Pharmacokinetics of Weekly Paclitaxel and Feasibility of Dexamethasone Taper in Japanese Patients with Advanced Non–small Cell Lung Cancer

AbstractPurposeWeekly paclitaxel combined with a platinum-based agent has been advocated as an alternative regimen for patients with advanced non–small cell lung cancer (NSCLC). Limited studies exist on the tolerability of weekly paclitaxel in Japanese patients with advanced NSCLC. Furthermore, the feasibility of dexamethasone taper in the premedication regimen for weekly paclitaxel has not been examined in these patients. To address this issue, we assessed the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of weekly paclitaxel in Japanese patients with advanced NSCLC in a dose-escalation Phase I trial and examined the feasibility of dexamethasone taper in these patients.MethodsWeekly 1-hour infusions of paclitaxel were administered at doses of 80 to 120 mg/m2 (dose escalation of 20 mg/m2). The 7-week treatment cycle consisted of 6 infusions followed by a 2-week treatment interval. Pharmacokinetics were assessed during the first cycle. Dexamethasone was commenced at 16 mg and doses were successively halved if hypersensitivity reactions were absent.FindingsA total of 15 patients with either Stage IIIB or IV NSCLC were enrolled. Although no dose-limiting toxicity was observed at 120 mg/m2, 4 of 6 patients with peripheral neuropathy required discontinuation of treatment. The maximum accepted dose and the recommended dose were 120 and 100 mg/m2, respectively. No grade ≥3 adverse events were observed at 100 mg/m2. The maximum drug concentration and AUC correlated with dose escalation. The pharmacokinetic parameters after the first and sixth infusions were similar, indicating that repeated administration of paclitaxel did not result in drug accumulation or affect its pharmacokinetic profile. Partial response was observed in 3 of 15 patients. Plasma adrenocorticotropic hormone and cortisol levels decreased during treatment but approached baseline levels after a dexamethasone-free interval.ImplicationsWeekly paclitaxel at 100 mg/m2 given as a 1-hour infusion for 6 weeks followed by a 2-week treatment interval was well tolerated by Japanese patients with advanced NSCLC. Dexamethasone taper was feasible in these patients, and no clear trend in plasma adrenocorticotropic hormone or cortisol levels was observed

Comparative Chemotherapeutic Efficacy in Non-small Cell Lung Cancer Patients with Postoperative Recurrence and Stage IV Disease

BackgroundWhether chemotherapy would be equally effective in non-small cell lung cancer patients with stage IV disease (group A) and postoperative recurrence (group B) remains unclear.Patients and MethodsIn a total of 642 non-small cell lung cancer patients with distant metastases treated by chemotherapy, the baseline patient characteristics, responses to chemotherapy and survival were compared between group A (n = 480) and group B (n = 162).ResultsAdenocarcinoma was the predominant histologic type, accounting for 78% of the patients in group A and 90% of the patients in group B (p < 0.001). Bone and brain metastases were more common in group A (p = 0.034 and p = 0.014, respectively), although pulmonary metastases were more common in group B (p < 0.001). The chemotherapy regimens used for the treatment did not differ between groups A and B. The response rates in group A and group B were 32 and 33%, respectively (p = 0.65). In contrast, the median progression-free survival (5.5 versus 4.2 months, p = 0.0065) and overall survival (21.3 versus 13.3 months, p < 0.001) were better in group B than in group A.ConclusionSurvival was superior in patients with postoperative recurrence than in those with stage IV disease, although the two groups showed comparable responses to chemotherapy

Radiotherapy quality assurance review in a multi-center randomized trial of limited-disease small cell lung cancer: the Japan Clinical Oncology Group (JCOG) trial 0202

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to analyze the radiotherapy (RT) quality assurance (QA) assessment in Japan Clinical Oncology Group (JCOG) 0202, which was the first trial that required on-going RT QA review in the JCOG.</p> <p>Methods</p> <p>JCOG 0202 was a multi-center phase III trial comparing two types of consolidation chemotherapy after concurrent chemoradiotherapy for limited-disease small cell lung cancer. RT requirements included a total dose of 45 Gy/30 fx (bis in die, BID/twice a day) without heterogeneity correction; elective nodal irradiation (ENI) of 30 Gy; at least 1 cm margin around the clinical target volume (CTV); and interfraction interval of 6 hours or longer. Dose constraints were defined in regards to the spinal cord and the lung. The QA assessment was classed as per protocol (PP), deviation acceptable (DA), violation unacceptable (VU), and incomplete/not evaluable (I/NE).</p> <p>Results</p> <p>A total of 283 cases were accrued, of which 204 were fully evaluable, excluding 79 I/NE cases. There were 18 VU in gross tumor volume (GTV) coverage (8% of 238 evaluated); 4 VU and 23 DA in elective nodal irradiation (ENI) (2% and 9% of 243 evaluated, respectively). Some VU were observed in organs at risk (1 VU in the lung and 5 VU in the spinal cord). Overall RT compliance (PP + DA) was 92% (187 of 204 fully evaluable). Comparison between the former and latter halves of the accrued cases revealed that the number of VU and DA had decreased.</p> <p>Conclusion</p> <p>The results of the RT QA assessment in JCOG 0202 seemed to be acceptable, providing reliable results.</p

Candidates for Intensive Local Treatment in cIIIA-N2 Non-Small Cell Lung Cancer: Deciphering the Heterogeneity

PurposeThe purpose of this study was to refine the heterogeneous clinical stage IIIA non-small cell lung cancer (NSCLC) with N2 nodes status (cIIIA-N2) by clinicopathological characteristics before treatment.Methods and MaterialsWe analyzed data of consecutive patients with cIIIA-N2 NSCLC diagnosed between 1997 and 2010 and treated by chemoradiation therapy (CRT). The appearance of the mediastinal lymph nodes (MLNs) was classified into discrete or infiltrative according to the criteria proposed by the American College of Chest Physicians. In addition, the extent of MLN involvement (MLNI) was classified as limited (close to the primary tumor) or extensive (including upper MLNI in the case of tumors in the lower lobes and vice versa).ResultsA total of 148 patients with cIIIA-N2 NSCLC was treated by CRT. The patient characteristics were as follows: males: 118; females: 30; median age: 62 years; appearance of the involved MLNs: 85 discrete, 63 infiltrative; extent of MLNI: 82 limited, 66 extensive; histology: 36 squamous, 112 nonsquamous. The median progression-free survival (PFS) and median overall survival (OS) in the entire subject population were 9.9 and 34.7 months, respectively. A discrete appearance of the involved MLNs and a limited extent of MLNI contributed significantly to a better PFS and OS. The percentages of cases with relapses within the irradiated field classified according to the characteristics of the MLNs were as follows; appearance of the MLNs (24.6% discrete, 18.9% infiltrative); extent of MLNI (25.9 limited, 17.9% extensive).ConclusionsThose with a discrete appearance of the involved MLNs and a limited extent of MLNI at diagnosis could show relatively more favorable outcomes and could be candidates for multimodality therapy

An open-label, phase 1 study evaluating safety, tolerability, and pharmacokinetics of linifanib (ABT-869) in Japanese patients with solid tumors

PURPOSE: This phase 1 study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of linifanib in Japanese patients with advanced solid tumors. METHODS: Patients were assigned to one of four sequential cohorts (0.05, 0.10, 0.20, or 0.25 mg/kg) of oral, once-daily linifanib on a 21-day cycle. Adverse events (AEs) were assessed per common terminology criteria for adverse events v3.0; tumor responses were assessed by response evaluation criteria in solid tumors. RESULTS: Eighteen patients were enrolled. Eleven (61%) received ≥3 prior therapies. Dose-limiting toxicities were Grade 3 ALT increase (0.10 mg/kg linifanib) and Grade 1 T-wave inversion (0.25 mg/kg linifanib) requiring dose interruption for >7 days and discontinuation on day 29. The most common linifanib-related AE was hypertension. Other significant treatment-related AEs included proteinuria, fatigue, and palmar-plantar erythrodysaesthesia. Linifanib pharmacokinetics were dose-proportional across 0.10–0.25 mg/kg. Two patients (11.1%) had confirmed partial responses, 12 had a best response of stable disease (11 had stable disease for ≥12 weeks), and four patients were not evaluable due to incomplete data. Four patients (lung cancer, breast cancer, thymic cancer, sarcoma) have continued linifanib for ≥48 weeks (range, 48–96+ weeks). CONCLUSION: Linifanib was well tolerated with promising preliminary clinical activity in Japanese patients. Later-phase global studies examining linifanib efficacy will include Japanese patients

Feasibility study of chemoradiotherapy followed by amrubicin and cisplatin for limited-disease small cell lung cancer

To evaluate the feasibility of amrubicin plus cisplatin (AP) following chemoradiotherapy for limited-disease small-cell lung cancer, chemo-naïve patients aged 20–70 years with a performance status of 0 or 1 and normal organ functions were treated with etoposide 100 mg/m2 on days 1–3, cisplatin 80 mg/m2 on day 1 and concurrent thoracic radiotherapy at 45 Gy/30 fractions (EP-TRT), followed by three cycles of amrubicin 40 mg/m2 on days 1–3 and cisplatin 60 mg/m2 on day 1 every 3 weeks. The EP-TRT could be completed in 21 patients (15 male and 6 female patients with a median age of 62 years). Of these, 2, 1 and 18 (86%) patients received one, two and three cycles of AP, respectively. Sixteen (76%) patients required granulocyte-colony stimulating factor (G-CSF) support. Grade 3/4 neutropenia occurred in all patients. Grade 3 febrile neutropenia was observed in 9 patients, lasting for 1 day in 5 patients. The incidences of grade 3/4 thrombocytopenia and anemia were 43 and 24%, respectively. Grade 3 infection and anorexia occurred in 2 and 3 patients, respectively. The response rate was 95%. The median (95% confidence interval [CI]) progression-free survival (PFS) was 41.9 (0–102) months, and the 5-year PFS rate (CI) was 41.9% (20.4–63.4%). The median overall survival (OS) has not been reached yet, and the 5-year OS rate (CI) was 57.8% (35.2–80.4%). In conclusion, EP-TRT followed by AP therapy was well-tolerated, although a large number of patients required G-CSF support