Use Of Anthracyclines Research Articles

First Analysis of a Phase II Study of Rituximab-Gemcitabine, Cyclophosphamide, Vincristine and Prednisolone (R-GCVP) for Diffuse Large B Cell Lymphoma (DLBCL) Patients Considered Unsuitable for Anthracycline Containing Chemo-Immunotherapy. An NCRI Lymphoma Clinical Studies Group Trial

Abstract 1634▪FN2▪This icon denotes a clinically relevant abstract Introduction:The treatment of patients with DLBCL who are unsuitable for anthracycline containing chemotherapy remains a clinical challenge. Gemcitabine is a nucleoside analogue which has proven efficacy in the relapse setting in both non Hodgkin's and Hodgkin's lymphoma. We therefore developed a protocol incorporating Gemcitabine in a first line approach combined with CVP-R chemo-immunotherapy in DLBCL patients considered unfit for anthracycline containing chemotherapy. Methods:We performed a prospective, multicentre phase II trial in patients with DLCBL who were considered unfit for anthracycline containing chemo-immunotherapy. Eligibility criteria included ejection fraction < 50%, or ejection fraction ≥ 50% but with the presence of attendant significant co-morbidities (including: ischaemic heart disease, hypertension, diabetes mellitus), and ECOG PS 0–3. Patients received 6 cycles of Rituximab (375 mg/m2 IV D1), Cyclophosphamide (750mg/m2 IV D1), Vincristine (1.4 mg /m2 IV D1), Prednisolone (100mg, orally D1–5) and Gemcitabine IV D1 and D8. The Gemcitabine dose, if tolerated was sequentially escalated from 750mg/m2 in cycle 1 to 875mg/m2 in cycle 2 to 1000mg/m2 in cycle 3 with the dose maintained at 1000mg/m2 for cycles 4–6. Cycles were repeated every 21 days with growth factor support administered on day 9 of each cycle (pegfilgrastrim 6mg s/c).The primary endpoint was to achieve an overall response rate of > 40% assessed by CT scan at the end of treatment according to the Cheson criteria. Secondary endpoints were progression free survival and overall survival. Results:62 patients were recruited from 32 UK sites over a 28 month period from April 2008 to July 2010. 66% were male. Median age was 76 years (range 52–90), 48 (77%) were > 70 years. 43 (69%) had stage III/IV disease and 46 (72%) had high – intermediate or high IPI (3–5) disease. ECOG performance status was ≥ 2 in 50% patients. Left ventricular ejection fraction (LVEF) was < 50% in 28 patients (45%). The 34 patients with LVEF ≥ 50% had significant co-morbidities, 22 (65%) had multiple co-morbidities. 44 (70%) received ≥ 3 cycles of treatment, reasons for early termination of treatment in the remaining 18 patients were progression (n=2), toxicity (n=5), death (n=6) patient choice (n=1) and other (n=4). 29 patients (47%) received the full 6 cycles. A total of 250 treatment cycles were delivered. Of the 44 patients who received ≥ 3 cycles of treatment, the dose of Gemcitabine was escalated to the full dose (1000mg/m2) in 67%. Day 8 Gemcitabine was delivered in 215/250 (86%) cycles of treatment. The overall response rate (CR/CRu/PR) at end of treatment for all 62 patients was 60%. For patients who received ≥ 3 cycles of treatment (n =44) the ORR was 79.5% at the end of treatment. There was no significant difference in ORR between those with LVEF <50% and those with LVEF ≥ 50% (71% vs 53%, p=0.155). At a median follow up of 18.2 months the 1 year progression free survival rate for all patients was 52.9% (95% CI 39.4–64.8). The 1 year overall survival (OS) rate is 62.4% (95% CI 48.5–73.6). For the group with LVEF <50% OS was 70.8% (95% CI: 48.4, 84.9) and LVEF group ≥ 50% OS was 55.9% (95% CI 37.1–71).Grade 3/4 haematological toxicity was observed in 54.1% patients. Grade 3/4 infection was observed in 24.6% of patients. The death rate observed related to infection for the whole cohort was 11%. Conclusion:This multicentre trial demonstrates that the R-GCVP regimen delivers excellent overall response rates with durable remissions in a group of patients where anthracycline use was precluded. The efficacy attained in this difficult group of patients provides a platform for testing the regimen in subsequent randomised phase II and phase III studies to confirm its efficacy. Disclosures:No relevant conflicts of interest to declare.

Therapy-Related Myelodysplasia/Acute Myeloid Leukemia (t-MDS/AML) After Conventionally-Treated Breast Cancer: Impact of Cytogenetics on Outcome After Allogeneic Hematopoietic Cell Transplantation (HCT),

Abstract 4149 Background: The outcome of early stage breast cancer has improved in recent years with use of effective combination chemotherapy, including cyclophosphamide, anthracyclines or taxanes. Patients who undergo lumpectomy also receive radiation therapy for locoregional control. t-MDS/AML are rare but serious consequences of these therapeutic exposures; historically with an overall poor prognosis. Translocations involving the mixed-lineage leukemia (MLL) gene on chromosome band 11q23, and core binding factor genes on 21q22 and 16q22, are hallmarks of t-MDS/AML resulting from treatment with topoisomerase II inhibitors (anthracyclines). Loss of part or whole of chromosomes 5 and/or 7 (5-/7- abnormality) are associated with t-MDS/AML after treatment with alkylating agents and radiation. Allogeneic HCT (sibling-related, unrelated or double-cord) offers the only curative option for some of these patients. However, the long-term outcome of post-breast cancer t-MDS/AML after allogeneic HCT has not been described, and subgroups with better or worse prognosis not identified. Methods: From 1997 to 2011, 28 patients with t-MDS/AML after treatment of breast cancer with conventional chemotherapy and/or radiation underwent allogeneic HCT at City of Hope. Overall survival defined from the time of allogeneic HCT to the last date of follow up or date of death, was estimated using Kaplan-Meier method. Cox regression techniques were utilized to understand predictors of overall survival. Results: Of the 28 patients, 16 had been treated for early-stage breast cancer (I/IIA), 11 had received treatment for locally advanced disease (IIB/ III) and 1 patient had metastatic disease. Twenty-five patients received combination chemotherapy as adjuvant therapy or for metastatic disease; this included cyclophosphamide (100%), doxorubicin (88%) and taxanes (52%). Details of chemotherapy are unknown for one patient. Twenty-one patients (75%) also received radiation (2 received radiation alone). Median age at time of diagnosis of t-MDS/AML was 56 years (range: 34–79); median time from diagnosis of breast cancer to diagnosis of t-MDS/AML was 2.4 years (range 1–12.3); median time from t-MDS/AML to allogeneic HCT was 0.55 year (range: 0.15–4.1). Ten patients presented with MDS and 18 with AML. Cytogenetic abnormalities included MLL - 11q23 abnormality (n=12), 5-/7- and/or complex abnormalities (n=9), t(15;17)(q22;q21.1) (n=1), t(8;21) (n=1), inv(16)(p13.1;q22) (n=2). Of the 28 patients, 27 were treated with induction therapy and 74% were in complete remission (CR) at the time of HCT. Fourteen patients (50%) received sibling-related HCT, 13 received matched unrelated donor (MUD) transplant and 1 received a double cord transplant. Two patients received second allogeneic HCT and one patient received donor lymphocyte infusion (DLI) for relapsed t-MDS/AML. Sixty-one percent received reduced-intensity conditioning with fludarabine/melphalan and others received full-intensity conditioning. Sixteen patients developed cGvHD after transplant. After a median follow up of 2.2 years, 8 patients had died (cause of death: t-MDS/AML [n=5], sepsis [n=1], GvHD [n=1], breast cancer [n=1]), with an overall survival of 78.2% at two years post-HCT for the entire cohort. The 2-year overall survival was 71.4% for sibling-related HCT and 84.4% for MUD (log-rank p=0.14). There was a difference in overall survival by the type of cytogenetic abnormalities. Thus, the 2-year survival rate for patients with 11q23 abnormality was 90.9% while that for patients with chromosome 5-/7- abnormalities or complex abnormalities was 62.5% (log rank p=0.27). Patients with cGvHD had better outcome compared with those without cGvHD (2 year survival 87.5% vs. 64.3%, log-rank p value=0.03). These findings were confirmed on multivariate regression analysis, which revealed chromosome 5-/7- or complex abnormalities to be associated with a significantly worse outcome (HR=6.9, p=0.035), while cGvHD was associated with a better outcome (HR=0.14, p=0.02) after adjustment for age at HCT. Conclusions: Although t-MDS/AML after conventional treatment of breast cancer has historically been shown to have a poor prognosis, allogeneic HCT in patients with available donors provides a chance of cure. Among patients undergoing allogeneic HCT, a superior outcome was observed in patients with 11q23 abnormalities and among those with cGvHD. Disclosures: No relevant conflicts of interest to declare.

Abstract C211: Dexrazoxane for the targeted prevention of anthracycline-induced cardiotoxicity (ACT) in the age of predictive biomarkers and pharmacogenomics.

Abstract Anthracycline-induced cardiotoxicity (ACT) is a life-threatening adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Clinical risk factors combined with specific biomarkers and predictive genetic risk profiling now offer novel avenues for high-risk patients who may benefit from preventive use of the cardioprotective agent dexrazoxane. The recent identifications of high sensitivity troponin assays and genetic variants associated with ACT (Herman et al; Lipshultz et al; Wojnowski et al.; Visscher et al.) accurately predict ACT before the myocardial damage has been done. In view of the published safety profile of dexrazoxane in long-term pediatric and adult prospective randomized trials (Lipshultz et al 2010/11; Cochrane reviews 2011) anthracycline-induced cardiotoxicity prevention with dexrazoxane should now be initiated with the first dose of doxorubicin or its analogues given rather than after the irreversible myocardial damage has already been done at the widely accepted cumulative dose of doxorubicin. A biomarker driven ‘targeted’ use of dexrazoxane in preselected high risk ACT-prone patients may lead to safer treatment options for the cost-effective anthracycline-containing chemotherapy schedules in children and adult cancer patietns with or without compromised hearts. This new preventive strategy should now be tested in randomised prospective clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C211.

Anthracycline dose intensification in young adults with acute myeloid leukemia

The initial treatment for acute myeloid leukemia (AML) has remained largely unchanged for nearly 40 years. Our growing understanding of the molecular pathology of AML has resulted in improved measures to risk stratify patients by recurrent cytogenetic and molecular abnormalities without marked advancement in its initial treatment. The most common regimen consists of a 3-day course of an anthracycline and a 7-day infusion of cytarabine. This regimen has been employed across the globe in various iterations for many years with modest improvements in results yet this remains the first choice for the treatment of younger adults with AML. Despite this, the chemotherapeutic agents in this regimen are only now being fully understood. Recent evidence has suggested that dose intensification of anthracycline in young adults has a significant survival benefit. In this paper we review the evidence behind the use of anthracyclines in the initial induction of AML in younger adults focusing on the choice and dose of this long used drug combination.

Moving forward with new data and approaches: a fresh look at anthracyclines in non-Hodgkin's lymphoma.

Anthracyclines have a central role in the management of non-Hodgkin's lymphoma (NHL). The cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment regimen has been the standard of care for more than 20 years. Further improvements have been made to the efficacy of this chemotherapy by reducing the dosing interval and adding rituximab to the regimen. A major limitation to the use of anthracyclines is the development of cardiotoxicity as a late adverse event. Strategies to reduce cardiac events include changes to the dosing schedule for doxorubicin, use of the chelating agent dexrazoxane and the use of liposome-encapsulated doxorubicin. This latter strategy has demonstrated good efficacy and reduced cardiotoxicity in patients with NHL, including those at risk of developing cardiac effects.

SIOG (International Society of Geriatric Oncology) Recommendations for Anthracycline Use in the Elderly

A taskforce of the International Society of Geriatric Oncology (SIOG) has recently submitted recommendations on the use of anthracyclines in elderly patients. Despite the aging of the population and the high proportion of elderly individuals in the population of patients with non-Hodgkin's lymphoma, the development of specialist expertise in the treatment of elderly patients with cancer is relatively recent. Treatment of the elderly is complex because they are a highly heterogeneous population, with large variations in health status, comorbidities and life expectancy. In addition, these patients are generally more susceptible than young patients to the cardiotoxic effects of anthracyclines. Strategies for assessing elderly patients with cancer, reducing the risk of congestive heart failure, and assessing the cardiotoxic effects of treatments are discussed. In addition, a summary of the SIOG recommendations is presented.

SIOG (International Society of Geriatric Oncology) and anthracycline use in the elderly

The management of cancer in elderly patients is a complex area that requires specialist expertise. Historically, elderly patients have been under-represented in clinical trials, though this situation is improving, and hence there is a lack of evidence on which to base authoritative guidelines. A comprehensive geriatric assessment can be useful in assessing the patient's overall health status and life expectancy, and hence in guiding treatment decisions. Elderly patients who are fit, or who have medical problems that are amenable to treatment, should receive the same care as younger patients, whereas unfit or frail patients may require interventions tailored to geriatric patients, such as non-aggressive treatment and that age per se should not be a contraindication to such treatment in an otherwise healthy elderly patient. However, anthracycline-related cardiotoxicity is a particular concern in elderly patients because this group is more susceptible to the cardiotoxic effects of anthracyclines than younger patients, and hence heart failure may develop at lower cumulative doses. A recent expert opinion on anthracycline use in elderly patients, published by the International Society of Geriatric Oncology (SIOG), recommends screening to identify patients at high risk of cardiotoxicity, the use of agents with a low cardiotoxicity risk, such as liposomal doxorubicin formulations, and regular monitoring of cardiac function during treatment.

Introduction

Since their introduction in the 1960s, anthracyclines such as doxorubicin have attained a central place in the management of a number of solid tumours and haematological malignancies. Anthracycline-based regimens constitute a standard of care in patients with metastatic breast cancer; anthracycline monotherapy compares favourably with taxanes alone, while combinations of anthracyclines and taxanes have been shown to be superior to anthracycline-based regimens in terms of response rates and progression-free survival. Similarly, in patients with early breast cancer, adjuvant therapy with anthracycline-based regimens significantly reduces breast cancer mortality, compared with cyclophosphamide-methotrexate-fluorouracil regimens. However, a major limitation to the use of anthracyclines is cumulative cardiotoxicity, which can result in irreversible congestive heart failure. A number of strategies to reduce cardiotoxicity have been investigated, including modification of the dosing regimen, use of cardioprotective agents, and the development of liposomal doxorubicin formulations. The central place of anthracyclines in breast cancer management is likely to continue: the challenge now is to identify those patients most likely to respond to, and benefit from, anthracyclinebased therapy.

Renal tumours: long-term outcome

Childhood cancer is rare, with an incidence of 100 new cases per million children and with renal tumours contributing 7% of cases. The introduction of multimodality treatment, surgery, radiotherapy and chemotherapy, has led to an exponential increase in the 5-year survival rate to >80%. However, this successful treatment has led to the development of late adverse effects. These treatment-related effects can cause premature deaths and increased morbidity compared with patients’ peers. Radiation causes damage to tissue and organs within the radiation field, affecting growth and function, and is largely responsible for the leading cause of death, namely, second malignant neoplasms. Another important late effect is cardiac dysfunction due to anthracycline use with or without cardiac radiation. In addition, a few patients have genetic abnormalities predisposing to Wilms tumour development, which result in renal dysfunction in the long term and may be exacerbated by cancer treatment regimens. Awareness of late consequences of cancer treatment is important, as early recognition can improve outcome. When presented with a patient with a history of renal tumours, it is vital to enquire about previous treatment to understand whether it is relevant to the presenting problem.

Pathologic response rate (pCR) and near-pathologic response rate (near-pCR) with docetaxel-carboplatin (TCarb) in early triple-negative breast cancer.

277 Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis unless a pathological complete response is achieved (Liedtke C et al. 2008: J Clin Oncol 26:1275-1281) or almost achieved (Symmans WF. 2007: J Clin Oncol 25:4414-4422). Sensitivity to platin compounds has been demonstrated in BRCA1-positive settings (Byrski T et al. 2010: J Clin Oncol 20:28:375-9; Silver DP. 2010: J Clin Oncol 28:1145-1153) with only limited numbers of patients (Byrski T et al. 2010: J Clin Oncol 20:28:375-9) or in sporadic breast cancer with heterogeneous cohorts (Sikov WM et al 2009: J Clin Oncol 27:4693-4700; Chang HR et al. 2010: Cancer 15; 116:4227-4237). Methods: This pivotal trial was to assess the efficacy of platinum and taxane-based combination therapy without the use of anthracyclines. 27 patients with primary TNBC (majority of them cT2, two cT3 and one cT4a) had to be unsuitable for standard anthracycline-based chemotherapy. They received 6 cycles, respectively in two cases only 5 cycles, of carboplatin AUC 6 and docetaxel 75 mg/m2 q3w. The primary endpoint was the pCR-rate, secondary endpoint toxicity. Results: 20 out of 27 (74%) patients had pathological complete response (52%) or near-complete response (22%)—ypT1mic and ypT1a—both being associated with a good prognosis. Seven remaining patients had still good partial response, leaving only low residual cancer burden, which was defined as ypT1. Treatment was well-tolerated: grade III and IV toxicities were neutropenia, thrombopenia, oedema, nausea, joint pain, nail changes, fatigue, hypertension, and alopecia. Conclusions: These results show a high efficacy of carboplatin AUC6 and docetaxel 75 mg/m2 q3w and good feasibility as primary chemotherapy for TNBC with a pCR- and near-pCR-rate of 74% and total response rate of 100%. The incorporation of anthracyclines and parp-inhibitors into further trial designs could enhance the efficacy of these compounds. The omission of exposure to anthracyclines in patients with considerable heart disease risks seems to be feasible with a good pCR-rate, the latter being a surrogate-marker for long-term survival.

HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data

Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer. We did a meta-analysis of individual patient data from five randomised adjuvant trials that compared anthracycline-based regimens with cyclophosphamide, methotrexate, and fluorouracil (CMF) regimens. We assessed the status of HER2 and TOP2A genes with fluorescent in-situ hybridisation. Tumour samples were submitted to an external laboratory for validation. We calculated hazard ratios (HR) to compare event-free survival (EFS) and overall survival in patients receiving anthracycline-based treatment with those receiving CMF in two HER2 cohorts (HER2 amplified and non-amplified tumours) and in three TOP2A cohorts (normal, amplified, and deleted tumours). We analysed data for 3452 patients for HER2 and 3102 patients for TOP2A. For EFS, HRs were 0·89 (95% CI 0·79-1·01) for HER2 non-amplified patients and 0·71 (0·58-0·86) for HER2-amplified patients (p(interaction)=0·0485); for overall survival, HRs were 0·91 (95% CI 0·79-1·05) for HER2 non-amplified patients and 0·73 (0·59-0·89) for HER2-amplified patients (p(interaction)=0·0718). In analysis of TOP2A status, HRs for EFS were 0·88 (0·78-1·00) for normal, 0·63 (0·46-0·87) for deleted, and 0·62 (0·43-0·90) for amplified (p(interaction)=0·0513); HRs for overall survival were 0·89 (0·78-1·03) for normal, 0·68 (0·49-0·95) for deleted, and 0·67 (0·46-0·98) for amplified (p(interaction)=0·1608). When patients with TOP2A-deleted and TOP2A-amplified tumours were grouped together (altered cohort) and compared with data from patients with normal TOP2A tumours, HRs for EFS were 0·64 (0·50-0·81) for altered and 0·88 (0·78-1·00) for normal (p(interaction)=0·0183); HRs for overall survival were 0·67 (0·52-0·86) for altered and 0·89 (0·78-1·03) for normal (p(interaction)=0·0455). Although HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2-amplified or TOP2A-aberrated tumours. Associazione Italiana Ricerca Cancro, Academy of Finland, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Scottish Breast Cancer Trials Group, NCIC Clinical Trials Group, Canadian Cancer Society Research Institute, Danish Council for Strategic Research, Pharmacia-Upjohn (now Pfizer), and Abbott Laboratories.

Anthracyclines, HER2, and TOP2A: the verdict

Should we restrict the use of anthracyclines in the adjuvant treatment of early breast cancer to patients with HER2-positive or TOP2A-amplified tumours? This question—which has been debated for a long time—is crucial for daily clinical practice because anthracyclines are one of the most active drugs in the treatment of breast cancer despite their related rare, but severe, late toxicities such as cardiotoxicity and secondary leukaemia. As far as HER2 is concerned, in 2008 the results of two meta-analyses 1 Gennari A Sormani MP Pronzato P et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst. 2008; 100: 14-20 Crossref PubMed Scopus (325) Google Scholar , 2 Dhesy-Thind B Pritchard KI Messersmith H et al. HER2/neu in systemic therapy for women with breast cancer: a systematic review. Breast Cancer Res Treat. 2008; 109: 209-229 Crossref PubMed Scopus (76) Google Scholar suggested that the question might be answered and that only patients with HER2-positive tumours benefited from anthracyclines, but contradictory results were published the same year, 3 Bartlett JM Munro A Cameron DA et al. Type 1 receptor tyrosine kinase profiles identify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial. J Clin Oncol. 2008; 26: 5027-5035 Crossref PubMed Scopus (87) Google Scholar refuelling the debate. Regarding the predictive value of TOP2A, reported data are even more confusing. 4 O'Malley FP Chia S Tu D et al. Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst. 2009; 101: 644-650 Crossref PubMed Scopus (170) Google Scholar The good news is that the debate is now closed thanks to the excellent study published by Angelo Di Leo and colleagues 5 Di Leo A Desmedt C Bartlett JMS et al. HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data. Lancet Oncol. 2011; (published online Sept 13.)https://doi.org/10.1016/S1470-2045(11)70231-5 Summary Full Text Full Text PDF PubMed Scopus (159) Google Scholar in The Lancet Oncology. The bad news is that the results of this meta-analysis are negative and that, after more than 15 years of research, we still have no predictive markers of anthracycline sensitivity available for daily practice. HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient dataAlthough HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2-amplified or TOP2A-aberrated tumours. Full-Text PDF Open Access

Pharmacogenomic Prediction of Anthracycline-Induced Cardiotoxicity in Children

Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants associated with ACT in patients treated for childhood cancer. We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands. We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10(-5) for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate-binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT. We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer—results at the time of surgery

BackgroundPreoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer. Strategies to improve efficacy include the use of anthracyclines, taxanes, and intensified dose with bone marrow support. Patients and methodsPatients received neoadjuvant epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 followed by paclitaxel 175 mg/m2 (EC→T), each 3-weekly for four cycles (n=370), or epirubicin 150 mg/m2 followed by paclitaxel 225 mg/m2 with pegfilgrastim followed by CMF (cyclophosphamide 500 mg/m2, methotrexate 40 mg/m2, fluorouracil 600 mg/m2) on days 1 and 8 (Edd→Tdd→CMF), each 2-weekly and for three cycles (n=363). Patients were randomly allocated to either simultaneous darbepoetin alfa (DA) (n=356) or none (n=377). ResultsPathological complete response (pCR) rate (breast) was higher with Edd→Tdd→CMF, 18.7% versus 13.2% with EC→T; P=0.043, ypT0/Tis; ypN0 was reported in 20.9% versus 14.3% respectively; P=0.019. Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate. Mean hemoglobin values maintained higher with DA (13.6 versus 12.6 g/dl). Edd→Tdd→CMF regimen showed more grade 3–4 mucositis, sensory neuropathy, and neurological complaints. Thromboembolic events were more frequent on DA (3% versus 6%; P=0.055). ConclusionDose-dense and -intensified neoadjuvant chemotherapy with Edd→Tdd→CMF was potentially superior to EC→T in terms of pCR. Primary use of DA did not affect pCR.

Adjuvant Endocrine Therapy for Breast Cancer: Don't Ditch the Switch!

The meta-analysis has been an invaluable tool in the evaluation of adjuvant therapy for breast cancer and has supported the use of tamoxifen, anthracyclines, and taxanes via the compilation of results from small trials that individually yielded less than dramatic results. Indeed, recent results of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis demonstrated the enduring benefit in 15-year recurrence-free and overall survival for 5 years of adjuvant tamoxifen for women of any age with earlystage steroid receptor–positive breast cancer (1). It also confirmed an age-related increase in the risks of thromboembolic events and endometrial cancer without an excess in non-breast cancer–related deaths. In recent years, the use of tamoxifen in postmenopausal women has been eclipsed by enthusiasm about aromatase inhibitors. Multiple studies have documented a greater reduction in breast cancer recurrence and a seemingly more favorable toxicity profile with aromatase inhibitors compared with tamoxifen, which has led to their widespread use over tamoxifen, despite the fact that an overall survival benefit with this approach has not been observed. These results have led to guidelines by entities such as the American Society of Clinical Oncology (2) and the National Comprehensive Cancer Network (3) stating that aromatase inhibitors should be considered in place of or in sequence with tamoxifen for most postmenopausal women with early-stage hormone receptor–positive breast cancer. The emergence of data from large trials of adjuvant aromatase inhibitors has enabled several meta-analyses to be performed, one of which is reported by Amir et al. (4) in this issue of the Journal. The authors hypothesized that the relative toxicity of aromatase inhibitors compared with tamoxifen could explain the discordant observation of their improved benefit in disease-free survival without enhanced overall survival benefit. Their meta-analysis was restricted to seven randomized controlled trials that enrolled 30 0 23 patients and compared 5 years of aromatase inhibitor, 5 years of tamoxifen, or a switch from one to the other as primary endocrine therapy. In addition to conventional breast cancer endpoints, they focused on six prespecified serious adverse events —cardiovascular disease, cerebrovascular disease, bone fracture, thromboembolic events, endometrial carcinoma, and other non-breast cancers. In large part, the analysis confirmed what we already know: Compared with tamoxifen, the use of aromatase inhibitors was associated with a statistically significant increase in bone fractures and decrease in endometrial cancer and thromboembolic events and no difference in the risks of second cancers. What we learned, however, was that there was no difference in the risk of cerebrovascular disease with tamoxifen compared with aromatase inhibitors, and the risk of cardiovascular disease was statistically significantly higher with aro matase inhibitors compared with tamoxifen, although the magnitude of the difference was small—an absolute difference in risk of 0.8% and a number needed to harm of 132. It is notable that use of up-front aromatase inhibitors was also associated with a nonstatistically significantly higher odds of death without breast cancer recurrence compared with the use of tamoxifen alone or switching from tamoxifen to aromatase inhibitors (odds ratio = 1.11, 95% confidence interval = 0.98 to 1.26, P = .09). Of particular interest was the finding that those treated with a switching strategy had a statistically significant reduction in the odds of death without breast cancer recurrence compared with those treated with 5 years of tamoxifen or 5 years of an aromatase inhibitor alone (odds ratio = 0.87, 95% 95% confidence interval = 0.77 to 0.99, P = .03). In absolute terms, the difference is exceedingly small—a 0.2% difference in absolute risk of death without breast cancer recurrence. From these findings, Amir et al. ( 4) concluded that the switching strategy allows patients to reap the positive benefits of the aromatase inhibitors while limiting potential toxicity.

Chemotherapy Definitions and Policies for Thymic Malignancies

Thymic malignancies are rare epithelial tumors that may be aggressive and difficult to treat.1 Thymomas are usually localized to the anterior mediastinum and are frequently eligible for upfront surgical resection, which is the mainstay of the curative-intent treatment.1 However, approximately 30% of patients present with an advanced tumor at the time of diagnosis, with invasion of neighboring organs, dissemination to the pleura, the pericardium, or less frequently extrathoracic organs. In such cases, chemotherapy has been used both to reduce the tumor burden—possibly allowing subsequent surgery or radiotherapy—and to achieve prolonged disease control. Recurrence after resection may be similarly treated with chemotherapy. Thymic carcinomas, although rare, are usually already advanced at the time of presentation, and systemic therapy is important for almost all of these patients. Knowledge regarding chemotherapy for thymic tumors has mainly been based on retrospective series,2–9 although several prospective trials have also been conducted.10–21 These studies have clearly demonstrated the chemosensitivity of thymoma, and to a lesser extent thymic carcinoma, to various cytotoxic agents and combinations. However, details of patient selection are often lacking (either disease extent or general condition), and the intent of the treatment sequence is often vague. Adoption of a common language and definition of terms is crucial for the International Thymic Malignancies Interest Group (ITMIG) effort to develop a international prospective database of thymic tumors. The article by Huang et al.22 provides definitions for survival and endpoints for recurrences assessment and discusses how to measure response to treatment. Herein, we discuss additional points with regard to chemotherapy, including treatment sequence, general modalities, and impact of corticosteroids.

Does Topoisomerase II–Alpha Gene Amplification Provide Useful Information for Treatment Selection in Patients With Breast Carcinoma?

TO THE EDITOR: Press et al 1 concluded that “TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy.” I do not believe that this conclusion is justified on the basis of the data they examined. To evaluate whether a marker is predictive for benefit from a drug, one should compare (either prospectively or by using archived specimens from a previous trial) outcomes for patients who were randomly assigned to receive a regimen containing the drug or the same regimen not containing the drug, and one should examine how this treatment effect (ie, hazard ratio) depends on marker status. 2 The studies Press et al 1 examined did not permit such an evaluation. The closest one could come to a direct analysis of whether TOP2A amplification is a predictive marker of anthracycline effectiveness was an analysis that Press et al did not comment on. In trial BCIRG-006 of the Breast Cancer International Research Group, patients with HER2amplified tumors were randomized to receive ACT (doxorubicin, cyclophosphamide, docetaxel), ACTH (ACT plus trastuzumab), or TCH (docetaxel, carboplatin, trastuzumab). A comparison of the ACTH regimen with the TCH regimen isolates the value of the anthracycline relative to carboplatin with both in the presence of trastuzumab. In Figure 3 of the article by Press et al, 1 outcomes for these two regimens seem equivalent both forTOP2A-amplified and forTOP2Aunamplified tumors. In the patients with amplified tumors, there were 35 events on treatment with ACTH compared with 42 events on treatment with TCH; in the patients with unamplified tumors, there were 87 events on ACTH compared with 92 on TCH. Consequently, on the basis of the only relevant direct randomized comparison of anthracycline use available in the authors’ data, there is no evidence that the efficacy of the anthracycline depends on TOP2A status. The authors base their conclusions on indirect evidence. In both the BCIRG-006 adjuvant study and the H0648g, the original trastuzumab metastatic disease licensing study, the investigators compared an anthracycline regimen not containing trastuzumab with the same anthracycline regimen administered with trastuzumab. They noted that trastuzumab did not seem to improve outcome in the small subset of patients with amplifiedTOP2A but that it did improve outcome for patients without TOP2A amplifications. The significant interaction in Table 3 is for the incremental effect of trastuzumab, not as stated for the incremental effect of anthracycline. They interpret this variation in trastuzumab treatment effect as indicating that the anthracycline is more effective in patients withTOP2A amplifications. The fact that trastuzumab is ineffective in patients with TOP2A amplifications receiving an anthracycline-based regimen does not necessarily mean that the anthracyclines are effective in that subset. Patients with large amplifications not focused on the HER2 gene may have tumors driven by genes other than HER2 and thus be less responsive to HER2 inhibition. The conclusion is also based on a limited number of events involved. This type of indirect analysis does not provide a strong level of evidence according to the scale introduced by Simon et al 2 for evaluating the medical utility of predictive biomarkers. The pragmatic question of importance is which patients should be considered good candidates for anthracycline-based regimens. Previous studies have indicated that patients without HER2-amplified tumors are unlikely to benefit from such regimens. 3,4 The data for BCIRG-006 indicates that, for patients with HER2-amplified tumors who will receive trastuzumab, the docetaxel/carboplatin regimen seems as effective as the ACT regimen, regardless of TOP2A status. This leaves little room for the use of anthracyclines and no reason for the measurement of TOP2A amplification status. The data for BCIRG-006 suggests that patients with amplified HER2 and TOP2A might do as well on ACT as on ACTH—ie, they might not benefit from trastuzumab in the presence of ACT. This conclusion of therapeutic equivalence requires independent confirmation in a larger study, however, as it is based on only 42 disease-free survival events on ACT compared with 35 on ACTH.

Predicting chemotherapy-induced hematotoxicity elderly patients with metastatic breast cancer treated by pegylated liposomal doxorubicin (PLD): A population-based analysis on data coming from the DOGMES phase II GINECO study.

e19740 Background: Use of anthracyclines is often limited in older patients due to cardiac toxicity and hematotoxicity (HT). Thanks to its improved toxicity profile, PLD allows use of doxorubicin in this population. We aim at modeling HT of PLD in MBC patients older than 70 years and at finding predictive factors of neutrophil nadir value. Methods: sixty patients, enrolled in the DOGMES prospective multicenter phase II trial, were treated with PLD 40 mg/m2 every 28 days for 6 cycles. Trial design included geriatric covariates assessment at inclusion and monitoring of blood counts every weeks for 3 cycles. Due to the long half-life of PLD, it was assumed that drug effect was constant over time. A non-linear mixed effects model as suggested by Friberg et al (J Clin Oncol 2002) was applied to neutrophil count. The model includes inter-occasion (IOV) and inter-individual (IIV) variabilities. Best model choice was based on goodness of fits plots and Akaike criteria. Results: Final model includes 1 IOV parameter on the mean transit time (MTT) and 4 IIV parameters on baseline count, MTT, proliferation rate, and power. Based on model, exact neutrophil nadir values from 53 patients and their 3 first cycles were computed. Then, predictive factors were assessed among the 66 measured covariates. Minimal estimated nadir value was 0.82x109/L and maximal value 8.38x109/L, median time in grade 2 was 4 days (1.1; 4.8). Conclusions: Three factors were predictive of the nadir value (diabetes, p = 0.00012; assistance at home, p = 0.037; frailty syndrome, p = 0.065) and explained 18.5% of variability in this value. These factors can be used to identify patients with higher risk of toxicity.

Anthracyline (A) use among women with breast cancer (BC).

1019 Background: Recent patterns of use of A vs taxane-based chemotherapy are unknown. Methods: Patients were identified from Medicare and private insurance datasets with the following criteria. 1) The 5% National Medicare file 1995−2008: Female bc treated with mastectomy or breast conserving surgery between 1/1996 and 6/2008, ³66 years, Medicare A and B coverage and no HMO, and chemotherapy 3 mo before−6 mo after surgery (n=5956). 2) Private insurance claims data: dx 4/98−6/07, female bc, age <65, breast surgery, and chemotherapy from 3 mo before −6 mo after surgery (n=25354). Patients receiving chemotherapy were classified as receiving either A-based chemotherapy (A +/− any other chemo) or taxane-based chemotherapy if codes for paclitaxel, docetaxel, or nab-paclitaxel were present with no codes for A. Chemotherapy use by year was calculated overall and by geographic area, and piecewise logistic regression analysis was used to determine changes over time. Results: 1) Medicare: A-based chemotherapy slowly increased from 1996 to 2005 (41% to 70.0% of patients) but fell sharply down to a low of 32.3% in 2008. A corresponding increase in taxane-based chemotherapy was seen, from 10.5% of patients in 2005 to 50.2% in 2008. By 2008, the majority of patients received taxane-based chemotherapy without an A. Regression analysis showed a significant increase in the use of taxane-based chemotherapy starting in the end of 2005. 2) Private insurance: Similar but less dramatic trends were seen with a fall of A chemotherapy from a peak of 86% in 2004 to 68% in 2007. Taxane-based chemotherapy increased to 28% of younger patients in 2007. While use remained stable in some states, A use declined up to 33% in other states. Analysis will be updated with the 2008−2009 private insurance data. Conclusions: Starting at the end of 2005, there has been a dramatic decline in the use of anthracyclines for women with breast cancer, with the sharpest decline among women over age 65. Anthracycline regimens are increasingly being replaced by taxane-based chemotherapy.

Therapeutic management of metastatic breast cancer across Europe: European observatory and survey (EOS).

e11556 Background: Metastatic breast cancer (MBC) is a heterogeneous disease with many treatment options, including single-agent or combination chemotherapy. We analyzed in a real-life setting the therapeutic decision for treating MBC with non-pegylated liposomal doxorubicin (Myocet, LED) or another chemotherapeutic agent (non-LED). Methods: A European, multicentre, prospective, 6-month cohort study, with a treatment group comparison at the time of inclusion (LED vs. non-LED), is currently recruiting across 8 countries adult women with confirmed MBC and scheduled first cycle of chemotherapy. LED and non-LED patients were matched on MBC chemotherapy line. Results: We analyzed 505 patients (360 LED, 145 non-LED) included from Jan-09 to Dec-10. 85% had a WHO performance status of 0-1 and the median age was 60 yrs. 22% were HER2-positive at initial diagnosis. The median number of metastatic sites per patient was 2, and main sites of metastases were bone (63%), liver (45%) and lung (39%). Comparison of 143 patient pairs showed that LED patients had smaller primary tumor size (25 vs. 30 mm, p=0.02), and more frequent progesterone-receptor-positive tumors (52% vs. 48%, p=0.048) than non-LED patients. LED patients also tended to be slightly older (median 61 vs. 58 yrs, p=0.06) and to have more frequent bony (63% vs. 53%, p=0.09) and peritoneal (7% vs. 4%, p=0.05) metastases. The previous use of anthracyclines was similar in both groups (59% vs. 54%, p=0.8). Overall, major reasons for choosing LED were: among patient-related factors: stage of disease (72%); among factors related to previous anti-cancer treatment: treatment failure (48%); and among factors related to the chosen treatment: patient eligibility (63%). Single agent chemotherapy was given to 36% of LED and 57% of non-LED patients. LED was mainly combined with cyclophosphamide (50%) and taxanes (14%). Non-LED agents were mainly taxanes (57%), cyclophosphamide (18%), vinorelbine (16%) and 5-fluorouracil (12%). Conclusions: EOS aims to give information on MBC epidemiology in Europe and on its management. Further data are needed to refine the analysis and to compare MBC management per country.