Evaluation of amrubicin as a third or later line of chemotherapy for advanced non-small cell lung cancer.

BACKGROUND: Currently, there are no standard cytotoxic treatments for non-small-cell lung cancer (NSCLC) patients beyond third-line therapy. The purpose of this study was to evaluate the efficacy of amrubicin monotherapy as a salvage treatment in heavily pretreated NSCLC patients. METHODS: The records of NSCLC patients who received amrubicin monotherapy as a third or later line of chemotherapy at a Kitasato University Hospital between January 2009 and December 2012 were retrospectively reviewed. Amrubicin was administered to patients by intravenous injection at a dose of 35 or 40 mg/m(2) daily on 3 consecutive days, and cycles were repeated at 3-week intervals. RESULTS: There were 36 patients who met the inclusion criteria. Their median number of prior chemotherapy treatments was 4 (range 2-7), and the median number of chemotherapy cycles per patient was 4 (range 1-9). Grade 3 or 4 hematologic toxicities included neutropenia (61.1%), leukopenia (58.3%), thrombocytopenia (22.2%) and anemia (11.1%). Febrile neutropenia occurred in 8 patients (22.2%). Nonhematologic toxicities were mild. The overall response rate, median progression-free survival time and median survival time were 8.3%, 1.7 months, and 6.3 months, respectively. Progression-free survival time was the same, i.e. 1.7 months in both groups i.e. the 35- and the 40-mg/m(2)-dose groups. CONCLUSION: Amrubicin exhibits modest activity and acceptable toxicity when used as a third or later line of chemotherapy for advanced NSCLC.

Pemetrexed for previously treated patients with non-small cell lung cancer and differences in efficacy according to thymidylate synthase expression.

The purpose of this study was to evaluate the efficacy of pemetrexed monotherapy in previously treated patients with advanced non-small cell lung cancer (NSCLC) including salvage treatment, and to evaluate whether thymidylate synthase (TS) expression is a predictor for pemetrexed efficacy. Hundred and four previously treated patients with advanced NSCLC who received pemetrexed monotherapy were retrospectively evaluated for clinical efficacy and toxicity. If available, tissue specimens of patients were also analyzed immunohistochemically for TS expression. The patients' median age was 65 years (range: 43-82). An overall response rate of 9.6% and a median progression-free survival (PFS) time of 3.4 months were achieved. The response rates for the second-line, third-line, fourth-line or further treatments were 9.1, 9.3 and 10.2% (p = 0.33); the median PFS were 3.3, 3.2 and 3.8 months (p = 0.21). The median follow-up duration was 14.9 months; the median overall survival (OS) was 11.9 months. The median PFS and OS were significantly longer in the TS-negative group than in the TS-positive group (5.8 months vs. 1.6 months; p = 0.03, and 14.7 months vs. 8.6 months; p = 0.04, respectively). Pemetrexed monotherapy could be considered as an option in the fourth or later lines of treatment of previously treated patients with advanced NSCLC as well as a second- or third-line treatment, and TS expression may be a potentially predictive factor for pemetrexed efficacy in NSCLC patients.

[Efficacy of chemotherapy with carboplatin-paclitaxel plus bevacizumab for previously treated patients with advanced non-small cell carcinoma].

BACKGROUND: There have been few reports on the efficacy or safety of combination therapy with carboplatin-paclitaxel plus bevacizumab(TC+Bev)in previously treated patients with non-small cell lung carcinoma(NSCLC). PURPOSE: The objective of this study was to assess the efficacy and safety of TC+Bev as second-line therapy and beyond for previously treated NSCLC patients. METHODS: A total of 17 patients previously treated with NSCLC at the Kitasato University Hospital between April 2010 and February 2012 were enrolled in this retrospective study. On day 1 all patients received a 200mg/m2 dose of paclitaxel by intravenous infusion over a 3-h period, followed by infusion of carboplatin at a dose corresponding to an AUC of 6.0 min mg/mL, and then by Bev at a dose of 15mg/m2. The treatment course was repeated every three or four weeks. Patients continued to receive Bev monotherapy every 3 weeks thereafter until evidence of disease progression or unacceptable toxicity developed. RESULTS: Median age: 60 years old(range 39-74 years old); gender: male/female, 6/11; PS 0-1/≥2, 17/0; clinical stage:III B/IV postoperative recurrence, 0/16/1; EGFR mutation status: positive/negative/unknown, 7/9/1; histological type: adenocarcinoma in all patients; median number of prior regimens: 3. 4(1-6); median number of cycles(induction phase): 3(1-6). The objective response rate and disease control rate were 17. 6% and 70. 6%, respectively, and the median progression-free survival time was 4. 7 months. There were no treatment-related deaths, and the toxicities of the treatment regimen were acceptable. CONCLUSION: TC+Bev therapy exhibits activity in previously treated NSCLC patients and has acceptable toxicity. Further study is warranted to confirm our results.

[Pemetrexed as second-line treatment and beyond for elderly patients with advanced non-small-cell lung cancer].

BACKGROUND: In Japan, the standard first-line therapy for elderly patients with advanced non-small lung cancer(NSCLC)is docetaxel(DOC)monotherapy. However, there is very limited information about second-line and beyond chemotherapy regimens for elderly patients with advanced NSCLC. Pemetrexed(PEM)monotherapy has been recognized as a standard regimen for advanced NSCLC in second-line settings, just as DOC monotherapy has been. PURPOSE: The objective of this study was to examine the efficacy and safety of PEM as second-line therapy and beyond for elderly patients. METHODS: The records of previously -treated elderly patients with advanced NSCLC, who had been treated with PEM as second-line therapy and beyond between July 2009 and December 2010, were retrospectively reviewed. RESULTS: median age: 73 years old(range 70-79 years old); gender: male/female, 11/8; PS 0-1/≥2, 19/0; clinical stage: III B/IV/postoperative recurrence, 4/10/5; pathology: adeno/LCNEC/other, 17/1/1 patient. The objective response-rate and disease control-rate were 15. 8% and 57. 9%, respectively. Median progression-free survival time was 3. 2 months. There were no treatment-related deaths, and most of the toxicities of the treatment regimen were mild and acceptable. CONCLUSION: PEM monotherapy exhibits activity in previously treated elderly NSCLC patients and has an acceptably low toxicity. Further study is warranted to confirm our results.

[A case of systemic IgG4-related disease with a middle-posterior mediastinal lesion].

A 62-year-old Japanese man visited our hospital for the examination of a middle-posterior mediastinal lesion noted on a chest CT image. Magnetic resonance imaging (MRI) showed swelling of the hypophysis, bilateral orbital muscles and bilateral lacrimal and submandibular glands. CT subsequently showed a middle-posterior mediastinal lesion, centrilobular nodules in the lung fields, swelling of the pulmonary hilar lymph nodes and soft tissue tumor around the bilateral ureteropelvic junctions. The patient's serum IgG4 level was elevated, and biopsy specimens from the lacrimal gland showed abundant IgG4-positive plasma cells. These findings were consistent with systemic IgG4-related disease. Following steroid treatment, the lesions reduced. To the best of our knowledge, there are only 2 case reports regarding systemic IgG4-related disease accompanied with a middle-posterior mediastinal lesion.

[A case of recurrent invasive thymic cancer showing a stable disease to carboplatin plus paclitaxel].

A 56-year-old man was admitted to our hospital because of increasing chest discomfort and abnormal chest shadow. Computed tomography (CT) of the chest revealed an anterior mediastinal mass, pleural dissemination and lung metastasis. Percutaneus needle biopsy guided by CT showed that the mass was advanced thymic cancer (stage IV b according to the classification proposed by Masaoka). After failure of combination chemotherapy of cisplatin, vincristine, doxorubicin and etoposide (CODE), he received 4 cycles of carboplatin plus paclitaxel and then achieved confirmed stable disease. In terms of toxicity profile, grade 4 anemia, grade 2 leucopenia and neutropenia were observed, and particularly non-severe toxicity was not observed in terms of non-hematologic toxicity. Carboplatin plus paclitaxel can be an active agent against pretreated thymic cancer.

Phase I and pharmacokinetic study of erlotinib administered in combination with amrubicin in patients with previously treated, advanced non-small cell lung cancer.

OBJECTIVES: We conducted a phase I trial of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose, the dose-limiting toxicities (DLTs), and the pharmacokinetics of this combination in patients with non-small cell lung cancer who had received previous chemotherapy. METHODS: A total of 9 patients with stage IV disease were treated at 3-week intervals with erlotinib once daily on days 1 through 21 plus a 5-minute intravenous injection of amrubicin on days 1 through 3. RESULTS: The dose levels evaluated were erlotinib (mg/body)/amrubicin (mg/m): 100/30 (n=3), 100/35 (n=3), and 150/30 (n=3). The maximum tolerated dose of erlotinib and amrubicin was 100 mg/body and 35 mg/m because 2 of the 3 patients experienced DLTs during the first cycle of treatment at the third dose level of 150 mg/body and 30 mg/m. Cessation of erlotinib administration for 8 days because of grade 3 leukopenia and grade 3 skin infection (erysipelas) were the DLTs. No drug-drug interactions between erlotinib and amrubicin were observed in this study. The overall response rate was 33%, including 3 partial responses, in the 9 patients. The median progression-free survival for all patients was quite long, 11.3 months, and the median overall survival has not yet been reached. CONCLUSIONS: Combined erlotinib plus amrubicin therapy seems to be highly effective, with acceptable toxicity, against non-small cell lung cancer. The recommended dose for phase II studies was erlotinib 100 mg once daily on days 1 through 21, and amrubicin 35 mg/m on days 1 through 3 administered every 21 days.

Successful chemotherapy with nab-Paclitaxel in a heavily treated non-small cell lung cancer patient: a case report.

Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancers. A 69-year-old female with postoperatively recurrent NSCLC was treated weekly with nanoparticle-albumin-bound paclitaxel (nab-paclitaxel) monotherapy every 4 weeks as a tenth line chemotherapy, and stable disease was achieved by seven cycles of this regimen. The patient developed grade 4 neutropenia and grade 3 leukopenia, but none of the other toxicities, including febrile neutropenia and peripheral neuropathy, were severe, and thus she was able to tolerate this salvage chemotherapy. To our knowledge this is the first report of the efficacy of nab-paclitaxel monotherapy in a heavily treated NSCLC patient.

Circulating tumor cells as a prognostic factor in patients with small cell lung cancer.

The detection of circulating tumor cells (CTCs) in peripheral blood is currently an important field of study. Detection of CTCs by the OBP-401 assay (TelomeScan®) has previously been reported to be useful in the diagnosis, prognosis and evaluation of therapeutic efficacy in breast and gastric cancer. The aim of the present study was to evaluate the OBP-401 assay as a novel method of detecting CTCs of small cell lung cancer (SCLC) patients and to evaluate whether CTC count is associated with prognosis. Prospectively, 30 consecutively diagnosed SCLC patients who had commenced chemotherapy or chemoradiotherapy were enrolled as subjects of the current study. Peripheral blood specimens were collected from the SCLC patients prior to and following the initiation of treatment and the viable CTCs were detected in the specimens following incubation with a telomerase-specific, replication-selective, oncolytic adenoviral agent, which was carrying the green fluorescent protein gene. CTCs were detected in 29 patients (96%). The group of 21 patients with a CTC count of <2 cells/7.5 ml prior to treatment (baseline) had a significantly longer median survival time than the group of eight patients with a CTC count of ≥2 cells/7.5 ml prior to treatment (14.8 and 3.9 months, respectively; P=0.007). The results of a multivariate analysis showed that the baseline CTC count was an independent prognostic factor for survival time (hazard ratio, 3.91; P=0.026). Among the patients that achieved a partial response to treatment, patients who had a CTC count of <2 cells/7.5 ml following two cycles of chemotherapy tended to have a longer median progression-free survival compared with patients who had a CTC count of ≥2 cell/7.5 ml (8.3 and 3.8 months, respectively; P=0.07). Therefore, CTCs may be detected via OBP-401 assay in SCLC patients and the CTC count prior to treatment appears to be a strong prognostic factor.

Successful chemotherapy with Carboplatin and s-1 for thymic carcinoma: a case report.

Thymic carcinoma is a rare but aggressive neoplasm. Although there is no clearly optimal first- or second-line chemotherapy regimen for thymic carcinoma, platinum-based chemotherapy has repeatedly been shown to be of benefit to patients with advanced thymic carcinoma. Some case reports have described S-1 as a novel agent with good activity against advanced thymic carcinoma. A 74-year-old female was diagnosed with thymic carcinoma complicated by pleural dissemination and pericardial effusion of carcinomatosa. She was treated with carboplatin on day 1 plus S-1 on days 1-14 in cycles repeated every 3 or 4 weeks. Four cycles of this regimen were administered, and a partial response was confirmed. There were no severe hematological or nonhematological toxicities, and no dose reduction was necessary. To our knowledge, this is the first report to demonstrate the efficacy of combination chemotherapy consisting of carboplatin and S-1 against thymic carcinoma.

Phase I trial of irinotecan and amrubicin with granulocyte colony-stimulating factor support in extensive-stage small-cell lung cancer.

PURPOSE: We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor, with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support to overcome the neutropenia associated with this particular combination. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 and the dose-limiting toxicities (DLTs) of this combination in extensive-stage small-cell lung cancer (ED-SCLC) patients. METHODS: Fifteen patients with ED-SCLC were treated at 3-week intervals with amrubicin on days 1-3 plus 60 mg/m(2) CPT-11 on days 1 and 8. In addition, prophylactic rhG-CSF (50 µg/m(2)) was given from day 4 to day 21, except on the day of CPT-11 administration. Amrubicin was started at 30 mg/m(2) and then escalated in 5 mg/m(2) increments until MTD was reached. RESULTS: The MTD of amrubicin was 35 mg/m(2), since 2 of 4 patients experienced DLTs during the first cycle of treatment at the 40 mg/m(2) dose level. Neutropenia, neutropenic fever, ileus, and diarrhea were the DLTs. There were 13 partial responses among the 13 assessable patients, yielding an overall response rate of 100 %. Median progression-free survival and overall survival were 7.4 months and 13.4 months, respectively. CONCLUSION: The combination of amrubicin and CPT-11 showed high activity against ED-SCLC with acceptable toxicity. Use of rhG-CSF allowed the dose of amrubicin to be raised 40 % above that in the original regimen (60 mg/m(2) CPT-11 and 25 mg/m(2) amrubicin).