Comparing modeling strategies combining changes in multiple serum tumor biomarkers for early prediction of immunotherapy non-response in non-small cell lung cancer

BACKGROUND: Patients treated with immune checkpoint inhibitors (ICI) are at risk of adverse events (AEs) even though not all patients will benefit. Serum tumor markers (STMs) are known to reflect tumor activity and might therefore be useful to predict response, guide treatment decisions and thereby prevent AEs.OBJECTIVE: This study aims to compare a range of prediction methods to predict non-response using multiple sequentially measured STMs.METHODS: Nine prediction models were compared to predict treatment non-response at 6-months (n = 412) using bi-weekly CYFRA, CEA, CA-125, NSE, and SCC measurements determined in the first 6-weeks of therapy. All methods were applied to six different biomarker combinations including two to five STMs. Model performance was assessed based on sensitivity, while model training aimed at 95% specificity to ensure a low false-positive rate.RESULTS: In the validation cohort, boosting provided the highest sensitivity at a fixed specificity across most STM combinations (12.9% -59.4%). Boosting applied to CYFRA and CEA achieved the highest sensitivity on the validation data while maintaining a specificity &gt;95%.CONCLUSIONS: Non-response in NSCLC patients treated with ICIs can be predicted with a specificity &gt;95% by combining multiple sequentially measured STMs in a prediction model. Clinical use is subject to further external validation.</p

Identification of protein biomarkers for prediction of response to platinum-based treatment regimens in patients with non-small cell lung cancer

The majority of patients with resected stage II-IIIA non-small cell lung cancer (NSCLC) are treated with platinum-based adjuvant chemotherapy (ACT) in a one-size-fits-all approach. However, a significant number of patients do not derive clinical benefit, and no predictive patient selection biomarker is currently available. Using mass spectrometry-based proteomics, we have profiled tumour resection material of 2 independent, multi-centre cohorts of in total 67 patients with NSCLC who underwent ACT. Unsupervised cluster analysis of both cohorts revealed a poor response/survival sub-cluster composed of ~ 25% of the patients, that displayed a strong epithelial-mesenchymal transition signature and stromal phenotype. Beyond this stromal sub-population, we identified and validated platinum response prediction biomarker candidates involved in pathways relevant to the mechanism of action of platinum drugs, such as DNA damage repair, as well as less anticipated processes such as those related to the regulation of actin cytoskeleton. Integration with pre-clinical proteomics data supported a role for several of these candidate proteins in platinum response prediction. Validation of one of the candidates (HMGB1) in a third independent patient cohort using immunohistochemistry highlights the potential of translating these proteomics results to clinical practice.</p

A randomised phase II study of extended pleurectomy/decortication preceded or followed by chemotherapy in patients with early-stage pleural mesothelioma:EORTC 1205

BACKGROUND: The role of surgery in pleural mesothelioma remains controversial. It may be appropriate in highly selected patients as part of a multimodality treatment including chemotherapy. Recent years have seen a shift from extrapleural pleuropneumonectomy toward extended pleurectomy/decortication. The most optimal sequence of surgery and chemotherapy remains unknown. METHODS: EORTC-1205-LCG was a multicentric, noncomparative phase 2 trial, 1:1 randomising between immediate (arm A) and deferred surgery (arm B), followed or preceded by chemotherapy. Eligible patients (Eastern Cooperative Oncology Group 0-1) had treatment-naïve, borderline resectable T1-3 N0-1 M0 mesothelioma of any histology. Primary outcome was rate of success at 20 weeks, a composite end-point including 1) successfully completing both treatments within 20 weeks; 2) being alive with no signs of progressive disease; and 3) no residual grade 3-4 toxicity. Secondary end-points were toxicity, overall survival, progression-free survival and process indicators of surgical quality. FINDINGS: 69 patients were included in this trial. 56 (81%) patients completed three cycles of chemotherapy and 58 (84%) patients underwent surgery. Of the 64 patients in the primary analysis, 21 out of 30 patients in arm A (70.0%; 80% CI 56.8-81.0%) and 17 out of 34 patients (50.0%; 80% CI 37.8-62.2%) in arm B reached the statistical end-point for rate of success. Median progression-free survival and overall survival were 10.8 (95% CI 8.5-17.2) months and 27.1 (95% CI 22.6-64.3) months in arm A, and 8.0 (95% CI 7.2-21.9) months and 33.8 (95% CI 23.8-44.6) months in arm B. Macroscopic complete resection was obtained in 82.8% of patients. 30- and 90-day mortality were both 1.7%. No new safety signals were found, but treatment-related morbidity was high. INTERPRETATION: EORTC 1205 did not succeed in selecting a preferred sequence of pre- or post-operative chemotherapy. Either procedure is feasible with a low mortality, albeit consistent morbidity. A shared informed decision between surgeon and patient remains essential.</p

A CT-assisted method of dosimetry in brachytherapy of lung cancer

Background: The toxicity of endobronchial brachytherapy (EB), in particular fatal haemoptysis and bronchial wall necrosis, has been correlated with the total dose, fraction size, volume encompassed by the 100% isodose, and a proximal tumor location. We describe a CT-based planning method which, by improving target volume definition and volumetric dose information, can improve the therapeutic ratio of EB. Materials and methods: Sixteen CT-assisted EB procedures were performed in patients who were treated with palliative high-dose rate EB. The CT data were used to analyze applicator position in relation to anatomy. An example of a three-dimensional optimized treatment plan was generated and analyzed using different types of dose-volume histograms. Results: The procedure was well tolerated by patients and no post-procedure complications were observed. The bronchial applicator was eccentrically positioned at the level of the carina/mainstem bronchus in 12 (of 14) CT scans. A planning CT prior to EB was not found to be useful as the final target volume and/or the final applicator position were not reliably predicted before the therapeutic bronchoscopy. CT-scans performed with the applicator in situ allowed the bronchial segments in the target volume to be identified and enabled dose prescription to the bronchial mucosa. Conclusions: CT-assisted EB is feasible and underlines the need for using centered applicators for proximally located tumors. By enabling accurate mucosal dose prescription, CT-assisted EB may reduce the toxicity of fractionated EB in the curative setting. However, faster on-line EB treatment planning is needed for the routine clinical application of this technique. Copyright (C) 2000 Elsevier Science Ireland Ltd

Experiences of healthcare professionals with support for mesothelioma patients and their relatives: Identified gaps and improvements for care

Objective: To assess perspectives and experiences of healthcare professionals and other relevant stakeholders regarding psychosocial support and palliative care in mesothelioma patients and their relatives, to identify gaps and to explore potential improvements in current healthcare. Methods: Individual, semi-structured interviews were conducted with healthcare professionals and other relevant stakeholders. Interviews were transcribed verbatim and analysed thematically using ATLAS.ti. Results: In total, 16 respondents participated in an interview (69% women; mean age: 51.8 years (SD 12.41; range 28–75)). Four key themes were identified: (1) availability of tailored psychosocial and palliative care, (2) timely integration and organisation of psychosocial support and palliative care, (3) differences in provided support and care between healthcare professionals and hospitals and (4) training of healthcare professionals and stakeholders on psychosocial problems. Conclusion: Our study showed that psychosocial support and palliative care for patients with mesothelioma could be improved. A more fluent transition between primary and secondary cancer care and early integration of psychosocial support and palliative care is advised. Lastly, more attention is needed for psychosocial and palliative care in the basic medical training of healthcare professionals

Transesophageal endoscopic ultrasound with fine needle aspiration in the preoperative staging of malignant pleural mesothelioma

Purpose: Surgical resection as part of a multimodality approach in malignant pleural mesothelioma (MPM) has a high morbidity and mortality. Because mediastinal lymph node (MLN) metastases are a negative prognostic factor, preoperative staging is of paramount importance. Transesophageal endoscopic ultrasound with real-time guided fine needle aspiration (EUS-FNA) enables accurate MLN staging in lung cancer. Experimental Design: The feasibility and yield of EUS-FNA in MLN staging were prospectively analyzed in patients with presumed early-stage MPM considered for multimodality therapy. MLN reference pathology was defined by either pathologic staging or the formal demonstration of malignant cells by either EUS-FNA or mediastinoscopy. Results: Thirty-two consecutive patients (81% males; median age, 61 years) with proven MPM underwent EUS-FNA. In 11 (34%) patients, a negative EUS-FNA or mediastinoscopy was not confirmed by surgical MLN dissection because of clinical deterioration or disease progression. In 21 (66%) patients, a formal pathology of the MLN was obtained and staging with EUS-FNA was positive in 4 (19%). Mediastinoscopy did not result in a greater yield of MLN metastasis as compared with EUS-FNA. Thoracotomy with complete lymph node dissection was done in 17 (81%). The overall prevalence of MLN metastasis was 24%, and the sensitivity of EUS-FNA was 80% (95% confidence interval, 28-99%) with a specificity of 100% (95% confidence interval, 79-100%). One patient had esophageal perforation related to EUS-FNA. Conclusions: EUS-FNA is feasible and sensitive for MLN staging in patients with MPM who are candidate for multimodality treatment. These data warrant further evaluation

Concentrations of Erlotinib in Tumor Tissue and Plasma in Non-Small-Cell Lung Cancer Patients After Neoadjuvant Therapy

INTRODUCTION: Tumors might not optimally respond to systemic therapy if minimal effective levels are not reached within the tumor. Erlotinib has mainly been studied in the adjuvant or palliative setting and, therefore, little is known about erlotinib tumor penetration. The purpose of this exploratory study was to investigate lung tumor tissue erlotinib concentrations after neoadjuvant therapy for non-small-cell lung cancer. PATIENTS AND METHODS: Patients were treated preoperatively with erlotinib (150 mg once daily for 3 weeks) up to 48 hours before surgery. Plasma samples were collected during treatment. Surgical resection involved radical resection of the lung tumor and tumor biopsies were frozen directly after surgery. Erlotinib and O-desmethyl erlotinib concentrations in lung tumor tissue and predose plasma were determined using high performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: Thirteen evaluable patients were included. The mean plasma and lung tumor tissue erlotinib levels were 1222 ng/mL (SD, 678) and 149 ng/g (SD, 153), respectively. In 2 individual patients, erlotinib and O-desmethyl erlotinib concentrations in lung tumor tissue were detectable up to 13 days and 7 days after erlotinib intake, respectively. Mean erlotinib tissue concentrations extrapolated to a time point directly after intake of erlotinib were approximated at > 200 ng/g tissue, which is greater than the reported half maximal inhibitory concentration (IC50) of wild type epidermal growth factor receptor (EGFR) (183 ng/mL). CONCLUSION: No strong accumulation of erlotinib in lung tumor tissue was observed. Nevertheless, extrapolated intratumoral concentrations during erlotinib therapy were greater than the IC50 of wild type EGFR