Peter Canney

Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials

BackgroundWe conducted a systematic review and meta-analysis to clarify the risk of early and late cardiotoxicity of anthracycline agents in patients treated for breast or ovarian cancer, lymphoma, myeloma or sarcoma.MethodsRandomized controlled trials were sought using comprehensive searches of electronic databases in June 2008. Reference lists of retrieved articles were also scanned for additional articles. Outcomes investigated were early or late clinical and sub-clinical cardiotoxicity. Trial quality was assessed, and data were pooled through meta-analysis where appropriate.ResultsFifty-five published RCTs were included; the majority were on women with advanced breast cancer. A significantly greater risk of clinical cardiotoxicity was found with anthracycline compared with non-anthracycline regimens (OR 5.43 95% confidence interval: 2.34, 12.62), anthracycline versus mitoxantrone (OR 2.88 95% confidence interval: 1.29, 6.44), and bolus versus continuous anthracycline infusions (OR 4.13 95% confidence interval: 1.75, 9.72). Risk of clinical cardiotoxicity was significantly lower with epirubicin versus doxorubicin (OR 0.39 95% confidence interval: 0.20, 0.78), liposomal versus non-liposomal doxorubicin (OR 0.18 95% confidence interval: 0.08, 0.38) and with a concomitant cardioprotective agent (OR 0.21 95% confidence interval: 0.13, 0.33). No statistical heterogeneity was found for these pooled analyses. A similar pattern of results were found for subclinical cardiotoxicity; with risk significantly greater with anthracycline containing regimens and bolus administration; and significantly lower risk with epirubicin, liposomal doxorubicin versus doxorubicin but not epirubicin, and with concomitant use of a cardioprotective agent. Low to moderate statistical heterogeneity was found for two of the five pooled analyses, perhaps due to the different criteria used for reduction in Left Ventricular Ejection Fraction. Meta-analyses of any cardiotoxicity (clinical and subclinical) showed moderate to high statistical heterogeneity for four of five pooled analyses; criteria for any cardiotoxic event differed between studies. Nonetheless the pattern of results was similar to those for clinical or subclinical cardiotoxicity described above.ConclusionsEvidence is not sufficiently robust to support clear evidence-based recommendations on different anthracycline treatment regimens, or for routine use of cardiac protective agents or liposomal formulations. There is a need to improve cardiac monitoring in oncology trials.

Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring.

More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin®▾) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care.

Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial

Summary Background Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. Methods In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2 at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m2 at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m2 at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. Findings All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0·95, 95% CI 0·85–1·08; p=0·44). 75·6% (95% CI 73·7–77·5) of patients in the experimental group and 74·3% (72·3–76·2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0·0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272). Interpretation This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy. Funding Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche.

Early closure of a randomized trial: Surgery and postoperative radiotherapy versus radiotherapy in the management of intra-oral tumours

Tumours of the oral cavity/oropharynx occur relatively infrequently in the UK. The management of such lesions, especially the squamous cell carcinomas, is still a little controversial. Some centres advocate radiotherapy while others adopt surgery and radiotherapy. In an attempt to resolve the question of which approach gives the better results, a multicentre randomized trial was established to compare surgery plus postoperative radiotherapy with radical radiotherapy alone. It was anticipated that 350 patients would be required to give a statistically significant result, but, after 35 patients had been entered, the trial was closed prematurely with a marked difference in overall survival in favour of the combination arm (P = 0.0006). At this analysis, carried out 23 months after trial closure, the survival difference between the two arms remains statistically significant for all causes of mortality (P = 0.001; relative death rate = 0.24; 95% CI 0.10-0.59).

Comparing Breast Cancer Multiparameter Tests in the OPTIMA Prelim Trial: No Test Is More Equal Than the Others

BACKGROUND Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population. METHODS Three hundred thirteen women with early breast cancer were randomized to standard (chemotherapy and endocrine therapy) or test-directed (chemotherapy if Oncotype DX recurrence score >25) treatment. Risk stratification was also determined with Prosigna (PAM50), MammaPrint, MammaTyper, NexCourse Breast (IHC4-AQUA), and conventional IHC4 (IHC4). Subtype classification was provided by Blueprint, MammaTyper, and Prosigna. RESULTS Oncotype DX predicted a higher proportion of tumors as low risk (82.1%, 95% confidence interval [CI] = 77.8% to 86.4%) than were predicted low/intermediate risk using Prosigna (65.5%, 95% CI = 60.1% to 70.9%), IHC4 (72.0%, 95% CI = 66.5% to 77.5%), MammaPrint (61.4%, 95% CI = 55.9% to 66.9%), or NexCourse Breast (61.6%, 95% CI = 55.8% to 67.4%). Strikingly, the five tests showed only modest agreement when dichotomizing results between high vs low/intermediate risk. Only 119 (39.4%) tumors were classified uniformly as either low/intermediate risk or high risk, and 183 (60.6%) were assigned to different risk categories by different tests, although 94 (31.1%) showed agreement between four of five tests. All three subtype tests assigned 59.5% to 62.4% of tumors to luminal A subtype, but only 121 (40.1%) were classified as luminal A by all three tests and only 58 (19.2%) were uniformly assigned as nonluminal A. Discordant subtyping was observed in 123 (40.7%) tumors. CONCLUSIONS Existing evidence on the comparative prognostic information provided by different tests suggests that current multiparameter tests provide broadly equivalent risk information for the population of women with estrogen receptor (ER)-positive breast cancers. However, for the individual patient, tests may provide differing risk categorization and subtype information.

Hormonal therapy for postmenopausal breast cancer : the science of sequencing

SummaryOestrogens play important roles in the natural history of breast cancer. Consequently, therapies have been developed to reduce oestrogen levels or to block signalling through oestrogen receptors (ER). These therapies include tamoxifen, selective oestrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and selective oestrogen receptor downregulators (SERDs). All have proven clinical efficacy in postmenopausal women with ER-positive breast cancer and can be effective in the neoadjuvant and adjuvant settings, and in the management of advanced disease. This range of endocrine therapies offers the opportunity for prolonging benefit from treatment and delaying tumour recurrence/progression by combining the different classes of drugs or by using them sequentially. Evaluation of the potential clinical benefits of concomitant or sequential endocrine therapies should be based on considerations of efficacy and safety profiles, mechanisms of action/resistance and effects on tumour biology. Evidence from preclinical models and from randomized clinical trials in patients with postmenopausal breast cancer suggests that concomitant endocrine therapies are no more effective than AIs alone. However, using AIs either as initial therapy or sequentially after tamoxifen appears to produce more benefits beyond the use of tamoxifen alone.Currently, there are no proven algorithms for the planned, sequential use of the full range of endocrine therapies, particularly for the majority of patients who present with early breast cancer. Prospective, randomized clinical trials are needed to determine the best use of therapies in particular settings, taking into account the spectrum of molecular phenotypes in different tumours.

Cost-effectiveness of oral ibandronate compared with intravenous (i.v.) zoledronic acid or i.v. generic pamidronate in breast cancer patients with metastatic bone disease undergoing i.v. chemotherapy

BackgroundIbandronate is the first third-generation bisphosphonate to have both oral and intravenous (i.v.) efficacy. An incremental cost-effectiveness model compared oral ibandronate with i.v. zoledronic acid and i.v. generic pamidronate in female breast cancer patients with metastatic bone disease, undergoing i.v. chemotherapy.MethodsA global economic model was adapted to the UK National Health Service (NHS), with primary outcomes of direct healthcare costs and quality-adjusted life years (QALYs). Efficacy, measured as relative risk reduction of skeletal-related events (SREs), was obtained from clinical trials. Resource use data for i.v. bisphosphonates and the cost of managing SREs were obtained from published studies. Hospital management and SRE treatment costs were taken from unit cost databases. Monthly drug acquisition costs were obtained from the British National Formulary. Utility scores were applied to time with/without an SRE to adjust survival for quality of life. Model design and inputs were validated through expert UK clinician review.ResultsTotal cost, including drug acquisition, was £386 less per patient with oral ibandronate vs. i.v. zoledronic acid and £224 less vs. i.v. generic pamidronate. Oral ibandronate gained 0.019 and 0.02 QALYs vs. i.v. zoledronic acid and i.v. pamidronate, respectively, making it the economically dominant option. At a threshold of £30,000 per QALY, oral ibandronate was cost-effective vs. zoledronic acid in 85% of simulations and vs. pamidronate in 79%.ConclusionsOral ibandronate is a cost-effective treatment for metastatic bone disease from breast cancer due to reduced SREs, bone pain, and cost savings from avoidance of resource use commonly associated with bisphosphonate infusions.

Selecting breast cancer patients for chemotherapy: the opening of the UK OPTIMA trial.

The mortality from breast cancer has improved steadily over the past two decades, in part because of the increased use of more effective adjuvant therapies. Thousands of women are routinely treated with intensive chemotherapy, which can be unpleasant, is expensive and is occasionally hazardous. Oncologists have long known that some of these women may not need treatment, either because they have a low risk of relapse or because they have tumour biology that makes them less sensitive to chemotherapy and more suitable for early adjuvant endocrine therapy. There is an urgent need to improve patient selection so that chemotherapy is restricted to those patients who will benefit from it. Here we review the emerging technologies that are available for improving patient selection for chemotherapy. We describe the OPTIMA trial, which has just opened to recruitment in the UK, is the latest addition to trials in this area, and is the first to focus on the relative cost-effectiveness of alternate predictive assays.

Abstract S2-01: The PRIME II trial: Wide local excision and adjuvant hormonal therapy ± postoperative whole breast irradiation in women ≥ 65 years with early breast cancer managed by breast conservation

Background. Local Recurrence rates after breast conserving surgery (BCS) are falling because of increasing use of effective systemic therapy. The question of whether whole breast radiotherapy (WBRT) can be omitted in carefully defined groups of older patients receiving appropriate systemic therapy has not been addressed. PRIME II is an International phase III RCT addressing this question. Methods. Between April 2003 and December 2009, 1326 patients were randomised to receive (n = 658) or nor receive (n = 668) radiotherapy (RT). Eligiblity criteria were ≥65 years, T1-2 (up to 3cm), N0, M0, hormone receptor positive, clear excision margins (≥ 1mm), axillary node negative women in receipt of adjuvant hormone therapy. Patients could have Grade 3 tumours or lympho-vascular invasion but not both. An accrual of 1300 was planned to detect a difference based on estimates of local recurrence of 2% in RT group and 5% in no RT arm at 5 years, with 80% power and 5% significance. The primary endpoint was ipsilateral breast tumour recurrence (IBTR). Secondary endpoints were regional recurrence, contralateral breast cancer, distant metastases and overall survival (OS). Median follow up is 5.0 years. Results IBTR at 5 years was 4.1% (95% CI 2.4, 5.7%) without RT, 1.3% (95% CI 0.2, 2.3%) with RT. The hazard ratio for IBTR in those IBTR receiving radiotherapy was 4.34 (1.79, 10.55) (p = 0.001). Overall actuarial survival at 5 years was 93.8% (95% CI 91.6, 95.9%) without RT and 94.2% (95% CI 92.2, 96.3%) with RT, (p = 0.24). No significant differences in regional recurrence (1.4% no RT vs 0.5% RT), contralateral breast cancer (0.9% no RT vs 1.5% RT), nor distant metastases (1.0% vs 0.3%) were seen. Breast cancer-free survival was 94.6% (95% CI 92.7, 96.5%)for no RT and 97.3% (95% CI 95.9, 98.8%) for those receiving RT (p = 0.003): this difference was due to the greater IBTR in no RT group. The majority of deaths were not linked to breast cancer (35 no RT vs 29 RT from a total of 87 deaths), with no influence of omission of RT (p = 0.27). Conclusions The randomised International Trial has shown that • Omission of RT in women ≥65 year of age with N0, ER positive breast cancer receiving endocrine therapy results in only a 4.1% 5 year IBTR • Although RT reduces IBTR significantly, the absolute reduction in this study is very small. • RT does not reduce the rate of regional recurrence, distant metastases or affect overall survival. • Omission of postoperative WBRT in this population based on the 5 year rate of IBTR appears safe, especially in the presence of comorbidities. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S2-01.

Carboplatin and 5-fluorouracil in advanced and recurrent squamous carcinoma of the head and neck

Twenty-six patients with advanced squamous carcinoma of the head and neck or local recurrence after surgery and/or radiotherapy received carboplatin 300 mg/m2 intravenously on day 1 and 5-fluorouracil 1 gm/m2 by continuous intravenous infusion for 4 days. The treatment was well tolerated with little toxicity. The overall response rate was 58%.