Retrospective analysis of safety and efficacy of low-dose docetaxel 60 mg/m2 in advanced non-small cell lung cancer patients previously treated with platinum-based chemotherapy

The efficacy and toxicity of low-dose docetaxel (60 mg/m2) were evaluated in patients with relapsed non-small-cell lung cancer (NSCLC) after platinum-containing chemotherapy. Docetaxel 60 mg/m2 was infused during 1 hour with no routine premedication, with courses repeated at 3-week intervals. Twenty-seven patients were analyzed retrospectively. The median age was 56 years (range, 32-72); 22 patients (81.5%) had adenocarcinoma, 26 (96.3%) had stage IV disease, and 23 (85.2%) were Eastern Cooperative Oncology Group performance status 0 to 1. Five patients (18.5%) had a partial response. Median progression-free survival time for all patients was 1.9 months, and median survival time was 9.4 months. The predominant toxicity was neutropenia, which was grade III or IV in 63% of patients. No neutropenic fever was observed. Other hematologic toxicities were mild (all grade II). Thus, low-dose docetaxel (60 mg/m2) yielded a response rate comparable to that achieved with moderate- to high-dose docetaxel (75-100 mg/m2) as second-line chemotherapy in platinum-pretreated NSCLC, and had less toxicity. Further investigation of the optimal docetaxel dose as second-line chemotherapy in NSCLC is warranted.     

Doctor-initiated clinical trials and the revised pharmaceutical affairs law

In Japan, clinical trials aiming at application for approval of new drugs take a long time and a lot of money, and their quality thought to be poor. Japanese pharmaceutical companies tend to conduct more clinical studies in the United States and/or Europe than in Japan. The Ministry of Health, Labour and Welfare (MHLW) announced a three-year plan to facilitate clinical trials in Japan; the establishment of a large-scale clinical trial network, the improvement of the clinical research infrastructure, and the utilization of doctor-initiated clinical trials. The revised Pharmaceutical Affairs Law enables doctors and medical institutions to perform clinical trials using unapproved products spontaneously without any corporate sponsorship. Drugs needed by some patients but unapproved because they are unprofitable for companies are expected to be approved under this system. MHLW stipulated the ethical and scientific quality standard of doctor-initiated clinical trials, which is consistent with the principles of the Declaration of Helsinki, and Good Clinical Practice (GCP). To establish a system that allows expedited approval of safer and more effective products, the integration of the functions of the current review bodies, such as the Organization for Pharmaceutical Safety and Research (OPSR) and the Pharmaceuticals and Medical Devices Evaluation Center (PMDEC), into an independent administrative agency is scheduled.     

Differential gene expression profiles and identification of the genes relevant to clinicopathologic factors in colorectal cancer selected by cDNA array method in combination with principal component analysis

The clinical outcome of patients with colorectal cancer frequently varies even if they are at the same clinicopathologic stage. Alternative superior tumor markers of colorectal cancer are needed for prediction of clinical outcome. To clarify the regulatory factors in colorectal cancers, we examined differential expression profiles using cDNA macroarray technique with surgically resected specimens obtained from the patients with colorectal cancer. The gene profiles by an average-linkage hierarchical clustering analysis were found to be almost separable into two groups: tumor group and normal mucosa group. The relationship between several clinicopathologic factors and cancer related genes were investigated by using statistical analyses including principal component analysis (PCA). c-myc-binding protein MM-1, and c-jun proto-oncogene were identified as possible markers of tumor histology and clinical prognosis and early growth response protein 1 (EGR1) was selected to play an important role in progression of clinical stage. We conclude that, with PCA method, we successfully selected the genes relevant to clinicopathologic factors using limited population of clinical samples.     

Selection of surrogate marker genes in primary central nervous system lymphomas for radio-chemotherapy by DNA array analysis of gene expression profiles

Primary central nervous system lymphomas (PCNSLs) are extra nodal B-cell non-Hodgkin's lymphomas with primary manifestation in the brain, and their incidence has been increasing among both immunocompetent and immunocompromised populations. Samples of oligodendroglioma (n=5), glioblastoma (n=7), PCNSL (n=6), and normal brain (n=3) were studied (total of 21 samples) using cDNA array technology. The hierarchical clustering algorithm was used to obtain a phylogenetic tree, and it revealed a striking feature: PCNSL was clearly separated. The genes encoding laminin receptor 2, thioredoxin peroxidase, and elongation factor-1 were selected as specific genes in PCNSL by principal component analysis (PCA). When Mann-Whitney tests were performed to identify genes responsible for the differences between responders and non-responders to the treatment schedule for PCNSL, 76 known genes were found to show significantly different expression patterns between the two groups at the P<0.01 level. The two groups were clearly separated by the re-clustering method using the selected genes related to response to chemo-radiotherapy. This is the first report describing the gene expression profiles of PCNSL. In conclusion, accumulation of data with respect to the expression profiles of PCNSL specimens, clinicopathological data, susceptibility to treatment, and outcome will provide information for identifying optimal therapeutic modalities for individual patients and novel therapeutic targets.     

Tumor response to chemotherapy: the validity and reproducibility of RECIST guidelines in NSCLC patients

We investigated the validity and inter-criteria reproducibility between RECIST (Response Evaluation Criteria in Solid Tumors) guidelines and WHO (World Health Organization) criteria, considering the decrease in patient numbers resulting from inclusion of the minimum lesion size criterion introduced in RECIST guidelines. RECIST guidelines are based on unidimensional measurement and exclusion of small lesions from measurement. The aims of the study were to examine: (1) the effect of the minimum lesion size criterion, (2) the validity of unidimensional and bidimensional measurements, i.e., their relationship with tumor volume, (3) the inter-criteria reproducibility between current RECIST guidelines and previous WHO criteria. One hundred and twenty patients with non-small cell lung cancer (NSCLC) in clinical trials were evaluated. By applying the minimum lesion size criterion, six cases became ineligible without any influence on precision of tumor volume measurement. In the validity study, actual tumor volume was regarded as the gold standard. Although the unidimensional measurement had a lower correlation with tumor volume value than the bidimensional measurement, both the unidimensional measurement and bidimensional measurement correlated sufficiently well with tumor volume changes and the assessed tumor volume response. In the inter-criteria reproducibility study between RECIST guidelines and WHO criteria, the response rate assessed by RECIST guidelines (19.3%) was almost the same as that assessed by WHO criteria (20.0%). In conclusion, RECIST guidelines are adequate for evaluating tumor response to chemotherapy in terms of both validity in relation to tumor volume and inter-criteria reproducibility with the WHO criteria.     

Topoisomerase i targeting agents in small-cell lung cancer

The topoisomerase I inhibitors such as irinotecan and topotecan are active agents against small-cell lung cancer that are effective in treating not only chemotherapy-naïve tumors but also progressed-stage tumors after treatment with cisplatin-based regimens, because their mechanism of antitumor activity differs from that of the agents included in standard chemotherapy for small-cell lung cancer. Etoposide plus cisplatin or etoposide plus cisplatin alternating with cyclophosphamide, doxorubicin, and vincristine is considered the standard regimen for small-cell lung cancer. No new standard combination chemotherapy for small-cell lung cancer has been developed over the past decade. Irinotecan with cisplatin is now established as a new standard chemotherapy for extensive-stage small-cell lung cancer based on the results of the Japan Clinical Oncology Group trial. Of course, confirmation through phase III studies will be extremely important. The Japan Clinical Oncology Group is intensively investigating other irinotecan-containing regimens and the incorporation of irinotecan into treatment of patients with limited-stage small-cell lung cancer.     

In vitro interactions of a new derivative of spicamycin, KRN5500, and other anticancer drugs using a three-dimensional model

Purpose: KRN5500 is a new derivative of spicamycin produced by Streptomyces alanosinicus and is known to have a wide range of antitumor activities against human cancer cell lines. Because of its unique structure, this compound seems to have a different mode of action from other antitumor drugs and nonoverlapping toxicities. Therefore, KRN5500 is expected to be a suitable candidate for combination chemotherapy. Methods: We investigated the effects of combinations of KRN5500 and other anticancer drugs on the growth of a human non-small-cell lung cancer cell line, PC14, using a revised three-dimensional model. Results: Synergism was observed when KRN5500 and cisplatin were combined at concentrations in the ranges 0.005 to 0.25 μg/ml and 0.025 to 0.25 μg/ml, respectively. In combination with carboplatin, an analog of cisplatin, and etoposide, a marked synergistic interaction was also found. Conclusion: These results suggest the usefulness of combinations of KRN5500 with cisplatin, carboplatin or etoposide for chemotherapy for non-small-cell lung cancer. Received: 27 April 1998 / Accepted: 15 September 1998     

The cyclin-dependent kinase inhibitor p27 as a prognostic factor in advanced non-small cell lung cancer: its immunohistochemical evaluation using biopsy specimens

The expression of p27, which is known as a cyclin-dependent kinase inhibitor, on surgically resected specimens has considerable value for the prognosis of non-small cell lung cancer (NSCLC) patients. We immunohistochemically investigated the expression of the p27 protein in the biopsy specimens taken from 69 advanced NSCLC patients and assessed its clinical value. There was no significant correlation between p27 positivity and clinical parameters, including sex, age, histological type, clinical stage, smoking index and performance status. Furthermore, p27 positivity was not associated with response to chemotherapy. However, the Kaplan-Meier curve demonstrated that low p27 expression was significantly related to poor prognosis (P = 0.0019, by the log-rank test). Using multivariate analysis, p27, age and serum total protein level were found to be the independent prognostic parameters. The p27 positivity in the biopsy specimens of advanced NSCLC appears to be a useful prognostic marker.     

Over-expression of p27kip1 induces growth arrest and apoptosis mediated by changes of pRb expression in lung cancer cell lines

p27kip1 is a cyclin-dependent kinase inhibitor which controls the G1 phase of the cell cycle in conjunction with pRb. p27 has been associated with cell-cycle arrest and apoptosis. In this study, we transferred the full-length human p27 cDNA using a replication-deficient recombinant adenoviral vector (Ax-p27) into lung cancer cell lines and evaluated the potential of this strategy for anti-cancer gene therapy. After infection with Ax-p27, the growth of H322, A549 and SQ-5 cells, which express pRb, was almost completely suppressed, though no such effect was found in H69 and Lu-135 cells, which do not express pRb. In addition, cell death from day 4 after infection with Ax-p27 was observed only in H322, A549 and SQ-5 cells but not in H69 and Lu-135 cells. The cell cycle of H322 cells treated with Ax-p27 became arrested at the G1 phase from day 1 to day 3 despite continued over-expression of p27. When we examined the changes in expression level of pRb and E2F-1, which play important roles in cell-cycle progression from G1 to S phase, down-regulation of pRb expression was detected in H322 cells 3 days after infection with Ax-p27. These data suggest that (i) the growth-inhibitory effect and induction of apoptosis by over-expression of p27 require expression of pRb and (ii) adenovirus-mediated p27 gene transfer may have promise as a novel strategy in cancer gene therapy.