The diagnosis of Refsum disease is suspected on the basis of clinical findings and a plasma phytanic acid concentration greater than 200 μmol/L in most affected individuals. Confirmation of the diagnosis requires either (1) molecular genetic testing to identify biallelic pathogenic variants in either PHYH (encoding phytanoyl-CoA hydroxylase), which accounts for more than 90% of Refsum disease, or PEX7 (encoding the PTS2 receptor), which accounts for less than 10% of Refsum disease; or (2) enzyme analysis to identify deficiency of either phytanoyl-CoA hydroxylase enzyme activity or the peroxisome-targeting signal type 2 receptor.

BACKGROUND:Stage III non-small cell lung cancer (NSCLC) still has a poor prognosis. Prior studies with individualized, accelerated, isotoxic dose escalation (INDAR) with 3D-CRT showed promising results, especially in patients not treated with concurrent chemo-radiotherapy. We investigated if INDAR delivered with IMRT would improve the overall survival (OS) of stage III NSCLC patients treated with concurrent chemotherapy and radiotherapy. PATIENTS AND METHODS:Patients eligible for concurrent chemo-radiotherapy were entered in this prospective study. Radiotherapy was given to a dose of 45 Gy/30 fractions BID (1.5 Gy/fraction), followed by QD fractions of 2 Gy until a total dose determined by the normal tissue constraints. The primary endpoint was OS, secondary endpoints were loco-regional relapses and toxicity. RESULTS:From May 4, 2009 until April 26, 2012, 185 patients were included. The mean tumor dose was 66.0 ± 12.8 Gy (36-73 Gy), delivered in a mean of 39.7 fractions in an overall treatment time of 38.2 days. The mean lung dose (MLD) was 17.3 Gy. The median OS was 19.8 months (95% CI 17.3-22.3) with a 5-year OS of 24.3%. Loco-regional failures as first site of recurrence occurred in 59/185 patients (31.8%). Isolated nodal failures (INF) were observed in 3/185 patients (1.6%). Dyspnea grade 3 was seen in 3.2% of patients and transient dysphagia grade 3 in 22%. CONCLUSIONS:INDAR with IMRT concurrently with chemotherapy did not lead to a sign of an improved OS in unselected stage III NSCLC patients.

Introduction: Two randomized studies have shown an increased progression-free survival (PFS) by adding a radical local treatment to systemic therapy in responding patients with oligometastatic NSCLC, but long-term data are lacking. We updated the results of our previous phase II trial with a minimal follow-up exceeding 7 years. Methods: This is a prospective single-arm phase II trial. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). No previous response to systemic treatment was needed. Results: Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 +/- 9.2 years (range, 44 to 81 years). Twenty-nine (74%) had N2 or N3 disease; 17 (44%) brain, 7 (18%) bone, and 4 (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% confidence interval: 7.6-19.4 months); 1-, 2-, 3-, 5-, and 6- year OS was 56.4%, 23.3%, 12.8%, 10.3%, 7.7%, and 5.1%, respectively. Median PFS was 12.1 months (95% confidence interval: 9.6-14.3 months); 1-, 2-, 3-, 5-, and 6- year OS was 51.3%, 13.6%, %, 12.8%, 7.7%, 7.7%, and 2.5%, respectively. Only three patients (7.7%) had a local recurrence. Conclusions: In patients who were not selected according to response to systemic treatment, the PFS at 5 years was 8%. Entering patients in trials combining local therapy with novel systemic agents (e.g., immunotherapy) remains mandatory. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Purpose or ObjectiveThe esophagus is an organ at risk in stereotactic radiotherapy for central lung tumors.We studied the correlation between esophagus toxicity and dosimetric/volumetric parameters in order to assess risks, and to derive a Normal Tissue Complication Probability (NTCP) model. Material and MethodsPatients with a central lung tumor from 2 centers who received stereotactic or hypofractionated radiotherapy (≤ 12 fractions) were retrospectively analyzed.Doses were recalculated to an equivalent dose of 2 Gy (EQD2) with an α/β ratio of 10 for acute toxicity (within 3 months).The esophagus was manually delineated and dose-volume histogram (DVH) parameters (Dmax, D1cc, D2cc, D5cc) were evaluated.The primary endpoint was esophagus toxicity as scored by CTCAE version 4.0.NTCP was calculated based on a logistic regression model and significant parameters (p-value < 0.05) were plotted into the logistic model curve.Overall survival was calculated using Kaplan-Meier analysis and groups were compared with the log-rank test. ResultsTwo-hundred-and-thirty-one patients (with 252 tumors) were eligible with median follow-up of 16 months (range 0.3 -84.3).No acute or late grade 3-5 esophagus toxicity was reported.Acute grade 1-2 toxicity was recorded in 38 patients (16.5%).All DVH parameters differed significantly between patients with toxicity versus those without toxicity; median Dmax of 62.2 Gy10 versus 31.6 Gy10, median D1cc of 40.8 Gy10 versus 18.8 Gy10, median D2cc of 35.6 Gy10 versus 16.3 Gy10 and median D5cc of 24.1 Gy10 versus 11.1 Gy10, respectively (p < 0.001 for all parameters, based on Mann-Whitney U test).Out of 27 patients who received a Dmax ≥ 54.7 Gy10 (equivalent of 5 x 7.5 Gy), 37% suffered from grade 1-2 esophagus toxicity.A Dmax ≥ 60.0 (equivalent of 5 x 8 Gy) resulted in toxicity in 1 out of 14 patients.A D1cc ≥ 44.7 Gy10 (equivalent of 5 x 6.5 Gy) resulted in toxicity in 6 out of 12 patients.A D1cc ≥ 49.6 Gy10 (equivalent of 5 x 7 Gy) resulted in toxicity in 5 out of 8 patients.Logistic regression showed significant correlations between all analyzed DVH parameters and toxicity, therefore NTCP-curves were calculated for all parameters (Figure 1 a-b).A 50% probability of acute grade 1-2 esophagus toxicity was found at a Dmax of 67 Gy10, D1cc of 42 Gy10, D2cc of 38 Gy10 and D5cc of 30 Gy10.No significant differences in overall survival were found between patients with and without toxicity: 2-year survival rate was 44% versus 51%, respectively (p = 0.428).Figure 1 a-b: NTCP models for the probability of grade 1-2 acute toxicity in the esophagus ConclusionAs no grades 3-5 esophagus toxicity were observed in our cohort, we conclude that a Dmax of 60.0 Gy10 (5 x 8 Gy) and a D1cc of 49.6 Gy10 (5 x 7 Gy) can be safely delivered using stereotactic radiotherapy.The NTCP-curves derived may serve as guidelines for central lung cancer undergoing stereotactic treatment.

There is increasing interest in the treatment of synchronous oligometastases of NSCLC. Two randomized studies demonstrated an increased PFS by adding a radical local treatment to systemic therapy in responding patients, but long-term data are lacking. We previously reported a median PFS of 12 months and a median OS of 13.5 months in 39 radically treated patients with synchronous oligometastases in a prospective study (De Ruysscher J Thorac Oncol 2012). As the minimal follow-up is now exceeding 6 years, we here report the long-term PFS and OS. Prospective single-arm phase II trial. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). No previous response to systemic treatment was required. Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44-81). Twenty-nine (74%) had local stage III; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% CI 7.6-19.4); 1-, 2-, 3-, 4-, 5, 6-year OS was 56.4%, 23.3%, 12.8 %, 10.3 %, 7.7 %, 5.1 % (2 patients), respectively. Median progression-free survival (PFS) was 12.1 months (95% CI 9.6-14.3); 1-, 2-, 3-, 4-, 5, 6-year PFS was 51.3%, 13.6 %,12.8 %, 7.7 %, 7.7 %, 2,5 % (1 patient), respectively. Of the 3 patients with a PFS after 5 years, 1 had a squamous cell cancer T2N2 with a single pathologically proven bone metastasis in the sternum, 1 had a NSCLC-NOS T4N0 with a single adrenal metastasis, and 1 a T1N2 adenocarcinoma with a pathologically proven contralateral lung metastasis. The latter patient is still free of disease. Two patients developed a second primary cancer: 1 tongue carcinoma after 70 months and 1 an adenocarcinoma in the contralateral lung after 71 months. Both patients died of their second cancer. Three patients (7.7 %) had a local recurrence, all in the PTV of their primary tumor. Only one patient was treated with a TKI (gefitinib) at progression. After radical treatment of oligometastases, approximately 8 % of the patients achieve a PFS after 5 years. Entering patients in trials combining local therapy with novel systemic agents (e.g. chemo-immunotherapy) remains mandatory.

PURPOSE:Automated techniques for estimating the contours of organs and structures in medical images have become more widespread and a variety of measures are available for assessing their quality. Quantitative measures of geometric agreement, for example, overlap with a gold-standard delineation, are popular but may not predict the level of clinical acceptance for the contouring method. Therefore, surrogate measures that relate more directly to the clinical judgment of contours, and to the way they are used in routine workflows, need to be developed. The purpose of this study is to propose a method (inspired by the Turing Test) for providing contour quality measures that directly draw upon practitioners' assessments of manual and automatic contours. This approach assumes that an inability to distinguish automatically produced contours from those of clinical experts would indicate that the contours are of sufficient quality for clinical use. In turn, it is anticipated that such contours would receive less manual editing prior to being accepted for clinical use. In this study, an initial assessment of this approach is performed with radiation oncologists and therapists. METHODS:Eight clinical observers were presented with thoracic organ-at-risk contours through a web interface and were asked to determine if they were automatically generated or manually delineated. The accuracy of the visual determination was assessed, and the proportion of contours for which the source was misclassified recorded. Contours of six different organs in a clinical workflow were for 20 patient cases. The time required to edit autocontours to a clinically acceptable standard was also measured, as a gold standard of clinical utility. Established quantitative measures of autocontouring performance, such as Dice similarity coefficient with respect to the original clinical contour and the misclassification rate accessed with the proposed framework, were evaluated as surrogates of the editing time measured. RESULTS:The misclassification rates for each organ were: esophagus 30.0%, heart 22.9%, left lung 51.2%, right lung 58.5%, mediastinum envelope 43.9%, and spinal cord 46.8%. The time savings resulting from editing the autocontours compared to the standard clinical workflow were 12%, 25%, 43%, 77%, 46%, and 50%, respectively, for these organs. The median Dice similarity coefficients between the clinical contours and the autocontours were 0.46, 0.90, 0.98, 0.98, 0.94, and 0.86, respectively, for these organs. CONCLUSIONS:A better correspondence with time saving was observed for the misclassification rate than the quantitative contour measures explored. From this, we conclude that the inability to accurately judge the source of a contour indicates a reduced need for editing and therefore a greater time saving overall. Hence, task-based assessments of contouring performance may be considered as an additional way of evaluating the clinical utility of autosegmentation methods.

Background and purposePatient’s gender and age may influence physicians in prescribing palliative radiotherapy. The purpose of this secondary analysis of the National Cancer Institute of Canada Clinical Trials Group Symptom Control Trial SC.20 was to explore the gender and age differences in pain and patient reported outcomes in cancer patients with bone metastases undergoing re-irradiation.Materials and methodsResponse to radiation was evaluated using the International Bone Metastases Consensus Endpoint Definitions. Patients completed the Brief Pain Inventory (BPI) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (C30) before and 2 months after re-irradiation.ResultsA total of 847 patients were analyzed. At baseline, men had more dyspnea, and mild pain. Older patients consumed less analgesic. More women reported clinically significant improvement in mood and enjoyment of life in the BPI after radiation. Similarly, younger patients reported better improvement in enjoyment of life. There were no significant gender or age differences in overall survival, response to radiation, or in C30 scores at 2 months.ConclusionSimilar benefit in terms of pain relief was observed across all patient groups. Cancer patients with bone metastases should be offered palliative re-irradiation irrespective of gender or age.Trial Registration: NCT00080912; https://clinicaltrials.gov/ct2/show/NCT00080912.

Radiotherapy (RT) plays a major role in the loco-regional treatment of lung cancer. An accurate definition of the target volumes and use of optimal dose and fractionation schedule are essential to ...

Previous studies by our group showed that that increasing the radiotherapy (RT) dose in an overall treatment time (OTT) of less than 6 weeks on basis of the isotoxic principle is feasible and could potentially increase the overall survival (OS) with non-concurrent chemo-RT without increasing the toxicity. No data were yet available for IMRT treated patients. From 04-05 2009 until 26-04-2012, 185 patients with stage III NSCLC, treated with concurrent chemo-RT were included in this single center phase II trial. OS update was done on June 7, 2017. The primary endpoint of this study was OS, with in-field nodal failures (INF) and toxicity as secondary endpoints. Patients received 1 cycle of cisplatin-etoposide followed by two cycles of the same chemotherapy with concurrent radiotherapy (IMRT, 45 Gy BID followed by 2 Gy QD to the maximal organ at risk constraint). Patient characteristics: Gender: Male: 61.1%, Female: 38.9%. Age 63.9 ± 8.9 years (44-86). Smoking: Never 2.9%, current 36.8%, former 60.3%. WHO performance status: 0 (36.2%) 1 (56.8%), 2 11 (5.9%), 3: 1 pt, 4:1 pt. Histology: Squamous 55 (29.7%), Adenocarcinoma 49 (26.9%), Large cell 26 (14.1%), NSCLC-NOS 55 (29.7%). GTV (T+N) 120.4 ± 132 ml (16.8-708.5), Total Tumor Dose 66.0 ± 12.8 Gy (36.0-73.0).Number of fractions: 39.7 ± 3.4 (24-44). OTT 38.2 ± 26.8 days (16-93) MLD 17.3 ± 3.0 Gy (4.9-21, 2). Mean Esophageal Dose 29.0 ± 9.3 Gy (6.3-54.1). OS: stage IIIA (n=42), median 16.7 Mo (8.7-24.7), 5-year 16.7%; stage IIIB (n=143) 20.3 (16.2-24.4), 5-year 27.3% (P=0.10). INF: 3/185 (1.6%). Loco-regional failures: 59/185 patients (31.8%) Toxicity: Dyspnea Grade Baseline Maximal score 0 102 (55.1%) 71 (38.4%) 1 68 (36.8%) 103 (55.7%) 2 15 (8.1%) 5 (2.7%) 3 0 6 (3.2%) 88% of patients experienced any grade of dysphagia: 22% experienced grade 1 dysphagia, 44% grade 2, while 22% experienced grade 3 dysphagia. Isotoxic accelerated radiotherapy delivered with IMRT and concurrently with chemotherapy leads to low INF and toxicity is comparable to the best series using standard fractionation schedules. Long term OS remains low and therefore other strategies are needed.

Background and purposeIsolated nodal failures (INF) are rare after 3D-conformal radiotherapy (3D-CRT) for stage III non-small cell lung cancer (NSCLC). Since incidental nodal irradiation doses are lower with Intensity Modulated Radiation Therapy (IMRT) than with 3D-CRT, INF may be higher after IMRT. We therefore investigated the incidence of INF after IMRT in stage III NSCLC patients.Materials and methodsStage III NSCLC patients undergoing radical radiotherapy using IMRT in the period January 2010 till March 2012 were included. The primary endpoint was the rate of INF, secondary endpoints included patterns of failure, progression free survival (PFS), overall survival (OS) and toxicity.Results183 stage III NSCLC patients were enrolled. With a median follow-up of 58.0months 2.2% of patients had an INF. The median PFS was 15.0months, the median OS 19.5months. Patterns of recurrence: 2.2% INF, 11.5% local and 2.7% loco-regional recurrence, 26.8% distant metastases only, 18.0% a combination of local/loco-regional and distant metastases, and 38.3% patients without recurrence. One INF was out of field, in adjacent lymph nodes. Acute toxicity was limited.DiscussionSelective nodal irradiation using IMRT in stage III NSCLC patients results in a low in-field incidence of INF (2.2%), similar to 3D-CRT, and may thus be considered safe.

Background: In this open-label phase I study, the maximum-tolerated dose of cetuximab with concurrent chemoradiotherapy (C-CRT) in stage III non-small-cell lung cancer together with individualized, isotoxic accelerated radiotherapy (RT) was investigated.Methods: Patients with stage III non-small-cell lung cancer, World Health Organization performance status 0-1, forced expiratory volume in 1 second more than 50%, carbon monoxide diffusing capacity more than 50%, weight loss less than 10%, and no severe comorbidity were enrolled. Patients without progression after one to two cycles of gemcitabine-carboplatin were included and treated with cetuximab 400 mg/kg d7 and 250 mg/kg weekly together with RT and cisplatin (50 mg/m(2) d1, 8; 40 mg/m(2) d22)-vinorelbine for 5 weeks. Vinorelbine was escalated in three steps; (1) 10 mg/m(2) d1, 8 and 8 mg/m(2) d22, 29; (2) 20 mg/m(2) d1, 8 and 8 mg/m(2) d22, 29; (3) 20 mg/m(2) d1, 8; 15 mg/m(2) d22, 29. An individualized prescribed RT dose based on normal tissue dose constraints was applied (e.g., mean lung dose 19 Gy). The primary endpoint was the maximum-tolerated dose 3 months after the end of C-CRT; secondary endpoints were toxicity and metabolic response as assessed by positron emission tomography.Results: Between September 2007 and October 2010, 25 patients (12 men, 13 women, mean age 59 years) were included. The mean RT dose was 62 +/- 6.6 Gy. The vinorelbine dose could be escalated to dose level 3. Twelve of 25 patients experienced greater than or equal to grade 3 toxicity (esophagitis 3, rash 1, diarrhea 1, cough 1, dyspnea 1, vomiting 1, and pulmonary embolism 1). No dose-limiting toxicities were observed. One patient with a complete pathological response in dose level 3 developed a fatal hemoptysis 4 months after RT. Metabolic remissions were observed in 19 of 22 patients.Conclusion: C-CRT with cetuximab and cisplatin-vinorelbine is safe to deliver at full dose. The recommended phase II dose is therefore cetuximab 400 mg/m(2) d7 and 250 mg/m(2) weekly, cisplatin 50 mg/m(2) d1, 8; 40 mg/m(2) d22 and vinorelbine 20 mg/m(2) d1, 8; 15 mg/m(2) d22, 29 for 5 weeks together with RT.

BackgroundDecision Support Systems, based on statistical prediction models, have the potential to change the way medicine is being practiced, but their application is currently hampered by the astonishing lack of impact studies. Showing the theoretical benefit of using these models could stimulate conductance of such studies. In addition, it would pave the way for developing more advanced models, based on genomics, proteomics and imaging information, to further improve the performance of the models.PurposeIn this prospective single-center study, previously developed and validated statistical models were used to predict the two-year survival (2yrS), dyspnea (DPN), and dysphagia (DPH) outcomes for lung cancer patients treated with chemo radiation. These predictions were compared to probabilities provided by doctors and guideline-based recommendations currently used. We hypothesized that model predictions would significantly outperform predictions from doctors.Materials and methodsExperienced radiation oncologists (ROs) predicted all outcomes at two timepoints: (1) after the first consultation of the patient, and (2) after the radiation treatment plan was made. Differences in the performances of doctors and models were assessed using Area Under the Curve (AUC) analysis.ResultsA total number of 155 patients were included. At timepoint #1 the differences in AUCs between the ROs and the models were 0.15, 0.17, and 0.20 (for 2yrS, DPN, and DPH, respectively), with p-values of 0.02, 0.07, and 0.03. Comparable differences at timepoint #2 were not statistically significant due to the limited number of patients. Comparison to guideline-based recommendations also favored the models.ConclusionThe models substantially outperformed ROs’ predictions and guideline-based recommendations currently used in clinical practice. Identification of risk groups on the basis of the models facilitates individualized treatment, and should be further investigated in clinical impact studies.