Hypofractionated versus standard fractionation radiotherapy for merkel cell carcinoma.

PURPOSE/OBJECTIVE(S): Merkel cell carcinoma (MCC) radiation treatment has historically consisted of standard 1.8-2 Gy fractions treated daily over 4-6 weeks. Hypofractionated treatment regimens have demonstrated tumor control and toxicity equivalence to standard fractionation regimens for common cutaneous malignancies such as basal cell and squamous cell carcinomas. Herein we report the outcomes of hypofractionated versus standard fractionation radiotherapy for MCC at our institution. MATERIALS/METHODS: The study involved a retrospective review of MCC patients treated with radiotherapy. Treatment characteristics and patient outcomes, including acute toxicities, disease recurrence and survival data were collected. The cumulative incidence of local and distant failures was estimated, with death as a competing risk. RESULTS: A total of 29 treatment courses for 24 patients were included, of which 13 involved standard fractionation with curative intent, 10 involved hypofractionated radiotherapy with curative intent, and 6 involved single fraction (8 Gy) palliative radiation. Half the patients were treated to a head/neck site. A subset of patients treated adjuvantly with curative intent included 8 standard fractionation and 8 hypofractionated radiotherapy patients. No statistically significant differences in local and/or distant failure or overall survival was observed between the patient groups. CONCLUSION: Hypofractionated radiotherapy for MCC was associated with similar treatment outcomes relative to standard fractionation. In our limited patient sample, hypofractionated radiation treatment achieved similar results with similar toxicity and fewer treatments. Further analysis of a larger patient population with longer follow up is needed to confirm treatment tolerability and efficacy.

DIFFERENTIAL TREATMENT EFFECTS OF STANDARD AND HYPOFRACTIONATED RADIATION REGIMENS IN GLIOBLASTOMA PATIENTS.

BACKGROUND: The identification of the subgroups with differential treatment effects (DTE) is important for decisionmaking in personalized treatment. The DTE analysis assists in identifying patients who are more likely to benefit from a particular treatment regimen. The aim of the study was to analyze DTE in terms of the survival of glioblastoma (GBM) patients in the groups of standard radiotherapy (SRT) and hypofractionated radiotherapy (HRT) by the multicluster modeling of homogenous groups while retaining the statistical characteristics of the overall primary study cohort. PATIENTS AND METHODS: The cohort of 159 patients with newly diagnosed GBM stratified according to the radiotherapy regimen (HRT group (n = 110/69.2%); SRT group (n = 49/30.8%)) was evaluated retrospectively. Forty-eight subgroups (multiclusters) were created by enumerating all possible combinations of 5 significant covariates (age, sex, the radicality of the surgical resection, chemotherapy, and Karnofsky performance status) of the Cox model. The DTE for the cancerspecific survival (CSS) within 48 modeled multiclusters were studied by comparing the interpolated Weibull CSS curves according to the Kolmogorov - Smirnov test. RESULTS: The findings showed that the SRT group was superior to the HRT group by CSS only in 3 of the modeled clusters presenting clinical scenarios with a non-radical tumor resection, no chemotherapy, and low Karnofsky functional status (≤ 70 scores) (Cluster 10: male aged < 60; Cluster 21: female aged ≥ 60; Cluster 22: male aged ≥ 60). Most of the studied clinical variants (45 of 48 multiclusters) did not demonstrate a significant difference when comparing the interpolated Weibull curves of the CSS for the SRT and HRT groups according to the Kolmogorov - Smirnov test (p ≥ 0.05). CONCLUSIONS: We propose a novel multicluster modeling approach that addresses DTE in relatively small samples of GBM patients receiving SRT or HRT. This original analytical method can be taken into consideration while designing new well-powered prospective trials aimed at the subgroup analysis in GBM patients who will be most beneficial from personalized treatment strategies.

Phase 3 Trial of Stereotactic Body Radiotherapy in Localized Prostate Cancer.

BACKGROUND: Whether stereotactic body radiotherapy (SBRT) is noninferior to conventionally or moderately hypofractionated regimens with respect to biochemical or clinical failure in patients with localized prostate cancer is unclear. METHODS: We conducted a phase 3, international, open-label, randomized, controlled trial. Men with stage T1 or T2 prostate cancer, a Gleason score of 3+4 or less, and a prostate-specific antigen (PSA) level of no more than 20 ng per milliliter were randomly assigned (in a 1:1 ratio) to receive SBRT (36.25 Gy in 5 fractions over a period of 1 or 2 weeks) or control radiotherapy (78 Gy in 39 fractions over a period of 7.5 weeks or 62 Gy in 20 fractions over a period of 4 weeks). Androgen-deprivation therapy was not permitted. The primary end point was freedom from biochemical or clinical failure, with a critical hazard ratio for noninferiority of 1.45. The analysis was performed in the intention-to-treat population. RESULTS: A total of 874 patients underwent randomization at 38 centers (433 patients in the SBRT group and 441 in the control radiotherapy group) between August 2012 and January 2018. The median age of the patients was 69.8 years, and the median PSA level was 8.0 ng per milliliter; the National Comprehensive Cancer Network risk category was low for 8.4% of the patients and intermediate for 91.6%. At a median follow-up of 74.0 months, the 5-year incidence of freedom from biochemical or clinical failure was 95.8% (95% confidence interval [CI], 93.3 to 97.4) in the SBRT group and 94.6% (95% CI, 91.9 to 96.4) in the control radiotherapy group (unadjusted hazard ratio for biochemical or clinical failure, 0.73; 90% CI, 0.48 to 1.12; P = 0.004 for noninferiority), which indicated the noninferiority of SBRT. At 5 years, the cumulative incidence of late Radiation Therapy Oncology Group (RTOG) grade 2 or higher genitourinary toxic effects was 26.9% (95% CI, 22.8 to 31.5) with SBRT and 18.3% (95% CI, 14.8 to 22.5) with control radiotherapy (P<0.001), and the cumulative incidence of late RTOG grade 2 or higher gastrointestinal toxic effects was 10.7% (95% CI, 8.1 to 14.2) and 10.2% (95% CI, 7.7 to 13.5), respectively (P = 0.94). CONCLUSIONS: Five-fraction SBRT was noninferior to control radiotherapy with respect to biochemical or clinical failure and may be an efficacious treatment option for patients with low-to-intermediate-risk localized prostate cancer as defined in this trial. (Funded by Accuray and others; PACE-B ClinicalTrials.gov number, NCT01584258.).

Dose escalation with stereotactic body radiotherapy for cervical cancer treatment.

BACKGROUND: Dose escalation with brachytherapy after pelvic irradiation is standard for treating cervical cancer. Its application can be impossible for some patients. Dose escalation with SBRT is widely used with high local control and acceptable toxicity rates in different body parts. The study enrolled patients who underwent SBRT treatment for dose escalation in the cervix. METHODS: Patients who were pathologically diagnosed and treated with cervical SBRT after definitive CRT were included in the study. A total of 30 Gy in 5 fractions for the high-risk volume was prescribed. The first response evaluation was performed three months after the completion of treatment. Treatment toxicity was documented according to the RTOG-EORTC scale. Oncological outcomes and toxicity were assessed. RESULTS: Between 02.2019 and 05.2023, 40 patients were treated with an SBRT boost after pelvic irradiation. The median follow-up time was 16 months (7-44 months). The median HR CTV was 47 cc (8,3-168,2 cc). There were 39 patients who achieved a complete response and one who achieved a partial response in the third month after treatment. There were two local or two regional recurrences. The 1-year metastasis-free survival was 88%, and the 1-year progression-free survival was 88%. During the follow-up period, one grade 3 gastrointestinal side effect was observed. CONCLUSIONS: SBRT which has low toxicity and reasonable locoregional control rates in a short follow-up period, may be an option for dose escalation in brachytherapy-ineligible cervical cancer patients.

Well calculated is better than quickly calculated: Comparison of Pencil beam and Monte Carlo algorithms according to the number of lesions and fractionation in radiosurgery of multiple brain metastases.

PURPOSE: In this work we compared pencil beam (PB) and Monte Carlo (MC) algorithms in single isocenter plans of multiple brain metastases radiosurgery (SIMM-SRS) plans using the quality indices reported for SRS. METHOD: The plans were evaluated concerning the prescribed dose, fractions and the number of metastases. The quality indices studied were mean dose (Dmean), D95, Paddick conformity index (PCI), Radiation Therapy Oncology Group (RTOG) homogeneity (HIRTOG) and quality of coverage indices (QRTOG), gradient index (GI), efficiency index for targets (Gη12Gy) and organs at risk (OARη12Gy) and V12-V18 for brain. RESULTS: The D95 for plans calculated with PB algorithm increased and differences were statistically significant (p < 0.001). For Dmean no differences were observed (p > 0.194). The PCI for the single-fraction cases showed statistical significant differences (p < 0.039). The PCI for the three-fraction cases did not show statistical significant difference (p < 0.569). However, the mean value of the index for all cases did not differ significantly between PB (0.84) and MC (0.81). The GI showed statistically significant differences, only for the plans with more than 10 metastases for a single-fraction (p = 0.0001). The Gη12Gy values reported are within the interval of 0.26-0.80, and for all cases, there were no statistically significant differences. CONCLUSION: Considering that MC is more accurate for small volumes and heterogeneities, and computational time is reasonable for clinical use, it should be selected in all cases for SIMM-SRS plans. We introduced the potential of novel indices as Gη12Gy, and OARη12Gy for clinical evaluation that potentially serve as optimization factor.

A cost-effectiveness analysis of stereotactic ablative radiotherapy versus conventionally fractionated radiotherapy in the management of stage 1 non-small-cell lung cancer: Results from the TROG 09.02 CHISEL study.

INTRODUCTION: Stereotactic ablative radiotherapy (SABR) is a standard of care treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC). The CHISEL trial was a phase 3 randomised controlled trial that compared SABR to conventional radiation therapy (CRT). Using patient-level data, we compared the cost-effectiveness of SABR and CRT for early-stage NSCLC. METHODS: Data on treatment exposure, outcomes (recurrence, survival) and quality of life (QoL; EORTC QLQ-C30) were sourced from the trial. Quality-adjusted life years (QALYs) were estimated for the trial period using Australian utility weights for the EORTC QLQ-C30-derived QLU-C10D. Costs related to simulation, planning, delivery, verification and post-treatment monitoring were estimated by applying Australian Medicare Benefits Schedule fees. The costs of post-progression therapy and grade ≥3 toxicity were estimated using trial data and relevant literature sources. Cost-effectiveness was investigated as the incremental cost per QALY gained for SABR compared to CRT. RESULTS: Complete QoL data were available for 21 patients: 14 in the SABR arm and 7 in the CRT arm. Mean QALYs discounted at 5% per annum were similar between arms: 12.68 months for SABR and 12.12 months for CRT. The mean costs of delivering SABR and CRT were $4763 and $6817, respectively. The costs of monitoring were similar in both arms, $4856 and $4853 for SABR and CRT. The mean costs of post-progression therapy were $24,572 for SABR and $42,801 for CRT. The mean costs of grade ≥3 toxicity were $809 in the SABR arm and $132 in the CRT arm. Therefore, the total mean cost for SABR over the period of interest was lower for SABR than CRT. Given lower mean costs and numerically higher QALYs for SABR compared with CRT, an incremental cost-effectiveness ratio was not calculated. CONCLUSION: Compared to CRT, SABR is a cost-effective treatment for early-stage NSCLC as the estimated upfront treatment cost and the cost of subsequent care are lower for SABR for comparable mean QALYs. Assessment of the lifetime QALYs and projections of cost estimation will provide a better indication of the long-term cost-effectiveness of SABR.

The effect of intra- and inter-fractional motion on target coverage and margins in proton therapy for uveal melanoma.

Introduction.This study aims to assess the effective lateral margin requirements for target coverage in ocular proton therapy (OPT), considering the unique challenges posed by eye motion and hypofractionation. It specifically addresses the previously unaccounted-for uncertainty contribution of intra-fractional motion, in conjunction with setup uncertainties, on dosimetric determination of lateral margin requirements.Method.The methodology integrates dose calculations from the in-house developed treatment planning system OCULARIS with measured intra-fractional motion, patient models from EyePlan and Monte Carlo (MC) sampling of setup uncertainties. The study is conducted on 16 uveal melanoma patients previously treated in the OPTIS2 treatment room at the Paul Scherrer Institute (PSI).Result.The retrospective simulation analysis highlights a significant impact of non-systematic factors on lateral margin requirements in OPT. Simulations indicate that reducing the 2.5 mm clinical lateral margin, represented by a 2.1 mm margin in this work, would have resulted in inadequate target coverage for two patients, revealing a greater impact of non-systematic factors on lateral margin requirements.Conclusions.This work characterizes intra-fractional motion in 16 OPT patients and identifies limitations of clinical margin selection protocols for OPT applications. A novel framework was introduced to assess margin sufficiency for target coverage. The findings suggest that prior research underestimated non-systematic factors and overestimated systematic contributions to lateral margin components. This re-evaluation highlights the critical need to prioritize the management of non-systematic uncertainty contributions in OPT.

[Choice of fractionation regimen for Grade IV gliomas depending on rapid early progression]. / Vybor rezhima fraktsionirovaniya pri gliomakh IV stepeni zlokachestvennosti v zavisimosti ot bystrogo rannego progressirovaniya (REP).

OBJECTIVE: To investigate the effect of two fractionation regimens on survival in patients with Grade IV gliomas depending on rapid early progression (REP). MATERIAL AND METHODS: Fractionation with prescribed doses of 2 and 3 Gy was alternately used in 140 patients with morphologically confirmed Grade IV glioma using a pairwise modeling strategy. RESULTS: REP was diagnosed in 60 (42.9%) out of 140 patients with Grade IV gliomas and 55 (45.5%) out of 121 patients with glioblastomas. Fatal outcome was observed in 111 (79.3%) patients, 99 (70.7%) ones died from progression of glioma. In case of no REP, the median overall survival as of December 2023 was 32.20 (95% CI 25.7-38.7) months, with REP - only 16.03 (95% CI 13.5-18.6) months (p<0.0001). Median survival was slightly lower in patients with glioblastoma - 28.2 and 16.5 months, respectively (p<0.0001).In patients with Grade IV gliomas and no REP, 3 Gy (n=40) fractionation regimen was followed by median overall survival 44.98 (95% Cl 15.3-74.6) months, 2 Gy (n=40) - 20.99 (95% CI 9.2-32.7) months (p=0.027). In case of glioblastoma, differences between fractionation regimes lose significance - medians 33.7 and 19.7 months, respectively (p=0.081). According to multivariate analysis, 3 Gy fractionation regimen is more effective than standard radiotherapy (p=0.009) in patients without REP, while significance of isoeffective doses <59.5Gy≥ is slightly lower (p=0.020). Radiotherapy on the background of temozolomide is equally important (p=0.007).In patients with grade 4 gliomas and REP, 3 Gy (n=30) fractionation regimen was followed by median overall survival 17.18 (95% CI 14.2-20.2) months, 2 Gy (n=30) - 12.88 (95% CI 5.4-20.3) months (p=0.849). In case of glioblastoma, Cox model classification matrix looks as follows: fractionation variant (p=0.423), isoeffective dose <59.5Gy≥ (p<0.0001), temozolomide during radiotherapy (p=0.701), functional status (p=0.485). CONCLUSION: In patients with Grade IV gliomas and no REP, 3 Gy fractionation regimen has significant advantages over standard radiotherapy regarding overall survival. In case of more aggressive course of tumor (REP), higher single dose does not improve treatment outcomes. Isoeffective dose ≥59.5Gy is of great importance.

Investigation of intrafractional spinal cord and spinal canal movement during stereotactic MR-guided online adaptive radiotherapy for kidney cancer.

BACKGROUND AND PURPOSE: This study aimed to investigate the intrafractional movement of the spinal cord and spinal canal during MR-guided online adaptive radiotherapy (MRgART) for kidney cancer. MATERIALS AND METHODS: All patients who received stereotactic MRgART for kidney cancer between February 2022 and February 2024 were included in this study. Patients received 30-42 Gy in 3-fraction MRgART for kidney cancer using the Elekta Unity, which is equipped with a linear accelerator and a 1.5 Tesla MRI. MRI scans were performed at three points during each fraction: for online planning, position verification, and posttreatment assessment. The spinal cord was contoured from the upper edge of Th12 to the medullary cone, and the spinal canal was contoured from Th12 to L3, using the first MRI. These contours were adjusted to the second and third MR images via deformable image registration, and movements were measured. Margins were determined via the formula "1.3×Σ+0.5×σ" and 95% prediction intervals. RESULTS: A total of 22 patients (66 fractions) were analyzed. The median interval between the first and third MRI scans were 38 minutes. The mean ± standard deviation of the spinal cord movements after this interval were -0.01 ± 0.06 for the x-axis (right-left), 0.01 ± 0.14 for the y-axis (caudal-cranial), 0.07 ± 0.05 for the z-axis (posterior-anterior), and 0.15 ± 0.08 for the 3D distance, respectively. The correlation coefficients of the 3D distance between the spinal cord and the spinal canal was high (0.92). The calculated planning organ at risk volume margin for all directions was 0.11 cm for spinal cord. The 95% prediction intervals for the x-axis, y-axis, and z-axis were -0.11-0.09 cm, -0.23-0.25 cm and -0.14-0.03 cm, respectively. CONCLUSIONS: Margins are necessary in MRgART to compensate for intrafractional movement and ensure safe treatment delivery.

Stereotactic body radiation therapy on abdominal-pelvic lymph node oligometastases: a systematic review on toxicity.

BACKGROUND AND PURPOSE: To review available data on toxicity during and/or after treatment of abdominal-pelvic lymph node oligometastases (A-P LN) with stereotactic body radiation therapy (SBRT) and to provide an overview of adverse events and its relation to dose or fractionation. MATERIAL AND METHODS: For this systematic review, we searched MEDLINE, Embase, Web of Science Core Collection, and CINAH for studies published between the database inception and October 3rd, 2023. Inclusion criteria were (1) patients with 1-5 A-P LN oligometastases, (2) treatment with SBRT to a median prescribed dose of ≥55 Gy BED10, and (3) description of acute and/or late toxicity. There were no language or date restrictions. RESULTS: A total of 35 studies, including 1,512 patients, were selected. Late grade 3 and 4 adverse events occurred in 0.6% and 0.1% of the patients treated for A-P LN oligometastases. All late adverse events grade ≥ 3 occurred after treatment of the tumor with a minimum BED10 of 72 Gy. Of the 11 patients with severe late toxicity, five patients were re-irradiated. Late grade 2 and 1 toxicity was reported in 3.4% and 8.3% of the patients. Acute toxicity grades 4, 3, 2, and 1 occurred in 0.1%, 0.2%, 4.4%, and 19.8% of the patients, respectively. INTERPRETATION: SBRT for A-P LN oligometastases show low toxicity rates. Nearly 50% of late adverse events ≥ grade 3 were associated with re-irradiation.

Brachial plexopathy following stereotactic body radiation therapy in apical lung malignancies: A dosimetric pooled analysis of individual patient data.

BACKGROUND AND OBJECTIVES: The aim of this study is to establish dosimetric constraints for the brachial plexus at risk of developing grade ≥ 2 brachial plexopathy in the context of stereotactic body radiation therapy (SBRT). PATIENTS AND METHODS: Individual patient data from 349 patients with 356 apical lung malignancies who underwent SBRT were extracted from 5 articles. The anatomical brachial plexus was delineated following the guidelines provided in the atlases developed by Hall, et al. and Kong, et al.. Patient characteristics, pertinent SBRT dosimetric parameters, and brachial plexopathy grades (according to CTCAE 4.0 or 5.0) were obtained. Normal tissue complication probability (NTCP) models were used to estimate the risk of developing grade ≥ 2 brachial plexopathy through maximum likelihood parameter fitting. RESULTS: The prescription dose/fractionation schedules for SBRT ranged from 27 to 60 Gy in 1 to 8 fractions. During a follow-up period spanning from 6 to 113 months, 22 patients (6.3 %) developed grade ≥2 brachial plexopathy (4.3 % grade 2, 2.0 % grade 3); the median time to symptoms onset after SBRT was 8 months (ranged, 3-54 months). NTCP models estimated a 10 % risk of grade ≥2 brachial plexopathy with an anatomic brachial plexus maximum dose (Dmax) of 20.7 Gy, 34.2 Gy, and 42.7 Gy in one, three, and five fractions, respectively. Similarly, the NTCP model estimates the risks of grade ≥2 brachial plexopathy as 10 % for BED Dmax at 192.3 Gy and EQD2 Dmax at 115.4 Gy with an α/ß ratio of 3, respectively. Symptom persisted after treatment in nearly half of patients diagnosed with grade ≥2 brachial plexopathy (11/22, 50 %). CONCLUSIONS: This study establishes dosimetric constraints ranging from 20.7 to 42.7 Gy across 1-5 fractions, aimed at mitigating the risk of developing grade ≥2 brachial plexopathy following SBRT. These findings provide valuable guidance for future ablative SBRT in apical lung malignancies.

Towards clinical application of ultra-high dose rate radiotherapy and the FLASH effect: Challenges and current status.

Ultra-high dose rate external beam radiotherapy (UHDR-RT) uses dose rates of several tens to thousands of Gy/s, compared with the dose rate of the order of a few Gy/min for conventional radiotherapy techniques, currently used in clinical practice. The use of such dose rate is likely to improve the therapeutic index by obtaining a radiobiological effect, known as the "FLASH" effect. This would maintain tumor control while enhancing tissues protection. To date, this effect has been achieved using beams of electrons, photons, protons, and heavy ions. However, the conditions required to achieve this "FLASH" effect are not well defined, and raise several questions, particularly with regard to the definition of the prescription, including dose fractionation, irradiated volume and the temporal structure of the pulsed beam. In addition, the dose delivered over a very short period induces technical challenges, particularly in terms of detectors, which must be mastered to guarantee safe clinical implementation. IRSN has carried out an in-depth literature review of the UHDR-RT technique, covering various aspects relating to patient radiation protection: the radiobiological mechanisms associated with the FLASH effect, the used temporal structure of the UHDR beams, accelerators and dose control, the properties of detectors to be used with UHDR beams, planning, clinical implementation, and clinical studies already carried out or in progress.

LatticeOpt: An automatic tool for planning optimisation of spatially fractionated stereotactic body radiotherapy.

PURPOSE: Lattice radiotherapy (LRT) is a three dimensional (3D) implementation of spatially fractionated radiation therapy, based on regular spatial distribution of high dose spheres (vertices) inside the target. Due to tumour shape heterogeneity, finding the best lattice arrangement is not trivial. The aim of this study was to develop the LatticeOpt tool to generate the best lattice structures on clinical cases for treatment planning. METHODS: Developed in MATLAB, LatticeOpt finds the 3D-spatial configurations that maximize the number of vertices within the gross target volume (GTV). If organs at risk (OARs) are considered, it chooses the solution that minimizes the overlapping volume histograms (OVH). Otherwise, the lattice structure with the minimum Hausdorff distance between vertices and GTV boundary is chosen to avoid unpopulated regions. Different lattice structures were created for 20 patients, with (OVHopt) and without (OVHunopt) OVH minimization. Imported into TPS (Eclipse, Varian), corresponding plans were generated and evaluated in terms of OAR mean and maximum doses, GTV vertex coverage and dose gradients, as well as pre-clinical plan dosimetry. RESULTS: Plans based on an optimized lattice structure (OVHopt, OVHunopt) had similar dose distributions in terms of vertex coverage and gradient index score. OAR sparing was observed in all patients, with a 4 % and 9 % difference for mean and max dose (both p-values <0.01), respectively. The best vertices dimensions and their relative distances were patient dependent. CONCLUSIONS: LatticeOpt was able to reduce the time-consuming procedures of LRT, as well as to achieve standardized and reproducible results, useful for multicentre studies.

Tumor volume changes after stereotactic, hypofractionated and conventional radiotherapy in paragangliomas of head and neck.

BACKGROUND: The aim of this study is comparison the effectiveness of stereotactic, hypofractionated and conventional radiotherapy assessed by the tumor volume changes of paraganglioma located in the head and neck region concerning fractional and total doses. METHODS: We analyzed 76 patients after radiotherapy due to paraganglioma who were assigned to 3 groups considering fractional (≤2 Gy, 3-5.5 Gy, ≥6 Gy) and total (≤20 Gy, 21-40 Gy, >40 Gy) doses. The volumes of irradiated tumors were measured and compared based on diagnostic images performed before and after the treatment. RESULTS: The mean tumor volume after the treatment with the lowest fractional dose (≤2 Gy) was decreased by 14.4 cm3. In patients treated with higher fractional doses (>2 Gy), the mean tumor volumes decreased by less than 1 cm3 for hypofractionated and stereotactic radiotherapy. 15.9 cm3 reduction of the mean tumor volume after the treatment with the highest RT total dose (>40 Gy) was stated. In patients treated with total doses ≤20 Gy and 21-40 Gy, the mean tumor volume was stable and reduced by 1.15 cm3, respectively. The analysis demonstrates a statistically significant (p < 0.05) treatment advantage in patients after the lowest fractional and highest total doses. CONCLUSION: The reduction of the tumor's volume was reported after conventional and unconventional radiotherapy. The most significant depletion of the paraganglioma volume was noted after a factional dose ≤2 Gy and a total dose >40 Gy.

Spatially fractionated GRID radiation potentiates immune-mediated tumor control.

BACKGROUND: Tumor-immune interactions shape a developing tumor and its tumor immune microenvironment (TIME) resulting in either well-infiltrated, immunologically inflamed tumor beds, or immune deserts with low levels of infiltration. The pre-treatment immune make-up of the TIME is associated with treatment outcome; immunologically inflamed tumors generally exhibit better responses to radio- and immunotherapy than non-inflamed tumors. However, radiotherapy is known to induce opposing immunological consequences, resulting in both immunostimulatory and inhibitory responses. In fact, it is thought that the radiation-induced tumoricidal immune response is curtailed by subsequent applications of radiation. It is thus conceivable that spatially fractionated radiotherapy (SFRT), administered through GRID blocks (SFRT-GRID) or lattice radiotherapy to create areas of low or high dose exposure, may create protective reservoirs of the tumor immune microenvironment, thereby preserving anti-tumor immune responses that are pivotal for radiation success. METHODS: We have developed an agent-based model (ABM) of tumor-immune interactions to investigate the immunological consequences and clinical outcomes after 2 Gy × 35 whole tumor radiation therapy (WTRT) and SFRT-GRID. The ABM is conceptually calibrated such that untreated tumors escape immune surveillance and grow to clinical detection. Individual ABM simulations are initialized from four distinct multiplex immunohistochemistry (mIHC) slides, and immune related parameter rates are generated using Latin Hypercube Sampling. RESULTS: In silico simulations suggest that radiation-induced cancer cell death alone is insufficient to clear a tumor with WTRT. However, explicit consideration of radiation-induced anti-tumor immunity synergizes with radiation cytotoxicity to eradicate tumors. Similarly, SFRT-GRID is successful with radiation-induced anti-tumor immunity, and, for some pre-treatment TIME compositions and modeling parameters, SFRT-GRID might be superior to WTRT in providing tumor control. CONCLUSION: This study demonstrates the pivotal role of the radiation-induced anti-tumor immunity. Prolonged fractionated treatment schedules may counteract early immune recruitment, which may be protected by SFRT-facilitated immune reservoirs. Different biological responses and treatment outcomes are observed based on pre-treatment TIME composition and model parameters. A rigorous analysis and model calibration for different tumor types and immune infiltration states is required before any conclusions can be drawn for clinical translation.

Randomised controlled trials on radiation dose fractionation in breast cancer: systematic review and meta-analysis with emphasis on side effects and cosmesis.

OBJECTIVE: To provide a comprehensive assessment of various fractionation schemes in radiation therapy for breast cancer, with a focus on side effects, cosmesis, quality of life, risks of recurrence, and survival outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to 23 October 2023). STUDY SELECTION: Included studies were randomised controlled trials focusing on conventional fractionation (CF; daily fractions of 1.8-2 Gy, reaching a total dose of 50-50.4 Gy over 5-6 weeks), moderate hypofractionation (MHF; fraction sizes of 2.65-3.3 Gy for 13-16 fractions over 3-5 weeks), and/or ultra-hypofractionation (UHF; schedule of only 5 fractions). DATA EXTRACTION: Two independent investigators screened studies and extracted data. Risk of bias and quality of evidence were assessed using the Cochrane Collaboration's tool and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach, respectively. DATA SYNTHESIS: Pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. Heterogeneity was analysed using Cochran's Q test and I2 statistic. Network meta-analysis was used to integrate all available evidence. MAIN OUTCOME MEASURES: The pre-specified primary outcome was grade ≥2 acute radiation dermatitis and late radiation therapy related side effects; secondary outcomes included cosmesis, quality of life, recurrence, and survival metrics. RESULTS: From 1754 studies, 59 articles representing 35 trials (20 237 patients) were assessed; 21.6% of outcomes showed low risk of bias, whereas 78.4% had some concerns or high risk, particularly in outcome measurement (47.4%). The RR for grade ≥2 acute radiation dermatitis for MHF compared with CF was 0.54 (95% CI 0.49 to 0.61; P<0.001) and 0.68 (0.49 to 0.93; P=0.02) following breast conserving therapy and mastectomy, respectively. Hyperpigmentation and grade ≥2 breast shrinkage were less frequent after MHF than after CF, with RRs of 0.77 (0.62 to 0.95; P=0.02) and 0.92 (0.85 to 0.99; P=0.03), respectively, in the combined breast conserving therapy and mastectomy population. However, in the breast conserving therapy only trials, these differences in hyperpigmentation (RR 0.79, 0.60 to 1.03; P=0.08) and breast shrinkage (0.94, 0.83 to 1.07; P=0.35) were not statistically significant. The RR for grade ≥2 acute radiation dermatitis for UHF compared with MHF was 0.85 (0.47 to 1.55; P=0.60) for breast conserving therapy and mastectomy patients combined. MHF was associated with improved cosmesis and quality of life compared with CF, whereas data on UHF were less conclusive. Survival and recurrence outcomes were similar between UHF, MHF, and CF. CONCLUSIONS: MHF shows improved safety profile, cosmesis, and quality of life compared with CF while maintaining equivalent oncological outcomes. Fewer randomised controlled trials have compared UHF with other fractionation schedules, but its safety and oncological effectiveness seem to be similar with short term follow-up. Given the advantages of reduced treatment time, enhanced convenience for patients, and potential cost effectiveness, MHF and UHF should be considered as preferred options over CF in appropriate clinical settings, with further research needed to solidify these findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023460249.

Randomized clinical trial on accelerated preoperative hyperfractionated radiotherapy versus preoperative hyperfractionated radio-chemotherapy in locally advanced rectal cancer.

OBJECTIVES: The aim of this study was to compare pathological response rates after preoperative hyperfractionated radiotherapy with co-administration of chemotherapy based on 5FU (HART-CT) versus preoperative hyperfractionated radiotherapy (HART) in patients with resectable rectal cancer. METHODS: Patients with T2/N+ or T3/any N rectal cancer were randomized either to HART twice a day (28 fractions of 1.5 Gy) to total dose 42 Gy or to HART-CT. Tumour regression grade was postoperatively assessed according to the 4-point scale as recommended by the American Joint Committee on Cancer (AJCC). The secondary endpoints included overall survival (OS), disease-free survival (DFS), toxicity of preoperative treatment, locoregional, and distant failure rates. There were 187 patients eligible for analysis: 95 in HART and 92 in the HART-CT. Median follow-up was 5.6 years. RESULTS: The analysis demonstrated a significantly higher chance of achieving pathologic complete response in HART-CT arm: complete response was achieved in 4/95, 4% (HART) and 11/92, 12% (HART-CT) (P = .045). The differences in OS and DFS, while tending to favour HART-CT, were not significant: OS (P = .13, hazard ratio [HR] = 0.82, 95% CI, 0.63-1.06) and DFS (P = .32; HR = 0.88, 95% CI, 0.69-1.13). The locoregional failure and distant metastases rates did not statistically differ between the trial arms. The rate of late complications was similar (P = .51), grade 3+ being 8% versus 11% in the HART/HART-CT group, respectively. CONCLUSIONS: The hyperfractionated preoperative radiotherapy with concurrent 5-Fu-based chemotherapy (HART-CT) improved pathological response rate compared to HART. This translated into favourable OS and DFS in HART-CT, but the differences did not reach the threshold for significance. ADVANCES IN KNOWLEDGE: A new hyperfractionated chemo-RT scheme is proposed. Histopathological major response (TRG 0-1) is associated with better clinical outcome.

Postoperative complications of hypofractionated and conventional fractionated radiation therapy in patients with implant-based breast reconstruction: A systematic review and meta-analysis.

INTRODUCTION: Post-mastectomy radiation therapy is an important component of adjuvant therapy for high-risk patients. However, radiation to reconstructed breasts can cause various complications. Recently, hypofractionated (HF) protocols have been adopted in several countries. Here, we aimed to assess the impact of HF protocols on implant-reconstructed breasts through a meta-analysis and systematic review of the currently available literature. METHODS: Records published until August 2023 were systematically searched in PubMed, Cochrane Library, and EMBASE databases. Keywords included hypofractionation radiotherapy, mastectomy, and breast reconstruction. Studies that utilized HF and conventional fractionation (CF) after prosthetic reconstruction were selected. Due to the rarity of events in outcomes, Mantel-Haenszel's odds ratios were calculated using a fixed-effect model to compare the complication rates between HF and CF groups. For analysis with high heterogeneity, a random effect model was used. RESULTS: Seven articles with 924 implant reconstructions, in which 506 (54.8 %) underwent HF were included. HF patients received 43.8 Gy on average, while CF patients received 51.2 Gy. Mean follow-up ranged from 10.6 to 35 months. Seven studies were included in the meta-analysis. HF groups had a significantly lower risk of capsular contracture (OR 0.25, 95 % CI 0.11-0.55), major revision surgery (OR 0.19, 95 % CI 0.05-0.80), and wound dehiscence (OR 0.24, 95 % CI 0.07-0.78) compared to CF groups. The risks of other complications were not statistically significant. CONCLUSION: This study indicates that HF protocols are associated with fewer complications than CF protocols in implant-reconstructed patients. These findings suggest that the application of HF PMRT in implant-reconstructed patients with breast cancer is plausible.

High-dose hyperfractionated simultaneous integrated boost radiotherapy versus standard-dose radiotherapy for limited-stage small-cell lung cancer in China: a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: For the past 20 years, twice-daily thoracic radiotherapy with concurrent chemotherapy has been the treatment of choice for limited-stage small-cell lung cancer (LS-SCLC), which has a poor prognosis. We aimed to assess the efficacy and safety of high-dose, accelerated, hyperfractionated, twice-daily thoracic radiotherapy (54 Gy in 30 fractions) versus standard-dose radiotherapy (45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. METHODS: This open-label, randomised, phase 3 trial was performed at 16 public hospitals in China. The key inclusion criteria were patients aged 18-70 years, with histologically or cytologically confirmed LS-SCLC, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and who were previously untreated or had received one course of cisplatin or carboplatin and etoposide. Eligible patients were randomly assigned (1:1) to receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions to the gross tumour volume or VMAT with a simultaneous integrated boost of 54 Gy in 30 fractions to the gross tumour volume starting 0-42 days after the first chemotherapy course. Both groups received 10 fractions of twice-daily thoracic radiotherapy per week. The planning target volume was 45 Gy in 30 fractions in both groups. Patients with responsive disease received prophylactic cranial radiotherapy (25 Gy in 10 fractions). Randomisation was performed using a centralised interactive web response system, stratified by ECOG performance status, disease stage, previous chemotherapy course, and chemotherapy choice. The primary outcome was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This study was registered at ClinicalTrials.gov, NCT03214003. FINDINGS: From June 30, 2017, to April 6, 2021, 224 patients (102 [46%] females and 122 [54%] males; median age 64 years [IQR 58-68]) were enrolled and randomly assigned to the 54 Gy group (n=108) or 45 Gy (n=116) group. The median follow-up was 46 months (IQR 33-56). The median overall survival was significantly longer in the 54 Gy group (60·7 months [95% CI 49·2-62·0]) than in the 45 Gy group (39·5 months [27·5-51·4]; hazard ratio 0·55 [95% CI 0·37-0·72]; p=0·003). Treatment was tolerable, and the chemotherapy-related and radiotherapy-related toxicities were similar between the groups. The grade 3-4 radiotherapy toxicities were oesophagitis (14 [13%] of 108 patients in the 54 Gy group vs 14 [12%] of 116 patients in the 45 Gy group; p=0·84) and pneumonitis (five [5%] of 108 patients vs seven [6%] of 116 patients; p=0·663). Only one treatment-related death occurred in the 54 Gy group (myocardial infarction). The study was prematurely terminated by an independent data safety monitoring board on April 30, 2021, based on evidence of sufficient clinical benefit. INTERPRETATION: Compared with standard-dose thoracic radiotherapy (45 Gy), high-dose radiotherapy (54 Gy) improved overall survival without increasing toxicity in a cohort of patients aged 18-70 years with LS-SCLC. Our results support the use of twice-daily accelerated thoracic radiotherapy (54 Gy) with concurrent chemotherapy as an alternative first-line LS-SCLC treatment option. FUNDING: Chinese Society of Clinical Oncology-Linghang Cancer Research, the Wu Jieping Medical Foundation, and Clinical Research Fund For Distinguished Young Scholars of Peking University Cancer Hospital and Beijing Municipal Administration of Hospitals Incubating Program.