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Platinum-based treatment for small cell lung cancer (SCLC) has been established since 1995. This study investigates treatment outcome of elderly patients (age >/=70 years) with SCLC over the past 20 years in a large UK cancer centre. Comparison of all-cause survival was assessed in patients presenting between two predefined time periods: 1982-1994 and 1995-2003. All the survival analysis were adjusted for stage and performance status and age if appropriate. Survival between different chemotherapy treatment regimens was compared. A total of 322 elderly patients (31% of all) registered between 1982-2003 received chemotherapy for SCLC. Patients presenting in 1995-2003 had an overall better median survival (43 vs 25 weeks) and a 1-year survival (37 vs 14%) than patients presenting in 1982-1994 (P<0.001). This applied to patients with both limited and extensive stage disease and all age groups. There was a trend towards the use of more platinum-based treatments in the later cohort but the use of radiotherapy remained constant. Patients who received platinum combinations (Carboplatin or Cisplatin) had significantly improved survival over those who received single agents or other combinations (P<0.001) and there was no significant difference between carboplatin and cisplatin (P=0.7). The analysis demonstrates that there has been a significant improvement in survival for elderly patients with lung cancer treated by chemotherapy in the past 20 years despite more very elderly patients being treated with a poorer performance status. This change is probably multifactorial and may be due to the increased use of platinum-based treatment and improved supportive care. [ABSTRACT FROM AUTHOR]

To examine whether weight loss at presentation influences outcome in patients who received chemotherapy for lung cancer or mesothelioma. Multivariate analysis of prospectively collected data 1994-2001. Data were available for age, gender, performance status, histology, stage, response, toxicity, progression-free and overall survival. The outcomes of patients with or without weight loss treated with chemotherapy for small cell lung cancer (SCLC; n=290), stages III and IV non-small-cell lung cancer (NSCLC; n=418), or mesothelioma (n=72) were compared. Weight loss was reported by 59, 58 and 76% of patients with SCLC, NSCLC and mesothelioma, respectively. Patients with weight loss and NSCLC (P=0.003) or mesothelioma (P=0.05) more frequently failed to complete at least three cycles of chemotherapy. Anaemia as a toxicity occurred significantly more frequently in NSCLC patients with weight loss (P=0.0003). The incidence of other toxicities was not significantly affected by weight loss. NSCLC patients with weight loss had fewer symptomatic responses (P=0.001). Mesothelioma patients with weight loss had fewer symptomatic (P=0.03) and objective responses (P=0.05). Weight loss was an independent predictor of shorter overall survival for patients with SCLC (P=0.003, relative risk (RR)=1.5), NSCLC (P=0.009, RR=1.33) and mesothelioma (P=0.03, RR=1.92) and an independent predictor of progression-free survival in patients with SCLC (P=0.01, RR=1.43). In conclusion, weight loss as a symptom of lung cancer predicts for toxicity from treatment and shorter survival. [ABSTRACT FROM AUTHOR]

Aims: The standard evaluation of older lung cancer or mesothelioma patients for systemic anti-cancer treatment, based on performance status, is inaccurate. We used the G8 questionnaire to assess a patient's fitness for chemotherapy and explored the correlations between G8 scores, treatment decisions and clinical outcomes., Materials and Methods: In total, 201 older patients (≥70 years) with advanced lung cancer or mesothelioma were prospectively assessed by standard clinical methods and a G8 questionnaire. Treatment decisions before and after reviewing the G8 score were documented. Patients were divided into low (<11), intermediate (11-14) and high (>14) G8 score groups. Patients' characteristics, treatment plans and clinical outcomes among each G8 score group were compared. Similar analyses were compared between good (<2) and poor (≥2) performance status., Results: 10.1% of patients' treatment plans changed after oncologists reviewed G8 scores. The G8 score correlated inversely with performance status. More patients with low G8 scores (22.5%) were offered the best supportive care compared with 4.5% in intermediate and 1.9% in high G8 score groups. More patients (30.1%) with low G8 scores had treatment changed from chemotherapy to best supportive care on the planned day of their treatment, compared with intermediate (7.5%) and high (6.1%) G8 score groups. High G8 score patients received higher chemotherapy intensity and survived longer than patients with intermediate or low G8 scores., Conclusions: The G8 score with two cut-off values can predict functional status, chemotherapy tolerability and prognosis in older patients with lung cancer or mesothelioma, thus supporting oncologists on treatment decisions for this population., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Introduction: Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC., Methods: Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate., Results: A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%., Conclusions: Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Vitamin supplementation reduces pemetrexed toxicity. Raised plasma homocysteine reflects deficiency in vitamin B12 and folate, and is suppressed by supplementation. This observational study of 112 patients receiving pemetrexed-based chemotherapy assessed homocysteine levels after 3 weeks of vitamin supplementation, hypothesising high levels would correlate with ongoing deficiency, thus increased toxicity., Material and Methods: Primary endpoint was the composite of proportion of patients with treatment delay/ dose reduction/ drug change or hospitalisation during the first six weeks of chemotherapy, comparing those with normal plasma homocysteine (successfully supplemented, SS) and those with high homocysteine (unsuccessfully supplemented, USS). Secondary endpoints included toxicity and analyses for depression. Post-hoc analysis examined correlation between interval of vitamin and folate supplementation and pemetrexed on primary endpoint and grade 3-4 toxicities., Results: Eighty-four patients (84%) were successfully supplemented (SS group). The proportion of patients undergoing a treatment delay/ dose reduction/ drug change or hospitalisation in SS group was 44.0% (95% confidence interval [CI] 33.2%-55.3%) and in USS group was 18.8% (95% CI 4.0%-45.6%) (p = 0.09). Twelve percent of patients gave a past history of depression however 66% of patients had an on study Hospital Anxiety and Depression (HAD) score of >7. Supplementation status was not associated with depression. The median overall survival (OS) was 11.8 months (95% CI 8.6-16.5) in the SS group and 8.8 months (95% CI 6.6-16.2) in the US group (p = 0.5). The number of days (<7 or ≥ 7 days) between vitamin B12 and folate initiation and pemetrexed administration, had no effect on the primary endpoint and grade 3-4 toxicities., Conclusion: On-treatment homocysteine levels were not a biomarker of toxicity or depression. Standard vitamin supplementation is adequate in the majority of patients receiving pemetrexed. High HAD score were noted in this population giving an opportunity for mental health intervention. The lead-in time for vitamin supplementation can be short., Competing Interests: The authors have declared that no competing interests exist.

Objective: To correlate changes in the apparent diffusion coefficient (ADC) from diffusion-weighted (DW)-MRI and standardised uptake value (SUV) from fluorothymidine ( 18 FLT)-PET/CT with histopathological estimates of response in patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant chemotherapy and track longitudinal changes in these biomarkers in a multicentre, multivendor setting., Methods: 14 patients with operable NSCLC recruited to a prospective, multicentre imaging trial (EORTC-1217) were treated with platinum-based neoadjuvant chemotherapy. 13 patients had DW-MRI and FLT-PET/CT at baseline (10 had both), 12 were re-imaged at Day 14 (eight dual-modality) and nine after completing chemotherapy, immediately before surgery (six dual-modality). Surgical specimens (haematoxylin-eosin and Ki67 stained) estimated the percentage of residual viable tumour/necrosis and proliferation index., Results: Despite the small numbers,significant findings were possible. ADC median increased ( p < 0.001) and SUV mean decreased ( p < 0.001) significantly between baseline and Day 14; changes between Day 14 and surgery were less marked. All responding tumours (>30% reduction in unidimensional measurement pre-surgery), showed an increase at Day 14 in ADC75 th centile and reduction in total lesion proliferation (SUV mean x proliferative volume) greater than established measurement variability. Change in imaging biomarkers did not correlate with histological response (residual viable tumour, necrosis)., Conclusion: Changes in ADC and FLT-SUV following neoadjuvant chemotherapy in NSCLC were measurable by Day 14 and preceded changes in unidimensional size but did not correlate with histopathological response. However, the magnitude of the changes and their utility in predicting (non-) response (tumour size/clinical outcome) remains to be established., Advances in Knowledge: During treatment, ADC increase precedes size reductions, but does not reflect histopathological necrosis., Competing Interests: Conflict of Interest: John Waterton has received compensation from Bioxydyn Ltd, a for-profit company engaged in the development and provision of imaging biomarker services. All other authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (© 2019 The Authors. Published by the British Institute of Radiology.)

Purpose: Afatinib, an irreversible ErbB family blocker, has demonstrated preclinical antitumor activity with chemotherapy., Methods: As part of a phase I trial in patients with advanced solid tumors (NCT00809133; 3 + 3 dose-escalation design), we determined the maximum tolerated dose (MTD) of afatinib with carboplatin (A/C) or with carboplatin plus paclitaxel (A/C/P). Starting doses: afatinib 20 mg/day, carboplatin AUC6 (A/C) with paclitaxel 175 mg/m 2 (A/C/P) (chemotherapy: Day 1 of 21-day cycles). The primary objective was to determine the MTDs; safety, pharmacokinetics and antitumor activity were also evaluated., Results: Thirty-eight patients received A/C (n = 12) or A/C/P (n = 26). No dose-limiting toxicities (DLTs) were reported with A(20 mg)/C(AUC6). One patient experienced DLT in the A(40 mg)/C(AUC6) cohort (grade 3 acneiform rash); A(40 mg)/C(AUC6) was determined as the recommended phase II dose (RP2D) for A/C. Two patients each had DLTs with A(20 mg/day)/C(AUC6)/P(175 mg/m 2 ): fatigue, infection, diarrhea, small intestine hemorrhage, dehydration, renal impairment, neutropenic sepsis (n = 1), mucositis (n = 1); A(40 mg)/C(AUC5)/P(175 mg/m 2 ): febrile neutropenia (n = 1), mucositis, fatigue (n = 1); and A(30 mg)/C(AUC5)/P(175 mg/m 2 ): stomatitis (n = 1), mucositis (n = 1). No DLT was observed with A(20 mg)/C(AUC5)/P(175 mg/m 2 ), determined as the RP2D for A/C/P. The most frequent drug-related adverse events were (A/C; A/C/P): rash (75%; 73%), fatigue (67%; 69%), and diarrhea (58%; 88%). Drug plasma concentrations were similar between cycles, suggesting no drug-drug interactions. Objective response rates in these heavily pretreated patients were A/C, 3/12 (25%); A/C/P, 5/26 (19%)., Conclusions: Afatinib 40 mg/day (approved monotherapy dose) with carboplatin AUC6, and afatinib 20 mg/day with carboplatin AUC5 and paclitaxel 175 mg/m 2 demonstrated manageable safety and antitumor activity. Afatinib > 20 mg/day in the triple combination was not well tolerated.

We investigated PD-L1 changes in response to MEK and AKT inhibitors in KRAS mutant lung adenocarcinoma (adeno-NSCLC). PD-L1 expression was quantified using immunofluorescence and co-culture with a jurkat cell-line transfected with NFAT-luciferase was used to study if changes in PD-L1 expression in cancer cell lines were functionally relevant. Five KRAS mutant cell lines with high PD-L1 expression (H441, H2291, H23, H2030 and A549) were exposed to GI50 inhibitor concentrations of a MEK inhibitor (trametinib) and an AKT inhibitor (AZD5363) for 3 weeks. Only 3/5 (H23, H2030 and A549) and 2/5 cell lines (H441 and H23) showed functionally significant increases in PD-L1 expression when exposed to trametinib or AZD5363 respectively. PD-L1 overexpression is not consistent and is unlikely to be an early mechanism of resistance to KRAS mutant adeno-NSCLC treated with MEK or AKT inhibitors.

The last decade has witnessed rapid advances in the discovery and development of immune checkpoint inhibitors in cancer medicine, particularly drugs targeting programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). The proven antitumor efficacy coupled with low rates of drug-related toxicities observed, albeit idiosyncratic, with these novel immunotherapeutics have led to the registration of multiple PD-1 and PD-L1 inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, in second-line advanced NSCLC, whereas durvalumab and avelumab are in late-phase clinical testing. Moreover, pembrolizumab has shown a survival advantage in the first-line setting; however, nivolumab failed to show a survival benefit possibly relating to patient selection based on PD-L1 expression. Current patient selection is based on PD-L1 expression, using the relevant companion diagnostic test, where patients with strong PD-L1 expression being more likely to respond to these novel agents. Ongoing clinical research focuses on the development of PD-1 and PD-L1 inhibitor monotherapy in neoadjuvant and adjuvant NSCLC. There is also much interest in using these drugs as a therapeutic backbone for rational combinations with other treatment modalities including cytotoxic chemotherapies in the first-line NSCLC, other immunotherapies such as cytotoxic T-lymphocyte-associated protein 4 antagonists, molecularly targeted agents including EGFR and ALK inhibitors, and radiotherapy. Concurrent treatment with radiotherapy is of particular interest owing to the potential for the abscopal effect, using radiotherapy to facilitate systemic treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Therapeutic options in locally advanced non-small cell lung cancer (NSCLC) have expanded in the past decade to include a palate of targeted interventions such as high dose targeted thermal ablations, radiotherapy and growing platform of antibody and small molecule therapies and immunotherapies. Although these therapies have varied mechanisms of action, they often induce changes in tumour architecture and microenvironment such that response is not always accompanied by early reduction in tumour mass, and evaluation by criteria other than size is needed to report more effectively on response. Functional imaging techniques, which probe the tumour and its microenvironment through novel positron emission tomography and magnetic resonance imaging techniques, offer more detailed insights into and quantitation of tumour response than is available on anatomical imaging alone. Use of these biomarkers, or other rational combinations as readouts of pathological response in NSCLC have potential to provide more accurate predictors of treatment outcomes. In this article, the robustness of the more commonly available positron emission tomography and magnetic resonance imaging biomarker indices is examined and the evidence for their application in NSCLC is reviewed., (Copyright © 2016 Elsevier Ltd. All rights reserved.)