An overview of recent overviews in the treatment of non-small cell lung cancer.
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Carcinoma, Non-Small-Cell Lung↗
Biomedical subjects
S G Spiro
Publications and source records attributed to S G Spiro.
A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer research Campaign trial.
We report the results of a randomised trial in extensive small-cell lung cancer (SCLC) of a novel approach to palliative chemotherapy. A widely used 3 weekly regimen was compared with the same drugs given at half the dose but twice the frequency with the same intended overall dose intensity (DI). A total of 167 patients defined as having extensive SCLC with adverse prognostic features were randomised to receive either a 3 weekly regimen of cisplatin 60 mg m-2 i.v. on day 1 and etoposide 120 mg m-2 i.v. on day 1 and 100 mg b.d. orally on days 2 and 3 alternating with cyclophosphamide 600 mg m-2 i.v., doxorubicin 50 mg m-2 i.v. and vincristine 2 mg i.v. all on day 1 for a maximum of six courses (3 weekly); or treatment with the same drugs but with each course consisting of half the 3 weekly dose given every 10 or 11 days for a maximum of 12 courses. In the 10/11 day regimen overall response rate was 58.9% (95% CI, 47.9-69.2%) with 12.8% complete responses (CR). For the 3 weekly treatment the overall response rate was 44.9% (95% CI, 35.0-55.5%) with 10.1% CR. Median survival was similar in the two arms at 6.4 months (95% CI, 4.9-7.3 months) and 5.8 months (95% CI, 4.0-6.6 months) respectively. Survival at 1 year was 9.9% (95% CI, 5.0-18.5%) and 8.9% (95% CI, 4.6-16.6%). The 95% CI for the difference in survival at 1 year is -7.09% to +9.09%. Haematological toxicity and treatment delays owing to infection were more frequent with the 10/11 day regimen but other toxicities were equal in both arms. Other aspects of quality of life were measured in a small representative cohort of patients using a daily diary card (DDC). There was a trend of improved quality of life on the 10/11 day arm, but there was little difference between the two treatments. The trial shows that a low-dose/high-frequency regimen with the same DI as conventionally scheduled chemotherapy gives similar response rates and survival. This and other modifications of the schedule may offer new approaches to palliative treatment of advanced cancer. However, in this trial there was no significant benefit in toxicity or other aspects of quality of life.
Adult↗
Assessment of 'quality of life' using a daily diary card in a randomised trial of chemotherapy in small-cell lung cancer.
BACKGROUND: Quality of life (QOL) was assessed using a daily diary-card within a multicentre randomised trial of treatment of small-cell lung cancer. The trial compared a weekly dose-intensive regimen with a 3-weekly conventional treatment in good prognosis patients, that is patients with limited disease or extensive disease with a good performance status (ECOG 0or 1) and alkaline phosphatase of less than one and a half times the upper limit of normal. The trial which has been previously reported detected no difference in response or survival. PATIENTS AND METHODS: Daily diary cards (DDCs) were collected for up to eight months from the first day of chemotherapy in a cohort of 75 patients at one centre. Percentages of scores over a specified level were calculated for each of the eight diary card questions and comparisons were made between treatment arms. RESULTS: During the period of chemotherapy compliance in completing DDCs was 72.5% in the weekly arm and 77.2% in the 3 weekly. Significantly worse scores were reported with weekly chemotherapy during this period for six of the eight parameters, namely: ;nausea, vomiting, happiness, appetite, general well-being and sleep. Recognised problems of QOL data collection, in particular, compliance, attrition and generalisability are highlighted by this study and are discussed in the paper. CONCLUSIONS: The QOL measurements indicate that 3 weekly chemotherapy is the preferred treatment. This study demonstrates that QOL measurements may be helpful in choosing between treatment alternatives where no difference in outcome is observed.
Adult↗
Phase II study of fotemustine in untreated inoperable non-small-cell lung cancer.
A total of 43 patients with advanced, previously untreated non-small-cell lung cancer (NSCLC) were treated with a novel nitrosourea, fotemustine, given at 100 mg/m2 on days 1 and 8. Maintenance treatment consisted of a single injection of 100 mg/m2 given every 21 days. 37 patients were evaluable for response. Of these, 5 patients had a partial response (13.5%; 95% confidence interval, 6%-28%). Toxicity comprised mainly anaemia and thrombocytopenia. Other toxicities were mild. This phase II study confirms that fotemustine is a moderately active and well-tolerated drug in NSCLC.
Aged↗
The selection of antibodies for targeted therapy of small-cell lung cancer (SCLC) using a human tumour spheroid model to compare the uptake of cluster 1 and cluster w4 antibodies.
Spheroids of a small-cell lung cancer (SCLC) cell line POC were used to evaluate the uptake and penetration of two antibodies recognising different SCLC antigens. Spheroids approximately 300-400 microns in diameter were incubated with 1 microgram ml-1 125I-labelled NY.3D11, an antibody which reacts with the cluster 1 group antigen (neural cell adhesion molecule; NCAM) and [125I]SWA11, which binds to the cluster w4 antigen. The rate of uptake of both antibodies was similar; an initially rapid phase was seen during the first 8 h and maximum uptake occurred by 24 h. The mean uptake per spheroid at 24 h was 0.97 ng for [125I]NY.3D11 and 0.45 ng for [125I]SWA11. An objective measurement of antibody penetration into spheroids was developed using a computerised image analysis of immunostained sections of spheroids. The concentration of antibody and incubation times were varied. Both antibodies penetrated the spheroids to a depth of 50 microns after 30 min. This increased to about 100 microns after 4 h incubation with 1 or 100 micrograms ml-1 SWA11. The results with 1 microgram ml-1 NY.3D11 were similar, but in the presence of 100 micrograms ml-1 NY.3D11 penetration into the spheroid was deep and diffuse. These results demonstrate a major concentration-dependent difference in the uptake and penetration of cluster 1 and cluster w4 antibodies in this spheroid model and they have implications for the selection of antibodies for targeted therapy of SCLC.
Antibodies, Monoclonal↗
Received dose-intensity: a randomized trial of weekly chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer.
PURPOSE: A prospective randomized trial to determine if granulocyte colony-stimulating factor (G-CSF) could increase the received dose-intensity (RDI) of weekly chemotherapy in patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Forty patients with SCLC with good prognostic features (all patients with limited disease [LD], and extensive-disease [ED] patients with Eastern Cooperative Oncology Group [ECOG] 0 or 1 and plasma alkaline phosphatase levels < 1.5 times the upper limit of normal) were randomized to receive weekly chemotherapy with or without G-CSF. G-CSF (5 micrograms/kg) was self-administered subcutaneously on days when chemotherapy was not given. Chemotherapy consisted of cisplatin 50 mg/m2 intravenously (IV) on day 1 and etoposide 75 mg/m2 IV on days 1 and 2 alternating weekly with ifosfamide 2 g/m2 IV (with mesna) and doxorubicin 25 mg/m2 on day 1, for a total of 12 courses. Dose modifications (dose reductions and treatment delays) were made according to defined hematologic criteria. RESULTS: Dose reductions were made at some point during treatment in 12 of 17 patients in the control arm and in 11 of 23 patients in the G-CSF arm (P = .20). The proportion of patients experiencing dose reductions due to leukopenia was significantly higher in the control arm (nine of 17) compared with the G-CSF arm (four of 23, P < .04). Cycle delays due to leukopenia were similar in both arms of the study. The RDI was 82% of projected in the control arm (95% confidence interval [CI], 79% to 84%) and 84% in patients receiving G-CSF (95% CI, 82% to 87%) (P value not significant). CONCLUSION: In this randomized trial, G-CSF significantly decreased dose reductions due to neutropenia. However, administration of G-CSF did not decrease dose reductions or treatment delays to a level that would allow an increase in received dose-intensity. Nonhematologic toxicities such as increased creatinine concentration also prevented an increase in the RDI in the G-CSF arm.
Adult↗
Thoracic radiotherapy and chemotherapy for small-cell lung cancer: the discussion continues.
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Carcinoma, Small Cell↗
Effect of arterial oxygen desaturation on six minute walk distance, perceived effort, and perceived breathlessness in patients with airflow limitation.
BACKGROUND: The effect of exercise induced hypoxaemia in determining submaximal exercise capacity, perceived breathlessness, and perceived exertion is not known. The purpose of this study was to investigate the relation of these variables to the results of lung function tests and the degree of hypoxaemia during submaximal exercise in patients with airflow limitation. METHODS: Forty two patients with chronic obstructive airways disease and 28 patients with chronic severe asthma were studied. Spirometry was performed and gas transfer (TLCO) and lung volumes were measured. Submaximal exercise capacity was assessed with a standardised six minute walk test. Arterial oxygen desaturation during the walk test was monitored by a portable pulse oximeter. Patients rated their perceived degree of respiratory impairment on a Medical Research Council (MRC) breathlessness scale before the walk. Perceived breathlessness was measured by means of a linear visual analogue scale and exertion on the Borg scale after the walk. RESULTS: The six minute walk distance was strongly correlated (r value) with TLCO (0.68), peak expiratory flow (PEF: 0.55), forced expiratory volume in one second (FEV1: 0.53), transfer coefficient KCO: 0.49), age (-0.49), and forced vital capacity (FVC: 0.48) but not with oxygen desaturation during the walk. Walk distance was also correlated with the breathlessness rating on the MRC scale (-0.52), but less strongly with perceived breathlessness (-0.35) and perceived exertion (-0.30). The prediction equation for the six minute walk distance in metres (6MD) generated by multiple regression analysis was 6MD = 387 + 29.7 (TLCO) -3.1 (age) + 0.35 (PEF 1/min), which accounted for 50% of the total variance in walk distance. The mean level of saturation during the walk correlated most significantly with TLCO (0.55), FEV1/FVC (0.54), and PEF (0.48), but not with walk distance or with the rating on any of the analogue scales. The prediction equation produced by multiple regression analysis for the mean level of saturation during the walk was MEANSAT(%) = 1.3(TLCO) + 1.5 (base-line saturation) - 0.01 (6MD) - 54. CONCLUSIONS: Oxygen desaturation during the six minute walk is not related to walk distance, nor does it determine the degree of perceived exertion or perceived breathlessness in patients with airflow limitation. Patients who consider themselves the most disabled by breathlessness have the shortest six minute walk distance but do not necessarily have appreciable desaturation.
Asthma↗
Sternomastoid muscle fatigue and twitch maximum relaxation rate in patients with steroid dependent asthma.
BACKGROUND: Long term oral corticosteroid treatment is a cause of myopathy of the skeletal muscles. The effect of long term treatment with oral corticosteroids on the respiratory muscles is uncertain. Respiratory muscle function and fatigue in sternomastoid muscle were investigated in a group of patients with chronic severe asthma who were taking oral corticosteroids. The results were compared with those from a group of patients with chronic airflow limitation who were not taking oral steroids. METHODS: Twelve patients with chronic severe asthma, taking a mean daily dosage of 8 mg of prednisolone for a mean (SD) of 16.8 (9.1) years, were compared with patients with chronic airflow limitation and individually matched for sex, age, and severity of airflow limitation. Lung function tests, maximal mouth pressures, and quadriceps and sternomastoid muscle strength were measured. The sternomastoid muscle was fatigued by maximal headlift exercise to 70% of initial headlift force and the endurance time noted. Sternomastoid fatigue was assessed by twitch maximum relaxation rate (TMRR) measured in the fresh state and for 30 minutes after exercise. RESULTS: There was no significant difference between the control group and the corticosteroid group for maximal mouth pressures, fresh state TMRR, and quadriceps and sternomastoid strength. The control group had a significantly longer mean (SD) endurance time than the corticosteroid group (121 (47) s v 86 (24) s), and also had significantly less slowing and faster recovery of the TMRR after exercise. The slowing and recovery of the TMRR in the corticosteroid group, however, was similar to that previously reported for normal subjects. CONCLUSION: Respiratory muscle weakness does not occur more often in patients taking oral corticosteroids. The corticosteroid group was more prone to fatigue than the control group, but was similar to normal subjects. This suggests that chronic airflow limitation may produce a training effect on the respiratory muscles that might be attenuated by long term oral corticosteroid treatment.
Aged↗
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.
Adult↗
Value of pulse oximetry in screening for long-term oxygen therapy requirement.
Pulse oximetry, combined with spirometry, was evaluated as a method of selecting chronic obstructive pulmonary disease (COPD) out-patients requiring definitive arterial blood gas analysis for long-term oxygen therapy (LTOT) assessment. A relatively high screening arterial oxygen saturation by pulse oximetry (SaO2) level was set, in order to maximize sensitivity. All 113 COPD out-patients attending the hospital clinic over a 6 month period were screened. Sixty had a forced expiratory volume in one second < 1.5 l and 26 had an SaO2 < or = 92%. These 26 underwent arterial blood gas analysis. Nine had an arterial oxygen tension < 7.3 kPa all with an arterial carbon dioxide tension (PaCO2) > 6 kPa. A further eight had a PaO2 < 8 kPa. This produced a sensitivity of 100% and specificity of 69% for oximetry in the detection of PaO2 < 7.3 kPa determined by direct arterial puncture and 100% and 86% respectively for detecting a PaO2 < 8 kPa. Although the poor specificity of oximetry in the crucial PaO2 range makes it unsuitable, when used alone, for prescription of LTOT, it may prove valuable in selecting patients who require further definitive arterial blood gas analysis.
Aged↗
Phase II study of Edatrexate in stage III and IV non-small-cell lung cancer.
A total of 49 patients with advanced, previously untreated non-small-cell lung cancer (NSCLC) were treated with a new antifolate, Edatrexate (10-ethyl-10-deaza-aminopterin; 10-EdAM). Patients received 80 mg/m2 weekly for 12 weeks, and responders received a further 6 cycles at 2-week intervals. Dose reductions were carried out for haematological toxicity and mucositis. Response was assessed prior to each treatment according to WHO criteria. Among the 45 evaluable patients, 6 [13.3%; 95% confidence interval (CI), 6%-26%] achieved a partial response (PR) and 9 (20%; 95% CI, 11%-34%) showed a minor response (MR; 25%-50% reduction in the sum of 2 perpendicular tumour diameters). In those receiving four or more cycles of treatment, the PR and MR rates were 17.6% and 26.4%, respectively. The resultant toxicity mainly constituted skin rash, mucositis and myelosuppression. Edatrexate is active against NSCLC and produces toxicity profile similar to that of methotrexate.
Aged↗
The value of CT scanning and percutaneous fine needle aspiration of adrenal masses in biopsy-proven lung cancer.
Pre-operative CT scans of 546 patients with biopsy-proven primary bronchial carcinoma were reviewed. Twenty-two patients had a solid adrenal tumour (2 bilateral). Sixteen underwent percutaneous fine needle aspiration (FNA). Malignant cells were aspirated in five, eight revealed benign cells and in three cases there was insufficient material for diagnostic purposes. Six patients did not undergo FNA, four of these were considered to have benign adenomas on CT. This was confirmed by the unchanged CT image at more than 21 months follow-up. The five subjects with FNA-proven metastases died at a median of 14 months (range 3-24 months). All five would have been regarded as operable on their staging chest CT scan. Five patients with a negative biopsy underwent surgery, two died of metastases at 6 and 11 months respectively and one died of post-operative complications. The other two have unchanged adrenal lesions on CT at 9 months and 25 months. The CT appearances of these lesions were analysed. Well defined, low attenuation lesions which had a smooth attenuation rim or only involved part of the gland were benign and the survivors had unchanged CT appearances at follow-up (six lesions in five patients). Of these four lesions were less than or equal to 2 cm in diameter. Low attenuation lesions without a rim were malignant (n = 2). These latter both measured more than 2 cm in diameter. The CT appearances of many adrenal lesions were insufficiently distinctive to exclude malignancy and biopsy was necessary to establish a diagnosis.
Adrenal Gland Neoplasms↗
Easy bruising as a side-effect of inhaled corticosteroids.
We wished to determine the prevalence of easy bruising in patients taking inhaled corticosteroids (ICS) compared with those who do not. Differences in age, dosage and duration of use of ICS between patients who bruised and those who did not were also investigated. Confidential questionnaire surveys were conducted over a 6 month study period amongst patients attending a respiratory out-patient clinic and taking regular ICS, and a control group of patients attending non-respiratory clinics and not taking any form of corticosteroids. Patients with bleeding disorders or taking oral steroids, non-steroidal anti-inflammatory drugs or anticoagulants were excluded from the study. Questionnaires from 202 respiratory patients using ICS (group A) were compared with 204 non-ICS patients (Group B) of similar age and sex distribution. Significantly more patients in Group A reported easy bruising than in group B (47 vs 22%, relative risk 2.18, 95% confidence interval (95% CI) 1.62-2.94), and it was the commonest reported symptom. In Group A, the patients that reported easy bruising tended to be older (61 vs 52 yrs), on higher daily dosages (1,388 vs 1,067 micrograms) and had been taking inhaled corticosteroids for longer (55 vs 43 months) than non-bruisers. Overall, females reported easy bruising more frequently than males in both groups. However, comparing Group A with Group B, males taking ICS had a higher relative risk for bruising than females (males, relative risk 5.80, 95% CI 2.38-14.13; females, relative risk 1.80, 95% CI 1.32-2.44).(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Topical↗
Chemotherapy and radiation therapy as compared with radiation therapy in stage III non-small-cell cancer.
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Carcinoma, Non-Small-Cell Lung↗
Sequential chemotherapy in good-prognosis patients with small-cell lung cancer.
A sequential combination chemotherapy regimen was evaluated in 23 patients with small-cell lung cancer (16, limited disease; 7, extensive disease). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, normal serum sodium and albumin levels and alkaline phosphatase values of less than 1.5 times the upper limit of normal. Treatment comprised ifosfamide and either vindesine or vincristine given on weeks 0, 2 and 4; cisplatin and etoposide given on weeks 6, 9 and 12; and doxorubicin and methotrexate given on weeks 15 and 17. The overall response rate at the end of chemotherapy was 91% and the complete response rate was 43%. Treatment was generally well tolerated and the delivered dose intensity was 83% of that projected. Median survival was 54 weeks, with 4 patients (17%) being alive 2 years after the completion of therapy.
Adult↗
A randomised trial of planned versus as required chemotherapy in small cell lung cancer: a Cancer Research Campaign trial.
In a study of chemotherapy as palliative treatment, 300 patients with untreated limited and extensive stage small cell lung cancer (SCLC), who did not have progressive disease after the first cycle of chemotherapy, were randomised to receive either regular 'planned' chemotherapy or chemotherapy given 'as required' (AR). All patients received the same chemotherapy: cyclophosphamide 1 gm m-2 i.v., vincristine 2 mg i.v., and etoposide 120 mg m-2 i.v. on day 1, and etoposide 100 mg b.d. orally on days 2 and 3. Planned chemotherapy was given regularly every 3 weeks. AR chemotherapy was given for tumour-related symptoms, or for radiological progression of disease. Both groups of patients were assessed every 3 weeks and a maximum of eight cycles of chemotherapy was given. A detailed quality of life assessment was made using daily diary cards. The median survival (MS) of patients given AR chemotherapy was not significantly worse than those receiving planned treatment [MS: Planned = 36 weeks (95% C.I. 32-40 weeks), AR = 32 weeks (95% C.I. 28-37 weeks) P = 0.960]. In the AR patients the median interval between treatments was 42 days. On average AR patients received half as much chemotherapy as planned patients. AR patients with a treatment-free interval (TFI) of more than 8 weeks between the first and second cycles of chemotherapy survived longer than those in whom this interval was less than 4 weeks; [MS: TFI greater than 8 = 47 weeks (95% C.I. 32-53 weeks); TFI less than 4 = 24 weeks (95% C.I. 17-34 weeks) P = 0.013]. Contrary to expectation, in the quality of life assessment the AR patients scored themselves as having more severe symptoms than patients receiving planned treatment. AR chemotherapy is a novel method of attempting to use cytotoxic drugs palliatively, which resulted in less drug treatment for approximately equivalent survival. However the palliative effect seen with as required treatment was less satisfactory than with planned chemotherapy.
Aged↗
Sternomastoid muscle twitch maximum relaxation rate: prolonged slowing with fatigue and post-tetanic acceleration.
1. The maximum rate of relaxation of stimulated twitches (twitch maximum relaxation rate) of the sternomastoid muscle was compared with its frequency-force curve (expressed as the ratio of force produced at a stimulation frequency of 20 Hz to that produced at 50 Hz, the 20:50 ratio) before and after fatiguing exercise of the sternomastoid muscle in 10 normal subjects. The mean (+/- SEM) fresh state twitch maximum relaxation rate was 9.51 (+/- 0.64)% force loss/10 ms and the mean (+/- SEM) 20:50 ratio was 73.4 (+/- 2.6)%. 2. The mean twitch maximum relaxation rate fell to 71.5 (+/- 2.2)% of the pre-fatigue value at 2 min after exercise, recovering to 73.1 (+/- 1.6)% by 5 min, 78.4 (+/- 2.34)% by 10 min and 80.6 (+/- 2.70)% by 60-min. The 20:50 ratio fell to 72.3 (+/- 3.56)% of pre-fatigue levels at 10 min after exercise and recovered to 78.8 (+/- 3.16)% by 60 min. There was no significant difference in the percentage falls between the two techniques. 3. Further studies were performed to determine the response of the twitch maximum relaxation rate to a prior brief tetanic stimulus or a brief maximal voluntary contraction of the muscle. Both tetanic stimulation and maximal voluntary contraction accelerated the twitch maximum relaxation rate to over 140% of the fresh state value. Both manoeuvres temporarily returned the slowed twitch maximum relaxation rate after fatiguing exercise back to the fresh state value. 4. The effect of fatiguing exercise on the time course of recovery of quadriceps twitch maximum relaxation rate was also studied in two subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗