Purpose Recent in vivo investigations have shown that short pulses of electrons at very high dose rates (FLASH) are less harmful to healthy tissues but just as efficient as conventional dose-rate radiation to inhibit tumor growth. In view of the potential clinical value of FLASH and the availability of modern proton therapy infrastructures to achieve this goal, we herein describe a series of technological developments required to investigate the biology of FLASH irradiation using a commercially available clinical proton therapy system. Methods and Materials Numerical simulations and experimental dosimetric characterization of a modified clinical proton beamline, upstream from the isocenter, were performed with a Monte Carlo toolkit and different detectors. A single scattering system was optimized with a ridge filter and a high current monitoring system. In addition, a submillimetric set-up protocol based on image guidance using a digital camera and an animal positioning system was also developed. Results The dosimetric properties of the resulting beam and monitoring system were characterized; linearity with dose rate and homogeneity for a 12 × 12 mm2 field size were assessed. Dose rates exceeding 40 Gy/s at energies between 138 and 198 MeV were obtained, enabling uniform irradiation for radiobiology investigations of small animals in a modified clinical proton beam line. Conclusions This approach will enable us to conduct FLASH proton therapy experiments on small animals, specifically for mouse lung irradiation. Dose rates exceeding 40 Gy/s were achieved, which was not possible with the conventional clinical mode of the existing beamline.

Experimental Set-up for FLASH Proton Irradiation of Small Animals Using a Clinical System

Importance Concurrent chemoradiotherapy is the standard-of-care curative treatment for many cancers but is associated with substantial morbidity. Concurrent chemoradiotherapy administered with proton therapy might reduce toxicity and achieve comparable cancer control outcomes compared with conventional photon radiotherapy by reducing the radiation dose to normal tissues. Objective To assess whether proton therapy in the setting of concurrent chemoradiotherapy is associated with fewer 90-day unplanned hospitalizations (Common Terminology Criteria for Adverse Events, version 4 [CTCAEv4], grade ≥3) or other adverse events and similar disease-free and overall survival compared with concurrent photon therapy and chemoradiotherapy. Design, Setting, and Participants This retrospective, nonrandomized comparative effectiveness study included 1483 adult patients with nonmetastatic, locally advanced cancer treated with concurrent chemoradiotherapy with curative intent from January 1, 2011, through December 31, 2016, at a large academic health system. Three hundred ninety-one patients received proton therapy and 1092, photon therapy. Data were analyzed from October 15, 2018, through February 1, 2019. Interventions Proton vs photon chemoradiotherapy. Main Outcomes and Measures The primary end point was 90-day adverse events associated with unplanned hospitalizations (CTCAEv4 grade ≥3). Secondary end points included Eastern Cooperative Oncology Group (ECOG) performance status decline during treatment, 90-day adverse events of at least CTCAEv4 grade 2 that limit instrumental activities of daily living, and disease-free and overall survival. Data on adverse events and survival were gathered prospectively. Modified Poisson regression models with inverse propensity score weighting were used to model adverse event outcomes, and Cox proportional hazards regression models with weighting were used for survival outcomes. Propensity scores were estimated using an ensemble machine-learning approach. Results Among the 1483 patients included in the analysis (935 men [63.0%]; median age, 62 [range, 18-93] years), those receiving proton therapy were significantly older (median age, 66 [range, 18-93] vs 61 [range, 19-91] years;P  Conclusions and Relevance In this analysis, proton chemoradiotherapy was associated with significantly reduced acute adverse events that caused unplanned hospitalizations, with similar disease-free and overall survival. Prospective trials are warranted to validate these results.

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Comparative Effectiveness of Proton vs Photon Therapy as Part of Concurrent Chemoradiotherapy for Locally Advanced Cancer

Objective: The aim of this study is to evaluate the preventive effects of carvedilol on doxorubicin-induced cardiotoxicity. Methods: In this trial, 70 female patients with breast cancer who were candidates to receive doxorubicin were enrolled, from which 30 were selected randomly to receive carvedilol 6.25 mg daily during chemotherapy, with the rest receiving placebo as the control group. Both groups were evaluated 1 week before and 1 week after chemotherapy by measuring the left ventricular ejection fraction and strain/strain rate. Results: Data analysis showed that the case group presented no significant reduction in strain and strain-rate parameters after intervention, while there was a significant reduction in these parameters in the control group (all p values Conclusion: This study shows that carvedilol can prevent doxorubicin-induced cardiotoxicity. Whether this prophylaxis should be considered as the preferred method needs further investigation.

Carvedilol Administration Can Prevent Doxorubicin-Induced Cardiotoxicity: A Double-Blind Randomized Trial.

Low grade gliomas (LGGs) constitute the largest, yet clinically and (molecular-) histologically heterogeneous group of pediatric brain tumors of WHO grades I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest. Around 40% of all LGG patients can be cured by complete neurosurgical resection and are followed by close observation. In case of relapse, second resection often is possible. Following incomplete resection observation is recommended, as long as there is no radiologic tumor growth and the patient does not suffer from significant, tumor-related symptoms. This also applies to patients with a diagnosis of LGG on the basis of radiological criteria. By contrast, clinical worsening and / or radiologic progression are an indication to treatment with either chemo- or radiotherapy. Overall survival is around 90%, and many patients survive with residual tumor, i. e. they suffer from chronic disease. All patients need comprehensive neuro-oncological care, the principles and details of which are summarized in the current guidelines. These represent standard of care for diagnostic work-up (including neuroimaging and neuropathology), and for therapeutic decisions (including the indications to non-surgical treatment) as well as concepts for neurosurgical intervention, chemotherapy and radiotherapy as well as surveillance and rehabilitation. The current treatment algorithm was compiled by members of the LGG working group of the SIOP-E brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports.

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SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma.

Incremental improvements in the treatment of children and adolescents with cancer have led to 5-year survival rates reaching nearly 85%. In the past decade, impressive progress has been made in understanding the biology of many pediatric cancers. With that understanding, multiple new agents have become available that offer the promise of more-effective and less-toxic treatment. These include agents that target various cell surface antigens and engage the adaptive immune system, as well as those that interfere with key signaling pathways involved in tumor development and growth. For local control, surgery and radiation techniques also have evolved, becoming less invasive or featuring new techniques and particles that more precisely target the tumor and limit the dose to normal tissue. Nevertheless, targeted agents, like conventional chemotherapy, radiotherapy, and surgery, may have off-target effects and deserve long-term follow-up of their safety and efficacy. These include injury to the endocrine, cardiovascular, and immunologic systems. New radiation and surgical techniques that theoretically reduce morbidity and improve long-term quality of life must also be validated with actual patient outcomes. Finally, with advances in genomics, information on host susceptibility to late effects is beginning to emerge. Such knowledge, coupled with improved metrics that better describe the spectrum of potential late effects across the entire lifespan, can lead to the development of decision models that project the potential long-term health outcomes associated with various treatment and follow-up strategies. These developments will help extend the current focus on precision medicine to precision survivorship, where clinicians, patients, and families will have a better grasp of the potential risks, benefits, and tradeoffs associated with the growing number of cancer treatment options.

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New Agents, Emerging Late Effects, and the Development of Precision Survivorship.

Consensus Report From the Stockholm Pediatric Proton Therapy Conference.

Anthracycline chemotherapy (AC) is associated with impaired left ventricular (LV) systolic function. LV ejection fraction (EF %) obtained by two-dimensional echocardiography is the current gold standard for detection and monitoring of LV systolic function. However, dependence on LVEF has been shown to be unreliable due to its inherent limitations. Speckle tracking echocardiography (STE) measures myocardial strain and is a sensitive method to detect LV systolic dysfunction with demonstrated utility in such detection in adult and pediatric cohort studies. Compare myocardial strain indices derived by STE with LVEF to detect ACT-induced LV systolic dysfunction. Prospective, cross-sectional measurements of LV myocardial strain indices derived from STE with LVEF. Pediatric cohort of 25 patients (pts): 17 females, eight males with a mean age 9.8 ± 5.8 years, who received anthracyclines (AC); median cumulative dose ≥150 ± 124.4 mg/m2, range 60–450 mg/m2 showing normal LV end-diastolic diameter (mm) and normal LVEF (≥55 %) underwent STE to obtain LV myocardial strain indices: strain and strain rate. The inter- and intraobserver variability for the strain indices was 5 %. Fifteen of 25 pts (60 %) showed abnormal global longitudinal peak systolic strain (GLPSS) and 19/25 pts (76 %) showed abnormal peak circumferential strain (PCS) compared to age-matched controls (p = 0.005). In contrast, no significant differences was observed in either indices with the dose of AC. Likewise, no significant changes in the systolic or diastolic strain rate were noted with the dose of AC (r
 2 = 0.0076 for peak E, r
 2 = 0.072 for peak A, p = NS). GLPSS and PCS were diminished and, however, correlated poorly with the cumulative dose of AC. These observations indicate an early onset of LV systolic dysfunction by the strain indices in pts who continue to show a normal LVEF implying presence of occult LV systolic dysfunction. These novel strain indices may assist in early detection of LV systolic dysfunction with implications for monitoring and prevention of AC-induced LV systolic dysfunction.

Abnormal Myocardial Strain Indices in Children Receiving Anthracycline Chemotherapy.

Neuroendocrine tumor (NET) of the appendix is the most common gastrointestinal epithelial tumor in children. The utility of serum markers or the indication for hemicolectomy has not been established in children. In 45 children diagnosed with appendiceal NET, 89% NETs were incidentally found following appendectomy performed for suspected acute appendicitis. The median age was 12 years, and 56% patients were female. Postoperative somatostatin scan (n=5), serum chromogranin A (n=4), and urine 5-HIAA (n=9) were all within normal limits. Pathology slides of 35 patients showed mesoappendiceal invasion in 29% patients, and vascular invasion in 6% patients. Seven patients (16%) underwent hemicolectomy for invasion of mesoappendix (n=5), tumor near the resection margin (n=1), and tumor size 1.5 cm with vascular invasion (n=1). Only 2 hemicolectomy specimens showed disease: one in the appendiceal stump and the other as a micrometastasis in a mesenteric lymph node. There were no recurrences and all patients were alive and without evidence of disease at last follow-up. Pediatric appendiceal NET tends to have a benign clinical course with excellent prognosis. In the absence of carcinoid syndrome, postoperative scans and serum biomarkers do not seem to be useful. With completely resected tumors, the indication for hemicolectomy is unclear.

M.F. Okcu

Papers

Consensus Report From the Stockholm Pediatric Proton Therapy Conference.

Abnormal Myocardial Strain Indices in Children Receiving Anthracycline Chemotherapy.

Neuroendocrine Tumor of the Appendix in Children

Clinical Outcomes of Children With Medulloblastoma After Proton Radiation Therapy

Proton Therapy for Pediatric AT/RT of the CNS