Breast tumour volume and blood flow measured by MRI after one cycle of epirubicin and cyclophosphamide-based neoadjuvant chemotherapy as predictors of pathological response.

OBJECTIVES: Better markers of early response to neoadjuvant chemotherapy (NACT) in patients with breast cancer are required to enable the timely identification of non-responders and reduce unnecessary treatment side-effects. Early functional imaging may better predict response to treatment than conventional measures of tumour size. The purpose of this study was to test the hypothesis that the change in tumour blood flow after one cycle of NACT would predict pathological response. METHODS: In this prospective cohort study, dynamic contrast-enhanced MRI was performed in 35 females with breast cancer before and after one cycle of epirubicin and cyclophosphamide-based NACT (EC90). Estimates of tumour blood flow and tumour volume were compared with pathological response obtained at surgery following completion of NACT. RESULTS: Tumour blood flow at baseline (mean ± SD; 0.32 ± 0.17 ml/min/ml) reduced slightly after one cycle of NACT (0.28 ± 0.18 ml/min/ml). Following treatment 15 patients were identified as pathological responders and 20 as non-responders. There were no relationships found between tumour blood flow and pathological response. Conversely, tumour volume was found to be a good predictor of pathological response (smaller tumours did better) at both baseline (area under the receiver operating characteristic curve 0.80) and after one cycle of NACT (area under the receiver operating characteristic curve 0.81). CONCLUSION & ADVANCES IN KNOWLEDGE: The change in breast tumour blood flow following one cycle of EC90 did not predict pathological response. Tumour volume may be a better early marker of response with such agents.

Bevacizumab for Newly Diagnosed Ovarian Cancers: Best Candidates Among High-Risk Disease Patients (ICON-7).

Bevacizumab is approved as a maintenance treatment in first-line setting in advanced-stage III-IV ovarian cancers, because GOG-0218 and ICON-7 phase III trials demonstrated progression-free survival benefits. However, only the subgroup of patients with high-risk diseases (stage IV, and incompletely resected stage III) derived an overall survival (OS) gain in the ICON-7 trial (4.8 months). The modeled CA-125 elimination rate constant K (KELIM) parameter, based on the longitudinal CA-125 kinetics during the first 100 days of chemotherapy, is a potential indicator of the tumor primary chemo-sensitivity. In the ICON-7 trial dataset, the OS of patients within the low- and high-risk disease groups was assessed according to treatment arms and KELIM. Among the patients with high-risk diseases, those with favorable standardized KELIM of at least 1.0 (n = 214, 46.7%) had no survival benefit from bevacizumab, whereas those with unfavorable KELIM less than 1.0 (n = 244, 53.2%) derived the highest OS benefit (absolute difference = 9.1 months, 2-sided log-rank P = .10; Cox hazard ratio = 0.78, 95% confidence interval = 0.58 to 1.04, 2-sided P = .09).

Role of front-line bevacizumab in advanced ovarian cancer: the OSCAR study.

OBJECTIVE: Two randomized phase III trials demonstrated the efficacy and safety of combining bevacizumab with front-line carboplatin/paclitaxel for advanced ovarian cancer. The OSCAR (NCT01863693) study assessed the impact of front-line bevacizumab-containing therapy on safety and oncologic outcomes in patients with advanced ovarian cancer in the UK. METHODS: Between May 2013 and April 2015, patients with high-risk stage IIIB-IV advanced ovarian cancer received bevacizumab (7.5 or 15 mg/kg every 3 weeks, typically for ≤12 months, per UK clinical practice) combined with front-line chemotherapy, with bevacizumab continued as maintenance therapy. Co-primary endpoints were progression-free survival and safety (NCI-CTCAE v4.0). Patients were evaluated per standard practice/physician's discretion. RESULTS: A total of 299 patients received bevacizumab-containing therapy. The median age was 64 years (range 31-83); 80 patients (27%) were aged ≥70 years. Surgical interventions were primary debulking in 21%, interval debulking in 36%, and none in 43%. Most patients (93%) received bevacizumab 7.5 mg/kg with carboplatin/paclitaxel. Median duration of bevacizumab was 10.5 months(range <0.1-41.4); bevacizumab and chemotherapy were given in combination for a median of three cycles (range 1-10). Median progression-free survival was 15.4 (95% CI 14.5 to 16.9) months. Subgroup analyses according to prior surgery showed median progression-free survival of 20.8, 16.1, and 13.6 months in patients with primary debulking, interval debulking, and no surgery, respectively. Median progression-free survival was 16.1 vs 14.8 months in patients aged <70 versus ≥70 years, respectively. The 1-year overall survival rate was 94%. Grade 3/4 adverse events occurred in 54% of patients, the most common being hypertension (16%) and neutropenia (5%). Thirty-five patients (12%) discontinued bevacizumab for toxicity (most often for proteinuria (2%)). CONCLUSIONS: Median progression-free survival in this study was similar to that in the high-risk subgroup of the ICON7 phase III trial. Median progression-free survival was shortest in patients who did not undergo surgery.

A functional form for a representative individual arterial input function measured from a population using high temporal resolution DCE MRI.

PURPOSE: To measure the arterial input function (AIF), an essential component of tracer kinetic analysis, in a population of patients using an optimized dynamic contrast-enhanced (DCE) imaging sequence and to estimate inter- and intrapatient variability. From these data, a representative AIF that may be used for realistic simulation studies can be extracted. METHODS: Thirty-nine female patients were imaged on multiple visits before and during a course of neoadjuvant chemotherapy for breast cancer. A total of 97 T1 -weighted DCE studies were analyzed including bookend estimates of T1 and model-fitting to each individual AIF. Area under the curve and cardiac output were estimated from each first pass peak, and these data were used to assess inter- and intrapatient variability of the AIF. RESULTS: Interpatient variability exceeded intrapatient variability of the AIF. There was no change in cardiac output as a function of MR visit (mean value 5.6 ± 1.1 L/min) but baseline blood T1 increased significantly following the start of chemotherapy (which was accompanied by a decrease in hematocrit). CONCLUSION: The AIF in an individual patient can be measured reproducibly but the variability of AIFs between patients suggests that use of a population AIF will decrease the precision of tracer kinetic analysis performed in cross-patient comparison studies. A representative AIF is presented that is typical of the population but retains the characteristics of an individually measured AIF.

Exploratory outcome analyses according to stage and/or residual disease in the ICON7 trial of carboplatin and paclitaxel with or without bevacizumab for newly diagnosed ovarian cancer.

OBJECTIVE: In the randomized phase 3 ICON7 trial (ISRCTN91273375), adding bevacizumab to chemotherapy for newly diagnosed ovarian cancer significantly improved progression-free survival (PFS; primary endpoint) but not overall survival (OS; secondary endpoint) in the intent-to-treat (ITT) population. We explored treatment effect according to stage and extent of residual disease. METHODS: Patients with stage IIB-IV or high-risk (grade 3/clear-cell) stage I-IIA ovarian cancer were randomized to receive six cycles of carboplatin and paclitaxel either alone or with bevacizumab 7.5 mg/kg every 3 weeks followed by single-agent bevacizumab for 12 further cycles (total duration 12 months). Post hoc exploratory analyses of subgroups defined by stage and extent of residual disease at diagnosis within the stage IIIB-IV population (European indication) was performed. RESULTS: The PFS benefit from bevacizumab was seen consistently in all subgroups explored. The PFS hazard ratio was 0.77 (95% confidence interval [CI], 0.59-0.99) in 411 patients with stage IIIB-IV ovarian cancer with no visible residuum and 0.81 (95% CI, 0.69-0.95) in 749 patients with stage IIIB-IV disease and visible residuum. As in the ITT population, no OS difference was detected in any subgroup except the previously described 'high-risk' subgroup. Safety results in analyzed subgroups were consistent with the overall population. CONCLUSIONS: Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. In patients with stage III with >1 cm residuum, stage IV or inoperable disease, this translates into an OS benefit. No OS benefit or detriment was seen in other subgroups explored.

The clinical impact of using complex molecular profiling strategies in routine oncology practice.

Molecular profiling and functional assessment of signalling pathways of advanced solid tumours are becoming increasingly available. However, their clinical utility in guiding patients' treatment remains unknown. Here, we assessed whether molecular profiling helps physicians in therapeutic decision making by analysing the molecular profiles of 1057 advanced cancer patient samples after failing at least one standard of care treatment using a combination of next-generation sequencing (NGS), immunohistochemistry (IHC) and other specific tests. The resulting information was interpreted and personalized treatments for each patient were suggested. Our data showed that NGS alone provided the oncologist with useful information in 10-50% of cases (depending on cancer type), whereas the addition of IHC/other tests increased extensively the usefulness of the information provided. Using internet surveys, we investigated how therapy recommendations influenced treatment choice of the oncologist. For patients who were still alive after the provision of the molecular information (76.8%), 60.4% of their oncologists followed report recommendations. Most treatment decisions (93.4%) were made based on the combination of NGS and IHC/other tests, and an approved drug- rather than clinical trial enrolment- was the main treatment choice. Most common reasons given by physicians to explain the non-adherence to recommendations were drug availability and cost, which remain barriers to personalised precision medicine. Finally, we observed that 27% of patients treated with the suggested therapies had an overall survival > 12 months. Our study demonstrates that the combination of NGS and IHC/other tests provides the most useful information in aiding treatment decisions by oncologists in routine clinical practice.

Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1-3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer. METHODS: In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase. Participants were randomly allocated (2:3:3), with five stratification factors and in alternating blocks, to receive placebo alongside chemotherapy and then placebo only maintenance (arm A; reference), cediranib 20 mg once-daily alongside chemotherapy then placebo only maintenance (arm B; concurrent), or cediranib 20 mg once-daily alongside chemotherapy then cediranib 20 mg once-daily maintenance (arm C; maintenance). Patients continued treatment to progression or excessive toxic effects. The primary efficacy endpoint was progression-free survival between arms A and C. Efficacy analysis was by intention to treat. Safety was assessed in all patients who received the allocated study drug. This trial is registered with ClinicalTrials.gov, number NCT00532194; the ISRCTN registry, number ISRCTN68510403; and ANZ Clinical Trials Registry, number ACTRN1261000016003. FINDINGS: We randomly assigned 486 [corrected] women between Nov 13, 2007, and Dec 23, 2011; results presented are for 456 patients randomly assigned subsequent to the 30mg safety phase. During a median of 19·5 months (IQR 14-26) follow-up, 113 (96%) of 118 women assigned to arm A and 141 (86%) of 164 assigned to arm C had disease progression. Median progression-free survival was 11·0 months (95% CI 10·4-11·7) in arm C and 8·7 months (7·7-9·4) in arm A (hazard ratio 0·56, 0·44-0·72, p<0·0001). 156 (90%) of 174 patients in arm B had disease progression, and median progression-free survival was 9·9 months (95% CI 9·4-10·5). Diarrhoea, neutropenia, hypertension, and voice changes were significantly more common, during chemotherapy with cediranib, and diarrhoea, hypothyroidism and voice changes were more common during maintenance. Poor compliance with cediranib was noted during maintenance treatment with toxic effects being the most common cause for discontinuation. INTERPRETATION: Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful improvement [corrected] in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up. FUNDING: Medical Research Council, Cancer Research UK, Canadian Cancer Society Research Institute, Cancer Australia, National Gynecological Cancer Centre, and AstraZeneca.

Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial.

BACKGROUND: The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest effect in patients at high risk of disease progression. We report the final overall survival results of the trial. METHODS: ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I-IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb-IV), with an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin [AUC 5 or 6] and paclitaxel 175 mg/m(2) of body surface area) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375. FINDINGS: Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48·9 months (IQR 26·6-56·2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44·6 months [95% CI 43·2-45·9] in the standard chemotherapy group vs 45·5 months [44·2-46·7] in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34·5 months [95% CI 32·0-37·0] with standard chemotherapy vs 39·3 months [37·0-41·7] with bevacizumab; log-rank p=0·03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49·7 months [95% CI 48·3-51·1]) in the standard chemotherapy group vs 48·4 months [47·0-49·9] in the bevacizumab group; p=0·20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported. INTERPRETATION: Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer. FUNDING: The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche.

Ovarian cancer: advances in first-line treatment strategies with a particular focus on anti-angiogenic agents.

Ovarian cancer is an important health concern worldwide. The majority of patients present with advanced disease, and despite initial chemosensitivity, most relapse and die from their disease. Better therapeutic options are urgently required. Maximal surgical debulking in combination with platinum/taxane chemotherapy has been the standard of care in advanced ovarian cancer since the mid-1990s. Trials investigating the addition of a third chemotherapeutic agent have disappointingly failed to demonstrate benefit. Intra-peritoneal therapy demonstrated improvements in outcomes in some trials, but at the cost of increased toxicity and inconvenience. Encouragingly, prospective data has now demonstrated benefits with bevacizumab in both the first-line and relapsed settings; however, interpretation is complex, particularly considering recent data demonstrating non-inferiority of neo-adjuvant chemotherapy with delayed primary surgery, and other data demonstrating a substantial improvement in outcome as a result of first-line paclitaxel dose fractionation. This article reviews the recent advances in ovarian cancer treatment and discusses current management and key areas for future research.

Mucinous tumours of the ovary.

Mucinous epithelial ovarian cancers (mEOC) are a relatively rare subset of ovarian cancers. Despite a relatively favourable outcome in early disease, the more frequent advanced presentation is associated with poorer response to platinum/taxane chemotherapies, and poorer survival, compared to serous ovarian cancers. We consider some of the fundamental clinico-pathological and molecular features, and existing clinical trial data regarding mEOC. Underlying molecular differences, between mEOC and serous cancers may contribute to the observed clinical differences, including an increased prevalence of K-RAS mutations in mEOC, more in keeping with gastrointestinal tumours. This observation contributes to the rationale for a trial ("mEOC") investigating the use of "ovarian" versus "gastrointestinal" style chemotherapy. Looking to potential future approaches, we speculate upon the potential impact of emerging technologies on the future investigation and management of mEOC.

A phase 3 trial of bevacizumab in ovarian cancer.

BACKGROUND: Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. METHODS: We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival. RESULTS: A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months. CONCLUSIONS: Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).

Phase III multicenter clinical trial of the sialyl-TN (STn)-keyhole limpet hemocyanin (KLH) vaccine for metastatic breast cancer.

PURPOSE: This double-blind, randomized, phase III clinical trial evaluated time to progression (TTP) and overall survival in women with metastatic breast cancer (MBC) who received sialyl-TN (STn) keyhole limpet hemocyanin (KLH) vaccine. Secondary endpoints included vaccine safety and immune response. EXPERIMENTAL DESIGN: The study population consisted of 1,028 women with MBC across 126 centers who had previously received chemotherapy and had had either a complete or a partial response or no disease progression. All women received one-time i.v. cyclophosphamide (300 mg/m(2)) 3 days before s.c. injection of 100 µg STn-KLH plus adjuvant (treatment group) or 100 µg KLH plus adjuvant (control group) at weeks 0, 2, 5, and 9. Subsequently, STn-KLH without adjuvant or KLH without adjuvant was then administered monthly for 4 months, and then quarterly until disease progression, without cyclophosphamide. RESULTS: STn-KLH vaccine was well tolerated; patients had mild to moderate injection-site reactions and reversible flu-like symptoms. Week-12 antibody testing revealed high specific IgG titers and a high rate of IgM-to-IgG seroconversion; the median IgG titers in STn-KLH recipients were 320 (anti-ovine submaxillary mucin) and 20,480 (anti-STn), with no detectable antimucin antibodies in the control group. The TTP was 3.4 months in the treatment group and 3.0 months in the control group. The median survival times were 23.1 months and 22.3 months, respectively. CONCLUSIONS: Although STn-KLH was well tolerated in this largest to date metastatic breast cancer vaccine trial, no overall benefit in TTP or survival was observed. Lessons were learned for future vaccine study designs.

The prognostic and predictive value of CA-125 regression during neoadjuvant chemotherapy for advanced ovarian or primary peritoneal carcinoma.

PURPOSE: To assess the significance of CA-125 regression as a prognostic indicator and predictor of optimal cytoreduction at interval debulking surgery (IDS) in women with ovarian or primary peritoneal carcinoma receiving neoadjuvant chemotherapy (NAC). METHODS: 63 women treated between 2004 and 2007 with neoadjuvant platinum-based chemotherapy followed by IDS were studied retrospectively. Pre-operative CA-125 values were used to calculate a regression coefficient (CA-125r) using exponential regression analysis. Outcome endpoints were overall survival (OS), time to CA-125 progression (TTC) by Rustin criteria and time to second-line treatment (TTS). RESULTS: Women with a CA-125 half-life greater than 18 days had a significantly worse OS compared to those with a half-life less than 12 days on univariate testing (HR 3.34, 95% CI 1.25-8.94, p = 0.017). On multivariable analysis, CA-125r was an independent predictor of OS [HR 1.18 (per 0.01 increase in CA-125r), 95% CI 1.01-1.40, p = 0.043]. CA-125r was independently predictive of TTC and TTS (HR 1.17, p ≈ 0.03 for each). CA-125r was also predictive of achieving optimal cytoreduction at IDS (AUC 0.756, p < 0.001). CONCLUSIONS: CA-125 regression rate during pre-operative NAC is of independent prognostic value. CA-125 regression rate strongly predicts for optimal cytoreduction.

Recent EORTC and MRC UK studies: implications for imaging ovarian cancer.

For many years the primary management of newly diagnosed advanced ovarian cancer has been cytoreductive surgery followed by chemotherapy, and the mainstay of follow-up of treated women has been serial assay of serum CA-125. The findings of 2 recent research protocols have a significant effect on these aspects of management.

First-line therapy for ovarian cancer with carboplatin followed by paclitaxel-gemcitabine (SCOTROC5): a feasibility study and comparative analysis of the SCOTROC series.

BACKGROUND: We have conducted a series of four feasibility studies in stage Ic-IV ovarian cancer exploring six sequential first-line schedules with the same entry criteria in a total of 339 patients. Here we present the results of the sixth study, and an analysis of the overall series. METHODS: In this trial patients received 4 cycles of carboplatin AUC 7 every 3 weeks, followed by 4 cycles of concurrent paclitaxel 175 mg/m(2) (day 1) and gemcitabine 1000 mg/m(2) (days 1 and 8) every 3 weeks. The primary end-point of the trial was feasibility of administering all cycles of planned chemotherapy to >60% of patients. RESULTS: Fifty-four patients were recruited to the trial between June 05 and June 06. A total of 40 (74.1%) patients received all 8 cycles of treatment. Reasons for early discontinuation included toxicity (n=8) and disease progression (n=4). The overall response rate was 73.7%, and the median progression free survival (PFS) was 14.2 months with a median follow-up of 24 months. A comparative analysis of all six regimens from the SCOTROC series suggests that the sequential schedule in which paclitaxel was given weekly (median PFS 19.5m) is most effective. CONCLUSION: The sequential schedule explored in this trial is feasible, but comparative efficacy analysis suggests that trials involving weekly paclitaxel should be prioritised for further study.

Dose-finding study of weekly docetaxel, epirubicin and capecitabine, as first-line treatment in advanced breast cancer.

BACKGROUND: Combinations of anthracycline, taxane and fluoropyrimidine are highly active in advanced breast cancer (ABC). In a phase II study of epirubicin 50 mg/m(2), docetaxel 75 mg/m(2), and infusional 5-FU 200 mg/m(2)/day, we found dose-limiting neutropenia and frequent central venous catheter complications. An alternative approach has been tested using weekly fractionation of docetaxel, and oral capecitabine. METHODS: Initially, six women with ABC were treated with epirubicin 60 mg/m(2) day 1, docetaxel 25 mg/m(2) days 1,8,15, and capecitabine 1,000 mg/m(2) twice daily days 1-14, every 21 days. Six further patients received the above with capecitabine escalated to 1,500 mg/m(2) RESULTS: Four DLTs occurred in six patients at the second dose level (febrile neutropenia in 2). There were frequent dose delays/reductions, and fatigue, nausea/vomiting, and diarrhoea were common. Overall, six of ten assessable patients achieved a partial response. CONCLUSIONS: An active regimen, but significant haematological toxicity precluded dose further escalation.

Development of antiangiogenic agents for ovarian cancer.

Epithelial ovarian cancer (EOC) remains a major source of cancer morbidity and mortality, despite advances in surgical and chemotherapeutic management. The molecular pathways that control angiogenesis have been demonstrated to be key to the pathogenesis of EOC, and have been shown to have prognostic significance. Increased understanding of the pathways and molecules involved in angiogenesis has allowed the identification of a number of targets for antiangiogenic therapies and the development of a variety of antiangiogenic drugs. There is now significant preclinical evidence, and a growing body of clinical data, demonstrating promising results with antiangiogenic drugs in the treatment of EOC. Single-agent VEGF inhibitor response rates in pretreated patients of between 15 and 20% have been reported, with much higher response rates when used in combination with chemotherapeutic agents. These benefits, however, must be balanced with the toxicities associated with these drugs, particularly the more serious ones, such as gastrointestinal perforation. The results of ongoing and future randomized clinical trials will confirm if, and how, antiangiogenic therapies should be integrated into the routine management of EOC. However, critical issues, such as the relative importance of combination remission induction regimens and maintenance therapy, remain poorly defined.

Proteomic profiling identifies afamin as a potential biomarker for ovarian cancer.

PURPOSE: To discover and validate serum glycoprotein biomarkers in ovarian cancer using proteomic-based approaches. EXPERIMENTAL DESIGN: Serum samples from a "discovery set" of 20 patients with ovarian cancer or benign ovarian cysts or healthy volunteers were compared by fluorescence two-dimensional differential in-gel electrophoresis and parallel lectin-based two-dimensional profiling. Validation of a candidate biomarker was carried out with Western blotting and immunoassay (n = 424). RESULTS: Twenty-six proteins that changed significantly were identified by mass spectrometric sequencing. One of these, confirmed by Western blotting, was afamin, a vitamin E binding protein, with two isoforms decreasing in patients with ovarian cancer. Validation using cross-sectional samples from 303 individuals (healthy controls and patients with benign, borderline, or malignant ovarian conditions and other cancers) assayed by ELISA showed significantly decreased total afamin concentrations in patients with ovarian cancer compared with healthy controls (P = 0.002) and patients with benign disease (P = 0.046). However, the receiver operating characteristic areas for total afamin for the comparison of ovarian cancer with healthy controls or benign controls were only 0.67 and 0.60, respectively, with comparable figures for CA-125 being 0.92 and 0.88 although corresponding figures for a subgroup of samples analyzed by isoelectric focusing for afamin isoform 2 were 0.85 and 0.79. Analysis of a further 121 samples collected prospectively from 9 patients pretreatment through to relapse indicated complementarity of afamin with CA-125, including two cases in whom CA-125 was noninformative. CONCLUSIONS: Afamin shows potential complementarity with CA-125 in longitudinal monitoring of patients with ovarian cancer, justifying prospective larger-scale investigation. Changes in specific isoforms may provide further information.

Routine chest radiography following imaging-guided placement of tunneled central lines: a waste of time, money, and radiation.

BACKGROUND: This study sought to evaluate routine chest radiography following placement of tunneled central lines using combined ultrasound and fluoroscopic guidance. MATERIALS AND METHODS: A prospective study of 150 consecutive patients who underwent placement of tunneled central lines in the vascular radiology suite. Ultrasound-guided vein puncture was performed with an 18-gauge needle in each case, and the access site was noted. Line position was confirmed by fluoroscopy. Following the procedure, 50 patients had both an on-table digital chest radiograph and a conventional chest radiograph. Subsequent patients had a digital radiograph and a fluoroscopic image grab. Final line tip position was scored, and complications were recorded. RESULTS: Line placement was optimal (95%) or acceptable (5%) in all patients. Line tip position could be satisfactorily evaluated on supine fluoroscopy. Mean fluoroscopic x-ray dose was 0.5 cGy/cm2. Digital chest x-ray dose was 9.0 cGy/cm2, and formal chest radiography dose was 12.0 cGy/cm2. The only complications were 2 carotid artery punctures without clinical sequelae. CONCLUSION: When lines are placed under imaging guidance with ultrasound to direct the venous puncture, complications are rare and are not likely to be clinically important. Conventional and digital chest radiographs do not contribute clinically relevant information but do add to the radiation dose, time, and expense of the procedure.