Phase II study of 3-hour infusion of paclitaxel in patients with previously untreated stage III and IV non-small cell lung cancer. West Japan Lung Cancer Group.

Sixty patients with previously untreated non-small cell lung cancer of stages III and IV were treated with a 210 mg/m2 dose of paclitaxel by means of a 3-hour infusion. The objective response rate was 32% (95% confidence interval, 20-45%): 1 complete response and 18 partial responses. The median duration of response was 15 weeks, and the projected median survival duration of all patients was 30 weeks. Grade 3-4 neutropenia occurred in 73% of patients. Other grade 3-4 adverse events included anemia (5%), vomiting/nausea (8%), peripheral edema (2%), alopecia (7%), elevation of AST (2%), peripheral neuropathy (3%), allergic reaction (2%), arthralgia/myalgia (3%), and interstitial pneumonitis (3%). Paclitaxel administered at 210 mg/m2 by means of a 3-hour infusion every 3 weeks demonstrated a notable activity against previously untreated advanced non-small cell lung cancer, with a 32% major response rate. Major toxicity was neutropenia. Hypersensitivity, neurotoxicity, arthralgia/myalgia and cardiac toxicity were mild and easily managed.

Randomized study of vinorelbine (VRB) versus vindesine (VDS) in previously untreated stage IIIB or IV non-small-cell lung cancer (NSCLC). The Japan Vinorelbine Lung Cancer Cooperative Study Group.

PURPOSE: We compared the activity of vinorelbine (VRB) and vindesine (VDS) in a randomized crossover study in patients with previously untreated stages IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Two hundred four patients were assessable for response and toxicity. VRB was administered at a dose of 25 mg/m2 weekly and VDS at a dose of 3 mg/m2 weekly. Patients who failed to respond after 4 cycles of initial monotherapy were switched to a combination chemotherapy (VRB-->VDS + cisplatin (P) or VDS-->VRB + P). RESULTS: Objective response was observed in 31.1% of patients in the VRB arm versus 8.9% of those in the VDS arm (P = 0.0002). The median duration of response to VRB was 18.5+ weeks (range, 7.9 to 107.5+ weeks) compared with 11.7+ weeks (range, 6.0 to 35.0+ weeks) for VDS. Of the 69 patients who failed to respond to initial monotherapy, 33 in the VRB group who subsequently received VDS + P did not respond and 13 (26.5%) of 49 initially on VDS who received subsequent VRB + P responded. The rates of grades 3 and 4 leukopenia were similar in the two monotherapy arms (VRB, 55.3% vs. VDS, 48.5%). However, grade 3 anemia was more frequent in the patients on VRB than in those on VDS. The incidence of peripheral neurotoxicity was significantly higher with VDS than with VRB (P = 0.002), but VRB induced a slightly higher rate of local cutaneous reaction than VDS (P = 0.012). With the combination of cisplatin and these vinca alkaloids, peripheral neurotoxicity was less frequent in the VRB group than in the VDS group. CONCLUSION: Our results demonstrate that VRB yields a higher response rate than VDS in stage IIIB or IV NSCLC, with the same extent of toxicity in terms of leukocytopenia. The peripheral neurotoxic effects were also milder with VRB than with VDS. In second-line chemotherapy, there was a notable difference in response between the VRB + P and VDS + P regimens.

[Epidemiologic survey of pleural plaques among inhabitants of Matsubase exposed to asbestos].

A high prevalence of pleural plaques (41.5%, 148/357) was found during a mass screening for lung cancer in Matsubase town in 1988. The inhabitants of this town were carefully studied each year from 1988 to 1993. The vast majority (81.2%) of inhabitants over the age of 20 years underwent chest roentgenography at least once during this period. Pleural plaques were detected by CT in 938 subjects, which is 17.3% of those studied and 4.1% of the total population. A total of 89 had an occupational history of asbestos exposure, 64 (71.9%) of whom had pleural plaques. However, these subjects with occupational exposure accounted for only 6.8% of the 938 subjects, and therefore most of the pleural plaques seemed to have been caused by general environmental exposure. The incidence of plaques was greater in older subjects: among those in the seventh decade of life it was more than eight times higher than among those in the fourth decade of life. Anthophyllite was detected in the main asbestos mill. The concentrations of asbestos fibers in the air and water near the old asbestos mills and factories were not high. The death rates and the adjusted mortality rates due to lung cancer in Matsubase were lower than in surrounding towns and lower than in Kumamoto prefecture as a whole. These results indicate that there is now no environmental contamination by asbestos fibers in Matsubase town. No cases of malignant mesothelioma have been confirmed in this town during the past 17 years.

[Early phase II study of oral administration of etoposide for 21 consecutive days in patients with non-small-cell lung cancer].

An early phase II clinical study was done to investigate the activity and the safety of oral administration of etoposide for 21 consecutive days in patients with non-small-cell lung cancer. An interim analysis was done after registration of 24 cases. One case was a dropout because of an insufficient administration period (4 days). The other 23 cases were complete: they comprised 9 cases of adenocarcinoma, 13 cases of squamous cell carcinoma, and 1 case of large cell carcinoma. Prior therapy had not been given in two cases. The doses used were 50 mg/person/day in 12 cases and 75 mg/person/day in 11 cases. The response observed was one case of at 50 mg/person/day to stage IV squamous cell carcinoma, 17 cases were no change, 5 cases were progressing disease, and giving a response rate of 4.3% in complete cases. Considering those results, we decided that it would be difficult to achieve a 20% response rate by the end of this study, and therefore the study was terminated. The side effects of the regimen were tolerable. In conclusion, etoposide was not active against non-small-cell lung cancer at the dosage and schedule employed. Further investigation is required to obtain a more effective form of therapy.

[Pulmonary alveolar proteinosis with coincidental thoracic injury. Successful bronchoalveolar lavage with a modified fiberoptic bronchoscope].

A 65-year-old laborer suffered thoracic injury in an accident. Ribs were fractured and chest X-ray films showed coincidental ground-glass, like opacities in both lung fields. CT indicated the possibility of pulmonary alveolar proteinosis, which was confirmed by histological examination of the specimen obtained during therapeutic bronchoalveolar lavage. A modified fiberoptic bronchoscope with a wedge device was used for segmental bronchoalveolar lavage. The wedge derice on a pediatric flexible fiberoptic bronchosiope allowed irrigation of six independent pulmonary segments, with no complication. Six months after discharge, the patient had no evidence of relapse.

Elevations of serum C-reactive protein occur independently of circulating interleukin-6 concentrations in patients with lung-cancer.

It has been suggested that a proportion of patients with cancer have an ongoing acute phase response indicated by a raised C-reactive protein (CRP). To examine whether an acute phase protein response is associated with circulating interleukin-6 (IL-6) concentrations in patients with lung cancer, we measured serum levels of CRP and interleukin (IL)-6 in 176 patients with lung cancer and 48 patients with other pulmonary diseases (28 diffuse pulmonary infiltrates, 15 benign lung tumors, and 5 bronchial asthmas). Serum CRP was detectable (greater-than-or-equal-to 2.5 mg/liter) in 57.4% of patients with lung cancer, 78.6% of patients with diffuse pulmonary infiltrates, 46.7% of patients with benign lung tumors, and 40.0% of patients with bronchial asthma. Serum IL-6 was detectable in all patients by a highly sensitive enzyme-immunoassay, the concentration ranging from 0.126 to 35.115 pg/ml. Although there was no significant difference in serum IL-6 levels among the histologic types of lung cancer, the IL-6 concentration was significantly higher in patients with advanced cancers than in those with early ones. Correlation analyses showed that there was no significant relationship between the CRP and IL-6 concentrations in the 176 patients with lung cancer (r=0.212, P=0.1243), while a highly significant correlation between both levels was observed in the 28 patients with diffuse pulmonary infiltrates (r=0.783, P=0.0005). These results indicate that the serum IL-6 level in patients with lung cancer is closely associated with the disease stage, but that a raised CRP concentration occurs independently of circulating IL-6 concentrations in patients with lung cancer.

A phase II study of vinorelbine, a new derivative of vinca alkaloid, for previously untreated advanced non-small cell lung cancer. Japan Vinorelbine Lung Cancer Study Group.

To evaluate the effectiveness of vinorelbine (NVB) in patients with non-small cell lung cancer (NSCLC), a late Phase II study was conducted. A total of 80 patients with Stage III or IV NSCLC who had no previous therapy were entered into the study. Seventy-nine patients were eligible for response and toxicity. NVB was administered weekly by intravenous injection at a dose of 25 mg/m2 in 20 ml of saline and was generally administered in four cycles or more, unless patients had disease progression. Of the 79 eligible patients, 23 (29.1%) showed a partial response (95% confidence interval, 19.1-40.4%). The median duration of partial responses was 14.7+ weeks. The median survival time for all patients was 40.1+ weeks. The major toxicity was leukopenia. Grade 3 and 4 leukopenia occurred in 48 patients (60.8%). Other toxicities of grade 3 or more included anemia (6.3%), local cutaneous reaction (3.8%), pneumonitis (1.3%), nausea and vomiting (1.3%), mucositis (1.3%) and constipation (1.3%). The absolute dose-intensity of NVB was 22.33 mg/m2/week. A weekly schedule of intravenous administration of 25 mg/m2/week of NVB was reasonable for maintenance of activity, and acceptable for toxicity in the chemotherapy of advanced NSCLC.

[Late phase II clinical study of KW-2307 in previously untreated patients with non-small cell lung cancer. KW-2307 Study Group (Lung Cancer Group)].

A late Phase II clinical study of KW-2307, a new vinca alkaloid derivative, in previously untreated patients with non-small cell lung cancer was jointly carried out in 26 medical institutions. Of 80 enrolled cases, 75 cases were eligible, and PR was attained in 23 cases (30.7%). The main adverse effect of this drug, leukopenia (neutropenia), was observed in 62.7% (83.3%) of Grade 3 and 4 cases, but they recovered rapidly. In addition to decreased hemoglobin in 67% (Grade 3 in 5.7%) of the cases, adverse effects included slight disorder of hepatic function, anorexia, nausea and vomiting, fever, general fatigue, phlebitis, paresthesia and interstitial pneumonia. Peripheral neuropathy such as paresthesia occurred rarely and was slight, if any.

[Double blind controlled study of ubenimex (Bestatin) against squamous cell lung cancer--a multicenter cooperative study].

To investigate effects of the combination of ubenimex, chemotherapy, and radiotherapy against unresectable advanced squamous cell carcinoma of the lung, a placebo controlled double-blind study was performed. Of 365 registered cases, there were 258 cases in the complete radiation group in which the treatment as specified in the protocol (irradiation of 40 Gy or more to the thorax subsequent to chemotherapy) was conducted; the 50% survival time was 449 days and 363 days in the ubenimex group and the placebo group, respectively. A significant (p = 0.0473) prolongation of the survival time was noted in the ubenimex group, and the response rate was 60.9% and 50.0% (p = 0.087). From these results it was confirmed that ubenimex, when used in combination with chemotherapy and radiotherapy, not only enhances the tumor-reducing effect but also prolongs the survival time.

[Phase I clinical study of combined cisplatin and carboplatin therapy in lung cancer].

A phase I clinical study (a dose escalation test) of combined cisplatin (CDDP) + carboplatin (CBDCA) therapy was carried out in patients with primary or secondary lung cancer (PS 0-2) who had given prior informed consent to the study. The dose level of CDDP was set at 80 mg/m2, while five dose levels (200, 250, 300, 350, 400 mg/m2) of CBDCA were used. Three patients were allocated to each CBDCA dose group. Blood samples were taken immediately before and 0.5, 1, 2, 4, 6 and 24 hours after injection, and were examined for total Pt and free Pt level. The maximum tolerated dose (MTD) was CDDP 80 mg/m2 + CBDCA 400 mg/m2. Thrombocytopenia and leukopenia served as dose limiting factors (DLF). Total Pt and free Pt levels in blood after this combined therapy were higher than those after treatment with CDDP alone. The results from this study suggest that CDDP 80 mg/m2 + CBDCA 350 mg/m2 would be a suitable dose for phase II study of this combined chemotherapy. A multi-center pilot study based on these findings is now under way.

[Bronchoalveolar lavage studies in a HTLV-1-positive case associated with interstitial pneumonia].

A 64-year-old housewife was hospitalized because of cough and dyspnea. Chest X-rays on admission showed diffuse interstitial shadows and loss of lung volume, suggesting acute interstitial pneumonia. Pulmonary function tests revealed decreased vital capacity and severe hypoxemia. Bronchoalveolar lavage studies showed that total cell counts and a proportion of lymphocytes were increased. Lymphocytes increased in lavage fluid consisted mainly of T cells with an elevated CD4+/CD8+ ratio. Furthermore, these lymphocytes spontaneously proliferated and responded well to recombinant IL-2 when cultured in vitro for 5 days, suggesting that lymphocyte activation occurred in the lung. Such lavage findings and lymphocytes activation in association with the presence of HTLV-1-specific IgA antibody in lavage fluid have been demonstrated in patients with HTLV-1-associated myelopathy. In this patient positive for HTLV-1, however, it could not be determined whether the pulmonary lesions were primarily related to HTLV-1 infection, because no IgA antibody specific for HTLV-1 was demonstrated in lavage fluid. In conclusion, when pulmonary abnormalities are found in HTLV-1 carriers, we should be careful in determining whether such pulmonary involvements are etiologically related to HTLV-1 infection.

[Analysis of pleural plaque found at lung cancer screening examination].

In the screening test of lung cancer, we found that there was a high prevalence of cases with pleural plaque recognized by chest X-ray film in inhabitants living in A town in Kumamoto Prefecture. We detected abnormal pleural plaque in 148 (41.5%) of 357 cases received lung cancer screening. These pleural plaques resulted in pleural thickening and calcification. Two or three mines of serpentine and an asbestos factory existed in this region from 1883 until 1970. Although twelve cases had a history of factory work, none had fibrous changes in the lung fields on chest X-ray films. It was considered that the pleural plaque probably resulted from exposure to low doses of asbestos in the atmosphere or contact with asbestos workers in their homes. The incidence of lung cancer in this region was not higher than that in other regions in Kumamoto Prefecture. There were no cases of malignant mesothelioma in our hospital during the past eleven years.

[A case of bronchiolitis obliterans organizing pneumonia (BOOP) showing acute respiratory failure treated with a mechanical ventilator].

Three weeks prior to admission, cough and dyspnea developed in a 49-year-old man and progressed to acute respiratory failure. The patient was treated with a mechanical ventilator. Open lung biopsy revealed diagnosis of BOOP. With corticosteroid therapy, the patient recovered dramatically.

Human T-cell leukemia virus type 1 associated with small cell lung cancer.

A patient with small cell lung cancer (SCLC) whose serum contained high levels of soluble interleukin-2 receptors is reported. Soluble interleukin-2 receptors in the supernatant of cultured SCLC cells obtained from the patient's pleural effusion while he had malignant pleuritis, increased almost linearly from the time of cell seeding. The expression of interleukin-2 receptors (Tac) on the SCLC cells were demonstrated by an immunofluorescence study. However, other lymphocytic markers, including OKT 11, OKT 4, OKT 8, B 1, and B 4, were not found on the cells with the exception of the natural killer cell marker, NKH-1. Southern blot analysis indicated the rearrangement of the T-cell receptor of the cancer cells. Moreover, monoclonal integration of human T-cell leukemia virus type 1 (HTLV-1) provirus in DNA from the cancer cells was also demonstrated. These observations suggest that some SCLC in HTLV 1 endemic areas are associated with HTLV-1.

Elevated serum levels of soluble interleukin-2 receptors in small cell lung carcinoma.

The presence of the soluble form of the interleukin-2 receptors (sIL-2R) was evaluated in the serum of 21 patients with small cell lung carcinoma (SCLC) and 37 patients with non-small cell lung carcinoma (non-SCLC) by means of an enzyme-linked immunosorbent assay. The sIL-2R level was measured serially in patients with SCLC both during and after therapy. The mean serum level of sIL-2R in patients with SCLC was 3.8 times higher than that of 47 healthy controls and was 1.9 times higher than in 37 patients with non-SCLC. Six patients with SCLC had very high levels of sIL-2R, ranging from five to 52 times the mean level observed in normal controls. Tumor cells in the pleural fluid of the patient with highest levels were positive with monoclonal antibodies to IL-2R (CD25), NKH-1, OKDR, and OKT9. A longitudinal study in this patient showed a good correlation between tumor activity and sIL-2R levels. Also, the sIL-2R levels decreased in patients responding to therapy. These results suggest that some SCLCs secrete sIL-2R and that the serial measurements of the serum sIL-2R levels can be used as a noninvasive tumor marker in this disease.