Despite the potential of exhaled breath analysis of volatile organic compounds to diagnose lung cancer, clinical implementation has not been realized, partly due to the lack of validation studies.
...This study addressed two questions. First, can we simultaneously train and validate a prediction model to distinguish patients with non-small cell lung cancer from non-lung cancer subjects based on exhaled breath patterns? Second, does addition of clinical variables to exhaled breath data improve the diagnosis of lung cancer?
In this multicenter study, subjects with non-small cell lung cancer and control subjects performed 5 min of tidal breathing through the aeoNose, a handheld electronic nose device. A training cohort was used for developing a prediction model based on breath data, and a blinded cohort was used for validation. Multivariable logistic regression analysis was performed, including breath data and clinical variables, in which the formula and cutoff value for the probability of lung cancer were applied to the validation data.
A total of 376 subjects formed the training set, and 199 subjects formed the validation set. The full training model (including exhaled breath data and clinical parameters from the training set) were combined in a multivariable logistic regression analysis, maintaining a cut off of 16% probability of lung cancer, resulting in a sensitivity of 95%, a specificity of 51%, and a negative predictive value of 94%; the area under the receiver-operating characteristic curve was 0.87. Performance of the prediction model on the validation cohort showed corresponding results with a sensitivity of 95%, a specificity of 49%, a negative predictive value of 94%, and an area under the receiver-operating characteristic curve of 0.86.
Combining exhaled breath data and clinical variables in a multicenter, multi-device validation study can adequately distinguish patients with lung cancer from subjects without lung cancer in a noninvasive manner. This study paves the way to implement exhaled breath analysis in the daily practice of diagnosing lung cancer.
The Netherlands Trial Register; No.: NL7025; URL: https://trialregister.nl/trial/7025.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Average discounted 5.81 QALYs for VATS and 5.86 QALYs for SBRT were found.•The average undiscounted costs of VATS are €29,269 versus €21,175 for SBRT.•SBRT is dominant in at least 74 % up to 94 % of ...the simulations.
Stage I non-small cell lung cancer (NSCLC) can be treated with either Stereotactic Body Radiotherapy (SBRT) or Video Assisted Thoracic Surgery (VATS) resection. To support decision making, not only the impact on survival needs to be taken into account, but also on quality of life, costs and cost-effectiveness. Therefore, we performed a cost-effectiveness analysis comparing SBRT to VATS resection with respect to quality adjusted life years (QALY) lived and costs in operable stage I NSCLC.
Patient level and aggregate data from eight Dutch databases were used to estimate costs, health utilities, recurrence free and overall survival. Propensity score matching was used to minimize selection bias in these studies. A microsimulation model predicting lifetime outcomes after treatment in stage I NSCLC patients was used for the cost-effectiveness analysis.
Model outcomes for the two treatments were overall survival, QALYs, and total costs. We used a Dutch health care perspective with 1.5 % discounting for health effects, and 4 % discounting for costs, using 2018 cost data. The impact of model parameter uncertainty was assessed with deterministic and probabilistic sensitivity analyses.
Patients receiving either VATS resection or SBRT were estimated to live 5.81 and 5.86 discounted QALYs, respectively. Average discounted lifetime costs in the VATS group were €29,269 versus €21,175 for SBRT. Difference in 90-day excess mortality between SBRT and VATS resection was the main driver for the difference in QALYs. SBRT was dominant in at least 74 % of the probabilistic simulations.
Using a microsimulation model to combine available evidence on survival, costs, and health utilities in a cost-effectiveness analysis for stage I NSCLC led to the conclusion that SBRT dominates VATS resection in the majority of simulations.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Treatment options for advanced non-small cell lung cancer (NSCLC) include immunotherapy. Elevated carcinoembryonic antigen (CEA) and cancer antigen 125 (Ca-125) levels are associated with poorer ...prognoses of resected NSCLC, but currently no predictive biomarkers exist for immunotherapy response. This study evaluated CEA and Ca-125 as predictive biomarkers for immunotherapy efficiency in patients with metastatic NSCLC.
The single-centre observational retrospective study includes NSCLC stage III/IV patients treated with programmed death-ligand 1 (PD-L1) inhibitors nivolumab or pembrolizumab. The primary study endpoint was treatment response assessed by CT-scan following RECIST-criteria 1.1. CEA/Ca-125 serum values were determined at initiation of treatment and repeated every 2 weeks. Values closest to the day of CT-scan were compared to baseline values.
A total of 136 patients were treated with mono-immunotherapy. Of these, 73 patients were included in the CEA group and 53 patients were included in the Ca-125 group. Baseline CEA and Ca-125 ranged from 8.14 to 5,909 and 1.1 to 4,238 respectively. The sensitivity for Ca-125 as predictor for tumor response was 62.9% (95% CI=61.8%-63.6%), specificity 61.1% (95% CI=60.2%-62.0%), with a positive predictive value (PPV) of 75.9% (95% CI=75.2%-76.7%). For CEA, the sensitivity was 72.0% (95% CI=71.5%-72.5%), specificity 47.1% (95% CI 46.4%-47.8%), with a PPV of 80.0% (95% CI=79.6%-80.4%).
Increased serum CEA might predict tumor progression in NSCLC patients treated with PD-L1 inhibitors. Unconfirmed progression accompanied by increased CEA would support discontinuation of the immunotherapy, while continuation would be advised when serum CEA is not increased.
Lung cancer is the largest cause of cancer-related deaths worldwide. Eighty-five percent of patients is diagnosed with non-small cell lung cancer (NSCLC). Almost a third of patients is aged over 75, ...but this group is poorly represented in clinical trials. This study compares the effects of therapy in non-operable stage III NSCLC in elderly patients compared to their younger counterparts.
This is a retrospective cohort study. Patients are divided into three groups; patients younger than 65, patients aged between 65 and 75 and patients of 75 years or older. Concurrent chemoradiotherapy is compared to sequential chemoradiotherapy using Cox regression analysis. The primary outcome is survival. A sub analysis is performed for the presence of toxicity using logistic regression.
Seven hundred and fifty patients were diagnosed with stage III NSCLC and treated with concurrent (442) or sequential (308) chemoradiotherapy. Concurrent chemoradiotherapy provides a decreased HR of death of 0.72 (0.560-0.85) compared to sequential chemoradiotherapy, even when corrected for age. Elderly patients receiving concurrent chemoradiotherapy do not have a significantly larger risk of toxicity.
Patients of all ages with stage III NSCLC benefit from concurrent chemoradiotherapy compared to sequential chemoradiotherapy. Age is not a deciding factor in this prospect, nor do the patients experience more severe toxicity than their younger counterparts.
This manuscript contains a large retrospective cohort study performed amongst non-small cell lung cancer (NSCLC) patients in the Netherlands. Elderly patients with stage III NSCLC who received concurrent or sequential chemoradiotherapy were compared to their younger counterparts. The elderly patients benefitted from concurrent versus sequential chemoradiotherapy and did not experience more toxicity.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PURPOSE OF REVIEWWith the development of targeted therapies, the treatment strategy of patients with advanced or metastatic non-small cell lung cancer (NSCLC) has changed tremendously. In this ...review, we focus on the different aspects of the treatment of oncogene-driven NSCLC.
RECENT FINDINGSPatients with an EGFR or ALK alteration show a better clinical outcome with tyrosine kinase inhibitor (TKI) treatment compared to chemotherapy.Patients with a ROS1 rearrangement or a BRAF V600E mutation show favorable clinical outcome with TKI treatment compared to chemotherapy, although randomized trials are not available.Patients on TKIs will eventually develop disease progression because of acquired resistance.The treatment with immunotherapy in EGFR and ALK-positive NSCLC patients did not improve overall survival over that of chemotherapy.Blood-based genetic analysis provides the opportunity to noninvasively screen patients for the presence of oncogenic drivers and to monitor resistance during TKI treatment.
SUMMARYTargeted molecular therapies are now standard of care for patients with oncogene-driven NSCLC with a good clinical benefit and minimal toxicity. The role of immunotherapy in patients with molecular alterations is still unclear. Blood-based genotyping has gained interest in the diagnostic and resistance monitoring setting for patients with NSCLC.
There is an ongoing debate on the optimal treatment for stage I NSCLC, with increasing evidence for comparable health outcomes after surgery and stereotactic body radiation therapy (SBRT). For ...clinical decision making, the experienced quality of life, summarized as health utility, is of importance to choosing between treatments. In this study, we evaluated differences in longitudinal health utility in stage I NSCLC in the first year after surgical resection versus after SBRT before any recurrence of disease. We also assessed the impact of potential prognostic variables on health utility.
Prospectively collected databases containing data on patients with stage I NSCLC treated with either SBRT or surgery were pooled from two large hospitals in the Netherlands. Quality of life data were measured by the Quality of Life Questionnaire–Core 30 questionnaire at baseline and 3, 6, and 12 months after treatment. Health utility (measured using the European Quality of Life Five-Dimension questionnaire) was calculated from the Quality of Life Questionnaire–Core 30 questionnaire by using a mapping algorithm. Propensity score matching was used to adjust for selection bias. Treatment effects were estimated for the matched patients by using a longitudinal mixed model approach.
After correction for Eastern Cooperative Oncology Group score, sex, and age, the difference in 1-year averaged health utility between the SBRT and surgery groups was 0.026 (95% confidence interval: 0.028–0.080). Differences in health utility decreased over time.
A small but not statistically significant difference in health utility was found between patients with stage I NSCLC treated with surgery and those treated with SBRT. Current analysis strengthens existing evidence that SBRT is an equivalent treatment option for early-stage NSCLC. Comparative cost-effectiveness remains to be determined.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
After curative treatment of primary non–small-cell lung cancer (NSCLC), patients undergo intensive surveillance with the aim to detect recurrences from the primary tumor or metachronous ...second primary lung cancer as early as possible and improve overall survival. However, the benefit of surveillance is debated. Available evidence is of low quality and conflicting. Microsimulation modeling facilitates the exploration of the impact of different surveillance strategies and provides insight into the cost-effectiveness of surveillance.
Methods
A microsimulation model was used to simulate a range of computed tomography (CT)–based surveillance schedules, differing in the frequency and duration of CT surveillance. The impact on survival, quality-adjusted life-years, costs, and cost-effectiveness of each schedule was assessed.
Results
Ten of 108 strategies formed the cost-effectiveness frontier; that is, these were the strategies with the optimal cost-health benefit balance. Per person, the discounted QALYs of these strategies varied between 5.72 and 5.81 y, and discounted costs varied between €9892 and €19,259. Below a willingness-to-pay threshold of €50,000/QALY, no scanning is the preferred option. For a willingness-to-pay threshold of €80,000/QALY, surveillance scanning every 2 y starting 1 y after curative treatment becomes the best option, with €11,860 discounted costs and 5.76 discounted QALYs per person. The European Society for Medical Oncology guideline strategy was more expensive and less effective than several other strategies.
Conclusion
Model simulations suggest that limited CT surveillance scanning after the treatment of primary NSCLC is cost-effective, but the incremental health-benefit remains marginal. However, model simulations do suggest that the guideline strategy is not cost-effective.
Full text
Available for:
NUK, OILJ, SAZU, UKNU, UL, UM, UPUK, VSZLJ
Metachronous oligo-metastatic disease is variably defined as one to five metastases detected after a disease-free interval and treatment of the primary tumour with curative intent. Oligo-metastases ...in non-small cell lung cancer (NSCLC) are often treated with curative intent. However additional metastases are often detected later in time, and the 5-year survival is low. Burdensome surgical treatment in patients with undetected metastases may be avoided if patients with a high versus low risk of undetected metastases can be separated. Because there is no clinical data on undetected metastases available, a microsimulation model of the development and detection of metastases in 100,000 hypothetical stage I NSCLC patients with a controlled primary tumour was constructed. The model uses data from the literature as well as patient-level data. Calibration was used for the unobservable model parameters. Metastases can be detected by a scheduled scan, or an unplanned scan when the patient develops symptoms. The observable information at time of detection is used to identify subgroups of patients with a different risk of undetectable metastases. We identified the size and number of detected oligo-metastases, as well as the presence of symptoms that are the most important risk predictors. Based on these predictors, patients could be divided into a low-risk and a high-risk group, having a model-based predicted probability of 8.1% and 89.3% to have undetected metastases, respectively. Currently, the model is based on a synthesis of the literature data and individual patient-level data that were not collected for the purpose of this study. Optimization and validation of the model is necessary to allow clinical usability. We describe the type of data that needs to be collected to update our model, as well as the design of such a validation study.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Surgical resection is the treatment of first choice for patients with stage I-II non-small cell lung cancer (NSCLC). However, stereotactic body radiotherapy (SBRT) has been shown to be a good ...alternative treatment.
Overall survival (OS), progression-free survival (PFS) and recurrence rates were compared between patients with stage I-II NSCLC treated with SBRT (n=53) and those treated with surgical resection (n=175). The propensity score method was used to correct for confounding by indication.
Before correction, the OS and PFS rates at 1 and 3 years were significantly different between SBRT and surgery, in favor of surgery. After correction, the OS and PFS after SBRT were not significantly different compared to surgery. The recurrence rates for the two treatments were also similar both before and after correction.
This retrospective study showed that clinical outcomes after SBRT are equal to those after surgery in patients with stage I-II NSCLC.
Epidermal growth factor receptor (EGFR) mutation testing is standard-of-care for advanced non-small cell lung cancer (NSCLC). Outcomes of second-/third-line compared to first-line tyrosine kinase ...inhibitors (TKIs) have shown conflicting results. We investigated utilization of molecular diagnostics and the outcomes of treatment with first-/second-line TKIs in patients with advanced NSCLC.
Retrospective analysis was carried out of 2,206 patients with stage IIIb/IV NSCLC treated between 2008 and 2014 in four hospitals in the Netherlands.
The rate of performing molecular diagnostics increased from 20.8% to 74.4% in the study period. The median overall survival of EGFR mutation-positive patients treated with TKIs was superior compared to EGFR mutation-negative patients treated with chemotherapy (720 vs. 274 days, p<0.0001). No difference in overall survival was found between EGFR mutation-positive patients treated only with TKIs compared to those treated with chemotherapy prior to TKIs, or upon progression under TKIs.
The rate of EGFR testing has improved, increasing the number of patients eligible for targeted therapy. Chemotherapy, prior or subsequent to TKIs, for the treatment of EGFR mutation-positive patients, did not result in significantly better overall survival compared to that achieved with TKIs alone.
PDF
