Recurrent Endometrial Adenocarcinoma 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.

Tumor immune microenvironment and implications for progression and survival in patients with recurrent endometrial cancer (182)

Objectives: The immunologic response to cancer influences disease progression and survival in ways that are not yet completely understood. The objective of this analysis was to understand markers of immune exhaustion and mismatch repair within the tumor immune microenvironment in patients with recurrent endometrial cancer. Methods: We identified patients matched with primary and recurrent endometrial adenocarcinoma at a single high-volume academic medical center. Histologic slides were reviewed to confirm the diagnosis of primary and recurrent cancer, and formalin-fixed paraffin-embedded tissue blocks were requested from archives. Immunohistochemistry (IHC) was performed using antibodies against CD3 and immune exhaustion markers (PD1, PDL1, CTLA4, TIM3, and TIGIT) to quantify the number of tumor-infiltrating lymphocytes (TILs). Peritumoral lymphocytes (PTLs) were evaluated in a semi-quantitative manner. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS), and the log-rank test was used to compare between groups. Conclusions: Among patients with endometrial cancer who ultimately develop recurrent disease, the number of TILs and expression of immune exhaustion markers at initial diagnosis are not associated with PFS but are associated with OS. Specifically, the higher number of lymphocytes and increased expression of exhaustion markers PD1, PDL1, and TIGIT at the time of initial diagnosis are associated with decreased OS. Further work is needed to determine the prognostic value of immune exhaustion markers for patients who develop recurrent endometrial cancer. Objectives: The immunologic response to cancer influences disease progression and survival in ways that are not yet completely understood. The objective of this analysis was to understand markers of immune exhaustion and mismatch repair within the tumor immune microenvironment in patients with recurrent endometrial cancer. Methods: We identified patients matched with primary and recurrent endometrial adenocarcinoma at a single high-volume academic medical center. Histologic slides were reviewed to confirm the diagnosis of primary and recurrent cancer, and formalin-fixed paraffin-embedded tissue blocks were requested from archives. Immunohistochemistry (IHC) was performed using antibodies against CD3 and immune exhaustion markers (PD1, PDL1, CTLA4, TIM3, and TIGIT) to quantify the number of tumor-infiltrating lymphocytes (TILs). Peritumoral lymphocytes (PTLs) were evaluated in a semi-quantitative manner. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS), and the log-rank test was used to compare between groups. Conclusions: Among patients with endometrial cancer who ultimately develop recurrent disease, the number of TILs and expression of immune exhaustion markers at initial diagnosis are not associated with PFS but are associated with OS. Specifically, the higher number of lymphocytes and increased expression of exhaustion markers PD1, PDL1, and TIGIT at the time of initial diagnosis are associated with decreased OS. Further work is needed to determine the prognostic value of immune exhaustion markers for patients who develop recurrent endometrial cancer.

ENPAC: phase II trial with safety lead of enzalutamide in combination with paclitaxel and carboplatin for advanced or recurrent endometrioid endometrial adenocarcinoma

Objectives: The androgen receptor (AR) is more widely expressed than the estrogen or progesterone receptor in endometrial cancer (EC), including up to 90% of endometrioid type. Enzalutamide binds to the AR thereby nuclear translocation of receptors and blocking the association of the AR with DNA. We sought to evaluate the efficacy of paclitaxel, carboplatin and enzalutamide in a phase II study of advanced or recurrent endometrioid EC. Methods: Women with chemo-naïve, advanced-stage or recurrent endometrioid EC with measurable disease and adequate end organ function were eligible. Documented AR expression was not required. A safety lead in of the triplet was performed to confirm dose. In phase II, patients received 28 days of enzalutamide (160mg daily) as a single agent before starting triplet therapy. Pre- and post-treatment biopsies were obtained during the single agent lead in for evaluation of molecular markers including AR receptor expression and activation, expression of AR-related genes/proteins, and DNA copy number alterations and mutations. Patients then received carboplatin (AUC 6 IV Q3wk), paclitaxel (175 mg/m2), and enzalutamide (160mg daily). Response per RECIST 1.1 was assessed every 3 cycles for a maximum of 9 cycles. Evaluable patients received at least 6 cycles of triplet therapy. Progression free survival (PFS) was calculated from date of treatment initiation to earliest date of progression, death, or last contact. This study was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Astellas Pharma Global Development, Inc. Results: Conclusions: The combination of enzalutamide, carboplatin, and paclitaxel was tolerable and had promising clinical outcomes in chemo-naïve advanced or recurrent endometrioid EC. Further analyses are ongoing regarding predictors of response and resistance to androgen-inhibitor therapy. Clinical Trials Registration: NCT02684227. The androgen receptor (AR) is more widely expressed than the estrogen or progesterone receptor in endometrial cancer (EC), including up to 90% of endometrioid type. Enzalutamide binds to the AR thereby nuclear translocation of receptors and blocking the association of the AR with DNA. We sought to evaluate the efficacy of paclitaxel, carboplatin and enzalutamide in a phase II study of advanced or recurrent endometrioid EC. Women with chemo-naïve, advanced-stage or recurrent endometrioid EC with measurable disease and adequate end organ function were eligible. Documented AR expression was not required. A safety lead in of the triplet was performed to confirm dose. In phase II, patients received 28 days of enzalutamide (160mg daily) as a single agent before starting triplet therapy. Pre- and post-treatment biopsies were obtained during the single agent lead in for evaluation of molecular markers including AR receptor expression and activation, expression of AR-related genes/proteins, and DNA copy number alterations and mutations. Patients then received carboplatin (AUC 6 IV Q3wk), paclitaxel (175 mg/m2), and enzalutamide (160mg daily). Response per RECIST 1.1 was assessed every 3 cycles for a maximum of 9 cycles. Evaluable patients received at least 6 cycles of triplet therapy. Progression free survival (PFS) was calculated from date of treatment initiation to earliest date of progression, death, or last contact. This study was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Astellas Pharma Global Development, Inc. The combination of enzalutamide, carboplatin, and paclitaxel was tolerable and had promising clinical outcomes in chemo-naïve advanced or recurrent endometrioid EC. Further analyses are ongoing regarding predictors of response and resistance to androgen-inhibitor therapy.

The Effects on Ishikawa Endometrial Cancer Cell Lines upon Treatment with Hormonal Agents and Novel Drug Target

Background and Hypothesis: Endometrial cancer is the most common gynecological malignancy in the US and will claim the lives of over 12,000 women in 2019. Women with high-risk histologic tumors, such as high-grade endometrial adenocarcinoma, represent over 50% of these deaths. Novel treatments are needed to treat these aggressive tumors. Decreased expression of the ribonuclease DICER is associated with high-grade and recurrent endometrial adenocarcinoma. To study the role of DICER in endometrial cancer, we used CRISPR/Cas9 to delete DICER in an endometrial cancer cell line. RNA sequencing revealed dysregulation of steroid hormone receptor signaling and high expression of APEX1 [apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1)]. Elevated levels of Ref-1/APE1 have been found in various tumor types, and Ref1/APE1 inhibitors are in clinical trials. We hypothesize that our DICER deleted cell lines will be hormone insensitive yet respond to Ref-1/APE1 inhibitors by decreasing cellular proliferation.
 Project Methods: Ingenuity Pathway Analysis provided an unbiased approach to determine dysregulated genes in steroid hormone signaling in our RNA transcriptomic data. QPCR was used to confirm gene expression in independent samples. Cells were treated with steroid hormones or Ref-1/APE1 inhibitors and proliferation was assessed using MTS.
 Results: DICER deleted cell lines had downregulated expression of steroid hormone receptors. Treatment with steroid hormones did not have a significant effect on proliferation. However, treatment with Ref-1/APE1 inhibitors resulted in a significant decrease in proliferation.
 Conclusion and Potential Impact: Ref-1/APE1 inhibitors affect cellular proliferation of endometrial cancer cell lines. Because survival has actually worsened for women with endometrial cancer, novel therapies such as Ref1/APE1 inhibitors deserve future study.

Durable response in a woman with recurrent low-grade endometrioid endometrial cancer and a germline BRCA2 mutation treated with a PARP inhibitor

A 42-year-old woman with a germline BRCA2 mutation and recurrent low-grade endometrioid endometrial adenocarcinoma experienced clinical and radiographic response to the poly (ADP ribose) polymerase (PARP) inhibitor, olaparib. Molecular and treatment factors are discussed.

Patterns of failure and the potential role for localized therapy inpatients with recurrent endometrial adenocarcinoma

Patterns of failure and the potential role for localized therapy inpatients with recurrent endometrial adenocarcinoma

Prognostic significance of tumor-associated macrophages in endometrial adenocarcinoma

ObjectiveEndometrial adenocarcinoma is one of the most common gynecologic malignancies worldwide and in stages confined to the uterus considered to have an excellent prognosis. However, in advanced or recurrent cases when surgery fails to achieve disease control other treatment options are less effective. Thus, new therapeutic avenues are needed. MethodsTo provide the rationale for the use of novel agents that target immune checkpoints 163 type I endometrial cancer samples were immunohistochemically screened for the presence of CD163+ tumor-associated macrophages and Foxp3+ regulatory T cells. Further, a D2-40-based evaluation of lymph vessel density and lymphovascular space invasion was carried out. Correlation analysis with clinicopathological parameters was performed; Kaplan–Meier curves were generated; multivariate analysis was undertaken as appropriate. ResultsA substantial amount of tumor-associated macrophages and regulatory T cells was detected in all specimens characterizing endometrial cancer as an immunogenic tumor. However, only the increased infiltration of tumor-associated macrophages was proportionally associated with advanced FIGO stages, high tumor grade, increased lymph vessel density, lymphovascular space invasion and lymph node metastasis. Thus, the presence of tumor-associated macrophages indicates aggressive tumor behavior and appeared to be an independent prognostic factor for recurrence-free survival. ConclusionsOur results make future therapeutic approaches that target tumor-associated macrophages reasonable to improve the outcome of women with advanced or recurrent endometrial adenocarcinoma.

Progestin re-treatment in patients with recurrent endometrial adenocarcinoma after successful fertility-sparing management using progestin

ObjectiveTo analyze the outcomes of second round of fertility-sparing management using progestin in patients with recurrent endometrial cancer after successful fertility-sparing management using progestin. MethodsWe reviewed 45 patients who had recurrence after achieving complete remission by fertility-sparing management using progestin for presumed stage IA, grade 1, endometrioid adenocarcinoma of the uterus. Of 45 patients, 33 tried progestin re-treatment at recurrence and were included in this study. ResultsRecurrent disease was atypical hyperplasia in 13 patients (39%) and grade 1 endometrioid adenocarcinoma in 20 patients (61%) which were confined to the endometrium. Thirty patients (91%) received medroxyprogesterone acetate (dose range, 80–500mg/day) and three patients (9%) received megestrol acetate (dose range, 80–160mg/day), with 29 patients receiving a dose of 500mg/day of medroxyprogesterone acetate. The median duration of treatment was 6months (range, 3–19months). Five patients failed to respond to progestin re-treatment and underwent definitive surgical treatment including hysterectomy. Twenty eight patients (85%) showed complete response to progestin re-treatment. The median follow-up time after progestin re-treatment in 28 patients who achieved complete remission was 51months (range, 24–160months). During follow-up, five patients had second recurrence after median time interval of 14months (range, 4–82months). All patients who tried progestin re-treatment are alive without evidence of disease. ConclusionProgestin re-treatment in patients with recurrent endometrial cancer was effective and safe. Therefore, this can be recommended for young women who still want to preserve fertility at recurrence after complete response to progestin.

Controversies in the Management of Endometrial Cancer

Endometrial cancer is the most common gynecologic malignancy among women in developed countries. Most are diagnosed at stage I and their probability of surviving the disease is excellent. Most women at diagnosis are older, obese, and have multiple comorbidities. These factors need to be considered when treating patients with this highly curable disease. When recurrences occur at the vaginal apex, almost 50% are salvaged with radiation therapy with or without surgical excision. However, treatment of nodal or distant recurrences or of advanced disease at diagnosis is more challenging. One of the challenges faced by those treating this disease is how to identify those women who are at risk of having occult metastatic disease at initial diagnosis and to provide effective adjuvant therapy that would prevent recurrences in this select group of patients while minimizing therapy-induced morbidity. In this special issue on endometrial cancer, the authors tackle some of these issues. The articles accurately and succinctly summarize the current approach to the treatment of this disease and looks at the future by discussing possible novel interventions for the treatment of advanced or recurrent disease. The controversies in the surgical management of endometrial cancer are discussed, as are the minimally invasive surgical techniques. The international group of authors and editors provide a worldwide perspective about areas of agreement, topics of controversies, and issues that need yet to be clearly defined. Authors from The Netherlands discuss the controversies in evaluating women with postmenopausal bleeding. They weight the convenience, but possible decreased accuracy, of transvaginal ultrasound against the invasiveness of endometrial biopsy, hysteroscopy, and DC Utrecht, The Netherlands; and the University of Florence, Italy discuss possible novel approaches to the treatment of advanced or recurrent endometrial adenocarcinoma. And finally, authors from Greece and the United Kingdom summarize the evidence for adjuvant and molecularly targeted therapy of endometrial cancer. In this special issue of Obstetrics and Gynecology International, the reader will conveniently find a comprehensive summary of the state-of-the-art diagnostic strategies, biology, and evidence-based treatment of endometrial cancer from an international perspective. Enrique Hernandez Andreas Obermair Paul J. Hoskins Javier F. Magrina Robert Mclellan

Sister Mary Joseph's nodule: Recurrent endometrial adenocarcinoma presenting as an umbilical metastasis

Sister Mary Joseph's nodule: Recurrent endometrial adenocarcinoma presenting as an umbilical metastasis

Recurrent endometrial cancer: patterns of recurrent disease and assessment of prognosis

To evaluate patterns of disease and identify factors predicting outcome in patients presenting with recurrent endometrial adenocarcinoma following primary surgery. A retrospective review was performed of the imaging and clinical data in 86 patients (median age 66 years, range 42-88 years) presenting with recurrent endometrial adenocarcinoma following primary surgery. Following primary surgery recurrent disease occurred within 2 years in 64% and within 3 years in 87%. Relapse was seen within lymph nodes in 41 (46%), the vagina in 36 (42%) the peritoneum in 24 (28%) and the lung in 21 (24%). Unusual sites of disease included spleen, pancreas, rectum, muscle and brain. Univariate survival analysis showed the factors significant for poor outcome were: multiple sites of disease, liver and splenic disease, haematogenous, peritoneal and nodal spread, poorly differentiated tumour, and early relapse. The presence of disease within the vagina, bladder or lung was not associated with poor prognosis. Multivariate analysis identified multiple sites of disease, liver and splenic metastases to be independent predictors of poor outcome. The most frequently observed sites of relapse are: lymph nodes, vagina, peritoneum and lung. Significant predictors of poor outcome in recurrent disease are multiple sites of disease and liver and splenic metastases.

A phase II evaluation of flavopiridol as second-line chemotherapy of endometrial carcinoma: A Gynecologic Oncology Group study

Objective. A phase II study was conducted to determine the efficacy of single agent flavopiridol therapy in patients with recurrent or persistent endometrial adenocarcinoma refractory to established treatments. Methods. Eligible patients with measurable disease who failed primary therapy including one cytotoxic regimen were eligible for the trial. They were treated with single agent flavopiridol (50 mg/m 2/day, IV bolus days 1, 2, 3). Treatment was repeated every 21 days with dose adjustments made for toxicity. Patients were treated until progression of disease or adverse side effects precluded further therapy. Results. A total of 26 patients were enrolled in the study of whom, 23 patients were eligible. There were no objective responses. Five patients had stable disease (22%), 15 (65%) had increasing disease, and response could not be assessed in 3 (13%). The most frequent side effects included anemia, neutropenia, and diarrhea, all of which appeared manageable. Conclusion. Flavopiridol as a single agent in the above dosing schedule appears to have minimal activity as second-line chemotherapy of endometrial adenocarcinoma.

Cytotoxic chemotherapy (Ct) for endometrial cancer: A systematic review and meta-analysis

5085 Background: This systematic review assesses the benefits and adverse effects of Ct in women with advanced, recurrent or metastatic endometrial adenocarcinoma. Methods: Randomised controlled trials (RCTs) comparing Ct versus another intervention (including alternative Ct) in advanced disease were considered eligible. Bibliographic databases, trials registers and reference lists of relevant publications were searched for RCTs. Eleven eligible trials were identified which accrued 1635 patients between 1977 and 2000. The majority of these trials investigated cisplatin or anthracycline-based regimens and there were no trials comparing Ct with endocrine therapy. Two reviewers extracted data from the trial reports and authors of included studies were contacted for further information, which was supplied in two cases. Results: There was wide variation in the methodological quality of the trials, with some accruing few patients, some stopping early and most excluding patients from the analysis. RR varied from 19–39%. Only 5 studies reported progression-free (PFS) and overall survival (OS) as end points, with some early trials giving no survival data after relapse. A limited meta-analysis of 563 patients in 3 trials comparing combination Ct with single agent Ct showed no significant gain in PFS or OS (OR=0.73, 95%CI 0.36–1.48, p=0.41) compared with combination Ct. Toxicity was in general higher with the combination Ct regimens. One trial showed a 3m OS benefit from the addition of paclitaxel to another combination regimen at the expense of added toxicity. Based on the evidence reviewed, there was no evidence of benefit from cytotoxic Ct in terms of symptom control or quality of life compared with best supportive care. Conclusions: The optimum Ct regimen for advanced endometrial adenocarcinoma has still to be defined, although our review suggests there may be grounds for including paclitaxel. Future trials should measure quality of life and symptom control in addition to PFS and OS. Furthermore, future trials need to consider the relative roles of endocrine therapy and cytotoxic Ct in patients with no prior drug therapy. No significant financial relationships to disclose.

Carboplatin and paclitaxel for the treatment of advanced or recurrent endometrial cancer

The purpose of this study was to determine the activity and toxicity of carboplatin and paclitaxel (taxol) in the treatment of advanced or recurrent endometrial cancer. This was a retrospective review of 18 consecutive patients with advanced (stage 4) or recurrent endometrial adenocarcinoma that had been treated with outpatient carboplatin and taxol. Taxol was delivered at 135 mg/m 2 over 3 hours, and carboplatin was delivery at an area under the curve of 5 over 1 hour. Cycles were repeated every 21 days. The overall response rate was 63% with 28% of patients who had a partial response and 35% of patients who had a complete response. Kaplan-Meier test was used to estimate the median survival time of 27 months and the median progression free survival time of 24 months. No patient had neutropenia, thrombocytopenia or grade 3 vomiting, neurosensory toxicity, or renal toxicity. Carboplatin and taxol for the treatment of advanced or recurrent endometrial cancer appear to be active regimens with minimal toxicity.

Paclitaxel and carboplatin with amifostine in advanced, recurrent, or refractory endometrial adenocarcinoma: a phase II study of the Southwest Oncology Group

Objectives To evaluate the response rate and progression free and overall survival of patients with advanced endometrial cancer treated with paclitaxel, carboplatin and amifostine. To evaluate the toxicity of amifostine when used in combination with carboplatin and paclitaxel. Methods Forty-seven eligible patients (median age: 66; range 45–82) with bidimensionally measurable advanced, recurrent, or refractory endometrial cancer were treated with carboplatin (AUC = 6), paclitaxel (175 mg/M2) and amifostine (740 mg/M2) every 4 weeks for 6 cycles or until disease progression or unacceptable toxicity. Results There were 4 CRs (8%) (2 confirmed, 2 unconfirmed) and 15 PRs (32%) (9 confirmed, 6 unconfirmed) for a total response rate of 40% (95% confidence interval [CI], 26% to 56%). The median progression-free survival (PFS) was 7 months (95% CI, 6–9 months) and a 6-month PFS rate of 64% (95% CI, 50% to 78%). The median overall survival was 14 months (95% CI, 12 to 17 months). Toxicity was tolerable. While 79% of patients developed Grade 3/4 neutropenia (30% Grade 3, 49% Grade 4), there were no episodes of Grade 4 febrile neutropenia and one episode of infection with grades 3–4 neutropenia. Conclusion The combination of paclitaxel and carboplatin with amifostine was well reasonably tolerated in this cohort. The regimen demonstrated significant activity in endometrial cancer, comparable to other multi-agent chemotherapy programs in terms of response rate and survival, and with a favorable toxicity profile.

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group

Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.

Is there any place for cytotoxic chemotherapy in endometrial cancer?

Cytotoxic chemotherapy has an established role in the treatment of many solid tumours that are considered to be incurable with any modern treatment method. Such treatment may result in an improvement in quality of life without influencing overall survival. In this chapter the evidence to support the use of chemotherapy in patients with advanced or recurrent endometrial adenocarcinoma is reviewed. The most effective single agent and combination treatments are outlined. Although evidence from randomized trials is limited, combination chemotherapy can lead to response rates of over 40% in patients with advanced disease. The role of chemotherapy as adjuvant treatment in patients with early-stage disease is less well defined and this treatment is not recommended outside a clinical trial. The role of chemotherapy for treatment of the aggressive histological variant, uterine papillary serous carcinoma is also discussed.

Cisplatin and vinorelbine in advanced and/or metastatic adenocarcinoma of the endometrium: A new highly active chemotherapeutic regimen

To date the systemic treatment of recurrent and/or metastatic adenocarcinoma of the endometrium (EAC), using both chemotherapy and hormonotherapy (HT), is far from satisfactory. The significant activity of vinorelbine (VNR), a relatively new semisynthetic vinca alkaloid, demonstrated in advanced breast cancer, bronchial adenocarcinoma, and in head and neck cancer, prompted us to carry out a phase II trial employing the combination of cisplatin and VNR in a pluri-institutional series of patients with recurrent and/or metastatic EAC. Thirty-five patients affected by recurrent and/or metastatic EAC have been treated with CDDP 80 mg/m2 on day 1 plus VNR 25 mg/m2 i.v. bolus on days 1 + 8. This cycle was repeated every 21 days. After three cycles patients were restaged for objective response. Analysis of response rate and duration, overall survival, and toxicity pattern were the main aims of the study. Twenty out of thirty-five patients achieved a major objective response for an overall response rate of 57% (95% confidence limits (CL): 39%-74%). Four patients had a complete response (11%; 95% CL: 3%-27%) with a median progression-free survival (PFS) of eight hundred fourteen days, while sixteen patients had a partial response (46%; 95% CL: 29%-63%) with a median PFS of one hundred eighty-four days. Six patients had stable disease and nine progressed. All patients who achieved a clinical complete response had only a single site of disease at entry, but no association was noted between number of involved sites and likehood of achieving PR. Median overall survival was 240 days, while that of patients with complete and partial response was 855 and 300 days, respectively. Treatment was quite well tolerated with few cases of grade 3-4 myelosuppression. Alopecia was virtually absent and neurotoxicity was mild. One patient complained of an acute pain syndrome at the tumor site. The CDDP + VNR regimen is quite active against recurrent and/or metastatic endometrial adenocarcinoma, at least in terms of objective response rate which is among the highest ever reported in medical literature. However. duration of objective response and median overall survival are in the disappointing range reported for other regimens. In our opinion the CDDP plus VNR regimen is good enough to be compared to the anthracycline-based regimens and may represent the basis for future development of newer active polychemotherapeutic schedules.

Pelvic Exenteration for Recurrent Endometrial Cancer

Pelvic exenteration is generally not considered an operation with curative value for women with recurrent endometrial carcinoma. We reviewed our experience with pelvic exenteration performed in patients with recurrent endometrial adenocarcinoma from 1947 through 1994. A total of 44 patients were identified, with a mean age of 60 years (range 35–69 years). Primary therapy usually consisted of total abdominal hysterectomy with bilateral salpingo-oophorectomy, with most receiving either pre- or postoperative radiotherapy. Prior to exenteration, 10 of 44 (23%) patients had never received any form of radiotherapy. The median interval between initial surgery and exenteration was 28 months (range 2–189 months). The type of exenteration performed was total in 23 patients (52%), anterior in 20 patients (46%), and posterior in 1 patient. Major postoperative complications occurred in 35 patients (80%) and included urinary/intestinal tract fistulas, pelvic abscess, septicemia, pulmonary embolism, and cerebrovascular accident. Median survival for the entire group of patients was 10.2 months. Nine patients (20%) achieved long-term survival (>5 years). Pelvic exenteration for recurrent endometrial cancer is associated with a high operative morbidity and poor overall survival. Although only 20% of patients achieved long-term survival, this procedure remains the only potentially curative option for the few patients with central recurrence of endometrial cancer who have failed surgical and radiation therapy.

Phase II Trial of Oral Etoposide in Recurrent or Refractory Endometrial Adenocarcinoma: A Southwest Oncology Group Study

Oral etoposide has activity in a wide variety of tumors and is well tolerated. Therefore, the efficacy of oral etoposide was assessed as a treatment of metastatic endometrial cancer. To be eligible for this group-wide Southwest Oncology Group trial, patients had to have histologically proven metastatic or recurrent endometrial carcinoma; no previous cytotoxic therapy; and adequate renal, hepatic, and hematologic function, and they had to have given informed consent. Therapy consisted of oral etoposide, 50 mg daily on days 1–21 on a 28-day schedule. Therapy was continued in the absence of toxicity or disease progression. Forty-four eligible women, with a median age of 68 years (range 38–84 years) were treated. Radiotherapy had been delivered to 33 and hormomal therapy to 21. The median duration of therapy was 69 days (range 7–510 days). The treatment was well tolerated. Only one patient had grade 4 neutropenia, and a second had grade 4 anemia. Three patients had grade 3 nausea. One complete and five partial responses (14%) were observed. An additional four patients had unconfirmed responses. Tumor regressions were noted in nodes, bone, and visceral organs. While oral etoposide has only a modest level of activity when used in chemonaive patients, the minimal toxicity of this drug makes it a candidate for use in combination chemotherapy.