Edoxaban for 12 Months Versus 3 Months in Patients With Cancer With Isolated Distal Deep Vein Thrombosis (ONCO DVT Study): An Open-Label, Multicenter, Randomized Clinical Trial.

BACKGROUND: The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding. METHODS: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point. RESULTS: From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03-0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75-2.41). The prespecified subgroups did not affect the estimates on the primary end point. CONCLUSIONS: In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03895502.

Cellular angiofibroma in the retroperitoneal space during pregnancy: A case report.

BACKGROUND: Cellular angiofibroma (CA) is a rare, benign mesenchymal tumor first described by Nucci et al. (Am J Surg Pathol 21:636-644, 1997. 10.1097/00000478-199706000-00002). It affects both men and women, although it is more common in middle-aged women. CA is well circumscribed and usually observed on the body surface, primarily in distal genital regions. Aggressive angiomyxoma and angiomyofibroblastoma are clinically and histologically similar; therefore, it may be necessary to distinguish between CA and these similar tumors. We present a rare case of CA, with atypical features, in the retroperitoneal space during pregnancy. CASE PRESENTATION: The presence of a 130 mm tumor was detected in a 19-year-old woman. The tumor, located in the retroperitoneal space, was found during first pregnancy examination. At 16 weeks of gestation, the woman developed nausea and fever, and it was diagnosed with acute pyelonephritis. After a few days, the amniotic membranes prematurely ruptured, leading to a miscarriage. The woman underwent a tumor resection, after miscarriage. This case presented with atypical features of CA. This included the young age of the patient, and presence of a tumor in the retroperitoneal space. CONCLUSION: In this case, the diagnosis of CA was difficult due to the rarity of the disease and its atypical clinical features. From this experience, we recommend that the discussion on the efficacy of surgical treatment and pregnancy outcomes should be done based on individual case, and not generalized.

Neoadjuvant chemotherapy followed by interval debulking surgery for advanced epithelial ovarian cancer: GOTIC-019 study.

INTRODUCTION: Three randomized controlled trials have resulted in extremely extensive application of the strategy of using neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) for patients with advanced epithelial ovarian cancer in Japan. This study aimed to evaluate the status and effectiveness of treatment strategies using NAC followed by IDS in Japanese clinical practice. PATIENTS AND METHODS: We conducted a multi-institutional observational study of 940 women with Federation of Gynecology and Obstetrics (FIGO) stages III-IV epithelial ovarian cancer treated at one of nine centers between 2010 and 2015. Progression-free survival (PFS) and overall survival (OS) were compared between 486 propensity-score matched participants who underwent NAC followed by IDS and primary debulking surgery (PDS) followed by adjuvant chemotherapy. RESULTS: Patients with FIGO stage IIIC receiving NAC had a shorter OS (median OS: 48.1 vs. 68.2 months, hazard ratio [HR]: 1.34; 95% confidence interval [CI] 0.99-1.82, p = 0.06) but not PFS (median PFS: 19.7 vs. 19.4 months, HR: 1.02; 95% CI: 0.80-1.31, p = 0.88). However, patients with FIGO stage IV receiving NAC and PDS had comparable PFS (median PFS: 16.6 vs. 14.7 months, HR: 1.07 95% CI: 0.74-1.53, p = 0.73) and OS (median PFS: 45.2 vs. 35.7 months, HR: 0.98; 95% CI: 0.65-1.47, p = 0.93). CONCLUSIONS: NAC followed by IDS did not improve survival. In patients with FIGO stage IIIC, NAC may be associated with a shorter OS.

Lenvatinib plus pembrolizumab in Japanese patients with endometrial cancer: Results from Study 309/KEYNOTE-775.

Study 309/KEYNOTE-775 is a phase 3 open-label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer with progression after platinum-based therapy. Primary endpoints of superiority for lenvatinib plus pembrolizumab were met for progression-free survival (PFS) and overall survival (OS) in all-comers (ie, regardless of mismatch repair [MMR] status) and patients with MMR proficiency (pMMR). We present results for the Japanese subset. Patients were randomized to oral lenvatinib 20 mg/day plus intravenous pembrolizumab 200 mg every 3 weeks (Q3W; up to 35 cycles of pembrolizumab) or TPC (intravenous doxorubicin 60 mg/m2 Q3W or paclitaxel 80 mg/m2 QW [3 weeks on/1 week off]). Primary endpoints were PFS by blinded independent central review per RECIST version 1.1 and OS. One hundred four patients were randomized in Japan (data cutoff, October 26, 2020; median follow-up, 11.8 [range, 1.1-26.9] months). Hazard ratios (HRs) for PFS with lenvatinib plus pembrolizumab versus TPC were 1.04 (95% CI, 0.63-1.73) in patients with pMMR and 0.81 (0.50-1.31) in all-comers. Hazard ratios for OS were 0.74 (0.41-1.34) with pMMR and 0.59 (0.33-1.04) for all-comers. Adverse events were manageable and led to discontinuation of one/both study drugs in 36.5% of patients in the lenvatinib plus pembrolizumab group versus 7.8% in the TPC group. Similar to the global Study 309/KEYNOTE-775 results, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum-based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population.

Characteristics of Cancers in Adolescents and Young Adults Compared with Those in Adults in Their 60s: A Single-Center Experience.

INTRODUCTION: Cancer is one of the main causes of death among adolescents and young adults (AYAs) aged 15-39 years. The improvement in overall 5-year survival in AYA cancer patients was far below than that of adult cancer patients. The purpose of this study was to clarify the features of cancer in AYAs by comparing them with those of controls. METHODS: Patients in the cancer registry of the University of Tsukuba Hospital between 2007 and 2017 (median age, 65 years) were included in this study. We used patients between the ages of 64 and 66 years as controls. We then obtained the age at diagnosis, sex, primary site, and pathological type. RESULTS: Among 27,281 cancer patients in the registry between 2007 and 2017, 1,947 (7.1%) patients were categorized into the AYA group, and 2,354 into the control group. Among men in the AYA group, central nervous system (CNS) tumors accounted for 22.7% of all cancers, followed by germ cell tumors, 22.5%, and hematopoietic malignancies, 12.5%. Among women in the AYA group, cervical cancer accounted for 35.9% of all cancers, followed by breast cancer, 14.6%, and CNS tumors, 11.6%. The proportion of specific cancer types relative to all cancers in the CNS, thyroid, adrenal glands, germ cells, cervix uteri, hematopoietic tissues, and sarcomas was higher in the AYA group than that in the control group. CONCLUSION: The present results for AYAs were in sharp contrast to those for adult cancers and may be related to different modes of pathogenesis in AYAs. The identification of high-risk groups of these tumors in the AYA generation is crucial for prevention and early detection and will be a major topic for future research. While most of adult cancers are treated independently by each medical department, AYA cancers need to be treated in collaboration with experts from several departments. It is desirable to address the issues involved in applying treatments established for adult cancers to AYA cancers on a cancer-by-cancer basis.

Differential roles of the Wip1-p38-p53 DNA damage response pathway in early/advanced-stage ovarian clear cell carcinomas.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is one of the most lethal types of ovarian cancer. Early-stage OCCC can be cured by surgery; however, advanced-stage disease shows poor prognosis due to chemoresistance unlike the more common high-grade serous carcinoma. METHODS: We explored the differential roles of the Wip1-p38-p53 DNA damage response pathway in respective early- or advanced-stage OCCC by immunohistochemistry of Wip1, phospho-p38, p53, and phospho-p53 from consecutive 143 patients. RESULTS: High Wip1 expression correlated with positive p53 (p=0.011), which in turn correlated with low nuclear phospho-p38 expression (p=0.0094). In the early stages, positive p53 showed trends toward worse overall survival (OS) (p=0.062), whereas in the advanced stages, high Wip1 correlated with worse OS (p=0.0012). The univariate and multivariate analyses of prognostic factors indicated that high Wip1 was significant and independent for worse OS (p=0.011) in the advanced stages, but not in the early stages. Additionally, high Wip1 showed trends toward shorter treatment-free interval (TFI) in the advanced stages, but not in the early stages (p=0.083 vs. 0.93). Furthermore, high Wip1 was significantly associated with positive p53 only in the patients with shorter TFI (<6 months), but not in those with longer TFI (≥6 months) (p=0.036 vs. 0.34). CONCLUSIONS: Wip1 appears to play a crucial role for the prognosis of OCCC through chemoresistance specifically in the advanced stages, implicating that Wip1 possibly serves as a reasonable therapeutic target for improving chemoresistance and poor prognosis of advanced-stage OCCC.

Correlation of World Health Organization 2010 Classification for Gastroenteropancreatic Neuroendocrine Neoplasms with the Prognosis of Ovarian Neuroendocrine Neoplasms: Kansai Clinical Oncology Group-Protocol Review Committee/Intergroup Study.

BACKGROUND: In 2014, the World Health Organization (WHO) released a classification system introducing neuroendocrine neoplasms (NENs) of the female reproductive tract, excluding the ovaries. This study aimed to evaluate whether retrospective adaption of the gastroenteropancreatic (GEP)-NEN classification is feasible for ovarian NENs (O-NENs) and correlates with prognosis. METHODS: Sixty-eight patients diagnosed with carcinoid, small cell carcinoma (pulmonary type), paraganglioma, non-small/large cell neuroendocrine carcinoma (NEC), mixed NEC, or undifferentiated carcinomas at 20 institutions in Japan were included in this retrospective cross-sectional study. We identified O-NENs through central pathological review using a common slide set, followed by reclassification according to WHO 2010 guidelines for GEP-NENs. A proportional hazards model was used to assess the association of prognostic factors (age, stage, performance status, histology, and residual disease) with overall survival (OS) and progression-free survival (PFS). RESULTS: Of the 68 enrolled patients, 48 were eligible for analysis. All carcinoids (n = 32) were reclassified as NET G1/G2, whereas 14 of 16 carcinomas were reclassified as NEC/mixed adeno-NEC (MANEC) (Fisher's exact test; p < 0.01). The OS/PFS was 49.0/42.5 months and 6.5/3.9 months for NET G1/G2 and NEC/MANEC, respectively. Histology revealed that NEC/MANEC was associated with increased risk of death (HR = 48.0; 95% CI, 3.93-586; p < 0.01) and disease progression (HR = 51.6; 95% CI, 5.54-480; p < 0.01). CONCLUSION: Retrospective adaption of GEP-NEN classification to O-NENs is feasible and correlates well with the prognosis of O-NENs. This classification could be introduced for ovarian tumors.

Pathological processes and pretreatment cytologic diagnosis of neuroendocrine carcinoma of the endometrium: addendum report of the Kansai Clinical Oncology Group/Intergroup study in Japan.

A previous retrospective study of a neuroendocrine carcinoma of the endometrium including 42 cases employed a central pathologic review to ensure the reliability of the findings. However, the pathological processes were not described in detail. In this study, we further analyzed these processes and the results of pretreatment endometrial cytology of neuroendocrine carcinoma. Of the 65 patients from 18 institutions registered in the study, 42 (64.6%) were diagnosed with neuroendocrine carcinoma of the endometrium based on the central pathological review. Thirteen of the 23 excluded cases conflicted from their original diagnoses: 5 (38.5%) were diagnosed with endometrioid adenocarcinoma, 5 (38.5%) with undifferentiated carcinoma, and 3 (23.1%) with carcinosarcoma. Immunohistochemical staining led to a change in diagnosis for 8 (61.5%) of the 13 cases. Pretreatment endometrial cytology was examined in 38 (90.5%) cases; 34 (89.5%) of these 38 cases were found, or suspected, to be positive. To ensure the selection of appropriate therapy and keeping patients correctly informed, it is important to distinguish neuroendocrine carcinoma from other similar histologic types. Endometrial cytology may help in the early detection of this disease.

Ovarian metastases from ileum cancer in a patient with germline EPCAM gene deletion successfully treated with surgical resection and CAPOX chemotherapy: a case report.

BACKGROUND: Despite recent findings that epithelial cell adhesion molecule (EPCAM) deletions can cause Lynch syndrome (LS), its clinical characteristics are still unknown. We present the first case of ileum cancer in a patient with germline EPCAM gene deletion, which was discovered during ovarian tumor surgery. CASE PRESENTATION: A 59-year-old woman presented with a history of colon cancer occurring at 38 and 55 years old. Five of her siblings had a history of colon cancer, and an elder sister had confirmed LS. As imaging examination revealed an ovarian tumor, and we performed hysterectomy and bilateral salpingo-oophorectomy. Careful observation during surgery revealed a cherry-sized tumor in the ileum, prompting partial ileal resection. Pathological examination showed the ovarian tumor to be a metastasis of ileum cancer. Genetic testing with blood-relative information using multiplex ligation-dependent probe amplification showed EPCAM exons 8 and 9 deletions, confirming LS. The patient received adjuvant chemotherapy with CAPOX (capecitabine and oxaliplatin) and has remained disease-free for 24 months. CONCLUSIONS: We were fortunate to identify ileum cancer that would have been difficult to find preoperatively through careful observation during ovarian tumor surgery and successfully treated the patient by using surgical resection and CAPOX chemotherapy. When treating patients with hereditary cancer syndromes including LS, we should keep all associated cancers in mind.

PD-L1 and CD4 are independent prognostic factors for overall survival in endometrial carcinomas.

BACKGROUND: Tumor microenvironment (TME) including the immune checkpoint system impacts prognosis in some types of malignancy. The aim of our study was to investigate the precise prognostic significance of the TME profile in endometrial carcinoma. METHODS: We performed immunohistochemistry of the TME proteins, PD-L1, PD-1, CD4, CD8, CD68, and VEGF in endometrial carcinomas from 221 patients. RESULTS: High PD-L1 in tumor cells (TCs) was associated with better OS (p = 0.004), whereas high PD-L1 in tumor-infiltrating immune cells (TICs) was associated with worse OS (p = 0.02). High PD-L1 in TICs correlated with high densities of CD8+ TICs and CD68+ TICs, as well as microsatellite instability (p = 0.00000064, 0.00078, and 0.0056), while high PD-L1 in TCs correlated with longer treatment-free interval (TFI) after primary chemotherapy in recurrent cases (p = 0.000043). High density of CD4+ TICs correlated with better OS and longer TFI (p = 0.0008 and 0.014). Univariate and multivariate analyses of prognostic factors revealed that high PD-L1 in TCs and high density of CD4+ TICs were significant and independent for favorable OS (p = 0.014 and 0.0025). CONCLUSION: The current findings indicate that PD-L1 and CD4+ helper T cells may be reasonable targets for improving survival through manipulating chemosensitivity, providing significant implications for combining immunotherapies into the therapeutic strategy for endometrial carcinoma.

Propensity score-matched analysis of systemic chemotherapy versus salvage hysterectomy for persistent cervical cancer after definitive radiotherapy/concurrent chemoradiotherapy.

BACKGROUND: The aim of the current study was to evaluate oncologic outcomes of patients who were treated with salvage hysterectomy (HT), compared to systemic chemotherapy (CT) for persistent cervical cancer after definitive radiotherapy (RT)/ concurrent chemoradiotherapy (CCRT). METHODS: Patients with persistent cervical cancer treated with definitive RT/CCRT at 35 institutions from 2005 to 2014 were reviewed retrospectively (n = 317). Those who underwent a HT for persistent cervical cancer after definitive RT/CCRT were matched with propensity scores for patients who underwent systemic CT. Oncologic outcomes between the two groups using a propensity score matched-cohort analysis were compared. RESULTS: A total of 142 patients with persistent cervical cancer after definitive RT/CCRT were included after matching (HT: 71, systemic CT: 71). All background factors between HT and CT groups were well balanced. Median overall survival was 3.8 and 1.5 years in the HT and CT groups, respectively (p = 0.00193, hazards ratio [HR] 0.41, 95% confidence interval [CI] 0.23-0.73), Increasing residual tumor size was significantly associated with a high incomplete resection rate (p = 0.016, Odds Ratio 1.11, 95%CI 1.02-1.22). Severe late adverse events occurred in 7 patients (9.9%) in the HT cohort. CONCLUSION: The current study demonstrated that, when compared to systemic CT, the adoption of salvage HT for patients with persistent cervical cancer after definitive RT/CCRT reduced mortality rate by about 60%. This indicates that salvage HT could be curative treatment for those patients. Further prospective clinical trials with regard to salvage HT after RT/CCRT are warranted.

Prevalence of venous thromboembolism at pretreatment screening and associated risk factors in 2086 patients with gynecological cancer.

AIM: Postoperative pulmonary embolism can be a fatal surgical complication and is thought to occur secondary to asymptomatic venous thromboembolism (VTE) that exists preoperatively in some patients. The purpose of this study was to clarify the frequency and risk factors of pretreatment VTE in gynecological cancer patients. METHODS: This study investigated 2086 patients with gynecological cancer (cervix, n = 754; endometrium, n = 862; ovary, n = 470) who underwent initial treatment between 2004 and 2017. Pretreatment VTE screening was performed with D-dimer (DD) levels in these patients. Based on this, the associated risk factors were retrospectively analyzed. RESULTS: Pretreatment VTE was discovered in 7.3% of patients with cervical cancer, 11.5% of those with endometrial cancer and 27.0% of those with ovarian cancer. Significant independent risk factors were: age greater than or equal to 60 years and tumor long diameter greater than or equal to 40 mm for cervical cancer; age greater than or equal to 60 years, stage III/IV advanced disease, clear cell carcinoma and tumor long diameter greater than or equal to 60 mm for endometrial cancer; and age greater than or equal to 60 years, clear cell carcinoma and massive ascites for ovarian cancer. CONCLUSION: Pretreatment asymptomatic VTE is very frequent in gynecological cancer patients. It may be beneficial to consider measuring DD or performing venous ultrasonography in patients with the above risk factors.

Predictors of favorable survival after secondary cytoreductive surgery for recurrent endometrial cancer.

OBJECTIVE: The selection criteria for secondary cytoreductive surgery (SCS) for recurrent endometrial cancer (EC) remain to be defined. The present study aimed to identify predictors for favorable survival after SCS for the disease. METHODS: We retrospectively reviewed the medical records of 112 patients who relapsed by 2016 among 1052 who were diagnosed with primary EC between 1985 and 2014. Characteristics associated with overall survival (OS) after SCS were identified using univariate and multivariate analyses. RESULTS: Twenty-nine of the 112 patients who relapsed underwent SCS. Complete resection was achieved in 18 (62%) patients, whose OS after SCS was significantly better than that of patients receiving incomplete resection (68 vs. 20 months; p = 0.001). Endometrioid histology and performance status (PS) 0 were significant and independent factors for a favorable OS (p = 0.005, and 0.049). The OS of patients with both factors was better than patients with one or no factors (median 75, 19 and 4 months; p = 0.001 and 0.00001). The number of predictors was associated with the rate of complete resection (p = 0.001). CONCLUSIONS: Patients with endometrioid histology and PS 0 should be offered SCS for recurrent EC. Prospective trials are warranted to verify this proposal.

Expression of Tissue Factor in Epithelial Ovarian Carcinoma Is Involved in the Development of Venous Thromboembolism.

OBJECTIVES: Our 2007 study of 32 patients with ovarian cancer reported the possible involvement of tissue factor (TF) in the development of venous thromboembolism (VTE) before treatment, especially in clear cell carcinoma (CCC). This follow-up study further investigated this possibility in a larger cohort. METHODS: We investigated the intensity of TF expression (ITFE) and other variables for associations with VTE using univariate and multivariate analyses in 128 patients with epithelial ovarian cancer initially treated between November 2004 and December 2010, none of whom had received neoadjuvant chemotherapy. Before starting treatment, all patients were ultrasonographically screened for VTE. The ITFE was graded based on immunostaining of surgical specimens. RESULTS: Histological types were serous carcinoma (n = 42), CCC (n = 12), endometrioid carcinoma (n = 15), mucinous carcinoma (n = 53), and undifferentiated carcinoma (n = 6). The prevalence of VTE was significantly higher in CCC (34%) than in non-CCC (17%, P = 0.03). As ITFE increased, the frequencies of CCC and VTE increased significantly (P < 0.001 and P = 0.014, respectively). Multivariate analysis identified TF expression and pretreatment dimerized plasmin fragment D level as significant independent risk factors for VTE development. These factors showed particularly strong impacts on advanced-stage disease (P = 0.021). CONCLUSIONS: The 2007 cohort was small, preventing multivariate analysis. This study of a larger cohort yielded stronger evidence that the development of VTE in epithelial ovarian cancer may involve TF expression in cancer tissues.

Clinicopathologic implications of DNA mismatch repair status in endometrial carcinomas.

OBJECTIVE: Endometrial carcinoma is the most common malignancy in women with Lynch syndrome caused by mismatch repair (MMR) deficiency. We investigated the clinicopathologic significance of deficient MMR and Lynch syndrome presumed by MMR analyses in unselected endometrial carcinomas. METHODS: We analyzed immunohistochemistry of MMR proteins (MLH1/MSH2/MSH6/PMS2) and MLH1 promoter methylation in primary endometrial carcinomas from 221 consecutive patients. Based on these results, tumors were categorized as sporadic or probable Lynch syndrome (PLS). Clinicopathologic variables and prognosis were compared according to MMR status and sporadic/PLS classification. RESULTS: Deficient MMR showed only trends towards favorable overall survival (OS) compared with intact MMR (p=0.13), whereas PLS showed significantly better OS than sporadic (p=0.038). Sporadic was significantly associated with older age, obesity, deep myometrial invasion, and advanced stage (p=0.008, 0.01, 0.02 and 0.03), while PLS was significantly associated with early stage and Lynch syndrome-associated multiple cancer (p=0.04 and 0.001). The trend towards favorable OS of PLS was stronger in advanced stage than in early stage (hazard ratio, 0.044 [95% CI 0-25.6] vs. 0.49 [0.063-3.8]). In the subset receiving adjuvant therapies, PLS showed trends towards favorable disease-free survival compared to sporadic by contrast with patients receiving no adjuvant therapies showing no such trend (hazard ratio, 0.045 [95% CI 0-20.3] vs. 0.81 [0.095-7.0]). CONCLUSIONS: The current findings suggest that analyzing MMR status and searching for Lynch syndrome may identify a subset of patients with favorable survival and high sensitivity to adjuvant therapies, providing novel and useful implications for formulating the precision medicine in endometrial carcinoma.

Analysis of East Asia subgroup in Study 309/KEYNOTE-775: lenvatinib plus pembrolizumab versus treatment of physician's choice chemotherapy in patients with previously treated advanced or recurrent endometrial cancer.

OBJECTIVE: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician's choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. METHODS: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. RESULTS: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1-43.0) months. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49-1.10) and 0.64 (0.44-0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45-1.02) and 0.61 (0.41-0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3-5, 74% and 72%), respectively. CONCLUSION: Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03517449.

The impact of renal function on clinical outcomes of patients with cancer-associated isolated distal deep vein thrombosis: Insights from the ONCO DVT study.

BACKGROUND: The multicenter, open-label, randomized clinical trial ONCO DVT compared 3-month and 12-month edoxaban treatment regimens for isolated distal deep vein thrombosis (DVT) and suggested potential benefits of prolonged edoxaban treatment in terms of thrombotic risk. However, the risk-benefit balance of prolonged edoxaban treatment in patients with renal function remains unclear. OBJECTIVES: To compare the safety and efficacy of 3-month and 12-month edoxaban treatment regimens in patients with cancer-associated isolated distal DVT and different renal functions. METHODS: This pre-specified subgroup analysis of the ONCO DVT study included 601 patients divided into subgroups according to renal function using a 50 mL/min creatinine clearance (Ccr) cutoff. The primary endpoint was symptomatic recurrent venous thromboembolism (VTE) and VTE-related death at 12 months and the major secondary endpoint was major bleeding at 12 months. RESULTS: Among the 601 patients, 131 (21.8 %) comprised the renal dysfunction subgroup. The primary endpoint occurred in 6 (9.7 %) and 1 (1.4 %) patients in the 3-month and 12-month edoxaban groups in the renal dysfunction subgroup, respectively, and in 16 (6.6 %) and 2 (0.9 %) patients in the no renal dysfunction subgroup, respectively. The major secondary endpoint occurred in 9 (14.5 %) and 7 (10.1 %) patients in the 12-month and 3-month edoxaban groups in the renal dysfunction subgroup, and in 13 (5.3 %) and 21 (9.3 %) patients in the no renal dysfunction subgroup, respectively. CONCLUSIONS: A 12-month edoxaban regiment was superior to a 3-month treatment in terms of thrombotic risk irrespective of renal function. A higher bleeding risk was not identified in patients with renal dysfunction who received prolonged edoxaban treatment.

Edoxaban for 12 vs. 3 months in cancer-associated isolated distal deep vein thrombosis according to different doses: insights from the ONCO DVT study.

BACKGROUND: The ONCO DVT study revealed the superiority of 12-month relative to 3-month edoxaban treatment for cancer-associated isolated distal deep vein thrombosis (DVT) regarding the thrombotic risk. METHODS AND RESULTS: In this pre-specified subgroup analysis of the ONCO DVT study, we stratified the patients into those with a standard edoxaban dose (60 mg/day; N = 151) and those with a reduced edoxaban dose (30 mg/day; N = 450) and evaluated the clinical outcomes for the 12- and 3-month treatments. The cumulative 12-month incidence of symptomatic recurrent venous thromboembolism was lower in the 12-month than 3-month group for both the 60 mg (1.3% vs. 11.6%, P = 0.02; odds ratio [OR], 0.12; 95% confidence interval [CI], 0.01-0.97) and 30 mg (1.1% vs. 7.6%, P = 0.002; OR, 0.14; 95% CI, 0.03-0.60) edoxaban subgroups, which was consistent across the edoxaban doses without a significant interaction (P = 0.90). The 12-month cumulative incidence of major bleeding was higher in the 12-month group than in the 3-month group for the 60 mg edoxaban subgroup (14.3% vs. 4.4%, P = 0.046; OR, 3.61; 95% CI, 0.97-13.52), whereas it did not significantly differ between the two groups for the 30 mg edoxaban subgroup (8.7% vs. 8.6%, P = 0.89; OR, 0.97; 95% CI, 0.49-1.91), signalling there was a potential interaction (P = 0.07). CONCLUSIONS: A 12-month edoxaban regimen for cancer-associated isolated distal DVT was consistently superior to a 3-month regimen, across the edoxaban doses for the thrombotic risk. However, caution was suggested for the standard dose of edoxaban due to the potential for an increased risk of bleeding with prolonged anticoagulation therapy. TRIAL REGISTRATION NUMBER: NCT03895502 (ONCO DVT Trial): https://classic.clinicaltrials.gov/ct2/show/NCT03895502.

Molecular biomarkers for facilitating genome­directed precision medicine in gynecological cancer (Review).

Prominent recent advancements in cancer treatment include the development and clinical application of next-generation sequencing (NGS) technologies, alongside a diverse array of novel molecular targeting therapeutics. NGS has enabled the high-speed and low-cost sequencing of whole genomes in individual patients, which has opened the era of genome-based precision medicine. The development of numerous molecular targeting agents, including anti-VEGF antibodies, poly (ADP-ribose) polymerase inhibitors and immune checkpoint inhibitors, have all improved the efficacy of systemic cancer therapy. Accumulating bench and translational research evidence has led to identification of various cancer-related biomarker profiles. In particular, companion diagnostics have been developed for some of these biomarkers, which can be clinically applied and are now widely used for guiding cancer therapies. Selecting biomarkers accurately will improve therapeutic efficacy, avoid overtreatment, enable earlier diagnosis and reduce the cost of preventing and treating gynecological cancer. Therefore, biomarkers are fast becoming indispensable tools in the practice of genome-directed precision medicine. In the present review, the current evidence of cancer-related biomarkers in the field of gynecological oncology, their molecular interpretations and future perspectives are outlined. The aim of the present review is to provide potentially useful information for the formulation of clinical trials.

Preoperative Venous Thromboembolism Screening and Postoperative Selective Anticoagulant Therapy Effectively Prevents Postoperative Symptomatic Venous Thromboembolism in Gynecological Malignancies: A 15-Year, Single-Center Study.

The aim of this study was to determine which type of prophylaxis was effective for postoperative symptomatic venous thromboembolism (VTE) in patients with gynecological malignancies. A total of 1756 consecutive patients undergoing laparotomy as first-line treatment were included. In Period 1 (2004-2009), low-molecular weight heparin (LMWH) was not available for postoperative VTE prophylaxis, but available in after Period 2 (2009-2013). In Period 3 (2013-2020), patients with pretreatment VTE could switch from LMWH to direct oral anticoagulant (DOAC) as of 2015. Preoperative VTE was screened by measuring D-dimer, followed by venous ultrasound imaging, and computed tomography and/or perfusion lung scintigraphy. Postoperative symptomatic VTE occurred with an incidence of 2.8% by the measures without prophylactic LMWH administration in Period 1. The incidence of postoperative symptomatic VTE was 0.6% in Period 2 and 0.3% in Period 3, being significantly reduced compared with Period 1 (P < .01 and < .0001). The incidences were not significantly different between Periods 2 and 3, but no patient switching to DOAC in Period 3 (n = 79) developed symptomatic VTE. Our preoperative VTE screening and postoperative selective LMWH administration were significantly preventive against postoperative symptomatic VTE.