Conventional Fractionation Radiotherapy Research Articles

Long-Term Analysis of NRG Oncology RTOG 0415: A Randomized Phase III Noninferiority Study Comparing Two Fractionation Schedules in Patients With Low-Risk Prostate Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.NRG Oncology RTOG 0415 is a randomized phase III noninferiority (NI) clinical trial comparing conventional fractionation (73.8 Gy in 41 fractions) radiotherapy (C-RT) with hypofractionation (H-RT; 70 Gy in 28) in patients with low-risk prostate cancer. The study included 1,092 protocol-eligible patients initially reported in 2016 with a median follow-up of 5.8 years. Updated results with median follow-up of 12.8 years are now presented. The estimated 12-year disease-free survival (DFS) is 56.1% (95% CI, 51.5 to 60.5) for C-RT and 61.8% (95% CI, 57.2 to 66.0) for H-RT. The DFS hazard ratio (H-RT/C-RT) is 0.85 (95% CI, 0.71 to 1.03), confirming NI (P < .001). Twelve-year cumulative incidence of biochemical failure (BF) was 17.0% (95% CI, 13.8 to 20.5) for C-RT and 9.9% (95% CI, 7.5 to 12.6) for H-RT. The HR (H-RT/C-RT) comparing biochemical recurrence between the two arms was 0.55 (95% CI, 0.39 to 0.78). Late grade ≥3 GI adverse event (AE) incidence is 3.2% (C-RT) versus 4.4% (H-RT), with relative risk (RR) for H-RT versus C-RT 1.39 (95% CI, 0.75 to 2.55). Late grade ≥3 genitourinary (GU) AE incidence is 3.4% (C-RT) versus 4.2% (H-RT), RR 1.26 (95% CI, 0.69 to 2.30). Long-term DFS is noninferior with H-RT compared with C-RT. BF is less with H-RT. No significant differences in late grade ≥3 GI/GU AEs were observed between assignments (ClinicalTrials.gov identifier: NCT00331773).

Treatment outcome of elderly patients (≥ 78 years) with head and neck squamous cell carcinoma: A single center experience.

Patients older than the expected age of the local population generally have limited life expectancy. The optimal treatment approach for very elderly patients with head and neck cancer remains uncertain. This study retrospectively analyzed patients over 78 years old, the expected age in 2019 for Chinese individuals, who underwent treatment for head and neck cancer at a tertiary cancer center in China. The study compared the overall survival rates among different treatment groups. The findings revealed that among patients eligible for surgery, radical resection yielded better outcomes compared to radiotherapy-based treatments, with a hazard ratio of 0.362 (95% CI 0.160-0.819, P = 0.015). Among patients who received radiotherapy, those who received a total dose exceeding 60 Gy had a significantly longer survival compared to those who received palliative doses, with median survival time of 31 months versus 14 months (P = 0.003). Among 78 patients who underwent conventional fractionated radiotherapy (CFRT), 15 patients (19.23%) experienced unscheduled treatment breaks with a median duration of 12 days. However, these treatment breaks did not appear to impact survival (P > 0.1). The study also suggested that altered fractionated radiotherapy, including hypofractionated radiotherapy (hypo-RT), could be a viable alternative to CFRT, offering similar survival outcomes with reduced treatment duration. In conclusion, eligible patients should be treated with curative intent, even if they are older than the expected age of the local population. When radiotherapy is indicated, altered fractionation, particularly hypo-RT, may be a favorable option to consider.

Trends in low-value cancer care during the COVID-19 pandemic.

To assess the association between the onset of the COVID-19 pandemic and change in low-value cancerservices. In this retrospective cohort study, we used administrative claims from the HealthCore Integrated Research Environment, a repository of medical and pharmacy data from US health plans representing more than 80 million members, between January 1, 2016, and March31, 2021. We used linear probability models to investigate the relation between the onset of the COVID-19 pandemic and 4 guideline-based metrics of low-value cancer care: (1) conventional fractionation radiotherapy instead of hypofractionated radiotherapy for early-stage breast cancer; (2) non-guideline-based antiemetic use for minimal-, low-, or moderate- to high-risk chemotherapies; (3) off-pathway systemic therapy; and (4) aggressive end-of-life care. We identified patients with new diagnoses of breast, colorectal, and/or lung cancer. We excluded members who did not have at least 6 months of continuous insurance coverage and members with prevalent cancers. Among 117,116 members (median [IQR] age, 60[53-69] years; 72.4% women), 59,729 (51.0%) had breast cancer, 25,751 (22.0%) had colorectal cancer, and 31,862(27.2%) had lung cancer. The payer mix was 18.7% Medicare Advantage or Medicare supplemental and 81.2% commercial non-Medicare. Rates of low-value cancer services exhibited minimal changes during the pandemic, as adjusted percentage-point differences were 3.93 (95%CI, 1.50-6.36) for conventional radiotherapy, 0.82 (95% CI, -0.62 to 2.25) for off-pathway systemic therapy, -3.62 (95% CI, -4.97 to -2.27) for non-guideline-based antiemetics, and 2.71(95% CI, -0.59 to 6.02) for aggressive end-of-life care. Low-value cancer care remained prevalent throughout the pandemic. Policy makers should consider changes to payment and incentive design to turn the tide against low-value cancer care.

Efficacy and Toxicity of Moderately Hypofractionated Radiation Therapy with Helical TomoTherapy Versus Conventional Radiation Therapy in Patients with Unresectable Stage III Non-Small Cell Lung Cancer Receiving Concurrent Chemotherapy: A Multicenter, Randomized Phase 3 Trial

PurposeThe standard treatment schedule for unresectable stage III non–small-cell lung cancer (NSCLC) is chemotherapy with concurrent radiotherapy (60 Gy delivered in 30 fractions), although moderately hypofractionated radiotherapy (Hypo-RT) has also been considered as an alternative strategy. This study aimed to compare the efficacy and toxicity of moderately Hypo-RT with helical TomoTherapy versus conventionally fractionated radiotherapy (Con-RT) in patients with unresectable stage III NSCLC receiving concurrent chemotherapy. Methods and MaterialsIn this randomized multicentre non-blinded phase III clinical trial, eligible patients were randomized at a 1:1 ratio to either the Hypo-RT group, (60 Gy in 20 fractions) or to the Con-RT group (60 Gy in 30 fractions). All patients received two cycles of concurrent platinum-based chemotherapy plus two cycles of consolidation therapy. The primary endpoint was 3-year overall survival (OS) in the intention-to-treat population. The secondary endpoints were progression-free survival (PFS) and treatment-related adverse events. ResultsA total of 146 patients were enrolled from July 27, 2018 to November 1, 2021. The median follow-up was 46 months. The 3-year OS rates in the Hypo-RT and the Con-RT groups were 58.4% and 38.4%, respectively (P = 0.02). The median OS from randomization was 41 months in the Hypo-RT group and 30 months in the Con-RT group (hazard ratio, 0.61; 95% confidence interval, 0.40–0.94; P = 0.02). There was no significant difference in the rates of grade ≥2 treatment-related adverse events between the two groups. ConclusionsModerately Hypo-RT using helical TomoTherapy may improve OS in patients with unresectable stage III NSCLC while maintaining toxicity rates. TRIAL REGISTRATION Chinese Clinical Trial RegistryChiCTR1800017367

Stereotactic body radiotherapy compared to conventionally fractionated radiotherapy for locally advanced or oligometastatic pancreatic cancer.

677 Background: Pancreatic cancer, particularly in its locally advanced and oligometastatic forms, poses a formidable therapeutic challenge. Radiotherapy remains an important treatment in an attempt to gain local control, however there is no consensus on whether stereotactic body radiotherapy (SBRT) is appropriate as compared to conventionally fractionated radiotherapy (CFRT). Herein, we report our experience. Methods: We conducted a retrospective analysis of patients with locally advanced and oligometastatic pancreatic cancer who received definitive radiotherapy at our institution between January 2010 and March 2023 with SBRT 30-50 Gy in 3-5 fractions or CFRT 50-60 Gy in 25-30 fractions. We excluded all patients with resectable disease who underwent surgery. Clinicopathological data, treatment regimens, and radiation parameters were collected and analyzed. Results: A total of 51 patients (17 females, 34 males; median age: 67.9 years). 24 patients (47.1%) were treated with CFRT, and 27 patients (52.9%) were treated with SBRT. Median time of follow-up for the entire cohort was 14.4 months. A total of 13 patients (25%) experienced a Local failure (LF) at a median time of 18.5 months, with no difference observed between CFRT and SBRT groups. Cancer-specific mortality (CSM) was statistically significant with a lower mortality rate in SBRT (37%) vs CFRT group (63%) (p&lt;0.004). Several treatment characteristics and dosimetric factors such as sex, age, receipt of chemotherapy, type of chemotherapy, use of elective nodal irradiation, GTV size, biologically equivalent dose (BED) corrected prescribed dose, minimum dose to GTV, or max dose to GTV did not predict local failure. There was no difference in QOL and toxicity between the two groups. Conclusions: In our cohort, local failure rates remain high and were similar between patients treated with SBRT compared to those treated with conventionally fractionated radiotherapy. We were unable to identify any specific predictors for local recurrence in this patient population. Our observation of a lower CSM rate among patients who received SBRT needs further study. The findings underscore the need to further improve radiotherapeutic approaches in an attempt to improve local control in locally advanced disease.

Use of Radiation Therapy for the Treatment of Breast Cancer in 2019 Versus 2020

PurposeThe COVID-19 pandemic disrupted medical care. Little is known about how radiation therapy (RT) ordering behavior changed during the pandemic. This study examined: 1. whether there was a change in the rate at which orders for lumpectomy were followed by orders for RT, and 2. whether there was a change in the percentage of RT orders that were for hypofractionated (HF) RT, rather than conventionally fractionated (CF) RT. Materials and MethodsPrior authorization order data from 2019 and 2020, pertaining to patients with commercial and Medicare Advantage health plans were reviewed to determine whether patients had an order for RT in the 90 days following lumpectomy, and if it was for CF or HF RT. Univariate analyses were conducted using Chi-square tests, and adjusted analyses were conducted using multivariate logistic regression, controlling for patient age, urbanicity, local median income, region, if the lumpectomy facility was academic, and if the lumpectomy facility was a hospital. ResultsIn 2019, 47.7% (2,200/4,610) of included lumpectomy orders were followed by an RT order within 90 days, in contrast to 45.6% (1,944/4,263) in 2020 (P=0.048). Of the RT orders meeting this study's definition of CF or HF, 75.3% (1,387/1,843) of orders placed in 2019 and 79.0% (1,261/1,597) of orders placed in 2020 were for HF (P=0.011). Adjusted analysis found patients receiving a lumpectomy order in the 1st quarter of 2020 had significantly reduced odds (OR: 0.84; 95% CI: 0.71-0.99) of receiving an order for RT following lumpectomy relative to those with orders placed in the 1st quarter of 2019. Adjusted analysis likewise found significant evidence of increased use of HF RT during the pandemic. ConclusionIn the population examined, physicians were less likely to order RT following lumpectomy in 2020 than in 2019, and if they did, were more likely to order HF RT.

A Comparative Study of the Toxicities and Local Recurrence of Conventional External Beam Radiotherapy versus Hypofractionated Radiotherapy in Breast Cancer Patients

Introduction: Breast cancer is the most common cancer amongst women, which is treated by a multi-modality approach consisting of surgery, chemotherapy, radiotherapy, hormonal therapy, targeted therapy and immunotherapy. Objective: The aim of the study is to compare the early and late treatment toxicities and the local recurrence following Conventional and Hypofractionated External Beam Radiotherapy in breast cancer patients after surgery. Methods: A randomized study was conducted for two years including 150 patients. The patients were divided into two arms, with Arm-A receiving a total dose of 50Gy/25# and the Arm-B receiving 40Gy/16#. Results: Early and late treatment toxicities were comparable in both the arms, except for skin toxicity which was more in the hypofractionated arm (Arm-B). Local Recurrence was observed in Arm-A in 1 patient at Month 17 of follow-up, and in Arm-B at Month 13 in 1 patient and at Month 21 in 1 patient. Conclusion: Hypofractionated radiotherapy given over a short period of time is comparable to Conventional fractionation radiotherapy without any significant statistical difference in terms of toxicities or local recurrence; with an added advantage of reduced treatment time, reduced duration of hospital stays, better patients’ compliance and reduced cost of treatment.

Obtaining organ-specific radiobiological parameters from clinical data for radiation therapy planning of head and neck cancers

Objective. Different radiation therapy (RT) strategies, e.g. conventional fractionation RT (CFRT), hypofractionation RT (HFRT), stereotactic body RT (SBRT), adaptive RT, and re-irradiation are often used to treat head and neck (HN) cancers. Combining and/or comparing these strategies requires calculating biological effective dose (BED). The purpose of this study is to develop a practical process to estimate organ-specific radiobiologic model parameters that may be used for BED calculations in individualized RT planning for HN cancers. Approach. Clinical dose constraint data for CFRT, HFRT and SBRT for 5 organs at risk (OARs) namely spinal cord, brainstem, brachial plexus, optic pathway, and esophagus obtained from literature were analyzed. These clinical data correspond to a particular endpoint. The linear-quadratic (LQ) and linear-quadratic-linear (LQ-L) models were used to fit these clinical data and extract relevant model parameters (alpha/beta ratio, gamma/alpha, d T and BED) from the iso-effective curve. The dose constraints in terms of equivalent physical dose in 2 Gy-fraction (EQD2) were calculated using the obtained parameters. Main results. The LQ-L and LQ models fitted clinical data well from the CFRT to SBRT with the LQ-L representing a better fit for most of the OARs. The alpha/beta values for LQ-L (LQ) were found to be 2.72 (2.11) Gy, 0.55 (0.30) Gy, 2.82 (2.90) Gy, 6.57 (3.86) Gy, 5.38 (4.71) Gy, and the dose constraint EQD2 were 55.91 (54.90) Gy, 57.35 (56.79) Gy, 57.54 (56.35) Gy, 60.13 (59.72) Gy and 65.66 (64.50) Gy for spinal cord, optic pathway, brainstem, brachial plexus, and esophagus, respectively. Additional two LQ-L parameters d T were 5.24 Gy, 5.09 Gy, 7.00 Gy, 5.23 Gy, and 6.16 Gy, and gamma/alpha were 7.91, 34.02, 8.67, 5.62 and 4.95.Significance. A practical process was developed to extract organ-specific radiobiological model parameters from clinical data. The obtained parameters can be used for biologically based radiation planning such as calculating dose constraints of different fractionation regimens.

Quality assurance in a phase III, multicenter, randomized trial of POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a planning benchmark case

PurposeTo report the planning benchmark case results of the POTENTIAL trial—a multicenter, randomized, phase 3 trial—to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer.MethodsAll participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission.ResultsThe plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively.ConclusionThe major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

Phase II multicenter trial: first-line immunochemotherapy with or without radiotherapy in metastatic esophageal squamous cell cancer (SCR-ESCC-01).

This randomized phase II trial (NCT05978193) combines low-dose radiotherapy (LDRT) and conventionally fractionated radiotherapy (CFRT) with immunochemotherapy for metastatic esophageal squamous cell carcinoma, aiming to assess the potential enhanced effect of radiotherapy on immunotherapy. Patients are administered a PD-1 inhibitor along with paclitaxel and platinum-based chemotherapy (arm B), or combined with LDRT and CFRT (arm A). Immunotherapy is given every 3 weeks with chemotherapy for 4 cycles, followed by immunotherapy maintenance therapy for up to 24months. In arm A, LDRT (2Gy, 2 fractions; delivered to the primary and all metastatic tumors) precedes each immunochemotherapy cycle for 4 cycles, followed by CFRT (40-50Gy, 20-25 fractions; delivered to the primary tumor) starting from the fifth immunotherapy cycle. The primary end point is median progression-free survival. Clinical Trial Registration: NCT05978193 (clinicaltrials.gov).

Efficacy and Safety of Radiotherapy Combined with Pyrotinib in the Treatment of HER2-Positive Breast Cancer with Brain Metastases.

To explore the efficacy and safety of pyrotinib combined with different radiotherapy modes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastasis (BM). This study is a retrospective analysis of patients diagnosed with BM who underwent treatment with pyrotinib between November 2018 and April 2023. A total of 66 patients were administered radiotherapy in conjunction with pyrotinib (Group A), while 26 patients received pyrotinib as a standalone treatment (Group B). Within Group A, 18 patients underwent conventional fractionated radiotherapy (2Gy/F), while 48 patients received hyperfractionated radiotherapy (HFRT) (≥3Gy/F). The primary endpoints were intracranial progression-free survival (IC-PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR) and clinical benefit rate (CBR). The ORR of Group A was 54.5% (36/66), while the ORR of Group B was 34.6% (9/26) (P= 0.047). The CBR of Group A was 89.4% (59/66) and that of Group B was 69.2% (18/26) (P= 0.041). The IC-PFS between Group A and Group B were 12 months and 8 months, respectively (P< 0.001), and the OS were 20 months and 16 months, respectively (P= 0.065). In Group A, the IC-PFS and OS between the conventional fractionation radiotherapy group and the HFRT group were 10 months and 12 months, respectively (P= 0.001) and 16 months and 24 months, respectively (P< 0.001). No serious adverse reactions were observed in Group A and Group B. For HER2-positive BC patients with BM, it is recommended to adopt the treatment mode of HFRT combined with pyrotinib, which can improve the local control and survival of patients.

A comparison of conventional and accelerated hypofractionated radiotherapy in definitive chemoradiation for locally advanced head and neck carcinoma: a retrospective cohort study.

The study evaluates accelerated hypofractionated radiotherapy (AHRT) compared to conventional fractionation radiotherapy (CFRT) in patients with locally advanced head and neck cancer (LAHNC) receiving definitive chemoradiation therapy. The study includes a retrospective cohort analysis of 120 patients. CFRT arm (n = 65) received 2 Gy per fraction to a dose of 70 Gy over 7 weeks in a three-volume approach, whereas the AHRT arm (n = 55) received 2.2 Gy per fraction to a dose of 66 Gy in 6 weeks with a two-volume approach. The primary outcome was overall survival (OS). With a median follow-up of 18.9 months, 23 patients died in the AHRT arm, and 45 deaths in the CFRT arm. The median OS was 23.4 and 37.63 months in the CFRT and AHRT arms, respectively (hazard ratio [HR] = 0.709; 95% confidence interval [CI], 0.425-1.18; p = 0.189). The median time to loco-regional control was 33.3 months in the CFRT arm and was not reached in the patient group receiving AHRT (HR = 0.558; 95% CI, 0.30-1.03; p = 0.065). The median progression-free survival was 15.9 months in the CFRT arm and 26.9 months in the AFRT arm (HR = 0.801; 95% CI, 0.49-1.28; p = 0.357). Out of 11 acute toxic deaths, eight were in the CFRT arm. The study showed a trend towards benefit in terms of locoregional control in the AHRT arm and similar OS. A longer follow-up of patients receiving AHRT is required to assess the benefit.

Long-Term Outcomes Following Fairly Brief Androgen Suppression and Stereotactic Radiation Therapy in High-Risk Prostate Cancer: Update from the FASTR/FASTR-2 Trials.

There has been emerging interest in the role of ultra-hypofractionated radiotherapy for high-risk prostate cancer, especially given its low α/β ratio. However, there is limited data on the long-term outcomes of this treatment strategy. The FASTR and FASTR-2 clinical trials were designed to assess the tolerability of stereotactic ablative body radiotherapy (SABR) in high-risk prostate cancer. FASTR was discontinued early due to unacceptable acute toxicity, whereas the acute toxicities in FASTR-2 were minimal. Herein, the long-term results from these trials are reported. Eligible patients had at least 1 high-risk feature as per the National Comprehensive Cancer Network criteria for high-risk prostate cancer, no evidence of metastatic disease, and either a score of 3+ on the Vulnerable Elderly Scale or declined standard therapy. A total of 19 patients from a single institution were enrolled on FASTR between 2011 and 2015. They received 40 Gy to the prostate and 25 Gy to the pelvic lymph nodes in 5 fractions delivered once weekly for 5 weeks, along with 1 year of androgen deprivation therapy (ADT). The excessive acute toxicity in FASTR prompted several modifications in FASTR-2, including the omission of nodal irradiation. A total of 30 patients from the same institution were enrolled on FASTR-2 between 2015 and 2017. They received 35 Gy to the prostate alone in 5 fractions delivered once weekly for 5 weeks, along with 18 months of ADT. A total of 44 patients were eligible for analysis, 16 from FASTR and 28 from FASTR-2. Most patients were >70 years old (77%). High-risk features included Gleason score ≥8 (46%), T3-T4 disease (27%) and baseline PSA >20 (50%). With a median follow-up of 6.4 years, the cumulative incidence of grade ≥3 genitourinary/gastrointestinal toxicity was 50% among FASTR patients and 7% among FASTR-2 patients. At 5 years, the combined rates of biochemical failure-free survival, freedom from distant metastases, prostate cancer-specific survival and overall survival were 72%, 90%, 92% and 83%, respectively. A total of 12 patients (27%) required further treatment. No significant differences in clinical outcomes were noted between the FASTR and FASTR-2 cohorts. SABR for high-risk prostate cancer is an attractive option for reducing treatment burden. Clinical outcomes and toxicity with the FASTR-2 protocol were comparable to conventionally-fractionated radiotherapy plus ADT. Larger prospective, randomized trials exploring the role of SABR with ADT in high-risk disease are necessary to better understand the efficacy and tolerability of this approach.

The Updated Landscape of Tumor Microenvironment and Pre-Metastasis Niches for Radiotherapy Resistant Tumors

In the current clinical work, hypo-fractionated radiotherapy (HFRT) and conventional fractionated radiotherapy (CFRT) are considered to be completely different treatments. However, the difference between the HFRT and CFRT in reprogramming the tumor immune microenvironment (TIME) is still inconclusive. Our previous work found that compared with HFRT, CFRT is more inclined to trigger immunosuppressive phenotype, but the underlying mechanism is still unclear. Based on this, we use single-cell mRNA sequencing to describe the landscape of TIME with HFRT and CFRT, and find the key targets or pathways to combine with radiotherapy. By simulating the in vivo radiotherapy strategy, we built recurrent murine cell lines mimicking CFRT and HFRT recurrent tumors (CFRT_R and HFRT_R tumors) with small animal radiation research platform (SARRP). Based on this unique model, we found that CFRT_R tumors can promote local relapse and lung metastasis significantly compared to HFRT_R tumors. Results of single-cell mRNA sequencing and FCAS also indicate that CFRT_R tumors possess more macrophages in the tumor site and neutrophils in the metastatic site. By using quantitative proteomics of secreted proteins, we prove that CFRT_R tumors secret more Ccl2, S100a11 and Slpi. Mechanically, CFRT_R tumors influence the polarization of M2 TAMs leading to tumor growth through secretion of Ccl2 and S100a11. Meanwhile, CFRT_R tumors also augment the infiltration of neutrophils in the lung through Slpi altering the lung immune landscape to support metastasis. ChIP and EMSA results also reveal that RelB is the core transcription factor of Ccl2, S100a11 and Slpi. Furthermore, local relapse and lung metastasis can be reversed by targeting non-canonical NF-kB pathway. The effect of CFRT_R and HFRT_R tumors in reprogramming TIME is different, CFRT_R tumors can trigger immunosuppressive phenotype compared to HFRT_R tumors by possessing more M2 TAMs in the tumor site and neutrophils in the metastatic site. The killing function of tumor infiltrated T cells can be inhibited by accumulated M2 TAMs, and abundant neutrophils in lungs contribute to the formation of the pre-metastatic niche. Targeting non-canonical NF-kB pathway can reverse local relapse and lung metastasis in CFRT_R tumors by suppressing Ccl2, S100a11 and Slpi secretion. In short, our study not only deepens the understanding of the immune landscape of CFRT and HFRT recurrence tumors, but also provides a novel therapy of CFRT recurrence patients.

A Phase II Randomized Clinical Trial to Assess Toxicity and Quality of Life of Breast Cancer Patients with Hypofractionated vs. Conventional Fractionation Radiotherapy with Regional Nodal Irradiation

To compare acute toxicity between conventional fractionated radiation therapy (CFRT) and hypofractionated radiation therapy (HFRT) 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. Unblinded randomized trial with a total of 86 patients treated with CFRT (n = 33; 50 Gy/25 fractions ± sequential boost [10 Gy/5 fractions]) versus HFRT (n = 53; 40 Gy/15 fractions ± concomitant boost [8 Gy/15 fractions]). Women included for enrollment were 18 years or older and diagnosed with breast carcinoma, staging T1-4, with at least one positive lymph node (American Joint Committee on Cancer - AJCC 8th). The surgery performed was mastectomy or breast-conservative surgery with the investigation of sentinel lymph node or axillary dissection. 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 the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) and the breast cancer-specific supplementary questionnaire (QLQ-BR23). The comparative analysis of categorical variables between the control and experimental groups used the Chi-square test and Fisher's exact test, while numerical variables basing on the Mann-Whitney U test. The intergroup comparison of the EORTC QLQ-C30 used the Generalized Equations Estimating method. All analyses used 2-sided α = 0.05 with R software version 4.1.2. Lymphedema determination compared volume differences between the affected and contralateral arms using the Casley-Smith volume formula. Grade 2 and grade 3 skin rash dermatitis were lower with HFRT than with CF-RT (28% vs. 52%, 0% vs. 6%; p = 0.022, respectively). HFRT vs. CFRT had lower rate of grade 2 hyperpigmentation (23% vs. 55%; p = 0.005). Overall rates of any physician-assessed grade ≥ 2 and grade ≥ 3 acute toxicities were no different between HFRT vs. CFRT arms. There was no statistical difference between the CFRT and the HFRT regarding cosmesis, lymphedema rate (13% vs. 12% HFRT vs. CFRT; p = 1.000, respectively), and functional and symptom scales during irradiation and after six months of treatment. HF-RT showed lower rates of acute toxicity, with no changes in quality-of-life outcomes.

Hypofractionated Accelerated Radiation Dose-Painting (HARD) vs. Standard Radiotherapy for Unresected Soft-Tissue Sarcoma

Conventionally fractionated radiotherapy (CFRT) offers modest local control (LC) for unresected soft tissue sarcoma (STS). Although STS has a low α/β (∼2 - 6) that may benefit from a hypofractionated radiotherapy regimen, it is often limited due to the toxicity risk to surrounding organs. A simultaneous integrated boost to gross disease (2.5 - 3 Gy/fraction), with lower doses to the intermediate and low risk target volume, may offer a safe isotoxic dose escalation approach. We hypothesize that this hypofractionated accelerated radiotherapy dose-painting (HARD) will improve local control compared to CFRT. We performed a single institution retrospective analysis of patients who received external beam radiotherapy with definitive intent (≥50 Gy) for unresected STS. CFRT was defined as 1.8 - 2 Gy/fraction (Gy/fx). HARD regimens consisted of 60 - 66 Gy at 3 Gy/fx or 70 Gy at 2.5 Gy/fx to gross disease, with 1.8 - 2.4 Gy/fx to intermediate and low risk regions. All anatomical sites and histologies were included. Local control (LC) was defined from date of current diagnosis, estimated by Kaplan-Meier methods via log-rank tests or Cox regression for univariate analysis (UVA), when appropriate. Cox regression multivariate analysis (MVA) included regimen, biological effective dose (α/β 6; BED6), lesion size, age, and grade. We identified 77 patients with primary and metastatic STS treated with HARD (n = 40) or CFRT (n = 37) between 1990 and 2022, with a median follow up of 24 months in surviving patients. The mean dose for CFRT and HARD are 56.8 Gy (50 - 77.4 Gy) and 64.9 Gy (60 - 70 Gy), respectively. HARD was comprised of 65% for 3 Gy/fx and 35% for 2.5 Gy/fx regimens. At the time of RT, grade 3 (69%) and extremity (39%) tumors were the most common. Tumor histology was very heterogenous across both cohorts, with undifferentiated pleomorphic sarcoma being the most common for HARD (33%) and CFRT (19%). HARD was more often utilized in stage IV patients (55% vs. 19%, p = 0.001) and had a higher mean BED6 (96 vs. 74.2 Gy, p < 0.001) than CFRT, but without differences in age (67 vs. 59 years), tumor size (8 vs. 10 cm), concurrent chemotherapy (35% vs. 30%), Karnofsky performance status (86 vs. 85), follow-up (19 vs. 28 months), and grade (all p > 0.1). On UVA, there was a LC benefit associated with higher BED6 (HR 0.94, 95% CI 0.9 - 0.98, p = 0.002) and the HARD regimen (2-year LC 95% vs. 62%, p < 0.001). On MVA, only HARD (HR 0.07, 95% CI 0.006 - 0.729, p = 0.027) was independently associated with LC. Although the HARD regimen and higher BED6 were both associated with significant improvement in LC, only the HARD regimen independently associated with a local control benefit for unresected STS. These results suggest biologic dose-intensification exploiting the low α/β of STS with an isotoxic hypofractionated regimen may be a favorable strategy for unresectable STS. Future prospective studies are necessary to validate these findings.

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.

Conventional vs. Hypo-Fractionated, Radiotherapy for High-Risk Prostate Cancer (PCS5), Randomized, Non-Inferiority, Phase 3 Trial: Posthoc Analysis of IMRT vs. 3D-CRT Radiation Therapy Associated Toxicities

The Prostate Cancer Study number 5 (PCS5), is a multi-centric non-inferiority, phase 3, randomized controlled trial of high-risk prostate cancer patients of treated with either conventionally fractionated radiotherapy (CFRT) or hypofractionated radiotherapy (HFRT). The 7 years' pre-planned analysis showed that HFRT (68 Gy in 25 fractions) was as effective and well tolerated as CFRT (76 Gy in 38 fractions). In this posthoc analysis we aim to report the genitourinary (GU) and gastrointestinal (GI) toxicities associated with radiation therapy techniques: intensity-modulated radiotherapy (IMRT) and 3D-conformal radiotherapy (3D-CRT). PCS5 randomized patients in a 1:1 ratio to receive either CFRT or HFRT. All patients received long term neoadjuvant, concurrent and adjuvant androgen suppression, with a median duration of 24 months. The toxicities were reported as per the Common Terminology Criteria for Adverse Events version 4. Acute toxicities were defined as presenting ≤ 180 days post-RT start and delayed > 180 days. The cumulative acute and delayed GI and GU toxicities were classified in grade groups: grade 1 or higher (G1+), G2+, and G3+. For each grade group, acute and delayed, we performed multivariable logistic regression analyses, adjusting for age, CTV volume, diabetes, fractionation (CRFT or HFRT), hypertension, and stage < T3b or ≥ T3b. For efficacy analyses cox-regression was utilized. A p-value < 0.05 was considered significant. Three hundred twenty of the 329 patients enrolled in the trial were included in this posthoc analyses. The mean age was 71.4 ± 6.1 years, and the mean CTV volume (n = 219) was 47.25 ± 19.9 cc. IMRT was used in 195 (60.6%) patients and 3D-CRT in 125 (39.1%) patients. Multivariable logistic regression showed a significant difference in favor of IMRT for GI G2+ acute toxicity (OR = 0.285 [0.14-0.59]; CI: 95%; p<0.001) and GI G2+ delayed toxicity (OR = 0.202 [0.60-0.69]; CI: 95%; p = 0.01). There were no differences in G3+ GI or GU toxicities and there were no grade 4 toxicities. There were no differences in efficacy at 7 years between the two treatment technics. Outcomes for IMRT vs. 3D-CRT respectively, overall survival (81.5% vs 79.2%; HR: 0.92 [0.55-1.53]; CI: 95%; p-value: 0.74), distant metastasis free survival (90,7% vs 92.8%; HR: 1.4 [0.63-3.1]; CI: 95%; p-value: 0.42), prostate cancer mortality (95.8% vs. 92.2%; HR: 0.93 [0.32-2.67]; CI: 95%; p-value: 0.89), and biochemical failure (85.1% vs 88%; HR: 1.35 [0.72-2.52]; CI: 95%; p-value: 0.35). This is the first phase 3 randomized controlled trial assessing the use of HFRT vs. CFRT, exclusively in high-risk prostate cancer patients. Given that our efficacy data at 7 years follow-up establishes moderate HFRT as a new standard of care and no difference between IMRT and 3D-CRT, we strongly recommend that patients who are treated with EBRT should receive IMRT, given the reduced acute and delayed grade 2 or higher GI toxicities.

Conventionally Fractionated vs. Hypofractionated Radiotherapy for Treatment of Unresectable Pancreatic Cancer: Local Control and Survival Outcomes in a Retrospective Single-Institutional Analysis

Unresectable pancreatic cancer (UPC) is associated with dismal survival outcomes, with a reported median survival of 8-12 months. The role of radiotherapy (RT) and the choice of optimal fractionation remains unclear. Our objective was analyzing the outcomes associated with local radiotherapy as well as determine the best radiotherapeutic approach to treat these patients. From a database of 209 radiation plans of patients treated for pancreatic cancer in a single institution between August 2007 to August 2021, patients with UPC were selected for this REB approved retrospective study. From the 209 plans, 136 unique patients were identified who had RT for UPC. The mean age of the cohort was 67.6 years, 10% were >80 years and 37% were female. Median follow-up was 9.3 months. 54 patients had distant metastases at the time of RT and were analyzed separately. Outcomes where analyzed based on whether patients received Conventionally fractionated RT (CFRT) (defined as >15 fractions) (n = 23 (17%)), Hypofractionated RT (HypoRT) (defined as ≤15 fractions and EQD2<40Gy for α/β = 3) (n = 40 (29%)) and those treated with Stereotactic Body RT (SBRT) (defined as ≤5 fractions and EQD2≥40Gy for α/β = 3) (n = 19 (14%)). The mean overall survival (OS) and freedom from progression (FFP) in the SBRT cohort was 17.2 and 7.4 months respectively, in the CFRT cohort was 22.6 and 9.9 months respectively and in the HypoRT cohort was 11.4 and 4.9 months respectively. All CFRT patients received chemotherapy. Mean OS was drastically lower in SBRT and HypoRT patients who did not receive any chemotherapy (11.9 and 3.4 months respectively). Patients with metastatic disease at presentation and receiving HypoRT had mean OS of 13.4 months. The average EQD2 for the cohorts were 45.4 Gy, 49.2 Gy and 30.3 Gy for CFRT, SBRT and HypoRT respectively. Our study demonstrates that CFRT with concurrent chemotherapy offers better therapeutic outcomes in patients with UPC compared to HypoRT. The role of dose escalated SBRT needs to be explored as an equal alternative.

Partial Stereotactic Ablative Radiotherapy in Bulky Urinary Tract Malignancy: An Update Clinical Outcomes and Dosimetric Analysis

Patients with bulky urinary tract malignancy have poor prognosis. Stereotactic ablative radiotherapy (SABR) needs careful consideration in abdominopelvic bulky tumors because of dose constraints on the OARs. We reported updated clinical outcomes to evaluate the safety and efficacy of partial stereotactic ablative radiotherapy(P-SABR) in bulky urinary tract malignancy. The study also aims to investigate the feasibility of P-SABR in dose and biologic effective dose (BED) escalation inside the tumors with equivalent toxicity. A total of 26 patients with urinary tract malignancy underwent P-SABR radiotherapy from January 2013 to September 2018 were retrospectively analyzed in this study. All the patients were in inoperable locally advanced or metastatic stage with tumor diameter > 4.0 cm. The P-SABR plan consisted of the SABR for gross tumor volume boost (GTVb) and following conventionally fractionated radiotherapy for planning target volume (PTV). The first SABR plan to GTVb was delivered in 15-32Gy/3-5f. The second conventionally fractionated radiotherapy plan to PTV was delivered in 40.0-58.08Gy/15-26f. The total P-SABR plan met the OARs constraints. Local control and overall survival were estimated. Acute and late toxicity were evaluated according to RTOG criteria. Paired conventionally fractionated radiotherapy (CFRT) plans were re-designed for all patients, with the same OARs dose constraints and total dose of PTV margin. Dosimetric and BED parameters were compared in P-SABR and paired CFRT plans. Median age of the patients was 66.5 years (range, 46-90 years). The tumor treated by P-SABR had a median diameter of 8.4 cm (4.1-19.5 cm) and a median volume of 99.2 cc (23.9-631.8 cc). Median follow-up time was 19.1 months. The local control at 1 and 2 years were 83.2%, 77.3%, respectively. The overall survival at 1 and 2 years were 72.2% ,45.5%, respectively. 6 cases have no local recurrence after 36 months. 4 cases remained alive after 60 months. Local symptoms improved in 15/16 cases after P-SABR. Multivariate analysis showed tumor diameter (≥8cm vs. <8cm) was the independent factor affecting local control and overall survival (P=0.033, P=0.016). No patient was observed radiotherapy directly induced ≥grade 3 toxicity. Compared with the paired CFRT plans, the P-SABR plans had no significant difference in most OAR dose parameters, except for the small intestine/colon V15, V45 with an increase of 14.6 cc, 3.4 cc. However, P-SABR plans increased the dose of PTV Dmean, Dmax by 8.7Gy, 14.4Gy (P < 0.001), respectively. In addition, the dose and BED of GTVb had a significant escalation of 15.8Gy and 30.2Gy (P<0.001) respectively in P-SABR plans. We had reported P-SABR is well-tolerated in bulky urinary tract malignancy in previous study. Updated outcomes showed P-SABR may have long-term local control in these people. Compared with traditional CFRT plans, P-SABR plans escalated the dose and BED inside bulky tumors with equivalent toxicity.