Sean Kehoe

Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial.

BACKGROUNDnThe international standard of care for women with suspected advanced ovarian cancer is surgical debulking followed by platinum-based chemotherapy. We aimed to establish whether use of platinum-based primary chemotherapy followed by delayed surgery was an effective and safe alternative treatment regimen.nnnMETHODSnIn this phase 3, non-inferiority, randomised, controlled trial (CHORUS) undertaken in 87 hospitals in the UK and New Zealand, we enrolled women with suspected stage III or IV ovarian cancer. We randomly assigned women (1:1) either to undergo primary surgery followed by six cycles of chemotherapy, or to three cycles of primary chemotherapy, then surgery, followed by three more cycles of completion chemotherapy. Each 3-week cycle consisted of carboplatin AUC5 or AUC6 plus paclitaxel 175 mg/m(2), or an alternative carboplatin combination regimen, or carboplatin monotherapy. We did the random assignment by use of a minimisation method with a random element, and stratified participants according to the randomising centre, largest radiological tumour size, clinical stage, and prespecified chemotherapy regimen. Patients and investigators were not masked to group assignment. The primary outcome measure was overall survival. Primary analyses were done in the intention-to-treat population. To establish non-inferiority, the upper bound of a one-sided 90% CI for the hazard ratio (HR) had to be less than 1.18. This trial is registered, number ISRCTN74802813, and is closed to new participants.nnnFINDINGSnBetween March 1, 2004, and Aug 30, 2010, we randomly assigned 552 women to treatment. Of the 550 women who were eligible, 276 were assigned to primary surgery and 274 to primary chemotherapy. All were included in the intention-to-treat analysis; 251 assigned to primary surgery and 253 to primary chemotherapy were included in the per-protocol analysis. As of May 31, 2014, 451 deaths had occurred: 231 in the primary-surgery group versus 220 in the primary-chemotherapy group. Median overall survival was 22.6 months in the primary-surgery group versus 24.1 months in primary chemotherapy. The HR for death was 0.87 in favour of primary chemotherapy, with the upper bound of the one-sided 90% CI 0.98 (95% CI 0.72-1.05). Grade 3 or 4 postoperative adverse events and deaths within 28 days after surgery were more common in the primary-surgery group than in the primary-chemotherapy group (60 [24%] of 252 women vs 30 [14%] of 209, p=0.0007, and 14 women [6%] vs 1 woman [<1%], p=0.001). The most common grade 3 or 4 postoperative adverse event was haemorrhage in both groups (8 women [3%] in the primary-surgery group vs 14 [6%] in the primary-chemotherapy group). 110 (49%) of 225 women receiving primary surgery and 102 (40%) of 253 receiving primary chemotherapy had a grade 3 or 4 chemotherapy related toxic effect (p=0.0654), mostly uncomplicated neutropenia (20% and 16%, respectively). One fatal toxic effect, neutropenic sepsis, occurred in the primary-chemotherapy group.nnnINTERPRETATIONnIn women with stage III or IV ovarian cancer, survival with primary chemotherapy is non-inferior to primary surgery. In this study population, giving primary chemotherapy before surgery is an acceptable standard of care for women with advanced ovarian cancer.nnnFUNDINGnCancer Research UK and the Royal College of Obstetricians and Gynaecologists.

Ovarian tumours in pregnancy: a literature review

Ovarian tumours in pregnancy are a diagnostic and management challenge that is increasingly being faced by the clinician. While most masses are benign and resolve spontaneously, there are others that persist and indicate the need for surgical management. Ultrasound not only detects asymptomatic masses but also helps to guide their management based on presence or absence of features suspicious of malignancy. The role of tumour markers in pregnancy is limited due to their non-specific nature. Most masses treated in pregnancy are benign (most commonly dermoids), and most malignancies are either of low malignant potential or germ cell tumours, usually early stage disease. Surgical management is indicated for symptomatic masses or those with increasing size or complexity indicating possible malignancy. Both laparoscopy and laparotomy have similar results with regard to obstetric outcome. Conservative management is preferred in the remainder. MRI may help in better characterization of doubtful masses. National tumour registries can help to establish guidelines.

Aggressive angiomyxoma: A case series and literature review

BACKGROUNDnAggressive angiomyxoma was identified as a distinct clinicopathologic entity in 1983 and since then fewer than 250 cases of these rare tumors have been reported in world literature. These tumors usually arise in the pelvis and perineal regions, most often in women of the reproductive age group; however a few cases of its occurrence outside the pelvis have also been reported.nnnPATIENTS AND METHODSnWe report a series of 7 women treated in our institute in the last 8 years. Relevant literature on aggressive angiomyxoma was looked at and various management options reviewed.nnnCONCLUSIONnAggressive angiomyxomas are locally aggressive, notorious for local recurrence and extremely rare to metastasize. While surgery remains the mainstay of treatment, there has been a definite shift towards less radical forms of excision, over the years. Various adjuvant treatment modalities have also been tried to reduce tumor recurrence.

Serum tumour markers in gynaecological cancers

Serum tumour markers have had a role in screening, diagnosis and monitoring of some gynaecological cancers. Women with suspected ovarian malignancies have as routine a CA125 serum test, and in conjunction with scans, the risk of malignancy can be calculated. Equally, this CA125, if elevated pre-operatively can be used to predict chemotherapeutic responses, and even disease relapse prior to any symptoms or clinical findings. Other useful markers in ovarian cancer are betaHCG and AFP produced by germ cell tumours. betaHCG is also of extreme importance in both the diagnosis and management of choriocarcinomas. The level of betaHCG determines the need, and with other indicators, the type of chemotherapeutic intervention. Other serum markers are known in cervical cancer, and possibly endometrial and vulval cancer-but their clinical utility is very limited. Novel markers may help in managing patients, and in the future permit screening for certain diseases.

Angiogenesis-inhibitors for the treatment of ovarian cancer

BACKGROUNDnMany women with ovarian cancer eventually develop resistance to conventional chemotherapy drugs, and so novel agents are being developed to target specific molecular pathways. One such class of drugs inhibits angiogenesis (the development of new blood vessels), which is essential for tumour growth. It is important to establish whether the addition of these new drugs to conventional chemotherapy regimens improves survival, and what the side-effects may be.nnnOBJECTIVESnTo compare the effectiveness and toxicities of angiogenesis inhibitors in the treatment of ovarian cancer.nnnSEARCH STRATEGYnWe sought to identify completed randomised controlled trials (RCTs) by searching The Cochrane Gynaecological Cancer Review Groups Trial Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE and EMBASE (1990 to October 2010). We also searched registers of clinical trials, and contacted investigators of completed and ongoing trials for further information.nnnSELECTION CRITERIAnRandomised controlled studies comparing angiogenesis inhibitors with either standard chemotherapy or no treatment, in women with ovarian cancer.nnnDATA COLLECTION AND ANALYSISnTwo independent authors carried out data collection and extraction. We used a random-effects model for pooling data.nnnMAIN RESULTSnWe did not find any fully-published, completed RCTs of angiogenesis inhibitors that met our inclusion criteria. We identified five abstracts of completed RCTs of four different angiogenesis-inhibiting agents, with a total of 3701 participants.Meta-analysis of two trials found no statistically significant difference in overall survival (OS) between women with newly-diagnosed advanced ovarian cancer who received concurrent and maintenance bevacizumab compared to those who received chemotherapy (carboplatin and paclitaxel) alone. However, women who received concurrent and maintenance bevacizumab had their risk of disease progression reduced by a quarter (hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.68 to 0.83; P < 0.001); they also had a significantly increased risk of severe gastrointestinal adverse events, moderate or severe hypertension and severe bleeding.One trial also compared chemotherapy to concurrent (but not maintenance bevacizumab), and found no statistically significant difference in OS or progression-free survival (PFS). xa0However, the women who received bevacizumab had a significantly higher risk of moderate or severe hypertension.A three-armed RCT, of paclitaxel alone or with low- or high-dose AMG 386, in women with recurrent ovarian cancer, found no statistically significant difference in OS. However, women who received low-dose AMG 386 had a third less risk of disease progression than those who received placebo (HR 0.57, 95% CI 0.36 to 0.91; P = 0.02). The trial found no evidence of increased adverse events in the intervention arms.Two relatively small RCTs (one of VEGF-Trap, the other of BIBF 1120) found no evidence of either significant survival benefit or increased severe adverse events, compared to placebo, but they both lacked statistical power.xa0All five trials had unclear risk of bias, largely because they have only been published in abstract form, and thus many methodological details are unclear. We identified twelve suitable ongoing trials.nnnAUTHORS CONCLUSIONSnThere is, as yet, no fully-published RCT evidence for the efficacy or safety of angiogenesis inhibitors for the treatment of ovarian cancer, but some preliminary results are available from five trials. There is some evidence from a meta-analysis of two trials that the addition of concurrent and maintenance bevacizumab to standard chemotherapy may reduce the risk of disease progression, in women with newly-diagnosed advanced ovarian cancer. There is also some evidence from a single trial that low-dose AMG 386 may reduce the risk of disease progression in women with recurrent ovarian cancer. However, there is currently no evidence that angiogenesis inhibitors improve OS, nor is there enough evidence to justify the routine use of angiogenesis inhibitors in treating women with ovarian cancer. We eagerly await both the more detailed results of these five completed trials, and the preliminary results of the several ongoing trials.

The role of frozen sections in gynaecological oncology: survey of practice in the United Kingdom

OBJECTIVEnTo assess the use of frozen section diagnosis in gynaecological oncology in the United Kingdom.nnnSTUDY DESIGNnA questionnaire was circulated electronically to gynaecological pathologists and surgeons. The results were collated and compared with the available literature on this subject.nnnRESULTSnOur survey showed that the use of frozen sections varies with the resource setting and the preferences and practices of the practitioners. Frozen sections are most often used in diagnosis of ovarian/pelvic masses and assessment of lymph nodes in cervical carcinoma.nnnCONCLUSIONnFrozen section diagnosis is of value in certain areas of gynaecological oncology, while it is of limited or no value in others. Each multidisciplinary team should develop their own local protocols for intraoperative frozen section examination and support developing expertise in frozen section diagnosis in the adopted areas of the practice.

Primary Surgery or Neoadjuvant Chemotherapy in Advanced Ovarian Cancer: The Debate Continues…

Primary debulking surgery (PDS) followed by platinum-based chemotherapy has been the cornerstone of treatment for advanced ovarian cancer for decades. Primary debulking surgery has been repeatedly identified as one of the key factors in improving survival in patients with advanced ovarian cancer, especially when minimal or no residual disease is left behind. Achieving these results sometimes requires extensive abdominal and pelvic surgical procedures and consultation with other surgical teams. Some clinicians who propose a primary chemotherapy approach reported an increased likelihood of leaving no macroscopic disease after surgery and improved patient-reported outcomes and quality-of-life (QOL) measures. Given the ongoing debate regarding the relative benefit of PDS versus neoadjuvant chemotherapy (NACT), tumor biology may aid in patient selection for each approach. Neoadjuvant chemotherapy offers the opportunity for in vivo chemosensitivity testing. Studies are needed to determine the best way to evaluate the impact of NACT in each individual patient with advanced ovarian cancer. Indeed, the biggest utility of NACT may be in research, where this approach provides the opportunity for the investigation of predictive markers, mechanisms of resistance, and a forum to test novel therapies.

Epidermal growth factor receptor blockers for the treatment of ovarian cancer

BACKGROUNDnOvarian cancer is the seventh most common cause of cancer death in women world-wide. Treatment consists of a combination of surgical debulking and platinum-based chemotherapy, alone or in combination with paclitaxel. Between 55% and 75% of women who respond to first-line therapy relapse within twoxa0years of completing treatment. Second-line chemotherapy is palliative and aims to reduce symptoms and prolong survival. Increased understanding about the molecular basis of ovarian cancer has led to the development of novel agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, and their effectiveness and toxicities in women with advanced ovarian cancer needs to be assessed.nnnOBJECTIVESnTo compare the effectiveness and toxicities of epidermal growth factor receptor (EGFR) inhibitors alone or in combination with standard chemotherapy in the treatment of ovarian cancer.nnnSEARCH STRATEGYnWe searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) Issue 4, 2010, MEDLINE and EMBASE up to October 2010. We also searched registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies, and contacted experts in the field.nnnSELECTION CRITERIAnRandomised controlled trials (RCTs) comparing anti-EGFR agents with or without conventional chemotherapy versus conventional chemotherapy alone or no treatment in women with histologically proven ovarian cancer.nnnDATA COLLECTION AND ANALYSISnTwo review authors independently abstracted data and assessed risk of bias. We reported adjusted hazard ratios (HRs) for overall and progression-free survival and risk ratios (RRs) comparing adverse events in women who received gemcitabine plus pertuzumab and gemcitabine plus placebo.nnnMAIN RESULTSnWe found only one completed and three ongoing RCTs that met our inclusion criteria. The completed trial randomised 131 women with relapsed ovarian cancer to receive gemcitabine and pertuzumab or placebo and gemcitabine (control). There was no statistically significant difference in overall survival (OS), progression-free survival (PFS) and response between women who received gemcitabine and pertuzumab and those who received control, although PFS approached borderline significance (adjusted HR = 0.66, 95% CI 0.43 to 1.03; P = 0.06). The trial reported a higher rate of adverse events in the gemcitabine and pertuzumab arm for most outcomes, but most were not statistically significant (although many approached borderline significance) because the trial lacked statistical power due to its relatively small size and the low number of observed events. The trial was at moderate risk of bias.nnnAUTHORS CONCLUSIONSnEGFR inhibitors, including pertuzumab, may add activity to conventional chemotherapy for treatment of platinum-resistant ovarian cancer. Certain subsets of women with particularly aggressive tumours resistant to conventional chemotherapy may benefit from EGFR inhibitor treatment. Further RCTs are necessary before EGFR inhibitors are introduced as first- or second-line treatment of ovarian cancer.

Routine Intraoperative Frozen Section Examination to Minimize Bimodal Treatment in Early-Stage Cervical Cancer.

Objective In early-stage cervical cancer, single modality therapy is the main objective, to minimize patient morbidity while offering equivalent cure rates. Intraoperative frozen section examination (FSE) of lymph nodes (LNs) can facilitate this aim, ensuring that radical surgery is avoided in patients requiring adjuvant therapy for metastatic LN involvement. We aimed to evaluate the accuracy of routine intraoperative FSE of pelvic LNs during the surgical staging of early-stage cervical cancers and identify a group at low risk for nodal metastases. Methods A retrospective cohort study of 94 women aged 23 to 80 years who underwent primary surgery and planned intraoperative FSE of the pelvic LNs at the gynecological cancer center in Oxford was performed. The diagnostic value of FSE and the prediction of metastatic nodal disease were assessed by use of preoperative and intraoperative variables. Results A total of 1825 LNs were submitted for FSE. Of 94 women (13.8%), 13 had positive LNs at FSE. Two false-negative cases were reported with micrometastases but no false-positive cases. Frozen section examination as a diagnostic test reached a sensitivity of 86.7% and a specificity of 100%. A regression model including grade I to II and tumor size of less than 20 mm identified a low-risk group for LN involvement. Conclusions In light of diverse practice patterns, FSE should be routinely offered to women with early-stage cervical cancer in a 1-step protocol. We equally devised a model to predict those patients at least risk of nodal disease, who may be spared of FSE.

Over-expression of DNMT3A predicts the risk of recurrent vulvar squamous cell carcinomas

OBJECTIVEnCancer initiation and progression has been linked to aberrant expression of the DNA methyltransferases (DNMT), the enzymes which establish and maintain DNA methylation patterns throughout the genome. In this study, we investigated if DNMT expression in vulvar squamous cell carcinomas (VSCC) was related to clinical outcome.nnnMETHODSnDNMT1, DNMT3A and DNMT3B expression was measured in a subset of cases drawn from a cohort of consecutive women treated for primary VSCC at the Pan Birmingham Gynaecological Cancer Centre between 2001 and 2008. Univariable and multivariable competing risk modelling was performed to identify whether DNMT expression was associated with local disease recurrence or disease morbidity.nnnRESULTSnOver-expression of DNMT3A in the invasive component of the tumour was seen in 44% of tumours and was associated with an increased risk of local vulvar recurrence (LVR) (HR=4.51, p=0.012). This risk was found to increase further after adjustment for disease stage (HR=6.00, p=0.003) and groin node metastasis (HR=4.81, p=0.008). Over-expression of DNMT3B was associated with an increased risk of LVR (HR=5.69 p=0.03), however this ceased to be significant after adjustment for groin node metastasis. In a subset analysis, over-expression of DNMT3A was found to be significantly more common in VSCCs that stained negative for CDKN2A.nnnCONCLUSIONSnThese observations are consistent with the possibility that epigenetic changes contribute to vulvar neoplasia and DNMT3A over-expression may be useful in predicting local disease recurrence.