Mark T. Wakabayashi

Prognostic Significance of B-Cells and pSTAT3 in Patients with Ovarian Cancer

Background Several previous studies have identified a strong association between T-cell infiltration and clinical outcome in ovarian cancer. The role of B-cells remains controversial, however. Methods Forty-nine paraffin-embedded omental specimens derived from patients with high grade epithelial ovarian cancer were assessed. Immunohistochemical analyses were performed to characterize expression of CD19+ B-cells and pSTAT3 as high (>50% positively staining cells [PSCs]) or low (<50% PSCs). The Kaplan-Meier method with log-rank test was used to determine the association between clinicopathologic parameters and overall survival (OS). A multi-variate Cox proportional hazards regression analysis including nature of debulking (primary vs secondary), histology, tumor grade, receipt of prior chemotherapy, B-cell infiltration and pSTAT3 expression was performed. Results Median OS was 160.6 months in those patients with low B-cell expression vs 47.3 months in those with high B-cell expression (P = 0.0015). Similarly, median OS was improved in those patients with low pSTAT3 expression (160.6 vs 47.9 months, P = 0.02). In a multivariate model to predict survival, only the degree of B-cell infiltration and clinical stage were retained. pSTAT3 expression did not enter the final model, possibly be due to a high positive correlation with B-cell infiltration (r = 0.82, P<0.0001). Conclusions Increased B-cell infiltration and pSTAT3 expression in omental tissue are associated with poorer survival.

Current Status on Biologic Therapies in the Treatment of Epithelial Ovarian Cancer

Treatment of epithelial ovarian cancer generally involves surgical staging followed by chemotherapy with a combination of a platinum and a taxane-containing agent. However, a majority of patients recur and ultimately succumb to their cancer. Novel therapies that target specific pathways involved in ovarian tumorigenesis are rapidly emerging. In ovarian cancer, targeted therapies have focused on both the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways. Single-agent bevacizumab, a VEGF inhibitor, demonstrated significant clinical activity in multiple phase II studies. Various combinations of cytotoxic and biologic agents with bevacizumab as well as newer anti-angiogenesis agents are being tested. In contrast, EGFR inhibitors have not shared the same clinical activity in epithelial ovarian cancers as compared to the VEGF inhibitors. Translational studies are needed to help design rational combinations of targeted agents and to help predict response to therapy.

Indications and Efficacy of the Human Papillomavirus Vaccine

Opinion statementIn the United States, there are 11,150 cases and 3670 deaths projected due to invasive cervical cancer for 2007. Approximately 500,000 new cases and 274,000 deaths will occur in women throughout the world. Human papillomavirus (HPV) has been designated by the World Health Organization (WHO) as a “necessary cause” of cervical cancer. There are 6.2 million new cases of HPV diagnosed each year. In addition to cervical cancer, the virus has also been implicated in vaginal, vulvar, penile, anal, and head and neck cancers. Current methods for prevention of cervical cancer include Pap smears, HPV testing, ablative procedures, cervical conization, and hysterectomy. These are costly as well as invasive. The HPV vaccine is the most recent breakthrough for the prevention of cervical cancer. The quadrivalent HPV vaccine (GardasilTM) covers types 6, 11, 16, & 18. The bivalent vaccine (CervarixTM) covers types 16 & 18, and is expected to come out in the early part of 2007. Approximately 70% of cervical cancer is caused by HPV types 16 & 18. HPV types 6 &11 are responsible for 90% of anogenital warts. Females of ages 11–12 and those prior to their sexual debut should be vaccinated, with all females in the age range of 9–26 also eligible. This vaccination strategy can prevent the above HPV infections, cervical dysplasia, and possibly cervical cancer.

Role of Robotic Surgery in Endometrial Cancer

Opinion statementUterine cancer is the most common gynecologic cancer in women in the United States with an estimated number of 40,100 women diagnosed in 2008, the great majority of which belongs to endometrial classification. The traditional approach to treatment of endometrial cancer has been primarily surgery via an open, laparotomy incision. Minimally invasive approaches with smaller incisions, i.e., laparoscopy for the management of endometrial cancer was initially reported in 1992; however, its adoption has been slow due to the prolonged learning curve needed to become proficient in such a technique. Robotic-assisted surgery, a further advancement of traditional laparoscopy, using computer-based controls has been developed enabling the performance of complex procedures that otherwise had been too difficult to accomplish in a minimally invasive fashion. Robotic-assisted laparoscopic radical prostatectomy is one such example that has gained rapid acceptance in recent years. Although the use of robotic-assisted laparoscopy for endometrial cancer is still in its early phase, this approach is anticipated to become similarly, a common approach to the management of endometrial cancer in the future.

L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice.

New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR)-redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (TCM) were then genetically modified to express an anti-L1-CAM CAR (CE7R), which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R+ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p.) administration of CE7R+ TCM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R+ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer.

Reporting of quality measures in gynecologic oncology programs at Prospective Payment System (PPS)-Exempt Cancer Hospitals: An early glimpse into a challenging initiative

OBJECTIVE The Affordable Care Act mandates the Prospective Payment System (PPS)-Exempt Cancer Hospitals Quality Reporting program. These 11 hospitals (which are paid fee-for-service rather than on a DRG system) began reporting measures (2 general safety, 2 breast, 1 colon) in 2013. Given this reporting mandate, we set out to determine whether the PPS-exempt gynecologic oncology programs could identify quality measures specific to the care of our patients. METHODS A list of 12 quality measures specific to gynecologic oncology was created (from sources including the National Quality Forum and the SGO). Measures already in use were not included. The list was ranked by the gynecologic oncology program directors at the PPS-exempt hospitals. Descriptive statistics (including mean and SD for rankings) were utilized. RESULTS Despite mandatory reporting of quality measures for PPS-exempt cancer hospitals, little consensus exists regarding specific gynecologic cancer measures. Documentation of debulking status, cancer survival, and offering minimally invasive surgery (for endometrial cancer) and intraperitoneal chemotherapy (for ovarian cancer) are important, but with widely variable responses (when ranked 1-12, standard deviations are 2-3). General issues regarding adherence to guidelines for the use of GCSF, documentation of functional status, and tracking of patient satisfaction scores were ranked the lowest. Three of the directors reported that their compensation is partially linked to quality outcomes. CONCLUSIONS There is wide variability in ranking of quality measures, and may relate to provider or institutional factors. Despite the mandatory reporting in PPS-exempt cancer hospitals, work remains to define gynecologic cancer quality measures.

Survivorship, Version 2.2017: Clinical practice guidelines in oncology

Many cancer survivors experience menopausal symptoms, including female survivors taking aromatase inhibitors or with a history of oophorectomy or chemotherapy, and male survivors who received or are receiving androgen-ablative therapies. Sexual dysfunction is also common in cancer survivors. Sexual dysfunction and menopause-related symptoms can increase distress and have a significant negative impact on quality of life. This portion of the NCCN Guidelines for Survivorship provide recommendations for screening, evaluation, and treatment of sexual dysfunction and menopausal symptoms to help healthcare professionals who work with survivors of adult-onset cancer in the posttreatment period.

Toxicities, complications, and clinical encounters during intraperitoneal chemotherapy in 17 women with ovarian cancer

PURPOSE OF THE RESEARCH Intraperitoneal (IP) chemotherapy is a viable and superior treatment to standard intravenous (IV) chemotherapy in women with small volume residual ovarian cancer following optimal debulking. Despite this clinical advantage, widespread adoption of the treatment regimen has been hampered by concerns related to toxicities and complications. The purpose of this descriptive study was to describe nursing implications related to toxicities, complications and clinical encounters in 17 women with ovarian cancer who received IP chemotherapy. METHODS AND SAMPLE Women with ovarian cancer who received IP chemotherapy at one NCI-designated comprehensive cancer center were accrued. Data related to IP chemotherapy summary, clinical encounters and admissions were obtained through comprehensive chart audits. KEY RESULTS Common treatment-related toxicities included nausea and vomiting, fatigue, hypomagnesia, pain, neuropathy, anemia, and constipation. Reasons for dose-modifications were multi-factorial, and were primarily related to catheter complications and chemotherapy toxicities. The number of clinical encounters was high, and they were primarily related to admissions for inpatient IP chemotherapy and follow-up clinic visits. CONCLUSIONS Treatment-related toxicities and complications were common in women with ovarian cancer who received IP chemotherapy. Use of IP chemotherapy results in multiple clinical encounters, such as outpatient clinic visits and inpatient admissions. Nursing is a critical part of the interdisciplinary approach in caring for women treated with IP chemotherapy. Interdisciplinary teams with high levels of knowledge and skills related to IP chemotherapy administration are needed to manage treatment-related toxicities and complications, and support multiple clinical encounters during treatment.

Survivorship: Fatigue, version 1.2014 - Clinical practice guidelines in oncology

Many posttreatment cancer survivors experience chronic pain, often leading to psychological distress; decreased activity, motivation, and personal interactions; and an overall poor quality of life. This section of the NCCN Guidelines for Survivorship provides screening and management recommendations for pain in survivors. A multidisciplinary approach is recommended, with a combination of pharmacologic treatments, psychosocial and behavioral interventions, physical therapy and exercise, and interventional procedures.

Association of Fluid Administration With Morbidity in Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy

Importance Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal cancers can be associated with significant complications. Randomized trials have demonstrated increased morbidity with liberal fluid regimens in abdominal surgery. Objective To investigate the association of intraoperative fluid administration and morbidity in patients undergoing CRS/HIPEC. Design, Setting, and Participants A retrospective analysis of information from a prospectively collected institutional database was conducted at a National Cancer Institute–designated comprehensive cancer center. A total of 133 patients from April 15, 2009, to June 23, 2016, with primary or secondary peritoneal cancers were included. Exposures Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Main Outcomes and Measures Morbidity associated with intraoperative fluid management calculated by the comprehensive complication index, which uses a formula combining all perioperative complications and their severities into a continuous variable from 0 to 100 in each patient. Results Of the 133 patients identified, 38% and 37% had diagnoses of metastatic appendiceal and colorectal cancers, respectively. Mean age was 54 (interquartile range [IQR], 47-64) years, and mean peritoneal cancer index was 13 (IQR, 7-18). Mitomycin and platinum-based chemotherapeutic agents were used in 96 (72.2%) and 37 (27.8%) of the patients, respectively. Mean intraoperative fluid (IOF) rate was 15.7 (IQR, 11.3-18.7) mL/kg/h. Mean comprehensive complication index (CCI) was 26.0 (IQR, 8.7-36.2). On multivariate analysis, age (coefficient, 0.32; 95% CI, 0.01-0.64; P = .04), IOF rate (coefficient, 0.97; 95% CI, 0.19-1.75; P = .02), and estimated blood loss (coefficient, 0.02; 95% CI, 0.01-0.03; P = .002) were independent predictors of increased CCI. In particular, patients who received greater than the mean IOF rate experienced a 43% increase in the CCI compared with patients who received less than the mean IOF rate (31.5 vs 22.0; P = .02). Conclusions and Relevance Intraoperative fluid administration is associated with a significant increase in perioperative morbidity in patients undergoing CRS/HIPEC. Fluid administration protocols that include standardized restrictive fluid rates can potentially help to mitigate morbidity in patients undergoing CRS/HIPEC.