Germline polymorphisms in patients with advanced nonsmall cell lung cancer receiving first-line platinum-gemcitabine chemotherapy: a prospective clinical study.

BACKGROUND: The authors assessed the impact of germline polymorphisms on clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC) who received platinum-gemcitabine (PG) chemotherapy. METHODS: In total, 137 patients with stage IIIB/IV NSCLC were included who received first-line PG chemotherapy (74% of patients received cisplatin, and 26% received carboplatin). Twenty-three germline polymorphisms that were identified in peripheral blood samples were analyzed for progression-free survival (PFS), treatment response, overall survival (OS), and toxicity. RESULTS: The median PFS was 5.8 months, the median OS was 10.2 months, and 44 patients (32%) had a partial treatment response. Carriers of the excision repair cross-complementation group 1 (ERCC1) mutant thymine (T) allele had a lower treatment response rate (29% vs 52%; P = .02), shorter PFS (adjusted hazard ratio [HR], 1.60; P = .04), and shorter OS (adjusted HR, 1.54; P = .05) compared with carriers of the wild-type cytosine/cytosine (CC) genotype. The xeroderma pigmentosum group A member 10 (XPD10) mutant adenine (A) allele (adjusted HR, 0.64; P = .04) and the x-ray cross-complementing group 1 (XRCC1) mutant guanine (G) allele (adjusted HR, 0.51; P = .02) also were independent predictors of OS. Carriers of the mutant adenosine triphosphate-dependent DNA helicase Q1 (RECQ1) C allele or the mutant cytidine deaminase (CDA) C allele were more likely to experience severe leukocytopenia (26% vs 10% [P = .03] and 28% vs 11% [P = .02], respectively) compared with wild-type genotype carriers. Patients who carried the homozygous mutant glutathione S-transferase π 1(GSTP1) GG genotype were at considerable risk for severe platinum-associated polyneuropathy (18% vs 3% in wild-type vs heterozygous mutant patients, respectively; P = .01). CONCLUSIONS: To the authors' knowledge, this is the first prospective study to date in patients with advanced NSCLC describing predictive germline polymorphisms not only for the clinical activity of PG chemotherapy (ERCC1, XPD10) but also for its toxicity (GSTP1, RECQ1, CDA). Nonplatinum-containing chemotherapy in carriers of the ERCC1 T allele or the XPD10 G allele should be studied prospectively.

Implementation of endoscopic ultrasound for lung cancer staging.

BACKGROUND: EUS-guided FNA is currently advocated in lung cancer staging guidelines as an alternative for surgical staging to prove mediastinal metastases. To date, training requirements for chest physicians to obtain competency in EUS for lung cancer staging are unknown. OBJECTIVE: To test a training and implementation strategy for EUS for the diagnosis and staging of lung cancer. DESIGN: Prospective national multicenter implementation trial. Nine (chest) physicians from 5 hospitals participated in a dedicated EUS educational program (investigation of 50 patients) for the diagnosis and staging of lung cancer. EUS outcomes of trainees were compared with those of the training center. SETTING: Four general hospitals, the national cancer center (implementation centers), and a tertiary referral center (expert center). PATIENTS: This study involved 551 consecutive patients with (suspected) lung cancer, all candidates for surgical staging, who underwent EUS in 1 of the 5 implementation centers (n = 346) or the single expert center (n = 205). Surgical-pathological staging was the reference standard in case no mediastinal metastases were found. RESULTS: EUS had a sensitivity of 83% versus 82% and accuracy of 89% versus 88% for mediastinal nodal staging (implementation center vs expert center). Surgery was spared because of EUS findings in 51% versus 54% of patients. A single complication occurred in each group. LIMITATION: Surgical-pathological verification of mediastinal nodes was not available in all patients staged negative at EUS. CONCLUSION: Chest physicians who participate in a dedicated training and implementation program for EUS in lung cancer staging can obtain results similar to those of experts for mediastinal nodal staging.

Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non-Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study.

Purpose The purpose of the current study was to investigate whether prophylactic cranial irradiation (PCI) reduces the incidence of symptomatic brain metastases in patients with stage III non-small-cell lung cancer (NSCLC) treated with curative intention. Patients and Methods Patients with stage III NSCLC-staged with a contrast-enhanced brain computed tomography or magnetic resonance imaging-were randomly assigned to either observation or PCI after concurrent/sequential chemoradiotherapy with or without surgery. The primary end point-development of symptomatic brain metastases at 24 months-was defined as one or a combination of key symptoms that suggest brain metastases-signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures, and focal neurologic symptoms-and magnetic resonance imaging or computed tomography demonstrating the existence of brain metastasis. Adverse effects, survival, quality of life, quality-adjusted survival, and health care costs were secondary end points. Results Between 2009 and 2015, 175 patients were randomly assigned: 87 received PCI and 88 underwent observation only. Median follow-up was 48.5 months (95% CI, 39 to 54 months). Six (7.0%) of 86 patients in the PCI group and 24 (27.2%) of 88 patients in the control group had symptomatic brain metastases ( P = .001). PCI significantly increased the time to develop symptomatic brain metastases (hazard ratio, 0.23; [95% CI, 0.09 to 0.56]; P = .0012). Median time to develop brain metastases was not reached in either arm. Overall survival was not significantly different between both arms. Grade 1 and 2 memory impairment (26 of 86 v seven of 88 patients) and cognitive disturbance (16 of 86 v three of 88 patients) were significantly increased in the PCI arm. Quality of life was only decreased 3 months post-PCI and was similar to the observation arm thereafter. Conclusion PCI significantly decreased the proportion of patients who developed symptomatic brain metastases with an increase of low-grade toxicity.

Comparison of clinical outcome after first-line platinum-based chemotherapy in different types of KRAS mutated advanced non-small-cell lung cancer.

OBJECTIVES: As suggested by in-vitro data, we hypothesize that subtypes of KRAS mutated non-small cell lung cancer (NSCLC) respond differently to chemotherapy regimens. METHODS: Patients with advanced NSCLC and known KRAS mutation, treated with first-line platinum-based chemotherapy, were retrieved from hospital databases. PRIMARY OBJECTIVE: to investigate overall response rate (ORR), progression free survival (PFS) and overall survival (OS) between different types of platinum-based chemotherapy per type of KRAS mutation. RESULTS: 464 patients from 17 hospitals, treated between 2000 and 2013, were included. The majority of patients had stage IV disease (93%), had a history of smoking (98%) and known with an adenocarcinoma (91%). Most common types of KRAS mutation were G12C (46%), G12V (20%) and G12D (10%). Platinum was combined with pemetrexed (n=334), taxanes (n=68) or gemcitabine (n=62). Patients treated with taxanes had a significant improved ORR (50%) compared to pemetrexed (21%) or gemcitabine (25%; p<0.01). Patients treated with bevacizumab in addition to taxanes (n=38) had the highest ORR (62%). The PFS was significantly improved in patients treated with taxanes compared to pemetrexed (HR=0.72, p=0.02), but not OS (HR=0.87, p=0.41). In patients with G12V, significantly improved ORR (p<0.01) was observed for taxanes, but not PFS or OS. Patients with G12C or G12D mutation had comparable ORR, PFS and OS in all treatment groups. CONCLUSION: KRAS mutated NSCLC patients treated with taxane-based chemotherapy had best ORR. Response to chemotherapy regimens was different in types of KRAS mutation. Especially patients with G12V had better response to taxane treatment.

Quantification of right-to-left shunt with (99m)Tc-labelled albumin macroaggregates and 100% oxygen in patients with hereditary haemorrhagic telangiectasia.

Pulmonary arteriovenous malformations (PAVMs) are often associated with hereditary haemorrhagic telangiectasia (HHT). The quantification of right-to-left shunts in patients with PAVMs is important in diagnosis and follow up. Traditionally, this shunt is measured by the 100% oxygen method, in which the value for the arteriovenous difference in oxygen content, Cao(2)-CVO(2) (where Cao(2) is the oxygen content of arterial blood and CVO(2) is the oxygen content of mixed venous blood) is estimated. Alternative methods consist of measurement of the systemic or renal uptake of (99m)Tc-labelled macroaggregates of albumin (MAA), which are trapped in pulmonary capillaries, but pass through PAVMs. We first measured Cao(2)-CVO(2) in 12 HHT patients before and after embolization of PAVMs. We obtained a mean value of 4.4 ml/100 ml, instead of the usual 5 ml/100 ml. Subsequently, we measured right-to-left shunt in 21 HHT patients using the 100% oxygen method and with two different methods involving (99m)Tc. We used the kidney-lung method (K/L method), in which it is assumed that the right kidney receives 10% of the cardiac output, and we also used a method with two tracers (HSA/MAA method): (1) (99m)Tc-labelled human serum albumin (HSA) (which passes through pulmonary capillaries) to measure the fraction of the cardiac output perfusing the kidneys, and (2) MAA to measure the shunt fraction. In 35 shunt measurements we evaluated this new technique and the K/L method, by comparing the results with those from the 100% oxygen method. There was poor agreement between the 100% oxygen method and the K/L method, with 95% limits of agreement for the shunt fraction of -15.2% to +15.2%. There was moderate agreement between the 100% oxygen method and the HSA/MAA method, with limits of agreement of -8.3% to +7.7%. We conclude that the different methods cannot replace each other, because the limits of agreement are too wide for clinical use.