Reasons for Long-term Opioid Prescriptions After Guideline-directed Opioid Prescribing and Excess Opioid Pill Disposal.

OBJECTIVES: The aim of this study was to determine the frequency and reasons for long-term opioid prescriptions (rxs) after surgery in the setting of guideline-directed prescribing and a high rate of excess opioid disposal. BACKGROUND: Although previous studies have demonstrated that 5% to 10% of opioid-naïve patients prescribed opioids after surgery will receive long-term (3-12 months after surgery) opioid rxs, little is known about the reasons why long-term opioids are prescribed. METHODS: We studied 221 opioid-naïve surgical patients enrolled in a previously reported prospective clinical trial which used a patient-centric guideline for discharge opioid prescribing and achieved a high rate of excess opioid disposal. Patients were treated on a wide variety of services; 88% of individuals underwent cancer-related surgery. Long-term opioid rxs were identified using a Prescription Drug Monitoring Program search and reasons for rxs and opioid adverse events were ascertained by medical record review. We used a consensus definition for persistent opioid use: opioid rx 3 to 12 months after surgery and >60day supply. RESULTS: 15.3% (34/221) filled an opioid rx 3 to 12 months after surgery, with 5.4% and 12.2% filling an rx 3 to 6 and 6 to 12 months after surgery, respectively. The median opioid rx days supply per patient was 7, interquartile range 5 to 27, range 1 to 447 days. The reasons for long-term opioid rxs were: 51% new painful medical condition, 40% new surgery, 6% related to the index operation; only 1 patient on 1 occasion was given an opioid rx for a nonspecific reason. Five patients (2.3%) developed persistent opioid use, 2 due to pain from recurrent cancer, 2 for new medical conditions, and 1 for a chronic abscess. CONCLUSIONS: In a group of prospectively studied opioid-naïve surgical patients discharged with guideline-directed opioid rxs and who achieved high rates of excess opioid disposal, no patients became persistent opioid users solely as a result of the opioid rx given after their index surgery. Long-term opioid use did occur for other, well-defined, medical or surgical reasons.

Management and prognosis of cervical cancer patients treated with definitive radiation therapy who have partial metabolic response on post-therapy positron emission tomography.

OBJECTIVE: To describe the management and outcomes of cervical cancer patients initially treated with radiation who had partial metabolic response (PMR) on three-month post-radiation 18F-fluorodeoxyglucose positron emissions tomography (FDG-PET). METHODS: Cervical cancer patients treated with radiation between 1997 and 2013 who had PMR on initial post-therapy FDG-PET were identified from a prospectively maintained database. Descriptive statistics were used to summarize patient demographics, tumor characteristics, surveillance methods, and treatment modalities. Kaplan-Meier methods were used to estimate progression-free (PFS) and overall survival (OS) for patients who underwent cervical biopsy prior to additional therapies and for patients who were managed with chemotherapy, radiation, surgery or no intervention. RESULTS: PMR was identified in 81/542 (15%) women on initial post-radiation PET. Thirty women underwent cervical biopsy, of whom 14 (47%) had persistent cancer. Nine underwent treatment, (three surgery, five chemotherapy alone and one chemotherapy and radiation) but all died of disease; PFS and OS were similar whether women had surgery, chemoradiation therapy, or no treatment. A second surveillance FDG-PET had PPV and NPV of 91% and 75% for progression, respectively, and identified the 19% percent of patients with persistent disease outside of the cervix. Cervical biopsy had a higher PPV (100%) and lower NPV (62.5%) for progression. At the end of the study period, 46 (57%) patients were dead of disease, including all 8 patients (100%) with para-aortic or supraclavicular involvement. CONCLUSIONS: If PMR is identified on three-month FDG-PET following completion of radiation for cervical cancer, repeat FDG-PET and/or biopsy are indicated to detect persistence and assist in counseling. PMR predicts poor outcomes, particularly for those with positive cervical biopsies and lymphatic involvement.

Interest in and uptake of genetic counseling for preconception carrier screening when offered to predominantly white reproductive-age persons seeking gynecologic care at a single U.S. academic medical center.

The objective of this study was to assess the level of interest in preconception carrier screening among reproductive-aged persons presenting for gynecologic care and to identify demographic factors predictive of pursuing screening. Patients aged 18-40 who were presenting for gynecologic care at a single U.S. academic medical center were provided with information about current options for preconception carrier screening and were offered genetic counseling referral with the possibility to undergo screening. Outcomes of interest were desire for genetic counseling referral and attendance at genetic counseling visit. Statistical analyses were performed as appropriate using R version 3.6.1 with variables significant at 0.1 included in a multivariable logistic regression. Of 193 participants, 79 (41%) desired genetic counseling referral. Participants aged 25-34 (OR 3.39, 95% CI 1.47-8.10) and nulliparas (OR 2.69, 95% CI 1.23-6.03) were more likely to desire referral. Thirty-five participants (44.3% of those who desired referral) attended a visit with genetic counseling. Having an advanced degree (OR 3.27, 95% CI 1.06-10.4) was associated with visit attendance. Thirteen participants underwent screening, and five were found to be a carrier of at least one X-linked or autosomal recessive condition. Surprisingly, presenting for a gynecologic visit directly related to planning a pregnancy was not associated with increased interest in preconception carrier screening. Nulliparas and those aged 25-34 likely expressed greater interest in referral due to high potential for future childbearing in these groups. The increased level of visit attendance in participants with advanced degrees is likely confounded by the high level of health literacy and financial resources in this group.

Cisplatin increases immune activity of monocytes and cytotoxic T-cells in a murine model of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is an immunologically active malignancy, but thus far immune therapy has had limited success in clinical trials. One barrier to implementation of efficacious immune therapies is a lack of knowledge of the effect of chemotherapy on the monocyte-derived component of the immune infiltrate within the tumor. We utilized the ID8 murine EOC model to investigate alterations within tumor ascites that occur following administration of platinum chemotherapy. Cisplatin treatment resulted in a significant increase in monocytes within the ascites of tumor bearing mice. We identified that CD11b+ cells from the ascites of mice that have been treated with cisplatin elicits an increase in IFN-É£ expression from CD8+ T-cells compared to CD11b+ cells from a mouse treated with vehicle control (604.0 pg/mL v. 4328.0 pg/mL; p < .0001). Splenocytes derived from tumor bearing mice released increase levels of IFN-É£ after treatment with cisplatin when incubated with dendritic cells (DCs) and tumor antigen (62.0 v. 92.1 pg/mL; p = .03). Cisplatin induced an increase in T-cell and monocyte/macrophage activation markers (CD62L and CD301). Levels of IL-10, IL-6, and VEGF in the cell free ascites of mice treated with cisplatin decreased (p > .05). These results indicate that treatment with cisplatin leads to an increase of anti-tumor activity within the ascites related to alterations in the ascites monocytes. Further investigation of these findings in humans is necessary to identify how these cells behave in different patient subgroups and if there is a role for monocyte directed therapy in conjunction with T-cell directed therapy and/or chemotherapy.

A Syngeneic Mouse Model of Epithelial Ovarian Cancer Port Site Metastases.

Epithelial ovarian cancer (EOC) is a deadly gynecologic malignancy, but animal models for the study of EOC pathophysiology and drug efficacy are limited. Based on the finding that women with EOC are at risk for metastasis at a trocar site after laparoscopy, we developed a syngeneic murine model of port-site metastasis of EOC. We leveraged the ID8 murine EOC cell line to induce intra-peritoneal tumors in mice. Once durable intraperitoneal tumor was confirmed with bioluminescence imaging, intra-abdominal wall tumors were induced by abdominal wall puncture with a hollow bore needle. This resulted in a robust system in which C57BL/6 mice developed metastatic deposits at a rate of 66.7% ±â€¯10.77; no intra-abdominal wall metastases were seen in control samples (P = .0003, CI 41.16-90.84). Immunodeficient NOD SCID gamma mice developed puncture site metastases in 70% ±â€¯10.0 of mice and also had no metastases documented in control sites (P = .002, CI 42.24-97.76). In addition we were able to demonstrate the presence of immune infiltrates within the metastatic deposits of C57BL/6 mice via IHC. Therefore, in this study we demonstrate the predictable development of invasive abdominal wall metastases in a syngeneic mouse model of EOC. This model enables studies of the metastatic process and provides a novel system in which to test the effect of therapies on a clinically-relevant model in an immune competent mouse.

Prospective Evaluation of Multinational Association of Supportive Care in Cancer Risk Index Score for Gynecologic Oncology Patients With Febrile Neutropenia.

BACKGROUND: The Multinational Association of Supportive Care of Cancer (MASCC) risk-index score has been validated as a stratification tool for febrile neutropenia (FN) risk in a heterogeneous group of cancer patients; recently, it has been deemed a suitable tool in gynecologic oncology patients in a retrospective study. This is a prospective multi-institutional study wherein we sought to validate MASCC score for stratifying FN morbidity in gynecologic oncology patients. METHODS: IRB approval was obtained at 4 institutions for prospective data collection of gynecologic cancer patients admitted with FN from 3/1/2013 to 9/1/2014. Participating institutions have a policy of inpatient management of FN patients receiving chemotherapy. Deidentified data was compiled and processed at the leading institution. RESULTS: In total, 31 patients met inclusion criteria. Most had advanced stage disease (67%). 100% of patients were receiving chemotherapy (57% for primary, 43% for recurrent disease). 55% had a positive culture. Median MASCC score was 21 (range, 10 to 26); 58% of patients were considered low risk. High risk patients more often had one (11% vs. 38%, P=0.09) or multiple (6% vs. 23%, P=0.28) severe complications, ICU admission (0% vs. 15%, P=0.17), and delay in next chemotherapy cycle (33% vs. 54%, P=0.25). No patients died from FN during the study period. CONCLUSIONS: This pilot data suggests that MASCC score may be a promising tool for determining suitability of outpatient management of FN in gynecologic oncology patients. Larger studies are warranted to achieve statistically significant results, which may enable us to effectively utilize this risk stratification tool for cost containment and avoidance of nosocomial infections.

The effect of a multidisciplinary palliative care initiative on end of life care in gynecologic oncology patients.

OBJECTIVES: To evaluate the effect of palliative care (PC) consultation on hospice enrollment and end-of-life care in gynecologic oncology patients. METHODS: A retrospective chart review of gynecologic oncology patients who died 1year before and after 2014 implementation of a PC initiative for patients at a single NCI-designated comprehensive cancer center. Patient demographics, admission and procedural history, anti-cancer therapy, and end-of- life care were collected retrospectively. Data was analyzed using Student's t-test, Mann-Whitney U test, Chi-Square test, or Fisher's exact test. RESULTS: We identified 308 patients. Median age at death was 63years (range 17 to 91). Most patients were white (78.2%), married (47.4%), and had ovarian (35.7%) or uterine cancers (35.4%). Introduction of the PC initiative was associated with increased PC consultations (40%, 53%, p=0.02), increased hospice enrollment (57%, 61%, p=0.29), and fewer procedures in the last 30days of life (44%, 31%, p=0.01). The rate of enrollment to inpatient hospice doubled from 12.5% to 25.7% (p=0.02) while time from inpatient hospice enrollment to death increased from 1.9 to 6.0days (p=0.02). Time from outpatient hospice enrollment to death increased from 26.2 to 35.4days (p=0.18). PC consultation was associated with a doubling of outpatient (40%) and inpatient (80%) hospice enrollment. CONCLUSIONS: The PC quality improvement initiative was associated with more palliative care consults, increased rates of inpatient and outpatient hospice utilization, increased time on hospice, and fewer procedures in the last 30days of life, although most women were not enrolled until the last days of life.

Intimate Partner Violence and Barriers to Cervical Cancer Screening: A Gynecologic Oncology Fellow Research Network Study.

OBJECTIVES: The aims of the study were to examine barriers to cervical cancer screening among women who have experienced intimate partner violence (IPV) and accessed domestic violence shelters, to compare barriers among those up-to-date (UTD) and not UTD on screening, and to evaluate acceptability of human papillomavirus self-sampling. MATERIALS AND METHODS: This is a cross-sectional survey in which domestic violence shelters in Ohio were identified and women completed an anonymous survey assessing UTD screening status, barriers related to screening, history of IPV, intention to follow up on abnormal screening, and acceptability of self-sampling. Characteristics of UTD and not UTD women were compared using Mann-Whitney U tests. RESULTS: A total of 142 women from 11 shelters completed the survey. Twenty-three percent of women were not UTD. Women who were not UTD reported more access-related barriers (mean = 2.2 vs 1.8; p = .006). There was no difference in reported IPV-related barriers between women who were not UTD and those who are UTD (mean = 2.51 in not UTD vs 2.24 in UTD; p = .13). Regarding future screening, of the women who expressed a preference, more women not UTD preferred self-sampling than UTD women (32% vs 14%; p = .05). CONCLUSIONS: In this study, access-related barriers were more commonly reported among women not UTD with screening. Addressing these barriers at domestic violence shelters may improve screening among not UTD women. Self-sampling may also be one feasible approach to support screening in this population.

Incorporation of porcine adenovirus 4 fiber protein enhances infectivity of adenovirus vector on dendritic cells: implications for immune-mediated cancer therapy.

One strategy in cancer immunotherapy is to capitalize on the key immunoregulatory and antigen presenting capabilities of dendritic cells (DCs). This approach is dependent on efficient delivery of tumor specific antigens to DCs, which subsequently induce an anti-tumor T-cell mediated immune response. Human adenovirus serotype 5 (HAdV5) has been used in human studies for gene delivery, but has limited infection in DCs, which lack the proper receptors. Addition of the porcine fiber knob (PK) from porcine adenovirus type 4 to HAdV5 allows the virus to deliver genetic material via binding to glycosylated surface proteins and bypasses the coxsackie-and-adenovirus receptor required by wild-type HAdV5. In this study we explored the potential therapeutic applications of an adenovirus with PK-based tropism against cancers expressing mesothelin. Infectivity and gene transfer assays were used to compare Ad5-PK to wild-type HAdV5. Mouse models were used to demonstrate peptide specificity and T-cell responses. We show that the PK modification highly augmented infection of DCs, including the CD141+ DC subset, a key subset for activation of naïve CD8+ T-cells. We also show that Ad5-PK increases DC infectivity and tumor specific antigen expression. Finally, vaccination of mice with the Ad5-PK vector resulted in enhanced T-cell-mediated interferon gamma (IFN-γ) release in response to both mesothelin peptide and a tumor line expressing mesothelin. Ad5-PK is a promising tool for cancer immunotherapy as it improves infectivity, gene transfer, protein expression, and subsequent T-cell activation in DCs compared to wild-type HAdV5 viruses.

Neoadjuvant chemotherapy versus primary cytoreductive surgery for stage IV uterine serous carcinoma.

OBJECTIVE: This study compares surgical and survival outcomes of women with stage IV uterine serous carcinoma (USC) treated with neoadjuvant chemotherapy (NAC) and interval cytoreduction to women treated with primary cytoreductive surgery (PCS) followed by adjuvant chemotherapy. METHODS: This retrospective dual cohort study included women diagnosed with stage IV USC at a single academic institution. Kruskal-Wallis and Fisher exact tests were used to compare demographics and surgical outcomes. Progression-free survival (PFS) and overall survival (OS) were estimated by using Kaplan-Meier methods. Comparison between study groups was tested by log-rank statistics. RESULTS: Ten women with stage IV USC who received NAC and 34 who underwent PCS met inclusion criteria. Neoadjuvant chemotherapy patients had a lower mean body mass index and were more often African American. Compared with PCS, the NAC cohort had shorter mean operative times (137 ± 66 vs 203 ± 80 minutes, P = 0.025) and were discharged from the hospital earlier (median length of stay, 3 vs 5 days; P = 0.002). Rates of debulking to no gross residual disease (70% NAC vs 32.3% PCS) or less than 1 cm of disease (30% NAC vs 50% PCS) did not differ (P = 0.10). Median follow-up time was 17.5 months. There was no difference in median PFS (10.4 vs 12 months, P = 0.29) or OS (17.3 vs 20.7 months, P = 0.23) for NAC and PCS cohorts. CONCLUSIONS: Women receiving NAC for stage IV USC had shorter surgeries and hospital stays than did those receiving PCS. There was no difference in PFS or OS, although our sample size was small. Neoadjuvant chemotherapy may be an appropriate therapy for select patients with advanced-stage USC.

Intestinal perforation in gynecologic oncology: do all patients benefit from surgical management?

OBJECTIVE: To identify those patients with gynecologic cancers and intestinal perforation in whom conservative management may be appropriate. METHODS: A retrospective review was performed of all gynecologic oncology patients with intestinal perforation at our institution between 1995 and 2011. The Kaplan-Meier method and Cox proportional hazards models were used to analyze factors influencing survival. RESULTS: Forty-three patients met the study criteria. The mean age was 59 years (range: 38-82 years). A large number of patients had peritoneal carcinomatosis and history of bowel obstruction. Surgery was performed in 28 patients, and 15 were managed conservatively. Overall mortality at 1, 3, 6, and 12 months was 26%, 40%, 47%, and 59%, respectively. Only cancer burden at the time of perforation was independently predictive of mortality. Patients with peritoneal carcinomatosis, distant metastasis, or both were at 42 times higher risk of death than those with no evidence of disease (95% CI: 3.28-639.83), and at 7 times higher risk of death than those with microscopic/localized disease (95% CI: 1.77-29.94). When adjusted for the extent of disease spread, management approach (conservative vs. surgical) was not a significant predictor of survival (p≥0.05). The length of hospital stay (19 days vs. 7 days) and the complication rate (75% vs. 26.7%) were significantly higher in the surgical group than in the non-surgical group (p<0.05). CONCLUSIONS: Patients who develop intestinal perforation in the setting of widely metastatic disease have a particularly poor prognosis. Aggressive surgical management is unlikely to benefit such patients and further impairs their quality of life.

A review of iniparib in ovarian cancer.

INTRODUCTION: Patients with metastatic ovarian cancer continue to experience high recurrence rates and significant morbidity from standard treatments. There is a great need for efficacious tumor-specific agents in ovarian cancer. Iniparib (BSI-201) is a targeted drug currently under investigation. AREAS COVERED: The authors identified the mechanistic and clinical data available on the role of iniparib in ovarian cancer. Iniparib was initially thought to act via the poly-ADP ribose polymerase 1 (PARP-1) pathway, but recent studies have shown only nonspecific interactions between the drug and PARP proteins. Although iniparib is only active in cancer cells, the exact mechanism of action remains unclear. Iniparib was well tolerated at all dose levels in Phase I studies of solid organ malignancies. Preliminary data from Phase II studies of iniparib for the treatment of platinum-sensitive and platinum-resistant recurrent ovarian cancer show improvement in survival compared to historic controls. There are currently no Phase III studies. EXPERT OPINION: Iniparib shows promise in early clinical trials; however, understanding the pathways of cytotoxicity will be crucial as cancer therapy becomes increasingly individualized.

Discussion: 'Comparison of cervical cancer screening strategies,' by Cox et al.

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research.

Vaginal intraepithelial neoplasia (VAIN) after radiation therapy for gynecologic malignancies: a clinically recalcitrant entity.

OBJECTIVES: Vaginal dysplasia is associated with prior radiation therapy (RT) for gynecologic malignancies. We reviewed our institution's experience with VAIN in patients who were treated with radiation therapy for a gynecologic malignancy. METHODS: A retrospective review of patients treated for VAIN was performed. All cases of patients followed and treated for VAIN after radiation therapy were identified (n=10), along with a cohort of patients with VAIN who did not have radiation therapy (n=23). RESULTS: Mean follow-up after initial diagnosis of VAIN was 37.6 months (range: 12 to 72). Cytologic screening events after diagnosis of VAIN (n=105) showed that patients with prior RT were more than twice as likely to have recurrent dysplasia (OR 3.625, 95% CI=from 1.454 to 9.0376) after treatment. Of patients who recurred, the mean time to first recurrence was 12.3 months in cases and 15.3 months in controls, which was not statistically significant (p=0.31). Screening practices at our institution ranged from 3 month to 12 month intervals. 3 patients in the RT group and 1 patient in the control group developed invasive squamous cell cancer of the vagina. CONCLUSIONS: Vaginal dysplasia after radiation therapy is more refractory to treatment than dysplasia not associated with radiation therapy, more likely to recur after surgical and ablative therapy, and may also be more likely to progress to invasive cancer. These data support the need for further study to determine the optimal follow-up screening interval and whether aggressive surgical or ablative treatment stems disease progression in this clinical scenario.