The use of real-world evidence to audit normal tissue complication probability models for acute esophageal toxicity in non-small cell lung cancer patients

Contains fulltext : 220483.pdf (publisher's version ) (Closed access)INTRODUCTION: The aim of this work is to assess the validity of real world data (RWD) derived from an electronic toxicity registration (ETR). As a showcase, the NTCP-models of acute esophageal toxicity (AET) for concurrent chemoradiation (CCRT) for NSCLC patients were used to validate the ETR of AET before/after dose de-escalation to the mediastinal lymph nodes. MATERIAL AND METHODS: One hundred and one patients received 24 × 2.75 Gy and 116 patients received de-escalated dose of 24 × 2.42 Gy to the mediastinal lymph nodes. The validity and completeness of the ETR was analyzed. The grade ≥2 AET probability was defined according the V50 Gy and V60 Gy NTCP-models from literature. Validity of the models was assessed by calibration and discrimination. Furthermore, sensitivity and specificity for different cut-off points were determined. RESULTS: The compliance of ETR was 73-80%, with sensitivity and specificity rates of 83% and 86% for grade ≥2 AET, respectively. Discrimination of both NTCP-models demonstrated a moderate accuracy (V50 model, AUC 0.71; V60-model, AUC 0.69). Dose de-escalation did not influence the accuracy of the V50-model; AUC before: 0.69, and AUC after: 0.71. For the V60-model the model-accuracy decreased after dose de-escalation; AUC before: 0.72 and AUC after: 0.62, respectively. CONCLUSION: RWD is a useful method to audit NTCP models in clinical practice. The NTCP models to predict AET in NSCLC patients showed moderate predictive accuracy. For clinical practice, the V50Gy seems to be most stable for dose de-escalation without compromising safety and efficacy

Dutch translation and linguistic validation of the U.S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™)

BACKGROUND: The U.S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) is a library of items for assessing symptomatic adverse events by patient self-report in oncology trials. The aim of this multi-site study was to generate and linguistically validate a Dutch language version of the U.S. PRO-CTCAE for use in the Netherlands and Dutch-speaking Belgium. METHODS: All 124 items in the PRO-CTCAE item library were translated into Dutch using established translation procedures, including dual forward translations, reconciliation, back-translation, reconciliation of the source with the back-translation, and expert reviews. Harmonization of the translation for use in both the Netherlands and Belgium was achieved via an iterative review process in which the translations were discussed and reconciled by consensus of PRO experts, clinicians and bilingual Dutch translators. The translated PRO-CTCAE™ items were completed by a geographically-diverse sample of Dutch speaking patients from the Netherlands (n = 40) and Belgium (n = 60), and who were currently receiving or who had recently completed cancer-directed therapy. Patients were diverse with respect to age, sex, educational attainment, and cancer diagnosis. Cognitive debriefing, using a semi-structured interview guide, probed for comprehension and clarity of PRO-CTCAE symptom terms, attributes (e.g. frequency, severity, interference), response choices, and understanding of 'at its worst' and 'in the last 7 days'. Items for which the patient data indicated possible difficulties were considered for revision. RESULTS: Three items underwent minor phrasing revision and retesting was not deemed necessary. The symptom term for stretch marks was poorly understood by 12.5% of participants, and this item was revised to include parenthetical phrasing. It was retested with 10 participants from Belgium (n = 5) and the Netherlands (n = 5) and demonstrated acceptable comprehension. CONCLUSIONS: The Dutch language version of PRO-CTCAE has been successfully developed and linguistically validated for use in oncology studies in the Netherlands and Dutch-speaking Belgium. Extending the availability of NCI PRO-CTCAE in languages beyond English increases international consistency in the capture of Patient-Reported outcomes in patients participating in cancer clinical trials

Safety and efficacy of reduced dose and margins to involved lymph node metastases in locally advanced NSCLC patients

Item does not contain fulltextBACKGROUND AND PURPOSE: (Chemo)Radiotherapy for locally advanced non-small lung cancer (LA-NSCLC) causes severe dysphagia due to the radiation dose to the mediastinal lymphadenopathy. Reducing the dose to the mediastinum and the margins to the planning target volume (PTV) might reduce severe toxicity rates. The results of both adaptations in LA-NSCLC patients receiving (chemo)radiotherapy were analysed. MATERIALS AND METHODS: 308 LA-NSCLC patients were included in an observational study. Both cohorts received hypofractionated RT (24 × 2.75 Gy) of 70 Gy (EQD2(10)) to the primary tumour. The reference-cohort (N = 170) received the same dose of 70 Gy (EQD2(10)) to the involved lymph nodes, while the reduction-cohort (N = 138) received 24 × 2.42 Gy, biologically equivalent to 60 Gy (EQD2(10)). Furthermore, the patient-specific PTV-margins for both the primary tumour and lymph nodes were reduced by 2-3 mm in the reduction-cohort after implementing a carina based correction strategy. The effects on toxicity, regional failure and overall survival (OS) were assessed. RESULTS: The acute grade 3 (G3) dysphagia and G3 pulmonary toxicity decreased significantly from 12.9% to 3.6% and 4.1% versus 0%, respectively. The regional failures were comparable: 5.9% versus 4.3% (p = 0.546). The median OS was significantly different: 26 months (reference-cohort) versus 35 months (reduction-cohort). After correction for confounders, the association between the reduction-cohort and OS remained significant (HR 0.63 versus HR 0.70). CONCLUSION: A reduction in PTV-margins and dose from 70 Gy to 60 Gy to the involved lymph nodes in LA-NSCLC patients receiving (chemo)radiotherapy did not result in an increase in regional failures. Moreover, significantly lower acute toxicities and an improved OS were observed in the reduction-cohort

Pre-hydration in cisplatin-based CCRT: Effects on tumour concentrations and treatment outcome

Item does not contain fulltextAIMS: Pre-hydration is routinely applied to reduce nephrotoxicity in concurrent cisplatin-based chemo-radiotherapy (CCRT). However, pre-hydration may also have systemic effects, potentially leading to lower tumour cisplatin concentrations. We investigated the impact of pre-hydration on tumour cisplatin concentrations in mice, and on treatment outcomes in a clinical cohort study. MATERIALS AND METHODS: Four groups of 20 mice received either no pre-hydration prior to full-dose (6mg/kg) or half-dose cisplatin, overnight dehydration prior to full-dose cisplatin (dehydration), or NaCl intraperitoneally prior to full-dose cisplatin (pre-hydration). Kidney function and tumour platinum concentration were measured. In patients, a retrospective study compared 2 historical NSCLC cohorts which received CCRT with daily cisplatin, with and without standard pre-hydration. Overall survival (OS) and progression free survival (PFS) were compared using Kaplan-Meier and cox-regression. RESULTS: Pre-hydration significantly decreased cisplatin tumour concentrations in mice, comparable to mice receiving half the dose. In 419 patients (211 without and 208 with pre-hydration) with median follow-up 22months, there were no significant differences in PFS (18 vs. 15months) or OS (23 vs. 23months). CONCLUSION: Pre-hydration reduces cisplatin tumour concentrations in mice, but it does not compromise treatment outcomes in NSCLC patients treated with daily cisplatin and radiotherapy

Local and regional treatment response by (18)FDG-PET-CT-scans 4 weeks after concurrent hypofractionated chemoradiotherapy in locally advanced NSCLC

Contains fulltext : 217576.pdf (Publisher’s version ) (Closed access

Development of symptomatic brain metastases after chemoradiotherapy for stage III non-small cell lung cancer: Does the type of chemotherapy regimen matter?

Contains fulltext : 165952.pdf (Publisher’s version ) (Open Access)OBJECTIVES: Symptomatic brain metastases (BM) occur frequently after chemoradiotherapy (CRT) for stage III NSCLC. Aim of the current study was to determine whether the specific chemotherapy used in a CRT regimen influences BM development. MATERIALS AND METHODS: Retrospective multicenter study including all consecutive stage III NSCLC who completed CRT. Primary endpoints: symptomatic BM development, whether this was the only site of first relapse. Differences between regimens were assessed with a logistic regression model including known BM risk factors and the specific chemotherapy: concurrent versus sequential (cCRT/sCRT), within cCRT: daily low dose cisplatin (LDC)-cyclic dose polychemotherapy; LDC-(non-)taxane cyclic dose; LDC-polychemotherapy subgroups of >/=50 patients. RESULTS: Between January 2006 and June 2014, 838 patients were eligible (737 cCRT, 101 sCRT). 18.2% developed symptomatic BM, 8.0% had BM as only site of first relapse. BM patients were significantly younger, female, had more advanced N-stage and had adenocarcinoma histology. In both cCRT and sCRT BM were found in 18% (p=0.904). In cyclic dose cCRT (N=346) and LDC (N=391) BM were found in 18.8% and 17.9%, respectively (p=0.757). In 7.2% and 8.7%, respectively, BM were the only site of first relapse (p=0.463). The chemotherapy used (cCRT versus sCRT) had no influence on BM development, not for all brain relapses nor as only site of first relapse (OR 0.88 (p=0.669), OR 0.93 (p=0.855), respectively). LDC versus cyclic dose cCRT was not significantly different: neither for all brain relapses nor as only site of first relapse (OR 0.96 (p=0.819), OR 1.21 (p=0.498), respectively). Comparable results were found for LDC versus cyclic dose non-taxane (N=277) and cyclic dose taxane regimens (N=69) and for cCRT regimens with >/=50 patients (LDC versus cisplatin/etoposide (N=188), cisplatin/vinorelbin (N=65), weekly cisplatin/docetaxel (N=60)). CONCLUSION: approximately 18% developed symptomatic BM after stage III diagnosis, not dependent on type of chemotherapy regimen used within a CRT treatment