Severe Treatment-related Complications Research Articles

Bayesian analysis of the Substrate Ablation vs. Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia trial.

Bayesian analyses can provide additional insights into the results of clinical trials, aiding in the decision-making process. We analysed the Substrate Ablation vs. Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia (SURVIVE-VT) trial using Bayesian survival models. The SURVIVE-VT trial randomized patients with ischaemic cardiomyopathy and monomorphic ventricular tachycardia (VT) to catheter ablation or antiarrhythmic drugs (AAD) as a first-line strategy. The primary outcome was a composite of cardiovascular death, appropriate implantable cardioverter-defibrillator shocks, unplanned heart failure hospitalizations, or severe treatment-related complications. We used informative, skeptical, and non-informative priors with different probabilities of large effects to compute the posterior distributions using Markov Chain Monte Carlo methods. We calculated the probabilities of hazard ratios (HR) being <1, <0.9, and <0.75, as well as 2-year survival estimates. Of the 144 randomized patients, 71 underwent catheter ablation and 73 received AAD. Regardless of the prior, catheter ablation had a >98% probability of reducing the primary outcome (HR < 1) and a >96% probability of achieving a reduction of >10% (HR < 0.9). The probability of a >25% (HR < 0.75) reduction of treatment-related complications was >90%. Catheter ablation had a high probability (>93%) of reducing incessant/slow undetected VT/electric storm, unplanned hospitalizations for ventricular arrhythmias, and overall cardiovascular admissions > 25%, with absolute differences of 15.2%, 21.2%, and 20.2%, respectively. In patients with ischaemic cardiomyopathy and VT, catheter ablation as a first-line therapy resulted in a high probability of reducing several clinical outcomes compared to AAD. Our study highlights the value of Bayesian analysis in clinical trials and its potential for guiding treatment decisions. ClinicalTrials.gov identifier: NCT03734562.

Endoscopic surgery versus intensity-modulated radiotherapy in locally advanced recurrent nasopharyngeal carcinoma: a multicenter, case-matched comparison

BackgroundThe management of locally advanced recurrent nasopharyngeal carcinoma (rNPC) is challenging. The objective of our study was to compare salvage endoscopic nasopharyngectomy (ENPG) with intensity-modulated radiotherapy (IMRT) in clinical outcomes and complications of locally advanced rNPC.MethodsPatients with histologically confirmed rNPC in rT3-4N0-3M0 stages were retrospectively enrolled between January 2013 and December 2019 in this multicenter, case-matched study. The baseline clinicopathological characteristics of patients were balanced by propensity score matching between the ENPG and IMRT groups. ENPG was performed in patients with easily or potentially resectable tumors. The oncological outcomes as well as treatment-related complications were compared between two groups.ResultsA total of 176 patients were enrolled and 106 patients were matched. The ENPG group (n = 53) and the IMRT group (n = 53) showed comparable outcomes in the 3-year overall survival rate (68.4% vs. 65.4%, P = 0.401), cancer-specific survival rate (80.9% vs. 74.4%, P = 0.076), locoregional failure-free survival rate (36.6% vs. 45.3%, P = 0.076), and progression-free survival rate (27.5% vs. 32.3%, P = 0.216). The incidence of severe treatment-related complications of patients in the ENPG group was lower than that in the IMRT group (37.7% vs. 67.9%, P = 0.002). The most common complications were post perioperative hemorrhage (13.2%) in ENPG group and temporal lobe necrosis (47.2%) in IMRT group, respectively.ConclusionSalvage ENPG exhibits comparable efficacy but less toxicities than IMRT in carefully screened patients with locally advanced rNPC, which may be a new choice of local treatment.Graphical abstract

Peroral endoscopic myotomy versus pneumatic dilation in treatment-naive patients with achalasia: 5-year follow-up of a randomised controlled trial

2-year follow-up data from our randomised controlled trial showed that peroral endoscopic myotomy is associated with a significantly higher efficacy than pneumatic dilation as initial treatment of therapy-naive patients with achalasia. Here we report therapeutic success rates in patients treated with peroral endoscopic myotomy compared with pneumatic dilation at the 5-year follow-up. We did a multicentre, randomised controlled trial in six hospitals in the Netherlands, Germany, Italy, Hong Kong, and the USA. Adults aged 18-80 years with newly diagnosed symptomatic achalasia (based on an Eckardt score >3) were eligible for inclusion. Patients were randomly assigned (1:1) to peroral endoscopic myotomy or pneumatic dilation using web-based randomisation with a random block size of 8 and stratification according to site. Randomisation concealment for treatment type was double blind until official study enrolment. Treatment was unmasked because of the different technical approach of each procedure. Patients in the pneumatic dilation group were dilated with a single series of 30-35 mm balloons. The need for subsequent dilations in the pneumatic dilation group, and the need for dilation after initial treatment in the peroral endoscopic myotomy group, was considered treatment failure. The primary outcome was therapeutic success (Eckardt score ≤3 in the absence of severe treatment-related complications and no need for retreatment). Analysis of the primary outcome was by modified intention to treat, including all patients randomly assigned to a group, excluding those patients who did not receive treatment or were lost to follow-up. Safety was assessed in all included patients. This study is registered at the Dutch Trial Registry, NTR3593, and is completed. Between Sept 21, 2012, and July 20, 2015, 182 patients were assessed for eligibility, 133 of whom were included in the study and randomly assigned to peroral endoscopic myotomy (n=67) or pneumatic dilation (n=66). 5-year follow-up data were available for 62 patients in the peroral endoscopic myotomy group and 63 patients in the pneumatic dilation group. 50 (81%) patients in the peroral endoscopic myotomy group had treatment success at 5 years, compared with 25 (40%) in the pneumatic dilation group, an adjusted absolute difference of 41% (95% CI 25-57; p<0·0001). Reasons for failure were no initial effect of treatment (one patient in the peroral endoscopic myotomy group vs 12 patients in the pneumatic dilation group) and recurrent symptoms causing treatment failure (11 patients in the peroral endoscopic myotomy group [seven patients between 2 and 5 years] vs 25 patients in the pneumatic dilation group [nine patients between 2 and 5 years]); one patient in the pneumatic dilation group had treatment failure due to an adverse event. Proton-pump inhibitor use (mostly daily) was significantly higher after peroral endoscopic myotomy than after pneumatic dilation among patients still in clinical remission (23 [46%] of 50 patients vs three [13%] of 24 patients; p=0·008). 5-year follow-up endoscopy of patients still in clinical remission showed reflux oesophagitis in 14 (33%) of 42 patients in the peroral endoscopic myotomy group (12 [29%] grade A or B, two [5%] grade C or D) and two (13%) of 16 patients in the pneumatic dilation group (two [13%] grade A or B, none grade C or D; p=0·19). No intervention-related serious adverse events occurred between 2 and 5 years after treatment. The following non-intervention-related serious adverse events occurred between 2 and 5 years: a stroke (one [2%]) in the peroral endoscopic myotomy group; and death due to a melanoma (one [2%]) and dementia (one [2%]) in the pneumatic dilation group. Based on this study, peroral endoscopic myotomy should be proposed as an initial treatment option for patients with achalasia. Although our study has shown that peroral endoscopic myotomy has greater long-term efficacy with a low risk of major treatment-related complications, this should not lead to abandonment of pneumatic dilation from clinical practice. Ideally, all treatment options should be discussed with treatment-naive patients with achalasia and a shared decision should be made. Fonds NutsOhra and European Society of Gastrointestinal Endoscopy.

EP News: Clinical

Arenal et al (J Am Coll Cardiol 2022;15:1441, PMID 35422240) compared catheter ablation (CA) with antiarrhythmic drug (AAD) as first-line therapy in patients with ventricular tachycardia in a prospective, multicenter, randomized trial of patients with ischemic cardiomyopathy and appropriate implantable cardioverter-defibrillator (ICD) shock. Patients were randomized to endocardial substrate–based CA or AAD (amiodarone + β-blockers, amiodarone alone, or sotalol ± β-blockers). The primary outcome was a composite of cardiovascular death, appropriate ICD shock, unplanned hospitalization for worsening heart failure, or severe treatment-related complications.

Substrate Ablation vs Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia

BackgroundIn patients with ischemic cardiomyopathy and an implantable cardioverter-defibrillator (ICD), catheter ablation and antiarrhythmic drugs (AADs) reduce ICD shocks, but the most effective approach remains uncertain. ObjectivesThis trial compares the efficacy and safety of catheter ablation vs AAD as first-line therapy in ICD patients with symptomatic ventricular tachycardias (VTs). MethodsThe SURVIVE-VT (Substrate Ablation vs Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia) is a prospective, multicenter, randomized trial including patients with ischemic cardiomyopathy and appropriated ICD shock. Patients were 1:1 randomized to complete endocardial substrate-based catheter ablation or antiarrhythmic therapy (amiodarone + beta-blockers, amiodarone alone, or sotalol ± beta-blockers). The primary outcome was a composite of cardiovascular death, appropriate ICD shock, unplanned hospitalization for worsening heart failure, or severe treatment-related complications. ResultsIn this trial, 144 patients (median age, 70 years; 96% male) were randomized to catheter ablation (71 patients) or AAD (73 patients). After 24 months, the primary outcome occurred in 28.2% of patients in the ablation group and 46.6% of those in the AAD group (hazard ratio [HR]: 0.52; 95% CI: 0.30-0.90; P = 0.021). This difference was driven by a significant reduction in severe treatment-related complications (9.9% vs 28.8%, HR: 0.30; 95% CI: 0.13-0.71; P = 0.006). Eight patients were hospitalized for heart failure in the ablation group and 13 in the AAD group (HR: 0.56; 95% CI: 0.23-1.35; P = 0.198). There was no difference in cardiac mortality (HR: 0.93; 95% CI: 0.19-4.61; P = 0.929). ConclusionsIn ICD patients with ischemic cardiomyopathy and symptomatic VT, catheter ablation reduced the composite endpoint of cardiovascular death, appropriate ICD shock, hospitalization due to heart failure, or severe treatment-related complications compared to AAD. (Substrate Ablation vs Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia [SURVIVE-VT]: NCT03734562)

Brachytherapy for Pediatric Patients at Gustave Roussy Cancer Campus: A Model of International Cooperation for Highly Specialized Treatments

Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers. We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy. We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy. This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability.

Unresectable bulky chest wall recurrent breast cancer controlled with CT-guided interstitial high-dose-rate brachytherapy and external beam radiotherapy with adjuvant hormonal therapy – case report

PurposeBulky chest wall recurrence after mastectomy presents a therapeutic challenge because of high-dose of radiation required to control the disease, and its proximity to low-tolerance organs at risk. We report a case of successful computed tomography (CT)-guided high-dose-rate (HDR) salvage interstitial brachytherapy (ISBT) boost.Material and methodsA 70-year-old female initially presented with a tumor in right breast, and was treated with mastectomy and adjuvant chemotherapy, followed by hormonal therapy for 5 years without adjuvant radiotherapy. In 2018, 20 years after the initial treatment, she developed unresectable chest wall recurrence that measured 10.5 cm × 7.3 cm × 4.5 cm, with bone and parietal pleura invasion. Biopsy revealed invasive pleomorphic lobular carcinoma [estrogen receptor (ER)-positive, progesterone receptor (PR)-negative, HER2-negative]. There was no evidence of metastatic disease.ResultsThe patient underwent external beam radiotherapy (EBRT) plus ISBT. After EBRT of 50 Gy in 25 fractions was completed, CT-guided ISBT was performed as an outpatient treatment. HDR dose was 16 Gy delivered in 2 fractions with 2 implants. Dose was prescribed to gross tumor volume. ISBT plans were created using inverse planning simulated annealing (IPSA) algorithm. Gross tumor volume D90% plus EBRT dose was 82 Gy equivalent dose of 2 Gy (EQD2), assuming α/β of 4 for breast carcinoma. The patient continued on hormonal therapy. At the 30-month follow-up, the patient remains in remission. The tumor could not be detected by magnetic resonance imaging (MRI) or positron emission tomography (PET). There were no severe treatment-related complications.ConclusionsCT-guided HDR ISBT boost can be a useful modality in individualizing treatment strategies for breast cancer patients with unresectable bulky chest wall recurrence.

Autologous stem-cell transplantation in systemic sclerosis-associated interstitial lung disease: early action in selected patients rather than escalation therapy for all.

Systemic sclerosis (SSc) is a rare rheumatic disease characterised by inflammation, vasculopathy and fibrosis of skin and internal organs. A common complication and a leading cause of death in SSc is interstitial lung disease (ILD). The current armamentarium of treatments in SSc-ILD mainly includes immunosuppressive therapies and has recently been expanded with anti-fibrotic agent nintedanib. Autologous stem cell transplantation (SCT) is increasingly used in progressive diffuse cutaneous SSc. This intensive treatment has been studied in three randomised trials and demonstrated to improve survival and quality of life. In the subsets of patients with SSc-ILD, SCT resulted in stabilisation and modest improvement of lung volumes and disease extent on high resolution computed tomography, but less impact was seen on diffusion capacity. Comparison of SCT outcomes with results from SSc-ILD trials is difficult though, as lung involvement per se was not an inclusion criterion in all SCT trials. Also, baseline characteristics differed between studies. The risk of severe treatment-related complications from SCT is still considerable and patients with extensive lung disease are particularly at risk of complications during transplantation. Therefore SCT should only be provided by experienced multidisciplinary teams in carefully selected patients. Future research needs to include comprehensive pulmonary evaluation and establish whether SCT early in the disease might prevent irreversible pulmonary damage and reduce treatment-related complications. Also, more insight in mechanisms of action of SCT in the lung and predictors for response will improve the use of this treatment in SSc-ILD. In this review the role of SCT in the treatment of SSc-ILD is summarised.

Clinical Significance of Vulnerability Assessment in Patients with Primary Head and Neck Cancer Undergoing Definitive Concurrent Chemoradiation Therapy

This study aimed to identify vulnerable patients with head and neck cancer undergoing concurrent chemoradiation therapy (CCRT) who are susceptible to higher treatment-related adverse effects and have poorer treatment tolerance. This study also aimed to determine whether comprehensive geriatric assessment, developed in the geriatric population, can predict vulnerability to treatment-related adverse events and survival even in nongeriatric patients with head and neck cancer, as well as the prevalence of vulnerability and its effect on toxicities and survival among these patients. This prospective cohort study examined 461 patients with primary head and neck cancer who underwent definitive CCRT during 2016 to 2017 at 3 medical centers across Taiwan. Vulnerability is defined as susceptibility to cancer- and treatment-related adverse events that result in poor treatment tolerance and unexpected emergent medical needs, such as hospitalization and emergency room visits. Vulnerability was assessed as impairment with ≥2 dimensions on comprehensive geriatric assessment, 7 days before CCRT. The association of vulnerability with treatment-related adverse events and survival was analyzed. The prevalence of vulnerability was 22.2%, 27.3%, 30.2%, and 27.9% among patients aged 20 to 34, 35 to 49, 50 to 64, and >65 years, respectively. Survival was poorer in vulnerable patients than in nonvulnerable patients (hazard ratio, 1.97; 95% confidence interval, 1.26-3.07; P = .003). Vulnerable patients showed a higher tendency toward CCRT incompletion (19.5% vs 6.1%, P < .001), hospitalization (34.6% vs 23.5%, P = .020), need for tubal feeding (29.3% vs 11.8%, P<.001), and longer length of hospital stay (8.1 days vs 4.0 days, P = .004) than nonvulnerable patients. Hematologic and nonhematologic toxicities were more severe in vulnerable patients than in nonvulnerable patients. Vulnerability, which is an urgent concern when it presents among patients with head and neck cancer, was independently associated with poorer survival and severe treatment-related complications. Vulnerability assessment should be routinely evaluated in all patients with primary head and neck cancer who are undergoing definitive CCRT, not only in such patients who are geriatric.

Surgical resection based on ontogenetic cancer field theory for cervical cancer: mature results from a single-centre, prospective, observational, cohort study.

Previous findings from our centre suggest that carcinoma of the cervix propagates within ontogenetic cancer fields, tissue compartments defined by staged morphogenesis. We aimed to determine whether surgical treatment that accounts for stage-associated, ontogenetic cancer fields and their associated lymphoid tissues results in locoregional tumour control without the need for adjuvant radiotherapy. We did the final clinical and histopathological evaluation of data from, the single-centre, observational, cohort study, the Leipzig School Mesometrial Resection Study. Patients of any age with stage IB1, IB2, IIA1, IIA2, or IIB cervical cancer (according to 2009 International Federation of Gynecology and Obstetrics [FIGO]) had total mesometrial resection or extended mesometrial resection and therapeutic lymph node dissection, done on the basis of ontogenetic cancer fields. We defined sentinel node, first-line, second-line, and third-line lymph node regions as progressive regional cancer fields. Primary outcomes were disease-specific survival and recurrence-free survival, and treatment-related morbidity (assessed with the Franco-Italian glossary). Applying Cox proportional hazard models, ontogenetic local (T) and regional (N) tumour staging was compared with pathological T and N staging. This trial is registered with the German Clinical Trials Register, number DRKS00015171. Between Oct 16, 1999, and June 27, 2017, 523 patients were treated per protocol and followed up for a median of 61·8 months (IQR 49·3-94·8). In 495 patients with cervical cancer treated with cancer field surgery, 5-year disease-specific survival was 89·4% (95% CI 86·5-92·4) and recurrence-free survival was 83·1% (79·7-86·6). In the per-protocol population of 523 patients, treatment-related morbidity comprised 112 (21%) grade 2 and 15 (3%) grade 3 complications. The most common moderate and severe treatment-related complications and sequelae were wound dehiscence (17 [3%]), hydronephrosis (17 [3%]), bowel obstruction (26 [5%]), and lymph oedema (33 [6%]). One patient (<1%), who received total mesometrial resection, died from postoperative brain infarction. Total or extended mesometrial resection with therapeutic lymph node dissection based on ontogenetic cancer fields results in good survival outcomes of patients with cervical cancer in our institution, but needs to be investigated further in multicentre trials. Leipzig School of Radical Pelvic Surgery, University of Leipzig Medical School, and the Gynecologic Oncology Research Foundation.

Assessment of the proposed EBMT pediatric criteria for diagnosis and severity grading of sinusoidal obstruction syndrome

Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). We assessed the proposed pediatric EBMT criteria along with the Baltimore and modified Seattle criteria in a population-based cohort. Eighty-seven children (1.1–17.3 years) undergoing myeloablative HSCT from 2010 to 2017 were consecutively included at the Danish National Transplantation Center. In total, 39 (44.8%) patients fulfilled the EBMT criteria and 30 patients (35%) fulfilled the criteria for severe or very severe SOS. Nine (10.3%) patients fulfilled the modified Seattle criteria while none met the Baltimore criteria. Patients fulfilling the EBMT criteria for SOS had longer primary admission (31 days (23–183) vs. 27 days (17–61), p = 0.001), were treated more intensively with diuretics within the first 3 months (29 days (0–90) vs. 3.5 days (0–90), p < 0.0001), and had a longer time to stable platelet counts >50 × 109/L (32 days (16–183) vs. 23 days (14–101), p < 0.0001). Two patients, fulfilling neither Baltimore nor Seattle criteria, but selectively fulfilling EBMT criteria, died of treatment-related acute inflammatory complications within 1 year post-HSCT. In conclusion, application of the pediatric EBMT diagnostic and severity criteria may be helpful in identifying patients at increased risk of severe treatment-related complications and mortality, although with a risk of over-diagnosing SOS.

Clinical outcome after high-precision radiotherapy for skull base meningiomas: Pooled data from three large German centers for radiation oncology

PurposeTo evaluate outcome in patients with base of skull meningiomas treated with modern high precision radiation therapy (RT) techniques. Patients and methods927 patients from three centers were treated with either radiosurgery or fractionated high-precision RT for meningiomas. Treatment planning was based on CT and MRI following institutional guidelines. For radiosurgery, a median dose of 13 Gy was applied, for fractionated treatments, a median dose of 54 Gy in 1.8 Gy single fractions was prescribed. Follow-up included a clinical examination as well as contrast-enhanced imaging. All patients were followed up prospectively after radiotherapy in the three departments within a strict follow-up regimen. The median follow-up time was 81 months (range 1–348 months). ResultsMedian local control was 79 months (range 1–348 months). Local control (LC) was 98% at 1 year, 94% at 3 years, 92% at 5 years and 86% at 10 years. There was no difference between radiosurgery and fractionated RT. We analyzed the influence of higher doses on LC and could show that dose did not impact LC. Moreover, there was no difference between 54 Gy and 57.6 Gy in the fractionated group. Side effects were below 5% in both groups without any severe treatment-related complications. DiscussionBased on the pooled data analysis this manuscript provides a large series of meningiomas of the skull base treated with modern high precision RT demonstrating excellent local control and low rates of side effects. Such data support the recommendation of RT for skull base meningiomas in the interdisciplinary tumor board discussions. The strong role of RT must influence treatment recommendations keeping in mind the individual risk–benefit profile of treatment alternatives.

Long-term outcomes of endoscopic submucosal dissection versus surgery in early gastric cancer meeting expanded indication including undifferentiated-type tumors: a criteria-based analysis.

Endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) meeting the expanded indication is considered investigational. We aimed to compare long-term outcomes of ESD and surgery for EGC in the expanded indication based on each criterion. This study included 1823 consecutive EGC patients meeting expanded indication conditions and treated at a tertiary referral center: 916 and 907 patients underwent surgery or ESD, respectively. The expanded indication included four discrete criteria: (I) intramucosal differentiated tumor, without ulcers, size>2cm; (II) intramucosal differentiated tumor, with ulcers, size≤3cm; (III) intramucosal undifferentiated tumor, without ulcers, size≤2cm; and (IV) submucosal invasion<500μm (sm1), differentiated tumor, size≤3cm. We selected 522 patients in each group by propensity score matching and retrospectively evaluated each group. The primary outcome was overall survival (OS); the secondary outcomes were disease-specific survival (DSS), recurrence-free survival (RFS), and treatment-related complications. In all patients and subgroups meeting each criterion, OS and DSS were not significantly different between groups (OS and DSS, all patients: p=0.354 and p=0.930; criteria I: p=0.558 and p=0.688; criterion II: p=1.000 and p=1.000; criterion III: p=0.750 and p=0.799; and criterion IV: p=0.599 and p=0.871). RFS, in all patients and criterion I, was significantly shorter in the ESD group than in the surgery group (p<0.001 and p<0.003, respectively). The surgery group showed higher rates of late and severe treatment-related complications than the ESD group. ESD may be an alternative treatment option to surgery for EGCs meeting expanded indications, including undifferentiated-type tumors.

Progression-Free Survival after Proton Therapy for Childhood Craniopharyngioma: Early Results From a Prospective Trial

Clinical trials that include proton therapy for children should be designed to compare disease control rates to those observed when using photon therapy. We designed a prospective phase II clinical trial to estimate progression-free for children with craniopharyngioma treated with proton therapy using a 5-mm clinical target volume (CTV) margin (NCT01419067) while monitoring for evidence that the 3-year PFS was unacceptably low compared to that observed for a historical cohort of patients treated with photon therapy (NCT00187226). The study accrued 94 children and young adults with craniopharyngioma who started proton therapy between 9/19/2011 and 02/22/2016 using the passive-scattering method at the University of Florida Health Proton Therapy Institute. The median age and range at the time of proton therapy was 9.4 years (range (2-20.2 years). Proton therapy was planned using an anatomically constrained CTV 5-mm margin surrounding the gross tumor volume (GTV) defined as residual tumor and post-operative tumor (when applicable) and 3-mm planning target volume margin. Patients were monitored once weekly using MR imaging. Cyst expansion required re-planning (n = 8), drainage (n = 4), or both (n = 2) to maintain coverage. The total prescribed dose was 54CGE in 30 fractions and the median elapsed days was 43 (range 40-50). Dated from the start of proton therapy, patients were followed at St. Jude Children’s Research Hospital in Memphis, Tennessee with clinical evaluation and MR imaging at baseline and every 3 months for the first year and then every 6 months through 5 years. Compliance with on-site follow-up was 98% and 869 on-site MRI evaluations contributed to this report. With a median follow-up 2.65 years (range 0.50-5.23 years), the progression-free survival estimated at 36 months was 97.8% ± 2.5%. More than 46 patients completed 3 years of follow-up at the time of this report. The results were compared to a cohort of 101 children with craniopharyngioma treated at St. Jude Children’s Research Hospital with photon-based conformal or intensity-modulated radiation therapy (54 Gy in 30 fractions) between 4/6/1998 and 1/22/2014. The progression-free survival estimate at 36 months was 96.0% ± 1.9% for the photon cohort. Using the targeting guidelines and proton therapy delivery methods described in this clinical trial, the progression-free survival estimates were comparable to those observed when using photon therapy. Prior reports from this series revealed similar risks of severe treatment-related complications. Final analysis will be performed 3 years after the last patient has been treated with proton therapy, with one additional year to calculate 95% exact confidence interval estimates of the binomial probability of completing three years free of failure and Kaplan-Meier estimates of PFS and overall survival.

Treatment of relapsed or refractory acute myeloid leukemia.

Prognosis for refractory or relapsed acute myeloid leukemia (AML) patients is poor, and allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only salvage option with curative potential for these patients. As the outcome of allogeneic HSCT in patients without complete remission (CR) status is unsatisfactory, it is important to attain a second CR before HSCT. An aggressive re-induction therapy for relapsed or refractory AML patients is often accompanied with severe infectious complications due to profound myelosuppression, which makes subsequent HSCT challenging. Furthermore, in AML patients with high-risk clinical features who do not achieve CR after remission induction chemotherapy (CT), allogeneic HSCT, preemptively performed immediately after re-induction CT or without prior CT, may induce durable remission in some patients. Determining the timing of HSCT and selecting a salvage regimen as a bridging therapy to HSCT are essential for avoiding severe treatment-related complications.

Restoration of Patency to Central Airways Occluded by Malignant Endobronchial Tumors Using Intratumoral Injection of Cisplatin.

Malignant airway obstruction is commonly found in patients with lung cancer and is associated with significant morbidity and mortality. Relieving malignant obstruction may improve symptoms, quality of life, and life expectancy. The objective of this study was to analyze our experience with bronchoscopic endobronchial intratumoral injection of cisplatin for malignant airway obstruction. We conducted a retrospective analysis of patients with malignant airway obstruction treated with bronchoscopic intratumoral injection of cisplatin. Patient characteristics, histology, degree of airway obstruction, procedural methods, treatment cycles, performance status, and therapeutic outcomes were evaluated. Tumor response was analyzed based on bronchoscopic measurements performed on completion the of final treatment session. Adverse events and overall survival were abstracted. Between January 2009 and September 2014, 22 patients (10 men, 12 women; mean age ± SD, 64.4 ± 9.5 yr) were treated with one to four injections of 40 mg of cisplatin mixed in 40 ml of 0.9% NaCl. Treatments were completed 1 week apart. The primary etiologies of airway obstruction included squamous cell carcinoma (n = 11), adenocarcinoma (n = 6), small cell carcinoma (n = 2), large cell undifferentiated carcinoma (n = 1), and metastatic endobronchial cancer (n = 2). Twenty-one of 22 patients were evaluable for response. The majority of patients (15/21, 71.4%) responded to therapy, defined as greater than 50% relative reduction in obstruction from baseline. Treatment response was obtained regardless of tumor histology, concurrent systemic therapy, number of treatment cycles administered, performance status, or use of additional ablative interventions. Responders had significantly improved overall survival as compared with nonresponders, although the difference was small. Severe treatment-related side effects or complications were not observed. Subject to the limitations of a single-center retrospective study and a subjective primary outcome measure, we have demonstrated the feasibility of improving the patency of central airways that are largely or completely occluded by endobronchial malignant tumor using intraluminal injection of cisplatin. Additional longer-term, larger-scale safety and comparative effectiveness studies of this palliative treatment modality are warranted.

Image-guided stereotactic radiotherapy for patients with vestibular schwannoma

Local tumor control and functional outcome after linac-based stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for vestibular schwannoma (VS) were assessed. In all, 250 patients with VS were treated: 190patients with tumors < 2cm diameter underwent SRS and 60patients with tumors >2 to 3.5cm underwent FSRT. Dose prescription for all cases with SRS (n = 190, 76 %) was 13.5Gy. For FSRT, mainly two hypofractionated schedules (n = 60, 24 %) with either 7fractions of 5Gy (total dose: 35Gy; n = 35) or 11fractions of 3.8Gy (total dose: 41.8Gy; n = 16) were used. The primary endpoint was local tumor control. Secondary endpoints were symptomatic control and morbidity. The median follow-up was 33.8months. The 3-year local tumor control was 88.9 %. Local control for SRS and FSRT was 88 and 92 %, respectively. For FSRT with 35 and 41.8Gy, local control was 90 and 100 %, respectively. There were no acute reactions exceeding gradeI. In 61cases (24.4 % of the entire cohort), trigeminal neuralgia was reported prior to treatment. At last follow-up, 16.3 % (10/61) of those patients reported relief of pain. Regarding facial nerve dysfunction, 45patients (18 %) presented with symptoms prior to RT. At the last follow-up, 13.3% (6/45) of those patients reported a relief of dysesthesia. Using SRS to treat small VS results in good local control rates. FSRT for larger lesions also seems effective. Severe treatment-related complications are not frequent. Therefore, image-guided stereotactic radiotherapy is an appropriate alternative to microsurgery for patients with VS.

A Randomized Trial for the Treatment of Refractory Status Epilepticus

Refractory status epilepticus (RSE) has a mortality of 16-39%; coma induction is advocated for its management, but no comparative study has been performed. We aimed to assess the effectiveness (RSE control, adverse events) of the first course of propofol versus barbiturates in the treatment of RSE. In this randomized, single blind, multi-center trial studying adults with RSE not due to cerebral anoxia, medications were titrated toward EEG burst-suppression for 36-48 h and then progressively weaned. The primary endpoint was the proportion of patients with RSE controlled after a first course of study medication; secondary endpoints included tolerability measures. The trial was terminated after 3 years, with only 24 patients recruited of the 150 needed; 14 subjects received propofol, 9 barbiturates. The primary endpoint was reached in 43% in the propofol versus 22% in the barbiturates arm (P = 0.40). Mortality (43 vs. 34%; P = 1.00) and return to baseline clinical conditions at 3 months (36 vs. 44%; P = 1.00) were similar. While infections and arterial hypotension did not differ between groups, barbiturate use was associated with a significantly longer mechanical ventilation (P = 0.03). A non-fatal propofol infusion syndrome was detected in one patient, while one subject died of bowel ischemia after barbiturates. Although undersampled, this trial shows significantly longer mechanical ventilation with barbiturates and the occurrence of severe treatment-related complications in both arms. We describe practical issues necessary for the success of future studies needed to improve the current unsatisfactory state of evidence.

Optimization of follow-up timing from study of patterns of first failure after primary treatment. An example from patients with NSCLC: A study of the REACT working group of ESTRO

Background and purpose The European Society for Therapeutic Radiology and Oncology was funded by the EU for a project on Recording providing Education, and Ameliorating the Consequences of Treatment (REACT). An important aim of follow-up (FU) after treatment for cancer is to detect various events associated with disease recurrence or metastatic spread or severe treatment-related complications as early as possible. Each tumour type may show a specific pattern and timing of these events related to different prognostic factors. The aim of this study was to propose a way of defining an optimal timing schedule for follow-up after treatment based on the analysis of failure patterns determined from follow-up data from prospective clinical trials. Material and methods Cox proportional hazards model was used to identify prognostic factors associated with each failure type (loco-regional recurrence (LR), distant metastasis (DM) or side effects (SE)). Competing risks methods were applied to estimate the cumulative incidence functions (CIF), adjusted on the significant prognostic factors. Equally spaced quantiles of the CIF were then used to estimate the corresponding optimised follow-up times depending on a pre-specified total number of visits. Follow-up data from the CHART bronchus clinical trial were used to analyse the pattern of time to first failure. Results A significantly higher risk of failure was observed for males (SE), stage III (DM) and conventional treatment (LR). Overall, patients treated with CHART needed 1 fewer visit in each category of patients compared to the Conventional group. For example, stage III male patients treated with CHART would need 8 visits during the first two years at 7, 11, 16, 24, 37, 52, 64 and 104 weeks rather than the 9 follow-up visits planned in the protocol. Similar patients treated with Conventional radiotherapy would need 8 visits at 3, 5, 7, 11, 15, 24, 52 and 104 weeks. Conclusions Use of these methods would allow timing of follow-up visits to be adapted according to tumour site and prognostic factors determined previously from audit or clinical trials. Application of this approach could optimize the timing of follow-up visits by placing them closer to the times when failures are expected to occur. It does not address the wider issues of follow-up such as who should do it or what should be done for which further studies are required.

Risk of long-term complications after TFG-β1–guided very-high-dose thoracic radiotherapy

Purpose To report the incidence of late complications in long-term survivors of very-high-dose thoracic radiotherapy (RT) treated on a prospective clinical trial. Methods and materials Patients with locally advanced or medically inoperable non–small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved lymph nodes to a dose of 73.6 Gy at 1.6 Gy twice daily. If the plasma transforming growth factor-β1 (TGF-β1) level was normal after 73.6 Gy, additional twice-daily RT was delivered to successively higher total doses until the maximal tolerated dose was reached. Patients within a given dose level were followed for 6 months before escalation to the next dose level was permitted. Late complications were defined according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Results Thirty-eight patients were enrolled between 1996 and 1999. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGF-β1 levels. Fourteen patients received dose escalation (80 Gy in 8; 86.4 Gy in 6). Grade 3 or greater late complications occurred in 4 of 24, 1 of 8, and 2 of 6 patients treated to 73.6, 80, and 86.4 Gy, respectively. The corresponding patient numbers with late Grade 4-5 toxicity were 3 of 24, 0 of 6, and 0 of 8. Overall, 7 (18%) of the 38 patients developed Grade 3–5 late toxicity. Nonpulmonary complications predominated (4 of 7). Five (71%) of seven serious complications developed within 11 months after RT; however, the remaining two complications (29%) occurred very late (at 43 and 62 months). The 5-year actuarial risk of late Grade 3–5 complications was 33%. Conclusion Long-term survivors of very-high-dose RT for non–small-cell lung cancer have a significant risk of severe treatment-related complications. At these high dose levels, the predominant toxicity may no longer be pulmonary. All Grade 4-5 complications occurred in patients whose dose was limited to 73.6 Gy because of a persistently elevated TGF-β1. Thus, persistently elevated plasma TGF-β1 levels toward the end of RT may identify patients at greatest risk of severe complications.