Stephen G. Spiro

Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group

PURPOSE Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy. PATIENTS AND METHODS Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial. RESULTS With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin. CONCLUSION Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.

Predicted normal values for maximal respiratory pressures in caucasian adults and children.

Maximal respiratory pressures at the mouth (PEmax and PImax) have been measured in 370 normal caucasian children and adults. Age, height, and weight were recorded for all subjects and incorporated in a stepwise multiple regression analysis to determine prediction equations for the maximal respiratory pressures in the children and adults for both sexes. In men PImax and PEmax were significantly correlated only with age (p less than 0.001 and less than 0.035 respectively), whereas in women they were correlated with height (p less than 0.035 and less than 0.03). In both boys and girls PImax was related to weight (p less than 0.0001 and less than 0.01 respectively) and PEmax to age (p less than 0.001 for both). The values for PImax and PEmax in adults were lower than in previously reported series, but in children the values obtained were similar to those reported for several smaller series.

Mitomycin, Ifosfamide, and Cisplatin in Unresectable Non–Small-Cell Lung Cancer: Effects on Survival and Quality of Life

PURPOSE Chemotherapy for non-small-cell lung cancer (NSCLC) remains controversial. We describe the two largest reported, randomized, parallel trials designed to determine whether the addition of chemotherapy influences duration and quality of life in localized, unresectable (mitomycin, ifosfamide, cisplatin [MIC]1 trial) and extensive (MIC2 trial) disease. PATIENTS AND METHODS Ambulatory patients with NSCLC, aged 75 years or younger, with localized disease, were randomized in MIC1 to receive up to four cycles of chemotherapy (CT: mitomycin 6 mg/m(2), ifosfamide 3 g/m(2), and cisplatin 50 mg/m(2)) every 21 days, followed by radical radiotherapy (CT + RT) or radiotherapy (RT) alone. Extensive-stage patients were randomized in MIC2 to identical chemotherapy plus palliative care (CT + PC) or palliative care (PC) alone. Short-term change in quality of life (QOL) was assessed in a subgroup of patients. Data from the two trials were combined to allow multivariate and stratified survival analyses. RESULTS Seven hundred ninety-seven eligible patients were randomized, 446 in MIC1 and 351 in MIC2. MIC CT improved survival in both trials (significantly in MIC2). The median survival time in MIC1 was 11.7 months (CT + RT) versus 9.7 months (RT alone) (P =.14); whereas in MIC2, median survival time was 6.7 months (CT + PC) compared with 4. 8 months (PC alone) (P =.03). QOL, assessed in 134 patients from start of trial to week 6, showed improvement with chemotherapy and deterioration with standard treatment. In the combined analysis of 797 randomized patients, the positive effect of MIC on survival was significant overall (P =.01) and after adjusting for prognostic factors (P =.01). CONCLUSION MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL.

Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data from 16 randomized controlled trials

PURPOSE Since our individual patient data (IPD) meta-analysis (MA) of supportive care and chemotherapy for non-small-cell lung cancer (NSCLC), published in 1995, many trials have been completed. An updated, IPD MA has been carried out to assess newer regimens and determine conclusively the effect of chemotherapy. METHODS Systematic searches for randomized controlled trials (RCTs) were undertaken, followed by central collection, checking, and reanalysis of updated IPD. Results from RCTs were combined to calculate individual and pooled hazard ratios (HRs). RESULTS Data were obtained from 2,714 patients from 16 RCTs. There were 1,293 deaths among 1,399 patients assigned supportive care and chemotherapy and 1,240 among 1,315 assigned supportive care alone. Results showed a significant benefit of chemotherapy (HR, 0.77; 95% CI, 0.71 to 0.83; P <or= .0001), equivalent to a relative increase in survival of 23% or an absolute improvement in survival of 9% at 12 months, increasing survival from 20% to 29%. There was no clear evidence that this effect was influenced by the drugs used (P = .63) or whether they were used as single agents or in combination (P = .40). Despite changes in patient demographics, the effect of chemotherapy in recent trials did not differ from those included previously (P = .77). There was no clear evidence of a difference or trend in the relative effect of chemotherapy across patient subgroups. CONCLUSION This MA of chemotherapy in the supportive care setting demonstrates conclusively that chemotherapy improves overall survival in all patients with advanced NSCLC. Therefore, all patients who are fit enough and wish to receive chemotherapy should do so.

Lung deposition patterns of directly labelled salbutamol in normal subjects and in patients with reversible airflow obstruction.

BACKGROUND--Earlier studies of aerosol deposition in the lungs have relied on indirect labelling of Teflon spheres of a similar size distribution to the drug in question and have assumed similar aerodynamic properties. Using a modification of a new technique for directly labelling salbutamol, the deposition of salbutamol within the lungs of normal subjects and patients with asthma has been studied with the use of a metered dose inhaler (MDI) alone, an MDI with a spacer device, and a dry powder inhaler (DPI). METHOD--Salbutamol was directly labelled with technetium-99m and placed in an MDI or DPI. Ten normal subjects and 19 patients with asthma inhaled 200 micrograms of salbutamol by means of the MDI alone, the MDI with a spacer device attached, and by DPI on separate days. Deposition was assessed by a dual headed gamma camera after inhalation of the drug. RESULTS--The total mean (SD) percentage deposition of the drug in the normal subjects was 21.6% (8.9%) with the MDI alone, 20.9% (7.8%) with the MDI with spacer, and 12.4% (3.5%) with the DPI. For the patients, the mean percentage deposition was 18.2% (7.8%) with the MDI alone, 19.0% (8.9%) with the MDI and spacer, and 11.4% (5.0%) with the DPI. Bronchodilatation achieved by the patients was similar with all three techniques. Mean peripheral lung deposition was significantly greater with a spacer device than when the MDI was used alone in both normal subjects (49.4% (6.1%) v 44.1% (9.9%)) and patients (38.6% (11.1%) v 30.4% (9.4%)). CONCLUSIONS--The deposition of directly labelled salbutamol from an MDI is greater than previously estimated by indirect labelling techniques. The deposition of labelled salbutamol from a DPI, however, is little different from that measured by indirect techniques.

Duration of chemotherapy in small cell lung cancer: a cancer research campaign trial

A total of 610 patients with small cell lung cancer were entered into a randomised trial designed to assess the effect of duration of initial chemotherapy on survival. Patients were randomised to receive either four or eight courses of cytotoxic chemotherapy with cyclophosphamide, vincristine and etoposide and also randomised to receive, on disease progression, either second line chemotherapy (methotrexate and doxorubicin) or symptomatic treatment only. In the whole study 196 (32.1%) had limited disease and 414 (67.9%) extensive disease. During initial chemotherapy the response rate (complete and partial responses) after four courses of treatment was 61% with no significant increase in patients receiving eight courses (63%). In those randomised to receive relapse chemotherapy the response rate was improved slightly for those who had originally received four courses of chemotherapy (25.6%) over those receiving eight (18.7%). The overall results show that of the four possible treatment randomizations, four courses of chemotherapy alone is inferior in terms of overall survival (30 weeks median survival) to the other three treatment options (39 weeks median survival, P less than 0.01). In patients responding to initial chemotherapy the disadvantage of four courses of chemotherapy alone was apparent (median survival of 40 weeks versus 49 weeks, P = 0.003) but not if drug treatment was given on relapse. The study shows that limiting treatment to four courses of chemotherapy alone is associated with inferior survival, but this is not the case if chemotherapy is given at relapse.

Gemcitabine Plus Carboplatin Versus Mitomycin, Ifosfamide, and Cisplatin in Patients With Stage IIIB or IV Non-Small-Cell Lung Cancer: A Phase III Randomized Study of the London Lung Cancer Group

PURPOSE This phase III randomized trial compared two chemotherapy regimens, gemcitabine plus carboplatin and mitomycin, ifosfamide, and cisplatin, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). The regimens were compared with regard to effects on survival, response rates, toxicity, and quality of life. PATIENTS AND METHODS Eligible patients had previously untreated stage IIIB or IV NSCLC suitable for cisplatin-based chemotherapy. Randomly assigned patients were to receive four cycles, each at 3-week intervals, of carboplatin area under the curve of 5 on day 1 plus gemcitabine 1,200 mg/m(2) on days 1 and 8 (GCa) or mitomycin 6 mg/m(2), ifosfamide 3g/m(2), and cisplatin 50 mg/m(2) on day 1 (MIC). RESULTS Between February 1999 and August 2001, 422 patients (GCa, n = 212; MIC, n = 210) were randomly assigned in the United Kingdom. The majority of patients received the intended four cycles (GCa, 64%; MIC, 61%). There was a significant survival advantage for GCa compared with MIC (hazard ratio, 0.76; 95% CI, 0.61 to 0. 93; P = .008). Median survival was 10 months with GCa and 7.6 months with MIC (difference, 2.4 months; 95% CI, 1.0 to 4.0), and 1-year survival was 40% with GCa and 30% with MIC (difference, 10%; 95% CI, 3% to 18%). Overall response rates were similar (42% for GCa v 41% for MIC; P = .84). More thrombocytopenia occurred with GCa (P = .03), but this was not associated with increased hospital admission or fatality. GCa caused less nausea, vomiting, constipation, and alopecia and was associated with fewer admissions for administration and better quality of life. CONCLUSION In patients with advanced NSCLC, GCa chemotherapy was shown to be a better-tolerated treatment that conferred a survival advantage over MIC.

Early Compared With Late Radiotherapy in Combined Modality Treatment for Limited Disease Small-Cell Lung Cancer: A London Lung Cancer Group Multicenter Randomized Clinical Trial and Meta-Analysis

PURPOSE To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC). PATIENTS AND METHODS Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks. RESULTS TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17). CONCLUSION This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT.

Adjuvant Cisplatin and Vinorelbine for Completely Resected Non-small Cell Lung Cancer: Subgroup Analysis of the Lung Adjuvant Cisplatin Evaluation

Background: To evaluate the impact of adjuvant cisplatin-vinorelbine in completely resected non-small cell lung cancer and identify patients likely to benefit from this regimen in the Lung Adjuvant Cisplatin Evaluation (LACE) database. The overall LACE meta-analysis showed survival benefit with cisplatin-based adjuvant chemotherapy (5-year survival benefit of 5.4%, hazard ratio [HR] 0.89, p = 0.004). Subgroup analysis for the cisplatin-vinorelbine regimen was prespecified in the LACE statistical analysis plan. Patients randomized to cisplatin-vinorelbine or observation were the largest subgroup (41%) and the most homogeneous in terms of drug doses and eligibility. Patients and Methods: The LACE-vinorelbine cohort included trials evaluating cisplatin-vinorelbine versus observation. Overall survival was the primary end point. Other studies randomizing patients to other chemotherapy or observation (LACE-other) were also evaluated. Results: The LACE-vinorelbine cohort included 1888 patients from four studies (Adjuvant Navelbine International Trialist Association, Big Lung Trial, International Adjuvant Lung Cancer Trial, and National Cancer Institute of Canada Clinical Trials Group JBR.10). Baseline characteristics were similar to the LACE-other but had fewer patients with stage IA (2% versus 11%). Survival improvement at 5 years was 8.9% with cisplatin-vinorelbine versus observation (HR 0.80, 95% confidence interval: 0.70–0.91, p <0.001). Stage was a significant predictor for survival (test for trend, p = 0.02; benefit at 5 years: 14.7% [stage III], 11.6% [stage II], and 1.8% [stage I]). Similar benefits were seen for disease-free survival (HR 0.75 [0.67–0.85, p <0.001], stage III [HR 0.62, 0.50–0.76], stage II [HR 0.69, 0.57–0.83], and stage I [HR 0.95, 0.767ndash;1.19]). The overall result was statistically superior to LACE-other (LACE other HR 0.95, 0.86–1.05, interaction p = 0.04). Conclusion: In subgroup analyses, adjuvant cisplatin-vinorelbine provides a superior survival benefit and can be recommended in completely resected stages II and III non-small cell lung cancer.

Contractile properties and fatigue of the diaphragm in man.

We studied the pressure developed by the diaphragm in response to stimulation of the phrenic nerve in the neck, in three normal men. When the phrenic was electrically stimulated at increasing frequencies the diaphragm responded by increasing transdiaphragmatic pressure to give a frequency-pressure curve similar to the frequency-force curve for other skeletal muscles. The subjects than breathed through an inspiratory resistance for as long as possible and the frequency-pressure curve was repeated. It was found that the diaphragm developed low frequency fatigue, in the same way as previously described for other muscles. We conclude that the diaphragm has contractile properties similar to these of other skeletal muscles. Low frequency fatigue of the diaphragm could contribute to respiratory failure in patients with lung disease.