Maria del Pilar Esteves Diz

Ten years of experience with endometrial cancer treatment in a single Brazilian institution: Patient characteristics and outcomes

Few reports have described the clinical and prognostic characteristics of endometrial cancer, which is increasing worldwide, in large patient series in Brazil. Our objective was to analyze the clinicopathological characteristics, prognostic factors, and outcomes of patients with endometrial cancer treated and followed at a tertiary Brazilian institution over a 10-year period.This retrospective study included 703 patients diagnosed with endometrial cancer who were treated at a public academic tertiary hospital between 2008 and 2018. The following parameters were analyzed: age at diagnosis, race, body mass index, serum CA125 level before treatment; histological type and grade, and surgical stage. Outcomes were reported relative to histological type, surgical staging, serum CA125, lymph-vascular space involvement (LVSI), and lymph-node metastasis. The median patient age at diagnosis was 63 (range, 27-93) years (6.4% were <50 years). Minimally invasive surgeries were performed in 523 patients (74.4%). Regarding histological grade, 468 patients (66.5%) had low-grade endometrioid histology and 449 patients (63.9%) had stage I tumors. Tumors exceeded 2.0 cm in 601 patients (85.5%). Lymphadenectomy was performed in 551 cases (78.4%). LVSI was present in 208 of the patients' tumors (29.5%). Ninety-three patients (13.2%) had recurrent tumors and 97 (13.7%) died from their malignant disease. The robust prognostic value of FIGO stage and lymph node status were confirmed. Other important survival predictors were histological grade and LVSI [overall survival: hazard ratio (HR) = 3.75, p < 0.001 and HR = 2.01, p = 0.001; recurrence: HR = 2.49, p = 0.004 and HR = 3.22, p = 0.001, respectively). Disease-free (p = 0.087) and overall survival (p = 0.368) did not differ significantly between patients with stage II and III disease. These results indicate that prognostic role of cervical involvement should be explored further. This study reports the characteristics and outcomes of endometrial cancer in a large population from a single institution, with systematic surgical staging, a predominance of minimally invasive procedures, and well-documented outcomes. Prognostic factors in the present study population were generally similar to those in other countries, though our patients' tumors were larger than in studies elsewhere due to later diagnosis. Our unexpected finding of similar prognoses of stage II and III patients raises questions about the prognostic value of cervical involvement and possible differences between carcinomas originating in the lower uterine segment versus those originating in the body and fundus. The present findings can be used to guide public policies aimed at improving the diagnosis and treatment of endometrial cancer in Brazil and other similar countries.

A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53 -mutant Ovarian Cancer

Abstract Purpose: Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53-mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53-mutated ovarian cancer. Patients and Methods: Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53-mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m2), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib. Results: A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9–9.9) vs. 7.3 months (5.6–8.2); HR 0.63 (95% CI, 0.38–1.06); two-sided P = 0.080], meeting the predefined significance threshold (P &amp;lt; 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%). Conclusions: Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.

Role of systematic pelvic and para‐aortic lymphadenectomy in delayed debulking surgery after six neoadjuvant chemotherapy cycles for high‐grade serous ovarian carcinoma

AbstractIntroductionWe analyzed the role of systematic pelvic and para‐aortic lymphadenectomy in delayed debulking surgery after six neoadjuvant chemotherapy (NACT) cycles for advanced high‐grade serous ovarian carcinoma.Materials and MethodsWe retrospectively reviewed patients with advanced ovarian carcinoma who underwent NACT with carboplatin‐paclitaxel between 2008 and 2016. Patients were included only if they had FIGO IIIC‐IVB high‐grade serous carcinoma with clinically negative lymph nodes after six NACT cycles (carboplatin‐paclitaxel) and underwent complete or near complete cytoreduction. Patients with partial lymphadenectomy or bulky nodes were excluded. Patients who underwent systematic pelvic and aortic lymphadenectomy and those who did not undergo lymph node dissection were compared. Progression‐free and overall survivals were analyzed using the Kaplan–Meier method.ResultsTotally, 132 patients with FIGO IIIC‐IVB epithelial ovarian carcinoma were surgically treated after NACT. Sixty patients were included (39 and 21 in the lymphadenectomy and nonlymphadenectomy group, respectively); 40% had suspicious lymph nodes before NACT. Patient characteristics, blood transfusion numbers, and complication incidence were similar between the groups. In the lymphadenectomy group, 12 patients (30.8%) had histologically positive lymph nodes and the surgical time was longer (229 vs. 164 min). The median overall survival in the lymphadenectomy and nonlymphadenectomy groups, respectively, was 56.7 (95% CI 43.4–70.1) and 61.2 (21.4–101.0) months (p = 0.934); the corresponding disease‐free survival was 8.1 (6.2–10.1) and 8.3 (5.1–11.6) months (p = 0.878). Six patients exclusively presented with lymph node recurrence.ConclusionsSystematic lymphadenectomy after six NACT cycles may have no influence on survival.

Quality of life of locally advanced cervical cancer patients after neoadjuvant chemotherapy followed by chemoradiation versus chemoradiation alone (CIRCE trial): a randomized phase II trial

The CIRCE trial (NCT01973101) investigated the efficacy, safety, and quality of life of the addition of neoadjuvant chemotherapy with cisplatin and gemcitabine to standard chemoradiation for locally advanced cervical cancer (stages IIB-IVA). The impact of both treatment arms on quality of life is reported in the present study. Patients completed the European Organization of Research and Treatment of Cancer questionnaire QLQ-C30 and CX24 before treatment and at 3, 6, 9, and 12 months after treatment. Linear mixed models were fitted to analyze differences in quality of life over time and between groups. Differences in mean quality of life scales >10 points and p2 and peripheral neuropathy >2. Mann-Whitney U tests were performed to assess differences between groups in quality of life at baseline. To evaluate differences between treatment arms, linear mixed models were fitted using the transformed quality of life scores as a dependent variable and time of follow-up and study arm as factors. A total of 107 patients were enrolled (n=55 neoadjuvant chemotherapy arm; n=52 chemoradiation arm). Quality of life compliance rates were higher for the chemoradiation group at every assessment time (ranging from 75-86.5% in the chemoradiation arm vs 55-81.8% in the neoadjuvant chemotherapy arm). For quality of life results at baseline, no statistically significant difference between the groups was seen. For both groups, most scales showed improvements over time, except for worsening of the summary score, sexual enjoyment, peripheral neuropathy, and menopausal symptoms. For chemoradiation, body image was lower (p<0.001) and patients presented more lymphedema (p<0.001) and sexual worry (p<0.001) at 12 months compared with baseline. Comparing study arms, neoadjuvant chemotherapy showed significantly lower scores in the menopausal symptoms scale (p=0.03) and higher scores for sexual/vaginal functioning (p=0.01). At 12 months, clinical differences were seen only for body image and menopausal symptoms scale, with neoadjuvant chemotherapy presenting better body image scores and a lower burden of menopausal symptoms. After treatment for locally advanced cervical cancer, patients improved in most quality of life aspects. However, worsening was observed in sexual enjoyment, peripheral neuropathy, and menopausal symptoms. To improve patients' quality of life, efforts should be made to prevent and treat these long term effects of locally advanced cervical cancer treatment.

Exploratory unsupervised machine learning of angiogenesis biomarkers in a phase II advanced cervical cancer trial of radiochemotherapy with or without neoadjuvant chemotherapy

In a prospective, randomized phase II study, exploratory data analysis was conducted to evaluate angiogenesis-associated plasma protein levels in patients with locally advanced cervical cancer METHODS: Participants were divided into two groups: Group A received neoadjuvant cisplatin and gemcitabine treatment (NAC) followed by chemoradiation with cisplatin and brachytherapy (CRT), while Group B received only CRT. Plasma samples were collected from patients in Group A at three time points: baseline, after NAC, and after CRT. Group B patients had samples taken at two time points: baseline and after CRT. The study analyzed an angiogenesis-associated panel of plasma proteins, including angiopoietin-2, G-CSF, endothelin-1, FGF-1, FGF-2, follistatin, IL-8, HGF, EGF, HB-EGF, PLGF, VEGF-A, VEGF-C, and VEGF- D. Receiver Operating Characteristic (ROC) analyses assessed the predictive value of baseline biomarkers for 12, 24, and 36-month survival outcomes. Additionally, Principal Component Analysis (PCA) was applied to post-CRT biomarker changes to identify coordinated modulation patterns. PCA was based on normalized delta values and eigenvector loadings, enabling identification of biomarkers aligned with Progression-Free Survival (PFS) and Overall Survival (OS). Significant differences were observed in the levels of HB-EGF, IL-8, PLGF, and VEGF-C between Groups A and B following CRT. Additionally, angiopoietin-2 levels showed a significant increase in Group B only. NAC treatment in Group A appeared to downregulate IL-8. CRT induced significant changes in HB-EGF, IL-8, PLGF, and VEGF-C levels in both groups. Patients in Group B demonstrated improved PFS and OS compared to those in Group A. Despite these differences in survival outcomes, the authors observed no significant intergroup differences in the tested biomarkers after completion of CRT. ROC analysis of baseline angiogenesis biomarkers demonstrated limited predictive sensitivity for survival outcomes. However, PCA of biomarker changes following CRT highlighted VEGF-A, HB-EGF, and angiopoietin-2 as variables associated with PFS and OS. Baseline biomarker levels were not predictive of long-term outcomes. In contrast, CRT alone modulated key angiogenic biomarkers, and post-CRT biomarker changes were associated with improved survival. Such biomarker alterations were not observed following NAC, which was not associated with clinical benefit in this study. These findings underscore the value of dynamic biomarker evaluation and highlight how treatment strategies differentially impact biomarker profiles in advanced cervical cancer.

Ultrasensitive detection and tracking of circulating tumor DNA to predict relapse and survival in patients with locally advanced cervical cancer: phase III CALLA trial analyses.

After chemoradiotherapy (CRT), 30%-50% of patients with locally advanced cervical cancer (LACC) relapse, highlighting the unmet need for prognostic biomarkers. In the global randomized CALLA trial (NCT03830866), the addition of durvalumab during and after CRT did not significantly improve progression-free survival (PFS) in a biomarker-unselected intent-to-treat population. We analyzed the association of ultrasensitive circulating tumor DNA (ctDNA) and circulating human papillomavirus (cHPV) DNA detection with relapse and survival in the largest dataset in LACC to date. In CALLA, adult women with stage IB2-IIB node-positive or IIIA-IVA any node-status LACC were randomized 1 : 1 to receive durvalumab + CRT or CRT alone. The NeXT Personal® (Personalis) ultrasensitive tumor-informed assay with up to 1800 patient-specific variants was used for ctDNA and cHPV DNA analysis at baseline, cycle 3 day 1 (C3D1, post-CRT), and C6D1 (3 months post-CRT). Correlations were analyzed between ctDNA/cHPV DNA detection and outcomes [PFS, overall survival (OS)]. ctDNA was detected in 98.9% (183/185) of baseline samples, with no difference between treatment arms. Detection levels of ctDNA were predictive of disease progression and survival at baseline: hazard ratios (95% confidence intervals) comparing PFS and OS, respectively, in the ctDNA less than median versus ctDNA greater than median subgroups were 0.61 (0.28-1.35) and 0.55 (0.23-1.35) with durvalumab + CRT, and 0.49 (0.26-0.95) and 0.65 (0.33-1.28) with CRT. Post-treatment trends were similar and independent of stage or lymph node status. ctDNA detection at C3D1 occurred a median of 164 days (95% confidence interval 85-250) days before clinical progression. Baseline cHPV DNA levels were similar but were only predictive following treatment. This study demonstrates the potential utility of ultrasensitive detection of ctDNA as a predictive and prognostic marker of disease progression and OS in LACC independent of disease stage.