Polymorphisms in the vitamin D receptor (VDR) gene have been shown in some studies to be associated with the risk of epithelial ovarian cancer (EOC) in Caucasian women. This association among African American women has been understudied.
Case-control data from the North Carolina Ovarian Cancer Study were analyzed using logistic regression to determine the association between seven VDR polymorphisms of functional significance and EOC in both Caucasians (513 cases, 532 controls) and African Americans (74 cases, 79 controls). In a follow-up analysis, associations were assessed between six SNPs in proximity of the Apa1 variant and a larger sample of African-Americans (125 cases, 155 controls).
African American women who carried at least one minor allele of Apa1 (rs7975232) were at higher risk for invasive EOC controlling for age and admixture with an odds ratio (OR) for association under the log-additive model of 2.08 (95% confidence interval (CI) = 1.19, 3.63, p = 0.010). No association was observed between any of the VDR variants and EOC among Caucasians. A follow-up analysis in a larger sample of African American subjects revealed a nearly two-fold increase in risk of invasive EOC in rs7971418, a SNP in proximity to the Apa1 SNP (R2 = 0.369) with a log-additive OR of 1.87 (95% CI = 1.20, 2.93, p = 0.006).
This is the first report showing VDR variants associated with ovarian cancer risk in African American women. A larger study of African American women is needed to confirm these findings.
Our results imply that vitamin D exposure is a possible modifiable risk factor of ovarian cancer among African Americans.
ovarian cancer; vitamin D receptor; polymorphisms; population risk factors; linkage disequilibrium
The cancer stem cell hypothesis has been put forward as a paradigm to describe varying levels of aggressiveness in heterogeneous tumors. Specifically, many subpopulations have been clearly demonstrated to possess increased tumorigenicity in mice, broad differentiating capacity, and resistance to therapy. However, it is still not clear the extent to which these experimental findings are potentially clinically significant. This review will describe the principles of this emerging hypothesis, ways in which it may be appropriate in ovarian cancer based on the clinical course of the disease, and how we might exploit it to improve outcomes in ovarian cancer patients.
The objective of our study was to compare the surgical outcomes of extraperitoneal laparoscopic, transperitoneal laparoscopic, and robotic transperitoneal para-aortic lymphadenectomy in endometrial cancer staging.
A retrospective review was performed from January 2007 to November 2012. Three groups were compared: extraperitoneal laparoscopic para-aortic lymphadenectomy and robotic hysterectomy and pelvic lymphadenectomy (“extraperitoneal group”; N=34); laparoscopic hysterectomy and transperitoneal pelvic and para-aortic lymphadenectomy (“transperitoneal laparoscopic group”; N=108); and robotic hysterectomy and transperitoneal pelvic and para-aortic lymphadenectomy (“transperitoneal robotic group”; N=52). Fisher’s exact test and Kruskal-Wallis test were used for statistical analysis, and statistical significance was defined as P< 0.05.
Median number of para-aortic lymph nodes obtained was higher in the extraperitoneal group than in the transperitoneal laparoscopic and robotic groups (10, 5, and 4.5 nodes, respectively; P<0.001). Among patients with BMI <35 kg/m2, the median number of para-aortic nodes harvested was higher in the extraperitoneal group than in the transperitoneal laparoscopic and robotic groups (9, 4, and 5 nodes, respectively; P<0.01). The same pattern was observed among patients with BMI ≥35 kg/m2 (10, 6, and 3 nodes, respectively) (P=0.001). There was no significant difference in median estimated blood loss between the extraperitoneal group and either the transperitoneal laparoscopic group (100 vs. 112.5 mL; P=0.06) or the transperitoneal robotic group (100 vs. 67.5 mL; P=0.23).
Extraperitoneal laparoscopic para-aortic lymphadenectomy resulted in a higher number of para-aortic lymph nodes removed than transperitoneal laparoscopic or robotic lymphadenectomy. The extraperitoneal approach should be considered for endometrial cancer staging.
Treatment failures in stage IIIC endometrial carcinoma (EC) are predominantly due to occult extrapelvic metastases (EPM). The impact of chemotherapy on occult EPM was investigated according to grade (G), G1/2EC vs G3EC.
All surgical-stage IIIC EC cases from January 1, 1999, through December 31, 2008, from Mayo Clinic were included. Patient-, disease-, and treatment-specific risk factors were assessed for association with overall survival, cause-specific survival, and extrapelvic disease-free survival (DFS) using Cox proportional hazards regression.
109 cases met criteria, with 92 (84%) having systematic lymphadenectomy (>10 pelvic and >5 paraaortic lymph nodes resected). In patients with documented recurrence sites, occult EPM accounted for 88%. Among G1/2EC cases (n = 48), the sole independent predictor of extrapelvic DFS was grade 2 histology (hazard ratio [HR], 0.28; 95% CI, 0.08–0.91; P = .03) while receipt of adjuvant chemotherapy approached significance (HR 0.13; 95% CI, 0.02, 1.01; P = .0511). The 5-year extrapelvic DFS with and without adjuvant chemotherapy was 93% and 54%, respectively (log-rank, P = .02). Among G3EC (n = 61), the sole independent predictor of extrapelvic DFS was lymphovascular space involvement (HR, 2.63; 95% CI, 1.16–5.97; P = .02). Adjuvant chemotherapy did not affect occult EPM in G3EC; the 5-year extrapelvic DFS for G3EC with and without adjuvant chemotherapy was 43% and 42%, respectively (log-rank, P = .91).
Chemotherapy improves extrapelvic DFS for stage IIIC G1/2EC but not stage IIIC G3EC. Future efforts should focus on prospectively assessing the impact of chemotherapy on DFS in G3EC and developing innovative phase I and II trials of novel systemic therapies for advanced G3EC.
Chemotherapy efficacy; Occult extrapelvic metastases; Stage IIIC endometrial cancer; Survival
To evaluate the effectiveness of definitive involved-field radiation therapy (IFRT) for selected patients with locoregionally-recurrent ovarian cancer.
We retrospectively reviewed records of 102 epithelial ovarian cancer patients treated with definitive IFRT (≥45 Gy). IFRT was directed to localized nodal (49%) and extranodal (51%) recurrences.
The median time from diagnosis to IFRT was 36 months (range, 1–311), and the median follow-up after IFRT was 37 months (range, 1–123). Patients received a median of three chemotherapy courses before IFRT (range, 0–9). Five-year overall (OS) and progression-free survival (PFS) rates after IFRT were 40% and 24% respectively; the 5-year in-field disease control rate was 71%.
Thirty-five patients (35%) had no evidence of disease at a median of 38 months after IFRT (range, 7–122), including 25 continuously without disease for a median of 61 months (range, 17–122) and 10 with salvage treatment following disease recurrence, disease-free for a median of 39 months after salvage treatment (range, 7–92).
Eight clear cell carcinoma patients had higher 5-year OS (88% versus 37%; p=0.05) and PFS (75% versus 20%; p=0.01) rates than other patients. Patients sensitive to initial platinum chemotherapy had a higher 5-year OS rate than platinum-resistant patients (43% versus 27%, p=0.03). Patients who required chemotherapy for recurrence after IFRT often benefitted from longer chemotherapy-free intervals after than before IFRT.
Definitive IFRT can yield excellent local control, protracted disease-free intervals, and even cures in carefully selected patients. RT should be considered a tool in the curative management of locoregionally-recurrent ovarian cancer.
Ovarian cancer; radiation therapy; clear cell carcinoma
To explore the yield and impact of perioperative imaging on management among patients undergoing surgical resection and treatment of uterine sarcomas.
A retrospective chart review was done for women with histologically confirmed uterine sarcomas treated at Barnes Jewish Hospital/Washington University from 2001–2007. Descriptive statistics, Cox multivariate models, and Kaplan-Meier plots were used to evaluate associations and survival.
A total of 92 patients were identified and 55(60%) were diagnosed with stage III–IV disease. Perioperative imaging was obtained in 84 (91%) cases, including chest x-ray in 66 (72%), computerized tomography (CT) of the abdomen and pelvis in 59 (64%), chest CT in 33 (36%), positron emission tomography (PET) in 8 (9%), and CT of the head, pelvic magnetic resonance imaging (MRI), or bone scan in a total of 2 (2.2%). Imaging identified abnormalities concerning for metastases in 30 (32%) studies. Thirty-four recurrences have been documented, and 21 (62%) of these treatment failures were extrapelvic. Multivariate analysis of this series noted that tomographic evidence of extrauterine disease predicted recurrence (p=0.028) and incomplete surgical resection (p=0.003, HR 6.0 95% CI 1.9–19.9) predicted disease free survival. Imaging contributed to change in surgical and postsurgical treatment decisions in 8 (9%) patients.
Pretreatment imaging studies change management in a minority of patients with newly diagnosed uterine sarcomas.
Patients with micrometastasis to para-aortic lymph nodes may benefit from extended field chemoradiation. To determine the rate of para-aortic node micrometastasis in patients with locally advanced cervical cancer undergoing laparoscopic extraperitoneal para-aortic lymphadenectomy
We prospectively identified consecutive patients diagnosed with stage IB2-IVA biopsy-proven cervical cancer. Eligible patients included those who were candidates for treatment with radiotherapy and concurrent chemotherapy and had no evidence of para-aortic lymphadenopathy (all lymph nodes < 2 cm in diameter) by preoperative computed tomography or magnetic resonance imaging. All patients underwent preoperative positron emission tomography/computed tomography and laparoscopic extraperitoneal para-aortic lymphadenectomy. All lymph nodes were assessed for metastasis by routine hematoxylin-eosin (H&E) staining. Ultrastaging (serial sectioning) and immunohistochemical analysis were performed in H&E-negative specimens.
Thirteen (22%) of 60 consecutive patients had para-aortic lymph node metastases detected on routine H&E staining. Of the remaining 47 patients, one (2.1%) had evidence of micrometastasis, which was detected by ultrastaging. This patient completed whole pelvic radiotherapy and chemotherapy but had a recurrence 27 months after completion of therapy.
The rate of para-aortic node micrometastasis in patients with locally advanced cervical cancer is low. The role of routine ultrastaging and immunohistochemical analysis in such patients remains uncertain. Future studies are needed to determine the clinical impact of para-aortic node micrometastasis in patients with locally advanced cervical cancer.
To help determine whether global collaborations for prospective gynecologic surgery trials should include hospitals in developing countries, we compared surgical and oncologic outcomes of patients undergoing laparoscopic radical hysterectomy at a large comprehensive cancer center in the United States and a cancer center in Colombia.
Records of the first 50 consecutive patients who underwent laparoscopic radical hysterectomy at The University of Texas MD Anderson Cancer Center in Houston (between April 2004 and July 2007) and the first 50 consecutive patients who underwent the same procedure at the Instituto de Cancerología–Clínica las Américas in Medellín (between December 2008 and October 2010) were retrospectively reviewed. Surgical and oncologic outcomes were compared between the 2 groups.
There was no significant difference in median patient age (US 41.9 years [range 23-73] vs. Colombia 44.5 years [range 24-75], P=0.09). Patients in Colombia had a lower median body mass index than patients in the US (24.4 kg/m2 vs. 28.7 kg/m2, P=0.002). Compared to patients treated in Colombia, patients who underwent surgery in the US had a greater median estimated blood loss (200 mL vs. 79 mL, P<0.001), longer median operative time (328.5 min vs. 235 min, P<0.001), and longer postoperative hospital stay (2 days vs. 1 day, P<0.001).
Surgical and oncologic outcomes of laparoscopic radical hysterectomy were not worse at a cancer center in a developing country than at a large comprehensive cancer center in the United States. These results support consideration of developing countries for inclusion in collaborations for prospective surgical studies.
To compare the open versus robotic surgical approaches and provide surgical outcome data on patients who have undergone radical trachelectomy (RT).
We identified patients who underwent open (ORT) or robotic radical trachelectomy (RRT) between September 2005–June 2011. Tumor characteristics, perioperative, operative and obstetrical outcomes were analyzed.
Thirty-seven patients with early stage cervical cancer that desired future fertility underwent attempted radical trachelectomy, and 32 patients (20 with 1B1, 11 with 1A2, and 5 with 1A1 with LVSI/poorly differentiated histology) had successful completion of RT. Five (1 open/4 robotic) underwent conversion to radical hysterectomy secondary to close (<5mm) endocervical margin (p=0.08). The median age at diagnosis was 28.9 years (range; 21.4–37.2), 70% were nulliparous, and 9 had a visible lesion. Twenty-five patients (68%) underwent ORT and 12 (32%) underwent RRT. RRT was associated with less blood loss (62.5 mL vs. 300 mL, p=0.0001) and decreased length of postoperative stay (1 vs. 4 days, p<0.001), with no difference in operative time or histopathologic outcomes. Twenty-three patients (62%) had no residual cervical disease on final pathology. Common long-term morbidities were irregular menstrual bleeding or amenorrhea (25%), cerclage erosion (13%), or cervical stenosis (9%). Although there was a higher rate of conversion to hysterectomy in the robotic surgery cohort, rates of serious morbidities among the cohorts were comparable (robotic: 33% vs. open: 24%, p=0.70). Eleven (36%) patients are actively attempting pregnancy and three have achieved pregnancy. The median time of follow up is 17.0 months (range 0.30–64.9 months). There are no documented recurrences.
RRT results in less blood loss and decreased length of hospital stay with no compromise in histopathologic outcomes.
robotic surgery; radical trachelectomy
To determine the proportion of young patients with early-stage invasive cervical cancer treated with radical hysterectomy who may have been eligible for fertility-sparing surgery consisting of cervical conization with pelvic lymph node dissection.
We retrospectively identified all patients with early-stage cervical cancer (stage IA2-IB1) who underwent a radical hysterectomy at The University of Texas M. D. Anderson Cancer Center between 1990 and 2009. We reviewed these patients’ records to identify patients who were < 40 years who had not previously undergone tubal ligation and who would have been considered candidates for cold-knife conization with pelvic lymph node dissection—i.e., women with tumors smaller than 2 cm, low-risk histology (squamous, adenocarcinoma, or adenosquamous), and no lymphovascular space invasion (LVSI).
A total of 507 patients with early-stage cervical cancer were identified who underwent radical hysterectomy during the review period. Of these women, 277 (55%) were 40 years or younger. Of these 277 patients, 75 (27%) had had a previous tubal ligation and 202 (73%) had not. Of these 202 patients potentially interested in fertility preserving surgery, 53 (26%) had favorable pathologic characteristics including low-risk histology, tumors ≤2cms in size and no LVSI present. Of these 53 patients, none had parametrial involvement or positive lymph nodes.
Among 202 women with age younger than 40 years and no previous tubal ligation who underwent radical hysterectomy, 53 (26%) may have been eligible for fertility-sparing surgery such as cold-knife conization with pelvic lymph node dissection.
The standard treatment for women with early-stage cervical cancer (IA2-IB1) remains radical hysterectomy with pelvic lymphadenectomy. In select patients interested in future fertility, the option of radical trachelectomy with pelvic lymphadenectomy is also considered a viable option. The possibility of less radical surgery may be appropriate not only for patients desiring to preserve fertility but also for all patients with low-risk early-stage cervical cancer. Recently, a number of studies have explored less radical surgical options for early-stage cervical cancer, including simple hysterectomy, simple trachelectomy, and cervical conization with or without sentinel lymph node biopsy and pelvic lymph node dissection. Such options may be available for patients with low-risk early-stage cervical cancer. Criteria that define this low-risk group include: squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma, tumor size <2 cm, stromal invasion <10mm, and no lymph-vascular space invasion. In this report, we provide a review of the existing literature on the conservative management of cervical cancer and describe ongoing multi-institutional trials evaluating the role of conservative surgery in selected patients with early-stage cervical cancer.
To assess the use of traditional and robotic assisted laparoscopy by Society of Gynecologic Oncology (SGO) members and to compare the results with those of our published survey in 2004.
Surveys were mailed to SGO members, and anonymous responses were collected by mail or through a web site. Data were analyzed and compared with those of our previous survey. In addition, we gathered information on the effect of robotic assisted surgery on the management of gynecologic malignancies.
Three hundred eighty-eight (46%) of 850 SGO members responded to the survey. Three hundred fifty-two (91%) indicated that they performed laparoscopic surgery in their practice (compared with 84% in the 2004 survey). The three most common laparoscopic procedures were laparoscopic hysterectomy and staging for uterine cancer (43%), diagnostic laparoscopy for adnexal masses (39%), and prophylactic bilateral oophorectomy for high-risk women (11%). Although 76% of respondents had received either limited or no laparoscopic training during their fellowship, 78% now believe that maximum or much emphasis should be placed on laparoscopic training (55% in the 2004 survey). Twenty-four percent of respondents indicated that they performed robotic assisted surgery, with 66% indicating that they planned to increase their use of the procedure in the next year.
We found an overall increase in the use of and perceived indications for minimally invasive surgery in gynecologic oncology among SGO members. Endometrial cancer staging has become an accepted indication for laparoscopy. In addition, most respondents were planning on increasing their use of robotic assisted surgery in the next year.
gynecologic oncology; laparoscopy; evaluation
To evaluate whether preoperative age impacts surgical outcomes, complication rates, and/or recurrence in women undergoing pelvic exenteration.
All women who underwent a pelvic exenteration for any gynecologic indication at our institution from 1993 to 2010 were included. Women were stratified into groups based on age in years (young: ≤50, middle: 51–64, and senior: ≥65). Baseline characteristics, surgical outcomes, early (<60 days) and late (≥60 days) postoperative complications, and recurrence/survival outcomes were ascertained. Fisher’s exact test or Kruskall-Wallis test was performed. Kaplan-Meier survival curves were compared.
161 patients were included (58 young, 62 in the middle, and 41 senior). Women in the young group predominately had a diagnosis of cervical cancer (82.8%) while women in the senior group primarily had a diagnosis of vulvar or vaginal cancer (70.7%). Senior women were also more likely to have hypertension (p< 0.0001) and pulmonary disease (p= 0.040). Operative time was significantly shorter for women in the senior group (8.5 hours) compared with the middle (9.5 hours) and young group (10.1 hours) (p=0.0089). There were no significant differences in early or late complications when stratified by age. The overall survival did not differ between age groups (p=0.3760).
Although hypertension and pulmonary disease were more frequent in the senior age group, duration of surgery, blood loss, length of hospital stay and complication rates did not increase with age. Advanced chronological age should not be considered a contraindication to a potentially curative surgical procedure.
Aggressive care interventions at the end of life (ACE) are reported metrics of sub-optimal quality of end of life care that are modifiable by palliative medicine consultation. Our objective was to evaluate the association of inpatient palliative medicine consultation with ACE scores and direct inpatient hospital costs of patients with gynecologic malignancies.
A retrospective review of medical records of the past 100 consecutive patients who died from their primary gynecologic malignancies at a single institution was performed. Timely palliative medicine consultation was defined as exposure to inpatient consultation ≥30 days before death. Metrics utilized to tabulate ACE scores were ICU admission, hospital admission, emergency room visit, death in an acute care setting, chemotherapy at the end of life, and hospice admission <3 days. Inpatient direct hospital costs were calculated for the last 30 days of life from accounting records. Data were analyzed using Fisher's Exact, Mann–Whitney U, Kaplan–Meier, and Student's T testing.
49% of patients had a palliative medicine consultation and 18% had timely consultation. Median ACE score for patients with timely palliative medicine consultation was 0 (range 0–3) versus 2 (range 0–6) p = 0.025 for patients with untimely/no consultation. Median inpatient direct costs for the last 30 days of life were lower for patients with timely consultation, $0 (range 0–28,019) versus untimely, $7729 (0–52,720), p = 0.01.
Timely palliative medicine consultation was associated with lower ACE scores and direct hospital costs. Prospective evaluation is needed to validate the impact of palliative medicine consultation on quality of life and healthcare costs.
Palliative medicine; Gynecologic malignancies; Aggressiveness of care; End of life care; Quality-of-life; Hospital costs
To determine the feasibility of using social media to perform cross-sectional epidemiologic and quality-of-life research on patients with rare gynecologic tumors, we performed a survey of patients with neuroendocrine tumors of the cervix using Facebook.
After approval from our Institutional Review Board, a support group of patients with neuroendocrine tumors of the cervix was identified on Facebook. Group members were asked to complete an survey comprising 84 questions evaluating clinical presentation; treatment; recurrence; quality of life; and sexual function.
The survey was posted for 30 days, during which 57 women responded from 8 countries across 4 continents treated at 51 centers. All respondents provided a detailed clinical and tumor history. The mean age was 38.5 years. The stage distribution was stage I, 36 patients (63%); II, 13 (23%); III, 2 (4%); and IV, 6 (11%). Forty-nine patients (86%) had small cell and 8 (14%) large cell tumors. Forty-five of the respondents (79%) had completed primary therapy, 53 (93%) had no evidence of disease, and 8 (14%) had recurrent disease. Forty-one patients (72%) reported symptoms at time of presentation. Thirty-seven patients (65%) received multimodality primary therapy. Quality of life instruments demonstrated high scores for anxiety and a negative impact of anxiety and cancer on functional and emotional well-being. Sexual function scores did not differ significantly between respondents and the PROMIS reference population.
Use of a social media network to perform epidemiologic and quality of life research on patients with rare gynecologic tumors is feasible and permits such research to be conducted efficiently and rapidly.
cervix; neuroendocrine; small cell; large cell; social media; Facebook
Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. Although greater progression free survival among diabetic patients with ovarian and breast cancer using metformin have been reported, no studies have assessed the association of metformin use with survival in women with endometrial cancer (EC).
We conducted a single-institution retrospective cohort study of all patients treated for uterine cancer from January 1999 through December 2009. Demographic, medical, social, and survival data were abstracted from medical records and the national death registry. Overall survival (OS) was estimated using Kaplan-Meier methods. Cox models were utilized for multivariate analysis. All statistical tests were two-sided.
Of 985 patients, 114 (12%) had diabetes and were treated with metformin, 136 (14%) were diabetic but did not use metformin, and 735 (74%) had not been diagnosed with diabetes. Greater OS was observed in diabetics with non-endometrioid EC who used metformin than in diabetic cases not using metformin and non-endometrioid EC cases without diabetes (log rank test (p=0.02)). This association remained significant (hazard ratio = 0.54, 95% CI: 0.30–0.97, p<0.04) after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment and presence of hyperlipidemia in multivariate analysis. No association between metformin use and OS in diabetics with endometrioid histology was observed.
Diabetic EC patients with non-endometrioid tumors who used metformin had lower risk of death than women with EC who did not use metformin. These data suggest that metformin might be useful as adjuvant therapy for non-endometrioid EC.
Metformin; endometrial cancer; non-endometrioid; adjuvant therapy; retrospective cohort study
Platelet-derived growth factor receptor alpha (PDGFRα) is believed to be associated with cell survival. We examined (i) whether PDGFRα blockade enhances the antitumor activity of taxanes in ovarian carcinoma and (ii) potential biomarkers of response to anti-PDGFRα therapy.
PDGFRα expression in 176 ovarian carcinomas was evaluated with tissue microarray and correlated to survival outcome. Human-specific monoclonal antibody to PDGFRα (IMC-3G3) was used for in vitro and in vivo experiments with or without docetaxel. Gene microarrays and reverse-phase protein arrays with pathway analyses were performed to identify potential predictive biomarkers.
When compared to low or no PDGFRα expression, increased PDGFRα expression was associated with significantly poorer overall survival of patients with ovarian cancer (P = 0.014). Although treatment with IMC-3G3 alone did not affect cell viability or increase apoptosis, concurrent use of IMC-3G3 with docetaxel significantly enhanced sensitization to docetaxel and apoptosis. In an orthotopic mouse model, IMC-3G3 monotherapy had no significant antitumor effects in SKOV3-ip1 (low PDGFRα expression), but showed significant antitumor effects in HeyA8-MDR (high PDGFRα expression). Concurrent use of IMC-3G3 with docetaxel, compared with use of docetaxel alone, significantly reduced tumor weight in all tested cell lines. In protein ontology, the EGFR and AKT pathways were downregulated by IMC-3G3 therapy. MAPK and CCNB1 were downregulated only in the HeyA8-MDR model.
These data identify IMC-3G3 as an attractive therapeutic strategy and identify potential predictive markers for further development.
Platelet-derived growth factor receptor alpha; Ovarian cancer; MAPK; EGFR; IMC-3G3
Current adjuvant therapy for advanced-stage, recurrent, and high-risk endometrial cancer (EC) has not reduced mortality from this malignancy, and novel systemic therapies are imperative. Oncolytic viral therapy has been shown to be effective in the treatment of gynecologic cancers, and we investigated the in vitro and in vivo efficacy of the Edmonston strain of measles virus (MV) and vesicular stomatitis virus (VSV) on EC.
Human EC cell lines (HEC-1-A, Ishikawa, KLE, RL95-2, AN3 CA, ARK-1, ARK-2, and SPEC-2) were infected with Edmonston strain MV expressing the thyroidal sodium iodide symporter, VSV expressing either human or murine IFN-β, or recombinant VSV with a methionine deletion at residue 51 of the matrix protein and expressing the sodium iodide symporter. Xenografts of HEC-1-A and AN3 CA generated in athymic mice were treated with intratumoral MV or VSV or intravenous VSV.
In vitro, all cell lines were susceptible to infection and cell killing by all 3 VSV strains except KLE. In addition, the majority of EC cell lines were defective in their ability to respond to type I IFN. Intratumoral VSV–treated tumors regressed more rapidly than MV-treated tumors, and intravenous VSV resulted in effective tumor control in 100% of mice. Survival was significantly longer for mice treated with any of the 3 VSV strains compared with saline.
VSV is clearly more potent in EC oncolysis than MV. A phase 1 clinical trial of VSV in EC is warranted.
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.
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.
Brivanib is reasonably well tolerated and worthy of further investigation based on PFS at six months in recurrent or persistent EMC.
Brivanib; endometrial cancer