Phase III randomized trial comparing moderate-dose cisplatin to combined cisplatin and carboplatin in addition to mitomycin and ifosfamide in patients with stage IV non-small-cell lung cancer.

A phase III randomized trial was conducted in patients with metastatic NSCLC, to determine if, in association with mitomycin (6 mg m(-2)) and ifosfamide (3 g m(-2)), the combination of moderate dosages of cisplatin (60 mg m(-2)) and carboplatin (200 mg m(-2)) - CarboMIP regimen - improved survival in comparison with cisplatin (50 mg m(-2)) alone - MIP regimen. A total of 305 patients with no prior chemotherapy were randomized, including 297 patients assessable for survival (147 in the MIP arm and 150 in the CarboMIP arm) and 268 patients assessable for response to chemotherapy. All but eight (with malignant pleural effusion) had stage IV disease. There was a 27% (95% CI, 19-34) objective response (OR) rate to MIP (25% of the eligible patients) and a 33% (95% CI, 24-41) OR rate to CarboMIP (29% of the eligible patients). This difference was not statistically significant (P = 0.34). Duration of response was not significantly different between both arms. There was also no difference (P = 0.67) in survival: median survival times were 28 weeks (95% Cl, 24-32) for MIP and 32 weeks (95% Cl, 26-35) for CarboMIP, with respectively 1-year survival rates of 24% and 23% and 2-year survival rates of 5% and 2%. The main toxicities consisted in emesis, alopecia, leucopenia and thrombocytopenia, that were, except alopecia, significantly more severe in the CarboMIP arm. Our trial failed to demonstrate a significant improvement in response or survival when patients with metastatic NSCLC were treated, in addition to ifosfamide and mitomycin, by combination of moderate dosages of cisplatin and carboplatin instead of moderate dosage of cisplatin alone. The results support the use of a moderate dose (50 mg m(-2)) of cisplatin in combination with ifosfamide and mitomycin for the chemotherapy of this disease.

[Sleep apnea and nocturnal ventilatory assistance (nCPAP): 5-year experience in the conventional system]. / Apnées du sommeil et assistance ventilatoire nocturne (nCPAP): cinq ans d'expérience dans le systeme conventionnel.

The reimbursement of nasal continuous positive airway pressure (nCPAP) by the Belgian social security, via a conventional system, has made since 1991 this treatment available to an increasing number of patients having moderate to severe sleep apnoea hypopnoea syndrome (SAHS). We have reviewed our experience in prescribing domiciliary nCPAP from 1991 to 1995. Three hundred twenty-five subjects with SAHS, predominantly male (89%) and/or obese (77%) subjects, have benefited. Mean use of nCPAP machine, assessed by reading the time counter, amounted 4.7 h per 24 h, with only 23% of non-compliant patients (use < 3 h per 24 h). In 205 patients nCPAP was effective in controlling SAHS-related symptoms. Cure, with successful weaning from nCPAP, was obtained in 16 patients, as a result of marked weight loss in 13 of them. Forty-six non-compliant subjects were not allowed by the physician to go on, and 40 subjects left nCPAP because of intolerance. Finally, 10 patients abandoned nCPAP because of inefficacy, ascribed to some associated condition, being predominant, and 8 patients died. Our results suggest that domiciliary nCPAP is an effective treatment for SAHS in a majority of subjects, but that this kind of treatment is prescribed lifelong, unless there is a marked weight loss. The Belgian conventional system, as it requires a regular follow-up, contributes to keep non-compliance within acceptable limits.

[Prognostic factors in advanced stage non-small cell bronchial cancer: experiences of the European Lung Cancer Working Party]. / Facteurs pronostiques des cancers bronchiques non à petites cellules au stade avancé: expérience de l'European Lung Cancer Working Party.

The European Lung Cancer Working Party has investigated prognostic factors for response, overall survival, long term survival in a population with advanced non small cell lung cancer registered in a clinical trial evaluating platinum derivatives-containing chemotherapy regimens. Various factors have been identified in multivariate analyses and were classified using RECPAM methodology. In addition to the clinical factors such as disease extent and performance status were shown, as significant predictors, rarely studied biological factors like pretherapeutic leucocyte and polynuclear levels. The obtention of an objective response to chemotherapy appeared to be a major prognostic factor for further survival.

Prognostic factors for response to chemotherapy containing platinum derivatives in patients with unresectable non-small cell lung cancer. (NSCLC).

PURPOSE: To identify pretreatment variables predicting response to platinum derivatives containing chemotherapy in patients with unresectable non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients included in one of the 7 consecutive clinical trials conducted by the European Lung Cancer Working Party between December 1980 and August 1991. All patients received a cisplatin or carboplatin containing chemotherapy. We analyzed 22 potential prognostic factors including sex, age, histology, performance status, weight loss, type of lesions, extent of disease, main metastatic sites and several biological parameters, namely white blood cell count (WBC), neutrophil count, platelet count, hemoglobinemia, creatininemia, serum alkaline phosphatases and LDH. RESULTS: On 1052 eligible patients. 107 were not assessable for response. The objective response rate was 26% (95% C.I.: 23, 29%). Univariate analysis identified as statistically significantly associated with a higher objective antitumoral response rate the following characteristics: a normal platelet count, the absence of skin metastasis, the absence of adrenal metastasis, a higher creatininemia, a normal hemoglobinemia, an older age and a normal WBC count. On a restricted set of variables including data from 777 patients, a multivariate logistic regression model disclosed age and platelet count as significantly and independently related to response rate. CONCLUSION: Clinical and demographic characteristics of patients with unresectable NSCLC, as well as routine laboratory parameters, could not accurately predict response to chemotherapy in a population of patients selected for a clinical trial. Future studies on this subject should include more sophisticated variables as new biomolecular makers.

[Isolated respiratory insufficiency in Arnold-Chiari malformation]. / Insuffisance respiratoire isolée sur malformation d'Arnold-Chiari.

We report on a 45-year old woman with daytime sleepiness, polycythemia, hypoxemia and hypercapnia, admitted to hospital on three occasions in a 10 month period for acute respiratory failure. Polysomnography demonstrated apneas of central type, testing of the respiratory drive suggested central alveolar hypoventilation and magnetic resonance imaging showed an Arnold-Chiari malformation with syringomyelia. The originality of this case is the absence of any neurologic sign, respiratory failure being the sole manifestation of the Arnold-Chiari malformation.

Perception of dyspnoea during acute changes in lung function in patients with either asthma or COPD.

The aim of the study was to evaluate the relationship between several lung function indices and perceived dyspnoea during bronchoconstriction. Acute changes in lung function were induced by inhaled histamine followed by terbutaline, in 12 asthmatics and 12 subjects with chronic obstructive pulmonary disease (COPD). A bipolar visual analogue scale (VAS), allowing subjects to report either improvement or worsening when moving off from a 'nochange' midpoint, was used to rate shortness of breath. Large swings in ratings were seen in all asthmatics and in seven out of 12 COPD subjects (high perceivers). Using linear regression of VAS rating against parallel change in lung function, on a within-subject basis, the highest degree of correlation between dyspnoea and objective response was found to involve the change in specific inspiratory resistance (sRin) in the asthmatics. In the five low perceivers, the ability to discriminate an increase in airway obstruction, estimated as the VAS/change in lung function slope, was very poor. Using a stepwise multiple regression analysis, the sensation of dyspnoea was found to be significantly related to the FEV1 and the sRin in the asthmatics, to the inspiratory vital capacity and the maximal inspiratory flow at 50% FVC (MIF50) in the COPD subjects with high perception, and to the MIF50 in the COPD subjects with low perception.

A four-drug combination chemotherapy with cisplatin, mitomycin, vindesine and 5 fluorouracile: a regimen associated with major toxicity in patients with advanced non-small cell lung cancer.

The purpose of this study was to determine the activity of a 4-drug combination chemotherapy: cisplatin, mitomycin C, vindesine and 5-fluorouracil (5-FU) in patients with advanced non-small cell lung cancer (NSCLC). Chemotherapy consisted of the administration of cisplatin (30 mg/m2 d 1-4), mitomycin C (10 mg/m2 d 1), vindesine (3 mg/m2 d 1) and 5-FU (1 g/m2 d 1-4 by continuous intravenous infusion). In patients older than 70 years, and in those who received prior irradiation or chemotherapy, cisplatin and 5-FU were omitted on day 4. Courses were repeated every 4 weeks and evaluation of response was performed after the first 2 courses. In case of response, treatment was continued until best response or untolerable toxicity. Among 182 eligible patients, 75% had received no prior therapy; 41% had locoregional disease and 59% metastatic disease; 41% lost more than 5% of their pretherapy body weight. A 34% objective response rate was observed in the 164 evaluable patients (31% in all the eligible patients) including 4 complete and 52 partial responses. Patients with locoregional disease had a significantly better response rate than those with metastases (44% vs 27%). The overall median survival was 26 weeks. Significant hematological toxicity was documented but the most serious adverse event was the occurrence of 18 (10%) cardiac or sudden deaths. These toxic deaths were significantly associated with a 5% loss of body weight prior to therapy. The addition of 5-FU to combination of cisplatin, mitomycin C and vindesine does not improve antitumoral effect but results in very significant cardiac toxicity.

A four-drug combination chemotherapy with cisplatin, mitomycin, vindesine and 5-fluorouracil. A regimen associated with major toxicity in patients with advanced non-small lung cancer. European Lung Cancer Working Party.

PURPOSE: To determine in patients with advanced non-small cell lung cancer the activity of a 4-drug combination chemotherapy. PATIENTS AND METHODS: Chemotherapy consisted of the administration of cisplatin (30 mg/m2 d 1-3 or 4), mitomycin C (10 mg/m2 d 1), vindesine (3 mg/m2 d 1) and 5-FU (1 g/m2 d 1-3 or 4 by continuous intravenous infusion. RESULTS: 182 were eligible patients. A 34% objective response rate was observed in the 164 evaluable patients. The overall median survival was 26 weeks. The most serious adverse event was the occurrence of 18 (10%) cardiac or sudden deaths. These toxic deaths were significantly associated with a > or = 5% loss of body weight prior to therapy. CONCLUSIONS: The regimen studied resulted in a very significant cardiac toxicity.

Dyspnoea and flow-volume curve during exercise in COPD patients.

The purpose of this study, in patients with chronic obstructive pulmonary disease (COPD), was to examine the relationship of dyspnoea, rated on a visual analogue scale (VAS), to 1) tidal ventilatory variables measured on exercise and 2) pre-exercise lung function. Twenty one patients (forced expiratory volume in one second (FEV1) mean (SD) 1.19 (0.32) l) were studied. During a preliminary test, the maximal workload was assessed and the upper end of the VAS was anchored. On the study day, the tidal flow-volume curve on exercise was monitored and dyspnoea was assessed serially every minute. In each individual, the relationship of dyspnoea to various tidal ventilatory variables was studied using linear regression analysis; results were reported squared correlation coefficients, slopes and dyspnoea thresholds. Subsequently, the relationship of slopes and thresholds to pre-exercise lung function was examined. In all patients, dyspnoea showed a close correlation with ventilation, tidal volume, breathing frequency and tidal flow. The tidal peak inspiratory flow was the best individual predictor of dyspnoea with a median r2 of 0.91. Patients with the poorest pre-exercise lung function exhibited the highest rates of increase in dyspnoea and the lowest thresholds, the strongest correlation being observed between the dyspnoea/ventilation slope and pre-exercise maximal peak inspiratory flow (r2 = 0.54). In conclusion, for individual COPD patients dyspnoea on exercise is closely related to inspiratory flow. The degree of pre-exercise ventilatory impairment accounts, at most, for only half of the variation in dyspnoea perception between subjects.

Long-term survival after chemotherapy containing platinum derivatives in patients with advanced unresectable non-small cell lung cancer. European Lung Cancer Working Party.

The study set out to determine the rate of long-term survivors (LTS) in patients treated with platinum-containing chemotherapy for advanced non-small cell lung cancer (NSCLC), to identify prognostic factors predicting long-term survival (> or = 2 years) and to report the LTS natural history. Eligible patients with advanced NSCLC treated by chemotherapy in one of seven trials conducted by the European Lung Cancer Working Party from December 1980 to August 1991 were included. All patients received cisplatin and/or carboplatin. Of these, 1052 patients were eligible and 24 variables were analysed as potential prognostic factors. Actuarial 2-year and 5-year survival rates were, respectively, 7.4 and 1.8%. All patients surviving for > or = 5 years had limited disease and were treated by complementary chest irradiation and/or surgery. Univariate prognostic factor analysis for LTS identified as significant no major weight loss, limited disease, no liver metastases, normal white blood cells and neutrophils and normal lactic dehydrogenase levels. By multivariate analysis, the only significant factor was limited disease. Objective response to chemotherapy was also found to be, as disease extent, a highly significant predictor for LTS. Thus, the two best prognostic factors for LTS were non-metastatic disease and response to chemotherapy.

How do patients with either asthma or COPD perceive acute bronchodilation?

The purpose of this study was to assess the perception of bronchodilation, as a change in shortness of breath on a bipolar visual analogue scale (VAS), in 16 asthmatics and 20 subjects with COPD. Bronchodilation was gradually induced by five consecutive terbutaline inhalations (cumulated dose 800 micrograms). The subjects were categorized into high and low perceivers, on the basis of a cut-off of 25% VAS line length (after the fifth inhalation). The quality of perception was studied on a within-subject basis by linear regression analysis of VAS ratings against changes in lung function, and was characterized in terms of strength of correlation (squared correlation coefficient, r2), slope, and VAS axis intercept. Fourteen out of 16 asthmatics, and 13 out of 20 COPD subjects, were high perceivers. In the COPD group, the high perceivers had a larger objective response--particularly in inspiratory vital capacity--than the low perceivers. The strongest correlation between subjective and objective response was obtained in asthmatics when the improvement in shortness of breath was evaluated against the decrease in specific inspiratory resistance (median r2 = 0.831). In COPD low perceivers, subjective and objective response were unrelated, while COPD high perceivers differed from the asthmatics by larger intercepts. The perceptual characteristics were unrelated to the degree of baseline obstruction, whilst a modest relationship (r = 0.51) was found between the increase in forced expiratory volume in one second (FEV1) and r2 of the VAS/delta FEV1 analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Dyspnea and inspiratory effort capacity in COPD]. / Dyspnée et capacité inspiratoire à l'effort dans la BPCO.

The aim of this work was to study the relationship between dynamic hyperinflation and dyspnoea perception on exercise in patients with chronic obstructive pulmonary disease (COPD). Seven men and three women with COPD (mean FEV1 45.9 +/- 9.8% predicted) were studied. The upper end of the visual analogue scale was anchored on a preliminary test on a cycle ergometer (day 1). On the study day (day 2) the relationship between dyspnoea and ventilatory indices during high intensity exercise was evaluated, using within-subject linear regression analysis. On a repeat study (day 3), the addition of inspiratory capacity (IC) manoeuvres allowed to monitor the end expiratory lung volume. The highest degree of within-subject correlation was observed between dyspnoea and the tidal peak inspiratory flow (PIFT), as well without (median r2 = 0.920, day 2) as with (median r2 = 0.880, day 3) IC manoeuvres. At maximal exercise, IC decreased in 8 out of 10 subjects (delta IC range -150 to -900 ml). A negative relationship was found between delta IC and the rate of increase in dyspnoea on exercise, measured as the dyspnoea/PIFT slope (r = 0.844, p < 0.01). Our results suggest that dynamic hyperinflation on exercise observed in most patients with COPD allows these subjects to minimize the rate of increase in dyspnoea on exercise.

Perceived effect on shortness of breath of an acute inhalation of saline or terbutaline: variability and sensitivity of a visual analogue scale in patients with asthma or COPD.

The purpose of the study was to validate a bipolar visual analogue scale (VAS) to assess the perceived effect on shortness of breath of an acute inhalation and to search for differences in perception between asthmatics and subjects with chronic obstructive pulmonary disease (COPD). Thirty two subjects with airway obstruction and a diagnosis of either asthma (n = 16) or COPD (n = 16) received three consecutive inhalations of isotonic saline, followed by two inhalations of 400 micrograms terbutaline. Saline was perceived by asthmatics as a slight improvement: VAS (median, 95% confidence interval) 9%, 0-18% of line length. COPD subjects could be separated into two subgroups: "high perceivers" (n = 8, VAS 43%, 33-53%) and "low perceivers" (n = 8, VAS 5%, 3-7%). The median intrasubject coefficient of variation of the three post-saline VAS ratings was 19.4% (asthma), 12.5% (COPD high perceivers), and 14.5% (COPD low perceivers). After terbutaline, asthmatics had, by selection, a larger increase in forced expiratory volume in one second (FEV1) than COPD subjects. However, for other indices (expiratory specific resistance, inspiratory vital capacity and maximal inspiratory flow at 50% forced vital capacity) the changes were smaller in COPD low perceivers than in both asthmatics and COPD high perceivers. The parallel improvement in VAS was 24%, 20-39% (asthma), 15%, 6-25% (COPD high perceivers) and 1%, -1-8% (COPD low perceivers). The most sensitive index was FEV1 in asthmatics, vital capacity in COPD subjects, VAS being among the most sensitive indices in the former, but among the least sensitive in the latter. We conclude that the sensitivity of this VAS to bronchodilation is better in asthmatics than in COPD subjects. The latter can however be separated into subgroups with high and low level of perception.

Dyspnoea assessed by visual analogue scale in patients with chronic obstructive lung disease during progressive and high intensity exercise.

BACKGROUND: A study was carried out to determine whether rating of dyspnoea by means of a visual analogue scale during a progressive exercise test is affected by the subject's awareness of the progressive nature of the protocol. METHODS: Nineteen patients with chronic obstructive lung disease (FEV1 mean (SE) 1.06 (0.07) 1) were studied. A preliminary incremental test was carried out with a work rate increasing by 10 watts every minute until the subject could no longer exercise, to determine the maximum work load (Wmax) and to anchor the upper end of the visual analogue scale. This was followed by two exercise tests performed one day apart in randomised sequence, with two different protocols. One was a 12 minute protocol that included two sudden bursts of three minute high intensity exercise, up to the subject's Wmax, each preceded by three minutes of low level exercise. The other test was a conventional three minute incremental test lasting 12 minutes. On both study days the only information given to the subject about the temporal profile of load was that a change would be made every three minutes. The relation between dyspnoea, as assessed by the visual analogue scale, and ventilation, measured during high intensity or progressive exercise, was studied. RESULTS: The mean (SE) rates of increase of dyspnoea with increasing ventilation (% of line length 1(-1) min) obtained by linear regression analysis were similar for the two tests (2.86 (0.20) for progressive exercise and 2.87 (0.25) for high intensity exercise); it was 2.59 (0.25) for the initial burst of high intensity exercise when the data on this were analysed separately. In six subjects with stable disease studied again two months later the reproducibility of the rating of dyspnoea was reasonably good for both protocols. CONCLUSION: The results suggest that in most patients with chronic obstructive lung disease the assessment of exercise induced dyspnoea by means of a visual analogue scale during a progressive exercise test is not affected by the subject's awareness of the progressive increase in work intensity.

Acute nonlymphocytic leukemia following chemotherapy with cisplatin and etoposide for non-small-cell carcinoma of the lung: case report.

A case of acute nonlymphocytic leukemia (ANLL) following chemotherapy with cisplatin (CDDP) and etoposide (VP16) for non-small-cell lung cancer (NSCLC) diagnosed 24 months before is reported. Although the fortuitous occurrence of two unrelated malignancies cannot be excluded, the hypothesis of secondary leukemia must be taken into account. The clinical and experimental data implying these agents, generally considered to be noncarcinogenic in man, in the occurrence of secondary malignancies are briefly discussed.

[Left ventricular function in obstructive chronic bronchopneumopathy]. / Etude de la fonction ventriculaire gauche en cas de bronchopneumopathie chronique obstructive.

Left ventricular (LV) function was studied, using echocardiography, radionuclide angiography and right catheterization, in 20 patients (mean age 60.9 +/- 1.5 years) with severe stable chronic obstructive pulmonary disease (COPD) and without known heart disease. The diagnosis of LV failure, suspected on clinical grounds in 8 of these patients, was confirmed by raised pulmonary capillary wedge pressure (PCWP) in only one patient. Nineteen subjects had normal PCWP and LV ejection fraction (LVEF) values, radionuclide LVEF and end diastolic LV dimension being the most powerful discriminators between the single abnormal patient and the others. Echocardiograms of sufficient quality were obtained in 11 out of the 19 normal patients and constantly showed LV dimensions in the lowest part of the normal range. The stroke volume index (SVI) - cardiac output being measured by thermodilution - was found to be decreased in 9 of 14 patients with normal LVEF values. We conclude that in patients with severe COPD (1) LV failure is quite unfrequent and the empirical use of digitalis should not be recommended, (2) radionuclide angiography is the most useful procedure for routine evaluation of LV function and (3) a decreased SVI is frequently found in patients with a small LV cavity and a normal LVEF, suggesting some degree of diastolic dysfunction of the left ventricle.

Lung function, maximum and submaximum exercise testing in COPD patients: reproducibility over a long interval.

This study was designed to investigate the reproducibility and clinical relevance of several lung function and exercise test indices in a sample of patients with stable severe chronic obstructive pulmonary disease (COPD). Twenty subjects (ages 67.8 +/- 2.0 years, forced expiratory volume in 1s, [FEV1] 39.7 +/- 2.8% predicted) receiving conventional medical therapy and pulmonary rehabilitation were tested 4 times at 1 month intervals. Testing procedures included lung function (inspiratory vital capacity [IVC], FEV1, plethysmographic functional residual capacity [FRC], specific conductance of the airways (sGaw), single breath transfer factor divided by the alveolar volume [TL/VA]); incremental, progressive, symptom-limited, cycle exercise (maximum work load [Wmax], maximum heart rate [HRmax], maximum ventilation [VEmax], maximum oxygen uptake [VO2max]); and 2 modes of submaximum exercise (12 min walking test [12 MWD] and endurance cycle test). The mean of the absolute value of the individual patient, session-to-session, variation was found to be 0.131 for FEV1, 102 ml/min for VO2max. The within-subject variability was the smallest for HRmax and IVC (mean intrasubject coefficient of variation, [CV intra] 5.0 and 6.5%) and the greatest for TL/VA, the work performed during the endurance cycle test (EW) and sGaw (CV intra 16.5, 19.4, and 22.7%), while it was reasonably low (8.1-10.2%) for all the other variables studied. Calculation of the F ratio of the intersubject variance to the residual (total minus intersubject) variance, interpreted as a signal-to-noise, ratio, yielded the following, in decreasing order: TL/VA, EW, VEmax, VO2max, IVC, FEV1, HRmax, Wmax, sGaw, 12 MWD, FRC. If we assume that a useful variable should combine a low within-subject variability (CV intra less than or equal to 10%) with a high signal-to-noise ratio, we conclude that, among all the variables studied, IVC, FEV1, VEmax, and VO2max are those with the greatest clinical potential for functional assessment in patients with COPD.

Enoxacin in acute exacerbations of chronic bronchitis: a comparison with amoxycillin.

A total of 43 hospitalized adult patients with acute exacerbations of chronic bronchitis or bronchiectasis due to Gram-negative bacteria were randomized to receive either enoxacin (400 mg bd) or amoxycillin (1,000 mg tid) for 7-12 days. Micro-organisms isolated included 24 Haemophilus influenzae (three beta-lactamases positive), 11 Branhamella catarrhalis (six beta-lactamase positive), two Pseudomonas aeruginosa and two Neisseria meningitidis in 37 evaluable patients. In the enoxacin group (23 patients) 82.6% of the patients were clinically cured or improved against 93% of patients in the amoxycillin group (14 patients). In the enoxacin group 76% of the pathogens were eradicated with two failures (P. aeruginosa), one relapse (H. influenzae) and three superinfections (Streptococcus pneumoniae). In the amoxycillin group, 71% of the pathogens were eradicated with 29% relapses. The differences between the two groups were not statistically significant. An increase in theophylline concentration occurred in 15 of 16 patients receiving simultaneous administration of theophylline, without clinical evidence of toxicity when theophylline dosage was reduced and enoxacin continued. Enoxacin appears to be as effective as amoxycillin in the treatment of acute exacerbations of chronic bronchitis due to susceptible Gram-negative bacteria.