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Simple Summary: The current review summarizes the new potential treatment strategies for patients with early-stage non-small cell lung cancer with immunotherapy and targeted therapies and defines the current challenges for making treatment decisions with these approaches in daily practice. The recent advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint blockers (ICBs) in early-stage non-small cell lung cancer (NSCLC) has dramatically modified treatment strategies by improving the prognosis in this setting. Osimertinib and alectinib, both TKIs, have shown significant improvements in outcomes for patients with resected EGFR- and ALK-positive NSCLC, respectively, changing the standard of care in these subgroups. More recently, the LAURA trial showed the efficacy of osimertinib after chemoradiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. Numerous trials are still ongoing to investigate neoadjuvant/perioperative TKIs in several oncogene-driven NSCLC. In addition, several ICBs have been tested and approved as adjuvant (atezolizumab and pembrolizumab), neoadjuvant (nivolumab), and perioperative treatments (pembrolizumab) for patients with resectable early-stage NSCLC. Despite these advances, many challenges remain regarding the use of TKIs and ICBs in this setting, including the optimal duration of adjuvant TKI or induction ICB therapy, the role of minimal residual disease to identify patients at high-risk of disease relapse and to guide adjuvant treatment decisions, and the role of adjuvant chemotherapy in resected oncogene-driven NSCLC. Furthermore, potential predictive biomarkers for efficacy are needed to eventually intensify the entire perioperative strategies. This review aims to summarize and discuss the available evidence, the ongoing trials, and the challenges associated with TKI- and ICB-based approaches in early-stage NSCLC. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop and evaluate a proof-of-concept opensource individualized Patient Decision Aid (iPDA) with a group of patients, physicians, and computer scientists. The iPDA was developed based on the International Patient Decision Aid Standards (IPDAS). A previously published questionnaire was adapted and used to test the user-friendliness and content of the iPDA. The questionnaire contained 40 multiple-choice questions, and answers were given on a 5-point Likert Scale (1-5) ranging from "strongly disagree" to "strongly agree." In addition to the questionnaire, semi-structured interviews were conducted with patients. We performed a descriptive analysis of the responses. The iPDA was evaluated by 28 computer scientists, 21 physicians, and 13 patients. The results demonstrate that the iPDA was found valuable by 92% (patients), 96% (computer scientists), and 86% (physicians), while the treatment information was judged useful by 92%, 96%, and 95%, respectively. Additionally, the tool was thought to be motivating for patients to actively engage in their treatment by 92%, 93%, and 91% of the above respondents groups. More multimedia components and less text were suggested by the respondents as ways to improve the tool and user interface. In conclusion, we successfully developed and tested an iPDA for patients with stage I-II Non-Small Cell Lung Cancer (NSCLC). [ABSTRACT FROM AUTHOR]

Osimertinib is prescribed to patients with metastatic non‐small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan‐Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR‐mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first‐line (40%), second‐line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4‐19.3), 13.9 (95% CI: 11.3‐16.1) and 8.7 months (95% CI: 4.6‐12.7), respectively. Patients with low BMI (<20.0 kg/m2) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (Cmin,SS; >271 ng/mL) had shorter PFS compared to a low Cmin,SS (<163 ng/mL; aHR 2.29; 95% CI: 1.13‐4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45‐0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36‐0.92). A trend towards longer PFS was seen for TP53 wild‐type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib. [ABSTRACT FROM AUTHOR]

Simple Summary: Synchronous oligometastatic non-small cell lung cancer (NSCLC) represents an intermediate state of metastatic disease with a limited number of metastases. It has been suggested that adding local radical treatment (LRT) in this setting may improve the survival outcomes, but there are no validated tools to better select those patients who are most likely to benefit from LRT. The presence of cachexia and sarcopenia at diagnosis seems to be linked to poorer outcomes in local or advanced NSCLC, but it is not clear if these factors can be used to guide the treatment decisions in oligometastatic NSCLC and to preclude a possible radical treatment in patients with baseline cachexia or sarcopenia. For this reason, we evaluated the impact of cachexia and sarcopenia on survival outcomes and toxicities in a group of patients with synchronous oligometastatic NSCLC on an intention-to-treat basis. Considering the different definitions of sarcopenia used among different studies, we used the Psoas Muscle Index (PMI) as a surrogate of sarcopenia. Progression-free survival was longer for patients without cachexia and sarcopenia compared to those with cachexia and/or sarcopenia. Among patients with advanced NSCLC, there is a group of patients with synchronous oligometastatic disease (sOMD), defined as a limited number of metastases detected at the time of diagnosis. As cachexia and sarcopenia are linked to poor survival, incorporating this information could assist clinicians in determining whether a radical treatment should be administered. In a retrospective multicenter study, including all patients with adequately staged (FDG-PET, brain imaging) sOMD according to the EORTC definition, we aimed to assess the relationship between cachexia and/or sarcopenia and survival. Of the 439 patients that were identified between 2015 and 2021, 234 met the criteria for inclusion and were included. The median age of the cohort was 67, 52.6% were male, and the median number of metastasis was 1. Forty-six (19.7%) patients had cachexia, thirty-four (14.5%) had sarcopenia and twenty-one (9.0%) had both. With a median follow-up of 49.7 months, median PFS and OS were 8.6 and 17.3 months, respectively. Moreover, a trend toward longer PFS was found in patients without cachexia and sarcopenia compared to those with cachexia and/or sarcopenia. In multivariate analysis, cachexia and sarcopenia were not associated with an inferior survival, irrespective of receiving radical treatment. High CRP was associated with inferior survival and could be a prognostic factor, helping the decision of clinicians in selecting patients who may benefit from the addition of LRT. However, despite the homogeneous definition of oligometastatic disease and the adequate staging, our subgroups were small. Therefore, further studies are needed to better understand our hypothesis and generating findings. [ABSTRACT FROM AUTHOR]

Simple Summary: Around 30% of patients with stage III non-small cell lung cancer (NSCLC) receiving radical chemoradiotherapy will develop symptomatic brain metastases (BM) during the disease course. Identifying risk factors for BM can help improve the management of these patients. The aim of this current study was to identify clinical risk factors, including gross tumor volume (GTV) radiomics features, for developing BM in patients with radically treated stage III NSCLC. We found that age, NSCLC subtype, and GTV of lymph nodes (GTVn) were significant factors for BM. GTVn radiomics features provided higher predictive value than GTV of primary tumor (GTVp) and GTV. Therefore, GTVp and GTVn should be separated in clinical and research practice. 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. [ABSTRACT FROM AUTHOR]

Pemetrexed is a cytotoxic drug for first‐line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin‐related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P =.196) or volume of distribution (+7% change, P =.002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming is recognized as one of the hallmarks of cancer. Alterations in the micro-environmental metabolic characteristics are recognized as important tools for cancer cells to interact with the resident and infiltrating T-cells within this tumor microenvironment. Cancer-induced metabolic changes in the micro-environment also affect treatment outcomes. In particular, immune therapy efficacy might be blunted because of somatic mutation-driven metabolic determinants of lung cancer such as acidity and oxygenation status. Based on these observations, new onco-immunological treatment strategies increasingly include drugs that interfere with metabolic pathways that consequently affect the composition of the lung cancer tumor microenvironment (TME). Positron emission tomography (PET) imaging has developed a wide array of tracers targeting metabolic pathways, originally intended to improve cancer detection and staging. Paralleling the developments in understanding metabolic reprogramming in cancer cells, as well as its effects on stromal, immune, and endothelial cells, a wave of studies with additional imaging tracers has been published. These tracers are yet underexploited in the perspective of immune therapy. In this review, we provide an overview of currently available PET tracers for clinical studies and discuss their potential roles in the development of effective immune therapeutic strategies, with a focus on lung cancer. We report on ongoing efforts that include PET/CT to understand the outcomes of interactions between cancer cells and T-cells in the lung cancer microenvironment, and we identify areas of research which are yet unchartered. Thereby, we aim to provide a starting point for molecular imaging driven studies to understand and exploit metabolic features of lung cancer to optimize immune therapy. [ABSTRACT FROM AUTHOR]

Keywords: coronavirus; pandemic; lung cancer; palliative care; telemedicine EN coronavirus pandemic lung cancer palliative care telemedicine 1 5 5 07/24/20 20200721 NES 200721 Introduction The COVID-19 pandemic causes a massive shift in the distribution of health care. This is especially true for lung cancer patients, with reported mortality rates of 25-55% ([3]-[6]), compared with up to 10% in other COVID-19 patients ([5]),which can be explained by the fact that several risk factors for severe COVID-19 can be found in the group of patients with lung cancer: cancer itself, its potentially immunosuppressive treatment, a high median age (>70 years), often a smoking history, and a high percentage of comorbidities ([7]-[10]). Table 1 Summary problems and possible solutions of palliative care for non-COVID lung cancer patients during the COVID-19 pandemic. Palliative Care During COVID-19 Palliative Care Services and Redeployment of Personnel Palliative care teams and hospice services have an essential role in response to COVID-19. [Extracted from the article]

Background: Non-small cell lung cancer (NSCLC) patients frequently develop brain metastases (BM), even though the initial imaging with brain CT or MRI was negative. Stage III patients have the highest risk to develop BM, with an incidence of approximately 30%. BM can lead to neurocognitive disorders, loss of quality of life (QoL), and they are the most important factors influencing patient’s overall survival (OS). Although a radical local treatment of BM may be possible with primary radiosurgery or after resection, the prognosis often remains poor. Preventing the development of BM through prophylactic cranial irradiation (PCI) may improve the outcome of these patients. Methods: Data from published randomized trials comparing PCI with non-PCI were sought using electronic database (PubMed) searching, hand searching, and by contacting experts. Trials were included if they considered a randomized comparison of PCI and non-PCI, enrolled NSCLC patients, excluded patients with recurrent or metastatic disease, and reported results on BM occurrence. Each randomized controlled trial (RCT) was assessed for methodological quality using the Cochrane collaboration’s tool for the assessment of risk of bias. Study estimates were pooled using a fixed effects sample-weighted meta-analysis approach to calculate an overall estimate and 95% confidence interval (CI). Results on PCI-related toxicity, QoL, and OS were only reported descriptively. Results: Seven RCTs were included in the meta-analysis. In total, 1,462 patients were analyzed, including 717 patients who received PCI and 745 patients who did not. The risk of developing BM was significantly decreased through PCI (13% reduction, RR 0.33; 95% CI 0.22–0.45). PCI-related toxicity and QoL data were limited. Acute toxicity mostly included fatigue, skin-related toxicity, and nausea or vomiting. Late toxicities such as headache, dyspnea, lethargy, and low grade cognitive impairments were also reported in some of the included RCTs. Results on OS were inconclusive. Conclusion: The risk of developing BM was reduced in patients who received PCI compared to patients who did not. To implement PCI as the standard treatment for patients with NSCLC, the impact of PCI-related toxicity on QoL should be further investigated, as well as long-term OS. A future individual patient data meta-analysis could produce definitive answers to this clinical question. [ABSTRACT FROM AUTHOR]

In a patient with a medical history of cancer, the most probable diagnosis of an 18FDG-avid pulmonary mass combined with intracranial abnormalities on brain imaging is metastasized cancer. However, sometimes a differential diagnosis with an infectious cause such as aspergillosis can be very challenging as both cancer and infection are sometimes difficult to distinguish. Pulmonary aspergillosis can present as an infectious pseudotumour with clinical and imaging characteristics mimicking lung cancer. Even in the presence of cerebral lesions, radiological appearance of abscesses can look like brain metastasis. These similarities can cause significant diagnostic difficulties with a subsequent therapeutic delay and a potential adverse outcome. Awareness of this infectious disease that can mimic lung cancer, even in an immunocompetent patient, is important. We report a case of a 65-year-old woman with pulmonary aspergillosis disseminated to the brain mimicking metastatic lung cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Over the last 5 years, immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of non-small cell lung cancer (NSCLC) as either monotherapy or in combination with chemo- and/or radiotherapy. However, despite these advances, outcome still remains poor for most patients and there is still a lot of room to improve prognosis in these patients. To date, we have no tools that allow us to identify the patients that will benefit from chemo- and/or radiotherapy combined with immunotherapy, what treatment-induced immune changes can be expected, and what are the most optimal treatment combinations. Therefore, prognostic and predictive immunological biomarkers are urgently needed. This prospective exploratory study aimed to identify potential prognostic and predictive immune-related proteins that are associated with progression-free survival in patients with stage I/III NSCLC. The results of this trial provide a good starting point to implement blood-based immune profiling analyses in future clinical trials. Radiotherapy (RT) and chemotherapy can induce immune responses, but not much is known regarding treatment-induced immune changes in patients. This exploratory study aimed to identify potential prognostic and predictive immune-related proteins associated with progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC). In this prospective study, patients with stage I NSCLC treated with stereotactic body radiation therapy (n = 26) and patients with stage III NSCLC treated with concurrent chemoradiotherapy (n = 18) were included. Blood samples were collected before (v1), during (v2), and after RT (v3). In patients with stage I NSCLC, CD244 (HR: 10.2, 95% CI: 1.8–57.4) was identified as a negative prognostic biomarker. In patients with stage III NSCLC, CR2 and IFNGR2 were identified as positive prognostic biomarkers (CR2, HR: 0.00, 95% CI: 0.00–0.12; IFNGR2, HR: 0.04, 95% CI: 0.00–0.46). In addition, analysis of the treatment-induced changes of circulating protein levels over time (Δv2/v3−v1) also identified CXCL10 and IL-10 as negative predictive biomarkers (CXCL10, HR: 3.86, 95% CI: 1.0–14.7; IL-10, HR: 16.92 (2.74–104.36)), although serum-induced interferon (IFN) response was a positive prognostic. In conclusion, we identified several circulating immunogenic proteins that are correlated with PFS in patients with stage I and stage III NSCLC before and during treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The historical standard treatment of metastatic non-small cell lung cancer (NSCLC) consisted of palliative chemotherapy, with limited influence on survival. With the introduction of immuno- and targeted therapy, the prognosis improved largely. A subset of NSCLC patients with limited metastatic disease, called oligometastatic, might obtain long-term survival by adding a local ablative treatment on all visible disease sites, in addition to the standard systemic treatment. The evidence for this combined treatment is still scarce and comes mainly from the pre-immunotherapy era. As radiotherapy might stimulate the immune system making immunotherapy more efficient, here we review the evidence before and in the era of immunotherapy, and discuss the challenges and prospects of the combined treatment. Oligometastatic cancer is recognized as a separate entity within the spectrum of metastatic disease. It was suggested that patients with oligometastatic disease can obtain long-term survival by giving local ablative therapy (LAT) to all visible disease locations. However, the true extent from which metastatic cancer should be called "oligometastatic" is unknown, although a consensus definition for oligometastatic disease is proposed by research organizations, such as the EORTC (maximum of five metastases in three organs). Different states of the oligometastatic disease are defined, such as synchronous vs. metachronous, oligopersistent vs. oligoprogressive disease. All clinical trials including patients with non-small cell lung cancer (NSCLC) are small and most are not randomized. Two small randomized phase II trials on synchronous disease showed an improvement in progression free survival, with the addition of LAT, and one also demonstrated an overall survival benefit. Immune checkpoint inhibitors (ICI) were not part of the treatment in these trials, while ICI significantly improved long-term outcomes of patients with metastatic NSCLC. Radiotherapy might improve the prognosis of patients treated with ICI because of its immunostimulatory effects and the possibility to eradicate metastatic deposits. Here, we summarize the data for adding ablative radiotherapy to the treatment of oligometastatic NSCLC, especially in the ICI era, and discuss the challenges of combined treatment. [ABSTRACT FROM AUTHOR]