Stanley W. Ashley

Overview of the main outcomes in breast-cancer prevention trials

BACKGROUND Early findings on the use of tamoxifen or raloxifene as prophylaxis against breast cancer have been mixed; we update available data and overview the combined results. METHODS All five randomised prevention trials comparing tamoxifen or raloxifene with placebo were included. Relevant data on contralateral breast tumours and side-effects were included from an overview of adjuvant trials of tamoxifen versus control. FINDINGS The tamoxifen prevention trials showed a 38% (95% CI 28-46; p<0.0001) reduction in breast-cancer incidence. There was no effect for breast cancers negative for oestrogen receptor (ER; hazard ratio 1.22 [0.89-1.67]; p=0.21), but ER-positive cancers were decreased by 48% (36-58; p<0.0001) in the tamoxifen prevention trials. Age had no apparent effect. Rates of endometrial cancer were increased in all tamoxifen prevention trials (consensus relative risk 2.4 [1.5-4.0]; p=0.0005) and the adjuvant trials (relative risk 3.4 [1.8-6.4]; p=0.0002); no increase has been seen so far with raloxifene. Venous thromboembolic events were increased in all tamoxifen studies (relative risk 1.9 [1.4-2.6] in the prevention trials; p<0.0001) and with raloxifene. Overall, there was no effect on non-breast-cancer mortality; the only cause showing a mortality increase was pulmonary embolism (six vs two). INTERPRETATION The evidence now clearly shows that tamoxifen can reduce the risk of ER-positive breast cancer. New approaches are needed to prevent ER-negative breast cancer and to reduce the side-effects of tamoxifen. Newer agents such as raloxifene and the aromatase inhibitors need to be evaluated. Although tamoxifen cannot yet be recommended as a preventive agent (except possibly in women at very high risk with a low risk of side-effects), continued follow-up of the current trials is essential for identification of a subgroup of high-risk, healthy women for whom the risk-benefit ratio is sufficiently positive.

Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer.

PURPOSE Osteolytic metastases often give rise to hypercalcemia, fracture, and bone pain, and occur commonly in patients with recurrent breast cancer. We assessed the bisphosphonate, clodronate, which has proven to be a useful treatment for hypercalcemia and may be a potent inhibitor of tumor-induced osteolysis, for its effect on reducing the osseous complications of metastatic breast cancer. PATIENTS AND METHODS We studied 173 patients with bone metastases due to breast cancer in a randomized, double-blind, placebo-controlled trial of oral clodronate 1,600 mg/d (85 patients) compared with an identical placebo (88 patients). RESULTS The patients in each wing were comparable in their clinical, radiologic, and biochemical characteristics at trial entry. In patients who received clodronate, there was a significant reduction compared with placebo in the total number of hypercalcemic episodes (28 v 52; P < .01), in the number of terminal hypercalcemic episodes (seven v 17; P < .05), in the incidence of vertebral fractures (84 v 124 per 100 patient-years; P < .025), and in the rate of vertebral deformity (168 v 252 per 100 patient-years; P < .001). The combined rate of all morbid skeletal events was significantly reduced (218.6 v 304.8 per 100 patient-years; P < .001). Trends were seen in favor of clodronate for nonvertebral fracture rates and radiotherapy requirements for bone pain (particularly spinal pain). No significant survival differences and no significant differences in side effects were observed between the two groups. CONCLUSIONS These findings indicate that oral clodronate has a beneficial effect on the skeletal morbidity associated with breast cancer and should be considered as antiosteolytic therapy in affected patients. It deserves further investigation as an adjuvant therapy in operable breast cancer and in patients with nonosseous recurrence who are at high risk for bone metastases.

Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial

Randomised, double-blind controlled trials have been started to determine whether tamoxifen can prevent or delay development of breast cancer in healthy women with a family history of the disease. We recruited a randomised cohort of 111 postmenopausal women (aged 46-71 years) from the Pilot Breast Cancer Prevention Trial at the Royal Marsden Hospital to study the effect of tamoxifen on the uterus and ovaries. The main outcome measures were obtained by transvaginal ultrasonography with colour doppler imaging and microscopic examination of endometrial biopsies removed at the time of the scan. There was no significant difference between tamoxifen (20 mg/day) and placebo groups in the age of the women, or the time of the scan (and sampling) after randomisation. Women taking tamoxifen had a significantly larger uterus and a lower impedance to blood flow in the uterine arteries. 39% of women taking tamoxifen had histological evidence of an abnormal endometrium compared with 10% in the control group. 10 patients in the tamoxifen group (16%) had atypical hyperplasia and another 5 (8%) had a polyp. Women with a histological abnormality had a significantly thicker endometrium and a decreased impedance to blood flow in the uterine arteries. There was no correlation between the presence of uterine abnormalities and the age of the women, or the concentrations of tamoxifen or desmethyl tamoxifen in the peripheral blood. These findings confirm that tamoxifen can cause potentially malignant changes in the endometrium of postmenopausal women. Transvaginal ultrasonography can be used to identify those women who should have endometrial samples removed for microscopic analysis.

Implementing the World Health Organization Surgical Safety Checklist: A Model for Future Perioperative Initiatives

In the fall of 2008, perioperative leaders at Brigham and Womens Hospital, Boston, Massachusetts, conducted a two-week trial of the World Health Organization Surgical Safety Checklist in the main OR. The checklist was incorporated by using a Plan-Do-Study-Act cycle. In 2009, we began a 14-week rollout of the surgical safety checklist to all our ORs. Critical factors that led to the success of this implementation included gaining executive leadership endorsement; recruiting volunteers from each discipline to lead the project; using quality methodologies to ensure a thoughtful, organizing implementation; providing frequent feedback and data; and confirming standardized use of the checklist by creating a policy.

Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma.

OBJECTIVE--To assess the risk of second brain tumour in patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. DESIGN--Long term follow up of a cohort of patients with pituitary adenoma and comparison of tumour occurrence with population incidence rates. SETTING--The Royal Marsden Hospital. SUBJECTS--334 patients with pituitary adenoma treated with conservative surgery and radiotherapy (median dose 45 Gy) and followed up for 3760 person years. MAIN OUTCOME MEASURES--Second intracranial tumour and systemic malignancy. RESULTS--Five patients developed a second brain tumour: two had astrocytoma, two meningioma, and one meningeal sarcoma. The cumulative risk of developing a second brain tumour over the first 10 years after treatment was 1.3% (95% confidence interval 0.4% to 3.9%) and over 20 years 1.9% (0.7% to 5.0%). The relative risk of a second brain tumour compared with the incidence in the normal population was 9.38 (3.05 to 21.89). There was no excess risk of any other type of second primary malignancy. CONCLUSIONS--There is an increased risk of second intracranial tumour in patients with pituitary adenoma treated with surgery and radiotherapy. Although radiation is likely to be the most important factor contributing to the excess risk, further study is required in a cohort of similar patients not receiving radiation.

The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas

OBJECTIVES We assessed the long‐term efficacy and toxicity of conservative surgery and radiotherapy in the control of pituitary adenomas.

Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers

To examine whether weight loss at presentation influences outcome in patients who received chemotherapy for lung cancer or mesothelioma. Multivariate analysis of prospectively collected data 1994–2001. Data were available for age, gender, performance status, histology, stage, response, toxicity, progression-free and overall survival. The outcomes of patients with or without weight loss treated with chemotherapy for small cell lung cancer (SCLC; n=290), stages III and IV non-small-cell lung cancer (NSCLC; n=418), or mesothelioma (n=72) were compared. Weight loss was reported by 59, 58 and 76% of patients with SCLC, NSCLC and mesothelioma, respectively. Patients with weight loss and NSCLC (P=0.003) or mesothelioma (P=0.05) more frequently failed to complete at least three cycles of chemotherapy. Anaemia as a toxicity occurred significantly more frequently in NSCLC patients with weight loss (P=0.0003). The incidence of other toxicities was not significantly affected by weight loss. NSCLC patients with weight loss had fewer symptomatic responses (P=0.001). Mesothelioma patients with weight loss had fewer symptomatic (P=0.03) and objective responses (P=0.05). Weight loss was an independent predictor of shorter overall survival for patients with SCLC (P=0.003, relative risk (RR)=1.5), NSCLC (P=0.009, RR=1.33) and mesothelioma (P=0.03, RR=1.92) and an independent predictor of progression-free survival in patients with SCLC (P=0.01, RR=1.43). In conclusion, weight loss as a symptom of lung cancer predicts for toxicity from treatment and shorter survival.

Early antibiotic treatment for severe acute necrotizing pancreatitis - A randomized, double-blind, placebo-controlled study

Background & Aims:In patients with severe, necrotizing pancreatitis, it is common to administer early, broad-spectrum antibiotics, often a carbapenem, in the hope of reducing the incidence of pancreatic and peripancreatic infections, although the benefits of doing so have not been proved. Methods:A multicenter, prospective, double-blind, placebo-controlled randomized study set in 32 centers within North America and Europe. Participants: One hundred patients with clinically severe, confirmed necrotizing pancreatitis: 50 received meropenem and 50 received placebo. Interventions: Meropenem (1 g intravenously every 8 hours) or placebo within 5 days of the onset of symptoms for 7 to 21 days. Main Outcome Measures: Primary endpoint: development of pancreatic or peripancreatic infection within 42 days following randomization. Other endpoints: time between onset of pancreatitis and the development of pancreatic or peripancreatic infection; all-cause mortality; requirement for surgical intervention; development of nonpancreatic infections within 42 days following randomization. Results:Pancreatic or peripancreatic infections developed in 18% (9 of 50) of patients in the meropenem group compared with 12% (6 of 50) in the placebo group (P = 0.401). Overall mortality rate was 20% (10 of 50) in the meropenem group and 18% (9 of 50) in the placebo group (P = 0.799). Surgical intervention was required in 26% (13 of 50) and 20% (10 of 50) of the meropenem and placebo groups, respectively (P = 0.476). Conclusions:This study demonstrated no statistically significant difference between the treatment groups for pancreatic or peripancreatic infection, mortality, or requirement for surgical intervention, and did not support early prophylactic antimicrobial use in patients with severe acute necrotizing pancreatitis.

Craniopharyngioma — long-term results following limited surgery and radiotherapy

Between 1950 and 1986 173 patients with craniopharyngioma were treated at the Royal Marsden Hospital with external beam radiotherapy either alone or following surgery. Four patients had complete tumour excision, 21 subtotal and 78 partial resection, 14 had biopsy alone, 34 aspiration alone and 22 had no surgery directed at tumour eradication. Seventy-seven (45%) were children (aged < 16 years). The 10 and 20 year progression-free survival (PFS) rates were 83% and 79%. There were no independent prognostic factors for PFS. The 10 and 20 year survival rates were 77% and 66% at a median follow-up of 12 years. After adjustment for mortality in the normal population, age and technique of radiotherapy (which corresponded with era of treatment) were significant independent prognostic factors for survival. The risk of death (corrected for mortality from natural causes and controlling for radiotherapy technique) for age groups 16-39 and > or = 40 was 0.58 and 0.40 respectively, relative to a risk of 1.0 for the age group < 16 years. Survival and PFS were not influenced by the extent of surgical excision. Visual field defect improved after radiotherapy in 36% of patients (38/106) and visual acuity in 30% (27/91). No patient developed radiation optic neuropathy. We conclude that limited surgery and radiotherapy achieve excellent long-term tumour control and survival with low morbidity.

A high incidence of vertebral fracture in women with breast cancer

SummaryBecause treatment for breast cancer may adversely affect skeletal metabolism, we investigated vertebral fracture risk in women with non-metastatic breast cancer. The prevalence of vertebral fracture was similar in women at the time of first diagnosis to that in an age-matched sample of the general population. The incidence of vertebral fracture, however, was nearly five times greater than normal in women from the time of first diagnosis [odds ratio (OR), 4.7; 95% confidence interval (95% CI), 2.3–9.9], and 20-fold higher in women with soft-tissue metastases without evidence of skeletal metastases (OR, 22.7; 95% CI, 9.1–57.1). We conclude that vertebral fracture risk is markedly increased in women with breast cancer.