Treatment Of Recurrent Endometrial Cancer Research Articles

Pelvic Exenteration for Recurrent Endometrial Cancer: A 15-Year Monocentric Retrospective Study.

Treatment options for recurrent endometrial adenocarcinoma are limited. In those cases, secondary surgical procedures such as pelvic exenteration form the only possible curative approach. The aim of this study was analyzing the outcomes of patients who underwent pelvic exenteration during the treatment of recurrent endometrial cancer intending to identify prognostic factors. More than 300 pelvic exenterations were performed. Fifteen patients were selected that received pelvic exenteration for recurrent endometrial adenocarcinoma. Data regarding patient characteristics, indication for surgery, complete cytoreduction, tumor grading and p53- and L1CAM-expression were collected and statistically evaluated. Univariate Cox regression was performed to identify predictive factors for long-term survival. The mean survival after pelvic exenteration for the whole patient population was 22.7 months, with the longest survival reaching up to 69 months. Overall survival was significantly longer for patients with a curative treatment intention (p = 0.015) and for patients with a well or moderately differentiated adenocarcinoma (p = 0.014). Complete cytoreduction seemed favorable with a mean survival of 32 months in contrast to 10 months when complete cytoreduction was not achieved. Pelvic exenteration is a possible treatment option for a selected group of patients resulting in a mean survival of nearly two years, offering a substantial prognostic improvement.

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer

ObjectiveTo evaluate adverse events (AEs) of combination lenvatinib plus pembrolizumab for the treatment of recurrent endometrial cancer (EC) and to assess outcomes by lenvatinib starting dose. MethodsWe retrospectively reviewed patients with recurrent EC treated with lenvatinib plus pembrolizumab at our institution between 10/1/2019–11/30/2021. Starting dose of lenvatinib was defined as standard (20 mg) or reduced (10 mg/14 mg). AEs were manually extracted through chart review and graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. PFS, overall survival (OS), and duration of response (DOR) were analyzed. ResultsForty-three patients were identified; median age was 67 years (range, 54–85). The most common histologies were serous (35%), endometrioid (23%), and carcinosarcoma (21%). Starting lenvatinib doses were 10 mg (n = 10), 14 mg (n = 10), and 20 mg (n = 23). Median number of cycles received was 8 (range, 1–42). Twenty-four patients (56%) required ≥1 lenvatinib dose reduction; 3 (7%) discontinued lenvatinib, and 1 (2%) discontinued pembrolizumab for intolerance or AE. Thirty-six patients (84%) experienced grade ≥ 3 AEs; hypertension, weight loss, anemia, fatigue, and thrombocytopenia were most common. The standard dose group experienced significantly shorter observed PFS vs the reduced dose group (P = .02). There was no difference in DOR (P = .09) or OS (P = .27) between the groups. ConclusionIn clinical practice, AEs associated with combination lenvatinib plus pembrolizumab were common and comparable to Study 309/KEYNOTE-775 findings. AEs were similar regardless of starting lenvatinib dose. Further dose optimization studies of lenvatinib plus pembrolizumab may be indicated in recurrent EC. Clinical trial data remain the gold standard to guide starting lenvatinib dosing.

Medroxyprogesterone as the Initial Systemic Treatment of Recurrent Endometrial Cancer: A Single Institutional Study.

Hormonal treatment is the preferred initial systemic therapy for patients with advanced or recurrent G1 or G2 endometrial cancer (EC) in terms of efficacy, toxicity, and economy. Few reports are available on the topic and we, therefore, conducted a retrospective study. Patients with EC who received high-dose medroxyprogesterone (MPA) at our Hospital between January 2010 and December 2022 were reviewed. Patients who were treated for fertility preservation or had a history of systemic chemotherapy other than adjuvant therapy were excluded. Sixteen patients who were eligible for study inclusion had recurrent G1 or G2 EC. Their median age was 65 years (range=51-82 years), median body mass index was 22.6 kg/m2 (range=15.3-43.2 kg/m2), and all patients had an ECOG Performance Status of 0. All patients received 200 mg/day of MPA, and eight patients concomitantly received 100 mg/day of aspirin. None of the patients experienced severe adverse events. One patient had grade 2 deep vein thrombosis. Two patients discontinued MPA treatment because of adverse events. The response rate was 44% [95% confidence interval (CI)=20-68%] and median progression-free survival (PFS) was 6.9 months (95% CI=7.5-26 months). Four of 16 patients had PFS longer than 12 months, all of whom had positive tissue estrogen receptor (ER) and progesterone receptor (PR), and PFS at 2 years was 35% (95% CI=10.2-59.8%). Hormone therapy is effective long-term in ER- and PR-positive EC and can be recommended as initial systemic therapy. Toxicity is mild and manageable.

The utilization of lenvatinib with pembrolizumab for the treatment of recurrent endometrial cancer.

e17627 Background: The landscape for the treatment of microsatellite-stable-recurrent endometrial cancer has changed with the published results of the KEYNOTE-775, demonstrating an overall response rate of 37.2% with Pembrolizumab and Lenvatinib 20 mg. However, recent retrospective studies have suggested that a lower dose of Lenvatinib may be safer and equally efficacious. We aimed to retrospectively review our institutional data to compare the efficacy and toxicity of Lenvatinib at a low (≤10 mg) vs. high (>10 mg) dose. Methods: Retrospective review of patients with recurrent endometrial cancer who received ≥ 3 cycles of Pembrolizumab with Lenvatinib. A Univariate analysis was used to estimate the 1-year progression-free survival (PFS) and overall survival (OS), and a Multivariate Cox PH regression model was used to estimate the hazard ratio (HR) with a 95% confidence interval (CI) and p<0.05. Results: 77 patients were included in this analysis, the median age and BMI were 70 years and 28.5 kg/m2, respectively (Table 1). Most tumors were PDL-1<1% (67.2%) and were microsatellite stable (95%). 4 patients had MSI-H. Most patients started at a lower dose (66%, median of 10 mg), and 34% of patients started at a higher dose (n=26, median of 14 mg). The most common dose was 10 mg (41%, n=32) and 13% of patients received 20 mg (n=10). In the lower dose group, 71% had ECOG 0-1 vs. 77% in the higher dose, and were more likely to have > 2 lines of treatment (45% vs. 22%). The median time to interruption was 41 vs. 51 days respectively. The PFS and OS were not statically different (Table 1). Multivariate analysis showed a significantly higher HR in the lower dose group (2.5 [CI 1.12-5.56], p=0.025). Conclusions: TheFDA-recommended dose of Lenvatinib of 20 mg is perceived to be difficult to tolerate and patients are often started on a lower dose. In this study, we observed that the time to interruption was longer in the higher dose than in the lower dose group. Though we failed to detect a significant differences in PFS/OS, when adjusted for age, we observed a significantly higher HR of progression or death in the lower dose group. Possible explanations for our observations are that patients who received a lower dose were older and frailer. Our findings call to question the common practice of starting Lenvatinib at a low dose. Further analysis is warranted to delineate the required dose that is both efficacious and safe. [Table: see text]

Proton beam therapy for the isolated recurrence of endometrial cancer in para-aortic lymph nodes: a case report

BackgroundProton beam therapy penetrates tumor tissues with a highly concentrated dose. It is useful when normal structures are too proximate to the treatment target and, thus, may be damaged by surgery or conventional photon beam therapy. However, proton beam therapy has only been used to treat recurrent endometrial cancer in a few cases; therefore, its effectiveness remains unclear.Case presentationWe herein report a case of the isolated recurrence of endometrial cancer in the para-aortic lymph nodes in a 59-year-old postmenopausal woman that was completely eradicated by proton beam therapy. The patient was diagnosed with stage IIIC2 endometrial cancer and treated with 6 courses of doxorubicin (45 mg/m2) and cisplatin (50 mg/m2) in adjuvant chemotherapy. Fifteen months after the initial therapy, the isolated recurrence of endometrial cancer was detected in the para-aortic lymph nodes. The site of recurrence was just under the left renal artery. Due to the potential risks associated with left kidney resection due to the limited surgical space between the tumor and left renal artery, proton beam therapy was administered instead of surgery or conventional photon beam therapy. Following proton beam therapy, the complete resolution of the recurrent lesion was confirmed. No serious complications occurred during or after treatment. There have been no signs of recurrence more than 7 years after treatment.ConclusionsProton beam therapy is a potentially effective modality for the treatment of recurrent endometrial cancer where the tumor site limits surgical interventions and the use of conventional photon beam therapy.

Abstract 3065: Establishment and characterization of a platform of endometrial cancer organoids

Abstract Background: Endometrial cancer is the most commonly diagnosed gynecologic cancer in the US; the incidence is rising, and survival rates for this cancer are decreasing. There is a paucity of effective treatment for recurrent endometrial cancer, especially high grade endometrial cancers (HGEC) which include serous, carcinosarcoma, endometrioid, and clear cell histologies. Models that mimic the clinical and molecular characteristics of HGEC are lacking. To support the development of next generation therapeutics for endometrial cancer, we report on the establishment of 3D endometrial patient-derived organoids (PDOs) from HGEC. Methods: 26 Tumors from 21 different patients with HGEC (Serous, Carcinosarcoma, Clear Cell and High-grade Endometrioid subtypes) who underwent surgical resection (n= 13), biopsy (n = 7), paracentesis (n = 3) or thoracentesis (n = 3) were passaged as 3D organoid cultures in Matrigel in an optimized media. Robust models (defined by average days to passage <14 days) were viably banked. 3 frozen models were also thawed and re-cultured to assess the viability post freezing. PDOs were collected for H&E staining and their histology was compared to the original diagnosis. DNA replication rate and the effect of replication stress on organoid growth were assessed by the DNA Fiber Assay and immunofluorescence (IF). Finally, an established clear cell endometrial cancer organoid model was engrafted in mice to generate a Patient-Derived Xenograft (PDX) model. Results: Endometrial PDOs were successfully developed from 19 of 26 original samples for an overall success rate of 73.1%. Successful PDOs were developed from multiple histologies, including 8 carcinosarcoma, 6 uterine serous, 2 endometrioid, 2 clear cell and 1 mixed uterine serous and endometrioid. Though biopsy samples had initially fewer viable cells, our overall success rate was similar at 85.7% compared to 84.6% for surgical resections and higher than 66.7% for paracenteses. Samples obtained via thoracentesis did not form PDOs. Endometrial PDOs were histologically validated to match the primary patient tumor. Freeze thawing had no effect on morphology and growth characteristics. DNA fiber assays could be successfully conducted in PDOs, with a reduction in replication rate observed in PDO models treated with ATR or WEE1 inhibitors, with concurrent increase in y-H2AX and decrease in pRPA2 observed by IF. We also successfully generated a validated PDX model from organoids. Studies to determine molecular fidelity between the original patient tumor and established organoids are ongoing. Conclusions: We describe the successful establishment of 19 endometrial PDO models which retain original tumor morphology and demonstrate sensitivity to drug-induced DNA damage. 3D endometrial organoids can therefore be used for further target discovery and validation as well as biomarker studies to advance targeted therapies for high-grade endometrial cancer. Citation Format: Aisha L. Saldanha, Ha V. Vo, Kevin Vasquez, Kenneth Ngo, Shrabasti Roychoudhury, Carina Feeney, Courtney H. Qi, Swati Narayan, Jennifer D. Curtis, Prafulla C. Gokhale, Dipanjan Chowdhury, Cloud P. Paweletz, Marisa R. Nucci, Ursula A. Matulonis, Elena Ivanova, Joyce F. Liu. Establishment and characterization of a platform of endometrial cancer organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3065.

Recurrent Endometrial Cancer: Local and Systemic Treatment Options.

Simple SummaryIn this review, we discuss the different treatment strategies in recurrent endometrial cancer. The incidence of endometrial cancer is rising. The available treatment options increase with the development of novel radiotherapy techniques and new systemic therapies. Dependent on the site of recurrence and previous therapy, the treatment of recurrent endometrial cancer can be curative or palliative. Newly emerging medical treatments, such as immunotherapy, might be of benefit in selected patients. Moreover, combinations of different treatments can lead to a better outcome. Recent insights on oligometastatic disease lead us to expect that ablative or radical local treatment for distant metastasis will be of benefit in selected patients. Due to the complexity of the cases, it is recommended to discuss individual cases in a multidisciplinary tumor board. Shared decision-making principles are recommended to maximize treatment personalization.The treatment of recurrent endometrial cancer is a challenge. Because of earlier treatments and the site of locoregional recurrence, in the vaginal vault or pelvis, morbidity can be high. A total of about 4 to 20% of the patients with endometrial cancer develop a locoregional recurrence, mostly among patients with locally advanced disease. The treatment options are dependent on previous treatments and the site of recurrence. Local and locoregional recurrences can be treated curatively with surgery or (chemo)radiotherapy with acceptable toxicity and control rates. Distant recurrences can be treated with palliative systemic therapy, i.e., first-line chemotherapy or hormonal therapy. Based on the tumor characteristics and molecular profile, there can be a role for immunotherapy. The evidence on targeted therapy is limited, with no approved treatment in the current guidelines. In selected cases, there might be an indication for local treatment in oligometastatic disease. Because of the novel techniques in radiotherapy, disease control can often be achieved at limited toxicity. Further studies are warranted to analyze the survival outcome and toxicity of newer treatment strategies. Patient selection is very important in deciding which treatment is of most benefit, and better prediction models based on the patient- and tumor characteristics are necessary.

Abstract LB236: Utilizing endometrial tumor organoids to model cancer immunomodulation

Abstract Endometrial cancer is the most common gynecologic malignancy in the United States. Most women present with early stage disease and have a favorable prognosis. However, the treatment options for recurrent endometrial cancer is limited. Immunotherapy has become increasingly popular in the treatment of recurrent endometrial cancer. A hallmark of malignant cells is immune-evasion at both the genetic level and in the tumor microenvironment. We hypothesized that an endometrial cancer organoid model could be utilized to study the tumor immune microenvironment. Major Histocompatibility Complex (MHC) is a protein receptor recognized with its antigen by immune cells to screen either non-self or tumorous cells. It has a crucial role in eliminating non-self cells, such as cancer cells. We first assessed the genes involved in the regulation of MHC I and II in cultured normal and tumor organoids. RNA-Sequencing of fifty-six patients from our living organoid biobank were analyzed and we found an immunologic cluster of high-grade endometrial cancers that display significant downregulation in both MHC I and II. This was confirmed with real time-PCR which showed that high-grade cancers organoids had downregulated MHC I and II compare to organoids derived from low-grade cancer tissues and benign tissues. We next sought to demonstrate that both normal and endometrial cancer organoids retain the ability to present external antigen by using DQ-Ovalbumin. We demonstrated that endometrial organoids retain the ability to present antigen, but cancer organoids display reduced efficiency in the antigen processing. Next, we stimulated endometrial cancer organoids with interferon-gamma (IFNg), a well known cytokine for enhancing immunological response, to increase the expression of MHC I and II in cancer organoids. IFNg led to a 2-6 fold increase in MHC expression in low-grade cancer organoids, but a 5-40 fold increase in expression in high-grade cancer organoids utilizing real time-PCR. Finally, we implement the organoid-immune cell co-culture system with patient-derived organoids and CD8+ cytotoxic T-Cells in the allogeneic and syngeneic settings. Endometrial cancer organoids and matched patient-derived cytotoxic T-Cells were co-cultured for 48 hours and imaged for 16 hours. Both migratory effect and tumor killing effect were compared. As expected, in the allogeneic setting CD8+ T-Cells efficiently colocalized and killed cancer cells in the vehicle and IFNg stimulated groups. In the syngeneic setting, CD8+ T-Cells did not colocalize or kill cancer cells in the vehicle, whereas they significantly colocalized and killed cancer cells when stimulated with IFNg. Our data demonstrate that high-grade endometrial cancer cells downregulate MHC I and II, suggesting that they can evade the host immune system. We also showed that this effect is patient-specific and can be overcome by stimulating with interferon-gamma. Furthermore, we demonstrated that increasing MHC I and II among cancer organoids enhances the target cell recognition and apoptosis induction by CD8+ T-cells. Collectively, our finding offers an approach to study the tumor microenvironment that can be individualized for each patient through the use of patient-derived cancer organoids. This technology can be further developed to study targeted therapies and provides a much needed pre-clinical model for the study of endometrial cancer. Citation Format: Aaron Nizam, Charlie Chung, Gary L. Goldberg, Semir Beyaz. Utilizing endometrial tumor organoids to model cancer immunomodulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB236.

Toxicity and efficacy of the combination of pembrolizumab with recommended or reduced starting doses of lenvatinib for treatment of recurrent endometrial cancer

ObjectiveWe reviewed our institutional data to evaluate toxicity and efficacy outcomes of pembrolizumab/lenvatinib in recurrent endometrial cancer in a “real-world” clinical setting and to compare the impact of reduced lenvatinib starting dose on outcomes. MethodsRetrospectively, we reviewed toxicity, treatment responses, and survival outcomes of patients with recurrent endometrial cancer who received ≥1 cycle of pembrolizumab/lenvatinib. We compared subgroups based on lenvatinib starting dose (recommended [20 mg] vs reduced [<20 mg]) and histologic type. ResultsWe analyzed 70 patients (recommended dose cohort, n = 16; reduced dose cohort, n = 54). The most common starting dose was 14 mg daily. Compared to the reduced dose cohort, the recommended dose cohort had a significantly higher mean number of lenvatinib dose reductions due to side effects (1.1 vs. 0.4; p = 0.003) and significantly shorter median time to treatment toxicity (1.3 vs. 3.7 days; p = 0.0001). Response rates did not differ significantly between the recommended and reduced dose cohorts (28.6% vs. 38.3%, respectively; p = 0.752). Two patients, both in the reduced dose cohort, had complete responses. Patients with carcinosarcoma histology had response and clinical benefit rates of 25% (3 of 12) and 58.3% (7 of 12), respectively. There were no differences between the 2 dose cohorts with respect to progression-free (p = 0.245) or overall survival (p = 0.858). ConclusionIn clinical practice, a lower starting dose of lenvatinib (14 mg daily) in combination with pembrolizumab was safe and efficacious in recurrent endometrial cancer. The combination produced responses in endometrial carcinosarcomas. Larger studies are required to validate these findings.

A randomized phase II study of cabozantinib and nivolumab versus nivolumab in recurrent endometrial cancer.

6010 Background: The efficacy of treatment for recurrent endometrial cancer (EC) remains limited. Vascular endothelial growth factor and inflammatory chemokines are proangiogenic factors and immune modulators involved in immune suppression. Reprogramming the tumor microenvironment by combining antiangiogenic and immunotherapy (IO) could enhance antitumor responses. Methods: A 2:1 randomized phase 2 trial compared the combination of cabozantinib and nivolumab (Arm A) versus nivolumab (Arm B) in recurrent EC. Primary endpoint was progression free survival (PFS) assessed by RECIST 1.1 (NCT03367741). Women with recurrent measurable EC were eligible. There were no limits on prior therapy, but at least one prior platinum-based chemotherapy was required. Patients (pts) were stratified according to MSI status and assessed by CT every 8 weeks. Cabozantinib was given at 40 mg daily (Arm A) and nivolumab at 240 mg, on D1 and D15 of a 28-day cycle for 4 cycles, followed by 480 mg every 4 weeks (Arms A &amp; B). Pts with carcinosarcoma or prior IO were enrolled in an exploratory cohort and received combination treatment (Arm C). A baseline biopsy was required for all pts. CyTOF analysis was performed on fresh biopsies. Results: 76 evaluable pts were enrolled (Arm A: 36, Arm B: 18, Arm C: 9 carcinosarcoma, and 20 post IO including 7 pts crossed over from Arm B). 55% of pts had received ≥3 prior lines of therapy. Two pts were MSI high in Arm A and none in Arm B. The Kaplan-Meier estimated median PFS was 5.3 (95% CI: 3.5-9.5) months in Arm A and 1.9 (95% CI: 1.6-3.8) months in Arm B, with a log-rank p = 0.07, which met the significance level of 0.1 used for sample size calculation. Objective response rate (ORR) was 25% for Arm A and 16.7% for Arm B; stable disease (SD) was seen in 44.4% vs 11.1%, respectively. Clinical benefit (ORR+SD) was significantly higher in arm A vs B (p &lt; 0.001). In Arm C-carcinosarcoma, one patient had a partial response (11.9 months duration) and four SD. In Arm C-prior IO, six pts responded and eight had SD. The most common related AEs in Arm A were diarrhea (47.2%), elevated liver enzymes (44.4%), fatigue (38.9%), anorexia, hypertension, and nausea (30.6%), mainly grade 1/2. Preliminary CyTOF analysis across treatment arms identified multiple immune subsets for further interrogation including activated CD8+ and CD4+ T cells. Conclusions: Cabozantinib plus nivolumab demonstrates improved PFS compared to nivolumab in heavily pre-treated women with recurrent EC. In-depth CyTOF analysis of the tumor microenvironment to identify predictive immune biomarkers of response is ongoing. Clinical trial information: NCT03367741.

Japan Society of Gynecologic Oncology 2018 guidelines for treatment of uterine body neoplasms.

The Fourth Edition of the Guidelines for Treatment of Uterine Body Neoplasm was published in 2018. These guidelines include 9 chapters: 1. Overview of the guidelines, 2. Initial treatment for endometrial cancer, 3. Postoperative adjuvant therapy for endometrial cancer, 4. Post-treatment surveillance for endometrial cancer, 5. Treatment for advanced or recurrent endometrial cancer, 6. Fertility-sparing therapy, 7. Treatment of uterine carcinosarcoma and uterine sarcoma, 8. Treatment of trophoblastic disease, 9. Document collection; and nine algorithms: 1-3. Initial treatment of endometrial cancer, 4. Postoperative adjuvant treatment for endometrial cancer, 5. Treatment of recurrent endometrial cancer, 6. Fertility-sparing therapy, 7. Treatment for uterine carcinosarcoma, 8. Treatment for uterine sarcoma, 9. Treatment for choriocarcinoma. Each chapter includes overviews and clinical questions, and recommendations, objectives, explanation, and references are provided for each clinical question. This revision has no major changes compared to the 3rd edition, but does have some differences: 1) an explanation of the recommendation decision process and conflict of interest considerations have been added in the overview, 2) nurses, pharmacists and patients participated in creation of the guidelines, in addition to physicians, 3) the approach to evidence collection is listed at the end of the guidelines, and 4) for clinical questions that lack evidence or clinical validation, the opinion of the Guidelines Committee is given as a “Recommendations for tomorrow”.

Toxicity Reduction with Radiopaque Hydrogel Spacer for Salvage Treatment of Recurrent Endometrial Cancer: A Case Report

Toxicity Reduction with Radiopaque Hydrogel Spacer for Salvage Treatment of Recurrent Endometrial Cancer: A Case Report

Ramelteon, a selective MT1/MT2 receptor agonist, suppresses the proliferation and invasiveness of endometrial cancer cells

The incidence of endometrial cancer is increasing, making it the fifth most common cancer worldwide. To date, however, there is no standard therapy for patients with recurrent endometrial cancer. Melatonin, a hormone secreted by the pineal gland, has been shown to have anti-tumor effects in various tumor types. Although melatonin is available as a supplement, it has not been approved for cancer treatment. Ramelteon, a selective melatonin receptor type 1 and 2 (MT1/MT2) receptor agonist, has been approved to treat sleep disorders, suggesting that ramelteon may be effective in the treatment of endometrial cancer. To determine whether this agent may be effective in the treatment of endometrial cancer, this study investigated the ability of ramelteon to suppress the proliferation and invasiveness of HHUA cells, an estrogen receptor-positive endometrial cancer cell line. Ramelteon at 10-8 M maximally suppressed the proliferation of HHUA cells, reducing the percentage of Ki-67 positive proliferating cells. This effect was completely blocked by luzindole, a MT1/MT2 receptor antagonist. Furthermore, ramelteon inhibited HHUA cell invasion and reduced the expression of the MMP-2 and MMP-9 genes. These results suggested that ramelteon may be a candidate for the treatment of recurrent endometrial cancer, with activity similar to that of melatonin.

EARLY RECURRENCE OF WELL-DIFFERENTIATED ENDOMETRIAL CANCER (A CASE REPORT)

Endometrial cancer is the 6-th most common malignancy in women worldwide, accounting for about 4.8 % of all female cancers. The treatment of recurrent endometrial cancer remains a major challenge. Some endometrial cancer recurrences, for example vaginal stump recurrence, are reported to be effectively treated with surgical resection and radiation therapy. Early recurrence of early-stage well-differentiated endometrial cancer is uncommon. Case report. Herein we report a rare case of recurrent well-differentiated endometrial cancer in a 65-year-old woman. The patient had recurrence 10 months after laparoscopic hysterectomy with bilateral salpingo-oophorectomy. Recurrent endometrial tumor with extension into the rectosigmoid colon, urinary bladder and the right ureter manifested itself clinically with severe pain requiring the use of opioids. The recurrent tumor was removed. Resection of the bladder, left ureter and upper ampular rectum was followed by anastomosis. The patient received multiple cycles of chemotherapy. Conclusion. Compliance with the principles of ablastics during the laparoscopic or laparotomic surgery helps to avoid recurrence in patients with prognostically favorable cancer. In case of recurrence, combined operations are the only possible chance of improving survival of patients with locally advanced or recurrent tumors, which are insensitive to chemoradiotherapy.

Clinical Behavior and Treatment of Endometrial Cancer.

Endometrial cancer is the most common gynecologic malignancy diagnosed in women in the developed nations. It affects a disproportionate number of reproductive-aged women. While the overall prognosis is good compared to other cancers affecting women, the pathogenesis and clinical behavior of endometrial cancer are heterogeneous. The risk factors associated with the type I and type II endometrial cancers and their pathogenesis will be discussed, as well as the evaluation and primary treatment of women with endometrial cancer. The chapter will also focus on risk stratification for recurrence after surgery and role of adjuvant treatments. Finally, the treatment of recurrent endometrial cancer will be presented.

Surgical Treatment of Recurrent Endometrial Cancer: Time for a Paradigm Shift.

Although surgery represents the cornerstone treatment of endometrial cancer at initial diagnosis, scarce data are available in recurrent setting. The purpose of this study was to review the outcome of surgery in these patients. Medical records of all patients undergoing surgery for recurrent endometrial cancer at NCI Milano between January 2003 and January 2014 were reviewed. Survival was determined from the time of surgery for recurrence to last follow-up. Survival was estimated using Kaplan-Meier methods. Differences in survival were analyzed using the log-rank test. The Fisher's exact test was used to compare optimal versus suboptimal cytoreduction against possible predictive factors. Sixty-four patients were identified. Median age was 66 years. Recurrences were multiple in 38 % of the cases. Optimal cytoreduction was achieved in 65.6 %. Median OR time was 165 min, median postoperative hemoglobin drop was 2.4 g/dl, and median length hospital stay was 5.5 days. Eleven patients developed postoperative complications, but only four required surgical management. Estimated 5-year progression-free survival (PFS) was 42 and 19 % in optimally and suboptimally cytoreduced patients, respectively. At multivariate analysis, only residual disease was associated with PFS. Estimated 5-year overall survival (OS) was 60 and 30 % in optimally and suboptimally cytoreduced patients, respectively. At multivariate analysis, residual disease and histotype were associated with OS. At multivariate analysis, only performance status was associated with optimal cytoreduction. Secondary cytoreduction in endometrial cancer is associated with long PFS and OS. The only factors associated with improved long-term outcome are the absence of residual disease at the end of surgical resection and histotype.

A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: A study of the Princess Margaret, Chicago and California Consortia

ObjectiveTreatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC. MethodsWe performed a multicenter, single arm, two-stage phase II study of sunitinib, 50mg daily administered on a 4weeks on–2weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate. Results34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (30.3%) had disease control for at least 6months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3months and 19.4months, respectively. Adverse events related to treatment were frequent. At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar–plantar erythrodysesthesia, diarrhea and hematologic. ConclusionSunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit.

Past, present, and future of hormonal therapy in recurrent endometrial cancer.

Endometrial cancer is a heterogeneous disease. Type I cancers are hormonally driven, typically present with a low grade at an early stage, and are of endometrioid histology. These cancers are often cured by surgery, and the rate of recurrence is low. Type II cancers are less differentiated, often appear at a later stage, and are of serous, clear cell, or high grade endometrioid histology. The risk of recurrence in these cancers is much higher than with type I tumors. Isolated pelvic recurrences can be treated with radiation or exenteration, but systemic disease is fatal. It is in these recurrent patients, where prolongation of progression-free survival is the goal, that hormonal therapy can have the greatest benefit. In selected patients, hormonal therapy can be as effective as cytotoxic chemotherapy, without the toxicity and at a much lower cost. Here we review the evidence for treatment of patients suffering from recurrent endometrial cancer with hormonal therapy and explore avenues for the future of hormonal treatment of endometrial cancer. Currently, progesterone is the hormonal treatment of choice in these patients. Other drugs are also used, including selective estrogen receptor modulators, aromatase inhibitors, and gonadotropin-releasing hormone antagonists. Hormonal treatment of recurrent endometrial cancer relies on expression of the hormone receptors, which act as nuclear transcription factors. Tumors that express these receptors are the most sensitive to therapy; it is for this reason that patient selection is vitally important to the successful treatment of recurrent endometrial cancer with hormonal therapy.

Evaluation of Pegylated Liposomal Doxorubicin Dose on the Adverse Drug Event Profile and Outcomes in Treatment of Recurrent Endometrial Cancer

This study aims to determine factors that may increase the likelihood of adverse drug events (ADEs) in patients with recurrent endometrial cancer treated with pegylated liposomal doxorubicin (PLD) as well as this agent's impact on clinical outcomes. The treatment records of patients with endometrial cancer who received PLD at The University of Texas, MD Anderson Cancer Center, from 1996 to 2006 were reviewed. Patient demographics, PLD dose, ADEs, use of supportive care interventions, disease progression, and survival were extracted. Logistical regression analysis was used to identify factors that were associated with higher incidence of ADEs and that influenced survival. A total of 60 patients with recurrent endometrial cancer were identified who experienced 122 ADEs. The most commonly reported ADEs were nausea (18.9%), palmar-plantar erythrodysesthesia (PPE; 16.4%), muscle weakness (12.3%), mucositis (10.7%), and peripheral neuropathy (9.8%). Seventeen patients (28%) required a dose reduction because of ADEs. However, only 5 (8.3%) patients discontinued therapy because of toxicity. Cooling mechanisms were used in 19 patients to prevent PPE, although 9 of these patients still experienced PPE. Treatment with 6 or more cycles of PLD was associated with increased incidence of neutropenia (P = 0.045), peripheral neuropathy (P = 0.004), and PPE (P < 0.001). No differences in progression-free survival or time to progression were found between the doses of PLD; however, there was an assessable trend toward increased survival with doses of 40 mg/m(2). Although there was no association with dose level and ADEs, more cycles received increased the incidence of toxicities, including PPE and neuropathy. There was no association between different doses of PLD and progression-free survival or time to progression.

Weekly ixabepilone with or without concurrent bevacizumab in the treatment of recurrent endometrial cancer.

e15526 Background: Ixabepilone for endometrial cancer has only been evaluated in phase II studies administered at 30-40 mg/m2 q21 days (GOG 129P, GOG 86P). The objective of this study is to describe the institutional experience using a weekly dosing strategy of ixabepilone ± bevacizumab in the treatment of paclitaxel/platinum-resistant recurrent endometrial cancer. Methods: Patients who received weekly ixabepilone (16-20 mg/m2 on days 1, 8, 15 of a 28-day cycle) ± bevacizumab (10 mg/kg on days 1, 15 of a 28-day cycle) off-protocol were identified retrospectively. Results: Thirteen patients were included. Demographic/disease characteristics are provided in Table 1. Median time to first recurrence was 15.9 months (IQR: 9.5-21.66). Patients received a mean of 4.8 ± 1.9 cycles of ixabepilone; treatment is ongoing in 4 patients. A total of 46% of patients demonstrated either a partial response (PR, 8%) or disease stabilization (SD, 38%). PR/SD was associated with a mean decline in CA-125 of 56%. Approximately 50% of patients received concurrent bevacizumab. Of patients who did not receive concurrent bevacizumab, 83% experienced progression and 17% demonstrated SD. Median survival after ixabepilone initiation was 12.7 and 6.9 months in patients treated with and without concurrent bevacizumab, respectively (HR 0.42 [0.09-1.98]). Grade 1/2 hematologic (thrombocytopenia, 15.4%) and gastrointestinal toxicities (emesis/constipation, 7.7%) were observed infrequently. Median overall survival of this cohort was 2.88 years. Conclusions: Ixabepilone shows encouraging activity and promising durability in patients with heavily pre-treated paclitaxel/platinum-resistant recurrent endometrial cancer. Weekly dosing at 16-20mg/m2 on days 1, 8, and 15 ± bevacizumab is well-tolerated. Additional investigation of this regimen and long-term follow-up is warranted. [Table: see text]