Local radiotherapy and measurable residual disease-driven immunotherapy in patients with early-stage follicular lymphoma (FIL MIRO): final results of a prospective, multicentre, phase 2 trial.

BACKGROUND: The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach. METHODS: This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11. FINDINGS: Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients. INTERPRETATION: Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested. FUNDING: AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.

Diverse Imaging Methods May Influence Long-Term Oncologic Outcomes in Oligorecurrent Prostate Cancer Patients Treated with Metastasis-Directed Therapy (the PRECISE-MDT Study).

Metastasis-directed therapy (MDT) has been tested in clinical trials as a treatment option for oligorecurrent prostate cancer (PCa). However, there is an ongoing debate regarding the impact of using different imaging techniques interchangeably for defining lesions and guiding MDT within clinical trials. Methods: We retrospectively identified oligorecurrent PCa patients who had 5 or fewer nodal, bone, or visceral metastases detected by choline or prostate-specific membrane antigen (PSMA) PET/CT and who underwent MDT stereotactic body radiotherapy with or without systemic therapy in 8 tertiary-level cancer centers. Imaging-guided MDT was assessed as progression-free survival (PFS), time to systemic treatment change due to polymetastatic conversion (PFS2), and overall survival predictor. Propensity score matching was performed to account for clinical differences between groups. Results: Of 402 patients, 232 (57.7%) and 170 (42.3%) underwent MDT guided by [18F]fluorocholine and PSMA PET/CT, respectively. After propensity score matching, patients treated with PSMA PET/CT-guided MDT demonstrated longer PFS (hazard ratio [HR], 0.49 [95% CI, 0.36-0.67]; P < 0.0001), PFS2 (HR, 0.42 [95% CI, 0.28-0.63]; P < 0.0001), and overall survival (HR, 0.39 [95% CI, 0.15-0.99]; P < 0.05) than those treated with choline PET/CT-guided MDT. Additionally, we matched patients who underwent [68Ga]Ga-PSMA-11 versus [18F]F-PSMA-1007 PET/CT, observing longer PFS and PFS2 in the former subgroup (PFS: HR, 0.51 [95% CI, 0.26-1.00]; P < 0.05; PFS2: HR, 0.24 [95% CI, 0.09-0.60]; P < 0.05). Conclusion: Diverse imaging methods may influence outcomes in oligorecurrent PCa patients undergoing MDT. However, prospective, head-to-head studies, ideally incorporating a randomized design, are necessary to provide definitive evidence and facilitate the practical application of these findings.

Application of the NSE score (Neurology-Stability-Epidural compression assessment) to establish the need for surgery in spinal metastases of elderly patients: a multicenter investigation.

PURPOSE: This retropective multicentric study aims to investigate the clinical applicability of the NSE score in the elderly, to verify the role of this tool as an easy help for decision making also for this class of patients. METHODS: All elderly patients (> 65 years) suffering from spinal metastases undergoing surgical or non-surgical treatment at the authors' Institutions between 2015 and 2022 were recruited. An agreement group (AG) and non-agreement group (NAG) were identified accordingly to the agreement between the NSE score indication and the performed treatment. Neurological status and axial pain were evaluated for both groups at follow-up (3 and 6 months). The same analysis was conducted specifically grouping patients older than 75 years. RESULTS: A strong association with improvement or preservation of clinical status (p < 0.001) at follow-up was obtained in AG. The association was not statistically significant in NAG at the 3-month follow-up (p 1.00 and 0.07 respectively) and at 6 months (p 0.293 and 0.09 respectively). The group of patients over 75 years old showed similar results in terms of statistical association between the agreement group and better outcomes. CONCLUSION: Far from the need or the aim to build dogmatic algorithms, the goal of preserving a proper performance status plays a key role in a modern oncological management: functional outcomes of the multicentric study group showed that the NSE score represents a reliable tool to establish the need for surgery also for elderly patients.

Understanding and Managing Pineal Parenchymal Tumors of Intermediate Differentiation: An In-Depth Exploration from Pathology to Adjuvant Therapies.

BACKGROUND: Pineal parenchymal cell tumors constitute a rare group of primary central nervous system neoplasms (less than 1%). Their classification, especially the intermediate subtype (PPTIDs), remains challenging. METHODS: A literature review was conducted, navigating through anatomo-pathological, radiotherapy, and neurosurgical dimensions, aiming for a holistic understanding of these tumors. RESULTS: PPTIDs, occupying an intermediate spectrum of malignancy, reveal diverse histological patterns, mitotic activity, and distinct methylation profiles. Surgical treatment is the gold standard, but when limited to partial removal, radiotherapy becomes crucial. While surgical approaches are standardized, due to the low prevalence of the pathology and absence of randomized prospective studies, there are no shared guidelines about radiation treatment modalities. CONCLUSION: Surgical removal remains pivotal, demanding a personalized approach based on the tumor extension. This review underscores the considerable variability in treatment approaches and reported survival rates within the existing literature, emphasizing the need for ongoing research to better define optimal therapeutic strategies and prognostic factors for PPTIDs, aiming for further and more detailed stratification among them.

Maintain Efficacy and Spare Toxicity: Traditional and New Radiation-Based Conditioning Regimens in Hematopoietic Stem Cell Transplantation.

Novelty in total body irradiation (TBI) as part of pre-transplant conditioning regimens lacked until recently, despite the developments in the field of allogeneic stem cell transplants. Long-term toxicities have been one of the major concerns associated with TBI in this setting, although the impact of TBI is not so easy to discriminate from that of chemotherapy, especially in the adult population. More recently, lower-intensity TBI and different approaches to irradiation (namely, total marrow irradiation, TMI, and total marrow and lymphoid irradiation, TMLI) were implemented to keep the benefits of irradiation and limit potential harm. TMI/TMLI is an alternative to TBI that delivers more selective irradiation, with healthy tissues being better spared and the control of the radiation dose delivery. In this review, we discussed the potential radiation-associated long-term toxicities and their management, summarized the evidence regarding the current indications of traditional TBI, and focused on the technological advances in radiotherapy that have resulted in the development of TMLI. Finally, considering the most recent published trials, we postulate how the role of radiotherapy in the setting of allografting might change in the future.

ESTRO-SIOPE guideline: Clinical management of radiotherapy in atypical teratoid/rhabdoid tumors (AT/RTs).

BACKGROUND AND PURPOSE: Treatment of patients with atypical teratoid/rhabdoid (AT/RT) is challenging, especially when very young (below the age of three years). Radiotherapy (RT) is part of a complex trimodality therapy. The purpose of this guideline is to provide appropriate recommendations for RT in the clinical management of patients not enrolled in clinical trials. MATERIALS AND METHODS: Nine European experts were nominated to form a European Society for Radiotherapy and Oncology (ESTRO) guideline committee. A systematic literature search was conducted in PubMed/MEDLINE and Web of Science. They discussed and analyzed the evidence concerning the role of RT in the clinical management of AT/RT. RESULTS: Recommendations on diagnostic imaging, therapeutic principles, RT considerations regarding timing, dose, techniques, target volume definitions, dose constraints of radiation-sensitive organs at risk, concomitant chemotherapy, and follow-up were considered. Treating children with AT/RT within the framework of prospective trials or prospective registries is of utmost importance. CONCLUSION: The present guideline summarizes the evidence and clinical-based recommendations for RT in patients with AT/RT. Prospective clinical trials and international, large registries evaluating modern treatment approaches will contribute to a better understanding of the best treatment for these children in future.

Cancer-specific dose and fractionation schedules in stereotactic body radiotherapy for oligometastatic disease: An interim analysis of the EORTC-ESTRO E2-RADIatE OligoCare study.

BACKGROUND AND INTRODUCTION: Optimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation. MATERIALS AND METHODS: Analysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/ß of 10 Gy for all primaries, and cancer-specific α/ß of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC). RESULTS: Of the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3-5) and median dose per fraction was 9.7 (IQR, 7.7-12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions. CONCLUSION: This real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503).

International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma.

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.The primary analysis of the Early positron emission tomography (ePET) Response-Adapted Treatment in localized Hodgkin Lymphoma H10 Trial demonstrated that in ePET-negative patients, the risk of relapse increased when involved-node radiotherapy (INRT) was omitted and that in ePET-positive patients, switching from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) significantly improved 5-year progression-free survival (PFS). Here, we report the final results of a preplanned analysis at a 10-year follow-up. In the favorable (F) ePET-negative group, the 10-year PFS rates were 98.8% versus 85.4% (hazard ratio [HR], 13.2; 95% CI, 3.1 to 55.8; P value for noninferiority = .9735; difference test P < .0001) in favor of ABVD + INRT; in the unfavorable (U) ePET-negative group, the 10-year PFS rates were 91.4% and 86.5% (HR, 1.52; 95% CI, 0.84 to 2.75; P value for noninferiority = .8577; difference test P = .1628). In ePET-positive patients, the difference in terms of PFS between standard ABVD and intensified BEACOPPesc was no longer statistically significant (HR, 0.67; 95% CI, 0.37 to 1.20; P = .1777). In conclusion, the present long-term analysis confirms that in ePET-negative patients, the omission of INRT is associated with lower 10-year PFS. Instead, in ePET-positive patients, no significant difference between standard and experimental arms emerged although intensification with BEACOPPesc was safe, with no increase in late adverse events, namely, second malignancies.

Management of radiation-induced oral mucositis in head and neck cancer patients: a real-life survey among 25 Italian radiation oncology centers.

AIM: Radiation-induced oral mucositis (RIOM) is the most frequent side effect in head and neck cancer (HNC) patients treated with curative radiotherapy (RT). A standardized strategy for preventing and treating RIOM has not been defined. Aim of this study was to perform a real-life survey on RIOM management among Italian RT centers. METHODS: A 40-question survey was administered to 25 radiation oncologists working in 25 different RT centers across Italy. RESULTS: A total of 1554 HNC patients have been treated in the participating centers in 2021, the majority (median across the centers 91%) with curative intent. Median treatment time was 41 days, with a mean percentage of interruption due to toxicity of 14.5%. Eighty percent of responders provide written oral cavity hygiene recommendations. Regarding RIOM prevention, sodium bicarbonate mouthwashes, oral mucosa barrier agents, and hyaluronic acid-based mouthwashes were the most frequent topic agents used. Regarding RIOM treatment, 14 (56%) centers relied on literature evidence, while internal guidelines were available in 13 centers (44%). Grade (G)1 mucositis is mostly treated with sodium bicarbonate mouthwashes, oral mucosa barrier agents, and steroids, while hyaluronic acid-based agents, local anesthetics, and benzydamine were the most used in mucositis G2/G3. Steroids, painkillers, and anti-inflammatory drugs were the most frequent systemic agents used independently from the RIOM severity. CONCLUSION: Great variety of strategies exist among Italian centers in RIOM management for HNC patients. Whether different strategies could impact patients' compliance and overall treatment time of the radiation course is still unclear and needs further investigation.

Cohort profile: the Turin prostate cancer prognostication (TPCP) cohort.

Introduction: Prostate cancer (PCa) is the most frequent tumor among men in Europe and has both indolent and aggressive forms. There are several treatment options, the choice of which depends on multiple factors. To further improve current prognostication models, we established the Turin Prostate Cancer Prognostication (TPCP) cohort, an Italian retrospective biopsy cohort of patients with PCa and long-term follow-up. This work presents this new cohort with its main characteristics and the distributions of some of its core variables, along with its potential contributions to PCa research. Methods: The TPCP cohort includes consecutive non-metastatic patients with first positive biopsy for PCa performed between 2008 and 2013 at the main hospital in Turin, Italy. The follow-up ended on December 31st 2021. The primary outcome is the occurrence of metastasis; death from PCa and overall mortality are the secondary outcomes. In addition to numerous clinical variables, the study's prognostic variables include histopathologic information assigned by a centralized uropathology review using a digital pathology software system specialized for the study of PCa, tumor DNA methylation in candidate genes, and features extracted from digitized slide images via Deep Neural Networks. Results: The cohort includes 891 patients followed-up for a median time of 10 years. During this period, 97 patients had progression to metastatic disease and 301 died; of these, 56 died from PCa. In total, 65.3% of the cohort has a Gleason score less than or equal to 3 + 4, and 44.5% has a clinical stage cT1. Consistent with previous studies, age and clinical stage at diagnosis are important prognostic factors: the crude cumulative incidence of metastatic disease during the 14-years of follow-up increases from 9.1% among patients younger than 64 to 16.2% for patients in the age group of 75-84, and from 6.1% for cT1 stage to 27.9% in cT3 stage. Discussion: This study stands to be an important resource for updating existing prognostic models for PCa on an Italian cohort. In addition, the integrated collection of multi-modal data will allow development and/or validation of new models including new histopathological, digital, and molecular markers, with the goal of better directing clinical decisions to manage patients with PCa.

Modern Stereotactic Radiotherapy for Brain Metastases from Lung Cancer: Current Trends and Future Perspectives Based on Integrated Translational Approaches.

Brain metastases (BMs) represent the most frequent metastatic event in the course of lung cancer patients, occurring in approximately 50% of patients with non-small-cell lung cancer (NSCLC) and in up to 70% in patients with small-cell lung cancer (SCLC). Thus far, many advances have been made in the diagnostic and therapeutic procedures, allowing improvements in the prognosis of these patients. The modern approach relies on the integration of several factors, such as accurate histological and molecular profiling, comprehensive assessment of clinical parameters and precise definition of the extent of intracranial and extracranial disease involvement. The combination of these factors is pivotal to guide the multidisciplinary discussion and to offer the most appropriate treatment to these patients based on a personalized approach. Focal radiotherapy (RT), in all its modalities (radiosurgery (SRS), fractionated stereotactic radiotherapy (SRT), adjuvant stereotactic radiotherapy (aSRT)), is the cornerstone of BM management, either alone or in combination with surgery and systemic therapies. We review the modern therapeutic strategies available to treat lung cancer patients with brain involvement. This includes an accurate review of the different technical solutions which can be exploited to provide a "state-of-art" focal RT and also a detailed description of the systemic agents available as effective alternatives to SRS/SRT when a targetable molecular driver is present. In addition to the validated treatment options, we also discuss the future perspective for focal RT, based on emerging clinical reports (e.g., SRS for patients with many BMs from NSCLC or SRS for BMs from SCLC), together with a presentation of innovative and promising findings in translational research and the combination of novel targeted agents with SRS/SRT.

Preoperative Radiotherapy with a Simultaneous Integrated Boost Compared to Chemoradiotherapy for cT3-4 Rectal Cancer: Long-Term Results of a Multicenter Randomized Study.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is the standard treatment for T3-4 rectal cancer. Here, we compared image-guided and intensity-modulated RT (IG-IMRT) with a simultaneous integrated boost (SIB) (instead of concomitant chemotherapy) versus CRT in a multi-centric randomized trial. METHODS: cT3-4 rectal cancer patients were randomly assigned to receive preoperative IG-IMRT 46 Gy/23 fractions plus capecitabine 825 mg/m² twice daily (CRT arm) or IG-IMRT 46 Gy/23 fractions with an SIB to the rectal tumor up to a total dose of 55.2 Gy (RTSIB arm). RESULTS: A total of 174 patients were randomly assigned between April 2010 and May 2014. Grade 3 acute toxicities were 6% and 4% in the CRT and RTSIB arms, respectively. The mean fractional change in SUVmax at 5 weeks after completion of preoperative RT were -55.8% (±24.0%) and -52.9% (±21.6%) for patients in the CRT arm and RTSIB arm, respectively (p = 0.43). The pathologic complete response rate was 24% with CRT compared to 14% with RTSIB. There were no differences in 5-year overall survival (OS), progression-free survival (PFS) or local control (LC). CONCLUSIONS: The preoperative RTSIB approach was not inferior to CRT in terms of metabolic response, toxicity, OS, PFS and LC, and could be considered an available option for patients unfit for fluorouracil-based CRT.

Outcomes for oligometastatic head and neck cancer treated with stereotactic body radiotherapy: Results from an international multi-institutional consortium.

BACKGROUND: We report the results of an international multi-institutional cohort of oligometastatic (OMD) head and neck cancer (HNC) patients treated with SBRT. METHODS: Patients with OMD HNC (≤5 metastases) treated with SBRT between 2008 and 2016 at six institutions were included. Treated metastasis control (TMC), progression-free survival (PFS), and overall survival (OS) were analyzed by multivariable analysis (MVA). RESULTS: Forty-two patients with 84 HNC oligometastases were analyzed. The TMC rate at 1 and 2 years were 80% and 66%, with a median time to recurrence of 10.1 months. The median PFS and OS were 4.7 and 23.3 months. MVA identified a PTV point maximum (BED)10 > 100 Gy as a predictor of improved TMC (HR = 0.31, p = 0.034), and a cumulative PTV > 48 cc as having worse PFS (HR = 2.99, p < 0.001). CONCLUSION: Favorable TMC and OS was observed in OMD HNCs treated with SBRT.

Bone marrow sparing in prostate cancer patients treated with Post-operative pelvic nodal radiotherapy - A proton versus photon comparison.

PURPOSE: Extending salvage radiotherapy to treat the pelvic lymph nodes (PLNRT) improves oncologic outcomes in prostate cancer (PCa). However, a larger treatment volume increases the extent of bone marrow (BM) exposure, which is associated with hematologic toxicity (HT). Given the potential long-term impact of BM dose in PCa, clinical studies on BM sparing (BMS) are warranted. Herein, we dosimetrically compared photon and proton plans for BMS. MATERIALS AND METHODS: Treatment plans of 20 post-operative PCa patients treated with volumetric-modulated arc photon therapy (VMAT) PLNRT were retrospectively identified. Contours were added for the whole pelvis BM (WPBM) and BM sub-volumes: lumbar-sacral (LSBM), iliac (ILBM), and lower pelvis (LPBM). Three additional plans were created: VMAT_BMS, intensity-modulated proton therapy (IMPT), and IMPT_BMS. Normal tissue complication probabilities (NTCP) for grade >3 hematologic toxicity (HT3+) were calculated for the WPBM volumes. RESULTS: Compared to the original VMAT plan, mean doses to all BM sub-volumes were statistically significantly lower for VMAT_BMS, IMPT, and IMPT_BMS resulting in average NTCP percentages of 20.5 ± 5.9, 10.7 ± 4.2, 6.1 ± 2.0, and 2.5 ± 0.6, respectively. IMPT_BMS had significantly lower low dose metrics (V300cGy-V2000cGy) for WPBM and sub-volumes except for LPBM V2000cGy compared to VMAT_BMS and ILBM V20Gy compared to IMPT. In most cases, V4000cGy and V5000cGy within ILBM and LSBM were significantly higher for IMPT plans compared to VMAT plans. CONCLUSIONS: BMS plans are achievable with VMAT and IMPT without compromising target coverage or OARs constraints. IMPT plans were overall better at reducing mean and NTCP for HT3+ as well as low dose volumes to BM. However, IMPT had larger high dose volumes within LSBM and ILBM. Further studies are warranted to evaluate the clinical implications of these findings.

Machine Learning for Predicting Clinician Evaluation of Treatment Plans for Left-Sided Whole Breast Radiation Therapy.

Purpose: The objective of this work was to investigate the ability of machine learning models to use treatment plan dosimetry for prediction of clinician approval of treatment plans (no further planning needed) for left-sided whole breast radiation therapy with boost. Methods and Materials: Investigated plans were generated to deliver a dose of 40.05 Gy to the whole breast in 15 fractions over 3 weeks, with the tumor bed simultaneously boosted to 48 Gy. In addition to the manually generated clinical plan of each of the 120 patients from a single institution, an automatically generated plan was included for each patient to enhance the number of study plans to 240. In random order, the treating clinician retrospectively scored all 240 plans as (1) approved without further planning to seek improvement or (2) further planning needed, while being blind for type of plan generation (manual or automated). In total, 2 × 5 classifiers were trained and evaluated for ability to correctly predict the clinician's plan evaluations: random forest (RF) and constrained logistic regression (LR) classifiers, each trained for 5 different sets of dosimetric plan parameters (feature sets [FS]). Importances of included features for predictions were investigated to better understand clinicians' choices. Results: Although all 240 plans were in principle clinically acceptable for the clinician, only for 71.5% was no further planning required. For the most extensive FS, accuracy, area under the receiver operating characteristic curve, and Cohen's κ for generated RF/LR models for prediction of approval without further planning were 87.2 ± 2.0/86.7 ± 2.2, 0.80 ± 0.03/0.86 ± 0.02, and 0.63 ± 0.05/0.69 ± 0.04, respectively. In contrast to LR, RF performance was independent of the applied FS. For both RF and LR, whole breast excluding boost PTV (PTV40.05Gy) was the most important structure for predictions, with importance factors of 44.6% and 43%, respectively, dose recieved by 95% volume of PTV40.05 (D95%) as the most important parameter in most cases. Conclusions: The investigated use of machine learning to predict clinician approval of treatment plans is highly promising. Including nondosimetric parameters could further increase classifiers' performances. The tool could become useful for aiding treatment planners in generating plans with a high probability of being directly approved by the treating clinician.

The impact of local control on widespread progression and survival in oligometastasis-directed SBRT: Results from a large international database.

PURPOSE: We investigated the impact of local control (LC) on widespread progression (WSP) and overall survival (OS) in patients treated to all extracranial oligometastases (OMs) at presentation to SBRT in this retrospective review across 6 international centers. MATERIALS/METHODS: Relationships between LC status of SBRT-directed OMs and OS and WSP (>5 new active/untreated lesions) were explored using Cox and Fine-Gray regression models, adjusting for radioresistant histology and pre-SBRT systemic therapy receipt. The association between LC and dosimetric predictors was analyzed with competing risk regression using death as a competing risk and across a wide range of simulated α/ßratios. RESULTS: In total, 1700 OMs in 1033 patients were analyzed, with 25.2% NSCLC, 22.7% colorectal, 12.8% prostate, and 8.1% breast histology. Patients who failed locally in any SBRT-directed OM within 6 mo were at 3.6-fold higher risk of death and 2.7-fold higher risk of WSP compared to those who remained locally-controlled (p < 0.001). Similar associations existed for each duration of LC investigated through 3 yrs post-SBRT. There was no significant difference in risk of WSP or death between patients who failed in a subset of SBRT-treated lesions vs. patients who failed in all lesions. Minimum dose (Dmin) to the GTV/ITV was most predictive of LC when compared to prescription dose, PTV Dmin, and PTV Dmax. Sensitivity analysis for achieving 1-yr LC > 95% found thresholds of 41.2 Gy and 55.2 Gy in 5 fractions for smaller (< 27.7 cc) and larger radioresistant lesions, respectively. CONCLUSION: This large multinational cohort suggests that the duration of LC following OM-directed SBRT strongly correlates with WSP and OS.

Treatment of Oligometastatic Non-Small Cell Lung Cancer: An ASTRO/ESTRO Clinical Practice Guideline.

PURPOSE: This joint guideline by American Society for Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) was initiated to review evidence and provide recommendations regarding the use of local therapy in the management of extracranial oligometastatic non-small cell lung cancer (NSCLC). Local therapy is defined as the comprehensive treatment of all known cancer-primary tumor, regional nodal metastases, and metastases-with definitive intent. METHODS: ASTRO and ESTRO convened a task force to address 5 key questions focused on the use of local (radiation, surgery, other ablative methods) and systemic therapy in the management of oligometastatic NSCLC. The questions address clinical scenarios for using local therapy, sequencing and timing when integrating local with systemic therapies, radiation techniques critical for oligometastatic disease targeting and treatment delivery, and the role of local therapy for oligoprogression or recurrent disease. Recommendations were based on a systematic literature review and created using ASTRO guidelines methodology. RESULTS: Based on the lack of significant randomized phase 3 trials, a patient-centered, multidisciplinary approach was strongly recommended for all decision-making regarding potential treatment. Integration of definitive local therapy was only relevant if technically feasible and clinically safe to all disease sites, defined as 5 or fewer distinct sites. Conditional recommendations were given for definitive local therapies in synchronous, metachronous, oligopersistent, and oligoprogressive conditions for extracranial disease. Radiation and surgery were the only primary definitive local therapy modalities recommended for use in the management of patients with oligometastatic disease, with indications provided for choosing one over the other. Sequencing recommendations were provided for systemic and local therapy integration. Finally, multiple recommendations were provided for the optimal technical use of hypofractionated radiation or stereotactic body radiation therapy as definitive local therapy, including dose and fractionation. CONCLUSIONS: Presently, data regarding clinical benefits of local therapy on overall and other survival outcomes is still sparse for oligometastatic NSCLC. However, with rapidly evolving data being generated supporting local therapy in oligometastatic NSCLC, this guideline attempted to frame recommendations as a function of the quality of data available to make decisions in a multidisciplinary approach incorporating patient goals and tolerances.