Role of chemotherapy in breast cancer

Breast cancer represents a major health problem, with more than a million new cases and 370,000 deaths worldwide yearly. Options and understanding of how to use cytotoxic chemotherapy in both advanced and early stage breast cancer have made substantial progress in the past 10 years, with numerous landmark studies identifying clear survival benefits for newer approaches. Despite this research, the optimal approach for any individual patient cannot be determined from a literature review or decision-making algorithm alone. Treatment choices are still predominantly based on practice determined by individual or collective experience and the historic development of treatment within a locality. In many situations treatment decisions cannot be divorced from economic considerations. Blanket application of international, national or local guidelines is usually impractical or inappropriate and careful consideration of the detailed circumstances of each patient is required to make optimal use of available options. Recent research has allowed us to refine breast cancers further into prognostic groups based on a gene expression profile. Clinical trials to prove the value of this approach are currently being designed. This review discusses the evidence for various chemotherapy regimens in the adjuvant and metastatic settings, and examines the current evidence for the timing of radiotherapy in the adjuvant setting.     

Left ventricular systolic and diastolic function after anthracycline chemotherapy in childhood

BACKGROUND: In childhood, late cardiotoxicity is characterized by inappropriately thin wall and consequent increased end-systolic wall stress, but the associations of impaired left ventricular geometry and function occurring under these circumstances need further investigation. HYPOTHESIS: The purpose of this study was to assess anthracycline late effects on the relationships occurring between increased end-systolic stress (ESS) and changes in both M-mode systolic measurements (i.e., endocardial and midwall fractional shortening) and Doppler diastolic indices in the pediatric age. METHODS: The population consisted of 101 children treated with anthracyclines for at least 12 months and 91 healthy children. Using M-mode echocardiography, end-systolic wall stress was calculated as index of afterload, and endocardial and midwall fractional shortening as systolic indices. Doppler transmitral measurements were made as diastolic indices. RESULTS: Patients treated with anthracyclines showed significantly lower relative wall thickness and left ventricular mass index, greater end-systolic wall stress, reduced endocardial and midwall fractional shortening and peak E/A ratio, prolonged deceleration, and isovolumic relaxation times. Direct relationships were found between end-systolic wall stress and both endocardial and midwall shortening. The use of midwall shortening in the relation showed a greater, but not significant increase (from 3 to 6%) in the proportion of patients with depressed systolic function than did endocardial shortening. In the anthracycline group, end-systolic wall stress was also inversely related to relative wall thickness and directly to isovolumic relaxation time. CONCLUSIONS: In childhood, reduced myocardial thickness and increased afterload explain much of systolic and diastolic dysfunction of late anthracycline toxicity. Midwall fractional shortening does not seem to add useful information for identifying subsets of children more prone to the development of heart failure.     

Clinical significance of the WHO grades of follicular lymphoma in a population-based cohort of 505 patients with long follow-up times

The prognostic value of grading follicular lymphoma has been debated since the 1980s. There is consensus that World Health Organization (WHO) grades 1 and 2 are indolent, but not whether grades 3A or 3B are aggressive. We retrospectively reviewed the follicular lymphoma diagnoses according to the 2008 WHO classification in all diagnostic specimens from a population-based cohort of 505 patients with a median follow-up time of 10·0years (range, 4·6-16·0). After excluding 43 patients with concomitant diffuse large B-cell lymphoma, 345 remained with grade 1-2, 94 with grade 3A, and 23 with grade 3B follicular lymphoma. Grades 1-2 and 3A seemed equally indolent, with indistinguishable clinical courses, even in patients receiving anthracyclines. Compared with grades 1-3A and independently of clinical factors, grade 3B correlated with higher mortality (P=0·008), but outcome was improved after upfront anthracycline-containing therapy (P=0·015). In contrast to grade 1-3A patients, grade 3B patients experienced no relapses or deaths beyond 5years of follow-up. Furthermore, patients with grade 3B were predominantly male and seldom presented with bone-marrow involvement. We conclude that follicular lymphoma grade 1-3A is indolent and incurable with conventional therapy. Grade 3B appears to be an aggressive but curable disease.     

Pharmacokinetics and its relation to toxicity of pegylated‐liposomal doxorubicin in chinese patients with breast tumours

Objectives: Pegylated liposomal doxorubicin (PLD) is a formulation of doxorubicin encapsulated with polyethylene glycol‐coated liposomes, which has prolonged circulation time and unique toxicity profile. This study deals with the pharmacokinetics and its relation to toxicity in Chinese patients with breast tumours. Methods: Twenty‐two Chinese female patients with breast tumours were received two PLD products in single dose of 50 mg/m² with a randomized, two‐period and cross‐over design. Blood was sampled immediately before and at 15, 30, 60 min, 1·17, 2, 5, 13, 25, 49, 73, 97, 121, 145 and 241 h after the PLD infusion. The plasma level of doxorubicin was determined with LC‐MS. Results: The pharmacokinetics of PLD was best described by a one‐compartment linear structural model with a long elimination T_1/2 (64 h), a slow clearance (0·025 L/h/m²) and a small volume of distribution (2·310 L/m²). The main toxicities were neutropenia (22/44), nausea (22/44), vomiting (8/44) and pigmentation (4/44). The nausea and neutropenia were positively correlated with AUC while negatively correlated with Cl (P < 0·05). Conclusions: The study confirms the different pharmacokinetic and toxicity profiles of PLD compared with non‐liposomal doxorubicin. The pharmacokinetic profiles in Chinese patients with breast tumours is different from those reported for European patients with metastatic breast cancer. The correlation between toxicities, neutropenia grade and nausea and two of the pharmacokinetic parameters, AUC and Cl, may be useful for guiding the dosing of the agent.     

State of the art review: Chemotherapy‐induced cardiotoxicity in children

Chemotherapy‐induced cardiotoxicity in adults and children is a topic with a growing interest in the cardiology literature. The ability to detect cardiac dysfunction in a timely manner is essential in order to begin adequate treatment and prevent further deterioration. This article aims to provide a review on the myocardial injury process, chemotherapeutic agents that lead to cardiotoxicity, the definition of cardiotoxicity, and the methods of timely detection and treatment.