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Small molecule inhibitors targeting epidermal growth factor receptor (EGFR) are known to be active against non-small cell lung cancer (NSCLC) although the pharmacodynamics of these agents on malignant pleural effusion (MPE) remains unclear. Here we describe a case of lung adenocarcinoma with massive MPE treated successfully by gefitinib and chest drainage. Using sequential MPE samples before and during gefitinib therapy, the morphological changes and apoptosis of cancer cells were analyzed. Apoptosis of cancer cells was detected as early as 4 hours on, but not before, gefitinib therapy, suggesting that the pharmacodynamic assessment of such molecular targeting agents might be feasible for MPE.

Introduction The aim of this study was to determine and evaluate the recommended dose of docetaxel in combination with a novel oral 5-fluorouracil analogue S-1 and evaluate the efficacy and safety in patients with previously treated non-small cell lung cancer. Methods In phase I, patients with previously treated non-small cell lung cancer were treated with docetaxel (starting dose 40 mg/m 2 ) intravenously on day 1 and oral administration of S-1 at a fixed dose of 80 mg/m 2 on days 1 to14 every 3 weeks. The recommended dose was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. Results The recommended dose of docetaxel was 40 mg/m 2 in combination with S-1 80 mg/m 2 /d. Of 30 patients enrolled in phase II part, 29 patients were eligible and analyzed. No complete response and 7 (24.1%) partial responses were observed, for an overall response rate of 24.1% (95% confidence interval, 10.3-43.5%). Median overall survival was 11.8 months. The 1-year survival rate was 42%. The grade 3 to 4 hematologic toxicities were neutropenia (34.5%), leukopenia (20.6%), and anemia (10.3%). The grade 3 to 4 nonhematological toxicities included fever 2 (6.9%), diarrhea 1 (3.4%), stomatitis 1 (3.4%), cerebral infarction 1 (3.4%), and pneumonitis 1 (3.4%). There was one treatment-related death due to relapse of drug induced pneumonitis. Conclusions This combination chemotherapy is highly active and well tolerated in previously treated patients with non-small cell lung cancer. These results are encouraging and warrant additional investigation.

Background: It is important to detect preinvasive bronchial lesions before they become invasive cancer, because detection of early cancer is expected to lead to a cure. Autofluorescence bronchoscopy is a useful device in the detection of preinvasive and cancerous lesions. Recently, a new autofluorescence bronchoscopic system, autofluorescence imaging (AFI) system, has been developed. Objectives: We evaluated the efficacy of AFI in the diagnosis of precancerous and cancerous lesions. Methods: A total of 31 patients underwent both conventional white-light bronchoscopy (WLB) and AFI from January 2002 to September 2004. We evaluated autofluorescence findings using a four-point scale: AFI-I, II, III, and B. The findings in WLB were evaluated on a three-point scale: WLB-I, II, and III. Abnormal areas by WLB and AFI were biopsied for histopathological examinations. Results: A total of 64 lesions were evaluated. When the AFI-III finding was regarded as positive in AFI and WLB-III as positive in WLB, sensitivity for severe dysplasia or worse was 94.7% with AFI and 73.7% with WLB, respectively. Conclusions: AFI is an effective system for the detection of precancerous and cancerous lesions.

Background Fluoroscopy-guided bronchoscopy is a safe and routine method used to obtain a histologic or cytologic specimen of peripheral lung nodules, but it has low sensitivity in diagnosing malignant tumors. Although feedback from rapid cytology tests are expected to improve diagnostic rates, the value of the routine use of rapid cytology tests has not been established. Materials and Methods We prospectively studied 657 patients with suspected peripheral malignant lung lesions on chest computed tomography who underwent fluoroscopy-guided bronchoscopy between January 2002 and December 2004. Rapid on-site cytopathologic examinations (ROSE) were performed during bronchoscopic examinations. The additional approach to the lesions was performed immediately after conventional bronchoscopic examinations when ROSE was not considered diagnostic. Results There were 528 patients diagnosed as having malignant lesions. In 477 of these patients (90.3%), final malignant diagnosis was established by the initial bronchoscopy. Among these, 84 patients (15.9%) were diagnosed only with the additional feedback from ROSE. Of 240 peripheral lesions ≤2 cm, 174 were found to be malignant. Without ROSE, 110 (63.2%) of peripheral malignant lesions were diagnosed by bronchoscopy. The integration of ROSE enabled us to diagnose an additional 40 patients (23.0%) by bronchoscopy. ROSE improved diagnostic yield independent of the site and histology of the lesions and experience of the operators. Conclusion ROSE increased the diagnostic yield of bronchoscopy from 74.4% to 90.3% and therefore is an effective reinforcement in bronchoscopic diagnosis of peripheral pulmonary malignancies. The use of ROSE in routine bronchoscopy should be encouraged.

Background . Pure ground-glass opacity (PGGO) is a new entity that has been clearly defined on high-resolution computed tomography (CT) during the last half decade. It is important to investigate the natural history of PGGO through long-term observation for the management of this new entity. Methods . We investigated 19 patients with PGGO(s) defined on high-resolution computed tomography and retained as PGGO for more than 2 years. The PGGOs of 11 patients were detected at annual mass screening by low-radiation–dose CT (low-dose CT), 7 at follow-up CT after cancer resection, and 1 incidentally on CT. After long-term observation, 10 of 19 patients underwent operation and 9 are currently being followed-up with CT. Their growth characteristics and histologic findings are reported. Results . The median follow-up period was 32 months, ranging from 24 to 124 months. The sizes of PGGOs at the time of discovery were 4 to 18 mm in largest diameter (average 8.6 mm). During follow-up, the size of PGGO showed no change in 8 patients, increased slightly (up to 5 mm) in 6 patients, and increased by more than 5 mm in 5 patients. Ten patients had limited resection (segmentectomy or wide wedge resection) with negative surgical margin by intraoperative lavage cytology of the resection margin of the lung. Of them, 5 patients had adenocarcinoma, 3 pulmonary lymphoproliferative disorder, and 1 each atypical adenomatous hyperplasia and focal fibrosis. There was no clear tendency between the degree of size change and histology. In all but 1 of 9 patients with follow-up only, the PGGOs showed either no change or only a slight increase within 5 mm in largest diameter. Conclusions . These data suggest that some PGGOs will never progress to clinical disease and would be included in the category of overdiagnosis bias. However, a prior history of lung cancer should significantly raise the index of suspicion, as 4 of 5 proven cancer cases in this small series fell into that category. Because of the difficulties of preoperative and intraoperative histodiagnosis of PGGO, minimally invasive surgery may be appropriate from the viewpoints of both diagnosis and curability.

The histologic types of lung cancer cases diagnosed in 1979-1980 (n=799) and 1987 (n=587) were independently reviewed by two pathologists in order to investigate the reproducibility of the diagnosis of the histologic type when the WHO classification (1981) was used. The specimens from 354 surgical cases and biopsy or cytology specimens from 1032 non-surgical cases were reviewed. The inter-observer agreement was 87.9% (kappa=0.79) for surgical cases and 81.4% (kappa=0.72) for non-surgical cases. When compared to the original diagnosis, the agreement was 86.8% (kappa=0.78) for surgical and 86.4% (kappa=0.79) for non-surgical cases in 1979-1980 and the agreement was 92.8% (kappa=0.87) for surgical and 89.1% (kappa=0.83) for non-surgical cases in 1987. By histologic type, no difference in the agreement was observed except for large cell carcinoma. The distribution of histologic types after the review differed only slightly (less than 6%) from the original distribution. This suggests that in Osaka, Japan, the diagnosis based on the WHO classification (1981) had only a limited influence on the distribution of histologic types, and is not a major reason for the changing trends in lung cancer incidence by histologic type.

Purpose: To evaluate the usefulness of transcutaneous needle biopsy (TCNB). Material and Methods: From May 1988 to December 1994, we performed TCNB under fluoroscopic control in 408 patients with mass lesions of the peripheral lung. The Surecut needle (1.5 mm) was selected mainly because of its ability to obtain specimens large enough for histological examination. Of the 408 patients, 286 had had previous bronchofiberscopic examinations but no definite diagnosis had been reached. Results: A definite diagnosis was obtained by TCNB in 305 (74.7%) of 408 cases (251 malignant neoplasms, 54 benign lesions). In malignant neoplasms, the pathological diagnosis based on cytology and histology together was more reliable than that based on cytology alone. Although the complications of this procedure (such as pneumothorax) were within the range of acceptability, care should be taken to avoid air embolism and the seeding of cancer cells along the needle tract. Conclusion: TCNB with the Surecut needle is a useful procedure with relatively low risk.

Sixty-three patients with extensive-stage small-cell lung cancer were randomized to receive either cyclophosphamide, vincristine, doxorubicin and etoposide (CODE) alone or CODE plus recombinant human granulocyte colony-stimulating factor (rhG-CSF). rhG-CSF administration in support of CODE chemotherapy resulted in increased mean total received dose intensity for all drugs (P = 0.03) with a significant improvement in survival (P = 0.004).

Early prediction of therapeutic outcome is important in determining whether the ongoing therapy is beneficial. In addition to anatomical response determined using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, recent studies have indicated that change in tumor glucose use on or after treatment correlates with histopathologic tumor regression and patient outcomes. This Perspective discusses the use of (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) for pharmacodynamic evaluation in a very early phase of treatment to predict clinical outcomes in patients with advanced non-small-cell lung cancer. We conducted a study to assess whether early metabolic response determined using FDG-PET correlated with clinical outcomes in patients treated with gefitinib or those treated with carboplatin plus paclitaxel (CP). Early metabolic response to gefitinib, but not CP, correlated with the late metabolic response, anatomical response, progression-free survival, and even overall survival. A rapid effect of molecular targeted agents might not be aptly evaluated using the conventional criteria, eg, RECIST, in a very early phase of treatment before volumetric shrinkage of the tumor. Based on the findings of several studies, and on the findings from our study, use of FDG-PET might enable prediction of clinical outcomes at a very early stage of treatment, especially in patients treated with molecular targeted agents with rapid clinical efficacy.

Data on 16 potential risk factors for myelosuppression were assessed in 134 patients who received either vindesine and cisplatin (VP) or mitomycin C, vindesine and cisplatin (MVP) for inoperable stage III or IV non-small cell lung cancer in a randomized trial. Determinant factors for myelosuppression were evaluated by using univariate analysis and the logistic regression model. Recursive partitioning and amalgamation (RPA) was also used to define patient subgroups frequently suffering from severe bone marrow toxicity. Overall, 33 (25%) of 134 patients experienced at least one episode of grade 4 leukopenia. In univariate analysis, age, body surface area, serum creatinine, and pretreatment hemoglobin concentration were associated with severe leukopenia. A multivariate analysis using the logistic regression method showed that only raised creatinine level was an independent predictor for grade 4 leukopenia (P = 0.049). The RPA model generated three distinct subgroups based on age, body surface area and regimen. The three subgroups were distinguished by the frequency of severe (grade 4) leukopenia (50%, 25%, and 2.4%, respectively) (P0.001). Grade 4 leukopenia occurred more frequently in patients in class 3 (ageor = 65 years and treatment with MVP). The RPA model was useful in identifying the risk factors for myelosuppression induced by cisplatin-based chemotherapy, and in defining patient subgroups with elevated risk of toxicity.

We attempted to clarify whether serum levels of a carboxy-terminal fragment of ProGRP, ProGRP(31-98), could serve as a more accurate tumour marker in patients with SCLC than neuron-specific enolase (NSE). ProGRP(31-98) and NSE were measured retrospectively in 101 newly diagnosed untreated patients with SCLC, 111 with non-small-cell lung cancer (NSCLC) and 114 patients with non-malignant lung diseases. ProGRP(31-98) and NSE levels were determined using a sandwich enzyme-linked immunosorbent assay. Sensitivity in SCLC patients was 72.3% for ProGRP(31-98) and 62.4% for NSE. Comparing the area under curve (AUC) of 'receiver operator characteristics' of ProGRP(31-98) with that of NSE, ProGRP(31-98) was the more powerful marker in the diagnosis of SCLC (P = 0.0001). Serum levels of ProGRP(31-98) were higher in the 40 patients with extensive disease than in the 61 patients with limited disease (P = 0.0082). ProGRP(31-98) was significantly higher in patients with pure small-cell carcinoma than in patients with mixed small-cell/large-cell carcinoma (P = 0.02). In serial measurement in 16 patients responding to treatment, a high degree of correlation was noted between the decrease in serum ProGRP(31-98) levels and clinical response during the second week after treatment (P = 0.0045). These results indicate that the determination of serum ProGRP(31-98) levels plays an important role in the diagnosis and treatment of SCLC patients.

Despite recent advances in control of acute emesis following cisplatin-based chemotherapy regimens, delayed emesis remains a significant cause of treatment-related morbidity and factors associated with delayed emesis have not yet been evaluated. A prospective randomised trial was conducted to compare the efficacy and toxicity of granisetron, dexamethasone plus prochlorperazine with granisetron alone in controlling cisplatin-induced delayed emesis and to identify the important factors that influence its occurrence and severity. Seventy cisplatin-naive patients with inoperable solid tumors participated in the trial. Patients who received 80 mg m-2 or 100 mg m-2 of cisplatin were randomly assigned to receive either granisetron 40 micrograms kg-1 intravenously (i.v.) on day 1, dexamethasone 20 mg i.v. on days 2 and 3 and prochlorperazine 5 mg orally thrice daily on days 1-5 or granisetron 40 micrograms kg-1 i.v. on day 1 alone. There was no difference in their acute antiemetic efficacy. A combination regimen was more effective than granisetron alone in preventing delayed symptoms, with superior rates of complete plus major responses of 77% vs 51% (P = 0.0460). Treatment arm was the only determinant factor for the occurrence of delayed emesis (P = 0.0101).

Two phase I trials of irinotecan (CPT-11) in combination with cisplatin were conducted. In both cases, the dose-limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twenty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 60 mg/m2. The other 13 patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 80 mg/m2 with the granulocyte colony-stimulating factor support (2 micrograms/kg x 16 days). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT-11 was 90 mg/m2 in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h after the start of CPT-11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3-4 diarrhea than those with a lower SN-38 level (P = 0.0003). Stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the development of diarrhea (P = 0.0021). We conclude that there is a clear relationship between the SN-38 concentration and diarrhea during chemotherapy with CPT-11 plus cisplatin.

Soluble cytokeratin fragment 19 levels were measured with an enzyme immunoassay method developed by Boehringer Mannheim (Enzymun-Test CYFRA 21-1) in the serum of 185 patients with lung cancer [149 with non-small-cell lung cancer (NSCLC) and 36 with small-cell lung cancer (SCLC)] and 97 patients with benign lung diseases in order to determine its clinical usefulness in the diagnosis of lung cancer and follow-up of treatment. We used the cut-off value of 3.5 ng ml-1, established by the Japan CYFRA research group. This cut-off value is based on calculations using the receiver operating characteristic approach instead of using the 95% specificity approach recommended by other authors. The resulting sensitivity and specificity for the group of all lung cancer patients were 65.4% and 84.5% respectively. The sensitivity was highest (76.1%) for squamous cell carcinoma and lowest (44.4%) for SCLC. For NSCLC patients, when CYFRA 21-1 levels were analysed by node (N) factor, patients who presented with mediastinal lymph node metastasis (N2 or N3) demonstrated higher serum CYFRA 21-1 levels (5.6; interquartile range 3.2-11.5 ng ml-1) than patients without mediastinal node metastasis (N0 or N1, 3.9; interquartile range 2.2-10.0 ng ml-1; Mann-Whitney U-test, P = 0.0373). We compared the discriminatory power of CYFRA 21-1 with that of other tumour markers including carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and neuron-specific enolase (NSE). The area under the curve (AUC) of each ROC curve was calculated using the CLABROC program for statistical analysis. CYFRA 21-1 appeared to have the most discriminatory power of the markers tested in the diagnosis of lung cancer. In serial measurements of 14 patients receiving chemotherapy or radiotherapy, a high degree of correlation was noted between serum levels of CYFRA 21-1 and extent of clinical response (Wilcoxon, P = 0.0093).

Background and Methods. Thirty-nine roentgenologically occult lung cancers in 29 patients were treated using photodynamic therapy (PDT) and/or thoracic radiotherapy (TRT) from January 1986 to March 1992. With the exception of one mixed-tumor case, all were squamous cell carcinomas. Results. Initial PDT achieved complete responses in 25 of 39 (64%) of the cancers. Of the remaining 14 cancers that showed less than complete response (CR), 10 of the 14 (71.4%) showed a CR when subsequently treated with TRT, yielding an overall CR rate of 89.7% for cancers treated. Although nine patients experienced recurrences, six of these had CR when treated with PDT and/or TRT. To date, 22 patients are alive. Causes of death in the patients enrolled in this study are as follows: pyothorax (2); heart failure due to pulmonary hypertension (1); chronic respiratory insufficiency (1); subsequent primary brain cancer (1); and subsequent primary lung cancer (1). Only one died of primary lung cancer. Conclusions. These findings suggest that PDT and/or TRT may be used as an alternative to surgery in the treatment of selected patients with roentgenologically occult lung cancer.

PURPOSE Since leukopenia was one of the dose-limiting toxicities of the combination of irinotecan (CPT-11) and cisplatin in a previous trial, we conducted a phase I trial to investigate whether support with recombinant human granulocyte colony-stimulating factor (rhG-CSF) would permit further intensification of the CPT-11 dose in combination with a fixed cisplatin dose. PATIENTS AND METHODS Twenty previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) were treated with CPT-11 on days 1, 8, and 15 in combination with cisplatin 80 mg/m2 intravenously on day 1. In addition, rhG-CSF (2 micrograms/kg/d) was administered on days 4 to 21, except on the days of CPT-11 treatment. The starting dose of CPT-11 was 70 mg/m2, and the CPT-11 dose was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS Diarrhea was the dose-limiting toxicity at 90 mg/m2. Two of six patients experienced either grade 3 or 4 diarrhea or grade 3 leukopenia during the first course of therapy at this dose level. Modest escalation of the CPT-11 dose from 80 to 90 mg/m2 resulted in a marked increase in the plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38). Occurrence of diarrhea was well correlated with the peak plasma concentration (Cmax) of SN-38 (P = .035). There were 10 partial responses (50%) among 20 patients. CONCLUSION The recommended dose for phase II studies is 80 mg/m2 of CPT-11, and 80 mg/m2 of cisplatin plus rhG-CSF. With the use of rhG-CSF, the CPT-11 dose can be increased 33% above that in the original regimen (60 mg/m2 of CPT-11 and 80 mg/m2 of cisplatin).

A 66-year-old woman with small-cell lung cancer was administered chemo-radiotherapy consisting of cisplatin (CDDP) and etoposide (ETP). From day 3, she developed vomiting and hyponatremia that persisted despite fluid infusion and cortico-steroid administration. On day 7, the hyponatremia worsened (serum sodium level, 109 mEq/L), leading to disturbed consciousness and convulsions. The serum sodium level gradually increased after intravenous administration of hypertonic saline; on day 22, the serum sodium level was almost normal without any neurological implication. We diagnosed this clinical condition as renal salt-wasting syndrome (RSWS) on the basis of dehydration and high urinary sodium excretion at the onset. In the second course of chemotherapy, CDDP was replaced with carboplatin (CBDCA); consequently, hyponatremia was not observed. Hyponatremia that develops after the administration of CDDP may be due to not only the syndrome of inappropriate secretion of anti diuretic hormone (SIADH) but also RSWS. When RSWS is suspected, hypertonic saline should be administered.

PURPOSE The purpose of this study was to determine the maximum-tolerated dose and the dose-limiting toxicities of CPT-11, a new derivative of camptothecin, in combination with a fixed dose of cisplatin in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Twenty-seven previously untreated patients with stage IIIB or IV NSCLC were assessable for toxicity, and 26 were assessable for response. The initial dose of CPT-11 was 30 mg/m2 given as a 90-minute intravenous (IV) infusion on days 1, 8, and 15 in combination with cisplatin (80 mg/m2 IV on day 1) given every 4 weeks. The dose of CPT-11 was escalated in increments of 10 mg/m2 until severe or life-threatening toxic effects were observed. RESULTS Significant toxicity was infrequent up to 60 mg/m2 of CPT-11. The maximum-tolerated toxicity was reached at a dose of 70 mg/m2. Three of six patients either had leukocyte count nadirs of less than 2,000/microL or experienced grade 4 diarrhea during the first cycle of therapy at 70 mg/m2. The major toxic effects were leukopenia and diarrhea. There were 14 partial responses (54%) among the 26 patients. CONCLUSIONS A combination of CPT-11 and cisplatin seems to be effective against NSCLC with acceptable toxicities. The recommended dose for phase II studies is 60 mg/m2 of CPT-11 on days 1, 8, and 15, and 80 mg/m2 of cisplatin on day 1 every 4 weeks.

BACKGROUND In the classification recently proposed by the Pathology Committee of International Association for the Study of Lung Cancer, small cell lung carcinoma (SCLC) was divided into three subtypes: pure SCLC, mixed small cell/large cell carcinoma (mixed SC/LC), and combined SCLC. METHODS To examine the clinical utility of this classification, histologic specimens, cytologic specimens obtained by brushing or fine-needle aspiration, and sputum cytologic specimens from 430 patients with SCLC were reviewed. RESULTS When the subtype of SCLC was determined from the biopsy specimen, cytologic specimen obtained by brushing or fine-needle aspiration, and sputum cytologic specimen, the frequency of mixed SC/LC was 25 of 299 (8.4%), 75 of 400 (18.8%), and 8 of 232 (3.4%), respectively. Whatever the diagnostic method, patients with mixed SC/LC showed a poorer response to treatment and worse prognosis than those with pure SCLC: a median survival of 144 days versus 285 days when classified with the use of biopsy specimens; 160 days versus 275 days with cytologic specimens obtained by brushing or fine-needle aspiration; and 47 days versus 259 days with sputum cytologic specimens, respectively. CONCLUSIONS These findings showed that mixed SC/LC should be separated from pure SCLC as a distinctive group and that cytologic studies of specimens obtained by brushing or fine-needle aspiration were sensitive and useful procedures for this purpose.

PURPOSE To evaluate the activity of CPT-11, which is a new derivative of camptothecin, against refractory or relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS Sixteen patients with refractory or relapsed SCLC were entered onto a prospective, non-randomized, single-institution phase II trial. All 16 patients had been pretreated heavily with some form of cisplatin-based combination chemotherapy. Five patients had received previous chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide (CODE) as an induction therapy. Six patients had been treated with concurrent cisplatin and etoposide plus chest x-ray. The median time off chemotherapy was 7.3 months (range, 1.9 to 15.1 months). Patients were treated with a CPT-11 starting dose of 100 mg/m2 body surface given as a 90-minute intravenous (IV) infusion every week with subsequent doses based on toxicity. Fifteen patients were assessable for toxicity, response, and survival. RESULTS Seven patients (47%; 95% confidence limits for an overall response rate, 21.4% to 71.9%) responded to CPT-11 with a median duration of response of 58 days. The major toxicities were myelosuppression (predominantly leukopenia), diarrhea, and pulmonary toxicity. CONCLUSION CPT-11 is an active agent against refractory or relapsed SCLC and deserves to be studied more closely as both a single agent and in combination with other drugs to treat patients with SCLC.

Objective: To establish cytological features of pulmonary pleomorphic carcinoma (PC) or giant cell carcinoma (GC), we evaluated the cytological characteristics of these tumors using a multidisciplinary approach. Study Design: Samples from 13 surgically resected and histologically confirmed PC or GC patients were collected from our institutes. Eight cases without prior chemotherapy before surgery were selected, and cytological features were analyzed. Results: The background contained numerous lymphocytes and neutrophils. The tumor cells were arranged in flat loose clusters, but some were in fascicles. The shape of the tumor cell was spindle or pleomorphic, and the sizes of the tumor cells varied by more than 5-fold. The tumor cells had an abundant, thick and well-demarcated cytoplasm. The location of the nucleus was centrifugal, and the nucleus was oval or irregularly shaped. Multinucleated giant cells were frequently observed. The size of the nucleus was more than 5 times that of normal lymphocytes, and its size also varied by more than 5-fold. The nuclear membrane was thin, and nuclear chromatin was coarsely granular, while the nucleolus was single and round. Conclusion: PC or GC has characteristic cytological features, however, spindle cells tended to be hardly observed in cytological specimens in some cases.

We retrospectively reviewed the contribution of widely used devices such as the standard fiberoptic bronchoscope in the diagnosis of peripheral pulmonary lesions (PPLs) in patients who presented with respiratory distress.We performed bronchoscopy for 106 PPLs in January-December 2007, and diagnosed access to the lesions to be difficult.For these lesions, we applied Sasada transbronchial angled forceps (STAF), transbronchial needle aspiration cytology (TBAC), thin bronchoscopy, and ultra-thin bronchoscopy, which are widely used devices, after routinely performing biopsy with standard forceps and saved each specimen separately, and finally compared the pathological diagnosis.The diagnostic yield obtained with specimens using standard forceps was 36.8%; however, the overall diagnosis was improved to 70.8% after we used these other devices and methods. We achieved diagnosis with STAF (10 lesions), followed by thin bronchoscopy (5 lesions), and ultra-thin bronchoscopy (14 lesions). No diagnosis was made by TBAC.We conclude that these widely employed devices can contribute to improvements in the diagnosis of cases of respiratory distress in which arrival to the lesions is difficult.

A 68-year-old man was referred to our hospital due to general fatigue, fever and weight loss. His chest radiograph showed a nodule (2.8 cm) in the right middle lobe. Computed tomography and positron emission tomography showed multiple metastases to the bone, liver and lymph nodes. The lung nodule was not accessible by standard transbronchial forceps. However, biopsy specimens obtained using Sasada Transbronchial Angled Biopsy Forceps (STAF) pathologically confirmed the diagnosis of malignant lymphoma. We report the case, and discuss the utility of STAF for lung lesions that are difficult to access with standard forceps.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) is a novel camptothecin derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its unique inhibitory effects on mammalian DNA topoisomerase I. Seventeen patients with advanced non-small-cell lung cancer were treated with CPT-11 at weekly dose levels ranging from 50 to 150 mg/m2. At least three weekly doses were given to all patients except four, and a total of 74 weekly doses were given to the 17 patients. The dose-limiting toxic effects were myelosuppression (predominantly leukopenia) and unpredictable diarrhea. Gastrointestinal toxic effects were severe and not well controlled by standard therapy in some patients. Interpatient variability of toxic effects was substantial (including two deaths) and did not correlate with the pharmacokinetic parameters of CPT-11 and 7-ethyl-10-hydroxycamptothecin, its major metabolite. Two previously untreated patients, who received doses of 100 and 125 mg/m2, had partial responses lasting 3.2 and 4.0 months, respectively. The maximum tolerated dose on this schedule was 100 mg/m2, which we also recommend as a starting dose for phase II studies. This schedule appears to allow a CPT-11 dose intensity which is double the dose intensity possible on a once-a-month schedule. However, careful supervision to assess gastrointestinal toxic effects and myelosuppression is indispensable because of wide individual differences in drug tolerance.

To facilitate the studies in cell biology and drug sensitivity of non-small cell lung cancer, cell samples from 55 patients have been used to establish cell lines in culture using a chemically defined medium (ACL-4). A total of 20 cell lines (36 percent) were directly established and characterized: 14 (44 percent) from pleural effusions, five (29 percent) from resected primary tumors, and one (25 percent) from ascitic fluids. They comprised 16 adenocarcinoma, two large cell carcinoma, one squamous cell carcinoma, and one malignant mesothelioma. Each cell line had distinct gross morphologic features and population doubling times from 21 to 75 h. The plating efficiency was 0.01 to 9.51 percent. The modal chromosome number varied from 45 to 108. Secretion of tumor markers (carcinoembryonic antigen, sialyl Lewis Xi, CA 50, CA 125, and CA 19-9) into the medium was also different in each cell line. Most of the cell lines have been xenografted into nude mice and found to be tumorigenic. Survival of 20 patients whose tumor cell specimens continually grew in culture at any time during their clinical course was significantly shorter than that of 35 patients with no in vitro tumor growth (median survival time of 28 weeks vs 53 weeks, p = 0.0093). Our study indicates that in vitro tumor cell growth appears to be an adverse prognostic factor in patients with non-small cell lung cancer. (Chest 1991; 100:429-38)

The demand for minimally invasive therapies is increasing in the treatment of small peripheral non-small cell lung cancer (NSCLC).Twelve patients with T1-2 N0 M0 peripheral NSCLC were treated by high-dose-rate brachytherapy with (192)Ir radioactive source.A (192)Ir source was introduced into the tumors percutaneously in five patients (percutaneous brachytherapy) or transbronchially in seven patients (transbronchial brachytherapy). Whereas irradiation was performed with a single fraction of 20 Gy in percutaneous brachytherapy, it was hypofractionated from 5 x 5 Gy to 2 x 12.5 Gy in transbronchial brachytherapy. Complications were generally mild in all patients, although focal radiation pneumonitis was observed in most patients. Primary recurrence occurred in three patients, including one with a T2 tumor and one treated by brachytherapy as a salvage treatment for recurrence after conformal radiotherapy. When brachytherapy is evaluated as a primary treatment for T1 N0 M0 NSCLC, local control rate is 88.9% and estimated 5-year survival rate is between 60% and 70%.Brachytherapy has a potential to be a method to treat peripheral T1 N0 M0 NSCLC.

Study objectives: We performed a clinical trial of laser-induced fluorescence endoscopy (LIFE) for detection of precancerous lesions and cancer including carcinoma in situ (CIS), which are difficult to detect by white-light bronchoscopy. Design: Results with LIFE were compared with the criterion standard, white-light bronchoscopy. The evaluation of these endoscopic results spectrofluorometrically was examined, and pixels of LIFE images composed of digital signals for the intensities of red and green were analyzed. Setting: Tertiary-level hospital treating referrals and subjects with suspicious results in mass screening. Patients: We examined 65 subjects with suspected lung cancer by both methods, and performed biopsy on 216 lesions. Results: The accuracy of diagnosis by white-light bronchoscopy, with histopathologic results as the standard, was 48.6%. The accuracy by LIFE was 72.7%. The sensitivity of conventional bronchoscopy for detection of severe dysplasia (21 biopsy specimens) or cancer (28 biopsy specimens) was 61.2% and specificity was 85.0%. With results by LIFE added, these values were 89.8% and 78.4%, respectively. Of nine patients with CIS, only LIFE showed one lesion, and only LIFE showed the extent of seven of the lesions. The autofluorescence of eight lesions was measured spectrofluorometrically; normal bronchial tissue, severe dysplasia, and cancerous tissue had spectral differences. The red/green intensity of cancers on histograms of LIFE images generally was greater than the ratios for metaplasia or normal bronchial wall. Conclusions: Use of both methods should facilitate early detection. Evaluation by spectrofluorometry and analysis of digital signal intensity of results by LIFE make results more objective. (CHEST 2000; 118:1776 ‐1782)

PURPOSE To determine the response rate, survival, and toxicity of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, in refractory or relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS Twenty-five patients with refractory or relapsed SCLC were entered onto the trial. All 25 patients had been pretreated with some form of cisplatin-based combination chemotherapy and had also received previous etoposide- or anthracyclinecontaining chemotherapy. The median time off chemotherapy was 6.7 months (range, 0.9 to 23.5). Patients were treated at 4-week intervals using CPT-11 (a starting dose of 70 mg/m2 intravenously on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3), with a subsequent dose based on toxicity. In addition, recombinant human granulocyte colony-stimulating factor (rhG-CSF; 2 microg/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. RESULTS All patients were assessable for toxicity and survival. Twenty-four patients were assessable for response. There were 14 partial responses (PRs) and three complete responses (CRs), for an overall response rate of 71% (95% confidence interval, 53% to 89%). The median response duration was 4.6 months. Median survival was 271 days. Major toxicities were myelosuppression (predominantly leukopenia) and diarrhea. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 56% and 20% of patients, respectively. Grade 3 to 4 diarrhea was observed in 4%. There was one treatment-related death due to severe myelosuppression. CONCLUSION A combination of CPT-11 and etoposide with rhG-CSF support is an active therapy against refractory or relapsed SCLC and deserves to be studied more extensively in a phase III trial.

Purpose: To compare the response rates, toxicities and survival durations of elderly patients (70 years of age or more) with those of younger patients ( less than 70 years of age) with non-small-cell lung cancer (NSCLC) treated with cisplatin-based chemotherapy. Patients and methods: We analyzed retrospectively the data of 203 assessable patients entered on a prospective randomized trial of cisplatin-based combination chemotherapy. Chemotherapy consisted of three dosage regimens: (1) vindesine and cisplatin (VP); (2) mitomycin, vindesine and cisplatin (MVP); or (3) etoposide and cisplatin alternating with vindesine and mitomycin (EP/VM). Results: A greater proportion of elderly patients had localized disease and more squamous cell carcinoma than non-elderly patients. The overall response rates were 44% in the elderly group and 28% in the non-elderly group. In the EP/VM arm, the response rate was significantly better in the elderly group than in the non-elderly group. The frequency of grade 4 leukocytopenia in the MVP and EP/VM arms in the elderly group was significantly greater than in the non-elderly group (P < 0.05). No differences were found in nonhematological toxicities between the two groups. There was no difference in overall survival between the groups. Conclusion: Elderly patients treated with mitomycin-containing regimens have higher hematologic toxicities than younger patients. The results of this study are consistent with the previously reported pharmaco logic data on mitomycin suggesting altered pharmacokinetics in elderly patients. The improved response rate in the elderly patients was probably because more elderly patients had earlier disease, squamous cell carcinoma and better performance status. Cisplatin-based chemotherapy was tolerable for most elderly NSCLC patients with good performance status.

A dose-escalation study of daily etoposide and carboplatin was carried out on 23 patients with advanced lung cancer using a starting dose of 40 mg/m 2 /day etoposide given orally for 21 days and 250 mg/m 2 carboplatin given intravenously (IV) on day 1. A total of 41 courses were given. Myelosuppression was the major dose-limiting toxicity. The maximum tolerated dose was reached at the fourth level with 40 mg/m 2 /day etoposide for 21 days and 400 mg/m 2 carboplatin on day 1, once every 4 weeks. Non-hematological toxicities were generally mild or reversible. The recommended doses of this combination chemotherapy are 40 mg/m 2 /day etoposide for 21 days and 350 mg/m 2 carboplatin on day 1. The response rate for non-small cell lung cancer and small cell lung cancer was 16.7% and 60% (95% confidence intervals of 3.6% to 41.4%, and 14.7% to 94.7%), respectively. A phase II study is necessary to define the efficacy and safety of this combination chemotherapy.

We conducted a prospective study to evaluate the significance of serum neuron-specific enolase (NSE) as a predictor of relapse of small cell lung cancer (SCLC). Patients entered into the study were drawn from those who had shown a complete or partial response to first-line chemotherapy with a concurrent decline in the NSE level to less than 10 ng/ml. When the serum NSE level increased to more than 15 ng/ml, the patient was restaged on the basis of clinical, radiological, and bronchoscopic examinations. During the period from August 1988 to December 1990, 57 patients with SCLC were enrolled and followed up until May 1992. Of these patients, 45 had clinical relapses, and 14 (31%) of them showed a clear elevation of the serum NSE level prior to the clinical recognition of relapse. Although one false-positive case was noted, this involved only a transient elevation of the NSE level. In patients who showed increased NSE levels, the relapses occurred in more difficult to detect silent sites such as the adrenal gland, liver, and deep lymph nodes. In addition, the percentage of patients demonstrating high NSE levels who were able to benefit from salvage chemotherapy was higher than for those who did not (RHO < 0.05). Our results indicate that serial NSE measurements are useful for the early prediction of SCLC relapse and should help to facilitate early administration of salvage chemotherapy for affected patients.

PURPOSE We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) support because of the overlapping neutrophil toxicity of both drugs. The aim was to determine the maximum-tolerated dose of CPT-11 combined with a fixed dose of etoposide in patients with advanced lung cancer, as well as the dose-limiting toxicities of this combination. PATIENTS AND METHODS Twenty-five patients with stage III or IV lung cancer, 15 (60%) with prior chemotherapy, were treated at 4-week intervals using CPT-11 (90-minute intravenous infusion on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3). In addition, rhG-CSF (2 micrograms/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. The starting dose of CPT-11 was 60 mg/m2, and it was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS The maximum-tolerated dose of CPT-11 was 90 mg/m2, since two of the three patients developed grade 3 to 4 leukopenia or grade 3 to 4 diarrhea during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the dose-limiting toxicities, while thrombocytopenia was only a moderate problem. Elimination of CPT-11 was biphasic, with a mean +/- SD beta half-life of 18.17 +/- 9.09 hours. The mean terminal half-life of 7-ethyl-10-hydroxycamptothecin (SN-38; the major metabolite of CPT-11) was 43.40 +/- 37.84 hours. There was one complete response (5%) and eight partial responses (38%) among 21 assessable patients, for an overall response rate of 43%. The response rates for small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) were 58% (seven of 12 patients) and 22% (two of nine patients), respectively. CONCLUSION The combination of CPT-11 and etoposide with rhG-CSF support seems to be active against lung cancer, especially SCLC, with acceptable toxicity. The recommended dose for phase II studies in previously untreated patients is 80 mg/m2 of CPT-11 (days 1, 8, and 15) and 80 mg/m2 of etoposide (days 1 to 3) plus 2 micrograms/kg of rhG-CSF (days 4 to 21, except when CPT-11 is given). In addition, 70 mg/m2 of CPT-11 appears to be the appropriate dose for previously treated patients receiving this regimen.

PURPOSE A phase II study was conducted between June 1989 and February 1992 to evaluate the activity and toxicity of photodynamic therapy (PDT) with photofrin II in centrally located early-stage lung cancer and to determine the complete response (CR) rate as the primary end point. PATIENTS AND METHODS Patients had histologically proven lung cancer and endoscopically superficial thickening or small protrusions. All lesions were located in subsegmental or larger bronchi. All patients had a performance status (PS) of 0 to 2 and arterial oxygen pressure tension (PaO2) > or = 60 mm Hg. No lymph node or distant metastases were present. All patients received photofrin II (2 mg/kg) intravenously 48 hours before PDT. Tumor lesions were superficially photoradiated by an argon dye laser or an excimer dye laser. RESULTS Of 54 patients with 64 carcinomas, 51 with 61 carcinomas were eligible for toxicity evaluation and 49 with 59 carcinomas were assessable for response. Of the 59 assessable carcinomas, 50 (84.8%; 95% confidence interval, 73.0% to 92.8%) showed a CR after initial PDT. The median duration of CR was 14.0+ months (range, 2.0+ to 32.4+). The multiple regression model indicates that estimated length of longitudinal tumor extent was the only independent prognostic factor for CR (P = .002). Five carcinomas that had a CR had a local recurrence at 6, 10, 12, 16, and 18 months after initial PDT, respectively. Toxicity assessment (World Health Organization [WHO] grade 2) showed transient elevation of ALT (1.9%), pulmonary toxicity (7.7%), and allergic reaction (7.7%), as well as sunburn (1.9%). CONCLUSION PDT with photofrin II has an excellent effect on patients with centrally located early-stage lung cancer who have limited tumor invasion extending over a small area (< or = 1 cm).

We studied tumor samples from 39 patients, who entered our study from January 1989 to May 1990, to assess whether the ability to establish a continually growing tumor cell line from fresh tumor specimens can be associated with decreased survival times in patients with small-cell lung cancer. The tumor samples were used to establish cell lines in culture using a serum-free medium supplemented with hydrocortisone, insulin, transferrin, estrogen, and selenium (HITES). Thirty-three of these specimens were obtained by fiberoptic bronchoscopy from primary sites during routine diagnostic procedures. A total of 11 (28%) cell lines were established: seven (21%) from 33 primary tumors and four (80%) from five peripheral lymph nodes. Survival times of the 11 patients whose tumor cell specimens continually grew in culture at any time during their clinical course were significantly shorter than those of the 28 patients whose tumor cell specimens did not grow in vitro (median survival time of 26 weeks versus 73 weeks; P = .0068). Cox's proportional hazards model, including sex, age, Eastern Cooperative Oncology Group performance status, stage, source of specimen, treatment, and in vitro tumor cell growth in the overall patient group, showed that cell line establishment (P = .0017) and no therapy (P = .0015) were the most important factors indicating poor survival time. For the subgroup of 23 primary tumor patients, the important factors (in decreasing order) that indicated decreased survival times were the establishment of a cell line (P = .0112) and with cyclophosphamide-doxorubicin-vincristine alternating with cisplatin-etoposide, versus cisplatin-vincristine-doxorubicin-etoposide therapy (P = .0463). Our study demonstrates that in vitro tumor cell growth is an adverse predominant prognostic factor in patients with small-cell lung cancer.

We conducted a randomized trial to compare the efficacy of imipenem/cilastatine (IPM/CS) monotherapy with that of a combination of latamoxef (LMOX) and tobramycin (TOB) in the initial management of fever and neutropenia in patients with lung cancer. Leukocytopenic febrile patients (less than 3,000 leukocytes per microliters; temperature greater than 38 degrees C) with lung cancer given induction therapy were randomly assigned to receive intravenous treatment with either 1 g IPM/CS twice daily or 2 g LMOX plus 90 mg TOB twice daily. A total 101 febrile episodes were studied. Fifty-one episodes were treated with IPM/CS and 50 with LMOX+TOB. Fifty-nine of the febrile episodes were bacteriologically confirmed, while an organism could not be isolated despite the presence of obvious clinical infection in the remaining 42. The response rate was 82% with IPM/CS and 80% with combination therapy. This difference was not statistically significant. The response rate regarding gram-negative infections was 10 out of 14 (71%) in the IPM/CS group and seven out of 12 (58%) in the LMOX+TOB group. This difference was also not significant (P = 0.484). The response rate in severely neutropenic patients (neutrophils less than 100/microliters) was low (P = 0.078). Three patients in the IPM/CS group were withdrawn from the study due to skin rash and vomiting. Therapy with IPM/CS monotherapy was as effective as a combination regimen.

Sensitivity and specificity were evaluated for lung cancer screening conducted at 8 municipalities in Osaka Prefecture during 1981-1985. As a screening policy, all attendants were examined by miniature chest X-ray, and the high-risk group, defined as those who smoked cigarettes or had bloody sputum, were also examined by 3-day pooled sputum cytology. A total of 33,599 screening tests for 19,028 people who were 40 years old or more at the time of screening were conducted, resulting in 33,490 miniature chest X-ray examinations for 18,992 people and 11,420 sputum cytologies for 7,070 people. As a result, 43 lung cancer cases were detected. All test-negatives were followed by means of record linkage with the files of the Osaka Cancer Registry up to the end of 1986. There were 24 cases who were diagnosed as having lung cancer without having given a positive screening result in 1981-1986. Assuming the preclinical detectable phase of lung cancer to be one year uniformly, the sensitivity and specificity for the lung cancer screening were estimated to be 71.6% and 95.3%, respectively. The feasibility of increasing the sensitivity is discussed.

Most patients with small-cell lung cancer usually relapse within 1 to 2 years. Relapses after a 5-year disease-free interval occur extremely rarely. This report describes a patient with limited-stage small-cell lung cancer who had achieved a complete response to combination chemotherapy followed by chest irradiation but developed small-cell lung cancer 9.4 years after the beginning of therapy. Small-cell lung cancer recurred in the same side of the lung, in the mediastinal nodes, and in the liver. The pattern of development of small-cell lung cancer suggests that the patient had a relapse rather than a metachronous lung cancer. To our knowledge, this is the second-latest relapse of small-cell lung cancer in the literature.

A randomized trial of combination therapy with bestatin (30 mg daily, every day) was performed in 238 patients with inoperable primary lung cancer from August, 1981 through April, 1984. Of the 238 patients, 227 were evaluable: 113 treated by bestatin combination therapy and 114 controls. There was no statistically significant difference in response rate or survival between the 2 groups. In squamous cell cancer response was observed in 34.5% of the bestatin group and 17.9% of the control group. The analysis, including Cox's proportional hazard model, revealed that the survival tended to be longer in the bestatin group (median survival 40 weeks) than in the control group (median survival 24 weeks; p = 0.051). This suggests that addition of bestatin might be beneficial in squamous cell cancer of the lung but further, more rigidly controlled, clinical trials are necessary before more definitive conclusions can be drawn.

Aiming at early detection of “hilar-type” lung cancer by sputum examination, we examined the morphological characteristics of what we call “early cancer” cells which were observed in the sputum of 22 cases of hilar-type early stage lung cancer. Two types of cells were found: “superficial-type” cancer cells and “parabasal-type” cancer cells. Cytological screening needs great care, because the cytoscreener is liable to mistake these cancer cells for normal-ranged epithelial cells. It has become easier to detect early lung cancer by looking for not only superficial-type cells but also parabasal-type cells.

One hundred and seventy-four patients with small cell lung cancer (SCLC) treated with combination chemotherapy, with or without chest radiation, were analyzed. Fourteen patients (8%) survived for 3 years or more. Three-year disease-free survival continued for 12 of the 101 patients (12%) with limited disease, and one of 75 (1%) with extensive disease (P less than 0.05). Patients' sex and performance status were not important in achieving long-term survival. All disease-free survivors, except two who could not be evaluated, achieved a complete response. Although the treatment programs had some influence on the long-term survival rates (P less than 0.05), thoracic radiation did not have significant impact on long-term survival. Three of the 13 patients (23%) developed second malignancies and died, and one of these patients also suffered from a progressive neurologic deterioration with dementia. Two other patients died free of SCLC. Consequently, eight have remained alive and free of disease. The last relapse was observed at 1.5 years from beginning of treatment. The disease-free survival may offer the hope of cure of SCLC. However, the survivors are at an increased risk of developing late complications including second malignancies and neurologic abnormalities. Therefore, careful follow-up will be necessary.

After stratification for the extent of disease, previously untreated patients with small cell lung cancer randomized to receive therapy with the four-drug combination of cyclophosphamide, oncovin, nimustine hydrochloride (ACNU), and procarbazine (CONP) every four weeks (continuous regimen) or to receive CONP alternating with the three-drug combination of etoposide (VP-16), adriamycin and cisplatin (VAD) at four-week intervals (alternating regimen). Sixty-nine patients were entered in the study. Of 34 evaluable patients receiving the continuous regimen, six (17.6%) achieved complete response (CR) and 16 (47.1%) achieved partial response (PR). Of 31 evaluable patients receiving the alternating regimen, 10 (32.3%) achieved CR, and 16 (51.6%) achieved PR. There was a tendency in favor of the alternating regimen in CR and over-all response rates (0.05 less than p less than 0.1). There were no significant differences between the regimens in response duration or survival. The projected median survival times were 9.2 months and 9.4 months for the continuous and alternating regimens, respectively. One patient receiving the continuous regimen and three receiving the alternating regimen have been living for more than two years. The major toxicity was myelosuppression in both regimens. One patient died of hemorrhage due to thrombocytopenia during induction with CONP, and one patient died of cisplatin-induced renal failure. We conclude that alternating non-cross resistant chemotherapy leads to improved CR and response rates, but does not improve survival.

A rare lung cancer consisting in part of small cell carcinoma of intermediate cell type and in part of well-differentiated papillotubular adenocarcinoma is described. Alcian blue-PAS staining was observed in the cytoplasm of the small cell carcinoma cells; the Grimelius argyrophil reaction was also positive in the cytoplasm of these cells. Electron microscopy revealed neurosecretory granules in the cytoplasm. At autopsy, a small cell carcinoma of intermediate cell type was found with both squamous features and gland formation. The cellularity and histological pattern of this tumor suggested the existence of a transitional pattern between small cell carcinoma of intermediate cell type, squamous cell carcinoma and adenocarcinoma. From the above findings, we think that small cell carcinoma including the intermediate cell type is derived from respiratory epithelial cells of endodermal origin with dedifferentiation of those cancer cells into neurosecretory cells.