Dose Fractionation Schedules Research Articles

Choosing Wisely Between Radiotherapy Dose-Fractionation Schedules: The Molecular Graded Prognostic Assessment for Elderly Glioblastoma Patients.

This study aimed to develop a graded prognostic assessment (GPA) model integrating genomic characteristics for elderly patients with glioblastoma (eGBM), and to compare the efficacy of different radiotherapy schedules. This multi-institutional retrospective study included patients aged ≥65 years who underwent surgical resection followed by radiotherapy with or without temozolomide (TMZ) for newly diagnosed eGBM. Based on the significant factors identified in the multivariate analysis for overall survival (OS), the molecular GPA for eGBM (eGBM-molGPA) was established. A total of 334 and 239 patients who underwent conventionally fractionated radiotherapy (CFRT) and hypofractionated radiotherapy (HFRT) were included, respectively, with 86% of patients receiving TMZ-based chemoradiation. With a median follow-up of 17.4 months (range, 3.3-149.9), the median OS was 18.7 months for CFRT+TMZ group, 15.1 months for HFRT+TMZ group, and 10.4 months for radiotherapy alone group (CFRT+TMZ vs. HFRT+TMZ: HR 1.52, p<0.001; CFRT+TMZ vs. radiotherapy alone: HR 2.52, p<0.001). In a combined analysis with the NOA-08 and NORDIC trials, CFRT+TMZ group exhibited the highest survival rates among all treatment groups. The eGBM-molGPA, which integrated four clinical and three molecular parameters, stratified patients into low-, intermediate-, and high-risk groups. CFRT+TMZ significantly improved OS compared to HFRT+TMZ or radiotherapy alone in the low-risk (p=0.023) and intermediate-risk groups (p<0.001). However, in the high-risk group, there was no significant difference in OS between treatment options (p=0.770). CFRT+TMZ may be more effective than HFRT+TMZ or radiotherapy alone for selected eGBM patients. The novel eGBM-molGPA model can guide treatment selection for this patient population.

Efficacy and safety of stereotactic radiotherapy on elderly patients with stage I-II central non-small cell lung cancer.

Many studies demonstrated the safety and efficacy of SBRT in the treatment of elderly patients with early-stage non-small cell lung cancer (NSCLC). However, those studies focused on patients with peripheral lung cancer. This study aimed to evaluate the clinical efficacy and toxicity of SBRT in elderly patients with stage I-II central NSCLC in single institution. From April 2009 to January 2020, a retrospective study was conducted on patients ≥ 65 years old with stage I-II NSCLC that was centrally localized and treated with SBRT at a single institution. Absolute C-reactive protein (CRP)/albumin ratio (CAR) and body mass index (BMI) recorded at pretreatment were analyzed. Endpoints included overall survival (OS), progression-free survival (PFS), cancer-specific death, noncancer-specific death, local progression (LP) and distant progression (DP). Stereotactic body radiation treatment (SBRT) was administered to a total of 44 patients. The most common dose fractionation schedule was 60 Gy given in 5 fractions. The median PFS of the cohort was 31 months (95% CI, 19.47-42.53 months). The median OS of all patients was 69 months (95% CI, 33.8-104.2 months). The median time to noncancer-specific death was 54.5 months. The median time to cancer-specific death was 36 months. The cumulative incidences of cancer-specific death at 1 year, 5 years, and 10 years were 11.63% (95%CI, 4.2-23.23%), 42.99% (95%CI, 27.56-57.53%), and 65.94% (95%CI, 45.76-80.1%), respectively. pre-SBRT BMI of ≤ 22.77 (HR 4.60, 95% CI 1.84-11.51, P=0.001) and pre-SBRT CAR of ≤0.91 (HR 5.19, 95% CI 2.15-12.52, P<0.000) were significant predictors of higher OS on multivariable analysis. The median times to LP and DP were 10 months and 11 months, respectively. In terms of acute toxicity, grade 1 including cough (38.64%), radiation pneumonitis (29.55%), anemia (25%), and fatigue (20.45%) was often observed. There was no evidence of grade 4 or 5 acute toxicity. In terms of late toxicity, 2 patients developed grade 1 pulmonary fibrosis during follow-up. This study showed that SBRT can effectively control local tumor progression, and have acceptable toxicity for elderly patients with centrally located stage I-II NSCLC. Lower pre-SBRT BMI and lower pre-SBRT CAR were associated with a decreased risk of cancer-specific death.

Abstract PO3-22-01: Characterization of peripheral T-cell dynamics in the patients with bone metastasis from breast cancer following stereotactic body radiotherapy

Abstract Purpose: Preclinical studies suggest that radiotherapy (RT) elicits various effects on antitumor T-cell responses. However, systemic T-cell responses upon RT in real-world cancer patients, including those with metastatic breast cancer, are poorly characterized. This study aims to investigate the detailed dynamics of peripheral T cells upon stereotactic body radiotherapy (SBRT) in metastatic breast cancer patients. Methods: Peripheral blood samples of 32 prospectively recruited patients who received SBRT to bone metastasis of breast cancer, which were acquired at pre-SBRT (W0), 1 week after SBRT (W1), and 4 weeks after SBRT (W4), were analyzed using multi-color flow cytometry and cytometric bead array. Most patients (n = 30) received SBRT of 1 fraction (n = 16) or 3 fractions (n = 14). We also performed a subgroup analysis of 22 patients who did not start a new systemic therapy within 1 month before SBRT (new systemic Tx &amp;gt;1mo) to exclude the effects of systemic therapies. Results: Peripheral PD-1+ CD8+ T cells, which are enriched for tumor-specific clonotypes, were activated with increased expression of Ki-67 at W1 compared to W0. Expression of Ki-67 on PD-1+ CD8+ T cells remained higher at W4 than W0, although it was not statistically significant. Moreover, expressions of Ki-67 and CTLA-4 on circulating regulatory T (TREG) cells were increased at W1 compared to W0. The suppressive (Foxp3hiCD45RA–) TREG cells also exhibited enhanced expressions of Ki-67 and CTLA-4 at W1. We defined immunologic responders (ImmRs) as patients with Ki-67 expression on PD-1+ CD8+ T cells at W1 greater than 1.5-times of W0, and otherwise immunologic non-responders (ImmNRs). Notably, fold changes in expressions of Ki-67 and CTLA-4 on TREG cells and proportion of suppressive TREG cells among total TREG cells at W1 over W0 were higher in ImmRs than ImmNRs. Similar phenotypical changes of T cells were observed in the subgroup analysis of the patients with new systemic Tx &amp;gt;1mo. The peripheral T-cell changes were not significantly different between the dose-fractionation schedules (1 fraction vs. 3 fractions) nor molecular subtypes of cancer. In patients with new systemic Tx &amp;gt;1mo, plasma level changes of TGF-β1, sCTLA-4, and s4-1BB at W1 compared to W0 were significantly higher in ImmRs compared to ImmNRs, while only change of s4-1BB was associated with the immunologic response. Conclusions: Our results suggest that circulating PD-1+ CD8+ T cells are activated upon SBRT. However, SBRT also results in the activation of circulating TREG cells, which was more prominent in patients with a significant activation of circulating PD-1+ CD8+ T cells. Alterations in plasma levels of TGF-β1, sCTLA-4, and s4-1BB are associated with the peripheral T-cell responses. Dose-fractionation schedule is not associated with the peripheral T-cell responses. Work supported by grants from the National Research Foundation of Korea (NRF-2023R1A2C3003782) Citation Format: Seung Hyuck Jeon, Eui-Cheol Shin, In Ah Kim. Characterization of peripheral T-cell dynamics in the patients with bone metastasis from breast cancer following stereotactic body radiotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-22-01.

A 15-Year Single-Institution Retrospective Study of Primary Pancreatic Cancer Treated with Non-Ablative Palliative Radiotherapy.

We studied the use of palliative radiotherapy (RT) among patients with primary, non-curable, locally advanced pancreatic cancer. In this subset of patients, with very poor survival, various palliative RT dose fractionation schemes are used; but, in the absence of a guideline, practice patterns vary, and dose choice is mainly based on the physician's intuition. We divided the patients into three groups, according to the dose fractionation schedules received: low (A), intermediate (B), and high (C) dose groups, to study the potential differences in outcome between the different dose prescriptions. Cohort: n = 184. Median age: 69 years. Male: n = 105 (57%), female: n = 79 (43%). Stage IV: n = 117 (64%). T4: n = 127 (69%). Tumor location: head: n = 109 (59%), body: n = 37 (20%), tail: n = 25 (14%), neck: n = 11 (6%), and uncinate: n = 2 (1%). Prior systemic therapy: n = 66 (36%). Most common dose fractionations received: 20 Gy in five fractions n = 67 (36%), 30 Gy in 10 fractions n = 49 (27%), and 8 Gy in one fraction n = 23 (13%). Group A: n = 33 (18%), median overall survival (OS) 19 days (95% CI 4-33). Group B: n = 84 (46%), median OS 52 days (95% CI 43-60). Group C: n = 67 (36%), median OS 126 days (95% CI 77-174). Median days to in-field progression: Group A 59 days (range 7-109), Group B 96 days (range 19-173), and Group C 97 days (range 13-475). To our knowledge, this is the largest reported retrospective cohort of patients receiving non-ablative palliative RT to treat their primary pancreatic tumors. Most patients had metastatic disease, T4 tumors of the pancreatic head and had not received prior systemic therapy. A significant survival benefit was seen favoring the high dose/longer RT fractionation group, presumably due to appropriate patient selection rather than an RT effect. Despite the relatively short median overall survival, one fifth of the patients were found to experience an in-field progression following RT.

A comparative study between two different dose fractionation schedules of cobalt-60-based HDR intracavitary brachytherapy in carcinoma cervix stages IIB-IIIC1.

High dose rate (HDR) intracavitary brachytherapy (ICBT) is an integral element in the treatment of carcinoma uterine cervix. The main objective of brachytherapy in carcinoma cervix is to deliver a lethal dose to tumor cells without inducing unacceptable damage to the surrounding normal tissue. Because the absorbed dose falls off rapidly, higher doses can be safely delivered to the targeted tissue over a short time. The quest for optimum dose and fractionation schedule in HDR ICBT is still ongoing, and there is no uniform consensus. This study aimed to assess the acute dose-related toxicities of HDR brachytherapy schedule of 7 Gy x 3 fractions over 6 Gy x 4 fractions in the treatment of cervical cancer. The aim of this study was to study the acute treatment-related gastrointestinal (GI) and genitourinary (GU) toxicities between two HDR brachytherapy regimens. This is a prospective institutional study carried out from May 2018 to September 2018. In this time period, 66 patients of cervical cancers fulfilling our inclusion criteria were treated with concurrent chemoradiation (CCRT) following brachytherapy. During treatment, patients were randomized to arm A-7 Gy per fraction for three fractions and arm B-6 Gy per fraction for four fractions. Acute GI and GU toxicities were assessed using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. All patients were kept for follow-up for 3 months in this study. There is no statistically significant difference between the two arms for acute GI and GU toxicities, and the results were comparable. Considering the increased hospital burden of locally advanced cervical cancer patients in the Indian context, the HDR brachytherapy schedule of 7 Gy per fraction is preferable to 6 Gy per fraction for a lesser fractionation schedule.

High-dose-rate brachytherapy in uterine cervix carcinoma: a comparison of dosimetry and clinical outcomes among three fractionation schedules.

To assess the differences among three dose-fractionation schedules of image-guided adaptive brachytherapy (IGABT) in cervical squamous cell carcinoma (CSCC) by comparing the dosimetry and clinical outcomes. Forty-five patients with CSCC who underwent chemoradiotherapy and IGABT were retrospectively enrolled and divided into three groups based on their dose-fractionation schedules of brachytherapy as: Group-5.5 (5.5 Gy × 6 fractions), Group-6.0 (6.0 Gy × 5 fractions), and Group-7.0 (7.0 Gy × 4 fractions). The analyzed dose-volume histogram parameters included D90% and D98% of the high-risk clinical target volume (HR-CTV), D90% and D98% of intermediate-risk clinical target volume (IR-CTV), and D0.1cc and D2cc of the organs-at-risk (OARs, namely the bladder, rectum, sigmoid and small intestine). Furthermore, the therapeutic efficacy and late toxicities were also compared among the three groups. The doses of HR-CTV and IR-CTV in Group-5.5 were found to be the highest among the three groups, followed by those in Group-6.0. Significant differences were found for the doses of HR-CTV between Group-5.5 and the other groups. There were no significant differences in the bladder, sigmoid and small intestine dose among the three groups. However, Group-6.0 yielded the lowest rectum received doses, with a significant difference in D0.1cc being detected between Group-6.0 and Group-5.5. The median follow-up time was 30.08 months [range, 6.57-46.3]. The numbers of patients with complete response in Group-5.5, Group-6.0 and Group-7.0 were 13, 14 and 14, respectively (P > 0.05). In regard to the toxicitiy, the incidence of radiation cystitis and proctitis in Group-6.0 was lower than that in Group-5.5 and Group-7.0 (P > 0.05). The dose-fractionation schedule of 6.0 Gy × 5 fractions provided the most beneficial effects with relatively low OARs doses, suggesting that this dose-fractionation schedule should be prioritized in the clinical application of brachytherapy in cervical cancer.

Thoracic Radiation Dose Fractionation Schedules for Limited-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis of Randomized Trials

The Intergroup randomized controlled trial (RCT) established 45 Gy in 30 fractions (F) twice-daily (BID) as the standard thoracic radiation therapy (TRT) regimen with concurrent platinum-based chemotherapy (PBC) for limited-stage small cell lung cancer (LS-SCLC) in 1999. Since then, several RCTs were conducted to investigate novel TRT dose fractionation schedules (DoFS). However, it is unclear which is the optimal DoFS. This study aimed to compare the efficacy and safety of various DoFS of TRT in LS-SCLC using 45 Gy in 30F BID as the reference comparator. We searched biomedical databases for eligible RCTs comparing at least two DoFS of TRT in LS-SCLC. The outcomes of interest were progression-free survival (PFS), overall survival (OS), treatment-related death, grade 3-5 pneumonitis and esophagitis. We employed GRADE approach to appraise the certainty of the evidence. Meta-analyses were performed using fixed effects frequentist network model. The ESMO-Magnitude of Clinical Benefit Score (MCBS) version 1.1 was used to judge the value of the novel DoFS. This study was registered with PROSPERO (CRD42022336338). We identified six RCTs including 2,111 patients and six DoFS (45 Gy in 25F once-daily (OD), 42 Gy in 15F OD, 66 Gy in 33F OD, 60 Gy in 40F BID, 65 Gy in 26F OD and 70 Gy in 35F OD) that were compared with 45 Gy in 30F BID. There was high certainty evidence showing that 65 Gy in 26F OD (hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.46-0.96) significantly improved PFS and 60 Gy in 40F BID (HR, 0.61; 95% CI, 0.41-0.91) significantly improved OS, compared to 45 Gy in 30F BID. There were no significant differences among the DoFS (42 Gy in 15F OD, 60 Gy in 40F BID, 65 Gy in 26F OD and 70 Gy in 35F OD) for PFS and OS. Both 65 Gy in 26F OD and 60 Gy in 40F BID were scored GRADE A on the ESMO-MCBS. The odds of grade 3-5 pneumonitis may be lower with 65 Gy in 26F OD (odds ratio (OR), 0.71; 95% CI, 0.12-4.32; low certainty) and higher with 60 Gy in 40F BID (OR, 6.60; 95% CI, 0.34-129.66); very low certainty). There were no significant differences among the DoFs (42 Gy in 15F OD, 66 Gy in 33F OD, 60 Gy in 40F BID, 65 Gy in 26F OD and 70 Gy in 35F OD) for treatment-related deaths or grade 3-5 esophagitis. There was no evidence to suggest that there were significant differences among the newer DoFS for PFS and OS with 45 Gy in 30F BID as the reference. Both 65 Gy in 26F OD and 60 Gy in 40F BID were judged to provide clinically meaningful benefit based on ESMO-MCBS. Treatment with 65 Gy in 26F OD may be an option if once-daily treatment is preferred. Treatment with 60 Gy in 40F BD may be considered for select patients with excellent performance status.

Characterization of Peripheral T-Cell Dynamics in the Patients with Bone Metastasis from Breast Cancer Following Stereotactic Body Radiotherapy

Preclinical studies suggest that radiotherapy (RT) elicits various effects on antitumor T-cell responses. However, systemic T-cell responses upon RT in real-world cancer patients, including those with metastatic breast cancer, are poorly characterized. This study aims to investigate the detailed dynamics of peripheral T cells upon stereotactic body radiotherapy (SBRT) in metastatic breast cancer patients. Peripheral blood samples of 32 prospectively recruited patients who received SBRT to bone metastasis of breast cancer, which were acquired at pre-SBRT (W0), 1 week after SBRT (W1), and 4 weeks after SBRT (W4), were analyzed using multi-color flow cytometry and cytometric bead array. Most patients (n = 30) received SBRT of 1 fraction (n = 16) or 3 fractions (n = 14). We also performed a subgroup analysis of 22 patients who did not start a new systemic therapy within 1 month before SBRT (new systemic Tx >1mo) to exclude the effects of systemic therapies. Peripheral PD-1+ CD8+ T cells, which are enriched for tumor-specific clonotypes, were activated with increased expression of Ki-67 at W1 compared to W0. Expression of Ki-67 on PD-1+ CD8+ T cells remained higher at W4 than W0, although it was not statistically significant. Moreover, expressions of Ki-67 and CTLA-4 on circulating regulatory T (TREG) cells were increased at W1 compared to W0. The suppressive (Foxp3hiCD45RA-) TREG cells also exhibited enhanced expressions of Ki-67 and CTLA-4 at W1. We defined immunologic responders (ImmRs) as patients with Ki-67 expression on PD-1+ CD8+ T cells at W1 greater than 1.5-times of W0, and otherwise immunologic non-responders (ImmNRs). Notably, fold changes in expressions of Ki-67 and CTLA-4 on TREG cells and proportion of suppressive TREG cells among total TREG cells at W1 over W0 were higher in ImmRs than ImmNRs. Similar phenotypical changes of T cells were observed in the subgroup analysis of the patients with new systemic Tx >1mo. The peripheral T-cell changes were not significantly different between the dose-fractionation schedules (1 fraction vs. 3 fractions) nor molecular subtypes of cancer. In patients with new systemic Tx >1mo, plasma level changes of TGF-β1, sCTLA-4, and s4-1BB at W1 compared to W0 were significantly higher in ImmRs compared to ImmNRs, while only change of s4-1BB was associated with the immunologic response. Our results suggest that circulating PD-1+ CD8+ T cells are activated upon SBRT. However, SBRT also results in the activation of circulating TREG cells, which was more prominent in patients with a significant activation of circulating PD-1+ CD8+ T cells. Alterations in plasma levels of TGF-β1, sCTLA-4, and s4-1BB are associated with the peripheral T-cell responses. Dose-fractionation schedule is not associated with the peripheral T-cell responses.

Liver Stereotactic Body Radiation Therapy (SBRT) to Downstage Patients with Hepatocellular Carcinoma prior to Liver Transplant

Orthotopic liver transplantation (OLT) marks the most successful treatment for hepatocellular carcinoma (HCC) patients meeting Milan criteria. The process of reducing the disease burden of HCC patients not currently meeting criteria for OLT with local therapy is referred to as "downstaging" and has proven to be a feasible approach. RTOG 1112 recently demonstrated the efficacy and acceptable toxicity of liver SBRT for treating HCC. However, limited data currently exists describing the efficacy of SBRT for downstaging HCC patients and facilitating OLT. A single institution IRB approved prospective liver SBRT registry was surveyed for all patients outside of Milan criteria (1 lesion >5 cm; 2-3 lesions >3 cm) without vascular invasion or extrahepatic disease. Patients felt least likely to become OLT candidates with downstaging (age >80, >4 lesions, lesion >12 cm) were excluded. The primary endpoints were downstaging and OLT. Secondary endpoints were time to transplant, local control (LC), recurrence free survival (RFS) and overall survival (OS). A total of 38 HCC patients with a median age of 65 years (range 28 - 80) met inclusion criteria. Median follow up was 14 months (IQR 3 - 35). At baseline, median KPS was 80 (range 60 - 100) with 16 Child-Pugh (CP) A (42%), 13 CP B (34%), and 9 CP C patients (24%). All patients were outside of Milan criteria and 25 patients (66%) were outside of UCSF criteria at time of SBRT. No patients had extrahepatic disease or vascular invasion. Median number of lesions, largest tumor size, and total sum of lesions were 2 (range 1 - 4), 5.0 cm (IQR, 4.0 - 6.5), and 6.6 cm (IQR 5.9 - 9.2), respectively. Prior to SBRT, 22 patients (58%) had received non-SBRT local therapy. At time of SBRT a variety of dose fractionation schedules were selected with a median BED10 of 78 (IQR 62 - 100). Concurrent sorafenib was used in 2 patients (8%). Following completion of SBRT, 21 patients (55%) were successfully downstaged at a median 3.0 months (IQR 1.9 - 6.1) after treatment, most frequently secondary to decrease in size of the largest lesion (86%). Twelve patients (32%) proceeded to undergo OLT at a median 7 months (IQR 3 - 14) after SBRT and 105 days (IQR 18 - 344) following successful downstaging. Of the 25 patients initially exceeding UCSF criteria, 7 (28%) underwent OLT. Among those receiving OLT, 5 patients (42%) remain alive without evidence of disease, 3 patients (25%) have recurred, 3 patients (33%) died within 2 years from transplant complications, and 1 patient (8%) died from an unrelated cause. LC at 2 years was 83%. Median RFS and OS for the overall cohort were 7 months (95% CI 0 - 21) and 24 months (95% CI 11 - 36), respectively. Among the transplant recipients, the median OS was 37 months (95% CI 30 - 44) compared to 15 months (95% CI 6 - 23) among those not receiving transplant. With careful patient selection, liver SBRT serves as a feasible downstaging method to facilitate OLT in HCC patients.

Choosing Wisely between Radiotherapy Dose-Fractionation Schedules: The Molecular Graded Prognostic Assessment (molGPA) for Elderly Glioblastoma (eGBM-molGPA)

This study aimed to develop a graded prognostic assessment (GPA) model integrating genomic characteristics in patients with elderly glioblastoma (eGBM), and compare the efficacy between conventionally fractionated radiotherapy (CFRT) vs. hypofractionated radiotherapy (HFRT) in each risk group. Patients aged ≥65 years who underwent surgical resection followed by radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed IDH-wildtype eGBM between 2006 and 2021 were included in this multicenter cohort study. Patients who were planned for a ≥6-week or ≤4-week radiotherapy were regarded as being treated with CFRT or HFRT, respectively. Based on the prognostic factors significantly identified through multivariate analysis for overall survival (OS), we developed the molecular GPA for eGBM (eGBM-molGPA) and assigned 0.0, 0.5, and 1.0 points in proportion to the corresponding hazard ratio (HR) of each factor. Then, the survival outcomes by treatment groups were evaluated according to the eGBM-molGPA scores. A total of 334 and 239 patients who underwent CFRT and HFRT were included, respectively, and 86% of patients were treated with TMZ-based chemoradiation. With a median follow-up of 17.4 months for survivors, the median OS was 18.7 months for CFRT plus TMZ group, 15.1 months for HFRT plus TMZ group, and 10.4 months for RT alone group, respectively (all p<0.001). In the multivariate analysis, Karnofsky performance scale, surgical extent, TMZ, and the methylation status of the MGMT promoter were identified as strong prognostic factors for OS, with an estimated HR of greater than 1.5 (all p<0.001). Additionally, subventricular zone involvement, temporalis muscle thickness, RT regimen, and the mutation status of TERT promoter and TP53 gene were found to be significant prognostic factors for OS, with an estimated HR of less than 1.5. The eGBM-molGPA was established based on these prognostic factors (Table 1) and patients were allocated to three risk groups, which included high risk (total score of 3.0-4.5), intermediate risk (1.5-2.5), and low risk (0.0-1.0). Patients treated with CFRT plus TMZ had significantly improved OS compared to those treated with HFRT plus TMZ or RT alone in the low and intermediate risk groups (p<0.001). However, in the high-risk group, there was no significant difference in OS between treatment options (p = 0.770). CFRT plus TMZ can be a more effective strategy for selected eGBM patients compared to HFRT. For high-risk patients, a protracted treatment schedule might not be beneficial. The novel eGBM-molGPA can be used as a clinical tool for choosing wisely among treatment options. Further prospective studies are warranted to establish optimal RT guidelines for eGBM patients.

Stereotactic Body Radiotherapy for Management of Pulmonary Oligometastases in Stage IV Colorectal Cancer: A Perspective

In pulmonary oligometastases from colorectal cancer (POM-CRC), metastasectomy is the primarily recommended treatment. Stereotactic body radiotherapy (SBRT) has been suggested as a viable alternative therapy. SBRT efficacy for POM-CRC is poorly delineated compared to selected non-CRC primaries. This perspective article aims to critically summarize the existing evidence regarding efficacy of SBRT in terms of overall survival (OS) and local control (LC), and factors modulating this, in the treatment of POM-CRC. Overall, reasonable LC and OS rates were observed. The wide range of expansions in planning target volume margins introduced variation in pretreatment protocols. Dose-fractionation schedules varied according to patient and tumor characteristics, though leverage of BED10 in select studies enabled standardization. An association between SBRT dose and improved OS and LC was observed across multiple studies. Prognostic factors that were associated with improved LC included: fewer oligometastases, absence of extra-pulmonary metastases, primary tumor histology, and smaller gross tumor volume. Differences in SBRT modality and techniques over time further confounded results. Many studies included patients receiving additional systemic therapies; preprotocol and adjuvant chemotherapies were identified as prognostic factors for LC. SBRT compared with metastasectomy showed no differences in short-term OS and LC outcomes. In conclusion, SBRT is an efficacious treatment for POM-CRC, in terms of OS and LC. Heterogeneity in study design, particularly pertaining to dose protocols, patient selection, and additional therapies should be controlled for future randomized studies to further validate SBRT efficacy.

Comparison of pain-relieving effects by number of irradiations, through propensity score matching and the international consensus endpoint.

Palliative radiotherapy for bone metastases utilizes various dose fractionation schedules. The pain-relieving effects of a single fraction (SF) and multiple fractions (MF) are largely debated due to the difficulty in matching patients' backgrounds and in assessing the effectiveness of pain relief. This study aimed to compare the pain-relieving effects of SF and MF palliative radiotherapy for bone metastases using propensity score matching and the international consensus endpoint (ICE). Our study included 195 patients irradiated for bone metastasis. The primary endpoint was the pain-relieving effects used by ICE. In addition, the evaluation was performed by using responder (complete response/partial response) and non-responder (pain progression/indeterminate response) categorization. The secondary endpoints were the discharge or transfer rate at one month after irradiation and postirradiation pathological fracture rate. Propensity score matching was used to adjust patient's characteristics and reduce selection bias. After adapting propensity score matching, the total number of patients was 74. There was no significant difference in the pain-relieving effects between SF and MF (p = 0.184). There were no significant differences in them between SF and MF when using responder and non-responder categorization (p = 0.163). Furthermore, there were no differences in the discharge or transfer rates (p = 0.693) and pathological fracture rates (p = 1.00). The combination of propensity score matching and ICE revealed no significant difference in the pain-relieving effects between SF and MF for bone metastases, thus, SF has no significant disadvantage compared to MF in pain-relieving effects.

Prevalence of palliative radiotherapy abstracts presented at the annual scientific meetings of the Canadian Association of Radiation Oncology: 2003-2021.

Approximately half of all radiotherapy (RT) is delivered with palliative intent. Clinical research in palliative RT aims to manage symptoms, improve quality of life (QoL), evaluate supportive care, and determine optimal dose-fractionation schedules. Our aim was to describe the prevalence of palliative research at the Canadian Association of Radiation Oncology (CARO) Annual Scientific Meeting (ASM) over time and compare this analysis to previously published work which evaluated the years 1992-2002. Published abstracts (2003-2021) were independently reviewed by two authors who categorized each as curative-intent; palliative-intent; pertaining to both populations; or neither. Abstracts were considered palliative if they described incurable malignancy and interventions primarily for symptom control or QoL. Type of study, primary, site treated, and symptoms palliated were recorded. Descriptive and summary statistics were calculated including one-way ANOVA test for trend. Three hundred thirty-nine out of 4566 abstracts (7.4%, range 2.4-13.9% per year) were classified as palliative. 7.7% (26/339) described phase I-III trials. The main primary site was the lung (39/339) and the most common metastatic site was the bone (34.2%). QoL, symptom and toxicity outcomes were reported in 31.6% (107/339), 37.8% (128/339) and 17.7% (60/339), respectively. The most common symptom investigated was pain (38/339). The proportion of abstracts classified as curative, palliative or reporting toxicity endpoints demonstrated significant change over time (all p<0.0001). While proportion of palliative themed abstracts has increased with time, there remains a significant gap before equivalence with the prevalence of palliative RT in clinical practice is achieved.

Practice patterns of adjuvant radiotherapy in women with stage I to II endometrial carcinoma: a real-world multi-institutional analysis in China

BackgroundThis study aimed to report clinical practice patterns of postoperative radiotherapy for stage I to II endometrial carcinoma (EC) patients treated in 13 Chinese medical centers.MethodsWe included early stage EC patients treated by hysterectomy and adjuvant RT between 2003 and 2017 from 13 institutions. Patients were classified into 4 risk groups based on ESMO-ESGO-ESTRO recommendations (2014).ResultsA total of 1,227 cases were analyzed. Along the 15 years of the study, an increasing tendency was found towards administration for vaginal brachytherapy (VBT) alone, while the proportion of external beam pelvic radiotherapy (EBRT) alone remained stable in the corresponding period. When radiation modalities were stratified by risk groups, proportion of VBT alone significantly increased in all risk groups. The higher the risk, the later VBT became the main adjuvant treatment modality. However, EBRT alone or with VBT remained the main adjuvant method for high-risk patients.There were 13 dose-fractionation schemes for VBT alone with the scheme of 30 Gy in 6 fractions prescribed at 0.5cm under the vaginal mucosa accounting for most. There were 17 schemes for VBT boost and the most common schedule was 10 Gy in 2 fractions. The upper 3–5cm part of vagina was the most frequent target. 89.6% of the practitioners performed two-dimensional VBT technique. The median dose for EBRT was 50 Gy. From 2003 to 2017, conventional radiotherapy was gradually replaced by three-dimensional conformal radiotherapy modality and intensity modulated radiotherapy.ConclusionWe report a significant shift from EBRT to VBT alone for high-intermediate-risk, intermediate-risk and low-risk EC patients from 2003 to 2017 while EBRT remained the main radiation modality for high-risk early stage patients. There has been remarkable heterogeneity among VBT dose fractionation schedules across China.Trial registrationThe clinical trial ID was ChiCTR-PRC-17010712. It was authorized by the Institutional Review Board of Peking Union Medical College Hospital (N0. S-K139).

Radioterapija raka dojke - promjene u shemama frakcioniranja kroz desetljeća

Traditionally, as a standard dose fractionation schedule, adjuvant radiotherapy for breast cancer has been performed using prescribed doses of 46–50 Gy divided into daily fractions of 1.8–2 Gy. Overall, radiotherapy treatment took 5 weeks. In the 1990s, schedules using higher daily doses (2.5–3 Gy), a smaller number of fractions (hypofractionation), and a reduced overall prescribed dose started in the context of clinical trials. First results revealed an equivalent cosmetic effect of hypofractionated protocols compared to standard fractionation, and after longer follow-up, hypofractionation was connected with better control of the disease. Hypofractionation started to be considered the new treatment standard. Results of newer clinical trials confirm the efficacy and safety of adjuvant breast cancer radiotherapy lasting 5 working days using daily fractions of 5.2 Gy in certain subgroups of breast cancer patients.

Comparative Analysis of Dosimetry and Treatment Outcomes of Two Different Dose Fractionation Schedules of HDR Brachytherapy in Carcinoma Cervix Amid Covid-19 Pandemic

Background: Cervical carcinoma is the fourth most common cancer and leading cause of cancer related deaths in women worldwide. Brachytherapy is an important part in the treatment of cervical cancer. Delivering HDR Intracavitary Brachytherapy in the Covid-19 era is challenging. Objective: To compare the dosimetry and treatment outcomes between two fractionation schedules of 9Gy in 2 fractions v/s 7Gy in 3 fractions of high dose rate Brachytherapy in patients with locally advanced carcinoma cervix. Methods: A randomized observational study was carried out on 80 histopathologically proven squamous cell carcinoma patients of cervix. All patients were treated with EBRT 50Gy in 25 fractions over a period of 5 weeks (2Gy/#) with concurrent weekly cisplatin 30mg/m2. After assessing fitness for brachytherapy, patients in the study arm received HDR intracavitary brachytherapy in 9Gy for 2 fractions v/s 7Gy for 3 fractions in the control arm. Results: The median time of follow-up was 14 months for the study (range 7 – 20 months). Local control rate was 89.75% for study arm and 92.30% for control arm. One year disease free survival in the study arm was 76.92% as compared to 74.35% in the control arm. Median disease-free survival was better in the study arm (14 months v/s 12 months) with a trend of significant benefit. Rectal and bladder toxicities were comparable in both the arms. Median dose to ICRU bladder and rectal point, and EQD2 dose in both arms were not found to be statistically significant. Conclusion: Both the regimes were found to be safe. Disease response and toxicities were also similar in both the arms. There was a better patient compliance with 9Gy for 2 fractions schedule in view of lesser number of fractions resulting in less hospital visit in the Covid-19 pandemic.

Single High-Dose Irradiation-Induced iRhom2 Upregulation Promotes Macrophage Antitumor Activity Through cGAS/STING Signaling

The clinical application of stereotactic body radiation therapy (SBRT) allows a high dose of radiation to be safely delivered to extracranial targets within the body; however, a high dose per fraction (hypofractionation) has opened the radiation oncology field to new questions on a variety of dose-fractionation schedules, especially the immunomodulatory effects of radiation therapy, which can change after various dose-fractionation schedules. We investigated the immunomodulatory effects of different fractionation schedules. We established a subcutaneous tumor model in wild-type C57BL/6J mice and STING (stimulator of interferon genes)-deficient mice. We then compared the tumor control efficacy of 3 different fractionation schedules: 2 Gy×8, 4.5 Gy×3, and 10 Gy×1, which are similar biologically effective doses. We found the fractionation schedule of 10 Gy×1 had a significantly higher antitumor effect, suggesting that a single high dose induced enhanced antitumor immunity compared with conventional fractionation (2 Gy×8) and moderate hypofractionation (4.5 Gy×3). However, in STING-deficient mice, differential tumor control was not observed among the 3 dose-fractionation schedules, suggesting that cGAS (cyclic GMP-AMP synthase)/STING signaling is involved in the antitumor immune effects of single high-dose schedules. Mechanistically, we found that conventional fractionation induced apoptosis; by comparison, a single high dose was more attuned to induced necroptosis, leading to the release of intracellular irradiation-induced double-stranded DNA (dsDNA) due to the loss of plasma membrane integrity, which then activated the dsDNA sensing signaling cGAS/STING in the recruited macrophage. Furthermore, iRhom2, a member of the conserved family of inhibitory rhomboid-like pseudoproteases, was upregulated in infiltrated macrophages in the single high-dose irradiation microenvironment. Therefore, iRhom2 positively regulates STING and directly promotes tumor necrosis factor α secretion. This exacerbates necroptosis of irradiated tumor cells, leading to continuous dsDNA release and enhancement of cGAS/STING signaling antitumor immunity in a positive feedback loop. iRhom2 amplifies antitumor signaling in a positive feedback loop mediated by cGAS/STING signaling and tumor necrosis factor-driven necroptosis after single high-dose radiation.

Choice of dose fractionation schedule in the palliation of non-metastatic rectal cancer: A single-centre retrospective review

Category: Outcomes of treatment (including chemotherapy, chemo-RT and RT)

Definitive Chemoradiotherapy vs. Trimodal Therapy for Locally Advanced Esophageal or Junctional Adenocarcinoma

<h3>Purpose/Objective(s)</h3> Randomized trials have not found trimodal therapy to improve overall survival (OS) compared to definitive chemoradiotherapy for esophageal cancer, but these studies were small and included few adenocarcinoma cases. We sought to compare OS between trimodal therapy and definitive chemoradiotherapy for locally advanced adenocarcinoma of the esophagus and gastroesophageal junction. <h3>Materials/Methods</h3> Patients with locally advanced esophageal or junctional adenocarcinoma undergoing either definitive trimodal therapy or chemoradiotherapy between 2004 and 2018 were retrospectively identified in the provincial cancer registry. The primary analysis was based on intention to treat as determined by chart review (trimodal therapy or definitive chemoradiotherapy). A per-protocol analysis was also completed, wherein patients not undergoing surgery were excluded from the trimodal group, and patients not receiving radiotherapy to at least 41.4 Gy in 23 fractions were excluded from both groups. Kaplan-Meier curves and the Cox proportional hazard model with covariates of age, sex, stage, chemotherapy regimen, and EQD2 (α/β = 4.0) were used to compare OS. <h3>Results</h3> A total of 484 patients were eligible for analysis with a median follow-up of 39.1 months. Median age was 62 with a preponderance of males (87%). Most patients with a clinical AJCC 8th edition stage were stage III (71%), followed by stage IV (21%). The most common dose fractionation schedule was 41.4 Gy in 23 fractions (74%), and the most common chemotherapy regimen was carboplatin/paclitaxel (78%). At the outset, 428 were planned for trimodal therapy and 56 were planned for definitive chemoradiotherapy. There were 67 patients (16%) planned for trimodal therapy who did not undergo surgery, and 15 patients (3%) did not receive at least 41.4 Gy in 23 fractions. By intention to treat, median survival was 24.1 months for trimodal therapy and 21.9 months for definitive chemoradiotherapy. Per protocol, median survival was 30.9 months for trimodal therapy compared to 28.2 months for definitive chemoradiotherapy. No difference in OS was detected either by intention to treat (Cox HR: 0.81; 95% CI: 0.52-1.26; p=0.4) or per protocol (Cox HR: 0.72; 95% CI: 0.42-1.24; p=0.2). <h3>Conclusion</h3> No difference in OS was detected between trimodal therapy and definitive chemoradiotherapy. Our HR was more favorable for definitive chemoradiotherapy than previous retrospective studies on esophageal adenocarcinoma, possibly reflecting the use of treatment intent to account for trimodal patients who fail to undergo surgery. These findings suggest that definitive chemoradiotherapy may be an alternative to trimodal therapy for selected patients after weighing any potential of trimodal therapy prolonging survival against operative morbidity, operative mortality risk, and cost, but further studies including randomized controlled trials are required.

Local Homogeneity of PET Images Visualizes Peri-Irradiation CD8 T Cell Exhaustion

<h3>Purpose/Objective(s)</h3> The functional states of CD8⁺ T cells are associated with response to immune checkpoint inhibitors (ICI) and might become a potential biomarker indicating the timing of ICI. CD8⁺ T cells undergoing exhaustion (Tex) exhibit progressive loss of effector functions as well as metabolic insufficiency, such as suppressed glycolysis and restricted glucose uptake. We assumed that metabolic characteristics of Tex might be reflected by PET radiomic features, which could be used to noninvasively visualize the peri-irradiation dynamics of Tex and predict the optimal timing of ICI integration. Here, we aim to investigate the dynamics of Tex after ablative irradiation and develop an ¹⁸F-FDG PET/CT radiomic approach to assess tumor infiltrating Tex basing on non-small cell lung cancer (NSCLC) xenograft experiments. <h3>Materials/Methods</h3> C57BL/6 mice were inoculated with 1M Lewis Lung Carcinoma (LLC) cells subcutaneously on the right flank. On day 10 post-tumor inoculation, 20Gy was delivered to the tumors in a single fraction. For the control (D0) and those irradiated (D3, D7, D14 and D21 post-irradiation), mice received micro PET-CT scans and were sacrificed immediately after scanning, with tumors and spleens collected. The abundance of tumor-infiltrating immune cell subsets were estimated by deconvoluting the tumor microarray data with CIBERSORTx. ICI-responsive early Tex (CD8⁺PD-1^intTcf-1⁺) and ICI-nonresponsive terminal Tex (CD8⁺PD-1^hiTIM-3⁺TOX⁺) were identified by flow cytometry. Tumors on PET/CT images were manually contoured, and radiomic features were extracted by a compact proton therapy machine. Robust features which passed Test-retest analysis will undergo further selection. Least absolute shrinkage and selection operator (LASSO) logistic regression was used to select radiomic features significantly correlated with the infiltration of early or terminal Tex. <h3>Results</h3> After ablative irradiation, the tumor CD8⁺ T cell infiltration increased from D3 through the peak on D14, and then declined sharply to a below-baseline level on D21. However, dysfunctional terminal Tex significantly predominated CD8⁺ T cells from D7 to D14 (69.44%∼ 76.35%), indicating a potential window for ICI treatment between D3-D7 post-irradiation. 40 (out of 57) CT and 9 (out of 61) PET radiomic features of good robustness were brought into LASSO regression. Gray Level Co-occurrence Matrix (GLCM)-inverse variance and Gray Level Run Length Matrix (GLRLM)-long run emphasis on PET images were found to be inversely correlated with the abundance of terminal Tex, showing more heterogeneous local distribution of FDG uptake correlated with higher T exhaustion. <h3>Conclusion</h3> The dynamics of Tex help identify the proper timing to combine ICI with irradiation. Local homogeneity of PET images may provide a noninvasive approach to visualize peri-irradiation T cell exhaustion, and exhibit the potential to estimate ICI timing among more radiation dose-fractionation schedules in future study.