The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). ...However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN.
Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100mg/m2 on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3weeks for up to 6 cycles; and cetuximab at an initial dose of 400mg/m2, followed by 250mg/m2 weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients.
Forty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7months and progression-free survival was 5.2months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia.
The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population.
UMIN000010507.
The results of an international review of separation processes for spent nuclear fuel (SNF) recycling in future closed fuel cycles are reported. This study was made by the Expert Group on Fuel ...Recycling Chemistry (EGFRC) organised by the Nuclear Energy Agency (NEA) of the Organisation for Economic Co-operation and Development (OECD). A unique feature of this study was that processes were classified according to a hierarchy of separations aimed at different elements within spent fuel (uranium; uranium-plutonium co-recovery; minor actinides; high heat generating radionuclides) and also the Head-end processes, used to prepare the SNF for chemical separation, were included. Separation processes covered both wet (hydrometallurgical) and dry (pyro-chemical) processes.
A bespoke methodology suitable for assessing the technological maturities of separation processes for SNF recycling was then designed based on the well-established Technology Readiness Level (TRL) scale but adapted for spent nuclear fuel separations. The innovative feature of this was the use of a matrix approach that enabled information on both the scale of testing and materials used in testing to be combined in the evaluation of the TRL. TRLs for the Head-end, hydrometallurgical and pyrochemical processes that had been reviewed by the study have been evaluated. It is clear that, whilst more R&D is needed in most cases to raise TRLs, suitable options exist to enable the recovery of all actinide elements plus the HHRs by wet or dry processes, even up to the extraordinarily difficult isolation of americium alone. The technology readiness levels (TRL) for most processes fall in the ‘proof of principle’ range with TRLs between 4 and 6, although this is an evaluation at the system level and some gaps in the individual process steps may still exist that strictly would reduce the overall TRL. That is, flowsheets have been proposed for processes and tested with active materials under increasingly relevant conditions, through to initial hot tests with small quantities of SNF. The results of this work were shown to be comparable to a parallel European study that evaluated TRLs for minor actinide partitioning processes.
Display omitted
•Results of an international study.•Advanced reprocessing and minor actinide partitioning technologies.•Review of progress in R&D on separation processes for advanced nuclear fuel cycles.•Technology Readiness Level assessment of separation processes.•Status of head-end, aqueous and pyro-chemical processes reviewed.
EGFR-TKI therapy produces a dramatic clinical response in patients with NSCLC harboring EGFR mutation. However, clinical outcomes should be improved further in this cohort. Thus, we conducted a ...randomized phase II study to investigate the efficacy and safety of combinational EGFR-TKI and chemotherapy, demonstrating that the combination might be a promising strategy for advanced EGFR-mutant NSCLC.
The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation.
Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/pemetrexed area under the curve (AUC) = 6 and 500 mg/m2; 3-weekly. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety.
All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen hazard ratio (HR) 0.71 (0.42–1.20), P = 0.20. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively HR 0.51 (0.26–0.99); P = 0.042. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients).
This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study.
University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN C000002789).
Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of ...patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL).
Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0–1 and adequate organ function were randomized to receive either oral S-1 80 mg/m2/day on days 1–21 plus cisplatin 60 mg/m2 on day 8 every 4–5 weeks, or docetaxel 60 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3–4 weeks, both up to six cycles.
A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837–1.227. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin.
Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC.
UMIN000000608.
The main step in the pyrometallurgical recycling process of spent nuclear fuel is a molten salt electrorefining. The knowledge of separation coefficients of actinides (U, Np, Pu and Am) and ...rare-earth metals (Y, La, Ce, Nd and Gd) is very important for this step. Usually the separation coefficients are evaluated from the formal standard potentials of metals in melts containing their own ions, i.e. values obtained by potentiometric method. Electrochemical experiments were carried out at 723–823
K in order to estimate separation coefficients in LiCl–KCl eutectic melt containing uranium and lanthanum trichlorides. The electrochemical behaviour of UCl
3 in LiCl–KCl melt was studied by different electrochemical methods. The diffusion coefficients of U(III) were determined by linear sweep voltammetry, chronopotentiometry and chronoamperometry. The standard rate constants of charge transfer for electroreduction of uranium, U(III)
+
3e
−
→
U, were calculated by the impedance spectroscopy method. The values of constants testify that electroreduction of U(III) to U is mainly controlled by the rate of charge transfer. La(III) discharge on uranium electrode was also investigated. It was shown that for the calculation of uranium and lanthanum separation coefficients it is necessary to determine the voltammetric peak potentials of U(III) and La(III), their concentration in the melt and the kinetic parameters relating to U(III) discharge such as transfer and diffusion coefficients, and standard rate constants of charge transfer.
Neutropenia is a common adverse reaction of chemotherapy. We assessed whether chemotherapy-induced neutropenia could be a predictor of survival for patients with non-small-cell lung cancer (NSCLC).
A ...total of 387 chemotherapy-naïve patients who received chemotherapy (vinorelbine and gemcitabine followed by docetaxel, or paclitaxel and carboplatin) in a randomised controlled trial were evaluated. The proportional-hazards regression model was used to examine the effects of chemotherapy-induced neutropenia and tumour response on overall survival. Landmark analysis was used to lessen the bias of more severe neutropenia resulting from more treatment cycles allowed by longer survival, whereby patients who died within 126 days of starting chemotherapy were excluded.
The adjusted hazard ratios for patients with grade-1 to 2 neutropenia or grade-3 to 4 neutropenia compared with no neutropenia were 0.59 (95% confidence interval (CI), 0.36-0.97) and 0.71 (95% CI, 0.49-1.03), respectively. The hazard ratios did not differ significantly between the patients who developed neutropenia with stable disease (SD), and those who lacked neutropenia with partial response (PR).
Chemotherapy-induced neutropenia is a predictor of better survival for patients with advanced NSCLC. Prospective randomised trials of early-dose increases guided by chemotherapy-induced toxicities are warranted.
A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of progesterone levels in rat plasma. Progesterone-d9 was used as an ...internal standard (IS). Samples were prepared using salting-out assisted liquid/liquid extraction (SALLE), and the extracts were injected directly onto the LC-MS/MS system. The chromatographic separation was achieved on a CAPCELL PAK C18 MGIII column (100 mm × 2.0 mm, i.d. 5 µm) using methanol and aqueous 0.1% formic acid solution gradient as the mobile phase with a constant flow rate of 0.45 mL/min. Electrospray ionization in the positive-ion mode was employed. Multiple reaction monitoring of the precursor to product ion pairs, from m/z 315.20 to m/z 109.10 for progesterone and from m/z 324.26 to m/z 113.07 for the IS, was used for quantification. Good linearity was observed over the concentration range of 0.05-20.00 ng/mL with a weighted (1/x(2)) linear regression. The intra- and inter-day precision (% relative standard deviation RSD) across 3 validation days over the entire concentration range was lower than 6.7%. Accuracy (% nominal) determined at 5 quality control concentrations was between 94.0 and 103.7%. The validation method was applied in a pharmacokinetic study evaluating progesterone levels after intramuscular or vaginal administration to ovariectomized (OVX) rats. The area under the plasma concentration-time curve (AUC) calculated after intramuscular administration was more than 4 times higher than the AUC measured following vaginal administration of a comparable dose.
Purpose
Gefitinib is an effective first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive
EGFR
mutations. However, whether second-line platinum ...combination chemotherapy after first-line gefitinib treatment shows similar effects to first-line platinum combination chemotherapy in these patients remains unclear. Therefore, we here aimed to investigate the efficacy of platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive
EGFR
mutations.
Methods/patients
We retrospectively evaluated the clinical effects of second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive
EGFR
mutations (exon 19 deletion or exon 21 L858R mutation) at five institutions. All patients were initially treated with gefitinib (250 mg/day) followed by platinum combination chemotherapy as second-line chemotherapy.
Results
Between January 2006 and December 2012, 42 patients 8 men, 34 women; median age, 63 years (range 39–75 years) were enrolled. The overall response rate, disease control rate, and median progression-free survival (PFS) were 26.2, 61.9 %, and 5.1 months, respectively, after the second-line treatment. The corresponding values for first-line gefitinib treatment were 69.0, 95.2 %, and 11.1 months, respectively. Moreover, second-line platinum combination chemotherapy with pemetrexed or bevacizumab-containing regimens was independently associated with improved PFS.
Conclusions
Second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive
EGFR
mutations was effective and showed equivalent outcomes to first-line platinum combination chemotherapy. After failure of first-line gefitinib therapy, second-line platinum combination chemotherapy with pemetrexed or bevacizumab might result in improved PFS.
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