Susan C. Modesitt

Ovarian and extraovarian endometriosis-associated cancer

OBJECTIVE To determine clinical characteristics of women with endometriosis‐associated intraperitoneal cancers, to assess differences based on the relationship of the cancer to the endometriosis, and to assess factors associated with survival. METHODS A search of medical records at The University of Texas M. D. Anderson Cancer Center from 1970 to 1999 identified patients who had synchronous endometriosis and intraperitoneal cancer. Demographic and clinicopathologic characteristics were evaluated for differences based on the relationship of the cancer to the endometriosis and for correlation with survival. RESULTS One hundred fifteen patients were identified: 25 patients with ovarian cancer arising in endometriosis, 21 with an extraovarian cancer arising in endometriosis, 33 patients with endometriosis and ovarian cancer in the same location but without a definite transition point, and 36 patients with ovarian cancer and incidental endometriosis. Women with extraovarian cancers arising in endometriosis were more likely to be postmenopausal (P < .001) and use hormone replacement (P < .001). The median age was 47 years, the most common histological tumor types were clear cell and endometrioid (23% each), and the most common stage was stage I (31%). The median survival was 35 months. Univariate survival analysis revealed that gravidity (P < .038), grade (P < .001), stage (P < .001), histology (P < .01), and type of chemotherapy (P < .011) correlated with survival. Multivariable analysis revealed that stage and gravidity independently predicted survival. CONCLUSION Women with endometriosis‐associated cancers are typically premenopausal, have a high incidence of endometrioid and clear cell histologies, and have early stage disease. Stage and gravidity independently predicted survival.

Risk of malignancy in unilocular ovarian cystic tumors less than 10 centimeters in diameter

OBJECTIVE To determine the natural history and to estimate the risk of malignancy of unilocular ovarian cystic tumors less than 10 cm in diameter followed conservatively by transvaginal ultrasound. METHODS From 1987 to 2002, 15,106 asymptomatic women at least 50 years old entered the University of Kentuckys Ovarian Cancer Screening Program and underwent initial transvaginal ultrasonography. If the screen revealed nothing abnormal, women were asked to repeat transvaginal ultrasonography yearly. If the screen revealed abnormalities, transvaginal ultrasonography was repeated in 4 to 6 weeks, along with Doppler flow ultrasonography and CA 125 testing. RESULTS Of the 15,106 women at least 50 years old, 2763 women (18%) were diagnosed with 3259 unilocular ovarian cysts. A total of 2261 (69.4%) of these cysts resolved spontaneously, 537 (16.5%) developed a septum, 189 (5.8%) developed a solid area, and 220 (6.8%) persisted as a unilocular lesion. During this time, 27 women received a diagnosis of ovarian cancer, and ten had been previously diagnosed with simple ovarian cysts. All ten of these women, however, developed another morphologic abnormality, experienced resolution of the cyst before developing cancer, or developed cancer in the contralateral ovary. No woman with an isolated unilocular cystic ovarian tumor has developed ovarian cancer in this population. CONCLUSION The risk of malignancy in unilocular ovarian cystic tumors less than 10 cm in diameter in women 50 years old or older is extremely low. The majority will resolve spontaneously and can be followed conservatively with serial transvaginal ultrasonography.

A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: A Gynecologic Oncology Group study

PURPOSE This multi-institutional phase II trial assessed the activity and toxicity of a new histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamic acid--SAHA) in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma. PATIENTS AND METHODS Women with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma who were platinum-resistant/refractory (progression-free interval <12 months since platinum) were eligible for trial entry if they had measurable disease, a good performance status, and good overall organ function. Women were treated with a 400 mg daily oral dose of vorinostat and continued on treatment until disease progression or unacceptable toxicity. The primary endpoints were progression-free survival (PFS) at 6 months and toxicity. Secondary endpoints were tumor response, duration of PFS and duration of overall survival (OS). RESULTS Twenty-seven women were enrolled through the Gynecologic Oncology Group (GOG) on the planned first stage of accrual for this trial and were eligible for analysis. Two women survived progression-free over 6 months, with one having a partial response. Two grade 4 toxicities were reported (one leukopenia and one neutropenia). The most common grade 3 toxicities were constitutional (3/27; 11%) and gastrointestinal (3/27, 11%). Other grade 3 toxicities included neutropenia, metabolic abnormalities, and thrombocytopenia (two patients each, 7%) as well as neurologic complaints and pain (1 patient each; 4%). CONCLUSION Vorinostat is well tolerated but had minimal activity as a single agent in unscreened patients with recurrent platinum-refractory ovarian or primary peritoneal carcinoma.

Malignant struma ovarii: a case report and analysis of cases reported in the literature with focus on survival and i131 therapy

BACKGROUND Malignant struma ovarii is a rare type of germ cell tumor that is most often diagnosed postoperatively. The natural history and optimal treatment regimen for the disease are essentially unknown due to the small numbers of published cases. CASE A 32-year-old woman presented with pelvic pain and an ovarian mass that was ultimately treated by total abdominal hysterectomy/bilateral salpingo-oophorectomy. Postoperatively, she was diagnosed with a malignant struma ovarii. The patient was subsequently treated with thyroidectomy and I(131) ablation and is currently disease free. A Medline literature search was performed and clinical data from 23 additional cases were compiled. CONCLUSION In this review of 24 cases, 16 patients were followed conservatively postoperatively while 8 received varied additional therapy (4 with I(131)). There were 8 recurrences and all occurred in the conservatively managed patients. I(131) for recurrent disease provided an initial complete response in 7 women. Treatment with thyroidectomy and I(131) should be considered in the first line of management for malignant struma ovarii.

The impact of obesity on the incidence and treatment of gynecologic cancers: a review.

Sixty-five percent of the adult population in the United States is overweight and 30% of the population is obese. There is mounting evidence that obesity is a risk factor for gynecologic cancers and may also adversely impact survival. The objectives of this review were to systematically evaluate and discuss the impact of overweight and obesity on endometrial, ovarian, and cervical cancer incidence and to review the data on the impact of obesity on treatment of these same gynecologic cancers. A PUBMED literature search was performed to identify articles in the English language that focused on the impact of obesity on cancer incidence and treatment. References of identified articles were also used to find additional related articles. Obesity profoundly increases the incidence of endometrial cancer, predominantly through the effects of unopposed estrogen. Although the data are less compelling in ovarian and cervical cancer, obesity may modestly increase the incidence of premenopausal ovarian cancer and might potentially increase cervical cancer incidence, perhaps as a result of the impact on glandular cancers or decreased screening compliance. Obese women with cancer have decreased survival; this may be disease-specific, the result of comorbid illnesses, or response to treatment. Obese women have increased surgical complications, may also have increased radiation complications, and there is no current consensus regarding appropriate chemotherapy dosing in the obese patient. Obesity is a serious health problem with significant effects on the incidence and treatment of the gynecologic malignancies. Target Audience: Obstetricians & Gynecologists, Family Physicians. Learning Objectives: After completion of this article, the reader should be able to summarize the clear evidence that obesity is a risk factor for many cancers, including gynecologic malignancies; describe the role of unopposed estrogen in gynecologic cancers; and explain that obese women overall have a poorer survival rate when afflicted with cancer.

SGO White Paper on Ovarian Cancer: Etiology, Screening and Surveillance☆

Ovarian cancer is a heterogeneous, rapidly progressive, highly lethal disease of low prevalence. The etiology remains poorly understood. Numerous risk factors have been identified, the most prominent involving an inherited predisposition in 10% of cases. Women with germline mutations associated with Hereditary Breast/Ovarian Cancer and Lynch syndromes have dramatically elevated risks (up to 46% and 12%, respectively). Risk-reducing salpingo-oophorectomy is the best method to prevent ovarian cancer in these high-risk women. Significant risk reduction is also seen in the general population who use oral contraceptives. Since up to 89% patients with early-stage disease have symptoms prior to diagnosis, increased awareness of the medical community may facilitate further workup in patients who otherwise would have had a delay. Despite enormous effort, there is no proof that routine screening for ovarian cancer in either the high-risk or general populations with serum markers, sonograms, or pelvic examinations decreases mortality. Further evaluation is needed to determine whether any novel biomarkers, or panels of markers, have clinical utility in early detection. Prospective clinical trials have to be designed and completed prior to offering of any of these new diagnostic tests. CA125 is currently the only biomarker recommended for monitoring of therapy as well as detection of recurrence. This commentary provides an overview on the background, screening and surveillance of ovarian cancer.

The North American Menopause Society recommendations for clinical care of midlife women

In celebration of the 25th anniversary of The North American Menopause Society (NAMS), the Society has compiled a set of key points and clinical recommendations for the care of midlife women. NAMS has always been a premier source of information about menopause for both healthcare providers and midli

Phase 1–2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer

BACKGROUND Biologically targeted therapies have been postulated as a viable strategy to improve outcomes for women with ovarian cancer. We assessed the safety, tolerance, pharmacokinetics, relevant circulating and image-derived biomarkers, and clinical activity of combination aflibercept and docetaxel in this population. METHODS For the phase 1 (pharmacokinetic) study, eligible patients had measurable, recurrent or persistent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with a maximum of two prior chemotherapy regimens. Aflibercept was administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose for the phase 2 study. Pharmacokinetics were assessed and dynamic imaging was done during a lead-in phase with single-agent aflibercept (cycle 0) and during combination therapy with intravenous docetaxel (75 mg/m(2)). Eligibility for the phase 2 study was the same as for phase 1. Patients were enrolled in a two-stage design and given aflibercept 6 mg/kg intravenously and docetaxel 75 mg/m(2) intravenously, every 3 weeks. The primary endpoint was objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.0. The trial has completed enrolment and all patients are now off study. The trial is registered at ClinicalTrials.gov, number NCT00436501. FINDINGS From the phase 1 study, the recommended phase 2 doses of aflibercept and docetaxel were found to be 6 mg/kg and 75 mg/m(2), respectively. Log-linear pharmacokinetics (for unbound aflibercept) were observed for the three dose levels. No dose-limiting toxicities were noted. 46 evaluable patients were enrolled in the phase 2 trial; 33 were platinum resistant (15 refractory) and 13 were platinum sensitive. The confirmed ORR was 54% (25 of 46; 11 patients had a complete response and 14 had a partial response). Grade 3-4 toxicities observed in more than two patients (5%) were: neutropenia in 37 patients (80%); leucopenia in 25 patients (54%); fatigue in 23 patients (50%); dyspnoea in ten patients (22%); and stomatitis in three patients (7%). Adverse events specifically associated with aflibercept were grade 1-2 hypertension in five patients (11%), and grade 2 proteinuria in one patient (2%). INTERPRETATION Combination aflibercept plus docetaxel can be safely administered at the dose and schedule reported here, and is associated with substantial antitumour activity. These findings suggest that further clinical development of this combination in ovarian cancer is warranted. FUNDING US National Cancer Institute, US Department of Defense, Sanofi-Aventis, Gynecologic Cancer Foundation, Marcus Foundation, and the Commonwealth Foundation.

Frailty: An outcome predictor for elderly gynecologic oncology patients☆

OBJECTIVES The objective of this pilot study was to determine if frailty predicts surgical complications among elderly women undergoing gynecologic oncology procedures. METHODS A cohort of gynecologic oncology patients age ≥ 65, undergoing surgery between March and December 2011 was identified. Frailty was evaluated using a validated assessment tool. The primary outcome measure was 30 day postoperative complication rate. RESULTS Forty women were approached for study entry and 37 (92%) enrolled. The mean age was 73 years (range 65-95). The majority of women had a malignancy and underwent a major abdominal surgical procedure. Twenty-one women (57%) were not frail, 10 (27%) were intermediately frail and 6 (16%) were frail. There was no difference in age or prevalence of medical comorbidities between groups. Frail women had a significantly higher BMI compared to intermediately frail and not frail women, (36.0, 31.5 and 26.1 kg/m(2), p=0.02). The rate of 30-day surgical complications increased with frailty score and was 24%, versus 67% for women who were not frail as compared to the frail (p=0.04). CONCLUSIONS Pre-operative frailty assessment is well accepted by gynecologic oncology patients and feasible in a clinic setting. Frail women had a higher BMI, indicating that low body weight is not a marker for frailty, and had a significantly higher rate of 30-day postoperative complications in this pilot study. Initial findings support the concept of measuring frailty as a possible predictor for postoperative morbidity that will allow for improved patient counseling and decision making.

Cancer in Obese Women: Potential Protective Impact of Bariatric Surgery

BACKGROUND The use of bariatric surgery has been increasing over the last several years in response to the obesity epidemic, and the objective of this study was to report on the types of cancer in morbidly obese women undergoing bariatric surgery and compare these with types of cancer in obese women without surgery. STUDY DESIGN A retrospective, observational study was conducted. The bariatric surgery database identified women who underwent operations between 1990 and 2006 at the University of Virginia. Medical records and the institutions and states cancer registries were searched for demographics and cancer data. Morbidly obese patients not undergoing bariatric surgery were used for comparison. RESULTS There were 1,482 women who had bariatric surgery, and 53 of these (3.6%) were diagnosed with cancer. The most common cancer site was the breast (n = 15, 28.3%) followed by the endometrium (n = 9, 17%) and the cervix (n = 6, 11.3%). The mean age at cancer diagnosis was 39.4 years. Most cancers (n = 34, 64.1%) were diagnosed before the bariatric surgery. Bariatric surgery patients with cancer were older than noncancer patients at time of surgery (mean age 44.7 versus 41.6 years; p=0.019), but otherwise did not differ significantly with regard to race, body mass index, or comorbid conditions. Compared with a control group of 3,495 morbidly obese women who had not undergone bariatric surgery, the surgery patients had fewer cancers (3.6% versus 5.8%, p=0.002), were younger (41.7 versus 46.9 years, p < 0.001), and were younger at cancer diagnosis (45.0 versus 56.8 years, p < 0.001). The most frequent cancers in the control obese women were endometrial, ovarian, and breast cancer. Both groups of obese women with endometrial, breast, ovarian, and colorectal cancers were younger at diagnosis compared with Virginia Cancer Registry means. CONCLUSIONS Breast and endometrial cancers remain the most common types in obese women and may occur at young ages; bariatric surgery may decrease cancer development in obese women.