Search

Background: Single-agent carboplatin at area under the curve 10 (AUC10) is an effective treatment for metastatic seminoma. As far as we are aware of, there have been no studies reporting its effects on short-term quality of life. The objective was to study the efficacy, safety and tolerability, using health-related quality of life, of carboplatin AUC10 chemotherapy in patients with metastatic seminoma., Patients and Methods: Forty-four patients with metastatic seminoma treated at Mount Vernon Cancer Centre with carboplatin AUC10 were included in this study. Response to treatment was determined by radiological imaging (Response Evaluation Criteria in Solid Tumors v 1.1) and serum tumour markers. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events Version 4.0. Quality of life treatment-related toxicities were assessed during treatment at pre-chemotherapy assessments. After treatment, toxicity was assessed using a defined telephone questionnaire consisting of four questions relating to hair loss, hearing impairment, days absent from work, and neuropathy., Results: At a median follow-up of 27.5 (range=4-84) months, no patient had experienced relapse. Grade 3/4 neutropenia was seen in 15 (35%) patients, nine (21%) required prophylactic granulocyte colony-stimulating factor, 13 (30%) patients had grade 3/4 thrombocytopenia. Commonest non-haematological toxicities were fatigue in 28 (65%) and nausea 14 (33%) patients. They were grade 1 in 82% and 92% of cases, respectively. Six out of 44 (14%) had residual tinnitus. One patient had residual grade 1 peripheral neuropathy. Ten patients continued to work throughout treatment and two patients were retired. Of the remaining patients, 16 (37%), took fewer than 5 days off work., Conclusion: Carboplatin AUC10 is a safe and effective treatment for stage II/III seminoma with better health-related quality of life than experienced with combination cisplatin-based chemotherapy., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: In Study 19, maintenance monotherapy with olaparib significantly prolonged progression-free survival vs placebo in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer., Methods: Study 19 was a randomised, placebo-controlled, Phase II trial enrolling 265 patients who had received at least two platinum-based chemotherapy regimens and were in complete or partial response to their most recent regimen. Patients were randomised to olaparib (capsules; 400 mg bid) or placebo. We present long-term safety and final mature overall survival (OS; 79% maturity) data, from the last data cut-off (9 May 2016)., Results: Thirty-two patients (24%) received maintenance olaparib for over 2 years; 15 (11%) did so for over 6 years. No new tolerability signals were identified with long-term treatment and adverse events were generally low grade. The incidence of discontinuations due to adverse events was low (6%). An apparent OS advantage was observed with olaparib vs placebo (hazard ratio 0.73, 95% confidence interval 0.55‒0.95, P = 0.02138) irrespective of BRCA1/2 mutation status, although the predefined threshold for statistical significance was not met., Conclusions: Study 19 showed a favourable final OS result irrespective of BRCA1/2 mutation status and unprecedented long-term benefit with maintenance olaparib for a subset of platinum-sensitive, recurrent ovarian cancer patients.

Objective: Etirinotecan pegol (EP) is a novel polyethylene glycol conjugated form of irinotecan with documented activity in platinum-resistant ovarian cancer (PROC). We report the results of the expanded portion of a phase II study of EP in patients with PROC who received prior pegylated liposomal doxorubicin (PLD) or who were unable to receive it., Methods: This multicenter, open-label, phase II study evaluated EP q21d for PROC. The primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.0. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Patient populations evaluated included a modified intent-to-treat (mITT) group consisting of all patients who received at least one dose and with measurable disease and a primary efficacy (pEFF) group (subset of the mITT population who received prior PLD)., Results: One hundred thirty-nine patients were enrolled. Of the 132 patients in the mITT group, 20 achieved an ORR (15.2%; 95% CI 9.5-22.4); median PFS and OS were 4.4 months and 10.2 months, respectively. In the pEFF group (n=104), 15 patients (14.4%; 95% CI 8.3-22.7) achieved an ORR; median PFS and OS were 4.4 months and 10.9 months, respectively. The most common grade 3/4 toxicities were diarrhea (20%), abdominal pain (17%), vomiting (14%), dehydration (13%), and nausea (13%). Severe diarrhea was reduced to 15% with strict adherence to screening and management guidelines., Conclusions: This study confirms the activity and safety of single-agent EP in patients with PROC, including patients who received prior PLD. Further evaluation earlier in the disease course and in combination is warranted., (Copyright © 2017. Published by Elsevier Inc.)

Aims: Trebananib, a peptide-Fc fusion protein, inhibits angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. This randomised, double-blind, placebo-controlled phase 3 study evaluated whether trebananib plus pegylated liposomal doxorubicin (PLD) improved progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer., Methods: Women with recurrent ovarian cancer (platinum-free interval ≤12 months) were randomised to intravenous PLD 50 mg/m 2 once every 4 weeks plus weekly intravenous trebananib 15 mg/kg or placebo. PFS was the primary end-point; key secondary end-points were objective response rate (ORR) and duration of response (DOR). Owing to PLD shortages, enrolment was paused for 13 months; the study was subsequently truncated., Results: Two hundred twenty-three patients were enrolled. Median PFS was 7.6 months (95% CI, 7.2-9.0) in the trebananib arm and 7.2 months (95% CI, 4.8-8.2) in the placebo arm, with a hazard ratio of 0.92 (95% CI, 0.68-1.24). However, because the proportional hazards assumption was not fulfilled, the standard Cox model did not provide a reliable estimate of the hazard ratio. ORR in the trebananib arm was 46% versus 21% in the placebo arm (odds ratio, 3.43; 95% CI, 1.78-6.64). Median DOR was improved (trebananib, 7.4 months [95% CI, 5.7-7.6]; placebo, 3.9 months [95% CI, 2.3-6.5]). Adverse events with a greater incidence in the trebananib arm included localised oedema (61% versus 32%), ascites (29% versus 9%) and vomiting (45% versus 33%)., Conclusions: Trebananib demonstrated anticancer activity in this phase 3 study, indicated by improved ORR and DOR. Median PFS was not improved. No new safety signals were identified., Trial Registration: ClinicalTrials.gov, NCT01281254., (Copyright © 2016. Published by Elsevier Ltd.)

Background: Maintenance monotherapy with the poly(ADP-ribose) polymerase inhibitor olaparib significantly prolongs progression-free survival over placebo in patients with platinum-sensitive relapsed serous ovarian cancer, with greatest benefit seen in patients with a BRCA1/2 mutation (BRCAm). Preservation of health-related quality of life (HRQoL) is important during maintenance therapy; we evaluated the effect of olaparib on HRQoL in this Phase II trial (NCT00753545, Study 19)., Methods: Patients received olaparib 400 mg b.i.d. (capsules) or placebo until progression. Patient-reported HRQoL and disease-related symptoms were evaluated using the FACT-Ovarian (FACT-O) questionnaire (completed at baseline and every 28 days until progression), the FACT/NCCN Ovarian Symptom Index (FOSI) and the Trial Outcome Index (TOI). TOI of the FACT-O was the primary measure., Results: Overall, 265 women were randomised to maintenance olaparib (n=136) or placebo (n=129). Compliance for HRQoL assessment was high (∼80% over time). Most patients in both arms reported a best response of 'no change' on TOI (81%) and other HRQoL measures. There were no statistically significant differences in time to worsening or improvement rates of TOI, FOSI and FACT-O scores in the overall, BRCAm and germline BRCAm populations., Conclusions: Maintenance treatment with olaparib was well tolerated and had no adverse impact on HRQoL in this study of patients with platinum-sensitive relapsed serous ovarian cancer who had responded to their most recent platinum-based therapy (partial or complete response). Interpretation of the HRQoL results in this population may differ from patients who have not responded to their most recent platinum-based therapy., Competing Interests: JAL has participated in an advisory board for AstraZeneca. PH has acted in an advisory role for AstraZeneca and received honoraria from AstraZeneca. CG has acted in an advisory role for AstraZeneca, Clovis, Roche and Nucana, received honoraria from AstraZeneca and Roche, and received research funding from AstraZeneca, Novartis and Aprea. MF has participated in advisory boards for AstraZeneca, Clovis, Pfizer and Roche and received honoraria from AstraZeneca, Pfizer and Roche. IV has acted in an advisory role for AstraZeneca. GR has participated in advisory boards for AstraZeneca and Clovis. CS has acted in an advisory role for AstraZeneca, Clovis and Eisai Australia, received honoraria from AstraZeneca and Roche, provided expert testimony on behalf of AstraZeneca and received remuneration for travel from AstraZeneca. RS-F has participated in an advisory board for AstraZeneca. TS has acted in an advisory role for AstraZeneca and Clovis and received honoraria from AstraZeneca and Clovis. DM has acted in an advisory role for AstraZeneca and received honoraria from AstraZeneca. AF, DP, SS and HM are employees of AstraZeneca and own stock. UM has acted in an advisory role for AstraZeneca and Tesaro. All remaining authors declare no conflicts of interest.

Background: In patients with platinum-sensitive recurrent serous ovarian cancer, maintenance monotherapy with the PARP inhibitor olaparib significantly improves progression-free survival versus placebo. We assessed the effect of maintenance olaparib on overall survival in patients with platinum-sensitive recurrent serous ovarian cancer, including those with BRCA1 and BRCA2 mutations (BRCAm)., Methods: In this randomised, placebo-controlled, double-blind, phase 2 trial involving 82 sites across 16 countries, patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more courses of platinum-based chemotherapy and had responded to their latest regimen were randomly assigned (1:1) using a computer-generated sequence to receive oral maintenance olaparib (as capsules; 400 mg twice a day) or a matching placebo by an interactive voice response system. Patients were stratified by ancestry, time to progression on penultimate platinum, and response to most recent platinum. Patients and investigators were masked to treatment assignment by the use of unique identifiers generated during randomisation. The primary endpoint of the trial was progression-free survival. In this updated analysis, we present data for overall survival, a secondary endpoint, from the third data analysis after more than 5 years' follow-up (intention-to-treat population). We did the updated overall survival analysis, described in this Article at 77% data maturity, using a two-sided α of 0·95%. As the study was not powered to assess overall survival, this analysis should be regarded as descriptive and the p values are nominal. We analysed randomly assigned patients for overall survival and all patients who received at least one dose of treatment for safety. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT00753545., Findings: Between Aug 28, 2008, and Feb 9, 2010, 265 patients were randomly assigned to olaparib (n=136) or placebo (n=129). 136 patients had deleterious BRCAm. The data cutoff for this analysis was Sept 30, 2015. An overall survival advantage was seen with maintenance olaparib versus placebo in all patients (hazard ratio [HR] 0·73 [95% CI 0·55-0·96]; nominal p=0·025, which did not meet the required threshold for statistical significance [p<0·0095]; median overall survival was 29·8 months [95% CI 26·9-35·7] for those treated with olaparib vs 27·8 months [24·9-33·7] for those treated with placebo), and in patients with BRCAm (HR 0·62 [95% CI 0·41-0·94] nominal p=0·025; 34·9 months [95% CI 29·2-54·6] vs 30·2 months [23·1-40·7]). The overall survival data in patients with BRCA wild-type were HR 0·83 (95% CI 0·55-1·24, nominal p=0·37; 24·5 months [19·8-35·0] for those treated with olaparib vs 26·6 months [23·1-32·5] for those treated with placebo). 11 (15%) of 74 patients with BRCAm received maintenance olaparib for 5 years or more. Overall, common grade 3 or worse adverse events in the olaparib and placebo groups were fatigue (11 [8%] of 136 patients vs four [3%] of 128) and anaemia (eight [6%] vs one [1%]). 30 (22%) of 136 patients in the olaparib group and 11 (9%) of 128 patients in the placebo group reported serious adverse events. In patients treated for 2 years or more, adverse events in the olaparib and placebo groups included low-grade nausea (24 [75%] of 32 patients vs two [40%] of five), fatigue (18 [56%] of 32 vs two [40%] of five), vomiting (12 [38%] of 32 vs zero), and anaemia (eight [25%] of 32 vs one [20%] of five); generally, events were initially reported during the first 2 years of treatment., Interpretation: Despite not reaching statistical significance, patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy after platinum-based chemotherapy appeared to have longer overall survival, supporting the reported progression-free survival benefit. Clinically useful long-term exposure to olaparib was seen with no new safety signals. Taken together, these data support both the long-term clinical benefit and tolerability of maintenance olaparib in patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer., Funding: AstraZeneca., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To assess surgical morbidity and mortality of maximal effort cytoreductive surgery for disseminated epithelial ovarian cancer (EOC) in a UK tertiary center., Methods/materials: A monocentric prospective analysis of surgical morbidity and mortality was performed for all consecutive EOC patients who underwent extensive cytoreductive surgery between 01/2013 and 12/2014. Surgical complexity was assessed by the Mayo clinic surgical complexity score (SCS). Only patients with high SCS ≥5 were included in the analysis., Results: We evaluated 118 stage IIIC/IV patients, with a median age of 63 years (range 19-91); 47.5 % had ascites and 29 % a pleural effusion. Median duration of surgery was 247 min (range 100-540 min). Median surgical complexity score was 10 (range 5-15) consisting of bowel resection (71 %), stoma formation (13.6 %), diaphragmatic stripping/resection (67 %), liver/liver capsule resection (39 %), splenectomy (20 %), resection stomach/lesser sac (26.3 %), pleurectomy (17 %), coeliac trunk/subdiaphragmatic lymphadenectomy (8 %). Total macroscopic tumor clearance rate was 89 %. Major surgical complication rate was 18.6 % (n = 22), with a 28-day and 3-month mortality of 1.7 and 3.4 %, respectively. The anastomotic leak rate was 0.8 %; fistula/bowel perforation 3.4 %; thromboembolism 3.4 % and reoperation 4.2 %. Median intensive care unit and hospital stay were 1.7 (range 0-104) and 8 days (range 4-118), respectively. Four patients (3.3 %) failed to receive chemotherapy within the first 8 postoperative weeks., Conclusions: Maximal effort cytoreductive surgery for EOC is feasible within a UK setting with acceptable morbidity, low intestinal stoma rates and without clinically relevant delays to postoperative chemotherapy. Careful patient selection, and coordinated multidisciplinary effort appear to be the key for good outcome. Future evaluations should include quality of life analyses.

Background: Maintenance treatment with the oral poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib (Lynparza) in Study 19 (study number, D0810C00019; ClinicalTrials.gov identifier, NCT00753545) significantly improved progression-free survival in comparison with a placebo for patients with platinum-sensitive, relapsed serous ovarian cancer with a BRCA1/2 mutation (BRCAm), but an interim analysis revealed no statistically significant overall survival (OS) benefit. However, 23% of the patients receiving the placebo switched to a PARP inhibitor after progression. To investigate whether this had a confounding effect on OS, this article reports an exploratory post hoc analysis that excluded all patients from sites where 1 or more placebo patients received postprogression PARP inhibitor treatment., Methods: In Study 19, 136 of the 265 patients receiving olaparib or a placebo had a BRCAm. Sixteen patients treated at 11 of the 82 investigational sites received a PARP inhibitor after progression; these sites were excluded from this analysis, and 97 BRCAm patients at 50 sites were included. OS was assessed with a Cox proportional hazards model analogous to the primary study analysis. A supporting rank-preserving structural failure time (RPSFT) model analysis was undertaken for all 136 BRCAm patients., Results: The OS hazard ratio (HR) was 0.52 (95% confidence interval [CI], 0.28-0.97) for the 97 BRCAm patients, whereas for the interim OS analysis with all 136 BRCAm patients, it was 0.73 (95% CI, 0.45-1.17). The supportive RPSFT analysis HR was approximately 0.66., Conclusions: The numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCAm patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity. Cancer 2016;122:1844-52. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background: Olaparib is poorly soluble, requiring advanced drug delivery technologies for adequate bioavailability. Sixteen capsules/day are required for the approved 400 mg twice-daily dose; a tablet formulation was developed to reduce pill burden. This clinical trial evaluated the optimal dose and administration schedule of the tablet formulation., Patients and Methods: Two stages of sequentially enrolled cohorts: stage 1, pharmacokinetic properties of tablet and capsule formulations were compared in patients with advanced solid tumours; stage 2, tablet dose escalation with expansion cohorts at doses/schedules of interest in patients with solid tumours and BRCAm breast/ovarian cancers., Results: Olaparib 200 mg tablets displayed similar Cmax,ss, but lower AUCss and Cmin,ss than 400 mg capsules. Following multiple dosing, steady-state exposure with tablets ≥300 mg matched or exceeded that of 400 mg capsules. After dose escalation, while 400 mg twice daily was the tablet maximum tolerated dose based on haematological toxicity, 65 % of patients in the randomized expansion phase eventually required dose reduction to 300 mg. Intermittent tablet administration did not significantly improve tolerability. Tumour shrinkage was similar for 300 and 400 mg tablet and 400 mg capsule cohorts., Conclusions: The recommended monotherapy dose of olaparib tablet for Phase III trials was 300 mg twice daily, simplifying drug administration from 16 capsules to four tablets per day., Clinical Trial Number: NCT00777582 (ClinicalTrials.gov).

"Clinical equipoise" is defined as the genuine uncertainty by the expert medical community of the most beneficial treatment. A survey performed in 2013 by a patient support group, Ovacome, of gynaecological oncologists in the UK on ultra-radical surgery in advanced ovarian cancer has shown that there is a wide variation in surgical practice across the country. In addition, there were mixed views on the quality of published evidence justifying it's performance, signifying a state of clinical equipoise. The survey also identified widespread insufficient infra-structural resources and lack of surgical training and skills. The majority of respondents would be prepared to undertake additional training to acquire the surgical skills and/or refer to other centres/surgeons already performing the surgery and/or recruit to surgical trials investigating ultra-radical surgery in advanced ovarian cancer.

Background: Postoperative atrial fibrillation (POAF) is the most frequent complication of cardiac surgery and is associated with increased morbidity and mortality. Pharmacologic prophylaxis is the main method of preventing POAF but needs to be targeted to patients at high risk of developing POAF. The CHA2DS2-VASc scoring system is a clinical guideline for assessing ischemic stroke risk in patients with atrial fibrillation. The present study evaluated the utility of this scoring system in predicting the risk of developing de novo POAF in cardiac surgery patients., Materials and Methods: A total of 2385 patients undergoing cardiac surgery at our institution from 2008-2014 were identified for analysis. Each patient was assigned a CHA2DS2-VASc score and placed into a low- (score of 0), intermediate- (1), or high-risk (≥2) group. A multivariate regression model was created to control for known risk factors of atrial fibrillation., Results: POAF occurred in 380 of 2385 patients (15.9%). Mean CHA2DS2-VASc scores among patients with POAF and without POAF were 3.6 ± 1.7 and 2.8 ± 1.7, respectively (P < 0.0001). Using multivariate analysis, as a patient's CHA2DS2-VASc score rose from 0-9, the risk of developing POAF increased from 8.2%-42.3%. Each point increase was associated with higher odds of developing POAF (adjusted odds ratio, 1.27; 95% confidence interval, 1.18-1.36, P < 0.0001). Compared with low-risk patients, patients in the high-risk group were 5.21 times more likely to develop POAF (P < 0.0001)., Conclusions: The CHA2DS2-VASc algorithm is a simple risk-stratification tool that could be used to direct pharmacologic prophylaxis toward patients most likely to experience POAF., (Published by Elsevier Inc.)

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., (Copyright © 2015 Oza et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Background: Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. We aimed to explore the hypothesis that olaparib is most likely to benefit patients with a BRCA mutation., Methods: We present data from the second interim analysis of overall survival and a retrospective, preplanned analysis of data by BRCA mutation status from our randomised, double-blind, phase 2 study that assessed maintenance treatment with olaparib 400 mg twice daily (capsules) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Randomisation was by an interactive voice response system, stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomisation, and ethnic descent. The primary endpoint was PFS, analysed for the overall population and by BRCA status. This study is registered with ClinicalTrials.gov, number NCT00753545., Findings: Between Aug 28, 2008, and Feb 9, 2010, 136 patients were assigned to olaparib and 129 to placebo. BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA mutation. Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11·2 months [95% CI 8·3-not calculable] vs 4·3 months [3·0-5·4]; HR 0·18 [0·10-0·31]; p<0·0001); similar findings were noted for patients with wild-type BRCA, although the difference between groups was lower (7·4 months [5·5-10·3] vs 5·5 months [3·7-5·6]; HR 0·54 [0·34-0·85]; p=0·0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0·88 [95% CI 0·64-1·21]; p=0·44); similar findings were noted for patients with mutated BRCA (HR 0·73 [0·45-1·17]; p=0·19) and wild-type BRCA (HR 0·99 [0·63-1·55]; p=0·96). The most common grade 3 or worse adverse events in the olaparib group were fatigue (in ten [7%] patients in the olaparib group vs four [3%] in the placebo group) and anaemia (seven [5%] vs one [<1%]). Serious adverse events were reported in 25 (18%) patients who received olaparib and 11 (9%) who received placebo. Tolerability was similar in patients with mutated BRCA and the overall population., Interpretation: These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment., Funding: AstraZeneca., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2'-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer., Methods: Patients progressing 6-12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma., Results: After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%)., Conclusions: With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.

Objective: Epithelial ovarian cancers (EOCs) are, although still treated as a single disease entity, often classified into type I tumors (low-grade serous, mucinous, endometrioid, clear cell) and type II tumors (high-grade serous, undifferentiated cancers, carcinosarcomas). The aim of our study was to determine the incidence, clinical relevance, and prognostic and predictive impact of somatic mutations in both types I and II EOCs., Methods: Two hundred sixty-two evaluable, primary, high-risk stage I (grade 3, or aneuploid grade 1 or 2, or clear cell) and stage II-IV EOCs, collected at the University Hospitals Leuven and within the European Organisation for Research and Treatment of Cancer 55971 trial, were genotyped for hotspot mutations in KRAS (COSMIC [Catalogue of Somatic Mutations in Cancer] coverage >97%), BRAF (>94%), NRAS (>97%), PIK3CA (>79%), PTEN, FBXW7 (>57%), AKT2, AKT3, and FOXL2, using Sequenom MassARRAY., Results: Of the 13% histopathologically classified type I tumors, 49% were KRAS or PIK3CA mutant versus only 2.9% in the type II tumors (87%). Mucinous subtypes harbored significantly more KRAS mutations than all nonmucinous tumors (50% vs 4%, P < 0.001). PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis. Moreover, low-grade serous tumors were more frequently KRAS or BRAF mutated (44%) than high-grade serous tumors (0.6%). KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival. Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%)., Conclusions: Somatic mutations are rare in type II EOCs, whereas type I EOCs contain distinct diseases with different driver mutations. In general, these tumors respond worse to standard paclitaxel carboplatin therapy. Clinical trials with molecular targeted therapy in the different subtypes of type I tumors are urgently needed using this theragnostic information.

Purpose: Etirinotecan pegol (NKTR-102) is a unique, long-acting topoisomerase-I inhibitor with prolonged systemic exposure to SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan. This randomized phase II trial investigated two dosing schedules of etirinotecan pegol in patients with platinum-resistant/refractory ovarian carcinoma., Patients and Methods: A total of 71 eligible patients were randomly assigned to receive etirinotecan pegol 145 mg/m(2) every 14 or 21 days until progression or unacceptable adverse events (AEs). The primary end point was objective response rate (ORR) by RECIST (version 1.0). Secondary end points included response by Gynecologic Cancer Intergroup criteria, duration of ORR, progression-free survival (PFS), and overall survival (OS)., Results: The overall confirmed ORR was 20% (95% CI, 10% to 30%): 20% for once every 14 days, and 19% for once every 21 days. Median response duration was 4.1 months for once every 14 days and 4.0 months for once every 21 days. Median PFS for every 14 and every 21 days was 4.1 and 5.3 months, respectively, and median OS was 10.0 and 11.7 months, respectively. Etirinotecan pegol was well tolerated, with the most common grade 3 to 4 AEs being dehydration (24%) and diarrhea (23%). Diarrhea, dehydration, nausea, and neutropenia were less frequent with the schedule of once every 21 days than with that of once every 14 days., Conclusion: Both schedules of etirinotecan pegol showed activity in patients with heavily pretreated ovarian cancer, with encouraging ORR and PFS rates. The schedule of once every 21 days was better tolerated and had slightly longer PFS and OS rates. The treatment schedule of etirinotecan pegol 145 mg/m(2) once every 21 days was selected for the expanded phase II study and is preferred for future phase III studies. These findings provide support to directly compare etirinotecan pegol versus one of the approved drugs (eg, pegylated liposomal doxorubicin or topotecan) in platinum-resistant ovarian cancer.

Objective: The EORTC 55971 trial compared primary debulking surgery (PDS) versus neo-adjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). The impact of both treatment arms on quality of life (QOL) is reported., Methods: Patients with stages IIIc or IV ovarian cancer completed the EORTC QLQ-C30 before treatment, at the third and sixth cycle of chemotherapy, and at 6- and 12-month follow-up., Results: Data of 404 patients (N=201 PDS arm; N=203 IDS arm) were included in the QOL analysis. Between treatment arms no statistically significant differences were found in any of the QOL functioning scales. Patients showed a clinically relevant improvement (>10 points) on the global health/QOL, role functioning, emotional functioning and social functioning scales during and after treatment independent of the type of treatment. Clinically relevant differences from baseline to the follow-up assessments were noted for fatigue, pain, insomnia, appetite loss, constipation, diarrhea indicating symptom control in both treatment arms. Institutions with good QOL compliance were associated with better outcomes. There was a statistical significant difference in the overall debulking status with 39.9% optimal debulking surgery in institutions with good QOL compliance compared to 19.9% in institutions with poor QOL compliance (p=0.0011). Overall survival (median 32.30 versus 23.29 months; p=0.0006) and progression free survival (median 12.35 versus 9.92 months; p=0.0002) were also significantly better., Conclusions: Survival and QOL after NACT followed by surgery was similar to survival and QOL after PDS followed by chemotherapy. However, institutions with good QOL compliance had better survival outcomes., (© 2013.)

Background: The aim of the study is to demonstrate that intrapatient dose escalation of carboplatin would improve the outcome in ovarian cancer compared with flat dosing., Patients and Methods: Patients with untreated stage IC-IV ovarian cancer received six cycles of carboplatin area under the curve 6 (AUC 6) 3 weekly either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2-6 based on nadir neutrophil and platelet counts (Arm B). The primary end-point was progression-free survival (PFS)., Results: Nine hundred and sixty-four patients were recruited from 71 centers. Dose escalation was achieved in 77% of patients who had ≥1 cycle. The median AUCs (cycle 2-6) received were 6.0 (Arm A) and 7.2 (Arm B) (P < 0.001). Grade 3/4 non-hematological toxicity was higher in Arm B (31% versus 22% P = 0.001). The median PFS was 12.1 months in Arm A and B [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.85-1.15; P = 0.93]. The median overall survival (OS) was 34.1 and 30.7 months in Arms A and B, respectively (HR 0.98; 95% CI 0.81-1.18, P = 0.82). In multivariate analysis, baseline neutrophil (P < 0.001), baseline platelet counts (P < 0.001) and the difference between white blood cell (WBC) and neutrophil count (P = 0.009) had a significant adverse prognostic value., Conclusions: Intrapatient dose escalation of carboplatin based on nadir blood counts is feasible and safe. However, it provided no improvement in PFS or OS compared with flat dosing. Baseline neutrophils over-ride nadir counts in prognostic significance. These data may have wider implications particularly in respect of the management of chemotherapy-induced neutropenia.

Ovarian cancer presents at advanced stage in around 75% of women, and despite improvements in treatments such as chemotherapy, the 5-year survival from the disease in women diagnosed between 1996 and 1999 in England and Wales was only 36%. Over 80% of patients with advanced ovarian cancer will relapse and despite a good chance of remission from further chemotherapy, they will usually die from their disease. Sequential treatment strategies are employed to maximise quality and length of life but patients eventually become resistant to cytotoxic agents. The expansion in understanding of the molecular biology that characterises cancer cells has led to the rapid development of new agents to target important pathways but the heterogeneity of ovarian cancer biology means that there is no predominant defect. This review attempts to discuss progress to date in tackling a more general target applicable to ovary cancer-angiogenesis.

Background: OXi4503 is a tubulin-binding vascular disrupting agent that has recently completed a Cancer Research UK-sponsored phase I trial. Preclinical studies demonstrated early drug-induced apoptosis in tumour endothelial cells at 1-3 h and secondary tumour cell necrosis between 6 and 72 h., Methods: To capture both possible outcomes of OXi4503 treatment on cell death, plasma samples for analysis by M30 and M65 ELISAs, which measure different circulating forms of cytokeratin 18 as biomarkers of apoptosis and necrosis, respectively, were collected from patients entered into the trial at early (4/6 h) and later time points (24h, day 8 and day 15)., Results: OXi4503 induced a selective dose-dependent elevation in M30 antigen levels (apoptosis) at 4/6 h and a similar elevation in M65 antigen levels at 24 h (necrosis) consistent with its preclinical cell death profile. For the purposes of investigating potential biomarker relationships to patient characteristics, the trial population was divided into three groups based on radiological and clinical response: (a) early progression, (b) progressive disease and (c) stable disease (SD)/partial response. A significant increase in antigen concentrations was measured by M65 at 24 h in the SD group compared with the two other groups (P=0.015, mean increase 30.9%)., Conclusion: These results provide pharmacodynamic evidence of drug mechanism of action in cancer patients and highlight the M65 ELISA as a potentially useful biomarker assay of response to OXi4503., (© 2012 Cancer Research UK)

Background: Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations., Methods: We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines., Results: Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75)., Conclusions: Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).

Background: Only one randomized trial has examined the value of performing routine CA125 measurements during follow-up of ovarian cancer. The results of this trial and implications of frequent CA125 measurements are examined., Patients and Methods: The Medical Research Council OV05/European Organisation for Research and Treatment of Cancer 55955 trial enrolled 1442 patients with a CA125 level within the normal range following platinum-based chemotherapy for epithelial ovarian cancer. If CA125 levels rose to more than twice the upper limit of normal, patients were randomized to immediate or delayed chemotherapy., Results: Those randomized in the early arm started chemotherapy a median of 4.8 months earlier than those on the delayed arm. There was no difference in survival between the early and delayed arms., Conclusions: Women should be advised not to have routine CA125 measurements, providing they are well and have no symptoms suggesting relapse. In asymptomatic patients with a rising CA125 level, chemotherapy can be delayed. Earlier stopping of maintenance therapy just because of rising CA125 might deny patients continuing benefit from that therapy. Use of CA125 to define progression could result in platinum-sensitive patients being falsely classified as platinum resistant.

Notwithstanding continuing efforts to improve the primary treatment for ovarian cancer, most patients will ultimately develop recurrent disease. The benefits of detection and early systemic treatment of recurrence are now in doubt following the presentation of the MRC/EORTC CA125 surveillance trial. The impact of secondary cytoreductive surgery on survival requires more investigation. The role of antiangiogenic and other biological agents such as PARP inhibitors is becoming increasingly important for patients as an addition or alternative to the more conventional cytotoxic therapies available. Uncertainties and choices abound both in the treatment of recurrent ovarian cancer and the timing of such interventions. This article not only explores how to treat these patients but also the controversial issue of when to treat. Educating and involving the patient in decisions about their treatment options is of paramount importance.

Background: Sagopilone, the first fully synthetic epothilone, has shown promising preclinical activity in tumour models. This open-label randomised phase II study investigated two infusion schedules of sagopilone in women with ovarian cancer., Patients and Methods: Women with ovarian cancer recurring within 6 months of end of last platinum-containing treatment received sagopilone 16 mg/m(2) as a 3- or 0.5-h i.v. infusion every 21 days for up to 6 weeks., Results: Sixty-three patients received sagopilone as a 3-h (n=38) or 0.5-h (n=25) infusion. There were nine confirmed tumour responses [by modified RECIST (n=8) and by Gynecologic Cancer Intergroup CA-125 criteria (n=1)] in 57 patients assessable for efficacy overall [three (13%) with 0.5-h and six (18%) with 3-h infusions]. The 0.5-h arm was closed when it failed to meet its target efficacy. Main drug-related adverse events were peripheral sensory neuropathy (73%; 16% grade 3), nausea (37%; 2% grade 3), fatigue (35%; 3% grade 3) and arthralgia (30%; 5% grade 3). Overall incidence of peripheral sensory neuropathy was similar in both treatment arms, with no grade 4 neuropathy events. No acute allergic infusion reactions were observed., Conclusion: Sagopilone is effective, with balanced tolerability, in patients with recurrent platinum-resistant ovarian cancer.

Purpose: Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer. We investigated the efficacy and safety of a novel agent, BIBF 1120, a triple angiokinase inhibitor, after chemotherapy for relapsed disease., Patients and Methods: We conducted a randomized, double-blind, controlled phase II trial in 83 patients who had just completed chemotherapy for relapsed ovarian cancer, with evidence of response, but at high risk of further early recurrence. The patients were randomly assigned to receive maintenance therapy using BIBF 1120 250 mg or placebo, twice per day, continuously for 36 weeks. End points were progression-free survival (PFS), toxicity, and overall survival., Results: Thirty-six-week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P = .06). Four patients continued on BIBF 1120, including two patients for another year or more. The proportion of patients with any grade 3 or 4 adverse events was similar between the groups (34.9% for BIBF 1120 v 27.5% for placebo; P = .49; mostly grade 3). However, more patients on BIBF 1120 experienced diarrhea, nausea, or vomiting (mainly grade 1 or 2 and no grade 4). There was a higher rate of grade 3 or 4 hepatotoxicity in patients on BIBF 1120 (51.2%) compared with patients on placebo (7.5%; P < .001), but this was rarely of clinical significance, and patients continued with the trial treatment. A single-level dose reduction to 150 mg was made in 15 patients, all on active drug., Conclusion: BIBF 1120 is well tolerated and associated with a potential improvement in PFS. The observed treatment effect is sufficient to justify further study within a large phase III trial.

Background: A previous dose-escalation trial of the vascular disrupting agent combretastatin A4 phosphate (CA4P) given before carboplatin, paclitaxel, or both showed responses in 7 of 18 patients with relapsed ovarian cancer., Patients and Methods: Patients with ovarian cancer that had relapsed and who could start trial therapy within 6 months of their last platinum chemotherapy were given CA4P 63 mg/m(2) minimum 18 h before paclitaxel 175 mg/m(2) and carboplatin AUC (area under the concentration curve) 5, repeated every 3 weeks., Results: Five of the first 18 patients' disease responded, so the study was extended and closed after 44 patients were recruited. Grade ≥2 toxic effects were neutropenia in 75% and thrombocytopenia in 9% of patients (weekly blood counts), tumour pain, fatigue, and neuropathy, with one patient with rapidly reversible ataxia. Hypertension (23% of patients) was controlled by glyceryl trinitrate or prophylactic amlodipine. The response rate by RECIST was 13.5% and by Gynecologic Cancer InterGroup CA 125 criteria 34%., Conclusions: The addition of CA4P to paclitaxel and carboplatin is well tolerated and appears to produce a higher response rate in this patient population than if the chemotherapy was given without CA4P. A planned randomised trial will test this hypothesis.

Background: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors., Patients and Methods: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD., Results: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts., Conclusion: In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.

There is now a greater understanding of the molecular pathways in ovarian cancer, and using this knowledge, a large number of new therapeutic agents can be tested. The success of these drugs will depend on selecting drugs that target known key dysfunctional molecular pathways. To make best use of these compounds, prognostic and predictive biomarkers need to be identified. Novel methods of assessment such as functional imaging need to be developed as additional biological end points to evaluate these therapies. Promising antitumor activity has been observed with some drugs, and careful consideration is needed to determine in what circumstances new agents, such as antiangiogenic compounds, could be considered as a standard therapy. These areas were discussed at the 4th Ovarian Cancer Consensus Conference.

Background: The vascular disrupting agent combretastatin A4 phosphate (CA4P) causes major regression of animal tumours when given as combination therapy., Methods: Patients with advanced cancer refractory to standard therapy were treated with CA4P as a 10-min infusion, 20 h before carboplatin, paclitaxel, or paclitaxel, followed by carboplatin., Results: Combretastatin A4 phosphate was escalated from 36 to 54 mg m(-2) with the carboplatin area under the concentration curve (AUC) 4-5, from 27 to 54 mg m(-2) with paclitaxel 135-175 mg m(-2), and from 54 to 72 mg m(-2) with carboplatin AUC 5 and paclitaxel 175 mg m(-2). Grade 3 or 4 neutropenia was seen in 17%, and thrombocytopenia only in 4% of 46 patients. Grade 1-3 hypertension (26% of patients) and grade 1-3 tumour pain (65% of patients) were the most typical non-haematological toxicities. Dose-limiting toxicity of grade 3 hypertension or grade 3 ataxia was seen in two patients at 72 mg m(-2). Responses were seen in 10 of 46 (22%) patients with ovarian, oesophageal, small-cell lung cancer, and melanoma., Conclusion: The combination of CA4P with carboplatin and paclitaxel was well tolerated in the majority of patients with adequate premedication and had antitumour activity in patients who were heavily pretreated.

Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

Functional imaging is becoming increasingly important in the evaluation of cancer patients because of the limitations of morphologic imaging, particularly in the assessment of response to therapy. Diffusion-weighted magnetic resonance (MR) imaging has been established as a useful functional imaging tool in neurologic applications for a number of years, but recent technical advances now allow its use in abdominal and pelvic applications. Diffusion-weighted MR imaging studies of female pelvic tumors have shown reduced apparent diffusion coefficient (ADC) values within cervical and endometrial tumors. In addition, this unique noninvasive modality has demonstrated the capacity to help discriminate between benign and malignant uterine lesions and to help assess the extent of peritoneal spread from gynecologic malignancies. Potential pitfalls can be avoided by reviewing diffusion-weighted MR imaging findings in conjunction with anatomic imaging findings. Increasing familiarity with ADC calculation and manipulation software will allow radiologists to provide new information for the care of patients with known or suspected gynecologic malignancies.

Background: Interrupting tumour blood flow and delivery of nutrients to cause tumour death is the aim of antiangiogenic and vascular disrupting agents (VDAs). ASA404 is the first VDA to enter Phase III trials., Objective: We review the preclinical and clinical data on this interesting agent and consider its place in modern therapeutics., Methods: PubMed database was searched for 'ASA404', 'AS1404', 'DMXAA', 'vascular disrupting agents', 'ASA404 clinical trials', 'AS1404 clinical trials', 'DMXAA clinical trials'., Results/conclusions: ASA404 is a tumour VDA that is well tolerated and has shown promise in the treatment of NSCLC in combination with paclitaxel and carboplatin. A confirmatory Phase III trial is currently ongoing.

Combretastatin-A4-phosphate (CA4P) acts most effectively against immature tumour vasculature. We investigated whether histological angiogenic profile can explain the differential sensitivity of human tumours to CA4P, by correlating the kinetic changes demonstrated by dynamic MRI (DCE-MRI) in response to CA4P, with tumour immunohistochemical angiogenic markers. Tissue was received from 24 patients (mean age 59, range 32-73, 18 women, 6 men). An angiogenic profile was performed using standard immunohistochemical techniques. Dynamic MRI data were obtained for the same patients before and 4 h after CA4P. Three patients showed a statistically significant fall in K(trans) following CA4P, and one a statistically significant fall in IAUGC(60). No statistically significant correlations were seen between the continuous or categorical variables and the DCE-MRI kinetic parameters other than between ang-2 and K(trans) (P=0.044). In conclusion, we found no strong relationships between changes in DCE-MRI kinetic variables following CA4P and the immunohistochemical angiogenic profile.

Ovarian germ cell tumors are rare but very curable at all stages of disease. There is good evidence that surveillance for stage I dysgerminomas is a safe option although many centers worldwide still advocate adjuvant chemotherapy for stage IA nondysgerminomatous tumors, despite the significant risk of developing long-term treatment side effects. Here, we review the safety of our ongoing surveillance program of all stage IA female germ cell tumors. Thirty-seven patients (median age 26, range 14-48 years) with stage I disease were referred to Mount Vernon and Charing Cross Hospitals between 1981 and 2003. Patients underwent surgery and staging followed by intense surveillance, which included regular tumor markers and imaging. The median period of follow-up was 6 years. Relapse rates for stage IA nondysgerminomatous tumors and dysgerminomas were 8 of 22 (36%) and 2 of 9 (22%), respectively, plus one patient with mature teratoma and glial implants also relapsed; 10 of these 11 patients (91%) were successfully cured with platinum-based chemotherapy. Only one patient died from chemoresistant disease. All relapses occurred within 13 months of initial surgery. The overall disease-specific survival of malignant ovarian germ cell tumors was 94%. Over 50% of patients who underwent fertility-sparing surgery went on to have successful pregnancies. We have confirmed again that surveillance of all stage IA ovarian germ cell tumors is very safe and that the outcome is comparable with testicular tumors. We question the need for potentially toxic adjuvant chemotherapy in nondysgerminoma patients who have greater than 90% chance of being salvaged with chemotherapy if they relapse later.

To provide a comprehensive overview on vascular targeting agents and the application of radiobiological principles in pre-clinical and clinical studies, we completed a comprehensive review of published medical studies on vascular targeting agents using Pub Med. Vascular targeting agents are now divided into vascular disrupting agents (VDAs), which target the pre-existing tumour vasculature, and angiogenesis inhibitors (AIs), which prevent the formation of new blood vessels. Modest success has been seen when VDAs and AIs are used as single agents and therefore combination therapies that can work in a complimentary and synergistic manner, targeting both the tumour cells and endothelial cells, are needed. Radiobiological principles have been used to increase our understanding of these agents, and can explain the increased efficacy of combination treatments. In particular, the alteration of the tumour microenvironment by AIs and VDAs can lead to enhanced efficacy when combined with chemotherapy or radiotherapy, with phase II/III trials showing encouraging results. The optimal use and scheduling of AIs and VDAs remains to be determined. Further understanding of the mechanisms of action of these potentially very exciting anti-neoplastic agents is urgently required.

As part of surveillance protocols for stage I germ cell tumours, many centres routinely measure human chorionic gonadotrophin (HCG), alpha feto-protein (AFP) as well as lactate dehydrogenase (LDH). In conjunction with regular imaging and clinical examination, does routine measurement of LDH add anything to our relapse/pick up rate? Records of 494 patients at Mount Vernon Hospital who relapsed on surveillance between 1985 and 2005 were examined. Of the 494 patients who relapsed, 125 had raised LDH at the time of relapse. 112 of these had a concurrent rise in either AFP, HCG or both, 11 had their disease detected on CT before the rise in LDH, one had a clinically palpable para-aortic mass and the final patient complained of back pain and his retroperitoneal disease was thus discovered on imaging. Routine measurement of LDH in patients on surveillance for stage I germ cell tumours does not add to the early detection of relapse.

Unlabelled: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare tumor typically affecting young women. It is an aggressive malignancy with a poor prognosis and few long-term survivors., Objective: Investigate the outcome of patients with SCCOHT., Method: Data were collected for patients with SCCOHT treated in Australia, Canada and Europe. Information included stage, surgery, chemotherapy, radiotherapy, recurrence and survival., Results: The median follow-up is 13 months for all patients and 35.5 months in surviving patients. Ten patients had FIGO stage I tumors, six stage III tumors and one stage unknown. All underwent surgical resection. Adjuvant platinum-based chemotherapy was given to all patients. Seven received adjuvant radiotherapy with either pelvic and para-aortic radiotherapy, average dose 46.5 Gy (40 Gy/25# - 50.4 Gy/23#), or pelvic and whole abdominal radiotherapy, average dose 45 Gy to pelvis and 25 Gy (22.5 Gy/22# - 30 Gy/25#) to abdomen. The median survival for stage I tumors was not reached and was 6 months for stage III tumors. For the ten patients with stage I tumors: six received adjuvant radiotherapy with five alive and disease-free; four received no adjuvant radiotherapy with one alive and disease-free, while three have relapsed with one alive and disease-free after resection. Of the seven patients with stage III or unknown stage tumors, all but one have died. Recurrences were most frequent in the pelvis and the abdomen. Patients receiving salvage treatment with chemotherapy and radiotherapy did poorly., Conclusion: We advocate a multi-modality treatment approach including surgery, chemotherapy with the addition of radiotherapy either sequentially or concurrently.

Background: Sleep-disordered breathing and hypoxemia frequently underlie many common medical conditions for which patients require hospitalization. Sleep apnea is associated with adverse cardiovascular, neurovascular, inflammatory, and metabolic consequences, many of which can be reversed with nasal continuous positive airway pressure. Although polysomnography is the gold standard for outpatient evaluation of sleep apnea, it has not been used for establishing the diagnosis or as a means to intervene with evidence-based therapy in the hospital setting., Setting: A 468-bed tertiary-care facility for adults in which an 801.11b wireless network supplements a typical hardwired local area network., Methodology: We developed a technique to perform 16-channel polysomnography on any patient in any location in the hospital without interfering with routine nursing care. Qualified sleep technicians are able to remotely adjust electrophysiologic and respiratory parameters, as well as control continuous positive airway pressure titration. The study can also be monitored from any location with Internet access using a HIPAA-compliant virtual private network., Results: Polysomnography was performed on 51 inpatients (age 26 to 89 years; 31 men). Mean (SD) body mass index measured 34.1 kg/m(2) (12.4). Cardiac disease (47%) and neurologic disease (27%) were the most frequent primary indications for admission. Data acquisition was not disrupted due to connectivity problems. The most frequent deficiencies were reduced sleep time (range 0.8-6.5 hours; mean [SD] 3.3 hours [1.6]) and reduced or absent rapid eye movement sleep. Mean (SD) apnea-hypopnea index measured 35.9 events per hour of sleep (SD 26.3) and 19.4 events per hour of total recording time (SD 17.5)., Conclusions: Polysomnography measurements transmitted across a wireless wide area network increases the capacity of the traditional hospital-based sleep laboratory. This technique can facilitate early implementation of appropriate therapy and may reverse underlying factors associated with the primary cause of hospitalization. Indications and standards of practice need to be specifically established for inpatient polysomnography.

CA125 is currently the most widely used tumor marker for ovarian epithelial cancer. The aim of this article is to provide guidelines for the routine clinical use of CA125 in patients with ovarian cancer. Due to lack of sensitivity for stage I disease and lack of specificity, CA125 is of little value in the detection of early ovarian cancer. At present, therefore, CA125, either alone or in combination with other modalities, cannot be recommended for screening for ovarian cancer in asymptomatic women outside the context of a randomized controlled trial. Preoperative levels in postmenopausal women, however, may aid the differentiation of benign and malignant pelvic masses. Serial levels during chemotherapy for ovarian cancer are useful for assessing response to treatment. Although serial monitoring following initial chemotherapy can lead to the early detection of recurrent disease, the clinical value of this lead-time is unclear. CA125 is the ovarian cancer marker against which new markers for this malignancy should be judged.

Epithelial ovarian cancer is the most lethal gynaecological cancer among women worldwide, with 6000 new cases diagnosed in the UK each year. Most women present with advanced disease, but, despite a good initial response to treatment, most relapse. The overall 5-year survival rate is 46%, although this drops to about 13% in women with advanced disease. Transvaginal ultrasound and the tumour marker CA125 are being investigated for screening in ongoing randomised trials. Treatment of ovarian cancer is dependent on clinical stage, and should always be managed within a multidisciplinary team. Most cases will require a pelvic clearance and adjuvant chemotherapy. Current guidelines by the National Institute of Clinical Excellence (NICE) recommend that first-line chemotherapy should include a platinum-based regimen with or without paclitaxel. Relapsed ovarian cancer is incurable; however, chemotherapy can improve quality of life and survival. Gene therapy, immunotherapy and signal transduction inhibitors are all potential future therapies, and are being investigated in ongoing clinical research. In this paper we review the literature on the epidemiology, pathology, clinical features and the current treatment options in epithelial ovarian cancer.

Aims: To provide a comprehensive overview of the current state of development of a novel class of anti-cancer drugs, the vascular disrupting agents (VDAs), previously known as vascular targeting agents (VTAs)., Materials and Methods: A comprehensive review, analysis and commentary of the published medical literature on VDAs was performed., Results: Tumour vascular targeting therapy exploits known differences between normal and tumour blood vessels. VDAs target the preexisting vessels of tumours (cf anti-angiogenics), and cause vascular shutdown leading to tumour cell death and rapid haemorrhagic necrosis within hours. It is becoming clear that VDAs have overlapping activity with anti-angiogenic drugs, which prevent the formation of new blood vessels. There are two types of VDA. First, biological or ligand-directed VDAs use antibodies, peptides or growth factors to target toxins or pro-coagulants to the tumour endothelium. In contrast, small molecule VDAs work either as tubulin-binding agents or through induction of local cytokine production. VDAs can kill tumour cells resistant to conventional chemotherapy and radiotherapy, and work best on cells in the poorly perfused hypoxic core of tumours, leaving a viable rim of well-perfused tumour tissue at the periphery, which rapidly regrows. Consequently, responses of tumours to VDAs given as single agents have been poor; however, combination therapy with cytotoxic chemotherapy, external-beam radiotherapy, and radioimmunotherapy, which target the peripheral tumour cells, has produced some excellent responses in animal tumours. VDAs are generally well tolerated with different side-effect profiles to current oncological therapies. Dynamic magnetic resonance imaging is most frequently used to obtain a pharmacodynamic end point to determine whether the VDA is acting on its intended target., Conclusions: VDAs are a promising new class of drug, which offer the attractive possibility of inducing responses in all tumour types with combination therapy.

The objective was to assess the long-term survival (5-15 years) in 463 women, with stages IIb-IV epithelial carcinoma of the ovary and to compare their survival with that of a normal population matched for age and sex. Statistical analysis of 463 women, with stages IIb-IV epithelial cancer of the ovary, who were participants in two consecutive North Thames Ovary Group randomized trials, which took place between 1985 and 1994, was performed. The median follow-up period was 10.5 years. The women were treated with debulking surgery, where possible, and adjuvant platinum chemotherapy. One of the randomized groups in the first North Thames trial also received total abdominal radiotherapy. Survival rates at 5, 10, and 15 years were assessed. Prognostic factors for long-term survival were determined using a mathematical model to separate early effects from late effects. The ratio of observed to expected deaths compared to the normal population was calculated. Overall survival at 5 years was 21% (95% confidence intervals 17.5-25%), at 10 years was 13.5% (95% confidence intervals 10.5-17%), and at 15 years was 12% (95% confidence intervals 9-16%). The important prognostic factors for long-term survival were disease-free or minimal residual disease (a single remaining deposit <2 cm) at initial surgery with tumor grade 1 and good performance status. Compared with the normal population (1995 data), the ratio of observed to expected deaths after start of chemotherapy at 5 years was 14.1 (P < 0.001 Fisher's exact test), at 9-10 years 4.9 (P = 0.0033, Fisher's exact test), while in the 11- to 15-year period it had dropped to 2.75 (P = 0.090, Fisher's exact test), which was not significantly different. Patients with advanced cancer of the ovary, who survive 11 years or longer, have a life expectancy which is very similar to that of a normal population of women of the same age. Women with advanced ovarian cancer have an improved chance of long-term survival following treatment if they present with minimal residual disease after primary surgical debulking, grade 1 tumors, and good performance status.

The objective of this study is to assess tumour response to neoadjuvant chemotherapy prior to radical hysterectomy in cervical cancer using magnetic resonance (MR) to monitor tumour volume and changes in molecular profile and to compare the survival to that of a control group. Eligibility included Stage Ib-IIb previously untreated cervical tumours >10 cm(3). Neoadjuvant chemotherapy in 22 patients (methotrexate 300 mg x m(-2) (with folinic acid rescue), bleomycin 30 mg x m(-2), cisplatin 60 mg m(-2)) was repeated twice weekly for three courses and followed by radical hysterectomy. Post-operative radiotherapy was given in 14 cases. A total of 23 patients treated either with radical surgery or chemoradiotherapy over the same time period comprised the nonrandomised control group. MR scans before and after neoadjuvant chemotherapy and in the control group documented tumour volume on imaging and metabolites on in vivo spectroscopy. Changes were compared using a paired t-test. Survival was calculated using the Kaplan-Meier method. There were no significant differences between the neoadjuvant chemotherapy and control groups in age (mean, s.d. 43.3+/-10, 44.7+/-8.5 years, respectively, P=0.63) or tumour volume (medians, quartiles 35.8, 17.8, 57.7 cm(3) vs 23.0, 15.0, 37.0 cm(3), respectively, P=0.068). The reduction in tumour volume post-chemotherapy (median, quartiles 7.5, 3.0, 19.0 cm(3)) was significant (P=0.002). The reduction in -CH(2) triglyceride approached significance (P=0.05), but other metabolites were unchanged. The 3-year survival in the chemotherapy group (49.1%) was not significantly different from the control group (46%, P=0.94). There is a significant reduction in tumour volume and -CH(2) triglyceride levels after neoadjuvant chemotherapy, but there is no survival advantage.

Purpose: In experimental systems, interference with coagulation can affect tumor biology. Furthermore, it has been suggested that low molecular weight heparin therapy may prolong survival in patients with cancer. The primary aim of this study was to assess survival at 1 year of patients with advanced cancer., Patients and Methods: Patients with advanced malignancy (N = 385) were randomly assigned to receive either a once-daily subcutaneous injection of dalteparin (5,000 IU), a low molecular weight heparin, or placebo for 1 year., Results: The Kaplan-Meier survival estimates at 1, 2, and 3 years after randomization for patients receiving dalteparin were 46%, 27%, and 21%, respectively, compared with 41%, 18%, and 12%, respectively, for patients receiving placebo (P =.19). In an analysis not specified a priori, survival was examined in a subgroup of patients (dalteparin, n = 55; and placebo, n = 47) who had a better prognosis and who were alive 17 months after randomization. In these patients, Kaplan-Meier survival estimates at 2 and 3 years from randomization were significantly improved for patients receiving dalteparin versus placebo (78% v 55% and 60% v 36%, respectively, P =.03). The rates of symptomatic venous thromboembolism were 2.4% and 3.3% for dalteparin and placebo, respectively, with bleeding rates of 4.7% and 2.7%, respectively., Conclusion: Dalteparin administration did not significantly improve 1-year survival rates in patients with advanced malignancy. However, the observed improved survival in a subgroup of patients with a better prognosis suggests a potential modifying effect of dalteparin on tumor biology.