Course Of RT Research Articles

Cost-Outcome of Radiotherapy for Local Control and Overall Survival Benefits in Breast Cancer

PurposeRadiotherapy (RT) is an integral component in the treatment of breast cancer. The aims of this study were to estimate the cost per 5-year Local Control (LC) and Overall Survival (OS) benefits of the first course of RT, based on breast cancer stage, and the potential cost savings with adoption of the FAST-Forward protocol. Methods and MaterialsAll RT activities for breast cancer RT July 2017-June 2020 and their associated costs were consolidated together. The average cost of treatment course was calculated (average cost per fraction X average no. of fractions). Cost per outcome was estimated based on published gains in 5-year LC and OS with optimal use of radiotherapy. Results481 patients with breast cancer were analysed. The average cost per fraction was $285 AUD (£148 GBP) for all stages. The average costs for 5-year LC and OS gain were $31,483 AUD (£16 392 GBP) and $235,435 AUD (£122 566 GBP) respectively for all stages.The estimated costs for 5-year LC outcomes were $29,675 AUD (£15 450 GBP), $34,675 AUD (£18 053 GBP) and $32,478 AUD (£16 910 GBP) for Stage I-III respectively. The estimated costs for 5-year OS were $455,909 AUD (£237 378 GBP), $532,727 AUD (£ 277 375 GBP) and $60,717 AUD (£31 614 GBP) for Stage I-III respectively.266 patients had characteristics that made them eligible for the FAST-Forward protocol. A cost saving of $2592–3864 AUD (£1350–2012 GBP) per patient was estimated had these patients been treated with the protocol. ConclusionsThe cost of RT for LC outcome is similar across stages. The greatest value for OS outcome was seen in patients with Stage III breast cancer, due to the greater survival benefit with RT in these patients compared with Stage I-II breast cancer. Significant cost savings can be made by implementing the FAST-Forward protocol.

DIPG-04. THE BENEFIT OF CRANIOSPINAL IRRADIATION (CSI) RESCUE IN PHASE 2 RANDOMIZED STUDY OF RADIOTHERAPY (RT), CONCOMITANT NIMOTUZUMAB AND VINORELBINE AND RE-IRRADIATION AT RELAPSE, VERSUS MULTIPLE ELECTIVE RADIOTHERAPY COURSES WITH CONCOMITANT VINORELBINE AND NIMOTUZUMAB FOR NEWLY DIAGNOSED CHILDHOOD AND ADOLESCENCE DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract BACKGROUND This trial evaluated feasibility,response,PFS/OS of a randomization comparing two different RT schedules for DIPG while administering the same systemic treatment. We moreover evaluated the benefit of craniospinal irradiation(CSI) in case of disseminated(D) relapse. METHODS Patients: 2-21 years-old with at least radiologically verified DIPG (MRI blindly reviewed at diagnosis,every 12 weeks thereafter) and symptoms duration below 6 months. Biopsy required if atypical imaging, also allowed after adequate consensus.Vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 were administered weekly for 12; thereafter every other week until tumor progression or for up to 2 years. Standard(ST) arm was full brainstem/focal tumor site RT at total dose of 54Gy(1.8Gy/day); for local progression re-irradiation was proposed at 19.8Gy, in case of dissemination CSI at 36Gy was offered.Experimental(SP) arm included three elective courses of RT at defined time-points(36Gy, 19.8Gy and 19.8Gy) with reirradiation for relapse at 9 Gy/36 Gy as above described. Incidences of local(L) and D progression were assessed in a competing risk setting. RESULTS 55 patients were included from 4 Italian centers,27 in ST,30 males, median age 7.1 years. Median follow-up 39.1 months. Fifteen patients needed a shunt,13 during treatment;23 were biopsied,in 21 according to local protocols.22/23 tumors had H3.3K27 mutation. 53 relapsed, 34 L,13 D,6 L+D.Fifteen/19 with a D component receiving CSI had a median survival of 7.6 months after relapse, significantly higher than that of the 4 without CSI(median 2.9 months,P=0.020). Patients submitted to biopsies had more D(P=0.017) and less L progression(P=0.058). SP irradiation and any reirradiation at relapse were feasible and never produced significant radionecrosis.Median EFS/OS for the whole series were 8.4/14 months, respectively; not significantly different between patients with local vs. disseminated relapses. CONCLUSIONS Reirradiation, even if CSI, confirmed feasible and benefitted patients OS.Randomization results will be later reported.

A phase II trial of reirradiation combined with pembrolizumab in patients with locoregional inoperable recurrence or second primary squamous cell carcinoma of the head and neck (HNSCC).

6049 Background: Better outcomes are needed for patients (pts) with locoregional inoperable recurrence or second primary HNSCC after prior radiation therapy. Methods: We conducted a phase II single arm trial of hyperfractionated reirradiation (ReRT, 1.2 Gy BID for total 60Gy to gross disease + margin without elective nodal radiation) plus pembrolizumab (P) (200mg q3 weeks starting day 1 of ReRT). P was continued until confirmed CR or if no CR, until disease progression or up to 24 months. All pts underwent a 3 month post ReRT PET/CT and subsequently CT neck/chest after every 3rd cycle of P. Pts included had: Locoregional recurrence or second primary HNSCC (excluding skin or salivary), were unresectable or not willing to undergo resection, one RT course completed at least 6 months prior, with >50% tumor volume treated at doses >45Gy, ECOG PS 0-1, a target lesion by RECIST, no distant metastasis, and no prior anti-PD-1/PD-L1. Primary endpoint was PFS, and the hypothesis was that the median PFS would increase from the historical control of 8 months (mo) to 12 mo, α=0.05, power 78%, n=48. Secondary endpoints: ORR by RECIST, OS, toxicity, QOL (EORTC). The Kaplan-Meier method was used to estimate PFS and OS. Results: In the 48 evaluable pts, median age was 65.5 (range 44-79), 62.5% male. Primary site: hypopharynx (8.3%), larynx (6.3%), nasopharynx (10.4%), oral cavity (43.7%), oropharynx (31.3%, one HPV+ pt). Median doses of P was 8, median RT dose was 60 Gy and 20.8% received proton RT, remainder IMRT. Median follow up was 49.1 months. The median PFS was 8.3 mo (95%CI 5.5-10.3), and median OS was 13.8 mo (95% CI 9.5-21.8). 1 and 3-year PFS were 28.9% and 22.3% respectively, and for OS 54.2% and 25.7%, respectively. 42 pts were evaluable for response and the ORR was 54.8% (33.3% CR, 21.4%PR), 21.4% SD, 23.8% PD. In an exploratory analysis, the median PFS was 13.8 mo (95% CI 9.1-NR) and the median OS was 57.8 mo (19.6-NR) in patients that had a response (CR/PR, n=23), with a 1 and 3-year PFS of 51.8% and 42.4%, respectively, and for OS 78.3% and 51.7%, respectively. All patients had at least one treatment related AE (TRAE), defined as possibly, probable, or definitely related to treatment. 39% of pts had a G3 TRAE and the most common ones were: aspiration, dehydration, anemia, dysphagia, dyspnea. 4 patients had a G5 TRAE (found down deceased, epistaxis, aspiration pneumonia, iRAE pneumonitis). Conclusions: Our prospective trial uniquely evaluated ReRT plus pembrolizumab in patients with locoregional recurrence/second primary HNSCC that did not undergo salvage surgery. The primary endpoint of PFS was not improved compared to historical control. PD-L1 biomarker analysis is ongoing and will be reported subsequently. Clinical trial information: NCT02289209 .

Real-World Use of Hypofractionated Radiotherapy for Primary CNS Tumors in the Elderly, and Implications on Medicare Spending.

For elderly patients with high-grade gliomas, 3-week hypofractionated radiotherapy (HFRT) is noninferior to standard long-course radiotherapy (LCRT). We analyzed real-world utilization of HFRT with and without systemic therapy in Medicare beneficiaries treated with RT for primary central nervous system (CNS) tumors using Centers for Medicare & Medicaid Services data. Radiation modality, year, age (65-74, 75-84, or ≥85 years), and site of care (freestanding vs hospital-affiliated) were evaluated. Utilization of HFRT (11-20 fractions) versus LCRT (21-30 or 31-40 fractions) and systemic therapy was evaluated by multivariable logistic regression. Medicare spending over the 90-day episode after RT planning initiation was analyzed using multivariable linear regression. From 2015 to 2019, a total of 10,702 RT courses (ie, episodes) were included (28% HFRT; 65% of patients aged 65-74 years). A considerable minority died within 90 days of RT planning initiation (n=1,251; 12%), and 765 (61%) of those received HFRT. HFRT utilization increased (24% in 2015 to 31% in 2019; odds ratio [OR], 1.2 per year; 95% CI, 1.1-1.2) and was associated with older age (≥85 vs 65-74 years; OR, 6.8; 95% CI, 5.5-8.4), death within 90 days of RT planning initiation (OR, 5.0; 95% CI, 4.4-5.8), hospital-affiliated sites (OR, 1.4; 95% CI, 1.3-1.6), conventional external-beam RT (vs intensity-modulated RT; OR, 2.7; 95% CI, 2.3-3.1), and no systemic therapy (OR, 1.2; 95% CI, 1.1-1.3; P<.001 for all). Increasing use of HFRT was concentrated in hospital-affiliated sites (P=.002 for interaction). Most patients (69%) received systemic therapy with no differences by site of care (P=.12). Systemic therapy utilization increased (67% in 2015 to 71% in 2019; OR, 1.1 per year; 95% CI, 1.0-1.1) and was less likely for older patients, patients who died within 90 days of RT planning initiation, those who received conventional external-beam RT, and those who received HFRT. HFRT significantly reduced spending compared with LCRT (adjusted β for LCRT = +$8,649; 95% CI, $8,544-$8,755), whereas spending modestly increased with systemic therapy (adjusted β for systemic therapy = +$270; 95% CI, $176-$365). Although most Medicare beneficiaries received LCRT for primary brain tumors, HFRT utilization increased in hospital-affiliated centers. Despite high-level evidence for elderly patients, discrepancy in HFRT implementation by site of care persists. Further investigation is needed to understand why patients with short survival may still receive LCRT, because this has major quality-of-life and Medicare spending implications.

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

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. 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. 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%. 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 and safety analysis in metastatic cancer patients treated with multiple courses of repeat radiation therapy

Background and purposeDue to advances in oncology, a growing proportion of patients is treated with repetitive courses of radiotherapy. The aim of this study is to analyze whether radiotherapy maintains its safety and efficacy profile in patients treated with multiple repeat courses of irradiation. Material and methodsAll patients treated between 2011 and 2019 at our institution were screened for a minimum of five repeat irradiation courses, to analyze treatment characteristics, survival, safety and efficacy. The type of re-irradiation was classified according to ESTRO-EORTC consensus guidelines. ResultsA total of n = 112 patients receiving n = 660 radiotherapy courses were included in this retrospective cohort study. The most frequent primary tumors were lung cancer in 41.9 % (n = 47) and malignant melanoma in 8.9 % (n = 10). The most frequent re-irradiation types were repeat irradiation and Type 2 re-irradiation in 309 (46.8 %) and 113 (17.1 %) cases, respectively. Median survival after the first course of radiotherapy was 3.6 (0.3–13.4) years. Response to radiotherapy was observed in 548 (83.0 %) cases and CTCAE toxicity grade ≥ 3 was observed in 21 (3.2 %) cases. An increasing number of RT courses (HR: 1.30, p=<0.0001), Type 1 re-irradiation (HR 3.50, p = 0.008) and KPS ≤ 80 % (HR: 2.02, p = 0.002) were associated with significantly worse treatment responses. Toxicity rates remained stable with increasing numbers of RT courses. ConclusionMultiple courses of repeat radiotherapy maintain a favorable therapeutic ratio of high response combined with reasonable safety profile.

A Prospective Phase II Dose Escalation Study Using IMRT for High Risk N0M0 Prostate Cancer.

Published data supports the use of very high dose intensity modulated radiotherapy (IMRT) in achieving high efficacy and low toxicity for high-risk prostate cancer (HRPCa). This phase II multi-institutional non-randomized prospective dose escalation study using intensity modulated radiotherapy (IMRT) for high risk N0M0 prostate cancer was designed to investigate dose escalation using 1.8 Gy increments from baseline 75.6 Gy up to maximum 81 Gy, once dose volume constraints were adhered to. Inclusion criteria were patients undergoing a radical course of RT for high and very high-risk disease, defined as one or more of the criteria ≥ T3*, ≥ Gleason 8, Prostate specific antigen (PSA) > 20ng/ml. All patients received Androgen Deprivation Therapy (ADT) and none had radiological evidence of distant metastatic disease. The primary objective was to determine if dose escalated IMRT for high risk localized prostate cancer could provide freedom from biochemical relapse (BR; PSA rising > nadir +2ng/mL or initiation of salvage hormone therapy) similar to that reported in the literature. The Kaplan-Meier method was used to estimate survival times. Secondary objectives included OS, Disease Free Survival (DFS), and the incidence and severity of Genito-urinary (GU), Gastro-intestinal (GI) and erectile dysfunction (ED) toxicities (CTCAE v.3). Toxicities and performance status were collected and graded weekly during RT, 2 months after completing RT, 8 months' post RT, and 6 monthly thereafter to year five and annually thereafter to year nine. A total of 230 evaluable patients were enrolled between April 2009 and June 2016. The median follow-up was 7.3 years. The cumulative proportion of patients surviving without BR at 5 years was 91% (95% Confidence Interval (CI): 86% to 94%). Overall survival at 5 and 7 years was 92% (88% to 95%) and 89% (83% to 92%) respectively, while the cumulative proportion of patients free from disease was 89% (84% to 93%) at 5 years and 81% (75% to 86%) at 7 years. The incidence of acute G2 and G3 toxicities were; GU; 57.8% G2, 12.6% G3, GI; 15.2% G2, 0.4% G3, ED; 30.0% G2 and 61.7% G3. The incidence of late G2, G3 and G4 toxicities were; GU; 40.9% G2, 8.7% G3, GI; 36.5% G2, 2.2% G3, 0.4% G4, ED; 11.7% G2 and 86.1% G3. The percentage of patients receiving each dose level was; 3.5% received 75.6Gy in 42 fractions, 2.2% received 77.4Gy in 43 fractions, 93% received 81Gy in 45 fractions. The findings indicate that high-dose IMRT is well tolerated and is associated with excellent long-term tumor-control outcomes in patients with localized high and very high-risk prostate cancer, with 91% of patients surviving at 5 years without biochemical relapse. The rates of long term G3 GU and GI toxicity were low at 8.7% and 0.4% respectively.

Pencil Beam Scanning Proton Stereotactic Body Radiation Therapy (SBRT): A Robust Single Institution Experience

To describe the feasibility of treating a complex and diverse group of patients using pencil beam scanning (PBS) proton stereotactic body radiation therapy (SBRT: 5 or fewer fractions, with a fraction size of at least 5 Gy). Our center treats on average 105-120 PBS proton treatments daily, of which 9.5% of treatment courses are proton SBRT. Statistics of disease sites, treatment planning parameters (target volume, prescriptions, number of fields, SFO vs. MFO), and treatment efficiencies (scheduled time slots, actual treatment time) are presented for 305 consecutive SBRT patients receiving 1507 fractions in the past three years. Thermoplastic masks or Vacuum-lock bags are used to immobilize SBRT patients and index the patients' treatment position. Imaging guidance of orthogonal kV images and volumetric cone-beam CT is routinely used for patient setup. SBRT patients are grouped based on the target locations: pelvis (31%), liver (17%), thoracic (13%), spine (8%), abdominal (8%), brain (7%), non-spine bone (7%), ocular (6%), and head and neck (2%). Only 112 patients (37%) were receiving their 1st RT course, whereas 113 (37%) had one prior in-field RT course, and 80 (26%) had multiple prior in-field RT courses. The median [IQR] target volume was 65.4 [29.3, 168] cc (range: 0.3-2475 cc). 72% of cases were planned with SFO and 28% with MFO. On average, 3.76 fields (range: 2 to 12) were planned for each treatment. 44% of the treatments were planned with three or fewer fields, and 10% received more than five fields, most of which involved repainting for moving targets. Over 97% of treatments were delivered in 5 fractions, with ∼3% delivered in 3 fractions. The median [IQR] prescription per treatment was 8 [7, 10] Gy (range: 5-18 Gy per treatment). 85% (84%) of the SBRT treatments were scheduled (delivered) in a 45-minute or shorter slot, and 6% (7%) of treatments were scheduled (delivered) in over a one-hour slot, most commonly for multiple isocenter treatments. 93% of treatments were delivered within 15 minutes of the planned treatment time or shorter. Deep-inspiration breath-hold (DIBH) was applied to 45% of liver SBRT cases, with the remaining 55% planned on 4D CT with (14%) or without (86%) abdominal compression. DIBH was applied in 13% of lung SBRT cases. The application of other motion mitigation approaches, such as volumetric repainting, was determined by the target motion amplitude and whether the patient could tolerate DIBH. In the most diverse and largest proton SBRT experience delivered in the world over the past 3 years, over 300 patients were treated, demonstrating the feasibility and efficiency of delivering proton SBRT in a very busy center. The planning and treatment parameter statistics reported serve as a helpful reference for the proton community.

Hyperfractionated Reirradiation for Locally Recurrent Thoracic Tumors

For patients with locally recurrent thoracic tumors or second primaries within previously irradiated volumes, hyperfractionated reirradiation (re-RT) may mitigate late toxicity compared to conventional fractionation, but clinical outcomes have not been extensively studied. We herein report our institutional experience with thoracic hyperfractionated reirradiation. We identified 26 cases among 23 patients treated with re-RT to either primary or metastatic thoracic tumors, 60 Gy in 50 fractions, twice daily over 5 weeks using highly conformal image guided RT with motion management. Nineteen patients had dosimetry data available. The primary outcome was Grade (G2) or higher toxicity rates per CTCAEv5.0. Secondary endpoints were 12-month local control (LC), progression free survival (PFS)-determined by treating physician and/or multidisciplinary tumor board-and overall survival (OS). Median follow-up was 13 months. Half had non-small cell lung cancer, 95.8% had ultracentral tumors, 57.7% had single prior thoracic RT course; 38.5%, 11.5% and 11.5% received concurrent chemotherapy, immunotherapy, and targeted agents, respectively. Minimum and median intervals between RT courses were 10 and 39.5 months, respectively; 94.7% of re-irradiation plans had overlapping 80% isodose volumes. Median OS and PFS were 13 and 10 months, respectively. Crude 12-month LC was 73.1%. Of those with a recurrence, the first recurrence occurred locally in 6 (54.6%), regionally in 3 (27.3%), and distantly in 8 (72.7%) patients. ≥G2 and ≥G3 toxicity rates were 30.8% and 7.69%, respectively (one G3 atrial fibrillation; one G5 pneumonitis). Using the American Radium Society guidelines for thoracic reirradiation, only 10.5% met all dose volume constraint recommendations. Definitive hyperfractionated thoracic re-RT was well tolerated with promising local control. ≥G3 toxicities were rare. Patients should be counseled on the low but potential risk of life-threatening toxicity. Consensus guidelines for dose constraints may be difficult to meet in reirradiation setting; in this cohort, rates of severe toxicity were low despite exceeding putative constraints in most patients.

Adverse Events Relating to Radiation Therapy in Patients with Collagen Vascular Disorders

To evaluate treatment related toxicity in patients with collagen vascular disorder (CVD) undergoing contemporary radiotherapy. This is a retrospective cohort study of patients with CVD undergoing radiation therapy from 2005 to 2022 at a single institution. CVD evaluated included lupus, scleroderma, rheumatoid arthritis, and Sjogren's syndrome or other nonspecific CVD. Patient characteristics, diagnostic and treatment information were extracted from various institutional EMR systems. This study was designated the status of EXEMPT by the institutional IRB. A total of 40 patients undergoing 44 treatment courses with a minimum follow up of 3 months are included in this study. Among the 40 patients identified, 8 were male and 32 were female, with a median age of 62 (range, 17 to 88). Out of the 40 patients in our study, 30 were diagnosed with lupus, 6 with scleroderma, and 4 with other CVDs. In regard to treatments, 38 were performed for malignant conditions and 6 for benign conditions. Treatment locations included 10 to the head and neck region, 16 to the thorax, 6 to the pelvis, and 11 to the skin, soft tissue, or other locations. Treatment modalities were protons for 6 treatments, photons for 33 treatments, and electrons for 5 treatments. Ten patients also received chemotherapy concurrently. Median follow up time was 33.2 months. Table 1 illustrates the extent of skin and subcutaneous reaction by treatment region and radiation doses. One patient, who had Grade 3 radiation dermatitis, underwent a short break in RT due to severity of symptoms. Three patients experienced severe, painful lupus flares during the course of RT, but were managed by medication; however, one was hospitalized due to severe pain and blistering of the skin. Two patients experienced radiation related dermal thickening and fibrosis of the treatment area skin. Contemporary radiation techniques may allow for the treatment of patients with significant collagen vascular disorders. In general, the treatments are well tolerated with the most common side effects relating to skin and subcutaneous tissue or flare up in generalized symptoms. However, the time to resolution of these symptoms may be longer and requires diligent care. Caution should be used in treating patients with CVD.

Oncologic Outcomes and Safety after Spinal Re-Irradiation with Stereotactic Body Radiation Therapy

Management of spinal metastases that fail radiation therapy is a challenge, presenting a fine balance between the risk of pain and neurologic deficits if the tumor is not controlled and the increased risks associated with exceeding the tolerance of the spinal cord and other adjacent critical structures. Data regarding SBRT in the re-irradiation setting is limited. The purpose of this study was to report oncologic outcomes and toxicities for patients that received re-irradiation using SBRT. Patients treated with spine SBRT for re-irradiation at a target which overlapped or abutted a previous conventional RT or SBRT field at a single institution between 2010 and 2021 were retrospectively reviewed. The cumulative constraint to the neural avoidance structures were a BED3 ≤75 Gy (above the conus) or ≤106 Gy (below the conus) accounting for 25% repair at 6 months and 50% repair at 1 year following the first course of RT. Radiographic local recurrence was defined as progressive disease on CT and/or MRI in the treatment volume or at the margin of the treatment field compared with imaging studies before SBRT. Cumulative incidence of local recurrence was reported with death as a competing event, and overall survival was estimated with Kaplan-Meier. Toxicity grades were determined according to NCI CTCAE version 4.0. Ninety patients (225 vertebrae) with a median age of 56.5 years (range: 27-84 years) were included in the analyses. The most common histologies were NSCLC (17.7%), kidney (15.6%), prostate (14.4%), and breast (7.8%). The majority (51.1%) of metastases were in the T-spine, while 31.1% were in the L-spine and 13.3% in the C-spine. The median prescription dose was 27 Gy (range: 14-40 Gy) in a median of 3 fractions (range: 1-5). The median prescription isodose line was 59% (range: 48%-97%). The median time to re-irradiation with SBRT was 14 months (range: 1-89 months), and the most common prior spinal radiation dose was 30 Gy (range: 8-50 Gy) in a median of 5 fractions (range: 1-15). The median maximal BED3 of the spinal cord from prior radiation and re-irradiation were 52.6 Gy and 31.8 Gy, respectively. The median follow-up was 8.7 months (range: 0.4-43.9 months). The 6-month, 1-year, and 2-year local control rates were 88.9%, 83.4%, and 78.9%, respectively. Only 6.7% of patients underwent salvage surgery, at a median of 9 months after SBRT. The median overall survival was 14.0 months, and overall survival was 54.4% at 1 year and 27.8% at 2 years post-SBRT. All toxicities were grade < 2 and no patients developed spinal cord myelopathy. These data suggest excellent local control and low toxicity following SBRT for re-irradiation of spinal metastases. Future prospective and multi-institutional studies are needed to explore the optimal dose fractionation regimen and cumulative normal tissue constraints to maximize local control and minimize toxicity.

Pattern Analysis of Daily Lesion Volume Trajectories for Early Prediction of Glioblastoma Progression During MR-Linac Radiotherapy

Distinguishing between true progression (TP) and pseudoprogression (PP) post-radiotherapy (RT) is of paramount importance for treatment management of patients with glioblastoma (GBM). MR-Linac systems allow for daily monitoring of tumor changes throughout the course of RT. We hypothesized that the patterns of tumor volume change during RT may enable early prediction of treatment response. Using an IRB-approved prospective cohort of GBM patients undergoing 30 fractions of chemoRT to 60 Gy on a 0.35T MR-Linac, tumor/edema (tumor lesion) regions of interest (ROI) were contoured on daily T2-weighted treatment set-up scans. The obtained tumor lesion (TL) volume changes during treatment were smoothed with a moving average Gaussian window over time. Non-negative Matrix Factorization (NMF) was applied to the data matrix D (N x F), containing the trajectories in its rows for each patient, where N is the number of patients analyzed and F is the number of fractions. NMF represents D as a linear combination of three temporal (hidden) patterns and their weights in each individual trajectory. The same analysis was performed for ΔD, containing the changes in volumes with reference to the first fraction. The calculated weights were scaled in [0, 1], expressed as probabilities (by ℓ1-normalization) and used as features in Linear Discriminant Analysis (LDA). The LDA model was trained to differentiate between no progression (NP), PP and TP, and assessed by leave-one-subject-out cross-validation. Thirty-six patients were screened for inclusion: 9 were excluded due to no T2 lesion (resection cavity only). Of the remaining 27 GBM patients analyzed, 10 had no tumor growth on first post-RT diagnostic MRI, 6 were determined to have PP based on regression or long-term stability of findings, and 11 had TP due to continued progression of disease past 6 months, rapid patient death from disease, or tissue sampling showing active malignancy. With the use of only 2 features, LDA achieved an overall accuracy of 70.4% classifying correctly: 6 (60%), 4 (67%), and 9 (82%) patients with NP, PP, and TP, respectively. The temporal NMF patterns (monotonous decrease, rapid increase during the third part of the treatment, etc.) indicate that there is enough signal to classify patients' response based on the pattern tumor volume changes during RT. We identified tumor dynamics' patterns during RT, indicative of differential behavior of tumor growth between TP and PP. Although with a limited number of patients, these initial results suggest that tumor volume changes during treatment may provide early markers of treatment response. This could allow physicians to adapt/intensify treatment in real time for poorly responding patients. Next steps include automating the process of real-time tumor volume monitoring by incorporating a deep learning solution for automatic volume delineation on daily treatment set-up scans.

Brachial Plexus Tolerance to Standard Fractionation Re-Irradiation: The Ohio State University Experience

Factors contributing to brachial plexopathy (BPP) in the re-irradiation setting need further assessment. Preliminary work revealed that higher the doses and the use of concurrent cisplatin were associated with higher risk of BPP. Here, we expand our cohort and increase our follow-up duration, given the late nature of BPP development. Sixty-two BP sites with 41 patients (pts), treated between 2015 and 2020 for recurrent H&N cancer, were assessed. Contours and plans were reviewed via a prospective multidisciplinary chart rounds prior to treatment delivery and re-verified by two authors prior to this analysis. Kaplan-Meier and logistic regression were used to test the correlation between variables and outcomes. ROC was used to evaluate the cutoff values. Common terminology criteria of adverse events were used to define BPP. The median age of pts was 63 (29-78) and 65% were males. Median prescription dose was 70 Gy (60-70) for the 1st course and 66 Gy (44-70) for the 2nd course. 13% received intraoperative radiotherapy (IORT) during salvage treatment ranging from 10-15 Gy. 30% of pts in the 1st course and 80% in the 2nd course of pts had surgery. Concurrent chemotherapy was delivered to 71% of pts in the 1st course (Cisplatin 34%, Cetuximab 22%, Carboplatin +/- Paclitaxel 15%) and 76% in the 2nd course (Carboplatin/Paclitaxel 41%, Cisplatin 19%, Cetuximab 12%, Nivolumab 4%). The median interval between courses was 26.5 months (8-221). The median cumulative Dmax (0.03cc) and mean dose to the BP were 96.5 Gy (51-144) and 61.5 Gy (15-110), respectively. The median V60, V70, V80, V90, and V100 were 3.6cc (0.03-10.4), 2.4cc (0-9.9), 1.3cc (0-9.3), 0.6cc (0-8.4), and 0.0015cc (0-7.2), respectively. The median follow-up after the completion of the 2nd RT course was 19 months (1.4-71.5). The 1-yr incidence of BPP was 17%, with a median time to onset of 8.9 months (1-16.6). Factors associated with development of BPP were cumulative Dmax > 100 Gy (HR 1.06, [CI 1.014-1.1], p = 0.009), cumulative mean dose >70 Gy (HR 1.05, [CI 1.01-1.09], p = 0.03), V80 > 1.6cc (HR 1.2. [CI 0.99- 1.52], p = 0.06), V90 > 1cc (HR 1.3, [CI 1.013-1.58], p = 0.038), V100 > 0.3cc (HR 1.33, [1.044-1.69], p = 0.021) and the usage of concurrent cisplatin during the 2nd course (HR 8.9, [CI 2.36-33.75], p = 0.001). Other factors including gender, age, surgery, treatment interval between the two courses, IORT, V60, and V70 were not associated with increased risk of BPP. The incidence of grade 1, grade 2, and grade 3 BPP were 9.6%, 3% and 2.4%, respectively. The 1-yr OS was 70% and LC was 60%. At a median follow up of 19 months, the 1-yr incidence of grade 2 and 3 BPP was approximately 5%. Cisplatin during the 2nd course, cumulative metrics of Dmax 100 Gy, mean 70 Gy, V80 1.6cc, V90 1cc and V100 0.3cc were associated with development of BPP. Prospective study, longer follow up, and higher numbers are warranted. To our knowledge, this represents the largest cohort and longest follow up yet reported for BPP in the re-irradiation setting.

Clinical Outcomes and Dosimetric Predictive Factors in Patients Undergoing Reirradiation for Recurrent Meningiomas

Re-irradiation (reRT) of intracranial meningiomas is often limited by radiation tolerance of the surrounding normal tissue and the risk of side effects. Aim of this retrospective study is to report outcomes, toxicity and prognostic factors of reRT in a large cohort of patients with recurrent meningiomas (RM) treated with different RT techniques. A multi-institutional database of intracranial meningioma patients who recurred after prior radiation treatment was collected. Patients underwent reRT with one of the following techniques: radiosurgery (SRS), multi-fraction stereotactic radiotherapy (f-SRT), proton therapy (PT), Intensity-Modulated radiotherapy (IMRT) and External Beam radiotherapy (EBRT). Biologically Equivalent Doses in 2 Gy-fractions (EQD2) and Biological Effective Dose (BED) for surrounding normal tissue and tumor were estimated for each RT course, assuming an a/b = 2 for brain tissue and a/b = 4 for meningioma. Progression-free survival (PFS) was the primary outcome measure. Secondary outcomes were overall survival (OS) and treatment-related toxicity, according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Kaplan-Meier curves were used to estimate the effect of several parameters on PFS and on OS; Cox regression models assessed predictors of PFS and OS. Between 2003 and 2021, 181 patients (pts) were included. They were re-treated with SRS (n = 75; 41.4%), f-SRT (n = 63; 34.8%), PT (n = 31; 17.1%) and conventional radiotherapy (n = 12; 6.7%). 78 pts were identified with WHO Grade I disease, 65 pts with Grade II and 10 pts had Grade III disease. 28 pts without histologic sampling were included among Grade I patients for further analysis. Median age at re-irradiation was 62 (range 20-89) and median KPS 90 (range 60-100). After a median follow-up of 4.6 years (IQR 1.7-6.8), 3-year PFS was 51.6% and 3-year OS 72.5%. At univariate analysis Ki67 >5% (HR 2.81, 95% CI 1.48-5.34, p = 0.002) and WHO grade > I (HR 3.08, 95% CI 1.80-5.28, p< 0.001) were correlated with worse PFS, whereas f-SRT (HR 0.32, 95% CI 0.19-0.55, p<0.001), longer time to reRT (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) favorably correlated with PFS. At multivariate Cox analysis only f-SRT, time to reRT and tumor BED kept their statistically significant prognostic impact on 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 0.47 95% CI 0.26-0.83, p = 0.01, respectively). In addition, larger tumor GTV had a statistically significant higher risk of acute and late toxicity (p = .0.004 and p = 0.005, respectively). Reirradiation of RM progressing after previous RT seems to be feasible, with encouraging outcomes and an acceptable toxicity profile. Prognostic factors in the treatment-algorithm have been identified and should be adopted in clinical daily practice.

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

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. 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. 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. 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.

LMAP-15 INTRACRANIAL RADIOTHERAPY WITH TUCATINIB FOR BRAIN METASTASIS FROM HER2-POSITIVE BREAST CANCER: A SINGLE-INSTITUTION SERIES

Abstract BACKGROUND Tucatinib, a HER-2 TKI, has demonstrated intracranial efficacy in the HER2CLIMB study. Treatment of brain metastases frequently includes stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT); however, HER2CLIMB did not detail outcomes with RT. METHODS Patients who received tucatinib at our institution from 2020-2022 were identified. Patients who had brain metastases and received intracranial RT within 6 months of receiving tucatinib were included. Patients with history of prior leptomeningeal disease (LMD) were excluded. The Kaplan-Meier (KM) method was used to estimate intracranial failure (ICF), overall survival (OS), and local control (LC). Adverse events and details regarding symptomatic radionecrosis were collected. RESULTS Between 2020 and 2022, 50 patients were treated with tucatinib. Forty patients had diagnosed brain metastasis and received intracranial RT. Median age at tucatinib start was 51 years (range: 33-83). All patients were HER-2+, 47.5% were HR+. Fifty-four separate RT courses were delivered within 6 months of tucatinib, including 45 courses of stereotactic RT (83%) and 9 (17%) WBRT. Twenty-three patients (57.5%) underwent concurrent tucatinib and intracranial RT, defined as RT within 2 months of tucatinib initiation. Median follow up for surviving patients was 18.9 months. Fifteen patients (37%) died at the time of analysis. Median OS was 25.1 months with 24-month KM OS of 52%. Median time to ICF was 12.5 months with 24-month KM ICF of 48%. At the time of ICF, 7 patients (17.5%) developed LMD. In total, 132 discrete lesions were treated with SRS. Ten lesions (7.5%) underwent local failure, with 24-month KM LC of 82%. Three patients (9.1%) undergoing SRS developed symptomatic radionecrosis; all completely resolved with dexamethasone. DISCUSSION In this first series reporting outcomes with RT and tucatinib, no evidence of excess toxicity was noted. Intracranial control appears favorable compared to previous reports. Concurrent RT with tucatinib should be assessed prospectively.

Re-irradiation for head and neck cancer: outcome and toxicity analysis using a prospective single institution database.

Re-irradiation (re-RT) in head and neck cancer is challenging. This study prospectively explored the feasibility of re-RT in patients with loco-regionally recurrent or second primary head and neck cancer (LRR/SP HNC). From 2004 to 2021, 61 LRR/SP HNC patients were treated with re-RT, defined as having a second course of RT with curative intent resulting in a cumulative dose of ≥100 Gy in an overlapping volume. Postoperative or definitive dynamic intensity-modulated and/or volumetric modulated re-RT was administered using twice daily hyperfractionation to 60 Gy combined with cisplatin or carboplatin/5-fluorouracil. Overall survival (OS), progression-free survival (PFS), locoregional control (LRC) and distant metastasis control (DMC) were analyzed and prognostic factors evaluated. Toxicity was prospectively recorded and graded. The median follow-up was 9.8 months. In 41 patients (67.1%), complete administration of the intended treatment was not feasible. In 9 patients (15%) re-RT was interrupted prematurely and in other 9, the complete re-RT dose was lower than 60 Gy, and 37 patients (61%) could not receive or complete chemotherapy. Two-year OS, PFS and LRC rates were 19%, 18% and 30%, respectively. 20 patients (33%) received the complete intended treatment, and 1- and 2-year OS rates were 70% and 47%, respectively. Charlson comorbidity index was an important predictor for treatment completion. Multivariate analysis revealed recurrent N stage 0-1, age, chemotherapy administration and re-RT dose of 60 Gy as prognostic factors for clinical outcomes. No grade 5 re-RT-related toxicity was observed. The most common new grade ≥3 acute toxicities were dysphagia (52%) and mucositis (46%). Late toxicity included grade ≥3 dysphagia in 5% and osteoradionecrosis in 10% of evaluable patients, respectively. 6 patients (10%) were alive after 9 years without progression and no late toxicity grade ≥3, except for 2 patients presenting with osteoradionecrosis. Hyperfractionated re-RT with 60 Gy combined with platinum-based chemotherapy was a curative treatment option with acceptable toxicity in LRR/SP patients. Patients with higher comorbidity had a higher probability of failing to receive and complete the intended therapy. Consequently, they derived unsatisfactory benefits from re-RT, highlighting the importance of patient selection.

Radiation-induced mucositis: A retrospective study of dexamethasone-lidocaine-vitamin B12 mouth rinse versus compound chlorhexidine mouthwash in nasopharyngeal carcinoma

Oral mucositis causes substantial morbidity during head and neck radiotherapy, especially nasopharyngeal carcinoma. During radiotherapy, patients develop severe oral mucositis, which leads to oral pain and difficulty in eating and interruption of radiotherapy, affects the treatment effect and increase the probability of recurrence. Although we have explored various methods to reduce the mucosal damage caused by radiotherapy, these methods still cannot reduce pain caused by mucositis clinically. Therefore, the use of Dexamethasone-Lidocaine-Vitamin B12 Mouth rinse (DLVBM) proved its role in reducing oral mucosal pain, reducing the weight loss of patients, and completing radiotherapy according to the course of treatment. 133 patients with nasopharyngeal carcinoma who received radiotherapy (a total dose of 70 Gy) in our hospital from January to December 2020–2021 were selected. 67 patients received DLVBM treatment for mucositis reaction, and 66 patients received Compound chlorhexidine mouthwash (CCM) to deal with mucositis. Symptoms related to oral mucosal pain score and body weight, mucosal healing time were analyzed retrospectively. We found that patients with the DLVBM group significantly reduced oral pain and reduced weight loss. However, there was no significant difference about the mucosal healing time between the DLVBM group and CCM group. DLVBM may be moderately more effective in preventing radiation-induced mucositis and mucositis-related pain, and their use may lead to less frequent RT course interruptions from mucositis.

Dosimetric impact of adaptive proton therapy in head and neck cancer - A review.

Intensity Modulated Proton Therapy (IMPT) in head and neck cancer (HNC) is susceptible to anatomical changes and patient set-up inaccuracies during the radiotherapy course, which can cause discrepancies between planned and delivered dose. The discrepancies can be counteracted by adaptive replanning strategies. This article reviews the observed dosimetric impact of adaptive proton therapy (APT) and the timing to perform a plan adaptation in IMPT in HNC. A literature search of articles published in PubMed/MEDLINE, EMBASE and Web of Science from January 2010 to March 2022 was performed. Among a total of 59 records assessed for possible eligibility, ten articles were included in this review. Included studies reported on target coverage deterioration in IMPT plans during the RT course, which was recovered with the application of an APT approach. All APT plans showed an average improved target coverage for the high- and low-dose targets as compared to the accumulated dose on the planned plans. Dose improvements up to 2.5 Gy (3.5 %) and up to 4.0 Gy (7.1 %) in the D98 of the high- and low dose targets were observed with APT. Doses to the organs at risk (OARs) remained equal or decreased slightly after APT was applied. In the included studies, APT was largely performed once, which resulted in the largest target coverage improvement, but eventual additional APT improved the target coverage further. There is no data showing what is the most appropriate timing for APT. APT during IMPT for HNC patients improves target coverage. The largest improvement in target coverage was found with a single adaptive intervention, and an eventual second or more frequent APT application improved the target coverage further. Doses to the OARs remained equal or decreased slightly after applying APT. The most optimal timing for APT is yet to be determined.

Early effectiveness and toxicity outcomes of reirradiation after breast conserving surgery for recurrent or new primary breast cancer

Breast reirradiation (reRT) after breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy for women presenting with recurrent or new primary breast cancer. There are limited data on safety of different fractionation regimens. This study reports safety and efficacy among women treated with repeat BCS and reRT. Patients who underwent repeat BCS followed by RT from 2015 to 2021 at 2 institutions were analyzed. Univariate logistic regression models were used to identify predictors of acute and late toxicities. Kaplan-Meier estimates were used to evaluate overall survival (OS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LR-RFS). Sixty-six patients were reviewed with median follow-up of 16months (range: 3-60months). At time of first recurrence, 41% had invasive carcinoma with a ductal carcinoma in situ (DCIS) component, 41% had invasive carcinoma alone and 18% had DCIS alone. All were clinically node negative. For the reirradiation course, 95% received partial breast irradiation (PBI) (57.5% with 1.5Gy BID; 27% with 1.8Gy daily; 10.5% with hypofractionation), and 5% received whole breast irradiation (1.8-2Gy/fx), all of whom had received PBI for initial course. One patient experienced grade 3 fibrosis, and one patient experienced grade 3 telangiectasia. None had grade 4 or higher late adverse events. We found no association between the fractionation of the second course of RT or the cumulative dose (measured as EQD2) with acute or late toxicity. At 2years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%. In this series of patients with recurrent or new primary breast cancer, a second breast conservation surgery followed by reirradiation was effective with no local recurrences and an acceptable toxicity profile across a range of available fractionation regimens at a median follow up of 16months. Longer follow up is required.