Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (<6 years old). There is a need for multicentre research on vertebral radiotherapy dose distributions for children, but until more valid data become available, these recommendations can provide a basis for daily practice for radiation oncologists who have patients that require vertebral radiotherapy.

Management of vertebral radiotherapy dose in paediatric patients with cancer: consensus recommendations from the SIOPE radiotherapy working group

Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (< 6 years old). There is a need for multicentre research on vertebral radiotherapy dose distributions for children, but until more valid data become available, these recommendations can provide a basis for daily practice for radiation oncologists who have patients that require vertebral radiotherapy.

Management of vertebral radiotherapy dose in paediatric patients with cancer : consensus recommendations from the SIOPE radiotherapy working group

Craniospinal irradiation (CSI) is commonly used for pediatric brain tumors with a propensity for spread in craniospinal fluid, principally medulloblastoma. Evolving technology has led to the use of highly conformal radiation therapy (RT) techniques for CSI, including proton therapy. Target delineation and plan coverage are critical for CSI, but there is ongoing controversy and variability in these realms, with little available data on practice patterns. We sought to characterize proton CSI practice patterns in the United States by examining CSI plans in the Pediatric Proton/Photon Consortium Registry (PPCR).PPCR was queried for data on proton CSI patients from 2015 to early 2020. Each plan was manually reviewed, determining patient position; prescription dose; and coverage of optic nerves, vertebral bodies, spinal nerve roots, sacral nerves, and cranial foramina, among other variables. Two radiation oncologists blinded to clinical data and treating institution assessed coverage at the 95% prescription isodose line and per published European Society for Paediatric Oncology guidelines. Variability in coverage was assessed with nonparametric tests and univariate and multivariate logistic regression.PPCR supplied data for 450 patients, 384 of whom had an evaluable portion of a CSI plan. Most patients (90.3%) were supine. Optic nerves were fully covered in 48.2%; sacral nerves in 87.7%; cranial foramina in 69.3%; and spinal nerves in 95.6%. Vertebral body (VB) sparing was used in 18.6% of skeletally immature cases, increasing over time (P < .001). Coverage in all categories was significantly different among treating institutions, on univariate and multivariate analyses. Cribriform plate deficits were rare, with marginal misses of the foramen ovale (17.4%) and frontal lobe (12%) most common.We found consistent variation based on treating institution in proton CSI practices including optic nerve, VB, sacral nerve, cranial, and spinal nerve coverage. These data may serve as a baseline quantification of current proton CSI practices in the United States as they continue to evolve. 

Variation in Proton Craniospinal Irradiation Practice Patterns in the United States: A Pediatric Proton Consortium Registry (PPCR) Study

Purpose Craniospinal irradiation (CSI) is an important component of therapy for many pediatric central nervous system malignancies. Proton therapy is increasingly available and used for minimizing radiation exposure to normal tissues. The absence of an exit dose with proton therapy mandates decisions regarding coverage of the vertebral bodies (VB) in non–skeletally mature patients. Although the contents within the thecal sac represent the true clinical target volume (CTV), some physicians target the entire VB in growing children because of concerns over asymmetrical growth. This study aims to assess current practice patterns regarding VB coverage for pediatric patients undergoing CSI. Methods and Materials Pediatric radiation oncologists were identified from the Particle Therapy Co-Operative Group pediatric subcommittee membership or affiliation with US proton centers. Potential participants were contacted by e-mail with a link to an institutional review board–approved, anonymized web-based survey distributed in June 2017 with follow-up in October 2017. The survey used skip logic and included up to 11 questions regarding practice patterns. Results Thirty-three physicians responded to the survey (39%), 5 of which were excluded for lack of recent pediatric proton CSI experience. Of the 28 included responses, 23 physicians sometimes treat the entire VB and 5 physicians report always treating the entire VB. Most common responses regarding anterior CTV expansion for uncertainty were no expansion (n = 9) and 3 to 4 mm (n = 8). Most physicians modify the anterior CTV margin to protect normal structures, most commonly esophagus (n = 15), thyroid (n = 6), heart (n = 5), bowel (n = 4), and pharynx (n = 2). Conclusions Vertebral body coverage in proton CSI varies among radiation oncologists in respect to target delineation, CTV expansions, and modifications for organs at risk. These data suggest the radiation oncology community may benefit from a standardized approach to pediatric proton-based CSI.

Practice Patterns Among Radiation Oncologists Treating Pediatric Patients With Proton Craniospinal Irradiation.

For children, craniospinal irradiation (CSI) with photons is associated with significant toxic effects. The use of electrons for spinal fields is hypothesized to spare anterior structures but the long-term effects remain uncertain. We studied late effects of CSI using electrons for spinal radiation therapy (RT).Records of 84 consecutive patients treated with CSI using electrons for the spine at a single institution between 1983 and 2014 were reviewed. Median age at RT was 5 (range, 1-14) years. The most common histologies were medulloblastoma/primitive neuroectodermal tumor (59%) and ependymoma (8%). The median prescribed dose to the entire spine was 30 Gy (range, 6-45). A subset of 48 (57%) patients aged 2 to 14 at RT with clinical follow-up for ≥5 years was analyzed for late effects. Height z scores adjusted for age before and after CSI were assessed using stature-for-age charts and compared with a t test.At median follow-up of 19 years (range, 0-38 years), the median survival was 22 years (95% confidence interval, 12-28 years) after RT, with 47 patients (56%) alive at last follow-up. On subset analysis for late effects, 19 (40%) patients developed hypothyroidism and 5 (10%) developed secondary malignancies. Other complications reported were esophageal stricture and periaortic hemorrhage in 1 and restrictive pulmonary disease in 1 patient. Median height z score before treatment was -0.4 (36th percentile; interquartile range, -1.0 to 0.0) and at last follow-up was -2.2 (first percentile; interquartile range, -3.1 to -1.6; P < .001). Of 44 patients with spinal curvature assessments, 15 (34%) had scoliosis with median Cobb angle 15° (range, 10°-35°) and 1 (2%) required surgery.Frequent musculoskeletal toxic effects and predominantly decreased height were seen with long-term follow-up. Scoliosis and hypothyroidism were each seen in at least one-third of long-term survivors. However, clinically evident esophageal, pulmonary, and cardiac toxic effects were infrequent. 

Late Effects of Craniospinal Irradiation Using Electron Spinal Fields for Pediatric Cancer Patients.

Purpose This study aimed to evaluate the impact on spine growth in children with medulloblastoma using either photon or electron craniospinal irradiation (CSI). Methods and materials This was a single institution retrospective review of children who were treated with CSI for medulloblastoma. Spine growth was measured on magnetic resonance imaging scans at defined locations on the basis of a published predictive model of spine growth after CSI. Differences between spine growth in the anterior, middle, and posterior aspect of the designated vertebral segments were also assessed. Differences between the groups treated with photons or electrons were assessed with student’s t test. Results A total of 19 patients (10 patients treated with electrons and 9 with photons) with a median follow-up time of 45.5 months (confidence interval, 34.9-55.1 months) were evaluated. Patients treated with electrons were younger than those who received photons (5.1 years [range, 3.8-9.0 years] vs 9.6 years [range, 3.5-12.9 years]); however, there were no differences in other clinical characteristics, treatment, or follow-up between the groups. Spine growth rate for patients treated with electrons fit the predictive model (104% ± 5.2%), but patients treated with photons had growth that was faster than predicted by the model (150% ± 47%) and different from that observed with electrons. The differences between treatment the modalities were statistically significant (P = .03). For patients treated with photons, there were no statistical differences between the growth rate of the anterior vertebral body compared with the posterior aspect, but for patients treated with electrons, a faster spine growth in the anterior L1-L5 lumbar spine was observed compared with the posterior lumbar spine (3.90 vs 2.52 mm/year; P = .006) without differences in the cervical or thoracic spine. Conclusions The use of electrons to treat the craniospinal axis in children with medulloblastoma resulted in no significant difference in spine growth compared with the predicted spine growth on the basis of previously published models using photons, but with a clinically insignificant faster spine growth rate in the anterior lumbar spine.

Spinal Growth Patterns After Craniospinal Irradiation in Children With Medulloblastoma.

Background Bevacizumab in combination with chemotherapy prolonged the progression-free survival (PFS) of patients with recurrent epithelial ovarian cancer (EOC) in large-scale randomized controlled trials. However, real-world data for the use of bevacizumab in Asian patients with EOC is lacking. This study investigated the efficacy of adding bevacizumab to chemotherapy and compared it with that of chemotherapy alone in patients with recurrent EOC using real-world data from an Asian population. Method We conducted a retrospective cohort study using data from a tertiary medical center in central Taiwan. Patients who had EOC with first relapse between 2011 and 2019 were enrolled. Patients’ medical histories, medication treatment, and relevant information were collected. The outcomes were PFS and overall survival (OS). The Kaplan-Meier plot was used to generate a survival curve for OS and PFS. Cox proportional hazard analysis was used to determine the associations of Bevacizumab treatment with OS and PFS with adjustment of relevant variables. Subgroup analyses were conducted to determine if there was a significant variation in the aforementioned associations. Results After a median follow-up of 23 months, 67% of patients in the Bevacizumab group and 81% of patients in the non-Bevacizumab group had disease progression or death. There was no significant between-group difference in OS (p = 0.475). The median duration of PFS was 18.9 and 9.6 months, respectively, favoring those who were treated with Bevacizumab. After multivariate adjustment, treatment with Bevacizumab was associated with a lower risk of disease progression (hazard ratio 0.33, 95% CI 0.13-0.85, p = 0.021). The improvement in PFS was consistent in the subgroups of different histological types, different disease stages at diagnosis, different treatment-free intervals, those undergoing or not undergoing secondary cytoreductive surgery, diverse chemotherapy regimens. Conclusion Our findings provided crucial insights into the efficacy of bevacizumab for the treatment of recurrent EOC in the real-world setting.

/pdf/real-world-efficacy-of-bevacizumab-in-patients-with-1mzfhpqc.pdf

Real-World Efficacy of Bevacizumab in Patients With Recurrent Epithelial Ovarian Cancer

Various prophylactic antibiotic regimens are used in the management of preterm premature rupture of membranes. We investigated the efficacy and safety of these regimens in terms of maternal and neonatal outcomes.We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to July 20, 2021.We included randomized controlled trials involving pregnant women with preterm premature rupture of membranes before 37 weeks of gestation and a comparison of ≥2 of the following 10 antibiotic regimens: control/placebo, erythromycin, clindamycin, clindamycin plus gentamicin, penicillins, cephalosporins, co-amoxiclav, co-amoxiclav plus erythromycin, aminopenicillins plus macrolides, and cephalosporins plus macrolides.Two investigators independently extracted published data and assessed the risk of bias with a standard procedure following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Network meta-analysis was conducted using the random-effects model.A total of 23 studies that recruited a total of 7671 pregnant women were included. Only penicillins (odds ratio, 0.46; 95% confidence interval, 0.27-0.77) had significantly superior effectiveness for maternal chorioamnionitis. Clindamycin plus gentamicin reduced the risk of clinical chorioamnionitis, with borderline significance (odds ratio, 0.16; 95% confidence interval, 0.03-1.00). By contrast, clindamycin alone increased the risk of maternal infection. For cesarean delivery, no significant differences were noted among these regimens.Penicillins remain the recommended antibiotic regimen for reducing maternal clinical chorioamnionitis. The alternative regimen includes clindamycin plus gentamicin. Clindamycin should not be used alone. 

Efficacy of Prophylactic Antibiotics for Preterm Premature Rupture of Membranes: A Systematic Review and Network Meta-analysis.

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Spinal Growth Patterns After Craniospinal Irradiation in Children With Medulloblastoma.

Real-World Efficacy of Bevacizumab in Patients With Recurrent Epithelial Ovarian Cancer

Efficacy of Prophylactic Antibiotics for Preterm Premature Rupture of Membranes: A Systematic Review and Network Meta-analysis.