Impact of pattern of recurrence on post-relapse survival according to surgical timing in patients with advanced ovarian cancer.

OBJECTIVE: Our study aimed to evaluate the association between timing of cytoreductive surgery and pattern of presentation of the first recurrence in patients with advanced ovarian cancer. We also aimed to assess the impact of the pattern of recurrence on post-relapse overall survival according to surgical timing. METHODS: This retrospective multicenter study evaluated patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV ovarian cancer. Patients had undergone either primary debulking surgery, early interval debulking surgery after 3-4 cycles of neoadjuvant chemotherapy, or delayed debulking surgery after 6 cycles, with minimal or no residual disease, between January 2008 and December 2015. Survival analyses were conducted using the Log-rank test and the Cox model. Cumulative incidences of the different patterns of recurrence were estimated using a competing risks methodology. RESULTS: A total of 549 patients were included: 175 (31.9%) patients had primary, 224 (40.8%) early interval, and 150 (27.3%) delayed debulking surgery. The cumulative incidence of peritoneal recurrences at 2 years was higher with increasing neoadjuvant cycles (24.4%, 30.9% and 39.2%; p=0.019). For pleural or pulmonary recurrences, it was higher after early interval surgery (9.9%, 13.0% and 4.1%; p=0.022). Median post-relapse overall survival was 33.5 months (95% confidence interval (CI) (24.3 to 44.2)), 26.8 months (95% CI (22.8 to 32.6)), and 24.5 months (95% CI (18.6 to 29.4)) for primary, early interval, and delayed debulking surgery groups, respectively (p=0.025). The pattern of recurrence in a lymph node (hazard ratio (HR) 0.42, 95% CI (0.27 to 0.64)), delayed surgery (HR 1.53, 95% CI (1.11 to 2.13)) and time to first recurrence (HR 0.95, 95% CI (0.93 to 0.96)) were associated with post-relapse overall survival. For primary and early interval surgery, lymph node recurrences were associated with significantly longer post-relapse overall survival. CONCLUSIONS: The pattern of first recurrence was associated with timing of surgery, with peritoneal recurrences being more frequent with the increasing number of cycles of neoadjuvant chemotherapy. Lymph node recurrences were associated with better prognosis, having higher post-relapse overall survival. This improved prognosis of lymphatic recurrences was not observed in patients who underwent delayed surgery.

PARa-aOrtic LymphAdenectomy in locally advanced cervical cancer (PAROLA trial): a GINECO, ENGOT, and GCIG study.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) fails to detect approximately 25% of aortic lymph node metastasis in patients with PET/CT stage IIIC1 cervical cancer. Surgical staging could lead to treatment modification and to improved para-aortic and distant control. PRIMARY OBJECTIVES: To demonstrate if chemoradiation with tailored external beam radiation field based on surgical staging and pathologic examination of the para-aortic lymph node is associated with improved 3-year disease-free survival compared with patients staged with PET/CT staging only. STUDY HYPOTHESIS: Surgical staging followed by tailored chemoradiation will improve disease-free survival while avoiding unnecessary prophylactic extended-field chemoradiation in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1 cervical cancer. TRIAL DESIGN: This is an international multicenter, randomized, phase III study. Eligible patients will be randomized 1:1 between PET/CT staging followed by chemoradiation (control arm), or surgical staging followed by tailored chemo-radiation (experimental arm). Randomization will be stratified by tumor stage according to TNM classification, center, and adjuvant treatment. MAJOR INCLUSION/EXCLUSION CRITERIA: Main inclusion criteria are histologically proven PET/CT FIGO stage IIIC1 cervical cancer. Main exclusion criteria include unequivocal positive common iliac or para-aortic lymph node at pre-therapeutic imaging PET/CT. PRIMARY ENDPOINTS: The primary endpoint is disease-free survival defined as the time from randomization until first relapse (local, regional, or distant), or death from any cause. SAMPLE SIZE: 510 eligible patients ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The estimated date for completing accrual will be Q2 2027. The estimated date for presenting results will be Q4 2030. TRIAL REGISTRATION NUMBER: NCT05581121.

The effect of major postoperative complications on recurrence and long-term survival after cytoreductive surgery for ovarian cancer.

OBJECTIVE: To assess the impact on survival of major postoperative complications and to identify the factors associated with these complications in patients with advanced ovarian cancer after cytoreductive surgery. METHODS: We designed a retrospective multicenter study collecting data from patients with IIIC-IV FIGO Stage ovarian cancer who had undergone either primary debulking surgery (PDS), early interval debulking surgery (IDS) after 3-4 cycles of neoadjuvant chemotherapy, or delayed debulking surgery (DDS) after 6 cycles, with minimal or no residual disease, from January 2008 to December 2015. Univariable and multivariable analyses were conducted to identify factors associated with major surgical complications (≥Grade 3). We assessed disease-free survival (DFS) and overall survival (OS) rates according to the occurrence of major postoperative complications. RESULTS: 549 women were included. The overall rate of major surgical complications was 22.4%. Patients who underwent PDS had a higher rate of major complications (28.6%) than patients who underwent either early IDS (23.2%) or DDS (14.0%). Multivariable analysis revealed that extensive peritonectomy and surgical timing were associated with the occurrence of major complications. Median DFS and OS were 16.9 months (95%CI = [13.7-18.4]) and 48.0 months (95%CI = [37.2-73.1]) for the group of patients with major complications, and 20.1 months (95%CI = [18.6-22.4]) and 56.7 months (95%CI = [51.2-70.4]) for the group without major complications. Multivariable analysis revealed that major surgical complications were significantly associated with DFS, but not with OS. CONCLUSIONS: Patients who experienced major surgical complications had reduced DFS, compared with patients without major morbidity. Extensive peritonectomy and surgical timing were predictive factors of postoperative morbidity.

Radical Hysterectomy After the LACC Trial: Back to Radical Vaginal Surgery.

OPINION STATEMENT: Classical radical vaginal hysterectomy first performed by Anton Pawlik in Prague in 1888 and popularized by Frederic Schauta is now a historical technique virtually abandoned due to painful perineal incision, a high rate of urinary dysfunction, and the inability to perform lymph node assessment. However, the heritage of this approach has been still used and taught in a few centers outside their Austrian birthplace. A combined vaginal and laparoscopic approach was developed in the 1990s by French and German surgeons who designed diverse surgical techniques for which a novel classification is proposed. All these techniques are different from the so-called laparoscopically assisted radical vaginal hysterectomy (LARVH), a term widely used for laparoscopic radical hysterectomies with vaginal extraction of the specimen. Interestingly, after the publication of the LACC trial (Laparoscopic Approach to Cervical Cancer), the radical vaginal approach has found a very timely application. The creation of a vaginal cuff before performing radical laparoscopic hysterectomy described in 2007 by Leblanc as "Schautheim" operation can be used as a protective maneuver to avoid tumor spillage and potentially overturn the negative outcome of minimally invasive surgery in early-stage cervical cancer. As a result, the combination of radical vaginal and laparoscopic steps of surgery is one possible evolution after the LACC trial that needs further investigation. The forgotten vaginal surgical technique needs a specific learning curve. The creation of a vaginal cuff should be mastered by every gynecological oncologist.

Survival impact of histological response to neoadjuvant chemotherapy according to number of cycles in patients with advanced ovarian cancer.

OBJECTIVE: We sought to evaluate the impact of chemotherapy response score according to the number of cycles of neoadjuvant chemotherapy, on disease-free survival and overall survival, in patients with advanced epithelial ovarian cancer ineligible for primary debulking surgery. METHODS: This multicenter retrospective study included patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV epithelial ovarian cancer who underwent 3-4 or 6 cycles of a platinum and taxane-based neoadjuvant chemotherapy, followed by complete cytoreduction surgery (CC-0) or cytoreduction to minimal residual disease (CC-1), between January 2008 and December 2015, in four institutions. Disease-free survival and overall survival were assessed according to the histological response to chemotherapy defined by the validated chemotherapy response score. RESULTS: A total of 365 patients were included: 219 (60.0%) received 3-4 cycles of neoadjuvant chemotherapy, and 146 (40.0%) had 6 cycles of neoadjuvant chemotherapy before cytoreductive surgery. There were no significant differences in early relapses, disease-free survival, and overall survival according to the number of neoadjuvant chemotherapy cycles. However, regardless of the number cycles of neoadjuvant chemotherapy, persistent extensive histological disease (chemotherapy response score 1-2) was significantly associated with a higher peritoneal cancer index, minimal residual disease (CC-1), and early relapses. Median disease-free survival in patients with complete or near-complete response (score 3) was 28.3 months (95% CI 21.6 to 36.8), whereas it was 16.3 months in patients with chemotherapy response score 1-2 (95% CI 14.7 to 18.0, p<0.001). CONCLUSION: In our cohort, the number of neoadjuvant chemotherapy cycles was not associated with disease-free survival or overall survival. Chemotherapy response score 3 improved oncological outcome regardless of the number of neoadjuvant chemotherapy cycles.

A multivariate analysis of the prognostic impact of tumor burden, surgical timing and complexity after complete cytoreduction for advanced ovarian cancer.

OBJECTIVE: To assess the survival benefit of primary debulking surgery (PDS) compared to interval debulking surgery (IDS) after complete cytoreduction (CC-0) or cytoreduction to minimal residual disease (CC-1) in advanced ovarian cancer. Secondary objective was to evaluate the effect of tumor load and surgical complexity on patients' survival. METHODS: A retrospective multicentric study was designed, including patients with IIIC-IV FIGO stage ovarian cancer who underwent PDS or IDS with CC-0 or CC-1 from January 2008 to December 2015 in four high-volume institutions. Patients were classified in three groups: PDS, IDS after 3-4 cycles of neoadjuvant chemotherapy (NACT), and IDS after 6 cycles. Disease-free survival (DFS) and overall survival (OS) were estimated. Univariable and multivariable analyses were conducted. RESULTS: We included 549 patients, 175 (31.9%) underwent PDS, 224 (40.8%) had IDS after 3-4 cycles of NACT, and 150 (27.3%) underwent IDS after 6 cycles. Median DFS in PDS, IDS at 3-4 cycles and IDS at 6 cycles were 23.0 months (95%CI = [20.0-29.3]), 18.0 months (95%CI = [15.9-20.0]) and 17.1 months (95%CI = [15.0-20.9]), respectively; p < .001. Median OS were 84.0 months (95%CI = [68.3-111.0]), 50.7 months (95%CI = [44.6-59.5]) and 47.5 months (95%CI = [39.3-52.9]), respectively; p < .001. In multivariable analysis, high peritoneal cancer index score and NACT were negatively associated to DFS and OS. Surgical complexity and CC-1 were negatively associated to DFS. CONCLUSION: PDS offered a survival gain of almost three years compared to IDS in patients with minimal or no residual disease after surgery. PDS should remain the standard of care for advanced ovarian cancer.

Clinical relevance of high-intermediate risk endometrial cancer according to European risk classification.

OBJECTIVE: Risk models in endometrial cancer define prognosis and indicate adjuvant therapy. One of the currently used classifications was designed in 2016 in collaboration with the European Society of Medical Oncology (ESMO), the European Society of Gynecologic Oncology (ESGO), and the European Society of Radiotherapy (ESTRO). A high-intermediate risk group was introduced within the intermediate risk group. The purpose of this study was to evaluate the clinical relevance of this subclassification. METHODS: A multicenter retrospective study was carried out at five international tertiary institutions. Patients diagnosed with intermediate risk endometrial cancer on the basis of definitive pathology findings were included. Patients were stratified into intermediate and high-intermediate risk groups. Incidence of nodal metastases, and disease free and overall survival were compared between the two risk groups in univariate and multivariate analysis. RESULTS: 477 patients were included: 325 (68%) patients were identified as intermediate and 152 (32%) as high-intermediate endometrial cancer patients. Nodal metastases were found in 18 patients (11.8%) in the high-intermediate risk endometrial cancer group and 16 patients (4.9%) in the intermediate risk group. Lymphovascular space invasion was found to be a strong predictive factor of lymph node involvement. High-intermediate risk was found to be an independent factor of disease free survival (hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.00 to 3.08; p=0.050) and overall survival (HR 1.99; 95% CI 1.10 to 3.60; p=0.022) in the multivariate analysis. CONCLUSIONS: The study validates the clinical significance of the intermediate risk endometrial cancer subclassification. Prognosis for high-intermediate risk endometrial cancer was significantly poorer. The prevalence of lymph node metastases was higher in this group of patients.

Frozen section examination of sentinel lymph nodes can be used as a decisional tool in the surgical management of early cervical cancer.

INTRODUCTION: Sentinel lymph node (SLN) detection has been shown to be accurate in detecting lymph node involvement in early-stage cervical cancer. The objective of this study was to evaluate the accuracy of frozen section examination in the assessment of SLN status, with the aim of adequately driving the intra-operative decision. METHODS: We designed a retrospective study including patients from two comprehensive cancer centers between January 2001 and December 2018 with early-stage cervical cancer (IA1-IB2 according to International Federation of Gynecology and Obstetrics (FIGO) 2018) undergoing SLN dissection. The SLN procedure was performed using a cervical injection with technetium-99m combined with blue dye or indocyanine green in most cases. RESULTS: A total of 176 patients fulfilled inclusion criteria. Bilateral mapping was detected in 153 (86.7%) of them. Nineteen of these patients (12.4%) had SLN involvement: 13 with macrometastases, three with micrometastases and three with isolated tumor cells (ITC). Macrometastatic disease was missed on frozen section in 3/13 FIGO 2018 stage IIIC patients. The three patients with ITC were also missed by frozen section examination.Considering only macrometastases as lymph node involvement, frozen section sensitivity was 76.9% (95% CI 49.7 to 91.8) and negative predictive value (NPV) was 97.9% (95% CI 94.0 to 99.3) in patients with bilateral detection. Including micrometastases, sensitivity was 81.2% (95% CI 57.0 to 93.4) and NPV remained at 97.9% (95% CI 93.9 to 99.3). CONCLUSIONS: With a prevalence of final-stage IIIC in patients with pre-operative early-stage cervical cancer of the order of 10% in this series, the NPV of frozen section examination of SLN is very high, with an inferior limit of the CI superior to 94%. Diagnostic accuracy remains acceptable even if micrometastases are considered. The impact of missed ITC has not been established. Frozen section examination can be incorporated in the intra-operative decision algorithm.

Utility of Laparoscopic Indocyanine Green-Guided Sentinel Node Biopsy in Open Cervical Cancer Surgery.

OBJECTIVE: Multiple tracers have been used to improve lymphatic mapping and to reduce the false-negative rate of the sentinel node detection in gynecologic cancers. Nowadays, 99mTc colloids combined with blue-dye technique is the most extended technique. New alternatives such as the fluorescent indocyanine green and near-infrared fluorescent imaging detection have been introduced in lymphatic mapping staging procedures because of its easier visualization compared with the previous tracers. METHODS: We used the laparoscopic infrared camera for the indocyanine green-guided sentinel node biopsy in a laparotomic radical hysterectomy in a pregnant patient after a cesarean section, with the aim of improving the detection rate of sentinel node biopsy in open surgery. RESULTS: The technique was used in the first patient with accurate detection of sentinel node and no complications during the procedure. CONCLUSIONS: The use of laparoscopic indocyanine green in open surgery may be a useful tool for the detection of sentinel node biopsy.

Molecular classification of endometrial carcinoma, is it the new era of precision medicine?

For many years endometrial cancer has been subdivided into oestrogen - dependent (type I) and oestrogen - independent (type II), according to classical Bokhman classification. Histopathological evaluation including type and grade of tumour, along with clinical factors have been considered as very important prognostic factors that impact treatment decision. However, histologically similar tumours may have different outcomes. Recent molecular findings and new histopathological parameters have given new concept on risk stratification. The Cancer Genome Atlas Research Network (TCGA) of tumours have brought new insights into endometrial cancer management. Four molecular subgroups have been described: POLE ultramutated (POLE mut), p53 mutant (p53abn), mismatch repair deficient (MMRd) and non-specific molecular profile (NSMP). This new subdivision has been recently introduced in the European risk stratification system.

Survival Analysis in Endometrial Carcinomas by Type of Surgical Approach: A Matched-Pair Study.

(1) Background: This study aimed to analyze the impact of surgical approach on survival rates in women diagnosed with endometrial cancer. (2) Methods: A retrospective multicenter cohort of 1382 women diagnosed with EC was performed. A total of 684 (49.5%) women underwent minimally invasive surgery, 233 (34%) underwent robotic-assisted laparoscopy (RAL), 451 (66%) underwent conventional laparoscopy (LPS), and 698 (50.5%) underwent open surgery (OP). Sociodemographic features, tumor characteristics, and survival rates were analyzed in the whole sample and in a matched-pair model. (3) Results: Women operated on by OP were significantly older, presented more comorbidities, and had more aggressive tumors. Disease-free (DFS), overall (OS), and specific survival related to EC (SS) amounts were significantly higher for MIS compared to OP (p < 0.001). When matched by age, body mass index, comorbidities, ASA score, histological type, grade, myometrial invasion, and FIGO stage, 798 patients were selected. DFS, OS, and SS amounts were similar between the MIS and OP groups. (4) Conclusions: The surgical approach for women with EC does not impact DFS or OS amounts when matched by homogeneous groups.

Tracers and corresponding detection devices: technetium colloids, blue dyes & NIR fluorescence.

Tracers and corresponding detection devices for the mapping of sentinel lymph nodes have been evolving since the first use of lymphangiogram methods in 1977 in penile carcinoma. Nowadays a variety of dyes and radiotracers have been validated for use in breast, vulvar and cervical cancer as well as melanoma. Each tumor site with its anatomical conditions requires different mapping protocol. While the combination of radiotracer and blue dye or radiotracer alone is an established method for breast surgery, vulvar cancer and melanoma, in pelvic sentinel lymph node mapping indocyanine green is currently gaining popularity. Near infrared fluorescence imaging is an emerging technique that enables a real-time image-guided procedure and is currently approved by the Food and Drug Administration as a sentinel lymph node mapping substance with standard of care. New tracers and devices are constantly under investigation to better understand the pathway of lymphatic drainage and increase the sensibility and sensitivity of the method. In the present review the evolution of available tracers and detection devices is discussed. An exhaustive review of current clinical indications of each method, its particularities and adverse effects is made. Finally, an update on ongoing clinical studies in sentinel lymph node mapping methods is presented.

Fertility Sparing Treatment in Gastric-Type Endocervical Carcinoma.

Fertility sparing management of cancer is one of the main components of quality-of-life issues. Early-stage cervical cancer, frequently diagnosed in women of reproductive age, can potentially be treated conservatively. However, some rare histological types of cervical cancer present with aggressive clinical behavior. Particularly, in the newly introduced concept of gastric-type endocervical carcinoma, fertility sparing management is 'a priori' not recommended. Even so, this issue remains undocumented. For this reason, a selected review of the current literature on gastric type endocervical carcinoma was carried out through PubMed. The keywords included "gastric-type cervical cancer", "gastric-type endocervical carcinoma", "conservative surgery", "conservative treatment", "fertility sparing surgery", "radical trachelectomy", "laparoscopic trachelectomy", "robotic trachelectomy", "laparotomic trachelectomy", "abdominal trachelectomy", "trachelectomy", "neoadjuvant chemotherapy", "conisation", and "cone resection". A search in the European Network on Cancer, Infertility and Pregnancy (INCIP) database was performed. The rarity of gastric-type endocervical carcinoma does not allow for conclusions on fertility sparing management with solid evidence. However, diffuse character of the disease and aggressive clinical behavior contraindicate a conservative treatment in young women with gastric type cervical cancer.

Sentinel lymph node in vulvar cancer.

Lymph node removal as a part of surgical management is a standard of care in vulvar cancer patients. Due to patient morbidities and difficulties in treatment of inguinal healing after lymph nodes removal, lymphatic mapping has emerged as an increasingly popular option over the past few years. At this time several different techniques have been described and variety of different dyes were used. In addition, an important aspect of the use of the sentinel lymph node (SLN) technique is the removal of a limited number of lymph nodes, which allows more detailed pathological examination. Moreover, the interpretation of pathological ultra-staging of SLNs, which can identify low-volume metastases for which the clinical significance and the ideal management, remain uncertain. Despite differences in techniques and dyes used, this minimally invasive procedure is currently recommended as an alternative to full inguinofemoral lymph node dissection in selected cases by all major international societies. As for now SLN concept became a standard of care in vulvar cancer. This technique, though simple as a concept, requires a learning curve and should only be used in expert centers. This article provides a review on literature on SLN technique in vulvar cancer, current recommendations and future lines of investigation.

Effect of tumor burden and radical surgery on survival difference between upfront, early interval or delayed cytoreductive surgery in ovarian cancer.

OBJECTIVE: We sought to evaluate the impact on survival of tumor burden and surgical complexity in relation to the number of cycles of neoadjuvant chemotherapy (NACT) in patients with advanced ovarian cancer (OC) with minimal (CC-1) or no residual disease (CC-0). METHODS: This retrospective study included patients with International Federation of Gynaecology and Obstetrics IIIC-IV stage OC who underwent debulking surgery at 4 high-volume institutions between January 2008 and December 2015. We assessed the overall survival (OS) of primary debulking surgery (PDS group), early interval debulking surgery after 3-4 cycles of NACT (early IDS group) and delayed debulking surgery after 6 cycles (DDS group) with CC-0 or CC-1 according to peritoneal cancer index (PCI) and Aletti score. RESULTS: Five hundred forty-nine women were included: 175 (31.9%) had PDS, 224 (40.8%) early IDS and 150 (27.3%) DDS. Regardless of Aletti score, median OS after PDS was significantly higher than after early IDS or DDS, but the survival difference was higher in women with an Aletti score <8. Among patients with PCI ≤10, median OS after PDS was significantly higher than after early IDS or DDS. In women with PCI >10, there were no differences between PDS and early IDS, but DDS was associated with decreased OS. CONCLUSION: The benefit of complete PDS compared with NACT was maximal in patients with a low complexity score. In patients with low tumor burden, there was a survival benefit of PDS over early IDS or DDS. In women with high tumor load, DDS impaired the oncological outcome.