Interventional radiotherapy (brachytherapy) for re-irradiation of recurrent head and neck malignancies: oncologic outcomes and morbidity.

Objective: Management of recurrent head and neck cancer (HNC) is challenging. One option in previously irradiated patients is re-irradiation using interventional radiotherapy (IRT), the modern form of brachytherapy. Re-irradiation using IRT can be delivered as an exclusive strategy for salvage or through a postoperative or perioperative approach after salvage surgery. The aim of the present study is to analyse a bicentric Italian series focusing on the use of IRT as a re-irradiation modality and assess the resulting evidence concerning oncologic outcomes and morbidity. Methods: This is a retrospective study performed in two referral centres in Italy: Policlinico Universitario Agostino Gemelli in Rome and Azienda Ospedaliera Universitaria in Sassari. All patients who had previously received a full course of external beam RT and have been re-irradiated using high-dose-rate IRT between December 2010 and June 2023 were included. Patients were retreated either by a combination of surgery and perioperative (either endocavitary or interstitial) IRT or by exclusive interstitial IRT. Results: Thirty-four patients were included in the present series, 2 of whom underwent more than one IRT re-irradiation. Notably, no patient reported specific IRT-related toxicities. Median follow-up, excluding patients who died of HNC, was 24.5 months. Two-year local relapse-free survival was 26%, disease-specific survival 39.1%, and overall survival 36.6%. Conclusions: The present series is the largest reported experience of re-irradiation by IRT for HNC in Italy. The very low rate of toxicity confirms IRT as the safest re-irradiation modality. It is noteworthy to underline that IRT is a multidisciplinary strategy based on the close cooperation between surgeons and radiation oncologists during every phase, from the recommendation of treatment and implantation in the operating theatre, to its prescription and dose painting.

Efficacy of salvage surgery versus re-irradiation for isolated regional lymph node recurrence in patients with nasopharyngeal carcinoma.

BACKGROUND: To compare the clinical characteristics and prognoses of patients with isolated regional lymph node recurrent nasopharyngeal carcinoma (irrNPC) who underwent surgery or re-irradiation treatment. METHODS: We retrospectively reviewed 124 irrNPC patients who underwent initial radiotherapy between January 2010 and December 2020. The staging of regional lymph node recurrence was as follows: 75.8% for rN1, 14.5% for rN2, and 9.7% for rN3. Fifty-five patients underwent regional lymph node surgery (Surgery group), and sixty-nine patients received salvage radiotherapy with or without chemotherapy (Re-irradiation group). The survival rate was compared using Kaplan‒Meier analysis and evaluated by the log-rank test. Cox proportional hazard models were used to analyze prognostic factors. RESULTS: The median follow-up time was 70 months, the 5-year overall survival (OS) was 74%, and the median survival time was 60.8 months. There were no significant differences in 5-year OS (75.6% vs. 72.4%, P = 0.973), regional recurrence-free survival (RRFS, 62.7% vs. 71.1%, P = 0.330) or distant metastasis-free survival (DMFS, 4.2% vs.78.7%, P = 0.677) between the Surgery group and Re-irradiation group. Multivariate analysis revealed age at recurrence, radiologic extra-nodal extension (rENE) status, and recurrent lymph node (rN) classification as independent prognostic factors for OS. The rENE status was an independent prognostic factor for DMFS. Subgroup analysis of the Surgery group revealed that the rN3 classification was an adverse prognostic factor for OS. Age at recurrence ≥ 50 years, GTV-N dose, and induction chemotherapy were found to be independent prognostic factors for OS, RRFS, and DMFS, respectively, in the Re-irradiation group. CONCLUSIONS: For NPC patients with isolated regional lymph node recurrence after initial radiotherapy, those who underwent surgery had survival prognosis similar to those who underwent re-radiotherapy with or without chemotherapy. A prospective study is needed to validate these findings.

Adjuvant re-irradiation vs. no early re-irradiation of resected recurrent glioblastoma: pooled comparative cohort analysis from two tertiary centers.

BACKGROUND: The optimal management strategy for recurrent glioblastoma (rGBM) remains uncertain, and the impact of re-irradiation (Re-RT) on overall survival (OS) is still a matter of debate. This study included patients who achieved gross total resection (GTR) after a second surgery after recurrence, following the GlioCave criteria. METHODS: Inclusion criteria include being 18 years or older, having histologically confirmed locally recurrent IDHwt or IDH unknown GBM, achieving MRI-proven GTR after the second surgery, having a Karnofsky performance status of at least 60% after the second surgery, having a minimum interval of 6 months between the first radiotherapy and the second surgery, and a maximum of 8 weeks from second surgery to the start of Re-RT. RESULTS: A total of 44 patients have met the inclusion criteria. The median OS after the second surgery was 14 months. All patients underwent standard treatment after initial diagnosis, including maximum safe resection, adjuvant radiochemotherapy and adjuvant chemotherapy. Re-RT did not significantly impact OS. However, MGMT promoter methylation status and a longer interval (> 12 months) between treatments were associated with better OS. Multivariate analysis revealed the MGMT status as the only significant predictor of OS. CONCLUSION: Factors such as MGMT promoter methylation status and treatment interval play crucial roles in determining patient outcomes after second surgery. Personalized treatment strategies should consider these factors to optimize the management of rGBM. Prospective research is needed to define the value of re-RT after second surgery and to inform decision making in this situation.

Hypofractionated re-irradiation with bevacizumab for relapsed chemorefractory glioblastoma after prior high dose radiotherapy: a feasible option for patients with large-volume relapse.

PURPOSE: There remains no standard of care for patients with recurrent and chemorefractory glioblastoma. Re-irradiation (reRT) provides an additional management option. However, published series predominantly focus on small reRT volumes utilizing stereotactic hypofractionated regimens. Concerns regarding toxicity have limited utilisation of reRT for larger recurrences, however this may be mitigated with use of bevacizumab (BEV). METHODS AND MATERIALS: A prospective database of patients managed with the EORTC-NCIC (Stupp) protocol 60 Gy chemoradiotherapy protocol for glioblastoma between 2007 and 2021 was reviewed for those patients receiving reRT for chemorefractory relapse. Serial MRI and PET were used to establish true progression and exclude patients with pseudoprogression or radionecrosis from reRT. The primary endpoint was overall survival (OS) from date of reRT. Prognostic factors were also assessed. RESULTS: 447 patients managed for glioblastoma under the Stupp protocol were identified, of which 372 had relapsed and were thus eligible for reRT. 71 patients underwent reRT. Median relapse-free survival from diagnosis for the reRT and overall cohorts were similar at 11.6 months (95%CI:9.4-14.2) and 11.8 months (95%CI:9.4-14.2) respectively. 60/71 (85%) reRT patients had received BEV prior to reRT and continued concurrent BEV during reRT. Of the 11 patients not managed with BEV during reRT, 10 required subsequent salvage BEV. ReRT patients were younger (median 53 vs. 59 years, p < 0.001), had better performance status (86% vs. 69% ECOG 0-1, p = 0.002) and more commonly had MGMT promoter-methylated tumours (54% vs. 40%, p = 0.083) compared to non-reRT patients. Median reRT PTV volume was 135cm3 (IQR: 69-207cm3). Median OS from reRT to death was 7.1 months (95%CI:6.3-7.9). Patients aged < 50, 50-70 and > 70 years had post-reRT median OS of 7.7, 6.4 and 6.0 months respectively (p = 0.021). Median post-reRT survival was longer for patients with ECOG performance status 0-1 compared to 2-3 (8.1 vs. 6.3 months, p = 0.039). PTV volume, site of relapse, MGMT promoter-methylation status and extent of initial surgical resection were not associated with post-reRT survival. ReRT was well-tolerated. Out of the 6 patients (8%) admitted to hospital after reRT, only one was for reRT toxicity. This was a CTCAE grade 3 radiation necrosis event in a patient managed without prior BEV. CONCLUSION: Patients with recurrent glioblastoma who have been previously treated with 60 Gy radiotherapy have a meaningful survival benefit from large volume re-irradiation which is well tolerated. ReRT should not be ignored as a salvage treatment option in patients with chemorefractory progressive disease.

Brain Re-Irradiation Or Chemotherapy: a phase II randomised trial of re-irradiation and chemotherapy in patients with recurrent glioblastoma (BRIOChe) - protocol for a multi-centre open-label randomised trial.

INTRODUCTION: Glioblastoma (GBM) is the most common adult primary malignant brain tumour. The condition is incurable and, despite aggressive treatment at first presentation, almost all tumours recur after a median of 7 months. The aim of treatment at recurrence is to prolong survival and maintain health-related quality of life (HRQoL). Chemotherapy is typically employed for recurrent GBM, often using nitrosourea-based regimens. However, efficacy is limited, with reported median survivals between 5 and 9 months from recurrence. Although less commonly used in the UK, there is growing evidence that re-irradiation may produce survival outcomes at least similar to nitrosourea-based chemotherapy. However, there remains uncertainty as to the optimum approach and there is a paucity of available data, especially with regards to HRQoL. Brain Re-Irradiation Or Chemotherapy (BRIOChe) aims to assess re-irradiation, as an acceptable treatment option for recurrent IDH-wild-type GBM. METHODS AND ANALYSIS: BRIOChe is a phase II, multi-centre, open-label, randomised trial in patients with recurrent GBM. The trial uses Sargent's three-outcome design and will recruit approximately 55 participants from 10 to 15 UK radiotherapy sites, allocated (2:1) to receive re-irradiation (35 Gy in 10 daily fractions) or nitrosourea-based chemotherapy (up to six, 6-weekly cycles). The primary endpoint is overall survival rate for re-irradiation patients at 9 months. There will be no formal statistical comparison between treatment arms for the decision-making primary analysis. The chemotherapy arm will be used for calibration purposes, to collect concurrent data to aid interpretation of results. Secondary outcomes include HRQoL, dexamethasone requirement, anti-epileptic drug requirement, radiological response, treatment compliance, acute and late toxicities, progression-free survival. ETHICS AND DISSEMINATION: BRIOChe obtained ethical approval from Office for Research Ethics Committees Northern Ireland (reference no. 20/NI/0070). Final trial results will be published in peer-reviewed journals and adhere to the ICMJE guidelines. TRIAL REGISTRATION NUMBER: ISRCTN60524.

Hypofractionated re-irradiation for diffuse intrinsic pontine glioma.

BACKGROUND: Re-irradiation (reRT) increases survival in locally recurrent diffuse intrinsic pontine glioma (DIPG). There is no standard dose and fractionation for reRT, but conventional fractionation (CF) is typically used. We report our institutional experience of reRT for DIPG, which includes hypofractionation (HF). METHODS: We reviewed pediatric patients treated with brainstem reRT for DIPG at our institution from 2012 to 2022. Patients were grouped by HF or CF. Outcomes included steroid use, and overall survival (OS) was measured from both diagnosis and start of reRT. RESULTS: Of 22 patients who received reRT for DIPG, two did not complete their course due to clinical decline. Of the 20 who completed reRT, the dose was 20-30 Gy in 2-Gy fractions (n = 6) and 30-36 Gy in 3-Gy fractions (n = 14). Median age was 5 years (range: 3-14), median interval since initial RT was 8 months (range: 3-20), and 12 received concurrent bevacizumab. Median OS from diagnosis was 18 months [95% confidence interval: 17-24]. Median OS from start of reRT for HF versus CF was 8.2 and 7.5 months, respectively (p = .20). Thirteen (93%) in the HF group and three (75%) in the CF group tapered pre-treatment steroid dose down or off within 2 months after reRT due to clinical improvement. There was no significant difference in steroid taper between HF and CF (p = .4). No patients developed radionecrosis. CONCLUSION: reRT with HF achieved survival duration comparable to published outcomes and effectively palliated symptoms. Future investigation of this regimen in the context of new systemic therapies and upfront HF is warranted.

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

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

Re-irradiation of recurrent head and neck cancers using pulsed reduced dose rate radiotherapy: An institutional series.

PURPOSE/OBJECTIVE(S): Pulsed reduced dose rate (PRDR) radiation (RT) is a re-irradiation (Re-RT) technique that potentially overcomes dose/volume constraints in the setting of previous RT. There is minimal data for its use for recurrent or secondary primary head and neck squamous cell carcinoma (HNSCC). In this study, we report preliminary data from our institution of a consecutive cohort of HNSCC patients who received PRDR Re-RT. MATERIALS/METHODS: Nine patients received PRDR Re-RT from August 2020 to January 2023 and had analyzable data. Intensity modulated RT was used for treatment delivery and a wait time between 20 cGy arc/helical deliveries was used to achieve the effective low dose rate. Data collected included patient demographic information, prior interventions, diagnosis, radiation therapy dose and fractionation, progression free survival, overall survival, and toxicity rates. RESULTS: The median time to PRDR-RT from completion of initial RT was 13 months (range, 6-50 months). All but one patient underwent salvage surgery prior to PRDR-RT. The median follow-up after Re-RT was 7 months. The median OS from PRDR-RT was 7 months (range, 1-32 months). Median PFS was 7 months (range, 1-32 months). One patient (11.1 %) had acute grade 3 toxicity, and two patients (22.2 %) had late grade 3 toxicities. There were no grade 4+ toxicities. CONCLUSION: PRDR Re-RT is a feasible treatment strategy for patients with recurrent or second primary HNSCC. Initial findings from this retrospective review suggest reasonable survival outcomes and potentially improved toxicity; prospective data is needed to establish the safety and efficacy of this technique.

Hypofractionated stereotactic re-irradiation for progressive glioblastoma: twelve years' experience of a single center.

PURPOSE: We aimed to evaluate the prognostic factors and the role of stereotactic radiotherapy (SRT) as a re-irradiation technique in the management of progressive glioblastoma. METHODS: The records of 77 previously irradiated glioblastoma patients who progressed and received second course hypofractionated SRT (1-5 fractions) between 2009 and 2022 in our department were evaluated retrospectively. Statistical Package for the Social Sciences (SPSS) version 23.0 (IBM, Armonk, NY, USA) was utilized for all statistical analyses. RESULTS: The median time to progression from the end of initial radiotherapy was 14 months (range, 6-68 months). The most common SRT schedule was 30 Gy (range, 18-50 Gy) in 5 fractions (range, 1-5 fractions). The median follow-up after SRT was 9 months (range, 3-80 months). One-year overall (OS) and progression-free survival (PFS) rates after SRT were 46% and 35%, respectively. Re-irradiation dose and the presence of pseudoprogression were both significant independent positive prognostic factors for both OS (p = 0.009 and p = 0.04, respectively) and PFS (p = 0.008 and p = 0.04, respectively). For PFS, progression-free interval > 14 months was also a prognostic factor (p = 0.04). The treatment was well tolerated without significant acute toxicity. During follow-up, radiation necrosis was observed in 17 patients (22%), and 14 (82%) of them were asymptomatic. CONCLUSION: Hypofractionated SRT is an effective treatment approach for patients with progressive glioblastoma. Younger patients who progressed later than 14 months, received higher SRT doses, and experienced pseudoprogression following SRT had improved survival rates.

Thoracic Reirradiation with Stereotactic Body Radiation Therapy (SBRT) for Recurrent Advanced Non-Small Cell Lung Cancer (NSCLC).

PURPOSE: Non-small cell lung cancer (NSCLC) local control remains suboptimal with rates around 75%. Stereotactic body radiation therapy (SBRT) is an option for isolated local recurrences of small-volume recurrences. This study investigates the safety and efficacy of 60 Gy in 8 fractions in large-volume local recurrences. METHODS AND MATERIALS: We conducted a retrospective chart review of patients treated with salvage SBRT for NSCLC lung parenchymal recurrence between July 2013 and February 2020. Reirradiation prescribed dose was 60 Gy in 8 fractions using the SBRT technique. The primary endpoint was local control at most recent follow-up or death. Secondary endpoints included overall survival, disease-free interval, cancer-specific survival, and treatment related toxicities. RESULTS: Seven patients met inclusion criteria. Median follow up time was 38 months (18.1-72.4). Median age was 67 years (63-80). Median time to reirradiation was 18.2 months (7.3-28.6). Retreatment median ITV was 57.9 cc (15.8-344.6), and PTV median was 113.6 cc (38.3-506.9). Local control was maintained in 4 of 7 patients (57.1%). Two of the 7 patients (28.6%) remained alive. Median disease-free interval was 22.5 months (11-65). Three of 7 patients (42.9%) had grade 2 toxicities. One patient (14.3%) had a grade 3 rib/chest wall toxicity with concurrent disease recurrence invading the chest wall. CONCLUSION: This study reports that SBRT of 60 Gy in 8 fractions was delivered safely and effectively to large volume recurrent NSCLC previously treated with radiation therapy. The disease-free interval of nearly 2 years is meaningful for patients' quality of life and duration of time off systemic therapy.

Re-irradiation for isolated neck recurrence in head and neck tumor: impact of rN category.

Unresectable, isolated lymph node recurrence after radiotherapy is rare but a candidate for re-irradiation. However, severe toxicity is anticipated. Therefore, this study aimed to explore the efficacy and toxicity of re-irradiation in isolated lymph node recurrence of head and neck lesions. We analyzed 46 patients who received re-irradiation for lymph node recurrence without local progression. The primary tumor sites included the oral cavity in 17 patients, the hypopharynx in 12, the oropharynx in seven, the larynx in three, the nasopharynx in two, and other sites. During a median follow-up time of 10 months, the median survival time was 10.6 months, and the 1-year overall survival rate was 45.5%. The 1-year local control and progression-free survival rates were 49.8% and 39.3%, respectively. According to univariate analysis, age (≥ 65 years), the interval between treatment (≥ 12 months), rN category (rN1), and gross tumor volume (GTV < 25 cm3) were predisposing factors for better survival. In the multivariate analysis, the rN category and interval were identified as statistically significant predictors. Late toxicity grade ≥ 3 occurred in four patients (8.6%). These were all Grade 5 carotid blowout syndrome, which associated with tumor invasion of the carotid artery and/ or high doses administration for the carotid artery. Small-volume rN1 tumor that recur after a longer interval is a feasible candidate for re-irradiation. However, strict patient selection and meticulous care for the carotid are required.

Post-mastectomy reirradiation for ipsilateral T3N0M0 breast tumor relapse: a population-based study.

INTRODUCTION: Post-mastectomy radiotherapy is commonly recommended for T3N0M0 breast cancer, particularly in the presence of adverse prognostic factors. However, for T3N0M0 ipsilateral recurrences following breast-conserving surgery and adjuvant radiotherapy, the situation is distinct. Recurrence alone signifies a negative prognostic factor. Moreover, tumor relapses within previously irradiated areas exhibit enhanced radioresistance, and reirradiation of the chest wall carries an escalated risk of radiation-induced toxicity. This study aimed to assess the impact of post-mastectomy reirradiation (PM-reRT) on patient outcomes in cases of ipsilateral T3N0M0 breast tumor recurrence, using data from the SEER database. MATERIALS AND METHODS: We identified all patients who underwent treatment for primary non-metastatic breast cancer with breast-conserving surgery followed by adjuvant radiotherapy in the SEER database; among them, those who later experienced a localized T3N0M0 breast tumor recurrence and underwent total mastectomy were included. The study's goal was to compare overall survival (OS) and cancer-specific survival (CSS) between patients who underwent only mastectomy versus those who had mastectomy followed by adjuvant PM-reRT for their ipsilateral T3N0M0 breast tumor relapse. RESULTS: From 2000 to 2020, the SEER database recorded 44 patients with an ipsilateral T3N0M0 breast tumor recurrence after initial conservative treatment, managed with total mastectomy. No statistically significant differences in OS or CSS were observed between patients undergoing mastectomy (MT) alone versus those receiving MT combined with PM-reRT (p = 0.68 and p = 0.86, respectively). Five-year OS rates for the MT and MT + PM-reRT cohorts were 49.5% [95% CI: 29.9-81.8] and 41.7% [10.0-100.0], respectively, while 5­year CSS rates were 51.6% [12.0-99.5] and 58.3% [15.2-100.0], respectively. CONCLUSION: For patients undergoing total mastectomy after an ipsilateral T3N0M0 breast tumor recurrence, subsequent to initial breast cancer treatment involving breast-conserving surgery and adjuvant radiotherapy, chest wall reirradiation does not enhance survival outcomes. As such, it should not be routinely performed.

Brachytherapy is an effective and safe salvage option for re-irradiation in recurrent glioblastoma (rGBM): A systematic review.

PURPOSE: To evaluate the clinical efficacy and toxicity of brachytherapy as a salvage therapy for patients with recurrent glioblastoma (rGBM). METHODS AND MATERIALS: We searched the PubMed, Embase, and Cochrane libraries from its inception to June 2023, for eligible studies in which patients underwent brachytherapy for rGBM. Outcomes of interest were mOS, mPFS, OS, PFS, and adverse events (AEs). For individual clinical survival outcomes and common AEs, weighted-mean descriptive statistics were calculated as a summary measure using study sample size as the weight. The calculation formula is as follows: weighted-mean = Σwx/Σw (w is the sample size and x is the outcome). RESULTS: This review included 29 studies with a total of 1202 rGBM patients, including 22 retrospective and 7 prospective studies. The results showed that from the time of brachytherapy, the mOS and mPFS were 6.8 to 24.4 months and 3.7 to 11.7 months. The OS of 6 months, 1 year, 18 months, 2 years, and 3 years after brachytherapy were 58.3 % to 85.2 % (weighted-mean 76.2 %), 26 % to 66 % (weighted-mean 41.9 %), 20 % to 37 % (weighted-mean 27.6 %), 11 % to 23 % (weighted-mean 14.8 %), and 8 % to 15 % (weighted-mean 12.1 %), respectively. The PFS of 6 months and 1 year after brachytherapy were 26.7 % to 86 % (weighted-mean 53.4 %) and 14 % to 81 % (weighted-mean 24.1 %). Most patients with rGBM will experience treatment failure again during the follow-up period, mainly local (10.7 % to 79.4 %) or marginal(3.6 % to 22.2 %) recurrence, followed by distant failure (6.7 % to 57.7 %). Although therapeutic AEs had not been uniformly reported, the overall toxicity rate was considered to be low. The common AEs reported included progressive neurologic deterioration, seizures, CSF leak, brain necrosis, hemorrhage, and infection/meningitis, with a weighted-mean incidence of 1.9 %, 2.4 %, 4.1 %, 5.4 %, 2.1 %, and 3.8 %, respectively. CONCLUSIONS: The evidence summarized above, albeit mostly level III, suggests that brachytherapy has acceptable safety and good post-treatment clinical efficacy for selected patients with rGBM. Well-designed, high-quality, large-sample randomized controlled and prospective studies are needed to further validate these findings.

Pattern of practice of re-irradiation for ipsilateral breast tumor recurrence in Italy: a survey by the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

PURPOSE: The Re-irradiation and the Breast Cancer Working Groups of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) conducted a survey to provide an overview of the policies for breast cancer (BC) re-irradiation (re-RT) among the Italian radiotherapy (RT) centers. METHODS: In October 2021, 183 RT centers were invited to answer a survey: after an initial section about general aspects, the questionnaire focused on radiation oncologists' (ROs) attitude toward re-RT in three different scenarios: ipsilateral breast tumor recurrence (IBTR) treated with second conservative surgery, IBTR treated with mastectomy and inoperable IBTR. Surveyed ROs were also asked to express their interest in being involved in a prospective trials. RESULTS: Seventy-seven/183 (42.0%) centers answered the Survey, only one RO per center was requested to answer. In particular, 86.5% ROs declared to have performed "curative" re-RT for IBTR during the previous two years (2019-2020): 76.7% respondents administered re-RT after second BCS, 50.9% after mastectomy, and 48.1% for inoperable IBTR. Re-RT practice varied widely among centers in terms of treatment volumes, dose and fractionation schedules, techniques and dose-volume constraints for organs at risks (OARs). Forty-six participants (59.7%) expressed their interest in participating in a prospective study investigating BC re-RT. CONCLUSIONS: About one out of three RT centers in Italy delivered re-RT for IBTR. Nevertheless, practice of re-RT varied widely among centers highlighting the needs for prospective studies to improve knowledge in this field.

Curative high-dose reirradiation for patients with recurrent head and neck adenoid cystic carcinomas: outcomes and analysis of patterns of failure.

BACKGROUND: To investigate the outcomes of patients who underwent curative reirradiation (reRT), with intensity-modulated radiation therapy (IMRT) or proton therapy (PT) for unresectable recurrent or second primary head and neck adenoid cystic carcinoma (HNACC). METHODS: Ten patients, mostly KPS 90%, were reirradiated (3/10 with IMRT and 7/10 with PT) at a median maximum dose to the CTV of 64.2 Gy from July 2011 to November 2021. Locations at the time of reRT were mainly the sinus (4/10) and the salivary glands (including the parotid and submandibular gland, 3/10). CTCAEv5 was used to assess acute and late toxicities. Follow-up was the time between the end of reRT and the date of last news. RESULTS: The median time between the two irradiations was 53.5 months (IQR: 18-84). After a median follow-up of 26 months (range, 12.5-51.8 months), six patients had developed a locoregional recurrence (LR), of which four occurred within the previously irradiated volume. Two and three-year locoregional failure-free survival (LFFS) and overall survival (OS) were 55.6% [95%CI: 31-99.7%], and 41% [18.5-94%] and 66.7% [42-100%] and 44.4% [21.4-92.3%], respectively. LFFS and OS were significantly better in the subgroup of sinus tumors (p = .013) and the subgroup of patients re-irradiated more than two years after the first course of irradiation (p = .01). Seven patients had impairments before the start of reRT, including hearing impairment (3/10) and facial nerve impairment (3/10). The most severe late toxicities were brain necrosis (2/10), osteoradionecrosis (1/10) and vision decreased (1/10). CONCLUSION: Curative reRT for HNACC is possible for selected cases, but the LR rate in the irradiated field and the risk of severe toxicity remain high. Improved selection criteria and more carefully defined target volumes may improve outcome in these patients. A further study including larger cohort of patients would be useful to confirm these results.

Carbon-Ion Radiation Therapy for Unresectable Locally Recurrent Colorectal Cancer: A Promising Curative Treatment for Both Radiation Therapy: Naïve Cases and Reirradiation Cases.

PURPOSE: It is difficult to effectively cure patients with unresectable locally recurrent colorectal cancers (LRCRCs) using conventional chemotherapy or chemoradiation therapy. Furthermore, treatment options vary depending on the patient's history of radiation therapy. Carbon-ion radiation therapy (CIRT) is a potentially curative treatment for these patients. Here, we compare the treatment outcomes of radiation therapy-naïve cases (nRT) and re-irradiation cases (reRT). METHODS AND MATERIALS: Patients with LRCRC treated with CIRT at QST Hospital between 2003 and 2019 were eligible. CIRT was administered daily 4 d/wk for 16 fractions. The total irradiated dose was set at 73.6 Gy (relative biologic effectiveness-weighted dose [RBE]) for nRT and 70.4 Gy (RBE) for reRT patients. RESULTS: We included 390 nRT cases and 83 reRT cases. The median follow-up period from the initiation of CIRT was 48 (5-208) months. The 3-year overall survival (OS) rates for nRT and reRT were 73% (95% CI, 68%-77%) and 76% (65%-84%), respectively. The 5-year OS rates were 50% (45%-55%) and 50% (38%-61%), respectively. These rates did not differ significantly (P = .55). The 3-year local control (LC) rates for nRT (73.6 Gy) and reRT (70.4 Gy) cases were 80% (75%-84%) and 80% (68%-88%), respectively. The 5-year LC rates were 72% (67%-78%) and 69% (55%-81%), respectively, without a significant difference (P = .56). CONCLUSIONS: Our results suggest that CIRT for LRCRC is a very effective and promising treatment for both nRT and reRT cases.

Reirradiation of head and neck squamous cell carcinomas: a pragmatic approach-part I: prognostic factors and indications to treatment.

INTRODUCTION: Reirradiation (reRT) of locally recurrent/second primary tumors of the head and neck region is a potentially curative treatment for patients not candidate to salvage surgery. Aim of the present study is to summarize available literature on both prognostic factors and indications to curative reRT in this clinical setting. MATERIALS AND METHODS: A narrative review of the literature was performed on two topics: (1) patients' selection according to prognostic factors and (2) dosimetric feasibility of reRT. Postoperative reRT and palliative intent treatments were out of the scope of this work. RESULTS: Patient-tumor and treatment-related prognostic factors were analyzed, together with dosimetric parameters concerning target volume and organs at risk. Based on available evidence, a stepwise approach has been proposed aiming to provide a useful tool to identify suitable candidates for curative reRT in clinical practice. This was then applied to two clinical cases, proposed at the end of this work. CONCLUSION: A second course of RT in head and neck recurrence/second primary tumors is a personalized approach that can be offered to selected patients only in centers with expertise and dedicated equipment following a multidisciplinary team discussion.

Reirradiation salvage radiotherapy for recurrent prostate cancer after primary low-dose brachytherapy.

PURPOSE: Local recurrence of prostate cancer after low-dose rate brachytherapy is a clinical problem with limited salvage treatment options. This prospective study evaluated the tolerability and outcome of salvage external beam radiation therapy (S-EBRT) for locally recurrent prostate cancer after primary low-dose rate prostate brachytherapy (LDR-BT). MATERIALS AND METHODS: Between October 2012 and 2022, 18 patients with biopsy-proven locally recurrent prostate cancer after primary LDR-BT and received S-EBRT. We evaluated biochemical failure (BF), overall survival (OS) and acute/late gastrointestinal and urinary toxicities (CTCAE v5.0 or CTCAE v4, only before 2017). RESULTS: Median follow-up was 32 months (range, 5-124). The median age was at S-EBRT 68 years (range 59-79). 34% (6/18) were low risk, 44% (8/18) intermediate risk, 5% (1/18) high risk, and 17% (3/18) not specified. All patients were treated with IMRT/VMAT and received 60 Gy (2.5 Gy/fraction) to the prostate and 40% (7/18) 55.2 Gy (2,3 Gy/fx) to the seminal vesicles. 56% received ADT The 3-year OS and biochemical relapse-free survival after S-EBRT were 100% and 89%, respectively, with a median PSA nadir 0,035 ng/mL (0,01-0,34). Acute cystitis was present in 72% (13/18) of patients (27% of Grade > 2). Urethritis was present in 78% (14/18) patients (16% of cases Grade > 3), and acute rectitis occurred in 22% (4/18) of patients (no cases Grade > 3). CONCLUSIONS: Our data suggest that the treatment of locally recurrent prostate cancer with S-EBRT could provide adequate disease control safely and be used as an additional treatment in the natural history of prostate cancer patients. However, the results are still early and the sample is small; larger studies with longer follow-up would be mandatory.

Phase 2 Trial of Consolidation Pembrolizumab After Proton Reirradiation for Thoracic Recurrences of Non-Small Cell Lung Cancer.

PURPOSE: Reirradiation (reRT) with proton beam therapy (PBT) may offer a chance of cure while minimizing toxicity for patients with isolated intrathoracic recurrences of non-small cell lung cancer (NSCLC). However, distant failure remains common, necessitating strategies to integrate more effective systemic therapy. METHODS AND MATERIALS: This was a phase 2, single-arm trial (NCT03087760) of consolidation pembrolizumab after PBT reRT for locoregional recurrences of NSCLC. Four to 12 weeks after completion of 60 to 70 Gy PBT reRT, patients without progressive disease received pembrolizumab for up to 12 months. Primary endpoint was progression-free survival (PFS), measured from the start of reRT. Secondary endpoints were overall survival (OS) and National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 toxicity. RESULTS: Between 2017 and 2021, 22 patients received PBT reRT. Median interval from prior radiation end to reRT start was 20 months. Most recurrences (91%) were centrally located. Most patients received concurrent chemotherapy (95%) and pencil beam scanning PBT (77%), and 36% had received prior durvalumab. Fifteen patients (68%) initiated consolidation pembrolizumab on trial and received a median of 3 cycles (range, 2-17). Pembrolizumab was discontinued most commonly due to toxicity (n = 5; 2 were pembrolizumab-related), disease progression (n = 4), and completion of 1 year (n = 3). Median follow-up was 38.7 months. Median PFS and OS were 8.8 months (95% CI, 4.2-23.7) and 22.8 months (95% CI, 6.9-not reached), respectively. There was only one isolated in-field failure after reRT. Grade ≥3 toxicities occurred in 10 patients (45%); 2 were pembrolizumab-related. There were 2 grade 5 toxicities, an aorto-esophageal fistula at 6.9 months and hemoptysis at 46.8 months, both probably from reRT. The trial closed early due to widespread adoption of immunotherapy off-protocol. CONCLUSIONS: In the first-ever prospective trial combining PBT reRT with consolidation immunotherapy, PFS was acceptable and OS favorable. Late grade 5 toxicity occurred in 2 of 22 patients. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC.