Mass Spectrometry as a Highly Sensitive Method for Specific Circulating Tumor DNA Analysis in NSCLC: A Comparison Study.

Plasma-based tumor mutational profiling is arising as a reliable approach to detect primary and therapy-induced resistance mutations required for accurate treatment decision making. Here, we compared the FDA-approved Cobas® EGFR Mutation Test v2 with the UltraSEEK™ Lung Panel on the MassARRAY® System on detection of EGFR mutations, accompanied with preanalytical sample assessment using the novel Liquid IQ® Panel. 137 cancer patient-derived cell-free plasma samples were analyzed with the Cobas® and UltraSEEK™ tests. Liquid IQ® analysis was initially validated (n = 84) and used to determine ccfDNA input for all samples. Subsequently, Liquid IQ® results were applied to harmonize ccfDNA input for the Cobas® and UltraSEEK™ tests for 63 NSCLC patients. The overall concordance between the Cobas® and UltraSEEK™ tests was 86%. The Cobas® test detected more EGFR exon19 deletions and L858R mutations, while the UltraSEEK™ test detected more T790M mutations. A 100% concordance in both the clinical (n = 137) and harmonized (n = 63) cohorts was observed when >10 ng of ccfDNA was used as determined by the Liquid IQ® Panel. The Cobas® and UltraSEEK™ tests showed similar sensitivity in EGFR mutation detection, particularly when ccfDNA input was sufficient. It is recommended to preanalytically determine the ccfDNA concentration accurately to ensure sufficient input for reliable interpretation and treatment decision making.

Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non-small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study.

PURPOSE: Second-line chemotherapy regimens have demonstrated poor benefit after failure of platinum-based chemotherapy in advanced non-squamous non-small-cell lung cancer (nsNSCLC). METHODS: In this multicentre, open-label phase III trial, patients with advanced nsNSCLC treated with one or two prior lines, including one platinum-based doublet, were centrally randomised to receive 90 mg/m2 of paclitaxel (D1, D8, D15) plus 10 mg/kg of bevacizumab (D1, D15) every 28 days or docetaxel (75 mg/m2) every 21 days; crossover was allowed after disease progression. Primary end-point was progression-free survival (PFS). ClinicalTrials.gov registration number: NCT01763671. RESULTS: One hundred sixty six patients were randomised (paclitaxel plus bevacizumab: 111, docetaxel: 55). The median PFS was longer in patients receiving paclitaxel plus bevacizumab than in patients receveing docetaxel [5·4 months versus 3·9 months, adjusted hazard ratio (HR) 0·61 (95% confidence interval [CI]: 0·44-0·86); p = 0·005]. Objective response rates (ORRs) were 22·5% (95% CI: 14·8-30·3) and 5·5% (95% CI: 0·0-11·5) (p = 0·006), respectively. Median overall survivals were similar (adjusted HR 1·17; p = 0·50). Crossover occurred in 21 of 55 (38·2%) docetaxel-treated patients. Grade III-IV adverse events (AEs) were reported in 45·9% and 54·5% of patients treated with paclitaxel and bevacizumab or docetaxel, respectively (p = NS), including neutropenia (19·3% versus 45·4%), neuropathy (8·3% versus 0·0%) and hypertension (7·3% versus 0·0%). Three patients died due to treatment-related AEs (1·8% in each group). CONCLUSION: Weekly paclitaxel plus bevacizumab as second- or third-line improves PFS and ORR compared with docetaxel in patients with nsNSCLC, with an acceptable safety profile. These results place weekly paclitaxel plus bevacizumab as a valid option in this population. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01763671.

Hepatic metastases from carcinomas of unknown primary site.

AIM: Hepatic metastases are often present at diagnosis of carcinoma of unknown primary site (CUP). The objective of this study was to describe the diagnostic and therapeutic strategies used. METHODS: One hundred and eighteen patients were treated at the Cancer Center of Montpellier from 1993 to 2002 for CUP initially metastatic to the liver. Initial characteristics, diagnostic tests, chemotherapies and outcome were retrospectively recorded. RESULTS: The most frequent histological types observed were adenocarcinoma, undifferentiated, neuroendocrine and squamous-cell carcinomas. Hepatic metastases revealed the cancer in 66 patients and were isolated in 32 patients. Other metastatic sites involved lymph nodes, lung and bone. Pretreatment computed tomography scans of the chest, abdomen and pelvis evaluation were available for more than 80% of patients. Colonoscopy, gastroscopy and bronchoscopy were performed in 58, 56 and 26% of patients respectively. One hundred and seven patients had received at least a front-line of chemotherapy. Seventy-four patients had received platin salt-based chemotherapy, 67 in front-line treatment and 10 in second line. In first-line chemotherapy, overall response rates with or without platin were 19.4 and 20% respectively. One hundred and two of 111 deaths were due to disease progress and seven toxic-related deaths occurred. The median survival was 6.6 months, and 7.8 and 4.6 months in the with or without platin groups respectively (P=0,35). The median survival for treated patients was 7 months. Multivariate analysis identified two prognostic factors: serum lacto-dehydrogenase level and performance status. CONCLUSIONS: According to this study, pretreatment evaluations, which were very extensive in some patients, were insufficient to identify the primary site of liver metastases. Because of the poor prognostic, chemotherapy, in absence of clinically demonstrated benefit, has to be reserved for patients with better prognosis. Prospective trials are needed to determine whether use or not of cisplatin should be proposed for standard protocols.

Gemcitabine and docetaxel after failure of cisplatin-based chemotherapy in patients with carcinoma of unknown primary site.

BACKGROUND: The prognosis of patients with carcinoma of unknown primary remains poor with an expected median survival of 6 to 12 months. We evaluated the activity of a chemotherapy regimen combining gemcitabine and docetaxel in patients who primarily failed cisplatin-based chemotherapy. PATIENTS AND METHODS: Fifteen patients received cycles of gemcitabine 1,000 mg/m2 on days 1 and 8 and docetaxel 75 mg/m2 on day 8 every 3 weeks. RESULTS: The median number of cycles per patient was 3. Overall toxicity was moderate. Four partial responses were observed among 14 patients with measurable disease. The median survival was 8 months from start of therapy and 23 months from diagnosis. CONCLUSION: These results were obtained in a small series of selected patients and require further confirmation in the front-line management of the disease.

A pilot study of gemcitabine in combination with oxaliplatin and vinorelbine in patients with metastatic bladder cancer.

AIM: To assess the safety and to obtain preliminary data on the efficacy of the three-drug combination chemotherapy with gemcitabine, oxaliplatin and vinorelbine in patients with metastatic bladder cancer. PATIENTS AND METHODS: Patients with metastatic or locally unresectable advanced bladder cancer who had received either no or one previous systemic chemotherapy regimen were eligible. All patients received intravenous gemcitabine 700 mg/m(2) and vinorelbine 25 mg/m(2) on day 1, then intravenous oxaliplatin 85 mg/m(2) on day 2, every 14 days. RESULTS: Fifteen patients were enrolled. Twelve patients were unfit for cisplatin. A median of five cycles per patient were delivered. The most common toxicities were neutropenia, nausea and vomiting, mucositis and diarrhoea. Two complete responses and one partial response were observed for an overall response rate of 23%. Median progression-free survival was 5.7 months and overall survival was 8.6 months. CONCLUSION: Although active and tolerable, the described three-drug combination chemotherapy showed no obvious incremental increase in efficacy compared with two-drug regimens. Further clinical trials are not recommended.

Gemcitabine and docetaxel as front-line chemotherapy in patients with carcinoma of an unknown primary site.

BACKGROUND: The current study was performed to evaluate the efficacy and toxicity of a noncisplatin-based chemotherapy regimen combining gemcitabine and docetaxel as front-line chemotherapy for patients with carcinoma of an unknown primary site. METHODS: Patients were to receive intravenous gemcitabine at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 and docetaxel at a dose of 75 mg/m2 over 1 hour on Day 8 in an outpatient setting. The schedule was repeated every 3 weeks for a maximum of 6 cycles. RESULTS: Thirty-five patients were assessable for response and survival. One complete and 13 partial responses were observed. The overall response rate was 40% (95% confidence interval, 28-52%). The median time to disease progression was 2 months (range, 1-4 months). The median overall survival time was 10 months (range, 0-32 months). Toxicity was reported to be manageable. CONCLUSIONS: The combination of gemcitabine and docetaxel was found to be active in patients with carcinomas of an unknown primary site. However, the overall outcome of these patients remains poor and novel treatment approaches are required.

Reducing the time interval between cycles using standard doses of docetaxel and lenogastrim support: a feasibility study.

BACKGROUND: As a single agent, 100 mg/m(2) of docetaxel every 3 weeks remains the standard schedule in the first-line treatment for metastatic disease. At this dose level, the major limiting toxicity is neutropenia. The current study was conducted to assess the feasibility of reducing time intervals between cycles while delivering standard doses of docetaxel with granulocyte-colony-stimulating factor (G-CSF; lenograstim). METHODS: In the first part of the study, 24 patients were randomized to receive 1 of 4 schedules: 100 mg/m(2) of docetaxel every 21 days without lenograstim; 100 mg/m(2) of docetaxel every 18 days with lenograstim; 100 mg/m(2) of docetaxel every 14 days with lenograstim; or 100 mg/m(2) of docetaxel every 10 days with lenograstim. In the second part of the study, 15 additional patients were included to confirm the feasibility of the recommended interval between cycles. RESULTS: Of the 39 patients treated, 14 patients (36%) withdrew from therapy because of Grade 3 (according to standard World Health Organization criteria) nonhematologic limiting toxicities. Only 3 patients were treated in the 10-day interval arm and were withdrawn because of toxicity--1 patient had Grade 3 asthenia after the second cycle and 2 patients had Grade 3 dermatitis after 4 cycles. Of the 24 patients treated in the 14-day intervals, Grade 3 limiting toxicities occurred in 8 patients (33%), including dermatitis in 3 patients; diarrhea, myalgia/arthralgia, or asthenia in 4 patients; and ungual toxicity in 1 patient. CONCLUSIONS: Introduction of G-CSF (lenograstim) as primary prophylaxis allowed the administration of docetaxel every 14 days with manageable toxicities. Further studies are now required to assess the impact in terms of response rates and survival in patients with cancer.