David Dodwell

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.

Maintaining Normal Hemoglobin Levels With Epoetin Alfa in Mainly Nonanemic Patients With Metastatic Breast Cancer Receiving First-Line Chemotherapy: A Survival Study

PURPOSE To evaluate the effect on survival and quality of life of maintaining hemoglobin (Hb) in the range of 12 to 14 g/dL with epoetin alfa versus placebo in women with metastatic breast cancer (MBC) receiving first-line chemotherapy. PATIENTS AND METHODS Eligible patients were randomly assigned to receive epoetin alfa 40,000 U once weekly or placebo for 12 months. Study drug was initiated if baseline Hb was < or = 13 g/dL or when Hb decreased to < or = 13g/dL during the study. The primary end point was 12-month overall survival (OS). RESULTS The study drug administration was stopped early in accordance with a recommendation from the Independent Data Monitoring Committee because of higher mortality in the group treated with epoetin alfa. Enrollment had been completed, with 939 patients enrolled (epoetin alfa, n = 469; placebo, n = 470). Most patients had Hb more than 12 g/dL at baseline (median Hb, 12.8 g/dL) or during the study. From the final analysis, 12-month OS was 70% for epoetin alfa recipients and 76% for placebo recipients (P = .01). Optimal tumor response and time to disease progression were similar between groups. The reason for the difference in mortality between groups could not be determined from additional subsequent analyses involving both study data and chart review. CONCLUSION In this trial, the use of epoetin alfa to maintain high Hb targets in women with MBC, most of whom did not have anemia at the start of treatment, was associated with decreased survival. Additional research is required to clarify the potential impact of erythropoietic agents on survival when the Hb target range is 10 to 12 g/dL.

Breast-cancer adjuvant therapy with zoledronic acid

BACKGROUND Data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer. We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients. METHODS In this open-label phase 3 study, we randomly assigned 3360 patients to receive standard adjuvant systemic therapy either with or without zoledronic acid. The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. The primary end point of the study was disease-free survival. A second interim analysis revealed that a prespecified boundary for lack of benefit had been crossed. RESULTS At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P=0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths--243 in the zoledronic acid group and 276 in the control group--were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P=0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P<0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups. CONCLUSIONS These findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer. (Funded by Novartis Pharmaceuticals and the National Cancer Research Network; AZURE Current Controlled Trials number, ISRCTN79831382.).

Longer-Term Assessment of Trastuzumab-Related Cardiac Adverse Events in the Herceptin Adjuvant (HERA) Trial

PURPOSE We investigated the incidence of cardiac adverse events in patients with early breast cancer in the Herceptin Adjuvant (HERA) trial who were treated with 1 year of trastuzumab after completion of (neo)adjuvant chemotherapy. PATIENTS AND METHODS The HERA trial is a three-group, randomized trial that compared 1 year or 2 years of trastuzumab with observation in women with human epidermal growth factor receptor-2 (HER2) -positive early breast cancer. Eligible patients had normal left ventricular ejection fraction (LVEF; >or= 55%) after completion of (neo)adjuvant chemotherapy with or without radiotherapy. Cardiac function was monitored throughout the trial. This analysis considers patients randomly assigned to 1 year of trastuzumab treatment or observation. RESULTS There were 1,698 patients randomly assigned to observation and 1,703 randomly assigned to 1 year of trastuzumab treatment; 94.1% of patients had been treated with anthracyclines. The incidence of discontinuation of trastuzumab because of cardiac disorders was low (5.1%). At a median follow-up of 3.6 years, the incidence of cardiac end points remained low, though it was higher in the trastuzumab group than in the observation group (severe CHF, 0.8% v 0.0%; confirmed significant LVEF decreases, 3.6% v 0.6%) In the trastuzumab group, 59 of 73 patients with a cardiac end point reached acute recovery; of these 59 patients, 52 were considered by the cardiac advisory board (CAB) to have a favorable outcome from the cardiac end point. CONCLUSION The incidence of cardiac end points remains low even after longer-term follow-up. The cumulative incidence of any type of cardiac end point increases during the scheduled treatment period of 1 year, but it remains relatively constant thereafter.

The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer

Background:Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups.Methods:In total, 205 patients received neoadjuvant CT±ZOL (CT+ZOL, n=102; CT, n=103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n=195), outcome differences between groups were assessed adjusting for potential response modifiers.Results:Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT+ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95% confidence interval: 3.5–20.4 mm; P=0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT+ZOL group (P=0.146). There was no difference in axillary nodal involvement (P=0.6315).Conclusion:These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.

CARDIAC DOSE FROM TANGENTIAL BREAST CANCER RADIOTHERAPY IN THE YEAR 2006

PURPOSE To quantify the radiation doses received by the heart and coronary arteries from contemporary tangential breast or chest wall radiotherapy. METHODS AND MATERIALS Fifty consecutive patients with left-sided breast cancer and 5 consecutive patients with right-sided breast cancer treated at a large United Kingdom radiotherapy center during the year 2006 were selected. All patients were irradiated with 6- or 8-MV tangential beams to the breast or chest wall. For each dose plan, dose-volume histograms for the heart and left anterior descending (LAD) coronary artery were calculated. For 5 of the left-sided and all 5 right-sided patients, dose-volume histograms for the right and circumflex coronary arteries were also calculated. Detailed spatial assessment of dose to the LAD coronary artery was performed for 3 left-sided patients. RESULTS For the 50 patients given left-sided irradiation, the average mean (SD) dose was 2.3 (0.7) Gy to the heart and 7.6 (4.5) Gy to the LAD coronary artery, with the distal LAD receiving the highest doses. The right and circumflex coronary arteries received approximately 2 Gy mean dose. Part of the heart received >20 Gy in 22 left-sided patients (44%). For the 5 patients given right-sided irradiation, average mean doses to all cardiac structures were in the range 1.2 to 2 Gy. CONCLUSIONS Heart dose from left-tangential radiotherapy has decreased considerably over the past 40 years, but part of the heart still receives >20 Gy for approximately half of left-sided patients. Cardiac dose for right-sided patients was generally from scattered irradiation alone.

Prevention of Anastrozole-Induced Bone Loss with Monthly Oral Ibandronate during Adjuvant Aromatase Inhibitor Therapy for Breast Cancer

Purpose: The aromatase inhibitor anastrozole is a highly effective well-tolerated treatment for postmenopausal endocrine-responsive breast cancer. However, its use is associated with accelerated bone loss and an increase in fracture risk. The ARIBON trial is a double-blind, randomized, placebo-controlled study designed to evaluate the impact of bisphosphonate treatment on bone mineral density (BMD) in women taking anastrozole. Experimental Design: BMD was assessed in 131 postmenopausal, surgically treated women with early breast cancer at two U.K. centers. Of these, 50 patients had osteopenia (T score −1.0 to −2.5) at either the hip or lumbar spine. All patients were treated with anastrozole 1 mg once a day and calcium and vitamin D supplementation. In addition, osteopenic patients were randomized to receive either treatment with ibandronate 150 mg orally every month or placebo. Results: After 2 years, osteopenic patients treated with ibandronate gained +2.98% (range −8.9, +19.9) and +0.60% (range −9.0, +6.9) at the lumbar spine and hip, respectively. Patients treated with placebo, however, lost −3.22% (range −16.0, +4.3) at the lumbar spine and −3.90% (range −12.3, +7.2) at the hip. The differences between the two treatment arms were statistically significant at both sites (P < 0.01). At 12 months, urinary n-telopeptide, serum c-telopeptide, and serum bone–specific alkaline phosphatase levels declined in patients receiving ibandronate (30.9%, 26.3%, and 22.8%, respectively) and increased in those taking placebo (40.3%, 34.9%, and 37.0%, respectively). Conclusions: Monthly oral ibandronate improves bone density and normalizes bone turnover in patients treated with anastrozole.

Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration

Patients with bone metastases from breast cancer often experience substantial skeletal complications – including debilitating bone pain – which negatively affect quality of life. Zoledronic acid (4 mg) has been demonstrated to reduce significantly the risk of skeletal complications in these patients and is administered via a short, 15-min infusion every 3 weeks, allowing the possibility for home administration. This study compared the efficacy and safety of zoledronic acid administered in the community setting vs the hospital setting in breast cancer patients with ⩾1 bone metastasis receiving hormonal therapy. After a lead-in phase of three infusions of 4 mg zoledronic acid in the hospital setting, 101 patients were randomized to receive three open-label infusions in the community or hospital setting, followed by three infusions in the opposite venue (a total of nine infusions). The Brief Pain Inventory (BPI) and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) were used to assess potential benefits of zoledronic acid therapy. At study end, analysis of the BPI showed significant reductions in worst pain (P=0.008) and average pain in the last 7 days (P=0.039), and interference with general activity (P=0.012). In each case, there were significantly greater improvements in pain scores after treatment in the community setting compared with the hospital crossover setting for worst pain (P=0.021), average pain (P=0.003), and interference with general activity (P=0.001). Overall global health status showed a significant median improvement of 8.3% (P=0.013) at study end. Physical, emotional, and social functioning also showed significant overall improvement (P=0.013, 0.005, and 0.043, respectively). Furthermore, physical, role, and social functioning showed significantly greater improvements after treatment in the community setting compared with the hospital crossover setting (P=0.018, 0.001, and 0.026, respectively). There was no difference between hospital and community administration in renal or other toxicity, with zoledronic acid being well tolerated in both treatment settings. These data confirm the safety and quality-of-life benefits of zoledronic acid in breast cancer patients with bone metastases, particularly when administered in the community setting.

Phase III Multicenter Clinical Trial of the Sialyl-TN (STn)-Keyhole Limpet Hemocyanin (KLH) Vaccine for Metastatic Breast Cancer

PURPOSE This double-blind, randomized, phase III clinical trial evaluated time to progression (TTP) and overall survival in women with metastatic breast cancer (MBC) who received sialyl-TN (STn) keyhole limpet hemocyanin (KLH) vaccine. Secondary endpoints included vaccine safety and immune response. EXPERIMENTAL DESIGN The study population consisted of 1,028 women with MBC across 126 centers who had previously received chemotherapy and had had either a complete or a partial response or no disease progression. All women received one-time i.v. cyclophosphamide (300 mg/m(2)) 3 days before s.c. injection of 100 μg STn-KLH plus adjuvant (treatment group) or 100 μg KLH plus adjuvant (control group) at weeks 0, 2, 5, and 9. Subsequently, STn-KLH without adjuvant or KLH without adjuvant was then administered monthly for 4 months, and then quarterly until disease progression, without cyclophosphamide. RESULTS STn-KLH vaccine was well tolerated; patients had mild to moderate injection-site reactions and reversible flu-like symptoms. Week-12 antibody testing revealed high specific IgG titers and a high rate of IgM-to-IgG seroconversion; the median IgG titers in STn-KLH recipients were 320 (anti-ovine submaxillary mucin) and 20,480 (anti-STn), with no detectable antimucin antibodies in the control group. The TTP was 3.4 months in the treatment group and 3.0 months in the control group. The median survival times were 23.1 months and 22.3 months, respectively. CONCLUSIONS Although STn-KLH was well tolerated in this largest to date metastatic breast cancer vaccine trial, no overall benefit in TTP or survival was observed. Lessons were learned for future vaccine study designs.

Estimating Cardiac Exposure From Breast Cancer Radiotherapy in Clinical Practice

PURPOSE To assess the value of maximum heart distance (MHD) in predicting the dose and biologically effective dose (BED) to the heart and the left anterior descending (LAD) coronary artery for left-tangential breast or chest wall irradiation. METHODS AND MATERIALS A total of 50 consecutive breast cancer patients given adjuvant left-tangential irradiation at a large U.K. radiotherapy center during 2006 were selected. For each patient, the following were derived using three-dimensional computed tomography (CT) planning: (1) mean dose and BED to the heart, (2) mean dose and BED to the LAD coronary artery, (3) MHD, (4) position of the CT slice showing the maximum area of the irradiated heart relative to the mid-plane slice, and (5) sternal and contralateral breast thickness (measures of body fat). RESULTS A strong linear correlation was found between the MHD and the mean heart dose. For every 1-cm increase in MHD, the mean heart dose increased by 2.9% on average (95% confidence interval 2.5-3.3). A strong linear-quadratic relationship was seen between the MHD and the mean heart BED. The mean LAD coronary artery dose and BED were also correlated with the MHD but the associations were weaker. These relationships were not affected by body fat. The mid-plane CT slice did not give a reliable assessment of cardiac irradiation. CONCLUSION The MHD is a reliable predictor of the mean heart dose and BED and gives an approximate estimate of the mean LAD coronary artery dose and BED. Doses predicted by the MHD could help assess the risk of radiation-induced cardiac toxicity where individual CT-based cardiac dosimetry is not possible.