Ichiro Takata

Phase III Trial Comparing Docetaxel and Cisplatin Combination Chemotherapy With Mitomycin, Vindesine, and Cisplatin Combination Chemotherapy With Concurrent Thoracic Radiotherapy in Locally Advanced Non–Small-Cell Lung Cancer: OLCSG 0007

PURPOSE To demonstrate the efficacy of docetaxel and cisplatin (DP) chemotherapy with concurrent thoracic radiotherapy (TRT) for patients with locally advanced non-small-cell lung cancer (LA-NSCLC). PATIENTS AND METHODS Patients age 75 years or younger with LA-NSCLC, stratified by performance status, stage, and institution, were randomly assigned to two arms consisting of DP (docetaxel 40 mg/m(2) and cisplatin 40 mg/m(2) on days 1, 8, 29, and 36) or mitomycin, vindesine, and cisplatin (MVP) chemotherapy with concurrent TRT. RESULTS Between July 2000 and July 2005, 200 patients were allocated into either the DP or MVP arm. The survival time at 2 years, a primary end point, was favorable to the DP arm (P = .059 by a stratified log-rank test as a planned analysis and P = .044 by an early-period, weighted log-rank as an unplanned analysis). There was a trend toward improved response rate, 2-year survival rate, median progression-free time, and median survival in the DP arm (78.8%, 60.3%,13.4 months, and 26.8 months, respectively) compared with the MVP arm (70.3%, 48.1%, 10.5 months, and 23.7 months, respectively), which was not statistically significant (P > .05). Grade 3 febrile neutropenia occurred more often in the MVP arm than in the DP arm (39% v 22%, respectively; P = .012), and grade 3 to 4 radiation esophagitis was likely to be more common in the DP arm than in the MVP arm (14% v 6%, P = .056). CONCLUSION DP chemotherapy combined with concurrent TRT is an alternative to MVP chemotherapy for patients with LA-NSCLC.

Prognostic factors for patients with advanced non-small cell lung cancer: Univariate and multivariate analyses including recursive partitioning and amalgamation

In an attempt to determine the prognostic significance of pretreatment factors for patients with advanced non-small cell lung cancer (NSCLC), 24 pretreatment clinical variables were analyzed for 185 patients with NSCLC who underwent chemotherapy and/or radiotherapy between 1985 and 1994. Following univariate analysis, we applied two multivariate statistical techniques. In a Cox regression mode, independently significant factors influencing patient survival included performance status (PS), disease stage, hemoglobin level, and serum calcium level. Recursive partitioning and amalgamation (RPA) resulted in three distinct prognostic subgroups based on PS, stage, weight loss, and hemoglobin level. The best survival was observed for patients with a good PS and Stage III disease who had a hemoglobin level > 11 g/dl. The worst survival was observed for patients with a poor PS and presence of weight loss irrespective of stage. All other patients had an intermediate prognosis. Median survival times were 95.1 weeks, 17.1 weeks and 39.3 weeks, respectively (P < 0.00005). The results of our analyses show that three important prognostic subgroups could readily be discerned using RPA.

Risk factors for development of radiation pneumonitis following radiation therapy with or without chemotherapy for lung cancer

PURPOSE To determine the risk factors contributing to development of radiation pneumonitis (RP) in patients with lung cancer who undergo radiation therapy to the thorax. METHODS AND MATERIALS Development and severity of RP were retrospectively analyzed for 89 patients with lung cancer who underwent radiation therapy with or without chemotherapy at the National Shikoku Cancer Center Hospital between 1991 and 1995. The severity of RP was determined using a modified grading scale based on that of the Radiation Therapy Oncology Group and the European Organization for the Research and Treatment of Cancer. RESULTS Fifty-two (58%) patients developed RP: 34 patients with Grade 1, 5 with Grade 2, 8 with Grade 3, and 5 with Grade 5 RP. Severe RP tended to develop earlier than less severe RP, but not to a significant extent (p = 0.151). On logistic regression analysis including both patient condition and treatment factors, development of Grade 1 or more severe RP was most frequently observed for Stage I-II disease (p = 0.011). The use of chemotherapy, large daily radiation dose, and once-daily fractionation (vs. twice-daily fractionation) were possibly related to the development of RP (p = 0.057, p = 0.069, and p = 0.092, respectively). For the group of 48 patients who underwent chemoradiation therapy, the use of large daily radiation dose was a significant risk factor for RP (p = 0.014). In addition, the use of once-daily fractionation was a marginally significant risk factor (p = 0.052). Among chemotherapy drugs administered, cisplatin was a favorable factor (p = 0.011), while adriamycin was a risk factor (p = 0.061). CONCLUSIONS In radiation therapy for lung cancer, administration of a large daily dose should be avoided in order to prevent RP, particularly when radiation therapy is combined with chemotherapy.

Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group

OBJECTIVE We examined the prognosis of patients with leptomeningeal metastasis (LM) from non-small cell lung cancer (NSCLC) and that stratified by epidermal growth factor receptor (EGFR) mutation status in LM patients receiving EGFR-tyrosine kinase inhibitors (TKIs). METHODS We retrospectively analyzed a series of 91 consecutive NSCLC patients with LM between 2001 and 2010. RESULTS Most of the LM patients had adenocarcinoma histology and a poor performance status (PS). The median survival time (MST) for all patients was 3.6 months. Adenocarcinoma and TKI treatment were associated with a better prognosis. Among the patients, 51 received EGFR-TKIs. Of these, the EGFR mutation status was assessed in 30 patients; 7 (23%) showed no mutation (group 1), 10 (33%) had a mutation in exon 21 (group 2), and 13 (43%) had deletions in exon 19 (group 3). Interestingly, PS was significantly improved in groups 2 and 3 but not in group 1. The MST in these subgroups was 1.4, 7.1, and 11.0 months in groups 1, 2, and 3, respectively (p<0.001). The median time to progression or symptom deterioration was 0.9, 2.0, and 7.8 months for groups 1, 2, and 3, respectively (p<0.001). A multivariate analysis showed that EGFR-mutant tumors were associated with a better prognosis in patients receiving EGFR-TKIs. CONCLUSIONS The prognosis for patients with LM from NSCLC was still poor. Survival after the initiation of EGFR-TKI treatment differed according to the type of EGFR mutation, suggesting the potential benefit of TKIs for patients with EGFR mutations, even though they suffered from LM.

Serum hepatocyte growth factor/scatter factor levels in small cell lung cancer patients

Serum hepatocyte growth factor/scatter factor (HGF/SF) levels were measured in 25 patients with small cell lung cancer (SCLC), 16 patients with benign lung diseases and 15 healthy subjects with an enzyme-linked immunosorbent assay. The patients with SCLC did not have bacterial or interstitial pneumonia. Patients with benign lung diseases included eight with bacterial pneumonia, three with interstitial pneumonia, and five with benign lung tumor. Serum HGF/SF levels were significantly higher in patients with SCLC (mean +/- S.D.: 0.40 +/- 0.17 ng/ml) than in healthy subjects (0.26 +/- 0.093 ng/ml) (P = 0.0083). Patients with bacterial pneumonia had significantly higher serum HGF/SF (0.52 +/- 0.19 ng/ml) than did those with benign lung tumors (0.27 +/- 0.058 ng/ml) and healthy subjects (P = 0.013 and P = 0.0019, respectively). By clinical stage of SCLC, HGF/SF levels were 0.34 +/- 0.12 and 0.47 +/- 0.20 ng/ml in patients with limited disease and extensive disease, respectively; this difference was not significant (P = 0.080). Although serum HGF/SF levels were increased in patients with SCLC, this increase might not have been related to tumor burden.

Characterization of non-small-cell lung cancer cell lines established before and after chemotherapy

We established several in vitro drug-resistant cell lines after continuous, long-term exposure of each drug to elucidate mechanisms of drug resistance. Whether drug resistance in these in vitro resistant cell lines reflects clinical drug resistance still remains unanswered. In this study, a pair of lung cancer cell lines was established from one patient with squamous cell carcinoma of the lung, with one line being established before and one line after combination chemotherapy (cisplatin/ifosfamide/vindesine). Combination chemotherapy selected resistant EBC-2/R cells, which showed cross-resistance to 4-hydroxyifosfamide (3.2-fold), cisplatin (2.3-fold), and methotrexate (3.7-fold) and collateral sensitivity to vindesine (0.77-fold) compared with parent EBC-2 cells. EBC-2/R cells showed decrease in intracellular accumulation of cisplatin, increase in intracellular concentration of glutathione (GSH), and overexpression of multidrug resistance-associated protein (MRP) 3 when compared with EBC-2 cells. A single cycle of chemotherapy was not sufficient to select other mechanisms of drug resistance, such as multidrug resistance-1/P-glycoprotein, MRPs 1, 2, 4, and 5, lung resistance-related protein, metallothionein IIa, glutathione S-transferase pi, gamma-glutamylcysteine synthetase (light and heavy chain), and excision repair cross complementing 1. Sequentially we established two cell lines, which cell lines showed the differences of the cisplatin resistance, expression level of MRP3, intracellular GSH level and intracellular accumulation of cisplatin. A pair of cell lines will be useful to elucidate resistant mechanisms of cisplatin in heterogeneous lung cancer cells.

Fractionated administration of irinotecan and cisplatin for treatment of non-small-cell lung cancer: a phase II study of Okayama Lung Cancer Study Group

A phase II study of fractionated administration of irinotecan (CPT-11) and cisplatin (CDDP) in patients with non-small-cell lung cancer (NSCLC) was conducted. Between January 1996 and January 1998, 44 previously untreated patients with stage IIIB or IV NSCLC were enrolled. CDDP at a dose of 60 mg m–2 was given first and followed by CPT-11 at a dose of 50 mg m–2. Both drugs were given by 1-hour infusion on days 1 and 8, and repeated every 4 weeks up to 4 cycles. 42 patients were evaluated for response and 44 for survival and toxicity. 20 patients (48%: 95% confidence interval 32–63%) achieved an objective response. The median duration of responses was 8 months, and the median survival time and the 1-year survival rate were 12.5 months and 56.8%, respectively. Major toxicities were neutropenia and diarrhoea. Grade 3 or 4 neutropenia occurred in 70.5% of the patients and one patient died of sepsis. Grade 3 or 4 diarrhoea was experienced in 25.0%, but manageable by conventional therapy. In conclusion, fractionated administration of CPT-11 and CDDP was highly effective for advanced NSCLC with manageable toxicities.

Combination of nedaplatin and vindesine for treatment of relapsed or refractory non-small-cell lung cancer.

Purpose: A phase II study of nedaplatin and vindesine was conducted to evaluate their efficacy and safety for treatment of relapsed or refractory non-small-cell lung cancer (NSCLC). Methods: Between August 1996 and September 1998, 48 patients who had previously received chemotherapy, thoracic radiotherapy, and/or surgery were enrolled in the study. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 to 2 and an age between 20 and 79 years. Treatment consisted of nedaplatin (80 mg/m2, day 1) and vindesine (3 mg/m2, days 1 and 8) every 3 to 4 weeks. Results: Of 48 patients, 7 (14.6%) exhibited an objective response. Four (50%) of eight chemotherapy-naive patients had a partial response. However, of the 40 patients who had received prior chemotherapy, a partial response was observed in only 3 (7.5%). At a median follow-up time of 85.1 weeks, the median survival time was 43.6 weeks (95% confidence interval 34.4–52.7) for patients who had received chemotherapy, with a survival rate of 40% at 1 year. Grade 3 or 4 neutropenia occurred in 43 of 48 patients (90%), and neutropenic fever was observed in 3 of the 43 patients, one of whom died of sepsis. Pharmacokinetic and pharmacodynamic analyses of platinum were performed in 43 patients during the first cycle of chemotherapy. Percent reduction in absolute neutrophil count was correlated not only with the area under the plasma ultrafilterable platinum concentration versus time curve (r=0.41, P=0.007) but also with the duration of ultrafilterable platinum concentration above 1 μg/ml (r=0.41, P=0.007). Patients with progressive disease exhibited a shorter duration of ultrafilterable platinum concentration over 1 μg/ml (P=0.046) than those with other responses. Conclusion: A combination of nedaplatin and vindesine was unsatisfactory as second-line chemotherapy for NSCLC, although the combination was well tolerated. The duration of ultrafilterable platinum concentration above 1 μg/ml was an important pharmacokinetic parameter for predicting both chemotherapy-induced neutropenia and treatment outcome.

Measurement of serum p53 protein in patients with small cell lung cancer and results of its clinicopathological evaluation

Serum p53 protein levels were measured in 36 patients with small cell lung cancer (SCLC) and 35 patients with benign lung diseases in order to evaluate the relationship of these levels to clinicopathological features of SCLC. Serum levels of p53 protein were measured by an enzyme-linked immunosorbent assay, p53 protein level was 23.92 +/- 6.78 pg/ml in patients with SCLC, and similar to that (17.47 +/- 2.86 pg/ml) in patients with benign lung diseases. By the clinical stage of SCLC, the mean level of p53 protein was 16.68 +/- 4.62 pg/ml in 21 patients with limited disease, and lower than that in 15 patients with extensive disease (34.05 +/- 14.84 pg/ml) (P = 0.23). The levels of p53 protein were not correlated with age, smoking index, or presence of cancer history for patients with SCLC. However, immunohistochemical examination disclosed a mild correlation between the expression of p53 protein by SCLC tumor and p53 protein serum level (r = 0.45, P = 0.02). Two patients with SCLC had an elevated serum level of p53 protein (> 2 S.D. above the mean for benign lung diseases). However, measurement of p53 protein serum level was not found to be clinically useful for detection of SCLC.

Intramedullary spinal cord recurrence after high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation for limited-disease small cell lung cancer

Intramedullary spinal cord metastasis is very rare in small-cell lung cancer (SCLC), and develops in only 2% of neurological disorders associated with SCLC according to previous reports. We describe here a patient with SCLC who developed intramedullary spinal cord recurrence after high-dose chemotherapy (HDCT) followed by autologous blood progenitor cell transplantation (ABPCT). A 59-year-old Japanese male was referred to us for diagnosis and treatment of an abnormal shadow on a chest radiograph. Based on transbronchial biopsy and staging procedures, he was diagnosed with limited-disease (LD)-SCLC. He received concurrent chemoradiotherapy followed by late intensification with HDCT supported by ABPCT. He achieved complete response and was discharged after receiving prophylactic cranial irradiation (PCI). However 6 months later, he noticed rapidly progressive weakness of the left lower extremity and bowel/bladder dysfunction. Magnetic resonance imaging (MRI) of the spinal cord disclosed an intramedullary tumor exhibiting an enhancement effect with Gd-DTPA at the 11-12th level of the thoracic vertebra. Immediately, radiotherapy to the spinal cord metastasis was given at a dose of 30 Gy, and his neurological disorders were completely resolved. At this time of reporting, he is doing well without recurrence. This case indicates that intramedullary spinal cord is one of the recurrence sites implicated after HDCT and PCI in LD-SCLC.