Mark Verrill

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.

Phase I Clinical and Pharmacokinetic Study of Pemetrexed and Carboplatin in Patients With Malignant Pleural Mesothelioma

PURPOSE To determine the maximum tolerated dose (MTD) of pemetrexed and carboplatin given in combination, to derive a recommended dose for phase II studies, and to explore its efficacy. We assessed toxicities and explored the activity of the drug combination exclusively in patients with malignant pleural mesothelioma (MPM). The pharmacokinetics of both agents was investigated. PATIENTS AND METHODS Twenty-seven patients (23 male, four female) with MPM were treated on five escalating dose levels. Doses ranged from pemetrexed 400 mg/m(2) (as a 10-minute intravenous infusion), followed by carboplatin area under the plasma concentration-time curve (AUC) 4 mg/mL.min (as a 30-minute intravenous infusion) to pemetrexed 500 mg/m(2), carboplatin AUC 6 mg/mL.min. All patients had a World Health Organization performance status of 1. A total of 163 courses of treatment were administered (median, six; range, one to 10). RESULTS The main toxicity was hematologic, particularly neutropenia, although this was characteristically short-lived and caused few clinical problems. The MTD was pemetrexed 500 mg/m(2), carboplatin AUC 6, because three of the five patients treated at this dose level experienced a dose-limiting toxicity. Eight partial responses (in 25 assessable patients) were observed for a response rate of 32%. Seventy percent of patients noticed an improvement in symptoms, usually (84%) after only two courses. Median time to progression was 305 days, and median survival time was 451 days. CONCLUSION The MTD was pemetrexed 500 mg/m(2) and carboplatin AUC 6 mg/mL.min. The recommended phase II dose of the combination is pemetrexed 500 mg/m(2) and carboplatin AUC 5 mg/mL.min. The combination is both active and well tolerated in MPM and deserves further exploration.

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.

Phase II Genomics Study of Ixabepilone as Neoadjuvant Treatment for Breast Cancer

PURPOSE This phase II study evaluated the efficacy and safety of ixabepilone as neoadjuvant therapy for invasive breast cancer not amenable to breast conservation surgery. Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations. PATIENTS AND METHODS Patients with invasive breast cancer >or= 3 cm were eligible. Ixabepilone 40 mg/m(2) was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle for four or fewer cycles. RESULTS One hundred sixty-one patients were treated. The overall complete pathologic response (pCR) rate was 18% in breast and 29% in estrogen receptor (ER) -negative patients. Gene expression data were available for 134 patients. ER gene expression (ER1) was inversely related to pCR in breast and had a positive predictive value (PPV) of 37% and negative predictive value (NPV) of 92%. A 10-gene penalized logistic regression (PLR) model developed from 200 genes predictive of ixabepilone sensitivity in preclinical experiments included ER and tau and had higher PPV (45%) and comparable NPV (89%) to ER1. Grade 3 to 4 adverse events (AEs) were reported for 32% of patients. Except for neutropenia and leukopenia, all grade 3 to 4 AEs occurred in <or= 3% of patients. Reversible peripheral neuropathy was experienced by 3% of patients. CONCLUSION ER, microtubule-associated protein tau, and a 10-gene PLR model that included ER were identified as predictors of ixabepilone-induced pCR. RESULTS indicate an inverse relation between ER expression levels and ixabepilone sensitivity. Neoadjuvant ixabepilone demonstrated promising activity and a manageable safety profile in patients with invasive breast tumors.

Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk

Anthracyclines are considered to be among the most active agents for the treatment of breast cancer. However, their use is limited by cumulative, dose-related cardiotoxicity. Such cardiotoxicity results in a permanent loss of cardiac myocytes and a progressive reduction in cardiac function following each subsequent dose of anthracycline. Initially, damage to the heart is subclinical; however, increasingly impaired cardiac function can result in cardiovascular symptoms, with serious cardiac injury resulting in chronic heart failure. Since the early detection and treatment of cardiotoxicity can reduce its clinical effects, it is important that oncologists are aware of these adverse effects and manage them appropriately. This review examines the risk factors for anthracycline-associated cardiotoxicity and offers recommendations on strategies to reduce the cardiotoxicity of anthracyclines in the management of patients with advanced breast cancer.

Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide

Background:Doxorubicin and cyclophosphamide (AC) therapy is an effective treatment for early-stage breast cancer. Doxorubicin is a substrate for ABCB1 and SLC22A16 transporters. Cyclophosphamide is a prodrug that requires oxidation to 4-hydroxycyclophosphamide, which yields a cytotoxic alkylating agent. The initial oxidation is catalysed by cytochrome P450 enzymes including CYP2B6, CYP2C9, CYP2C19 and CYP3A5. Polymorphic variants of the genes coding for these enzymes and transporters have been identified, which may influence the systemic pharmacology of the two drugs. It is not known whether this genetic variation has an impact on the efficacy or toxicity of AC therapy.Methods:Germ line DNA samples from 230 patients with breast cancer on AC therapy were genotyped for the following SNPs: ABCB1 C1236T, G2677T/A and C3435T, SLC22A16 A146G, T312C, T755C and T1226C, CYP2B6*2, *8, *9, *3, *4 and *5, CYP2C9*2 and *3, CYP3A5*3 and CYP2C19*2. Clinical data on survival, toxicity, demographics and pathology were collated.Results:A lower incidence of dose delay, indicative of less toxicity, was seen in carriers of the SLC22A16 A146G, T312C, T755C variants. In contrast, a higher incidence of dose delay was seen in carriers of the SLC22A16 1226C, CYP2B6*2 and CYP2B6*5 alleles. The ABCB1 2677A, CYP2B6*2, CYP 2B6*8, CYP 2B6*9, CYP 2B6*4 alleles were associated with a worse outcome.Conclusion:Variant alleles in the ABCB1, SLC22A16 and CYP2B6 genes are associated with response to AC therapy in the treatment of breast cancer.

A Phase I and Pharmacokinetic Study of Paclitaxel Poliglumex (XYOTAX), Investigating Both 3-Weekly and 2-Weekly Schedules

Purpose: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. Experimental Design: Nineteen patients were investigated on the 3-weekly phase Ia study and 11 patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. Results: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m2 (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m2. Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m2. Pharmacokinetic investigations indicated a prolonged half-life of >100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m2 in phase Ia and one in a patient with gastric carcinoma at 175 mg/m2 in phase Ib. Conclusion: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.

Neuropsychological functioning following systemic treatment in women treated for breast cancer: a review

The aim of this review was to evaluate the effect of treatment and illness-related factors on neuropsychological functioning in women treated for breast cancer. Eight studies were identified examining neuropsychological test performance following systemic treatment. Six of the eight studies suggest that neuropsychological functioning may be impaired following treatment. However, there are a number of important methodological issues which limit interpretation of these results. Therefore, it is unclear whether neuropsychological outcome differs according to a range of treatment, biomedical and psychological factors. Larger samples with longitudinal follow-up are required in order to examine the treatment-related factors that best predict cognitive deficits.

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.