Henrik Falconer

Extensive cytoreductive surgery in stage IV ovarian cancer may not be a justified treatment strategy

Complete macroscopic surgical cytoreduction improves survival in advanced ovarian cancer. However, our previous results suggest that the survival benefits of aggressive surgery to achieve complete macroscopic resection may vary across different subgroups. This study aimed to identify a potential poor-prognosis subgroup among patients with complete macroscopic resection. This cohort study included all patients with advanced ovarian cancer who underwent complete macroscopic resection in a public and centralized health care system setting. Two 3-year cohorts were compared: pre-implementation (cohort 1, n = 101) and post-implementation (cohort 2, n = 172) of a very high surgical proficiency setting. Overall survival was compared by relative risks (RR) stratified by stage and surgical extent. Cox regression estimated hazard ratios (HR) adjusted for relevant covariates. In patients with stage IV, median survival was 33 (cohort 2) vs 47 months (cohort 1), 7-year RR 1.01 (95 % CI 0.78 to 1.31). When extensive surgery was required in stage IV median survival was 27 (cohort 2) vs 58 months (cohort 1), 5-year RR 0.91 (95 % CI 0.81 to 1.01). By contrast, in stage III, median survival was 93 (cohort 2) vs 59 (cohort 1) months, 7-year RR 0.76 (95 % CI 0.59 to 0.98), with the greatest difference when less extensive surgery was required; Not reached vs 65 months, 7-year RR 0.62 (95 % CI, 0.43 to 0.88). Adjusted analysis confirmed improved survival in cohort 2 only after less extensive surgery, HR 0.56 (95 % CI, 0.33-0.95). The implementation of a very high surgical proficiency setting was not associated with improved survival in patients with stage IV despite complete macroscopic resection, as opposed to patients with stage III.

Effect of intraperitoneal ropivacaine during and after cytoreductive surgery on time-interval to adjuvant chemotherapy in advanced ovarian cancer: a randomised, double-blind phase III trial

In a previous phase II trial, intraperitoneal local anaesthetics shortened the time interval between surgery and adjuvant chemotherapy, an endpoint associated with improved survival in advanced ovarian cancer. Our objective was to test this in a phase III trial. A double-blind, phase III parallel superiority trial was conducted at two university hospitals in Sweden, within a public and centralised healthcare system. Women >18 yr with advanced ovarian cancer scheduled for cytoreductive surgery, an ASA physical status of 1-3 with no speech/language issues, were eligible. Participants were randomly assigned using a central computerised system to receive either ropivacaine 0.2% or saline 0.9% (placebo) intraperitoneally during and after surgery. The primary endpoint was time to return to intended oncologic therapy (RIOT), analysed using t-test and linear regression adjusted for centre. Of the 225 women randomised between August 2020 and December 2023 (ropivacaine n=113; placebo n=112), 175 were included in the modified intention-to-treat analysis (ropivacaine n=86; placebo n=89). Median age: ropivacaine group 64 yr (56-73 yr), placebo group: 66 yr (57-74 yr). The mean RIOT in the ropivacaine group was 26.5 days vs 25.8 days in the placebo group, with a mean difference of 0.7 days (-2.2 to 3.4 days; P=0.65). Per-protocol analysis of 166 women yielded similar results, mean difference of 0.5 days (-2.4 to 3.4 days; P=0.74) days. There were no differences in short-term recovery or postoperative morbidity. Intraperitoneal local anaesthetic did not shorten the time to RIOT among women undergoing surgery for advanced ovarian cancer in this trial. ClinicalTrials.gov (NCT04065009), European Union Clinical Trials Register (2019-003299-38/SE).

Development of a surgical competency assessment tool for sentinel lymph node dissection by minimally invasive surgery for endometrial cancer

Sentinel lymph node dissection is widely used in the staging of endometrial cancer. Variation in surgical techniques potentially impacts diagnostic accuracy and oncologic outcomes, and poses barriers to the comparison of outcomes across institutions or clinical trial sites. Standardization of surgical technique and surgical quality assessment tools are critical to the conduct of clinical trials. By identifying mandatory and prohibited steps of sentinel lymph node (SLN) dissection in endometrial cancer, the purpose of this study was to develop and validate a competency assessment tool for use in surgical quality assurance. A Delphi methodology was applied, included 35 expert gynecological oncology surgeons from 16 countries. Interviews identified key steps and tasks which were rated mandatory, optional, or prohibited using questionnaires. Using the surgical steps for which consensus was achieved, a competency assessment tool was developed and subjected to assessments of validity and reliability. Seventy percent consensus agreement standardized the specific mandatory, optional, and prohibited steps of SLN dissection for endometrial cancer and informed the development of a competency assessment tool. Consensus agreement identified 21 mandatory and three prohibited steps to complete a SLN dissection. The competency assessment tool was used to rate surgical quality in three preselected videos, demonstrating clear separation in the rating of the skill level displayed with mean skills summary scores differing significantly between the three videos (F score=89.4; P<0.001). Internal consistency of the items was high (Cronbach α=0.88). Specific mandatory and prohibited steps of SLN dissection in endometrial cancer have been identified and validated based on consensus among a large number of international experts. A competency assessment tool is now available and can be used for surgeon selection in clinical trials and for ongoing, prospective quality assurance in routine clinical care.

Pelvic sentinel lymph node biopsy in endometrial cancer—a simplified algorithm based on histology and lymphatic anatomy

To achieve the full potential of sentinel lymph node (SLN) detection in endometrial cancer, both presumed low- and high-risk groups should be included. Perioperative resource use and complications should be minimized. Knowledge on distribution and common anatomical sites for metastatic SLNs may contribute to optimizing the concept while maintaining sensitivity. Proceeding from previous studies, simplified algorithms based on histology and lymphatic anatomy are proposed. Data on mapping rates and locations of pelvic SLNs (metastatic and non-metastatic) from two previous prospective SLN studies in women with endometrial cancer were retrieved. Cervically injected indocyanine green was used as a tracer and an ipsilateral re-injection was performed in case of non-display of the upper and/or lower paracervical pathways. A systematic surgical algorithm was followed with clearly defined SLNs depicted on an anatomical chart. In high-risk endometrial cancer patients, removal of SLNs was followed by a pelvic and para-aortic lymphadenectomy. 423 study records were analyzed. The bilateral mapping rates of the upper and lower paracervical pathways were 88.9% and 39.7%, respectively. 72% of all SLNs were typically positioned along the upper paracervical pathway (interiliac and/or proximal obturator fossa) and 71 of 75 (94.6%) of pelvic node positive women had at least one metastatic SLN at either of these positions. Women with grade 1-2 endometroid cancers (n=275) had no isolated metastases along the lower paracervical pathway compared with two women with high-risk histologies (n=148). SLNs along the upper paracervical pathway should be identified in all endometrial cancer histological subtypes; removal of nodes at defined typical positions along the upper paracervical pathway may replace a site-specific lymphadenectomy in case of non-mapping despite tracer re-injection. Detection of SLNs along the lower paracervical pathway can be restricted to high-risk histologies and a full pre-sacral lymphadenectomy should be performed in case of non-display.

Association between pelvic inflammatory disease and subsequent salpingectomy on the risk for ovarian cancer

Salpingectomy is associated with a lower risk for ovarian cancer, suggesting that the fallopian tubes constitute the origin of the disease. It is unclear whether the observed effect is mediated by pelvic inflammatory disease (PID); a major indication for salpingectomy and implicated in the aetiology of ovarian cancer. In this population-based cohort study, we used nationwide registry-based data on women exposed for PID with and without subsequent salpingectomy (n = 97,912) compared with the unexposed population (n = 5,429,174) between 1973 and 2010. The effect of hormone treatment was considered in a subanalysis. Of the exposed women, 9538 women underwent salpingectomy during the study period. There was a significant association between PID and ovarian cancer (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.31-1.59), whereas an inverse association was observed for exposed women with subsequent salpingectomy (HR 0.55, 95% CI 0.36-0.83). Salpingectomy performed on other indications (n = 24,895) was associated with a lower incidence of ovarian cancer (HR 0.72, 95% CI 0.56-0.93). No effect modification was observed for the use of oral contraceptives or hormonal replacement therapy. Salpingectomy is associated with a lower incidence of ovarian cancer regardless of indication.

Beyond oncologic outcomes: fertility and ovarian preservation as key priorities

A combination of second trimester oral metronidazole and no sexual intercourse during second and third trimester may reduce late miscarriage and premature delivery after fertility sparing radical trachelectomy

Women with a previous trachelectomy have an increased risk of premature delivery and second trimester miscarriage. In this study we aim to evaluate factors and regimes possibly affecting the risk for prematurity following fertility sparing robotic radical trachelectomy (RRT) in cervical cancer. A retrospective study of the reproductive outcome following RRT with a cervical cerclage performed at one of four academic centers between 2007 and 2019. Factors possibly related to premature delivery, such as postoperative non-pregnant cervical length, previous vaginal deliveries, preservation of the uterine arteries, and the use of a second trimester oral metronidazole/no sexual intercourse regime, were assessed. 109 women remained for analyses after excluding recurrences before pregnancy (n = 8), secondary hysterectomy (n = 2), and women with less than six months follow up (n = 10). 74 pregnancies occurred in 52/71 women attempting to conceive, 56 of which developed past the first trimester. Two of 22 women (9%) who were prescribed an oral metronidazole regime (400 mg × 2 from gestational week 15 + 0 to 21 + 6 and abstaining from sexual intercourse for the duration of the pregnancy) had a premature delivery, compared with 13/31 (42%) where the regime was not applied (p = 0.009). The association remained after regression analyses including possible contributing factors as of above, none of which associated with prematurity at regression analyses (p = 0.001). The observed four-fold reduction in premature delivery indicates that an oral metronidazole/no sexual intercourse regime may reduce second trimester miscarriage and premature deliveries following an RRT. No association was observed for other investigated factors.

Is robot‐assisted laparoscopy safe for surgical treatment of cervical cancer?

Oncological outcomes after radical hysterectomy followed by adjuvant (chemo)radiation or no further treatment in women with cervical cancer FIGO 2018 IB2-IIA2 – A multinational population-based cohort study

The role of adjuvant treatment after radical hysterectomy for early-stage cervical cancer with intermediate-risk factors remains uncertain. In this international population-based cohort study, we investigated the potential benefit of adjuvant treatment on overall survival (OS) and recurrence-free survival (RFS). Utilizing population-based registers from Sweden, Denmark, and the Netherlands, we included women with early-stage cervical cancer FIGO 2018 stages IB2-IIA2 with tumor size >20 mm and negative lymph nodes. All women underwent radical hysterectomy followed by either adjuvant radiotherapy or chemoradiotherapy (AT) or no further treatment (NFT). Survival outcomes were analyzed to assess the impact of AT. A total of 976 women with early-stage cervical cancer, treated between 2010 and 2017, were analyzed. At five years, there were no significant differences in OS (87.7 % vs. 91.9 %) or RFS (79.8 % vs. 82.6 %) between the AT (309 women, 32 %) and NFT (667 women, 68 %) groups. Selecting women with the intermediate risk factors: tumor size > =4cm or tumor size 2-3,9 cm with the presence of lymphovascular space invasion, no significant differences in OS or RFS were observed between AT and NFT. In addition, a multivariable analysis found that tumor size and lymphovascular space invasion predicted adverse survival outcomes. In this population-based cohort study, adjuvant therapy after radical hysterectomy was not associated with a survival benefit in women with FIGO 2018 IB2-IIA2 cervical cancer. These findings corroborate earlier findings on the role of adjuvant therapy for cervical cancer with intermediate-risk factors and support de-escalation to avoid radiation harm for this patient population.

The IPLA-OVCA Trial, Intra-Peritoneal Local Anaesthetics in Ovarian Cancer

Surgery and chemotherapy combined constitute first line treatment in women with advanced ovarian cancer. The aim of surgery apart from staging is cytoreduction, i.e. surgical resection of tumour. Radical resection of all tumour visible by the naked eye followed by adjuvant chemotherapy is associated with best chance of prolonged survival. However, because of tumour dissemination in the peritoneal cavity, radical surgery is often very extensive with surgery in all quadrants of the abdomen and multi-organ resection with substantial risk of postoperative severe complications and subsequent delay in administration of adjuvant chemotherapy. Longer time-interval between surgery to start of adjuvant chemotherapy has been associated with decrease in survival. Surgery presents opportunities not only for eradicating tumours but, paradoxically, also for proliferation and invasion of residual cancer cells. It increases the shedding of malignant cells into the blood and lymphatic circulations, inhibits their apoptosis and potentiates their invasion capacity. Additionally, the immune system, the inflammatory system and the neuroendocrine system react to surgery with important changes, which have been proven to promote progression of cancer. Several anaesthesia-related factors play an important role in perioperative tumorigenesis such as inhalational anaesthetics, opiate analgesics, local anaesthetics and regional anaesthesia, all of which may impact short-term morbidity and long-term mortality. A previous randomized placebo-controlled pilot study suggests that women who receive local anesthetics intraperitoneally preoperatively have a significantly decreased time-interval to initiation of adjuvant chemotherapy. In a prospective, randomised, multi-centre study, we plan to further assess if intraperitoneal local anaesthetics administered perioperatively during 72 h leads to early start of chemotherapy compared to placebo in patients undergoing cytoreductive surgery for FIGO stage III-IV ovarian cancer.