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The effects of extra-pleural pneumonectomy (EPP) on survival and quality of life in patients with malignant pleural mesothelioma have, to our knowledge, not been assessed in a randomised trial. We aimed to assess the clinical outcomes of patients who were randomly assigned to EPP or no EPP in the context of trimodal therapy in the Mesothelioma and Radical Surgery (MARS) feasibility study. MARS was a multicentre randomised controlled trial in 12 UK hospitals. Patients aged 18 years or older who had pathologically confirmed mesothelioma and were deemed fit enough to undergo trimodal therapy were included. In a prerandomisation registration phase, all patients underwent induction platinum-based chemotherapy followed by clinical review. After further consent, patients were randomly assigned (1:1) to EPP followed by postoperative hemithorax irradiation or to no EPP. Randomisation was done centrally with computer-generated permuted blocks stratified by surgical centre. The main endpoints were feasibility of randomly assigning 50 patients in 1 year (results detailed in another report), proportion randomised who received treatment, proportion eligible (registered) who proceeded to randomisation, perioperative mortality, and quality of life. Patients and investigators were not masked to treatment allocation. This is the principal report of the MARS study; all patients have been recruited. Analyses were by intention to treat. This trial is registered, number ISRCTN95583524. Between Oct 1, 2005, and Nov 3, 2008, 112 patients were registered and 50 were subsequently randomly assigned: 24 to EPP and 26 to no EPP. The main reasons for not proceeding to randomisation were disease progression (33 patients), inoperability (five patients), and patient choice (19 patients). EPP was completed satisfactorily in 16 of 24 patients assigned to EPP; in five patients EPP was not started and in three patients it was abandoned. Two patients in the EPP group died within 30 days and a further patient died without leaving hospital. One patient in the no EPP group died perioperatively after receiving EPP off trial in a non-MARS centre. The hazard ratio [HR] for overall survival between the EPP and no EPP groups was 1·90 (95% CI 0·92–3·93; exact p=0·082), and after adjustment for sex, histological subtype, stage, and age at randomisation the HR was 2·75 (1·21–6·26; p=0·016). Median survival was 14·4 months (5·3–18·7) for the EPP group and 19·5 months (13·4 to time not yet reached) for the no EPP group. Of the 49 randomly assigned patients who consented to quality of life assessment (EPP n=23; no EPP n=26), 12 patients in the EPP group and 19 in the no EPP group completed the quality of life questionnaires. Although median quality of life scores were lower in the EPP group than the no EPP group, no significant differences between groups were reported in the quality of life analyses. There were ten serious adverse events reported in the EPP group and two in the no EPP group. In view of the high morbidity associated with EPP in this trial and in other non-randomised studies a larger study is not feasible. These data, although limited, suggest that radical surgery in the form of EPP within trimodal therapy offers no benefit and possibly harms patients. Cancer Research UK ( CRUK/04/003), the June Hancock Mesothelioma Research Fund, and Guy's and St Thomas' NHS Foundation Trust.

The optimum endocrine treatment for postmenopausal women with advanced hormone-receptor-positive breast cancer that has progressed on non-steroidal aromatase inhibitors (NSAIs) is unclear. The aim of the SoFEA trial was to assess a maximum double endocrine targeting approach with the steroidal anti-oestrogen fulvestrant in combination with continued oestrogen deprivation. In a composite, multicentre, phase 3 randomised controlled trial done in the UK and South Korea, postmenopausal women with hormone-receptor-positive breast cancer (oestrogen receptor [ER] positive, progesterone receptor [PR] positive, or both) were eligible if they had relapsed or progressed with locally advanced or metastatic disease on an NSAI (given as adjuvant for at least 12 months or as first-line treatment for at least 6 months). Additionally, patients had to have adequate organ function and a WHO performance status of 0–2. Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250 mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). Randomisation was done with computer-generated permuted blocks, and stratification was by centre and previous use of an NSAI as adjuvant treatment or for locally advanced or metastatic disease. Participants and investigators were aware of assignment to fulvestrant or exemestane, but not of assignment to anastrozole or placebo. The primary endpoint was progression-free survival (PFS). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, numbers NCT00253422 (UK) and NCT00944918 (South Korea). Between March 26, 2004, and Aug 6, 2010, 723 patients underwent randomisation: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4·4 months (95% CI 3·4–5·4) in patients assigned to fulvestrant plus anastrozole, 4·8 months (3·6–5·5) in those assigned to fulvestrant plus placebo, and 3·4 months (3·0–4·6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (hazard ratio 1·00, 95% CI 0·83–1·21; log-rank p=0·98), or between those assigned to fulvestrant plus placebo and exemestane (0·95, 0·79–1·14; log-rank p=0·56). 87 serious adverse events were reported: 36 in patients assigned to fulvestrant plus anastrozole, 22 in those assigned to fulvestrant plus placebo, and 29 in those assigned to exemestane. Grade 3–4 adverse events were rare; the most frequent were arthralgia (three in the group assigned to fulvestrant plus anastrozole; seven in that assigned to fulvestrant plus placebo; eight in that assigned to exemestane), lethargy (three; 11; 11), and nausea or vomiting (five; two; eight). After loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation is no better than either fulvestrant alone or exemestane. Cancer Research UK and AstraZeneca.

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE 100 C or endocrine therapy: letrozole 2.5 mg, daily for 18–23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95 % CI 57–81) were randomised. 12 (54.5, 95 % CI 32.2–75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95 % CI 36.4–79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2–4 and at surgery [fold change: 0.24 (95 % CI 0.12–0.51) and 0.24; (95 % CI 0.15–0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95 % CI 1.47–3.00), letrozole 1.47(95 % CI 0.98–2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95 % CI 1.56–4.41), letrozole 0.95 (95 % CI 0.71–1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

Tamoxifen preserves bone in postmenopausal women, but non-steroidal aromatase inhibitors accelerate bone loss and increase fracture risk. We aimed to study the effect on bone health in a subgroup of women included in the Intergroup Exemestane Study (IES), a large randomised trial that compared the switch to the steroidal aromatase inhibitor exemestane with continuation of tamoxifen in the adjuvant treatment of postmenopausal breast cancer. Results were analysed from 206 evaluable patients from the IES, in which postmenopausal women with histologically confirmed and completely resected unilateral breast cancer (that was oestrogen-receptor positive or of unknown status), who were disease-free after 2–3 years of treatment with tamoxifen were randomised to continue oral tamoxifen 20 mg/day or switch to oral exemestane 25 mg/day to complete a total of 5 years of adjuvant endocrine therapy. The primary endpoint was change in bone-mineral density (BMD) assessed by dual energy X-ray absorptiometry. Changes in biochemical markers of bone turnover were also analysed in this substudy, and the incidence of fractures in the entire study reported. The IES is registered on the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN11883920. Within 6 months of switching to exemestane, BMD was lowered by 0·051 g/cm 3 (2·7%; 95% CI 2·0–3·4; p<0·0001) at the lumbar spine and 0·025 g/cm 3 (1·4%; 0·8–1·9; p<0·0001) at the hip compared with baseline. BMD decreases were only 1·0% (0·4–1·7; p=0·002) and 0·8% (0·3–1·4; p=0·003) in year 2 at the lumbar spine and hip, respectively. No patient with BMD in the normal range at trial entry developed osteoporosis. Bone resorption and formation markers increased at all time points in women receiving exemestane (p<0·001). With a median follow-up in all IES participants (n=4274) of 58 months, 162 (7%) and 115 (5%) patients in the exemestane and tamoxifen groups, respectively, had fractures (odds ratio 1·45 [1·13–1·87]; p=0·003). These results indicate that the increase in survival shown previously with the IES switch strategy is achieved at the expense of some detriment to skeletal health, so the risk-benefit ratio to women needs to be individually assessed.

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.

Background: The ACTION trial was initiated to provide evidence from a randomised trial on the effects of chemotherapy in women aged over 70 years where evidence for risk and benefit are lacking. Methods: This was a randomised, phase III clinical trial for high risk, oestrogen receptor (ER) negative/ER weakly positive early breast cancer. The trial planned to recruit 1000 women aged 70 years and older, randomised to receive 4 cycles of anthracycline chemotherapy or observation. The primary endpoint was relapse-free interval. The trial included a pilot phase to assess the acceptability and feasibility of recruitment. Results: The trial opened at 43 UK centres. Information on number of patients approached was available from 38 centres. Of the 43 eligible patients that were approached, 39 were not randomised due to patients declining entry. After 10 months only 4 patients had been randomised and after discussion with the research funder, the trial was closed and funding terminated. Conclusion: Despite widespread support at several public meetings, input from patient groups including representation on the Trial Management Group, the trial failed to recruit due to the inability to convince patients to accept randomisation. It would therefore seem that randomising the patients to receive chemotherapy vs observation is not a viable design in the current era for this patient population.

The adjuvant use of aromatase inhibitors in breast cancer is associated with adverse effects on bone health. We previously reported a decline in bone mineral density (BMD) following the switch from tamoxifen to exemestane in the Intergroup Exemestane Study (IES). Here we report effects of endocrine treatment withdrawal on BMD, bone turnover markers (BTM) and fracture rates. 4,724 patients took part in IES, and 206 patients were included in a bone sub-study. BMD and BTM were assessed pre-randomization, during and after the end of treatment (EOT). To evaluate treatment withdrawal effects, 12- and 24-month post EOT BMD results are available for 122 and 126 patients, respectively. Similar patient numbers had BTM measured post EOT. Following treatment withdrawal, the differences in BMD observed between the two endocrine strategies were partially reversed. At 24 months from EOT, spine BMD increased by 1.53% (95%CI 0.63-2.43; p = 0.001) after stopping exemestane and fell by 1.93% (95%CI −2.91 to 0.95; p = 0.0002) following tamoxifen withdrawal. A similar pattern of changes was observed at the hip. At 2 years post EOT, BMD changes from baseline were similar with both treatment strategies. Corresponding inverse changes in BTM were seen, with an increase following tamoxifen withdrawal and a reduction after exemestane. A higher number of fractures occured during exemestane treatment, but fracture rates were similar after treatment withdrawal. With the switch strategy used in IES, the on treatment adverse bone effects of exemestane are reversed. Ongoing monitoring of BMD is therefore not routinely required.