Carboplatin dosing in the treatment of ovarian cancer: An NRG oncology group study.

OBJECTIVE: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl). METHODS: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event. RESULTS: AUC statistics (range, 0.52-0.64) showed log(CrClJelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively. CONCLUSION: The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials.

Molecular Characterization of Non-responders to Chemotherapy in Serous Ovarian Cancer.

Nearly one-third of patients with high-grade serous ovarian cancer (HGSC) do not respond to initial treatment with platinum-based therapy. Genomic and clinical characterization of these patients may lead to potential alternative therapies. Here, the objective is to classify non-responders into subsets using clinical and molecular features. Using patients from The Cancer Genome Atlas (TCGA) dataset with platinum-resistant or platinum-refractory HGSC, we performed a genome-wide unsupervised cluster analysis that integrated clinical data, gene copy number variations, gene somatic mutations, and DNA promoter methylation. Pathway enrichment analysis was performed for each cluster to identify the targetable processes. Following the unsupervised cluster analysis, three distinct clusters of non-responders emerged. Cluster 1 had overrepresentation of the stage IV disease and suboptimal debulking, under-expression of miRNAs and mRNAs, hypomethylated DNA, "loss of function" TP53 mutations, and the overexpression of genes in the PDGFR pathway. Cluster 2 had low miRNA expression, generalized hypermethylation, MUC17 mutations, and significant activation of the HIF-1 signaling pathway. Cluster 3 had more optimally cytoreduced stage III patients, overexpression of miRNAs, mixed methylation patterns, and "gain of function" TP53 mutations. However, the survival for all clusters was similar. Integration of genomic and clinical data from patients that do not respond to chemotherapy has identified different subgroups or clusters. Pathway analysis further identified the potential alternative therapeutic targets for each cluster.

Changes in spiritual well-being and psychological outcomes in ovarian cancer survivors.

OBJECTIVE: Because of the poor prognosis of ovarian cancer and concomitant distress, understanding contributors to positive well-being is critical. This study examines spiritual growth as a domain of posttraumatic growth and its contribution to longitudinal emotional outcomes in ovarian cancer. METHODS: Ovarian cancer patients (N = 241) completed measures assessing spirituality (Functional Assessment of Chronic Illness Therapy-Spiritual Well-being-12; subscales: faith, meaning, and peace), depression (Center for Epidemiologic Studies Depression Scale), cancer-specific anxiety (Impact of Event Scale), and total mood disturbance (TMD; Profile of Mood States) prior to surgery and 1-year postsurgery. Stressful life events in the year after diagnosis were measured at 1-year postsurgery. Regressions examined the association between changes in spirituality and depression, anxiety, and TMD at 1-year postsurgery. Additionally, spiritual change was examined as a moderator of the effect of recent life events on mood. RESULTS: Increases in peace were related to lower depression (ß = -.40, P < .001), anxiety (ß = -.20, P = .004), and TMD (ß = -.41, P < .001) at 1 year. Changes in meaning and faith were unrelated to all outcomes. Additionally, changes in peace moderated the effect of stressful life events on depression (ß = -.14, P = .027), anxiety (ß = -.16, P = .05), and TMD (ß = -.17, P = .01), such that those with a high number of life events paired with a decrease in peace experienced the worst psychological outcomes at 1 year. CONCLUSION: These findings suggest that the quality of peace may be the most adaptive facet of spiritual growth in cancer patients. Furthermore, changes in peace appear to moderate the effect of life events on psychological well-being.

Intraoperative autologous blood transfusion use during radical hysterectomy for cervical cancer: long-term follow-up of a prospective trial.

PURPOSE: A primary operative complication of radical hysterectomy for cervical cancer is hemorrhage. Intraoperative autologous blood transfusion (ABT) may be beneficial in reducing the need for homologous blood transfusion. METHODS: Our institution published a prospective cohort study examining the use of ABT in cervical cancer patients undergoing radical hysterectomy in 1995. Patients who were initially consented to participate in this prospective trial using intraoperative ABT (cell saver) were evaluated with a median follow-up of 3 years. We sought to update this original report with 16-year follow-up data collected from the clinical charts, Tumor Registry, and the Social Security Death Index. RESULTS: Two groups of patients undergoing radical hysterectomy were compared: patients who received ABT, and those who did not. Of the 71 original patients, all were included in this updated review, with an average follow-up of 12.4 years for both groups. Originally, thirty-one patients received an ABT. In this group, 1 patient was lost to follow-up, and 4 (12.9 %) are deceased including 1 (3 %) with disease. In the non-autologous group, there were 7 (17.5 %) patient deaths, including 3 (7.5 %) with disease. Eighty-three percent were alive after 12 years in both groups. The ABT group had 1 patient (3 %) who developed a secondary malignancy, a colon adenocarcinoma. The non-autologous group had 2 patients (5 %) who developed a secondary malignancy; one patient developed multiple myeloma and one patient developed a verrucous cancer of the tongue. CONCLUSIONS: Autologous blood transfusion during radical hysterectomy for cervical cancer appears safe and effective.

Selective suppression of cervical cancer Hela cells by 2-O-ß-D-glucopyranosyl-L-ascorbic acid isolated from the fruit of Lycium barbarum L.

Lycium barbarum fruit has been used as a Chinese traditional medicine and dietary supplement for centuries. 2-O-ß-D-Glucopyranosyl-L-ascorbic acid (AA-2ßG), a novel stable vitamin C analog, is one of the main biologically active components of the fruit. In this report, we investigated the cytotoxic and antiproliferative effect of AA-2ßG against cancer cells in vitro and identified the proteins with significantly differential expression in the cervical cancer cells (Hela) cultured in the presence of AA-2ßG proteomic analysis. Our results demonstrated that the cytotoxic and antiproliferative activity of AA-2ßG on cancer cell lines were in a cell type-, time-, and dose-dependent manner. Similar to vitamin C, the AA-2ßG selectively induced cell death repressed the proliferation of Hela cells by the mechanism of cell apoptosis and cell cycle arrest induced by AA-2ßG through a mechanism of stabilizing p53 protein. However, the biological activity of inhibition of cell proliferation in other malignant cancer cell lines or primary cells were varied, as demonstrated by either moderate inhibition or slight promotion following treatment with AA-2ßG. Comparative analysis of the proteomic profiles and immunoblot analysis identified 15 proteins associated with repressing cell apoptosis and/or stimulating cell proliferation in Hela cells that were downregulated in the presence of AA-2ßG or vitamin C. These data indicate that a mechanism of the AA-2ßG and vitamin C mediated antitumor activity by downregulating the expression of proteins involved in cell apoptosis and proliferation and consequently inducing Hela cell apoptosis and cell cycle arrest, suggesting that AA-2ßG and vitamin C may share a similar mechanism of inducing Hela cell apoptosis. These results also suggest that the L. barbarum fruit may be a potential dietary supplement and anticancer agent aimed at the prevention and treatment of cervical cancer.

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.