Comparison of induction chemotherapy before radiotherapy with radiotherapy only in patients with locally advanced squamous cell carcinoma of the lung. The Swedish Lung Cancer Study Group.

The aim of this randomised trial was to investigate the effect of induction chemotherapy before radiotherapy on survival in 302 patients with non-resectable squamous cell carcinoma of the lung. Radiotherapy, 56 Gy to the chest, was given to 154 patients and combined treatment, with chemotherapy preceding the radiotherapy, to 148 patients. Chemotherapy consisted of three courses of cisplatin (120 mg/m2) and etoposide (100 mg/m2 i.v. for 3 days) administered every fourth week. Median survival was 10.5 months in the radiotherapy arm and 11 months in the combined treatment arm. The 2-year survival rate was 17% in the radiotherapy arm and 21% in the combined treatment arm. Addition of chemotherapy seemed to significantly improve survival, according to the Cox multivariate analysis (P = 0.04), but as only a trend according to life-table analysis (P = 0.11). Chemotherapy also accomplished a trend towards improved local control (P = 0.08) and towards decreased metastatic disease (P = 0.10). 2 patients in the combined treatment arm, but none in the radiotherapy arm, died from toxicity. The conclusion was that the value of the chemotherapy used in this study was very modest, but the results strongly support further research for more efficient drugs and combinations.

Full chemotherapy in elderly patients with small cell bronchial carcinoma.

Data on small cell lung cancer (SCLC) in elderly patients with full chemotherapy are sparse. We present material of 345 patients treated with chemotherapy (CT) with no age limits. CT was given with 2 different types of 4-drug combinations, including cyclophosphamide, doxorubicin, vincristine, methotrexate, lomustine and etoposide. Radiotherapy 40 Gy was given to 85% of the limited disease (LD) and 15% of the extensive disease (ED) patients. In 345 consecutive SCLC patients (50% LD and 50% ED) with a median survival time (MST) of 10 months and a disease-free 5-year survival 3.8%. Multivariate analysis showed clear correlation between stage of disease and survival as well as between age and survival though less pronounced. One hundred and ten patients were > 70 years of age with a median survival time of 7.4 months (LD 12.3 and ED 4.6) and 235 patients < 70 years of age had a median survival time of 10.9 months (LD 14.4 and ED 7.5) and a disease-free 5-year survival of 5.1%. The survival differences were statistically significant. Treatment toxicity was higher in patients > 70 years of age. Seventy-seven patients 70-75 years of age had an MST of 9.5 months (LD 13.2 and ED 6.2) and a disease-free 5-year survival of 1.3%. The survival differences between patients 70-75 years old and those < 70 years of age were small but statistically significant in LD at 5% level but not in ED. There were more septicemias per courses CT given in all patients 70-75 years of age and also more lethal septicemias in ED patients. Patients with LD SCLC 70-75 years of age might benefit from full treatment in terms of median and long-term survival.

Improved care of patients with small cell lung cancer. Nutritional and quality of life aspects.

A comprehensive cancer care project was carried out in Uppsala with the aim of improving the overall situation for patients treated with intensive chemotherapy with curative intent. This report gives the results in 58 patients with small cell lung cancer (SCLC), focusing on the nutritional aspects of the care and chemotherapy-related adverse effects. Responses, survival and simple nutritional parameters were compared with a historical control group (n = 81), and quality-of-life parameters with a pre-project group (n = 22). Groups were comparable with respect to pre-treatment characteristics. In contrast to the historical control group, weight, body mass index and S-albumin did not decrease during treatment in patients diagnosed during the project period. Yet, food intake in the study group was low, and for most patients below what is recommended. Survival, proportion of responses and response duration did not differ from those of the control group. Compared with the pre-project quality-of-life controls, a number of scores were more favourable for study patients (n = 36) interviewed in association with the 8th treatment course by a Swedish version of the Cancer Inventory of Problem Situations (CIPS). The global score was lower in the study group than in the pre-project group (0.80 vs 1.20, p < 0.001). Significant differences in a favourable direction were also seen in several higher order factors and miscellaneous subscales constituting the CIPS. On individual items, the study group expressed less problems with appetite/food taste in hospital, nervousness before chemotherapy and worry about adverse effects. The greatest differences in positive direction for the study group were seen within areas where the project focused on caring activities. We therefore conclude that a cancer care project with the present goals and means of intervention can improve the quality of life in patients with SCLC treated with intensive chemotherapy.

Etoposide versus methotrexate in small cell bronchial carcinoma. A randomized study of two types of four-drug chemotherapy regimens.

Seventy-nine patients with small bronchial carcinoma randomly received cyclophosphamide, doxorubicin, vincristine, and methotrexate, alternating after four cycles with cyclophosphamide, lomustine, vincristine and methotrexate or the same with replacement of methotrexate by etoposide in lomustine cycles. Patients with limited disease received radiotherapy with 40 Gy. In 34 patients with extensive disease the total response in the groups with and without etoposide was 89% and 69% and the median survival 10.9 and 8.2 months respectively. In 45 patients with limited disease, the complete remission rates in the groups with and without etoposide were 57% and 67%, partial remission rates 38% and 25%, and the median survival times 12.3 and 17.8 months respectively. The disease-free survival exceeding 5 years in the respective groups was 4.2% and 14.3%. A slightly better response in extensive disease and a tendency to better long-term survival in limited disease was noted but the price was increased toxicity in the latter group.

Clinical and serologic markers of stage and prognosis in small cell lung cancer. A multivariate analysis.

The respective pretreatment prognostic impacts of the following markers were evaluated in 125 patients with small cell lung cancer (SCLC): lactic dehydrogenase (LDH), serum thymidine kinase (S-TK), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and tissue polypeptide antigen (TPA). More traditional clinical and serologic markers were also evaluated. Univariate analysis showed that all of the biochemical markers mentioned above, the Karnofsky index (KI) and the patient's sex were related to both the stage of disease (limited/extensive disease: LD/ED) and to survival. The strongest marker for the clinical stage was S-TK, whereas TPA showed the strongest relationship with survival. Multivariate analyses produced a model consisting of S-TK, CEA, NSE, and the patient's sex for determining the clinical stage. To compare the prognostic capacity of easily determined biochemical and simple clinical variables to the more resource-demanding variable of the clinical stage, three multivariate analyses in relation to survival were performed: (1) biochemical markers and simple clinical variables; (2) LD/ED and simple clinical variables; and (3) all available variables. The model obtained from the first analysis included TPA, KI, age, and the patient's sex; the model from the second analyses included LD/ED, patient's age, and KI; and the model from the third analysis, TPA, KI, age, sex, and LD/ED. Indices based on these three multivariate models were calculated for each patient and the prognostic capacity of these indices was compared. Pretreatment serum marker levels also had the capacity to predict both the grade and the duration of the response to therapy.

Neuron-specific enolase as a follow-up marker in small cell bronchial carcinoma. A prospective study in an unselected series.

The value of measurement of serum neuron-specific enolase (NSE) as a follow-up marker was investigated in 88 patients with small cell bronchial carcinoma. Of these, 42 had extensive disease and 46 had limited disease. The mean NSE levels before treatment, at response, and at recurrence in extensive disease were 107, 10, and 52 ng/ml, respectively, and the corresponding levels in limited disease were 35, 10, and 19 ng/ml, respectively. All differences were statistically clearly significant. However, the sensitivity of NSE in serum at response was 66% and at recurrence, 38%. The predictive value of an NSE decrease at response was 88%, and at recurrence, 72%. It is concluded that NSE changes during follow-up support the evaluation of the outcome but cannot be used as a monitoring agent in an individual patient.

Hearing and cochlear morphology in patients treated with a combination of cytostatics.

Patients with small-cell carcinoma of the lung were treated at the Department of Lung Medicine. They all received the same combination treatment with repeated doses of doxorubicin, vincristine, cyclophosphamide and methotrexate. In 26 patients, hearing was tested with repeated audiograms during treatment. The follow-up time varied between one and 19 months (mean, 6 months). There was no significant impairment of hearing during the follow-up period. Postmortem fixation of the temporal bones was performed in 7 patients and the cochlear morphology studied. No specific alterations in cochlear morphology which could be attributed to the cytostatics were found.

Local failure in patients treated with radiotherapy and multidrug chemotherapy for small cell lung cancer.

Fifty-three patients with small cell carcinoma of the lung were treated with chemotherapy and radiotherapy, 40 Gy in the chest tumour. Intrathoracic failure occurred in 89% of the cases with extensive disease and in 60% of those with limited disease. Since 86% of all failures were localized within the target volume, one can conclude that in most cases the radiation dose was too low for eradication of the tumour. The treatment technique resulted in dose inhomogeneities of more than +/- 5% in 45% of the cases. The high local failure rate might indicate the need of improved radiotherapy, in the first place higher radiation dose. However, 82% of the patients with limited disease and local failure and 50% of those without local failure also developed distant metastases. This might indicate that the curative potential of improved thoracic radiotherapy probably is limited. Besides, lethal treatment toxicity affected particularly patients in whom local cure had been achieved, indicating the difficulty of increasing the treatment intensity without increasing the lethal toxicity in potentially curable cases.

Neuron-specific enolase in small-cell carcinoma of the lung: the value of combined immunocytochemistry and serum determination.

The value of neuron-specific enolase (NSE) as a marker for small-cell carcinoma of the lung has been the subject of several reports. Taken together, about 70 per cent of patients with small-cell carcinoma had a raised serum concentration of NSE, and in a majority of patients NSE could be detected immunocytochemically in tumor biopsy speciments. This study examined the diagnostic value of combined immunocytochemical detection and serum determination of NSE in 96 unselected patients with small-cell carcinoma. Seventy-one patients had raised serum concentrations and in 69 a positive immunoreaction for NSE was demonstrated in the biopsy cells. However, for 87 (91%) of the patients, both or either of the NSE assays were positive. The combined use of immunocytochemistry and serum determinations thus gave better information on tumor NSE expression than either method alone. When patients with small or mechanically maltreated biopsy specimens were excluded, the accuracy of the combined assays was even higher (47/49, 96%). We therefore conclude that NSE, although not a specific marker for small-cell carcinoma of the lung, is useful as a complement to conventional diagnostic procedures and, when assayed both in biopsy material and in patient sera, tumor NSE expression can be demonstrated with a high precision.

A randomized study of radiation treatment in small cell bronchial carcinoma treated with two types of four-drug chemotherapy regimens.

Of an unselected series of 133 patients with small cell bronchial carcinoma, 110 patients (54 with extensive disease and 56 with limited disease) were randomly allocated to receive either chemotherapy with cyclophosphamide, doxorubicin, vincristine, and methotrexate, alternating after four cycles with cyclophosphamide, lomustine, vincristine, and methotrexate, or the same chemotherapy combinations together with irradiation at 40 Gy to the primary tumor area and the adjacent mediastinum. In patients with extensive disease the total response rates were 70% and 86% and the median survival 7.6 and 9.2 months, respectively. There were no long-term survivors, and no advantage was gained from radiation combination treatment. The results confirm previously reported findings. In limited disease the complete remission rates were 68% and 64%, the partial remission rates 26% and 28%, and the median survival was 14.8 and 15.4 months, respectively. There were no statistically significant differences favoring either treatment regimen. The disease-free survival exceeding 2 years in the two respective groups was 6.5% and 25%; this difference was not statistically significant. A slight advantage of combined radiation and chemotherapy in the direction of better long-term survival was confirmed by the 4-year disease-free survival rate of 12% as compared with 0% in the nonirradiation group. This difference was statistically significant. There was considerable toxicity with both treatment regimens. The addition of radiation treatment to the chemotherapy most likely benefits patients with limited disease. The overall median survival of all the unselected 133 patients (nonrandomized included) was 10.3 months, and the cure rate was 3%.

Nuclear DNA content in squamous cell carcinoma, small cell carcinoma, and bronchiolo-alveolar carcinoma of the lung.

Nuclear DNA content in individual, morphologically identified tumor cells from 33 squamous lung carcinomas, 20 small cell lung carcinomas, and 10 bronchiolo-alveolar carcinomas were analyzed by means of cytophotometry on Feulgen-stained histologic and cytologic specimens. Twenty-eight of the squamous cell carcinomas and 17 of the small cell carcinomas had high and scattered DNA values, indicative of high malignancy potentials. None of the bronchiolo-alveolar carcinomas showed such high DNA values. These results are in line with clinical experience that squamous cell and small cell carcinoma are associated with rapid progression and death in patients, whereas bronchiolo-alveolar carcinomas have a more indolent course.

Increased expression of N-myc in human small cell lung cancer biopsies predicts lack of response to chemotherapy and poor prognosis.

Amplified and increased expression of the myc family of protooncogenes (c- and N-myc) has been described to be associated with rapid proliferation in a number of cell lines, including small cell lung cancer (SCLC). In SCLC, c-myc was demonstrated to be amplified in a subset of SCLC cell lines denoted as variant type, which show a more aggressive way of growth in vitro. The N-myc oncogene, which has extensive homology in the second exon with c-myc, has been shown to be implicated in the oncogenesis of several primary tumors, including SCLC. The authors describe, using in situ hybridization, that increased expression of the N-myc oncogenes in primary biopsies from 15 untreated patients with SCLC are strongly associated with poor response to chemotherapy, rapid tumor growth, and short survival.

Serum calcium in bronchial carcinoma: a population-based study.

Serum calcium (s-Ca) was measured in 245 patients with bronchial carcinoma. Mean s-Ca (+/- SD) was 2.52 +/- 0.14 mmol/l in the cancer patients, compared to 2.48 +/- 0.14 mmol/l in a control group (p less than 0.01). Sixty-one (25%) of the patients with bronchial carcinoma had hypercalcaemia (s-Ca greater than or equal to 2.60 mmol/l), compared to 16% of the controls. Squamous cell carcinoma was the histological type most often associated with hypercalcaemia. Patients with hypercalcaemia were not overrepresented among those with bone metastases. During follow-up another 32 patients developed hypercalcaemia. Altogether 93 patients (38%) became hypercalcaemic at some time in the course of the disease. In 20 patients s-Ca fell below 2.60 mmol/l after radiotherapy, after operation, or spontaneously. The survival time was significantly shorter for patients with s-Ca above 2.68 mmol/l on admission than for those with s-Ca below this value.

Corynebacterium parvum in malignant pleural effusion. A randomized prospective study.

In a randomized trial, pleurodesis was attempted with Corynebacterium parvum in one group and bleomycin in another. Patients with malignant pleural effusion which required repeated drainage were treated with instillation of one of these agents after complete drainage of the pleural effusion. There were 32 patients who could be evaluated. Sixty-five per cent of the patients treated with C. parvum had no recurrence after one treatment and another 29% after two treatments. In the bleomycin group, two patients needed only one treatment while the remainder - 13 out of 15 patients - needed further drainage treatments even after two instillations of the drug. The difference was highly significant (p less than 0.001).

C3b receptor-mediated phagocytosis in sarcoidosis with extra-thoracic manifestations.

Two groups of sarcoidosis patients were studied. One group of 24 patients had previously had erythema nodosum (EN+), and the other group of 54 patients had never had any such extrathoracic manifestation of the disease (EN-). The two groups were similar with respect to age, disease duration, chest radiographic appearance, and granuloma mass as estimated from the serum concentration of lysozyme. Neutrophil phagocytic function was studied by a kinetic method which allows distinction between Fc- and C3b-receptor-mediated uptake. Fc-receptor function was normal in both groups. The function of C3b receptors was normal in the EN+ groups but significantly reduced in the EN- group. This observation indicates that sarcoidosis associated with erythema nodosum may represent a separate disease entity with respect to the pathogenetic mechanism involved in granuloma formation.

Neutrophil phagocytosis in sarcoidosis. Reduced C3b receptor-mediated phagocytosis in active and silent sarcoidosis.

The phagocytic and complement receptor function of polymorphonuclear neutrophils (PMN) from patients with sarcoidosis was studied using a kinetic assay which allows the distinction to be made between Fc receptor-mediated and C3b receptor-mediated particle uptake. The study included one group (A) of patients with active disease (n = 20), and one group (B) with silent or inactive disease who since 10 years had no symptoms or radiological signs of sarcoidosis (n = 11). Abnormal C3b receptor function was observed in both groups but the impairment was most pronounced in the A group. The presence of C3b receptor dysfunction in both groups with a quantitative difference between the groups, is compatible with C3b receptor dysfunction being a primary causal factor of sarcoidosis.

Sedimentation rate, leucocytes, platelet count and haemoglobin in bronchial carcinoma: an epidemiological study.

Erythrocyte sedimentation rate (ESR), leucocyte count, platelet count, haemoglobin concentration (Hb) and survival were studied in an epidemiological material of 258 patients with bronchial carcinoma. The mean ESR was elevated (48.1 mm/h) and, more so in squamous cell and small cell carcinoma than in large cell and adenocarcinoma. Leucocytosis, over 9 X 10(9)/l, was found in 39% of the patients and thrombocytosis, over 400 X 10(9)/l, in 13% of the patients. Nine per cent of the patients were anaemic, with Hb lower than 11 g/l. There was a statistically significant positive correlation between ESR, leucocyte count and platelet count, but a negative correlation was found between these 3 variables and Hb. ESR, leucocyte count and platelet count also correlated to survival at a statistically significant level. Multiple regression analysis of these laboratory variables showed that they explain about 8% of the great variations in survival time.

Neurone specific enolase: a useful diagnostic serum marker for small cell carcinoma of the lung.

Among lung cancers small cell carcinoma is the most sensitive to chemotherapy and radiation. This has emphasised the importance of an accurate diagnosis of this cell type, and the present study examined the use of serum neurone specific enolase (NSE) as a diagnostic marker for small cell carcinoma. NSE was measured in pretreatment sera from 103 patients with small cell carcinoma and in sera from relevant controls, including patients with other lung cancers, non-malignant lung diseases, and healthy adults. Serum NSE concentration was raised (greater than 25 ng/ml) in 72% of patients with small cell carcinoma. Ninety one per cent of patients with extensive disease and 50% of patients with limited disease were serum NSE positive. Patients with extensive disease in general had higher serum NSE concentrations than patients with limited disease. No definite difference in serum NSE positivity could be shown between oat cell and intermediate cell subtypes. Out of 51 patients with other lung cancers, four (8%) had a raised serum concentration, whereas all patients with non-malignant diseases and healthy individuals had normal serum NSE concentrations. Serum NSE determination seems to be a valuable tool for the diagnosis of small cell carcinoma.