MR-guided SBRT boost for patients with locally advanced or recurrent gynecological cancers ineligible for brachytherapy: feasibility and early clinical experience

Background and purpose Chemoradiotherapy (CRT) followed by a brachytherapy (BT) boost is the standard of care for patients with locally advanced or recurrent gynecological cancer (LARGC). However, not every patient is suitable for BT. Therefore, we investigated the feasibility of an MR-guided SBRT boost (MRg-SBRT boost) following CRT of the pelvis. Material and methods Ten patients with LARGC were analyzed retrospectively. The patients were not suitable for BT due to extensive infiltration of the pelvic wall (10%), other adjacent organs (30%), or both (50%), or ineligibility for anesthesia (10%). Online-adaptive treatment planning was performed to control for interfractional anatomical changes. Treatment parameters and toxicity were evaluated to assess the feasibility of MRg-SBRT boost. Results MRg-SBRT boost was delivered to a median total dose of 21.0 Gy in 4 fractions. The median optimized PTV (PTVopt) size was 43.5ccm. The median cumulative dose of 73.6Gy10 was delivered to PTVopt. The cumulative median D2ccm of the rectum was 63.7 Gy; bladder 72.2 Gy; sigmoid 65.8 Gy; bowel 59.9 Gy (EQD23). The median overall treatment time/fraction was 77 min, including the adaptive workflow in 100% of fractions. The median duration of the entire treatment was 50 days. After a median follow-up of 9 months, we observed no CTCAE ≥ °II toxicities. Conclusion These early results report the feasibility of an MRg-SBRT boost approach in patients with LARGC, who were not candidates for BT. When classical BT-OAR constraints are followed, the therapy was well tolerated. Long-term follow-up is needed to validate the results.

Effect of Previous Alkylating Agent Exposure on Follicle Numbers in Cryopreserved Prepubertal and Young Adult Ovarian Tissue after Long-Term Xenografting

Purpose and methods: To elucidate whether previous cancer treatment affects graft recovery and follicle numbers, morphology, and development in grafts, cryopreserved ovarian biopsies obtained from 18 cancer patients aged 1–24 years with and without exposure to chemotherapy were xenografted as 1 mm3 fragments to immunodeficient mice for 22 weeks with exogenous stimulation. Results: Graft recovery showed no association with chemotherapy exposure, pubertal stage, or leukemia contamination. Total follicle number per recovered graft varied between 0 and 1031 in the chemotherapy-exposed and between 0 and 502 in the non-chemotherapy-exposed group. Atretic follicles formed the largest proportion of the follicle pool in chemotherapy-exposed grafts. Increased atresia correlated with exposure to alkylating agents (mean ± SD 8866.2 ± 9316.3 mg/m2) but not with anthracyclines, pubertal stage, or leukemia contamination. Conclusion: The observation confirms the harmful effects of alkylating agents on ovarian tissue. Therapy at the median cumulative dose of 8866 mg/m2 leads to the decreased quality of cryopreserved ovarian follicles in children and young adults.

Analysis of using high-precision radiotherapy in the treatment of liver metastases regarding toxicity and survival

Background Hepatic metastases occur frequently in the context of many tumor entities. Patients with colorectal carcinoma have already developed liver metastases in 20% at the time of diagnosis, and 25–50% develop metastases in the further course of the disease and therapy. The frequent manifestation and the variable appearance of liver metastases result in an interdisciplinary challenge, regarding treatment management. The aim of this study was to evaluate high-precision stereotactic body radiotherapy (SBRT) for liver metastases. Methods A cohort of 115 patients with 150 irradiated liver metastases was analyzed. All metastases were treated between May 2004 and January 2020 using SBRT. A contrast-enhanced computed tomography (CT) was performed in all patients for treatment planning, followed by image-guided high-precision radiotherapy using cone-beam CT. A median cumulative dose of 35 Gy and a median single dose of 7 Gy was applied. Results Median OS was 20.4 months and median LC was 35.1 months with a 1-year probability of local failure of 18% (95%-CI: 12.0–24.3%). In this cohort, 18 patients were still alive at the time of evaluation. The median FU-time in total was 11.4 months and for living patients 26.6 months. 70.4% of patients suffered from acute toxicities. There were several cases of grade 1 and 2 toxicities, such as constipation (13.9%), nausea (24.4%), loss of appetite (7.8%), vomiting (10.4%), diarrhea (7.8%), and abdominal pain (16.5%). 10 patients (8.7%) suffered from grade 3 toxicities. Late toxicities affected 42.6% of patients, the majority of these affected the gastrointestinal system. Conclusion SBRT is becoming increasingly important in the field of radiation oncology. It has evolved to be a highly effective treatment for primary and metastasized tumors, and offers a semi-curative treatment option also in the case of oligometastatic patients. Overall, it represents a very effective and well-tolerated therapy option to treat hepatic metastases. Based on the results of this work and the studies already available, high-precision radiotherapy should be considered as a valid and promising treatment alternative in the interdisciplinary discussion.

Sedation Usage in COVID-19 Acute Respiratory Distress Syndrome: A Multicenter Study

Background Patients with COVID-19 acute respiratory distress syndrome (ARDS) have been shown to have high sedation requirements. Objective The purpose of this study was to compare sedative use between patients with COVID-19 ARDS and non-COVID-19 ARDS. Methods This was a retrospective study of patients with COVID-19 ARDS compared with historical controls of non-COVID-19 ARDS who were admitted to 2 hospitals from March 1, 2020, to April 30, 2020, and April 1, 2018, to December 31, 2019, respectively. The primary outcome was median cumulative dose of propofol (µg/kg) at 24 hours after intubation. Results There were 92 patients with COVID-19 ARDS and 37 patients with non-COVID-19 ARDS included. Within the first 24 hours of intubation, patients with COVID-19 ARDS required higher total median doses of propofol: 51 045 µg/kg (interquartile range, 26 150-62 365 µg/kg) versus 33 350 µg/kg (9632-51 455 µg/kg; P = 0.004). COVID-19 patients were more likely receive intravenous lorazepam (37% vs 14%; P = 0.02) and higher cumulative median doses of midazolam by days 5 (14 vs 4 mg; P = 0.04) and 7 of intubation (89 vs 4 mg; P = 0.03) to achieve the same median Richmond Analgesia-Sedation Scale scores. COVID-19 ARDS patients required more ventilator days (10 vs 6 days; P = 0.02). There was no difference in 30-day mortality. Conclusion and Relevance Patients with COVID-19 ARDS required higher doses of propofol and benzodiazepines than patients with non-COVID-19 ARDS to achieve the same median levels of sedation.

Intravenous Thyroxine Administration in Hospitalized Patients, a Common but Unreported Practice: a Single Institution Recent Experience

Background: Intravenous levothyroxine (IVT4) is FDA-approved for the treatment of myxedema coma (ME). ATA guidelines also acknowledge other rare situations, mostly such where oral/enteral access is compromised for prolonged periods, in which IVT4 may be appropriate. We noticed that at our hospital, IVT4 is administered more frequently than expected. Aim of study: To assess the extent of IVT4 administration, the indications for such a treatment, and its outcome at a tertiary facility. Study design and Methods: A retrospective study of IVT4 administered to adult inpatients at Tel Aviv-Sourasky Medical Center between January 2017 and July 2020. A list of dispensed T4 vials during the period of interest was generated from the hospital pharmacy computerized database. Patients’ charts were searched for relevant clinical and laboratory data. Results: 107 patients (62 W/45 M), age 62.5±17.3 y (range 20-97) received IV T4, in the course of 113 hospitalizations. 94 subjects had primary hypothyroidism (PH), 10 had central hypothyroidism, while 3 subjects had no documented evidence of hypothyroidism. ME was likely in only 4 cases (3.5%). The leading stated indication for IVT4 was profound hypothyroidism in 57 instances (50.4%), jeopardized enteral route in 11 (9.7%), while no clear or justifiable indication was found in 39 cases (34.5%). An official endocrine consult backed treatment 74 times (65.5%). In subjects with PH, median serum TSH prior to treatment was 36.4 mIU/L (IQR 8-42), while free T4 was 0.4 ng/dl (IRQ 0.22-0.61, normal 0.8-1.7). In subjects with no ME, altered consciousness was present in 19%, bradycardia in 6.3% and 4.5% were hypothermic. The median initial dose of IV-T4 was 150 μg (range 20-500). Repeated administrations ranged from 1 to 29 times, with a median cumulative dose of 250 μg (IQR 150-400, range 20-3300). We could not identify adverse events directly attributable to IV-T4. Of the 113 admissions, 61 ended in patient’s recovery and discharge (54%), 22 (19.5%) in transfer to a rehab or nursing facility, while there were 30 cases of death (26.5%). Only one of the 4 patients with presumed ME died. In a logistic regression model, that also included age, gender, and ICU admission, the only variable that significantly predicted death was a need for artificial ventilation (OR:27.8, CI 3.5-189). In contrast, free T4, TSH, hospitalization length, altered consciousness, and other potential variables, were excluded from the equation. Conclusions: IVT4 administration is a common practice at our hospital. In a small minority of cases (13.2%), it is given for approved clinical conditions, while in all the others it appears to be unjustified. Reports on this practice are all but absent from the literature. Studies from other institutions are needed to determine its global extent, safety, and efficacy. Until it is proven safe and cost-effective, greater caution should be exercised before allowing it.

Appropriate Number of Docetaxel Cycles in Castration-Resistant Prostate Cancer Patients Considering Peripheral Neuropathy and Oncological Control

<b><i>Background:</i></b> The number of cycles of docetaxel required for castration-resistant prostate cancer (CRPC) is unclear. This study estimated peripheral neuropathy (PN) incidence and the optimal number of treatment cycles in patients receiving docetaxel for CRPC. <b><i>Patients and Methods:</i></b> The study retrospectively reviewed 82 patients receiving docetaxel for CRPC at an institution between January 2005 and January 2017. Docetaxel (70 or 75 mg/m²) was administered every 3 weeks, and prednisone 5 mg or dexamethasone 0.5 mg was administered twice a day. <b><i>Results:</i></b> PN (grade ≥2) was noted in 32 (39.0%) patients. The median cumulative dose of docetaxel associated with PN was 675 mg/m². No factor significantly predicted the occurrence of PN. The prostate-specific antigen progression rate, prostate cancer-specific survival, and overall survival were significantly better with ≥8 cycles of docetaxel than with &#x3c;8 cycles (<i>p</i> &#x3c; 0.05). <b><i>Conclusion:</i></b> The incidence of PN is high, and 8 treatment cycles are optimal for patients receiving docetaxel for CRPC.

Efficacy and safety of liposomal irinotecan plus fluorouracil/leucovorin after progression on conventional irinotecan-containing chemotherapy for metastatic pancreatic adenocarcinoma.

382 Background: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has demonstrated its clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on prior gemcitabine-based chemotherapy. However, its role in patients who previously treated with conventional irinotecan has not been investigated. We analyzed clinical outcomes of nal-IRI + 5-FU/LV in mPAC patients after progression on conventional irinotecan-containing chemotherapy. Methods: In this multicenter retrospective analysis, a total of 35 patients with mPAC who received nal-IRI + 5-FU/LV after progression on irinotecan-containing regimen, between January 2017 and March 2020, were included. The ratio of time-to-progression (TTP) with nal-IRI + 5-FU/LV to TTP with conventional irinotecan (TTPr) was correlated with duration and cumulative dose of prior conventional irinotecan. Results: The median age was 58 years (range, 35-73) and 16 patients (46%) were male. All patients received prior irinotecan as the component of FOLFIRINOX. The median duration of prior irinotecan was 4.6 months (range, 0.5-16.8) and median cumulative dose of prior irinotecan was 1230 mg (range, 150-4650). Objective response rate of nal-IRI + 5-FU/LV was 2.9% (1 partial response) and stable disease was achieved in 31.4% (n = 11). With median follow-up duration of 9.2 months [95% CI, 7.8-10.5], the median PFS and OS were 2.0 months [95% CI, 1.4-2.6] and 4.4 months [95% CI, 3.6-5.7], respectively. 6-month PFS rate was 16.3% and OS rate was 37.5%. The median TTPr was 0.41 (range 0.07-2.07) and this showed negative correlation between cumulative dose of prior irinotecan (R = -0.37, p = 0.041). There was a tendency for the negative correlation between TTPr and duration of prior irinotecan (R = -0.35, p = 0.062). Most common grade 3-4 toxicities were neutropenia (20%) and fatigue (8.6%). Conclusions: Nal-IRI + 5-FU/LV showed only modest efficacy for mPAC patients who progressed on conventional irinotecan-containing chemotherapy. Cumulative dose of prior conventional irinotecan may be correlated with the efficacy of nal-IRI + 5-FU/LV.

Clinical outcomes of liposomal irinotecan plus fluorouracil/leucovorin for metastatic pancreatic adenocarcinoma in patients previously treated with conventional irinotecan-containing chemotherapy

Introduction: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has shown clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on gemcitabine-based chemotherapy. However, its role in patients with mPAC previously treated with conventional irinotecan-containing chemotherapy has not been appropriately investigated. Methods: In this retrospective analysis, patients with mPAC who received nal-IRI plus 5-FU/LV after conventional irinotecan-containing regimen between January 2017 and March 2020, were identified from two referral cancer centers in South Korea. The ratio of time to progression (TTP) with nal-IRI plus 5-FU/LV to TTP with conventional irinotecan (TTPr) was analyzed with respect to the duration and cumulative dose of conventional irinotecan treatment. Results: In total, 35 patients treated with nal-IRI plus 5-FU/LV after the irinotecan-containing regimen were analyzed. The median age was 58 years and 16 (46%) patients were male. The median duration of conventional irinotecan therapy was 4.6 months at a median cumulative dose of 1230 mg. The objective response rate of nal-IRI plus 5-FU/LV was 2.9%, and stable disease was achieved in 11 (31.4%) patients. During the median follow-up of 9.2 [95% confidence interval (CI): 7.8–10.5] months, the median progression-free survival (PFS) and overall survival (OS) were 2.0 (95% CI: 1.4–2.6) months and 4.4 (95% CI: 3.6–5.7) months, respectively. The 6-month PFS and OS rates were 16.3% and 37.5%, respectively. The median TTPr was 0.41 (range, 0.07–2.07), showing a negative correlation with the cumulative dose of prior irinotecan therapy (R = −0.37, p = 0.041). A tentative negative correlation between TTPr and duration of prior irinotecan therapy was observed ( R = −0.35, p = 0.062). The most common grade 3–4 toxicities were neutropenia (20%) and fatigue (8.6%). Conclusion: Nal-IRI plus 5-FU/LV showed modest effectiveness and manageable toxicities for patients with mPAC previously treated with conventional irinotecan-containing chemotherapy. The cumulative dose of prior conventional irinotecan therapy may be inversely correlated with the effectiveness of nal-IRI plus 5-FU/LV.

Fracture risk in systemic lupus erythematosus patients over 28 years

Objectives Chronic glucocorticoid use is complicated by osteoporosis and increases the risk of fragility fractures. EULAR guidelines on SLE management recommend reducing chronic glucocorticoid dosage to ≤7.5 mg/day to minimize this risk. We examined the relationship of glucocorticoid dose to fragility fracture risk in a cohort of SLE patients. Methods Retrospective analysis of SLE patients attending University College Hospital over 28 years was undertaken. Collected data included consecutive steroid dose, dual-energy X-ray absorptiometry scans and fragility fractures. Results We collected data on 250 patients with a median of 17 years’ follow-up. Fragility fractures were diagnosed in 28 (11.2%) patients and the mean ± s.d. age of first fracture was 51 ± 16 years. A total of 94% received glucocorticoids, the average dose being 6.20 mg/day. Patients with fragility fractures had a lower average daily dose (5.36 vs 6.23 mg/day) but a higher median cumulative dose (25.19 vs 20.96 g). These differences were not significant (P = 0.127 and 0.229, respectively). Some 93% of patients received vitamin D, and 85% received calcium. Cox regression analysis showed older age at SLE diagnosis, osteoporosis and secondary hyperparathyroidism were associated with fragility fractures. Glucocorticoid dose was not significantly associated with the occurrence of fragility fractures. Twenty-two patients with fractures were treated with bisphosphonates, two with denosumab and two with teriparatide. Conclusions We found no significant association between glucocorticoid treatment and fragility fractures in our group of patients; however, a prospective study including more patients not treated with CS would be necessary to confirm these results.

Pharmacoepidemiology of Furosemide in the Neonatal Intensive Care Unit

<b><i>Background:</i></b> Furosemide is commonly used off-label in the neonatal intensive care unit (NICU), but current dosing practices vary widely. <b><i>Objectives:</i></b> To describe dosing practices including route, dose, and duration of exposure to furosemide in a large number of community and tertiary NICUs across North America. <b><i>Method:</i></b> Using the Pediatrix Medical Group Clinical Data Warehouse, we identified infants who received ≥1 dose of furosemide between 1997 and 2016. We excluded infants with incomplete dosing data. We calculated average daily furosemide dose, cumulative dose, total days of exposure, and maximum daily dose. We compared dosing between infants born at &#x3c;32 weeks gestational age (GA) and ≥32 weeks GA. <b><i>Results:</i></b> A total of 18,572 infants had complete dosing data. The median (interquartile value) postnatal age at first exposure was 11 days (4, 26), the median maximum daily dose was 1.0 mg/kg (0.97, 1.6), the median average daily dose was 1.0 mg/kg (0.88, 1.1), and the median cumulative dose was 2.0 mg/kg (1.0, 4.5). The median total duration of exposure was 2 days (1, 4). A total of 177 (1%) infants received <i>≥</i>4 mg/kg/day of furosemide. Infants born &#x3c;32 weeks GA were an older age at initial furosemide exposure compared to those born ≥32 weeks GA: 19 versus 4 days, <i>p</i> &#x3c; 0.001. <b><i>Conclusions:</i></b> Most infants received short courses of furosemide within the labeled dosing parameters. Further studies are needed to assess the safety and efficacy of furosemide in the NICU.