Learning from the QUEST multicentre feasibility randomization trials in breast reconstruction after mastectomy.

BACKGROUND: Breast reconstruction aims to improve health-related quality of life after mastectomy. However, evidence guiding patients and surgeons in shared decision-making concerning the optimal type or timing of surgery is lacking. METHODS: QUEST comprised two parallel feasibility phase III randomized multicentre trials to assess the impact of the type and timing of latissimus dorsi breast reconstruction on health-related quality of life when postmastectomy radiotherapy is unlikely (QUEST A) or highly probable (QUEST B). The primary endpoint for the feasibility phase was the proportion of women who accepted randomization, and it would be considered feasible if patient acceptability rates exceeded 25 per cent of women approached. A companion QUEST Perspectives Study (QPS) of patients (both accepting and declining trial participation) and healthcare professionals assessed trial acceptability. RESULTS: The QUEST trials opened in 15 UK centres. After 18 months of recruitment, 17 patients were randomized to QUEST A and eight to QUEST B, with overall acceptance rates of 19 per cent (17 of 88) and 22 per cent (8 of 36) respectively. The QPS recruited 56 patients and 51 healthcare professionals. Patient preference was the predominant reason for declining trial entry, given by 47 (53 per cent) of the 88 patients approached for QUEST A and 22 (61 per cent) of the 36 approached for QUEST B. Both trials closed to recruitment in December 2012, acknowledging the challenges of achieving satisfactory patient accrual. CONCLUSION: Despite extensive efforts to overcome recruitment barriers, it was not feasible to reach timely recruitment targets within a feasibility study. Patient preferences for breast reconstruction types and timings were common, rendering patients unwilling to enter the trial.

Current attitudes of head and neck oncologists in the United Kingdom to induction chemotherapy for locally advanced head and neck cancer: a survey of centres participating in a national randomised controlled trial.

OBJECTIVES: Induction chemotherapy (IC) followed by chemoradiation (CRT) for locally advanced squamous cell head and neck cancer (SCCHN) remains controversial in the absence of clear evidence to define its role. As part of a prospective, randomised, multicentre study of CRT for stage III/IV laryngeal/hypopharyngeal cancers (ART DECO, CRUK/10/018), we have examined the attitudes of oncologists in the United Kingdom (UK) to IC. MATERIALS AND METHODS: Head and neck oncologists across the UK who expressed an interest in participating in the ART DECO trial were asked to complete a short written questionnaire designed to identify current UK practice of IC for stage III-IVb SCCHN. Completed questionnaires were returned to the clinical trials office prior to patient recruitment. RESULTS: Clinicians from twenty-five/48 centres (52.1%) responded. Twenty centres (80%) elected to use IC in the trial. For stage III disease, 80% of centres did not prescribe IC for T1N1 disease and 60% did not offer IC for T3N0 disease. Patients with bulky primary tumours or extensive nodal disease were more likely to receive IC. Thirteen prescribing centres (65%) use 3 drugs (docetaxel, cisplatin, and 5-fluorouracil) compared to 7 (35%) using 2 drugs (cisplatin and 5-fluorouracil). Fifteen centres (75%) prescribed 2 cycles of IC, and 5 (25%) prescribed 3 cycles. There was variation in the dosage for both the 2- and 3-drug regimens. CONCLUSION: Results suggest that clinical practice in the UK is currently divided between a 2- versus 3-drug regimen for IC for specific subgroups of patients. A consensus regarding the optimal combinations and dosages is required before further optimization of systemic therapy with other cytotoxics and biological agents is attempted.

Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG.

BACKGROUND: In patients who underwent radical resection for gastric cancer, we investigate the relative efficacy of combined 5-fluorouracil+adriamycin or epirubicin and methotrexate with leucovorin rescue (FAMTX or FEMTX) compared with a control arm. PATIENTS AND METHODS: This report is a prospective combined analysis of two randomized clinical trials conducted on patients who underwent radical resection for histologically proven adenocarcinoma of the stomach or esophago-gastric junction. Three hundred and ninety-seven untreated patients, 206 from 23 European Organization for Research and Treatment of Cancer (EORTC) institutions and 191 from 16 International Collaborative Cancer Group (ICCG) institutions, were randomized. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method and the treatments were compared for these end-points by means of the log-rank test, retrospectively stratified by trial. RESULTS: In a planned combined analysis of the two trials, no significant differences were found between the treatment and control arms for either DFS (hazards ratio: 0.98, P=0.87) or OS (hazards ratio: 0.98, P=0.86). The 5-year OS was 43% in the treatment arm and 44% in the control arm and the 5-year DFS was 41% and 42%, respectively. CONCLUSION: Neither FAMTX nor FEMTX can be advocated as adjuvant treatment in patients who undergo resection for gastric cancer.

High dose chemotherapy and autologous stem cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomised trial.

BACKGROUND: The purpose of this study was to assess whether a short course of anthracycline containing chemotherapy followed by high dose therapy with autologous stem-cell support improves disease-free and overall survival as compared with conventional, anthracycline containing chemotherapy, in patients with primary breast cancer and four or more histologically involved lymph nodes. PATIENTS AND METHODS: Two hundred and eighty one patients entered into a randomised clinical trial were allocated to receive standard, conventional treatment (5-fluorouracil, epirubicin and cyclophosphamide-FEC for six cycles) or FEC for three cycles followed by high dose therapy consisting of cyclophosphamide, thiotepa and carboplatin and stem cell rescue (HDT). To be eligible, patients had to be free of overt metastatic disease and be < or =60 years of age. Analyses were according to intention to treat. RESULTS: At a median follow up of 68 months, 118 patients have experienced a relapse or death from breast cancer (62 in the FEC followed by HDT arm and 56 in the conventional FEC arm) and a total of 100 patients have died (54 in the FEC followed by HDT arm and 46 in the conventional FEC arm). No significant difference was observed in relapse-free survival [hazard ratio 1.06, 95% CI 0.74-1.52, p = 0.76] or overall survival [hazard ratio 1.18, 95% CI 0.80-1.75, p = 0.40]. Five patients died from treatment related causes, three as a consequence of HDT and two in the conventional FEC arm. CONCLUSIONS: At the present time, no benefit has been observed from replacing three cycles of conventional chemotherapy with the HDT regimen described here. Patients should continue to receive conventional chemotherapy as adjuvant therapy for breast cancer.

Aromatase inhibitors as adjuvant therapies in patients with breast cancer.

There is increasing evidence that endocrine therapy has an important role in patients with oestrogen receptor positive breast cancer. Several large meta-analyses have reinforced the value of both ovarian ablation and tamoxifen in improving survival. Over the past decade, aromatase inhibitors have become the treatment of choice for second-line therapy of metastatic breast cancer, and the third generation inhibitors have now an established reputation for good patient tolerability. Early studies indicated that aminoglutethimide/hydrocortisone could benefit postmenopausal patients with primary breast cancer, and in 2001, the ATAC study showed that the third generation aromatase inhibitor, anastrozole, seemed superior to tamoxifen in that anastrozole-treated patients had a longer disease-free survival. Other studies will report on the relative merits of the steroidal inhibitor exemestane as well as non-steroidal letrozole. The exact duration and sequencing of treatment, together with the long-term effects on bone are at present, unknown.

The prevalence of cerebral infarcts in the Asymptomatic Carotid Surgery Trial (ACST) in relation to prior contralateral symptoms.

BACKGROUND: The ACST has randomised over 1670 patients to determine if carotid endarterectomy (CEA) prolongs stroke free survival versus best medical treatment alone. Some patients have had contralateral symptoms to the side under investigation, for which CEA may have been performed. This study aims to determine the prevalence of hemispheric cerebral infarcts in relation to prior contralateral symptoms. METHODS: Patients with preoperative CT or MR scans were divided into those with prior contralateral stroke, cortical TIA, amaurosis fugax or no symptoms. RESULTS: There were 1144 patients with preoperative CT and 170 patients with MR scans. Incidence of contralateral hemispheric CT and MR infarcts were 19% (222/1144) and 20% (34/170) respectively. Those with prior contralateral stroke (141) had the highest incidence of hemispheric CT infarcts (62%). Those with TIA (129) had a 30% incidence of CT infarct. Incidence of hemispheric CT infarcts were 17% with amaurosis fugax (46) and 10% with no prior symptoms (803). Mantel-Haenszel test for linear association was significant (p < 0.001) for increasing severity of symptoms. Considering MR scans, those with prior contralateral stroke (17) had the highest incidence of hemispheric MR infarcts (53%). Patients with TIA (23) or amaurosis fugax (6) had a 27% incidence of MR infarction. Those with no prior symptoms (121) had a 14% incidence of MR infarcts. Mantel-Haenszel test was significant (p < 0.001). CONCLUSIONS: In the ACST, currently asymptomatic patients have an incidence of contralateral hemispheric CT and MR infarcts proportional to the severity of prior contralateral symptoms.

Prevalence of asymptomatic CT infarcts in the ongoing Asymptomatic Carotid Surgery Trial (ACST).

BACKGROUND: The ACST has randomised over 1670 patients to determine if carotid endarterectomy (CEA) prolongs stroke free survival when compared with best medical treatment alone. This study aims to assess the prevalence of asymptomatic cerebral infarcts in patients grouped by sex, age, mean blood pressure (MBP), total cholesterol, diabetes and coronary artery disease (CAD). METHODS: The type of study was retrospective. Patients with preoperative CT scans were included. In those with previous stroke, only the contralateral cerebral hemisphere was studied for presence of infarcts. One thousand one hundred and forty-two patients were studied. RESULTS: The proportion of patients with CT infarcts was 19% (211/1142). Men (155/777) had a higher incidence of CT infarction (20% vs 15%, p = 0.01). Mean age was 68 years and mean MBP was 107 mmHg. The incidence of CT infarcts was not associated with age or MBP. Diabetics or those with definite CAD had no difference in the incidence of cerebral infarction. Diabetics with definite CAD (51/796) had a greater incidence of CT infarcts (33% vs 21%, p = 0.03) compared with those without evidence of CAD and diabetes together (745/796). CONCLUSIONS: In ACST, CT infarcts are more prevalent in men compared to women, and in diabetics with CAD. There was no difference in the incidence of CT infarction by age, mean BP, or by the presence of diabetes or CAD alone.

Are we detecting and operating on high risk patients in the asymptomatic carotid surgery trial? The Asymptomatic Carotid Surgery Trial Collaborators.

OBJECTIVE: This study aims to determine whether asymptomatic carotid surgery trial (ACST) centres have entered and can identify high risk patients using duplex. DESIGN: Retrospective study. MATERIALS AND METHODS: Eighty-six vascular laboratories collaborating in ACST were studied, Equipment, operator experience, methodology and interpretation criteria were assessed. The ACST randomisation data were examined to determine whether patients believed to be at higher risk of stroke because of tight stenosis, contralateral occlusion or echolucent plaque were randomised. RESULTS: Laboratories (92%) had colour duplex and 62% of all operators had > 3 years experience in carotid evaluation. The Doppler angle used to obtain peak velocity was 30-60 degrees in 65%, 60 degrees in 28% and 60-80 degrees in 6% of laboratories. Sixty-two per cent reported diameter reduction, 27% area reduction, and 11% used both methods. One-third of 1657 randomised patients were reported to have ipsilateral echolucent plaque. Median ipsilateral stenosis was 80%, 8% had contralateral occlusion and 8.5% had bilateral > 80% stenosis. CONCLUSIONS: Centres in ACST use experienced operators, high quality equipment and conscientious data recording. Variations in methods of determining carotid stenosis exist, but can be smoothed by simple data collection. Patients at higher perceived risk of stroke are being entered and with continued recruitment it should be possible to determine whether surgery improves disabling stroke-free survival.

Carotid duplex ultrasonography: importance of standardisation. Asymptomatic Carotid Surgery Trial Collaborators and Vascular Laboratories.

BACKGROUND: Carotid duplex ultrasonography (CDUS) is an established non-invasive tool for assessing patients with suspected carotid bifurcation disease. Current trends show an increased dependence on CDUS in recommending patients for stroke prevention surgery. The aim of the study was to evaluate routine practice in vascular laboratories across 26 countries participating in The Asymptomatic Carotid Surgery Trial (ACST), and to determine the areas which are in need of future standardisation if CDUS is to be the primary tool in recommending patients for CEA. METHODS: Retrospective. Information was gathered from questionnaires, and 22 on-site visits of vascular laboratories between August 1996 to September 1997. SETTING: Clinical vascular laboratory practice. PARTICIPANTS: Eligible participants were vascular laboratories of ACST collaborators. MEASURES: Laboratories were compared in 7 categories: ultrasound equipment, operators, experience, protocols, stenosis evaluation, interpretation criteria, and reporting. RESULTS: Information on 117 respondents showed that (i) experience: at least one operator in each laboratory had more than 3 years experience; (ii) equipment: 88% (103/117) had colour duplex capability; (iii) operators: 54% of laboratories had exams performed by technologists, 33% vascular surgeons, 28% radiologists, and 35% other. The most significant findings were in (iv) stenosis evaluation: only 29% (33/117) were using a standardised Doppler angle (this single factor may greatly alter exam results); and (v) interpretation criteria; with >41 different criteria reported. These specific laboratory variations can affect those patients considered appropriate for CEA. CONCLUSIONS: This study highlights the most significant areas for future standardisation to be Doppler angle and interpretation criteria, if CDUS is to be a primary tool in recommending patients for CEA, when indicated by clinical trial results.

Stereological estimation of blood vessel surface and volume densities in human normal and rhinitic nasal mucosa.

A technique is proposed for applying well-established stereological methods to study fixed nasal biopsy material to obtain an unbiased estimate of blood vessel surface and volume densities. Biopsies of the nasal mucosa from the anterior 10 mm of an inferior turbinate were obtained from 18 subjects (15 males, 3 females with a mean age of 28.5 years [range: 17-54 years]), ten of whom had perennial allergic rhinitis, and eight control subjects. The mucosal tissue volumes were estimated by water displacement. Zamboni's-fixed cryostat sections (10 microns thick), stained with haematoxylin and eosin, were examined histologically. Computerised images of randomly selected tissue sections were analysed with point-counting and intercept-counting techniques to determine large blood vessel volume and surface densities, respectively. There were no significant differences between the volumes of tissue analysed from the control and rhinitic subjects (p = 0.35). The average volume density of the vessels was similar in the control group (6.17 +/- 1.41%) and the rhinitic group (7.8 +/- 5.59%; p = 0.38), but with a greater variability in the rhinitic group. Surface density estimations were 3.14 +/- 0.74 mm-1 in the control group and 3.10 +/- 1.41 mm-1 in the rhinitic group. Therefore, on average, the volume and surface densities of the cavernous blood vessels in rhinitis were unaltered and there was no evidence of vascular remodelling.

Identification of bombesin-immunoreactive cells in rat, human, and other mammalian pituitaries, their ontogeny and the effect of endocrine manipulations in the rat.

Bombesin and gastrin-releasing peptide are homologous peptides which have biological activity in mammals. The distribution of bombesin immunoreactivity in rat, guinea pig, cat, dog, pig, cow, monkey, and human pituitaries was investigated using immunocytochemistry with various different antisera. Polyclonal antisera identified bombesin-immunoreactive (IR) cells in the anterior pituitaries of all species except monkey and human, although positive nerves were present in the human posterior lobe. In contrast, a monoclonal antibody demonstrated bombesin-IR cells in anterior and intermediate lobe (or equivalent) of all species. Both types of antibodies identified the anterior pituitary cells as somatotrophs, which may be significant because bombesin and related peptides influence pituitary growth hormone secretion. Differences in bombesin immunoreactivity were seen in male and female rats, with males having more positive cells, and females showing more intense immunoreactivity in those cells which were positive. Ontogenetic studies in rats revealed that bombesin-IR cells were first seen at birth. The effect of estrogen on bombesin-IR cells was studied using ovariectomized and estrogen-treated female rats. Estrogen treatment decreased very significantly the number of bombesin-IR cells, compared with controls, whereas ovariectomy increased significantly the frequency of bombesin-IR cells, so that the staining pattern began to resemble that seen in normal male rats. No bombesin-IR cells were detected in pituitaries from thyroidectomized rats. These results suggest that immunoreactive bombesin/gastrin-releasing peptide in the pituitary is modulated by endocrine status and this peptide may be involved in paracrine interactions in this tissue.