Multi-Institutional Study of Referral Patterns for Gynecologic Oncology Consultation.

PURPOSE: Evaluation by a gynecologic oncologist (GO) is associated with improved clinical outcomes for patients with gynecologic cancers, yet little is known about health care factors that influence patients' referrals to GO. METHODS: Medical records of 50 consecutive new patients seen in GO clinics at each of six referral centers across the United States were reviewed. Patient and disease characteristics were collected along with referral indication, evaluation and referral dates, diagnostic procedures, provider specialties, and zone improvement plan (ZIP) code of up to three referring providers per patient. The primary outcome was interval between first evaluation and referral. Univariate associations were evaluated with Chi-square and Wilcoxon rank-sum tests and multivariable associations with negative binomial regression models. Secondary outcome was prolonged time to GO referral, defined as greater than the 75th percentile. Logistic regression was used for multivariable modeling. RESULTS: Three hundred patient records were analyzed. The median time from first health care encounter to referral was 15 days (IQR, 5-43). The mean distance from residence to GO was 39.8 miles (standard deviation, 53.8). Seventy-one percent of GO referrals were initiated by obstetrician-gynecologists, 9% by family physicians, and 6% internists. Presentation-to-referral interval was 76% shorter for patients evaluated by an emergency medicine clinician (exp(Beta), 0.24; 95% CI, 0.11 to 0.53; P < .001). Public insurance was associated with 1.47 times longer time to referral compared with private insurance (exp(Beta), 1.47; 95% CI, 1.05 to 2.04; P = .001). Residents of nonmetropolitan ZIP codes were less likely to have prolonged time to referral (odds ratio [OR], 0.288; P = .017). Distance from residence to GO (per 10 miles) increased the likelihood of prolonged time to referral (OR, 1.10; P = .010). CONCLUSION: Interventions are needed to improve recognition and referral of patients for gynecologic oncology evaluation. Community outreach and engagement with obstetrician-gynecologists should be prioritized to improve times to referral.

Shifts in gut and vaginal microbiomes are associated with cancer recurrence time in women with ovarian cancer.

Many studies investigating the human microbiome-cancer interface have focused on the gut microbiome and gastrointestinal cancers. Outside of human papillomavirus driving cervical cancer, little is known about the relationship between the vaginal microbiome and other gynecological cancers, such as ovarian cancer. In this retrospective study, we investigated the relationship between ovarian cancer, platinum-free interval (PFI) length, and vaginal and gut microbiomes. We observed that Lactobacillus-dominated vaginal communities were less common in women with ovarian cancer, as compared to existing datasets of similarly aged women without cancer. Primary platinum-resistance (PPR) disease is strongly associated with survivability under one year, and we found over one-third of patients with PPR (PFI < 6 months, n = 17) to have a vaginal microbiome dominated by Escherichia (>20% relative abundance), while only one platinum super-sensitive (PFI > 24 months, n = 23) patient had an Escherichia-dominated microbiome. Additionally, L. iners was associated with little, or no, gross residual disease, while other Lactobacillus species were dominant in women with >1 cm gross residual disease. In the gut microbiome, we found patients with PPR disease to have lower phylogenetic diversity than platinum-sensitive patients. The trends we observe in women with ovarian cancer and PPR disease, such as the absence of Lactobacillus and presence of Escherichia in the vaginal microbiome as well as low gut microbiome phylogenetic diversity have all been linked to other diseases and/or pro-inflammatory states, including bacterial vaginosis and autoimmune disorders. Future prospective studies are necessary to explore the translational potential and underlying mechanisms driving these associations.

Factors influencing clinical trial enrollment among ovarian cancer patients.

OBJECTIVE: To characterize patients who did not enroll on a clinical trial and identify barriers that may limit enrollment among patients with advanced epithelial ovarian cancer (EOC) presenting for first-line chemotherapy. METHODS: We conducted a retrospective review of patients diagnosed with stage II-IV EOC from 10/2009-4/2013, a time period during which multiple trials were available to all EOC patients, including optimally debulked, suboptimally debulked, or undergoing neoadjuvant chemotherapy. Enrollment status, demographics, tumor characteristics, and treatment details were recorded. SAS version 9.3 was used for all analyses. RESULTS: 144 patients met study criteria; 67% were enrolled on a trial. Enrolled patients were significantly younger (median 61 vs 68years, p=0.002). Stage (p=0.30), race (p=0.75), and performance status (p=0.38) were similar between enrolled and non-enrolled patients. Distance did not impact enrollment, as nearly half of patients in both groups lived >50miles from the treatment center (39.0% vs 47.8%, p=0.36). Mode of chemotherapy administration significantly differed based on participation (all p<0.05). Despite similar residual disease status (p=1.00) and number of chemotherapy regimens received (p=0.59), patients treated on trial had a higher 3-year survival rate (70.7% vs 51.7%, p=0.031). The difference in median progression-free survival approached significance (20.2 vs 9.2months, p=0.091). CONCLUSION: In an institution where the culture is to offer clinical trials to all eligible patients, 33% of front-line EOC patients did not participate. Increasing age was associated with non-participation. Modifiable barriers must be overcome so that trial enrollment can better reflect true EOC demographics.

Contribution of age to clinical trial enrollment and tolerance with ovarian cancer.

INTRODUCTION: Increasing age has been correlated with shorter survival in ovarian cancer patients, a finding attributed to diminished tolerance of standard therapy. Elderly patients, however, are less likely to enroll on clinical trials; thus, limited data exists to evaluate their response to front line treatment. This study describes how elderly patients on trial fared, with respect to toxicity and response, compared to younger women. METHODS: A retrospective cohort study was performed of ovarian cancer patients enrolled in front line chemotherapy trials at our institution between 2000 and 2013. Patients were dichotomized by age: <70 and ≥70years. Clinical, pathologic, and treatment characteristics were recorded and analyzed using SAS version 9.3. RESULTS: 336 patients were enrolled. Of these, 79 (23.5%) were ≥70yrs. Demographics were similar between the two groups. Compared to patients <70, those ≥70 completed a comparable number of chemotherapy cycles (p=0.16) and had similar numbers of dose modifications (p=0.40) and delays (p=0.26). Both hematologic and non-hematologic toxicities occurred at similar rates as well. Age≥70 (HR 1.8, 95% CI 1.27-2.54, p=0.0009), stage III/IV (HR 3.44, 95% CI 1.08-10.95, p=0.036), and residual disease (HR 2.63, 95% CI 1.82-3.78, p<0.0001) were independently predictive of shorter overall survival. CONCLUSION: Our data continues to support reports of shorter survival for older women with ovarian cancer. With physician bias removed and similar chemotherapy tolerance noted, our study suggests that inherent tumor biology may be a significant contributor. Further research is needed to identify the mechanisms which contribute to the inequality that age imposes on outcomes.

Initiation of a formalized precision medicine program in gynecologic oncology.

OBJECTIVE: In an effort to better incorporate precision medicine into clinical practice, we initiated a pilot project to screen, discuss, and genetically characterize patients with metastatic or recurrent gynecologic malignancies for whom no curative standard of care exists. METHODS: In 7/2014, we initiated a multi-disciplinary Precision Medicine Board (PMB) whose purpose was to apply molecular profiling to select and prioritize early phase clinical trial enrollment for high-risk gynecologic malignancies. Additional objectives were to record outcomes and enable scientific discussions of mutations which may foster local translational research. FoundationOne was the preferred genomic platform; results were reviewed by a team comprised of disease site specialists, phase I trialists, and basic and translational scientists affiliated with the Gynecologic Cancer Program. A detailed database for each patient was created and is followed prospectively for treatment use and resultant outcomes. RESULTS: To date, we have presented 62 cases with interpretable FoundationOne testing on 60 tumor samples (31 ovarian, 18 uterine, 9 cervical, and 4 other female genital tract). Significant genomic alterations were commonly found in all tumor types (median: 3); TP53 (45%) and PIK3CA (27%) were the most frequently noted mutations; however, molecular profiling resulted in identification of few actionable mutations (6%). To date, we have matched 4 patients on therapies based on actionable mutations. CONCLUSIONS: The predominant function of our PMB is establishment of a forum to enhance research while providing clinical care for refractory malignancies. We have matched patients with specific mutations to ongoing trials and are developing investigator-initiated studies based on trends within genomic profiling results. Longer-term follow up will be required to determine the success of this strategy.

Cost-utility comparison of neoadjuvant chemotherapy versus primary debulking surgery for treatment of advanced-stage ovarian cancer in patients 65 years old or older.

OBJECTIVE: Treatment for advanced-stage epithelial ovarian cancer (AEOC) includes primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT). A randomized controlled trial comparing these treatments resulted in comparable overall survival (OS). Studies report more complications and lower chemotherapy completion rates in patients 65 years old or older receiving PDS. We sought to evaluate the cost implications of NACT relative to PDS in AEOC patients 65 years old or older. STUDY DESIGN: A 5 year Markov model was created. Arm 1 modeled PDS followed by 6 cycles of carboplatin and paclitaxel (CT). Arm 2 modeled 3 cycles of CT, followed by interval debulking surgery and then 3 additional cycles of CT. Parameters included OS, surgical complications, probability of treatment initiation, treatment cost, and quality of life (QOL). OS was assumed to be equal based on the findings of the international randomized control trial. Differences in surgical complexity were accounted for in base surgical cost plus add-on procedure costs weighted by occurrence rates. Hospital cost was a weighted average of diagnosis-related group costs weighted by composite estimates of complication rates. Sensitivity analyses were performed. RESULTS: Assuming equal survival, NACT produces a cost savings of $5616. If PDS improved median OS by 1.5 months or longer, PDS would be cost effective (CE) at a $100,000/quality-adjusted life-year threshold. If PDS improved OS by 3.2 months or longer, it would be CE at a $50,000 threshold. The model was robust to variation in costs and complication rates. Moderate decreases in the QOL with NACT would result in PDS being CE. CONCLUSION: A model based on the RCT comparing NACT and PDS showed NACT is a cost-saving treatment compared with PDS for AEOC in patients 65 years old or older. Small increases in OS with PDS or moderate declines in QOL with NACT would result in PDS being CE at the $100,000/quality-adjusted life-year threshold. Our results support further evaluation of the effects of PDS on OS, QOL and complications in AEOC patients 65 years old or older.

Human risk of infection with Borrelia burgdorferi, the Lyme disease agent, in eastern United States.

The geographic pattern of human risk for infection with Borrelia burgdorferi sensu stricto, the tick-borne pathogen that causes Lyme disease, was mapped for the eastern United States. The map is based on standardized field sampling in 304 sites of the density of Ixodes scapularis host-seeking nymphs infected with B. burgdorferi, which is closely associated with human infection risk. Risk factors for the presence and density of infected nymphs were used to model a continuous 8 km×8 km resolution predictive surface of human risk, including confidence intervals for each pixel. Discontinuous Lyme disease risk foci were identified in the Northeast and upper Midwest, with a transitional zone including sites with uninfected I. scapularis populations. Given frequent under- and over-diagnoses of Lyme disease, this map could act as a tool to guide surveillance, control, and prevention efforts and act as a baseline for studies tracking the spread of infection.

Association of third-year medical students' first clerkship with overall clerkship performance and examination scores.

CONTEXT: Anecdotal experience has suggested that third-year medical students whose first clerkship is internal medicine may have superior performance throughout the academic year. OBJECTIVE: To determine whether the order of clerkships by specialty is associated with student performance. DESIGN, SETTING, AND PARTICIPANTS: Clerkship performance records of medical students at all 4 campuses of the University of Illinois College of Medicine who completed their third-year core clerkships from July 2000 through June 2008 (N = 2236) were reviewed. MAIN OUTCOME MEASURES: Analysis of covariance was used to test for between-group differences (by first clerkship) in mean National Board of Medical Examiners subject examination scores (range, 0-100), preceptor ratings of clerkship clinical performances (range, 12-30), total overall clerkship grades (range, 12-30), and United States Medical Licensing Examination (USMLE) Step 2 scores, adjusted for sex, campus, and USMLE Step 1 score. RESULTS: First clerkship specialty was significantly associated with mean subject examination scores (family medicine, 71.96 [95% confidence interval {CI}, 70.90-72.98], internal medicine, 73.86 [95% CI, 73.33-74.39], obstetrics/gynecology, 72.36 [95% CI, 71.64-73.04], pediatrics, 73.11 [95% CI, 72.38-73.84], psychiatry, 72.17 [95% CI, 71.52-72.81], surgery, 72.37 [95% CI, 71.73-73.02]; P < .001) and overall clerkship grades (family medicine, 24.20 [95% CI, 23.90-24.90], internal medicine, 25.33 [95% CI, 25.07-25.60], obstetrics/gynecology, 24.68 [95% CI, 24.32-25.05], pediatrics, 24.92 [95% CI, 24.59-25.27], psychiatry, 24.61 [95% CI, 24.33-25.01], surgery 24.97 [95% CI, 24.64-25.30]; P = .01). There was no significant association with preceptor ratings or USMLE Step 2 scores. Pairwise comparisons for mean total overall clerkship grades showed a significant difference for students taking internal medicine first compared with obstetrics/gynecology (mean difference, 0.65; 95% CI, 0.18-1.12), psychiatry (mean difference, 0.66; 95% CI, 0.20-1.12), and family medicine (mean difference, 0.93; 95% CI, 0.37-1.50). CONCLUSION: Among students at 4 campuses of a US medical school, clerkship order was significantly associated with performance on clerkship subject examinations and overall grades but not with clerkship clinical performance or USMLE Step 2 scores.

Induced abortions and the risk of all cancers combined and site-specific cancers in Shanghai.

Although some previous case-control studies found an increased risk of breast cancer in women who had an induced abortion, the evidence from prospective studies suggests that induced abortions do not cause breast cancer. We have assessed risks of 12 types of cancer in women who have had induced abortions in a prospective study in China. Female textile workers (n = 267,400) completed a baseline questionnaire (1989-1991) that ascertained information on the major risk factors for breast cancer, contraceptive use, and induced abortions and were actively followed until July 2000. Cox Proportional Hazards analysis was used to calculate incidence rate ratios for specific types of cancer in women who ever had an induced abortion and by number of induced abortions. Women who had had an abortion were not at increased risk of cancer. There was a significant reduction in risk of uterine corpus cancer in women who had ever had an induced abortion, and a significant decreasing trend in risk with increasing number of induced abortions. No convincing associations with other cancers were observed. Women who have induced abortions after a live birth are not at increased risk of cancer and induced abortions may reduce risk of cancer of the corpus uteri.