Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort.

BACKGROUND: Previous studies have shown decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. We investigated infertility and time to pregnancy in female childhood cancer survivors, and analysed treatment characteristics associated with infertility and subsequent pregnancy. METHODS: The Childhood Cancer Survivor Study (CCSS) is a cohort study including 5 year cancer survivors from 26 Canadian and US institutions who were younger than 21 years at the time of diagnosis between Jan 1, 1970, and Dec 31, 1986, and a sibling control group. We included women aged 18-39 years who had ever been sexually active. We gathered demographic, medical, and reproductive data via a baseline questionnaire, and quantified exposure to alkylating agents and radiation therapy. Self-reported infertility, medical treatment for infertility, time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analysed. FINDINGS: 3531 survivors and 1366 female sibling controls who enrolled between Nov 3, 1992, and April 4, 2004, were included. Compared with their siblings, survivors had an increased risk (relative risk [RR] 1·48 [95% CI 1·23-1·78]; p<0·0001) of clinical infertility (ie, >1 year of attempts at conception without success), which was most pronounced at early reproductive ages (RR 2·92 [95% CI 1·18-7·20], p=0·020, in participants ≤24 years; 1·61 [1·05-2·48], p=0·029, in those aged 25-29 years; and 1·37 [1·11-1·69], p=0·0035, in those aged 30-40 years). Despite being equally likely to seek treatment for infertility, survivors were less likely than were their siblings to be prescribed drugs for treatment of infertility (0·57 [95% CI 0·46-0·70], p<0·0001). Increasing doses of uterine radiation and alkylating agent chemotherapy were strongly associated with infertility. Although survivors had an increased time to pregnancy compared with their siblings (p=0·032), 292 (64%) of 455 participants with self-reported clinical infertility achieved a pregnancy. INTERPRETATION: A more comprehensive understanding of infertility after cancer is crucial for counselling and decision making about future conception attempts and fertility preservation. FUNDING: National Cancer Institute, American Lebanese Syrian Associated Charities, Swim Across America.

On determining the BMD from multiple outcomes in developmental toxicity studies when one outcome is intentionally missing.

Public health concerns over the occurrence of developmental abnormalities that can occur as a result of prenatal exposure to drugs, chemicals, and other environmental factors has led to a number of developmental toxicity studies and the use of the benchmark dose (BMD) for risk assessment. To characterize risk from multiple sources, more recent analytic methods involve a joint modeling approach, accounting for multiple dichotomous and continuous outcomes. For some continuous outcomes, evaluating all subjects may not be feasible, and only a subset may be evaluated due to limited resources. The subset can be selected according to a prespecified probability model and the unobserved data can be viewed as intentionally missing in the sense that subset selection results in missingness that is experimentally planned. We describe a subset selection model that allows for sampling pups with malformations and healthy pups at different rates, and includes the well-known simple random sample (SRS) as a special case. We were interested in understanding how sampling rates that are selected beforehand influence the precision of the BMD. Using simulations we show how improvements over the SRS can be obtained by oversampling malformations, and how some sampling rates can yield precision that is substantially worse than the SRS. We also illustrate the potential for cost saving with oversampling. Simulations are based on a joint mixed effects model, and to account for subset selection, use of case weights to obtain valid dose-response estimates.

Long-term follow-up after preoperative trastuzumab and chemotherapy for HER2-overexpressing breast cancer.

BACKGROUND: Neoadjuvant chemotherapy and trastuzumab is an established treatment for locally advanced HER2-positive breast cancer, providing favorable rates of clinical response and pCR. Minimal data describe long-term outcomes after neoadjuvant HER2-directed therapy. This study aimed to explore long-term efficacy and toxicity after neoadjuvant trastuzumab and chemotherapy for HER2-positive breast cancer. PATIENTS AND METHODS: Eligible patients participated in 1 of 2 single-arm phase II neoadjuvant trials, receiving either paclitaxel/trastuzumab (TH) or vinorelbine/trastuzumab (NH) for stage II-III HER2-positive disease. Postoperative chemotherapy, with or without trastuzumab, was offered. Charts were reviewed to identify recurrence, death, and treatment-related toxicities. Association of long-term outcomes with baseline characteristics and pathological response to primary therapy was explored. RESULTS: Eighty patients were identified; 33 (41.3%) received TH and 47 (58.8%) received NH. Fourteen (17.5%) had pCR at surgery. Most (96.3%) received anthracycline-based adjuvant chemotherapy; 78.7% of NH patients also received adjuvant trastuzumab. At a median follow-up of 8.8 years, 23 (28.8%) patients have experienced recurrence, with 16 breast cancer-related deaths. Four-year RFS in patients with pCR was 92.9% (95% confidence interval [CI], 79.4%-100%) versus 72.4% without pCR (95% CI, 63.9%-82.1%). All initial symptomatic cardiotoxicity resolved during extended follow-up. New symptomatic cardiotoxicity in long-term follow-up was rare, primarily occurring in patients requiring retreatment with a cardiotoxic agent. CONCLUSION: Neoadjuvant chemotherapy and trastuzumab for HER2-positive breast cancer resulted in favorable long-term survival with minimal late toxicity. Trends in this data set suggest an association between pCR and improved long-term RFS. Retreatment with cardiotoxic agents might increase risk of late cardiotoxicity.

Phase II Study of Lapatinib in Combination With Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: Clinical Outcomes and Predictive Value of Early [18F]Fluorodeoxyglucose Positron Emission Tomography Imaging (TBCRC 003).

PURPOSE: Lapatinib plus trastuzumab improves outcomes relative to lapatinib alone in heavily pretreated, human epidermal growth factor receptor 2-positive metastatic breast cancer (MBC). We tested the combination in the earlier-line setting and explored the predictive value of [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) for clinical outcomes. PATIENTS AND METHODS: Two cohorts were enrolled (cohort 1: no prior trastuzumab for MBC and ≥ 1 year from adjuvant trastuzumab, if given; cohort 2: one to two lines of chemotherapy including trastuzumab for MBC and/or recurrence < 1 year from adjuvant trastuzumab). The primary end point was objective response rate by RECIST v1.0; secondary end points included clinical benefit rate (complete response plus partial response plus stable disease ≥ 24 weeks) and progression-free survival. [(18)F]FDG-PET scans were acquired at baseline, week 1, and week 8. Associations between metabolic response and clinical outcomes were explored. RESULTS: Eighty-seven patients were registered (85 were evaluable for efficacy). The confirmed objective response rate was 50.0% (95% CI, 33.8% to 66.2%) in cohort 1 and 22.2% (95% CI, 11.3% to 37.3%) in cohort 2. Clinical benefit rate was 57.5% (95% CI, 40.9% to 73.0%) in cohort 1 and 40.0% (95% CI, 25.7% to 55.7%) in cohort 2. Median progression-free survival was 7.4 and 5.3 months, respectively. Lack of week-1 [(18)F]FDG-PET/computed tomography ([(18)F]FDG-PET/CT) response was associated with failure to achieve an objective response by RECIST (negative predictive value, 91% [95% CI, 74% to 100%] for cohort 1 and 91% [95% CI, 79% to 100%] for cohort 2). CONCLUSION: Early use of lapatinib and trastuzumab is active in human epidermal growth factor receptor 2-positive MBC. Week-1 [(18)F]FDG-PET/CT may allow selection of patients who can be treated with targeted regimens and spared the toxicity of chemotherapy.

Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era.

BACKGROUND: Trastuzumab is associated with improvements in overall survival (OS) among patients with HER2-positive metastatic breast cancer (MBC); however disease course and patterns of care in individual patients are highly variable. METHODS: 113 HER2-positive patients diagnosed with MBC from 1999 to 2005 who received trastuzumab-based therapy were retrospectively identified to allow for a minimum of 5 years of follow-up time. Median OS and median duration of therapy were determined using Kaplan-Meier methodology and group comparisons were based on the log-rank test. Hazard ratios (HR) were obtained using a Cox proportional hazards model. RESULTS: Median OS was 3.5 years (95% CI 3.0-4.4) from time of initiation of first therapy in the metastatic setting. On univariate analysis, central nervous system (CNS) disease at first recurrence was associated with a shorter OS compared with liver and/or lung metastases or other sites (CNS: 1.9 years CI 0.1-5.9, liver/lung: 3.2 years CI 2.5-4.2, other: 4.6 years CI 2.7-8.0; p = 0.05), however, this was not predictive of survival outcome in multivariate analysis. CNS metastases developed in 62 (55%) patients by the time of death or last follow-up. Median duration of therapy was similar up to 6 lines of treatment, and ranged from 5.2 months to 7.2 months. CONCLUSIONS: The natural history of HER2-positive MBC has evolved with trastuzumab-based therapy with median OS now exceeding 3 years. CNS disease is a major problem with continued risk of CNS progression over time. Patients demonstrate clinical benefit to multiple lines of HER2-directed therapy.

A Novel Application of a Bivariate Regression Model for Binary and Continuous Outcomes to Studies of Fetal Toxicity.

Public health concerns over the occurrence of birth defects and developmental abnormalities that may occur as a result of prenatal exposure to drugs, chemicals, and other environmental factors has led to an increasing number of developmental toxicity studies. Because fetal pups are commonly evaluated for multiple outcomes, data analysis frequently involves a joint modeling approach. In this paper, we focus on modelling clustered binary and continuous outcomes in the setting where both outcomes are potentially observable in all offspring but, due to practical limitations, the continuous outcome is only observed in a subset of offspring. The subset is not a simple random sample (SRS) but is selected by the experimenter under a prespecified probability model.While joint models for binary and continuous outcomes have been developed when both outcomes are available for every fetus, many existing approaches are not directly applicable when the continuous outcome is not observed in a SRS. We adapt a likelihood-based approach for jointly modelling clustered binary and continuous outcomes when the continuous response is missing by design and missingness depends on the binary trait. The approach takes into account the probability that a fetus is selected in the subset. Through the use of a partial likelihood, valid estimates can be obtained by a simple modification to the partial likelihood score. Data involving the herbicide 2,4,5-T are analyzed. Simulation results confirm the approach.

Caring for cancer survivors: a survey of primary care physicians.

BACKGROUND: The number of long-term US cancer survivors is expected to double by the year 2050. Although primary care physicians (PCPs) provide the majority of care for long-term cancer survivors, to the authors' knowledge, few data to date have detailed PCP practice patterns, attitudes, and challenges in caring for long-term cancer survivors. METHODS: Self-administered surveys were mailed to 406 community- and academic-based general internal medicine physicians in Denver, Colorado. Survey development included in-depth physician interviews and pretesting. Of the 299 responses, 72 were ineligible; an analysis of the data from 227 surveys is presented. RESULTS: The response rate was 76%. Community-based PCPs comprised 70% of completed surveys. Reported care patterns were assessed to create a multidimensional care score reflecting levels of attention to 4 areas of survivorship care: monitoring for cancer recurrence, management of late effects, sexual functioning, and mental health. Only 24% of PCPs met criteria for routinely providing more multidimensional survivorship care. More recent medical school graduates reported providing less multidimensional survivorship care when compared with their more experienced colleagues. Approximately 82% of PCPs believed that primary care guidelines for adult cancer survivors are not well defined, and 47% of PCPs cited inadequate preparation and lack of formal training in cancer survivorship as a problem when delivering care to long-term survivors. CONCLUSIONS: Although PCPs provide the bulk of care for long-term survivors within the survivorship phase of the cancer trajectory, only a small subset have reported providing multidimensional survivorship care. Results underscore a need for substantially increased training in survivorship care to support the delivery of multidimensional primary care for long-term survivors.