NHS-IL2 combined with radiotherapy: preclinical rationale and phase Ib trial results in metastatic non-small cell lung cancer following first-line chemotherapy.

BACKGROUND: NHS-IL2 (selectikine, EMD 521873, MSB0010445) consists of human NHS76 (antibody specific for necrotic DNA) fused to genetically modified human interleukin 2 (IL-2) and selectively activates the high-affinity IL-2 receptor. Based on an evolving investigational concept to prime the tumor microenvironment with ionizing radiation prior to initiating immunotherapy, 2 related studies were conducted and are reported here. The first, a preclinical study, tests the systemic effect of the immunocytokine NHS-IL2 and radiotherapy in a lung carcinoma animal model; the second, a phase Ib trial in patients with metastatic non-small cell lung carcinoma (NSCLC), was designed to determine the safety and tolerability of NHS-IL2 in combination with radiotherapy directly following first-line palliative chemotherapy. METHODS: Tumor-bearing C57Bl/6 mice were treated with NHS-IL2 alone (5 mg/kg; days 7-9), fractionated radiotherapy (3.6 Gy; days 0-4) plus cisplatin (4 mg/kg; day 0), or the triple combination. Metastatic NSCLC patients who achieved disease control with first-line palliative chemotherapy were enrolled in the phase Ib trial. Patients received local irradiation (5x 4 Gy) of a single pulmonary nodule. Dose-escalated NHS-IL2 was administered as 1-h intravenous infusion on 3 consecutive days every 3 weeks. RESULTS: NHS-IL2 plus radiotherapy induced immune response activation and complete tumor growth regressions in 80%-100% of mice. In patients with metastatic NSCLC treated with NHS-IL2 (3, 3, and 7 patients in the 0.15-mg/kg, 0.30-mg/kg, and 0.45-mg/kg cohorts, respectively), maximum tolerated dose was not reached. Most frequently reported adverse events were fatigue, anorexia, and rash. Transient increases in leukocyte subsets were observed. In 3 patients, thyroid gland dysfunction occurred. No objective responses were reported; long-term survival was observed in 2 patients, including 1 patient with long-term tumor control. CONCLUSIONS: Combining NHS-IL2 with radiotherapy achieved synergistic antitumor activity in preclinical studies, supporting the use in lung cancer patients. This combination was well tolerated and 2 of 13 patients achieved long-term survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT00879866.

Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score.

BACKGROUND: Malignant pleural effusion (MPE) causes debilitating breathlessness and predicting survival is challenging. This study aimed to obtain contemporary data on survival by underlying tumour type in patients with MPE, identify prognostic indicators of overall survival and develop and validate a prognostic scoring system. METHODS: Three large international cohorts of patients with MPE were used to calculate survival by cell type (univariable Cox model). The prognostic value of 14 predefined variables was evaluated in the most complete data set (multivariable Cox model). A clinical prognostic scoring system was then developed and validated. RESULTS: Based on the results of the international data and the multivariable survival analysis, the LENT prognostic score (pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group (ECOG) performance score (PS), neutrophil-to-lymphocyte ratio and tumour type) was developed and subsequently validated using an independent data set. Risk stratifying patients into low-risk, moderate-risk and high-risk groups gave median (IQR) survivals of 319 days (228-549; n=43), 130 days (47-467; n=129) and 44 days (22-77; n=31), respectively. Only 65% (20/31) of patients with a high-risk LENT score survived 1 month from diagnosis and just 3% (1/31) survived 6 months. Analysis of the area under the receiver operating curve revealed the LENT score to be superior at predicting survival compared with ECOG PS at 1 month (0.77 vs 0.66, p<0.01), 3 months (0.84 vs 0.75, p<0.01) and 6 months (0.85 vs 0.76, p<0.01). CONCLUSIONS: The LENT scoring system is the first validated prognostic score in MPE, which predicts survival with significantly better accuracy than ECOG PS alone. This may aid clinical decision making in this diverse patient population.

Comparison of modified Borg scale and visual analog scale dyspnea scores in predicting re-intervention after drainage of malignant pleural effusion.

BACKGROUND: Dyspnea is the most common symptom in patients with malignant pleural effusion (MPE). Treatment decisions are primarily based on the perception of dyspnea severity. AIMS: To study dyspnea perception following therapeutic thoracentesis using the visual analog scale (VAS) dyspnea score and modified Borg scale (MBS). To investigate whether patient reported outcome (PRO) measures can predict pleural re-interventions. PATIENTS AND METHODS: Consecutive patients presenting with symptomatic MPE and planned for therapeutic thoracentesis were asked to complete MBS and VAS dyspnea scores (both at rest and during exercise) daily for 14 consecutive days. Physicians, unaware of the results of these PRO measures, decided on the necessity of a re-intervention, according to routine care. PRO measures were analyzed and correlated with performed re-interventions and the volume of removed fluid. RESULTS: Forty-nine out of 64 consecutive patients returned the diaries. Twenty-eight patients (57 %) had a re-intervention within 30 days. Patients who required a re-intervention reported significantly higher MBS than patients who did not. The extent of increase in MBS during exercise was related to the need for re-intervention. Regarding the MBS during exercise, median time to maximal relief was 2 days. Re-intervention was required sooner when larger volumes were drained. CONCLUSION: Patient reported outcomes are useful tools to assess treatment effect of therapeutic thoracentesis. Median time to maximal relief is 2 days. MBS rather than VAS dyspnea score appears to be more prognostic for repeat pleural drainage within 30 days.

The use of indwelling pleural catheters for the management of malignant pleural effusion--direct costs in a Dutch hospital.

BACKGROUND: Indwelling pleural catheters (IPCs) are increasingly used in the treatment of malignant pleural effusion (MPE). In general, these catheters have been reported to manage MPE efficiently. Unfortunately, insurance companies in the Netherlands do not reimburse these catheters in either first-line treatment or following failed talc pleurodesis. OBJECTIVES: Investigation of direct costs of IPC placement. METHODS: Retrospective analysis of a prospectively collected database. Direct costs for both catheters and vacuum bottles were calculated. Indicators for indirect costs such as adverse events and complications and the need for additional home care for drainage were registered. RESULTS: Mean costs for IPC amounted to EUR 2,173 and were different between tumor types - mesothelioma: EUR 4,028, breast: EUR 2,204, lung: EUR 1,146 and other: EUR 1,841; p = 0.017. Four patients were admitted to hospital for treatment of complications. Mean costs for IPC placement was similar when inserted as frontline treatment and after failed pleurodesis. Approximately 75% of patients did not need any help from specialized home care. CONCLUSION: Direct costs for IPC placement turn out to be acceptable when compared with estimated hospitalization costs for pleurodesis treatment. Randomized controlled trials have to be performed to compare the cost-effectiveness of IPCs compared to pleurodesis.

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer.

BACKGROUND: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. OBJECTIVE: We aimed to develop alternative dosing regimens to reduce drug expenses. METHODS: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. RESULTS: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. CONCLUSIONS: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.

Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology.

Circulating tumor cell (CTC) counts are an established prognostic marker in metastatic prostate, breast and colorectal cancer, and recent data suggest a similar role in late stage non-small cell lung cancer (NSCLC). However, due to sensitivity constraints in current enrichment-based CTC detection technologies, there are few published data about CTC prevalence rates and morphologic heterogeneity in early-stage NSCLC, or the correlation of CTCs with disease progression and their usability for clinical staging. We investigated CTC counts, morphology and aggregation in early stage, locally advanced and metastatic NSCLC patients by using a fluid-phase biopsy approach that identifies CTCs without relying on surface-receptor-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. HD-CTCs were analyzed in blood samples from 78 chemotherapy-naïve NSCLC patients. 73% of the total population had a positive HD-CTC count (>0 CTC in 1 mL of blood) with a median of 4.4 HD-CTCs mL⁻¹ (range 0-515.6) and a mean of 44.7 (±95.2) HD-CTCs mL⁻¹. No significant difference in the medians of HD-CTC counts was detected between stage IV (n = 31, range 0-178.2), stage III (n = 34, range 0-515.6) and stages I/II (n = 13, range 0-442.3). Furthermore, HD-CTCs exhibited a uniformity in terms of molecular and physical characteristics such as fluorescent cytokeratin intensity, nuclear size, frequency of apoptosis and aggregate formation across the spectrum of staging. Our results demonstrate that despite stringent morphologic inclusion criteria for the definition of HD-CTCs, the HD-CTC assay shows high sensitivity in the detection and characterization of both early- and late-stage lung cancer CTCs. Extensive studies are warranted to investigate the prognostic value of CTC profiling in early-stage lung cancer. This finding has implications for the design of extensive studies examining screening, therapy and surveillance in lung cancer patients.

[Catamenial pneumothorax: an intriguing cause of recurrent pneumothorax in women]. / Catameniale pneumothorax.

BACKGROUND: Thoracic endometriosis (TE) is one of the causes of secondary pneumothorax in women. According to the literature, 1 in 3 premenopausal women with pneumothorax can be diagnosed with 'catamenial pneumothorax'. The diagnosis is often not or only belatedly made in practice, even though treatment is significantly different than that of primary pneumothorax. CASE DESCRIPTION: A 40-year-old woman came to the emergency department because of dyspnoea and right-sided chest pain. The patient had recurrent pneumothorax and chest pain related to the menstrual cycle. Thoracoscopy revealed thoracic endometriosis. The endometriosis lesions were removed and the patient subsequently received hormonal menstrual suppression treatment. CONCLUSION: In premenopausal women with pneumothorax or a recurrence of pneumothorax, it is important to consider catamenial pneumothorax. Infertility, earlier proven abdominal endometriosis and chest pain linked to menstruation are indications of thoracic endometriosis or catamenial pneumothorax.

Pleural pressure swing and lung expansion after malignant pleural effusion drainage: the benefits of high-temporal resolution pleural manometry.

BACKGROUND: Malignant pleural effusion is a common complication in end-stage cancer patients and can cause severe dyspnea. Therapeutic thoracentesis is often limited to 1 to 1.5 L. Pleural manometry can be used to recognize a not-expanded lung. METHODS: Interval pleural pressure measurements with a high temporal resolution were performed after each removal of 200 mL of fluid to observe pleural pressure swings. Pleural elastance was defined as the difference in pleural pressure divided by the change in volume. Chest x-rays were performed to evaluate lung expansion, reexpansion pulmonary edema, and fluid residue. RESULTS: Thirty-four procedures in 30 patients were eligible for analysis. Four patients had incomplete lung expansion after drainage. No reexpansion pulmonary edema was observed. Pleural pressure swing after 200 mL drainage was higher when the lung did not expand. Pleural elastance after removal of 500 mL was higher in the not-expanded subgroup. CONCLUSIONS: We demonstrated that a high pleural pressure swing after removal of only 200 mL was related to incomplete lung expansion. We confirmed the association between pleural elastance and lung expansion.

Clinical outcomes of indwelling pleural catheter-related pleural infections: an international multicenter study.

BACKGROUND: Indwelling pleural catheters (IPCs) offer effective control of malignant pleural effusions (MPEs). IPC-related infection is uncommon but remains a major concern. Individual IPC centers see few infections, and previous reports lack sufficient numbers and detail. This study combined the experience of 11 centers from North America, Europe, and Australia to describe the incidence, microbiology, management, and clinical outcomes of IPC-related pleural infection. METHODS: This was a multicenter retrospective review of 1,021 patients with IPCs. All had confirmed MPE. RESULTS: Only 50 patients (4.9%) developed an IPC-related pleural infection; most (94%) were successfully controlled with antibiotics (62% IV). One death (2%) directly resulted from the infection, whereas two patients (4%) had ongoing infectious symptoms when they died of cancer progression. Staphylococcus aureus was the causative organism in 48% of cases. Infections from gram-negative organisms were associated with an increased need for continuous antibiotics or death (60% vs 15% in gram-positive and 25% mixed infections, P = .02). The infections in the majority (54%) of cases were managed successfully without removing the IPC. Postinfection pleurodesis developed in 31 patients (62%), especially those infected with staphylococci (79% vs 45% with nonstaphylococcal infections, P = .04). CONCLUSIONS: The incidence of IPC-related pleural infection was low. The overall mortality risk from pleural infection in patients treated with IPC was only 0.29%. Antibiotics should cover S aureus and gram-negative organisms until microbiology is confirmed. Postinfection pleurodesis is common and often allows removal of IPC. Heterogeneity in management is common, and future studies to define the optimal treatment strategies are needed.

Circulating tumor cells in non-small cell lung carcinoma.

Circulating tumor cells (CTCs) are associated with survival of cancer patients. Several methods have been developed to detect circulating tumor cells. The number of CTCs in NSCLC is lower than in other solid tumors. To date, trials are ongoing for a better understanding of CTCs. Besides association with prognosis, CTCs can be used to assess the efficacy of treatment and they are important substrates for molecular profiling of the tumor..