Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.

PURPOSE: Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS: Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS: A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION: Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.

The prevalence of obstructive sleep apnea in hypertensives.

This study was designed to measure the prevalence of obstructive sleep apnea in untreated and treated hypertensive patients by comparing them with normotensive subjects, taking into account the possible confounding variables body mass index, age, sex, and alcohol consumption. Subjects with no known sleep disorders were recruited, had full polysomnography, and had their blood pressure assessed with a 24-h ambulatory monitor. Subjects with a mean 24-h blood pressure greater than 140/90, and receiving no treatment for, or with no history of, hypertension were classified as untreated hypertensives; those receiving antihypertension medication were classified as treated hypertensives; those with a mean 24-h blood pressure less than 140/90 and no history of hypertension were classified as normotensives. Thirty-eight percent of the 34 untreated and 38% of the 34 treated hypertensives, and 4% of the 25 normotensives had apnea-hypopnea indexes greater than 5. Logistic regression analysis showed that body mass index (p = 0.001), age (p = 0.07), sex (p = 0.07), treated hypertension (p = 0.05), and untreated hypertension (p = 0.06) were associated with the presence of sleep apnea, but that alcohol consumption (p = 0.82) was not. It is concluded that there is a relationship between sleep apnea and hypertension that, although partially explained by the confounding variables body mass index, age, and sex, persists when these are allowed for.

A methodology for measuring clinical outcomes in an acute care teaching hospital.

The purpose of this study was to assess risk-adjusted outcomes following renal failure, gastrointestinal haemorrhage, stroke, myocardial infarction and heart failure. Length of stay, death and unplanned readmission were compared by treating medical unit adjusting for the four risk factors: severity, comorbidity, sex and age. A significant difference in risk-adjusted deaths and length of stay occurred among units treating heart failure, in length of stay among units treating renal failure, and in deaths among units treating gastrointestinal haemorrhage. A significant difference in death, length of stay and unplanned readmission occurred among units treating stroke. No significant difference in outcomes occurred among units treating myocardial infarction. Outcomes were predicted by age, severity and comorbidity. In conclusion, severity and comorbidity together with age were shown to be good predictors of outcomes. The methodology is considered unsuitable as a regular quality assurance activity.

Update on lung cancer.

Lung cancer is common, largely smoking related and thus preventable. Focal non small cell disease is surgically resectable but presentation with mediastinal and metastatic disease is common and has a poor prognosis. Small cell lung cancer is chemosensitive but has a very poor prognosis. Widespread screening programs are not currently considered cost-effective. New preventive and therapeutic approaches are the way forward and a multidisciplinary approach is clearly needed.

Exertional oxygen of limited benefit in patients with chronic obstructive pulmonary disease and mild hypoxemia.

It is unclear whether short-term benefits from supplemental oxygen translate into improved quality of life in patients with severe COPD. In a 12 wk double-blind randomized crossover study, we assessed the effects of supplemental air and oxygen on exercise performance (step tests and 6 min walking distance [6MWD]) initially and after two 6 wk periods at home using exertional cylinder air or oxygen. We measured quality of life at baseline and after the two 6 wk domiciliary periods. The 26 patients (24 males) had a mean age of 73 +/- 6 yr; mean FEV1, 0.9 +/- 0.4 L; mean DLCO, 10.6 +/- 2.4 ml/min/mm Hg; mean resting PO2, 69 +/- 8.5 (range 58 to 82) mm Hg; mean PCO2, 41 +/- 3.3 mm Hg; and mean resting SaO2, 94 +/- 2.1 (mean +/- SD). Laboratory tests were performed breathing intranasal air or oxygen at 4 L/min, and measurements were made of SaO2 and Borg dysnea scores. Supplemental oxygen increased 6MWD and steps by small, statistically significant increments acutely at baseline and after 6 and 12 wk, without corresponding falls in Borg score. Degree of desaturation at baseline did not correlate with increase in 6MWD or steps achieved at baseline or at 6 or 12 wk, nor with the domiciliary gas used. There was no difference in 6MWD or steps achieved while breathing supplemental oxygen after 6 wk of domiciliary oxygen compared with domiciliary air. Small improvements in quality of life indices were found after domiciliary oxygen, and mastery also improved after domiciliary air. There were no differences in quality of life, however, when domiciliary oxygen was compared with domiciliary air. Although oxygen supplementation induced small acute increments in laboratory exercise performance, such improvements had little impact on the patients' daily lives.

Preoperative risk evaluation for lung cancer resection: predicted postoperative product as a predictor of surgical mortality.

We assessed the capacity to predict surgical mortality, complications, and functional loss by using the results of resting and exercise respiratory function. Measurements were made before and 4 mo after lung resection in 54 consecutive patients with bronchogenic carcinoma. Predicted postoperative (ppo) FEV1 and DLCO were derived using quantitative lung perfusion scans when baseline FEV1 was < 55% predicted, and by proportional loss of pulmonary segments (total = 19 segments) when FEV1 was > 55% predicted. The patients were aged 67 +/- 7 (mean +/- SD) yr, with an FEV1 of 76 +/- 23% predicted, FEV1/FVC of 55 +/- 13%. and DLCO of 85 +/- 22% predicted. Eleven of the patients had pneumonectomy, 29 had lobectomy, 12 had wedge resection, and two had no resection. Wilcoxon and stepwise logistic regression analyses were used to determine which indices best predicted outcome. Postoperative values were correlated (r = 0.87, p < 0.0001) with actual 4/12 postoperative values of FEV1% and of DLCO (r = 0.56, p < 0.0001). The best predictors (all p < 0.05) for each outcome, in order of usefulness, were as follows. For surgical mortality: (1) the predicted postoperative product (PPP) of ppo FEV1% x ppo DLCO%; (2) ppo DLCO%; (3) ppo FEV1%, and (4) RV, FRC, and SaO2 on the maximal step exercise test. For respiratory complications: body mass index (BMI) (for patients undergoing lobectomy or wedge resection only). For cardiac complications: (1) age; (2) SaO2 at baseline and on the maximal step exercise test; (3) PaO2; (4) PaCO2; and (5) minute ventilation at maximal exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic persistent cough: use of ipratropium bromide in undiagnosed cases following upper respiratory tract infection.

The clinical effects of inhaled ipratropium bromide were studied in 14 non-smoking patients with persistent post-viral infective cough employing a controlled double-blind, cross-over trial. Patients were selected if they demonstrated no apparent underlying cause for their persistent cough after appropriate radiological and respiratory function tests including methacholine reactivity and bronchoscopic examination. Inhaled ipratropium bromide (320 micrograms day-1) produced significantly less day and night time cough (P < 0.05) with overall clinical improvement in 12 cases, five of whom had total resolution of their cough. We conclude that ipratropium bromide is an effective treatment in non-smoking adults with protracted cough following clinical upper respiratory tract infection.

Angiotensin-converting enzyme in bronchoalveolar lavage fluid in sarcoidosis.

This is the first Australian study of angiotensin converting enzyme (ACE) in bronchoalveolar lavage fluid in 51 patients with sarcoidosis. The aim was: 1) to establish the range of lavage ACE in healthy smokers and non-smoking patients with sarcoidosis. 2) to evaluate the clinical usefulness of lavage ACE. Seventeen control subjects and 51 sarcoid patients all underwent bronchoalveolar lavage, the latter also having 67Gallium scan, spirometry and carbon monoxide uptake. Eighteen patients had all tests repeated six months later. Lavage ACE was significantly higher in sarcoid non-smokers than control non-smokers (p < 0.05). In the 51 sarcoid patients, lavage ACE/albumin ratios were 10-fold higher than serum ACE/albumin ratios (p < 0.0001). In sarcoid patients with raised intrathoracic 67Gallium uptake, lavage ACE was significantly higher than those patients with normal uptake (p < 0.05). Expressing lavage ACE as ACE/albumin ratios reduced the statistical significance of correlations with other parameters, eg, lavage % lymphocytes, and lavage IgG. Lavage ACE levels changed concordantly with lung function 67Gallium scan and lavage lymphocytes, albumin and IgG. However, the wide distribution of lavage ACE in control and sarcoid subjects and the influence of smoking history severely limits its clinical application.

An evaluation of three elements of pulmonary rehabilitation.

In this study of 39 patients with severe chronic airflow limitation, an independent group design examined the effect on exercise performance of a six-week program of leg muscle training, inspiratory muscle training and postural drainage. Exercise performance was reassessed at three months after the completion of the training program. MANOVA analysis of the 12-minute walking distance test showed a significant training effect (p < 0.001) with the largest effect occurring with leg muscle training (873 to 952 metres), a placebo response with postural drainage (886 to 925 metres) and minimal change with inspiratory muscle training (911 to 920 metres). There was a carry over effect at three months with leg muscle training, that was not seen in the other groups.

Cardiopulmonary response to oxygen therapy in hypoxaemic chronic airflow obstruction.

The acute change in pulmonary artery pressure in response to oxygen may have prognostic value for patients with chronic obstructive pulmonary disease treated with long term domiciliary oxygen. A study was carried out to elucidate the mechanism of the acute cardio-respiratory response to oxygen in such patients and to determine whether it can be quantified non-invasively. The effects of acute oxygen administration (100% for 20 minutes and 28% oxygen for 24 hours) were assessed by non-invasive means and right heart catheterisation in 17 patients with severe stable hypoxaemic chronic obstructive pulmonary disease. Measurements included change in the ratio of dead space to tidal volume (VD/VT), effective pulmonary capillary blood flow (by rebreathing and single breath soluble gas uptake: QRB, QSB), left ventricular ejection fraction (radionuclide ventriculography), and M mode echocardiographic estimates of ventricular diameters and fractional shortening. These values were compared with those obtained from right heart catheter measurements of pulmonary artery pressure, cardiac index (thermodilution and direct carbon dioxide Fick: QTD, QFICK), and pulmonary vascular resistance. Oxygen administration resulted in a significant fall in pulmonary artery pressure, QTD, and QRB and a significant increase in VD/VT. The fall in QRB after 100% oxygen breathing for 20 minutes correlated strongly with the fall in pulmonary artery pressure (r = 0.86). There was no correlation between the fall in pulmonary artery pressure and the fall in QSB or the risen in VD/VT. Left ventricular ejection fraction did not change significantly. Echocardiography was technically unsatisfactory because of lung hyperinflation. Apart from a possible relation between VO2max and fall in pulmonary artery pressure after 24 hours of 28% oxygen breathing (r = 0.49, p less than 0.1) none of the baseline respiratory function measurements predicted the fall in pulmonary artery pressure or QRB. It is concluded that the cardiopulmonary response to acute oxygen breathing in patients with hypoxic chronic obstructive pulmonary disease includes a reduction in pulmonary artery pressure and cardiac output and a redistribution of pulmonary blood flow, and that rebreathing measurements of effective pulmonary blood flow can be used to quantify this response non-invasively.

Threshold pressure training, breathing pattern, and exercise performance in chronic airflow obstruction.

The effects of six weeks of threshold pressure inspiratory muscle training (IMT) on inspiratory muscle performance, breathing pattern and exercise performance were studied in eight patients with severe airflow obstruction. The results indicated that IMT improved inspiratory muscle performance but did not affect exercise performance or breathing pattern during maximal exercise.

Measurement of effective pulmonary blood flow by soluble gas uptake in patients with chronic airflow obstruction.

A study was designed to assess the accuracy and reproducibility of rebreathing and single breath soluble gas uptake measurements of effective pulmonary blood flow (Q) in patients with airways obstruction. Both rebreathing (RB) and single breath (SB) estimates of Q were compared with direct Fick and thermodilution (TD) measurements of cardiac output at rest and during exercise in eight patients with chronic, poorly reversible airflow obstruction with mean FEV1 65% predicted and mean FEV1/FVC 53%. The mean (SD) resting values obtained were QRB 3.47 (0.46), QSB 4.75 (1.15), QFick 4.77 (0.97), and QTD 5.15 (0.98). QRB was significantly lower than the other three estimates, which did not differ significantly from each other. Exercise produced significant increases in all four estimates for the group. The mean exercise values were QRB 6.23 (1.19), QSB 7.62 (1.97), QFick 8.97 (1.96), and QTD 9.09 (1.00), both QRB and QSB being significantly less than QFick and QTD. Analysis of variance of the rest, exercise, and combined data showed highly significant relationships with the TD and Fick measurements for both QRB and QSB over the range of values studied. In addition, the reproducibility of QRB and QSB was assessed in 15 other patients with chronic airflow obstruction (mean FEV1 42% predicted, FEV1/FVC 43%) and in 10 normal subjects. The coefficients of intrasubject variability for a single measurement for QRB were 8.7% in normal subjects and 10.2% in patients and for QSB were 11.7% in normal subjects and 16.1% in patients. The group differences from morning to afternoon, between days, and over a month were not significant in the normal subjects. In the patients QRB was slightly higher in the afternoon than in the morning of the same day, but the differences between days and over a month were not significant for either test. Although both tests detected the increase in pulmonary blood flow during exercise, the single breath test was more accurate at rest. Some underestimation was present for rebreathing at rest and for both tests during exercise, but this can be allowed for. In patients with mild airflow obstruction the reproducibility of the soluble gas uptake methods was similar to that of invasive catheter methods of cardiac output estimation. The single breath test in particular was, however, less reproducible in patients with more severe airflow obstruction, and the rebreathing method may be more useful for detecting increases in pulmonary blood flow in these patients.

Congenital lobar emphysema requiring surgery in adult life.

We report a case of congenital lobar emphysema requiring surgery in early adult life to relieve respiratory symptoms of late onset. Regional lung function studies helped to predict the outcome of surgery which was successful in relieving symptoms.

Lobar occlusion in the preoperative assessment of patients with lung cancer.

Bronchial occlusion during exercise was used to predict the functional effects of subsequent pulmonary resection in six high risk patients with lung cancer and severe airflow obstruction. Each patient underwent transnasal fibreoptic bronchoscopy whilst cycling in steady state at a load which had been selected as equivalent to walking at a brisk pace for that patient. The effects on minute ventilation and oxygen uptake were observed during occlusion of the bronchus to the diseased lobe. If the patient was able to continue cycling and maintain the same work load during occlusion this was regarded as indicating that he would withstand resection of the occluded lung tissue. In five of the patients, postoperative studies were performed. All were able to maintain the same level of steady state exercise postoperatively as that maintained during bronchial occlusion preoperatively. Resection resulted in a decrease in static lung volumes. Other routine whole lung function tests, walking capacity and incremental exercise indices, however, were largely unchanged.

Factors affecting the decline of ventilatory function in chronic bronchitis.

Ninety six middle aged male patients with chronic bronchitis with relatively well preserved ventilatory function who were resident in Queensland, New South Wales, or Victoria took part in a prospective study to determine the relationship of various factors to the rate of decline of the FEV1. Thirty of the subjects withdrew, leaving 66 to be followed for four to six years. The mean rate of decline of the FEV1 was 58.6 (SD 51.4) ml/year. The subjects' ventilatory responses to bronchodilator and to methacholine (measures of bronchial lability) were significantly related to each other and to sputum eosinophilia. With a linear model for the data on 57 patients who had methacholine and skin tests the rate of decline of the FEV1 was found, after adjustment had been made for other variables, to be significantly related to State of residence, current smoking, response to bronchodilator, age, and occupational exposure to dust. Response to bronchodilator was interchangeable with response to methacholine. With the five variables in the model none of the following factors was related to the rate of decline of the FEV1:FEV1 on entry, FEV1% predicted normal, FEV1/VC%, skin test reaction, occupation on entry, history of sinusitis and rhinitis, and height. When data from all 66 subjects were introduced into the model, in addition to the five significant individual variables (FEV1/VC% X response to bronchodilator) was significantly related to the rate of decline of the FEV1. Of these prognostic indices, response to bronchodilator was independent of the initial FEV1, FEV/VC%, and FEV1% predicted. The difference between States, which was not explained by differences due to sampling or withdrawal of subjects, was due to a low rate of decline in Queensland.

Severe thoracic systemic lupus erythematosus.

The effects of corticosteroid administration to eight patients with severe thoracic systemic lupus erythematosus (SLE) were assessed in a prospective study over a mean period of 26 months by serial measurements of respiratory function, ESR, and a clinical score. Initial assessment of respiratory function showed severe restrictive ventilatory defects and impairment of carbon monoxide uptake not wholly attributable to the small lung volumes. ESR and clinical score showed high correlation coefficients with FEV1 in all patients, with VC and TLC in seven patients, and with TLCO in four patients, indicating that changes of respiratory function were reflecting the activity of the disease. This study shows that in patients with severe thoracic SLE it is valid to use serial measurements of respiratory function to assess the response to treatment and that pronounced and sustained improvement of respiratory function can be expected.

Disseminated cryptococcosis after transurethral resection of the prostate.

A 63-year-old man presenting with acute retention and dysuria underwent transurethral resection of the prostate for suspected benign prostatic hypertrophy. Ten days postoperatively he developed disseminated cryptococcosis. Re-examination of the prostatic chips revealed cryptococcal prostatitis. Treatment consisted of amphotericin, flucytosine and transfer factor along with wedge resection of a pulmonary toruloma. He remains well 12 months after cessation of treatment. This appears to be the first case report in Australia of cryptococcal prostatitis with dissemination after transurethral resection of the prostate.

Labetalol, beta blockers, and acute deterioration of chronic airway obstruction.

The effects on lung function of labetalol (a combined alpha and beta adrenergic receptor blocker) and three beta adrenergic receptor blockers (propranolol, atenolol, metoprolol) have been assessed in patients with chronic airflow obstruction using a double-blind trial. With the dosages used, all drugs produced an equivalent fall of blood pressure. Propranolol was the only drug that significantly increased airways obstruction (FEV1, specific airways resistance). Following salbutamol, labetalol was associated with a significantly greater improvement of airflow than either propranolol or metoprolol. On these acute studies, the order of preference for beta blocking drugs in management of hypertension in patients with obstructive airways disease, would be labetalol, (atenolol) or (metoprolol) and then propranolol.

A double-blind comparison of verapamil and labetalol in hypertensive patients with coexisting chronic obstructive airways disease.

A randomized, double-blind, cross-over trial was carried out in nine hypertensive patients with coexisting chronic obstructive lung disease to evaluate the hypotensive efficacy and safety of verapamil and labetalol. The effects on respiratory function were also assessed. Verapamil in doses of 160 mg twice daily was equally effective as 200 mg twice daily of labetalol. Labetalol significantly reduced both forced expiration volume at 1 s (FEV1) and forced vital capacity (FVC), suggesting a bronchoconstrictor effect. Verapamil was devoid of any such effect. Neither drug caused significant side effects.

Dead space and tidal volume of the giraffe compared with some other mammals.

The ventilation, tidal volume and anatomical dead-space were measured in a living giraffe and compared with similar measurements in a camel, red deer, llama and man. The giraffe had a resting tidal volume of about 3.3 litres with a dead-space/tidal-volume ratio of 0.34. The giraffe breathes slowly, apparently because of the unusually small diameter of its trachea relative to its length, compared with known measurement in other mammals.