Multi-centre evaluation of variation in cumulative dose assessment in reirradiation scenarios.

BACKGROUND AND PURPOSE: Safe reirradiation relies on assessment of cumulative doses to organs at risk (OARs) across multiple treatments. Different clinical pathways can result in inconsistent estimates. Here, we quantified the consistency of cumulative dose to OARs across multi-centre clinical pathways. MATERIAL AND METHODS: We provided DICOM planning CT, structures and doses for two reirradiation cases: head & neck (HN) and lung. Participants followed their standard pathway to assess the cumulative physical and EQD2 doses (with provided α/ß values), and submitted DVH metrics and a description of their pathways. Participants could also submit physical dose distributions from Course 1 mapped onto the CT of Course 2 using their best available tools. To assess isolated impact of image registrations, a single observer accumulated each submitted spatially mapped physical dose for every participating centre. RESULTS: Cumulative dose assessment was performed by 24 participants. Pathways included rigid (n = 15), or deformable (n = 5) image registration-based 3D dose summation, visual inspection of isodose line contours (n = 1), or summation of dose metrics extracted from each course (n = 3). Largest variations were observed in near-maximum cumulative doses (25.4 - 41.8 Gy for HN, 2.4 - 33.8 Gy for lung OARs), with lower variations in volume/dose metrics to large organs. A standardised process involving spatial mapping of the first course dose to the second course CT followed by summation improved consistency for most near-maximum dose metrics in both cases. CONCLUSION: Large variations highlight the uncertainty in reporting cumulative doses in reirradiation scenarios, with implications for outcome analysis and understanding of published doses. Using a standardised workflow potentially including spatially mapped doses improves consistency in determination of accumulated dose in reirradiation scenarios.

Bias due to statistical handling of death and reirradiation in the assessment of duration of response after palliative radiotherapy: a scoping review and analysis of clinical data.

OBJECTIVES: We investigated the influence of handling death and reirradiation on the estimation of duration of response (DOR). METHODS: First, we performed a scoping review on methods to assess DOR in palliative radiotherapy. Second, we performed three different analyses on a subgroup of patients from a previously published prospective study. The first analysis was a competing risks analysis considering relapse of pain as the event of interest and death and reirradiation as competing events (Analysis A). The second and third analyses were standard survival analyses where the event of interest was a composite outcome of relapse of pain, death, or reirradiation (Analysis B) and relapse of pain (Analysis C), respectively. RESULTS: Death was considered as an event of interest in less than half of the papers, while reirradiation was not considered in any of the studies. Competing risks analysis was not performed in any of the studies. In the analysis of clinical data, competing risks analysis showed that relapse of pain predominated as the cause of the end of response. Median DOR was correctly estimated to be 4.1 months in Analyses A and B, but was overestimated to be 8.1 months in Analysis C. CONCLUSIONS: Death and reirradiation should be treated as the events of interest that mark the end of response (as in Analyses A and B) to avoid overestimation of treatment efficacy and an invalid assumption of independent censoring. ADVANCES IN KNOWLEDGE: The definition of end of response remains inconclusive in the assessment of DOR. We recommend competing risks analysis (Analysis A), by which we can estimate cumulative incidence of each event type and evaluate the necessity of reirradiation.

Assessment of therapeutic outcome and role of reirradiation in patients with radiation-induced glioma.

BACKGROUND: We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and 2 mutation status in patients with radiation-induced glioma (RIG). METHODS: We retrospectively reviewed the clinical characteristics and treatment outcomes of 11 patients with high-grade glioma who satisfied Cahan's criteria for RIG in our database during 2001-2021. IDH 1/2 mutations were analyzed by Sanger sequencing and/or pyrosequencing. RESULTS: The RIGs included glioblastoma with IDH 1/2 wild-type (n = 7), glioblastoma not otherwise specified (n = 2), anaplastic astrocytoma with IDH1/2 wild-type (n = 1), and anaplastic astrocytoma not otherwise specified (n = 1). The median period from primary disease and RIG diagnosis was 17 years (range: 9-30 years). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and survival times were 11.3 and 28.3 months. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n = 5) tended to be longer than that of patients that received chemotherapy alone (n = 6) (17.0 vs 8.1 months). However, the median survival time was similar (29.6 vs 27.4 months). Local recurrence was observed in 5 patients treated with chemotherapy alone, whereas in 2 patients among 4 patients treated with reirradiation and chemotherapy. None of the patients developed radiation necrosis. In one case, the primary tumor was diffuse astrocytoma with IDH2 mutant, and the secondary tumor was glioblastoma with IDH 1/2 wild-type. Based on the difference of IDH2 mutation status, the secondary tumor with IDH 1/2 wild-type was diagnosed as a de novo tumor that was related to the previous radiation therapy. CONCLUSIONS: RIG can occur beyond 20 years after successfully treating the primary disease using radiotherapy; thus, cancer survivors should be informed of the long-term risk of developing RIG and the need for timely neuroimaging evaluation. Reirradiation combined with chemotherapy appears to be feasible and has favorable outcomes. Determining the IDH1/2 mutational status is useful to establish RIG diagnosis when the primary tumor is glioma.

Re-irradiation of canine non-lymphomatous nasal tumours using stereotactic radiation therapy (10 Gy x 3) for both courses: Assessment of outcome and toxicity in 11 dogs.

No uniformly beneficial treatments exist for dogs with non-lymphomatous nasal tumours (NLNT) that relapse after radiotherapy (RT). Reirradiation may prolong survival and improve quality of life. In this retrospective study, we describe outcomes for 11 dogs that had CT-confirmed locoregional progression of NLNT after an initial course of stereotactic RT (SRT#1; 10 Gy × 3) and were then re-treated with the same type of protocol (SRT#2, also 10 Gy × 3). The median time between SRT #1 and SRT #2 was 243 days (95% CI: 78-385 days). Ten dogs (91%) had a clinical benefit after SRT#1; five dogs (45%) had clinical benefit after SRT#2. Adverse events after SRT#2 included nasocutaneous or oronasal fistula formation (N = 3 at 180, 270, and 468 days), seizures (N = 2 at 78 and 330 days), bacterial or fungal rhinitis (N = 2 at 240 and 385 days), and facial swelling (N = 1 at 90 days). All 11 dogs have died, due to disease progression, presumed radiotoxicity, or declining quality of life; in most cases, it was difficult to discern between these conditions. The median overall survival time (OST) from SRT#1 was 745 days (95% CI: 360-1132). The median overall survival time (OST) from SRT #2 was 448 days (95% CI: 112-626). For these dogs, survival was prolonged, but adverse events after SRT#2 were common (8/11; 73%). Therefore, before consenting to re-irradiation with this protocol, pet owners should be counselled about survivorship challenges, including risk for severe toxicities, and persistence of clinical signs.

Operating procedures, risk management and challenges during implementation of adaptive and non-adaptive MR-guided radiotherapy: 1-year single-center experience.

BACKGROUND: Main purpose was to describe procedures and identify challenges in the implementation process of adaptive and non-adaptive MR-guided radiotherapy (MRgRT), especially new risks in workflow due to the new technique. We herein report the single center experience for the implementation of (MRgRT) and present an overview on our treatment practice. METHODS: Descriptive statistics were used to summarize clinical and technical characteristics of treatment and patient characteristics including sites treated between April 2019 and end of March 2020 after ethical approval. A risk analysis was performed to identify risks of the online adaptive workflow. RESULTS: A summary of the processes on the MR-Linac including workflows, quality assurance and possible pitfalls is presented. 111 patients with 124 courses were treated during the first year of MR-guided radiotherapy. The most commonly treated site was the abdomen (42% of all treatment courses). 73% of the courses were daily online adapted and a high number of treatment courses (75%) were treated with stereotactic body irradiation. Only 4/382 fractions could not be treated due to a failing online adaptive quality assurance. In the risk analysis for errors, the two risks with the highest risk priority number were both in the contouring category, making it the most critical step in the workflow. CONCLUSION: Although challenging, establishment of MRgRT as a routinely used technique at our department was successful for all sites and daily o-ART was feasible from the first day on. However, ongoing research and reports will have to inform us on the optimal indications for MRgRT because careful patient selection is necessary as it continues to be a time-consuming treatment technique with restricted availability. After risk analysis, the most critical workflow category was the contouring process, which resembles the need of experienced staff and safety check paths.

Prospective Longitudinal Assessment of Quality of Life and Activities of Daily Living as Patient-Reported Outcome Measures in Recurrent/Progressive Glioma Treated with High-dose Salvage Re-irradiation.

AIMS: To evaluate quality of life (QOL) and activities of daily living (ADL) longitudinally in patients treated with salvage re-irradiation for recurrent/progressive glioma. Secondary end points included post-re-irradiation survival. MATERIALS AND METHODS: Patients with diffuse glioma, aged 18-70 years with preserved performance status and unequivocal evidence of recurrence/progression with a minimum 2-year time interval from index radiation therapy were eligible. QOL was assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) and brain cancer module (BN20). ADL was assessed using a modified Barthel's index. Assessments were carried out longitudinally, first before re-irradiation, at completion of re-irradiation and subsequently periodically on follow-up. Summary scores were calculated from raw scores as per the EORTC scoring manual; higher functional scores and lower symptom scores indicating better QOL. Summary mean scores for the modified Barthel's index were also calculated, with lower scores indicating higher disability. Differences between the summary scores at different time points were tested using the Friedman test. RESULTS: In total, 225 assessments were carried out in 60 patients accrued on the study. A significant improvement in scores was noted for physical function (P < 0.001), emotional function (P = 0.002), cognitive function (P = 0.009) and social functioning (P = 0.047) over time. Role function scores (P = 0.182) and global health status scores (P = 0.074) remained stable. Among symptom scores, fatigue showed a statistically significant improvement over time (P = 0.01), whereas other symptom scores remained largely stable. There was a significant increase in the modified Barthel's index score over time (P = 0.001), suggesting greater functional independence. At a median follow-up of 12.9 months, the 1-year Kaplan-Meier estimates with 95% confidence intervals of post-re-irradiation progression-free survival and overall survival were 45.1% (31.5-58.7%) and 62.2% (49.2-75.2%), respectively. CONCLUSIONS: High-dose salvage re-irradiation in carefully selected patients with recurrent/progressive glioma is associated with stable QOL (preserved functional domains and reduced symptom burden) and improvement in ADL (greater functional independence) over time with encouraging survival outcomes.

Digital biomarkers: Importance of patient stratification for re-irradiation of glioma patients - Review of latest developments regarding scoring assessment.

PURPOSE: To review scoring assessments in re-irradiation of high-grade glioma (HGG) patients and how to use scoring for patient stratification. The next aim was to investigate the different approaches employed by the scoring systems and the way they can be applied to build homogeneous patient groups for a reliable prognosis. METHODS: We searched the Medline/Pubmed and Web of science databases for relevant articles regarding scores for re-irradiation of recurrent HGG. All references were divided into the following groups: novel score establishment (n = 5), score validation (n = 6), not relevant to this evaluation (n = 26). RESULTS: We identified five scoring systems. Two are modifications of an already existing score. Calculations differ immensely from easy point addition to a more complex formula with including three up to 10 individual parameters. Six validation articles were found for three of the scores; one was validated four times. Two scores were never validated. CONCLUSION: For recurrent HGG, the clinical situation remains demanding. Due to the heterogeneity of data at re-irradiation, patient stratification is important. Several scoring systems have been developed to predict prognosis. As a digital biomarker, scores are of high value regarding quick patient assessment and therapy decision making. For the next generation of digital biomarkers, easy calculation, and inclusion of easily available parameters are crucial.

Re-irradiation for recurrent glioma: outcome evaluation, toxicity and prognostic factors assessment. A multicenter study of the Radiation Oncology Italian Association (AIRO).

INTRODUCTION: The prognosis of glioma is dismal, and almost all patients relapsed. At recurrence time, several treatment options are considered, but to date there is no a standard of care. The Neurooncology Study Group of the Italian Association of Radiation Oncology (AIRO) collected clinical data regarding a large series of recurrent glioma patients who underwent re-irradiation (re-RT) in Italy. METHODS: Data regarding 300 recurrent glioma patients treated from May 2002 to November 2017, were analyzed. All patients underwent re-RT. Surgical resection, followed by re-RT with concomitant and adjuvant chemotherapy was performed. Clinical outcome was evaluated by neurological examination and brain MRI performed, 1 month after radiation therapy and then every 3 months. RESULTS: Re-irradiation was performed at a median interval time (IT) of 16 months from the first RT. Surgical resection before re-RT was performed in 19% of patients, concomitant temozolomide (TMZ) in 16.3%, and maintenance chemotherapy in 29%. Total doses ranged from 9 Gy to 52.5 Gy, with a median biological effective dose of 43 Gy. The median, 1, 2 year OS were 9.7 months, 41% and 17.7%. Low grade glioma histology (p  ≪ 0.01), IT > 12 months (p = 0.001), KPS > 70 (p = 0.004), younger age (p = 0.001), high total doses delivered (p = 0.04), and combined treatment performed (p = 0.0008) were recorded as conditioning survival. CONCLUSION: our data underline re-RT as a safe and feasible treatment with limited rate of toxicity, and a combined ones as a better option for selected patients. The identification of a BED threshold able to obtain a greater benefit on OS, can help in designing future prospective studies.

The breast graded prognostic assessment is associated with the survival outcomes in breast cancer patients receiving whole brain re-irradiation.

INTRODUCTION: Whole brain (WB) re-irradiation for breast cancer patients with progressive brain metastasis after first-course WB radiotherapy (WBRT) is controversial. In this study, we sought to investigate the association between the molecular sub-classifications and breast-specific Graded Prognostic Assessment (GPA, which includes the Karnofsky performance status, molecular subtypes, and age as its indices) and the outcomes of breast cancer patients who received WB re-irradiation. METHODS: Twenty-three breast cancer patients who received WB re-irradiation for relapsed and progressive intracranial lesions after first-course WBRT between 2004 and 2016 were retrospectively reviewed. Patients were divided according to the 4 molecular subtypes of luminal A/B (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), luminal HER2 (HR+/HER2+), HER2 (HR-/HER2+), and triple negative (HR-/HER2-). The clinical and radiological responses and survival rates after WB re-irradiation were analyzed. RESULTS: At 1 month after WB re-irradiation, 13 of 23 patients (56.5%) exhibited disappearance or alleviation of neurological symptoms. The median survival time after WB re-irradiation was 2.93 months (95% confidence interval [CI], 1.79-4.08). After WB re-irradiation, patients with HER2-negative tumors had poorer median survival times than those with HER2-positive tumors (2.23 vs. 3.0 months, respectively; p = 0.022). Furthermore, patients with high breast GPA scores (2.5-4.0, n = 11) had longer median survivals than those with low-scores (0-2.0, n = 12) after WB re-irradiation (4.37 vs. 1.57 months, respectively; p < 0.005). CONCLUSIONS: WB re-irradiation may be a feasible treatment option for certain breast cancer patients who develop brain metastatic lesions after first-course WBRT when these lesions are ineligible for radiosurgery or surgery.

Systematic assessment of clinical outcomes and toxicities of proton radiotherapy for reirradiation.

Reirradiation (reRT) for locoregional recurrences poses unique challenges and risks; re-treatment using proton beam radiotherapy (PBT) could prove advantageous. Assessing clinical outcomes and toxicity profiles, this systematic review comprehensively evaluated available evidence regarding PBT reRT. Fourteen original investigations across central nervous system (CNS) (n=6), head/neck (H&N) (n=4), lung (n=2), and gastrointestinal (n=2) malignancies were analyzed. PBT for recurrent uveal melanoma achieved 5-year eye retention of 55%; for chordomas, reRT afforded a 2-year local control and overall survival (OS) of 85% and 80%, respectively. Multiple PBT reRT studies for adult gliomas illustrate no grade ≥3 toxicities. Two pediatric CNS tumor studies demonstrated the safety and efficacy of reRT, with one total grade 3 toxicity and achievement of longer-term OS. PBT for H&N malignancies shows appropriate local/locoregional control and favorable toxicity profiles versus historical photon-based methods, including low (9-10%) rates of feeding tube placement. PBT for recurrent lung cancer can achieve favorable survival with expected toxicities/complications of reRT, especially with concurrent chemotherapy and centrally located recurrences. Lastly, PBT reRT in gastrointestinal malignancies induced very few high-grade complications. Hence, based on the limited existing data, PBT is a notably safe reRT modality for effective salvage of recurrent disease. Institutional experiences must continue to be reported: dosimetric correlations, late toxicities, and advanced PBT techniques.

Improving Outcomes for Esophageal Cancer using Proton Beam Therapy.

Radiation therapy (RT) plays an essential role in the management of esophageal cancer. Because the esophagus is a centrally located thoracic structure there is a need to balance the delivery of appropriately high dose to the target while minimizing dose to nearby critical structures. Radiation dose received by these critical structures, especially the heart and lungs, may lead to clinically significant toxicities, including pneumonitis, pericarditis, and myocardial infarction. Although technological advancements in photon RT delivery like intensity modulated RT have decreased the risk of such toxicities, a growing body of evidence indicates that further risk reductions are achieved with proton beam therapy (PBT). Herein we review the published dosimetric and clinical PBT literature for esophageal cancer, including motion management considerations, the potential for reirradiation, radiation dose escalation, and ongoing esophageal PBT clinical trials. We also consider the potential cost-effectiveness of PBT relative to photon RT.