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1.  Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial 
British Journal of Cancer  2013;108(5):1021-1026.
Background:
This open-label, multicentre, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer.
Methods:
Women with measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle. The primary end point was clinical benefit response, defined as an objective response or prolonged stable disease of 16 weeks or more.
Results:
In all, 45 patients were treated with single-agent ridaforolimus. Clinical benefit was achieved by 13 patients (29%), including 5 (11%) with confirmed partial responses and 8 (18%) with prolonged stable disease. All patients with clinical benefit response received ridaforolimus for more than 4 months. In this heavily pretreated population, the 6-month progression-free survival was 18%. Ridaforolimus was generally well tolerated: adverse events were predictable and manageable, consistent with prior studies in other malignancies. Overall, the most common adverse events were diarrhoea (58%) and mouth sores (56%); most common grade 3 or higher adverse events were anaemia (27%) and hyperglycaemia (11%).
Conclusion:
Single-agent ridaforolimus has antitumor activity and acceptable tolerability in advanced endometrial cancer patients. Further clinical evaluation of ridaforolimus is warranted.
doi:10.1038/bjc.2013.59
PMCID: PMC3619076  PMID: 23403817
mammalian target of rapamycin inhibitor; ridaforolimus; endometrial cancer; clinical benefit response; stable disease
2.  Optimal treatment of early-stage ovarian cancer 
Annals of Oncology  2014;25(6):1165-1171.
There is evidence of a long-term benefit of adjuvant post operative chemotherapy for early-stage ovarian cancer. The magnitude of benefit is greatest in patients at a higher risk of recurrence defined as stage 1B/1C grade 2/3, any stage 1 grade 3 or clear cell histology. The use of single agent carboplatin is recommended.
Background
There is no clear consensus regarding systemic treatment of early-stage ovarian cancer (OC). Clinical trials are challenging because of the relatively low incidence and good prognosis. Initial results of the International Collaborative Ovarian Neoplasm (ICON)1 trial demonstrated benefit in both overall survival (OS) and recurrence-free survival (RFS) with adjuvant chemotherapy. We report results of 10-year follow-up to establish whether benefits are maintained longer term and discuss how this and other available evidence from randomised trials can be used to guide treatment options regarding the need for, and choice of, adjuvant chemotherapy regimen.
Patients and methods
ICON1 recruited women with OC following primary surgery in whom there was uncertainty as to whether adjuvant chemotherapy was indicated. Patients were randomly assigned to adjuvant or no adjuvant chemotherapy. Platinum-based chemotherapy was recommended and 87% received single-agent carboplatin. Analyses of long-term treatment benefits and interaction with risk groups were carried out. A high-risk group of women was defined with stage 1B/1C grade 2/3, any stage 1 grade 3 or clear-cell histology.
Results
With a median follow-up of 10 years, the estimated hazard ratio (HR) for RFS was 0.69 [95% confidence interval (CI) 0.51–0.94, P = 0.02] and OS 0.71 (95% CI 0.52–0.98, P = 0.04) in favour of chemotherapy. In absolute terms, there was a 10% (60%–70%) improvement in RFS and a 9% (64%–73%) improvement in OS; the benefit of chemotherapy might be greater in high-risk disease (18% improvement in OS). Uncertainty remains about the optimal chemotherapy regimen. The only randomised trial data available are from a subset of 120 stage 1 patients in ICON3 where the treatment difference, comparing carboplatin with carboplatin/paclitaxel was estimated with relatively wide CIs [progression-free survival HR = 0.71 (95% CI 0.39–1.32) and OS HR = 0.98 (95% CI 0.49–1.93)].
Conclusions
Extended follow-up from ICON1 confirms that adjuvant chemotherapy should be offered to women with early-stage OC, particularly those with high-risk disease.
Clinical trial numbers
ISRCTN11916376 for ICON1 and ISRCTN57157825 for ICON3.
doi:10.1093/annonc/mdu116
PMCID: PMC4037858  PMID: 24631948
early-stage ovarian cancer; adjuvant chemotherapy; ICON1; ICON3
3.  Metastasis to the right stellate ganglion and vagal nerve: pathological alterations causing sudden death. A case report 
SUMMARY
Sudden death in a 66-year-old woman with squamous cell carcinoma of the oral cavity and exclusive metastatic involvement of the right stellate ganglion and right nerve vagus is reported. The patient also suffered from paroxysmal atrial fibrillation treated with quinidine. An autopsy showed exclusive metastases to the right stellate ganglion and vagus nerve, along with decreased nerve fibre density in the ventricular myocardium suggesting that Wallerian axon degeneration of cardiac fibres was responsible for sudden death.
PMCID: PMC3468933  PMID: 23093818
Sudden death; Squamous cell carcinoma; Head and neck pathology; Stellate ganglion
4.  The interplay between NCAM and FGFR signalling underlies ovarian cancer progression 
ecancermedicalscience  2011;5:226.
Epithelial ovarian carcinoma (EOC) is an aggressive neoplasm, which has often disseminated to peritoneal cavity at the time of diagnosis. In order to better understand the molecular mechanisms behind EOC progression, we investigated the expression and functional role of neural cell adhesion molecule (NCAM) in this tumour type.
doi:10.3332/ecancer.2011.226
PMCID: PMC3223954  PMID: 22276065
5.  Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6–12 months) subpopulation of OVA-301 phase III randomized trial 
Annals of Oncology  2010;22(1):39-48.
Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD) over PLD alone in relapsed ovarian cancer. The optimal management of patients with partially platinum-sensitive relapse [6–12 months platinum-free interval (PFI)] is unclear.
Patients and methods: Within OVA-301, we therefore now report on the outcomes for the 214 cases in this subgroup.
Results: Trabectedin/PLD resulted in a 35% risk reduction of disease progression (DP) or death [hazard ratio (HR) = 0.65, 95% confidence interval (CI), 0.45–0.92; P = 0.0152; median progression-free survival (PFS) 7.4 versus 5.5 months], and a significant 41% decrease in the risk of death (HR = 0.59; 95% CI, 0.43–0.82; P = 0.0015; median survival 23.0 versus 17.1 months). The safety of trabectedin/PLD in this subset mimicked that of the overall population. Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), although patients in the trabectedin/PLD arm had a slightly lower proportion of further platinum (49% versus 55%). Importantly, patients in the trabectedin/PLD arm survived significantly longer after subsequent platinum (HR = 0.63; P = 0.0357; median 13.3 versus 9.8 months).
Conclusion: This hypothesis-generating analysis demonstrates that superior benefits with trabectedin/PLD in terms of PFS and survival in the overall population appear particularly enhanced in patients with partially sensitive disease (PFI 6–12 months).
doi:10.1093/annonc/mdq352
PMCID: PMC3003616  PMID: 20643862
pegylated liposomal doxorubicin; platinum-free interval; relapsed ovarian cancer; trabectedin
6.  Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval 
Annals of Oncology  2010;22(1):49-58.
Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD; CentoCor Ortho Biotech Products L.P., Raritan, NJ, USA). over single-agent PLD in 672 patients with relapsed ovarian cancer, particularly in the partially platinum-sensitive subgroup [platinum-free interval (PFI) of 6–12 months]. This superiority has been suggested to be due to the differential impact of subsequent (platinum) therapy.
Patients and methods: A detailed analysis of subsequent therapies and survival outcomes in the overall population and in the subsets according to platinum sensitivity was therefore conducted.
Results: Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), including further platinum-based regimens (49% versus 55%). Patients in the trabectedin/PLD arm received subsequent chemotherapy at a later time (median delay 2.5 months versus PLD arm). Overall survival from subsequent platinum was significantly prolonged in the partially platinum-sensitive disease subset (hazard ratio = 0.63; P = 0.0357).
Conclusion: The superiority of trabectedin/PLD over single-agent PLD in OVA-301 cannot be explained by differences in the extent or nature of subsequent therapies administered to these patients. On the other hand, these exploratory analyses support the hypothesis that the enhanced survival benefits in the partially platinum-sensitive subset might be due to an extended PFI leading to longer survival with subsequent platinum.
doi:10.1093/annonc/mdq353
PMCID: PMC3003617  PMID: 20643863
pegylated liposomal doxorubicin; platinum-free interval; relapsed ovarian cancer; trabectedin
7.  Phase II of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer, previously treated with platinum and taxanes 
Annals of Oncology  2009;21(4):759-765.
Background: A prospective phase II study was conducted to evaluate the efficacy and toxicity of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer.
Patients and methods: Patients had a maximum of three prior chemotherapy lines with no more than two prior platinum-containing regimens and a progression-free interval after the last dose of platinum <12 months. A total dose of 4 mg/m2/cycle (0.8 mg/m2/day from day 1 to day 5) was administered, repeated every 28 days.
Results: From June 2005 to December 2005, 69 assessable patients were enrolled. The best overall response to study treatment by combined CA-125 and RECIST criteria was partial response in 17 patients (24.6%) and disease stabilization in 22 patients (31.9%). The median time to progression and overall survival were 3.8 and 16.2 months, respectively. A total of 312 cycles were administered. Neutropenia grade 4 and thrombocytopenia grade 4 occurred in 17.4% and 7.2% of patients, respectively. Diarrhea grade 4 was never observed. Asthenia and fatigue were reported by 36.2% and 18.8% of patients, but were all grade 2 or less.
Conclusion: Gimatecan is a new active agent in previously treated ovarian cancer with myelosuppression as main toxicity.
doi:10.1093/annonc/mdp514
PMCID: PMC2844948  PMID: 19906760
camptothecin; gimatecan; ovarian cancer recurrence
8.  Long QT syndrome and torsade de pointes after anthracycline chemotherapy 
ecancermedicalscience  2009;3:147.
Summary
Anthracycline chemotherapy, which represents the treatment of choice for many hematologic and metastatic cancers, unfortunately carries with it the possibility of both early cardiotoxic phenomena, occuring during chemotherapy, and also late cardiotoxic manifestations, occuring even months or years from the completion of treatment.
The clinical manifestations of early cardiotoxicity commonly include: ventricular premature beats, supraventricular tachycardia, cardiomyopathy and sudden death.
This study confirms the necessity for close cardiac monitoring of patients undergoing anthracycline therapy. Such monitoring should not only comprise echocardiographic monitoring for left ventricular systo-diastolic dysfunction, but also electrocardiographic monitoring (QTc) in order to exclude electrophysiological changes possibly related to life threatening arrhythmias (10).
doi:10.3332/ecancer.2009.147
PMCID: PMC3223993  PMID: 22276012
9.  A phase II randomised clinical trial comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced epithelial ovarian cancer: long-term survival analysis 
British Journal of Cancer  2008;98(4):720-727.
To test the feasibility and efficacy of epirubicin and ifosfamide added to first-line chemotherapy with cisplatin and paclitaxel in a phase II randomised clinical trial. Patients with histologically proven epithelial ovarian cancer were randomly assigned to receive first-line polychemotherapy with cisplatin/paclitaxel/epirubicin (CEP) or cisplatin/paclitaxel/ifosfamide (CIP) for six cycles every 21 days. Two hundred and eight patients were randomised between the two treatment arms and the median number of cycles per patient was six. Toxicity was predominantly haematological with both regimens; however, anaemia, leucopaenia, neutropaenic fever and use of granulocyte colony-stimulating factors and transfusion were significantly more frequent in the CIP treatment arm. Response rates were 85% (95% confidence interval (CI) 77–93%) in the CIP arm and 90% (95% CI 84–96%) in the CEP arm; complete response rates were 48 and 52%. After a median follow-up of 82 months, median overall survival (OS) was 51 and 65 months; 5-year survival rates were respectively 43 and 50%. In this clinical trial, both regimens showed good efficacy, but toxicity was heavier with the CIP regimen. Considering that more than 50% of patients were suboptimally debulked after the first surgery, OS seems to be longer than is commonly reported. This unexpected finding might be a consequence of the close surgical surveillance and aggressive chemotherapeutic approach.
doi:10.1038/sj.bjc.6604231
PMCID: PMC2259172  PMID: 18253120
ovarian cancer; first-line chemotherapy; epirubicin; ifosfamide; triplets; long-term survival
10.  QTc prolongation assessment in anticancer drug development: clinical and methodological issues 
ecancermedicalscience  2009;3:130.
Cardiac safety assessments are commonly employed in the clinical development of investigational oncology medications. In anti-cancer drug development there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can potentially influence decision making at many levels during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Given the potential for serious and irreversible morbidity from cardiac adverse events, it is understandable that cardiac safety results can have broad impact on study conduct and patient management. The methodologies for risk management of QTc prolongation for non cardiac drugs have been developed out of experiences primarily from drugs used to treat non life-threatening illnesses in a chronic setting such as antibiotics or antihistamines. Extrapolating these approaches to drugs for treating cancer over an acute period may not be appropriate. Few specific guidelines are available for risk management of cardiac safety in the development and use of oncology drugs. In this manuscript, clinical and methodological issues related to QTc prolongation assessment will be reviewed. Discussions about limitations in phase-I design and oncology drug development will be highlighted. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. A thoughtful risk management plan generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development programme essential for oncology agents with cardiac safety concerns.
doi:10.3332/ecancer.2009.130
PMCID: PMC3223992  PMID: 22275999
11.  Cardio-oncology: a new medical issue 
ecancermedicalscience  2008;2:126.
Due to the increasing number of long-term cancer survivors, the ageing of the population, as well as the increased incidence and prevalence of oncologic and cardiovascular diseases, the number of patients presenting oncologic and cardiologic co-morbidities are increasing. Accordingly, there is a rapidly growing need for a comprehensive and proficient management of patients in whom the two co-morbidities exist, and for cancer patients whose clinical history and oncologic treatment put them at higher risk for developing cardiovascular problems, in order to provide the optimal treatment in every situation, and to avoid the possibility that the development of the second disease does not lead to a reduction of therapeutic opportunities for the patient. A new discipline, cardio-oncology, has been created to deal with this need. Its aim is to investigate new strategies, collect new evidence-based indications and develop interdisciplinary expertise in order to manage this growing category of patients. Cardio-oncology deals with the following main clinical and research areas: early diagnosis of cardiotoxicity, risk stratification and preventions, treatment and monitoring of cardiotoxicity.
doi:10.3332/ecancer.2008.126
PMCID: PMC3234071  PMID: 22275992
12.  Robotic modified radical hysterectomy with pelvic lymphadenectomy 
Radical hysterectomy, the complete removal of a woman’s uterus, is usually performed via an abdominal incision that requires a 3–5 day hospital stay and a 6–8 week recovery period. Now, in a handful of hospitals around the world, new robotic technology allows doctors to perform this procedure through small incisions that require a recovery time of only one night in the hospital and a significantly shorter recovery period at home. Watch such a procedure being carried out at the European Institute of Oncology.
doi:10.3332/ecancer.2008.55
PMCID: PMC3223972  PMID: 22275954
14.  Diagnosis of persistent ovarian carcinoma with three-step immunoscintigraphy 
British Journal of Cancer  2000;82(3):616-620.
The diagnosis of recurrent ovarian carcinoma is usually determined at surgical re-exploration since the main non-invasive diagnostic tests have low accuracy. It would be desirable to have a high accuracy non-invasive diagnostic procedure. With this aim, we have assessed the utility of three-step immunoscintigraphy. Thirty patients were intravenously injected with biotinylated monoclonal antibodies MOv18 and B72.3, followed by avidin–streptavidin injection and finally by111In-biotin. Tumour recurrences were imaged 2 h post radioactivity injection. All patients underwent surgical re-exploration 3–4 days after immunoscintigraphy; the presence of tumour in the area of immunoscintigraphic uptake was evaluated in the biopsied material. Twenty-one patients studied were true-positive, five were true-negative, four were false-positive and none was false-negative. The diagnostic accuracy, positive predictive value and negative predictive value were 87%, 84% and 100% respectively. If these findings are confirmed in a larger number of patients, we expect immunoscintigraphy to be introduced as a cost-effective procedure in the follow-up of patients who have received surgery for ovarian carcinoma, since it promises to reliably identify patients who do not require surgical re-exploration, and guide biopsies when they are indicated. © 2000 Cancer Research Campaign
doi:10.1054/bjoc.1999.0972
PMCID: PMC2363313  PMID: 10682674
ovarian carcinoma; monoclonal antibodies; avidin–biotin
15.  Sentinel node biopsy in early vulvar cancer 
British Journal of Cancer  2000;82(2):295-299.
Lymph node pathologic status is the most important prognostic factor in vulvar cancer; however, complete inguinofemoral node dissection is associated with significant morbidity. Lymphoscintigraphy associated with gamma-probe guided surgery reliably detects sentinel nodes in melanoma and breast cancer patients. This study evaluates the feasibility of the surgical identification of sentinel groin nodes using lymphoscintigraphy and a gamma-detecting probe in patients with early vulvar cancer. Technetium-99m-labelled colloid human albumin was administered perilesionally in 37 patients with invasive epidermoid vulvar cancer (T1–T2) and lymphoscintigraphy performed the day before surgery. An intraoperative gamma-detecting probe was used to identify sentinel nodes during surgery. A complete inguinofemoral node dissection was then performed. Sentinel nodes were submitted separately to pathologic evaluation. A total of 55 groins were dissected in 37 patients. Localization of the SN was successful in all cases. Eight cases had positive nodes: in all the sentinel node as positive; the sentinel node was the only positive node in five cases. Twenty-nine patients showed negative sentinel nodes: all of them were negative for lymph node metastases. Lymphoscintigraphy and sentinel-node biopsy under gamma-detecting probe guidance proved to be an easy and reliable method for the detection of sentinel node in early vulvar cancer. This technique may represent a true advance in the direction of less aggressive treatments in patients with vulvar cancer. © 2000 Cancer Research Campaign
doi:10.1054/bjoc.1999.0918
PMCID: PMC2363267  PMID: 10646880
vulvar cancer; lymph node; lymphoscintigraphy; sentinel node; lymphadenectomy
16.  Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group. 
British Journal of Cancer  1998;78(11):1479-1487.
The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.
Images
PMCID: PMC2063202  PMID: 9836481
17.  Prognostic factors in advanced epithelial ovarian cancer. (Gruppo Interregionale Cooperativo di Oncologia Ginecologica (GICOG)). 
British Journal of Cancer  1990;62(3):444-450.
The data on 914 patients enrolled in four randomised trials in advanced ovarian cancer, consecutively conducted by the same cooperative group between 1978 and 1986, were analysed with the aims of: (1) determining the impact of selected prognostic variables on survival; (2) finding, from the interaction of favourable prognostic factors and treatment, an approximate estimate of the magnitude of the survival advantage associated with the use of platinum-based combination chemotherapy. The overall 3-year survival in this series of patients is twice that reported historically (22%; 95% CL 18.7-25.4). The proportional hazard regression model was used to perform the analysis on survival. Residual tumour size, age, FIGO stage and cell type were all independent determinants of survival. Differences in survival from the various prognostic groups were impressive with 5-year survival rates ranging from 7 to 62%. However, these differences were not qualitative (i.e. the kinetics of survival were similar for the best and the worst groups) suggesting that current prognostic factors are of little use for selecting 'biologically' different sub-populations. Platinum-based regimens were associated to an overall prolonged median survival, but this benefit was not observable in the subgroup with most favourable prognosis (less than 2 cm residual tumour size). The implications of these observations for clinical research and ovarian cancer patients care are discussed.
PMCID: PMC1971438  PMID: 2119684
18.  Effect of a streptococcal preparation (OK432) on natural killer activity of tumour-associated lymphoid cells in human ovarian carcinoma and on lysis of fresh ovarian tumour cells. 
British Journal of Cancer  1983;48(4):515-525.
The streptococcal preparation OK432 was studied for its effects on natural killer (NK) activity of peripheral blood lymphocytes (PBL) from normal donors and from ovarian cancer patients, and of tumour-associated lymphocytes (TAL) from peritoneal effusions. OK432 augmented NK activity against the susceptible K562 line and induced killing of the relatively resistant Raji line. Freshly isolated ovarian carcinoma cells were relatively resistant to killing by unstimulated PBL and TAL. OK432 induced significant, though low, levels of cytotoxicity against 51Cr-labelled ovarian carcinoma cells. Augmentation of killing of fresh tumour cells by OK432 was best observed in a 20 h assay and both autologous and allogeneic targets were lysed. PBL were separated on discontinuous Percoll gradients. Unstimulated and OK432-boosted activity were enriched in the lower density fractions where large granular lymphocytes (LGL) and activity against K562 were found. Thus, OK432 augments NK activity of PBL and TAL in human ovarian carcinomas and induces low, but significant, levels of killing of fresh tumour cells. Effector cells involved in killing of fresh ovarian tumours copurify with LGL on discontinuous gradients of Percoll.
PMCID: PMC2011501  PMID: 6626452

Results 1-18 (18)