Median Cumulative Dose Research Articles

Neoadjuvant Therapy Regimens for Hilar Cholangiocarcinoma Before Liver Transplant.

Patients with unresectable hilar cholangiocarcinoma (hCCA) may be eligible for curative treatment through liver transplantation (LT). Neoadjuvant protocols often include radiotherapy (RT), however, there is no standard RT approach. The purpose of this study is to characterize practice patterns of RT use before transplantation for hCCA. A survey was administered to radiation oncologists practicing at LT centers identified through the U.S. Organ Procurement and Transplant Network and the International Cholangiocarcinoma Research Network. The survey consisted of 13 questions regarding RT details as well as approaches to systemic therapy. For cross-regimen comparison, the cumulative RT tumor dose was standardized using the EQD2 method. Twenty-three centers utilizing neoadjuvant therapy for hCCA were identified. Most respondents (96%) use both chemotherapy and RT as part of their protocol. Elective nodal volumes commonly included the portal vein lymph nodes (91%) and celiac artery lymph nodes (70%). After an initial 45 Gy plan, a wide range of sequential boost regimens was used. The median cumulative dose including boosts to the gross disease was 58 Gy (EQD2) with a wide range of 40 to 110 Gy. Five (22%) include brachytherapy as part of their treatment plan. The majority (96%) used concurrent chemotherapy with fluoropyrimidines. These results suggest significant variability of neoadjuvant RT use for hCCA before LT. A wide range of doses and fractionation schemes are utilized with cumulative doses ranging from 40 to 110 Gy (EQD2). A further study evaluating the efficacy and toxicity of these various approaches is warranted to better inform best practices.

Obinutuzumab Can Be Administered as a 90-minute Short Duration Infusion in Patients With Previously Untreated Follicular Lymphoma: GAZELLE End of Induction Analysis.

Obinutuzumab Can Be Administered as a 90-minute Short Duration Infusion in Patients With Previously Untreated Follicular Lymphoma: GAZELLE End of Induction Analysis.

Low incidence of cardiotoxicity in patients with non-Hodgkin lymphoma receiving EPOCH after prior anthracycline exposure.

To describe the incidence of cardiotoxicity in patients with anthracycline exposure who subsequently receive EPOCH for non-Hodgkin lymphoma (NHL). We conducted a retrospective cohort study of adults with anthracycline exposure who subsequently received EPOCH for NHL at Memorial Sloan Kettering Cancer Center. The primary outcome was cumulative incidence of arrhythmia, heart failure (HF), left ventricular (LV) dysfunction, or cardiac death. Among 140 patients, most had diffuse large B-cell lymphoma. Inclusive of EPOCH, median cumulative doxorubicin-equivalent dose was 364 mg/m2 ; exposure was 400 mg/m2 or higher in 41%. With median 36-month follow-up, 23 cardiac events were noted in 20 patients. Cumulative incidence of cardiac events at 60 months was 15% (95% confidence interval [CI]: 9%-21%). When limited to LV dysfunction/HF, cumulative incidence at 60 months was 7% (95% CI: 3%-13%), with most events occurring after the first year. Univariate analysis indicated only history of cardiac disease and dyslipidemia to be associated with cardiotoxicity; no other risk factors, including cumulative anthracycline dose, were identified. In this retrospective cohort, representing the largest experience in this setting with extended follow-up, cumulative incidence of cardiac events was low. Rates of LV dysfunction or HF were particularly low, suggesting infusional administration may mitigate risk despite prior exposure.

Ovarian Stimulation Does Not Induce Thyrotropin Receptor Autoantibodies in Women with Thyroid Autoimmunity.

Women of subfertile couples with thyroid autoimmunity (TAI) have an increased risk of miscarriage when pregnant after an assisted reproductive technology (ART) treatment. This might amongst others be due to the presence of thyrotropin receptor antibodies (TSH-R-Ab) that can impede the development of the corpus luteum. TSH-R-Ab can be present in women with TAI and/or be induced by the ovarian stimulation procedure (OS) that is performed to initiate the ART. In this prospective pilot study, we determined the presence of both binding and functional TSH-R-Ab (stimulating or blocking) with five different assays before and after OS in ten women (eleven cycles) with TAI of subfertile couples and in one woman without TAI. Mean (SD) age was 38.8 (±3.2) years, median (range) cumulative OS dose 1413 (613-2925) IU/L. Median baseline serum levels of thyrotropin, free thyroxine, and thyro-peroxidase antibodies were 2.33 (2.23-2.61) mIU/L, 16.8 (14.4-18.5) pmol/L and 152 (86-326) kIU/L, respectively. Oestradiol levels increased during OS from 40 (26-56) ng/L to 963 (383-5095) ng/L; p < 0.01. TSH-R-Ab measurements in all subject samples were below the cut-off of the corresponding immunoassay and four bioassays before or after OS.

Association of Perioperative Cryoprecipitate Transfusion and Mortality After Cardiac Surgery

BackgroundCryoprecipitate is often transfused in patients undergoing cardiac surgery. However, its safety and effectiveness remain uncertain. MethodsThis study was a propensity score–matched analysis of data from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database. The study included adults undergoing cardiac surgery between 2005 and 2018 across 38 sites. The association between perioperative cryoprecipitate transfusion and clinical outcomes was estimated, with a primary outcome of operative mortality. ResultsOf 119,132 eligible patients, 11,239 (9.43%) patients received cryoprecipitate. The median cumulative dose was 8 U (interquartile range, 5-10 U). After propensity score matching, we matched 9055 cryoprecipitate recipients to 9055 control subjects. Postoperative cryoprecipitate transfusion was associated with reduced operative mortality (odds ratio [OR], 0.82; 99% CI, 0.69-0.97; P = .002) and long-term mortality (hazard ratio, 0.92; 99% CI, 0.87-0.97; P = .0042). It was also associated with a reduction in acute kidney injury (OR, 0.85; 99% CI, 0.73-0.98; P = .0037) and all-cause infection (OR, 0.77; 99% CI, 0.67-0.88; P < .0001). These findings were observed despite increased rates of return to the operating room (OR, 1.36; 99% CI, 1.22-1.51; P < .0001) and cumulative 4-hour postoperative chest tube output (adjusted mean difference in mL, 97.69; 99% CI, 81.65;113.74; P < .0001). ConclusionsIn a large, multicenter cohort study and after propensity score matching, perioperative transfusion of cryoprecipitate was associated with reduced operative and long-term mortality.

Proton beam therapy in repeat irradiation of recurrent head and neck tumors: analysis of short-term results

Introduction. Recurrence of head and neck tumors occurs in 50 % of cases and usually has locoregional character. Due to the characteristics of dose distribution, proton beam therapy is a promising treatment option for patients with recurrences of tumors in this location who previously underwent radiation therapy.Aim. To evaluate the effectiveness and tolerability of repeat irradiation using active scanning proton beam therapy in patients with recurrent head and neck tumors who previously underwent radiation therapy.Materials and methods. Between November of 2015 and December of 2020, 40 patients with locoregional recurrence of head and neck tumors underwent treatment using active scanning proton beam therapy at the A. F . Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center. Median cumulative dose of primary irradiation was 64.5 Gy. Median time between primary and repeat irradiation was 35.7 months, mean irradiated volume of the repeat course was 94.5 cm3. Proton beam therapy was performed using standard mode (2 isoGy) and accelerated hypofractionation (2.4 isoGy / 3 isoGy) with mean equivalent cumulative dose of 56.4 Gy (α / β = 10). Radiation toxicity was evaluated using the Radiation Therapy Oncology Group European (RTOG) / Organization for Research and Treatment of Cancer (EORTC) scale.Results. Treatment response was achieved in 34 (85 %) patients: in 17 (42.5 %) patients, stable disease was observed; in 10 (25 %) patients, partial response was observed; and in 7 (17.5 %) patients, complete response was observed. In 6 (15 %) cases, disease progression was diagnosed at first follow-up examination. One- and two-year locoregional control, progression-free survival and overall survival were 58.4 / 19.8; 44.5 / 19.8 and 82.3 / 38.8 % respectively with median follow-up duration of 14.2 months. Median survival was 19.5 months. Grade III and above early radiation toxicity was observed in 3 (7.5 %) patients. In total, 6 (15 %) cases of grade III complications and 2 (5 %) episodes of carotid artery rupture leading to death were observed. Overall frequency of complications of grade III and higher was 20 %.Conclusion. Repeat irradiation using proton beam therapy can be considered an effective and safe treatment method for patients with recurrent head and neck tumors. Dosimetric and radiobiological benefits of proton beams allow to achieve balance between high doses and radiation exposure in previously irradiated tissues.

Acute Kidney Injury in the ICU during Ganciclovir Treatment, an Observational Study

The aim of this study is to investigate the relationship between ganciclovir exposure with TDM and the development of AKI in ICU patients. This retrospective single-center observational cohort study included adult ICU patients treated with ganciclovir who had a minimum of one ganciclovir trough serum level. Patients receiving less than two days of treatment and patients with fewer than two measurements of serum creatinine, RIFLE scores, and/or renal SOFA scores were excluded. Acute kidney injury incidence was assessed with the difference between the final and first values of the renal SOFA score, RIFLE score, and serum creatinine. Nonparametric statistical tests were performed. In addition, the clinical relevance of these results was evaluated. A total of 64 patients were included with a median cumulative dose of 3150 mg. The mean difference in serum creatinine during ganciclovir treatment was reduced by 7.3 μmol/L (p = 0.143). The RIFLE score decreased by 0.04 (p = 0.912), and the renal SOFA score was reduced by 0.07 (p = 0.551). This single-center observational cohort study showed that ICU patients using ganciclovir with TDM-guided dosing did not develop acute kidney injury as measured by serum creatinine, RIFLE score, and renal SOFA score.

Linear association between radioactive iodine dose and second primary malignancy risk in thyroid cancer.

We aimed to investigate whether the risk of second primary malignancy (SPM) in patients with thyroid cancer (TC) receiving radioactive iodine (RAI) therapy rises in a cumulative, dose-dependent manner compared with those not undergoing RAI. Using the Korean National Health Insurance Service National Health Information Database (2002-2019), we investigated hazard ratios of SPM associated with RAI in TC. SPM was defined as a second primary malignancy diagnosed at least 1 year after TC diagnosis. Of 217 777 patients with TC (177 385 women and 40 392 men; mean [SD] age, 47.2 [11.6] years), 100 448 (46.1%) received RAI therapy. The median (IQR) follow-up duration was 7.7 (5.5-10.3) years, and the median (IQR) cumulative RAI dose was 3.7 (1.9-5.6) GBq. From 2004 to 2019, SPM incidence rates were 7.30 and 6.56 per 1000 person-years in the RAI and non-RAI groups, respectively, with an unadjusted hazard ratio of 1.09 (95% confidence interval = 1.05 to 1.13); this rate remained at 1.08 (95% confidence interval = 1.04 to 1.13) after adjustment for multiple clinical confounding factors. Notably, SPM risk increased significantly, from 3.7 GBq with full adjustments, and a strong linear association between cumulative RAI dose and SPM was observed in the restricted cubic spline analysis. Regarding cancer subtypes, myeloid leukemia and salivary gland, trachea, lung and bronchus, uterus, and prostate cancers were the most significantly elevated risks in patients who underwent RAI therapy. This study identified that SPM risk increased linearly in a dose-dependent manner in patients with TC undergoing RAI therapy compared with those not undergoing RAI therapy.

Postnatal corticosteroids and developmental outcomes in extremely preterm or extremely low birth weight infants: The Victorian Infant Collaborative Study 2016-17 cohort.

Systemic postnatal corticosteroids are used to treat or prevent bronchopulmonary dysplasia (BPD) in extremely preterm (EP) or extremely low birth weight (ELBW) infants but are associated with long-term harm. We aimed to assess the relationship between cumulative postnatal corticosteroid dose and neurodevelopmental outcomes. Longitudinal cohort study of all EP/ELBW livebirths in Victoria, Australia 2016-2017. Perinatal data were collected prospectively. Neurodevelopmental assessment was performed at 2 years' corrected age. Linear and logistic regression were used to determine relationships between cumulative corticosteroid dose and neurodevelopment, adjusted for gestational age, birth weight, sex and major intraventricular haemorrhage. Seventy-six EP/ELBW infants received postnatal corticosteroids to treat or prevent BPD, 62/65 survivors were seen at 2 years. Median (IQR) cumulative postnatal corticosteroid dose was 1.36 (0.92-3.45) mg/kg dexamethasone equivalent. Higher cumulative corticosteroid dose was associated with increased odds of cerebral palsy, adjusted OR (95% CI) 1.47 (1.04, 2.07). Higher cumulative corticosteroid dose was also associated with lower cognitive and motor developmental scores, however, this weakened after adjustment for confounding variables: cognitive composite score adjusted coefficient (95% CI) -1.3 (-2.7, 0.1) and motor composite score adjusted coefficient (95% CI) -1.3 (-2.8, 0.2). Higher cumulative postnatal corticosteroid dose in EP/ELBW infants is associated with increased odds of cerebral palsy at 2 years' corrected age. Adequately powered studies are needed to assess the independent effects of cumulative steroid dose on neurodevelopmental outcomes.

Real-world Outcomes With Cumulative Bortezomib Dose and Efficacy in the Treatment of Transplant-ineligible Multiple Myeloma With Cyclophosphamide, Bortezomib, and Dexamethasone.

Higher cumulative dose of bortezomib, a key component of Multiple Myeloma (MM) treatment regimens, has been shown to improve outcomes in MM patients, but must be balanced with toxicities including peripheral neuropathy. In this study, we studied the effect of cumulative bortezomib dose on survival, depth of response, and discontinuation rate in transplant ineligible MM patients. Data from 70 patients treated with Cyclophsophamide, Bortezomib, and Dexamethasone (CyBorD) in a single Canadian center were grouped according to above vs below median cumulative bortezomib dose and analyzed for progression-free survival (PFS), overall survival (OS), depth of response, and discontinuation rate. There was a trend for lower discontinuation rate (45.7% vs. 68.6%, P=.052) and significantly lower rate of neuropathy-related discontinuation (5.7% vs. 22.9%, P=.035) in patients who received higher than 43.1 mg/m² of bortezomib. The higher-dose group showed a trend for higher rate of complete response (14.3% vs. 5.7%, P=.225) and significantly higher rate of very good partial response or better (77.1% vs. 51.4%, P=.024). There was significantly longer PFS (24.3 vs. 9.1 months, P=.012) and a trend for longer OS (22.4 vs. 61.3 months, P=.061) in the higher-dose group. In landmark analysis after 180 days, PFS (23.5 vs. 24.3 months, P=.941) and OS were similar in both groups. Higher cumulative bortezomib dose showed a lower rate of discontinuation, longer survival, and deeper response. Determining risk of treatment intolerance remains important for treatment.

Safety and efficacy of high-dose clobetasol propionate 0.05% in cutaneous lichen planus.

Cutaneous lichen planus is a highly pruritic dermatosis with an unmet need in its management. The aim of this study was to evaluate the short-term effect and tolerance of high doses of clobetasol propionate 0.05% in cutaneous lichen planus. We conducted a single-center retrospective cohort study from 2017 to 2021. All adults treated with high-dose (>5g/day) clobetasol propionate 0.05% for cutaneous lichen planus were included. Patients with less than 10% affected body surface area at initial presentation or who received concomitant systemic therapy were excluded. The primary endpoint was the rate of complete remission by week 16. Secondary endpoints included maximum daily and median cumulative doses, reduction in pruritus and occurrence of adverse events. Fifty-seven patients, 60% female, with a mean age of 48 years (min-max,18-83) were included. Cutaneous lichen planus had been present for a median duration of 2months at initial presentation (min-max, 1-4) and involved a median body surface area of 27%. Pruritus was reported by 55/57 (96%) patients. At week 16, 41/57 (72%) patients had achieved complete remission without treatment modification, among whom 25/41 (61%) had achieved it at week 6. The median daily and cumulative doses were, respectively, 20 g/day (IQR, 10-20) and 560 g (IQR, 320-925). Three patients experienced mild adverse events. No statistical association was demonstrated between the duration of the disease before treatment initiation and clinical response. In conclusion, high-dose clobetasol propionate 0.05% seems to be an effective, well-tolerated, and easy-to-implement treatment for cutaneous lichen planus.

797: SEDATION PRACTICES IN COVID-19 VERSUS NON-COVID-19 ACUTE RESPIRATORY DISTRESS SYNDROME PATIENTS

Introduction: Coronavirus disease 2019-associated acute respiratory distress syndrome (CARDS) has been associated with high opioid and sedative requirements in patients requiring mechanical ventilation (MV). The purpose of this study was to characterize opioid and sedative use in patients with CARDS compared to those with non-CARDS. Methods: A retrospective cohort study compared adult patients admitted to an intensive care unit (ICU) on MV with CARDS or non-CARDS between January 2018 and May 2020. Patients receiving at least one opioid or sedative infusion for at least 48 hrs were included. Patients were excluded if they were transferred from an outside hospital while on MV, deemed comfort care, admitted for status epilepticus, ischemic, or hemorrhagic stroke and/or cardiac arrest, admitted with a tracheostomy, or received extracorporeal membrane oxygenation. Statistical analysis was conducted using descriptive statistics with the appropriate statistical tests depending on the distribution type. The primary objective was to compare the use of opioid and sedative agents administered to patients with CARDS and non-CARDS. Secondary objectives included neuromuscular blocking agent (NMBA) use, time on mechanical ventilation (MV), in-hospital and ICU length of stay (LOS). Results: A total of 59 CARDS and 19 non-CARDS patients were included. Opioid infusions were used in 100% of non-CARDS patients and 98% of CARDS patients during the first 10 days of MV (p=0.57). There was significantly higher use of propofol in CARDS patients compared to non-CARDS patients (100% vs 89%, p=0.01) and higher median daily dose (3847mg vs 2992mg; p=0.018). No difference in median cumulative dose of BZD was observed in the CARDS group vs non-CARDS group (50mg vs 9mg; p=0.131). Time on mechanical ventilation was significantly longer in the CARDS group compared to the non-CARDS group (17 days vs 11 days, p=0.003). Comparably, 73% of CARDS received NMBA vs 53% in non-CARDS, p=0.05. There was significantly higher in-hospital LOS (36 days vs 48 days, p=0.005) and ICU LOS (15 days vs 31 days, p=0.002) in the CARDS group compared to the non- CARDS group. Conclusions: Patients with CARDS were more likely to receive NMBA and required higher dosages of propofol. CARDS patients were on MV longer and had longer hospital and ICU LOS.

1660. Dalbavancin Utilization Registry Investigating Value and Effectiveness (DRIVE): Outcomes Report on Real-World Use

Abstract Background Dalbavancin (dalba), a long-acting lipoglycopeptide approved by the US FDA and EMA for acute bacterial skin and skin structure infections (ABSSSI) has potent activity against Gram-positive pathogens including MRSA. We describe the real-world use of dalba in patients with ABSSSI, bloodstream infections (BSI), bone and joint infection (BJI), or other infections (OI) from a retrospective registry study of dalba. Methods Dalbavancin Utilization Registry Investigating Value and Effectiveness (DRIVE) was a phase 4 observational, multicenter, retrospective cohort study of the real-world use of dalba in adults geographically spread across the US. Patients were treated entirely at the physicians’ discretion. Data were collected from 25 Mar 2017–27 Nov 2018 and included patient demographics, diagnosis, microbiology, antibiotic use, clinical outcome, and safety until 60 days after last dalba dose. A post hoc analysis applied definitions for clinical success and failure similar to the dalba phase 3 clinical trials. Results The Safety Population comprised 1168 patients treated at 31 healthcare sites. Of 957 evaluable patients, 815 (85.2%) had ABSSSI, 48 (5.0%) had BSI, 87 (9.0%) had BJI, and 7 (0.7%) had OI. Clinical success was achieved in 91.7%, 89.6%, 86.2%, and 100% of patients with ABSSSI, BSI, BJI, and OI, respectively (Figure 1). Median cumulative dose of dalba for the index infection was 1500 mg for all categories, most commonly as 1 infusion (86.7% ABSSSI, 63.1% BSI, 41.4% BJI, 37.5% OI; Figure 2). 36.9% of patients with BSI and 58.6% with BJI received ≥ 2 infusions. Most patients were treated as outpatients (87.8%, 76.9%, 89.2%, 100%, with ABSSSI, BSI, BJI, and OI, respectively). Mean (SD) total cost of care associated with dalba use (medications, hospital stay, surgeries/procedures) was 5261.2 (1604.55), 7710.5 (7144.1), 8393.5 (5296.8), and 6305.8 (3338.1) USD for patients with ABSSSI, BSI, BJI, and OI, respectively. Adverse events evaluated as possibly related to dalba were reported in 33/1168 (2.8%) patients: 29 (2.9%) with ABSSSI, and 4 (3.6%) with BJI. Conclusion Dalba demonstrated high rates of clinical success and safety in the real-world setting when used to treat patients for suspected or confirmed Gram-positive infections. Disclosures Bruce M. Jones, Pharm.D., FIDSA, BCPS, AbbVie: Advisor/Consultant|AbbVie: Honoraria|La Jolla: Honoraria|Melinta: Advisor/Consultant|Paratek: Honoraria|Regeneron: Honoraria Kerry O. Cleveland, MD, AbbVie: Honoraria|Cumberland: Honoraria|Merck: Honoraria|Pfizer: Honoraria Pedro L. Gonzalez, MD, MT, AbbVie: Employee of AbbVie at the time of study conduct and analysis.|AbbVie: Stocks/Bonds|Becton Dickinson: Employee Urania Rappo, MD, AbbVie: Employee of Allergan, before its acquisition by AbbVie, at the time of study conduct and analysis|BiomX: Employee Todd Riccobene, PhD, AbbVie: Employee|AbbVie: Stocks/Bonds Rosie D. Lyles, MD, MHA, MSc, AbbVie: AbbVie Employee|AbbVie: Stocks/Bonds.

PSAT261 Use of Steroids Pre- and Post-Teprotumumab in Thyroid Eye Disease Patients

Abstract Background Thyroid eye disease (TED), an autoimmune disease, causes inflammation of the periorbital fat and muscle often leading to eye-bulging (proptosis), double-vision (diplopia), pain, redness and swelling. Steroids are effective in reducing inflammation, but have limited efficacy for proptosis and diplopia, and higher doses can be associated with adverse effects. Teprotumumab, an anti-insulin like growth factor-1 receptor inhibitory antibody, demonstrates significant improvements in proptosis, diplopia and inflammatory symptoms.1 Here we examined steroid use in the period leading up to, and the period after a full course of teprotumumab. Methods Deidentified claims data (IQVIA) from patients completing 8 infusions of teprotumumab (full course) before Dec 31, 2020 were examined for steroid use before and after treatment. To ensure that claims data were adequately captured, patients must have been in the database for at least 1 year before and 6 months after teprotumumab and have had a claim within 4 months of the first dose. The median cumulative dose of steroids (prednisone equivalent) was also determined. Results 565 patients met the inclusion criteria with a mean age of 59.5 (13.3) years. 407 (72%) were female and 158 (28%) were male. 460 (81%) had ≥1 steroid prescription at any time before, during, or after teprotumumab within 69 months before teprotumumab and 16 months afterward with 78% use before, 10% use during and 25% after. 314 (56%) had ≥1 steroid prescription within 1 year before or 6 months after a course of teprotumumab. Of 283 patients who received steroids within 1 year pre-teprotumumab, the median cumulative dose per patient (MCDPP) increased from 295 to 607 mg 3-0 months prior to teprotumumab initiation and 82% (233) stopped steroid use after teprotumumab initiation. The MCDPP decreased by 80% (607mg to 120mg) in the 0-3 months pre-teprotumumab to 3-6 months post-teprotumumab. Finally, the number of patients receiving steroids 3-6 months after teprotumumab decreased by 74% from 3-0 months pre-teprotumumab. Conclusions While reasons for the escalating incidence, and magnitude, of steroid use pre-teprotumumab and reduced use post-teprotumumab could not be definitively determined, remote steroid use increased up until teprotumumab initiation with a majority of patients who had a steroid in the year preceding teprotumumab having no steroid use in the 6 months after teprotumumab. Further, the number of patients receiving steroids and the median cumulative dose of steroids post-teprotumumab was reduced by more than 70% and 80%, respectively from pre-teprotumumab doses, indicating that teprotumumab is a steroid sparing agent. Follow-up analyses will confirm the duration of this effect. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Pulsed Reduced Dose Rate (PRDR) Intensity Modulated Radiotherapy for Recurrent Primary Central Nervous System Malignancies: Dosimetric and Clinical Results

<h3>Purpose/Objective(s)</h3> Pulsed reduced dose rate (PRDR) intensity-modulated radiotherapy (IMRT) is a reirradiation approach that may reduce the risk of toxicities in the setting of prior radiotherapy (RT) for recurrent central nervous system (CNS) malignancies. However, toxicities and cumulative doses (in EQD2) to CNS structures are not uniformly reported. We shared our institutional outcomes of PRDR and reported cumulative doses for CNS organs-at-risk (OARs) <h3>Materials/Methods</h3> Consecutive patients diagnosed with recurrent primary CNS tumors treated with PRDR from April 2017 to September 2021 were evaluated. Data collected included number of prior interventions, diagnosis, tumor grade, RT dose and fractionation, cumulative OAR doses, progression-free survival (PFS), overall survival (OS), and adverse events. A systematic review of literature was also performed, and results were compared to this study. <h3>Results</h3> Eighteen patients met inclusion criteria (11 WHO grade 4 glioma, 6 grade 3 glioma, and 1 grade 2 glioma). All patients had at least 1 surgery (range 1-4) and 2 systemic therapy regimens (range 2-6) before PRDR. The median dose for the first course of RT was 59.4 Gy (range: 50-75 Gy) in 33 fractions and the median time from the initial RT to PRDR was 35.6 months (range: 7.0-122.0 months). The median PRDR dose was 45 Gy (range: 36-59.4 Gy) in 25 fractions; the median cumulative EQD2 dose was 107.6 Gy (93.1-132.5 Gy). The median target volume was 134.9 cc (range: 17.9-696.6 cc). The median cumulative EQD2 Dmax values for the brain and brainstem were 111.4 Gy (range: 82.4-175.2 Gy), and 85.4 Gy (range: 14.8-111.6 Gy). At a median follow-up of 6.2 months, grade 2+ treatment-related toxicities were seen in 12 (66.7%) patients. Symptomatic radiation necrosis occurred in 3 (16.7%) patients, the median EQD2 brain Dmax for these patients was 115.9 Gy (110.4-156.7 Gy). In addition, two patients had grade 3 toxicity (fatigue and hearing impairment); no Grade 4+ toxicities were observed. The median PFS and OS after PRDR were 6.3 months (95% Cl: 0.9-11.6 months) and 8.6 months (95% Cl: 4.9-12.3 months), respectively. The systematic review analyzed 5 peer-reviewed studies reporting outcomes for reirradiation with PRDR for 188 patients. The median PRDR dose was 50 Gy (range: 22-60 Gy) in 25 fractions with a median cumulative dose of 110.3 Gy to a median tumor volume of 369.1 cc. At a median follow-up of 8.7 months, the total number of grade 3+ toxicities was 24, but time-dependent analyses were not uniformly reported. <h3>Conclusion</h3> This study supports PRDR reirradiation as a feasible and appropriate strategy for recurrent primary CNS tumors where other options have been exhausted. Despite high cumulative EQD2 to the OARs, the risk of developing high-grade toxicities remains acceptable; the median cumulative brain EQD2 dose for developing necrosis is 115.9 Gy.

Clinical Outcomes in Patients Receiving Pencil Beam Proton Re-Irradiation for New or Locoregionally Recurrent Breast Cancer

<h3>Purpose/Objective(s)</h3> Local-regional recurrence of breast cancer (BC) after prior radiation (RT) presents clinical and dosimetric challenges. Proton beam therapy (PBT), and in particular pencil beam scanning (PBS), offers a unique dosimetric advantage due to its lack of exit dose and high conformality, which may allow safer delivery of a second RT course. Recently, there has been a retrospective report of 46 patients (pts) treated with uniform or PBS PBT. Here, we present the largest series to date using PBS PBT. We analyzed treatment patterns, toxicities, and clinical outcomes of BC pts receiving PBS-proton reradiating (reRT). Our hypothesis was that PBS PBT reRT to breast/chest wall (CW) provides reasonable local control (LC) and toxicities. <h3>Materials/Methods</h3> A single-institution retrospective IRB-approved analysis was conducted of all pts who underwent reRT for recurrent or new BC, between 4/2017 and 11/2021. Descriptive statistics were used to describe pt, tumor and treatment characteristics. Local failure-free survival (LFFS), distant metastasis-free survival (DMFS), and overall survival (OS) were measured from reRT start to the first event, by Kaplan-Meier method. Pts who remained alive were censored at last follow-up. Toxicities were scored according to CTCAE v4.0. Comparisons of pts, tumor, and treatment characteristics between those with any grade ≥ 3 acute toxicity (AT) or any late toxicity (LT) vs. none were performed using two-sample t-tests and chi-square tests. Multivariable analysis for LFFS and OS was conducted using cox-proportional hazards models. Statistical software used for analysis. <h3>Results</h3> A total of 68 pts with breast/CW reRT with PBS PBT were identified. Only pts who completed treatment were included in analyses (3 pts were excluded; final N=65). Median follow-up was 26.6 months. The median age was 61 yrs (range 30-89). 60% of pts were white, 32% black and 8% from other races. 65% of treated BCs were hormone positive, 1% HER2/neu enriched and 34% triple negative. Median time between initial and reRT was 52 months (range 6-328). Median cumulative previous RT dose (EQD2) was 48.4 Gy (range 43.2-66.0). Median cumulative PBS PBT dose (EQD2) was 57.0 Gy (range 30.2-76.9). 8 pts (12%) underwent BID treatment, 22 pts (34%) received concurrent hyperthermia and 13 pts (20%) underwent concurrent chemotherapy. 14 pts (22%) experienced grade 3 AT, including 13 dermatitis (20%) and 1 fatigue and pain (1.5%). No grade 4/5 toxicities were observed. 6 pts were lost in follow-up. 33 pts (56%) experienced any grade LT (skin changes [N=21; 36%], soft tissue fibrosis [N=7; 12%], CW discomfort [N=10; 17%], arm discomfort [N=6; 10%], lymphedema [N=11; 19%] and rib fracture [N=3; 5%]). At 2 yrs, LFFS=93% and DMFS=88%. OS was 89%. No explanatory variables were associated with toxicity or survival outcomes <h3>Conclusion</h3> Our analysis indicates that PBS PBT reRT for BC is well tolerated and offers meaningful rates of LC, toxicities and survival.

EUSOM: Phase 2 Trial of Avasopasem Manganese (GC4419) for Oral Mucositis in Patients Receiving Chemoradiotherapy for Locally Advanced, Nonmetastatic Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> Severe oral mucositis (SOM; gr 3–4 on the WHO scale) occurs in about 70% of patients receiving chemoradiotherapy (CRT) for head and neck cancer (HNC). Current treatment approaches focus primarily on symptoms. (Elad 2020) Avasopasem (AVA; GC4419) is an investigational selective dismutase mimetic that rapidly converts superoxide to hydrogen peroxide, potentially interrupting SOM development. (Riley 2007, Sonis 2001) In a phase 2 study, AVA vs placebo reduced SOM duration, incidence, and severity (gr 4 incidence) in patients with locally advanced HNC undergoing CRT (Anderson 2019), prompting initiation of the phase 3 ROMAN study (NCT03689712). The objective of the phase 2 EUSOM open-label trial was to assess the feasibility (safety and efficacy) of a vasospasm in European patients receiving CRT for locally advanced squamous cell carcinoma of the head and neck. <h3>Materials/Methods</h3> In EUSOM (NCT04529850), patients with locally advanced, nonmetastatic HNC in Belgium, Czech Republic, Germany, Poland, Spain and Switzerland received AVA 90 mg IV before each daily fraction (2.0–2.2 Gy, M–F) of intensity-modulated radiation therapy (IMRT; 60–72 Gy over appx. 7 weeks), with investigator's choice of cisplatin 100 mg/m² q3wks x 3 or 40 mg/m² weekly x 6–7. WHO grade of OM was assessed twice weekly through IMRT then weekly for 4 weeks. The primary endpoint was safety. SOM incidence, severity (gr 4), and duration were secondary endpoints. <h3>Results</h3> N=38 enrolled, 37 (median age 61 [range 45–79]; 81% male) received ≥1 dose of AVA, 33 received ≥ 60 Gy IMRT and ≥ 5 wks AVA (per protocol). Primary tumor: oral (n=15), oropharyngeal (n=20), or other (n=2). AVA median duration of exposure was 6.7 weeks. Median cumulative IMRT dose was 69.3 Gy (range 14–74). Mean cumulative cisplatin dose was 245.5 mg/m² and 212.3 mg/m², respectively, for patients receiving q3w (11/37) and weekly (26/37) schedules; 91% and 58%, respectively, received ≥200 mg/m². The most frequent adverse events (AEs) were lymphopenia, nausea, leukopenia, and anemia. Hypotension occurred in 19% (n=7, 3 gr 3) and was the most frequent AVA-related AE (n=5). Serious AEs (N=18; 49%) included pneumonia (n=3), COVID-19 (n=2), and hypotension (n=2, 1 AVA-related leading to AVA discontinuation). SOM efficacy for the full and per protocol population (≥60 Gy RT and ≥25 infusion of AVA; n=33) are shown in the table. <h3>Conclusion</h3> The AE profile observed in EUSOM was comparable to published data and suggested that vasospasm was well tolerated in these patients. SOM incidence appeared lower than historic expectations. Funder Galera Therapeutics, Inc.

Flying over the "No Fly Zone:" Re-Irradiation of Ultracentrally Located Thoracic Tumors Utilizing Hypofractionated Stereotactic Body Radiotherapy

<h3>Purpose/Objective(s)</h3> The feasibility and safety of re-irradiation for ultracentrally located thoracic tumors has been reported, however there is very little information detailing outcomes, toxicity and cumulative dosimetry data to define the maximal tolerant dose of radiation to organs at risk (OAR). This study presents detailed dosimetry summary data of re-irradiation with an attempt to enrich the literature in this regard. <h3>Materials/Methods</h3> Fifteen individuals undergoing 10-fraction hypofractionated stereotactic body re-irradiation (re-hfSBRT) for the management of ultracentrally located thoracic tumors between 2009 and 2020 at a single institution were retrospectively reviewed. Cumulative dosimetric variables were generated from the construction of the cumulative plan sum, initial and re-irradiation treatment plans, using oncology imaging informatics system planning software. Treatment outcomes, toxicity and detailed dosimetry of OARs were analyzed. <h3>Results</h3> At a median follow up of 10 months, one- and three-year overall survival (OS), progression free survival (PFS) and local control (LC) were 52% and 28%, 33% and 28%, and 76% and 61%, respectively. Treatment related adverse events were low with 5 individuals (33%) developing ≥ grade 2 pneumonitis (Grade 2 = 4, Grade 3 = 1). Dosimetric parameters were not associated with the development of clinically relevant pneumonitis. No adverse events involving central OARs (esophagus, great vessels, primary bronchial tree) were documented. Median cumulative mean lung dose (MLD) was 24 Gy (range: 10-33 Gy), with a V20 of 33% (range: 11-51%). Median esophageal, primary bronchial tree, and great vessel maximum doses (Dmax) were 93.2 Gy (range: 50-148 Gy), 163 Gy (range: 77-204 Gy), and 191 Gy (range: 129-262 Gy), respectively. <h3>Conclusion</h3> The current study is the first to provide detailed cumulative dosimetric data from a cohort of patients treated with re-irradiation with ultracentrally located thoracic tumors. Despite unfavorable anatomic tumor location given an intimate association to critical OARs, delivering an ablative dose with a 10-fraction hfSBRT course can serve as a feasible option for these challenging cases.

Comparative Evaluation of Brachial Plexus Sparing for Comprehensive Reirradiation of High Risk Recurrent or New Primary Breast Cancer

<h3>Purpose/Objective(s)</h3> Recurrent or new primary breast cancer with an indication for comprehensive regional nodal irradiation (RNI) in the setting of prior radiotherapy (RT) to the supraclavicular area (SCV) and upper axilla presents a unique treatment challenge due to cumulative brachial plexus (BP) dose tolerance. Brachial plexopathy is a debilitating potential consequence of RT, and BP dose monitoring is needed for comprehensive reirradiation (reRT). We hypothesize that pencil beam scanning proton therapy (PBS-PT) and photon volumetric-modulated arc therapy (VMAT) are conformal techniques that allow BP relative dose-sparing, while maintaining target volume (TV) dose. A comparative evaluation was performed to assess each approach. <h3>Materials/Methods</h3> In this IRB-approved retrospective study, all patients with ipsilateral recurrent or new primary breast cancer previously treated with photon RT, then receiving PBS-PT reRT to TV with at least partial BP overlap, were identified. VMAT plans were developed by photon breast dosimetrists using matched individualized BP dose constraints (BP maximum 17.1-53.9 Gy) used in the PBS-PT course. BP and TV DVH parameters were assessed. Patient and tumor characteristics, treatment parameters, clinical outcomes, and toxicities were collected. The median follow-up from the start of reRT was 10.5 months. <h3>Results</h3> Ten consecutive patients were identified. Median patient age was 58 years (41-82), with median time between RT courses of 48 months (15-276). Median first, second, and cumulative RT doses were 50.4 Gy (42.6-60.0), 50.4 Gy(RBE) (45.0-64.4), and 102.4 Gy(RBE) (95.0-120.0), respectively. PBS-PT and VMAT plans matched BP doses, with the median maximum and mean BP cumulative doses 86.6 Gy (RBE) and 60.7 Gy (RBE) for PBS-PT and 87.5 Gy and 60.2 Gy for VMAT, respectively. TV coverage of V85% (volume receiving 85% of prescription dose), V90%, and V95% were generally lower for VMAT vs. IMPT plans: axilla level II were 84.8%, 91.8%, and 75.7% vs. 90.9% (p=0.17), 88.3% (p=0.04), and 84.5% (p<0.01); axilla level III were 89.8%, 75.1%, and 64.0% vs. 95.4% (p=0.39), 91.8% (p=0.12), and 86.5% (p=0.32); and SCV were 83.0%, 74.3%, and 67.2% vs. 90.9% (p=0.41), 82.1% (p=0.13), and 68.2% (p=0.76), respectively. One patient developed symptoms of brachial plexopathy with neuropathy in the ulnar nerve distribution without pain or weakness. This patient had the highest maximum cumulative BP dose of the entire cohort (106.1 Gy(RBE)). <h3>Conclusion</h3> VMAT and PBS-PT provide conformal RT plans that can provide BP dose sparing but some surrounding compromise of the adjacent TV at risk. In this cohort, PBS-PT improved BP sparing and TV coverage versus VMAT. Further study with uniform TV and prescription parameters will be useful for direct comparison of the two modalities as the approach to this clinical situation continues to be refined. Longer follow-up will be needed to characterize the implication of cumulative BP dose on risk of developing clinically-significant brachial plexopathy.

Predictive Factors for Survival and Radiation Necrosis in Patients with Recurrent High-Grade Glioma Treated with Re-Irradiation

<h3>Purpose/Objective(s)</h3> To analyze the predictors of survival and radiation necrosis in adult patients (pts) with recurrent high-grade gliomas (rHGG) who have undergone re-irradiation (ReRT). <h3>Materials/Methods</h3> All adult pts with rHGG who had ReRT from 2009 to 2020 at one institution were retrospectively reviewed. Demographic, clinical, dosimetric, and radiological data were obtained from the electronic medical records. The primary outcome was to identify predictors of overall survival (OS) and radiation necrosis (RN). The secondary outcome was to identify patterns of failure after ReRT, which was defined as in-field, marginal or distant if >95% of the recurrence volume was in the 80% isodose line (IDL), between 80%-20% IDL, or outside 20% IDL, respectively. OS, progression-free survival (PFS), and RN were estimated by the Kaplan-Meier method. Toxicity was recorded according to CTCAE V5.0. <h3>Results</h3> Were included 79 pts with a median age of 52 yrs (range, 19-79), 62% were male, 85% had grade 4 glioma at presentation and 98% at ReRT. IDH was wildtype/mutated/unknown in 73%/11%/15% of pts. 92% had concurrent/adjuvant temozolamide at the primary treatment. 34% had re-resection prior to ReRT. 16% had concurrent bevacizumab at ReRT. The most common fractionation schedules at the primary treatment were 40 Gy/15Fx (9%) and 50-60 Gy/28-33Fx (91%), and at ReRT were 17-24 Gy/1Fx (9%), 20-35 Gy/5Fx (38%), 25-35 Gy/10Fx (48%) and 36-54 Gy/18-30Fx (5%). The median cumulative equivalent dose in 2 Gy fractions (EQD2, a/b=2) was 103 Gy (range, 81-216). The median OS and PFS were 9.9 (95% CI 8.3-11.6) and 4.1 mos (95% CI 3.6-5.4), respectively. The OS and PFS rate at 6/12 months were 69.6%/34.2% and 29.1%/7.5%, respectively. The prognostic factors for OS on multivariate analyses (MVA) were interval from initial treatment to first progression ≥16.3mos (HR=0.35, 95% CI 0.20-0.59, p<0.001), re-resection prior ReRT (HR=0.43, 95% CI 0.25-0.73, p=0.002), ECOG ≥1 at ReRT (HR=1.90, 95% CI 1.10-3.30, p=0.022) and PTV volume at ReRT ≥112cc (HR=2.63, 95% CI 1.55-4.44, p≤0.001). Toxicities G2 and G3 were 22% (8.8% RN) and 5% (2.5% RN), respectively. Concurrent use of bevacizumab (p<0.001) and EQD2 ≤98 Gy (p<0.001) were predictors for lower incidence of RN on MVA. Exploratory analysis suggested three risk groups for RNs based on cumulative EQD2: ≤100 Gy (RN = 4%), 100-111 Gy (RN = 13%), and ≥111 Gy (RN = 20%). The failures after ReRT were in-field, marginal or distant in 67%, 6%, and 27% of pts who had follow-up MRI, respectively. <h3>Conclusion</h3> Re-irradiation is a safe and effective treatment for GBM. We describe predictive factors for OS and RN to guide patient section. Focus on pts with the most favorable OS may aid in identifying pts most likely to benefit from ReRT.