Management of Early Stage Cervical Cancer

Cibula et al presented the final survival results of the SENTIX trial (NCT02494063).15 This international, multicenter, prospective, single arm study investigated sentinel lymph node biopsy without systematic pelvic lymphadenectomy in patients with early stage cervical cancer. Patients with International Federation of Gynaecology and Obstetrics (FIGO) 2018 stage 1A1–lymphovascular space invasion to stage 1B2 and no preoperatively suspicious lymph nodes were prospectively enrolled. All patients underwent bilateral sentinel lymph node biopsy with frozen section, followed by hysterectomy or trachelectomy. Patients who were positive for sentinel lymph nodes on frozen section were excluded. A total of 594 patients were included. Ultrastaging detected metastatic sentinel lymph nodes in 36 (6.1%) and isolated tumor cells in 20 (3.4%) patients. Patients with metastatic nodes underwent adjuvant (chemo) radiotherapy. The 2 year disease free survival was 93.3%, and overall survival was 97.9%. After a median follow-up of 47 months, 54 (9.1%) patients relapsed and 20 (3.4%) of these patients died. No negative impact of sentinel lymph node metastasis was observed on multivariable analysis. The study showed that 2 year disease free survival and overall survival in patients after sentinel lymph node biopsy are excellent and comparable with those after pelvic lymphadenectomy trials. The authors concluded that sentinel lymph node biopsy with ultrastaging without further lymphadenectomy was not associated with an increased risk of recurrence.

Tumor size is a prognostic factor influencing the radicality of the surgery. In another analysis from the SENTIX trial (NCT02494063), the authors evaluated the accuracy of preoperative tumor size assessment by pelvic magnetic resonance imaging or ultrasound.16 Of the 680 patients, T stage was postoperatively upgraded in 187 (27.5%) and downgraded in 74 (10.9%) patients. A difference of ≥10 mm between imaging and pathology was found in 155 (22.8%) patients (underestimated in 105 and overestimated in 50). The discrepancy increased in larger tumors and in patients diagnosed with biopsy instead of conization. Based on the current threshold for radicality, underestimation of size led to inadequate surgery in 9% of patients and overestimation led to overly radical surgery in 5.1% of patients.

Manzour et al reported the results of the SUCCOR (SUCCOR-Surgery in Cervical Cancer Comparing Different Surgical Aproaches in Stage IB1 Cervical Cancer) study after 10 years of follow-up.17 Case report forms were sent to investigators of 1272 patients who were treated with radical hysterectomy for stage IB1 cervical cancer to collect data on late recurrences and relapses. According to the data collected from 556 patients, 8.81% had relapse during a median follow-up time of 102 months. Overall survival was 97% at 5 years and 91% at 10 years of follow-up, while disease free survival was 93% and 90%, respectively; 78% of recurrences occurred in the first 5 years. Patients with recurrence had a 24-fold increased risk of death. There was no significant difference in post-recurrence survival between the groups.

In a study by Mahner et al, the authors presented a subanalysis of the SHAPE (Radical Versus Simple Hysterectomy and Pelvic Node Dissection With Low-risk Early Stage Cervical Cancer) trial, which aimed to understand the prognostic role of the preoperative loop electrosurgical excision procedure/conization and surgical approach.18 19 From 680 patients who underwent simple (n=338) or radical (n=342) hysterectomy, minimally invasive surgery was performed in 524 (77%) and open surgery in 156 (23%) patients. Median follow-up was 4.5 years. A total of 19 recurrences occurred following minimally invasive surgery (3.6%) and six following open surgery (3.8%). Among 174 patients (82%, n=143 minimally invasive surgery; 18%, n=31 open) with clear margins after the loop electrosurgical excision procedure/conization, 2 (1.4%) developed pelvic recurrences after minimally invasive surgery and none after open surgery. In the whole cohort, nine patients had an extrapelvic recurrence, 7/524 (1.3%) following minimally invasive surgery and 2/156 (1.3%) after open surgery. However, no extrapelvic recurrence occurred after either minimally invasive surgery or open surgery among patients who had previous the loop electrosurgical excision procedure/conization with clear margins. Of the 14 deaths observed, 11 (2.1%) occurred after minimally invasive surgery and 3 (1.9%) after open surgery but none after previous loop electrosurgical excision procedure/conization with clear margins.

Lymphovascular space invasion is a negative prognostic factor requiring radical surgery in early stage cervical cancer, which has recently been questioned. Dagher et al evaluated the outcomes in lymphovascular space invasion positive stage IA1–IB1 disease treated with non-radical surgery and bilateral lymphatic staging between 2009 and 2019.20 The study included 71 patients: 26 (37%) had lymphovascular space invasion and 45 (63%) did not, and 31 (44%) patients had stage IA1, 15 (21%) stage IA2, and 25 (35%) stage IB1 disease. Forty-four patients underwent conization and 27 underwent type A hysterectomy as a definitive surgical treatment. Patients with lymphovascular space invasion were significantly younger and more likely to have squamous histology. No recurrences or deaths occurred among patients with lymphovascular space invasion versus two recurrences among those without. The authors concluded that less radical surgery may be safe for selected patients with stage IA1–IB1 disease with lymphovascular space invasion.

Management of Locally Advanced Cervical Cancer

The INTERLACE trial (NCT01566240) was designed to evaluate the impact of adding induction chemotherapy before standard chemoradiation on overall survival and progression free survival in the management of locally advanced cervical cancer.21 In this study, 500 patients with squamous, adeno, or adenosquamous carcinoma were randomized (1:1) to receive either chemoradiation alone or 6 weeks of induction chemotherapy with carboplatin and paclitaxel followed by chemoradiation in week 7. Most patients had stage IIB and IIIB disease. After a median follow-up of 64 months, patients in the induction chemotherapy arm showed a significant improvement in 5 year progression free survival (73% vs 64%, p=0.013) and 5 year overall survival rates (80% vs 72%, p=0.04) compared with those who received chemoradiation alone. The study also found a lower incidence of distant recurrences in the induction chemotherapy arm and demonstrated that this combined approach could be a viable new standard of care for locally advanced cervical cancer. Thirty per cent of patients in the experimental arm did not complete treatment because of treatment related adverse events. Unfortunately, only 30% of patients received standard image guided radiotherapy so that the benefit of neoadjuvant chemotherapy in the context of modern standard radiotherapy is unknown.

In a study by Lorusso et al, the authors reported the efficacy, safety, and prespecified patient reported outcome from the phase 3 ENGOT-cx11/GOG 3047/KEYNOTE-A18 study (NCT04221945).22 Patients with FIGO 2009 stages IB2–IIB with node positive disease or stage III–IVA cervical cancer were randomized to receive fives cycles of pembrolizumab+concurrent chemoradiation followed by 15 cycles of pembrolizumab or five cycles of placebo+concurrent chemoradiation followed by 15 cycles of placebo. A total of 1060 patients were randomized to pembrolizumab+concurrent chemoradiation (n=529) or placebo+concurrent chemoradiation (n=531). At the protocol specified first interim analysis, median follow-up was 17.9 months. Pembrolizumab+concurrent chemoradiation showed a statistically significant improvement in progression free survival versus placebo+concurrent chemoradiation. Twenty-four month progression free survival was 67.8% with pembrolizumab+concurrent chemoradiation versus 57.3% with placebo+concurrent chemoradiation; median progression free survival was not reached in either group (hazard ratio (HR)=0.70, 95% confidence interval (CI) 0.55 to 0.89; p=0.0020). With only 103 events (42.9% maturity), the addition of pembrolizumab to concurrent chemoradiation showed a favorable trend in overall survival (HR=0.73, 95% CI 0.49 to 1.07). The incidence of grade ≥3 adverse events was 67% in the pembrolizumab+concurrent chemoradiation group and 60% in the placebo+concurrent chemoradiation group.

A total of 1008 patients were included in patient reported outcome analyses (pembrolizumab+concurrent chemoradiation, n=502; placebo+concurrent chemoradiation, n=506).23 In both arms, The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) global health status/quality of life (QLQ-C30 GHS/QoL), physical functioning (QLQ-C30 PF), and the EuroQoL 5-Dimension 5-Level questionnaire (EQ-5D-5L) visual analog scale scores decreased from baseline at weeks 3 and 6 but improved relative to baseline at week 12 and subsequent weeks. There were no clinically meaningful between group differences in changes in patient reported outcome scores from baseline to week 36. Pignata et al concluded that pembrolizumab+concurrent chemoradiation can be considered as a new standard of care for this population.

Management of Metastatic or Recurrent Cervical Cancer

The BEATcc trial (NCT03556839) evaluated the efficacy of adding atezolizumab to the standard first line regimen of bevacizumab plus chemotherapy for metastatic (stage IVB), persistent, or recurrent cervical cancer, regardless of PD-L1 status.24 In this phase 3 study, 410 patients with recurrent, metastatic, or persistent cervical cancer were randomized (1:1) to receive either the standard regimen or the same regimen with atezolizumab until disease progression or severe toxicity. After a median follow-up of 32.9 months, the study showed a significant improvement in both progression free survival (13.7 vs 10.4 months, p=0.0001) and interim overall survival (32.1 vs 22.8 months, p=0,0046) for patients treated with atezolizumab. The objective response rate was higher (84% vs 72%) in the atezolizumab group. The safety profiles were within expectations, although grade ≥3 adverse events were slightly higher in the atezolizumab group (79% vs 75%).

The phase 3 innovaTV 301 study (NCT04697628) evaluated tisotumab vedotin, an antibody–drug conjugate, for the treatment of recurrent or metastatic cervical cancer in patients whose disease had progressed during or after standard of care therapy.25 The study included 502 patients. After a median follow-up of 10.8 months, the results showed a 30% reduction in the risk of death (HR=0.70, 95% CI 0.54 to 0.89; p=0.0038) and superior progression free survival (HR=0.67, 95% CI 0.54 to 0.82; p<0.0001) for the tisotumab vedotin group. Specifically, median overall survival was 11.5 months with tisotumab vedotin versus 9.5 months with chemotherapy. The objective response rate was significantly higher in the tisotumab vedotin group (17.8%) compared with chemotherapy (5.2%; p<0.0001). Treatment related adverse events of special interests for tisotumab vedotin were consistent with the previous known safety profile, including bleeding, and neurologic and ocular toxicity: peripheral sensory neuropathy in 26.8% of patients (most of them grades 1–2), grade 1–2 conjunctivitis in 30.4% of patients, keratitis in 15.6% of patients (most of them grades 1–2), and grade 1–2 epistaxis in 22.8% of patients.

Management of Advanced or Recurrent Endometrial Cancer

Colombo et al presented the results of AtTEnd/ENGOT-EN7 (NCT03603184), a phase 3, double blind, randomized controlled trial, evaluating the efficacy and safety of atezolizumab combined with carboplatin and paclitaxel in patients with advanced (n=148) or recurrent (n=369) endometrial cancer.26 Atezolizumab or placebo was continued as maintenance therapy until disease progression. A significant improvement in progression free survival was observed in the mismatch repair deficient subgroup (HR=0.36, 95% CI 0.23 to 0.57; p<0.05) and in all comers (HR=0.74, 95% CI 0.61 to 0.91; p<0.05) of the atezolizumab arm compared with the placebo arm. The duration of response in the mismatch repair deficient subgroup and the interim analysis of overall survival in all comers showed a trend in favor of atezolizumab. Treatment related adverse events in the atezolizumab cohort were anticipated and manageable. However, no statistically significant benefit in the subgroup of patients with proficient mismatch repair was observed. No relevant differences in grade ≥3 rates were found between both groups.

Boere et al assessed the time to deterioration of patient reported outcomes between trial arms in the RUBY trial (NCT03981796).27 28 Post hoc analyses were conducted using the EORTC quality of life (QOL) questionnaire core 30 (QLQ-C30) and endometrial cancer 24 (QLQ-EN24). In the mismatch repair deficient/microsatellite instability high subgroup (n=118), better results were seen in most QLQ-C30 domains in the dostarlimab arm. Global quality of life and role functioning showed delayed time to permanent deterioration. In the overall population, neither QLQ-C30 nor QLQ-EN24 showed differences between the arms. No detriment was observed in the overall population. The results support the use of dostarlimab, carboplatin, and paclitaxel as a standard of care in patients with mismatch repair deficient/microsatellite instability high primary advanced or recurrent endometrial cancer.

Novák et al reported the immune related adverse events in the RUBY trial (NCT03981796) according to the Common Terminology Criteria for Adverse Events V.4.03.29 Immune related adverse events related to dostarlimab or placebo were reported by 38.2% in the dostarlimab+carboplatin–paclitaxel arm and by 15.4% in the placebo+carboplatin–paclitaxel arm; grade ≥3 immune related adverse events related to dostarlimab or placebo were reported by 12.4% and 3.3% of patients, respectively. Only 7.9% and 3.7% of patients discontinued dostarlimab and placebo, respectively, due to an immune related adverse event. There were no deaths related to immune related adverse events. Management and resolution rates were similar in the placebo+carboplatin–paclitaxel arm. Most immune related adverse events were mild and resolved, while a small number of patients discontinued dostarlimab. The profile of adverse events ovbserved in the dostarlimab+carboplatin–paclitaxel arm showed similar trends to those observed with dostarlimab monotherapy.

Two additional analyses of the RUBY trial results were presented regarding the progression free survival 2–progression free survival 1 and overall survival by molecular classification.30 31 In the mismatch repair deficient/microsatellite instability high group (dostarlimab+carboplatin–paclitaxel, n=53; placebo+carboplatin–paclitaxel, n=65), the dostarlimab+carboplatin–paclitaxel arm had longer median progression free survival 2–progression free survival 1 (17.7 vs 10.5 months; HR=0.77). Among the proficient mismatch repair (microsatellite stable) group, the dostarlimab+carboplatin–paclitaxel arm had longer median progression free survival 2–progression free survival 1 (7.9 vs 7.1 months; HR=0.82), where the survival curves diverged increasingly at ~3 months and maintained it thereafter. Similarly, the RUBY trial dostarlimab+carboplatin–paclitaxel arm had a longer median progression free survival 2–progression free survival 1 (7.9 vs 7.3 months; HR=0.82). The RUBY trial population included 400 patients (81.0%) with mutational data: POLE, mismatch repair deficient/microsatellite instability high, TP53mut, and non-specific molecular profile (n=5 (1.3%), n=91 (22.8%), n=88 (22.0%), and n=216 (54.0%), respectively). The results for progression free survival and overall survival showed superiority of the dostarlimab+carboplatin–paclitaxel arm for the non-specific molecular profile and superiority for mismatch repair deficient/microsatellite instability high and TP53mut.

Immune checkpoint inhibitors have shown encouraging activity in endometrial cancer, particularly in mismatch repair deficient cases, and have been accepted as standard of care in patients with advanced endometrial cancer following systemic therapy.32 33 ENGOT-en9/LEAP-001 phase 3 trial (NCT03884101) compared lenvatinib plus pembrolizumab with chemotherapy as first line treatment in 842 patients with advanced or recurrent endometrial cancer.34 The final analysis showed no superiority of lenvatinib plus pembrolizumab in overall survival and progression free survival compared with the standard regimen. Immune checkpoint inhibitors have fallen short of expectations with limited activity in the first line treatment of advanced endometrial cancer, highlighting the need for better biomarkers to identify patients who will benefit from checkpoint inhibitors.

Maintenance Therapy in Endometrial Cancer

Westin et al analyzed the survival results of DUO-E/GOG-3041/ENGOT-EN10 (NCT04269200), a phase 3 randomized controlled trial that evaluated durvalumab in combination with standard first line carboplatin and paclitaxel, followed by durvalumab with or without olaparib in a total of 718 patients with advanced or recurrent endometrial cancer.35 The addition of durvalumab alone or durvalumab+olaparib to carboplatin and paclitaxel improved median progression free survival in both arms compared with placebo with carboplatin and paclitaxel (10.2, 15.1, and 9.6 months, respectively, p<0.05). The greater benefit of durvalumab was particularly evident in the mismatch repair deficient group. However, in the proficient mismatch repair group, a significant benefit with a longer median progression free survival could be detected solely after adding olaparib to carboplatin and paclitaxel+durvalumab, compared with carboplatin and paclitaxel alone (15.0 vs 9.9 and 9.7 months, respectively). A similar trend was achieved in overall survival rates (carboplatin and paclitaxel+durvalumab+olaparib versus carboplatin and paclitaxel: HR=0.59, 95% CI 0.42 to 0.83; p<0.05; carboplatin and paclitaxel+durvalumab vs carboplatin and paclitaxel: HR=0.77, 95% CI 0.56 to 1.07, p=0.120) in the initial interim analysis. The safety profile of all three treatment arms was comparable.

Nishio et al reported on the ethnicity based efficacy of atezolizumab as maintenance therapy in the AtTEnd/ENGOT-EN7 trial (NCT03603184).36 Twenty per cent of all patients constituted the Asian cohort. In contrast with the non-Asian cohort, the Asian cohort had a lower median age (63 vs 67 years), lower body mass index (23.1 vs 28.7), and better performance status (82% vs 66%). In addition, newly diagnosed metastatic disease (45% vs 30%) and its surgical treatment (82% vs 42%) were more common in the Asian cohort. The non-Asian cohort were more likely to have received previous radiation therapy for recurrent disease (50% vs 16%). Interestingly, histological examination of the Asian cohort revealed a lower rate of mismatch repair deficient (20% vs 24%) and a higher rate of PD-L1 positive tumors (68.2% vs 38.8%). Treatment tolerability in the Asian cohort appeared inferior to the non-Asian cohort, with more grade 3–5 adverse events (75% vs 63%). The authors concluded that atezolizumab improved progression free survival in mismatch repair deficient tumors independent of ethnicity, while in proficient mismatch repair the drug did not work.

Sehouli et al presented a subgroup analysis of ENGOT-EN5/GOG-3055/SIENDO (NCT03555422), a randomized, double blind, phase 3 trial evaluating the updated efficacy and safety of selinexor (n=77) versus placebo (n=36) as maintenance therapy in wild-type TP53 (TP53wt) endometrial cancer.37 With a median follow-up of 28.9 months, selinexor demonstrated superior progression free survival compared with placebo (27.4 vs 5.2 months, HR=0.41, 95% CI 0.25 to 0.69; nominal one sided p=0.0002). Progression free survival improved regardless of microsatellite stability whereas in TP53wt/microsatellite stable (proficient mismatch repair (microsatellite stable)), median progression free survival was not achieved with selinexor versus 4.9 months with placebo. They observed an encouraging overall survival trend in the TP53wt subgroup (HR=0.76, 95% CI 0.36 to 1.59) as well as in the TP53wt/proficient mismatch repair (microsatellite stable) subgroup (HR=0.57, 95% CI 0.24 to 1.35). These findings suggest that TP53wt status may predict selinexor efficacy.

Lymphovascular Space Invasion and Prognosis in Endometrial Cancer

Dagher et al reported the results of a multicenter retrospective cohort study of FIGO 2009 stage I node negative endometrial adenocarcinoma, investigating the influence of the extent of lymphovascular space invasion on local and distant recurrence.38 They included 1555 patients with substantial lymphovascular space invasion (n=65, 4.2%), focal lymphovascular space invasion (n=119, 7.7%), or no lymphovascular space invasion (n=1371, 88%)) with a median follow-up of 61 months (range 0.8–164). They reported 56 local recurrences, 43 distant recurrences, and 73 deaths without recurrence. Stage IB was detected in 35 (54%), 44 (37%), and 115 (8.4%) of patients with substantial lymphovascular space invasion, focal lymphovascular space invasion, and no lymphovascular space invasion, respectively (p<0.001). Adjuvant treatment rates varied significantly between groups (substantial lymphovascular space invasion 55%, focal lymphovascular space invasion 67%, and no lymphovascular space invasion 15%; p<0.001). They found that substantial lymphovascular space invasion had an increased risk of distant recurrence compared with no lymphovascular space invasion, but not for local recurrence (adjusted HR (aHR)=2.29, 95% CI 1.17 to 4.46) compared with focal lymphovascular space invasion (aHR=0.59, 95% CI 0.36 to 0.96). They reported that age at surgery, histological grade, and depth of myoinvasion were independently associated with local or distant recurrence.

Genetic and Molecular Testing in Endometrial Cancer

In a study by Feng et al, the authors conducted exome-wide association analysis in search of novel endometrial cancer risk genes by evaluating data from the UK Biobank (1587 EC cases), Gaussian ancestry (159 324 controls), Chinese patients with endometrial cancer (n=239), and Chinese controls from ChinaMAP (n=10 588).39 The authors identified 50 genes characterized by pathogenic loss-of-function and 26 genes with pathogenic loss-of-function combined with a disruptive missense mutation that were associated with endometrial cancer and may be useful in the future for the development of screening tools.

In a retrospective analysis by Tuerlinckx et al, the authors evaluated clinicopathological differences between CTNNB1 mutated (CTNNB1mut) and CTNNB1 wild-type (CTNNB1wt) endometrial tumors.40 Among 243 patients included in the study, 41 (16.9%) had a CTNNB1 mutation. Tumors with a CTNNB1 mutation were associated with endometrioid histopathology (p<0.001), low grade (p=0.015), and could be classified as having a non-specific molecular profile (p<0.001). The authors did not demonstrate a survival difference, neither in the overall population or in the non-specific molecular profile subgroup. Progression free survival (HR=0.73, 95% CI 0.25 to 2.12) and overall survival (HR=0.41, 95% CI 0.05 to 3.29) between CTNNB1mut and CTNNB1wt endometrial cancer in the overall population was similar. Analysis in endometrioid/non-specific molecular profile subgroups also showed no differences in progression free survival (HR=1.17, 95% CI 0.32 to 4.36) and overall survival (HR=0.50, 95% CI 0.06 to 4.10) for CTNNB1mut versus CTNNB1wt .

Real World Data from ESGO Database

Concin et al shared the results of a multicenter study evaluating the prognostic impact of ESGO quality indicators for advanced ovarian cancer surgery.1 Involving 72 ESGO accredited centers and 10 520 patients with advanced stage ovarian cancer from 2020 to 2022, the endpoints were progression free survival, overall survival, and adherence to each quality indicator. The results showed a 2 year progression free survival rate of 45.4% and an overall survival rate of 77.9%. Progression free survival was highest (63.1%) in patients undergoing upfront surgery with no residual disease, emphasizing the importance of maximal surgical effort to achieve complete cytoreduction. The study confirms the value of ESGO quality indicators in predicting outcomes in advanced ovarian cancer and underscores the need for upfront surgery to improve progression free survival.

Maintenance Therapy in Ovarian Cancer

The standard of care for patients with poly-ADP ribose polymerase inhibitor (PARPi) naïve, late recurrent, and platinum sensitive ovarian cancer patients is platinum based chemotherapy with PARPi. In the phase 3 ANITA trial (NCT03598270), patients with measurable high grade serous, endometrioid, or undifferentiated recurrent ovarian cancer, who had received up to two previous lines of chemotherapy and had a platinum free interval of more than 6 months, were randomized 1:1 to a carboplatin doublet plus either atezolizumab (1200 mg every 3 weeks or equivalent) or placebo for six cycles, followed by maintenance niraparib with continued atezolizumab or placebo until disease progression or unacceptable toxicity.41 Primary results showed no improvement in progression free survival with the addition of atezolizumab to platinum based chemotherapy and maintenance niraparib, but a subgroup analysis showed different effects according to the patient’s BRCA mutation status.42 Compared with the BRCA non-mutated population, the BRCA mutated population included more patients previously exposed to PARPi and/or a treatment free interval exceeding 12 months. In the BRCA mutated subgroup, median progression free survival, objective response rate, and median maintenance progression free survival numerically favored the atezolizumab containing therapy (12.7 months vs 11.9 months, respectively), while HR values favored the standard arm, although the sample size limited the interpretation of these findings.

In a study by Loverix et al, the authors presented the Leuven PARPi Benefit test, which was designed to overcome the difficulties of homologous recombination deficiency testing in ovarian cancer.43 The results of the proposed test were compared with the Myriad myChoice CDxPLUS (Myriad) test in a training and validation cohort of the PAOLA-1 trial. In the validation cohort, the Leuven PARPi Benefit test classified 47.5% of samples as positive compared with 56.6% with the Myriad test. At 2 years, progression free survival of Leuven PARPi Benefit Test positive patients was 78.1% versus 32.1% with olaparib versus placebo, respectively (HR=0.32, 95% CI 0.181 to 0.566). For Myriad homologous recombination deficiency test positive patients, this was 69.2% versus 34.4% with olaparib versus placebo, respectively (HR=0.40, 95% CI 0.248 to 0.661). For patients with Leuven PARPi Benefit Test positive/BRCA wild-type (BRCAwt) tumors, progression free survival was 70.8% versus 22.2% at 2 years (HR=0.18, 95% CI 0.068 to 0.487). For patients with Myriad test positive/BRCAwt tumors, progression free survival was 53.6% versus 29.4% (HR=0.35, 95% CI 0.173 to 0.700). There was no difference in 2 year progression free survival with either a negative Leuven PARPi Benefit test or a negative Myriad homologous recombination deficiency test. In conclusion, the Leuven PARPi Benefit test provided an alternative approach to predict PARPi benefit for patients with ovarian cancer.

The NORA trial (NCT03705156) evaluated overall survival in patients with platinum sensitive recurrent ovarian cancer receiving an individualized starting dose of niraparib maintenance therapy regardless of germline BRCA mutation (gBRCAm) status.44 Patients with platinum sensitive recurrent ovarian cancer who had responded to their last platinum based chemotherapy were randomized to receive niraparib or placebo once daily. Niraparib 200 mg was used for those with a body weight <77 kg and/or platelet count <150×10³ /µL, and otherwise 300 mg. A total of 265 patients were randomized (177 niraparib, 88 placebo). At the data cut-off date of August 14, 2023, median follow-up for overall survival was 57.9 months (interquartile range 54.8–61.6). Forty-one (46.6%) of the placebo treated patients received subsequent PARPi therapy. With 138 (52.1%) overall survival events reported, median overall survival (95% CI) in the overall population was 51.5 months (41.4 to 58.9) with niraparib and 47.6 months (33.3 to not evaluable) with placebo (HR=0.86, 95% CI 0.60 to 1.23). Niraparib maintenance therapy using an individualized starting dose demonstrated a favorable overall survival trend versus placebo in patients with platinum sensitive recurrent ovarian cancer, regardless of gBRCAm status.

FLAMES (A Study of IMP4297 as Maintenance Treatment Following First-line Chemotherapy in Patients With Advanced Ovarian Cancer) evaluated the efficacy and safety of senaparib, a selective PARPi, as first line maintenance therapy in Chinese patients with newly diagnosed advanced ovarian cancer.45 A total of 404 patients who had a complete or partial response to initial platinum based chemotherapy were randomized to receive senaparib or placebo. The primary endpoint, progression free survival, significantly favored senaparib, with a HR of 0.43, indicating a 57% reduction in the risk of progression or death, both in BRCAmut (HR=0.43, 95% CI 0.24 to 0.76; p<0.01) and BRCAwt (HR=0.43, 95% CI 0.30 to 0.61; p<0.01) subgroups. Notably, senaparib maintenance therapy showed a well tolerated safety profile. Despite the high incidence of adverse events leading to dose modifications in the senaparib group, no myelodysplastic syndromes or fatal events were reported.

Bevacizumab After Previous Antiangiogenic Treatment in Recurrent Ovarian Cancer

The efficacy and safety of bevacizumab following previous antiangiogenic therapy and second line platinum based chemotherapy were investigated in patients with recurrent ovarian cancer in the phase AGO-OVAR 2.21 trial (NCT01837251).46 Clinical characteristics of patients with previous antiangiogenic therapy and controls without previous antiangiogenic therapy were compared. Of 682 enrolled patients, 324 (47.5%) have received previous antiangiogenic therapy. During the trial, the overall relative risk (RR) for all bevacizumab associated adverse events, including hypertension, thrombosis, proteinuria, and fistula, was 44.3% versus 60.3% (RR=0.73, p<0.0001) in patients after previous antiangiogenic therapy compared with antiangiogenic therapy naïve patients. RR was comparable for adverse event subgroups. Progression free survival was shorter among patients with previous antiangiogenic therapy than in controls: median 11.0 versus 14.2 months (HR=1.60, 95% CI 1.35 to 1.89, p<0.0001). Overall efficacy of bevacizumab in combination with chemotherapy in platinum eligible disease was demonstrated regardless of previous treatment. Safety profile was within the expected range.

Antibody Drug Conjugate and Immunotherapy in Ovarian Cancer

Patients with platinum resistant ovarian cancer relapse within 6 months after completion of first line treatment, and the probability of a response to platinum retreatment is <10%.47 48 To date, no treatment has shown a survival benefit in this poor prognosis group with the exception of the antibody drug conjugate mirvetuximab (Elahere).47–50 This single arm, phase 2 trial evaluated the efficacy and safety of another antibody drug conjugate, upifitamab rilsodotin (targeting NaPi2b), in 268 platinum resistant ovarian cancer patients.51 The objective response rate in the NaPi2b positive and overall populations (objective response rates 13.1% and 15.6%, 95% CI 9.3 to 17.7 and 10 to 22.7, respectively) did not show a significant improvement over historical single agent chemotherapy, with a high frequency of dose reductions and discontinuations (25% and 18.7%, respectively). Five events of grade 5 emergent bleeding were reported. Unfortunately, the antibody drug conjugate upifitamab rilsodotin could not live up to the high expectations after the success of mirvetuximab, but the focus on the poor prognosis group of platinum resistant ovarian cancer is very desirable to provide further evidence for their specific therapy.

In a post hoc analysis by You et al, the authors evaluated the benefit of adding atezolizumab to first line chemotherapy in ovarian cancer patients with an unfavorable KELIM (score<1.0).52 A total of 597 patients received atezolizumab and 602 received placebo with ≥3 CA125 measurements. In the multivariate analysis, both unfavorable KELIM score and suboptimal surgery were independently associated with decreased progression free survival. The addition of atezolizumab improved progression free survival in patients with a poorer prognosis (n=269) in both the neoadjuvant and adjuvant settings. No significant progression free survival benefit was observed with atezolizumab based on KELIM score assessment alone.

Tumor Treating Fields in Platinum Resistant Ovarian Cancer

Vergote et al conducted a randomized ENGOT-ov50/GOG-3029/INNOVATE-3 phase 3 trial (NCT03940196) in patients with platinum resistant ovarian cancer comparing tumor treating field and paclitaxel versus paclitaxel alone.53 Patients with ECOG 0–1 and less than five previous lines of chemotherapy, including a maximum of two after platinum resistance, were recruited. From March 2019 to November 2021, 280 of 558 patients were treated with tumor treating fields (200 kHz at least 18 hours/day) plus weekly paclitaxel (80 mg/m²) and 278 with paclitaxel alone. Median overall survival was 12.2 and 11.9 months in the experimental and control arms, respectively. Grade 3 adverse events were observed in 60%, none of which were tumor treating field related, but 83.6% had device related grade 1 and 2 skin adverse effects. Tumor treating field+paclitaxel did not show an improvement in overall survival, except for those not previously treated with pegylated liposomal doxorubicin.

Ovarian Cancer and Endometriosis

In a study by Dondi et al, the authors compared and analyzed the characteristics of patients diagnosed with endometriosis related ovarian cancer (n=29), endometriosis associated ovarian cancer (n=17), and ovarian cancer not related or associated with endometriosis (n=48).54 The results showed that mean age at diagnosis was lower in patients with endometriosis related ovarian cancer (57 years) and endometriosis associated ovarian cancer (61 years) compared with patients with ovarian cancer not related or associated with endometriosis (65 years). Patients with endometriosis related ovarian cancer (66.7%) and endometriosis associated ovarian cancer (69%) were more likely to develop unilateral masses compared with ovarian cancer not related or associated with endometriosis (41.3%). Endometrial pathology was more frequently diagnosed in patients with endometriosis related ovarian cancer (48%) compared with endometriosis associated ovarian cancer (17.6%) and ovarian cancer not related or associated with endometriosis (10.5%). Endometriosis related ovarian cancer was also characterized by higher CA-19.9 levels (mean 756 U/mL versus <30 U/mL in endometriosis associated ovarian cancer and ovarian cancer not related or associated with endometriosis) and lower FIGO stage: I–II in 75.8% of cases compared with FIGO stages I–II in 29.4% of endometriosis associated ovarian cancer and 25% of ovarian cancer not related or associated with endometriosis.

Adjuvant Chemotherapy in High Grade Uterine Sarcomas

Gallego-Martinez et al reported the results of a multicenter, observational, retrospective study in patients with surgically resected FIGO stage I to IV high grade uterine sarcoma with or without adjuvant chemotherapy, with overall survival as the primary endpoint.55 Potential prognostic variables were selected, based on previous evidence, and inverse probability weighting was performed to establish two homogeneous groups regarding the use of adjuvant chemotherapy. Risk stratification into three groups (high, intermediate, and low) was defined based on baseline variables associated with an increased risk of death in the multivariate analysis (p<0.05). The study included 746 patients from 47 centers in 22 countries. Median overall survival in the high risk group was 29.93 and 19.15 months with or without adjuvant chemotherapy, respectively (HR=0.48 (0.26–0.88), p=0.02). There were no differences in the intermediate and low risk groups. The authors stated that this is the first study to show a clear benefit in overall survival for a high risk group of patients with high grade uterine sarcoma receiving adjuvant chemotherapy.

Primary Tumor Site and Prognosis in Vulvar Cancer

In a population based retrospective study by Liu and Miao, the authors examined the association between primary tumor site and prognosis in 3465 patients with vulvar squamous cell carcinoma (n=2389) and non-squamous cell carcinoma histologic types of vulvar carcinoma (n=1076).56 No statistically significant association between primary tumor site and prognosis was observed in the case of vulvar squamous cell carcinoma. However, in patients with non-squamous cell carcinoma histologic types, labium minus (HR=1.85, 95% CI 1.27 to 2.71; p=0.001) and clitoris sited (HR=2.37, 95% CI 1.47 to 3.85; p<0.001) primary tumors were associated with worse cancer specific survival compared with labium majus sited disease.

Exome DNA Sequencing in Squamous Vulvar Cancer

Carreras-Dieguez et al presented results of a study examining the whole exome DNA sequencing of 60 patients with squamous cell carcinoma of the vulva.57 The results showed that 10 of the analyzed specimens were collected from human papillomavirus (HPV) associated disease, 37 were associated with TP53 mutation, and in 13 cases neither HPV etiology nor TP53 mutation was detected. The most frequently detected mutations involved the following genes: TP53 (66.7%), FAT1 (28.3%), CDKN2A (25%), RNF213 (23.3%), NFE2L2 (20%), and PIK3CA (20%). RAD50, TP53, NFE2L2, PIK3CA, and DNM2 were identified as tumor drivers. The worst survival was observed in patients with combined TP53 mutation and CCND1 gains.

Prehabilitation in Gynecological Oncology

In a study by Dhanis et al, the authors evaluated preoperative functional status for gynecological oncology patients.58 The study included 107 patients undergoing surgery for endometrial, ovarian, and vulvar cancer. The authors showed significant improvements in VO2max of 0.83 mL/kg/min (p=0.017), in indirect 1-RM of 16 kg (p<0.001), and grip strength of 1.2 kg (p=0.008). The authors acknowledged that significantly more participants were at low risk for malnutrition after multimodal prehabilitation than before (62% vs 70%; p=0.005), and a significant one point reduction in Patient-Generated Subjective Global Assessment score was found (p=0.002). Based on these findings, the authors demonstrated that multimodal prehabilitation has the ability to improve functional capacity preoperatively.

Indocyanine Green Fluorescence Angiography for the Prevention of Anastomotic Leakage

In a study by Xhindoli et al, the authors reported updates of their findings on the use of indocyanine green fluorescence angiography for the prevention of anastomotic leakage after colorectal resection during cytoreductive surgery for advanced ovarian cancer.59 60 The authors observed that the use of indocyanine green fluorescence angiography, which was introduced at their institution in 2020, helped to reduce the incidence of anastomotic leakage from 8.8% (34/386) to 1.9% (3/158). Multivariate analysis confirmed that the use of indocyanine green fluorescence angiography was an independent protective factor against the development of anastomotic leakage (OR=0.29, 95% CI 0.08 to 0.99, p=0.05), while concurrent small bowel resection and residual tumor were identified as independent predictors of colorectal anastomotic leakage.

Personalized Drug Sensitivity Models

Zhang et al evaluated the individual therapy response of newly diagnosed ovarian cancer patients to various systemic and targeted therapies using a three-dimensional bioprinting model.61 The study included 45 patients: 38 high grade serous, four ovarian clear cell carcinoma, one ovarian sarcoma, one endometrioid carcinoma, and one neuroendocrine tumor. Diverse responses to treatment with paclitaxel, carboplatin, cisplatin, doxorubicin, niraparib, olaparib, anlotinib, and lenvatinib were observed, demonstrating the importance of personalized therapy.

BRCA1 and BRCA2 Populational Screening

In this analysis, Sun et al evaluated the benefit of BRCA1/BRCA2 testing in the general population over 30 years compared with family history based testing.62 In this study, the authors showed that population based BRCA testing could potentially prevent an additional 32 841 new breast cancer cases and 6387 ovarian cancer cases in the Canadian population, and prevent 2516 breast cancer deaths and 2103 ovarian cancer deaths. In addition, the authors demonstrated the cost effectiveness of population based BRCA testing in Canada.