Quality of life and treatment response among women with platinum-resistant versus platinum-sensitive ovarian cancer treated for progression: A prospective analysis

Objective

Most women with ovarian cancer relapse and undergo further chemotherapy however evidence regarding the benefits of this for women with platinum-resistant disease is limited. Our objective was to determine whether there was a quality of life improvement or treatment response among women treated for platinum-resistant recurrent ovarian cancer.

Methods

We combined data from 2 studies where women treated with chemotherapy for recurrent ovarian cancer (n = 172) completed a quality of life questionnaire every 3 months. Cancers were classified as platinum-resistant if they progressed within 6 months of completing first-line chemotherapy. Mixed effects models were used to analyze change in quality of life during the first 6 months after second-line chemotherapy.

Results

One-quarter of women (n = 44) were classified as having platinum-resistant disease. Overall, their quality of life did not significantly increase or decrease, following commencement of second-line chemotherapy (least square mean scores = 107, 105, 103 at chemotherapy start, 3 and 6 months later, respectively), although 26% of these women reported a meaningful increase and 31% reported a meaningful decline. One-third of the platinum-resistant group responded (11% complete and 21% partial response) to second-line chemotherapy, and this figure increased to 54% among the subset (36%) re-treated with platinum-based agents with or without other agents. Preliminary analyses suggest that quality of life may be higher at chemotherapy initiation in women whose disease responded (median score 121 vs 110).

Conclusions

Overall, quality of life appears to be maintained in women with platinum-resistant ovarian cancer who receive further chemotherapy and some women respond to re-treatment.     

Fertility sparing treatment of complex atypical hyperplasia and low grade endometrial cancer using oral progestin

Objective

Oral progestin is an alternative to hysterectomy for women with complex atypical hyperplasia (CAH) or grade one endometrial cancer (G1EC) who wish fertility preservation. We evaluated treatment efficacy and fertility outcomes in this population.

Methods

Women < 45 y treated with oral progestin for CAH or G1EC were identified from two cancer centers. Data were obtained from medical records and telephone questionnaires. Time until complete response (CR), and from CR until recurrence was censored for patients without events and analyzed for associations with patient and treatment characteristics; cumulative incidence functions were used to estimate event probability over time.

Results

44 patients were identified, 19 (43%) with CAH and 25 (57%) with G1EC. Median age was 36.5 y (26–44). 24 (55%) achieved CR (median time: 5.7 months). Older age was associated with a lower likelihood of CR (HR 0.84, p = 0.0003, 95% CI, 0.8–0.9). CR probability appeared to plateau after 12 months of therapy. Among those with CR, 13 (54%) recurred (median time 3.5 y). 24 patients (55%) underwent hysterectomy; 3 (13%) were upstaged. 11 (25%) underwent fertility treatment with the following outcomes: 6 (55%) no pregnancy, 2 (18%) at least one live infant, and 3 (27%) spontaneous abortion. One achieved a live birth without intervention.

Conclusion

Oral progestin is an effective temporizing fertility-sparing treatment for women with CAH/G1EC. Fertility specialist involvement is recommended due to the low live birth rate without intervention. Progestin therapy should be re-evaluated at 1 year in non-responders due to a low probability of success. Hysterectomy is recommended after childbearing due to a high recurrence rate.     

A phase II evaluation of pazopanib in the treatment of recurrent or persistent carcinosarcoma of the uterus: A Gynecologic Oncology Group study

Objective

Carcinosarcomas of the female genital tract, also called malignant mixed müllerian tumors, are aggressive biphasic tumors. Second-line treatment options in the recurrent/persistent setting have yielded marginal responses. Given the potential role of angiogenesis in the gynecological carcinomas, pazopanib, a VEGFR inhibitor, was investigated in the management of patients with recurrent carcinosarcoma of the uterus.

Methods

Eligible patients had histologically confirmed carcinosarcoma of the uterus, a maximum of two prior lines of therapy, adequate renal, hepatic and hematologic function and a performance status of 0–2. Pazopanib was administered orally at 800 mg. Two dose reductions were allowed. The primary objective was to ascertain the activity of pazopanib as measured by the proportion of patients who survive progression-free for at least six months and the proportion of patients that have objective tumor responses. Secondary objectives included the frequency and severity of adverse events as assessed by CTCAE v4.0.

Results

Of the 22 enrolled patients, 19 were eligible and evaluable for toxicity and survival. No patients had a partial or complete response (90% confidence interval [CI]: 0%, 14.6%). Three patients (15.8%) had PFS ≥ 6 months (90% CI: 4.4%, 35.9%). The median PFS was 2.0 months (first and third quartiles were 1.6 and 4.0 months, respectively). The median overall survival was 8.7 months (first and third quartiles were 2.6 and 14.0 months, respectively).

Conclusion

Pazopanib demonstrated minimal activity as a second or third line treatment for advanced uterine carcinosarcoma. Potential clinical trial participation should be discussed with the patients.     

First trimester assessment of Pentraxin-3 levels in women with primary unexplained recurrent pregnancy loss

Objective

To evaluate the potential role of measuring first-trimester maternal Pentraxin-3 levels in patients with primary unexplained recurrent pregnancy loss.

Study design

A case control study was conducted in Ain Shams University Maternity Hospital. Cases included 45 women with primary unexplained recurrent pregnancy loss and early pregnancy failure admitted for medical or surgical termination of pregnancy. Controls (45 women) included a matched group of apparently healthy pregnant women who had at least one previous uneventful pregnancy with no previous obstetric history of adverse pregnancy outcomes. Maternal venous blood samples were collected for assay of Pentraxin-3 using enzyme-linked immunosorbent assay. The main outcome measure was the pregnancy outcome in women with elevated Pentraxin-3 levels.

Results

90 participants were statistically analyzed. In the patient group, the mean Pentraxin-3 level was 12.00 ± 4.07 ng/ml, while in the control group it was 1.69 ± 0.91 ng/ml. The difference was statistically significant (p < 0.001). In the patient group, Pentraxin-3 showed a significant positive correlation with the number of previous miscarriages (p = 0.038).

Conclusion

Abnormally elevated Pentraxin-3 levels indicate the presence of an abnormally exaggerated intrauterine inflammatory or innate immune response that may cause pregnancy failure in women with primary unexplained recurrent pregnancy loss.     

Endometrial echo complex thickness in postmenopausal endometrial cancer

Objective

To determine the preoperative pelvic ultrasonographic characteristics of postmenopausal women diagnosed with endometrial cancer (EC) at our institution.

Methods

Postmenopausal women with EC who underwent preoperative transvaginal pelvic ultrasound from 1999–2009 were identified from our institutional database. The histologic diagnosis was based on pathologic findings in the hysterectomy specimen. Endometrial echo complex (EEC) thickness was abstracted from ultrasound reports. In all instances, ultrasound preceded the biopsy by a maximum of 3 months. Means with standard deviations were calculated for all categorical data. Differences between type 1 and type 2 ECs were determined using Mann–Whitney U tests and Chi squared/Fisher's exact tests, as appropriate. A p-value of < 0.05 was considered statistically significant.

Results

Among 250 patients with postmenopausal EC, 156 had type 1 EC while 94 had type 2 EC. Thirty-six percent of the cohort had an EEC ≤ 4 mm, including 37% of patients with type 1 EC and 34% of patients with type 2 EC (p = 0.63). There were no significant differences between type 1 and type 2 ECs in any demographic characteristic, other than likelihood of postmenopausal bleeding.

Conclusions

Current expert opinion recommends no further diagnostic procedure in a woman with postmenopausal bleeding and an EEC ≤ 4 mm. These results indicate that a sizable proportion of women with EC have EECs ≤ 4 mm during their initial evaluation. An EEC ≤ 4 mm does not completely rule out endometrial cancer and cannot supplant histologic evaluation.     

A systematic review comparing cisplatin and carboplatin plus paclitaxel-based chemotherapy for recurrent or metastatic cervical cancer

Introduction

The prognosis of advanced/recurrent cervical cancer patients is generally poor with 1-year survival ranging between 15 and 20%. Cisplatin (CDDP) based treatments are considered the most effective regimens; unfortunately toxicity is an issue in a population in which the treatment remains palliative in the finality. Carboplatin (CBDCA), with its more favorable non toxicity profile and the convenience of outpatient administration, may be a suitable alternative to CDDP in combination regimens.

Materials and methods

We performed a systematic review of the literature comparing CDDP and CBDCA based chemotherapy for advanced cervical cancer (recurrent, persistent or metastatic disease). Only studies that met the following criteria were considered for the present review: 1) patients treated with CDDP/paclitaxel or CBDCA/paclitaxel combinations as first line chemotherapy for metastatic disease; 2) one or more of the following data available: overall response rate (RR), progression free survival (PFS) or time to progression (TTP), overall survival (OS); 3) single-arm retrospective or prospective study; and 4) at least 20 patients enrolled.

Results

17 eligible studies comprehensive of 1181 patients were included in the final analysis. The objective RR was 48.5% for CBDCA and 49.3% for CDDP-based chemotherapy. Median PFS for CDDP and CBDCA-based treatments was 6.9 months and 5 months respectively (p = 0.03); the corresponding figures for median OS were 12.87 and 10 months respectively (p = 0.17).

Discussion

Our study indicates that CBDCA may represent an attractive and valid alternative to the more toxic and equally effective CDDP in the treatment of advanced or recurrent cervical cancer.     

A Phase II evaluation of ixabepilone (IND #59699, NSC #710428) in the treatment of recurrent or persistent leiomyosarcoma of the uterus: An NRG Oncology/Gynecologic Oncology Group Study

Objective

The combination of gemcitabine and docetaxel is the standard first-line therapy for recurrent or metastatic uterine leiomyosarcoma. There is no standard second-line therapy. Ixabepilone is a semi-synthetic analog of epothilone B that binds to the same site on beta tubulin as paclitaxel and may be a more potent polymerizer of tubulin. We sought to determine the activity of ixabepilone as a single agent as second-line treatment for patients with metastatic uterine leiomyosarcoma who had received taxane based therapy.

Methods

Eligible women with unresectable uterine leiomyosarcoma progressing after prior cytotoxic therapy containing a taxane were treated with ixabepilone 40 mg/m² on day one of a 21 day cycle. Patients with prior pelvic radiation were treated without dose reduction. Response Evaluation Criteria in Solid Tumors (RECIST) response was assessed by computed tomography (CT).

Results

Twenty-three of 26 women were evaluable (two wrong histology, one never treated) with two of 23 receiving 1 cycle of therapy. There were no complete or partial responses. Stable disease (SD) was seen in four patients (17.4%, median 3.4 months). Seventeen patients (73.9%) had increasing disease (PD) and two patients were inevaluable per RECIST. One patient had SD over 6 cycles of treatment. Median PFS for all 23 patients was 1.4 months and overall survival was 7.0 months. The predominant grade 3 or 4 toxicity was uncomplicated myelosuppression: neutropenia grade 3 (13%), grade 4 (17%), and anemia grade 3 (22%).

Conclusion

Ixabepilone as a single agent is not an active second-line therapy for uterine leiomyosarcoma previously treated with a taxane.     

A prospective feasibility study of radiation and concurrent bevacizumab for recurrent endometrial cancer

Objectives

To determine the toxicity and survival rates in a trial of concurrent bevacizumab and external beam radiation (EB) for patients with recurrent endometrial or ovarian cancer.

Methods

Nineteen women with recurrent endometrial (n = 15) or ovarian (n = 4) cancer with gross disease involving the vaginal cuff, and/or pelvic nodes and/or para-aortic nodes, cancer were enrolled between 2008 and 2010. All patients received bevacizumab during radiation. Toxicity was assessed at baseline, weekly during treatment and every 3 months for at least 1 year after treatment.

Results

All patients completed EB on schedule. For the 15 patients with recurrent endometrial cancer, the 1- and 3-year progression-free survival (PFS was) 80%/67% and overall survival (OS) was 93%/80%. Patients that had a vaginal cuff recurrence alone had a 1- and 3-year PFS of 75%/63% and OS of 100%/75%. Two patients with pelvic node involvement did not recur throughout the entire follow-up period. The 5 patients with para-aortic node involvement had a 1- and 3-year PFS of 80%/60% and OS of 80%/80%. Of the 4 ovarian cancer patients 3 relapsed with 1- and 3-year PFS of 80%/40% and OS of 100%/60%. Toxicities included thrombosis and 1 embolic event in the setting of metastastic disease. No gastrointestinal perforations were noted.

Conclusions

Delivering bevacizumab with concurrent radiation provides excellent local tumor control and survival for women with recurrent endometrioid endometrial cancer, particularly those with unresectable nodes. Caution must be used in those at highest risk of developing metastatic disease given the increased risk of thromboembolic events. This regimen may be considered for recurrent gynecologic malignancies in future trials.     

Applicability of the concept of “platinum sensitivity” to recurrent endometrial cancer: The SGSG-012/GOTIC-004/Intergroup study

Objective

The concept of “platinum sensitivity” has been widely applied in the management of recurrent ovarian cancer. This study aimed to evaluate the applicability of this concept to recurrent endometrial cancer.

Patients and methods

In this multicenter retrospective cohort study, the clinical data of patients with recurrent endometrial cancer, who had a history of receiving first-line platinum-based chemotherapy and who received second-line platinum-based chemotherapy at the time of recurrence between January 2005 and December 2009 were reviewed.

Results

A total of 262 patients from 30 centers with initial FIGO stage classifications of I (29), II (23), III (122), and IV (88) were enrolled. In total, 153 endometrioid adenocarcinomas, 34 serous adenocarcinomas, 17 clear cell adenocarcinomas, 36 carcinosarcomas, and 22 “other” tumors were documented. The response rates for patients with platinum-free intervals of < 6 months, 6–11 months, 12–23 months, and ≥ 24 months were 25%, 38%, 61%, and 65%, respectively. The median progression-free survival after second-line platinum-based chemotherapy for patients with platinum-free intervals of < 12 months and ≥ 12 months was 4.4 (95% confidence interval (CI) = 3.7–5.8) months and 10.3 (95% CI = 8.2–12.6) months, respectively (log-rank P < 0.0001), and the median overall survival was 13.8 (95% CI = 10.6–18.1) months and 40.9 (95% CI = 25.3–54.2) months, respectively (log-rank P < 0.0001).

Conclusion

Platinum-free interval is a predictor of response and survival after second-line platinum-based chemotherapy in patients with recurrent endometrial cancer. The concept of “platinum sensitivity” could be applicable to recurrent endometrial cancer.     

Impact of obesity on the results of fertility-sparing management for atypical hyperplasia and grade 1 endometrial cancer

Objectives

The aim of the present study was to evaluate the impact of obesity on reproductive and oncologic outcomes on the success of fertility-sparing management.

Methods

This retrospective multicenter cohort study included women treated conservatively for atypical hyperplasia (AH) and endometrial cancer (EC) to preserve fertility. Five inclusion criteria were defined: (i) the presence of AH or grade 1 EC confirmed by two pathologists; (ii) adequate radiological examination before conservative management; (iii) available body mass index (BMI) at the beginning of treatment; and (iv) a minimum follow-up time of six months.

Results

Forty patients fulfilled the inclusion criteria (17 had EC, and 23 had AH), mean age and BMI were 33 years and 29 kg/m² respectively. Among the 15 obese patients, after medical treatment, 10 patients responded (67%) and three relapsed, whereas in the 25 non-obese patients, 19 responded (76%) and three relapsed (p = 0.72). The overall pregnancy rate and follow-up time were 35% and 35 months respectively. Among the 15 obese patients, after medical treatment, two patients became pregnant, whereas in the 25 non-obese patients, 12 became pregnant (p = 0.04).

Conclusion

Despite similar response and recurrence rates, our results suggest that fertility-sparing management for AH and EC is associated with a lower probability of pregnancy in obese patients.     

Secondary cytoreductive surgery in patients with isolated platinum-resistant recurrent ovarian cancer: A retrospective analysis

Objective

To analyze the impact of secondary cytoreductive surgery (SCS) on survival outcome in a retrospective series of isolated platinum-resistant recurrent ovarian cancer.

Methods

We evaluate a consecutive series of 268 ovarian cancer patients with platinum-resistant relapse. Isolated recurrence was defined as the presence of a single nodule, in a single anatomic site, and was observed in 27 cases (10.1%). In all women the presence of isolated relapse was assessed at radiological evaluation, and surgically confirmed in the SCS group.

Results

Among the 27 patients with isolated recurrence, 16 (59.3%) received chemotherapy alone, and 11 (40.7%) complete SCS followed by non-platinum based chemotherapy. No significant differences were observed in the distribution of baseline clinico-pathological characteristics, pattern of recurrent disease, duration of PFI, and type of salvage chemotherapy between the two groups. In the SCS group, 6 patients (54.5%) showed isolated peritoneal relapse and 5 women (45.4%) showed isolated lymph nodal recurrence, and were treated with peritonectomy and lymphadenectomy, according with site of relapse. Two post-operative complications (18.2%) occurred: asymptomatic lymphocele and groin wound dehiscence. SCS significantly prolonged median time to first progression (12 months vs 3 months; p-value = 0.016), median time to second progression (8 months vs 3 months; p-value = 0.037), and post-relapse survival (PRS) (32 months vs 8 months; p-value = 0.002). Residual tumor at 1st surgery (X² = 5.690; p-value = 0.017), duration of PFI (X² = 5.401; p-value = 0.020), and complete SCS (X² = 4.250; p-value = 0.039) retains independent prognostic role for PRS in multivariate analysis.

Conclusions

SCS prolongs PRS compared to chemotherapy alone in isolated platinum-resistant recurrent ovarian cancer.     

A phase II trial of brivanib in recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group Study

Purpose

Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC).

Patients and Methods

Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of ≤ 2. Treatment consisted of brivanib 800 mg orally every day until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at six months and objective tumor response. Expression of multiple angiogenic proteins and FGFR2 mutation status was assessed.

Results

Forty-five patients were enrolled. Forty-three patients were eligible and evaluable. Median age was 64 years. Twenty-four patients (55.8%) received prior radiation. Median number of cycles was two (range 1–24). No GI perforations but one rectal fistula were seen. Nine patients had grade 3 hypertension, with one experiencing grade 4 confusion. Eight patients (18.6%; 90% CI 9.6%–31.7%) had responses (one CR and seven PRs), and 13 patients (30.2%; 90% CI 18.9%–43.9%) were PFS at six months. Median PFS and overall survival (OS) were 3.3 and 10.7 months, respectively. When modeled jointly, VEGF and angiopoietin-2 expression may diametrically predict PFS. Estrogen receptor-α (ER) expression was positively correlated with OS.

Conclusion

Brivanib is reasonably well tolerated and worthy of further investigation based on PFS at six months in recurrent or persistent EMC.     

A comparison of psychological stress among women with and without reproductive failure

Objective

To determine whether women with recurrent implantation failure (RIF) after in vitro fertilization (IVF), similar to women with recurrent pregnancy loss, have significantly higher stress levels than women without reproductive failure, and to compare stress levels between women with RIF and women with recurrent pregnancy loss.

Methods

In a questionnaire-based study between September 2009 and January 2011, psychological stress was measured among patients attending recurrent pregnancy loss and RIF clinics at the Royal Hallamshire Hospital, Sheffield, UK. Participants completed the Fertility Problem Inventory (FPI), the Perceived Stress Scale (PSS), and the Positive and Negative Affect Schedule (PANAS) on their first visit to their respective clinic. Thirty fertile control women also completed the 3 validated questionnaires.

Results

Compared with the control group, women with RIF and recurrent pregnancy loss had significantly higher scores in the FPI (RIF, P < 0.001; recurrent pregnancy loss, P = 0.003) and the PANAS negative affect domain (RIF, P = 0.004; recurrent pregnancy loss, P = 0.001), and lower scores in the PANAS positive affect domain (RIF, P < 0.001; recurrent pregnancy loss, P < 0.001). Whereas the perceived stress score (PSS) of the recurrent pregnancy loss group was significantly higher than that of the control group (P = 0.006), the score of the RIF group was not, although the difference tended toward statistical significance (P = 0.058).

Conclusion

The study findings confirm the stressful nature of RIF and recurrent pregnancy loss.     

A prospective study evaluating the clinical relevance of a chemoresponse assay for treatment of patients with persistent or recurrent ovarian cancer

Objective

Use of in vitro chemoresponse assays for informing effective treatment selection is a compelling clinical question and a topic of debate among oncologists. A prospective study was conducted evaluating the use of a chemoresponse assay in recurrent ovarian cancer patients.

Methods

Women with persistent or recurrent ovarian cancer were enrolled under an IRB-approved protocol, and fresh tissue samples were collected for chemoresponse testing. Patients were treated with one of 15 protocol-designated treatments empirically selected by the oncologist, blinded to the assay results. Each treatment was classified by the assay as: sensitive (S), intermediate (I), or resistant (R). Patients were prospectively monitored for progression-free survival (PFS) and overall survival (OS). Associations of assay response for the physician-selected treatment with PFS and OS were analyzed.

Results

A total of 262 evaluable patients were enrolled. Patients treated with an assay-sensitive regimen demonstrated significantly improved PFS and OS while there was no difference in clinical outcomes between I and R groups. Median PFS was 8.8 months for S vs. 5.9 months for I + R (hazard ratio [HR] = 0.67, p = 0.009). The association with assay response was consistent in both platinum-sensitive and platinum-resistant tumors (HR: 0.71 vs. 0.66) and was independent of other covariates in multivariate analysis (HR = 0.66, p = 0.020). A statistically significant14-month improvement in mean OS (37.5 months for S vs. 23.9 months for I + R, HR = 0.61, p = 0.010) was demonstrated.

Conclusions

This prospective study demonstrated improved PFS and OS for patients with either platinum-sensitive or platinum-resistant recurrent ovarian cancer treated with assay-sensitive agents.     

Predictive value of circulating tumor cells (CTCs) in newly-diagnosed and recurrent ovarian cancer patients

Objective

To determine whether circulating tumor cells (CTCs), as detected and enumerated by the Veridex CellSearch^TM system, could predict for clinical outcomes in women with newly diagnosed or recurrent epithelial ovarian cancer.

Methods

Serial measurements of CTC s and paired serum CA125 were collected in a series of 78 women with newly diagnosed or recurrent ovarian cancer seen at our institution over a period of 15 months. Clinical data were abstracted from patient medical records. CTCs were detected and enumerated by the CellSearch^TM protocol, and patients were divided into CTC negative (< 2 CTCs) or positive (≥ 2 CTCs) groups. CTC groups were correlated with clinical characteristics and outcomes. A longitudinal analysis of CTC change and CA125 trends was also performed.

Results

At least one CTC was isolated from the peripheral blood of over 80% of the women participating in this study, with a range from 0 to 8. No correlations were observed between CTC numbers and clinical characteristics or outcomes. Although both serum CA125 and CTC number exhibited an overall significant decreasing trend over time, there was no correlation observed between change in CTCs and CA125.

Conclusion

Using the FDA-approved CellSearch^TM system, CTCs can be isolated from women with newly diagnosed or recurrent ovarian cancer. However, CTC numbers do not significantly correlate with clinical characteristics or patient outcomes. Future studies should focus on phenotypic characterization of CTCs and whether different isolation protocols yield a higher number of CTCs or add prognostic value.     

Tratamiento de la endometriosis con 5 mg o 25 mg diarios de mifepristona durante 6 meses. Ensayo clínico aleatorizado,doble ciego

Objectives

To evaluate the safety and efficacy of 5 mg and 25 mg doses of mifepristone for the treatment of endometriosis.

Design

Randomized double-blind study.

Setting

Eusebio Hernández Hospital, Havana, Cuba.

Subjects

Twenty-six women laparoscopically diagnosed with endometriosis were included.

Treatment

Group I received one tablet of 25 mg mifepristone daily and group II received one tablet of 5 mg mifepristone daily for 6 months. Laparoscopy and endometrial biopsy were performed before and after treatment.

Variable to evaluate efficacy

Reduction in the intensity of dysmenorrhea measured by a visual analogue scale.

Results

In both groups reductions in the intensity of dysmenorrhea and dyspareunia were highly significant compared with initial values (P <.001). All the women were amenorrheic after 45 days of treatment.

Conclusions

At doses of 5 mg or 25 mg, mifepristone could be an alternative for the treatment of endometriosis.     

Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: A gynecologic oncology group study

Objectives

To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma.

Background

Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy.

Methods

We performed a randomized phase II trial of intravenous temsirolimus 25 mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20 mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma.

Results

There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded.

Conclusions

Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.     

Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer

Background

Metformin has been associated with reduced cancer risk. The mechanisms underlying this cancer protective effect remain unknown.

Methods

“Window of opportunity” study of metformin in women with operable endometrial cancer (EC). Eleven newly diagnosed, untreated, non-diabetic patients with EC received metformin 500 mg tid from diagnostic biopsy to surgery. Fasting plasma insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 1 (IGFBP-1) and insulin-like growth factor binding protein 7 (IGFBP-7) measurements were taken before and after metformin treatment. Ki-67, pAMPK, and pS6 immunohistochemistry staining was performed on the endometrial cancer before and after metformin treatment and was compared to a control group of 10 women with EC who did not receive metformin.

Results

Metformin was administered for a mean of 36.6 days. None of the patients suffered side effects requiring withdrawal from the study. The study group comprised 8 patients with endometrioid EC, and 3 non-endometrioid EC, with a mean follow-up time of 57 months. Mean plasma insulin (p = 0.0005), IGF-1 (p = 0.001), and IGFBP-7 (p = 0.0098) were significantly reduced after metformin treatment. A clear reduction in ki-67 and pS6 expression was observed by both conventional light microscope analysis and digital image analysis with a significant mean reduction in percentage of cells staining for ki-67 (9.7%, P = 0.02) and pS6 (31%, P = 0.03). In the non-treated control group expression was similar between the biopsy and the surgical specimens.

Conclusions

This pilot trial presents biological evidence consistent with anti-proliferative effects of metformin in women with EC in the clinical setting.     

Evaluation of FAS and caspase-3 in the endometrial tissue of patients with idiopathic infertility and recurrent pregnancy loss

Objective

To investigate expression of BcL-2, FAS, FAS ligand (FASL) and cleaved caspase-3 in the endometrial tissue of women with idiopathic infertility (with two consecutive failed cycles of in vitro fertilization) and women with idiopathic recurrent pregnancy loss. The control group consisted of fertile women.

Study design

Endometrial tissue samples from fertile women (n = 25), women with idiopathic infertility (n = 25) and women with idiopathic recurrent pregnancy loss (n = 25) were collected on the seventh or eighth postovulatory day of their menstrual cycles for evaluation. Expression of BcL-2, FAS, FASL and cleaved caspase-3 was assessed using immunohistochemical methods.

Results

Expression of BcL-2 and FAS was significantly higher and lower, respectively, in the women with idiopathic infertility than in the other groups (p < 0.01). Expression of cleaved caspase-3 was significantly lower in the women with idiopathic infertility than in the other groups (p < 0.01). Expression of FASL was similar in all three groups.

Conclusion

Disturbances in endometrial apoptosis may be a contributing factor in patients with idiopathic infertility and recurrent pregnancy loss.     

The results of gynecologic surveillance in families with hereditary nonpolyposis colorectal cancer

Objective

We aimed to estimate the incidence rate of endometrial cancer (EC) and to evaluate the results of EC-surveillance in hereditary nonpolyposis colorectal cancer (HNPCC) families.

Methods

All at-risk women recommended for EC-surveillance by the HNPCC-register—2959 women (19,334 women years)—were included. Data on EC-surveillance were available for 871 women (6894 women years), who had performed 1945 surveillance visits. The average surveillance period was 7.9 (range 0.1−21.7) years and 46% of the women had had less than 3 years between their visits.

Results

During 19,334 women years, 60 women with gynecological malignancies or premalignancies were diagnosed. Thirty-nine women had EC. Of these, 31 were from families with identified MMR gene mutations with the median age at diagnosis of 54 (39–83) years (Incidence Rate, IR = 0.63 per 100 women years) and four women from each Amsterdam (AMS)-positive and AMS-like families (median age 64 (55–73) years, IR = 0.06 and 0.05 per 100 women years, respectively, p < .0001).Among the 871 surveilled women, 13 EC were found: 7/13 cases were diagnosed by surveillance examination—two as prevalent cancers, diagnosed at the first visit—and 6/13 based on symptoms. In addition, five complex atypical hyperplasias and four ovarian cancers (OCs) were diagnosed. All these women were MMR mutation carriers.

Conclusion

Based on 19,334 women years of EC-surveillance, our analysis provides a thorough estimation of the EC risk in women with an MMR mutation, or suspected of having Lynch syndrome. We conclude that EC surveillance should only be targeted at MMR-mutation carriers.