Randomized Trial of Cytoreductive Surgery for Relapsed Ovarian Cancer.

BACKGROUND: Treatment for patients with recurrent ovarian cancer has been mainly based on systemic therapy. The role of secondary cytoreductive surgery is unclear. METHODS: We randomly assigned patients with recurrent ovarian cancer who had a first relapse after a platinum-free interval (an interval during which no platinum-based chemotherapy was used) of 6 months or more to undergo secondary cytoreductive surgery and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Patients were eligible if they presented with a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, defined as an Eastern Cooperative Oncology Group performance-status score of 0 (on a 5-point scale, with higher scores indicating greater disability), ascites of less than 500 ml, and complete resection at initial surgery. A positive AGO score is used to identify patients in whom a complete resection might be achieved. The primary end point was overall survival. We also assessed quality of life and prognostic factors for survival. RESULTS: A total of 407 patients underwent randomization: 206 were assigned to cytoreductive surgery and chemotherapy, and 201 to chemotherapy alone. A complete resection was achieved in 75.5% of the patients in the surgery group who underwent the procedure. The median overall survival was 53.7 months in the surgery group and 46.0 months in the no-surgery group (hazard ratio for death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.02). Patients with a complete resection had the most favorable outcome, with a median overall survival of 61.9 months. A benefit from surgery was seen in all analyses in subgroups according to prognostic factors. Quality-of-life measures through 1 year of follow-up did not differ between the two groups, and we observed no perioperative mortality within 30 days after surgery. CONCLUSIONS: In women with recurrent ovarian cancer, cytoreductive surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone. (Funded by the AGO Study Group and others; DESKTOP III ClinicalTrials.gov number, NCT01166737.).

Role of Hyperthermic Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery as Consolidation Therapy for Advanced Epithelial Ovarian Cancer.

BACKGROUND: Patients with advanced epithelial ovarian cancer who undergo incomplete surgery followed by six cycles of chemotherapy could benefit from second-look or consolidation cytoreductive surgery (CCRS). The primary goal of this study was to evaluate the overall survival (OS) in patients undergoing complete CCRS and the factors affecting survival. The secondary goal was to study the benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. METHODS: This was a retrospective analysis of 173 patients with CCRS with (n = 118) or without (n = 55) HIPEC treated at 12 French centers. Only patients having a completeness of cytoreduction (CC) 0/1 resection and a minimum of 5 years of follow-up were included. HIPEC was performed systematically for all patients except those treated at the four centers that did not perform HIPEC. RESULTS: The median Peritoneal Cancer Index was 6 (range 0-33). Closed HIPEC was performed in 59 (34.1%) patients and open HIPEC was performed in 56 (32.3%) patients. Grade 3-4 complications occurred in 64 (36.9%) patients. The median OS was 35.67 months (95% confidence interval [CI] 29.8-46.1) and was significantly longer for CCRS + HIPEC (31.4 months without HIPEC and 42.5 months with HIPEC; p = 0.022). On multivariate analysis, closed HIPEC (hazard ratio [HR] 0.46, 95% CI 0.29-0.73; p < 0.001) resulted in a longer OS, and age > 65 years (HR 2.17, 95% CI 1.14-4.11; p = 0.018) and bowel resection (HR 1.98, 95% CI 1.27-3.08; p = 0.020) led to a shorter OS. On multivariate logistic regression analysis, closed HIPEC (odds ratio 0.18; p = 0.001) was associated with a lower risk of dying at 5 years. CONCLUSIONS: CCRS was performed with an acceptable morbidity and resulted in good overall survival. The role of HIPEC in addition to CCRS should be evaluated in prospective, randomized studies and the closed technique prospectively compared with the open technique.

Impact of surgery and chemotherapy in ovarian sex cord-stromal tumors from the multicentric Salomé study including 469 patients. A TMRG and GINECO group study.

OBJECTIVE: Identifying prognostic factors and evaluating the impact of adjuvant chemotherapy in patients with sex cord stromal tumors (SCST) is crucial. In this study, we aimed to address these challenges. METHODS: We conducted a retrospective analysis of data from 13 centers of the French Rare malignant gynecological tumors (TMRG) network. We enrolled 469 adult patients with malignant SCST who received upfront surgery since 2011 to July 2015. RESULTS: 75% were diagnosed with adult Granulosa cell tumors, and 23% had another subtype. With a median follow-up of 6.4 years, 154 patients (33%) developed a first recurrence, 82 (17%) two recurrences, and 49 (10%) three recurrences. Adjuvant chemotherapy was administered in 14.7% of patients at initial diagnosis. In relapse, perioperative chemotherapy was administered in 58.5%, 28.2%, and 23.8% of patients, respectively, in the first, second, and third relapse. In the first-line therapy, age under 70 years, FIGO stage, and complete surgery were associated with longer progression-free survival (PFS). Chemotherapy had no impact on PFS in early-stage disease (FIGO I-II). The PFS was similar using BEP or other chemotherapy regimens (HR 0.88 [0.43; 1.81]) in the first-line therapy. In case of recurrence, PFS was statistically prolonged by complete surgery, but perioperative chemotherapy use did not impact PFS. CONCLUSION: Chemotherapy use did not impact survival in the first-line or relapse setting in SCST. Only surgery and its quality demonstrated benefit for PFS in ovarian SCST in any lines of treatment.

Efficacy of chemotherapy according to BRCA status in patients with high-grade serous ovarian carcinoma at first platinum-sensitive relapse.

OBJECTIVE: Chemotherapy for high-grade serous ovarian cancers in platinum-sensitive relapse includes carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin. According to in vitro data, BRCA mutated patients are sensitive to replicative stress agents but BRCA status is not yet used for the choice of chemotherapy at relapse. Our aim was to assess these doublets according to BRCA status in first platinum-sensitive relapse. METHODS: The ESME ovarian cancer database comprises a multicenter retrospective cohort of patients with ovarian cancer treated in French cancer centers between January 2011 and December 2017. Patients with high-grade serous ovarian cancers at first platinum-sensitive relapse who received one of these doublets were included. The objective was to compare progression-free survival of each chemotherapy doublet according to BRCA status. RESULTS: Among the 10 263 patients in the database, 1539 patients had a first platinum-sensitive relapse: 825 BRCA wild type patients (53.6%) and 304 BRCA mutated patients (19.8%) (7 patients had a homologous recombination mutation and BRCA status was unkown for 403 patients). Median progression-free survival was longer in BRCA mutated patients than in BRCA wild type patients when receiving carboplatin/pegylated liposomal doxorubicin without maintenance treatment (15.8 vs 11.8 months; p<0.001). In contrast, we observed no difference in patients treated with carboplatin/paclitaxel (14.6 vs 14.3 months, respectively; p=0.70) or in those treated with carboplatin/gemcitabine (12.0 vs 9.8 months, respectively; p=0.18). In BRCA wild type patients without maintenance, better progression-free survival occurred with carboplatin/paclitaxel (median progression-free survival 14.3 months) than with carboplatin/gemcitabine and carboplatin/pegylated liposomal doxorubicin (9.8 and 11.8 months, respectively; p=0.017). In BRCA mutated patients without maintenance, there was no difference between the three doublets (median progression-free survival of 14.6, 12.0, and 15.8 months with carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin, respectively; p=0.40). CONCLUSION: While treatment with carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin shows comparable efficacy in BRCA mutated patients, treatment with carboplatin/paclitaxel appears to be more effective than carboplatin/gemcitabine and carboplatin/pegylated liposomal doxorubicin in BRCA wild type patients with high-grade serous ovarian cancers at first platinum-sensitive relapse.

Optimal timing of interval debulking surgery for advanced epithelial ovarian cancer: A retrospective study from the ESME national cohort.

OBJECTIVE: Interval debulking surgery is recommended after 3-4 cycles (standard IDS) of neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer (EOC) not able to received upfront complete debulking surgery. However, real world practices frequently report performing IDS after ≥5 NAC cycles (delayed IDS). The aim of this work was to evaluate the impact on survival of the number of NACT cycles before IDS. METHODS: We identified from a French national database, women with newly diagnosed EOC who underwent IDS from January 2011 to December 2016. Progression free survival (PFS) and overall survival (OS) were compared using Cox model with adjustments for confounding factors provided by two propensity score methods: inverse probability of treatment weighting (IPTW) and matched-pair analysis. RESULTS: 928 patients treated by IDS for which our propensity score could be applied were identified. After a median follow-up of 49.0 months (95% CI [46.0;52.9]); from the IPTW analysis, median PFS was 17.6 months and 11.5 months (HR = 1.42; CI 95% [1.22-1.67]; p < 0.0001); median OS was 51.2 months and 44.3 months (HR = 1.29; CI 95% [1.06-1.56]; p = 0.0095) for the standard and delayed IDS groups. From the matched-pair analysis (comparing 352 patients for each group), standard IDS was associated with better PFS (HR = 0,77; CI 95% [0.65-0.90]; p = 0.018) but not significantly associated with better OS (HR = 0,84; CI 95% [0.68-1,03]; p = 0.0947). CONCLUSIONS: Carrying IDS after ≥5 NACT cycles seems to have a negative effect on patients survival. The goal of IDS surgery is complete resection and should not be performed after >3-4 NACT cycles.

Clinicopathological characterization of a real-world multicenter cohort of endometrioid ovarian carcinoma: Analysis of the French national ESME-Unicancer database.

BACKGROUND: Prognostic significance of endometrioid epithelial ovarian cancer (EOC) is controversial. We compared clinical, pathological, and biological features of patients with endometrioid and serous EOC, and assessed the independent effect of histology on outcomes. METHODS: We conducted a multicenter retrospective analysis of patients with EOC selected from the French Epidemiological Strategy and Medical Economics OC database between 2011 and 2016. Our main objective was to compare overall survival (OS) in endometrioid and serous tumors of all grades. Our second objectives were progression-free survival (PFS) and prognostic features. RESULTS: Out of 10,263 patients included, 3180 cases with a confirmed diagnosis of serous (N = 2854) or endometrioid (N = 326) EOC were selected. Patients with endometrioid histology were younger, more often diagnosed at an early stage, with lower-grade tumors, more frequently dMMR/MSI-high, and presented more personal/familial histories of Lynch syndrome-associated cancers. BRCA1/2 mutations were more frequently identified in the serous population. Endometrioid patients were less likely to receive chemotherapy, with less bevacizumab. After median follow-up of 51.7 months (95CI[50.1-53.6]), five-year OS rate was 81% (95CI[74-85]) in the endometrioid subgroup vs. 55% (95CI[53-57] in the serous subset (p < 0.001, log-rank test). In multivariate analyses including [age, ECOG-PS, FIGO, grade, and histology], the endometrioid subtype was independently associated with better OS (HR = 0.38, 95CI[0.20-0.70], p= 0.002) and PFS (HR = 0.53, 95CI[0.37-0.75], p < 0.001). CONCLUSIONS: Clinicopathological features at diagnosis are not the same for endometrioid and serous EOC. Endometrioid histology is an independent prognosis factor in EOC. These observations suggest the endometrioid population requires dedicated clinical trials and management.

Laparoscopic management of advanced epithelial ovarian cancer after neoadjuvant chemotherapy: a phase II prospective multicenter non-randomized trial (the CILOVE study).

OBJECTIVE: The aim of this study was to explore the feasibility and safety of the laparoscopic approach after neoadjuvant chemotherapy among selected chemosensitive patients with advanced ovarian cancer. METHODS: The CILOVE study was a phase II prospective non-randomized multicenter study. It aimed to enroll 47 women with unresectable disease at the time of initial diagnosis (International Federation of Gynecology and Obstetrics (FIGO) stage IV and/or diffuse extensive carcinomatosis for advanced FIGO stage IIIC or patients unfit to withstand radical primary surgery), in response to chemotherapy and fit to undergo laparoscopy. RESULTS: Among the 48 patients enrolled in the trial, 44 (92%) patients underwent exploratory staging laparoscopy and, as a result, 41 patients were eligible for cytoreductive surgery. Among them, 32 were intended to be managed by laparoscopy and nine patients were managed by laparotomy. The conversion rate to laparotomy was 9.4% (3/32) and the reasons were multiple surgical adhesions (n=1), miliary carcinomatosis and adhesion to the intraperitoneal mesh (n=1), and poor laparoscopic evaluation of transverse colon involvement (n=1). All except one patient had optimal cytoreduction (97% complete cytoreduction, 3% incomplete cytoreduction (residual tumor <2.5 mm)). The median operative time was 267 min (range 146-415) and the median estimated blood loss was 150 mL (range 0-500). Two patients had intra-operative complications: one diaphragm rupture that was repaired during laparoscopy and one bradycardia. Six patients experienced early post-operative complications (<1 month), but there were no grade 3 and 4 complications (3 infections, 1 lymphoedema, 2 hemorrhage). After cytoreductive laparoscopy, the percentage of patients without progression at 12 months was 87.5%. CONCLUSIONS: Interval ovarian cytoreduction by a laparoscopic approach is safe and feasible for patients with a favorable response to chemotherapy. With the widespread use of neoadjuvant chemotherapy in the management of advanced ovarian cancer, a minimally invasive approach may be a potential option.

How should we stage and tailor treatment strategy in locally advanced cervical cancer? Imaging versus para-aortic surgical staging.

Para-aortic lymph node status at initial assessment is the most important prognostic factor and a key point for the therapeutic strategy in patients with locally advanced cervical cancer. Undiagnosed lymph node metastasis is a major clinical problem as the finding of positive para-aortic lymph nodes leads to treatment modification, with a possible impact on disease free survival. When aortic lymph node disease is discovered, radiotherapy is extended to the para-aortic area, and other treatment modalities may be considered. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is the most accurate imaging examination to assess para-aortic extension in patients with locally advanced cervical cancer. The gold standard to identify para-aortic extension remains histologic evaluation of the lymph nodes. Indeed, PET/CT fails to detect approximately 10-15% of patients with negative PET/CT aortic nodes who have lymph node metastasis on pathologic staging. Patients with positive pelvic lymph nodes have para-aortic extension in 25-30% of cases, and surgical staging will lead to treatment modification and probably to improved para-aortic and distant control. Surgical staging also avoids unnecessary toxicity associated with extended field radiation in approximately 75% of patients with pelvic lymph node metastasis. The best modality to identify para-aortic extension is histological evaluation of the lymph nodes, but the survival benefit of surgical staging remains controversial. On the other hand, current studies include a majority of patients without pelvic lymph node spread, who are likely to be those who will benefit the least from surgical staging.

Analysis of tumour-infiltrating lymphocytes reveals two new biologically different subgroups of breast ductal carcinoma in situ.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) have been demonstrated to significantly influence prognosis and response to therapy of invasive breast cancer (IBC). Thus, it has been suggested that TIL density or/and immunophenotype could serve as biomarkers for selection of IBC patients for immunotherapy. However, much less is known about significance of TILs in breast ductal carcinoma in situ (DCIS). METHODS: We retrospectively investigated TIL density and immunophenotype in 96 pure DCIS and 35 microinvasive carcinomas (miCa). TIL density was assessed on H&E-stained breast biopsy sections as the percentage of tumour stromal area occupied by TILs, and classified into 4 grades: 0 (0%-9%), 1 (10-29%), 2 (30-49%) and 3 (50%-100%). TIL immunophenotype was assessed by immunohistochemistry for CD8, CD4, FoxP3, CD38 or CD20. RESULTS: Compared to pure DCIS, miCa contained significantly more cases with TIL density grade 3 (p = 0.028). Concordantly, CD8+, CD4+ and CD38+ cells were more numerous in miCa than in pure DCIS. In the pure DCIS subgroup with TIL density grades 2 and 3, all TIL subpopulations were more numerous than in the pure DCIS with TIL density grades 0 and 1, however the ratio between T-lymphocytes (CD8+ and CD4+) and B-lymphocytes (CD20+) was significantly lower (p = 0.029). On the other side, this ratio was significantly higher in miCa, in comparison with pure DCIS having TIL density grades 2 and 3 (p = 0.017). By cluster analysis of tumour cell pathobiological features we demonstrated similarity between miCa and the pure DCIS with TIL density grades 2 and 3. The only significant difference between those two categories was in the ratio of T- to B-TILs, higher in miCa. CONCLUSION: Results indicate that TIL density level can distinguish 2 biologically different DCIS subgroups, one of which (DCIS with ≥30% TILs, the TIL-rich DCIS) is like miCa. Similarity of TIL-rich pure DCIS and miCa as well as the role of B-lymphocytes in DCIS invasiveness are worth further investigating with regards to the potential development of immunotherapy-based prevention of DCIS progression.

Which Surgical Attitude to Choose in the Context of Non-Resectability of Ovarian Carcinomatosis: Beyond Gross Residual Disease Considerations.

BACKGROUND: In ovarian cancer, the increased rate of radical surgery comprising upper abdominal procedures has participated to improve overall survival (OS) in advanced stages by increasing the rate of complete cytoreductions. However, in the context of non-resectability, it is unclear whether radical surgery should be considered when it would lead to microscopic but visible disease (≤1 cm). We aimed to compare the survival outcomes among patients with incomplete cytoreduction according to the extent of surgery. METHODS: Overall, 148 patients presenting with advanced stage ovarian carcinomas were included in this retrospective study, regardless of treatment schedule. These patients were stratified according to the extent of surgery (standard or radical). Complete cytoreduction at the time of debulking surgery could not be carried out in all cases. RESULTS: Among our study population (n = 148), 96 patients underwent standard procedures (SPs) and 52 underwent radical surgeries (RP). Patients in the SP group had a lower Peritoneal Index Cancer (PCI) at baseline (12.6 vs. 14.9; p = 0.049). After PCI normalization, we observed similar OS in the SP and RP groups (39.7 vs. 43.1 months; p = 0.737), while patients in the SP group had a higher rate of residual disease >10 mm (p < 10(-3)). Patients in the RP group had an increased rate of relapse (p = 0.005) but no difference in disease-free survival compared with the SP group (22.2 for SP vs. 16.3 months; p = 0.333). Residual disease status did not impact survival outcomes. CONCLUSIONS: In the context of non-resectable, advanced stage ovarian cancer, standard surgery seems as beneficial as radical surgery regarding survival outcomes and should be considered to reduce surgery-associated morbidity.

Prospective Clinical Utility Study of the Use of the 21-Gene Assay in Adjuvant Clinical Decision Making in Women With Estrogen Receptor-Positive Early Invasive Breast Cancer: Results From the SWITCH Study.

BACKGROUND: The 21-gene Oncotype DX Recurrence Score assay is a validated assay to help decide the appropriate treatment for estrogen receptor-positive (ER+), early-stage breast cancer (EBC) in the adjuvant setting. The choice of adjuvant treatments might vary considerably in different countries according to various treatment guidelines. This prospective multicenter study is the first to assess the impact of the Oncotype DX assay in the French clinical setting. METHODS: A total of 100 patients with ER+, human epidermal growth factor receptor 2-negative EBC, and node-negative (pN0) disease or micrometastases in up to 3 lymph nodes (pN1mi) were enrolled. Treatment recommendations, physicians' confidence before and after knowing the Recurrence Score value, and physicians' perception of the assay were recorded. RESULTS: Of the 100 patients, 95 were evaluable (83 pN0, 12 pN1mi). Treatment recommendations changed in 37% of patients, predominantly from chemoendocrine to endocrine treatment alone. The proportion of patients recommended chemotherapy decreased from 52% pretest to 25% post-test. Of patients originally recommended chemotherapy, 61% were recommended endocrine treatment alone after receiving the Recurrence Score result. For both pN0 and pN1mi patients, post-test recommendations appeared to follow the Recurrence Score result for low and high values. Physicians' confidence improved significantly. CONCLUSION: These are the first prospective data on the impact of the Oncotype DX assay on adjuvant treatment decisions in France. Using the assay was associated with a significant change in treatment decisions and an overall reduction in chemotherapy use. These data are consistent with those presented from European and non-European studies.

Exenterative surgery for recurrent gynaecological malignancies.

BACKGROUND: Cancer is a leading cause of death worldwide. Gynaecological cancers (i.e. cancers affecting the ovaries, uterus, cervix, vulva and vagina) are among the most common cancers in women. Unfortunately, given the nature of the disease, cancer can recur or progress in some patients. Although the management of early-stage cancers is relatively straightforward, with lower associated morbidity and mortality, the surgical management of advanced and recurrent cancers (including persistent or progressive cancers) is significantly more complicated, often requiring very extensive procedures. Pelvic exenterative surgery involves removal of some or all of the pelvic organs. Exenterative surgery for persistent or recurrent cancer after initial treatment is difficult and is usually associated with significant perioperative morbidity and mortality. However, it provides women with a chance of cure that otherwise may not be possible. In carefully selected patients, it may also have a place in palliation of symptoms. The biology of recurrent ovarian cancer differs from that of other gynaecological cancers; it is often responsive to chemotherapy and is not included in this review. OBJECTIVES: To evaluate the effectiveness and safety of exenterative surgery versus other treatment modalities for women with recurrent gynaecological cancer, excluding recurrent ovarian cancer (this is covered in a separate review). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to February 2013. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of clinical guidelines and review articles and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) or non-randomised studies with concurrent comparison groups that included multivariate analyses of exenterative surgery versus medical management in women with recurrent gynaecological malignancies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. No studies were found; therefore no data were analysed. MAIN RESULTS: The search strategy identified 1311 unique references, of which seven were retrieved in full, as they appeared to be potentially relevant on the basis of title and abstract. However, all were excluded, as they did not meet the inclusion criteria of the review. AUTHORS' CONCLUSIONS: We found no evidence to inform decisions about exenterative surgery for women with recurrent cervical, endometrial, vaginal or vulvar malignancies. Ideally, a large RCT or, at the very least, well-designed non-randomised studies that use multivariate analysis to adjust for baseline imbalances are needed to compare exenterative surgery versus medical management, including palliative care.

Analysis of a continuous series of 34 young patients with early-stage cervical cancer selected for a vaginal radical trachelectomy: should "staging" conization be systematically performed before this procedure?

OBJECTIVE: Vaginal radical trachelectomy (VRT) is the most widely evaluated form of conservative management of young patients with early-stage (IB1) cervical cancer. Patients with nodal involvement or a tumor size greater than 2 cm are not eligible for such treatment. The aim of this study is to report the impact of a "staging" conization before VRT. METHODS: This is a retrospective study of 34 patients potentially selected for VRT for a clinical and radiologic cervical tumor less than 2 cm. Among them, 28 underwent finally a VRT (20 of them having a previous conization before this procedure) and 6 patients with macroscopic cervical cancer, confirmed by punch biopsies, "eligible" for VRT (<2 cm) had undergone "staging" conization (without further VRT) to confirm the tumor size and lymphovascular space involvement (LVSI) status. RESULTS: Six patients having "staging" conization before VRT had finally been deemed contraindications to VRT due to the presence of a histologically confirmed tumor greater than 2 cm and/or associated with multiple foci of LVSI. Among 28 patients who underwent VRT, 1 received adjuvant chemoradiation (this patient recurred and died of disease). Two patients treated with RVT (without postoperative treatment) recurred. Ten pregnancies (9 spontaneous and 1 induced) were observed in 9 patients. Among 4 patients with macroscopic "visible" tumor who do not underwent a "staging" conization before VRT, 2 recurred. Among 11 patients who underwent VRT and having LVSI, 3 recurred. CONCLUSIONS: These results suggest that if a conization is not performed initially, it should then be included among the staging procedures to select patients for VRT.

Pre-treatment surgical para-aortic lymph node assessment in locally advanced cervical cancer.

BACKGROUND: This is an updated version of the original Cochrane review published in The Cochrane Library, Issue 4, 2011.Cervical cancer is the most common cause of death from gynaecological cancers worldwide. Locally advanced cervical cancer, FIGO stage (International Federation of Gynaecology and Obstetrics) equal or more than IB1 is treated with chemotherapy and external beam radiotherapy followed by brachytherapy. If there is metastatic para-aortic nodal disease, radiotherapy is extended to cover this area. Due to increased morbidity, ideally extended-field radiotherapy is given only when para-aortic nodal disease is confirmed. Therefore, accurate assessment of the extent of the disease is very important for planning the most appropriate treatment. OBJECTIVES: To evaluate the effectiveness and safety of pre-treatment surgical para-aortic lymph node assessment for woman with locally advanced cervical cancer (FIGO stage IB2 to IVA). SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2012, Issue 10), MEDLINE and EMBASE (up to November 2012). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared surgical para-aortic lymph node assessment and dissection with radiological staging techniques, in adult women diagnosed with locally advanced cervical cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant trials met the inclusion criteria, abstracted data and assessed risk of bias. One RCT was identified so no meta-analyses were performed. MAIN RESULTS: We found only one trial, which included 61 women, that met our inclusion criteria. This trial reported data on surgical versus clinical staging and an assessment of the two surgical staging techniques; laparoscopic (LAP) versus extraperitoneal (EXP) surgical staging. The clinical staging was either a contrast-enhanced computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of the abdomen and pelvis to determine nodal status.In this trial, clinical staging appeared to significantly prolong overall and progression-free survival compared to surgical staging. There was no statistically significant difference in the number of women who experienced severe (grade 3 or 4) toxicity.There was no statistically significant difference in the risk of death, disease recurrence or progression, blood loss, severe toxicity and the duration of the operational procedure between LAP and EXP surgical staging techniques.The strength of the evidence is weak in this review as it is based on one small trial that was at moderate risk of bias. AUTHORS' CONCLUSIONS: Since the last version of this review no new studies were found.From the one available RCT we found insufficient evidence that pre-treatment surgical para-aortic lymph node assessment for locally advanced cervical cancer is beneficial, and it may actually have an adverse effect on survival. However, this conclusion is based on analysis of a small single trial and therefore definitive guidance or recommendations for clinical practice cannot be made.Therefore, the decision to offer surgical pre-treatment assessment of para-aortic lymph nodes in locally advanced cervical cancer needs to be individualised. The uncertainty regarding any impact on survival from pre-treatment para-aortic lymph node assessment should be discussed openly with the women.

Prophylactic Radical Fimbriectomy with Delayed Oophorectomy in Women with a High Risk of Developing an Ovarian Carcinoma: Results of a Prospective National Pilot Study.

Risk-reducing salpingo-oophorectomy is the gold standard for the prophylaxis of ovarian cancer in high-risk women. Due to significant adverse effects, 20-30% of women delay or refuse early oophorectomy. This prospective pilot study (NCT01608074) aimed to assess the efficacy of radical fimbriectomy followed by a delayed oophorectomy in preventing ovarian and pelvic invasive cancer (the primary endpoint) and to evaluate the safety of both procedures. The key eligibility criteria were pre-menopausal women ≥35 years with a high risk of ovarian cancer who refused a risk-reducing salpingo-oophorectomy. All the surgical specimens were subjected to the SEE-FIM protocol. From January 2012 to October 2014, 121 patients underwent RF, with 51 in an ambulatory setting. Occult neoplasia was found in two cases, with one tubal high-grade serous ovarian carcinoma. Two patients experienced grade 1 intraoperative complications. No early or delayed grade ≥3 post-operative complications occurred. After 7.3 years of median follow-up, no cases of pelvic invasive cancer have been noted. Three of the fifty-two patients developed de novo breast cancer. One BRCA1-mutated woman delivered twins safely. Twenty-five patients underwent menopause, including fifteen who had received chemotherapy for breast cancer, and twenty-three underwent menopause before the delayed oophorectomy, while two did not undergo a delayed oophorectomy at all. Overall, 46 women underwent a delayed oophorectomy. No abnormalities were found in any delayed oophorectomy specimens. Radical fimbriectomy followed by delayed oophorectomy appears to be a safe and well-tolerated risk-reducing approach, which avoids early menopause for patients with a high risk of breast and ovarian cancer.

Maximal cytoreduction in patients with FIGO stage IIIC to stage IV ovarian, fallopian, and peritoneal cancer in day-to-day practice: a Retrospective French Multicentric Study.

OBJECTIVES: To evaluate the outcome of maximal cytoreductive surgery in patients with stage IIIC to stage IV ovarian, tubal, and peritoneal cancer regarding overall survival (OS) and disease-free survival (DFS). MATERIALS AND METHODS: Five hundred twenty-seven patients with stage IIIC (peritoneal) and stage IV (pleural) ovarian, fallopian tube, and peritoneal carcinoma underwent surgery between January 2003 and December 2007 in 7 gynecologic oncology centers in France. Patients undergoing primary and interval debulking surgery were included, whichever the number of chemotherapy cycles. The extent of disease, type of surgical procedure, and amount of residual disease were recorded. A multivariate analysis of the outcome was performed, taking into account the stage, grade, and timing of surgery. RESULTS: Median DFS was 17.9 months, but median OS was not reached at the time of analysis. Complete cytoreductive surgery, without evident residual tumor at the end of the procedure, was obtained in 71% of all patients (primary surgery, 33%). After neoadjuvant therapy, the rate of complete debulking surgery was higher (74%) compared to primary cytoreductive surgery (65%). Twenty-three percent of patients needed "ultra radical surgery" to achieve this goal. The most significant predictive factor for DFS and OS was complete cytoreductive surgery compared to any amount, even minimal (1-10 mm), of residual disease. In the group of patients with complete cytoreductive surgery, the patients undergoing surgery before chemotherapy showed better DFS than those having first chemotherapy. CONCLUSION: The findings confirm that complete cytoreduction is the criterion standard of surgery in the management of advanced ovarian, peritoneal, and fallopian tube cancer, whatever the timing of surgery. With experienced teams, surgery was completed, without evident residual tumor in 71% of the cases.

Interval debulking surgery after neoadjuvant chemotherapy in advanced ovarian cancer - retrospective study comparing surgery after 3 cycles or more of chemotherapy.

OBJECTIVE: To evaluate and compare overall survival and progression-free survival in two groups of patients with advanced ovarian cancer, managed by neoadjuvant chemotherapy (3 cycles or more) followed by interval debulking surgery. Secondary objectives regarded surgical morbidity and extent of cytoreduction. MATERIAL AND METHODS: We conducted a retrospective study, in a referral center, evaluating the management of patients diagnosed with advanced ovarian cancer (FIGO IIIC-IV) beneficiating of interval surgery after neoadjuvant chemotherapy. We compared two groups, one in which patients underwent 3 cycles of chemotherapy before surgery, and a second group in which patients underwent more than 3 cycles. RESULTS: 140 patients underwent interval surgery after neoadjuvant chemotherapy. Among these patients, 45 patients underwent 3 or less cycles (group 1) and 95 patients more than 3 cycles (group 2). There was no statistical difference for overall and progression free survival. The mean overall survival was 58,4 months for group 1 and 58,3 for group 2 (p.value = 0.56). The mean progression free survival was 30,5 months for group 1 and 23,8 months for group 2 (p.value = 0.17). More posterior pelvectomies were realized in group 1 compared to group 2 with a statistically significant difference (p=0,01). There was no difference regarding complete macroscopic difference during the surgery between the 2 groups (p=0,09). CONCLUSION: Debulking surgery is an invasive and heavy procedure and is not always possible in first line. Neoadjuvant chemotherapy followed by interval debulking surgery is an accepted alternative. The number of administered cycles is questionable, and does not seem to have a significant impact on overall survival and progression free survival. However, surgical morbidity is significantly reduced by increased cycles of chemotherapy.

Therapeutic Challenges in Patients with Gynecologic Carcinosarcomas: Analysis of a Multicenter National Cohort Study from the French Prospective TMRG Network.

BACKGROUND: Gynecological carcinosarcomas are rare and aggressive diseases, with a poor prognosis. The rarity of these tumors explains the lack of robust and specific data available in the literature. The objective of this study was to investigate the impact of initial adjuvant treatment and recurrent therapeutic strategies. PATIENTS AND METHODS: A multicentric cohort study within the French national prospective Rare Malignant Gynecological Tumors (TMRG) network was conducted. Data from all included carcinosarcomas diagnosed between 2011 and 2018 were retrospectively collected. RESULTS: 425 cases of uterine and ovarian carcinosarcomas (n = 313 and n = 112, respectively) were collected and analyzed from 12 participating centers. At diagnosis, 140 patients (48%) had a FIGO stage III-IV uterine carcinosarcoma (UCS) and 88 patients (83%) had an advanced ovarian carcinosarcoma (OCS) (FIGO stage ≥ III). Two hundred sixty-seven patients (63%) received adjuvant chemotherapy, most preferably carboplatin-paclitaxel regimen (n = 227, 86%). After a median follow-up of 47.4 months, the median progression-free survival (mPFS) was 15.1 months (95% CI 12.3-20.6) and 14.8 months (95% CI 13.1-17.1) for OCS and UCS, respectively. The median overall survival for OCS and UCS was 37.1 months (95% CI 22.2-49.2) and 30.6 months (95% CI 24.1-40.9), respectively. With adjuvant chemotherapy followed by radiotherapy, mPFS was 41.0 months (95% CI 17.0-NR) and 18.9 months (95% CI 14.0-45.6) for UCS stages I-II and stages III-IV, respectively. In the early stage UCS subgroup (i.e., stage IA, n = 86, 30%), mPFS for patients treated with adjuvant chemotherapy (n = 24) was not reached (95% CI 22.2-NR), while mPFS for untreated patients (n = 62) was 19.9 months (95% IC 13.9-72.9) (HR 0.44 (0.20-0.95) p = 0.03). At the first relapse, median PFS for all patients was 4.2 months (95% CI 3.5-5.3). In the first relapse, mPFS was 6.7 months (95% CI 5.1-8.5) and 2.2 months (95% CI 1.9-2.9) with a combination of chemotherapy or monotherapy, respectively (p < 0.001). CONCLUSIONS: Interestingly, this vast prospective cohort of gynecological carcinosarcoma patients from the French national Rare Malignant Gynecological Tumors network (i) highlights the positive impact of adjuvant CT on survival in all localized stages (including FIGO IA uterine carcinosarcomas), (ii) confirms the importance of platinum-based combination as an option for relapse setting, and (iii) reports median PFS for various therapeutic strategies in the relapse setting.

Real-World Data on Newly Diagnosed BRCA-Mutated High-Grade Epithelial Ovarian Cancers: The French National Multicenter ESME Database.

BACKGROUND: In spite of the frequency and clinical impact of BRCA1/2 alterations in high-grade epithelial ovarian cancer (HGEOC), real-world information based on robust data warehouse has been scarce to date. METHODS: Consecutive patients with BRCA-mutated HGEOC treated between 2011 and 2016 within French comprehensive cancer centers from the Unicancer network were extracted from the ESME database. The main objective of the study was the assessment of clinicopathological and treatments parameters. RESULTS: Out of the 8021 patients included in the ESME database, 266 patients matching the selection criteria were included. BRCA1 mutation was found in 191 (71.8%) patients, while 75 (28.2%) had a BRCA2 mutation only; 95.5% of patients received a cytoreductive surgery. All patients received a taxane/platinum-based chemotherapy (median = six cycles). Complete and partial response were obtained in 53.3% and 20.4% of the cases, respectively. Maintenance therapy was administered in 55.3% of the cases, bevacizumab being the most common agent. After a median follow up of 51.7 months, a median progression-free survival of 28.6 months (95% confidence interval (CI) [26.5; 32.7]) and an estimated 5-year median overall survival of 69.2% (95% CI [61.6; 70.3]) were reported. Notably, BRCA1- and BRCA2-mutated cases exhibited a trend towards different median progression-free survivals, with 28.0 (95% CI [24.4; 32.3]) and 33.3 months (95% CI [26.7; 46.1]), respectively (p-value = 0.053). Furthermore, five-year OS for BRCA1-mutated patients was 64.5% (95% CI [59.7; 69.2]), while it was 82.5% (95% CI [76.6; 88.5]) for BRCA2-mutated ones (p-value = 0.029). CONCLUSIONS: This study reports the largest French multicenter cohort of BRCA-mutated HGEOCs based on robust data from the ESME, exhibiting relevant real-world data regarding this specific population.