Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group.

BACKGROUND: The palliative role of chemoradiation in the treatment of patients with locally advanced, inoperable non-small-cell lung cancer stage III and negative prognostic factors remains unresolved. METHODS: Patients not eligible for curative radiotherapy were randomised to receive either chemoradiation or chemotherapy alone. Four courses of intravenous carboplatin on day 1 and oral vinorelbin on days 1 and 8 were given with 3-week intervals. Patients in the chemoradiation arm also received radiotherapy with fractionation 42 Gy/15, starting at the second chemotherapy course. The primary end point was overall survival; secondary end points were health-related quality of life (HRQOL) and toxicity. RESULTS: Enrolment was terminated due to slow accrual after 191 patients from 25 Norwegian hospitals were randomised. Median age was 67 years and 21% had PS 2. In the chemotherapy versus the chemoradiation arm, the median overall survival was 9.7 and 12.6 months, respectively (P<0.01). One-year survival was 34.0% and 53.2% (P<0.01). Following a minor decline during treatment, HRQOL remained unchanged in the chemoradiation arm. The patients in the chemotherapy arm reported gradual deterioration during the subsequent months. In the chemoradiation arm, there were more hospital admissions related to side effects (P<0.05). CONCLUSION: Chemoradiation was superior to chemotherapy alone with respect to survival and HRQoL at the expense of more hospital admissions due to toxicity.

Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC. A phase III randomised controlled trial by the Norwegian Lung Cancer Study Group.

BACKGROUND: Platinum-based doublet chemotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC), but earlier studies have suggested that non-platinum combinations are equally effective and better tolerated. We conducted a national, randomised study to compare a non-platinum with a platinum combination. METHODS: Eligible patients had stage IIIB/IV NSCLC and performance status (PS) 0-2. Patients received up to three cycles of vinorelbine 60 mg m(-2) p.o.+gemcitabine 1000 mg m(-2) i.v. day 1 and 8 (VG) or vinorelbine 60 mg m(-2) p.o. day 1 and 8+carboplatin area under the curve=5 (Calvert's formula) i.v. day 1 (VC). Patients ≥75 years received 75% of the dose. Endpoints were overall survival, health-related quality of life (HRQoL), toxicity, and the use of radiotherapy. RESULTS: We randomised 444 patients from September 2007 to April 2009. The median age was 65 years, 58% were men and 25% had PS 2. Median survival was VG: 6.3 months; VC: 7.0 months, P=0.802. Vinorelbine plus carboplatin patients had more grade III/IV nausea/vomiting (VG: 4%, VC: 12%, P=0.008) and grade IV neutropenia (VG: 7%, VC: 19%, P<0.001). Infections, HRQoL and the use of radiotherapy did not differ significantly between the treatment groups. CONCLUSION: The two regimens yielded similar overall survival. The VG combination had only a slightly better toxicity profile.

Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity.

This randomised phase III study in advanced non-small cell lung cancer (NSCLC) patients was conducted to compare vinorelbine/carboplatin (VC) and gemcitabine/carboplatin (GC) regarding efficacy, health-related quality of life (HRQOL) and toxicity. Chemonaive patients with NSCLC stage IIIB/IV and WHO performance status 0-2 were eligible. No upper age limit was defined. Patients received vinorelbine 25 mg m(-2) or gemcitabine 1000 mg m(-2) on days 1 and 8 and carboplatin AUC4 on day 1 and three courses with 3-week cycles. HRQOL questionnaires were completed at baseline, before chemotherapy and every 8 weeks until 49 weeks. During 14 months, 432 patients were included (VC, n=218; GC, n=214). Median survival was 7.3 vs 6.4 months, 1-year survival 28 vs 30% and 2-year survival 7 vs 7% in the VC and GC arm, respectively (P=0.89). HRQOL, represented by global QOL, nausea/vomiting, dyspnoea and pain, showed no significant differences. More grade 3-4 anaemia (P<0.01), thrombocytopenia (P<0.01) and transfusions of blood (P<0.01) or platelets (P<0.01) were observed in the GC arm. There was more grade 3-4 leucopoenia (P<0.01) in the VC arm, but the rate of neutropenic infections was the same (P=0.87). In conclusion, overall survival and HRQOL are similar, while grade 3-4 toxicity requiring interventions are less frequent when VC is compared to GC in advanced NSCLC.

Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer.

This randomised multicentre trial was conducted to establish the optimal duration of palliative chemotherapy in advanced non-small-cell lung cancer (NSCLC). We compared a policy of three vs six courses of new-generation platinum-based combination chemotherapy with regard to effects on quality of life (QoL) and survival. Patients with stage IIIB or IV NSCLC and WHO performance status (PS) 0-2 were randomised to receive three (C3) or six (C6) courses of carboplatin (area under the curve (AUC) 4, Chatelut's formula, equivalent to Calvert's AUC 5) on day 1 and vinorelbine 25 mg m(-2) on days 1 and 8 of a 3-week cycle. Key end points were QoL at 18 weeks, measured with EORTC Quality of Life Questionnaire (QLQ)-C30 and QLQ-LC13, and overall survival. Secondary end points were progression-free survival and need of palliative radiotherapy. Two hundred and ninety-seven patients were randomised (C3 150, C6 147). Their median age was 65 years, 30% had PS 2 and 76% stage IV disease. Seventy-eight and 54% of C3 and C6 patients, respectively, completed all scheduled chemotherapy courses. Compliance with QoL questionnaires was 88%. There were no significant group differences in global QoL, pain or fatigue up to 26 weeks. The dyspnoea palliation rate was lower in the C3 arm at 18 and 26 weeks (P<0.05), but this finding was inconsistent across different methods of analysis. Median survival in the C3 group was 28 vs 32 weeks in the C6 group (P=0.75, HR 1.04, 95% CI 0.82-1.31). One- and 2-year survival rates were 25 and 9% vs 25 and 5% in the C3 and C6 arm, respectively. Median progression-free survival was 16 and 21 weeks in the C3 and C6 groups, respectively (P=0.21, HR 0.86, 95% CI 0.68-1.08). In conclusion, palliative chemotherapy with carboplatin and vinorelbine beyond three courses conveys no survival or consistent QoL benefits in advanced NSCLC.

Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial.

The aim of this study was to assess the effect of a low-dose testosterone on body composition and pulmonary function, as well as on quality of life, sexuality, and psychological symptoms in patients with chronic obstructive pulmonary disease (COPD). Twenty-nine men with moderate to severe COPD were allocated to receive either 250 mg of testosterone or placebo intra-muscularly, every fourth week, during the 26 weeks study period. Fat-free mass increased in the treatment group (P<0.05), and a significant difference between the treatment and the control group was seen after 26 weeks (P<0.05). Fat mass decreased in the treatment group (P<0.05), and there was a significant difference between the treatment and the control group after 12 weeks (P<0.01). A significantly better erectile function was reported in the treatment group at the final visit (P<0.05), and the overall sexual quality of life was significantly better in the treatment group after 12 weeks (P<0.05). No improvement in pulmonary function was found. In conclusion, administration of a low-dose testosterone to men with COPD for 26 weeks was associated with improvement of body composition, better erectile function and sexual quality of life. Furthermore, there were no clinical or biochemical side effects.

Multicenter phase II trial of paclitaxel, cisplatin, and etoposide with concurrent radiation for limited-stage small-cell lung cancer.

PURPOSE: To investigate the feasibility, efficacy, and safety of adding paclitaxel to cisplatin/etoposide chemotherapy and concurrent thoracic radiotherapy (TRT) in treatment of limited-stage small-cell lung cancer (LD-SCLC). PATIENTS AND METHODS: Patients received five courses of chemotherapy (paclitaxel 175 mg/m2 1-hour intravenous [IV] infusion day 1; cisplatin 50 mg/m(2) IV day 1; etoposide 100 mg/m2 IV day 1; oral etoposide 100 mg bid days 2 to 5) at 3-week intervals. TRT (42 Gy administered in 15 fractions) was administered concurrent with chemotherapy cycle 3. All patients were evaluated before starting TRT and 4 weeks after termination of chemotherapy. Patients achieving complete remission (CR) were administered prophylactic cranial irradiation. RESULTS: Thirty-nine patients were included, and the median age was 63 years. The median follow-up was 36 months (range, 19 to 57 months). The overall response rate was 92% (CR, 81%; partial response, 11%), and the median survival was 21 months. The 1- and 2-year disease-specific survival rates were 69% and 37%, respectively. Of 29 CR patients, 83% have relapsed. Brain metastasis was as frequent as local recurrences (42%). Hematologic toxicity included grade 3 to 4 leukopenia in 74% of patients and grade 3 thrombocytopenia in 10%. One treatment-related death occurred as a result of severe neutropenia and septicemia. Hematotoxicity caused dose reductions in 31% of courses. One patient had an anaphylactic reaction during the first paclitaxel infusion. Paclitaxel-related neuropathy and myalgia were reversible. Grade 3 esophagitis was seen in five patients during and shortly after TRT. CONCLUSION: This novel multimodal regimen is effective and well tolerated in patients with LD-SCLC. It compares favorably with previously published phase II studies.

A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC).

This was an open-label randomized Phase III study of 207 patients with either unresectable or metastatic non-small cell lung cancer (NSCLC) who were treated with docetaxel plus best supportive care (BSC) or best supportive care alone. Patients in the chemotherapy arm of the study received docetaxel 100 mg/m(2) as a 1 h intravenous infusion every 21 days until they showed evidence of progressive disease, or estimated maximum benefit obtained or unacceptable side effects. Patients who received docetaxel were pretreated with oral dexamethasone. Patients in the BSC arm should not receive chemotherapy or anticancer therapy except for palliative radiotherapy. Overall survival obtained in the docetaxel arm was significantly longer than in the BSC arm (P=0.026). Two-year survival in the docetaxel arm was 12%, whereas none of the BSC patients survived after 20 months. The response rate was 13.1% (95% CI, 7.5-18.8%). There was a significantly longer time to progression in the docetaxel versus the BSC arm (P<0.001), and statistically significant improvement of clinical symptoms with docetaxel compared to BSC. The quality-of-life descriptors were in favor of docetaxel, and the difference was significant for pain, dyspnea and emotional functioning. The safety profile of docetaxel for this study was similar to that already reported in this patient population.

[Intrapleural fibrinolysis with streptokinase in th treatment of loculated empyema]. / Intrapleural fibrinolyse med streptokinase i behandlingen av lokulaere empyemer.

Intrapleural fibrinolytic treatment is increasingly used in patients with loculated empyema. In this paper, we report our experience with fibrinolytic therapy in eight patients with empyema not responding to drainage and antibiotics. Mean patient age was 47 (range 3-76), and mean duration of symptoms 14 weeks (range 1-24). The patients were treated with 250,000 IU streptokinase in four hours, 1-6 intrapleural instillations (except 50,000 IU for the child). Between 500 and 4,500 cc fluid was drained. Mean drainage time was 14 days (range 6-20). Mean time spent in hospital was 20 days (range 15-25). No microbiological agent was isolated in three patients. All patients recovered. One patient experienced a hypersensitivity reaction following streptokinase treatment for more than one week. Fibrinolysis with streptokinase should be used in patients with loculated empyema when drainage and antibiotics fail.

Mitoxantrone in malignant pericardial effusion.

When occurring, malignant pericardial effusion (MPE) is usually a late phenomenon in most malignancies. Several treatment modalities, including chemotherapy, radiotherapy, pericardial window operation, pericardiotomy, catheter pericardiocentesis and local cytotoxic or sclerotherapy, have been employed. Mitoxantrone is reported as having potential in malignant pleural effusion. Between 1992-97, 5 patients (breast cancer-4 pts, ovarian cancer-1 pt) were admitted to the University Hospital of Tromsø due to a life-threatening MPE. They were all treated with ultrasound-guided pericardiocentesis followed by instillation of mitoxantrone (10 mg). Evaluation at a median follow-up of 59 days (range 28-294 days), 2 patients achieved CR, 1 PR and 2 patients have PD. Two patients are alive 213 and 294 days following therapy. Intrapericardial mitoxantrone instillation is a safe and simple way of handling MPE in malignancies sensitive to mitoxantrone.

[Decentralized special training in pulmonary medicine. A project using telemedicine]. / Desentralisert spesialistutdanning i lungesykdommer. Et prosjekt med bruk av telemedisin.

In arctic Norway, where there is a lack of specialists in pulmonary medicine two postgraduate students, already qualified as specialists in internal medicine at Tromsø Regional Hospital, applied to continue their training at their respective local hospitals. The regional hospital in Tromsø has a long tradition of telemedicine, with network links to local hospitals in the region, and is equipped for interactive consultation and the bilateral transmission of x-rays and video recordings, and digital transmission of x-rays. Accordingly, supported by their supervisor, the two postgraduate students applied to the committee for postgraduate education in pulmonary medicine to have a year's work at their respective local hospitals, supervised via the telemedicine facilities, accepted as equivalent to a six-month module of the normal syllabus. The project was approved and executed as planned. The registrars, who were responsible for pulmonary service at their local hospitals, served four days a month at the regional hospital, and their supervisor visited the local hospitals one day each month. All internal education at the regional hospital was made available by means of a weekly interactive televised link-up, x-rays being displayed on screen as transmitted digitally; bronchoscopies were shown by video, and ad hoc tutorials arranged as needed. Evaluated by the national committee, the project was found satisfactory, and the registrars were duly qualified.

Magnetic resonance imaging of the thorax in the evaluation of asbestosis.

The purpose of the study was to evaluate the accuracy of magnetic resonance imaging (MRI) in detecting subclinical morphological changes caused by asbestos exposure. Conventional chest radiographs according to the International Labour Organisation (ILO) categories 0-11 and spirometric data were compared with MRI in 17 men with mean (+/-2SD) asbestos exposure time of 24.6+/-13.0 yrs. Mean age was 62.0+/-9.4 yrs. The inclusion criterion was an ILO score of 2 or more. Electrocardiographic registrations and antirespiratory movement artefact techniques were used in all MRI examinations to avoid movement artefacts. Mean ILO grading was found to be 7.7+/-3.8 on chest radiography and 9.8+/-2.0 with MRI (p=0.01). Five patients had a higher ILO stage as evaluated by MRI, but in nine patients the staging remained unchanged. MRI revealed mediastinal adenopathy in four patients. Forced expiratory volume in one second (expressed as a percentage of the predicted value) was negatively correlated with ILO score as assessed by MRI (r=-0.4, p=0.032). Magnetic resonance imaging seems to be more sensitive than conventional radiographs in detecting subclinical fibrosis as well as the extent of pleural asbestosis.

Intrapleurally instilled mitoxantrone in metastatic pleural effusions: a phase II study.

Thirty cases (breast cancer-20 cases, malignant lymphoma-4 cases, different malignancies-6 cases) of histologically/cytologically verified malignant pleural effusion (MPE) in 29 patients were treated with intrapleurally instilled mitoxantrone (30 mg). The therapy was well tolerated. At evaluation, 25 patients had died of progressive disease. The median survival was 3 months (range 0.3-21.3 months). There were 26 responders (12 complete responses (CR), 14 partial responses (PR)), whereas 4 patients relapsed and 3 of these had an early relapse (within 3 months). Patients achieving PR or CR had a low risk (15%) of treatment failure. Five patients were subjected to a pharmacokinetic evaluation. This demonstrated rapidly declining plasma and pleural exudate levels of mitoxantrone within the first 6 hours. At 24 hours after instillation, mitoxantrone was only detected in circulating mononuclear cells. This study shows that mitoxantrone is efficacious in the treatment of MPE, and may represent a cost-effective alternative.

Sex hormone responses in healthy men and male patients with chronic obstructive pulmonary disease during an oral glucose load.

The responses of serum testosterone, sex hormone-binding globulin (SHBG) and luteinizing hormone (LH) to an oral glucose tolerance test (OGTT) were investigated in 16 healthy subjects as well as in 11 normoxaemic and 10 hypoxaemic chronic obstructive pulmonary disease (COPD) patients. The latter group were investigated on two occasions, with and without oxygen therapy. Testosterone and apparent free testosterone concentration (AFTC) fell significantly in the healthy subjects as well as in the hypoxaemic patients on oxygen therapy (p < 0.01), whereas LH increased in all groups during the OGTT (p < 0.05). There were significantly higher SHBG levels (p < 0.01), and lower AFTC levels (p < 0.05) in the hypoxaemic group compared to the healthy subjects. In the hypoxaemic group short-term oxygen therapy increased basal AFTC significantly (p < 0.05). With oxygen therapy, the 120-min glucose levels fell significantly from 9.1 +/- 3.2 to 7.6 +/- 2.7 mmol l-1 (mean +/- SD) in the hypoxaemic group (p < 0.05). In conclusion, we have found the serum testosterone and AFTC levels to decrease after an oral glucose load in healthy subjects, together with a compensatory increase in LH. The same pattern is seen in COPD patients. The hypoxaemic patients have a reduced AFTC which is partly reversed by oxygen therapy.

Cardiovascular responses to tests for autonomic dysfunction in patients with chronic obstructive pulmonary disease with and without continuous long-term oxygen therapy.

The aim of this study was to investigate autonomic neuropathy, with and without oxygen therapy, in patients with chronic obstructive pulmonary disease (COPD). Four cardiovascular tests for autonomic function were used, and in addition, basal pancreatic polypeptide (PP) was measured. The following COPD patients were studied: 10 normoxemic (mean PaO2 10.9 +/- SD 1.1 kPa), 10 hypoxemic (PaO2 7.6 +/- 0.7 kPa before, and 10.6 +/- 1.4 kPa after 24 h oxygen therapy), and 6 hypoxemic on long-term oxygen therapy (LTOT) (PaO2 10.3 +/- 1.3 kPa before, and 7.0 +/- 0.8 kPa after 4 h of low dose or oxygen free interval). Twenty healthy age-matched subjects served as controls. In the individual tests the hypoxemic and the LTOT groups had a significantly decreased heart rate response to the Valsalva manoeuvre (ratio 1.23 +/- 0.17 and 1.12 +/- 0.07 versus control's 1.45 +/- 0.26 (p < 0.01 and 0.005, respectively) and versus the normoxemic group 1.46 +/- 0.30 (p < 0.05)) and the hypoxemic as well as the LTOT group had a significantly decreased heart rate response to standing up (ratio 0.97 +/- 0.04 and 0.97 +/- 0.07, respectively, versus the controls 1.06 +/- 0.09 (p < 0.005 and 0.05)). The blood pressure response to standing up and to sustained handgrip did not differ significantly between the groups. In spite of apparent autonomic dysfunction, PP levels in the LTOT group were significantly higher than in the controls (p < 0.01-0.001) and the normoxemic group (p < 0.05-0.01). Twenty-four hours of oxygen treatment in the hypoxemic group or four hours of oxygen withdrawal in the LTOT group did not change the results significantly. In conclusion, our findings are consistent with the previous notion of neurological dysfunction from hypoxemia, but this may not be corrected by the use of short term oxygen treatment. This contrasts to previous findings in which longer term oxygen did correct some of these problems.

Impaired glucose tolerance in patients with chronic hypoxic pulmonary disease.

This study investigated glucose metabolism and glucose-mediated hormone responses in patients with chronic respiratory hypoxaemia. Glucose as well as insulin, glucagon, adrenaline, cortisol and growth hormone (GH) were measured before and at 30, 60 and 120 min during an oral glucose-tolerance test. The following chronic obstructive pulmonary disease (COPD) patients were studied: 10 normoxaemic (mean paO2 10.9 +/- 0.4 kPa), 10 hypoxaemic (mean paO2 7.6 +/- 0.2 kPa before, and 10.6 +/- 0.4 after 24-h oxygentherapy, and 6 hypoxaemic patients on long-term oxygen therapy (LTOT) (mean paO2 10.9 +/- 0.7 kPa before, and 7.1 +/- 0.3 after 4 h with less than 0.5 litre oxygen per minute). The hypoxaemic patients were tested both with and without (or reduced) oxygen therapy. Twenty healthy sex- and age-matched subjects served as controls. Plasma glucose at 120 min was significantly higher in LTOT patients than in controls (p < 0.01), normoxaemic patients (p < 0.01) or hypoxaemic patients (p < 0.01). The areas under the curve for plasma glucose and insulin were significantly higher in both the LTOT and hypoxaemic groups compared to controls (p < 0.01 and 0.05, respectively). Glucose values for normoxaemic COPD patients were similar to those for controls. Glucagon, adrenaline, cortisol and GH levels did not differ significantly between the groups. A 4-h low-dose or oxygen-free interval in the LTOT group or 24 h of oxygen supplementation in the hypoxaemic group did not affect glucose and hormone levels significantly. It is concluded that severely hypoxaemic COPD patients have altered glucose metabolism which cannot be readily explained by changes in gluco-regulatory hormones or short-term alterations in oxygenation.

[An answer to an inquiry on diffuse panbronchiolitis. Now it has found its way here!]. / Svar på efterlysning av diffus panbronkiolit. Nu har den hittat hit!

Diffuse panbronchiolitis (DPB) is a disease characterised by chronic inflammation in the region of respiratory bronchioles. The condition has mainly been observed in Japanese patients, though isolated cases have been reported from other countries. In a review published in Läkartidningen (37/94), the question was raised of why this disease had not been seen in Scandinavia, and whether this might be the result of missed diagnosis. The diagnostic criteria were listed, and the question was posed of whether (Scandinavian) physicians existed who had encountered patients with chronic sinusitis, persistent cough and inexplicable nodular changes in lung x-rays. As a direct result of this enquiry, the present article reports what may well be the first Scandinavian patient to fulfil all the diagnostic criteria of DPB. The patient responded with improved lung function and normalised blood gases to a combined treatment regimen comprising immunosuppression (cyclophosphamide and prednisolone) and nebulised antibiotics (gentamicin).

Pulmonary function 3-13 months after pneumonectomy, lobectomy or bilobectomy for lung cancer.

Pulmonary function was studied 3 and 12 months after pulmonary resection for lung cancer in 37 patients, ten of whom had undergone pneumonectomy, 17 lobectomy and eight bilobectomy. The resection was right-sided in 25 cases and left-sided in 12. Tumour site and diameter were registered, arterial blood gases measured and spirometry performed Three months after all types resection there was significant decrease in forced vital capacity (FVC), and forced expiratory volume/1 second (FEV1), but not in FEV1/FVC%. At 12 months pneumonectomy had reduced FVC to 58% of predicted values, FEV1 to 50% and FEV1/FVC% to 70%. After lobectomy the corresponding figures were 86%, 73% and 67% and after bilobectomy they were 88%, 78% and 70%. Between 3 and 12 months postoperatively, FVC increased in all groups, significantly in those with lobectomy or bilobectomy (p<0.01 and 0.05, respectively).

Intrapleural bleomycin in the treatment of chylothorax.

Chylothorax is an accumulation of thoracic lymph or chyle in the pleural cavity. It is a rare condition and is usually caused by trauma or malignant disease. We present three cases with chylothorax due to malignant non-Hodgkin's lymphoma [high grade malignant (1 case) and low grade malignant (2 cases)] treated with pleurodesis with bleomycin and systemic chemotherapy (CHOP, CNOP, trofosfamide). Complete remissions (CR) were achieved in all three cases. Two patients had a recurrent chylothorax 3 and 12 months after initial treatment. They were treated with a second intrapleural installation of bleomycin and continuing systemic chemotherapy (CNOP, trofosfamide) and are still alive in CR with a follow-up period of 28 and 30 months respectively. One patient died of relapsing non-Hodgkin's lymphoma after 23 months of follow-up. There was no sign of recurrent chylothorax. We conclude that chylothorax caused by lymphoma can be satisfactorily controlled by pleurodesis with bleomycin combined with systemic chemotherapy. Immediate action is necessary to prevent great loss of lipids and proteins. The underlying malignancy must be controlled to achieve a good prognosis.