Challenges and knowledge gaps with immune checkpoint inhibitors monotherapy in the management of patients with non-small-cell lung cancer: a survey of oncologist perceptions.

BACKGROUND: Immune checkpoint-inhibitors (ICIs) are changing outcomes in different cancer settings, notably for patients with non-small-cell lung cancer (NSCLC). There are, however, still important gaps of evidence for clinical practice when using these novel treatments. In this study, we assessed physicians' opinion and experience on challenges for clinical practice with ICIs monotherapy in NSCLC. METHODS: A survey was conducted on experienced physicians treating patients with NSCLC with ICIs. Two rounds of pilot tests were carried out for validation among a group of experts. Topics under analysis were in relation to treatment of elderly populations, performance status, brain metastases, use of steroids or antibiotics, the effects of gut microbiome, autoimmune diseases, human immunodeficiency virus infection, solid organ transplants, use of anti-programmed cell death protein 1 versus anti-programmed death-ligand 1 drugs, atypical tumour responses, predictors of response, duration of treatment and a final open question on additional relevant challenges. RESULTS: Two hundred and twenty-one answers were collected, including 106 (48%) valid answers from experts for final analysis (physicians who have treated at least 20 patients with NSCLC with ICIs). The vast majority agreed that the selected topics in this study are important challenges ahead and more evidence is needed. Moreover, predictors of response, treating brain metastasis, shorter duration of treatment, the effects of gut microbiome and concomitant use of steroids were voted the most important topics to be further addressed in prospective clinical research. CONCLUSIONS: This survey contributed to understanding which are the main challenges for clinical practice with ICIs monotherapy in NSCLC. It can also contribute to guide further clinical research, considering the opinions and experience of those who regularly treat NSCLC patients with ICIs.

An accelerated, clinical-grade protocol to generate high yields of type 1-polarizing messenger RNA-loaded dendritic cells for cancer vaccination.

BACKGROUND: Many efforts have been devoted to improve the performance of dendritic cell (DC)-based cancer vaccines. Ideally, a DC vaccine should induce robust type 1-polarized T-cell responses and efficiently expand antigen (Ag)-specific cytotoxic T-cells, while being applicable regardless of patient human leukocyte antigen (HLA) type. Production time should be short, while maximally being good manufacturing practice (GMP)-compliant. We developed a method that caters to all of these demands and demonstrated the superiority of the resulting product compared with DCs generated using a well-established "classical" protocol. METHODS: Immunomagnetically purified monocytes were cultured in a closed system for 3 days in GMP-compliant serum-free medium and cytokines, and matured for 24 h using monophosphoryl lipid A (MPLA)+ interferon-gamma (IFN-γ). Mature DCs were electroporated with messenger RNA (mRNA) encoding full-length antigen and cryopreserved. "Classical" DCs were cultured for 8 days in flasks, with one round of medium and cytokine supplementation, and matured with tumor necrosis factor alpha (TNF-α) + prostaglandin E2 (PGE2) during the last 2 days. RESULTS: Four-day MPLA/IFN-γ-matured DCs were superior to 8-day TNF-α/PGE2-matured DCs in terms of yield, co-stimulatory/co-inhibitory molecule expression, resilience to electroporation and cryopreservation and type 1-polarizing cytokine and chemokine release after cell thawing. Electroporated and cryopreserved DCs according to our protocol efficiently present epitopes from tumor antigen-encoding mRNA, inducing a strong expansion of antigen-specific CD8+ T-cells with full cytolytic capacity. CONCLUSION: We demonstrate using a GMP-compliant culture protocol the feasibility of generating high yields of mature DCs in a short time, with a superior immunogenic profile compared with 8-day TNF-α/PGE2-matured DCs, and capable of inducing vigorous cytotoxic T-cell responses to antigen from electroporated mRNA. This method is now being applied in our clinical trial program.

Patterns of care for non-small cell lung cancer patients in Belgium: A population-based study.

Guidelines recommend surgery for Stage I-II, chemoradiation for Stage III and systemic therapy for Stage IV non-small cell lung cancer (NSCLC). However, patient related factors and patient preferences influence treatment decisions. We investigated patterns of care for Belgian NSCLC patients in 2010-2011, based on population-based data from the Belgian Cancer Registry and administrative databases. The relationship between patient characteristics, institutional diagnostic volume, type of treatment and survival was investigated. Overall, 20.8% of patients received no oncological treatment. 59% and 22.1% of Stage I-II patients received primary surgery or (chemo)radiation respectively. 34% of Stage III patients received chemoradiation and 17% of Stage IIIA patients had surgery. 70% of Stage IV patients received chemotherapy or targeted therapy. Moderate variability between centres was observed. For Stage IV, systemic therapy was less frequently used in higher volume centres and 1-year survival was lower in centres that had ≥ 50 new patients yearly. Although not all NSCLC patients received treatment as ideally recommended by guidelines, these results do not necessarily represent poor quality of care as patient characteristics and preferences need to be taken into account. Treatment options targeted towards patients with co-morbidity or unfit patients is warranted to improve outcomes of all NSCLC patients.

Circulating cell-free nucleic acids and platelets as a liquid biopsy in the provision of personalized therapy for lung cancer patients.

Lung cancer is the predominant cause of cancer-related mortality in the world. The majority of patients present with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Treatment for NSCLC is evolving from the use of cytotoxic chemotherapy to personalized treatment based on molecular alterations. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of circulating cell-free nucleic acids (cfNA), consisting of both circulating cell-free (tumoral) DNA (cfDNA-ctDNA) and RNA (cfRNA), as a liquid biopsy in lung cancer. The development of sensitive and accurate techniques such as Next-Generation Sequencing (NGS); Beads, Emulsion, Amplification, and Magnetics (BEAMing); and Digital PCR (dPCR), have made it possible to detect the specific genetic alterations (e.g. EGFR mutations, MET amplifications, and ALK and ROS1 translocations) for which targeted therapies are already available. Moreover, the ability to detect and quantify these tumor mutations has enabled the follow-up of tumor dynamics in real time. Liquid biopsy offers opportunities to detect resistance mechanisms, such as the EGFR T790M mutation in the case of EGFR TKI use, at an early stage. Several studies have already established the predictive and prognostic value of measuring ctNA concentration in the blood. To conclude, using ctNA analysis as a liquid biopsy has many advantages and allows for a variety of clinical and investigational applications.

Integrating early palliative care (EPC) in the management of lung cancer: The role of the thoracic oncologist.

Early introduction of palliative care in the management of patients with metastatic lung cancer is recommended since it improves quality of life and improves survival rates. In many hospitals the focus of palliative teams is often on terminal care due to limited resources. How is Early palliative care (EPC) in this setting implemented in daily oncologic care? It seems obvious that thoracic oncologists will have to become involved in EPC for lung cancer patients. In this review we want to determine the assignments for the thoracic oncologist in EPC and to give some practical tools how we started EPC in collaboration with the palliative team.

Treatment patterns and survival analysis in 9014 patients with malignant pleural mesothelioma from Belgium, the Netherlands and England.

INTRODUCTION: Pleural mesothelioma has a dismal prognosis and is refractory to local treatment. Combination chemotherapy can increase median survival by several months and was gradually introduced in the period 2003-2006. Elderly patients may be unfit for chemotherapy but little is known about age-related treatment practice. To determine treatment patterns and current survival outcome, three large population-based registries were queried in a uniform manner. METHODS: Data from the Belgian Cancer Registry, the Netherlands Cancer Registry and the UK National Lung Cancer Audit were analyzed for patients diagnosed with pleural mesothelioma since 2007. Treatment patterns and survival rates were compared between countries and age-groups. RESULTS: The study included 900, 2306 and 5808 patients from Belgium, the Netherlands and England, respectively. Fifty-nine percent of patients were 70 years or older and 84% were men. Chemotherapy use decreased with advancing age and was used more often in Belgium (60%) than in the Netherlands (41%) and England (37%). For patients aged 70-79 years, chemotherapy use was 55%, 36% and 34% in the respective countries. Median survival was 10.7 months in Belgium versus 9.2 months for the Netherlands and 9.5 months for England. Survival rates decreased with advancing age. On average, median survival was 5.6 months longer for patients treated with chemotherapy, irrespective of age. CONCLUSIONS: Combined analysis of data from three countries with high mesothelioma rates demonstrates that chemotherapy has become standard treatment for younger patients. Elderly patients currently account for more than half of all cases and less toxic treatment options will be required to improve their prospects.

Routine implementation of EGFR mutation testing in clinical practice in Flanders: 'HERMES' project.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the recommended first-line treatment in metastatic EGFR-mutation-positive non-small cell lung cancer (NSCLC) patients. Such a personalized treatment requires fast EGFR mutation testing. This study was performed to determine the turn around time (TAT) for EGFR mutation testing on tumour samples of NSCLC in the clinical care in the region of Antwerp (Belgium). The secondary aim was to determine the frequency of EGFR mutations in this Flemish population. Tumour tissue was prospectively obtained from lung cancer patients in participating hospitals and sent from the local pathology laboratory (lab) to two central laboratories (labs) where EGFR-mutation analysis was performed. Results were returned from the central labs to the clinicians and the local pathology lab. TAT was defined as the interval between the request from the oncologist and the result obtained by the oncologist. One hundred and seven specimens were analysed. The clinician got the result from the local lab in a median time of 10 days (3-37 days) and from the central lab in 9 days (3-29 days). We detected seven mutations (7%) in this study population, all occurring in tumours with an adenocarcinoma histology, four (57%) in men and five (71%) in (ex-)smokers. There were six exon 19 deletions and one L858R mutation. It is possible to implement EGFR-mutation testing with timely reporting of the EGFR-mutation status. EGFR-mutation occurs in 7% of Flemish patients with NSCLC. Patients with advanced non-squamous NSCLC should be tested for EGFR mutation regardless of their gender and smoking history.

A rare cause of haemoptysis.

A 59-year-old man was admitted with haemoptysis, several months after a car accident. A diagnostic work-up including laboratory testing, chest radiograph and bronchoscopy could not explain the haemoptysis. A pancreatic-pulmonary fistula was suspected by additional CT scan. Magnetic resonance cholangiopancreaticography confirmed the diagnosis, followed by surgical exploration and repair.

The effect of radical treatment and rehabilitation on muscle mass and strength: a randomized trial in stages I-III lung cancer patients.

OBJECTIVES: Little is known about the impact of an oncological treatment on muscle mass and strength in patients with lung cancer and the impact of a subsequent rehabilitation program. This study investigates the effect of radical treatment and post-treatment pulmonary rehabilitation on muscle mass and strength in patients with lung cancer and the relationship between muscle mass and strength. METHODS: Lung cancer patients, candidate for radical treatment, were randomly (2:1) allocated after radical treatment to either standard follow up (CON) or a 12-week rehabilitation training program (RT). Muscle mass was estimated by bioelectric impedance and CT-scan. Muscle strength was estimated by measuring quadriceps force (QF) with a hand held dynamometer. All variables were measured before (M1) and after radical treatment (M2), and at the earliest 12 weeks after randomization (M3). Data are presented as means with standard deviation. RESULTS: 45 lung cancer patients (age: 65 years (9)) participated in the study. At M2, both muscle cross sectional area (MCSA) and QF were significantly decreased (p<0.05). 28 patients were randomized. 13/18 RT and 9/10 CON patients ended the trial. At M3, RT-patients improved significantly their MCSA compared to CON-patients (ΔMCSA: 6 cm(2) (6) (p=0.003) vs. 1cm(2) (11) (p=0.8)). CONCLUSION: Muscle mass and strength: (1) are decreased at presentation in a substantial part of lung cancer patients; (2) are significantly negatively affected by radical treatment and (3) completely recover after a 12 week structured rehabilitation program, whereas a further decline was observed in CON-patients.

Survival outcomes in patients with advanced non-small cell lung cancer treated with erlotinib: expanded access programme data from Belgium (the TRUST study).

Erlotinib has been shown to prolong progression-free (PFS) and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC). We report here on effectiveness data on the subsample of 261 patients from 40 centres in Belgium involved in the TRUST study. Median age was 63 years. Most (69.0%) were male and current/former smokers (84.7%); with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (74.3%), stage IV disease (75.1%) and adenocarcinoma by histology (54.0%). Erlotinib was administered mainly as second- (47.1%) or third-line treatment (48.3%). Response rate was 6.5%; disease control rate 58.3%. Median PFS was 2.2 months. Better PS (P = 0.0384), stage IIIB disease (P = 0.0018) and presence of rash (P < 0.0001) were associated with longer PFS. OS rates at 1, 2 and 3 years were 26.4%, 10.9% and 6.4% respectively. Median OS was 5.9 months. Female gender (P = 0.007), better PS (P < 0.0001), stage IIIB disease (P = 0.0355) and presence of rash (P < 0.0001) were associated with longer OS. The findings confirm the therapeutic benefit of erlotinib in a broad range of patients in a sample from a country with a historically high lung cancer morbidity and mortality burden. Several determinants of PFS and OS are identified.

Management of malignant pleural mesothelioma: have we made any progress?

As the incidence of malignant pleural mesothelioma (MPM) is increasing in the next decades, treatment is a challenge. The past 2 years have seen a number of promising achievements in the management of patients with MPM. Treatment of a symptomatic malignant pleural effusion through indwelling pleural catheter (IPC) may allow for an individualized treatment. Advances in the systemic treatment with targeted agents will undoubtedly gain by the discovery of a driver mutation which may be selectively targeted. In the meantime, the addition of monoclonal antibodies to a standard chemotherapy backbone might result in a modest improvement in outcome in patients selected for the presence of the ligand. New techniques in radiation therapy, pleural intensity-modulated radiotherapy, helical tomography and proton-therapy are exciting advances in multimodality treatment enhancing local control and therefore improving overall survival. The role of surgery remains controversial and should be further explored. Surgical procedures consist of extrapleural pneumonectomy or lung sparing operations like debulking of the parietal and visceral pleura by (extended) pleurectomy/decortication. Where the treatment in multimodality therapy may lead to improved disease-free survival and overall survival, the type of cyto-reductive procedure should be selected on institutional and surgeon's experience. The increase in mesothelioma incidence is matched only by the increasing number of researchers and studies. It is up to the clinicians to support these efforts by stimulating their patients to participate in this clinical research.

Radiation-induced oesophagitis in lung cancer patients. Is susceptibility for neutropenia a risk factor?

BACKGROUND: Radiation-induced oesophagitis is a major side effect of concurrent chemotherapy and radiotherapy. A strong association between neutropenia and oesophagitis was previously shown, but external validation and further elucidation of the possible mechanisms are lacking. METHODS AND PATIENTS: A total of 119 patients were included at two institutions. The concurrent group comprised 34 SCLC patients treated with concurrent carboplatin and etoposide, and concurrent chest irradiation, and 36 NSCLC patients with concurrent cisplatin and etoposide, and concurrent radiotherapy, while the sequential group comprised 49 NSCLC patients received sequential cisplatin and gemcitabine, and radiotherapy. RESULTS: Severe neutropenia was very frequent during concurrent chemoradiation (grade: 4 41.4%) and during induction chemotherapy in sequentially treated patients (grade 4: 30.6%), but not during radiotherapy (only 4% grade 1). In the concurrent group, the odds ratios of grade 3 oesophagitis vs. neutropenia were the following: grade 2 vs. grade 0/1: 5.60 (95% CI 1.55-20.26), p = 0.009; grade 3 vs. grade 0/1: 10.40 (95% CI 3.19-33.95); p = 0.0001; grade 4 vs. grade 0/1: 12.60 (95% CI 4.36-36.43); p < 0.00001. There was no correlation between the occurrence of neutropenia during induction chemotherapy and acute oesophagitis during or after radiotherapy alone. In the univariate analysis, total radiation dose (p < 0.001), overall treatment time of radiotherapy (p < 0.001), mean oesophageal dose (p = 0.038) and neutropenia (p < 0.001) were significantly associated with the development of oesophagitis. In a multivariate analysis, only neutropenia remained significant (p = 0.023). CONCLUSION: We confirm that neutropenia is independently correlated with oesophagitis in concurrent chemoradiation, but that the susceptibility for chemotherapy-induced neutropenia is not associated with radiation-induced oesophagitis. Further studies focusing on the underlying mechanisms are thus warranted.

Are EUS-FNA and EBUS-TBNA specimens reliable for subtyping non-small cell lung cancer?

With endosonography, the diagnosis and staging of non-small cell lung cancer (NSCLC) increasingly relies on small samples. The discrimination between squamous and non-squamous subtypes is now important for therapy tailoring. We analyzed the agreement between fine needle aspirates obtained by endosonography and matched biopsy samples for subtyping NSCLC. Patients with a positive endoscopic fine needle aspirate and a matched biopsy were identified. The level of diagnostic agreement was estimated with biopsy samples as golden standard. In 951 patients investigated with endosonography, we identified 92 with NSCLC on the positive fine needle aspirate and on the matched biopsy. Squamous cell carcinoma was diagnosed in 34 (37%) and 44 (48%) of fine needle aspirate and biopsy samples; while non-squamous carcinoma was diagnosed in 58 (63%) and 48 (52%) respectively. The agreement between needle aspirate and biopsy for the subtyping of NSCLC was 76% (kappa=0.52). In cases with cell block preparation, the agreement for subtyping was 96% (kappa=0.91) vs 69% (kappa=0.39) in cases without cell blocks. Therefore, the diagnostic agreement between endosonographic fine needle aspirates and biopsy specimens for subtyping NSCLC is moderate with a disagreement in 1 out of 4 patients. However, cell block preparation increased the agreement and thus the reliability of the fine needle specimens obtained during endosonography, for subtyping NSCLC considerably. In conclusion, for patients with NSCLC in whom subtyping is relevant, a diagnostic technique yielding larger samples (FNA with cell block preparation or biopsies) should be preferred.

Asthma, atopy and COPD in sub-Saharan countries: the challenges.

Asthma and COPD are the most important chronic airways diseases worldwide. Urbanization and westernization of African countries are important factors for the development of chronic respiratory diseases. Unfortunately for many reasons, only few studies on atopy, asthma and COPD have been carried out in Africa and risk factors are not well known on the continent. Moreover, in many African countries drugs for asthma and COPD are either lacking or expensive. There is a need for setting up clear strategies to stop progression of asthma and COPD by reducing risk factors such as tobacco consumption and environment pollution.

A randomized phase II study comparing induction or consolidation chemotherapy with cisplatin-docetaxel, plus radical concurrent chemoradiotherapy with cisplatin-docetaxel, in patients with unresectable locally advanced non-small-cell lung cancer.

BACKGROUND: In stage III non-small-cell lung cancer (NSCLC), the role of systemic chemotherapy preceding or following concurrent chemo-radiotherapy (CT-RT) is unclear. We carried out a randomized phase II study to study the toxicity involved-field CT-RT with either induction or consolidation cisplatin-docetaxel (Taxotere). PATIENTS AND METHODS: Patients were randomly assigned to receive two cycles of docetaxel (D) 75 mg/m(2) on day 1 and cisplatin (C) 40 mg/m(2) on days 1 and 2, either preceding (IND arm) or following (CON arm) concurrent CT-RT, where 66 Gy was delivered using involved-fields concurrent with weekly D 20 mg/m(2) and C 20 mg/m(2). Patients at higher risk for lung toxicity (V(20) > 35%) crossed over to IND arm. Seventy patients were needed to exclude grade (G)3-4 esophagitis in >25%. RESULTS: Of the 70 eligible patients, 26 were treated in IND and 34 CON; five with V(20) >35% switched from CON to IND. The differences in G3-4 esophagitis observed (32/2% IND versus 21/3% CON) were not significantly different from the hypothesized 25% rate. Rates of G≥2 pneumonitis were similar, but IND arm had less G3-4 neutropenia. One-year survival was 63.2% [95% confidence interval (CI) 48.4% to 78.0%] and 65.5% (95% CI 48.2% to 82.8%) for the IND and CON arms, respectively. CONCLUSION: Both study arms merit further testing in patients with limited volume stage III NSCLC.

Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial.

The European Organisation for Research and Treatment of Cancer (EORTC; protocol 08031) phase II trial investigated the feasibility of trimodality therapy consisting of induction chemotherapy followed by extrapleural pneumonectomy and post-operative radiotherapy in patients with malignant pleural mesothelioma (with a severity of cT3N1M0 or less). Induction chemotherapy consisted of three courses of cisplatin 75 mg·m⁻² and pemetrexed 500 mg·m⁻². Nonprogressing patients underwent extrapleural pneumonectomy followed by post-operative radiotherapy (54 Gy, 30 fractions). Our primary end-point was "success of treatment" and our secondary end-points were toxicity, and overall and progression-free survival. 59 patients were registered, one of whom was ineligible. Subjects' median age was 57 yrs. The subjects' TNM scores were as follows: cT1, T2 and T3, 36, 16 and six patients, respectively; cN0 and N1, 57 and one patient, respectively. 55 (93%) patients received three cycles of chemotherapy with only mild toxicity. 46 (79%) patients received surgery and 42 (74%) had extrapleural pneumonectomy with a 90-day mortality of 6.5%. Post-operative radiotherapy was completed in 37 (65%) patients. Grade 3-4 toxicity persisted after 90 days in three (5.3%) patients. Median overall survival time was 18.4 months (95% CI 15.6-32.9) and median progression-free survival was 13.9 months (95% CI 10.9-17.2). Only 24 (42%) patients met the definition of success (one-sided 90% CI 0.36-1.00). Although feasible, trimodality therapy in patients with mesothelioma was not completed within the strictly defined timelines of this protocol and adjustments are necessary.

A randomized phase II study comparing two schedules of the 21-day regimen of gemcitabine and carboplatin in advanced non-small cell lung cancer.

PURPOSE: Carboplatin area under the curve (AUC) 5 ml/min on day 1 with gemcitabine 1,250 mg/m(2) on day 1 and day 8 is a widely used regimen in advanced non-small cell lung cancer. Grade 3-4 thrombocytopenia and neutropenia are frequent. The aim of this study is to investigate whether toxicity of gemcitabine/carboplatin could be reduced by administering carboplatin on day 8 instead of day 1 without a decrease in response rate (RR). METHODS: Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8, carboplatin AUC 5 on day 1 (arm A) or day 8 (arm B). Drugs were administered over a 21-day cycle. Toxicity and RR were evaluated weekly and every second cycle, respectively. RESULTS: 71 patients were enrolled into the study. We found 79% (95% CI 61-91%) grade 3-4 toxicity (neutropenia and thrombocytopenia) in arm A and 50% (95% CI 32-68%) in arm B; 66% grade 3-4 thrombocytopenia in arm A and 26% in arm B. We observed 30% grade 4 hematological toxicity in arm A and 3% in arm B. In arm A an overall RR of 20% (95% CI 7.7-38.6%) was seen, and 18.2% (95% CI 7-35.5%) in arm B. CONCLUSIONS: Although the study was prematurely closed, the current data are of interest. The schedule with carboplatin on day 8 is associated with substantially lower grade 3-4 neutropenia and thrombocytopenia with comparable dose intensity and RR.