Tumor characterization using radiolabeled anti-cancer drugs in NSCLC patients

Hendrikse, N.H. [Promotor]Smit, E.F. [Promotor]Lammertsma, A.A. [Promotor]Yaqub, M.M. [Copromotor

Feasibility of salvage resection following locoregional failure after chemoradiotherapy and consolidation durvalumab for unresectable stage III non-small cell lung cancer

Introduction: In patients with unresectable stage III non-small cell lung cancer, high-dose chemoradiotherapy (CRT) followed by consolidation durvalumab improves the 5-year overall survival compared to CRT alone. The feasibility and safety of salvage surgery for such patients who subsequently develop locoregional failure (LRF) is unclear. We evaluated our institutional experience with radical-intent salvage surgery in this patient population. Materials and methods: Details of patients undergoing salvage surgery for locoregional failure after CRT and durvalumab were identified from an institutional surgical database. Each patient's case underwent multidisciplinary discussion at initial disease presentation, and again at time of progression. Results: Ten patients underwent salvage surgery for LRF after prior concurrent (n = 9) or sequential (n = 1) platinum-based high-dose chemo-radiotherapy followed by durvalumab. Consolidation durvalumab was completed in 4 patients, and discontinued in 6, due to either toxicity or disease progression. Median time between end of radiotherapy to detection of LRF was 19 months (range 6-75). Seven patients underwent a lobectomy, 1 a bilobectomy and 2 patients a pneumonectomy. Postoperative morbidity (Clavien-Dindo grade III-V) and 90-day mortality were 10% and 0%, respectively. Median follow-up after surgery was 7 months (range 1-25) during which 2 patients died (both 9 months post-operatively), one due to distant progression, and one of sepsis/ bleeding. Eight patients are alive at 1-23 months post-surgery, with 6 showing no evidence of disease. Conclusions: Our results suggest that salvage pulmonary resection can be performed safely in selected patients with LRF following chemoradiotherapy and durvalumab. This radical-intent treatment option merits consideration by multidisciplinary lung tumor boards.Thoracic Surger

Superior sulcus tumors invading the spine: multimodal treatment outcomes from the preimmunotherapy era

Introduction: Curative-intent treatment of superior sulcus tumors (SSTs) of the lung invading the spine presents considerable challenges. We retrospectively studied outcomes in a single center, uniformly staged patient cohort treated with induction concurrent chemoradiotherapy followed by surgical resection (trimodality therapy).Methods: An institutional surgical database from the period between 2002 and 2021 was accessed to identify SSTs in which the resection included removal of at least part of the vertebral body. All patients were staged using fluorodeox-yglucose positron emission tomography (/computed tomography), computed tomography scan of the chest/upper abdomen, and brain imaging. Surgical morbidity was assessed using the Clavien-Dindo classification. Overall and disease-free survival were calculated using the Kaplan Meier method.Results: A total of 18 patients were included: 8 complete and 10 partial vertebrectomies were performed, with six of the eight complete vertebrectomies involving two vertebral levels, resulting in Complete surgical resection (R0) in 94%. Nine patients had a 1-day procedure, and nine were staged over 2 days. The median follow-up was 30 months (inter quartile range 11-57). The 90-day postoperative morbidity was 44% (grade III/IV), with no 90-day surgery-related mortality. There were 83% who had a major pathologic response, associated with improved survival (p 1/4 0.044). The 5-year overall and disease-free survival were 55% and 40%, respectively. Disease progression occurred in 10 patients, comprising locoregional recurrences in two and distant metastases in eight patients.Conclusions: Multimodality treatment in selected patients with a superior sulcus tumor invading the spine is safe and results in good survival. Such patients should be referred to expert centers. Future research should focus on improving distant control (e.g. [neo]adjuvant immunotherapy).(c) 2023 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Thoracic Surger

Identifying advanced stage NSCLC patients who benefit from afatinib therapy using 18F-afatinib PET/CT imaging

Objectives: Non-small cell lung cancer (NSCLC) tumors harboring common (exon19del, L858R) and uncommon (e.g. G719X, L861Q) activating epidermal growth factor receptor (EGFR) mutations are best treated with EGFR tyrosine kinase inhibitors (TKI) such as the first-generation EGFR TKI erlotinib, second-generation afatinib or third-generation osimertinib. However, identifying these patients through biopsy is not always possible. Therefore, our aim was to evaluate whether 18F-afatinib PET/CT could identify patients with common and uncommon EGFR mutations. Furthermore, we evaluated the relation between tumor 18F-afatinib uptake and response to afatinib therapy.Materials and methods: 18F-afatinib PET/CT was performed in 12 patients: 6 EGFR wild type (WT), 3 EGFR common and 3 EGFR uncommon mutations. Tumor uptake of 18F-afatinib was quantified using TBR_WB60-90 (tumor-to-whole blood activity ratio 60-90 min post-injection) for each tumor. Response was quantified per lesion using percentage of change (PC): [(response measurement (RM)?baseline measurement (BM))/BM]?100. Statistical analyses were performed using t-tests, correlation plots and sensitivity/specificity analysis.Results: Twenty-one tumors were identified. Injected dose was 348 ? 31 MBq. Group differences were significant between WT versus EGFR (common and uncommon) activating mutations (p = 0.03). There was no significant difference between EGFR common versus uncommon mutations (p = 0.94). A TBR_WB60-90 cut-off value of 6 showed the best relationship with response with a sensitivity of 70 %, a specificity of 100 % and a positive predictive value of 100 %.Conclusion: 18F-afatinib uptake was higher in tumors with EGFR mutations (common and uncommon) compared to WT. Furthermore, a TBR_WB60-90 cut-off of 6 was found to best predict response to therapy. 18F-afatinib PET/ CT could provide a means to identify EGFR mutation positive patients who benefit from afatinib therapy.Pathogenesis and treatment of chronic pulmonary disease

Cellular pharmacology studies of anticancer agents: recommendations from the EORTC-PAMM group

An increasing number of manuscripts focus on the in vitro evaluation of established and novel anti-tumour agents in experimental models. Whilst the design of such in vitro assays is inherently flexible, some of these studies lack the minimum information necessary to critically evaluate their relevance or have been carried out under unsuitable conditions. The use of appropriate and robust methods and experimental design has important implications for generating results that are reliable, relevant, and reproducible. The Pharmacology and Molecular Mechanisms (PAMM) group of the European Organization for Research and Treatment of Cancer (EORTC) is the largest group of academic scientists working on drug development and bundle decades of expertise in this field. This position paper addresses all researchers with an interest in the preclinical and cellular pharmacology of anti-tumour agents and aims at generating basic recommendations for the correct use of compounds to be tested for anti-tumour activity using a range of preclinical cellular models of cancer