Mike Hawkins

Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared With Polyethylated Castor Oil–Based Paclitaxel in Women With Breast Cancer

PURPOSE ABI-007, the first biologically interactive albumin-bound paclitaxel in a nanameter particle, free of solvents, was compared with polyethylated castor oil-based standard paclitaxel in patients with metastatic breast cancer (MBC). This phase III study was performed to confirm preclinical studies demonstrating superior efficacy and reduced toxicity of ABI-007 compared with standard paclitaxel. PATIENTS AND METHODS Patients were randomly assigned to 3-week cycles of either ABI-007 260 mg/m(2) intravenously without premedication (n = 229) or standard paclitaxel 175 mg/m(2) intravenously with premedication (n = 225). RESULTS ABI-007 demonstrated significantly higher response rates compared with standard paclitaxel (33% v 19%, respectively; P = .001) and significantly longer time to tumor progression (23.0 v 16.9 weeks, respectively; hazard ratio = 0.75; P = .006). The incidence of grade 4 neutropenia was significantly lower for ABI-007 compared with standard paclitaxel (9% v 22%, respectively; P < .001) despite a 49% higher paclitaxel dose. Febrile neutropenia was uncommon (< 2%), and the incidence did not differ between the two study arms. Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard paclitaxel arm (10% v 2%, respectively; P < .001) but was easily managed and improved rapidly (median, 22 days). No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time. CONCLUSION ABI-007 demonstrated greater efficacy and a favorable safety profile compared with standard paclitaxel in this patient population. The improved therapeutic index and elimination of corticosteroid premedication required for solvent-based taxanes make the novel albumin-bound paclitaxel ABI-007 an important advance in the treatment of MBC.

Risk of venous thromboembolism in users of hormone replacement therapy

BACKGROUND The association between current use of oral contraceptives and increased risk of venous thromboembolism (VTE) has been firmly established. Although data-sheets for hormone replacement therapy (HRT) carry similar warnings as regards VTE, evidence of an association is inconclusive. We carried out a hospital-based case-control study to investigate whether current use of HRT is associated with VTE. METHODS We screened all women aged 45-64 years admitted to hospitals in the area of the Oxford Regional Health Authority with a suspected diagnosis of VTE between February, 1993, and December, 1994. We recruited 81 cases of idiopathic VTE and 146 hospital controls with disorders of eyes, skin, ears, respiratory and alimentary tracts, kidneys, bones, and joints, and trauma; controls were matched to cases for age-group and date and district of admission. To increase the study power, an additional 22 cases of idiopathic VTE and 32 hospital controls admitted before February, 1993, were recruited retrospectively. Participants were questioned about medical and gynaecological history, use of oral contraceptives and HRT, use of other drugs within the previous 3 months, and lifestyle and socioeconomic characteristics. Detailed diagnostic data were extracted from the notes of eligible cases. Matched analyses, adjusted for body-mass Index, socioeconomic group, and history of varicose veins, were undertaken by conditional logistic regression. FINDINGS 44 (42.7%) cases and 44 (24.7%) controls were current users of HRT. The adjusted odds ratio for VTE in current users of HRT compared with non-users (never-users and past users combined) was 3.5 (95% CI 1.8-7.0; p < 0.001). No association was found with past use, and risk appeared to be highest among short-term current users (adjusted likelihood ratio test of trend in odds ratios across different durations of current use, p = 0.011). INTERPRETATION Current HRT use is associated with risk of VTE. The increased risk may be concentrated in new users. The number of extra cases appears to be only about one in 5000 users per year. These findings need to be weighed against the probable benefits of long-term treatment, including reductions in risks of osteoporotic fracture and coronary heart disease, and the probable modest increase in risk of breast cancer.

Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.

ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast congruent with ovary > prostate > colon. The LD(50) and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007.

Beckwith-Wiedemann syndrome and assisted reproduction technology (ART)

Beckwith-Wiedemann syndrome (BWS) is a model imprinting disorder resulting from mutations or epimutations affecting imprinted genes on chromosome 11p15.5.1 The classical clinical features of BWS are macroglossia, pre- and/or postnatal overgrowth, and anterior abdominal wall defects (umbilical hernia or exomphalos). Additional more variable features include hemihypertrophy, neonatal hypoglycaemia, facial naevus flammeus, ear pits and creases, renal anomalies, and an increased risk of embryonal tumours.2 Most cases of BWS are sporadic and ∼20% of these have uniparental disomy (paternal isodisomy) for a variable region of chromosome 11 which always includes the 11p15.5 imprinted gene cluster.3–5 Up to 60% of sporadic BWS patients have epigenetic changes at differentially methylated regions within 11p15.5 that are associated with alterations in the imprinting or expression of paternally expressed genes, such as IGF2 and KCNQ1OT , or maternally expressed genes, such as H19 and CDKN1C .1 Thus, 5–10% have epigenetic alterations at the IGF2 / H19 loci (the maternal H19 and IGF2 alleles display paternal allele methylation and expression patterns with biallelic IGF2 expression and silencing of H19 expression),6 and 40–50% have loss of maternal allele methylation at a differentially methylated region (KvDMR1) within an intron of KCNQ1 . KvDMR1 loss of methylation is associated with biallelic expression of KCNQ1OT .7–9 The epigenetic alterations at H19 / IGF2 or KvDMR1 are thought to result from defects at two putative imprinting control centres (BWSIC1 and BWSIC2, respectively).1 The precise nature of the putative BWSIC2 is unknown and therefore the origin of these putative BWSIC2 defects is unknown. Weksberg et al 10 showed a clear association between monozygotic twinning and BWS with KvDMR1 loss of methylation and suggested two possible explanations: (1) that discordance for BWS in monozygotic twins is caused by unequal splitting of the inner cell mass …

Role of Cancer Treatment in Long-Term Overall and Cardiovascular Mortality After Childhood Cancer

PURPOSE The purpose of this study was to assess the role of treatment in long-term overall and cardiovascular mortality after childhood cancer. PATIENTS AND METHODS We studied 4,122 5-year survivors of a childhood cancer diagnosed before 1986 in France and the United Kingdom. Information on chemotherapy was collected, and the radiation dose delivered to the heart was estimated for 2,870 patients who had received radiotherapy. RESULTS After 86,453 person-years of follow-up (average, 27 years), 603 deaths had occurred. The overall standardized mortality ratio (SMR) was 8.3-fold higher (95% CI, 7.6-fold to 9.0-fold higher) in relation to the general populations in France and the United Kingdom. Thirty-two patients had died as a result of cardiovascular diseases (ie, 5.0-fold [95% CI, 3.3-fold to 6.7-fold] more than expected). The risk of dying as a result of cardiac diseases (n = 21) was significantly higher in individuals who had received a cumulative anthracycline dose greater than 360 mg/m(2) (relative risk [RR], 4.4; 95% CI, 1.3 to 15.3) and in individuals who received an average radiation dose that exceeded 5 Gy (RR, 12.5 and 25.1 for 5 to 14.9 Gy and > 15 Gy, respectively) to the heart. A linear relationship was found between the average dose of radiation to the heart and the risk of cardiac mortality (estimated excess [corrected] RR at 1 Gy, 60%). CONCLUSION This study is the first, to our knowledge, to establish a relationship between the radiation dose received by the heart during radiotherapy for a childhood cancer and long-term cardiac mortality. This study also confirms a significant excess risk of cardiac mortality associated with a high cumulative dose of anthracyclines.

Long-term cause-specific mortality among survivors of childhood cancer.

CONTEXT Survivors of childhood cancer are at increased risk of premature mortality compared with the general population, but little is known about the long-term risks of specific causes of death, particularly beyond 25 years from diagnosis at ages when background mortality in the general population starts to increase substantially. OBJECTIVE To investigate long-term cause-specific mortality among 5-year survivors of childhood cancer in a large-scale population-based cohort. DESIGN, SETTING, AND PATIENTS British Childhood Cancer Survivor Study, a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer before age 15 years between 1940 and 1991 in Britain and followed up until the end of 2006. MAIN OUTCOME MEASURES Cause-specific standardized mortality ratios (SMRs) and absolute excess risks (AERs). RESULTS Overall, 3049 deaths were observed, which was 11 times the number expected (SMR, 10.7; 95% confidence interval [CI], 10.3-11.1). The SMR declined with follow-up but was still 3-fold higher than expected (95% CI, 2.5-3.9) 45 years from diagnosis. The AER for deaths from recurrence declined from 97 extra deaths (95% CI, 92-101) per 10,000 person-years at 5 to 14 years from diagnosis, to 8 extra deaths (95% CI, 3-22) beyond 45 years from diagnosis. In contrast, during the same periods of follow-up, the AER for deaths from second primary cancers and circulatory causes increased from 8 extra deaths (95% CI, 7-10) and 2 extra deaths (95% CI, 2-3) to 58 extra deaths (95% CI, 38-90) and 29 extra deaths (95% CI, 16-56), respectively. Beyond 45 years from diagnosis, recurrence accounted for 7% of the excess number of deaths observed while second primary cancers and circulatory deaths together accounted for 77%. CONCLUSION Among a cohort of British survivors of childhood cancer, excess mortality from second primary cancers and circulatory diseases continued to occur beyond 25 years from diagnosis.

Developing strategies for long term follow up of survivors of childhood cancer

The treatment of childhood cancer has been increasingly successful over the past 30 years. Most paediatric cancers are now curable with multiagent chemotherapy in combination with surgery and radiotherapy. The overall survival five years after diagnosis is now 70% for all paediatric malignancies. The incidence is low (1200-1300 children affected each year in Britain), but with the sustained improvement in survival the number of long term survivors is increasing—about 850 additional survivors of childhood cancer each year. With this improved survival, it is important to increase our knowledge of any long term costs in the form of physical and psychosocial adverse health outcomes. This review looks at the evidence relating to long term clinical follow up after childhood cancer and considers ways to develop such follow up for the future. An awareness of the possible long term complications is important not only for optimising health care for the current survivors but also for modifying future treatment protocols to avoid therapies that are associated with unacceptable morbidity or mortality. We have summarised the evidence on selected long term complications; this evidence is inevitably based on retrospective studies. In the final section we discuss the development of a strategy for the clinical follow up of long term survivors. #### Summary points Long term follow up strategies are needed because of increasing numbers of survivors of childhood cancers Models for follow up need to be developed and formally evaluated Increasing numbers of survivors may have medical problems that will require ongoing specialist follow up The role, training programmes, and career structure of the late effects nurse practitioner needs to be developed The primary care physician may have an important role in long term follow up There is a need for prospective evaluation of new treatments and randomised studies of clinical interventions to resolve substantial uncertainties for …

Long-term Risks of Subsequent Primary Neoplasms Among Survivors of Childhood Cancer

CONTEXT Survivors of childhood cancer are at excess risk of developing subsequent primary neoplasms but the long-term risks are uncertain. OBJECTIVES To investigate long-term risks of subsequent primary neoplasms in survivors of childhood cancer, to identify the types that contribute most to long-term excess risk, and to identify subgroups of survivors at substantially increased risk of particular subsequent primary neoplasms that may require specific interventions. DESIGN, SETTING, AND PARTICIPANTS British Childhood Cancer Survivor Study--a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer at younger than 15 years between 1940 and 1991 in Great Britain, followed up through December 2006. MAIN OUTCOME MEASURES Standardized incidence ratios (SIRs), absolute excess risks (AERs), and cumulative incidence of subsequent primary neoplasms. RESULTS After a median follow-up time of 24.3 years (mean = 25.6 years), 1354 subsequent primary neoplasms were ascertained; the most frequently observed being central nervous system (n = 344), nonmelanoma skin cancer (n = 278), digestive (n = 105), genitourinary (n = 100), breast (n = 97), and bone (n = 94). The overall SIR was 4 times more than expected (SIR, 3.9; 95% confidence interval [CI], 3.6-4.2; AER, 16.8 per 10,000 person-years). The AER at older than 40 years was highest for digestive and genitourinary subsequent primary neoplasms (AER, 5.9 [95% CI, 2.5-9.3]; and AER, 6.0 [95%CI, 2.3-9.6] per 10,000 person-years, respectively); 36% of the total AER was attributable to these 2 subsequent primary neoplasm sites. The cumulative incidence of colorectal cancer for survivors treated with direct abdominopelvic irradiation was 1.4% (95% CI, 0.7%-2.6%) by age 50 years, comparable with the 1.2% risk in individuals with at least 2 first-degree relatives affected by colorectal cancer. CONCLUSION Among a cohort of British childhood cancer survivors, the greatest excess risk associated with subsequent primary neoplasms at older than 40 years was for digestive and genitourinary neoplasms.

The British Childhood Cancer Survivor Study: Objectives, methods, population structure, response rates and initial descriptive information.

In Britain 75% of individuals diagnosed with childhood cancer survive at least 5 years. The British Childhood Cancer Survivor Study was established to determine the risks of adverse health and social outcomes among survivors. To be eligible individuals were diagnosed with childhood cancer in Britain between 1940 and 1991 and survived at least 5 years. The entire cohort of 17,981 form the basis of population‐based studies of late mortality and the risks/causes of second malignant neoplasms using national registration systems.

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment

SummaryThe variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer.