Proton and photon radiotherapy in stage III NSCLC: Effects on hematological toxicity and adjuvant immune therapy.

BACKGROUND AND PURPOSE: Concurrent chemo-radiotherapy (CCRT) followed by adjuvant durvalumab is standard-of-care for fit patients with unresectable stage III NSCLC. Intensity modulated proton therapy (IMPT) results in different doses to organs than intensity modulated photon therapy (IMRT). We investigated whether IMPT compared to IMRT reduce hematological toxicity and whether it affects durvalumab treatment. MATERIALS AND METHODS: Prospectively collected series of consecutive patients with stage III NSCLC receiving CCRT between 06.16 and 12.22 (staged with FDG-PET-CT and brain imaging) were retrospectively analyzed. The primary endpoint was the incidence of lymphopenia grade ≥ 3 in IMPT vs IMRT treated patients. RESULTS: 271 patients were enrolled (IMPT: n = 71, IMRT: n = 200) in four centers. All patients received platinum-based chemotherapy. Median age: 66 years, 58 % were male, 36 % had squamous NSCLC. The incidence of lymphopenia grade ≥ 3 during CCRT was 67 % and 47 % in the IMRT and IMPT group, respectively (OR 2.2, 95 % CI: 1.0-4.9, P = 0.03). The incidence of anemia grade ≥ 3 during CCRT was 26 % and 9 % in the IMRT and IMPT group respectively (OR = 4.9, 95 % CI: 1.9-12.6, P = 0.001). IMPT was associated with a lower rate of Performance Status (PS) ≥ 2 at day 21 and 42 after CCRT (13 % vs. 26 %, P = 0.04, and 24 % vs. 39 %, P = 0.02). Patients treated with IMPT had a higher probability of receiving adjuvant durvalumab (74 % vs. 52 %, OR 0.35, 95 % CI: 0.16-0.79, P = 0.01). CONCLUSION: IMPT was associated with a lower incidence of severe lymphopenia and anemia, better PS after CCRT and a higher probability of receiving adjuvant durvalumab.

Computed tomography-based radiomics for the differential diagnosis of pneumonitis in stage IV non-small cell lung cancer patients treated with immune checkpoint inhibitors.

INTRODUCTION: Immunotherapy-induced pneumonitis (IIP) is a serious side-effect which requires accurate diagnosis and management with high-dose corticosteroids. The differential diagnosis between IIP and other types of pneumonitis (OTP) remains challenging due to similar radiological patterns. This study was aimed to develop a prediction model to differentiate IIP from OTP in patients with stage IV non-small cell lung cancer (NSCLC) who developed pneumonitis during immunotherapy. METHODS: Consecutive patients with metastatic NSCLC treated with immunotherapy in six centres in the Netherlands and Belgium from 2017 to 2020 were reviewed and cause-specific pneumonitis events were identified. Seven regions of interest (segmented lungs and spheroidal/cubical regions surrounding the inflammation) were examined to extract the most predictive radiomic features from the chest computed tomography images obtained at pneumonitis manifestation. Models were internally tested regarding discrimination, calibration and decisional benefit. To evaluate the clinical application of the models, predicted labels were compared with the separate clinical and radiological judgements. RESULTS: A total of 556 patients were reviewed; 31 patients (5.6%) developed IIP and 41 patients developed OTP (7.4%). The line of immunotherapy was the only predictive factor in the clinical model (2nd versus 1st odds ratio = 0.08, 95% confidence interval:0.01-0.77). The best radiomic model was achieved using a 75-mm spheroidal region of interest which showed an optimism-corrected area under the receiver operating characteristic curve of 0.83 (95% confidence interval:0.77-0.95) with negative and positive predictive values of 80% and 79%, respectively. Good calibration and net benefits were achieved for the radiomic model across the entire range of probabilities. A correct diagnosis was provided by the radiomic model in 10 out of 12 cases with non-conclusive radiological judgements. CONCLUSION: Radiomic biomarkers applied to computed tomography imaging may support clinicians making the differential diagnosis of pneumonitis in patients with NSCLC receiving immunotherapy, especially when the radiologic assessment is non-conclusive.

Association of Pretreatment Physical and Geriatric Parameters with Treatment Tolerance and Survival in Elderly Patients with Stage I-II Non-Small Cell Lung Cancer: An Evaluation of Usual Care Data.

In this study, the association of pretreatment physical and geriatric parameters with treatment tolerance and survival in elderly patients with stage I−II NSCLC was evaluated. Retrospective data for patients aged ≥70 years, diagnosed between 2016 and 2020 with stage I−II NSCLC, and who underwent surgery or stereotactic ablative radiotherapy (SABR) in a large Dutch teaching hospital were retrieved from medical records. Associations of pretreatment physical and geriatric parameters with treatment tolerance and survival were analyzed. Of 160 patients, 49 of 104 (47%) patients who underwent surgery and 21 of 56 (38%) patients who received SABR did not tolerate treatment. In univariable analysis, World Health Organization (WHO) performance status ≥ 2, short nutritional assessment questionnaire score > 1, short physical performance battery score ≤ 9, and geriatric-8 score ≤ 14 were significantly associated with postoperative complications. Forced expiratory volume of one second < 80% of predicted was significantly associated with intolerance of SABR. In multivariable analysis, WHO performance status ≥ 2 and diffusing capacity for carbon monoxide < 80% were significantly associated with decreased overall survival. This is the first study that investigated the association between pretreatment physical and geriatric parameters and treatment outcomes in patients with stage I−II NSCLC. Evaluation of physical and geriatric parameters before treatment initiation seems highly recommended to select patients who might benefit from preventive interventions before and/or during treatment.

Investigation of the added value of CT-based radiomics in predicting the development of brain metastases in patients with radically treated stage III NSCLC.

Introduction: Despite radical intent therapy for patients with stage III non-small-cell lung cancer (NSCLC), cumulative incidence of brain metastases (BM) reaches 30%. Current risk stratification methods fail to accurately identify these patients. As radiomics features have been shown to have predictive value, this study aims to develop a model combining clinical risk factors with radiomics features for BM development in patients with radically treated stage III NSCLC. Methods: Retrospective analysis of two prospective multicentre studies. Inclusion criteria: adequately staged [18F-fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG-PET-CT), contrast-enhanced chest CT, contrast-enhanced brain magnetic resonance imaging/CT] and radically treated stage III NSCLC, exclusion criteria: second primary within 2 years of NSCLC diagnosis and prior prophylactic cranial irradiation. Primary endpoint was BM development any time during follow-up (FU). CT-based radiomics features (N = 530) were extracted from the primary lung tumour on 18-FDG-PET-CT images, and a list of clinical features (N = 8) was collected. Univariate feature selection based on the area under the curve (AUC) of the receiver operating characteristic was performed to identify relevant features. Generalized linear models were trained using the selected features, and multivariate predictive performance was assessed through the AUC. Results: In total, 219 patients were eligible for analysis. Median FU was 59.4 months for the training cohort and 67.3 months for the validation cohort; 21 (15%) and 17 (22%) patients developed BM in the training and validation cohort, respectively. Two relevant clinical features (age and adenocarcinoma histology) and four relevant radiomics features were identified as predictive. The clinical model yielded the highest AUC value of 0.71 (95% CI: 0.58-0.84), better than radiomics or a combination of clinical parameters and radiomics (both an AUC of 0.62, 95% CIs of 0.47-076 and 0.48-0.76, respectively). Conclusion: CT-based radiomics features of primary NSCLC in the current setup could not improve on a model based on clinical predictors (age and adenocarcinoma histology) of BM development in radically treated stage III NSCLC patients.

Robotic Thymectomy for Thymomas: A Retrospective Follow-up Study in the Netherlands.

BACKGROUND: The Maastricht University Medical Center+ is a Dutch center of expertise appointed by the Netherlands Federation of University Medical Centers for the treatment of thymomas. The aim of this study was to investigate the long-term oncologic, surgical, and neurologic outcomes of all patients who underwent a robotic thymectomy for a thymoma at Maastricht University Medical Center+. METHODS: We retrospectively analyzed the clinical-pathologic data of all consecutive patients with a thymoma who underwent robotic thymectomy using the DaVinci robotic system at Maastricht University Medical Center+ between April 2004 and December 2018. Follow-up data were collected from 60 referring Dutch hospitals. RESULTS: In total, 398 robotic thymectomies were performed, and 130 thymomas (32.7%) were found. Median follow-up time was 46 months; median procedure time, 116 minutes; and median hospitalization time, 3 days. In 8.4% of patients, a conversion was performed, and in 20.8%, a complication was registered. The majority of myasthenic patients with a thymoma went into remission, mostly within 12 to 24 months after thymectomy (81%). No statistical difference was found in the number of complications, conversions, incomplete resections, or deaths between patients with myasthenia gravis and nonmyasthenic patients. Thirty-six patients (27.7%) underwent postoperative radiotherapy. The recurrence rate was 9.1%, and the 5-year thymoma-related survival rate was 96.6%. CONCLUSIONS: Robotic thymectomy was found to be safe and feasible for early stage thymomas, most advanced-stage thymomas, and thymomatous myasthenia gravis. A national guideline could contribute to the improvement of the oncologic follow-up of thymic epithelial tumors in the Netherlands.

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium.

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.

Reporting of Incidence and Outcome of Bone Metastases in Clinical Trials Enrolling Patients with Epidermal Growth Factor Receptor Mutated Lung Adenocarcinoma-A Systematic Review.

Bone metastases, occurring in 30-60% of patients with non-small cell lung cancer (NSCLC), are associated with decreased survival, cancer-induced bone pain, and skeletal-related events (SREs). Those with an activating epidermal growth factor mutation (EGFR+) seem to be more prone to develop bone metastases. To gain more insight into bone metastases-related outcomes in EGFR+ NSCLC, we performed a systematic review on Pubmed (2006-2021). Main inclusion criteria: prospective, phase II/III trials evaluating EGFR-tyrosine kinase inhibitors, ≥10 EGFR+ patients included, data on bone metastases and/or bone-related outcomes available. Out of 663 articles, 21 (3176 EGFR+ patients) met the eligibility criteria; 4 phase III (one double blind), 17 phase II trials (three randomized) were included. In seven trials dedicated bone imaging was performed at baseline. Mean incidence of bone metastases at diagnosis was 42%; 3-33% had progression in the bone upon progression. Except for one trial, it was not specified whether the use of bone target agents was permitted, and in none of the trials, occurrence of SREs was reported. Despite the high incidence of bone metastases in EGFR+ adenocarcinoma, there is a lack of screening for, and reporting on bone metastases in clinical trials, as well as permitted bone-targeted agents and SREs.

Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response.

BACKGROUND: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma. METHODS: We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS. FINDINGS: Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid-derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4+ T-helper, CD8+ T- and NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS. INTERPRETATION: Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies.

Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial.

BACKGROUND: Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy. METHODS: We did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m2 on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847. FINDINGS: Between March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36·5 months (95% CI 34·2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6·2 months [95% CI 4·6-8·7]) than in the supportive care group (3·2 months [2·8-4·1]; hazard ratio [HR] 0·48 [95% CI 0·33-0·71]; p=0·0002). The benefit was confirmed by masked independent central review (HR 0·49 [0·33-0·72]; p=0·0002). Grade 3-4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection. INTERPRETATION: Switch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma. FUNDING: Dutch Cancer Society (Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding) and Stichting NVALT studies.

Are patients with stage III non-small cell lung cancer treated with chemoradiotherapy at risk for cardiac events? Results from a retrospective cohort study.

OBJECTIVES: Dyspnoea is one of the symptoms frequently encountered after treatment with chemoradiotherapy (CRT) in stage III non-small cell lung cancer (NSCLC). Long-term data on mild to moderately severe cardiac events as underlying cause of dyspnoea in patients with stage III NSCLC are lacking. Therefore, the incidence of new cardiac events, with a common terminology criteria for adverse events (CTCAE) score of ≥2 within 5 years after diagnosis, were analysed. DESIGN: Retrospective multicentre cohort study of patients with stage III NSCLC treated with CRT from 2006 to 2013. The medical files of the treated patients were reviewed. OUTCOME MEASURES: The primary endpoint of the study was the incidence of new cardiac events with a CTCAE score of ≥2 within 5 years after diagnosis. Secondary endpoint was to identify risk factors associated with the development of a cardiac event. RESULTS: Four hundred and sixty patients were included in the study. Of all patients, 150 (32.6%) developed a new cardiac event. In patients with a known cardiac history (n=138), 44.2% developed an event. The most common cardiac events were arrhythmia (14.6%), heart failure (7.6%) and symptomatic coronary artery disease (6.8%). Pre-existent cardiac comorbidity (HR 1.96; p<0.01) and WHO-performance score ≥2 (HR 2.71; p<0.01) were significantly associated with developing a cardiac event. The majority of patients did not have pre-existent cardiac comorbidity (n=322). Elevated WHO/International Society of Hypertension score was not identified as a significant predictor for cardiac events. CONCLUSION: One-third of patients with stage III NSCLC treated in daily clinical practice develop a new cardiac event within 5 years after CRT. All physicians confronted with patients with NSCLC should take cardiac comorbidity as a serious possible explanation for dyspnoea after treatment with CRT.

Changes in problematic activities of daily living in persons with COPD during 1 year of usual care.

INTRODUCTION: Persons with chronic obstructive pulmonary disease (COPD) are often limited in performing their activities of daily living (ADLs). However, it remains unknown whether and to what extent problematic ADLs change over time and whether exacerbation-related hospitalisations affect problematic ADLs. Therefore, we investigated self-reported problematic ADLs of persons with COPD during 1 year of usual care (i.e. without a specific experimental intervention). METHODS: Stable persons with moderate to very severe COPD (n = 137) were included in this longitudinal study (registered in the Dutch Trial Register [NTR 3941]). Participants were visited at home at baseline and after 1 year. Participants with an exacerbation-related hospitalisation during follow-up were visited additionally within 2 weeks after hospital discharge. During all visits, participants' personalised problematic ADLs were assessed using the Canadian Occupational Performance Measure (COPM), and perceived performance and satisfaction of important problematic ADLs were rated on a 10-point scale. RESULTS: In total, 90% of the participants reported at least one new important problematic ADL after 1 year. In the subgroup of participants with an exacerbation-related hospitalisation (n = 31), 92% of the participants reported new problematic ADLs 2 weeks after discharge and 90% reported new problematic ADLs again after 1 year. Only the satisfaction score of problematic ADLs as mentioned during baseline improved after 1-year follow-up in all participants (p = .002) and in participants without an exacerbation-related hospitalisation (n = 106; p = .014). CONCLUSION: Problematic ADLs changed during 1 year of usual care, which underlines the need for regular assessment of problematic ADLs and referral to treatment options like monodisciplinary occupational therapy and/or a comprehensive pulmonary rehabilitation programme.

Guideline adherence of mediastinal staging of non-small cell lung cancer: A multicentre retrospective analysis.

OBJECTIVES: Mediastinal lymph node staging of NSCLC by initial endosonography and confirmatory mediastinoscopy is recommended by the European guideline. We assessed guideline adherence on mediastinal staging, whether staging procedures were performed systematically and unforeseen N2 rates following staging by endosonography with or without confirmatory mediastinoscopy. MATERIAL AND METHODS: We performed a multicentre (n = 6) retrospective analysis of NSCLC patients without distant metastases, who were surgical candidates and had an indication for mediastinal staging in the year 2015. All patients who underwent EBUS, EUS and/or mediastinoscopy were included. Surgical lymph node dissection was the reference standard. Guideline adherence was based on the 2014 ESTS guideline. RESULTS: 330 consecutive patients (mean age 69 years; 61% male) were included. The overall prevalence of N2/N3 disease was 42%. Initial mediastinal staging by endosonography was done in 84% (277/330; range among centres 71-100%; p < .01). Confirmatory mediastinoscopy was performed in 40% of patients with tumour negative endosonography (61/154; range among centres 10%-73%; p < .01). Endosonography procedures were performed 'systematically' in 21% of patients (57/277) with significant variability among centres (range 0-56%; p < .01). Unforeseen N2 rates after lobe-specific lymph node dissection were 8.6% (3/35; 95%-CI 3.0-22.4) after negative endosonography versus 7.5% (3/40; 95% CI 2.6-19.9) after negative endosonography and confirmatory mediastinoscopy. CONCLUSION: Although adherence to the European NSCLC mediastinal staging guideline on initial use of endosonography was good, 30% of endosonography procedures were performed insufficiently. Confirmatory mediastinoscopy following negative endosonography was frequently omitted. Significant variability was found among participating centres regarding staging strategy and systematic performance of procedures. However, unforeseen N2 rates after mediastinal staging by endosonography with and without confirmatory mediastinoscopy were comparable.

Chest tube drainage versus video-assisted thoracoscopic surgery for a first episode of primary spontaneous pneumothorax: a systematic review and meta-analysis.

Primary spontaneous pneumothorax affects up to 28 patients per 100 000 population yearly and is commonly resolved by chest tube drainage. However, drainage is also known to be associated with ipsilateral recurrence rates ranging from 25% to 43%. Preventive video-assisted thoracoscopic surgery (VATS) may be an effective alternative to diminish these recurrence rates and its associated morbidity. The aim of this study was to compare the efficacy of chest tube drainage and VATS as first line treatments of an initial episode of primary spontaneous pneumothorax. The MEDLINE, EMBASE, CENTRAL and Clinicaltrials.gov databases were searched through 16 September 2018. Data regarding the ipsilateral recurrence rate and the length of hospitalization were extracted and submitted to meta-analysis using the random-effects model and the I2 test for heterogeneity. Two randomized controlled trials and 2 observational studies were included, enrolling a total of 479 patients. Pairwise analysis demonstrated significantly reduced ipsilateral recurrence rates [odds ratio 0.15, 95% confidence interval (CI) 0.07-0.33; P < 0.00001] and length of hospitalization (standardized mean difference -2.19, 95% CI -4.34 to -0.04; P = 0.046) in favour of VATS. However, a significant level of heterogeneity was detected for the length of hospitalization (I2 = 97%; P < 0.00001). Subgroup analysis that stratified study design found no statistical differences regarding recurrence rate. In conclusion, VATS can be an effective and attractive alternative to standard chest tube drainage, with reduced ipsilateral recurrence rates and length of hospitalization. However, given the low quality of the majority of included studies, more well-designed randomized controlled trials are necessary to strengthen the current evidence.

Survival of patients with non-small cell lung cancer having leptomeningeal metastases treated with immune checkpoint inhibitors.

INTRODUCTION: Patients with non-small cell lung cancer (NSCLC) experience leptomeningeal metastases (LM) in 3-9% of cases. Because overall survival (OS) and performance status are very poor, they are mostly excluded from clinical trials. Here, we evaluated survival of patients with NSCLC having LM treated with immune checkpoint inhibitors (ICIs). METHODS: A prospectively collected list of patients with advanced NSCLC treated with ICIs between November 2012 and July 2018 in 7 European centres was merged. All patients with LM before ICI start were selected, data were retrospectively added and patients were classified according to the National Comprehensive Cancer Network (NCCN) LM prognostic classification (good/poor). Progression-free survival (PFS) and OS on ICIs were evaluated. RESULTS: Nineteen of 1288 (1.5%) patients had LM; 73.7% had synchronous brain metastases; 73.7% had neurological symptoms at the start of ICIs and 52.6% were in the NCCN LM good prognosis group. Programmed death ligand-1 (PD-L1) expression was known for 42.1% of patients (87.5% positive). Median follow-up was 13 months from the start of ICIs, and median (95% confidence interval [CI]) PFS on ICIs was 2.0 (1.8-2.2) months. Six-month PFS rate was 21.0% and was significantly higher in the NCCN good versus poor prognostic group: 40% vs 0% (p = 0.05). Twelve-month PFS rate was 0%. Median (95% CI) OS from the start of ICIs was 3.7 (0.9-6.6) months. Six-month OS rate was 36.8%, and 12-month OS rate was 21.1%; both were not statistically significantly different for the good versus poor NCCN prognostic group (p = 0.40 and p = 0.56, respectively). CONCLUSION: Some patients with NSCLC having LM do benefit from ICI treatment; specifically, those in the NCCN LM good prognosis group can obtain a long survival.

Screening for brain metastases in patients with stage III non-small-cell lung cancer, magnetic resonance imaging or computed tomography? A prospective study.

INTRODUCTION: Non-small-cell lung cancer (NSCLC) guidelines advise to screen stage III NSCLC patients for brain metastases (BMs), preferably by magnetic resonance imaging (MRI) or when contraindicated or not accessible a dedicated contrast enhanced-computed tomography (dCE-CT), which can be incorporated in the staging 18Fluodeoxoglucose-positron emission tomography (18FDG-PET-CE-CT). In daily practice, often a dCE-CT is performed instead of a MRI. The aim of the current study is to evaluate the additive value of MRI after dCE-CT, incorporated in the 18FDG-PET-CE-CT. PATIENTS AND METHODS: It is an observational prospective multicentre study (NTR3628). Inclusion criteria included stage III NSCLC patients with a dCE-CT of the brain incorporated in the 18FDG-PET and an additional MRI of the brain. Primary end-point is percentage of patients with BM on MRI without suspect lesions on dCE-CT. Secondary end-points are percentage of patients with BM on dCE-CT and percentage of patients with BM ≤ 1 year of a negative staging MRI. RESULTS: Sixteen (7%) patients with extracranial stage III had BM on dCE-CT and were excluded. One hundred forty-nine patients were enrolled. 7/149 (4.7%) had BM on MRI without suspect lesions on dCE-CT. One hundred eighteen patients had a follow-up of at least 1 year (four with BM on baseline MRI); eight of the remaining 114 (7%) patients developed BM ≤ 1 year after a negative staging brain MRI. CONCLUSION: Although in 7% of otherwise stage III NSCLC patients, BMs were detected on staging dCE-CT, MRI brain detected BMs in an additional 4.7%, which we consider clinically relevant. Within 1 year after a negative staging MRI, 7% developed BM.

Individualized accelerated isotoxic concurrent chemo-radiotherapy for stage III non-small cell lung cancer: 5-Year results of a prospective study.

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 ±â€¯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.

Progression-Free Survival and Overall Survival Beyond 5 Years of NSCLC Patients With Synchronous Oligometastases Treated in a Prospective Phase II Trial (NCT 01282450).

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.

Knowledge gaps in patients with COPD and their proxies.

BACKGROUND: Although proxies of patients with chronic obstructive pulmonary disease (COPD) need health-related knowledge to support patients in managing their disease, their current level of knowledge remains unknown. We aimed to compare health-related knowledge (generic and COPD-related knowledge) between patients with COPD and their resident proxies. METHODS: In this cross-sectional study, we included stable patients with moderate to very severe COPD and their resident proxies (n = 194 couples). Thirty-four statements about generic health and COPD-related topics were assessed in patients and proxies separately. Statements could be answered by 'true', 'false', or 'do not know'. This study is approved by the Medical Research Ethics Committees United (MEC-U), the Netherlands (NL42721.060.12/M12-1280). RESULTS: Patients answered on average 17% of the statements incorrect, and 19% with 'do not know'. The same figure (19%) for the incorrect and unknown statements was shown by proxies. Patients who attended pulmonary rehabilitation previously answered more statements correct (about three) compared to patients who did not attend pulmonary rehabilitation. More correct answers were reported by: younger patients, patients with a higher level of education, patients who previously participated in pulmonary rehabilitation, patients with better cognitive functioning, and patients with a COPD diagnosis longer ago. CONCLUSIONS: Proxies of patients with COPD as well as patients themselves answer about two third of 34 knowledge statements about COPD correct. So, both patients and proxies seem to have an incomplete knowledge about COPD and general health. Therefore, education about general health and COPD should be offered to all subgroups of patients with COPD and their proxies. TRIAL REGISTRATION: This study is registered in the Dutch Trial Register ( NTR3941 ). Registered 19 April 2013.

Patient versus proxy-reported problematic activities of daily life in patients with COPD.

BACKGROUND AND OBJECTIVE: Loved ones (proxies) of patients with COPD are confronted with the patients' limitations in activities of daily living (ADLs). However, it remains unknown whether proxies are able to correctly estimate the problematic ADLs of the patient. Therefore, we aimed to investigate the level of agreement between patient-reported and proxy-reported problematic ADLs of the patient. METHODS: Stable outpatients with moderate to very severe COPD (n = 194) and their resident proxies (n = 194) were included in this cross-sectional study. Patients' problematic ADLs were assessed in the domains 'self-care', 'mobility', 'productivity' and 'leisure' using the Canadian Occupational Performance Measure (COPM) in both patients and resident proxies. Furthermore, the perceived performance and satisfaction for important problematic ADLs were rated on a 10-point scale. RESULTS: In total, 830 problematic ADLs were reported by patients, and 735 by proxies. Agreement in reporting problematic ADLs within a domain was poor (productivity and leisure; κ; = 0.20 and 0.16, respectively) to fair (self-care and mobility; κ = 0.32 and 0.22, respectively). Similar performance and satisfaction scores, for equally reported problematic ADLs, were given by 24.0% and 17.6% of the pairs, respectively. CONCLUSION: Proxies were often not able to identify the patients' most important problematic ADLs. Moreover, when patient and proxy agreed about the presence of a specific problematic ADL, the perception of the performance and the satisfaction with that performance differed within most pairs. This emphasizes the importance of involving proxies, besides patients alone, in identifying patients' problematic ADLs.

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

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.