Phase II trial of S-1 plus cisplatin combined with bevacizumab for advanced non-squamous non-small cell lung cancer (TCOG LC-1202).

BACKGROUND: S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The addition of bevacizumab has been shown to significantly improve overall survival (OS) in patients with advanced non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however, failed to show an OS advantage in patients who received cisplatin plus gemcitabine. METHODS: Chemotherapy-naive patients with Stage IIIB, IV or recurrent non-SQ NSCLC were treated with a 3-week cycle of S-1 80 mg/m2 on days 1-14, cisplatin 60 mg/m2 on day 8 and bevacizumab 15 mg/kg on day 8 for 4-6 cycles. Patients without progressive disease (PD) received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 80 mg/m2 every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile and Quality of life (QOL). RESULTS: From June 2013 to January 2015, 39 eligible patients were enrolled from eight institutions. Thirty-one patients (79%) completed four cycles of induction chemotherapy, and maintenance chemotherapy was initiated in 23 patients (59%). Median PFS, OS and ORR were 7.3 months (95% CI: 5.9-8.7), 21.4 months (95% CI: 14.7-not reached) and 64%, respectively. The most common grade 3/4 toxicities were leukopenia (12.8%), neutropenia (23.0%) and hypertension (28.2%). QOL analyses showed detrimental effects after initiation of the regimen. CONCLUSIONS: S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced NSq-NSCLC. RR was anticipated to be high with acceptable toxicities.

An MR comparison study of cardiogenic and noncardiogenic pulmonary edema in animal models.

PURPOSE: To apply magnetic resonance (MR) imaging to differential diagnosis of cardiogenic pulmonary edema (CPE) and noncardiogenic pulmonary edema (NCPE). MATERIALS AND METHODS: In the CPE group, MR measurements were performed on 5 rats just before and 3 h after administration of 21 ± 2% body weight of normal saline. In the NCPE group, measurements were similarly performed on 5 animals just before and 48 h after 0.75 mg/body of lipopolysaccharide intratracheal administration. Animals were killed for bronchoalveolar lavage fluid (BALF) or pathological analysis after MR measurements. RESULTS: The relation between signal intensity and the T(2)* value of MR imaging was different in the two groups. The T(2)* in the NCPE group was significantly longer than that in the CPE group at the same signal intensity level. The lactate levels measured by in vivo MR spectroscopy did not show a difference between the CPE and NCPE groups, although the lactate BALF levels of the two groups were significantly different. CONCLUSION: The relation between signal intensity and T(2)* value was useful for the differentiation between these two pulmonary diseases. The measurable lactate level in pulmonary lesions suggests the applicability of MR spectroscopy to pulmonary disease.

Fractionated administration of carboplatin/paclitaxel reduces neurotoxicity in patients with advanced non-small cell lung cancer.

The combination of carboplatin/paclitaxel is commonly used as chemotherapy for advanced non-small cell lung cancer. However, the relatively high incidence of neurotoxicity remains a problem. This study was undertaken to determine whether the fractionated administration regimen can reduce the neurotoxicity. Patients with stage III or IV non-small cell lung cancer were randomized to the nonfractionated (NF) dose group, which received paclitaxel (200 mg/m(2)) and carboplatin (area under the concentration-time curve=6) on day 1, or the fractionated dose (F) group, which received paclitaxel (100 mg/m(2)) and carboplatin (area under the concentration-time curve=3) on days 1 and 8. The cycle was repeated every 3 weeks. Peripheral neuropathy was objectively evaluated by measuring the current perception threshold (CPT) in the median nerve using a neurometer. Fourteen and 13 patients were assigned to the NF and F groups, respectively. The incidence of subjective numbness was significantly lower in the F group (15.4%) than in the NF group (57.1%). The CPT value determined at 2000 Hz showed significant increases in the NF group compared with the pretreatment baseline, but no significant changes were observed in the F group. The response rate was comparable in both groups. The fractionated administration of carboplatin/paclitaxel combination therapy showed a significant reduction in neurotoxicity. Measurement of CPT by a neurometer is a useful tool to evaluate the neurotoxicity of anticancer drugs objectively.

Proton magnetic resonance spectroscopy of lung cancer in vivo.

Proton magnetic resonance spectroscopy (1H-MRS) has demonstrated that in vitro, lung cancer has higher lactate and choline signals than those of normal tissues. The detection of these metabolites in lung cancer in vivo by 1H-MRS would be useful for clinical diagnoses of lung cancer. We report the in vivo detection of lactate and choline in lung cancer by 1H-MRS in a 41-year-old Asian man who was diagnosed with pT4N0M0 ⅢA stage, right upper lobe lung adenocarcinoma. A lactate-lipid peak was observed near 1.33 ppm in the spectrum of lung cancer in vivo at TE  =  30 ms, and it was inverted at TE  =  135 ms, indicating that a lactate signal is contained in the lactate-lipid peak. A choline peak was also observed near 3.2 ppm in the spectrum with fat suppression at TE  =  135 ms. An accumulation of similar cases will help determine the appropriate applications of 1H-MRS for lung cancer.

Clinical Significance of the Relationship between Progression-Free Survival or Postprogression Survival and Overall Survival in Patients with Extensive Disease-Small-Cell Lung Cancer Treated with Carboplatin plus Etoposide.

Background. The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with small-cell lung cancer (SCLC). Therefore, by using individual-level data, we aimed to determine the relationships between progression-free survival (PFS) or postprogression survival (PPS) and OS after first-line chemotherapies in patients with extensive disease-SCLC (ED-SCLC) treated with carboplatin plus etoposide. Methods. Between July 1998 and December 2014, we analyzed 63 cases of patients with ED-SCLC who were treated with carboplatin and etoposide as first-line chemotherapy. The relationships of PFS and PPS with OS were analyzed at the individual level. Results. Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.90, p < 0.05, and R (2) = 0.71) and PFS was moderately correlated with OS (r = 0.72, p < 0.05, and R (2) = 0.62). Type of relapse (refractory/sensitive) and the number of regimens administered after disease progression after the first-line chemotherapy were both significantly associated with PPS (p < 0.05). Conclusions. PPS has a stronger relationship with OS than does PFS in ED-SCLC patients who have received first-line chemotherapy. These results suggest that treatments administered after first-line chemotherapy affect the OS of ED-SCLC patients treated with carboplatin plus etoposide.

Clinical impact of post-progression survival on overall survival in elderly patients with extensive disease small-cell lung cancer.

BACKGROUND: The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with small-cell lung cancer (SCLC). Therefore, the objective of our study was to determine the relationships between progression-free survival (PFS) or post-progression survival (PPS) and OS after first-line chemotherapy in elderly patients with extensive disease-SCLC (ED-SCLC), using individual level data. METHODS: Between July 1998 and December 2014, we analyzed 57 cases of elderly patients with ED-SCLC who were treated with carboplatin and etoposide as first-line chemotherapy. The relationships between PFS and PPS with OS were analyzed at an individual level. RESULTS: Spearman rank correlation and linear regression analyses showed that PPS was strongly correlated with OS (r = 0.92, P < 0.05, R 2 = 0.83) and PFS was moderately correlated with OS (r = 0.76, P < 0.05, R 2 = 0.25). The best response at second-line treatment and the number of regimens after progression beyond first-line chemotherapy were both significantly associated with PPS (P < 0.05). CONCLUSIONS: PPS has a stronger impact on OS than PFS in elderly ED-SCLC patients after first-line chemotherapy. In addition, the response at second-line treatment and the number of additional regimens after first-line treatment are significant independent prognostic factors for PPS. These results suggest that OS in elderly ED-SCLC patients may be influenced by treatments subsequent to first-line chemotherapy; however, this remains to be verified with prospective studies.

A simple way to acquire T(1)-weighted MR images of rat liver with respiratory triggering.

To acquire high-resolution T(1)-weighted images of the liver in rats, for which breath-holding cannot be ensured, respiratory triggering is essential. At the respiratory rate of 30-60 times/min in rats, however, T(1)-weighted images cannot be obtained with simple triggering. As a simple solution to this, we applied multiple repeated acquisitions with one trigger signal. With this technique, sufficient T(1) contrast could be easily achieved in rat liver enhanced by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid infusion.

Gefitinib prevents bleomycin-induced lung fibrosis in mice.

RATIONALE: Transforming growth factor-alpha and epidermal growth factor (EGF), the ligands for EGF receptor (EGFR), stimulate fibroblast proliferation and play an important role in the pathogenesis of pulmonary fibrosis. Therefore, inhibition of the EGFR signal by an EGFR tyrosine kinase inhibitor (EGFR-TKI) may prevent pulmonary fibrosis. However, there is a possibility that blocking the EGFR signal may inhibit epithelial cell repair, thereby exaggerating lung fibrosis. OBJECTIVE: To investigate the effect of EGFR-TK inhibition on lung fibrosis. METHODS: We looked at the effects of the EGFR-TKIs gefitinib (20, 90, 200 mg/kg) and AG1478 (12 mg/kg) on a bleomycin-induced lung fibrosis model in mice. MEASUREMENTS AND MAIN RESULTS: Gefitinib prevented lung fibrosis at all three doses. Furthermore, in those mice that did not receive bleomycin treatment, gefitinib at 200 mg/kg did not induce lung fibrosis. Immunohistochemistry revealed that phosphorylation of EGFR in lung mesenchymal cells induced by bleomycin was inhibited by gefitinib. AG1478 also attenuated the lung fibrosis. In vitro studies further demonstrated that the addition of gefitinib or AG1478 suppressed the EGFR ligand-induced proliferation of lung fibroblasts. CONCLUSIONS: These findings suggest that, in the preclinical setting, EGFR-TKIs may have a protective effect on lung fibrosis induced by bleomycin. Because these molecular targeted drugs may have differing effects depending on species and individuals, a cautious interpretation is warranted.