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Management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) when cisplatin is contraindicated is controversial. We aimed to assess whether radiotherapy with concurrent and adjuvant durvalumab would improve outcomes compared with radiotherapy with cetuximab. NRG-HN004 was designed as an open-label, multicentre, parallel-group, randomised, phase 2/3 trial with safety lead-in conducted at 89 academic and community medical centres in North America. Eligible patients were aged 18 years or older with American Joint Committee on Cancer 8th edition stage III–IVB p16-negative HNSCC or unfavourable stage I–III p16-positive oropharyngeal or unknown primary carcinoma, who had a contraindication to cisplatin (Eastern Cooperative Oncology Group [ECOG] performance status 2, renal or hearing impairment, peripheral neuropathy, aged at least 70 years with moderate or severe comorbidity, or aged younger than 70 years with severe comorbidity). Patients were randomly assigned (2:1) by permuted block randomisation (multiples of 6) to intravenous durvalumab 1500 mg starting 2 weeks before radiotherapy then every 4 weeks starting week 2 of radiotherapy (seven cycles) or intravenous cetuximab 400 mg/m2 1 week before radiotherapy then 250 mg/m2 weekly beginning week 1 of radiotherapy (eight cycles), with intensity-modulated radiotherapy (70 Gy in 35 fractions over 7 weeks). Stratification factors were tumour and nodal stage, ECOG performance status and comorbidity, and primary site and p16 status. The phase 2 primary endpoint was progression-free survival in the intention-to-treat population. There was one prespecified interim futility analysis at 50% of progression-free survival information. If the observed hazard ratio was 1·0 or more, favouring cetuximab, early stopping would be considered. Extended follow-up analysis was post hoc. This trial is registered with ClinicalTrials.gov, NCT03258554, and is closed to enrolment. Following a ten-patient safety lead-in, the phase 2 trial enrolled 190 patients from March 12, 2019, to July 30, 2021, 186 of whom were randomly assigned (123 to durvalumab and 63 to cetuximab). Median age was 72 years (IQR 64–77), 30 (16%) patients were women and 156 (84%) were men. Phase 2 accrual was suspended in July 30, 2021, following an interim futility analysis, and permanently closed in Sept 1, 2022. The phase 3 part of the trial was not conducted. At a median follow-up of 2·3 years (IQR 1·9–3·1) for the extended follow-up (data cutoff July 31, 2023; post-hoc analysis), 2-year progression-free survival was 50·6% (95% CI 41·5–59·8) in the durvalumab group versus 63·7% (51·3–76·1) in the cetuximab group (hazard ratio 1·33 [95% CI 0·84–2·12]; p=0·89). Adverse events were similar in both groups. The most common grade 3–4 adverse events were dysphagia (26 [22%] of 119 patients in the durvalumab group vs 18 [30%] of 61 patients in the cetuximab group), lymphopenia (33 [28%] vs 20 [33%]), and oral mucositis (13 [11%] vs 11 [18%]). Four (3%) patients in the durvalumab group and one (2%) in the cetuximab group died from treatment-related adverse events (death not otherwise specified, laryngeal oedema, lung infection, and respiratory failure in the durvalumab group and sudden death not otherwise specified in the cetuximab group). Our findings suggest that durvalumab did not improve outcomes compared with cetuximab in patients with HNSCC with contraindications to cisplatin. Further trials are needed to define the standard of care for this population. US National Cancer Institute and AstraZeneca.

All phases of lipopolysaccharide (LPS)-induced fever are mediated by prostaglandin (PG) E2. It is known that the second febrile phase (which starts at approximately 1.5 h post-LPS) and subsequent phases are mediated by PGE2 that originated in endotheliocytes and perivascular cells of the brain. However, the location and phenotypes of the cells that produce PGE2 triggering the first febrile phase (which starts at approximately 0.5 h) remain unknown. By studying PGE2 synthesis at the enzymatic level, we found that it was activated in the lung and liver, but not in the brain, at the onset of the first phase of LPS fever in rats. This activation involved phosphorylation of cytosolic phospholipase A2 (cPLA2) and transcriptional up-regulation of cyclooxygenase (COX)-2. The number of cells displaying COX-2 immunoreactivity surged in the lung and liver (but not in the brain) at the onset of fever, and the majority of these cells were identified as macrophages. When PGE2 synthesis in the periphery was activated, the concentration of PGE2 increased both in the venous blood (which collects PGE2 from tissues) and arterial blood (which delivers PGE2 to the brain). Most importantly, neutralization of circulating PGE2 with an anti-PGE2 antibody both delayed and attenuated LPS fever. It is concluded that fever is initiated by circulating PGE2 synthesized by macrophages of the LPS-processing organs (lung and liver) via phosphorylation of cPLA2 and transcriptional up-regulation of COX-2. Whether PGE2 produced at the level of the blood-brain barrier also contributes to the development of the first phase remains to be clarified.

Abstract BACKGROUND: The standard treatment of resected brain metastasis is whole-brain radiotherapy (WBRT). To avoid the potential toxicity of WBRT and to improve local control, we have used radiosurgery alone to the surgical cavity. OBJECTIVE: To demonstrate the rates of local control, new intracranial metastasis, and overall survival using this treatment scheme without WBRT. METHODS: Eighty-five consecutive patients with brain metastasis were treated with surgical resection of at least 1 lesion followed by radiosurgery alone to the surgical cavity and any unresected lesions from August 2000 to March 2011. Sixty-eight percent had gross total resections. After surgery, radiosurgery was delivered to the surgical cavity with a 2- to 3-mm margin. The median marginal radiosurgery dose was 16 Gy, and median target volume was 13.96 cm3. Follow-up imaging and clinical examination were obtained every 2 to 3 months. RESULTS: Median follow-up time was 11.2 months. Overall local control was 81.2%. The 6-month, 1-year, and 2-year rates of local control were 88.7%, 81.4%, and 75.7%, respectively. Forty-seven patients (55%) developed new intracranial metastases at a median time of 5.6 months. For the entire population, the rate of new metastases was 32.1%, 58.1%, and 62.9% at 6 months, 1 year, and 2 years, respectively. Median overall survival time was 12.1 months. From initial treatment until death or last follow-up, only 30 patients (35%) received WBRT as salvage treatment. CONCLUSION: Radiosurgery to the surgical cavity without WBRT achieved excellent local control of resected brain metastasis. Close imaging follow-up allows early intervention for any new metastasis.

Introduction The morbidity sequelae of advanced cancer are often irreversible. Early palliative radiation can prevent, delay, and even improve these consequences. Treatment may be delayed due to a packed computed tomography (CT) simulation schedule or other logistics, including the cost and burden of arranging ambulance transportation when radiation centers are off-site. Objectives The primary objective was to determine the feasibility of using a recent diagnostic CT scan in lieu of a dedicated simulation CT to generate an adequate plan without sacrificing dosimetric goals and subsequent efficacy or tolerability. Secondary objectives included how much the lesion has grown, and how much earlier treatment could start if planned on a diagnostic CT scan. Materials/Methods For each inpatient treated with palliative radiation, a prior recent diagnostic CT scan was imported into the RayStation (RaySearch Laboratories, Stockholm, Sweden) planning system. From these diagnostic scans, planning treatment volumes (PTV) and organs at risk (OAR) were contoured using the same technique as the patient's actual treatment. The primary outcome was to compare both the PTV coverage and OAR dose between the plan generated from the diagnostic CT compared to that from the simulation CT. Our secondary outcomes include the mean time between CT simulation and first treatment, change in tumor volume between diagnostic scan and CT simulation, and the hottest 1% of each plan (D1). Results Between May and August 2019, a total of 22 inpatients were treated palliatively. Of those 22 patients, 10 patients (ages 32-92 years, median 64.5 years, 50% spine) met study criteria and had a diagnostic CT scan that was obtained within 14 days of simulation CT that was also compatible with our planning software. In the plans that were delivered, a mean of 98.8% (range 94.4-100%) of PTV was covered by at least 95% prescription dose. In the diagnostic CT plans, a mean of 95.4% (range 84.5-100%) of PTV was covered by at least 95% prescription dose. The difference between plans trended towards significance (p=0.061). When looking at patients receiving treatment to the spine or having a diagnostic CT within four days of the simulation CT, there was no statistically significant difference between the two plans (p=0.032 and 0.030, respectively). The OARs received, on average, 1.4% less mean radiation dose in the hypothetical plans (p=0.911). All OAR constraints were met in both groups. The mean time between diagnostic CT and CT simulation was 5.9 days and between CT simulation and first treatment was 1.9 days (range 0-5 days). The mean change in tumor volume was 22.64% smaller in the diagnostic CT scan plan. The D1 was an average 1% hotter in the hypothetical plans (p=0.16). Conclusion In hospitalized patients with an indication for palliative radiation, treatment planning on a pre-existing recent diagnostic CT scan produces comparable dose distributions without increases in dose to OARs when compared to the use of CT simulation scans, particularly for the treatment of the spine or when a very recent diagnostic CT is available. Bypassing CT simulation in select cases allows for earlier delivery of radiation with less patient and logistical burden. In combination with daily image guidance, this may translate to more timely delivery of radiation, less cost and burden to critically ill patients, and improved palliative benefit.Introduction The morbidity sequelae of advanced cancer are often irreversible. Early palliative radiation can prevent, delay, and even improve these consequences. Treatment may be delayed due to a packed computed tomography (CT) simulation schedule or other logistics, including the cost and burden of arranging ambulance transportation when radiation centers are off-site. Objectives The primary objective was to determine the feasibility of using a recent diagnostic CT scan in lieu of a dedicated simulation CT to generate an adequate plan without sacrificing dosimetric goals and subsequent efficacy or tolerability. Secondary objectives included how much the lesion has grown, and how much earlier treatment could start if planned on a diagnostic CT scan. Materials/Methods For each inpatient treated with palliative radiation, a prior recent diagnostic CT scan was imported into the RayStation (RaySearch Laboratories, Stockholm, Sweden) planning system. From these diagnostic scans, planning treatment volumes (PTV) and organs at risk (OAR) were contoured using the same technique as the patient's actual treatment. The primary outcome was to compare both the PTV coverage and OAR dose between the plan generated from the diagnostic CT compared to that from the simulation CT. Our secondary outcomes include the mean time between CT simulation and first treatment, change in tumor volume between diagnostic scan and CT simulation, and the hottest 1% of each plan (D1). Results Between May and August 2019, a total of 22 inpatients were treated palliatively. Of those 22 patients, 10 patients (ages 32-92 years, median 64.5 years, 50% spine) met study criteria and had a diagnostic CT scan that was obtained within 14 days of simulation CT that was also compatible with our planning software. In the plans that were delivered, a mean of 98.8% (range 94.4-100%) of PTV was covered by at least 95% prescription dose. In the diagnostic CT plans, a mean of 95.4% (range 84.5-100%) of PTV was covered by at least 95% prescription dose. The difference between plans trended towards significance (p=0.061). When looking at patients receiving treatment to the spine or having a diagnostic CT within four days of the simulation CT, there was no statistically significant difference between the two plans (p=0.032 and 0.030, respectively). The OARs received, on average, 1.4% less mean radiation dose in the hypothetical plans (p=0.911). All OAR constraints were met in both groups. The mean time between diagnostic CT and CT simulation was 5.9 days and between CT simulation and first treatment was 1.9 days (range 0-5 days). The mean change in tumor volume was 22.64% smaller in the diagnostic CT scan plan. The D1 was an average 1% hotter in the hypothetical plans (p=0.16). Conclusion In hospitalized patients with an indication for palliative radiation, treatment planning on a pre-existing recent diagnostic CT scan produces comparable dose distributions without increases in dose to OARs when compared to the use of CT simulation scans, particularly for the treatment of the spine or when a very recent diagnostic CT is available. Bypassing CT simulation in select cases allows for earlier delivery of radiation with less patient and logistical burden. In combination with daily image guidance, this may translate to more timely delivery of radiation, less cost and burden to critically ill patients, and improved palliative benefit.

Background Among patients with osseous metastases, breast cancer (BC) patients typically have the best prognosis. In the palliative setting, BC is often considered a single disease, but based on receptor status there are four distinct subtypes: luminal A (LA), luminal B (LB), triple negative (TN), and HER2‐enriched (HER2). We hypothesize that survival and palliative outcomes following palliative RT for osseous metastases correlate with breast cancer subtype (BCS). Methods We identified 3,895 BC patients with known receptor status who received palliative RT for osseous metastases from 2004–2013 in the National Cancer Database. Kaplan–Meier method with log‐rank testing and univariate/multivariate Cox‐regression was used to identify survival factors. Incomplete radiation courses, 30‐day mortality rate, and percentage remaining life spent receiving RT (PRLSRT) were calculated. Results Subtypes were 54% LA, 33% LB, 8% TN, and 5% HER2 with median survival of 34.1, 28.2, 5.3, and 15.7 months, respectively (p < 0.001). Overall 82% of patients received ≥10 fractions. Although BCS had limited effect on radiation regimens, TN received nearly twice as many single or hypofractionated (≤5 fractions) treatments, but the overall rate of these fraction schemes was low at 3.7 and 13.7%, respectively. Compared to LA and LB, TN and HER2 patients had worse palliative outcomes; higher rates of incomplete courses at 18.8% and 18.3% versus 12.7%–14.4%; higher 30‐day mortality post‐radiotherapy at 21.5% and 16.0% versus 6.3%–7.9%, and higher median PRLSRT of 7.7% and 3.7% versus 2.2%–2.4% for LA and LB. On multivariate analysis, BCS was associated with overall survival with TN (HR 3.7), HER2 (HR 1.75), and LB (HR 1.28) fairing worse than LA (p < 0.001). Conclusions BCS correlated with survival and palliative outcome following radiation to osseous metastases. BCS should be considered by physicians when planning palliative RT to maximize quality‐of‐life, avoid unnecessary treatment, and ensure palliative benefits. This study demonstrates the impact of breast cancer subtype on survival and palliative outcomes after palliative radiation for osseous metastases. Patients with triple negative and HER2‐enriched subtypes had shorter survival, higher 30 and 90‐day mortality, had more incomplete treatments, spent more of their remaining lives receiving radiation treatments, but received similar radiation regimens compared to Luminal A and Luminal B patients. This correlation should be considered when selecting palliative radiotherapy regimens to avoid unnecessary treatment and improve palliative outcomes for poor‐prognosis patients.

Background Stereotactic body radiation therapy (SBRT) is an emerging option for unresectable hepatocellular carcinoma (HCC) without consensus regarding optimal dose schemas. This analysis identifies practice patterns and factors that influence dose selection and overall survival, with particular emphasis on dose and tumor size. Materials/Methods Query of the National Cancer Database (NCDB) identified patients with unresectable, nonmetastatic HCC who received SBRT from 2004 to 2013. Biological Effective Dose (BED) was calculated for each patient in order to uniformly analyze different fractionation regimens. Results A total of 456 patients met the inclusion criteria. The median BED was 100 Gy (22.5‐208.0), which corresponded to the most common dose fractionation (50 Gy in five fractions). Various factors influenced dose selection including tumor size (P < 0.001), tumor stage (P = 0.002), and facility case volume (<0.001). On multivariate analysis, low BED (<75 Gy, HR 2.537, P < 0.001; 75‐100 Gy, HR 1.986, P = 0.007), increasing tumor size (HR 1.067, P = 0.032), elevated AFP (HR 1.585, P = 0.019), stage 3 (HR 1.962, P < 0.001), low‐volume facilities (1‐5 cases HR 1.687, P = 0.006), and a longer time interval from diagnosis to SBRT (>2 to ≤4 months, HR 1.456, P = 0.048; >4 months, HR 2.192, P < 0.001) were associated with worse survival. Conclusion SBRT use is increasing for HCC, and multiple regimens are clinically employed. Although high BED was associated with improved outcomes, multiple factors contributed to the dose selection with favorable patients receiving higher doses. Continued efforts to enhance radiation planning and delivery may help improve utilization, safety, and efficacy. Stereotactic body radiation therapy is growing in use and acceptance for treating unresectable hepatocellular carcinoma. There is a wide variety of dose schemas used in clinical practice. Multiple factors are associated with dose selection and fractionation, with more favorable patients receiving higher doses and having better outcomes.

IntroductionInfertility is a common complication of endometriosis. While in vitro fertilisation-embryo transfer (IVF) successfully treats endometriosis-associated infertility, there is some evidence that pregnancy rates may be diminished in women seeing fertility treatment for endometriosis-associated infertility compared with other etiologies of infertility. The use of gonadotropin releasing hormone (GnRH) agonist prior to IVF has been suggested to improve success, however studies have been small and rarely reported live birth rates. Recent approval of an oral GnRH antagonist for endometriosis provides a novel option for women with endometriosis who are undergoing IVF. There have been no studies on the efficacy of GnRH antagonists for the treatment of endometriosis-related infertility.Methods and analysisThis study is a multicentre, prospective, randomised, double-blind, placebo-controlled trial to study the efficacy of GnRH antagonist pretreatment for women with endometriosis who are undergoing IVF. A total of 814 patients with endometriosis undergoing fertility treatment will be enrolled and randomised 1:1 into two groups: elagolix 200 mg two times per day or placebo for 8 weeks, prior to undergoing IVF. All participants will then undergo IVF treatment per local protocols. The primary outcome is live birth. Secondary outcomes include oocyte number, fertilisation rate, embryo morphology and implantation rates, as well as rates of known endometriosis-related obstetrical outcomes (pregnancy-induced hypertension, antepartum haemorrhage, caesarean delivery and preterm birth).Ethics and disseminationThe PREGnant trial was approved by the Institutional Review Board at Johns Hopkins University. Results will be published in a peer-reviewed journal.Trial registration numberNCT04173169.

ObjectiveThe negative impact of comorbidity on survival in women with endometrial carcinoma (EC) is well-known. Few validated comorbidity indices are available for clinical use, such as the Charlson Comorbidity Index (CCI), the Age-Adjusted CCI (AACCI), and the Adult Comorbidity Evaluation-27 (ACE-27). The aim of the study is to determine which index best correlates with survival endpoints in women with EC.Materials and MethodsWe identified 1132 women with early-stage EC treated at an academic center. Three scores were calculated for each patient using CCI, AACCI, and ACE-27 at the time of hysterectomy. Univariate and multivariable modeling was used to determine predictors of survival.ResultsFor each of the studied comorbidity indices, the highest scores were significantly correlated with poorer overall survival. The hazard ratio of death from any cause was 3.92 for AACCI, 2.25 for CCI, and 1.57 for ACE-27. All 3 indices were independent predictors of overall survival with a P value of less than 0.001 on multivariate analysis. In addition, lymphovascular space invasion, lower uterine segment involvement, and tumor grade were predictors of overall survival. Lymphovascular space invasion, grade (P < 0.001), and high AACCI score were the only significant predictors of recurrence-free survival (RFS). Lymphovascular space invasion and tumor grade were the only 2 predictors of disease-specific survival.ConclusionsAlthough all 3 studied comorbidity indices were significant predictors of overall survival in women with early-stage EC, AACCI showed a stronger association. It should be considered for evaluating comorbidity in women with early-stage EC.

PURPOSE/OBJECTIVEThe optimal adjuvant treatment of type II endometrial carcinoma after hysterectomy remains controversial. The objective of this study was to determine the effect of adjuvant radiation therapy (RT) on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival in patients with early-stage type II endometrial carcinoma. MATERIALS AND METHODSIn this institutional review board–approved study, our database of 1450 patients with endometrial cancer was reviewed. Seventy-nine surgically staged patients with 2009 International Federation of Gynecology and Obstetrics (FIGO) stages I and II serous and clear cell carcinoma were treated from 1991 to 2010. These patients were then divided into 2 groups; one group received adjuvant RT, and the other group included patients who did not receive adjuvant RT. RESULTSThe median age of the study cohort is 65 years, and the median follow-up is 47 months. Thirty-nine patients (49%) received adjuvant RT, and 40 patients did not. The 5-year RFS was significantly improved in patients who received RT (84% vs 58%; P = 0.002). Similarly, 5-year DSS was significantly improved in patients who received RT (87% vs 58%; P = 0.023) with a trend toward improved 5-year overall survival (74% vs 58%; P = 0.088). On multivariate analysis, lack of angiolymphatic invasion (P < 0.001 and P < 0.001), adjuvant RT (P < 0.001 and P = 0.004), and lack of lower uterine segment involvement (P = 0.007 and P = 0.009) were independent predictors of improved RFS and DSS, respectively. CONCLUSIONSIn the current study of surgically staged patients with type II endometrial carcinoma International Federation of Gynecology and Obstetrics stages I and II, adjuvant radiation therapy with or without chemotherapy resulted in a significant improvement in recurrence-free and disease-specific survival.