Long-term assessment of quality of life in the Intergroup Exemestane Study: 5 years post-randomisation.

BACKGROUND: The Intergroup Exemestane Study (IES) (ISRCTN11883920) demonstrated improved survival for postmenopausal women with ER-positive/unknown primary breast cancer who switched to exemestane after 2-3 years tamoxifen, compared with those continuing on tamoxifen to complete 5 years therapy. This was achieved without detriment to on-treatment quality-of-life (QoL). We report on- and post-treatment QoL impact in IES. METHODS: A total of 582 patients from 8 countries participated in the QoL substudy. Functional Assessment of Cancer Therapy-Breast (FACT-B) and endocrine symptom subscale (ES) were completed at baseline, 3, 6, 9, 12, 18, 24, 30, 36, 48 and 60 months. The primary endpoint was FACT-B Trial Outcome Index (TOI); secondary endpoints included severity of individual endocrine symptoms. RESULTS: Both the groups showed gradual improvement in overall QoL and lessening of total endocrine symptoms post treatment compared with baseline (P<0.002). There was no evidence of any between-group differences in TOI. Vasomotor complaints remained high on treatment. Vaginal discharge was more frequent (P<0.01) with tamoxifen up to 24 months from baseline. In both the groups, post-treatment libido did not recover to baseline levels. CONCLUSION: Clinical benefits of switching to exemestane are accompanied by good overall QoL. Although some symptoms persist, the majority of endocrine symptoms improve after treatment completion.

Long-term endometrial effects in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES)--a randomised controlled trial of exemestane versus continued tamoxifen after 2-3 years tamoxifen.

BACKGROUND: The antiestrogen tamoxifen may have partial estrogen-like effects on the postmenopausal uterus. Aromatase inhibitors (AIs) are increasingly used after initial tamoxifen in the adjuvant treatment of postmenopausal early breast cancer due to their mechanism of action: a potential benefit being a reduction of uterine abnormalities caused by tamoxifen. PATIENTS AND METHODS: Sonographic uterine effects of the steroidal AI exemestane were studied in 219 women participating in the Intergroup Exemestane Study: a large trial in postmenopausal women with estrogen receptor-positive (or unknown) early breast cancer, disease free after 2-3 years of tamoxifen, randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years adjuvant treatment. The primary end point was the proportion of patients with abnormal (> or =5 mm) endometrial thickness (ET) on transvaginal ultrasound 24 months after randomisation. RESULTS: The analysis included 183 patients. Two years after randomisation, the proportion of patients with abnormal ET was significantly lower in the exemestane compared with tamoxifen arm (36% versus 62%, respectively; P = 0.004). This difference emerged within 6 months of switching treatment (43.5% versus 65.2%, respectively; P = 0.01) and disappeared within 12 months of treatment completion (30.8% versus 34.7%, respectively; P = 0.67). CONCLUSION: Switching from tamoxifen to exemestane significantly reverses endometrial thickening associated with continued tamoxifen.

Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial.

BACKGROUND: Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. METHODS: 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. RESULTS: After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded. CONCLUSIONS: Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.

Neural influences on human esophageal and salivary alkali secretion.

Esophageal secretion HCO3- ions occurs in opossum and man and may contribute to mucosal defense. Using a perfusion technique, neuroregulatory influences on esophageal and salivary HCO3- secretion were investigated in 24 healthy human subjects. The sight and smell of food increased median salivary HCO3- output from 424 to 573 mumol/15 min (P = 0.014), without significantly altering esophageal HCO3- secretion (74-105 mumol/15 min, P = 0.24). Atropine reduced both salivary (610 to 68, 17, 10, and 3 mumol/15 min in successive periods; P < 0.028) and esophageal HCO3- output (108 to 78, 35, 18, and 7 mumol/10 cm/15 min; P < 0.028, respectively. Following atropinization, cholinergic stimulation failed to increase salivary secretion but did "unmask" a small rise in esophageal alkali output (7 to 27 mumol/10 cm/15 min, P = 0.036), implicating a noncholinergic mechanism. Cold-induced pain activated sympathetic reflexes and reduced esophageal HCO3- output (91 to 64 mumol/10 cm/15 min, P = 0.041) without influencing salivary secretion. These observations support a role for the autonomic nervous system in modulating human esophageal and salivary HCO3- secretion.

Effect of topical oesophageal acidification on human salivary and oesophageal alkali secretion.

Recent human studies suggest that oesophageal HCO3- secretion, in conjunction with salivary HCO3- secretion and secondary oesophageal peristalsis, is important for the protection of oesophageal mucosa from refluxed gastric contents. This study evaluated simultaneously the responsiveness of oesophageal and salivary HCO3- secretion to oesophageal acidification in eight healthy subjects. A 10 cm segment of oesophagus was perfused at a constant rate of 5 ml/min with a specially designed tube assembly. Saline was used initially, and then 10 mM and 100 mM HCl. The perfusates contained 3H-polyethylene glycol (PEG) as a concentration marker to determine volumes. Corrections were applied for a small degree of contamination by swallowed saliva and refluxed gastric alkali. Oesophageal perfusion with 10 mM HCl did not cause symptoms (nausea and heartburn), but tripled the oesophageal HCO3- output from a baseline of 51 mumol/10 cm/10 min (p = 0.021), while doubling the rate of salivary HCO3- secretion from a median basal value of 140 mumol/10 min (p = 0.021). Oesophageal perfusion with 100 mM HCl was associated with symptoms of nausea and heartburn in all subjects. The median oesophageal HCO3- output increased 32 fold to 1659 mumol/10 cm/10 min (interquartile range 569 to 3373; p = 0.036), and salivary HCO3- secretion approximately tripled from basal values (p = 0.036). In conclusion, oesophageal acidification stimulates both salivary and oesophageal HCO3- secretion, responses which may be protective to the oesophageal epithelium.

Measurement of bicarbonate output from the intact human oesophagus.

Injury of the oesophageal mucosa can result from exposure to refluxed gastric acid and pepsin. Competence of the lower oesophageal sphincter and peristaltic activity serve to reduce contract time between luminal acid and oesophageal mucosa, but intraluminal neutralisation of residual acid by bicarbonate may also be important in preventing oesophageal mucosal injury. Whereas swallowed saliva contains bicarbonate, recent experiments have also demonstrated alkali secretion from the mammalian oesophagus. Bicarbonate secretion from the human oesophagus was therefore examined with an intubation technique and perfusion of the oesophagus with a non-absorbable marker. Saliva, gastric, and oesophageal aspirates were collected and bicarbonate concentrations determined by measurements of pH and pCO2 or by back titration. In 32 normal subjects (17 women, 15 men) median basal oesophageal bicarbonate secretion determined by a pH/pCO2 method was 416 (range 139-1050) mumol/hour/10 cm. In a subgroup of 15 experiments median oesophageal bicarbonate output was 489 (range 157-1033) mumol/hour/10 cm (pH/pCO2 method) compared with a median alkali output of 563 (range 135-799) mumol/hour/10 cm as determined by back titration. The difference was not significant. Salivary contamination of the oesophagus accounted for 25% of all bicarbonate measured within the oesophagus and refluxed gastric bicarbonate accounted for 2.5%. Bicarbonate secretion from the normal human oesophagus may, in combination with swallowed salivary bicarbonate, play a part in preventing oesophageal mucosal damage due to refluxed gastric acid and pepsin.