David Bender

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.

Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients

Noradrenergic pathways have been implicated in growth and progression of ovarian cancer. Intratumoral norepinephrine (NE) has been shown to increase with stress in an animal cancer model, but little is known regarding how tumor NE varies with disease stage and with biobehavioral factors in ovarian cancer patients. This study examined relationships between pre-surgical measures of social support, depressed mood, perceived stress, anxiety, tumor histology and tumor catecholamine (NE and epinephrine [E]) levels among 68 ovarian cancer patients. We also examined whether associations observed between biobehavioral measures and tumor catecholamines extended to other compartments. Higher NE levels were found in advanced stage (p=0.006) and higher grade (p=0.001) tumors. Adjusting for stage, grade, and peri-surgical beta blockers, patients with a perceived lack of social support had significantly higher tumor NE (β=-0.29, p=0.012). A similar trend was seen for social support and ascites NE (adjusting for stage, peri-surgical beta blockers and caffeine: β=-0.50, p=0.075), but not for plasma NE. Other biobehavioral factors were not related to tumor, ascites, or plasma NE (p values >0.21). Tumor E was undetectable in the majority of tumors and thus E was not further analyzed. In summary, these results suggest that tumor NE provides distinct information from circulating plasma concentrations. Tumor NE levels were elevated in relationship to tumor grade and stage. Low subjective social support was associated with elevated intratumoral NE. As beta-adrenergic signaling is related to key biological pathways involved in tumor growth, these findings may have implications for patient outcomes in ovarian cancer.

Social Influences on Clinical Outcomes of Patients With Ovarian Cancer

PURPOSE Previous research has demonstrated relationships of social support with disease-related biomarkers in patients with ovarian cancer. However, the clinical relevance of these findings to patient outcomes has not been established. This prospective study examined how social support relates to long-term survival among consecutive patients with ovarian cancer. We focused on two types of social support: social attachment, a type of emotional social support reflecting connections with others, and instrumental social support reflecting the availability of tangible assistance. PATIENTS AND METHODS Patients were prospectively recruited during a presurgical clinic visit and completed surveys before surgery. One hundred sixty-eight patients with histologically confirmed epithelial ovarian cancer were observed from the date of surgery until death or December 2010. Clinical information was obtained from medical records. RESULTS In a Cox regression model, adjusting for disease stage, grade, histology, residual disease, and age, greater social attachment was associated with a lower likelihood of death (hazard ratio [HR], 0.87; 95% CI, 0.77 to 0.98; P = .018). The median survival time for patients with low social attachment categorized on a median split of 15 was 3.35 years (95% CI, 2.56 to 4.15 years). In contrast, by study completion, 59% of patients with high social attachment were still alive after 4.70 years. No significant association was found between instrumental social support and survival, even after adjustment for covariates. CONCLUSION Social attachment is associated with a survival advantage for patients with ovarian cancer. Clinical implications include the importance of screening for deficits in the social environment and consideration of support activities during adjuvant treatment.

Diurnal cortisol dysregulation, functional disability, and depression in women with ovarian cancer.

Multiple alterations in circadian rhythms have been observed in cancer patients, including the diurnal rhythm of the adrenal hormone cortisol. Diurnal cortisol alterations have been associated with cancer‐related physiological processes as well as psychological stress. Here we investigate alterations in diurnal cortisol rhythm in ovarian cancer patients, and potential links with depression, life stress, and functional disability.

Preoperative Serum Tissue Factor Levels Are an Independent Prognostic Factor in Patients With Ovarian Carcinoma

PURPOSE Tissue factor (TF) is a procoagulant that plays an important part in tumor angiogenesis. We sought to determine the role of preoperative serum TF levels in predicting clinical outcome in patients with ovarian cancer. MATERIALS AND METHODS TF expression was determined by reverse transcriptase polymerase chain reaction in ovarian cell lines. Using enzyme-linked immunosorbent assay, we assessed preoperative serum TF levels in 98 women with invasive epithelial ovarian carcinoma, 30 with low malignant potential (LMP) tumors, 16 with benign tumors, and a separate validation group of 39 women with adnexal masses. Clinical information was gathered from chart review. RESULTS TF was expressed in four of the five ovarian cancer cell lines, but absent in the nontransformed cells. Ovarian cancer patients had a median preoperative serum TF level of 85.2 pg/mL, which was significantly higher than in those with LMP tumors (12.8 pg/mL; P < .01) and benign adnexal disease (30.7 pg/mL; P < .01). TF >or= 190 pg/mL was significantly associated with decreased patient survival (P < .01). After adjusting for other clinical variables in a multivariate Cox regression model, TF >or= 190 pg/mL was an independent prognostic factor (P < .01). Analysis of serum TF levels from the validation set confirmed that high TF (>or=190 pg/mL) was associated with a 3.4-fold increase in risk of death from disease (P = .02) and shorter survival (P = .01). CONCLUSION Preoperative serum TF levels are significantly elevated in patients with ovarian carcinoma. Elevated preoperative TF level is an independent prognostic factor for death from disease.

Cortisol and inflammatory processes in ovarian cancer patients following primary treatment: Relationships with depression, fatigue, and disability

Elevations in the pro-inflammatory cytokine interleukin-6 (IL-6) and alterations in the anti-inflammatory hormone cortisol have been reported in a variety of cancers. IL-6 has prognostic significance in ovarian cancer and cortisol has been associated with fatigue, disability, and vegetative depression in ovarian cancer patients prior to surgery. Ovarian cancer patients undergoing primary treatment completed psychological self-report measures and collected salivary cortisol and plasma IL-6 prior to surgery, at 6 months, and at 1 year. Patients included in this study had completed chemotherapy and had no evidence of disease recurrence. At 6 months, patients showed significant reductions in nocturnal cortisol secretion, plasma IL-6, and a more normalized diurnal cortisol rhythm, changes that were maintained at 1 year. The reductions in IL-6 and nocturnal cortisol were associated with declines in self-reported fatigue, vegetative depression, and disability. These findings suggest that primary treatment for ovarian cancer reduces the inflammatory response. Moreover, patients who have not developed recurrent disease by 1 year appear to maintain more normalized levels of cortisol and IL-6. Improvement in fatigue and vegetative depression is associated with the normalization of IL-6 and cortisol, a pattern which may be relevant for improvements in overall quality of life for ovarian cancer patients.

Preservation of immune function in cervical cancer patients during chemoradiation using a novel integrative approach

Patients receiving chemoradiation for cervical cancer are at risk for distress, chemoradiation-related side-effects, and immunosuppression. This prospective randomized clinical trial examined effects of a complementary therapy, Healing Touch (HT), versus relaxation training (RT) and usual care (UC) for (1) supporting cellular immunity, (2) improving mood and quality of life (QOL), and (3) reducing treatment-associated toxicities and treatment delay in cervical cancer patients receiving chemoradiation. Sixty women with stages IB1 to IVA cervical cancer were randomly assigned to receive UC or 4 ×/weekly individual sessions of either HT or RT immediately following radiation during their 6-week chemoradiation treatment. Patients completed psychosocial assessments and blood sampling before chemoradiation at baseline, weeks 4 and 6. Multilevel regression analyses using orthogonal contrasts tested for differences between treatment conditions over time. HT patients had a minimal decrease in natural killer cell cytotoxicity (NKCC) over the course of treatment whereas NKCC of RT and UC patients declined sharply during chemoradiation (group by time interaction: p = 0.018). HT patients showed greater decreases in two different indicators of depressed mood (CES-D depressed mood subscale and POMS depression scale) compared to RT and UC (group by time interactions: p<0.05). No between group differences were observed in QOL, treatment delay, or clinically-rated toxicities. HT may benefit cervical cancer patients by moderating effects of chemoradiation on depressed mood and cellular immunity. Effects of HT on toxicities, treatment delay, QOL, and fatigue were not observed. Long-term clinical implications of findings are not known.

Modulation of TcR/CD3-zeta chain expression by a circulating factor derived from ovarian cancer patients

In women with ovarian cancer, suppression of components of the immune system may promote tumour development. Previous studies in ovarian cancer have demonstrated that decreased expression and function of the T-cell receptor (TcR)-associated signal transducing zeta-chain correlates with deficient immune responsiveness of T cells. In this study, sera and ascitic fluids obtained from woman with advanced ovarian cancer were found to suppress the expression of TcR-associated zeta chain. This suppression of zeta chain expression was dose-dependent and was not observed with biologic fluids obtained from healthy women.The factor responsible for the loss of zeta chain was purified from ascites and characterized as a protein with an appropriate molecular weight of 14 kD. Suppression of T-cell TcR-zeta was specific, since neither lck nor ZAP-70 expression was affected, while zeta chain was almost completely suppressed. This selective suppression of TcR-zeta expression by the 14 kD ascites-derived factor was shown to operate at the mRNA level. By defining the mechanism through which this protein modulates TcR-zeta chain levels, it might be possible to ultimately prevent the suppressive influences of the tumour microenvironment and restor immune competence in patients with ovarian carcinoma.

Two successful pregnancies after conservative treatment of endometrial cancer and assisted reproduction

OBJECTIVE To report successful pregnancies after conservative management of FIGO grade I adenocarcinoma of the endometrium. DESIGN Retrospective chart review. SETTING University-based assisted reproduction and oncology units. PATIENT(S) One patient who had two separate pregnancies. INTERVENTION(S) High-dose progestin (megestrol acetate) therapy for adenocarcinoma, followed by assisted reproduction with donor oocyte. MAIN OUTCOME MEASURE(S) Histologic evaluation of endometrium after megestrol acetate and at completion of childbearing, and successful pregnancies and deliveries. RESULT(S) The patient had complete resolution of adenocarcinoma with progestin therapy and successful delivery of two pregnancies after assisted reproduction. CONCLUSION(S) Conservative management of International Federation of Gynecology and Obstetrics grade I adenocarcinoma of the endometrium allows preservation of childbearing.

Sleep disturbance, cytokines, and fatigue in women with ovarian cancer.

Pro-inflammatory cytokines, such as interleukin-6 (IL-6), have been implicated in the underlying processes contributing to sleep regulation and fatigue. Despite evidence for sleep difficulties, fatigue, and elevations in IL-6 among women with ovarian cancer, the association between these symptoms and IL-6 has not been investigated. To address this knowledge gap, we examined relationships between sleep disturbance, fatigue, and plasma IL-6 in 136 women with ovarian cancer prior to surgery. These relationships were also examined in 63 of these women who were disease-free and not receiving chemotherapy one year post-diagnosis. At both time-points, higher levels of IL-6 were significantly associated with sleep disturbances (p<0.05), controlling for potentially confounding biological and psychosocial covariates. Higher IL-6 was significantly associated with fatigue prior to surgery (p<0.05); however, when sleep disturbance was included in the model, the relationship was no longer significant. IL-6 was not significantly associated with fatigue at one year. Changes in sleep over time were significantly associated with percent change in IL-6 from pre-surgery to one year, adjusting for covariates (p<0.05). These findings support a direct association of IL-6 with sleep disturbances in this population, whereas the relationship between IL-6 and fatigue prior to surgery may be mediated by poor sleep. As this study is the first to examine cytokine contributions to sleep and fatigue in ovarian cancer, further research is warranted to clarify the role of biological correlates of sleep and fatigue in this population.