Emma Gibbs

Chemotherapy vs tamoxifen in platinum-resistant ovarian cancer : A phase III, randomised, multicentre trial (Ovaresist)

Background:Chemotherapy in platinum-resistant ovarian cancer (PROC) aims for palliation and prolonging of progression-free survival (PFS). This study compares Health-related Quality of Life (HRQoL) and efficacy between single-agent chemotherapy and tamoxifen in PROC.Methods:Patients with PROC were randomised (2 : 1) to chemotherapy (weekly paclitaxel 80 mg m−2 or four weekly pegylated liposomal doxorubicin 40 mg m−2) or tamoxifen 40 mg daily. The primary end point was HRQoL. Secondary end points were PFS by RECIST and overall survival (OS).Results:Between March 2002 and December 2007, 156 and 82 patients were randomised to chemotherapy and tamoxifen, respectively. In the chemotherapy arm, a significantly larger proportion of patients experienced a worsening in their social functioning. There was no difference in the proportion of patients experiencing improvement of gastrointestinal symptoms. Median PFS on tamoxifen was 8.3 weeks (95% CI, 8.0–10.4) compared with 12.7 weeks (95% CI, 9.0–16.3) on chemotherapy (HR, 1.54; 95% CI, 1.16–2.05; log-rank P=0.003). There was no difference in OS between the treatment arms.Conclusions:Patients on chemotherapy had longer PFS but experienced more toxicity and poorer HRQoL compared with tamoxifen. Control over gastrointestinal symptoms was not better on chemotherapy. These data are important for patient counselling and highlight the need to incorporate HRQoL end points in studies of PROC.

Safety and efficacy of single-agent bevacizumab-containing therapy in elderly patients with platinum-resistant recurrent ovarian cancer : Subgroup analysis of the randomised phase III AURELIA trial

BACKGROUND The AURELIA trial demonstrated significantly improved progression-free survival (PFS) with bevacizumab added to chemotherapy for platinum-resistant ovarian cancer (PROC). METHODS Patients with PROC were randomised to receive investigator-selected single-agent chemotherapy alone or with bevacizumab. Post-hoc exploratory analyses assessed efficacy, safety and patient-reported outcomes according to age <65 versus ≥65years. RESULTS In the 133 patients (37%) aged ≥65years, baseline hypertension was more frequent and ascites was less common than in patients <65years. The magnitude of PFS benefit from bevacizumab was similar in patients ≥65 versus <65years (hazard ratio 0.44 [95% CI, 0.31-0.64] versus 0.49 [95% CI, 0.37-0.64], respectively, treatment-age interaction p=0.58), with similar improvements in response rates. Grade≥3 hypertension was more common with bevacizumab than chemotherapy alone in both subgroups, and more common in older than younger patients irrespective of treatment. However, there was no excess of other adverse events of specific interest for bevacizumab, including venous thromboembolic events, in older patients. More patients receiving bevacizumab in the younger but not the older subgroup showed improved gastrointestinal/abdominal symptoms. CONCLUSION In exploratory analyses, PFS and response rate improvement with bevacizumab were consistent in older and younger patients. Grade≥3 hypertension was more common in elderly bevacizumab-treated patients; careful monitoring is recommended. Overall, bevacizumab-containing therapy was well tolerated in a selected population aged ≥65years, suggesting a favourable benefit:risk profile. However, geriatric assessments are needed to improve selection of elderly patients potentially gaining symptom and quality of life improvements from bevacizumab-containing therapy. CLINICAL TRIALS REGISTRATION ClinicalTrials.govNCT00976911.

Bevacizumab with or after chemotherapy for platinum-resistant recurrent ovarian cancer: exploratory analyses of the AURELIA trial

Background In the open-label randomized phase III AURELIA trial, adding bevacizumab to chemotherapy for platinum-resistant ovarian cancer (PROC) significantly improved progression-free survival and response rate versus chemotherapy alone, but not overall survival (OS). We explored the effect of bevacizumab use after disease progression (PD) in patients randomized to chemotherapy alone. Patients and methods In AURELIA, 361 women with PROC were randomized to chemotherapy alone or with bevacizumab. Patients initially randomized to chemotherapy were offered bevacizumab after PD. Post hoc analyses assessed efficacy and safety in three subgroups: chemotherapy alone, chemotherapy followed by bevacizumab after PD, and chemotherapy plus bevacizumab at randomization. Results Of the 182 patients randomized to chemotherapy alone, 72 (40%) received bevacizumab after PD and 110 (60%) never received bevacizumab. There were no significant differences in patient and disease characteristics between these subgroups at baseline or the time of PD. Compared with patients never receiving bevacizumab, the risk of death was significantly reduced in patients receiving bevacizumab either upfront with chemotherapy [hazard ratio (HR) = 0.68, 95% confidence interval (CI) 0.52-0.90] or after PD (HR = 0.60, 95% CI 0.43-0.86). The tolerability of bevacizumab was similar with administration upfront or after PD. Conclusions Post-PD bevacizumab use may have confounded OS results in AURELIA. In these exploratory analyses of non-randomized subgroups, bevacizumab use, either with chemotherapy or after PD on chemotherapy alone, improved OS compared with no bevacizumab. Combining bevacizumab with chemotherapy at first appearance of platinum resistance maximises the likelihood of patients receiving this active treatment for PROC. ClinicalTrials.gov: NCT00976911.

Smartphone use in dermatology for clinical photography and consultation: Current practice and the law

Smartphones are rapidly changing the way doctors capture and communicate clinical information, particularly in highly visual specialties such as dermatology. An understanding of how and why smartphones are currently used in clinical practice is critical in order to evaluate professional and legal risks, and to formulate policies that enable safe use of mobile technologies for the maximal benefit of practitioners and patients.

Quality of life predicts overall survival in women with platinum-resistant ovarian cancer: an AURELIA substudy

Background Women with platinum-resistant ovarian cancer are a heterogeneous group whose median overall survival is 12 months. We hypothesized that their quality of life (QoL) scores would be prognostic. Patients and methods Data from AURELIA (n = 326), a randomized trial of chemotherapy with or without bevacizumab, were used to identify baseline QoL domains [EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 and OV28] that were significantly associated with overall survival in multivariable Cox regression analyses. Patients were classified as having good, medium, or poor risk. Cutpoints were validated in an independent dataset, CARTAXHY (n = 136). Multivariable analyses of significant QoL domains on survival were adjusted for clinicopathological prognostic factors. The additional QoL information was assessed using C statistic. Results In AURELIA, all domains, except cognitive function, predicted overall survival in univariable analyses. Physical function (P < 0.001) and abdominal/gastrointestinal symptom (P < 0.001) scores remained significant in multivariable models. In high (score <67), medium (67-93), and low (>93) risk categories for physical function, median overall survival was 11.0, 14.7, and 19.3 months, respectively (P < 0.001). In CARTAXHY, median overall survival was 7.9, 16.2, and 23.9 months (P < 0.001), respectively. For high- (>44), medium- (13-44), and low- (<13) risk categories for abdominal/gastrointestinal symptoms, median overall survival was 11.9, 14.3, and 19.7 months in AURELIA (P < 0.001) and 10.5, 19.6, and 24.1 months in CARTAXHY (P = 0.02). Physical function (P = 0.02) and abdominal/gastrointestinal symptoms (P = 0.03) remained independent prognostic factors after adjustment for clinicopathological factors. The C statistic of the full model was 0.71. For QoL factors alone, patient factors alone and disease factors alone, the C statistics were 0.61, 0.61, and 0.67 respectively. Conclusions Physical function and abdominal/gastrointestinal symptom scores improved predictions of overall survival over clinicopathological factors alone in platinum-resistant ovarian cancer. This additional prognostic information could improve trial stratification, patient-doctor communication about prognosis, and clinical decision-making. Clinical trial registration NCT00976911.

Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial

BACKGROUND In the phase 3 SOLO2 trial (ENGOT Ov-21), maintenance therapy with olaparib tablets significantly prolonged progression-free survival (primary endpoint) compared with placebo in patients with a germline BRCA1 or BRCA2 (BRCA1/2) mutation and platinum-sensitive, relapsed ovarian cancer who had received two or more lines of previous chemotherapy. The most common subjective adverse effects included fatigue, nausea, and vomiting, which were typically low grade and self-limiting. Our a-priori hypothesis was that maintenance olaparib would not negatively affect health-related quality of life (HRQOL) and additionally that the prolongation of progression-free survival with olaparib would be underpinned by additional patient-centred benefits. METHODS In SOLO2, 196 patients were randomly assigned to olaparib tablets (300 mg twice daily) and 99 to placebo. Randomisation was stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (>6-12 vs >12 months). The prespecified primary HRQOL analysis evaluated the change from baseline in the Trial Outcome Index (TOI) score during the first 12 months of the study. To be assessable, patients had to have an evaluable score at baseline and at least one evaluable follow-up form. Secondary planned quality-of-life (QOL) analyses included the duration of good quality of life (defined as time without significant symptoms of toxicity [TWiST] and quality-adjusted progression-free survival [QAPFS]). Efficacy and QOL outcomes were analysed in all randomly assigned patients (the full analysis set), and safety outcomes were analysed in all randomly assigned patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01874353, and is closed to new participants. FINDINGS The adjusted average mean change from baseline over the first 12 months in TOI was -2·90 (95% CI -4·13 to -1·67) with olaparib and -2·87 (-4·64 to -1·10) with placebo (estimated difference -0·03; 95% CI -2·19 to 2·13; p=0·98). Mean QAPFS (13·96 [SD 10·96] vs 7·28 [5·22] months; difference 6·68, 95% CI 4·98-8·54) and mean duration of TWiST (15·03 [SD 12·79] vs 7·70 [6·42] months; difference 7·33, 95% CI 4·70-8·96) were significantly longer with olaparib than with placebo. INTERPRETATION Olaparib maintenance therapy did not have a significant detrimental effect on HRQOL compared with placebo. There were clinically meaningful patient-centred benefits in both TWiST and QAPFS despite the adverse effects associated with olaparib. These patient-centred endpoints support the improvement in progression-free survival, the primary endpoint in SOLO2, and should be included in future trials of maintenance therapies. FUNDING AstraZeneca.

Immunogenicity and Safety of Monovalent Acellular Pertussis Vaccine at Birth: A Randomized Clinical Trial

Importance An alternative option to maternal vaccination to prevent severe pertussis in infants is vaccination at birth. Data are needed on the immunogenicity and safety of a birth dose of monovalent acellular pertussis (aP) vaccine. Objective To compare IgG antibody responses to vaccine antigens at 6, 10, 24, and 32 weeks of age between newborn infants receiving the aP vaccine and hepatitis B vaccine (HBV) or HBV alone. Design, Setting, and Participants A randomized clinical trial was conducted at 4 sites in Australia (Sydney, Melbourne, Adelaide, and Perth) between June 11, 2010, and March 14, 2013, among 440 healthy term (>36 weeks’ gestation) infants aged less than 5 days at recruitment. Statistical analysis was performed from March 1, 2015, to June 2, 2016. Intervention Newborns received HBV and, after stratification by maternal receipt of adult-formulated aP-containing vaccine (tetanus toxoid, reduced diphtheria toxoid, and pertussis antigen content [Tdap]) prior to pregnancy, were block randomized to receive the aP vaccine (without diphtheria or tetanus) within 5 days of birth or not. At 6, 16, and 24 weeks, infants received a hexavalent vaccine with pediatric-formulated diphtheria, tetanus and pertussis antigens (DTaP), Haemophilus influenzae type b (Hib), HBV, and polio vaccine, as well as the 10-valent pneumococcal conjugate vaccine. Main Outcomes and Measures Detectable (>5 enzyme-linked immunosorbent assay units per milliliter) and geometric mean concentrations of IgG antibody to pertussis toxin (PT), pertactin, and filamentous hemagglutinin at 6, 10, and 24 weeks stratified by maternal Tdap history, and antibody at 32 weeks to HBV, Hib, polio, diphtheria, tetanus, and pneumococcal serotypes. The primary outcome was detectable IgG to both PT and pertactin at 10 weeks. Results A total of 440 infants (207 girls and 233 boys; median gestation, 39.2 weeks) were randomized to receive the aP vaccine plus HBV (n = 221) or HBV only (control group; n = 219). At 10 weeks, 192 of 206 infants who received the aP vaccine (93.2%) had detectable antibodies to both PT and pertactin vs 98 of 193 infants in the control group (50.8%) (P < .001), with the geometric mean concentration for PT IgG 4-fold higher among the group that received the aP vaccine. At age 32 weeks, all infants (n = 181 with sera available for testing) who received the aP vaccine at birth had detectable PT IgG and significantly lower IgG geometric mean concentrations for Hib, hepatitis B, diphtheria, and tetanus antibodies. Local and systemic adverse events were similar between both groups at all time points. Conclusions and Relevance The monovalent aP vaccine is immunogenic and safe in neonates and, if licensed and available, would be valuable for newborns whose mothers did not receive the Tdap vaccine during pregnancy. Trial Registration http://anzctr.org.au Identifier: ACTRN12609000905268

Comparison of the effect of caseload midwifery program and standard midwifery-led care on primiparous birth outcomes: a retrospective cohort matching study

BACKGROUND The effectiveness of continuity of care during the perinatal period is well documented, but implementing continuity of care model to practice requires evaluation. AIM To evaluate the effect of a caseload midwifery program (CMP) on birth outcomes and rates of perinatal interventions at a metropolitan tertiary hospital in Australia, compared with standard midwifery-led care (SMC). METHODS This was a retrospective, matched-cohort study. We extracted the data of 1000 nulliparous women from records of 19,001 women who gave birth at the hospital from 2011 to 2014. We used basic statistical tests to compare baseline demographic data, and logistic regression to calculate odds ratios, to evaluate maternal and neonatal outcomes. RESULTS Adjusted regression analysis for the primary outcome showed that compared with women who received SMC, women who received care through CMP had an increased rate of normal vaginal birth (69% vs. 50%, OR = 1.79, 95%, CI = 1.38-2.32). Assessment of secondary outcomes showed that the women in CMP group had decreased rates of instrumental birth (15% vs. 26%, OR = 0.48, 95% CI = 0.35-0.66), episiotomy (23% vs. 40%, OR = 0.43, 95% CI = 0.33-0.57), epidural analgesia (33% vs. 43%, OR = 0.64, 95% CI = 0.50-0.83) and amniotomy (35% vs. 50%, OR = 0.56, 95% CI = 0.43-0.72). The CMP group also had greater rates of water immersion (54% vs. 22%, OR = 4.18, 95% CI = 3.17-5.5), physiological 3rd stage (7% vs. 1%, OR = 11.71, 95% CI = 3.56-38.43) and 2nd degree tear (34% vs. 24%, OR = 1.60, 95% CI = 1.21-2.11). There were no significant differences between the two groups for rates of other secondary outcomes including Caesarean section, cervical ripening procedures, third- and fourth-degree tears, postpartum haemorrhage and neonatal outcomes. CONCLUSION CMP care is associated with increased rate of normal vaginal birth which supports wider implementation of the model. In addition, using routinely collected data and a cohort matching design can be an effective approach to evaluate maternal and neonatal outcomes.

Validation of the accuracy of postpartum haemorrhage data in the ObstetriX database: A retrospective cohort study

BACKGROUND Data related to postpartum haemorrhage (PPH) are important clinical parameters which can be applied to all places of birth, and their recording can be missed by busy clinicians providing critical care to women. We compared the accuracy of electronic ObstetriX records to the paper-based medical records of the women who sustained PPH. METHODS In this retrospective cohort study over a period of one month, 363 electronic records were compared to the paper-based medical records. The volume of blood loss for each patient and interventions for PPH were compared across birth unit, operating theatre and postpartum ward. The kappa statistic for agreement between the two types of recording methods was calculated. RESULTS There was substantial agreement between the ObstetriX records and medical records for the volume of blood loss at birth (kappa = 0.74), but poor agreement between records for the cumulative total volume of blood loss (kappa = 0.18). More women who experienced PPH and delivered in the operating theatre had errors in their ObstetriX records compared to women who had PPH with births in the birth unit (50% vs 16%; n = 73, P = 0.005). Interventions for PPH were found to be poorly recorded in ObstetriX, with 84% (n = 64/76) of women who experienced PPH having none of the interventions they received recorded. CONCLUSIONS The ObstetriX database was not a generally reliable source of data relating to PPH. However, some data were recorded reliably, in particular, the volume of blood loss at birth.

Data maturity and follow-up in time-to-event analyses

We propose methods to determine the minimum number of subjects remaining at risk after which Kaplan-Meier survival plots for time-to-event outcomes should be curtailed, as, once the number remaining at risk drops below this minimum, the survival estimates are no longer meaningful in the context of the investigation. The size of the decrease of the Kaplan-Meier survival estimate S(t) at time t if one extra event should occur is considered in two ways. In the first approach, the investigator sets a maximum acceptable absolute decrease in S(t) should one extra event occur. In the second, a minimum acceptable number of subjects still at risk is calculated by comparing the size of the decrease in S(t) if an extra event should occur with the variability of the survival estimate had all subjects been followed to that time (confidence interval approach). We recommend calculating both limits for the number still at risk and then making an informed choice in the context of the particular investigation. We explore further how the amount of information actually available can assist in considering issues of data maturity for studies whose outcome of interest is a survival percentage at a particular time point. We illustrate the approaches with a number of published studies having differing sample sizes and censoring issues. In particular, one study was the subject of some controversy regarding how far in time the Kaplan-Meier plot should be extended. The proposed methods allow for limits to be calculated simply using the output provided by most statistical packages.