A randomized clinical trial assessing a pragmatic intervention to improve supportive care for family caregivers of patients with lung cancer.

OBJECTIVE: Family caregivers (FCs) of cancer patients often experience high distress. This randomized clinical trial assessed the feasibility and preliminary effects of an intervention to improve FC supportive care. METHOD: A pragmatic and minimal intervention to improve FC supportive care was developed and pretested with FCs, oncology team, and family physicians to assess its relevance and acceptability. Then, FCs of lung cancer patients were randomized to the intervention or the control group. The intervention included (1) systematic FC distress screening and problem assessment in the first months after their relative cancer diagnosis, and every 2 months after; (2) privileged contact with an oncology nurse to address FC problems, provide emotional support and skills to play their caregiving role; (3) liaison with the family physician of FCs reporting high distress (distress thermometer score ≥4/10) to involve them in the provision of supportive care. Distress, the primary outcome, was measured every 3 months, for 9 months. Secondary outcomes included quality of life, caregiving preparedness, and perceived burden. At the end of their participation, a purposive sample of FC from the experimental group was individually interviewed to assess the intervention usefulness. Content analysis was performed. RESULTS: A total of 109 FCs participated in the trial. FC distress decreased over time, but this reduction was observed in both groups. Similar results were found for secondary outcomes. However, FCs who received the intervention felt better prepared in caregiving than controls (p = 0.05). All 10 interviewed FCs valued the intervention, even though they clearly underused it. Knowing they could contact the oncology nurse served as a security net. SIGNIFICANCE OF RESULTS: Although the intervention was not found effective, some of its aspects were positively perceived by FCs. As many of them experience high distress, an improved intervention should be developed to better support them.

Discovery of a putative blood-based protein signature associated with response to ALK tyrosine kinase inhibition.

BACKGROUND: ALK tyrosine kinase inhibition has become a mainstay in the clinical management of ALK fusion positive NSCLC patients. Although ALK mutations can reliably predict the likelihood of response to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, they cannot reliably predict response duration or intrinsic/extrinsic therapeutic resistance. To further refine the application of personalized medicine in this indication, this study aimed to identify prognostic proteomic biomarkers in ALK fusion positive NSCLC patients to crizotinib. METHODS: Twenty-four patients with advanced NSCLC harboring ALK fusion were administered crizotinib in a phase IV trial which included blood sampling prior to treatment. Targeted proteomics of 327 proteins using MRM-MS was used to measure plasma levels at baseline (including pre-treatment and early treatment blood samples) and assess potential clinical association. RESULTS: Patients were categorized by duration of response: long-term responders [PFS ≥ 24 months (n = 7)], normal responders [3 < PFS < 24 months (n = 10)] and poor responders [PFS ≤ 3 months (n = 5)]. Several proteins were identified as differentially expressed between long-term responders and poor responders, including DPP4, KIT and LUM. Next, using machine learning algorithms, we evaluated the classification potential of 40 proteins. Finally, by integrating the different analytic methods, we selected 22 proteins as potential candidates for a blood-based prognostic signature of response to crizotinib in NSCLC patients harboring ALK fusion. CONCLUSION: In conjunction with ALK mutation, the expression of this proteomic signature may represent a liquid biopsy-based marker of long-term response to crizotinib in NSCLC. Expanding the utility of prognostic biomarkers of response duration could influence choice of therapy, therapeutic sequencing, and potentially the need for alternative or combination therapy.Trial registration ClinicalTrials.gov, NCT02041468. Registered 22 January 2014, https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1.

Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial.

BACKGROUND: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. METHODS: The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 µg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m(2) (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. FINDINGS: From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25.6 months (95% CI 22.5-29.2) with tecemotide versus 22.3 months (19.6-25.5) with placebo (adjusted HR 0.88, 0.75-1.03; p=0.123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30.8 months (95% CI 25.6-36.8) compared with 20.6 months (17.4-23.9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0.78, 0.64-0.95; p=0.016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19.4 months [95% CI 17.6-23.1] vs 24.6 months [18.8-33.0], respectively; adjusted HR 1.12, 0.87-1.44; p=0.38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. INTERPRETATION: We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. FUNDING: Merck KGaA (Darmstadt, Germany).

Use of Palliative Oxygen in Cancer Patients.

Background: Despite the lack of evidence to support the use of palliative oxygen to relieve dyspnea at the end of life, its prescription is widespread and often supported by local and national practice guidelines. Objectives: The objectives of this study were (1) to determine to what extent oxygen prescriptions meet the proposed prescription criteria in our institution, (2) to examine the indication of individual prescriptions in relation to the severity of dyspnea and (3) to review the utilization of opioids in patients receiving palliative oxygen. Methods: Retrospective chart review of cancer patients who were prescribed palliative oxygen between April 2015 and January 2020 through a respiratory home care program in Quebec City, Canada. According to provincial prescription guidelines, palliative oxygen was provided and reimbursed in case of severe hypoxemia (pulse oximetry saturation at rest < 88%) in cancer patients with an estimated prognosis of less than 3 months. Results: 134 patients receiving palliative oxygen were included; 25 (19%) did not fulfill reimbursement criteria. Median survival was 44 days. At initiation of palliative oxygen, 48 patients (36%) had only mild or moderate dyspnea (Medical Research Council dyspnea score 1-3), 26 (19%) did not receive opioids, and 9 (7%) were prescribed palliative oxygen without being dyspneic or receiving opioids. Conclusion: Most prescriptions of palliative oxygen met the proposed prescription criteria in our institution. Half of those who received palliative oxygen were only mildly dyspneic and/or were not receiving opioids at the time of the prescription.

Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes.

Rearrangements in the anaplastic lymphoma kinase (ALK) gene are found in approximately 5% of non-small cell lung carcinoma (NSCLC). Here, we present a comprehensive genomic landscape of 11 patients with ALK+ NSCLC and investigate its relationship with response to crizotinib. Using whole-exome sequencing and RNAseq data, we identified four rare ALK fusion partners (HIP1, GCC2, ERC1, and SLC16A7) and one novel partner (CEP55). At the mutation level, TP53 was the most frequently mutated gene and was only observed in patients with the shortest progression-free survival (PFS). Of note, only 4% of the genes carrying mutations are present in more than 1 patient. Analysis of somatic copy number aberrations (SCNA) demonstrated that a gain in EML4 was associated with longer PFS, and a loss of ALK or gain in EGFR was associated with shorter PFS. This study is the first to report a comprehensive view of the ALK+ NSCLC copy number landscape and to identify SCNA regions associated with clinical outcome. Our data show the presence of TP53 mutation as a strong prognostic indication of poor clinical response in ALK+ NSCLC. Furthermore, new and rare ALK fusion partners were observed in this cohort, expanding our knowledge in ALK+ NSCLC.

Effectiveness of an intervention to improve supportive care for family caregivers of patients with lung cancer: study protocol for a randomized controlled trial.

BACKGROUND: Family caregivers (FC) often experience higher distress levels than their relative with cancer. Many cancer centers have implemented distress screening programs, but most of them concentrate their efforts on patients, with little attention to their FC. To fill this gap, a pragmatic intervention has been designed to improve supportive care for FC of patients with lung cancer. This article describes the study protocol of a single-center randomized controlled trial to assess its effectiveness. METHODS/DESIGN: A total of 120 lung cancer patients and their FC are randomly assigned to the experimental group (exposed to intervention, N = 60) or to the control group (usual care, N = 60). The intervention includes: (1) systematic FC distress screening and problem assessment near their relative's cancer diagnosis, and every 2 months, (2) privileged contact with an oncology nurse (ON) away from the patient to address FC problems and (3) liaison by the ON with the family physician of FC reporting high distress (thermometer score ≥5/10), or problems relying on FP expertise. In both groups, FC, patient and process-of-care outcomes are measured at baseline and every 3 months, up to 9 months. The primary endpoint is FC distress measured by the Hospital Anxiety and Depression Scale (HADS) and the Psychological Distress Index used in the Quebec Health Survey (PDQHS). Individual interviews with 10 FC and a focus group with the oncology team will be conducted at the study end to further document the effectiveness of the intervention and its impact on quality of life (for FC) and practice organization (for the oncology team). DISCUSSION: This trial will assess the effectiveness of an innovative intervention based on interprofessional collaboration between primary care and oncology care. It targets a population in great need, yet often neglected, and has the potential to clearly improve patient and caregiver experience of cancer care, and reduce the burden of disease. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02531464 . Registered on 15 July 2015.

A Distress Protocol for Respiratory Emergencies in Terminally Ill Patients With Lung Cancer or Chronic Obstructive Pulmonary Disease.

A combination of opioid, midazolam, and scopolamine (that we call "distress protocol" [DP]) is used to induce transient sedation when emergencies occur in palliative care. We wished to describe the prescription and administration of DP in terminally ill patients with either lung cancer or chronic obstructive pulmonary disease (COPD). In a retrospective study, 96 of 100 patients with cancer and 85 of 100 patients with COPD had a DP prescribed. Thirty patients with cancer and 29 with COPD received at least 1 DP. All patients receiving a DP for an appropriate indication were sedated within 30 minutes. There was no difference in survival from DP administration among patients who received it and those who did not.

New insights into the retinal circulation: inflammatory lipid mediators in ischemic retinopathy.

Ischemic proliferative retinopathy develops in various retinal disorders, including retinal vein occlusion, diabetic retinopathy and retinopathy of prematurity. Ischemic retinopathy remains a common cause of visual impairment and blindness in the industrialized world due to relatively ineffective treatment. Oxygen-induced retinopathy (OIR) is an established model of retinopathy of prematurity associated with vascular cell injury culminating in microvascular degeneration, which precedes an abnormal neovascularization. The retina is a tissue particularly rich in polyunsaturated fatty acids and the ischemic retina becomes highly sensitive to lipid peroxidation initiated by oxygenated free radicals. Consequently, the retina constitutes an excellent model for testing the functional consequences of membrane lipid peroxidation. Retinal tissue responds to physiological and pathophysiological stimuli by the activation of phospholipases and the consequent release from membrane phospholipids of biologically active metabolites. Activation of phospholipase A(2) is the first step in the synthesis of two important classes of lipid second messengers, the eicosanoids and a membrane-derived phospholipid mediator platelet-activating factor (PAF). These lipid mediators accumulate in the retina in response to injury and a physiologic role of these metabolites in retinal vasculature remains for the most part to be determined; albeit proposed roles have been suggested for some. The eicosanoids, in particular the prostanoids, thromboxane (TXA2) and PAF are abundantly generated following an oxidant stress and contribute to neurovascular injury. TXA2 and PAF play an important role in the retinal microvacular degeneration of OIR by directly inducing endothelial cell death and potentially could contribute to the pathogenesis of ischemic retinopathies. Despite these advances there are still a number of important questions that remain to be answered before we can confidently target pathological signals. This review focuses on mechanisms that precede the development of neovascularization, most notably regarding the role of lipid mediators that partake in microvascular degeneration.

Stereotactic Ablative Radiation Therapy for the Treatment of Early-stage Non-Small-Cell Lung Cancer: CEPO Review and Recommendations.

BACKGROUND: Lung cancer is the second most diagnosed cancer and the leading cause of cancer-related mortality in Canada. Surgical resection is the treatment of choice for patients with stage I non-small-cell lung cancer (NSCLC). However, 20% to 30% of them are deemed medically inoperable and may be offered radiation therapy. Standard external-beam radiation therapy (EBRT) is associated with high rates of local recurrence and poor long-term survival. Stereotactic ablative radiation therapy (SABR) is increasingly being proposed for inoperable patients, and the use of this treatment modality for operable patients is also being contemplated. The objective of this guideline is to review the efficacy and safety of SABR in these two clinical situations and to develop evidence-based recommendations. METHOD: A review of the scientific literature published up to December 2013 was performed. A total of 44 publications were included. RECOMMENDATIONS: Considering the evidence available to date, the Comité de l'évolution des pratiques en oncologie recommends the following: (1) for medically operable patients with stage T1-2N0M0 NSCLC, surgery remains the standard treatment because comparative data regarding the efficacy of SABR and surgery are currently insufficient for SABR to be considered an equivalent alternative to surgery for these patients; (2) for medically inoperable patients with stage T1-2N0M0 NSCLC or medically operable patients who refuse surgery, SABR should be preferred to standard EBRT (grade B recommendation); (3) the biological equivalent dose (BED(10)) used for SABR treatment should be at least 100 Gy (grade B recommendation); (4) for patients with a central tumor, a large-volume tumor (large planning target volume) or severe pulmonary comorbidity, a risk-adaptive schedule should be used (dose reduction or increase in the number of fractions; grade B recommendation); (5) the choice of using SABR to treat NSCLC should be discussed within tumor boards; treatment with SABR (or with standard EBRT) should not be considered for patients whose life expectancy is very limited because of comorbidities (grade D recommendation).

Tailored therapy in lung cancer.

Historically, all non-small cell lung cancers were essentially grouped together and considered to be a single disease. However, it is now recognized that non-small cell lung cancer actually comprises a genetically diverse group of tumours. This, in turn, affords a new opportunity for the development of effective treatments tailored to individual tumours and patients. Advances in molecular biology have made possible the development of drugs against specific molecular targets on cancer cells, most notably the tyrosine kinase inhibitors. The relevant literature and current practice guidelines are discussed. In addition, other related areas of active investigation, including tumour vaccines and pharmacogenetics, are briefly reviewed.

What is the most practical, optimal, and cost effective method for performing follow-up after lung cancer surgery, and by whom should it be done?

Surgery is the treatment of choice for early stage non-small cell lung cancer. In this context, postoperative follow-up is important to diagnose late postoperative complications, as well as to detect recurring cancer or new primaries as early as possible. There is, however, no high-quality evidence regarding the benefits of monitoring programs on survival and quality of life. Most studies recommend clinical and radiological follow-up (radiograph or chest computed tomography) performed more intensively during the first two years and annually thereafter. The physician doing the follow-up can be the thoracic surgeon, the diagnosing physician, or the family physician.

Feasibility and effectiveness of a home-based exercise training program before lung resection surgery.

BACKGROUND: Patients with lung cancer often experience a reduction in exercise tolerance, muscle weakness and decreased quality of life. Although the effectiveness of pulmonary rehabilitation programs is well recognized in other forms of cancers and in many pulmonary diseases, few researchers have studied its impact in patients with lung cancer, particularly in those awaiting lung resection surgery (LRS). OBJECTIVES: To investigate the feasibility of a short, home-based exercise training program (HBETP) with patients under investigation for non-small cell lung cancer and potential candidates for LRS, and to determine the effectiveness of this program on exercise tolerance, skeletal muscle strength and quality of life. METHODS: Sixteen patients with lung cancer awaiting LRS participated in a four-week HBETP including moderate aerobic activities (walking and cycling) and muscle training performed three times weekly. Before and after the intervention, a cardiopulmonary exercise test, a 6 min walk test and the assessment of muscle strength and quality of life were performed. RESULTS: Thirteen patients completed the four-week HBETP and all the patients completed >75% of the prescribed exercise sessions. The duration of the cycle endurance test (264±79 s versus 421±241 s; P<0.05) and the 6 min walk test distance (540±98 m versus 568±101 m; P<0.05) were significantly improved. Moreover, the strength of the deltoid, triceps and hamstrings were significantly improved (∆ post-pre training 1.82±2.83 kg, 1.32±1.75 kg and 3.41±3.7 kg; P<0.05, respectively). CONCLUSION: In patients with lung cancer awaiting LRS, HBETP was feasible and improved exercise tolerance and muscle strength. This may be clinically relevant because poor exercise capacity and muscle weakness are predictors of postoperative complications.

Effect of chemotherapy in patients with resected small-cell or large-cell neuroendocrine carcinoma.

INTRODUCTION: Surgical resection of an undiagnosed lung lesion may lead to unintentional removal of small-cell lung cancer (SCLC). The benefit of perioperative chemotherapy in resected SCLC or large-cell neuroendocrine carcinomas (LCNEC) is not clear. METHODS: This retrospective analysis included limited disease SCLC and LCNEC that had been surgically removed between 1979 and 2007 at a single institution. Perioperative treatments were analyzed, and survival followed up. Log rank tests were used to compare overall survival. RESULTS: Among 74 patients who had a tumor resection, 45 received chemotherapy, four had preoperative radiotherapy, and 21 had postoperative radiotherapy. Eleven patients were women. The median age was 64 in the surgery group and 58 in the surgery plus chemotherapy group, and four and 11 patients in these groups, respectively, had LCNEC. There were 10 node positive tumors and only two incomplete resections in the surgery group versus 27 node positive tumors and three incomplete resections in the surgery plus chemotherapy group. The median follow-up was shorter in the group with surgery alone: 4.5 years (1.4-7) versus 5.8 years (0.6-19.6). Among the patients with a survival or a follow-up of at least 6 months, the median survival was 2.3 and 6.1 years in the surgery (n = 20) and surgery plus chemotherapy (n = 39) groups, respectively, such that the hazard ratio for death was 0.48 (95% confidence interval, 0.24-0.99, p = 0.04). CONCLUSION: These results suggest that perioperative chemotherapy may be beneficial in patients with resected SCLC or LCNEC.

Feasibility of a randomized controlled trial testing nifedipine vs. placebo for the treatment of preterm labor.

AIMS: Nifedipine is believed to be a superior tocolytic agent on the basis of efficacy and side-effect profile, but was never prospectively evaluated in a placebo-controlled randomized clinical trial (RCT). In our study, we sought to identify limitations in participation for a would-be RCT comparing nifedipine to placebo. METHODS: A prospective feasibility study was conducted at Ste-Justine Hospital, a tertiary care center, on women between 24 and 34 weeks' gestation, presenting to the labor and delivery room with obstetrical complaints. Patient information was collected and would-be participants were identified on the basis of pre-established clinical and ultrasound criteria as well as on willingness to participate, as determined by the study research nurse. RESULTS: During a 6-month period, 483 women presenting with signs and symptoms of preterm labor (PTL) were eligible for further evaluation. A total of 321 (66.5%) women were excluded for obstetrical and medical reasons whereas 125 (25.9%) did not meet strict inclusion criteria (cervical length <25 mm or positive fetal fibronectin). When using strict criteria, only 37 women (7.6%) were found to be eligible for study participation. Subject willingness to participate as assessed by the research nurse was 50%. CONCLUSIONS: If adhering to strict inclusion/exclusion criteria, the feasibility of an appropriately sampled RCT testing tocolytic therapy against a placebo would require a large concerted multicenter effort to meet sample size demands.