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Radiotherapy (RT) plays a fundamental role in the definitive treatment of carcinoma of the head and neck cancer, but loco regional relapse happens up to 40% of the patients despite optimal initial multidisciplinary treatment, as well as second neoplasmstumors. Management of these scenarios is challenging, as re-treating an already irradiated field has a narrow balance between disease control benefit and toxicity risk. We aimed to provide data of outcomes in terms of disease control, survival and toxicity of re-irradiated patients, to facilitate selection and stratification of those who could benefit more. Retrospective analysis of patients with loco-regional relapse or second primary head and neck carcinomastumor who were re-irradiated between 2009 and-2023 in a previously irradiated field (≥50 Gy) using 3D or IMRT/VMAT, and conventional fractionation. Data about event-free survival (EFS), overall survival (OS), acute and chronic toxicity according to CTCAEv54 wereas collected from clinical reports. Sixty patients were re-irradiated. Most of them (78%) were male and 98% were ECOG 1-0. Mean age at diagnosis was 60 years (median 59y, range 51-67y). First diagnosis tumor histology was SCC in 94% of the patients, and was alsowas the most frequent histology (98%) for the second primary alsotumor. Most common site for both, first and second tumortumor was oral cavity (49% and 38%, respectively). Time between two RT treatments was at least 2 years in 63% of the patients, with no patients treated with less than 6 month6-month period (mean time to second RT 40.4 months, median 30.5 months, range range 19.5-54.5 months). Most of the patient retreated underwent adjuvant RT (n=32, 58%), reaching a mean dose of 59.95Gy (70.00-48.40) in addition to concomitant chemotherapy (67%). Re-irradiation was more mostly used in an adjuvant context (55%). Systemic concomitant treatment was 65%, with preference for triweekly regimens (34%). After second treatment, 58% of the patients had complete response, 40% had a partial response or stable disease, and only one patient progressedhad progression. Mean total dose for re-irradiation was 60 Gy (median 60 Gy, range 54-70 Gy). Only 22 of the re-irradiation treatment volumes included cervical areas. IMRT/VMAT was the preferred treatment technique (76%). All treatments were normo-fractionated treatments. Mean follow up is was 2.7 years from the end of RT. All patients had at least a 6-months follow up. Acute toxicity after re- irradiation was very common (95%), occurring in 70% of the patients presented mucositis and 67% epithelitis. Long- term toxicity consisted of dysphagia (45 patients74), osteonecrosis (6 patients), fistula (5 patients), trismus (5 patients G3-4). Carotid rupture happened in one patient. Mean time to progression was 20.4 months. Kaplan Kaplan-Meier analysis for event- free survival (EFS) shows better outcomes in patients who received re-irradiation at least 2 years after the first irradiation, with a median time to event of 9.59 6 months (95%CI 4.14-9.92m) compared with 4.94 months in patients who had earlier re-irradiation (95%CI 6.14-22.11m), with no statistically significant differences (Figure 1). No statistically significant differences in time to event according to total dose of re-irradiation were seen, as well as between patients with adjuvant or radical intention. Median overall survival (OS) was 18.2 months (95%CI 14.061-40.1m) (Figure 2). At 51 months, 15 patients are still alive. OS is better in patients receiving RT more than 2 years after the first treatment (22.67 months vs 18.23 months), with differences maintained over the follow up. Patients who were treated with more than 50 Gy seem to have better median OS (19.7m vs 13.37m4m) without statistically significant differences. [Display omitted] Our analysis shows that patients with head and neck cancer with good performance status who undergo a re-irradiation treatment with curative intent present prolonged survival and disease control after the treatment, which seems benefited when second irradiation happens later than 2 years after the first course of RT, for both adjuvant and radical RT strategies. [ABSTRACT FROM AUTHOR]

As radiotherapy (RT) is fundamental for definitive treatment of head and neck carcinomas and novel modulated techniques permit more selected patients to be re-irradiated, we aimed to collect data about chronic and acute toxicity after second irradiation and evaluate correlation with dosimetric parameters, for future specification of organ at risk constraints. Retrospective analysis of 60 patients treated at our institution for loco-regional relapse or second primary head and neck tumor, re-irradiated between 2009 and 2023 to a previously irradiated location (>50Gy) using 3D or IMRT with a total dose of 60Gy (mean 60Gy, range 54-70Gy) at 2-2.1Gy/Fx. Data about acute and chronic toxicity was collected from clinical reports, according to CTCAEv5. We were able to evaluate dosimetric data about 59 patients. For data extraction, rigid registration was made with TPS Eclipse. Sum plan of both treatments was created (dose distribution were not converted to EQD2 because of TPS limitations) on the most recent CT scan. Dosimetric data were extracted using homemade script from API Eclipse. Planning and calculation system: Eclipse (v10-v15.6). Calculation algorithm: AAA for IMRT plans, Acuros XB for VMAT plans. Acute toxicity after re-irradiation was very common (95%). 70% presented mucositis (28 out of 32 were G1-2) and 67% epithelitis (35 out of 40 were G1-2). Chronic toxicity after second RT consisted of dysphagia (74,5% of the patients, with 23 patients requiring use of nasogastric tube (NGT) or Percutaneous Endoscopic Gastrostomy (PEG), of which 16 were attributed to RT toxicity and not to prior treatment sequelae), osteonecrosis (6 patients), fistula (5 patients), trismus (24% G1-2, 3.3% G3-4). Carotid rupture happened in one patient. Of 6 patients presenting osteonecrosis, 3 were grade 3, with no patients with grade 4 toxicity. Looking at the plan sum, these all three patients had received a total D0.035 > 100Gy to the mandible bone, and received a higher mean dose (113.7Gy vs 100.8Gy) to the mandible compared with patients who presented milder or no toxicity (Figure 1). For dysphagia, we analysed mean dose to pharynx constrictor muscles. We can see that those needing PEG/NGT (G3 toxicity) receive a higher mean dose (61Gy vs 53Gy) than those who don't need it. Of the 16 patients who required these interventions due to RT toxicity (not because of surgery sequelae or similar), the received dose is still higher (60.4Gy) than the mean dose received in patients without PEG or NGT (Figure 2). Univariate model showed that those who required NGT or PEG after re-irradiation because of RT toxicity present higher risk of events, with HR of 3.05 (1.57-5.92, p<0.001). No statistically significant differences were seen for treatment technique (IMRT vs 3D) or other variables, also for the multivariable analysis. [Display omitted] Toxicity after re-irradiation in head and neck càncer patients is not negligible. Despite acute effects are the most frequent ones, regarding long term toxicity, dysphagia is the most frequent and the one with more impact in the quality of life of the patient, but this, as well as the other toxicities are rare to have a severe presentation (G3 or more). Our data seems to show a correlation between dose to the mandible bone and G3 osteonecrosis, but interpretation must be cautious, as the limitations of this analysis include the rigid dose registration instead of deformable, no EQD2 dose summation and the relevance of anatomic variations due to surgeries and tumor growth. Further investigations regarding these issues could help to improve the management of re-irradiation dosimetry evaluation. [ABSTRACT FROM AUTHOR]

More than 1/3rd of head and neck cancer patients eventually fail loco-regionally or appear as second primary, despite ever-improving treatment options.1,2 Recommended potentially curative treatment options include salvage surgery if the disease is amenable to surgery, or reirradiation.2 Reirradiation of head and neck cancers presents a dilemma in terms of achieving adequate doses to the target, maintaining the organ-at-risks (OAR) dose constraints within limits, and managing toxicities emerging during and after the treatment.3–5 Intensity-modulated radiotherapy (IMRT) has slowly evolved to be the modality of choice for re-irradiation owing to its ability to improve disease control and reduce treatment-related toxicity.6 We present the data of re-irradiated head and neck cancer patients treated at our centre with IMRT. This was a retrospective single-arm observational analysis. Details of head and neck cancer patients treated at our hospital with re-irradiation were retrieved. After reviewing all the treatment records, the follow-up details were assembled. All the cases were treated with IMRT with or without concurrent chemotherapy. All the patients received radiation and re-irradiation with a dose-per-fraction of 1.8 to 2Gray with adjuvant or definitive intent, for five days a week for six weeks or above. The dose prescribed was preferably 60 – 66Gy in 30-33 fractions. Dose constraints used for OARs were: Spinal cord Dmax <=45Gy, and brainstem and optic apparatus Dmax <=54Gy.3,5 Special care was also taken to limit the cumulative dose of carotid arteries to <120Gy.7 The mean dose of parotid was limited at 23Gy, although target volume coverage was given priority, whenever the two were in proximity. Patients were immobilised using a 5-clamp head and neck thermoplastic mask. 3 mm slice thickness contrast-enhanced computed tomography (CT) images were obtained from vertex to 2 cm below the carina using Siemens Emotion 6 (Somatom, Germany). The treatment planning was done on MONACO (Version 5.11). The target volumes for definitive treatment were contoured as per ICRU 62.8 The decision to include nodes depended on certain factors: previous history of nodal positivity, nature of irradiation in the first radiotherapy schedule, nature and location of primary during second irradiation, definitive/adjuvant intent of re-irradiation, surgical resection of nodes, duration between the irradiation treatments, dose volumes used and dosimetric parameters achieved for OARs in the first radiotherapy. Patients were treated by using linear accelerator (Elekta Compact and Synergy; Elekta, Crawley, UK). All patients were followed up on a regular basis. Response assessment scans were done after 3 months of treatment completion. Overall Survival (OS) was defined time from start date of re-irradiation to the date of death or date of last clinical follow-up. Progression-free survival (PFS) was defined as interval from the start date of RT to any documented recurrence. Analysis was performed with the SPSS statistical (version 23.0; IBM, Armonk, NY, USA). All potential prognostic factors were analysed. the patients were divided into three prognostic subgroups using Multi-Institution Re-irradiation (MIRI) recursive partitioning analysis (RPA).9 Seventy-three cases were included in the final analysis. During the re-irradiation schedule, 34/73 cases were treated with definitive irradiation, whereas 39 cases were treated with postoperative adjuvant radiotherapy. Median interval between both the RT schedules was 55 months (range: 13-197). Median follow-up duration after re-irradiation was 23 months (range: 4-74). Median initial RT dose was 60 Gy (range: 58-66) and median re-irradiation dose was 60Gy (range: 54-66). The median initial RT and re-irradiation dose was 2Gy (range: 1.8-2). There were 41 events in PFS. The 2-year and 4-year PFS rates were 55.8% and 29.2%. The estimated 4-year DFS definitive re-irradiation versus adjuvant radiotherapy were 28.7 vs 29.3% (p-0.786). There was no statistically significant difference for 3-year OS of de novo versus post-operative cases (54.7 vs 56.3%, p-0.559). No significant differences in DFS or OS were elucidated for duration of re-irradiation for a 2-year period (48.6 vs 39.7, p-0.648) and 3-year period (3yr DFS – 48 vs 57.5%, p-0.091). Patients recurring within 2 years of primary radiation had poorer OS than those recurring after 2 years. (57.14 vs 49.25%, p-0.039). Patients with more than 3 high-risk factors during adjuvant reirradiation post-surgery had poor OS. (38.46 vs 31.5%, p-0.043). The number of cases in RPA Class I, II, and III were 16, 49 and 8, respectively. The 2-year DFS for Class I, II and III, were 62.5%, 59.7% and 12.5% (p<0.0001). Re-irradiation in head and neck cancers is tolerable and toxicities are acceptable. A larger cohort and a longer duration of study will help in discerning the factors that will help in reducing the toxicities and improving outcomes further. [ABSTRACT FROM AUTHOR]

• Delineation in LRRC is complex due to heterogeneous disease and absence of guidelines. • Inter-observer variation in LRRC is large. • Multidisciplinary target volume definition is essential. • QA data from PelvEx II trial will provide further insight in target volumes. Neoadjuvant chemoradiotherapy (nCRT) is used in locally recurrent rectal cancer (LRRC) to increase chances of a radical surgical resection. Delineation in LRRC is hampered by complex disease presentation and limited clinical exposure. Within the PelvEx II trial, evaluating the benefit of chemotherapy preceding nCRT for LRRC, a delineation guideline was developed by an expert LRRC team. Eight radiation oncologists, from Dutch and Swedish expert centres, participated in two meetings, delineating GTV and CTV in six cases. Regions at-risk for re-recurrence or irradical resection were identified by eleven expert surgeons and one expert radiologist. Target volumes were evaluated multidisciplinary. Inter-observer variation was analysed. Inter-observer variation in delineation of LRRC appeared large. Multidisciplinary evaluation per case is beneficial in determining target volumes. The following consensus regarding target volumes was reached. GTV should encompass all tumour, including extension into OAR if applicable. If the tumour is in fibrosis, GTV should encompass the entire fibrotic area. Only if tumour can clearly be distinguished from fibrosis, GTV may be reduced, as long as the entire fibrotic area is covered by the CTV. CTV is GTV with a 1 cm margin and should encompass all at-risk regions for irradical resection or re-recurrence. CTV should not be adjusted towards other organs. Multifocal recurrences should be encompassed in one CTV. Elective nodal delineation is only advised in radiotherapy-naïve patients. This study provides a first consensus-based delineation guideline for LRRC. Analyses of re-recurrences is needed to understand disease behaviour and to optimize delineation guidelines accordingly. [ABSTRACT FROM AUTHOR]

• Misinterpretation of radiation-induced contrast enhancement (RICE) is frequent with a rate of 39% that were misinterpreted as tumor progression at initial RICE occurrence. • A tumor-specific therapy including chemotherapy or re-irradiation led to a RICE size progression in 86% and 92% of cases, respectively and RICE symptom progression in 57% and 65% of cases, respectively. • A RICE-specific therapy such as corticosteroids or Bevacizumab for larger or symptomatic RICE led to a RICE size regression in 81% of cases with symptom stability or regression in 62% of cases. • For RICE, correct diagnosis and treatment decisions are challenging and critical and should be made interdisciplinarily. Radiation-induced contrast enhancements (RICE) are a common side effect following radiotherapy for glioma, but both diagnosis and handling are challenging. Due to the potential risks associated with RICE and its challenges in differentiating RICE from tumor progression, it is critical to better understand how RICE prognosis depends on iatrogenic influence. We identified 99 patients diagnosed with RICE who were previously treated with either photon or proton therapy for World Health Organization (WHO) grade 1–3 primary gliomas. Post-treatment brain MRI-based volumetric analysis and clinical data collection was performed at multiple time points. The most common histologic subtypes were astrocytoma (50%) and oligodendroglioma (46%). In 67%, it was graded WHO grade 2 and in 86% an IDH mutation was present. RICE first occurred after 16 months (range: 1–160) in median. At initial RICE occurrence, 39% were misinterpreted as tumor progression. A tumor-specific therapy including chemotherapy or re-irradiation led to a RICE size progression in 86% and 92% of cases, respectively and RICE symptom progression in 57% and 65% of cases, respectively. A RICE-specific therapy such as corticosteroids or Bevacizumab for larger or symptomatic RICE led to a RICE size regression in 81% of cases with symptom stability or regression in 62% of cases. While with chemotherapy and re-irradiation a RICE progression was frequently observed, anti-edematous or anti-VEGF treatment frequently went along with a RICE regression. For RICE, correct diagnosis and treatment decisions are challenging and critical and should be made interdisciplinarily. [ABSTRACT FROM AUTHOR]

• Voxel-wise optimization of re-irradiation plans using radiobiologically equivalent deformable dose mapping. • Robustness tool incorporated to aid informed clinical decision-making. • Dosimetric advantages over manual approaches and reduced time consumption. • Re-irradiation workflow fully implemented in commercial software. Re-irradiation in radiotherapy presents complexities that require dedicated tools to generate optimal re-treatment plans. This study presents a robust workflow that considers fractionation size, anatomical variations between treatments, and cumulative bias doses to improve the re-irradiation planning process. The workflow was automated in MIM® Software and the Elekta© Monaco® treatment planning system. Prior treatment doses are deformably mapped, converted to equivalent dose in 2 Gy fractions (EQD2), and accumulated onto the re-treatment planning CT. Two MIM extensions were developed to estimate voxel-wise dose mapping uncertainties and to convert the cumulative EQD2 into a physical dose distribution equivalent to the re-treatment fractionation size. This dose distribution is used in Monaco as bias to optimize the re-irradiation plan. The workflow was retrospectively tested with data from 14 patients, and the outcomes were compared to the manually optimized plans (MOPs) clinically utilized. Bias-dose guided plans (BDGPs) demonstrated a median reduction of the critical organ at risk (OAR) cumulative EQD2 metrics of 240 cGy (range: 1909 cGy, −187 cGy, p = 0.002). BDGPs allowed higher target coverage in cases where the MOP approach implied dose de-escalation of the target. The dose mapping uncertainties resulted in OAR cumulative EQD2 metrics increments ranging from 10 cGy to 730 cGy. We introduced a re-irradiation planning workflow using commercially available software that accounts for anatomic and fraction size variations and improves planning efficiency. Employing voxel-level bias dose guidance demonstrated OAR-sparing benefits while maximizing prescription dose coverage to targets. The workflow's robustness tools aid informed clinical decision-making. [ABSTRACT FROM AUTHOR]

• Monocentric cohort of n = 223 recurrent glioma patients treated with re-irradiation. • Evaluation of re-irradiation dose escalation and concomitant therapy with bevacizumab (BEV) and temozolomide (TMZ) regarding post-recurrence survival and risk of radionecrosis. • Simultaneous integrated boost concept of 43.2 Gy feasible, effective and safe in this cohort. • Radionecrosis less frequent for concurrent BEV and post-recurrence survival benefit for concurrent TMZ treatment. • Basis for individualized selection of best concurrent therapy and optimal dose for re-irradiation. Re-irradiation (reRT) is an effective treatment modality for patients with recurrent glioma. Data on dose escalation, the use of simulated integrated boost and concomitant therapy to reRT are still scarce. In this monocentric cohort of n = 223 patients we investigated the influence of reRT dose escalation as well as the concomitant use of bevacizumab (BEV) with regard to post-recurrence survival (PRS) and risk of radionecrosis (RN). Patients with recurrent glioma treated between July 2008 and August 2022 with reRT with BEV, reRT with temozolomide (TMZ) and reRT without concomitant systemic therapy were retrospectively analyzed. PRS and RN-free survival (RNFS) were calculated for all patients using the Kaplan–Meier estimator. Univariable and multivariable cox regression was performed for PRS and for RNFS. The reRT Risk Score (RRRS) was calculated for all patients. Good, intermediate and poor risk of the RRRS translated into 11 months, 9 months and 7 months of median PRS (univariable: p = 0.008, multivariable: p = 0.013). ReRT was applied with a dose of ≤36 Gy (n = 140) or >36 Gy (n = 83). Concomitant bevacizumab (BEV) therapy was performed in n = 122 and concomitant temozolomide (TMZ) therapy in n = 32 patients. Median PRS was 10 months in patients treated with >36 Gy and 8 months in patients treated with ≤36 Gy (univariable: p = 0.032, multivariable: p = 0.576). Regarding concomitant TMZ therapy, median PRS was 14 months vs. 9 months for patients treated with or without TMZ (univariable: p = 0.041, multivariable: p = 0.019). No statistically significant influence on PRS was seen for concomitant BEV therapy in this series. RN was less frequent for reRT with concomitant BEV, (17/122; 13.9 %) than for reRT without BEV (30/101; 29.7 %). Regarding RNFS, the hazard ratio for reRT with BEV was 0.436 (univariable; p = 0.006) and 0.479 (multivariable; p = 0.023), respectively. ReRT dose did not show statistical significance in regards to RN (univariable: p = 0.073, multivariable: p = 0.404). RNFS was longer for patients receiving concomitant BEV to reRT than for patients treated with reRT only (mean 31.7 vs. 30.9 months, p = 0.004). In this cohort, in patients treated with concomitant BEV therapy RN was less frequently detected and in patients treated with concomitant TMZ longer PRS was observed. Based on these results, the best concomitant therapy and the optimal dose should be decided on a patient-by-patient basis. [ABSTRACT FROM AUTHOR]

• Postoperative re-irradiation and hyperthermia is effective in recurrent breast cancer. • CEM43T50 incorporates both hyperthermia treatment duration and median temperature. • Thermal dose CEM43T50 was significantly associated with better locoregional control. • Three-year locoregional control was 92% vs. 74% for high vs. low thermal dose group. • Grade 3-4 late toxicity was similar for the low and high thermal dose subgroups. To investigate the impact of hyperthermia thermal dose (TD) on locoregional control (LRC), overall survival (OS) and toxicity in locoregional recurrent breast cancer patients treated with postoperative re-irradiation and hyperthermia. In this retrospective study, 112 women with resected locoregional recurrent breast cancer treated in 2010–2017 with postoperative re-irradiation 8frx4Gy (n = 34) or 23frx2Gy (n = 78), combined with 4–5 weekly hyperthermia sessions guided by invasive thermometry, were subdivided into 'low' (n = 56) and 'high' TD (n = 56) groups by the best session with highest median cumulative equivalent minutes at 43 °C (Best CEM43T50) < 7.2 min and ≥7.2 min, respectively. Actuarial LRC, OS and late toxicity incidence were analyzed. Backward multivariable Cox regression and inverse probability weighting (IPW) analysis were performed. TD subgroups showed no significant differences in patient/treatment characteristics. Median follow-up was 43 months (range 1–107 months). High vs. low TD was associated with LRC (p = 0.0013), but not with OS (p = 0.29) or late toxicity (p = 0.58). Three-year LRC was 74.0% vs. 92.3% in the low and high TD group, respectively (p = 0.008). After three years, 25.0% and 0.9% of the patients had late toxicity grade 3 and 4, respectively. Multivariable analysis showed that distant metastasis (HR 17.6; 95%CI 5.2–60.2), lymph node involvement (HR 2.9; 95%CI 1.2–7.2), recurrence site (chest wall vs. breast; HR 4.6; 95%CI 1.8–11.6) and TD (low vs. high; HR 4.1; 95%CI 1.4–11.5) were associated with LRC. TD was associated with LRC in IPW analysis (p = 0.0018). High thermal dose (best CEM43T50 ≥ 7.2 min) was associated with significantly higher LRC for patients with locoregional recurrent breast cancer treated with postoperative re-irradiation and hyperthermia, without augmenting toxicity. [ABSTRACT FROM AUTHOR]

• Results of a prospective phase II study for recurrent HGG patients are provided. • Re-irradiation has proven to be a safe and effective treatment at HGG relapse. • No impairment in neurocognitive functions has been recorded follow re-irradiation. Standard of care for recurrent high grade glioma (HGG) is missing. Several treatment options have been investigated including re-irradiation (re-RT). Results are promising but provided by retrospective studies. We designed a single arm prospective phase II study aiming to evaluate efficacy, and toxicity of re-irradiation. Adults patients with good performance status, HGG diagnosis reclassified according to the new 2021 fifth edition WHO CNS classification, an interval time (IT) from previous RT ≥ 6 months were included. Outcome was evaluated by MRI imaging at 1 month, and every 3 months thereafter. Toxicities were evaluated in terms of radionecrosis occurrence, and neurocognitive status. Ninety recurrent HGG patients were treated, 11 oligodendroglioma grade 3, 18 astrocytoma grade 3 and 4, and 61 glioblastoma grade 4. The median age was 54 years, and majority had KPS 90–100. The median IT between first-RT and re-RT was 24 months. Re-surgery has been performed in 56.6%, and chemotherapy in 53.3%. The median follow up time was 64 months; median overall survival (OS) time,1,2,3-year OS rates were 17 months (95%CI 14–19), 66.7%±4.9, 32.6%±5.0, and 22.2 ± 4.7. Prognostic factors impacting on survival were age (p = 0.0154), IT between first RT and re-RT (p = 0.0051), glioma grade (p = 0.0090), and IDH status (p = 0.0001). Radionecrosis grade 2–3 occurred in 9 (10%) patients; neurocognitive functions remained stable until disease progression. Re-RT proved to be a safe and feasible treatment option with low toxicity. Younger patients with grade 3 IDH mutated gliomas, and a longer IT had the better outcome. Trial registration number : NCT02567539 [ABSTRACT FROM AUTHOR]

• International expert survey of optimum practice for pelvic SABR re-irradiation. • Consensus established regarding multiple aspects of the treatment pathway. • Further research needed, especially concerning cumulative normal tissue constraints. Stereotactic Ablative Radiotherapy (SABR) is increasingly used to treat metastatic oligorecurrence and locoregional recurrences but limited evidence/guidance exists in the setting of pelvic re-irradiation. An international Delphi study was performed to develop statements to guide practice regarding patient selection, pre-treatment investigations, treatment planning, delivery and cumulative organs at risk (OARs) constraints. Forty-one radiation oncologists were invited to participate in three online surveys. In Round 1, information and opinion was sought regarding participants' practice. Guidance statements were developed using this information and in Round 2 participants were asked to indicate their level of agreement with each statement. Consensus was defined as ≥75% agreement. In Round 3, any statements without consensus were re-presented unmodified, alongside a summary of comments from Round 2. Twenty-three radiation oncologists participated in Round 1 and, of these, 21 (91%) and 22 (96%) completed Rounds 2 and 3 respectively. Twenty-nine of 44 statements (66%) achieved consensus in Round 2. The remaining 15 statements (34%) did not achieve further consensus in Round 3. Consensus was achieved for 10 of 17 statements (59%) regarding patient selection/pre-treatment investigations; 12 of 13 statements (92%) concerning treatment planning and delivery; and 7 of 14 statements (50%) relating to OARs. Lack of agreement remained regarding the minimum time interval between irradiation courses, the number/size of pelvic lesions that can be treated and the most appropriate cumulative OAR constraints. This study has established consensus, where possible, in areas of patient selection, pre-treatment investigations, treatment planning and delivery for pelvic SABR re-irradiation for metastatic oligorecurrence and locoregional recurrences. Further research into this technique is required, especially regarding aspects of practice where consensus was not achieved. [ABSTRACT FROM AUTHOR]

• The use of re-irradiation resulted in improved clinical outcomes compared to systemic therapy alone for patients with local-regionally recurrent head and neck cancer. • Re-irradiation improved 2-year overall survival and progression-free survival compared to systemic therapy alone for patients with local-regionally recurrent head and neck cancer. • The likelihood of developing any new grade 3+ toxicity was significantly higher among patients treated by re-irradiation compared to those treated by systemic therapy. The optimal management of local-regionally recurrent head and neck cancer that is not amenable to surgical resection is uncertain. We sought to compare outcomes among patients treated with and without re-irradiation in this setting. A review of institutional registries identified 65 patients with local-regionally recurrent squamous cell carcinoma of the head and neck who were ineligible for surgery. Forty patients (62 %) opted for re-irradiation with the remaining 25 patients (38 %) undergoing initial systemic therapy alone. All patients had measurable disease. Forty-three patients (66 %) were male and twenty-two (33 %) were female. The median age at the time of recurrence was 59 years (range, 39–84 years). The most common primary sites of disease were the oropharynx, (n = 25), oral cavity (N = 19), and nasopharynx (n = 11). The median interval from completion of prior radiation to the diagnosis of recurrent disease was 35 months (range, 2–102 months). Re-irradiation improved 2-year overall survival, (32 % versus 11 %), progression-free survival (31 % versus 7 %), and local–regional control (39 % versus 3 %) compared to systemic therapy alone (p < 0.05, for both). The likelihood of developing any new grade 3+ toxicity was significantly higher among patients treated by re-irradiation compared to those treated by systemic therapy (53 % vs. 28 %, p < 0.001). There were 3 treatment-related fatalities, all of which occurred in the re-irradiation group. The incidence of grade 3+ late toxicity was 48 % and 12 % for patients in the re-irradiation and systemic therapy cohorts, respectively (p < 0.001). Although re-irradiation improved overall survival compared to systemic therapy for appropriately selected patients with local-regionally recurrent head and neck cancer, the relatively high risk of toxicity must be considered. [ABSTRACT FROM AUTHOR]

• The optimal non-surgical management for LRRC is unknown. • Median OS after SABR reirradiation is encouraging. • Optimization of SABR for LRRC could further improve QoL and outcomes. • Further data is required before SABR is established as an alternative to surgery. Locally recurrent rectal cancer (LRRC) is associated with considerable morbidity, poor quality of life and an overall survival of 9 months. The non-operative treatment of LRRC is an understudied area, there is no consensus on management in this setting. We aim to perform a retrospective, multicentre analysis of patients treated with SABR reirradiation. All patients were identified who received SABR re-irradiation for LRRC, at 3 UK centres, between August 2015 and September 2020. Eligible patients had pelvic recurrence and were either not suitable/opted not for surgery, or margin positive after exenturative surgery. Patients were treated with 30 Gy in 5 fractions and followed up with clinical review and CT scan at 3, 6, 12, 18 and 24 months. 69 patients with 81 lesions were identified and median follow up was 28 months. Median progression free survival (PFS) and overall survival (OS) were 12.1 months (10.4, 17.7) and 38.7 months (28.9,-) respectively. 2-year OS was 0.77 (0.66, 0.89). 58.3% of deaths were as a result of consequences of local relapse. 42.6% of patients had local relapse at death or last follow up. Our outcomes are encouraging for a population who had R1 resections, refused or were refused surgery; as they are similar to those in surgical series. Prospective data including details of survival, local relapse and QOL; with an optimised SABR technique, is required to establish SABR as an alternative to surgery. [ABSTRACT FROM AUTHOR]

Loco-regional recurrence (LRR) is the predominant pattern of failure in locally-advanced head and neck cancer (HNC), both in squamous cell carcinoma (SCC) and non-squamous histotypes. Despite the proven role of radiotherapy (RT) as primary treatment strategy, there is sparse evidence on the use of reirradiation (ReRT) in recurrent HNC (rHNC). Various regimens of hypofractionation have been described in the literature, without a clear consensus. The aim of our single-centre study is to evaluate the clinical outcome of unresectable rHNC patients treated with Cyberknife-based (CK) hypofractionated reRT. We retrospectively analyzed data from consecutive patients with rHNC who received CK reRT at our institution. All eligible patients had a recurrent, non-metastatic, previously irradiated unresectable HNC. Each case was discussed at a multidisciplinary level before treatment. Local control (LC), progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and log rank test with time measured from the date of last day of reRT to date of local recurrence, progression of disease or death, respectively. [Display omitted] First curatively intended course of RT was delivered from 1997 to 2020, concomitantly with chemotherapy or not. Thirty-five patients received Cyberknife (CK)-based hypofractionated reRT. The majority of patients (22, 63%) had a diagnosis of SCC and 13 patients (37%) had other histotypes than SCC. The median age of the cohort was 62 years at diagnosis. The CK reRT was performed from 2012 to 2022. The most commonly adopted schedules of reRT were 25Gy (57%) and 30Gy (43%) in 5 fractions on alternating days. After a median follow-up of 12 months (range 2-48), 6 out of 35 patients were alive. Causes of death were related to HNC in 12 patients and in 9 to other causes. The median LC and the 1-year LC rate were 10 months (95% CI 6,6-13,4 months) and 42%, respectively. The median PFS and OS and the 1-year PFS and OS rates were 8 months (95% CI 6.1-9,8 months), 18 months (95% CI 11,8-24,1 months) and 15% and 71% (Figure 1), respectively. At univariate analysis, a negative correlation between time to CK reRT < 12 months and LC (p 0.01) was reported. Moreover, a positive trend association between time from first to second irradiation ≥ 12 months and OS (p 0.09) was shown, in line with findings available from the literature. A significantly better OS was found in patients aged < 65 years (p 0.045). From our analysis, hypofractionated ReRT can be viewed as a well-tolerated treatment option for rHNC with potential for prolonged local control in appropriately selected patients. [ABSTRACT FROM AUTHOR]

Stereotactic Radiation Therapy (SBRT) has been implemented for re-iradiation of recurrent or second primary cancers of the head and neck to improve the therapeutic ratio in this difficult scenario. We reviewed our experience at a single institution. After IRB approval, a database of patients receiving re-irradiation was queried. Patients were excluded if receiving conventionally fractionated radiotherapy (RT), non-squamous histology, were enrolled on non-published clinical trials, or metastatic disease. All patients were seen in a multi-disciplinary clinic and/or reviewed in multi-disciplinary tumor board. All patients were ineligible for or refused surgical intervention. Patients were simulated with thermoplastic masks and 2 mm cuts on CT scan with and without contrast. Additional imaging including PET and/or MRI were fused. Gross tumor volume (GTV) was delineated and expanded 2-3 mm for the planning target volume. Elective nodes were not targeted. Minimum dose to PTV was 90% of prescription, with 110 - 130% prescription allowed within GTV/PTV. SBRT was delivered every other day for 5 fractions, with daily cone beam CT imaging, and 6 degree of freedom couch correction. Locoregional control (LRC), progression free survival (PFS), and overall survival (OS) were calculated from the end of RT and estimated via Kaplan-Meier method and comparisons made via log-rank test. Multi-variate cox regression model of OS was performed. Acute (during within three months from completion of treatment) and late (three or more months from completion of treatment) grade 3-5 CTCAE toxicities were collected. A total of 76 patients were available for analysis, with a median follow up of 31.5 months for patients alive at last contact, and 12 months for the entire cohort. Median age was 66 (range 36 – 92) with a median RT interval of 29.5 months (range 5 -315). Median dose of initial RT was 70 Gy (range 44 – 79.2 Gy). The majority of patients were former smokers (n=45, 59.2%), followed by never smokers (n=20, 26.3%), and current smokers (n=11, 14.5%). There were 56 men (73.7%) and 20 women (26.3%). Performance status was zero (n=22, 28.9%) and 1-2 (n=54, 71.1%), with 50 patients being recurrent (65.8%) and 26 having a second primary (34.2%). All patients were treated with 5 fractions to a median dose of 40 Gy (range 25 – 40 Gy). Systemic therapy was utilized in 29 patients (38.2%), primarily concurrently (n=27). Concurrent systemic therapy was cisplatin (n=20, 26.3%), cetuximab (n=4, 5.3%), or immunotherapy (n=3, 3.9%). Median gross tumor volume (GTV) was 11.42 cc (range 0.93 – 58.31 cc). Acute grade 3-4 toxicity was seen in 5 patients (6.6%), consisting of feeding tube in 2, aspiration pneumonia in 1, tracheostomy in 1, and stroke in 1. Actuarial rates for the entire cohort at 1 and 2-years for LRC were 43.5% and 33.3%, for PFS, 40.6% and 31.1%, and OS 49.6% and 33.1%. On univariate analysis median GTV, treatment site (nasopharynx/base of skull/neck/skin vs other), and recurrence were prognostic for OS. On multivariate analysis, GTV (HR 1.037, 95% CI 1.018 – 1.056, p < 0.001) and recurrent disease (HR 0.344, 95% CI 0.194 – 0.609, p < 0.001). For the subset of patients (n=26) with a GTV ≤ 11.4 cc and recurrent disease, 2-year OS was 80.1% with a median OS of 37 months. Of 73 patients followed for more than 3 months post treatment, 15 (20.5%) developed a late grade 3-4 toxicity, including feeding tubes in 7, aspiration pneumonia in 3, soft tissue necrosis in 3, or a cranial neve deficit in 3. SBRT for re-irradiation for patients with smaller, recurrent squamous cell carcinomas of the head and neck had the best performance. While severe acute toxicities are low, additional studies are needed to improve survival and decrease the risk of late toxicity. [ABSTRACT FROM AUTHOR]

• Cumulative dose distributions were calculated using non-rigid registration. • Thoracic re-irradiation has a good local efficacy and overall survival. • Treatment related toxicity was low within the reported dose range. • Interval between rt-courses was predictive for overall survival. Thoracic re-irradiation remains a challenge regarding the balance of local efficacy and acceptable toxicities. In this retrospective analysis we analyzed dosimetrical and clinical data of patients treated with thoracic re-irradiation based on accumulated EQD2Gy doses. We retrospectively analyzed the data of 42 consecutive single-institutional patients treated with repeated courses of thoracic radiotherapy from 12/2011 to 01/2017. Accumulated EQD2 dose distributions were calculated and dose parameters for organs at risk and target volumes were analysed. The median prescription dose was 42.2 Gy (10–70.6 Gy) for all RT courses. The median Dmean of both lungs was 10.1 Gy 3 (range: 1.9 Gy 3 –17.9 Gy 3) with a maximum D0.1 cc of 253.86 Gy 3. The median D0.1 cc of the esophagus was 62.2 Gy 3 with a maximum of 103.78 Gy 3. The maximum D0.1 cc for the bronchial tree was 187.33 Gy 3 (median 74.35 Gy 3) and for the Aorta 216.1 Gy 3 (median 70.9 Gy 3). Median OS after first re-irradiation was 19 months (range 1–45 months). 12-month local control after a course of re-irradiation was 52.6%. 80% of patients suffered from a G1–G2 toxicity, most frequently coughing. One patient suffered from a G5 complication probably unrelated to re-irradiation. Even though several organs at risk received maximum accumulated doses of >100 Gy 3 , thoracic reirradiation resulted in an acceptable toxicity profile. Local tumor control and overall survival remained encouraging even after multiple courses of thoracic radiotherapy. [ABSTRACT FROM AUTHOR]

• Local recurrent prostate cancer. • Re-irradiation. • Tumor control. • Salvage brachytherapy. • Late side effects. To assess the long-term results of protocol-based ultrasound-guided salvage pulsed-dose rate brachytherapy in locally recurrent prostate cancer following previous radiation therapy. A total of 82 patients (median age 69 years) with locally recurrent prostate cancer after previous external beam radiation therapy (43/82, 52.4%), prostatectomy and adjuvant radiation therapy (24/82, 29.3%) or brachytherapy (15/82, 18.3%) were treated with sole salvage interstitial pulsed-dose rate brachytherapy (PDR-BT). The treatment regimen consisted of two PDR-BT sections with 30 Gy (single pulse dose 0.6 Gy/h, 24 h per day) each up to a total reference dose of 60 Gy (EQD2 = 71.5 Gy-eq). The endpoints of the present analysis are cumulative local recurrence-rate, PSA-free survival, overall survival and the treatment-associated late toxicity according to the "Common Toxicity Criteria" with a median follow-up of 49 months (range, 12–129 months). The 5-y. overall cumulative local recurrence rate was 17.7% with no significant differences between low, intermediate and high-risk groups. Differences in PSA-free survival were marginally non-significant, at 67.3%, 70.4% and 63.8% for low, intermediate and high risk group, respectively. No grade 3 gastrointestinal late side effects have been observed. The most common late side effect was urinary incontinence grade 1–3 and urinary frequency/urgency grade 1–3 in 18.3% (15/82) and 17.1% (14/82) of patients, respectively. PDR salvage brachytherapy in local recurrent previously irradiated prostate cancer is efficient with low late toxicity. Salvage-brachytherapy represents a valuable therapeutic option for the treatment of previously irradiated locally recurrent prostate cancer. [ABSTRACT FROM AUTHOR]

• Re-irradiation (re-RT) of intracranial recurrent meningiomas is still matter of debate and limited by radiation tolerance of the surrounding tissue and the increased risk of side effects. • Re-RT is increasingly considered in current clinical practice, but its efficacy and safety for brain tumors are still under investigation. The optimal choice of patient selection, RT modalities and dose for re-irradiation are not well established yet. • This retrospective analysis aims at providing data about clinical outcomes, toxicities and prognostic factors in a cohort of 181 intracranial recurrent meningioma patients treated in 8 different Italian centers with different RT modalities. Re-irradiation (re-RT) for recurrent intracranial meningiomas is hindered by the limited radiation tolerance of surrounding tissue and the risk of side effects. This study aimed at assessing outcomes, toxicities and prognostic factors in a cohort of patients with recurrent meningiomas re-treated with different RT modalities. A multi-institutional database from 8 Italian centers including intracranial recurrent meningioma (RM) patients who underwent re-RT with different modalities (SRS, SRT, PT, EBRT) was collected. Biologically Equivalent Dose in 2 Gy-fractions (EQD2) and Biological Effective Dose (BED) for normal tissue and tumor were estimated for each RT course (α/β = 2 for brain tissue and α/β = 4 for meningioma). Primary outcome was second progression-free survival (s-PFS). Secondary outcomes were overall survival (OS) and treatment-related toxicity. Kaplan–Meier curves and Cox regression models were used for analysis. Between 2003 and 2021 181 patients (pts) were included. Median age at re-irradiation was 62 (range 20–89) and median Karnofsky Performance Status (KPS) was 90 (range 60–100). 78 pts were identified with WHO grade 1 disease, 65 pts had grade 2 disease and 10 pts had grade 3 disease. 28 pts who had no histologic sampling were grouped with grade 1 patients for further analysis. Seventy-five (41.4 %) patients received SRS, 63 (34.8 %) patients SRT, 31 (17.1 %) PT and 12 (6.7 %) EBRT. With a median follow-up of 4.6 years (interquartile range 1.7–6.8), 3-year s-PFS was 51.6 % and 3-year OS 72.5 %. At univariate analysis, SRT (HR 0.32, 95 % CI 0.19–0.55, p < 0.001), longer interval between the two courses of irradiation (HR 0.37, 95 % CI 0.21–0.67, p = 0.001), and higher tumor BED (HR 0.45 95 % CI 0.27–0.76, p = 0.003) were associated with longer s-PFS; in contrast, Ki67 > 5 % (HR 2.81, 95 % CI 1.48–5.34, p = 0.002) and WHO grade > 2 (HR 3.08, 95 % CI 1.80–5.28, p < 0.001) were negatively correlated with s-PFS. At multivariate analysis, SRT, time to re-RT and tumor BED maintained their statistically significant prognostic impact on s-PFS (HR 0.36, 95 % CI 0.21–0.64, p < 0.001; HR 0.38, 95 % CI 0.20–0.72, p = 0.003 and HR 0.31 95 % CI 0.13–0.76, p = 0.01, respectively). Acute and late adverse events (AEs) were reported in 38 (20.9 %) and 29 (16 %) patients. Larger tumor GTV (≥10 cc) was significantly associated with acute and late toxicity (p < 0.001 and p = 0.009, respectively). In patients with recurrent meningiomas, reirradiation is a feasible treatment option associated with acceptable toxicity profile. Prognostic factors in the decision-making process have been identified and should be incorporated in daily practice. [ABSTRACT FROM AUTHOR]

• In our study, LRRC patients who underwent re-irradiation showed a pooled median survival period of >2 years. • Patients who underwent surgery had better survival than those who did not, but late complications of grade ≥3 significantly increased (Odds ratio: 6.39). • Symptomatic palliation was as effective with pooled ratio of 75.2%. • Our study provides practical information for clinical decision making, and suggests the need for research to identify patients who can benefit from aggressive local treatment including re-RT and surgery. Re-irradiation might yield local control (LC) or palliation for locoregionally recurrent rectal cancer (LRRC), but iatrogenic complications are a possible hindrance. We aimed to evaluate the efficacy of re-irradiation to determine optimal treatment of LRRC. We performed a systematic review of PubMed, MEDLINE, Cochrane Library, and Embase. A total of 17 studies involving 744 patients with LRRC were included; median OS ranging from 10 to 45 months (median: 24.5 months). Pooled 1-, 2-, and 3-year OS rates for all patients were 76.1%, 49.1%, and 38.3%, respectively. For patients who underwent re-irradiation and surgery (OP group), these pooled rates were 85.9%, 71.8%, and 51.7%, respectively. For patients who underwent re-irradiation but not surgery (non-OP group), pooled 1-, 2-, and 3-year OS rates were 63.5%, 34.2%, and 23.8%, respectively. The OS difference between both groups was significant for all 3 years (P < 0.05). Pooled 1-, 2-, and 3-year LC rates for the OP group were 84.4%, 63.8%, and 46.9%, and for the non-OP group were 72.0%, 54.8%, and 44.6%, respectively, without significant differences. Pooled grade ≥3 acute and late complication rates were 11.7% and 25.5% in the OP and non-OP groups, respectively. Patients who underwent surgery had a higher risk of grade ≥3 late complications (odds ratio: 6.39). Pooled symptomatic palliation rate was 75.2%. Re-irradiation with or without surgery for LRRC showed oncologic and palliative efficacy. Salvage treatment including re-irradiation and surgery showed higher survival, but the late complication was significantly increased with concomitant surgery. [ABSTRACT FROM AUTHOR]

• Carbon ion radiotherapy is useful for inoperable head and neck cancers. • Re-irradiation with carbon ion radiotherapy after recurrence was explored. • Long-term efficacy and toxicity profiles were examined in recurrent disease. • Re-irradiation using carbon ions is moderately efficacious, with moderate toxicity. • Carbon ion radiotherapy is a viable treatment option for recurrent head and neck tumors. Locoregional recurrence after carbon-ion radiotherapy (CIRT) for primary head and neck malignancies, such as malignant mucosal melanoma, adenoid cystic carcinoma, and sarcoma, occurs occasionally. However, the treatment options are limited. We report on the toxicity and efficacy of re-irradiation using carbon ions for recurrent head and neck malignancies after CIRT. Data of 48 patients with recurrent head and neck malignancies treated with re-irradiation with CIRT at our institution (2007–2016) were retrospectively analyzed. Twenty-one patients (43.8%) had malignant mucosal melanoma, 17 (35.4%) had adenoid cystic carcinoma, six (12.5%) had bone and soft tissue sarcomas, and four patients (8.3%) had other disease types. Tumor recurrences at re-irradiation were located in the paranasal cavity (n = 18, 37.5%), nasal cavity (n = 9, 18.8%), nasopharynx (n = 4, 8.3%), orbit (n = 3, 6.3%), cavernous sinus (n = 3, 6.3%), and at other sites (n = 11, 22.9%). The median dose of initial CIRT and that at re-irradiation were 57.6 Gy and 54.0 Gy (relative biological effectiveness [RBE]), respectively. None of the patients received concurrent chemotherapy. The median follow-up period after re-irradiation was 27.1 months. Five patients (10.4%) developed Grade 3 acute toxicities and 18 (37.5%) developed Grade ≥3 late toxicities, including Grade 5 central nervous system necrosis in one patient. The 2-year local control, locoregional control, progression-free survival, and overall survival rates were 40.5, 33.5%, 29.4%, and 59.6%, respectively. Re-irradiation using carbon ions may be a reasonable treatment option with tolerable toxicity for patients with recurrent head and neck malignancies after CIRT. [ABSTRACT FROM AUTHOR]

• Sole brachytherapy was effective and safe for inoperable salivary gland cancers. • Brachytherapy can be considered on salivary gland cancers after multiple irradiation. • Brachytherapy can significantly reduce pain caused by salivary gland cancers. Salivary gland cancers (SGCs) are hard to treat when inoperable, and sole brachytherapy appears to be a promising therapeutic strategy. This study aimed to evaluate the effectiveness, safety, and capability of pain palliation using sole brachytherapy for inoperable, recurrent, and irradiated SGCs. Patients with inoperable SGCs treated using sole brachytherapy at Peking University School and Hospital of Stomatology were retrospectively included. Patients were divided into primary and recurrent groups and irradiated and non-irradiated groups. Local control (LC), overall survival (OS), radiation-relevant toxicities, and Visual Analogue Scale (VAS) score for pain, were recorded and evaluated. A total of 176 patients from 2006 to 2020 were included. The 5-year LC rate was 48.6 %; for the primary, recurrent, non-irradiated and irradiated groups, the rates were 72.6 %, 39.5 %, 56.8 %, and 34.5 %, respectively. The 5-year OS rates was 52.6 %; for the primary, recurrent, non-irradiated, and irradiated groups, the rates were 62.9 %, 48.6 %, 58.9 %, and 42.3 %, respectively. The mean ± standard deviation of posttreatment VAS score of pain was 2.154 ± 2.989, which was significantly decreased from the score of 6.923 ± 2.280 prior to brachytherapy. Skin hyperpigmentation, mucositis, and dysphagia were the most frequently reported adverse events. Brachytherapy as a sole modality, was retrospectively proven effective and safe in the management of inoperable SGCs and was beneficial in multiple irradiation and pain control. [ABSTRACT FROM AUTHOR]

Highlights • Treatment options after relapsed head and neck rhabdomyosarcoma (HNRMS) are limited. • A salvage AMORE procedure is often one of the few remaining curative options. • In this study we show the results of salvage AMORE treatment in our institution. • If salvage AMORE is considered feasible, it could result in long-term survival. • The 5-year overall survival was 54% in this cohort of 18 patients. Abstract Background and purpose Survival after relapse of head and neck rhabdomyosarcoma (HNRMS) after prior external beam radiotherapy (EBRT) is poor, since options for adequate local treatment are often lacking. In this study we describe our experience with salvage AMORE in patients with relapsed HNRMS after prior EBRT. Materials and methods Patients with relapsed HNRMS after prior EBRT in which salvage AMORE treatment was considered feasible were analysed; this includes patients with parameningeal, head and neck non-parameningeal and orbital localization. AMORE treatment consisted of Ablative surgery, MOuld technique brachytherapy and surgical REconstruction. Results In total 18 patients received salvage AMORE treatment; nine patients had relapsed parameningeal (PM) RMS, two patients had relapsed head and neck non-parameningeal RMS (HN-nonPM) and seven patients had relapsed orbital RMS. Local control rate was 67% and 5-year overall survival was 54% (95% confidence interval: 31–78%); 3/9 patients with PM RMS, 0/2 patients with HN-nonPM RMS and 6/7 patients with orbital RMS were alive after a median follow-up of 8.6 years. One patient with PM RMS survived more than 5 years after which he died from a secondary cancer. Six patients developed a local relapse (of which one patient also developed a distant metastasis) and two patients developed distant metastases. Conclusions Salvage AMORE treatment is a feasible and effective local therapy approach even after prior EBRT. Since salvage AMORE treatment is sometimes the only curative option in patient with relapsed HNRMS, we encourage physicians to consider salvage AMORE treatment for patients with relapsed HNRMS after prior EBRT. [ABSTRACT FROM AUTHOR]

Highlights • Median OS of patients eligible for ReRT is 9.7 months in our series. • Registered toxicity rates are low (severe acute toxicity 13% and radionecrosis 8%). • The reirradiation risk score of Niyazi et al. was successfully validated. • Collaboration among medical centers is necessary to achieve optimized treatment regimen. Abstract Purpose or objective Re-irradiation is a generally accepted method for salvage treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. This study aims to compare the efficacy and safety of different treatment regimens and to independently externally validate a recently published reirradiation risk score. Material and methods We retrospectively analyzed a cohort of patients with recurrent malignant glioma treated with salvage conventionally fractionated (CFRT), hypofractionated (HFRT) or stereotactic radiotherapy (SRT) between 2007 and 2017 at the University Medical Centers in Utrecht and Groningen. Results Of the 121 patients included, 60 patients (50%) underwent CFRT, 22 (18%) HFRT and 39 (32%) SRT. The primary tumor was grade II-III in 52 patients and grade IV in 69 patients with median Overall Survival (mOS) since first surgery of 113 [Interquartile range: 53.2–137] and 39.7 [24.6–64.9] months respectively (p < 0.01). Overall, mOS from the first day of re-irradiation was 9.7 months [6.5–14.6]. No significant difference in mOS was found between the treatment groups. In multivariate analysis, the Karnofsky performance scale ≥70% (p < 0.01), re-irradiation for first recurrence (p = 0.02), longer time interval between RT start dates (p < 0.01) and smaller planning target volume (p < 0.05) were significant favorable prognostic factors. The reirradiation risk score was validated. Conclusion In our series, mOS after reirradiation was sufficient to justify use of this modality. Until a reliable treatment decision tool is developed based on larger retrospective research, the decision for re-irradiation schedule should remain personalized and based on a multidisciplinary evaluation of each patient. [ABSTRACT FROM AUTHOR]

Highlights: • 2/3 of ADClow areas are found outside MRI contrast enhancement and FET uptake areas. • Restricted diffusion areas are only partially included in the re-irradiation volume. • Recurrences co-localize better with baseline GdT1w-MRI and FET-PET/CT than with ADC. Abstract Background and purpose GTV definition for re-irradiation treatment planning in recurrent glioblastoma (rGBM) is usually based on contrast-enhanced MRI (GdT1w-MRI) and, for an increased specificity, on amino acid PET. Diffusion-weighted (DWI) MRI and ADC maps can reveal regions of high cellularity as surrogate for active tumor. The objective of this study was to compare the localization and quality of diffusion restriction foci (GTV-ADClow) with FET-PET (GTV-PET) and GdT1w-MRI (GTV-GdT1w-MRI). Material and methods We prospectively evaluated 41 patients, who received a fractionated stereotactic re-irradiation for rGBM. GTV-PET was generated automatically (tumor-to-background ratio 1.7–1.8) and manually customized. GTV-ADClow was manually defined based on DWI data (3D diffusion gradients, b = 0, 1000 s/mm2) and parametric ADC maps. The localization of recurrence was correlated with initial GdT1w-MRI and PET data. Results In 30/41 patients, DWI-MRI showed areas with restricted diffusion (mean ADC-value 0.74 ± 0.22 mm2/s). 66% of GTVs-ADClow were located outside the GdT1w-MRI volume and 76% outside increased FET uptake regions. Furthermore, GTVs-ADClow were only partially included in the high dose volume and received in mean 82% of the reference dose. An adjusted volume including GdT1w-MRI, PET-positive and restricted diffusion areas would imply a GTV increase of 48%. GTV-PET and GdT1w-MRI correlated better with the localization of re-recurrence in comparison to GTV-ADClow. Conclusion Unexpectedly, GTV-ADClow overlapped only partially with FET-PET and GdT1w-MRI in rGBM. Moreover, GTV-ADClow correlated poorly with later rGBM-recurrences. Seeing as a restricted diffusion is known to correlate with hypercellularity, this imaging discrepancy could only be further explained in histopathological studies. [ABSTRACT FROM AUTHOR]

Abstract Background and purpose Limited data exist detailing the role of salvage reirradiation following local-regional recurrence (LR) in previously irradiated pediatric patients with rhabdomyosarcoma (RMS). Materials and methods We evaluated outcomes and prognostic factors in a multi-institutional cohort of 23 patients with LR-only (N = 19) or LR with distant failure (N = 4) RMS managed with (N = 12) or without (N = 11) re-irradiation who were treated from 1996 to 2012. Results At a median follow-up of 4.6 years from LR, 7 (30%) patients were alive and 5 (22%) had no evidence of disease. Median OS and PFS from LR were 19.3 and 16.9 months, respectively. LFFS and DFFS at 3 years from relapse were 54% and 56%, respectively. Salvage re-irradiation occurred in 12 (52%) patients, with 9 (75%) receiving resection before re-irradiation. Patients classified as low-risk at diagnosis with favorable primary tumor location had improved 3-year PFS 80% (95% CI 51.6–100%) vs. 47.1% (95% CI 27.3–81.2%), p = 0.066], and OS 80% [(95% CI 22.4–100%) vs. 47.1% (95% CI 27.3–81.3%), p = 0.051] following LR. Median LFFS and OS in unirradiated vs. re-irradiated patients was 12.4 vs. 19.6 (p = 0.1) and 18.8 vs. 26.1 months (p = 0.46). No patients experienced ≥grade 4 acute toxicity from re-irradiation. LR failure was a component of cancer-related death in 60% vs. 40% of the unirradiated and re-irradiated group (p = 0.02). Conclusion Salvage re-irradiation appears tolerable with acceptable morbidity and may reduce the risk of subsequent LR as a component of death in patients with LR RMS. [ABSTRACT FROM AUTHOR]

Highlights • This study focuses on the re-irradiation for pancreatic cancer, which is rarely investigated, yet an important treatment option for recurrence of pancreatic cancer. Besides, it is the largest series of two courses of stereotactic body radiation therapy for pancreatic cancer. • To the best of our knowledge, a novel prognostic score was firstly developed for selecting patients amenable to re-irradiation for pancreatic cancer. • This scoring system may provide insights for individualized treatment. Abstract Purpose To develop a predictive model for stratification of patients with pancreatic cancer who may achieve survival benefits from re-irradiation with stereotactic body radiation therapy (SBRT). Methods The score was developed based on clinical predictors of OS in 31 patients receiving two courses of SBRT with Cox proportional hazards model. Results were then validated in another cohort with 11 participants to assess the performance of the score. Results In the training cohort, the median BED 10 of the first and second SBRT was 59.5 Gy (48–85.5 Gy) and 50.2 Gy (43.7–66.9 Gy) in 5–8 fractions, while in the validation cohort, the median BED 10 of the first and second SBRT was 59.5 Gy (52.5–66.9 Gy) and 47.7 Gy (40.6–54.8 Gy) in 5–8 fractions. The interval between the first and second SBRT of the training cohort and validation cohort was 10.5 months (6.1–24.3 months) and 12.8 months (6.5–29.1 months), respectively. Multivariable analysis showed that tumor stage (P = 0.005), BED 10 (P = 0.006) and CA19-9 response (P = 0.04) were significantly predictive of overall survival, which formed SCAD score (named after the initials of factors). Patients with the score < 3 points had a superior OS compared with those with the score ≥ 3 points in the validation cohort (median OS has not been reached vs. 15.9 months, P = 0.032). Conclusions The SCAD score may have the potential to identify individuals benefiting from re-SBRT and be a step toward more personalized medicine. [ABSTRACT FROM AUTHOR]

Abstract Background A previous randomized trial in recurrent Head and Neck squamous-cell carcinoma (HNSCC) has shown re-irradiation combined with chemotherapy after salvage surgery significantly improved disease-free survival (DFS). The objective of this randomized trial was to compare two methods of re-irradiation in terms of toxicity and survival. Patients and methods Patients with recurrence/second primary in previously irradiated area were randomly allocated to receive either 60 Gy over 11 weeks with concomitant 5FU – hydroxyurea (VP-arm), or 60 Gy (1.2 Gy twice daily) over 5 weeks with cetuximab (HFR-arm). Primary endpoint was treatment interruption >15 days (acute toxicity). Results Twenty-six patients were included in VP-arm and 27 in HFR-arm. One patient in VP-arm experienced >15 days interruption due to toxicity, and none in HFR-arm. In both arms, all patients received at least 60 Gy. In VP-arm, 8/26 patients had chemotherapy delay and/or dose reduction. In HFR-arm, 4/27 patients had <6 cycles cetuximab. There was no significant difference in overall survival (Median OS: 37.4 months vs 21.9 months, p = 0.12). Toxicities and DFS were not different between 2 arms. Conclusions Twice daily schedule of re-irradiation of 60 Gy/5 weeks with cetuximab was tolerable and no significant difference in treatment delays occurred between two arms. [ABSTRACT FROM AUTHOR]

Introduction A majority of high-grade gliomas relapse despite combined surgery, radiotherapy and chemotherapy. There is no consensus on standard treatment for recurrent high-grade gliomas, or defined efficacy of adjuvant re-RT after re-Op. This retrospective study evaluated the benefit and safety of re-RT after re-Op (re-Op/RT). Materials and methods A total of 84 patients with recurrent high-grade gliomas who underwent reoperation from 2009 to 2015 were analyzed. All patients received neurosurgical intervention and adjuvant radiotherapy previously before recurrence. At recurrence and after reoperation, treatment options were discussed in multidisciplinary clinic or brain tumor joint conference. For re-RT, cumulative EQD 2 (equivalent dose in 2 Gy fractions at α / β  = 2) was below 106.9 Gy. Result Median progression free survival (PFS) was 6.5 months; 3.5 months with re-Op, 9.0 months with re-Op/RT ( p  = 0.025). Age <50, time interval to recur ≥12 months, WHO pathologic grade III, methylated MGMT promotor, and re-RT were factors enhancing PFS in the multivariate analysis. Median overall survival (OS) was 18.3 months: 12.7 months with re-Op, and 28.1 months with re-Op/RT ( p  = 0.066). Three risk factors (age >50, WHO grade IV, and unmethylated promoter of MGMT) were significantly associated with poor OS in multivariate analysis. Benefit of re-RT in both OS and PFS was established in patients carrying 2 or more risk factors. During re-RT, 4 patients (8%) had grade 2 or higher toxicity, and 3 patients (6%) did not complete re-RT. No radionecrosis was observed. Conclusion Re-RT after re-Op was tolerable with a cumulative median EQD 2 of 99.3 Gy and resulted in clear benefit in PFS and marginal gain in OS. Survival gain with re-Op/RT was more prominent in patients with two or more risk factors (age ≥50, WHO pathologic grade IV, unmethylated MGMT promoter), and needs to be validated. [ABSTRACT FROM AUTHOR]

[Display omitted] • First international survey on the patterns of care of re-irradiation. • Re-irradiation is predominantly employed in the brain, pelvis, and head and neck region. • Variable decision-making regarding minimum interval, contraindications and dose constraints. • Advanced radiation techniques and imaging are used, but dose accumulation methods diverge. • Prospective studies are needed to support evidence-based re-irradiation. Re-irradiation is an increasingly utilized treatment for recurrent, metastatic or new malignancies after previous radiotherapy. It is unclear how re-irradiation is applied in clinical practice. We aimed to investigate the patterns of care of re-irradiation internationally. A cross-sectional survey conducted between March and September 2022. The survey was structured into six sections, each corresponding to a specific anatomical region. Participants were instructed to complete the sections of their clinical expertise. A total of 15 multiple-choice questions were included in each section, addressing various aspects of the re-irradiation process. The online survey targeted radiation and clinical oncologists and was endorsed by the European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC). 371 physicians from 55 countries across six continents participated. Participants had a median professional experience of 16 years, and the majority (60%) were affiliated with an academic hospital. The brain region was the most common site for re-irradiation (77%), followed by the pelvis (65%) and head and neck (63%). Prolonging local control was the most common goal (90–96% across anatomical regions). The most common minimum interval between previous radiotherapy and re-irradiation was 6–12 months (45–55%). Persistent grade 3 or greater radiation-induced toxicity (77–80%) was the leading contraindication. Variability in organs at risk dose constraints for re-irradiation was observed. Advanced imaging modalities and conformal radiotherapy techniques were predominantly used. A scarcity of institutional guidelines for re-irradiation was reported (16–19%). Participants from European centers more frequently applied thoracic and abdominal re-irradiation. Indications did not differ between academic and non-academic hospitals. This study highlights the heterogeneity in re-irradiation practices across anatomical regions and emphasizes the need for high-quality evidence from prospective studies to guide treatment decisions and derive safe cumulative dose constraints. [ABSTRACT FROM AUTHOR]

We conducted a multicentre real-world study to assess the outcomes of radical salvage re-irradiation for non-melanoma skin cancer (nMSC) recurrences following definitive or postoperative radiotherapy. Data on patients treated between 2006 and 2022 with re-irradiation for nMSCs were retrospectively collected from five high-volume brachytherapy centers. The primary endpoint was local control (LC). Secondary endpoints included overall survival, progression-free survival, and adverse events (AEs). The Kaplan-Meier estimator and Cox Proportional-Hazards Model were utilised in the analysis. A total of 58 patients with a median age of 78.4 years with recurrences of previously irradiated nMSC in the head and neck region were included in the analysis. The majority had cutaneous basal cell carcinoma (BCC; 91.4%), and were irradiated with high-dose-rate brachytherapy (HDR-BT; 91.4%). The most common locations included the nasal region (36.2%) and external ear (18.9%). The 1-year LC was 73.1% and decreased to 41.7% at three years. The size of the re-irradiated lesion was the single independent prognostic factor in Cox analysis (per mm; HR 1.07; 95% CI 1.04–1.11; p < 0.001). Grade 3 or worse AEs were reported in 7 cases (12.1%). Re-irradiation for nMSCs, predominantly administered with brachytherapy for radiorecurrent BCC, is associated with high recurrence rates, and the risk of failure significantly increases with the size of the treated lesion. Re-irradiation could be an option for selected elderly patients with small, localised, inoperable recurrences after RT to achieve local control or defer systemic treatment; however, prospective trials are necessary to confirm its safety and efficacy. • Recurrence rate after re-irradiation is much higher compared to primary treatment. • Lesion size is the most important clinical prognostic factor for local control. • The rate of serious adverse effects seems to be moderate. • Re-irradiation could be an option for inoperable elderly patients with small lesions. • Prospective trials are necessary to confirm safety and efficacy. [ABSTRACT FROM AUTHOR]

• The prognostic role of induction chemotherapy (IC) prior to salvage radiotherapy for locally recurrent nasopharyngeal carcinoma (lrNPC) was inconclusive. • IC plus re-irradiation or CCRT showed no significant survival benefits compared with the patients following re-irradiation or CCRT alone; • A prognostic risk stratification model was developed and validated based on the clinical features and serum LDH at recurrence. • IC was associated with increased OS in the intermediate-risk subgroup after Inverse probability of treatment weighting (IPTW). To investigate the role of additional induction chemotherapy (IC) prior to re-irradiation in locally recurrent nasopharyngeal carcinoma (lrNPC). A total of 480 patients from three cancer treatment centers who received re-irradiation between 2012 and 2020 were retrospectively analyzed. Overall survival (OS) was determined using the Kaplan-Meier method and compared with log-rank method. Inverse probability of treatment weighting (IPTW) was performed to match the patients in pairwise treatment groups. Multivariate analysis using the Cox proportional hazards regression method identified predictors of OS. The risk stratification model was defined by the risk score calculated with the sum of coefficients. In the entire cohort, the addition of IC was associated with similar OS compared with radiotherapy alone (P = 0.58) or with concomitant chemoradiation (P = 0.76). A risk stratification model was constructed and validated based on significant prognostic factors (coefficient) including male (0.6), age ≥ 60 years (0.9), volume of recurrence gross tumor volume ≥ 16 cc (0.7), and lactate dehydrogenase (LDH)-ratio ≥ 0.5 (0.4). In the intermediate-risk group (sum of coefficient: 0.9–––1.6), patients with IC plus re-irradiation had a significantly better OS than those who received re-irradiation (P = 0.03). After adjustments for several potentially confounding variables with IPTW, survival benefit of IC was also observed (P = 0.031). However, no significant difference in OS for the additional IC prior to re-irradiation was demonstrated in the low- (sum of coefficient: <0.9) and high-risk group (sum of coefficient: > 1.6). Additional IC prior to re-irradiation was associated with improved OS in the intermediate-risk group of lrNPC, whereas there was no difference for the low-risk and high-risk group. Prospective validation is required to validate these findings. [ABSTRACT FROM AUTHOR]

Background and purpose Patient’s gender and age may influence physicians in prescribing palliative radiotherapy. The purpose of this secondary analysis of the National Cancer Institute of Canada Clinical Trials Group Symptom Control Trial SC.20 was to explore the gender and age differences in pain and patient reported outcomes in cancer patients with bone metastases undergoing re-irradiation. Materials and methods Response to radiation was evaluated using the International Bone Metastases Consensus Endpoint Definitions. Patients completed the Brief Pain Inventory (BPI) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (C30) before and 2 months after re-irradiation. Results A total of 847 patients were analyzed. At baseline, men had more dyspnea, and mild pain. Older patients consumed less analgesic. More women reported clinically significant improvement in mood and enjoyment of life in the BPI after radiation. Similarly, younger patients reported better improvement in enjoyment of life. There were no significant gender or age differences in overall survival, response to radiation, or in C30 scores at 2 months. Conclusion Similar benefit in terms of pain relief was observed across all patient groups. Cancer patients with bone metastases should be offered palliative re-irradiation irrespective of gender or age. Trial Registration: NCT00080912; https://clinicaltrials.gov/ct2/show/NCT00080912. [ABSTRACT FROM AUTHOR]

Background and purpose To perform a systematic review regarding the use of stereotactic ablative radiotherapy (SABR) for the re-irradiation of recurrent malignant disease within the pelvis, to guide the clinical implementation of this technique. Material and methods A systematic search strategy was adopted using the MEDLINE, EMBASE and Cochrane Library databases. Results 195 articles were identified, of which 17 were appropriate for inclusion. Studies were small and data largely retrospective. In total, 205 patients are reported to have received pelvic SABR re-irradiation. Dose and fractionation schedules and re-irradiated volumes are highly variable. Little information is provided regarding organ at risk constraints adopted in the re-irradiation setting. Treatment appears well-tolerated overall, with nine grade 3 and six grade 4 toxicities amongst thirteen re-irradiated patients. Local control at one year ranged from 51% to 100%. Symptomatic improvements were also noted. Conclusions For previously irradiated patients with recurrent pelvic disease, SABR re-irradiation could be a feasible intervention for those who otherwise have limited options. Evidence to support this technique is limited but shows initial promise. Based on the available literature, suggestions for a more formal SABR re-irradiation pathway are proposed. Prospective studies and a multidisciplinary approach are required to optimise future treatment. [ABSTRACT FROM AUTHOR]

Introduction The purpose of this study was to evaluate the safety and efficacy of PET and MRI guided re-irradiation of recurrent high-grade glioma (HGG) and to assess the impact of radiotherapy dose, fractionation and irradiated volume. Material and methods Patients with localized, recurrent HGG (grades III-IV) and no other treatment options were eligible for a prospective phase I trial. Gross tumor volumes for radiotherapy were defined using T1-contrast enhanced MRI and 18 F-fluoro-ethyl tyrosine PET. Radiotherapy was delivered using volumetric modulated arc therapy with a 2-mm margin. The dose prescription of four consecutive groups was (1) 35 Gy/10fr., (2) 42 Gy/10fr., (3) 29.5 Gy/5fr. and (4) 35 Gy/10fr. to larger tumor volumes (100–300 cm 3 ), respectively. Results Thirty-one patients were treated of which 81% had glioblastoma. The median progression-free survival was 2.8 months (95%CI: 2.1–3.5) and the median overall survival was 7.0 months (95%CI: 3.5–10.5). Early side effects were mild and included headache and fatigue. Seven patients were progression-free beyond 10 weeks and were evaluable for late toxicity. Among these patients, three (43%) suffered late adverse events which included radionecrosis and irreversible white matter changes. Conclusion Re-irradiation showed limited efficacy and 43% of patients achieving disease control suffered late toxicity that was manageable but not negligible. [ABSTRACT FROM AUTHOR]

Purpose To investigate carbon-ion radiotherapy (CIRT) for in-field recurrence of stage I non-small cell lung cancer (NSCLC) initially treated with CIRT. Materials and methods From January 2007 to March 2014, patients initially treated for stage I NSCLC with CIRT and relapsed in-field were candidates. Overall survival (OS) rate, local control (LC) rate, progressive free survival (PFS) rate, dose to the lungs and skin, and adverse effects were analyzed. Results Twenty-nine patients were eligible. Median age at re-irradiation was 74 years (range 53–90). Median observation period from the first day of re-irradiation was 29 months (4–88 months). Median prescribed dose was 46.0 Gy (RBE) as initial treatment and 66.0 Gy (RBE) in 12 fractions as re-irradiation. Two-year OS, LC, and PFS rates after re-irradiation were 69.0% (95% CI: 50.3–83.0), 66.9% (95% CI: 47.5–81.9), and 51.7% (95% CI: 34.1–68.9). Median skin maximum dose was 53.8 Gy (RBE) (range 4.4–103.1) and median of mean lung dose was 7.3 Gy (RBE) (range 2.6–14.0). There were no severer than grade 2 adverse effects except one (3.4%) grade 3 bacterial pneumonia, which was not considered radiation-induced. Conclusion CIRT for stage I NSCLC local recurrence is an acceptable definitive re-treatment. [ABSTRACT FROM AUTHOR]

• The STRIDeR (Support Tool for Re-Irradiation Decisions guided by Radiobiology) pathway uses background dose to guide radiobiologically meaningful, anatomically-appropriate re-irradiation treatment planning within a commercial treatment planning system. • Uniquely, the pathway can optimise voxel-by-voxel in equivalent dose in 2 Gy fractions (EQD2) • The EQD2 optimisation was used to produce re-irradiation treatment plans to illustrate the use of the STRIDeR pathway. • A selective approach to deformable image registration was employed to take account of anatomical change between treatment courses. • The development of scientifically-driven and standardised strategies such as the STRIDeR pathway, to improve and learn from re-irradiation, is essential to optimise the therapeutic ratio for future patients. The STRIDeR (Support Tool for Re-Irradiation Decisions guided by Radiobiology) project aims to create a clinically viable re-irradiation planning pathway within a commercial treatment planning system (TPS). Such a pathway should account for previously delivered dose, voxel-by-voxel, taking fractionation effects, tissue recovery and anatomical changes into account. This work presents the workflow and technical solutions in the STRIDeR pathway. The pathway was implemented in RayStation (version 9B DTK) to allow an original dose distribution to be used as background dose to guide optimisation of re-irradiation plans. Organ at risk (OAR) planning objectives in equivalent dose in 2 Gy fractions (EQD2) were applied cumulatively across the original and re-irradiation treatments, with optimisation of the re-irradiation plan performed voxel-by-voxel in EQD2. Different approaches to image registration were employed to account for anatomical change. Data from 21 patients who received pelvic Stereotactic Ablative Radiotherapy (SABR) re-irradiation were used to illustrate the use of the STRIDeR workflow. STRIDeR plans were compared to those produced using a standard manual method. The STRIDeR pathway resulted in clinically acceptable plans in 20/21 cases. Compared to plans produced using the laborious manual method, less constraint relaxation was required or higher re-irradiation doses could be prescribed in 3/21. The STRIDeR pathway used background dose to guide radiobiologically meaningful, anatomically-appropriate re-irradiation treatment planning within a commercial TPS. This provides a standardised and transparent approach, offering more informed re-irradiation and improved cumulative OAR dose evaluation. [ABSTRACT FROM AUTHOR]

• Using modern RT-techniques, re-irradiation of head and neck cancer patients is feasible and routinely done in german university centers. • Precise patient selection is of utmost importance since patients performance status and possibly tracheostomy seem to be the strongest prognostic parameters. • Higher irradiation doses above 50 Gy EQD2 improve PFS and OS. To determine efficacy and prognostic parameters of definitive re-irradiation of locoregionally recurrent squamous cell carcinoma of the head and neck (HNSCC). Patients with locoregionally recurrent or second primary HNSCC undergoing re-irradiation with modern radiotherapy technique were eligible for this multicentric retrospective analysis. Main endpoints were overall survival (OS), progression-free survival (PFS) and locoregional control (LC). Univariate analyses were performed using the Kaplan Meier Method (log-rank). For multivariable analysis, Cox regression was used. A total of 253 patients treated between 2009 and 2020 at 16 university hospitals in Germany were included. The median follow up was 27.4 months (range 0.5–130). The median OS and PFS were 13.2 (CI: 10.7 – 15.7) months and 7.9 (CI: 6.7 – 9.1) months, respectively, corresponding to two-year OS and PFS rates of 29 % and 19 %. Rates of locoregional progression and "in-field-failure" were 62 % and 51 % after two years. Multivariable Cox regression analysis identified good ECOG performance status and high radiation dose as independent prognostic parameters for OS. Doses above 50 Gy (EQD2) achieved longer median OS of 17.8 months (vs 11.7 months, p < 0.01) and longer PFS of 9.6 months (vs 6.8 months, p < 0.01). In addition, there was a trend for worse survival in patients with tracheostomy (multivariable, p = 0.061). Concomitant systemic therapy did not significantly impact PFS or OS. Re-irradiation of locally recurrent or second primary HNSCC is efficient, especially if doses above 50 Gy (EQD2) are delivered. ECOG performance score was the strongest prognostic parameter for OS and PFS. [ABSTRACT FROM AUTHOR]

Background and Purpose In this multicentric in silico trial we compared photon, proton, and carbon-ion radiotherapy plans for re-irradiation of patients with squamous cell carcinoma of the head and neck (HNSCC) regarding dose to tumour and doses to surrounding organs at risk (OARs). Material and Methods Twenty-five HNSCC patients with a second new or recurrent cancer after previous irradiation (70 Gy) were included. Intensity-modulated proton therapy (IMPT) and ion therapy (IMIT) re-irradiation plans to a second subsequent dose of 70 Gy were compared to photon therapy delivered with volumetric modulated arc therapy (VMAT). Results When comparing IMIT and IMPT to VMAT, the mean dose to all investigated 22 OARs was significantly reduced for IMIT and to 15 out of 22 OARs (68%) using IMPT. The maximum dose to 2% volume ( D 2 ) of the brainstem and spinal cord were significantly reduced using IMPT and IMIT compared to VMAT. The data are available on www.cancerdata.org . Conclusions In this ROCOCO in silico trial, a reduction in mean dose to OARs was achieved using particle therapy compared to photons in the re-irradiation of HNSCC. There was a dosimetric benefit favouring carbon-ions above proton therapy. These dose reductions may potentially translate into lower severe complication rates related to the re-irradiation. [ABSTRACT FROM AUTHOR]

Background and purpose Positron emission tomography (PET) provides quantitative metabolic information and potential biomarkers of treatment outcome. We aimed to determine the prognostic value of early 18 F-fluoroethyl-tyrosine ( 18 F-FET) PET scans acquired during re-irradiation for recurrent high-grade glioma (HGG). Material and methods A phase I clinical trial of re-irradiation of HGG was carried out. MRI and 18 F-FET PET were used for target delineation and follow-up. Images were acquired at baseline, during radiotherapy and 4 weeks post-treatment and compared by measuring the metabolically active biological tumor volume (BTV) and maximal activity ( T max / B ). Correlations with outcomes were assessed by multivariate Cox regression analysis. Results Thirty-one patients were included and all patients have died. The median overall survival was 7.0 mos. Both baseline BTV and baseline MRI volume (necrotic/cystic cavities subtracted) were prognostic for overall survival (OS) in multivariate analysis (HR = 1.3 p < 0.01 and HR = 1.3 p < 0.01, respectively). Early changes in BTV and T max / B were observed but they carried no independent prognostic information. Conclusions Baseline biological tumor volume (BTV) defined by 18 F-FET PET was prognostic for OS in multivariate analysis, as was MRI volume (necrotic/cystic cavities subtracted). Tumor volume may aid in identifying patients whose life expectancy is too short to warrant re-irradiation. [ABSTRACT FROM AUTHOR]

Purpose To establish a survival prediction model in the setting of a randomized trial of re-irradiation for painful bone metastases. Methods Data were randomly divided into training and testing sets with an approximately 3:2 ratio. Baseline factors of gender, primary cancer site, KPS, worst-pain score and age were included with backward variable selection to derive a model using the training set. A partial score was assigned by dividing the value of each statistically significant regression coefficient by the smallest statistically significant regression coefficient. The survival prediction score (SPS) was obtained by adding together partial scores for the variables that were statistically significant. Three risk groups were modelled. Results The training set included 460 patients and the testing set 351 patients. Only KPS and primary cancer site reached the 5%-significance level. Summing up the partial scores assigned to KPS (90–100, 0; 70–80, 1; 50–60, 2) and primary cancer site (breast, 0; prostate, 1.3; other, 2.6; lung, 3) totalled the SPS. The 1/3 and 2/3 percentiles of the SPS were 2 and 3.6. For the testing set, the median survival of the 3 groups was not reached, 11.3 (95% C.I. 8.5 – not reached) and 5.2 months (95% C.I. 3.7–6.5). The 3, 6 and 12 month survival rates for the worst group were 64.4% (95% C.I. 55.3–72.1%), 43.0% (95% C.I. 34.0–51.8%) and 19.7% (95% C.I. 12.4–28.1%) respectively, similar to that in the training set. Conclusion This survival prediction model will assist in choosing dose fractionation. We recommend a single 8 Gy in the worst group identified. [ABSTRACT FROM AUTHOR]

Background and purpose Randomized studies have shown that adding hyperthermia (HT) to re-irradiation (re-RT) improves treatment outcome for patients with breast cancer recurrences. We evaluated the efficacy and side effects in patients treated with re-RT and HT for irresectable locoregional breast cancer recurrences. Material and methods From September 1996 to December 2011, 248 patients with a macroscopic breast cancer recurrence were treated with re-RT and HT. Radiotherapy (RT) was applied to a dose of 32 Gy in 4 Gy fractions, twice weekly. HT was prescribed once weekly after RT. Primary endpoints for this analysis were complete response (CR) and local control (LC). Secondary endpoints were overall survival (OS), and toxicity. Patient-, tumor-, and treatment-related characteristics predictive for the endpoints were identified in univariate and multivariate analyses. Results The median follow-up period was 32 months. The CR rate was 70%. At 1, 3, and 5 years LC was 53%, 40% and 39%, and OS was 66%, 32%, and 18%, respectively. OS after 10 years was 10%. Thermal burns developed in 23% patients, healing with conservative measures. The incidence of 5 years late grade 3 toxicity was 1%. A few patients survived more than 10 years without evidence of disease. Conclusions The combination of re-RT and HT results in a high rate of long-term LC with acceptable late toxicity, and many patients remained locally controlled for the rest of their survival period. [ABSTRACT FROM AUTHOR]

Background and purpose To report disease control, survival and treatment-associated toxicity with the use of proton therapy (PRT) for re-irradiation of intracranial ependymoma. Materials and methods Twenty patients underwent 33 PRT re-irradiation courses for recurrent or metastatic lesions between June 2004 and February 2015 at Massachusetts General Hospital. Results The majority of patients were female (60%), with infratentorial tumors (90%), anaplastic histology (55%), and initially received 55.8 GyRBE (52.2–59.4) involved field (IF) PRT. First failure was local (55%), distant (30%) or both (15%) at a median time of 23.9 months (9.9–98.5) from first treatment. Salvage therapy included re-resection (75%), chemotherapy (60%) and IFPRT (70%) to a median dose 50.4 GyRBE (35–55.8) in the majority of patients. The median follow-up was 37.8 months (5.5–138.0). Three year OS and PFS are 78.6% (95% CI 67.6–89.6) and 28.1% (95% CI 15.6–40.6), respectively. Longer OS was significantly associated with surgical resection of recurrent disease (HR 9.19, 95% CI 1.27–66.44, p = 0.028). The pattern of second failure after re-irradiation was directly related to the pattern of first failure ( p < 0.01). Three of 14 patients (21.4%) locally re-treated experienced grade 2 radiation-associated treatment change. Conclusions Proton therapy appears safe and efficacious for the re-treatment of recurrent intracranial ependymoma. [ABSTRACT FROM AUTHOR]

Purpose The NCIC CTG Symptom Control.20 randomized trial (SC.20) confirmed the effectiveness of re-irradiation to painful bone metastases. This companion study correlates urinary markers of osteoclast activity with response to re-irradiation, survival and skeletal related events (SREs). Methods Pain response was assessed using the International Consensus Endpoints. Urinary markers of bone turnover-pyridinoline (PYD), deoxypyridinoline (DPD), N-telopeptide (NTX), Alpha and Beta cross-laps of C-telopeptide (CTX)-before and 1 month after re-irradiation were correlated to response to re-irradiation and then to both, either or none of the initial and re-irradiation: frequent responders (response to both); eventual responders (response to re-irradiation only); eventual non-responders (response to initial radiation only), and absolute non-responders (no response to both). Results Significant differences between 40 responders and 69 non-responders to re-irradiation existed for PYD ( p = 0.03) and DPD ( p = 0.04) at baseline. When patients were categorized as frequent responders ( N = 34), eventual responders (6), eventual non-responders (59) and absolute non-responders (10), the mean values of all markers in the absolute non-responders at baseline and the follow-up were about double those for the other three groups with statistically significant difference for DPD ( p = 0.03) at baseline. Absolute non-responders had the worst survival. The few occurrences of the SREs did not allow meaningful comparisons among the groups. Conclusion There were significant differences between responders and non-responders to re-irradiation for PYD and DPD at baseline. The urinary markers in the absolute non-responders were markedly elevated at both baseline and follow-up with a statistically significant difference for DPD at baseline. [ABSTRACT FROM AUTHOR]

Background Treatment of local relapse in adenoid cystic carcinoma (ACC) following prior radiation remains a challenge: without the possibility of surgical salvage patients face the choice between palliative chemotherapy and re-irradiation. Chemotherapy yields response rates around 30% and application of tumouricidal doses is difficult due to proximity of critical structures. Carbon ion therapy (C12) is a promising method to minimize side-effects and maximize re-treatment dose in this indication. We describe our initial results for re-irradiation in heavily pre-treated ACC patients. Methods Patients treated with carbon ion therapy between 04/2010 and 05/2013 ( N = 52 pts, median age: 54 a) were retrospectively evaluated regarding toxicity (NCI CTC v.4), tumour response (RECIST) and control rates. 48 pts (92.3%) received carbon ions only, 4 pts received IMRT plus C12. Results 4 pts were treated following R1-resection, 43 pts for inoperable local relapse. Most common tumour sites were paranasal sinus (36.5%), parotid (19.2%), and base of skull (17.3%). Pts received a median dose of 51 GyE C12/63 Gy BED and cumulative dose of 128 Gy BED [67–182 Gy] after a median RT-interval of 61 months. Median target volume was 93 ml [9–618 ml]. No higher-grade (>°II) acute reactions were observed, 7 pts showed blood–brain-barrier changes (°I/II: 8 pts; °III: 2 pts), 1 pt corneal ulceration, xerophthalmia 7 pts, °IV bleeding 1 pt, tissue necrosis 2 pts, otherwise no significant late reactions. Objective response rate (CR/PR) was 56.6%. With a median follow-up of 14 months [1–39 months] local control and distant control at 1a are 70.3% and 72.6% respectively. Of the 18 pts with local relapse, 13 pts have recurred in-field, 1 pt at the field edge, 3 pts out of field, and one in the dose gradient. Conclusion Despite high applied doses, C12 re-irradiation shows moderate side-effects, response rates even in these heavily pre-treated patients are encouraging and present a good alternative to palliative chemotherapy. Though most local recurrences occur within the high-dose area, further dose escalation should be viewed with caution. [ABSTRACT FROM AUTHOR]

Background and purpose Loco-regionally recurrent head and neck cancer (HNC) in the setting of prior radiotherapy carries significant morbidity and mortality. The role of re-irradiation (re-RT) remains unclear due to toxicity. We determined prognostic factors for loco-regional control (LRC) and formulated a nomogram to help clinicians select re-RT candidates. Material and methods From July 1996 to April 2011, 257 patients with recurrent HNC underwent fractionated re-RT. Median prior dose was 65 Gy and median time between RT was 32.4 months. One hundred fifteen patients (44%) had salvage surgery and 172 (67%) received concurrent chemotherapy. Median re-RT dose was 59.4 Gy and 201 (78%) patients received IMRT. Multivariate Cox proportional hazards were used to identify independent predictors of LRC and a nomogram for 2-year LRC was constructed. Results Median follow-up was 32.6 months. Two-year LRC and overall survival (OS) were 47% and 43%, respectively. Recurrent stage (P = 0.005), non-oral cavity subsite (P < 0.001), absent organ dysfunction (P < 0.001), salvage surgery (P < 0.001), and dose >50 Gy (P = 0.006) were independently associated with improved LRC. We generated a nomogram with concordance index of 0.68. Conclusion Re-RT can be curative, and our nomogram can help determine a priori which patients may benefit. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Management for in-field failures after thoracic radiation is poorly defined. We evaluated SBRT as an initial or second course of treatment re-irradiating in a prior high dose region. Materials and methods: Thirty-three patients were treated with re-irradiation defined by the prior 30Gy isodose line. Kaplan–Meier estimates were performed for local (LC), regional (RC), distant control (DC), and overall survival (OS). The plans when available were summed to evaluate doses to critical structures. Patient and treatment variables were analyzed on UVA for the impact on control and survival measures. Results: Median follow-up was 17months. Treatment for sequential courses was as follows: (course1:course2) EBRT:SBRT (24 patients), SBRT:SBRT (7 patients), and SBRT:EBRT (3 patients). Median re-irradiation dose and fractionation was 50Gy and 10 fractions (fx), with a median of 18months (6–61) between treatments. Median OS was 21months and 2year LC 67%, yet LC for >1 fraction was 88% (p =0.006 for single vs. multiple). 10 patients suffered chronic grade 2–3 toxicity (6 chest wall pain, 3 dyspnea, 1 esophagitis) and 1 grade 5 toxicity with aorta-esophageal fistula after 54Gy in 3 fx for a central tumor with an estimated EQD2 to the aorta of 200Gy. Conclusion: Tumor control can be established with re-irradiation using SBRT techniques for in-field thoracic failures at the cost of manageable toxicity. [Copyright &y& Elsevier]

Abstract: The purpose of this review was to determine the efficacy of re-irradiation in patients with bone metastases. A literature search was conducted in Ovid Medline, OldMedline, Embase, Embase Classic, and Cochrane Central Register of Controlled Trials using relevant subject headings and keywords such as bone metastases, radiotherapy and palliative care. The resulting articles were sorted for inclusion for palliative external beam radiation retreatment response rate data. The literature search produced 2164 references and 15 articles were included in the final selection. Complete, partial and overall response rates were calculated to be 20%, 50% and 68%, respectively. Information on treatment toxicities was scarce. The efficacy of re-irradiation is comparable to initial radiation treatment. However, aspects of re-irradiation treatment including dose fractionation, related adverse events and toxicities require further corroboration. [Copyright &y& Elsevier]

Abstract: Purpose: Recurrent head and neck cancer is associated to a poor survival prognosis. A high toxicity rate is demonstrated when surgery and/or radiotherapy and/or chemotherapy are combined. Furthermore, the duration of treatment is often not ethically compatible with the expected survival (median survival<1year). Normal tissues tolerance limits the use of reirradiation and stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. After completion of a feasibility study, results of a multicentric study (Lille, Nancy & Nice) using SBRT with cetuximab are reported. The aim of the study was to deliver non toxic short course SBRT (2weeks) in order to get the same local control as the one demonstrated with longer protocols. Methods and materials: Patients with inoperable recurrent, or new primary tumor in a previously irradiated area, were included (WHO<3). Reirradiation (RT) dose was 36Gy in six fractions of 6Gy to the 85% isodose line covering 95% of the PTV with 5 injections of concomitant cetuximab (CT). All patients had previous radiotherapy, 85% had previous surgery and 48% previous chemotherapy. Results: Between 11/2007 and 08/2010, 60 were included (46 men and 14 women), 56 received CT+RT, 3 were not treated and 1 received only CT. Median age was 60 (42–87)) and all 56 patients had squamous carcinoma and received concomitant cetuximab. Mean time between previous radiotherapy and the start of SBRT was 38months. Cutaneous toxicity was observed for 41 patients. There was one toxic death from hemorrhage and denutrition. Median follow-up was 11.4months. At 3months, response rate was 58.4% (95% CI: 43.2–72.4%) and disease control rate was 91.7% (95% CI: 80.0–97.7%). The one-year OS rate was 47.5% (95% CI: 30.8–62.4). Conclusion: These results suggest that short SBRT with cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. This combination may be the reference treatment is this population. [Copyright &y& Elsevier]

Purpose: Evaluation of efficacy and side effects of combined re-irradiation and hyperthermia electively or for subclinical disease in the management of locoregional recurrent breast cancer. Methods and materials: Records of 198 patients with recurrent breast cancer treated with re-irradiation and hyperthermia from 1993 to 2010 were reviewed. Prior treatments included surgery (100%), radiotherapy (100%), chemotherapy (42%), and hormonal therapy (57%). Ninety-one patients were treated for microscopic residual disease following resection or systemic therapy and 107 patients were treated electively for areas at high risk for local recurrences. All patients were re-irradiated to 28–36Gy (median 32) and treated with 3–8 hyperthermia treatments (mean 4.36). Forty percent of the patients received concurrent hormonal therapy. Patient and tumor characteristics predictive for actuarial local control (LC) and toxicity were studied in univariate and multivariate analysis. Results: The median follow-up was 42months. Three and 5year LC-rates were 83% and 78%. Mean of T90 (tenth percentile of temperature distribution), maximum and average temperatures were 39.8°C, 43.6°C, and 41.2°C, respectively. Mean of the cumulative equivalent minutes (CEM43) at T90 was 4.58min. Number of previous chemotherapy and surgical procedures were most predictive for LC. Cumulative incidence of grade 3 and 4 late toxicity at 5years was 11.9%. The number of thermometry sensors and depth of treatment volume were associated with acute hyperthermia toxicity. Conclusions: The combination of re-irradiation and hyperthermia results in a high LC-rate with acceptable toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Re-irradiation has attracted attention as a potential therapy for recurrent head and neck tumors. However, carotid blowout syndrome (CBS) has become a serious complication of re-irradiation because of the associated life-threatening toxicity. Determining of the characteristics of CBS is important. We conducted a multi-institutional study. Methods and patients: Head and neck carcinoma patients (n =381) were treated with 484 re-irradiation sessions at 7 Japanese CyberKnife institutions between 2000 and 2010. Results: Of these, 32 (8.4%) developed CBS, which proved fatal that median survival time after CBS onset was 0.1month, and the 1-year survival rate was 37.5%. The median duration between re-irradiation and CBS onset was 5months (range, 0–69months). Elder age, skin invasion, and necrosis/infection were identified as statistically significant risk factors after CBS by univariate analysis. The presence of skin invasion at the time of treatment found only in postoperative case, is identified as only statistically significant prognostic factor after CBS in multivariate analysis. The 1-year survival rate for the group without skin invasion was 42%, whereas no patient with skin invasion survived more than 4months (0% at 1year, p =0.0049). Conclusions: Careful attention should be paid to the occurrence of CBS if the tumor is located adjacent to the carotid artery. The presence of skin invasion at CBS onset is ominous sign of lethal consequences. [Copyright &y& Elsevier]

Abstract: For patients with locally-recurrent lung cancer, high dose thoracic re-irradiation can prolong survival. Deformable image registration improves the accuracy with which initial treatments are accounted for compared to rigid image registration. Using deformable image registration will improve correlative toxicity data, and may reduce toxicity for selected patients undergoing re-irradiation. [Copyright &y& Elsevier]