Dose intensification of carboplatin and etoposide as first-line combination chemotherapy in small cell lung cancer.
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Adult↗
Biomedical subjects
I E Smith
Publications and source records attributed to I E Smith.
Immunohistochemical assay for epidermal growth factor receptor on paraffin-embedded sections: validation against ligand-binding assay and clinical relevance in breast cancer.
Epidermal growth factor receptor (EGFR) has been the subject of much research since it was first described as a prognostic factor in breast cancer. The assay methods used and results obtained vary widely between studies. In this study 88 primary breast cancers were assayed for EGFR using a novel immunohistochemical assay performed on paraffin-embedded sections. The monoclonal antibody used was raised against purified, denatured EGFR, reacts with an epitope on the external domain and does not interfere with ligand binding. Twenty-two per cent of the tumours were EGFR positive using this assay. The results obtained were significantly correlated with those obtained by ligand-binding assay (r = 0.621, P = 0.011). The concordance rate was 82% (P < 0.001). The majority of discordant results could be explained by the presence of benign breast tissue and other non-malignant elements which could be seen to express EGFR on the immunohistochemical assay and were excluded from the score for this, but would be incorporated into ligand-binding assay results. The well-established inverse relationship between EGFR (as measured by this assay) and oestrogen receptor (ER) was seen (chi 2 = 24.9, P < 0.0001). In addition, in this exploratory study on a limited tumour set, EGFR was a significant adverse prognostic factor (on univariate but not multivariate analysis) for both relapse-free survival (P = 0.02) and overall survival (P = 0.03) when measured by this immunohistochemical assay, but was not significant when measured by ligand-binding assay.
Adult↗
A pilot study of mitomycin, cisplatin and continuous infusion 5-fluorouracil (MCF) in advanced non-small-cell lung cancer.
A pilot study of continuous infusional 5-fluorouracil 200 mg m-2 per 24 h by ambulatory pump and Hickman line for the entire treatment cycle with mitomycin C 8 mg m-2 i.v. on day 1 and cisplatin 75 mg m-2 i.v. on day 1, both repeated every 28 days, was carried out in 31 previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Of 31 patients assessable for response, one attained a complete remission and eight a partial remission, an overall response rate of 29%. Haematological toxicity was minimal, with only 3% of patients developing WHO grade III/IV neutropenia and 13% grade III/IV thrombocytopenia. Significant side-effects included moderate to severe emesis (41%), mucositis (34%), diarrhoea (31%) and palmar-plantar syndrome (14%). Seven patients (23%) had Hickman line complications requiring line removal. Continuous infusional chemotherapy with this regimen is active in advanced non-small-cell lung cancer, but its complexity and associated treatment toxicity offer little advantage over equally active but simpler and less toxic cisplatin-based regimens.
Adenocarcinoma↗
Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer.
The role of chemotherapy in the palliation of patients with advanced stage (IIIB and IV non-small-cell lung cancer (NSCLC) remains controversial. We have carried out a chemotherapy study emphasising symptom relief, a topic not normally discussed in previous similar studies. A total of 120 patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) were treated with a moderate-dose palliative chemotherapy regimen consisting of mitomycin C 8 mg m-2 i.v. on day 1 (alternate courses), vinblastine 6 mg m-2 i.v. on day 1 and cisplatin 50 mg m-2 i.v. on day 1 (MVP), repeating every 21 days for a maximum of six courses. Thirty-eight of 118 assessable patients (32%) achieved an objective response. Patients with locally advanced disease (stage IIIB) had a significantly better response rate (52%) than those with metastatic disease (25%) (P < 0.01). In 76 out of 110 (69%) patients, with tumour-related symptoms including 24 out of 31 patients (78%) with locally advanced disease, symptoms completely disappeared or substantially improved. In only 15 patients (14%) did symptoms progress during treatment. Symptomatic improvement was achieved after one course of chemotherapy in 61% and after two courses in 96% of responding patients. The schedule was well tolerated. Only 19% developed WHO grade 3/4 nausea/vomiting, and only 3% developed significant alopecia. Other toxicities were minimal. MVP is a pragmatic inexpensive chemotherapy regimen that offers useful symptom palliation in patients with advanced NSCLC and merits a 1-2 course therapeutic trial in such patients. The schedule should also be assessed as primary (neoadjuvant) chemotherapy before radical radiotherapy for locally advanced NSCLC in a randomised trial.
Adult↗
A progressive care programme for prolonged ventilatory failure: analysis of outcome.
Forty consecutive patients who could not be weaned from mechanical ventilation in the intensive care unit (ICU) entered a multidisciplinary progressive care programme (PCP). The mean number of hours per day of ventilatory support was 19.9 at the time of transfer but only 6.7 at discharge. Eleven patients did not require ventilation after discharge, 24 received ventilation non-invasively and only three via a tracheostomy. Survival at discharge from hospital was 90% compared with the predicted survival of 53% from the Apache II scores on admission to the ICU. Seventy-six percent were alive 1 yr after discharge and 80% of patients were discharged directly from the PCP to their homes. Mental and emotional scores in a quality of life questionnaire (SF 36) were normal, but physical function remained limited.
Adult↗
Choosing a negative pressure ventilation pump: are there any important differences?
Five negative pressure ventilator pumps were assessed to determine whether there were any differences in performance which were likely to be of clinical importance. The pumps tested were the NEV-100 (Lifecare Inc.), the Negavent Respirator DA-1 (Dima Italia), the Thompson Maxivent (Puritan Bennett), the CCP-001 and Newmarket pumps (Si-Plan Electronics Research Ltd). A patient model was employed to investigate the relationship between the pressure waveform of each pump and the tidal volume generated, the stability of performance on a continuous 8 h test, and the response to a change in leak. On the continuous tests, the stability was better than +/- 1% for the inspiratory/expiratory (I:E) ratio and rate, and better than +/- 10% for the peak negative pressure for all of the pumps. The Negavent and NEV-100 pumps generated a square wave of pressure and for the same peak negative pressure produced a tidal volume up to 30% greater than the CCP-001 and the Newmarket pumps, which produced a half sine wave. The Maxivent produced an intermediate waveform, with a plateau at peak negative pressure but a curved decay back to atmospheric pressure. It is argued that if the pressure of the pumps producing a half sine wave is made more negative to compensate and produce an equivalent tidal volume, they are more likely to induce upper airway obstruction. The leak compensation of the NEV-100 and Negavent pumps was nearly complete but took several breaths to develop, the CCP-001 and Newmarket pumps had a very rapid compensation but this was less complete, whilst the Maxivent has no mechanism for leak compensation. From these results, it seems that in patients liable to upper airway obstruction the NEV-100 and Negavent pumps would be advantageous, whilst when rapidly changing leaks impair the efficiency of negative pressure ventilation the CCP-001 and Newmarket pumps would be preferable. The Maxivent pump seems to offer no advantages.
Air Pressure↗
High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer.
PURPOSE: To investigate the efficacy of continuous infusion fluorouracil (5FU) with every-3-week epirubicin and cisplatin (ECF) as primary chemotherapy instead of immediate mastectomy for patients with large, potentially operable, breast cancer. PATIENTS AND METHODS: Fifty patients with large operable breast cancer, median tumor diameter 6 cm (range, 3 to 12), were treated with 5FU 200 mg/m2/d via a Hickman line using an ambulatory pump for 6 months with epirubicin 50 mg/m2 intravenously (IV) and cisplatin 60 mg/m2 IV every 3 weeks for eight courses. Subsequent surgery and/or radiotherapy was determined by clinical response. RESULTS: Forty-nine patients achieved an overall response (98%; 95% confidence interval [CI], 94% to 100%), including 33 complete clinical remissions (CRs) (66%; 95% CI, 53% to 79%). Only three patients (6%) still required mastectomy. Tumor cellularity was markedly reduced on repeat needle biopsy following 3 weeks of treatment in 81% of patients versus only 36% in similar patients after conventional chemotherapy (P < .002). Severe (World Health Organization [WHO] grade 3 to 4) toxicity was rare, with nausea/vomiting being the most common, occurring in 20% of patients. CONCLUSION: Primary infusional ECF appears to be more active on clinical and histopathologic grounds than conventional chemotherapy for large operable breast cancer and is well tolerated. This approach now merits randomized comparison to determine if high CR rates may translate into improved survival.
Adult↗
Protracted infusional chemotherapy in breast cancer: the Royal Marsden Hospital experience.
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Adult↗
In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer.
Thirteen postmenopausal women with advanced breast cancer were enrolled in an open randomized Phase I trial of a new p.o. active aromatase inhibitor, CGS 20267 (letrozole). The primary aim of the trial was to assess the impact of two doses of letrozole (0.5 and 2. 5 mg/day) on the peripheral aromatization of androstenedione to estrone. An in vivo isotopic technique was used to measure peripheral aromatization in each patient before treatment. The patients were then randomly assigned to one of the two doses, and measurements of aromatization were repeated after 6 weeks. At 0.5 mg and 2.5 mg/day, letrozole inhibited aromatization by 98.4% (97.3 to >99.1) and >98.9% (98.5 to >99.1; geometric means and ranges), respectively. Plasma estrogen levels were also measured before and during treatment. At the dose of 0.5 mg/day estrone and estradiol levels fell by 82.0% and 84.1% (geometric means), respectively. At the dose of 2.5 mg/ day, the estrogens fell by 80.8% and 68.1%, respectively. There were no significant differences between the doses in aromatase inhibition. No formal statistical analysis was performed on the estrogen data. Letrozole is therefore a highly effective inhibitor of aromatase, causing near complete inhibition of the enzyme in peripheral tissues at the doses investigated. The falls in estrogen levels were greater than those seen with earlier generation aromatase inhibitors.
Adult↗
ABC of breast diseases. Role of systemic treatment for primary operable breast cancer.
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Aged↗
Clinical and endocrine effects of the oral aromatase inhibitor vorozole in postmenopausal patients with advanced breast cancer.
Vorozole is an orally active, nonsteroidal aromatase inhibitor. Twenty-four postmenopausal patients with advanced breast cancer who had relapsed after treatment with tamoxifen received three separate daily doses of vorozole (1, 2.5, and 5 mg) each for 1 month in a randomized, double-blind, phase II study. There was significant suppression (P < 0.001) of serum estradiol at all three doses (median reduction, 91, 90, and 89%, respectively). There was a significant trend (P = 0.02) for estradiol to be suppressed below the detection limit of the assay (3 pmol/liter) more frequently with an increasing dose of vorozole; 13, 31, and 40% respectively. Estrone and estrone-sulfate levels were likewise reduced at each dose by 52-55% and 64-69%, respectively. There was no significant effect at any dose on aldosterone, testosterone, androstenedione, 17 alpha-hydroxyprogesterone, or thyroid-stimulating hormone levels. A small reduction in cortisol was seen at the 5 mg dose, although the relevance is unclear given that 17 alpha-hydroxyprogesterone levels did not rise. Eight patients (33%) achieved an objective response (2 complete remission, 6 partial remission) with a median response duration of 13 months. Four patients (17%) achieved disease stabilization for more than 6 months. Patients who had responded previously to tamoxifen were more likely to respond to vorozole. There were no significant clinical side effects and the drug was well tolerated. These data suggest that vorozole is a potent and selective oral aromatase inhibitor for use in postmenopausal breast cancer.
Aged↗
Palliative chemotherapy for advanced non-small cell lung cancer.
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Antineoplastic Agents↗
Endocrine changes with the aromatase inhibitor fadrozole hydrochloride in breast cancer.
Fadrozole hydrochloride is a potent aromatase inhibitor with proven clinical effectiveness. However, its optimal dose and its effects on serum aldosterone levels/electrolyte balance have been disputed. To resolve these issues, a double-blind randomised endocrine study of three doses of fadrozole hydrochloride [0.5 mg twice daily (bd); 1.0 mg bd; 2.0 mg bd] was conducted in 80 (68 evaluable) postmenopausal patients with advanced breast cancer over a period of 3 months. There were substantial falls in the serum levels of oestradiol, oestrone and oestrone sulphate. For oestrone only, there was a significant effect of dose (on-treatment means: 0.5 mg, 38.0 pmol/l; 1.0 mg, 25.0 pmol/l; 2.0 mg, 23.9 pmol/l). All oestrogens showed a similar pattern in relation to time, with the 3-month mean being higher than those at 1 and 2 months, and this was significant for oestradiol (P = 0.012). There was an indication that complete suppression of oestradiol and oestrone was not maintained throughout the 12-h dosing period, but the data and its interpretation are complicated by a minor diurnal rhythm in these parameters. There were significant increases in 17-hydroxyprogesterone and androstenedione which may be due to a block of 11 beta-hydroxylase. There was a statistically non-significant fall in aldosterone levels (P = 0.06) during treatment (median pretreatment, 446 pmol/l; median decrease, 125 pmol/l). However, the concurrent significant fall in the plasma sodium: potassium ratio indicated that changes in aldosterone secretion did occur. None of these effects on adrenal pathways was of a degree which is likely to have clinically relevant consequences. It is concluded that fadrozole hydrochloride achieves near maximal suppression of oestrogens at 1 mg bd, and that its effects on aldosterone synthesis are unlikely to be of clinical significance.
Adult↗
Modulation of Bcl-2 and Ki-67 expression in oestrogen receptor-positive human breast cancer by tamoxifen.
The expression of the bcl-2 proto-oncogene, which is associated with prolonged cell survival and prevention of programmed cell death, was investigated in human primary breast carcinomas prior to and following endocrine therapy with the anti-oestrogen, tamoxifen. Using the BCL-2-100 antibody, a 26-kD protein was detected by western immunoblot in the cytosols of oestrogen receptor (ER)+ve human breast cancers. In a cross-sectional study, the immunohistochemical expression of Bcl-2 was observed in 32% of invasive breast cancers, but in 65% of tumours treated with tamoxifen (P = 0.009). There was a significant association of Bcl-2 with ER status, with 64% of untreated and 88% of tamoxifen-treated Bcl-2-positive tumours being ER+ve. A significantly lower Ki-67 score was found in tamoxifen-treated tumours which were Bcl-2-positive compared with Bcl-2-negative (9.3 versus 24.6%, P = 0.01). In a separate series of sequential Trucut biopsies from 18 patients, the frequency of Bcl-2 expression was increased in ER+ve tumours from 3/12 to 8/11 following tamoxifen (P = 0.04). This was also associated with a significant reduction in mean Ki-67 score from 32 to 12% (P = 0.0004). The observations from this study clearly indicate that Bcl-2 in human breast cancer is associated with ER status, and that expression is enhanced in ER+ve tumours following tamoxifen, in association with reduced cell proliferation.
Aged↗
Activity of docetaxel (Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the EORTC.
Docetaxel (Taxotere) is a new cytotoxic compound with a broad spectrum of activity in preclinical studies. This paper reports a phase II trial in patients with previously-treated small cell carcinoma of the lung. 34 patients received 100 mg/m2 of docetaxel in an intravenous infusion given over 1 h every 21 days. Seven partial responses were reported (25% of 28 evaluable patients). Duration of response was 3.5-12.6 months. Toxicities were predominantly neutropenia, alopecia and asthenia. Docetaxel is a new compound with activity in previously-treated patients with small cell lung cancer, and is suitable for evaluation in combination with other cytotoxic drugs active in this disease.
Adult↗
Rupture of the thoracic duct following treatment of mediastinal seminoma.
Chylothorax is a rare condition that may occur as a complication of malignancy. There is only one prior report of chylothorax complicating metastatic testicular seminoma. We report a further patient in which the development of the chylothorax occurred a result of a favourable response to chemotherapy.
Chylothorax↗
Signet-ring cell lymphoma of bone marrow.
A case of signet-ring cell lymphoma affecting bone marrow is reported. The tumour presented as multiple lytic lesions in the lumbosacral spine. A bone biopsy specimen showed the typical appearances of signet-ring cell lymphoma, and the cells stained positively with antiserum to CD20, though neither immunoglobulin light or heavy chains could be shown within the vacuoles. The patient subsequently responded to chemotherapy.
Bone Marrow↗
Aggressive management of doxorubicin-induced cardiomyopathy associated with 'low' doses of doxorubicin.
There is a dose-effect relationship between doxorubicin and the incidence of symptomatic cardiac failure. It is generally thought that doses below 500-550 mg/m2 are safe but, when objective measures of cardiac function are used, it becomes apparent that degrees of cardiac failure occur at doses below this. We present here the case histories of two patients who developed very severe cardiac failure at cumulative doses well below 500 mg/m2 but who survived their initial cardiac illness due to aggressive intervention. In one case, the patient was successfully treated by orthotopic cardiac transplantation.
Adolescent↗