Patient-reported outcomes after personalised dose-escalation for stage II-III non-small-cell lung cancer patients: Results from the randomised ARTFORCE PET-Boost trial.

BACKGROUND AND PURPOSE: The ultimate challenge in dose-escalation trials lies in finding the balance between benefit and toxicity. We examined patient-reported outcomes (PROs), including health-related quality of life (HRQoL) in patients with locally advanced non-small cell lung cancer (LA-NSCLC), treated with dose-escalated radiotherapy. MATERIALS AND METHODS: The international, randomised, phase 2 ARTFORCE PET-Boost study (NCT01024829) aimed to improve 1-year freedom from local failure rates in patients with stage II-III NSCLC, with a ≥ 4 cm primary tumour. Treatment consisted of an individualised, escalated fraction dose, either to the primary tumour as a whole or to its most FDG-avid subvolume (24 x 3.0-5.4 Gy). Patients received sequential or concurrent chemoradiotherapy, or radiotherapy only. Patients were asked to complete the EORTC QLQ-C30, QLQ-LC13, and the EuroQol-5D at eight timepoints. We assessed the effect of dose-escalation on C30 sum score through mixed-modelling and evaluated clinically meaningful changes for all outcomes. RESULTS: Between Apr-2010 and Sep-2017, 107 patients were randomised; 102 were included in the current analysis. Compliance rates: baseline 86.3%, 3-months 85.3%, 12-months 80.3%; lowest during radiation treatment 35.0%. A linear mixed-effect (LME) model revealed no significant change in overall HRQoL over time, and no significant difference between the two treatment groups. Physical functioning showed a gradual decline in both groups during treatment and at 18-months follow-up, while clinically meaningful worsening of dyspnoea was seen mainly at 3- and 6-months. CONCLUSION: In patients with LA-NSCLC treated with two dose-escalation strategies, the average patient-reported HRQoL remained stable in both groups, despite frequent patient-reported symptoms, including dyspnoea, dysphagia, and fatigue.

18F-FDG-PET guided vs whole tumour radiotherapy dose escalation in patients with locally advanced non-small cell lung cancer (PET-Boost): Results from a randomised clinical trial.

BACKGROUND AND PURPOSE: We aimed to assess if radiation dose escalation to either the whole primary tumour, or to an 18F-FDG-PET defined subvolume within the primary tumour known to be at high risk of local relapse, could improve local control in patients with locally advanced non-small-cell lung cancer. MATERIALS AND METHODS: Patients with inoperable, stage II-III NSCLC were randomised (1:1) to receive dose-escalated radiotherapy to the whole primary tumour or a PET-defined subvolume, in 24 fractions. The primary endpoint was freedom from local failure (FFLF), assessed by central review of CT-imaging. A phase II 'pick-the-winner' design (alpha = 0.05; beta = 0.80) was applied to detect a 15 % increase in FFLF at 1-year. CLINICALTRIALS: gov:NCT01024829. RESULTS: 150 patients were enrolled. 54 patients were randomised to the whole tumour group and 53 to the PET-subvolume group. The trial was closed early due to slow accrual. Median dose/fraction to the boosted volume was 3.30 Gy in the whole tumour group, and 3.50 Gy in the PET-subvolume group. The 1-year FFLF rate was 97 % (95 %CI 91-100) in whole tumour group, and 91 % (95 %CI 82-100) in the PET-subvolume group. Acute grade ≥ 3 adverse events occurred in 23 (43 %) and 20 (38 %) patients, and late grade ≥ 3 in 12 (22 %) and 17 (32 %), respectively. Grade 5 events occurred in 19 (18 %) patients in total, of which before disease progression in 4 (7 %) in the whole tumour group, and 5 (9 %) in the PET-subvolume group. CONCLUSION: Both strategies met the primary objective to improve local control with 1-year rates. However, both strategies led to unexpected high rates of grade 5 toxicity. Dose differentiation, improved patient selection and better sparing of central structures are proposed to improve dose-escalation strategies.

Bronchial Stenosis in Central Pulmonary Tumors Treated With Stereotactic Body Radiation Therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) in lung tumors has an excellent local control due to the high delivered dose. Proximity of the proximal bronchial tree (PBT) to the high dose area may result in pulmonary toxicity. Bronchial stenosis is an adverse event that can occur after high dose to the PBT. Literature on the risk of developing bronchial stenosis is limited. We therefore evaluated the risk of bronchial stenosis for tumors central to the PBT and correlated the dose to the bronchi. METHODS AND MATERIALS: Patients with a planning tumor volume (PTV) ≤2 cm from PBT receiving SBRT (8 × 7.5 Gy) between 2015 to 2019 were retrospectively reviewed. Main bronchi and lobar bronchi were manually delineated. Follow-up computed tomography scans were analyzed for bronchial stenosis and atelectasis. Bronchial stenosis was assessed using Common Terminology Criteria for Adverse Events Version 4.0 (CTCAEv4). Patient, tumor, dosimetric factors and survival were evaluated between patients with and without stenosis using uni- and multivariate and Kaplan-Meier analysis. RESULTS: Fifty-one patients were analyzed with a median age of 70 years and World Health Organization (WHO) performance status ≤1 in 92.2%. Median follow-up was 36 months (interquartile range [IQR], 19.6-45.4) and median overall survival 48 months (IQR 21.5-59.3). In 15 patients (29.4%) bronchial stenosis was observed on follow-up computed tomography scan. Grade 1 stenosis was seen in 21.6% (n = 11), grade 2 in 7.8% (n = 4). No grade ≥3 stenosis was observed. Median time to stenosis was 9.6 months (IQR 4.4-19.2). Patients who developed stenosis had significantly larger gross tumor volume with a median of 19 cm3(IQR 7.7-63.2) versus 5.2 cm3 (IQR 1.7-11.3, P <.01). Prognostic factors in multivariate analysis for stenosis were age (P = .03; odds ratio [OR] 1.1), baseline dyspnea (P = .02 OR 7.7), and the mean lobar bronchus dose (P = .01; OR 1.1). CONCLUSIONS: Low-grade (≤2) lobar bronchial stenosis is a complication in approximately one-third of patients after SBRT for lung tumors with a PTV ≤2 cm from PBT. Prognostic risk factors were age, baseline dyspnea and mean dose on a lobar bronchus.

Importance of tumour volume and histology in trimodality treatment of patients with Stage IIIA non-small cell lung cancer-results from a retrospective analysis.

OBJECTIVES: Chemoradiotherapy (CRT) has been the backbone of guideline-recommended treatment for Stage IIIA non-small cell lung cancer (NSCLC). However, in selected operable patients with a resectable tumour, good results have been achieved with trimodality treatment (TT). The objective of this bi-institutional analysis of outcomes in patients treated for Stage IIIA NSCLC was to identify particular factors supporting the role of surgery after CRT. METHODS: In a 2-centre retrospective cohort study, patients with Stage III NSCLC (seventh edition TNM) were identified and those patients with Stage IIIA who were treated with CRT or TT between January 2007 and December 2013 were selected. Patient characteristics as well as tumour parameters were evaluated in relation to outcome and whether or not these variables were predictive for the influence of treatment (TT or CRT) on outcome [overall survival (OS) or progression-free survival (PFS)]. Estimation of treatment effect on PFS and OS was performed using propensity-weighted cox regression analysis based on inverse probability weighting. RESULTS: From a database of 725 Stage III NSCLC patients, 257 Stage IIIA NSCLC patients, treated with curative intent, were analysed; 186 (72%) with cIIIA-N2 and 71 (28%) with cT3N1/cT4N0 disease. One hundred and ninety-six (76.3%) patients were treated by CRT alone (high-dose radiation with daily low-dose cisplatin) and 61 (23.7%) by TT. The unweighted data showed that TT resulted in better PFS and OS. After weighting for factors predictive of treatment assignment, patients with a large gross tumour volume (>120 cc) had better PFS when treated with TT, and patients with an adenocarcinoma treated with TT had better OS, regardless of tumour volume. CONCLUSIONS: Patients with Stage IIIA NSCLC and large tumour volume, as well as patients with adenocarcinoma, who were selected for TT, had favourable outcome compared to patients receiving CRT. This information can be used to assist multidisciplinary team decision-making and for stratifying patients in studies comparing TT and definitive CRT.

Stage I non-small cell lung cancer: Treatment modalities, Dutch daily practice and future perspectives.

OBJECTIVES: Several treatment modalities are available for patients with stage I non-small cell lung cancer (NSCLC). Over the past decade, these treatment modalities have been further investigated and might have changed current treatment regimens. In this review we present an overview of the treatment options, developments and future perspectives for stage I NSCLC. Furthermore, we describe the current use of these treatment modalities in the Netherlands. MATERIALS AND METHODS: A bibliographical search was performed in PubMed and the Cochrane Library for publications concerning treatment modalities for stage I NSCLC. In addition, evidence-based guidelines of the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) were studied. RESULTS: The guideline-recommended treatment for operable stage I NSCLC patients is a lobectomy with systematic lymph node dissection. Inoperable patients or those refusing surgery are offered stereotactic ablative radiotherapy (SABR). Percutaneous ablation, such as radiofrequency ablation, is a non-surgical minimally invasive technique offered to those who are ineligible for surgery or SABR. The role of systemic therapy is currently limited. However, the efficacy of immunotherapy is being investigated in clinical trials. In the Netherlands, an increasing use of SABR and a relative decrease in resection rates have been observed. CONCLUSION: Surgery and SABR are currently the prevailing treatment modalities for stage I NSCLC patients. Despite optimization of treatment regimens, survival of patients with stage I NSCLC remains to be improved. Future studies are required to optimize treatment strategies, but also to investigate factors influencing treatment decision-making for patients with stage I NSCLC.

Is pneumonectomy justifiable for patients with a locoregional recurrence or persistent disease after curative intent chemoradiotherapy for locally advanced non-small cell lung cancer?

OBJECTIVES: Locoregional recurrence and persistent/progressive disease after curative-intent definitive chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is challenging to manage, as salvage options are limited. Selected patients might be candidates for resection. This study evaluated the outcomes of patients after salvage surgery for locoregional recurrence, focusing specifically on morbidity and mortality after salvage pneumonectomy. MATERIALS AND METHODS: This retrospective study included patients from 2 tertiary referral hospitals who underwent salvage pulmonary resection for locoregional recurrence or disease persistence/progression >12 weeks after completion of curative intent high dose (>60 Gy) CRT. Disease-free (DFS) and overall survival (OS) were estimated and the influence of patient and treatment characteristics on these endpoints was assessed. RESULTS: A total of 30 patients treated between 2015-2017 were identified with a median age of 60 years (range 42-72 years), 67 % were male. Median follow-up was 47 months (95 % CI 46-NR). Pneumonectomy was performed in 13/30 (43 %) patients and lobectomy in 17/30 (57 %). Median DFS and OS after pneumonectomy/lobectomy were 14/6 and NR/17 months, respectively. 30 and 90-day mortality for pneumonectomy/lobectomy were 0/12 % and 0/24 % respectively. More favorable survival was seen after pathologically radical resection, i.e. R0, and when surgery was performed more than 12 months after completion of CRT. CONCLUSION: Salvage surgery, including pneumonectomy is associated with acceptable outcomes in selected patients with recurrent or persistent/progressive NSCLC after curative-intent high dose CRT. Patients should be assessed for the probability of an R0 resection, and patients with a locoregional recurrence more than 12 months after treatment with CRT may benefit most from salvage surgery.

Results of neoadjuvant chemo(radio)therapy and resection for stage IIIA non-small cell lung cancer in The Netherlands.

Introduction: Concurrent chemoradiotherapy remains the main treatment strategy for patients with stage IIIA non-small cell lung cancer (NSCLC); stage cT3N1 or cT4N0-1 may be eligible for surgery and potentially resectable stage IIIA (N2) NSCLC for neoadjuvant therapy followed by resection. We evaluated treatment patterns and outcomes of patients with stage IIIA NSCLC in The Netherlands.Material and Methods: Primary treatment data of patients with clinically staged IIIA NSCLC between 2010 and 2016 were extracted from The Netherlands Cancer Registry. Patient characteristics were tabulated and 5-year overall survival (OS) was calculated and reported.Results: In total, 9,591 patients were diagnosed with stage IIIA NSCLC. Of these patients, 41.3% were treated with chemoradiotherapy, 11.6% by upfront surgery and 428 patients (4.5%) received neoadjuvant treatment followed by resection. The 5-year OS was 26% after chemoradiotherapy, 40% after upfront surgery and 54% after neoadjuvant treatment followed by resection. Clinical over staging was seen in 42.3% of the patients that were operated without neoadjuvant therapy.Conclusion: In The Netherlands, between 2010 and 2016, 4.5% of patients with stage IIIA NSCLC were selected for treatment with neoadjuvant therapy followed by resection. The 5-year OS in these patients exceeded 50%. However, the outcome might be overestimated due to clinical over staging.

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

BACKGROUND 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 (EQD210) to the primary tumour. The reference-cohort (N = 170) received the same dose of 70 Gy (EQD210) to the involved lymph nodes, while the reduction-cohort (N = 138) received 24 × 2.42 Gy, biologically equivalent to 60 Gy (EQD210). 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.

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

BACKGROUND AND PURPOSE: To investigate associations of early post-treatment 18Fluorodeoxyglucose-positron-emission-tomography (FDG-PET)-scans with local (LF), regional (RF), distant failure (DF) and overall survival (OS) in locally advanced non-small cell lung cancer (LA-NSCLC)-patients treated with concurrent chemoradiotherapy. MATERIALS AND METHODS: Forty-seven stage IIIA-B NSCLC-patients included in a randomized phase II-trial (NTR2230) received 66 Gy (24x2.75 Gy) with low dose Cisplatin +/- Cetuximab. FDG-PET-scans were performed at baseline and 4 weeks post-treatment (range, 1.6-10.1). SUVmax, SUVmean, metabolic tumor volume (MTV), total lesion glycolysis (TLG) and gross tumor volume were calculated separately for the primary tumor and the involved lymph nodes to generate baseline, post-treatment, and relative response metrics defined as (metricpre-metricpost)/metricpre. Univariable cox regression analyses were performed to investigate associations between PET-metrics and outcomes. RESULTS: Metrics resulted from the post-treatment scan and relative response were associated with outcome, but baseline metrics were not. Primary tumor metrics were stronger associated with all outcomes than lymph node metrics. Both the volumetric (TLG/MTV) and intensity (SUVmax/SUVmean) PET-metrics were associated with OS. The intensity metrics were associated with LF, while the volumetric PET-metrics were associated with RF/DF. This was in contrast to the nodal metrics, demonstrating only an association between RF and the relative response of TLG/MTV. No preference was found between PET volumetric and intensity metrics associated with outcome. CONCLUSION: Early post-treatment PET-metrics are associated with treatment outcome in LA-NSCLC patients treated with chemoradiotherapy. Both volumetric and intensity PET-metrics are useful, but more for the primary tumor than for lymph nodes.

Differential analysis of local and regional failure in locally advanced non-small cell lung cancer patients treated with concurrent chemoradiotherapy.

BACKGROUND AND PURPOSE: Concurrent chemoradiotherapy (CCRT) is the standard treatment in locally advanced non-small cell lung cancer (NSCLC) patients. In clinical practice, the primary tumor (PT) and involved lymph nodes (LNs) receive the same radiotherapy dose. This study investigates differences between local failure (LF) and regional failure (RF). MATERIAL AND METHODS: Patients were irradiated with 66 Gy in 24 fractions (using IMRT) combined with daily low dose cisplatin. The PT and LNs were contoured on the planning CT-scan registered with a (18)FDG-PET-scan. Log10(Volume) and SUVmax of PT and LNs, location (LNs versus PT), performance status, age and gender were tested as prognostic factors for lesion failure using cox regression analysis. RESULTS: In total, 226 patients were analyzed. LF or RF as first event was seen in 37 PT (16%) and 14 LNs (6%). Log10(Volume), location and SUVmax were significantly associated with failure in univariate analysis. In multivariate analysis, only log10(Volume) remained as a significant factor. CONCLUSIONS: A LF and RF as first event of respectively 16% and 6% were observed in locally advanced NSCLC patients treated with CCRT. This difference was primarily associated with the difference in log10(Volume) of the primary tumor and lymph nodes.

Nephrotoxicity as a Dose-Limiting Factor in a High-Dose Cisplatin-Based Chemoradiotherapy Regimen for Head and Neck Carcinomas.

PURPOSE: Loco-regional control and organ preservation are significantly improved with concomitant cisplatin/radiotherapy and are compromised with less than 5% grade 3 nephrotoxicity (creatinine clearance 15-29 mL/min). However, although clinically important, in none of the randomized trials is grade 2 nephrotoxicity (defined as creatinine clearance 59-30 mL/min) mentioned. In this study, we assessed nephrotoxicity in daily practice among patients treated with high-dose cisplatin (100 mg/m² on days 1, 22, and 43), concurrently with chemoradiotherapy (CCRT) and the impact on treatment modifications. METHODS: 208 patients with advanced-stage malignancies of the head and neck region were evaluated. All patients were treated with high-dose cisplatin CCRT. The main outcome parameters were nephrotoxicity (defined as creatinine clearance grade 2 or more) and cumulative doses of cisplatin and radiation. RESULTS: 133 patients (64%) completed all pre-planned courses of cisplatin. Nephrotoxicity was the main reason to discontinue the chemotherapy. Grade 3 nephrotoxicity was seen in 16 patients (8%) while grade 2 nephrotoxicity was seen in 53 patients (25%). Thirty six patients (17%) could not complete the pre-planned chemotherapy due to nephrotoxicity. CONCLUSIONS: In head and neck cancer patients, nephrotoxicity grade 2 is under-reported but is the major factor for discontinuing cisplatin during CCRT.

A prospective study: current problems in radiotherapy for nasopharyngeal carcinoma in yogyakarta, indonesia.

INTRODUCTION: Nasopharyngeal carcinoma (NPC) has a high incidence in Indonesia. Previous study in Yogyakarta revealed a complete response of 29% and a median overall survival of less than 2 years. These poor treatment outcome are influenced by the long diagnose-to-treatment interval to radiotherapy (DTI) and the extended overall treatment time of radiotherapy (OTT). This study reveals insight why the OTT and DTI are prolonged. METHOD: All patients treated with curative intent radiotherapy for NPC between July 2011 until October 2012 were included. During radiotherapy a daily diary was kept, containing information on DTI, missed radiotherapy days, the reason for missing and length of OTT. RESULTS: Sixty-eight patients were included. The median DTI was 106 days (95% CI: 98-170). Fifty-nine patients (87%) finished the treatment. The median OTT for radiotherapy was 57 days (95% CI: 57-65). The main reason for missing days was an inoperative radiotherapy machine (36%). Other reasons were patient's poor condition (21%), public holidays (14%), adjustment of the radiation field (7%), power blackout (3%), inoperative treatment planning system (2%) and patient related reasons (9%). Patient's insurance type was correlated to DTI in disadvantage for poor people. CONCLUSION: Yogyakarta has a lack of sufficient radiotherapy units which causes a delay of 3-4 months, besides the OTT is extended by 10-12 days. This influences treatment outcome to a great extend. The best solution would be creating sufficient radiotherapy units and better management in health care for poor patients. The growing economy in Indonesia will expectantly in time enable these solutions, but in the meantime solutions are needed. Solutions can consist of radiation outside office hours, better maintenance of the facilities and more effort from patient, doctor and nurse to finish treatment in time. These results are valuable when improving cancer care in low and middle income countries.