Ignace Vergote

Phase 3 randomised study of canfosfamide (Telcyta®, TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer

RATIONALEnCanfosfamide HCl (CAN) is a glutathione analogue prodrug that is activated by glutathione S-transferase P1-1 and induces apoptosis. CAN is synergistic in vitro with carboplatin, paclitaxel and anthracyclines.nnnMETHODSnPatients with platinum-refractory or -resistant ovarian cancer (OC) who had progressed on second-line therapy with pegylated liposomal doxorubicin (PLD) or topotecan (TOPO), were randomised between CAN 1000 mg/m(2) IV q 3 weeks or to either PLD 50mg/m(2) IV q 4 weeks or TOPO 1.5mg/m(2) IV d1-5 q 3 weeks.nnnRESULTSnAbout 461 patients were randomised after stratification for ECOG performance status, prior therapy, and bulky (>5 cm) disease. Groups were well balanced. In the control arm 58% and 42% were treated with PLD and TOPO, respectively. CAN was well tolerated with the most common grade 3-4 toxicities of 5% anaemia, 4% neutropaenia (no febrile neutropaenia), 4% thrombocytopaenia, and 7% vomiting. Progression-free survival (PFS) and overall survival (OS) were significantly higher in the control arm (p<0.001 and p<0.01, respectively). In a subgroup analysis PFS and OS tended to be higher with PLD than with TOPO.nnnCONCLUSIONnCAN was well tolerated. This is the first randomised study showing an increased OS with third-line therapy. This might have important consequences for other recurrent OC trials.

Neoadjuvant chemotherapy in advanced ovarian cancer: On what do we agree and disagree?

Following the recent publication of the randomized study in stages IIIC and IV ovarian cancer of the European Organisation for Treatment and Research—Gynaecological Cancer Group (EORTC-GCG) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group [1], a lot of controversy on the role of neoadjuvant chemotherapy and primary debulking in advanced ovarian cancer emerged [2–5]. At the recent Gynecologic Cancer InterGroup (GCIG) consensus conference a majority of 21 out of 23 member groups supported the statement: “Delayed primary surgery after neoadjuvant chemotherapy is an option for selected patients with stage IIIC or IV ovarian cancer as included in the EORTC55971” [6]. However, two member groups (the Arbeitsgemeinschaft Gynaekologische Onkologie [AGO] Study Group Germany and the AGO-Austria) voted for the minority statement “Neoadjuvant chemotherapy cannot be regarded as adequate routine therapy of advanced ovarian cancer and should be limited to selected patients with very advanced International Federation ofGynecology andObstetrics stage IIIC or IV disease and contraindications against upfront debulking surgery or tumor dissemination, implying no chance for complete resection.” The latter was also the official statement of the German Society of Gynecologic Oncology [7]. The authors discussed the role of neoadjuvant chemotherapy in advanced ovarian cancer on many conferences. However, the authors believe it is important to summarize in this paper in which groups of patients we agree that primary debulking should be the preferred treatment strategy and in which patients will probably not benefit from upfront surgery and alternative strategies as neoadjuvant chemotherapy followed by interval debulking should be preferred. Furthermore, we summarize in which groups of patients with advanced ovarian cancer we disagree on the preferred treatment policy. The opinions expressed in this paper are solely the opinion of the authors and not of the Cooperative groups or Societies the authors are member of.

Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma.

OBJECTIVEnPatients with endometrial carcinoma who progress after first-line chemotherapy have a poor prognosis. Phosphoinositide 3-kinase (PI3K) inhibitors are investigational treatment options in this setting. This study evaluated the efficacy and safety of the PI3K inhibitor pilaralisib (SAR245408; XL147) in advanced or recurrent endometrial carcinoma.nnnMETHODSnThis Phase II, multicenter, single-arm, open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma, who had received one or two prior chemotherapy regimens. Patients received pilaralisib 600mg capsules or 400mg tablets once daily. Primary endpoints were objective response rate (ORR), proportion of patients with progression-free survival (PFS) >6months and safety. Molecular profiling in archival tumor tissue and circulating tumor DNA were performed to identify molecular markers associated with response or resistance to pilaralisib.nnnRESULTSn67 patients were enrolled, of which 50 and 17 patients had received one or two prior regimens, respectively. Complete or partial tumor responses occurred in two patients each (ORR 6.0%); three had tumors with normal PTEN expression and PIK3R1 mutations and one had a tumor with PTEN protein deficiency. However, there was no association between molecular alterations and clinical activity. Rate of PFS>6months was 11.9%. The most commonly reported treatment-related adverse events (AEs) were rash (40.3%), diarrhea (37.3%) and fatigue (28.4%). The most commonly reported treatment-related grade ≥3 AEs were rash (9.0%), diarrhea (4.5%) and increased alanine aminotransferase (4.5%).nnnCONCLUSIONSnPilaralisib was associated with a favorable safety profile and minimal antitumor activity in advanced or recurrent endometrial carcinoma.

Patterns of care in surgery for ovarian cancer in Europe

Quality of surgery is one of the most important determinants of the outcome in ovarian cancer patients. Surgery by a gynaecological oncologist in a specialised, high-volume environment and removal of all visible tumours are associated with a higher likelihood of favourable outcome for patients with advanced-stage ovarian cancer. Population-based studies in Europe however show that a substantial number of patients do not receive optimal surgical care. Less than half of the patients suffering from advanced-stage ovarian cancer are operated by a gynaecological oncologists. Also the proportion of patients operated in a high-volume or specialised hospital is lower than 50%. In a substantial number of patients, minimum standard procedures are not performed and optimal tumor debulking is not achieved. To improve the quality of care, efforts are needed to develop and implement robust evidence-based European guidelines, provide surgical training for gynaecological oncologists and establish comprehensive cancer networks with sufficient resources.

European Society of Gynaecologic Oncology Quality Indicators for Advanced Ovarian Cancer Surgery

Objectives The surgical management of advanced ovarian cancer involves complex surgery. Implementation of a quality management program has a major impact on survival. The goal of this work was to develop a list of quality indicators (QIs) for advanced ovarian cancer surgery that can be used to audit and improve the clinical practice. This task has been carried out under the auspices of the European Society of Gynaecologic Oncology (ESGO). Methods Quality indicators were based on scientific evidence and/or expert consensus. A 4-step evaluation process included a systematic literature search for the identification of potential QIs and the documentation of scientific evidence, physical meetings of an ad hoc multidisciplinarity International Development Group, an internal validation of the targets and scoring system, and an external review process involving physicians and patients. Results Ten structural, process, or outcome indicators were selected. Quality indicators 1 to 3 are related to achievement of complete cytoreduction, caseload in the center, training, and experience of the surgeon. Quality indicators 4 to 6 are related to the overall management, including active participation to clinical research, decision-making process within a structured multidisciplinary team, and preoperative workup. Quality indicator 7 addresses the high value of adequate perioperative management. Quality indicators 8 to 10 highlight the need of recording pertinent information relevant to improvement of quality. An ESGO-approved template for the operative report has been designed. Quality indicators were described using a structured format specifying what the indicator is measuring, measurability specifications, and targets. Each QI was associated with a score, and an assessment form was built. Conclusions The ESGO quality criteria can be used for self-assessment, for institutional or governmental quality assurance programs, and for the certification of centers. Quality indicators and corresponding targets give practitioners and health administrators a quantitative basis for improving care and organizational processes in the surgical management of advanced ovarian cancer.

Primary surgery or neoadjuvant chemotherapy in ovarian cancer: What is the value of comparing apples with oranges?

In this issue of Gynecologic Oncology, Chi et al. [1] discuss the role of neoadjuvant chemotherapy in advanced ovarian cancer, and compare the results of the recently published randomized study in stage IIIc and IV ovarian cancer of the European Organisation for Treatment and Research—Gynaecological Cancer Group (EORTC—GCG) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group [2], with their retrospective analysis of patients with Stage IIIc or IV ovarian cancer treated in the same time period at the Memorial Sloan– Kettering Cancer Center. Until recently the standard of care of all patients with advanced ovarian cancer FIGO (International Federation of Gynaecology and Obstetrics) stages III and IV has been primary debulking surgery followed by paclitaxel and carboplatin chemotherapy. However, no prospective, randomized controlled trials are available, proving that primary debulking surgery improves the prognosis of patients with ovarian cancer. Alternatively to primary debulking surgery, neoadjuvant chemotherapy can be administered before attempting an interval debulking surgery. This approach has been advocated by some authors, especially for the treatment of stage IV ovarian cancer or for patients with a very high metastatic tumor load, or in patients with a poor general condition [3]. In contrast to a number of retrospective series, the authors of a meta-analysis concluded that neoadjuvant chemotherapy is associated with a worse prognosis when compared to primary debulking surgery [4]. However, a more recent meta-analysis of 21 non-randomized trials concluded that survival was similar in patients treated with neoadjuvant chemotherapy followed by interval debulking surgery compared to primary debulking surgery followed by chemotherapy, and criticized the meta-analysis of Bristow et al. because patients treated with more neoadjuvant chemotherapy presented more often with Stage IV disease and received less paclitaxel [5]. In the randomized EORTC-NCIC study 718 patients were enrolled [2]. All patients had Stage IIIc or IV ovarian cancer diagnosed before randomization and most of them had very extensive disease. The overall and progression-free survival was similar in both groups. Postoperative infections, venous complications, fistula, hemorrhage and postoperative mortality tended to be higher after primary debulking surgery than after interval debulking surgery. In this issue of the journal, Chi et al. report on the survival and complications in 285 patients with ovarian cancer FIGO Stage IIIc or IV who underwent primary debulking surgery out of 342 patients with Stages IIIc and IV disease treated at the Memorial Sloan–Kettering Cancer Center during the time period [1]. The authors excluded, as in the EORTC–NCIC study, patients with borderline or non-epithelial tumors and those without evidence of metastases≥2 cm preoperatively, and conclude that the survival results in their series are superior to the survival

Current perspectives on recommendations for BRCA genetic testing in ovarian cancer patients

Traditionally, BRCA genetic testing has been undertaken to identify patients and family members at future risk of developing cancer and patients have been referred for testing based on family history. However, the now recognised risk of ovarian cancer (OC) patients, even those with no known family history, harbouring a mutation in BRCA1/2, together with the first poly adenosine diphosphatexa0ribose polymerase inhibitor (PARPi; olaparib [Lynparza]) being licenced for the treatment of BRCA-mutated OC, has led to reconsideration of referral criteria for OC patients. Provided here is a review of the existing data and guidelines in the European Union, relating to recommendations, as well as considerations, for the referral of OC patients for BRCA genetic testing. Based on this review of newly updated guidance and up-to-date evidence, the following is recommended: all patients with invasive epithelial OC (excluding borderline or mucinous), including those with fallopian tube and peritoneal cancers, should be considered as candidates for referral for BRCA genetic testing, irrespective of age; genetic testing should ideally be offered at diagnosis, although patients can be referred at any stage; retrospective testing should be offered to patients in long-term follow-up because of the implications for family members and individual future breast cancer risk; and germline BRCA testing of a blood/saliva sample should initially be conducted and, if negative, tumour tissue should be tested (to identify non-germline [somatic] BRCA PARPi therapy candidates).

A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma

BACKGROUNDnCabozantinib (XL184), an orally bioavailable inhibitor of vascular endothelial growth factor receptor 2xa0and MET, was assessed in a cohort of ovarian carcinoma patients as part of a phase 2 randomised discontinuation trial (RDT) with cohorts from nine different tumour types.nnnPATIENTS AND METHODSnPatients received 100-mg cabozantinib daily. Those with stable disease (SD) per Response Evaluation Criteria in Solid Tumorsxa0at week 12 were randomised to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) after random assignment.nnnRESULTSnSeventy patients with ovarian carcinoma, 50% of whom were platinum refractory/resistant, were enrolled in this RDT. Median PFS from day 1 was 5.5 months for all patients. The ORR at week 12 was 21%; one patient achieved a complete response (CR), and 14 patients (20%) achieved a confirmed partial response (PR). The overall disease control rate (CRxa0+xa0PRxa0+xa0SD) at week 12 was 50%. Throughout the study, 70% of the patients with ≥1 postbaseline scan had tumour regression, and randomisation was discontinued early. For patients with SD randomised to cabozantinib, PFS was 5.9 months after randomisation. The most common grade 3/4 adverse events were diarrhoea (14%), palmar-plantar erythrodysesthesia syndrome (6%), asthenia (6%), hypertension (6%)xa0and neutropenia (6%). Dose reductions were required in 37% of the patients during the first 12 weeks.nnnCONCLUSIONnCabozantinib demonstrates clinical activity, with acceptable toxicities, in patients with ovarian carcinoma based on ORR and regression of tumour target lesions.nnnREGISTRATIONnThis trial is registered at ClinicalTrial.gov (NCT00940225).