Fractionation Regimens Research Articles

The Role of Radiotherapy in the Management of Vaginal Melanoma: A Literature Review with a Focus on the Potential Synergistic Role of Immunotherapy.

Among the mucosal melanomas, vaginal melanomas are very rare tumors, accounting for less than 20% of melanomas arising from the female genital tract. They occur most frequently in women in post-menopausal age, but younger patients may also experience this neoplasm, mainly located in the lower third of the vagina or the anterior wall. The optimal management of this tumor remains controversial, with surgery reported as the most frequently adopted approach. However, a clear benefit of surgical treatment in terms of survival has not yet been demonstrated. Conversely, radiotherapy may represent an attractive non-invasive alternative, and there are several favorable reports of the role of radiation therapy, either delivered with photons, brachytherapy, or hadrontherapy. A wide range of techniques and fractionation regimens are reported with substantially good tolerance to the treatment, and acute G3 or higher toxicities are reported only in the case of concurrent immunotherapy. Of note, due to the rarity of the disease, there is a lack of high-level evidence for the optimal therapeutic option. In this scenario, recent studies theorize the possibility of developing combinatorial approaches of radiotherapy with immunotherapy based on cutaneous melanomas reports. In this review, we aim to summarize the evidence available in the literature supporting the role of definitive radiotherapy for vaginal melanomas, with a focus on the combination of RT with immunotherapy, in terms of optimal timing and biological rationale.

RADIOTHERAPY SIMULATION METHODS USED IN LABORATORY STUDIES OF RADIATION DAMAGE TO THE DENTITION: A SYSTEMATIC REVIEW

Objective To investigate the radiation simulation methods used in vitro and ex vivo studies to assess the direct effects of radiation on dental microhardness, chemical, and biochemical alterations. Study Design Searches were performed in PubMed, Scopus, Embase, and grey literature. Preclinical studies that examined the effect of radiation on permanent teeth were included. We used the modified CONSORT checklist of items for reporting preclinical studies to assess the risk of bias. Results Thirty-two studies met the inclusion criteria. The average radiation dose of in vitro studies was 53 (±22) Gy and 69 (±1) Gy in ex vivo studies. Twenty-two studies used five different fractionation schemes. Twenty-two of the included studies did not report the radiotherapy modality of those reporting, and 6 m-V was the energy most often used. Twenty studies used linear accelerators, and seven used Cobalt-60 with the source-surface-distance of radiation ranging from 1.5 to 100 cm. Distilled water was the most reported storage solution for the dental structure used. Conclusion The heterogeneity between radiation simulation methods used in the laboratory studies, such as radiation dose, radiotherapy modality, fractionation regime, and the storage solutions used, limit the conclusion regarding the direct effect of radiation on dental microstructure changes. To investigate the radiation simulation methods used in vitro and ex vivo studies to assess the direct effects of radiation on dental microhardness, chemical, and biochemical alterations. Searches were performed in PubMed, Scopus, Embase, and grey literature. Preclinical studies that examined the effect of radiation on permanent teeth were included. We used the modified CONSORT checklist of items for reporting preclinical studies to assess the risk of bias. Thirty-two studies met the inclusion criteria. The average radiation dose of in vitro studies was 53 (±22) Gy and 69 (±1) Gy in ex vivo studies. Twenty-two studies used five different fractionation schemes. Twenty-two of the included studies did not report the radiotherapy modality of those reporting, and 6 m-V was the energy most often used. Twenty studies used linear accelerators, and seven used Cobalt-60 with the source-surface-distance of radiation ranging from 1.5 to 100 cm. Distilled water was the most reported storage solution for the dental structure used. The heterogeneity between radiation simulation methods used in the laboratory studies, such as radiation dose, radiotherapy modality, fractionation regime, and the storage solutions used, limit the conclusion regarding the direct effect of radiation on dental microstructure changes.

Radiotherapy combined with immune checkpoint inhibitors in locally advanced/metastatic esophageal squamous cell carcinoma: clinical trials, efficacy and future directions.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy worldwide and often diagnosed at advanced stages with poor prognosis. Combination of radiotherapy and immunotherapy seems to be a promising approach for treating ESCC. This comprehensive review article summarizes the current state of combination of radiotherapy and immunotherapy in locally advanced/metastatic ESCC, delineates the clinical trials that merit attention, and outlines unresolved issues and future research directions in this field. The clinical trial findings suggest that radio-immunotherapy combination may improve tumor response and overall survival with manageable side effects, highlighting the importance of patient selection and the necessity for further research to optimize treatment strategies. Issues such as irradiation dosage, fractionation regimen, irradiation site and technique of radiotherapy, as well as the timing, sequence and duration of combination therapy will all affect treatment outcomes, justifying further in-depth investigation.

Stereotactic body radiotherapy for spine metastases: a review of 24 Gy in 2 daily fractions.

Stereotactic body radiotherapy (SBRT) has proven to be a highly effective treatment for selected patients with spinal metastases. Randomized evidence shows improvements in complete pain response rates and local control with lower retreatment rates favoring SBRT, compared to conventional external beam radiotherapy (cEBRT). While there are several reported dose-fractionation schemes for spine SBRT, 24 Gy in 2 fractions has emerged with Level 1 evidence providing an excellent balance between minimizing treatment toxicity while respecting patient convenience and financial strain. We provide an overview of the 24 Gy in 2 SBRT fraction regimen for spine metastases, which was developed at the University of Toronto and tested in an international Phase 2/3 randomized controlled trial. The literature summarizing global experience with 24 Gy in 2 SBRT fractions suggests 1-year local control rates ranging from 83-93.9%, and 1-year rates of vertebral compression fracture ranging from 5.4-22%. Reirradiation of spine metastases that failed prior cEBRT is also feasible with 24 Gy in 2 fractions, and 1-year local control rates range from 72-86%. Post-operative spine SBRT data are limited but do support the use of 24 Gy in 2 fractions with reported 1-year local control rates ranging from 70-84%. Typically, the rates of plexopathy, radiculopathy and myositis are under 5% in those series reporting mature follow up, with no cases of radiation myelopathy (RM) reported in the de novo setting when the spinal cord avoidance structure is limited to 17 Gy in 2 fractions. However, re-irradiation RM has been observed following 2 fraction SBRT. More recently, 2-fraction dose escalation with 28 Gy, with a higher dose constraint to the critical neural tissues, has been reported suggesting improved rates of local control. This regimen may be important in those patients with radioresistant histologies, high grade epidural disease, and/or paraspinal disease. The dose-fractionation of 24 Gy in 2 fractions is well-supported by published literature and is an ideal starting point for centers looking to establish a spine SBRT program.

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

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

Radiotherapy for Mobile Spine and Sacral Chordoma: A Critical Review and Practical Guide from the Spine Tumor Academy.

Chordomas are rare tumors of the embryologic spinal cord remnant. They are locally aggressive and typically managed with surgery and either adjuvant or neoadjuvant radiation therapy. However, there is great variability in practice patterns including radiation type and fractionation regimen, and limited high-level data to drive decision making. The purpose of this manuscript was to summarize the current literature specific to radiotherapy in the management of spine and sacral chordoma and to provide practice recommendations on behalf of the Spine Tumor Academy. A systematic review of the literature was performed using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) approach. Medline and Embase databases were utilized. The primary outcome measure was the rate of local control. A detailed review and interpretation of eligible studies is provided in the manuscript tables and text. Recommendations were defined as follows: (1) consensus: approved by >75% of experts; (2) predominant: approved by >50% of experts; (3) controversial: not approved by a majority of experts. Expert consensus supports dose escalation as critical in optimizing local control following radiation therapy for chordoma. In addition, comprehensive target volumes including sites of potential microscopic involvement improve local control compared with focal targets. Level I and high-quality multi-institutional data comparing treatment modalities, sequencing of radiation and surgery, and dose/fractionation schedules are needed to optimize patient outcomes in this locally aggressive malignancy.

Consensus Quality Measures and Dose Constraints for Lung Cancer From the Veterans Affairs Radiation Oncology Quality Surveillance Program and ASTRO Expert Panel

For patients with lung cancer, it is critical to provide evidence-based radiation therapy to ensure high-quality care. The US Department of Veterans Affairs (VA) National Radiation Oncology Program partnered with the American Society for Radiation Oncology (ASTRO) as part of the VA Radiation Oncology Quality Surveillance to develop lung cancer quality metrics and assess quality of care as a pilot program in 2016. This article presents recently updated consensus quality measures and dose-volume histogram (DVH) constraints. A series of measures and performance standards were reviewed and developed by a Blue-Ribbon Panel of lung cancer experts in conjunction with ASTRO in 2022. As part of this initiative, quality, surveillance, and aspirational metrics were developed for (1) initial consultation and workup; (2) simulation, treatment planning, and treatment delivery; and (3) follow-up. The DVH metrics for target and organ-at-risk treatment planning dose constraints were also reviewed and defined. Altogether, a total of 19 lung cancer quality metrics were developed. There were 121 DVH constraints developed for various fractionation regimens, including ultrahypofractionated (1, 3, 4, or 5 fractions), hypofractionated (10 and 15 fractionations), and conventional fractionation (30-35 fractions). The devised measures will be implemented for quality surveillance for veterans both inside and outside of the VA system and will provide a resource for lung cancer-specific quality metrics. The recommended DVH constraints serve as a unique, comprehensive resource for evidence- and expert consensus-based constraints across multiple fractionation schemas.

Optimal Levels of Isoeffective Doses for Two Fractionation Modes in Glioblastoma

Purpose: Determination of the optimal level of a/b for the calculation of isoeffective doses in glioblastoma.
 Material and methods: Two fractionation modes were studied in 141 patients with primary glioblastoma (GBM). Fractionation with the prescribed dose of 2 and 3 Gy was used alternately (a study involving a pairwise selection strategy). In addition, 34 GBM patients treated in the pilot study of the National Medical Research Radiological Centre earlier were added to the database, the total number of patients was 175 people.
 Results: As of December 2022, 134 (76.6 %) of 175 treated patients had a fatal outcome. In the range of values of the coefficient a/b from 5.0 to 10.0, the indicator a/b=7.5 turned out to be the most informative. According to the criterion of overall survival, a favorable level of isoeffective dose exceeds 59.5 Gy.
 The median overall survival in the group with an isoeffective dose of >=59.5 Gy was 22.3 months (95 % Cl: 17.7–26.9), in the group with a lower dose level – 10.3 months (p<0.0001).
 According to monovariate analysis at an isoeffective dose of >=59.5 Gy for fractionation regimens with a prescribed dose of 2 and 3 Gy, survival rates were almost identical (p=0.745). There were no differences in overall survival in the groups with prescribed doses of 2 and 3 Gy, taking into account the use of temozolomide on the background of radiation therapy (OR=1,087; p=0.677).
 In the older age group, a/b= 7.5 should be used to determine the level of isoeffective dose. The median overall survival with an isoeffective dose of >=59.5 Gy was 20.57 months (n=98; 95 % Cl: 17.7–23.4), with a lower dose level – 6.35 months (n=24; p<0.0001). In persons younger than 50 years of age, a decrease in the a/b coefficient should be expected.
 Conclusion: From our point of view, the obtained data on the equivalence of regimens with a prescribed dose of 2 and 3 Gy indicate the correct choice of the level of a/b in glioblastoma and the selection of the minimum level of isoeffective dose (59.5 Gy) according to the criterion of overall survival.

Influence of Homogeneous Dose Distribution Inside the Cancer Target on Local Control in Glioblastomas

Purpose: Assessment of the effect of homogeneous distribution inside the radiation target on local control in glioblastoma.
 Material and methods: In patients under the age of 50, fractionation with the prescribed dose of 2 and 3 Gy was alternately used: the first patient was prescribed a regimen with a dose of 3 Gy, the next – with a dose of 2 Gy (a study involving a pairwise selection strategy). The same approach is used for the older age group (50 years and more). A total of 141 patients had morphologically confirmed glioblastoma (grade 4). 10 patients who had not completed a full course of radiation therapy were excluded. Additionally, 27 patients with GBM were added, treated in the experimental study of National Medical Research Radiological Centre without methodological features. In total, 158 patients were included in the study. 74 patients were treated with the prescribed dose of 2 Gy, 84 had a dose of 3 Gy.
 Results: The median homogeneity index in our study was 7.5 (95% Cl: 6,7-8,3). The minimum HI indicator was at the level of 2.5, the maximum – 36.9. We managed to identify the most informative level of the homogeneity index according to the criterion of local control. The median disease-free survival in the group with HI>=8.5 was 7.9 months (n=62; 95 % Cl: 1.6-14.2), in the group with a lower level of homogeneity - 5.4 months (n=96; p=0.024). The significance of the highlighted HI range depended on the fractionation mode used. The median relapse–free survival with fractionation of 3 Gy in the group with HI>=8.5 was 12.7 months (n=38), in the group with a lower level of homogeneity - 8.3 months (n=46; p=0.020). In the group with fractionation regime of 2 Gy: 6.4 and 3.8 months, respectively (n=24/50; p=0.336). The median overall survival in the group with HI>=8.5 was 27.2 months, in the group with a lower level of homogeneity – 21.2 months (p=0.904).
 Conclusion: The level of homogeneity has no significance according to the criterion of overall survival. Despite the fact that this predictor is of value only in scientific terms, the fact of its influence on local control allows to continue research in this direction. This primarily concerns the fractionation regimen with a prescribed dose of 3 Gy.

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

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

A Single-Institution Retrospective Study of Three-Fraction HDR Accelerated Partial Breast Irradiation

Accelerated partial breast irradiation (APBI) delivered with high-dose-rate brachytherapy is a standard of care treatment typically delivered over 10 fractions. The TRIUMPH-T multi-institutional study recently demonstrated promising results using a shorter three fraction regimen, however there are limited additional published series using this regimen. Here, we report our experience and outcomes for patients treated as per the TRIUMPH-T regimen. This study was a retrospective single-institution analysis of patients who underwent lumpectomy followed by APBI (22.5 Gy in 3 fractions delivered over 2-3 days) using a Strut Adjusted Volume Implant (SAVI) applicator between November 2016 and January 2021. Dose-volume metrics were obtained from the clinically treated plan. Chart review was performed to determine locoregional recurrence and toxicities according to CTCAE v5.0. Between 2016 and 2021, 31 patients were treated per the TRIUMPH-T protocol. Median followup was 31 months from completion of brachytherapy. There were no acute/late Grade 3 or higher toxicities. Cumulative late Grade 1 and 2 toxicities were seen in 58.1% and 9.7% of patients, respectively. Of note, four patients experienced locoregional recurrence: three ipsilateral breast tumor recurrences and one nodal recurrence. All three ipsilateral breast tumor recurrences occurred in patients who would be classified as "cautionary" based on ASTRO consensus guidelines due to age ≤50, lobular histology, or high grade. Three-fraction HDR brachytherapy APBI was well-tolerated with no grade 3 or higher toxicities and an acceptably small percentage of grade 2 toxicities. Given the small sample size, the number of recurrences suggests that attention to appropriate patient selection is necessary until more long-term followup data is available.

Clinical and Therapeutic Considerations for Older Adults with Head and Neck Cancer.

Approximately 30% of patients with head and neck squamous cell carcinoma (HNSCC) are at least 70 years of age, and this percentage is expected to increase as the population increases and lives longer. Elderly patients are underrepresented in head and neck oncology clinical trials, and there is minimal evidence on the management of HNSCC for this population. Subsequently, despite their best intentions, physicians may unknowingly recommend an ill-suited course of therapy, which may result in suboptimal oncological or functional outcomes or adverse events. Surgical approaches have the potential to carry a higher risk of morbidity and mortality in older adults, especially in patients with multiple comorbidities. Definitive radiation therapy treatment in patients with HNSCC frequently involves 7 weeks of daily radiation, sometimes with concurrent chemotherapy, and this demanding treatment can be difficult for older adult patients, which may lead to treatment interruptions, potential removal of concurrent systemic therapy, compromised outcomes, and diminished quality of life. There are clinical trials currently underway investigating altered fractionation regimens and novel, less toxic systemic treatments in this population. This review provides an overview of how best to approach an older adult with HNSCC, from initial work-up to treatment selection.

Selection of fractionation regimens of stereotactic body radiotherapy in patients with early stage lung cancer

Stereotactic body radiotherapy for early stage non-small-cell lung cancer was, is, and will remain the key subject of discussions between radiation oncologists and surgeons. Despite the positive treatment outcomes reported in some large studies on efficacy of the stereotactic radiotherapy, its use instead of surgery may not always be an unconditional decision. However, stereotactic radiotherapy opens new treatment options in patients who are inoperable or refused surgery. This is possibly due to the high accuracy of modern linear accelerators, which allow to reduce the toxicity of radiotherapy and achieve an almost identical overall survival rate compared to surgery.

Development and Validation of a Normal Tissue Complication Probability Model for Lymphedema After Radiation Therapy in Breast Cancer

To develop and test a multivariable normal tissue complication probability (NTCP) model predicting lymphedema in patients with breast cancer receiving radiotherapy. We retrospectively reviewed 1345 patients with breast cancer who received radiotherapy from two independent institutions. The patients were divided into a training cohort (Institution A, n=368, all treated with 3D conformal external beam RT [3DCRT] with 2Gy/fraction) and an external validation cohort (Institution B, n=977, treated either with 3DCRT or with volumetric modulated RT and either with 1.8-2.0Gy/fraction or with 2.67Gy/fraction). Axillary-lateral thoracic vessel juncture (ALTJ) was delineated. The multivariable model was generated using dosimetric and clinical parameters. The performance of the model was comprehensively validated internally and externally. During a median follow-up of 78.7 months for the entire cohort, 97 patients (7.2%) developed lymphedema. The multivariable model that took into account the number of lymph nodes dissected (LNDno), as well as the volume of the ALTJ receiving a dose ≥ 35Gy EQD2 (ALTJ V35), showed good agreement between predicted and observed results for both internal and external validation (Hosmer-Lemeshow p-value > 0.05). The area under the curve (AUC) and negative log-likelihood (NLL) values for the multivariable NTCP model were 0.89 and 0.19 in internal validation and 0.83 and 0.19 in external validation. In addition, the multivariable model performance was acceptable for hypofractionated regimens (AUC 0.70) and VMAT (AUC 0.69). LNDno and ALTJ V35 were found to be the most important factors influencing lymphedema after radiotherapy. We first developed and validated the multivariable NTCP model for the lymphedema incidence in patients with breast cancer after radiotherapy. The multivariable NTCP model showed excellent performance and robustness in predicting lymphedema in both internal and completely independent external validations. The multivariable model for lymphedema prediction was robust and reliable for different treatment modalities and fractionation regimens.

Predicting Severity of Radiation Induced Lymphopenia in Individual Proton Therapy Patients for Varying Dose Rate and Fractionation Using Dynamic 4-Dimensional Blood Flow Simulations

PurposeRadiation-induced lymphopenia has gained attention recently as the result of its correlation with survival in a range of indications, particularly when combining radiation therapy (RT) with immunotherapy. The purpose of this study is to use a dynamic blood circulation model combined with observed lymphocyte depletion in patients to derive the in vivo radiosensitivity of circulating lymphocytes and study the effect of RT delivery parameters. Methods and MaterialsWe assembled a cohort of 17 patients with hepatocellular carcinoma treated with proton RT alone in 15 fractions (fx) using conventional dose rates (beam-on time [BOT], 120 seconds) for whom weekly absolute lymphocyte counts (ALCs) during RT and follow-up were available. We used HEDOS, a time-dependent, whole-body, blood flow computational framework, in combination with explicit liver blood flow modeling, to calculate the dose volume histograms for circulating lymphocytes for changing BOTs (1 second-300 seconds) and fractionations (5 fx, 15 fx). From this, we used the linear cell survival model and an exponential model to determine patient-specific lymphocyte radiation sensitivity, α, and recovery, σ, respectively. ResultsThe in vivo–derived patient-specific α had a median of 0.65 Gy−1 (range, 0.30-1.38). Decreasing BOT to 1 second led to an increased average end-of-treatment ALC of 27.5%, increasing to 60.3% when combined with the 5-fx regimen. Decreasing to 5 fx at the conventional dose rate led to an increase of 17.0% on average. The benefit of both increasing dose rate and reducing the number of fractions was patient specificࣧpatients with highly sensitive lymphocytes benefited most from decreasing BOT, whereas patients with slow lymphocyte recovery benefited most from the shorter fractionation regimen. ConclusionsWe observed that increasing dose rate at the same fractionation reduced ALC depletion more significantly than reducing the number of fractions. High-dose-rates led to an increased sparing of lymphocytes when shortening the fractionation regimen, particularly for patients with radiosensitive lymphocytes at elevated risk.

Different Re-Irradiation Techniques after Breast-Conserving Surgery for Recurrent or New Primary Breast Cancer.

Breast re-irradiation (reRT) after breast-conserving surgery (BCS) using external beam radiation is an increasingly used salvage approach for women presenting with recurrent or new primary breast cancer. However, radiation technique, dose and fractionation as well as eligibility criteria differ between studies. There is also limited data on efficacy and safety of external beam hypofractionation and accelerated partial-breast irradiation (APBI) regimens. This paper reviews existing retrospective and prospective data for breast reRT after BCS, APBI reRT outcomes and delivery at our institution and the need for a randomized controlled trial using shorter courses of radiation to better define patient selection for different reRT fractionation regimens.

Palliative appropriateness criteria: external validation of a new method to evaluate the suitability of palliative radiotherapy fractionation

BackgroundRecently, the palliative appropriateness criteria (PAC) score, a novel metric to aid clinical decision-making between different palliative radiotherapy fractionation regimens, has been developed. It includes baseline parameters including but not limited to performance status. The researchers behind the PAC score analyzed the percent of remaining life (PRL) on treatment. The latter was accomplished by calculating the time between start and finish of palliative radiotherapy (minimum 1 day in case of a single-fraction regimen) and dividing it by overall survival in days from start of radiotherapy. The purpose of the present study was to validate this novel metric.Patients and methodsThe retrospective validation study included 219 patients (287 courses of palliative radiotherapy). The methods were identical to those employed in the score development study. The score was calculated by assigning 1 point each to several factors identified in the original study and using the online calculator provided by the PAC developers.ResultsMedian survival was 6 months and death within 30 days from start of radiotherapy was recorded in 13% of courses. PRL on treatment ranged from 1 to 23%, median 8%. Significant associations were confirmed between online-calculated PAC score, observed survival, and risk of death within 30 days from the start of radiotherapy. Patients with score 0 had distinctly better survival than all other groups. The score-predicted median risk of death within 30 days from start of radiotherapy was 22% in our cohort. A statistically significant correlation was found between predicted and observed risk (p < 0.001). The original and present study were not perfectly concordant regarding number and type of baseline parameters that should be included when calculating the PAC score.ConclusionThis study supports the dual strategy of PRL and risk of early death calculation, with results stratified for fractionation regimen, in line with the original PAC score study. When considering multifraction regimens, the PAC score identifies patients who may benefit from shorter courses. Additional work is needed to answer open questions surrounding the underlying components of the score, because the original and validation study were only partially aligned.

Outcomes following brachytherapy boost for intermediate- and high-risk prostate cancer: A retrospective bicenter study by the SFRO brachytherapy group

IntroductionRadiotherapy dose escalation improves biochemical control in intermediate- or high-risk prostate cancer. Brachytherapy boost was shown to further improve biochemical control compared to radiotherapy alone in three randomized trials. The SFRO brachytherapy group sought to evaluate the efficacy and toxicity of BT-boost for intermediate and high-risk prostate cancer in real life, and to determine prognostic factors for efficacy and toxicity. Material and methodA retrospective study was conducted, including all patients with intermediate- or high-risk prostate cancer treated with a combination of external beam radiotherapy (EBRT) and high dose-rate brachytherapy boost (HDR-BB), from 2006 until December 2019 at two centers. Patient characteristics, initial disease, treatment and follow-up were collected. Results709 patients from two centers were analyzed given a short follow-up in the other centers. Out of those, 277 were intermediate risk (170 favorable and 107 unfavorable) and 432 were high risk. The median EBRT and HDR-BB doses were 46 Gy (35–50) and 14 Gy (10–20). After a median follow-up of 62 months, biochemical control at 5 years was 87.5 % for the overall population, 91 % and 85 % for intermediate- and high-risk cancers, respectively. At 5 years, biochemical and clinical relapse-free survival, metastasis-free survival and local control rates were 83 %, 90 % and 97 % respectively. 5-years overall survival was 94 %. Late grade 2 or higher GU or GI toxicity was found in 36 patients (5 %) and 9 patients (1.3 %). ConclusionThis bicenter analysis shows the efficacy and tolerability of HDR-BB as a complement to external radiotherapy. Further improvements such as combination with new hormonal agents or new brachytherapy-radiotherapy fractionation regimens are warranted to improve further the outcomes and therapeutic ratio.

Early effectiveness and toxicity outcomes of reirradiation after breast conserving surgery for recurrent or new primary breast cancer

Breast reirradiation (reRT) after breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy for women presenting with recurrent or new primary breast cancer. There are limited data on safety of different fractionation regimens. This study reports safety and efficacy among women treated with repeat BCS and reRT. Patients who underwent repeat BCS followed by RT from 2015 to 2021 at 2 institutions were analyzed. Univariate logistic regression models were used to identify predictors of acute and late toxicities. Kaplan-Meier estimates were used to evaluate overall survival (OS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LR-RFS). Sixty-six patients were reviewed with median follow-up of 16months (range: 3-60months). At time of first recurrence, 41% had invasive carcinoma with a ductal carcinoma in situ (DCIS) component, 41% had invasive carcinoma alone and 18% had DCIS alone. All were clinically node negative. For the reirradiation course, 95% received partial breast irradiation (PBI) (57.5% with 1.5Gy BID; 27% with 1.8Gy daily; 10.5% with hypofractionation), and 5% received whole breast irradiation (1.8-2Gy/fx), all of whom had received PBI for initial course. One patient experienced grade 3 fibrosis, and one patient experienced grade 3 telangiectasia. None had grade 4 or higher late adverse events. We found no association between the fractionation of the second course of RT or the cumulative dose (measured as EQD2) with acute or late toxicity. At 2years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%. In this series of patients with recurrent or new primary breast cancer, a second breast conservation surgery followed by reirradiation was effective with no local recurrences and an acceptable toxicity profile across a range of available fractionation regimens at a median follow up of 16months. Longer follow up is required.

Radiotherapy Fraction in Limited-Stage Small Cell Lung Cancer in the Modern Era: A Systematic Review and Meta-Analysis of 8006 Reconstructed Individual Patient Data.

The optimal thoracic radiotherapy (TRT) dose and fractionation for limited-stage small cell lung cancer (LS-SCLC) using modern techniques remain unclear. We conducted systematic review and meta-analyses of the efficacy and safety differences between definitive hypofractionated TRT (HypoTRT), conventional TRT (ConvTRT) and hyperfractionated TRT (HyperTRT), especially in the modern era. Eligible randomized controlled trials (RCTs), real-world cohorts, and single-arm trials published between 1990 and 2021 were identified. Two meta-analyses of overall survival (OS) were conducted: (i) a random-effects meta-analysis based on reconstructed individual-patient data (IPD) of all studies; and (ii) a Bayesian network meta-analysis based on study-level aggregated data (AD) of RCTs. The incidences of severe radiation-related toxicities were compared using the random-effects meta-regression model. Overall, 53 of the 30,031 publications met the inclusion criteria, and a total of 8006 IPD were reconstructed. After adjusting for key treatment variables and stratification by study type, there were no significant differences in the OS rates between the altered fractionation regimens (HypoTRT vs. HyperTRT, aHR [adjusted HR] = 1.05, 95% CI 0.93-1.19; ConvTRT vs. HyperTRT, aHR = 1.00, 95% CI 0·90-1.11; HypoTRT vs. ConvTRT, aHR = 1.05, 95% CI 0.91-1.20). In the modern era, the survival outcomes of all three schedules, while remaining comparable, have improved significantly. Results of the AD-based network meta-analysis were consistent with those of IPD analysis, and HypoTRT was ranked as the best regimen (SUCRA = 81%). There were no significant differences in toxicities between groups when using modern radiation techniques. In the modern era, no significant differences in OS or severe radiation-related toxicities were observed between altered schedules in LS-SCLC. HypoTRT may be associated with moderate and non-significant OS improvements, which should be further confirmed in prospective randomized phase III trials.