Patients with regionally extensive non-small cell lung cancer (predominantly by virtue of metastases to mediastinal lymph nodes, less commonly by direct extension into the mediastinum) were treated predominantly with chest radiation therapy alone until the early 1980s. At that time, because of the high local recurrence rate, the higher likelihood of distant metastases, and the poor 5-year survival rates, studies were begun in these patients attempting to substitute a different local treatment modality (surgery) or to use both radiation therapy and surgery to decrease local recurrence rates and to add chemotherapy as a systemic therapy to decrease distant metastases. LCSG 831 explored the use of CAP (cyclophosphamide, doxorubicin, cisplatin) chemotherapy plus radiation therapy as preoperative or neoadjuvant therapy. Thirty-nine patients entered this phase 2 trial with 33 undergoing resection. Median survival was 11 months, and 1-year survival was 43%. These results are compared with the results of other similar trials. Explanations for the poor and differing results are suggested as are possible ways to improve study design and results.

Prospective morbidity and mortality rates associated with resection of lung cancer that are reflective of the current trend toward preoperative therapy are not readily available in the current literature. To determine their prevalence, we prospectively analyzed the results of 783 resections performed within contributing Lung Cancer Study Group (LCSG) centers. There were 543 men and 240 women with a mean age of 63.44 years. Of the 783 resections, there were 411 lobectomies, 135 pneumonectomies, and 237 other procedures. Thirty patients died postoperatively (mortality, 3.8%) and 211 had a major complication (27%). Complications occurred more commonly in men (34.3%, p = 0.001), in patients age 60 or older (34.0%, p = 0.001), and in patients with a Karnofsky index < 9 (44%, p < 0.001). There was no significant difference between mortality, significant morbidity rates for lobectomy (28.2%), and pneumonectomy (31.9%), or for simple (28.3%) and extended resection (31.9%). The seemingly higher incidence of major postoperative events reported in this series not only reflects the prospective nature of this analysis but also the fact that over 25% of patients were in other therapeutic trials involving neoadjuvant or postoperative adjuvant regimens. Within that context, these data appear to be a reasonable estimate of modern surgical morbidity rates in the treatment of lung cancer.

Three hundred twenty-eight patients with limited stage small cell lung cancer were enrolled in a trial to evaluate surgical treatment for such patients responding to chemotherapy. Cyclophosphamide, doxorubicin, and vincristine were administered every 21 days for five cycles. Patients achieving at least partial response who had confirmation of pure small cell histologic features by pathology review and who were fit enough for thoracotomy were randomized to undergo or not to undergo pulmonary resection. All randomized patients received radiotherapy to the chest and brain. Two hundred seventeen (66%) of the patients achieved objective response (90 complete response; 127 partial response). One hundred forty-six patients were randomized (66% of responders, 44% of all patients): 70 to surgery and 76 to no surgery. Results of surgery were 83% resection rate, 19% pathologic complete remission rate, and 9% with residual non-small cell histologic features only, for a total of 28% eradication of small cell lung cancer. The survival curves for the two arms are not different (log rank p = 0.78). Median survivals were 12 months for all enrolled patients and 16 months for those who were randomized. Actuarial 2-year survival is 20%. The results of this trial do not support the addition of pulmonary resection to the multimodality treatment of small cell lung cancer.

The Lung Cancer Study Group, in order to investigate lesser resection within the community as definitive management for T1N0 lung cancers, in 1982 began a prospective trial of limited resection compared to lobectomy for these patients. First reported results demonstrated no significant differences for stratification and other prognostic variables, and no differences in postoperative complication rates. Interim analysis 3 years later suggested a higher local recurrence rate in the limited resection arm of the study. Further comprehensive analysis will be forthcoming.

The purpose of this trial (Lung Cancer Study Group [LCSG] 853) was to perform a comparative study of immediate combination chemotherapy (cyclophosphamide, doxorubicin, cisplatin [CAP]) vs delayed combination chemotherapy (CAP) administered at the time of first systemic relapse in patients with completely resected stage II and stage III non-small cell cancer of the lung. We randomly assigned 188 patients with resected stage II or stage III non-small cell lung cancer of the lung (squamous, 53%; nonsquamous, 47%) to receive either immediate or delayed combination chemotherapy. Careful intraoperative staging was performed in all patients. Before randomization, patients were stratified according to stage--II (hilar nodes positive) vs III (mediastinal nodes positive or T3)--and histologic features (squamous vs nonsquamous). Ninety-four patients were randomized to receive immediate CAP vs 94 patients randomized to receive delayed CAP. Prognostic variables such as extent of disease, histologic features, sex, race, TN status, and Karnofsky performance status were equally distributed between randomized groups. The treatment groups differed with respect to greater than 10% weight loss. Forty-one percent of patients had stage II disease and 59% of patients had stage III disease. Median time to recurrence (19.5 months) and survival (32.7 months) did not differ between treatment groups. Immediate combination chemotherapy was associated with a 12% reduction in risk of recurrence and an 18% reduction in risk of death, although these rates were not statistically significant. Histologic features, sex, race, Karnofsky performance status, nodal status, and weight change were associated with higher risks of recurrence.

Two recent studies in resectable non-small cell lung cancer by the Lung Cancer Study Group (LCSG) suggested an advantage to adjuvant therapy with cyclophosphamide, doxorubicin (Adriamycin), and cisplatin (CAP). Neither study had a no-treatment control arm. The purpose of this study was to compare the CAP regimen with no treatment in patients with resectable early-stage non-small cell lung cancer.

This study was conducted to determine the effect of adjuvant chemotherapy on locally advanced resected non-small cell lung cancer. Anatomic eligibility requirements were either positive resection margins or tumor involvement of the highest sampled mediastinal lymph node. One hundred seventy-two patients were randomized to receive either postoperative thoracic irradiation alone or together with six cycles of CAP chemotherapy (cyclophosphamide, doxorubicin, and cisplatin). The chemotherapy arm showed significantly longer recurrence-free survival (p = 0.004). This benefit accrued to patients with both nonsquamous (p = 0.01) and squamous (p = 0.08) cell carcinoma. At 1 year following randomization, there was a 14% difference in survival favoring the chemotherapy arm. Chemotherapy significantly reduced distant metastases. Median survival was 20 months for the chemotherapy arm and 13 months for the radiotherapy alone arm. The 2-year survival rate for the entire study population was 35%. Toxic reactions were primarily predictable hematologic, GI, and alopecia toxicity expected from CAP. Esophagitis was not a significant problem.

Among patients with lung cancer approximately 44% have disease limited to the chest. Patients with early lesions treated surgically have better survival rates than those with more advanced primary disease or nodal involvement. Postoperative irradiation should reduce local or regional recurrence and hopefully reduce systemic relapse.

The Lung Cancer Study Group (LCSG) randomized 141 patients with resected stage II and III adenocarcinoma and large cell undifferentiated carcinoma to receive postoperative combined chemotherapy with cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy or bacillus Calmette-Guerin (BCG) and levamisole immunotherapy. Careful intraoperative staging was performed on all patients. Before randomization, patients were stratified by stage, weight loss, cardiac arrhythmia, and institution. Prognostic variables such as stage, age, weight loss, and nodal involvement were equally distributed between the two groups. Disease-free survival was significantly prolonged in the group receiving chemotherapy. There was no evidence of a deleterious effect of the immunotherapy. This study indicates that postoperative CAP chemotherapy is effective in prolonging disease-free survival in these patients.

This article reviews the design and findings of LCSG Protocol 771, a randomized double-blind comparison of postoperative adjuvant intrapleural bacillus Calmette-Guérin (BCG) against saline solution placebo control in 473 patients with resected T1N0, T1N1, or T2N0 non-small cell lung cancer. Patients were randomized from August 30, 1977, through October 20, 1980, and follow-up ended on January 1, 1990. There was no evidence of improved survival or time to recurrence among patients given BCG in contrast to earlier promising findings. A calculation suggests that false-positive results due to chance are not uncommon in small preliminary studies, indicating the need for larger confirmatory trials such as LCSG Protocol 771. Other contributions from this Protocol are also reviewed, including data on BCG toxicity, immunologic effects, patterns of recurrence, and identification of prognostic risk groups.

To characterize the pulmonary response of asthmatic and healthy nonsmoking adult men to 0.20 ppm ozone by controlled chamber exposure.

Inhaled anticholinergics may be the first-line therapy for stable COPD. However, the effect of inhaled anticholinergic agents on exercise capacity is still controversial. Fourteen patients with stable COPD (age, 64.6 +/- 5.9 years) completed a randomized, double-blind placebo-controlled crossover trial. All the patients were studied by symptom-limited progressive cycle ergometry before and 90 min after the inhalation of either oxitropium bromide, 800 micrograms, or an identical placebo. Spirometry was assessed before and after each exercise test. While FEV1 averaged 0.85 +/- 0.34 L at 90 min after the inhalation of placebo, FEV1 was 1.01 +/- 0.41 L at 90 min after the inhalation of oxitropium, 800 micrograms (significant from placebo, p < 0.001). The maximal workload of 94.0 +/- 25.8 W after oxitropium administration was significantly greater than the 87.6 +/- 24.7 W measured after placebo (p < 0.01). The maximal minute ventilation was 40.2 +/- 12.3 L/min after oxitropium inhalation and 36.8 +/- 10.5 after placebo inhalation (p < 0.05). The differences in maximal oxygen consumption, maximal carbon dioxide production, and maximal heart rate between oxitropium and placebo inhalation also were statistically significant (p < 0.05, p < 0.05, and p < 0.01, respectively). There was a significant correlation between the change in maximal workload and the change in FEV1 before and after inhalation (r = 0.625, p < 0.01). The inhalation of oxitropium bromide, 800 micrograms, can improve the exercise capacity of patients with stable COPD. It is suggested that the effect is due to the bronchodilation induced by this drug.

To study the effect of intravenous (i.v.) terbutaline on potassium (K) and magnesium (Mg) distribution, ECG changes, and prevalence of ventricular ectopic beats in healthy subjects.

The acute respiratory distress syndrome (ARDS) is a disorder of diffuse lung injury secondary to a wide variety of clinical insults (eg, sepsis) and is manifested by impaired oxygenation, pulmonary edema, and decreased static and dynamic compliance. More recently, airflow resistance has been shown to be increased in humans with ARDS. We designed a prospective, randomized, placebo-controlled, crossover trial to determine the presence and reversibility of increased airflow resistance in ARDS. We studied eight mechanically ventilated patients with ARDS (criteria: PaO2 < or = 70 mm Hg with FIO2 < or = 0.4; diffuse bilateral infiltrates; and pulmonary artery wedge pressure < or = 18 mm Hg). Each was intubated with a No. 8.0 orotracheal tube. We measured dynamic compliance (Cdyn), static compliance (Cstat), airflow resistance across the lungs (RL), shunt fraction (Qs/Qt on FIO2 = 1.0), minute ventilation (VE), PaO2/PAO2, and dead space to tidal volume ratio (VD/VT). Patients were blindly assigned to receive either metaproterenol (1 mL 0.5% in 3 mL saline solution) or saline solution (4 mL) aerosolized over 15 min 6 h apart and in random order so that patients served as their own controls. Metaproterenol significantly reduced RL, peak and plateau airway pressure, and increased Cdyn. Metaproterenol tended to increase PaO2/PAO2, but had no effect on pulmonary shunt or dead space ventilation. We conclude that the increase in airflow resistance of ARDS is substantially reversed by aerosolized metaproterenol without affecting dead space. These data suggest that abnormalities of RL are at lest partially due to bronchospasm.

In 12 patients with severe adult respiratory distress syndrome (ARDS), pulmonary gas exchange and hemodynamics were evaluated before, during, and after a 2-h period of pressure-controlled mechanical ventilation with the patient in the prone position. Ventilation-perfusion relationships (VA/Q) were assessed by a multiple inert gas elimination technique. Pressure-controlled mechanical ventilation in the prone position resulted in an overall increase (p < or = 0.05) of arterial oxygenation after 120 min (98.4 +/- 50.3 to 146.2 +/- 94.9 mm Hg). Whereas eight patients revealed an improvement of PaO2 of more than 10 mm Hg after 30 min in the prone position (responders), four patients reacted to positional changes with a deterioration of arterial oxygenation (nonresponders). Data about the continuous distribution of ventilation-perfusion ratios revealed that in the responder group positioning caused a decrease of shunt perfusion of 11 +/- 5% and a concomitant increase of normal VA/Q by 12 +/- 4% after 30 min. There was no change demonstrable within low VA/Q areas. Returning the patient to the supine position reversed the improvement in gas exchange. The nonresponder group did not show any significant alteration in the distribution of VA/Q during the study. We concluded that improvement of oxygenation during pressure-controlled mechanical ventilation in the prone position is due to a shift of blood flow away from shunt regions, thus increasing areas with normal VA/Q. This redistribution of blood flow is most likely caused by a recruitment of previously ateletatic but nondiseased areas induced by altered gravitational forces.

To evaluate the safety and effectiveness of antibiotics in reducing the infectious complications following closed tube thoracostomy for isolated chest trauma.

To determine the influence of needle gauge in Mantoux skin testing for tuberculosis.

Thirty-three patients with T3,N2,M0 or T4,N2,M0, non-small-cell lung cancer (NSCLC) took part in a phase 2 study in an attempt to evaluate the feasability of neoadjuvant chemotherapy followed by surgery and thoracic radiotherapy. Chemotherapy consisted of daily administration of the following treatment: etoposide, 100 mg/m2; cisplatin, 25 mg/m2; ifosfamide, 1.5 g/m2; and mesna, 1.8 g/m2 for 4 days. Three cycles were planned starting every 21 days. Responding patients underwent a thoracotomy in order to attempt a resection and then received a 45 Gy of thoracic radiotherapy. The results of response and resection rates have been published and the present final report deals with the long-term results. Chemotherapy induced a 55 percent partial response rate and a 15 percent complete response rate allowing a complete resection in 55 percent of the patients. Complete remission was histologically confirmed for the five complete responders. Although the median survival was short (10 months), six patients were long-term survivors (3-year survival rate: 19 percent). Survival was significantly influenced by the type of resection: patients for whom a complete resection was possible survived the longest with a median survival three times that of the other patients. Modalities of relapses differed according to the results of surgery: 8 of the 15 patients who did not undergo a complete surgical resection experienced a local relapse during the first 18 months of follow-up whereas in the complete resection group, central nervous system metastasis was the main site of relapse. We conclude that the neoadjuvants ifosfamide, cisplatin, and etoposide in patients with locally advanced NSCLC are feasible to use and allow a 19 percent 3-year survival rate. These results are the rationale of an ongoing randomized study comparing neoadjuvant chemotherapy followed by surgery and surgery alone. This study is designed to test whether neoadjuvant chemotherapy improves survival of patients with locally advanced NSCLC.

We recently reported that inhaled acetaldehyde causes bronchoconstriction indirectly via histamine release in patients with asthma. The purpose of this study was to investigate a role of thromboxane A2 in acetaldehyde-induced bronchoconstriction in asthmatic airways. We investigated the bronchial response to inhalation of ascending doses (5, 10, 20, and 40 mg/ml) of acetaldehyde in nine asthmatic subjects who were treated with placebo or OKY-046, a selective thromboxane A2 synthetase inhibitor, of 200 mg twice a day for 3 days, and 200 mg on the fourth day (test day) in a double-blind, randomized, placebo-controlled, crossover fashion. Percentage decreases in FEV1 caused by 20 and 40 mg/ml of acetaldehyde inhalation were significantly (p < 0.05 and p < 0.01, respectively) prevented by the pretreatment with OKY-046. Geometric mean value (geometric standard error of the mean) of acetaldehyde concentration producing a 20 percent fall in FEV1 (PC20-Ac-CHO) was significantly (p < 0.01) greater with the OKY-046 pretreatment (72.2 [1.1] mg/ml) than with the placebo pretreatment (19.8 [1.2] mg/ml). We conclude that thromboxane A2 is one of contributors to acetaldehyde-induced bronchoconstriction in asthmatic subjects. It suggests that thromboxane A2 may play an important role in endogenous histamine-induced bronchoconstriction caused by acetaldehyde in asthmatic airways. We believe that this is a first report on the interaction between endogenous histamine and thromboxane A2 in asthmatic subjects.

Enprofylline is a new xanthine derivative that shares theophylline's bronchodilator properties but is free of theophylline's adenosine receptor antagonist activity. We compared the long-term efficacy and tolerability of enprofylline and theophylline given over a 1-year period to adults with asthma.