Feasibility trial for adjuvant chemotherapy with docetaxel plus cisplatin followed by single agent long-term administration of S-1 chemotherapy in patients with completely resected non-small cell lung cancer: Thoracic Oncology Research Group Study 0809.

BACKGROUND: We conducted a multicentre feasibility study for single agent long-term S-1 chemotherapy following docetaxel plus cisplatin in patients with curatively resected stage II-IIIA non-small cell lung cancer. METHODS: Patients received three cycles of docetaxel (60 mg m(-2)) plus cisplatin (80 mg m(-2)) and then received S-1 (40 mg m(-2) twice daily) for 14 consecutive days with a 1-week rest for >6 months (maximum, 1 year). The primary end point was feasibility, which was defined as the proportion of patients who completed eight or more cycles of S-1 chemotherapy. If the lower 95% confidence interval (CI) of this proportion was 50% or more, then the treatment was considered as feasible. The sample size was set at 125 patients. RESULTS: One hundred and thirty-one patients were enrolled, of whom 129 patients were eligible and assessable. In all, 109 patients (84.5%) completed 3 cycles of docetaxel plus cisplatin and 66 patients (51.2%, 95% CI: 42.5-59.8) completed 8 or more cycles of S-1 treatment. Grade 3/4 toxicities during the S-1 chemotherapy included anaemia (7.3%), neutropaenia (3.7%), and anorexia (3.7%). CONCLUSION: The toxicity level was acceptable, although the results did not meet our criterion for feasibility. Modification of the treatment schedule for S-1 chemotherapy might improve the treatment compliance.

Radiographic and pathological analysis of small lung adenocarcinoma using the new IASLC classification.

AIM: To analyse the correlation between computed tomography (CT) findings of small lung adenocarcinomas and the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification of Lung Adenocarcinoma. MATERIALS AND METHODS: A retrospective review of 300 lung adenocarcinoma lesions (size ≤20 mm) after surgical resection in 295 consecutive patients was performed. Tumours were defined as air-containing type if the ratio of the maximum dimension of the tumour on mediastinal windows to the maximum dimension of the tumour on lung windows was ≤50%, and as solid-density type if the ratio was >50%. The incidence between CT findings (air bronchogram, vascular involvement, pleural tags, notches, and spiculation) and pathological findings were investigated. RESULTS: Of the 142 air-containing lesions, 114 were adenocarcinoma in situ (AIS), 28 were minimally invasive adenocarcinoma (MIA), and none of the lesions were invasive adenocarcinoma. Of the 158 solid-density lesions, 30 were AIS, 24 were MIA, and 104 were invasive adenocarcinoma. Notches and pleural tags were commonly observed in cases of invasive adenocarcinoma (p < 0.05). CONCLUSIONS: In the air-containing type of small lung adenocarcinomas, AIS and MIA were observed but no cases of invasive adenocarcinoma were found. The presence of notches and pleural tags were a significant factor in invasive adenocarcinoma.

Phase II study of nedaplatin and irinotecan with concurrent thoracic radiotherapy in patients with locally advanced non-small-cell lung cancer.

BACKGROUND: Current international guidelines recommend the use of platinum-based chemotherapy with thoracic radiotherapy (TRT) for patients with locally advanced non-small-cell lung cancer (NSCLC). METHODS: Patients with unresectable stage IIIA or IIIB NSCLC were treated with nedaplatin (NP) at 50 mg m(-2) and irinotecan (CPT) at 60 mg m(-2) on days 1 and 8 every 4 weeks for two to four cycles with concurrent TRT (2 Gy per day, total 60 Gy). RESULTS: All 35 patients were able to receive a total of 60 Gy. Adverse effects and events in chemotherapy with TRT were grade 3 or 4 anaemia, neutropenia and thrombocytopenia, which occurred in 3.0%, 32.8% and 6.0% of patients, respectively. There was no grade 3 pneumonitis or oesophagitis. Adverse effects and events in chemotherapy alone were mild. There was no treatment-related death. An overall response rate was 94.3%. The median progression-free and overall survivals were 13.0 and 36.0 months, respectively. The 5-year disease-free and overall survival rates were 25.7% and 40.0%, respectively. CONCLUSION: NP and CPT treatment with concurrent TRT is effective and safe for patients with unresectable, locally advanced NSCLC.

Secretion of intelectin-1 from malignant pleural mesothelioma into pleural effusion.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but fatal tumour. Although most MPM patients show pleural effusion at even the early stage, it is hard to diagnose as MPM at the early stage because a sensitive and reliable diagnostic marker for MPM has not been found in plasma or pleural effusion. METHODS: In this study, we investigated whether intelectin-1 was specifically contained in MPM cells and the pleural effusion of MPM patient by immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. RESULTS: Malignant pleural mesothelioma cell lines, but not lung adenocarcinoma cell lines, secreted intelectin-1. In immunohistochemistry, epithelioid-type MPMs, but neither pleura-invading lung adenocarcinomas nor reactive mesothelial cells near the lung adenocarcinomas, were stained with anti-intelectin antibodies. Pleural effusion of MPM patients contained a higher concentration of intelectin-1 than that of lung cancer patients. CONCLUSION: These results suggest that detection of intelectin-1 may be useful for a differential diagnosis of epithelioid-type MPM in immunohistochemistry and that a high concentration of intelectin-1 in pleural effusion can be used as a new marker for clinical diagnosis of MPM.

Correlation of therapeutic outcome in non-small cell lung cancer and DNA damage assayed by polymerase chain reaction in leukocytes damaged in vitro.

A pilot study was conducted in patients with advanced non-small cell lung cancer to examine whether the gene-specific damage in mononuclear cells (MNCs) incubated with cisplatin in vitro correlates with chemotherapeutic outcome in cisplatin-based chemotherapy. Twenty-one patients received cisplatin-based chemotherapy, consisting of cisplatin (80 mg/m2 i.v. on day 1), vindesine (3 mg/m2 i.v. on days 1 and 8), with or without mitomycin (8 mg/m2 i.v. on day 1). MNCs from peripheral blood were obtained from each patient before chemotherapy. The cells were incubated with cisplatin for 3 h in vitro and the 2.7-kb fragment of the hypoxanthine phosphoribosyltransferase gene was amplified by PCR for quantitation of DNA damage. There was a 4-fold interpatient variation in DNA damage in MNCs. Seven of 21 patients had a partial response to chemotherapy. When the dose of cisplatin required to reduce amplification of the hypoxanthine phosphoribosyltransferase sequence by 63% (D63 value) of MNCs was compared in each patient (defined by a Poisson distribution as the dose that produced an average of one lesion per single strand of the 2.7-kb fragment), the mean D63 value in patients showing a partial response (n = 7; 52 +/- 11 micrograms/ml) was significantly lower than that in patients showing no change (n = 10; 81 +/- 20 micrograms/ml; P = 0.0045) and in patients with disease progression (n = 4; 115 +/- 34 micrograms/ml; P = 0.0012). The mean D63 in patients with no change was also significantly lower than that in the patients with disease progression (P = 0.0386). Seven (70%) of 10 patients with a D63 value < 70 micrograms/ml were responders. No relationship was observed between the D63 values and hematological and nonhematological toxicities. It is suggested that DNA damage in MNCs incubated by cisplatin treatment in vitro in responders was greater than that in nonresponders. Gene-specific damage in MNCs from peripheral blood incubated with cisplatin in vitro assayed by PCR may predict the chemotherapeutic response in cisplatin-based chemotherapy for non-small cell lung cancer.

Phase I clinical trial of irinotecan (CPT-11), 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, and cisplatin in combination with fixed dose of vindesine in advanced non-small cell lung cancer.

Irinotecan hydrochloride (CPT-11), a semisynthetic derivative of camptothecin, has been demonstrated to be active against solid tumors such as non-small cell lung cancer and colorectal cancer. Two combination phase I trials were undertaken to determine the maximum tolerated dose of CPT-11 in combination with cisplatin and vindesine in patients with advanced non-small cell lung cancer. All 46 patients (age 32-73 years) entered into these trials had a good performance status (Eastern Cooperative Oncology Group score, 0-1) and had received no prior chemotherapy or radiotherapy. In the first trial, 14 stage IV and 2 stage IIIb patients were studied; in the second trial 30 patients with stage IV disease were accrued. In the first trial, CPT-11 was given as a 90-min i.v. infusion on days 1 and 8 in combination with a fixed dose of cisplatin (100 mg/m2, i.v., on day 1) and vindesine (3 mg/m2, i.v., on days 1 and 8), every 4 weeks. The starting dose of CPT-11 was 25 mg/m2, and the dose was increased in increments of 25 mg/m2. In the second trial, the doses of either CPT-11 (days 1 and 8) or cisplatin (day 1) were escalated with a fixed dose of vindesine (same dose as the first study) given in a 4-week cycle. The starting doses of CPT-11 and cisplatin were 20 and 60 mg/m2, respectively, and the dose of either CPT-11 or cisplatin was increased in increments of 20 mg/m2. At least 3 patients were entered at each dose level in both trials. Use of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was not permitted in this trial. In the first trial, grade 4 granulocytopenia and grade > or = 3 diarrhea were dose limiting at 50 mg/m2 CPT-11, which represented the maximum tolerated dose. At the subsequent dose of CPT-11, 7 new patients were requited at the 50% reduced dose level of 37.5 mg/m2 on days 1 and 8. Nine patients were evaluated for response, and 4 of them achieved a partial response. In spite of a low dose of CPT-11 (25-37.5 mg/m2), the maximum concentration in plasma of CPT-11 (> 0.4 micrograms/ml) reached > 10-fold the in vitro concentration of CPT-11 required for 50% inhibition of growth. In the second trial, the dose-limiting toxicities were grade 4 granulocytopenia lasting for > or = 7 days and grade > or = 3 diarrhea.(ABSTRACT TRUNCATED AT 400 WORDS)

Phase I study of CPT-11 and etoposide in patients with refractory solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD) and acceptable dose level of a cytotoxic regimen of CPT-11, a new camptothecin derivative, in combination with etoposide (VP-16) and to describe the principal toxicities associated with it. PATIENTS AND METHODS: Patients with refractory solid tumors received VP-16 and CPT-11 daily for 3 consecutive days (days 1 through 3) every 3 or 4 weeks. Groups entered the trial at escalating CPT-11/VP-16 dose levels of 40/60, 60/60, 60/80, and 80/60 mg/m2. Thirty-four patients entered this study, of whom 33 were assessable for toxicity and 22 for therapeutic efficacy. RESULTS: Granulocytopenia was so severe that this regimen required supportive therapy with recombinant human granulocyte colony-stimulating factor (G-CSF). The majority of the patients experienced a 5% weight loss and diarrhea was the dose-limiting toxicity. The MTDs were 60/80 and 80/60 mg/m2 administered on days 1 through 3. Five of seven previously untreated patients with non-small-cell lung cancer (NSCLC) achieved partial responses (PRs) to this therapy, as did two with NSCLC who had received prior chemotherapy, two with head and neck cancer, and one with an adenocarcinoma (primary tumor unknown). CONCLUSION: The recommended dose of CPT-11/VP-16 for this regimen with G-CSF is 60/60 mg/m2 on days 1 through 3 every 3 to 4 weeks. We suggest that the combination of topoisomerase I and II inhibitors is likely to be an effective treatment strategy. The activity of this regimen against NSCLC is particularly encouraging and should be evaluated in a phase II trial.

Phase II study of irinotecan and etoposide in patients with metastatic non-small-cell lung cancer.

PURPOSE: To determine the effects of irinotecan (CPT-11) given in combination with etoposide (VP-16) in metastatic non-small-cell lung cancer (NSCLC), to evaluate response and survival rates, and to determine the qualitative and quantitative toxicities of the combination chemotherapy. PATIENTS AND METHODS: Sixty-one metastatic NSCLC patients received concurrent administration of CPT-11 and VP-16 for 3 days with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support. RESULTS: Fifty-nine patients were assessable for response and all 61 patients were assessable for toxicity and survival. Fifty-six patients were treated with two or more courses of chemotherapy. Thirteen patients achieved a partial response (PR), 36 showed no change (NC), and 10 showed progressive disease (PD). The overall response rate was 21.3% (95% confidence interval, 12.9% to 33.1%). The median duration of PRs was 141 days (range, 62 to 299). Of the hematologic toxicities, 14 (23%) and 24 (39%) patients experienced grade 3 or 4 leukopenia and neutropenia, respectively. The toxicities were feasible. Treatment-related death occurred in one patient who suffered hypovolemic shock induced by hematemesis. The median survival time was 10.0 months and the 1-year survival rate was 36.1%. CONCLUSION: Combination chemotherapy with concurrent administration of CPT-11 and VP-16 with rhG-CSF support was only modestly effective against metastatic NSCLC, with feasible toxicities of moderate diarrhea and pulmonary toxicity. The results were equivalent to those expected with either cisplatin-based chemotherapy or with CPT-11 alone.

Detection of K-ras mutations of bronchoalveolar lavage fluid cells aids the diagnosis of lung cancer in small pulmonary lesions.

An increased prevalence of K-ras oncogene mutation in lung adenocarcinoma has been shown by PCR-primer-introduced restriction with enrichment for mutation alleles (PCR-PIREMA) experiments. In the present study we investigated whether this method is useful for the diagnosis of lung cancer in small pulmonary lesions, which are difficult to diagnose cytologically as lung cancer by bronchoscopic examination. We examined bronchoalveolar lavage fluid (BALF) cells from 33 patients with single nodular pulmonary lesions of less than 2 cm in diameter (measured on chest computed tomography scans) for K-ras (codon 12) mutation, by PCR-PIREMA. Transbronchial fiberscopic examinations had not revealed lung cancer cytologically in any of the patients. The final diagnoses for the 33 lesions were 20 adenocarcinomas, 5 cases of focal fibrosis, 5 cases of pneumonia, 1 case of tuberculosis, 1 hamartoma, and 1 case of lymph node swelling. BALF cell lysates were amplified and digested with a restriction enzyme to detect the K-ras oncogene. Only the normal K-ras was observed after the first amplification and digestion for each of the 33 patients. Three amplifications and digestions were performed for each sample. We detected mutation of K-ras in BALF cells from 15 (75%) of 20 lung cancer patients and in cells from only 4 (31%) of 13 patients with nonmalignant lesions. The detection rate of the K-ras mutation in lung cancer was significantly greater than that in nonmalignant lesions (P = 0.012). Our results indicate that the detection of the codon 12 K-ras mutation in BALF cells by PCR-PIREMA aids the diagnosis of lung cancer in patients with small pulmonary lesions with negative cytological findings.

Serum levels of cytokines in patients with untreated primary lung cancer.

To evaluate the relationships between serum endogenous cytokine levels and their clinical implications in cancer patients, we measured the serum levels of endogenous granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin 6 (IL-6) in patients with untreated primary lung cancer. The serum G-CSF level was measured using a chemiluminescent ELISA, and the other cytokine levels were measured using ELISA. Fifty healthy adults and 183 patients with primary lung cancer were studied. The mean M-CSF level in the lung cancer patients (1106.4 units/ml) was significantly higher than that in the healthy adults (836 units/ml, P = 0.0001). In patients with large cell carcinoma, endogenous G-CSF, M-CSF, and IL-6 levels were significantly higher than those in patients with carcinomas of other cell types (P < 0.05). Univariate analysis showed that survival of 159 non-small cell lung cancer patients with high (more than cutoff level) G-CSF, M-CSF, and IL-6 levels was significantly poorer than that of patients with low levels (Wilcoxon's test, P = 0.018, P < 0. 0001, and P < 0.0001, respectively). Survival of patients with high levels of two or more cytokines was poorer than that of those with high levels of one cytokine or normal cytokine levels (P < 0.0001). Multivariate analysis using Cox's proportional hazards model showed that high M-CSF and C-reactive protein levels correlated significantly with poor survival (P = 0.037 and 0.037, respectively). Our preliminary data suggest that high M-CSF levels in non-small cell lung cancer may be of poor prognostic value.

A randomised clinical trial of vindesine plus cisplatin versus mitomycin plus vindesine and cisplatin in advanced non-small cell lung cancer.

This trial was carried out to evaluate the therapeutic benefit of the addition of mitomycin to vindesine plus cisplatin (80 mg/m2) in 126 previously untreated non-small cell lung cancer (NSCLC) patients. 124 patients were evaluable for toxicity and survival and 122 for response. No patient achieved complete response. The partial response rate (PR) in the vindesine plus cisplatin (VP) and mitomycin plus vindesine and cisplatin (MVP) groups were 23% (14/62) vs. 35% (21/60) (P = 0.13) with a median duration of response of 23 vs. 37 weeks (P = 0.071), respectively. Time to progression (TTP) and survival time (ST) were similar for both treatment arms [median TTP; 14 vs. 21 weeks (P = 0.10), median ST; 9.1 vs. 10.5 months (P = 0.94), respectively]. No difference in the frequency of side-effects was observed except that WHO grade 3 and 4 leukopenia was higher in the MVP group. In multivariate analysis, the significant predictors of survival were serum albumin, sex, performance status, lactate dehydrogenase and stage. In conclusion, the addition of mitomycin to the VP regimen appears to have limited value in advanced NSCLC.

Late toxicities and complications in three-year survivors of small cell lung cancer.

123 patients with small cell lung cancer (SCLC) presented to the National Cancer Center Hospital (Tokyo) between 1978 and 1986. 22 of 71 patients with limited stage disease (LD) and none of 52 patients with extensive disease (ED) survived for 3 years. 15 of the 22 three year survivors had significant late complications. All patients received chemotherapy and either thoracic irradiation, resection or both. No prophylactic cranial irradiation was given. 4 patients developed cardiac failure, 2 with a dilated cardiomyopathy, despite the fact that no patient received over 420 mg/m2 of doxorubicin. 12 patients of the 17 who received thoracic irradiation developed radiation pneumonitis and 3 required hospitalisation for severe haemoptysis (2) or cavity formation (1). 1 patient who received nimustine developed a fatal myelodysplastic syndrome and 2 additional patients developed second primary tumours in the oesophagus (1) and stomach (1). Mild peripheral neuropathy (WHO grade 1) was persistent in 3 patients and asymptomatic azotemia (WHO grade 1) in 7. Despite advances in the treatment of SCLC there are very few asymptomatic long-term survivors.

Radiation sensitivities in various anticancer-drug-resistant human lung cancer cell lines and mechanism of radiation cross-resistance in a cisplatin-resistant cell line.

To determine whether there exists cross-resistance between anticancer drugs and radiation, six drug-resistant human lung cancer cell lines and their parental cell lines were examined for radiosensitivity using a growth-inhibition assay. Only one cisplatin-resistant cell line, PC-9/CDDP, showed cross-resistance to radiation. The other three cisplatin-resistant cell lines (PC-7/CDDP, PC-4/CDDP, and H69/CDDP), an etoposide-resistant cell line (H69/VP) and a camptothecin-resistant cell line (PC-7/CPT) did not show cross-resistance to radiation. To analyze the mechanism of radiation resistance in PC-9/CDDP cells, the formation and repair of radiation-induced DNA single-strand breaks (ssb) and double-strand breaks (dsb) were examined by alkaline elution and neutral elution respectively. Although the formation of DNA ssb and repair of both DNA ssb and DNA dsb were the same for both cell lines, the formation of DNA dsb in PC-9/CDDP cells was significantly less than those in PC-9 cells. Measurement of intracellular glutathione content in all of the cell lines revealed that only PC-9/CDDP cells had a significant increase of glutathione content compared to the parental cells. Buthionine sulfoximine treatment of PC-9/CDDP cells caused an increase of DNA dsb to the same levels as in PC-9 cells after irradiation and caused a complete radiosensitization. These results indicate that cross-resistance to radiation in drug-resistant cells in a rare phenomenon, and increased glutathione content may play a crucial role in the emergence of cross-resistance to radiation in the drug-resistant cells.

The influence of ageing on cisplatin pharmacokinetics in lung cancer patients with normal organ function.

This study was performed to identify any relationship between age and cisplatin (CDDP) pharmacokinetics in lung cancer patients. CDDP was given at a dose of 80 mg/m2 by 1-h intravenous infusion to 23 lung cancer patients. All patients had normal renal, hepatic, and bone marrow functions. We measured ultrafilterable platinum (U-Pt) and total plasma platinum (T-Pt) using atomic absorption spectrometry. There was significant correlation between the age of the patients and U-Pt pharmacokinetic parameters such as the area under the plasma concentration versus time curve (AUC), total clearance (Cl), and peak plasma concentration (Cmax) as well as the AUC of T-Pt (P < 0.05). We performed univariate regression analysis to examine the influence of factors aside from age on the AUC of U-Pt and T-Pt. Creatinine and GPT levels were significantly related to the AUC of U-Pt, and creatinine clearance and creatinine concentrations were significantly related to the AUC of T-Pt. Therefore, stepwise multiple-regression models for the AUC of U-Pt and T-Pt were developed to assess an age effect. Age was consistently an independent and significant predictor of the AUC of U-Pt and T-Pt.

A prognostic-factor risk index in advanced non-small-cell lung cancer treated with cisplatin-containing combination chemotherapy.

Prognostic factors for response and survival were retrospectively evaluated in 192 previously untreated patients with advanced non-small-cell lung cancer (NSCLC) who had received either vindesine plus cisplatin or mitomycin plus vindesine plus cisplatin as initial treatment. Univariate analysis demonstrated that squamous-cell histology, early stage, and a small number of metastatic sites were favorable prognostic factors for response to chemotherapy. Multivariate analysis using Cox's proportional hazard model indicated that the number of metastatic sites was the only significant pretreatment factor for response (P = 0.0005). Multivariate regression analysis revealed that the number of metastatic sites (P = 0.0002), sex (P = 0.0009), serum albumen levels (P = 0.0018), performance status (P = 0.0026) and lactic dehydrogenase values (P = 0.0026) contributed independently to survival. On the basis of these five prognostic factors, a prognostic index for survival was used to define three prognostic groupings (good, intermediate, and poor) for survival (median survival, 16.5 vs 9.4 vs 4.6 months; P = 0.0001). This particular regression model should aid in the design and analysis of new treatment strategies and may be useful for indirect comparisons of different studies carried out in similar patient populations.

Phase II study of (glycolate-O,O') diammineplatinum(II), a novel platinum complex, in the treatment of non-small-cell lung cancer.

A total of 68 patients with non-small-cell lung cancer who either had not previously been treated (38) or had undergone prior therapy (30) were treated in a phase II study of (glycolate-O,O') diammineplatinum(II) (NSC 375 101D; 254-S), a new platinum complex. The drug was given as a single intravenous infusion at a dose of 100 mg/m2 every 4 weeks. All 68 patients could be evaluated for response and 62, for toxicity. Objective responses were seen in 10 of 68 cases (14.7%; 95% confidence interval, 7.3%-25.4%), and the median duration of response was 15 weeks (range, 8-23 weeks). The response rates were similar for previously untreated and treated patients (13% and 17%, respectively), including three previously treated with cisplatin. Myelosuppression was the dose-limiting toxicity. Thrombocytopenia (less than 100,000 platelets/mm3) and leukocytopenia (less than 3,000 WBC/mm3) were observed in 22 (35%) and 18 (29%) patients, respectively. Mild to moderate nausea and vomiting occurred in 45 cases (73%). No significant renal or neurotoxicity was observed. We conclude that as a single agent, 254-S is well tolerated but appears to have marginal activity against non-small-cell lung cancer.

Gene-specific damage produced by cisplatin, ormaplatin and UV light in human cells as assayed by the polymerase chain reaction.

The level of DNA damage in the total genome of leukocytes from patients receiving cisplatin therapy has been previously correlated with therapeutic outcome. Based on the fact that unrepaired damage in transcribed genes has been well correlated with sensitivity to a number of DNA damaging agents, the correlations with therapeutic response might be improved if the level of DNA damage in specific genes was assessed. We previously established a polymerase chain reaction (PCR)-based assay to measure cisplatin lesions in specific genes. The major advantages of this assay include its potential to quantify DNA lesions produced by any DNA damaging agent, and to measure it in minute samples of cells. This assay has been further improved to realize this potential. Specifically, cells were damaged with cisplatin, a related analogue ormaplatin, and ultraviolet light, and PCR was performed on the DNA from 1000 cells after direct lysis with no purification. Human HL-60 cells were used to compare the efficacy of the various agents to damage the alpha-fetoprotein gene. This was then extrapolated to damage in the total genome and compared to the cytotoxicity for each agent. At a dose that killed 50% of the cells, ormaplatin, cisplatin and ultraviolet light produced 19,200, 48,000, and 1,080,000 lesions per cell, demonstrating that ormaplatin lesions were the most effective at killing cells. Mononuclear cells were obtained from freshly isolated blood from five individuals. These cells were damaged with the three agents, and PCR of the alpha-fetoprotein gene was performed. No significant difference between the individuals was observed in the level of DNA damage produced by any of the agents.(ABSTRACT TRUNCATED AT 250 WORDS)

A feasibility study of continuous etoposide infusion combined with thoracic radiation for non-small cell lung cancer.

We conducted a feasibility study of continuous etoposide infusion, which was expected to suppress DNA repair after radiation, combined with radiation in patients with advanced non-small cell lung cancer (NSCLC). Between July 1995 and January 1997, 10 patients with NSCLC were registered. Thirty-six mg/m2/day etoposide was infused continuously for a mean of 19 days (range 14-26). Patients tolerated a mean total dose of accelerated hyperfractionated thoracic radiotherapy (1.5 Gy twice per day) of 52.6 Gy (range 33-60). The primary tumors of 7 patients showed partial responses and distant metastasis progression occurred before primary tumor progression in all 7 responders. The hematological adverse effects of chemoradiotherapy were grade 3 or 4 leukopenia in all 10 patients, grade 3 anemia developed in 3, and 2 had grade 3 thrombocytopenia. Six patients contracted infections and one of them died of pneumonia. The major non-hematological adverse effect was esophagitis, which was grade 3 in 3 patients, one of whom died of renal dysfunction. The serum etoposide concentrations were 1.6-2.0 microgram/ml, except in one patient, who had liver dysfunction due to B-type hepatitis. DNA repair gene XRCC1 mRNA expression in peripheral blood mononuclear cells was analyzed, using the reverse transcriptase-polymerase chain reaction, in 8 patients and was suppressed during etoposide infusion in 2. No relationship was observed between serum etoposide concentration and XRCC1 expression and clinical outcome. In conclusion, continuous etoposide infusion combined with thoracic radiation induces severe toxicity and should be given only after careful consideration.

Randomized study of dose or schedule modification of granulocyte colony-stimulating factor in platinum-based chemotherapy for elderly patients with lung cancer.

It is generally believed that elderly patients are less able to tolerate aggressive cancer chemotherapy than their younger counterparts. Bone marrow cellularity diminishes with age and elderly patients may have decreased tolerance to myelosuppressive agents. Between November 1995 and October 1999, 68 chemotherapy-naive elderly (70 or more years old) patients with histologically or cytologically proven lung cancer who were to receive platinum-based chemotherapy were enrolled in this study. All patients had adequate cardiac, hematological, liver and renal function to receive chemotherapy. Patients were randomized into 3 groups. Patients in groups 1 and 2 received 2 microg/kg and 4 microg/kg granulocyte colony-stimulating factor (G-CSF, lenograstim), respectively, when grade 3 leukopenia (<2,000/microl) or neutropenia (<1,000/microl) appeared after chemotherapy. Patients in group 3 received 2 microg/kg G-CSF when grade 2 leukopenia (<3,000/microl) or neutropenia (<1,500/microl) appeared after chemotherapy. G-CSF was stopped in all groups when the leukocyte count increased to over 10,000/microl or the neutrophil count exceeded 5,000/microl. Full blood cell counts were examined 3 times a week after chemotherapy. All patients received platinum-based chemotherapy. Eighteen, 16 and 22 patients (78%, 73% and 96%) in groups 1, 2 and 3, respectively, received G-CSF when leukopenia or neutropenia appeared. The durations of G-CSF treatment required by groups 1 and 3 (5.7+/-3.6 and 6.6+/-3.2 days, respectively) did not differ significantly, but the duration of treatment required by group 2 (3.7+/-2.8 days) was significantly shorter than that of group 1 (p=0.048). The duration of grade 4 neutropenia in group 2 (0.7+/-1.1 days) was marginally shorter than that in group 1 (1.6+/-2.1 days, p=0.076). The neutrophil nadir of group 2 (949+/-757/microl) was marginally higher than that of group 1 (592+/-438/microl, p=0.058). No patients in group 2 experienced grade 4 neutropenia for 4 days or more or a neutrophil nadir less than 100/microl a significant difference from group 1, where 22% and 17% of patients experienced these events (p=0.02 and p=0.04, respectively). Similarly, no infections requiring antibiotics after chemotherapy occurred in patients in group 2, a significant difference from group 1 (26%, p=0.01). The rates of neutropenia and infection in groups 1 and 3 did not differ significantly. The peak plasma concentration of G-CSF in group 2 was significantly higher than in group 1 (p=0.0018), but did not differ significantly between groups 1 and 3. Doubling the dose of G-CSF could help to decrease neutropenia and prevent infection after chemotherapy in elderly patients with lung cancer.

Increased expression levels of cyclin-dependent kinase inhibitor p27 correlate with good responses to platinum-based chemotherapy in non-small cell lung cancer.

In order to determine whether expression of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer (NSCLC) correlates with chemotherapeutic response, resected tumors from 22 patients with recurrent lung cancer who had undergone complete resection and received chemotherapy after the initial tumor recurrence were subjected to p27 immunostaining. Histological examination of the resected tumors revealed 14 adenocarcinomas, 7 squamous cell carcinomas and one adenosquamous cell carcinoma. Fifty percent or less and over 50% of the cells in the resected tumors of 11 patients each (groups 1 and 2, respectively) were p27-immunopositive. All but one patient received platinum-based chemotherapy after recurrence. Only one in group 1 achieved a partial response (PR) in chemotherapy whereas 2 and 4 in group 2 achieved complete and PRs, respectively. The chemotherapy response rate of group 2 (54%) was significantly higher than that of group 1 (9%, p=0.022). The times to recurrence after tumor resection of the 2 groups did not differ significantly (log-rank p=0.23, Wilcoxon p=0. 32), but survival after chemotherapy of group 2 was significantly better than that of group 1 (log-rank p=0.045, Wilcoxon p=0.028). It is suggested that high p27 expression levels in tumors may predict the good responses to platinum-based chemotherapy for NSCLC.