigate, both in vitro and in a quasi-humanoid phantom, the biological effects (using a dose-scaling approach) of radiation in the out-of-field peripheral organs delivered by 6 MV volumetric modulated arc therapy (VMAT) SBRT in a prostate cancer model. Healthy prostate cells were irradiated in a phantom at locations corresponding to the prostate, intestine, lung, thyroid, and brain. Seven 10 Gy fractions of VMAT SBRT were delivered to the target in a single session without intermission (scaled-up method). Radiochromic films were used to measure the doses. The radiobiological response was assessed by measuring DNA breaks, the cell survival fraction, and differences in gene expression profile. Our results showed a strong, multiparametric radiobiological response of the cells in the prostate. Outside of the radiation field, the highest doses were observed in the intestine and lung. A small increase (not statistically significant) in DNA damage and cell death was observed in the intestines. Several gene groups (cell cycle, DNA replication) were depleted in the lung and thyroid (DNA replication, endocytosis), but further analysis revealed no changes in the relevant biological processes. This study provides extensive evidence of the types and extent of radiobiological responses during VMAT SBRT in a prostate cancer model. Additional research is needed to determine whether the radiobiological effects observed in the peripheral organs are validated in a clinical context.

Long-term outcomes after definitive radiotherapy with modern techniques for unresectable soft tissue sarcoma

IntroductionThe use of definitive radiotherapy (dRT) in unresectable soft-tissue sarcomas (STS) is still controversial and recent data are scarce. We report clinical results of this therapeutic option. MethodsWe retrospectively included STS patients treated between 2009 and 2020, with dRT for unresectable or with a measurable residual disease after R2 surgery. Response rate, local failure (LF), progression-free survival (PFS) and overall survival (OS) were evaluated. Results116 patients with localized/locally advanced STS were treated from 2009 to 2020, with a median age of 71 years (range 18–92). Most tumors were deep-seated (96.6%), grade 2–3 (85.1%), located in the trunk or extremities (74.2%). Helical tomotherapy, volumetric modulated arc therapy, or stereotactic radiotherapy was performed in 39.7%, 19% and 8.6% of patients, respectively. The median equivalent dose in 2 Gy fractions (EQD2) was 60 Gy (IQR 52–65). At first follow-up, 66 (58.9%) and 25 (22%) patients had stable disease and partial response. After a median follow-up of 54.8 months (IQR 40.3–95.4), 3-year LF, PFS and OS were 43.2%, 16.6% and 34%, respectively. Median OS was 21.4 months (95%CI 14–26). The multivariate analysis identified grade 3 and AJCC T3-T4 stage to be associated with both shorter PFS and OS (all p < 0.001). Macroscopically incomplete resection and EQD2 ≥ 64 Gy were associated with better OS (p = 0.016 and p = 0.007). Acute and late severe adverse events occurred in 24 (19.7%) and 5 (4.3%) patients. ConclusionIn unresectable STS patients, definitive modern radiotherapy is a safe and effective treatment yielding long term control in selected patients.

Normal tissue complication probabilities of lung SABR patients from a UK centre and its implication on personalised radiotherapy

Abstract Introduction: This work reports on the normal tissue complication probabilities (NTCP) from a UK cohort of previously treated peripheral lung SABR patients (n = 198) supplementing our previous publication on tumour control probabilities (TCP). Each patient was recalculated for alternative schedules. Materials and Methods: NTCP for 3 (54 Gy), 5 (55 and 60 Gy) and 8 (50 Gy) fraction (#) schemes were calculated with the Lyman Kutcher Burman (LKB) model in the software platform ‘Biosuite’ (Version 12·01) for lung and chest wall. Patients treated with 5 # or 8 # were then recomputed for alternative fractionations and doses (3 # and 5 #, for both 55 Gy and 60 Gy). Results: The mean lung NTCP (NTCPLUNG, for the outcome of radiation pneumonitis) was 2·8% (range 0·6 – 10·6). The mean chest wall NTCP (NTCPCW, for the outcome of rib fracture) was 1·4% (range 0·0–55·9). There were no statistically significant differences observed between male and female, tumour status or fractionation groups except for the NTCPLUNG between 5 # and 3 #. When recalculating NTCP and TCP individually, for 8 # patients, no differences were observed between mean TCP, NTCPLUNG or NTCPCW compared with 3 # or 5 # indicating that fractionation reduction is possible. Parity was observed between the 60 Gy group when recalculated for 55 Gy. For the 60 Gy in 5 # group, the NTCPCW increased significantly when recalculated for 3 #. Conclusion: NTCPs achievable with current UK planning techniques have been presented indicating SABR Consortium compliant centres are likely to have low complication population risks (&lt; 3 %). 5 # schedules could be justified for 8 # patients, thereby reducing the number of treatment visits. Where there is a large overlap of PTV and chest wall, this indicates an NTCP/TCP calculation is required to investigate if fractionation reduction is individually appropriate.

Lung Inflammation Predictors in Combined Immune Checkpoint-Inhibitor and Radiation Therapy-Proof-of-Concept Animal Study.

Purpose: Combined radiotherapy (RT) and immune checkpoint-inhibitor (ICI) therapy can act synergistically to enhance tumor response beyond what either treatment can achieve alone. Alongside the revolutionary impact of ICIs on cancer therapy, life-threatening potential side effects, such as checkpoint-inhibitor-induced (CIP) pneumonitis, remain underreported and unpredictable. In this preclinical study, we hypothesized that routinely collected data such as imaging, blood counts, and blood cytokine levels can be utilized to build a model that predicts lung inflammation associated with combined RT/ICI therapy. Materials and Methods: This proof-of-concept investigational work was performed on Lewis lung carcinoma in a syngeneic murine model. Nineteen mice were used, four as untreated controls and the rest subjected to RT/ICI therapy. Tumors were implanted subcutaneously in both flanks and upon reaching volumes of ~200 mm3 the animals were imaged with both CT and MRI and blood was collected. Quantitative radiomics features were extracted from imaging of both lungs. The animals then received RT to the right flank tumor only with a regimen of three 8 Gy fractions (one fraction per day over 3 days) with PD-1 inhibitor administration delivered intraperitoneally after each daily RT fraction. Tumor volume evolution was followed until tumors reached the maximum size allowed by the Institutional Animal Care and Use Committee (IACUC). The animals were sacrificed, and lung tissues harvested for immunohistochemistry evaluation. Tissue biomarkers of lung inflammation (CD45) were tallied, and binary logistic regression analyses were performed to create models predictive of lung inflammation, incorporating pretreatment CT/MRI radiomics, blood counts, and blood cytokines. Results: The treated animal cohort was dichotomized by the median value of CD45 infiltration in the lungs. Four pretreatment radiomics features (3 CT features and 1 MRI feature) together with pre-treatment neutrophil-to-lymphocyte (NLR) ratio and pre-treatment granulocyte-macrophage colony-stimulating factor (GM-CSF) level correlated with dichotomized CD45 infiltration. Predictive models were created by combining radiomics with NLR and GM-CSF. Receiver operating characteristic (ROC) analyses of two-fold internal cross-validation indicated that the predictive model incorporating MR radiomics had an average area under the curve (AUC) of 0.834, while the model incorporating CT radiomics had an AUC of 0.787. Conclusions: Model building using quantitative imaging data, blood counts, and blood cytokines resulted in lung inflammation prediction models justifying the study hypothesis. The models yielded very-good-to-excellent AUCs of more than 0.78 on internal cross-validation analyses.

Dose Accumulation for Multicourse Gynecological Reirradiation: A Methodological Narrative and Clinical Examples

Reirradiation (re-RT) is a suitable and potentially curative treatment option for in-field locoregional recurrences in gynecological malignancies. Lack of clear guidelines on prescription, dose-response relationship, and clinical outcomes limits its clinical use. This clinical narrative describes the methodology for integration of deformable image registration (DIR) for cumulative dose assessment in the setting of re-RT for gynecologic malignancies, using the tools available within a commercial treatment planning system. Four patients who received re-RT for locoregional recurrence or second cancer within previously irradiated areas for a gynecologic primary were identified. Patient-specific DIR for deformable dose mapping and accumulation was retrospectively performed using intensity-based algorithm provided by the Varian Medical Systems Velocity AI version 4.1. Cumulative equivalent doses in 2 Gy fractions (EQD2) delivered to overlapping targets and organs at risk were generated and compared with the physically summated doses. For both approaches, brachytherapy (BT) component was physically summated in cases where the BT applicator caused significant anatomic distortion. The mean maximum cumulative overlapping target dose was 119.4 Gy10 (range, 84.7 Gy10-144.9 Gy10). The mean cumulative doses received by 2 cm3 of bladder, rectum, sigmoid, and bowel were 114.6 Gy3 (101.1-133.4 Gy3), 98.7 Gy3 (67-136.2 Gy3), 92.5 Gy3 (70.4-107 Gy3), and 89.9 Gy3 (81.1-102.8 Gy3), respectively. In the setting of in-field nodal recurrence, DIR-based dose summation was associated with lower cumulative organs at risk doses than those estimated with physical summation, except in one case with a higher bowel dose. In cases where re-RT was given for local recurrence/second primary, variation in sigmoid doses was observed between the 2 dose-summation strategies across all 3 cases, but it was inconsistent with bladder, rectum, or the bowel. DIR-based dose accumulation can be used to guide re-RT planning and can provide clinically relevant information, especially in cases with nodal recurrences. Registration of BT data sets remain challenging and requires an individualized assessment when applying these algorithms to clinical practice.

Local Control after Locally Ablative, Image-Guided Radiotherapy of Oligometastases Identified by Gallium-68-PSMA-Positron Emission Tomography in Castration-Sensitive Prostate Cancer Patients (OLI-P).

Simple SummaryIn this clinical trial, 63 patients with a total of 89 prostate cancer metastases identified on PSMA-PET were included, none of them undergoing androgen deprivation therapy. We showed that local ablative radiotherapy controls >90% of the metastases, but progression at other sites is common after two years. Local ablative radiotherapy may be an option to at least temporarily avoid systemic therapy in selected patients.Progression of prostate-specific antigen (PSA) values after curative treatment of prostate cancer patients is common. Prostate-specific membrane antigen (PSMA-) PET imaging can identify patients with metachronous oligometastatic disease even at low PSA levels. Metastases-directed local ablative radiotherapy (aRT) has been shown to be a safe treatment option. In this prospective clinical trial, we evaluated local control and the pattern of tumor progression. Between 2014 and 2018, 63 patients received aRT of 89 metastases (MET) (68 lymph node (LN-)MET and 21 bony (OSS-)MET) with one of two radiation treatment schedules: 50 Gy in 2 Gy fractions in 34 MET or 30 Gy in 10 Gy fractions in 55 MET. The mean gross tumor volume and planning target volume were 2.2 and 14.9 mL, respectively. The median follow-up time was 40.7 months. Local progression occurred in seven MET, resulting in a local control rate of 93.5% after three years. Neither treatment schedule, target volume, nor type of lesion was associated with local progression. Regional progression in the proximity to the LN-MET was observed in 19 of 47 patients with at least one LN-MET (actuarial 59.3% free of regional progression after 3 years). In 33 patients (52%), a distant progression was reported. The median time to first tumor-related clinical event was 16.6 months, and 22.2% of patients had no tumor-related clinical event after three years. A total of 14 patients (22%) had another aRT. In conclusion, local ablative radiotherapy in patients with PSMA-PET staged oligometastatic prostate cancer may achieve local control, but regional or distant progression is common. Further studies are warranted, e.g., to define the optimal target volume coverage in LN-MET and OSS-MET.

A feasibility study of a modified treatment strategy combined external beam radiation therapy and brachytherapy for cervical cancer.

PurposeTo evaluate the feasibility of a modified treatment strategy combined external beam radiation therapy (EBRT) and brachytherapy (BT) for cervical cancer through a dosimetry analysis.Material and methodsThis study retrospectively selected 12 cervical cancer patients treated with the conventional treatment strategy, which consisted of 45─50 Gy/25 fractions of EBRT using volumetric‐modulated arc therapy (VMAT) and image‐guided BT with a fraction dose of 5─7 Gy. The modified treatment strategy decreased the central EBRT dose while increasing the number of BT fractions. New target volumes were additionally contoured, and new VMAT EBRT plans were generated for the modified treatment strategy. The dosimetric parameters for evaluation included the doses to the most irradiated 2 cc (D2cc) of the organs at risk (OARs) and doses to at least 90% (D90) of the gross tumor volume (GTV) and high‐risk clinical target volume (HR‐CTV). The total doses to OARs and targets obtained by adding the equivalent doses in 2 Gy fraction (EQD2) from the EBRT and BT plans were used for quantitative comparison between the modified and conventional treatment strategies.ResultsComparison to the conventional treatment strategy, the modified treatment strategy resulted in a higher bladder D2cc, a slightly lower rectal D2cc and a similar HR‐CTV D90, all with no significant differences (p > 0.05). The GTV D90 of the modified treatment strategy was significantly higher than that of the conventional treatment strategy (p < 0.01).ConclusionThe modified treatment strategy can significantly increase the BT dose while remaining the total doses to the bladder and rectum basically unchanged, demonstrating its feasibility and promising prospect in clinical use.