Associations of Pretreatment Physical Status Parameters with Tolerance of Concurrent Chemoradiation and Survival in Patients with Non-small Cell Lung Cancer.

OBJECTIVE: The aim of this study was to evaluate associations between pretreatment physical status parameters and tolerance of concurrent chemoradiation (cCHRT) and survival among patients with stage III non-small cell lung cancer (NSCLC). METHODS: A retrospective cohort study was conducted among patients with stage III NSCLC who had received cCHRT between 2006 and 2015. Multivariate independent associations were analysed between the pretreatment parameters age, Charlson comorbidity index, World Health Organization performance status (WHO performance status), body mass index (BMI), fat-free mass index (FFMI), maximal handgrip strength, forced expiratory volume in one second and carbon monoxide lung diffusion capacity on the one hand with tolerance of cCHRT (defined as a received radiation dose at least equal to the prescribed radiation dose) and survival on the other hand. RESULTS: 527 of 577 patients (91.3%) tolerated cCHRT. A WHO performance status ≥ 2 (odds ratio (OR) 0.43) and BMI < 18.5 kg/m2 (OR 0.36) were associated with poorer tolerance of cCHRT. In the total group, a WHO performance status ≥ 2 (hazard ratio (HR) 1.73), low FFMI (HR 1.23) and intolerance of cCHRT (HR 1.55) were associated with poorer survival. CONCLUSION: In patients with stage III NSCLC receiving cCHRT, poor WHO performance status and BMI < 18.5 kg/m2 were independently associated with tolerance of cCHRT. Physical status parameters and intolerance of cCHRT were independently associated with poorer survival. Besides using this information for treatment decisions, optimizing physical status in patients at risk for intolerance of cCHRT might be a next step for improving treatment outcomes.

Early detection of hospitalized patients with COVID-19 at high risk of clinical deterioration: Utility of emergency department shock index.

BACKGROUND: The COVID-19 outbreak has put an unprecedented strain on Emergency Departments (EDs) and other critical care resources. Early detection of patients that are at high risk of clinical deterioration and require intensive monitoring, is key in ED evaluation and disposition. A rapid and easy risk-stratification tool could aid clinicians in early decision making. The Shock Index (SI: heart rate/systolic blood pressure) proved useful in detecting hemodynamic instability in sepsis and myocardial infarction patients. In this study we aim to determine whether SI is discriminative for ICU admission and in-hospital mortality in COVID-19 patients. METHODS: Retrospective, observational, single-center study. All patients ≥18 years old who were hospitalized with COVID-19 (defined as: positive result on reverse transcription polymerase chain reaction (PCR) test) between March 1, 2020 and December 31, 2020 were included for analysis. Data were collected from electronic medical patient records and stored in a protected database. ED shock index was calculated and analyzed for its discriminative value on in-hospital mortality and ICU admission by a ROC curve analysis. RESULTS: In total, 411 patients were included. Of all patients 249 (61%) were male. ICU admission was observed in 92 patients (22%). Of these, 37 patients (40%) died in the ICU. Total in-hospital mortality was 28% (114 patients). For in-hospital mortality the optimal cut-off SI ≥ 0.86 was not discriminative (AUC 0.49 (95% CI: 0.43-0.56)), with a sensitivity of 12.3% and specificity of 93.6%. For ICU admission the optimal cut-off SI ≥ 0.57 was also not discriminative (AUC 0.56 (95% CI: 0.49-0.62)), with a sensitivity of 78.3% and a specificity of 34.2%. CONCLUSION: In this cohort of patients hospitalized with COVID-19, SI measured at ED presentation was not discriminative for ICU admission and was not useful for early identification of patients at risk of clinical deterioration.

Cluster-randomised trial of a nurse-led advance care planning session in patients with COPD and their loved ones.

RATIONALE: Advance care planning (ACP) is uncommon in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To assess whether a nurse-led ACP-intervention can improve quality of patient-physician end-of-life care communication in patients with COPD. Furthermore, the influence of an ACP-intervention on symptoms of anxiety and depression in patients and loved ones was studied. Finally, quality of death and dying was assessed in patients who died during 2-year follow-up. METHODS: A multicentre cluster randomised-controlled trial in patients with advanced COPD was performed. The intervention group received an 1.5 hours structured nurse-led ACP-session. Outcomes were: quality of patient-physician end-of-life care communication, prevalence of ACP-discussions 6 months after baseline, symptoms of anxiety and depression in patients and loved ones and quality of death and dying. RESULTS: 165 patients were enrolled (89 intervention; 76 control). The improvement of quality of patient-physician end-of-life care communication was significantly higher in the intervention group compared with the control group (p<0.001). The ACP-intervention was significantly associated with the occurrence of an ACP-discussion with physicians within 6 months (p=0.003). At follow-up, symptoms of anxiety were significantly lower in loved ones in the intervention group compared with the control group (p=0.02). Symptoms of anxiety in patients and symptoms of depression in both patients and loved ones were comparable at follow-up (p>0.05). The quality of death and dying was comparable between both groups (p=0.17). CONCLUSION: One nurse-led ACP-intervention session improves patient-physician end-of-life care communication without causing psychosocial distress in both patients and loved ones.

Effects of exercise prehabilitation and/or rehabilitation on health-related quality of life and fatigue in patients with non-small cell lung cancer undergoing surgery: A systematic review.

BACKGROUND: This systematic review aimed to appraise the current available evidence regarding the effects of exercise prehabilitation and rehabilitation on perceived health-related quality of life (HRQoL) and fatigue in patients undergoing surgery for non-small cell lung cancer (NSCLC). METHODS: Studies were selected according to Cochrane guidelines and assessed for methodological quality and therapeutic quality (the international CONsensus on Therapeutic Exercise aNd Training (i-CONTENT)). Eligible studies included patients with NSCLC performing exercise prehabilitation and/or rehabilitation and postoperative HRQoL and fatigue up to 90-days postoperatively. RESULTS: Thirteen studies were included. Exercise prehabilitation and rehabilitation significantly improved postoperative HRQoL in almost half of the studies (47%), although none of the studies demonstrated a decrease in fatigue. Methodological quality and therapeutic quality were poor in respectively 62% and 69% of the studies. CONCLUSION: There was an inconsistent effect of exercise prehabilitation and exercise rehabilitation on improving HRQoL in patients with NSCLC undergoing surgery, with no effect on fatigue. Due to the low methodological and therapeutic quality of included studies, it was not possible to identify the most effective training program content to improve HRQoL and reduce fatigue. It is recommended to investigate the impact of a high therapeutic qualified exercise prehabilitation and exercise rehabilitation on HRQoL and fatigue in larger studies.

The Association of Gross Tumor Volume and Its Radiomics Features with Brain Metastases Development in Patients with Radically Treated Stage III Non-Small Cell Lung Cancer.

PURPOSE: To identify clinical risk factors, including gross tumor volume (GTV) and radiomics features, for developing brain metastases (BM) in patients with radically treated stage III non-small cell lung cancer (NSCLC). METHODS: Clinical data and planning CT scans for thoracic radiotherapy were retrieved from patients with radically treated stage III NSCLC. Radiomics features were extracted from the GTV, primary lung tumor (GTVp), and involved lymph nodes (GTVn), separately. Competing risk analysis was used to develop models (clinical, radiomics, and combined model). LASSO regression was performed to select radiomics features and train models. Area under the receiver operating characteristic curves (AUC-ROC) and calibration were performed to assess the models' performance. RESULTS: Three-hundred-ten patients were eligible and 52 (16.8%) developed BM. Three clinical variables (age, NSCLC subtype, and GTVn) and five radiomics features from each radiomics model were significantly associated with BM. Radiomic features measuring tumor heterogeneity were the most relevant. The AUCs and calibration curves of the models showed that the GTVn radiomics model had the best performance (AUC: 0.74; 95% CI: 0.71-0.86; sensitivity: 84%; specificity: 61%; positive predictive value [PPV]: 29%; negative predictive value [NPV]: 95%; accuracy: 65%). CONCLUSION: Age, NSCLC subtype, and GTVn were significant risk factors for BM. GTVn radiomics features provided higher predictive value than GTVp and GTV for BM development. GTVp and GTVn should be separated in clinical and research practice.

Pulmonary function three to five months after hospital discharge for COVID-19: a single centre cohort study.

Some COVID-19 survivors suffer from persistent pulmonary function impairment, but the extent and associated factors are unclear. This study aimed to characterize pulmonary function impairment three to five months after hospital discharge and the association with disease severity. Survivors of COVID-19 after hospitalization to the VieCuri Medical Centre between February and December 2020 were invited for follow-up, three to five months after discharge. Dynamic and static lung volumes, respiratory muscle strength and diffusion capacity were measured. The cohort comprised 257 patients after a moderate (n = 33), severe (n = 151) or critical (n = 73) COVID-19 infection with a median follow-up of 112 days (interquartile range 96-134 days). The main sequelae included reduced diffusion capacity (36%) and reduced maximal expiratory pressure (24%). Critically ill patients were more likely to have reduced diffusion capacity than moderate (OR 8.00, 95% CI 2.46-26.01) and severe cases (OR 3.74, 95% CI 1.88-7.44) and lower forced vital capacity (OR 3.29, 95% CI 1.20-9.06) compared to severe cases. Many COVID-19 survivors, especially after a critical disease course, showed pulmonary function sequelae, mainly DLCO impairments, three to five months after discharge. Monitoring is needed to investigate the persistence of these symptoms and the longer-term implications of the COVID-19 burden.

Feasibility of Rehabilitation during Chemoradiotherapy among Patients with Stage III Non-Small Cell Lung Cancer: A Proof-of-Concept Study.

Rehabilitation during chemoradiotherapy (CHRT) might (partly) prevent reduction in physical fitness and nutritional status and could improve treatment tolerance in patients with stage III non-small cell lung cancer (NSCLC). The aim of this proof-of-concept study was to investigate the feasibility of a multimodal program for rehabilitation during CHRT. A home-based multimodal rehabilitation program (partly supervised moderate-intensity physical exercise training and nutritional support) during CHRT was developed in collaboration with patients with stage III NSCLC and specialized healthcare professionals. A predetermined number of six patients with stage III NSCLC (aged > 50 years) who underwent CHRT and participated in this program were monitored in detail to assess its feasibility for further development and optimization of the program. The patient's level of physical functioning (e.g., cardiopulmonary exercise test, six-minute walking test, handgrip strength, body mass index, fat free mass index, energy and protein intake) was evaluated in order to provide personalized advice regarding physical exercise training and nutrition. The program appeared feasible and well-tolerated. All six included patients managed to perform the assessments. Exercise session adherence was high in five patients and low in one patient. The performed exercise intensity was lower than prescribed for all patients. Patients were motivated to complete the home-based rehabilitation program during CHRT. Preliminary effects on physical and nutritional parameters revealed relatively stable values throughout CHRT, with inter-individual variation. Supervised and personalized rehabilitation in patients with stage III NSCLC undergoing CHRT seems feasible when the intensity of the physical exercise training was adjusted to the possibilities and preferences of the patients. Future research should investigate the feasibility of a supervised and personalized rehabilitation program during CHRT with a low-to-moderate exercise intensity with the aim to prevent physical decline during CHRT.

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.

Integrin expression profiling identifies integrin alpha5 and beta1 as prognostic factors in early stage non-small cell lung cancer.

BACKGROUND: Selection of early stage non-small cell lung cancer patients with a high risk of recurrence is warranted in order to select patients who will benefit from adjuvant treatment strategies. We evaluated the prognostic value of integrin expression profiles in a retrospective study on frozen primary tumors of 68 patients with early stage non-small cell lung cancer. METHODS: A retrospective study was performed on frozen primary tumors of 68 early stage non-small cell lung cancer patients with a follow up of at least 10 years. From all tumor tissues, RNA was isolated and reverse transcribed into cDNA. qPCR was used to generate mRNA expression profiles including integrins alpha1, 2, 3, 4, 5, 6, 7, 11, and V as well as integrins beta1, 3, 4, 5, 6, and 8. RESULTS: The expression levels of integrins alpha5, beta1 and beta3 predicted overall survival and disease free survival in early stage NSCLC patients. There was no association between integrin expression and lymph node metastases. Comparison between the histological subtypes revealed a distinct integrin signature for squamous cell carcinoma while the profiles of adenocarcinoma and large cell carcinoma were largely the same. CONCLUSION: Integrin expression in NSCLC is important for the development and behavior of the tumor and influences the survival of the patient. Determining the integrin expression profile might serve as a tool in predicting the prognosis of individual patients.

Inter-reader reproducibility of dynamic contrast-enhanced magnetic resonance imaging in patients with non-small cell lung cancer treated with bevacizumab and erlotinib.

UNLABELLED: Objectives When evaluating anti-tumor treatment response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) it is necessary to assure its validity and reproducibility. This has not been well addressed in lung tumors. Therefore we have evaluated the inter-reader reproducibility of response classification by DCE-MRI in patients with non-small cell lung cancer (NSCLC) treated with bevacizumab and erlotinib enrolled in a multicenter trial. MATERIALS AND METHODS: Twenty-one patients were scanned before and 3 weeks after start of treatment with DCE-MRI in a multicenter trial. The scans were evaluated by two independent readers. The primary lung tumor was used for response assessment. Responses were assessed in terms of relative changes in tumor mean trans endothelial transfer rate (K(trans)) and its heterogeneity in terms of the spatial standard deviation. Reproducibility was expressed by the inter-reader variability, intra-class correlation coefficient (ICC) and dichotomous response classification. RESULTS: The inter-reader variability and ICC for the relative K(trans) were 5.8% and 0.930, respectively. For tumor heterogeneity the inter-reader variability and ICC were 0.017 and 0.656, respectively. For the two readers the response classification for relative K(trans) was concordant in 20 of 21 patients (k=0.90, p<0.0001) and for tumor heterogeneity in 19 of 21 patients (k=0.80, p<0.0001). CONCLUSIONS: Strong agreement was seen with regard to the inter-reader variability and reproducibility of response classification by the two readers of lung cancer DCE-MRI scans.

Galectin expression profiling identifies galectin-1 and Galectin-9Δ5 as prognostic factors in stage I/II non-small cell lung cancer.

Approximately 30-40% of the patients with early stage non-small cell lung cancer (NSCLC) will present with recurrent disease within two years of resection. Here, we performed extensive galectin expression profiling in a retrospective study using frozen and paraffin embedded tumor tissues from 87 stage I/II NSCLC patients. Our data show that galectin mRNA expression in NSCLC is confined to galectin-1, -3, -4, -7, -8, and -9. Next to stage, univariable Cox regression analysis identified galectin-1, galectin-9FL and galectin-9Δ5 as possible prognostic markers. Kaplan-Meier survival estimates revealed that overall survival was significantly shorter in patients that express galectin-1 above median levels, i.e., 23.0 (2.9-43.1) vs. 59.9 (47.7-72.1) months (p = 0.020) as well as in patients that express galectin-9Δ5 or galectin-9FL below the median, resp. 59.9 (41.9-75.9) vs. 32.8 (8.7-56.9) months (p = 0.014) or 23.2 (-0.4-46.8) vs. 58.9 (42.9-74.9) months (p = 0.042). All three galectins were also prognostic for disease free survival. Multivariable Cox regression analysis showed that for OS, the most significant prognostic model included stage, age, gal-1 and gal-9Δ5 while the model for DFS included stage, age and gal-9Δ5. In conclusion, the current study confirms the prognostic value of galectin-1 and identifies galectin-9Δ5 as novel potential prognostic markers in early stage NSCLC. These findings could help to identify early stage NSCLC patients that might benefit most from adjuvant chemotherapy.

Monitoring response to antiangiogenic therapy in non-small cell lung cancer using imaging markers derived from PET and dynamic contrast-enhanced MRI.

UNLABELLED: With antiangiogenic agents, tumor shrinkage may be absent, despite survival benefit. The present study assessed the predictive value of molecular imaging for the identification of survival benefit during antiangiogenic treatment with bevacizumab and erlotinib in patients with advanced non-small cell lung cancer. METHODS: Patients were evaluated using an imaging protocol including CT, 18F-FDG PET, H2(15)O PET, and dynamic contrast-enhanced MRI to derive measurements on tumor size, glucose metabolism, perfusion, and microvascular permeability. The percentage change in imaging parameters after 3 wk of treatment as compared with baseline was calculated and correlated with progression-free survival (PFS). RESULTS: Forty-four patients were included, and 40 underwent CT and 18F-FDG PET at both time points. Complete datasets, containing all imaging modalities, were available for 14 patients. Bevacizumab and erlotinib treatment resulted in decreased metabolism, perfusion, and tumor size. A decrease in standardized uptake value or tumor perfusion of more than 20% at week 3 was associated with longer PFS (9.7 vs. 2.8 mo, P=0.01, and 12.5 vs. 2.9 mo, P=0.009, respectively). Whole-tumor Ktrans (the endothelial transfer constant) was not associated with PFS, but patients with an increase of more than 15% in the SD of tumor Ktrans values-that is, an increase in regions with low or high Ktrans values-after 3 wk had shorter PFS (2.3 vs. 7.0 mo, P=0.008). A partial response, according to the response evaluation criteria in solid tumors (RECIST), at week 3 was also associated with prolonged PFS (4.6 vs. 2.9 mo, P=0.017). However, 40% of patients with a partial response as their best RECIST response still had stable disease at week 3. In these cases tumor perfusion was already decreased and Ktrans heterogeneity showed no increase, indicating that the latter parameters seem to be more discriminative than RECIST at the 3-wk time point. CONCLUSION: PET and dynamic contrast-enhanced MRI were able to identify patients who benefit from bevacizumab and erlotinib treatment. Molecular imaging seems to allow earlier response evaluation than CT.

Use of H2(15)O-PET and DCE-MRI to measure tumor blood flow.

Positron emission tomography (PET) with H2(15)O and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provide noninvasive measurements of tumor blood flow. Both tools offer the ability to monitor the direct target of antiangiogenic treatment, and their use is increasingly being studied in trials evaluating such drugs. Antiangiogenic therapy offers great potential and, to an increasing extent, benefit for oncological patients in a variety of palliative and curative settings. Because this type of targeted therapy frequently results in consolidation of the tumor mass instead of regression, monitoring treatment response with the standard volumetric approach (Response Evaluation Criteria in Solid Tumors) leads to underestimation of the response rate. Monitoring direct targets of anticancer therapy might be superior to indirect size changes. In addition, measures of tumor blood flow contribute to a better understanding of tumor biology. This review shows that DCE-MRI and H2(15)O-PET provide reliable measures of tumor perfusion, provided that a certain level of standardization is applied. Heterogeneity in scan acquisition and data analysis complicates the interpretation of study results. Also, limitations inherent to both techniques must be considered when interpreting DCE-MRI and H2(15)O-PET results. This review focuses on the technical and physiological aspects of both techniques and aims to provide the essential information necessary to critically evaluate the use of DCE-MRI and H2(15)O-PET in an oncological setting.