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Background: Small cell lung carcinoma (SCLC) has poor prognosis and remains orphan from targeted therapy. MET is activated in several tumour types and may be a promising therapeutic target., Methods: To evaluate the role of MET in SCLC, MET gene status and protein expression were evaluated in a panel of SCLC cell lines. The MET inhibitor PHA-665752 was used to study effects of pathway inhibition in basal and hepatocyte growth factor (HGF)-stimulated conditions. Immunohistochemistry for MET and p-MET was performed in human SCLC samples and association with outcome was assessed., Results: In MET mutant SCLC cells, HGF induced MET phosphorylation, increased proliferation, invasiveness and clonogenic growth. PHA-665752 blocked MET phosphorylation and counteracted HGF-induced effects. In clinical samples, total MET and p-MET overexpression were detected in 54% and 43% SCLC tumours (n = 77), respectively. MET phosphorylation was associated with poor median overall survival (132 days) vs p-MET negative cases (287 days) (P < 0.001). Phospho-MET retained its prognostic value in a multivariate analysis., Conclusions: MET activation resulted in a more aggressive phenotype in MET mutant SCLC cells and its inhibition by PHA-665752 reversed this phenotype. In patients with SCLC, MET activation was associated with worse prognosis, suggesting a role in the adverse clinical behaviour in this disease.

Background: There is a need for early detection methods for lung cancer. Radiologic imaging may be more sensitive for peripheral cancers than for cancers arising in the central airways, from which bronchial epithelial cells are exfoliated into the sputum., Methods: Sputum samples were collected at baseline and periodically thereafter in a cohort of smokers and former smokers with chronic obstructive lung disease. The association between cytologic atypia and incident lung cancer was assessed by hazard ratios (HR; 95% confidence intervals) using Cox regression and by odds ratios (95% confidence intervals) using logistic regression, adjusting for potential confounding factors., Results: We observed 174 incident lung cancers in a cohort of 2,521 people over 9,869 person-years of observation. Risk for incident lung cancer was increased among those with cytologic atypia graded as moderate or worse (adjusted HR, 2.37; 1.68-3.34). The association between sputum atypia and lung cancer incidence was greatest for those sputum samples collected 5 months or less before the diagnosis of lung cancer (odds ratio, 10.32; 5.34-19.97). The association was substantially stronger for squamous cell lung cancers (HR, 5.13; 2.89-9.10) than for adenocarcinomas (HR, 1.85; 0.94-3.65)., Conclusion: Cytologic atypia is a marker for increased lung cancer risk. These cytologic changes seem to arise from late events that are most apparent for cancers arising in the central respiratory airways. Whether cytologic atypia might complement radiologic imaging in a combined approach to lung cancer, early detection requires additional evaluation of those two methods used together.

Pulmonary neuroendocrine tumors are currently considered to consist of three grades of malignancy, ranging from typical and atypical carcinoids to large-cell neuroendocrine carcinoma and small-cell carcinoma. The study reported here is the first population-based study of the demographics of patients with neuroendocrine tumors grouped by histological subtype. A cancer registry-based analysis of patients in Denmark in whom bronchial neuroendocrine tumor was diagnosed in 1978-97 was performed and the patients were followed up to 31 December 1999. Typical carcinoid was diagnosed in 105 patients, atypical carcinoid in 192, large-cell neuroendocrine carcinoma in 50 and small-cell carcinoma in 11,998. The recorded incidence of neuroendocrine tumors other than small-cell carcinoma increased by twofold among men (from 0.24 to 0.53 per 100,000 inhabitants per year) and by threefold in women (from 0.14 to 0.41 per 100,000 inhabitants per year) during the study period, while the incidence of small-cell carcinoma decreased among men and levelled off among women. The prognosis of patients with bronchial neuroendocrine tumors varied with the degree of malignancy; the 5-year survival rate ranged from 87% for patients with typical carcinoids, to 44, 15 and 2% for patients with atypical carcinoids, large-cell neuroendocrine carcinoma and small-cell carcinoma, respectively. In Denmark, the incidence of neuroendocrine tumours is increasing. Our findings support the pathological categorization of neuroendocrine tumors into three grades of malignancy. More research is needed to establish the etiological factors in the development of pulmonary neuroendocrine tumors.

Purpose: A prospective randomized trial in small-cell lung cancer (SCLC) was performed to determine if intensification of the platinum dose by giving cisplatin and carboplatin in combination to patients with SCLC yields higher response rates and survival, than carboplatin alone in a combination chemotherapy regimen., Patients and Methods: Between September 1992 and October 1997, 280 patients were included in a two armed prospective randomized trial, stratified by stage of disease, LDH and performance status. The treatment was in arm A: three courses induction chemotherapy with carboplatin (AUC = 4, day 1), cisplatin (35 mg/m2, days 2 and 3), teniposide (50 mg/m2, day 1-5), vincristine (1.3 mg/m2, day 1) every four weeks, followed by cyclophosphamide (3 g/m2, day 84), 4-epirubicin (4-epidoxorubicin) (150 mg/m2, day 112), and finally one course cisplatin, carboplatin, teniposide and vincristine, (days 140-144). Arm B also comprised a total of six courses, identical to those in arm A except for omission of cisplatin., Results: There were no significant differences in the overall treatment outcome for A vs. B, in terms of response rates (72% in both arms), complete response rates (40% and 34%, respectively), or median survival (314 days and 294 days, respectively). However, for patients with limited disease both the CR rate (54% vs. 37%, P < 0.05), overall survival (log-rank test, P < 0.05), and the two-year survival rate (11% vs. 6%, P < 0.05) were higher in the high-dose platinum arm compared to the carboplatin alone arm., Conclusions: The intensification of platinum dose (cisplatin plus carboplatin) in combination chemotherapy significantly increased the complete response rate, overall survival and number of two-year survivors among SCLC patients with limited disease compared to combination therapy with carboplatin alone, suggesting that a more aggressive treatment to this category of patients is worthwhile, while no difference in treatment outcome was observed for patients with extensive disease.

Background: The aim was to define the MTD of topotecan (TPT) given before cisplatin in patients with previously untreated SCLC., Patients and Methods: Alternating cycles A and B to a total of 6 cycles were given. Cycle A: TPT days 1-5 and cisplatin (50 mg/m2) day 5. Cycle B consisted of teniposide, carboplatin, vincristine, and cisplatin. TPT was escalated at doses 0.75, 1.0, 1.25, and 1.5 mg/m2. DLT was defined for the first cycle as grade 4 neutropenia with fever or when lasting > 7 days, or grade 4 thrombocytopenia., Results: Fifteen patients with limited disease and six patients with extensive disease were included. No episodes of DLT were recorded in the first cycles A and consequently 1.5 mg/m2 was defined as MTD. At 1.5 mg/m2 (11 patients, 30 cycles), four and three episodes of grade 4 thrombocytopenia and neutropenia lasting more than seven days occurred in subsequent cycles A. Thrombocytopenia and anaemia were cumulative as more cycles were administrated. Non-hematological toxicity was mild. The response rate was 86% (95% confidence interval (95% CI): 64%-97%) with 33% (95% CI: 15%-57%) achieving CR., Conclusions: 1.5 mg/m2 TPT can be delivered safely with 50 mg/m2 cisplatin on day 5 in patients with previously untreated SCLC.

Based on an increased frequency of early death (death within the first treatment cycle) in our two latest randomized trials of combination chemotherapy in small-cell lung cancer (SCLC), we wanted to identify patients at risk of early non-toxic death (ENTD) and early toxic death (ETD). Data were stored in a database and logistic regression analyses were performed to identify predictive factors for early death. During the first cycle, 118 out of 937 patients (12.6%) died. In 38 patients (4%), the cause of death was sepsis. Significant risk factors were age, performance status (PS), lactate dehydrogenase (LDH) and treatment with epipodophyllotoxins and platinum in the first cycle (EP). Risk factors for ENTD were age, PS and LDH. Extensive stage had a hazard ratio of 1.9 (P = 0.07). Risk factors for ETD were EP, PS and LDH, whereas age and stage were not. For EP, the hazard ratio was as high as 6.7 (P = 0.0001). We introduced a simple prognostic algorithm including performance status, LDH and age. Using a prognostic algorithm to exclude poor-risk patients from trials, we could minimize early death, improve long-term survival and increase the survival differences between different regimens. We suggest that other groups evaluate our algorithm and exclude poor prognosis patients from trials of dose intensification.

During the past two decades many different treatment regimens of combination chemotherapy have been applied in extensive stage small-cell lung cancer (SCLC). This study was carried out to identify whether these modifications have resulted in an improved overall survival for extensive stage during the past two decades. In total, 1111 patients with extensive stage SCLC were included in six consecutive randomised trials in our setting from 1973 until 1992. Of these, 526 patients treated in the early period (1973-1981) were compared with 585 patients treated in the late period (1981-1992) with respect to pretreatment prognostic factors, staging, treatment and outcome. No change in the distribution of prognostic factors was detected and the frequency of patients with extensive stage was equal in the two periods, and no difference in overall response rates and survival was observed (P = 0.49). Median survival in the two periods was 208 days and 215 days, respectively. No stage migration or treatment-related improved outcome was observed in extensive disease. We suggest restricting aggressive treatment to patients with favorable prognosis and long-term survival as a realistic aim.

Purpose: The introduction of platinum compounds and epipodophyllotoxins in combination with vincristine as induction chemotherapy in small-cell lung cancer (SCLC) was investigated in order to: (1) compare the efficacy of cisplatin with that of carboplatin in combination with teniposide and vincristine as inducers of remission over three cycles; (2) compare the toxicity pattern of carboplatin and of cisplatin when given in combination regimens; and (3) compare a chemotherapeutic regimen consisting of three alternating combinations with that of regimens consisting of four alternating combinations., Patients and Methods: From November 1985 to September 1991, 484 consecutive, previously untreated patients with SCLC, performance status 0-4, entered a three armed randomized trial with three cycles of cisplatin (arm I) or carboplatin (arm II) in combination with teniposide and vincristine alternating with three treatment blocks of cyclophosphamide, etoposide, lomustine and vincristine (block A), doxorubicin and vincristine (block B) and cisplatin, hexamethylmelamine and vindesine (block C) versus alternating treatment with block A, B and C (arm III)., Results: No difference in efficacy or toxicity was found between cisplatin and carboplatin at the present dosages. Induction chemotherapy with teniposide plus cisplatin or carboplatin did not result in higher complete response rates (objective response rates 63%, 72% and 65%, respectively) or in significantly greater toxicity, but overall survival was superior compared with the arm III (log-rank test, P = 0.02). The median survival difference was 7 weeks, and two year survival 15% versus 9%. The Cox regression analysis identified the arm III, poor performance status and elevated LDH as factors with statistically significant negative impact on survival., Conclusion: Cisplatin and carboplatin produced similar response and survival rates and similar toxicity. Induction with platinum and epipodophyllotoxins did not improve objective response rates, but significantly improved survival without increasing the toxicity.

The present article is a review of recent treatment protocols for patients with small cell lung cancer (SCCL) treated in Copenhagen from 1985 to 1990. Furthermore, preliminary data on long-term survivors (> 5 years) from 9 treatment protocols since 1973 are reviewed. For 484 patients < or = 70 years old, no survival difference was observed between 2 platinum (cis-platinum or carboplatin) containing regimens, while the survival was better in these two induction regimens compared to an alternating control arm. For patients > 70 years old, Etoposide (VP-16) and Teniposide (VM-26) were compared in a randomized fashion. Both drugs were highly active, and no significant difference in activity was observed. All together 1527 patients have been included in clinical trials in the Copenhagen Lung Cancer Study Group since 1973. The rates of 5- and 10-years survivors were 3.5% and 1.8% respectively. Long-term survival can be achieved in all stages of SCCL.

An immunohistochemical study has been carried out on fibre optic-biopsy specimens from patients with small cell lung cancer (SCLC) who had either died within 3 months, or who had survived more than 2 years. Long term survivors (LTS) were identified from completed clinical trials at major UK centres and were matched for age and sex within the trial with short term survivors (STS). The panel of immunohistochemical markers included those previously reported to be associated with prognosis, and reagents representative of both neuroendocrine and epithelial differentiation. A preliminary screen of 17 antibodies identified 11 as consistently reactive on paraffin-embedded material using streptavadin-biotin immunoperoxidase. Of 186 identified patients, 110 biopsy samples were retrieved. Of these, 70 gave sufficient material for analysis. All sections were scored by three observers without knowledge of the prognosis. The analysis failed to identify any antigen whose expression was correlated with prognosis. We conclude that, in fibre-optic biopsy specimens, immunohistochemical analysis does not add prognostic information in SCLC.

One hundred six patients with small cell lung cancer (SCLC) were prospectively evaluated with regard to the prognostic impact of abdominal CT-scan in the pretreatment staging when compared to ultrasonography of the abdomen. Staging based on abdominal ultrasonography (US) plus bilateral bone marrow examinations gave as a result that 47 patients had extensive disease (ED) (44%). Seventeen patients with proven ED at time of referral were not included in this study. Abdominal CT-scan was performed in 76 of the 106 patients. Thirty patients of these 76 patients (39%) were classified as having ED after staging including US, but abdominal metastases were disclosed in another ten patients at the subsequent CT-scan. Liver metastases seen in two patients at ultrasonography were overlooked on the CT-scans. Median survival of the 36 patients classified as having limited disease (LD) after both procedures was 458 days, which was significantly better compared to 330 days for the ten patients with stage migration from LD to ED based on CT-scan, (p less than 0.05) and compared to 242 days in the 30 patients with ED demonstrated by both US and CT-scans (p less than 0.05). The prognostic impact of the CT-scan was further investigated in a multivariate analysis (Cox). Stage disease, performance status, LDH and alkaline phosphatase were significant prognostic factors in a proportional hazards model based on the original 106 patients. Patients in the best prognostic group were characterized by LD, good performance status (0-1) and normal LDH and alkaline phosphatase serum values. This group consisted of 22 patients (21%).(ABSTRACT TRUNCATED AT 250 WORDS)

Using conventional examination (CE) of H&E stained slides from bone marrow aspirates, metastases can be detected in approximately 25% of patients with small cell lung cancer. We investigated a panel of monoclonal antibodies using immunohistochemistry in the diagnosis of bone marrow infiltration from SCLC and compared the results with CE. Seven monoclonal antibodies raised against epithelial antigens (CAM 5.2, MOV 15, NCCST 433, PE 35, LCA1/L38, HMFG 1 AND HMFG 2) were applied on bone marrow sections from three groups of patients (pts): (1) 19 pts in whom SCLC-metastases were detected by CE, (2) 44 pts with SCLC in whom metastases could not be detected by CE, and (3) 20 pts with non-malignant bone marrow diseases. All the antibodies except LCA1/L38 were positive in 60-90% of the slides with infiltrating tumour cells in group 1. No positive tumour cells were detected in group 2. A few plasma cells and megakaryocytes were slightly positive for MOV 15 and NCCST 433, but no other positive cells were detected in group 3. In conclusion, the monoclonal antibodies used in this study may be useful for diagnostic purposes when a suspicious looking infiltration is detected by CE. However, these antibodies could not detect metastatic tumour cells in the bone marrow sections from patients in whom CE did not reveal any tumour cells.

The presence of 'small cell lung cancer antigens' was evaluated in pretreatment biopsies of primary SCLC, liver metastases, and/or bone marrow metastases from 46 patients. The antigen expression was detected immunohistochemically by applying monoclonal antibodies to routinely formalin-fixed and paraffin embedded tissue. The antibodies applied were second workshop codes: 3(CAM 5.2), 45 (MOV15), 54 (NCCST433), 75 (PE35), 81 (HMFG-1), 95 (LCA1/L38) and HMFG-2 123C3, F4 and MOC-21. High expression was observed for WS 3, 45, 75, 81 and HMFG-2, both in the primaries and metastases. A good correlation was observed between the presence of antigens in primary biopsies and metastases, but there was a general tendency toward a lower proportion of positive tumour cells in the metastases compared to the primaries. For WS 45, 54, 75 and 95 the difference between primaries and bone marrow was statistically significant, and this was also true for WS 45 and 81 in the liver. The clinical relevance is discussed.

An analysis has been made of the relationship between neuron specific enolase (NSE) in serum and immunohistochemically identified occurrence of NSE in the primary tumour in 56 patients with small cell lung cancer (SCLC). Patients were referred to the Finsen Institute for treatment during a period of 18 months. Forty-six tumours (82%) were NSE positive. To compare this staining with the occurrence of NSE in serum, a histological staining index (HSI) was established by semiquantitative gradation of the staining. No significant differences were found between distribution of serum NSE values in different HSI categories, and a high ranking in HSI was not associated with a high level of serum NSE. Both univariate and multivariate analysis selected serum NSE and not HSI as the most influential prognostic factor in SCLC.

The outcome of two different alternating regimens of chemotherapy was investigated in a prospective controlled trial in limited-stage small-cell lung cancer (SCLC). Both regimens comprised cyclophosphamide, lomustine, vincristine, methotrexate, doxorubicin and etoposide administered in different schedules. The investigative regimen (B) included simultaneous administration of cyclophosphamide + lomustine alternating with cyclophosphamide + doxorubicin, and with doxorubicin + lomustine. The hypothetical superiority of this regimen was based on data from experimental animal tumors suggesting potentiated efficacy of the three specific combinations. A total of 234 patients were included, and 113 vs 108 patients were eligible. Median survival in both groups was 48 weeks (p = 0.89). Complete remissions were observed in 36/101 and in 42/99 patients evaluable for response. There was no significant difference in response duration. At restaging after 18 months of chemotherapy 27 patients (16%) and 22 patients (16%), respectively, were free of disease. Six patients, three in each arm, are still alive, 8+ to 10.5+ years after diagnosis. Scheduled doses of the six agents were the same in the two regimens except for a 30% reduction of every second dose of cyclophosphamide in regimen B. Nevertheless, regimen B resulted in significantly more leukopenic patients, septicemic episodes, and blood transfusions, and the dosage of etoposide was more often reduced in arm B than in arm A. The increased toxicity was not associated with improved treatment results.

Flow-cytometric DNA analysis yields information on ploidy and proliferative characteristics of a cell population. The analysis was implemented on small-cell anaplastic carcinoma of the lung using a rapid detergent technique for the preparation of fine-needle aspirates for DNA determination and a newly developed procedure for storing aspirates at -80 degrees. Thirty-eight different metastases in 30 consecutive patients with small-cell anaplastic carcinoma of the lung were examined with a total of 273 fine-needle aspirations. The results on ploidy are reported in this paper. The degree of contamination of the aspirates with normal cells was determined by differential counts. The ratio of the peak channel numbers for the G1 phase of the tumor cells to that of the diploid standard (DNA index) was calculated and used for ploidy identification. Twenty-nine patients were evaluable with respect to DNA index determination. The coefficient of variation of the DNA index determinations was estimated as 0.039. In 23 (79%) patients, only one cell line could be detected. Evidence of the presence of 2 tumor cell clones with different ploidy was obtained in the remaining 6 (21%) patients. Of the 35 malignant clones thus demonstrated, 26 (74%) were significantly different from diploid (p less than or equal to 0.01). Four (11%) were hypodiploid, 3 (9%) were hypotriploid, and 19 (54%) were hypo- or near-tetraploid. Clonal heterogeneity in the tumors of 21% of the patients is a conservative estimate. Assessment of the detection limit set by the methodology used and the restricted number of samples studied in each patient indicate that the true occurrence of clonal heterogeneity in small-cell carcinoma of the lung may be much higher.

Considerable attention has been devoted to the diagnosis of small cell lung carcinoma (SCLC) and its subtypes. In the literature contradictory opinions have been published concerning the clinical implications of subtyping, largely because of the different criteria used by different pathologists. This article is a consensus report by the Pathology Committee of the International Association for the Study of Lung Cancer. The following classification of SCLC is recommended: (1) Small cell carcinoma. This subtype includes most of the tumors previously included in the oat cell and intermediate subtypes. More than 90% of untreated SCLC fall into this category. (2) Mixed small cell/large cell carcinoma. This subtype, which may be associated with a poor prognosis and response to therapy, contains a spectrum of cell types ranging from typical SCLC to larger cells having prominent nucleoli and resembling large cell carcinoma. (3) Combined small cell carcinomas. Typical SCLC elements are intimately admixed with areas of differentiated squamous cell or adenocarcinoma. This simplified classification of SCLC will facilitate uniformity in the diagnosis and further our understanding of the clinical significance of the rarer SCLC with variant morphologies.

A consecutive series of 104 autopsies on patients treated in protocol for small cell carcinoma of the lung (SCCL) was studied with respect to metastatic pattern at autopsy in relation to pretreatment WHO 1981 classification, and extent and significance of non-SCCL tumor tissue at autopsy. The only significant difference in the metastatic pattern at autopsy between patients with pretreatment oat cell or intermediate subtype was metastases to the brain. Thus, the frequency of brain metastases was 17/35 (49%) in patients with oat cell type compared to 2/18 (11%) in patients with intermediate type (P less than 0.05). At autopsy 13 of 98 patients (13%) had non-SCCL tumor tissue in at least one site. These patients had a significantly shorter survival (P = 0.020) compared to patients with pure SCCL at autopsy. Furthermore, none of these 13 patients had obtained complete remission. Whether these morphologic variations had been present at the pretreatment stage of the disease or were due to the chemotherapeutic treatment could not be solved in the present study. However, the results might indicate that mixed SCCL/non-SCCL histology is a negative prognostic factor in the treatment of SCCL. Prospective studies including more extensive pretreatment tissue sampling seem to be required.

Two hundred-twelve consecutive patients with small cell carcinoma of the lung were studied in order to correlate the risk of developing intracranial metastases to the initial stage of the disease (locoregional versus extensive) and to evaluate the prognostic significance of developing intracranial dissemination of the disease. Clinically detected intracranial metastases were observed in four percent at the time of primary diagnosis, and an additional 18 percent developed metastases during treatment. As regards clinically observed metastases during treatment, no difference was found between the two initial staging groups. Intracranial metastases without clinical evidence of progressive disease elsewhere were demonstrated in 10 out of 205 patients (5%). The median survival time after clinical presentation of intracranial metastases was 85 days for patients with locoregional disease versus 60 days for patients with extensive disease. A significantly shorter survival time was observed for patients with intracranial metastases at 0, 100, 200 and 300 days after start of treatment compared to patients still alive without metastases at those times. Brain autopsy was performed in 82 patients and was positive in 42 (51%). No statistical difference in the frequency of brain metastases was demonstrated when compared to the initial stage of the disease. No difference was observed between the two initial staging groups of patients with regard to risk of developing brain metastases. Autopsy substantiated that there was no difference between patients with and without brain metastases as regards survival. However, clinical intracranial metastases were followed by a short survival time, and only a small fraction of the patients developed clinically isolated intracranial relapse.

Bilateral bone-marrow examinations from the posterior iliac crests were routinely performed as a pretreatment staging procedure in 89 consecutive patients with small-cell anaplastic carcinoma of the lung. Bone-marrow involvement was found in 20 patients (22.5%), in 9 (10.1%) only on one side, and in 11 (12.4%) on both sides. Aspiration was found to be significantly superior to biopsy, being positive in 25 examinations as compared with 14 positive biopsies. Compared with unilateral bone-marrow examination the positive findings increased by approximately 30%. Bilateral bone-marrow examinations are recommended in patients in whom the detection of bone-marrow metastases will have therapeutic implications.

Carriers of Z-gene alpha 1-antitrypsin deficiency (A-1-ATD) have characteristic periodic acid Schiff (PAS) positive diastase resistant globules in hepatocytes. In order to determine a possible relationship between Z-gene A-1-ATD and small cell carcinoma of the lung (SCCL), we examined liver blocks from 88 consecutive autopsies performed on patients with SCCL and from a control group of 88 patients with carcinoma not primarily located in the lung or the liver. Histological evidence of Z-gene-A-1-ATD was 4.5% in both groups, corresponding to the expected frequency of Z-gene carriers in a Scandinavian population. It is therefore unlikely that Z-gene A-1-ATD has a role in the development of SCCL.

Two hundred-twelve consecutive patients with small cell carcinoma of the lung were included in an evaluation of clinical and diagnostic neurologic findings of intracranial metastases. A correlation of premortem findings to postmortem examination of the brain was obtained in 87 of the patients. Clinical intracranial metastases were diagnosed in 21.2% on the basis of symptoms and signs. At autopsy 44 of the 87 patients (50%) had metastases. Lesions located to the posterior cranial fossa were demonstrated in 53% of the positive autopsies. A correlation of 96% existed between significant premortem clinical findings and positive autopsy, while 33% had clinically "silent" metastases at autopsy. A neuro-oncologic examination was performed in 49 patients at the time of presentation of neurologic symptoms. Twenty-eight patients were considered to have intracranial metastases. Gait disturbances were the presenting signs in more than 50% of the patients. Brain metastases were demonstrated at autopsy in 14 of 15 patients considered to have intracranial metastases by the neuro-oncologist, and clinically "silent" metastases were observed in one out of 10 patients. Radionuclide brain scan was negative in seven of 13 patients in spite of "positive" neuro-oncological examination had a subsequent positive autopsy. Cerebrospinal fluid examination was of no value in the diagnosis of brain metastases. It is concluded that a careful clinical examination by a neuro-oncologist is of great value in early detection of brain metastases, especially in diagnosing metastases to the posterior cranial fossa.

In order to evaluate the consistency in diagnosing the morphologic subtypes of small cell carcinoma of the lung (SCCL), 93 microscopic slides were blindly classified by three panelists according to the World Health Organization's (WHO) Lung Tumor Classifications of 1967 and 1981. Unanimity in the diagnosis of SCCL as the main cell type was obtained in 91 and 94% respectively. With regard to the diagnosis of the various morphologic subtypes unanimity among the three panelists was achieved in 38% according to the WHO 1967 classification and in 54% using the 1981 classification. It is concluded that the criteria used for SCCL as a distinct histopathologic entity were reproducible among the different panelists. However, different criteria were applied in the diagnosis of the morphologic subtypes of SCCL. This fact could explain the contradictory results of clinical studies reported in the literature concerning subtyping of SCCL.

In a 2-year period, 146 patients with small cell carcinoma of the lung, staged as having extensive disease, were randomized to receive either continuous chemotherapy consisting of (a) 1-(2-chloroethyl-3-cyclohexyl-1-nitrosourea, cyclophosphamide, methotrexate, and vincristine followed by (b) 4'-demethylepipodophyllotoxin 9-[4,6-O-(R) ethylidene-beta-D-glucopyranoside] and doxorubicin at progression of disease or a regimen of (a) alternating with (b). Seventy-six patients received the continuous regimen; 70 patients received alternating treatment. Response rates were 68 and 72%, respectively. The median duration of response was 16 weeks in patients receiving continuous treatment compared to 28 weeks in patients receiving alternating treatment (p less than 0.05). No survival time difference was observed between the groups, median survival being 36 and 38 weeks, respectively. Four patients became long-term survivors (5.6 +, 5.5 +, 5.1, and 4.7 + years). All received alternating therapy. Six toxic deaths were observed among patients receiving continuous therapy compared to only one death among those in the alternating regimen. In conclusion, alternating combination chemotherapy leads to prolonged duration of remission. Duration of survival is not prolonged in uncured patients, but an increased possibility of long-term disease-free survival cannot be precluded.

Two hundred and eighty-eight patients with extensive small-cell carcinoma of the lung (SCCL) were entered into a three-arm prospective randomized trial. The purpose was both to compare etoposide with methotrexate (MTX) in a combination chemotherapy regimen otherwise consisting of vincristine (VCR), lomustine (CCNU), and cyclophosphamide (CTX) and to evaluate a treatment design based on cell kinetic observations suggesting enhanced sensitivity to etoposide three to six days after administration of VCR, CCNU, and CTX. In all three treatment arms, VCR, CCNU, and CTX were administered on day 1 of a 28-day cycle. In arm A, MTX was administered on days 14 and 17, while in arm B, MTX was replaced by etoposide administered on days 14 through 17. In arm C, MTX was also replaced by etoposide, but administered on days 3 through 6. Overall survival was significantly longer for patients treated with "early" etoposide (arm C; median, 33 weeks) as compared with arm A (MTX; median, 23 weeks) (P less than .05), but not statistically different from "late" etoposide administration (arm B; median, 27 weeks). However, for patients with initial favorable performance status (0 + 1), a significantly longer survival was obtained for those treated with early etoposide (arm C. median, 51 weeks) as compared with patients in arm A (median, 32 weeks) and arm B (median, 36 weeks) (P less than .05). Two-year survival was obtained in six patients (7%) in arm C compared with three patients (3%) in arm B and none in arm A. The study confirmed that etoposide is an active drug in the treatment of SCCL and when combined with CTX, CCNU, and VCR, the cell kinetic approach of an early administration yields the best results.

Postmortem material from 537 patients included in various protocols of intensive combination chemotherapy or chemoradiotherapy for the management of small-cell anaplastic carcinoma of the lung (SCLC) has been reviewed. Patterns of residual or recurrent disease were analyzed in relation to pretreatment clinical parameters. Residual primary tumor (P less than .05), regional lymph node involvement (P less than .01), hepatic (P less than .01), bone (P less than .05), and renal metastases (P less than .05) were all significantly less frequent among patients with initially limited-stage disease compared with extensively staged patients. The frequency of residual intrathoracic tumor and metastatic pattern did not significantly differ between partial responders (PRs) and nonresponders (NRs). Patients with limited disease achieving a complete remission had a lower frequency of intrathoracic tumor (P less than .001) at autopsy compared with limited-stage PRs. However, for extensive-stage patients the pattern of residual disease was essentially independent of tumor response. Prior surgery was associated with a reduced burden of metastases only in those who underwent a radical resection. The addition of radiotherapy to the primary tumor and mediastinum failed to modify the autopsy distribution of residual tumor compared with that in patients treated with chemotherapy alone. Metastatic patterns were similar with or without prophylactic abdominal radiotherapy, while prophylactic cranial irradiation (PCl) did not prevent the development of cerebral metastases in patients whose systemic response to treatment was either partial or nonexistent. However, a beneficial effect of PCl in compete responders (CRs) was not excluded.

Three hundred seventy-five consecutive patients treated with intensive chemotherapy in the same institution are included in this study in order to evaluate the prognostic significance of the World Health Organization's (WHO) subclassification of small cell lung cancer. Morphologic subtyping, based on primary biopsy specimens, was obtained in 200 patients. Oat cell type was diagnosed in 106 patients (53%), while intermediate subtype was diagnosed in 93 patients (47%), including 27 patients (14%) with small cell/large cell morphologic features. One patient had combined oat cell type. No difference in survival period was observed between the group of patients classified as oat cell versus the group with intermediate subtype. However, a significantly shorter survival period was demonstrated for patients with small cell/large cell features compared with patients with pure small cell carcinoma (median 168 days versus 280 days, P less than 0.01). It is concluded that there is no difference in survival period between patients with oat cell and intermediate subtype of small cell lung cancer using the criteria of the WHO. However, it might be of prognostic importance to identify patients with tumors demonstrating small cell/large cell features.

An electron microscopic study of 28 small cell carcinomas of the lung is presented. Cytoplasmic secretory granules, characteristic of endocrine cells of the human foetal lung were observed in a variable number of tumor cells. Two groups of tumors could be distinguished based on the morphology of the cytoplasmic secretory granules. Twenty-three tumors showed cells with granules resembling type 1 or P1 cells of the human fetal lung, and 5 tumors with granules resembling type 3 cells of the human fetal lung. No relationship was found between the light microscopic WHO classification of small cell carcinoma of the lung and the results obtained by electron microscopy. Increased serum calcitonin as well as inappropriate ADH secretion may be correlated with one of the two types of small cell carcinoma, but further investigations are needed.

To elucidate the ectopic hormonal pattern in patients with small cell carcinoma of the lung, plasma ACTH, serum calcitonin, serum gastrin, plasma glucagon, serum insulin, plasma secretin, plasma VIP, serum growth hormone, serum hCG/LH, the total of serum hCG and hCG-beta-subunit,serum alpha-subunit, serum human placental lactogen, urine ADH, urine 5-HIAA, urine VMA, urine HVA, and urine hCG-LH were measured prior to therapy in 75 patients. Twenty-two patients (29%) had elevated plasma ACTH, and 18 of these had concomitant increased values of corticosteroid in a 24-hour urine sample. Forty-eight patients (64%) were found to have elevated serum calcitonin, and one-third of the patients were diagnosed as having the ectopic ADH syndrome. Serum gastrin concentrations were increased in 20% of the patients, but the elevations were marginal in almost all cases. None of the remaining substances was found to be significantly elevated. Concentrations of plasma ACTH, serum calcitonin, and urine ADH were not found to be correlated with the stage of the disease, and no correlation of these substances with the histological subtypes of small cell carcinoma was disclosed.