The Effects of Natural Epigenetic Therapies in 3D Ovarian Cancer and Patient-Derived Tumor Explants: New Avenues in Regulating the Cancer Secretome.

High mortality rates in ovarian cancer have been linked to recurrence, metastasis, and chemoresistant disease, which are known to involve not only genetic changes but also epigenetic aberrations. In ovarian cancer, adipose-derived stem cells from the omentum (O-ASCs) play a crucial role in supporting the tumor and its tumorigenic microenvironment, further propagating epigenetic abnormalities and dissemination of the disease. Epigallocatechin gallate (EGCG), a DNA methyltransferase inhibitor derived from green tea, and Indole-3-carbinol (I3C), a histone deacetylase inhibitor from cruciferous vegetables, carry promising effects in reprograming aberrant epigenetic modifications in cancer. Therefore, we demonstrate the action of these diet-derived compounds in suppressing the growth of 3D ovarian cancer spheroids or organoids as well as post-treatment cancer recovery through proliferation, migration, invasion, and colony formation assays when compared to the synthetic epigenetic compound Panobinostat with or without standard chemotherapy. Finally, given the regulatory role of the secretome in growth, metastasis, chemoresistance, and relapse of disease, we demonstrate that natural epigenetic compounds can regulate the secretion of protumorigenic growth factors, cytokines, extracellular matrix components, and immunoregulatory markers in human ovarian cancer specimens. While further studies are needed, our results suggest that these treatments could be considered in the future as adjuncts to standard chemotherapy, improving efficiency and patient outcomes.

Outcomes of the "BRCA Quality Improvement Dissemination Program": An initiative to improve patient receipt of cancer genetics services at five health systems.

OBJECTIVE: A quality improvement initiative (QII) was conducted with five community-based health systems' oncology care centers (sites A-E). The QII aimed to increase referrals, genetic counseling (GC), and germline genetic testing (GT) for patients with ovarian cancer (OC) and triple-negative breast cancer (TNBC). METHODS: QII activities occurred at sites over several years, all concluding by December 2020. Medical records of patients with OC and TNBC were reviewed, and rates of referral, GC, and GT of patients diagnosed during the 2 years before the QII were compared to those diagnosed during the QII. Outcomes were analyzed using descriptive statistics, two-sample t-test, chi-squared/Fisher's exact test, and logistic regression. RESULTS: For patients with OC, improvement was observed in the rate of referral (from 70% to 79%), GC (from 44% to 61%), GT (from 54% to 62%) and decreased time from diagnosis to GC and GT. For patients with TNBC, increased rates of referral (from 90% to 92%), GC (from 68% to 72%) and GT (81% to 86%) were observed. Effective interventions streamlined GC scheduling and standardized referral processes. CONCLUSION: A multi-year QII increased patient referral and uptake of recommended genetics services across five unique community-based oncology care settings.

Implementation and outcome evaluations of a multi-site improvement program in cancer genetics.

Program evaluation can identify the successes and challenges of implementing clinical programs, which can inform future dissemination efforts. A cancer genetics improvement program, disseminated from the Lead Team's institution to five health systems (Participating Sites), was genetic counselor led, using virtual implementation facilitation to support Participating Sites' performance of quality improvement (QI) activities over several years. Program implementation and outcome evaluations were performed and included evaluation of program delivery and initial effects of the program on Participating Sites. A logic model guided evaluation of program implementation (inputs, activities, outputs, delivery/fidelity, and coverage/reach) and initial outcomes (short-term and intermediate outcomes). Data were collected from program documents and an Evaluation Survey of Participating Site team members (21 respondents), compared against the Lead Team's expectations of participation, and analyzed using descriptive statistics. All program inputs, outputs, and activities were available and delivered as expected across the five Participating Sites. The most frequently used activities and inputs were facilitation-associated meetings and meeting resources, which were rated as useful/helpful by the majority of respondents. Nearly all respondents noted improvement in short-term outcomes following participation: 82.4% reported increased awareness of clinical processes, 94.1% increased knowledge of QI methods, 100% reported increased perceived importance of QI, 94.1% increased perceived feasibility of QI, and 76.5% reported increased problem-solving skills and self-efficacy to use QI at their site. Intermediate outcomes (identifying barriers, developing interventions, improved teamwork, and capacity) were achieved following program participation as indicated by the results of the program document review and Evaluation Survey responses. Implementation challenges at Participating Sites included staffing constraints, difficulties obtaining buy-in and participation, and developing interventions over time. The multi-site improvement program was delivered and implemented with high levels of fidelity and resulted in improved short and intermediate outcomes. Future research will evaluate long-term, patient-level outcomes associated with site-specific QI interventions.

Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial.

PURPOSE: This phase III randomized trial (NCT00954174) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS). PATIENTS AND METHODS: Adults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on PI with a type I error of 5% for a one-tailed test. RESULTS: The study enrolled 536 patients with UCS and 101 patients with OCS, with 449 and 90 eligible, respectively. Primary analysis was on patients with UCS, distributed as follows: 40% stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent. Among eligible patients with UCS, PC was assigned to 228 and PI to 221. PC was not inferior to PI. The median OS was 37 versus 29 months (HR = 0.87; 90% CI, 0.70 to 1.075; P < .01 for noninferiority, P > .1 for superiority). The median progression-free survival was 16 versus 12 months (HR = 0.73; P = < 0.01 for noninferiority, P < .01 for superiority). Toxicities were similar, except that more patients in the PC arm had hematologic toxicity and more patients in the PI arm had confusion and genitourinary hemorrhage. Among 90 eligible patients with OCS, those in the PC arm had longer OS (30 v 25 months) and progression-free survival (15 v 10 months) than those in the PI arm, but with limited precision, these differences were not statistically significant. CONCLUSION: PC was not inferior to the active regimen PI and should be standard treatment for UCS.

Epigenetic Therapy Augments Classic Chemotherapy in Suppressing the Growth of 3D High-Grade Serous Ovarian Cancer Spheroids over an Extended Period of Time.

Recurrent high-grade serous ovarian cancer (HGSC) is clinically very challenging and prematurely shortens patients' lives. Recurrent ovarian cancer is characterized by high tumor heterogeneity; therefore, it is susceptible to epigenetic therapy in classic 2D tissue culture and rodent models. Unfortunately, this success has not translated well into clinical trials. Utilizing a 3D spheroid model over a period of weeks, we were able to compare the efficacy of classic chemotherapy and epigenetic therapy on recurrent ovarian cancer cells. Unexpectedly, in our model, a single dose of paclitaxel alone caused the exponential growth of recurrent high-grade serous epithelial ovarian cancer over a period of weeks. In contrast, this effect is not only opposite under treatment with panobinostat, but panobinostat reverses the repopulation of cancer cells following paclitaxel treatment. In our model, we also demonstrate differences in the drug-treatment sensitivity of classic chemotherapy and epigenetic therapy. Moreover, 3D-derived ovarian cancer cells demonstrate induced proliferation, migration, invasion, cancer colony formation and chemoresistance properties after just a single exposure to classic chemotherapy. To the best of our knowledge, this is the first evidence demonstrating a critical contrast between short and prolonged post-treatment outcomes following classic chemotherapy and epigenetic therapy in recurrent high-grade serous ovarian cancer in 3D culture.

Can Cannabidiol Affect the Efficacy of Chemotherapy and Epigenetic Treatments in Cancer?

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. This review focuses on the widespread therapeutic potential of CBD with regard to enhanced wound healing, lowered toxicity profiles of chemotherapeutics, and augmented antitumorigenic effects. The current literature is sparse with regard to determining the clinically relevant concentrations of CBD given the biphasic nature of the compound's response. Therefore, there is an imminent need for further dose-finding studies in order to determine the optimal dose of CBD for both intermittent and regular users. We address the potential influence of regular or occasional CBD usage on therapeutic outcomes in ovarian cancer patients. Additionally, as the development of chemoresistance in ovarian cancer results in treatment failure, the potential for CBD to augment the efficacy of conventional chemotherapeutic and epigenetic drugs is a topic of significant importance. Our review is focused on the widespread therapeutic potential of CBD and whether or not a synergistic role exists in combination with epigenetic and classic chemotherapy medications.

Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall Survival and Adverse Event Analysis of a Phase III Trial (NRG Oncology/GOG0209).

PURPOSE: Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP. METHODS: GOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m2 and cisplatin 50 mg/m2 (day 1), followed by paclitaxel 160 mg/m2 (day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m2 and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints. RESULTS: From 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37 v 41 months, respectively; hazard ratio [HR], 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13 v 14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade > 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC (P = .40). More grade ≥ 3 thrombocytopenia (23% v 12%), vomiting (7% v 4%), diarrhea (6% v 2%), and metabolic (14% v 8%) toxicities were reported with TAP. Neutropenia (52% v 80%) was more common with TC. Small HRQoL differences favored TC. CONCLUSION: With demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer.

Bilateral ovarian micrometastatic adenocarcinoma upon prophylactic oophorectomy concurrent with low anterior resection for rectal cancer.

BACKGROUND: This case report draws attention to the debated role of prophylactic oophorectomy in women undergoing definitive surgical resection of colon and rectal cancers. It can be challenging to discern the indications and appropriate patient population for this procedure based on the current literature. Potential benefits include treatment and prevention of metastatic disease, preventing development of primary ovarian cancer, and prolonging survival. Negative effects include an increase in operative time and potential morbidity, development of osteoporosis, the risk of cardiac events, and decreasing sexual function. Multiple patient factors such as age, menopausal status, patient preference, presence of hereditary conditions, exposure to radiation, site, and stage of disease should be considered. CASE PRESENTATION: We present a case in which a premenopausal 49-year-old female underwent a prophylactic bilateral salpingo-oophorectomy concurrently with a low anterior resection following neoadjuvant chemoradiation for clinical stage III rectal cancer. On pathologic examination, resection margins and all 14 lymph nodes harvested were negative for malignancy. Interestingly, she was found to have micrometastatic adenocarcinoma in the bilateral ovaries which had appeared grossly normal at the time of surgery. CONCLUSIONS: After consideration of the current literature, patient preference, and our clinical judgment, our patient ultimately had a therapeutic effect after undergoing prophylactic bilateral oophorectomy concurrently with a low anterior resection for rectal cancer. The addition of prophylactic oophorectomy in a select population, specifically women 50 years of age or younger and/or women who are in the premenopausal state, may carry a survival benefit in the setting of definitive surgical resection of colon and rectal cancers.

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus, an NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. METHODS: Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40mg/m2 as a 3hour IV infusion on day 1 of a 21daycycle. Treatment was continued until disease progression or unacceptable toxicity occurred. RESULTS: Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68years. ECOG performance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2-25.1%); all were partial responses. Stable disease for at least 8weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7mo and 7.7mo, respectively, with a median follow-up of 37mo. Six month PFS was 20.6%. Major grade≥3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. CONCLUSION: In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity.

Disease extent at secondary cytoreductive surgery is predictive of progression-free and overall survival in advanced stage ovarian cancer: An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: GOG 152 was a randomized trial of secondary cytoreductive surgery (SCS) in patients with suboptimal residual disease (residual tumor nodule >1cm in greatest diameter) following primary cytoreductive surgery for advanced stage ovarian cancer. The current analysis was undertaken to evaluate the impact of disease findings at SCS on progression-free survival (PFS) and overall survival (OS). METHODS: Among the 550 patients enrolled on GOG-152, two-hundred-sixteen patients were randomly assigned following 3cycles of cisplatin and paclitaxel to receive SCS. In 15 patients (7%) surgery was declined or contraindicated. In the remaining 201 patients the operative and pathology reports were utilized to classify their disease status at the beginning of SCS as; no gross disease/microscopically negative N=40 (19.9%), no gross disease/microscopically positive N=8 (4.0%), and gross disease N=153 (76.1%). RESULTS: The median PFS for patients with no gross disease/microscopically negative was 16.1months, no gross disease/microscopically positive was 13.5months and for gross disease was 11.7months, P=0.002. The median OS for patients with no gross disease/microscopically negative was 51.5months, no gross disease/microscopically positive was 42.6months and for gross disease was 34.9months, P=0.018. CONCLUSION: Although as previously reported SCS did not change PFS or OS, for those who underwent the procedure, their operative and pathologic findings were predictive of PFS and OS. Surgical/pathological residual disease is a biomarker of response to chemotherapy and predictive of PFS and OS.

Phase II trial of nab-paclitaxel in the treatment of recurrent or persistent advanced cervix cancer: A gynecologic oncology group study.

BACKGROUND: Metastatic and recurrent, platinum resistant cervix cancer has an extremely poor prognosis. The Gynecologic Oncology Group has studied >20 cytotoxic drugs or drug combinations in the second-line, phase II setting of advanced, drug resistant cervix cancer. METHODS: Nanoparticle, albumin-bound paclitaxel (nab-paclitaxel) was administered at 125 mg/m(2) IV over 30 minutes on days 1, 8 and 15 of each 28 day cycle to 37 women with metastatic or recurrent cervix cancer that had progressed or relapsed following first-line cytotoxic drug treatment. A flexible, 2-stage accrual design that allowed stopping early for lack of treatment activity was utilized. Because of slow patient accrual, the second stage was not completed. RESULTS: Of 37 patients enrolled, 2 were ineligible due to no prior cytotoxic chemotherapy, which left 35 eligible patients evaluable for response and tolerability. All of the eligible patients had 1 prior chemotherapy regimen and 27 of them had prior radiation therapy with concomitant cisplatin. The median number of nab-paclitaxel cycles were 4 (range 1-15). Ten (28.6%; CI 14.6%-46.3%) of the 35 patients had a partial response and another 15 patients (42.9%) had stable disease. The median progression-free and overall survival were 5.0 and 9.4 months, respectively. The only NCI CTCAE grade 4 event was neutropenia in 2 patients (5.7%) which resolved following dose reduction. Grade 3 neurotoxicity was reported in 1 (2.9%) patient and resolved to grade 2 following dose discontinuation. CONCLUSIONS: Nab-paclitaxel has considerable activity and moderate toxicity in the treatment of drug resistant, metastatic and recurrent cervix cancer.

A phase I trial of dose-dense (biweekly) carboplatin combined with paclitaxel and pegfilgrastim: a feasibility study in patients with untreated Stage III and IV ovarian, tubal or primary peritoneal cancer: a Gynecologic Oncology Group study.

PURPOSE: Dose-dense regimens have been shown to improve outcome when given as adjuvant therapy to patients with breast cancer compared with their three weekly counterparts. We investigated the feasibility of a dose-dense regimen with carboplatin/paclitaxel followed by pegfilgrastim in patients with advanced ovarian cancer. We also investigated the toxicities including the percentage of patients with grade 2 or greater peripheral neurotoxicity and the clinical response of this regimen. PATIENTS AND METHODS: Women with untreated Stage III or IV epithelial ovarian, (fallopian) tubal, or primary peritoneal cancer were treated with carboplatin area under the curve (AUC) 5 and paclitaxel 175 mg/m(2) day one, and pegfilgrastim 6 mg day two every 2 weeks for six cycles. RESULTS: Between 9/06 and 9/08, 43 patients enrolled. Thirty-one patients completed six or more cycles of therapy. The dose limiting toxicities resulting in treatment discontinuation included: grade 3 and 4 neuropathy, grade 4 thrombocytopenia, grade 4 thrombocytopenia/grade 3 febrile neutropenia, and grade 4 supraventricular tachycardia. Twelve patients (30%) had >or=grade 2 neuropathy from this regimen. The overall response rate in patients with measurable disease was 58% (11 out of 19). CONCLUSION: Dose-dense carboplatin/paclitaxel appears to be effective. However, based on dose limiting toxicities occurring when administering 6 cycles of treatment, it is not feasible. Given the neuropathy and thrombocytopenia, we do not recommend 6 cycles of this regimen without modification.

A phase II evaluation of weekly gemcitabine and docetaxel for second-line treatment of recurrent carcinosarcoma of the uterus: a gynecologic oncology group study.

BACKGROUND: The objective of this study was to estimate antitumor activity and toxicity of weekly docetaxel and gemcitabine as second-line chemotherapy for patients with recurrent uterine carcinosarcoma. METHODS: Patients with recurrent carcinosarcoma of the uterus who had failed one regimen of chemotherapy, had a Gynecologic Oncology Group (GOG) performance status of 0-2 and had measurable disease were included. Treatment consisted of gemcitabine 600 mg/m(2) and docetaxel 35 mg/m(2) intravenously on days 1, 8 and 15 of a 28-day cycle until disease progression or intolerable adverse effects. This study employed an optimal but flexible two-stage design with an early stopping rule. If more than 3 out of 22-24 or more than 4 out of 25-29 patients responded, accrual to the second stage was to be initiated. RESULTS: Twenty-eight patients were enlisted. Three patients were not eligible after pathology review. One patient was never treated. Twenty-four patients were evaluable. Nine patients had previous radiation therapy. There were no complete responses. Partial responses were seen in two patients (8.3%), stable disease in eight (33.3%) and progressive disease in 12 patients (50%). Two patients were not evaluable (8.3%). The median progression-free survival was 1.8 months. The median survival was 4.9 months. The treatment caused myelosuppression, mainly neutropenia, but also thrombocytopenia and anemia. Dose modifications became necessary in the majority of patients. In five patients, treatment was discontinued due to toxicity. CONCLUSIONS: This regimen of docetaxel and gemcitabine is not active in patients with recurrent carcinosarcoma of the uterus as second-line chemotherapy.

A phase 2 evaluation of irofulven as second-line treatment of recurrent or persistent intermediately platinum-sensitive ovarian or primary peritoneal cancer: a Gynecologic Oncology Group trial.

This multicenter phase 2 trial was conducted by the Gynecologic Oncology Group to evaluate the activity and the safety of irofulven in patients with recurrent epithelial ovarian cancer. Eligible patients had documented recurrent ovarian cancer 6 to 12 months after receiving a front-line platinum-based regimen and no other chemotherapy. Patients were required to have measurable disease, performance status of 0 to 2, and adequate bone marrow, hepatic, and renal functions before study entry. The dose of irofulven was 0.45 mg/kg intravenously on days 1 and 8 every 21 days. Responses were defined by Response Evaluation Criteria in Solid Tumors. Fifty-five of 61 enrolled patients were evaluable for response and toxicity. There were 7 partial responses (12.7%), and 30 patients (54.6%) had stable disease. Median progression-free and overall survival were 6.4 months (1.3-37.5 months) and 22.1 months or more (2.8-57.8+ months), respectively. Patients received a median of 3 cycles (range, 1-21) of protocol therapy. Grade 4 hematologic toxicity was limited to reversible neutropenia and thrombocytopenia. Grade 4 nonhematologic toxicity was limited to one patient with anorexia and another with hypomagnesemia. Irofulven administered at this dose and schedule was well tolerated but had modest activity as a single agent.

Associations between ERBB2 amplification and progression-free survival and overall survival in advanced stage, suboptimally-resected epithelial ovarian cancers: a Gynecologic Oncology Group Study.

OBJECTIVE(S): The Gynecologic Oncology Group (GOG) examined the association between ERBB2 amplification and clinical covariates, tumor response, disease status post-chemotherapy, progression-free survival (PFS), and overall survival (OS) in epithelial ovarian cancer (EOC). METHODS: Women with suboptimally-resected, advanced stage EOC who participated in GOG-111, a multi-center randomized phase III trial of cyclophosphamide+cisplatin versus paclitaxel+cisplatin, and provided a tumor block through the companion protocol GOG-9404 were eligible. ERBB2 amplification was examined using fluorescence in situ hybridization (FISH) with probes for ERBB2 and the centromere of chromosome 17 (CEP17). RESULTS: ERBB2 amplification, defined as >2 copies of ERBB2/CEP17, was a rare event in EOC with 7% (9/133) of women exhibiting between 2.2 and 33.7 copies of ERBB2/CEP17, and was not associated with patient age, race, GOG performance status, stage, cell type, grade, measurable disease status, volume of ascites, tumor response or disease status post-chemotherapy. Women with >2 verses < or =2 copies of ERBB2/CEP17 did not have a reduced risk of disease progression (hazard ratio [HR]=0.56; 95% confidence interval [CI]=0.27-1.16; p=0.120) or death (HR=0.57; 95% CI=0.26-1.23; p=0.152), and ERBB2 amplification was not an independent prognostic factor for PFS or OS. ERBB2 amplification, defined as >4 copies of ERBB2/nuclei, was observed in 9% (12/133) of women with levels ranging from 4.2 to 49.2 copies of ERBB2/nuclei, and was associated with older age and volume of ascites, but not with the other clinical covariates or outcome. CONCLUSION(S): ERBB2 amplification is a rare event and has no predictive or prognostic value in suboptimally-resected, advanced stage EOC treated with platinum-based combination chemotherapy.

Radiation therapy with concomitant paclitaxel and cisplatin chemotherapy in cervical carcinoma limited to the pelvis: a phase I/II study of the Gynecologic Oncology Group.

OBJECTIVES: To determine the maximum tolerated dose (MTD) of weekly paclitaxel and cisplatin chemotherapy concurrent with whole pelvic irradiation in women with locally advanced cervical cancer. METHODS: Consenting patients with stage IB2, IIA, IIB, IIIB and IVA carcinoma of the cervix (all cell types) were eligible for this phase I/II trial. Chemotherapy agents were administered in escalating doses to cohorts of three patients at each dose level, pending evaluation of toxicities from the previous dose level. RESULTS: Thirty-five eligible women were enrolled on this study, of whom 13 comprised the phase I component. The MTD was determined to be cisplatin 40 mg/m2 and paclitaxel 40 mg/m2 administered weekly for six cycles with external beam radiation therapy. An additional 21 patients were enrolled in the phase II component at the previously determined MTD, yielding a total of 22 patients at the MTD, of whom 19 were evaluable. Among the evaluable patients treated at the MTD, two had grade 3 or 4 gastrointestinal (GI) toxicities (representing 5 of 113 cycles administered to this cohort) and seven experienced grade 3 or 4 neutrophil toxicity, none occurring prior to the fourth cycle. Thrombocytopenia was rare. Radiation therapy was successfully completed in 52% of patients at 8 weeks and in 79% of patients at 9 weeks, with a median of 59 days. CONCLUSIONS: Paclitaxel and cisplatin combination chemotherapy concurrent with whole pelvic irradiation can be safely administered at the described MTD.

Pain evaluation in patients receiving intravenous patient-controlled analgesia after surgery.

STUDY OBJECTIVE: To evaluate the effectiveness of intravenous patient-controlled analgesia (PCA) in patients after surgery. DESIGN: Prospective, observational study. SETTING: University teaching hospital. PATIENTS: Sixty patients with American Society of Anesthesiologists physical status I-III receiving intravenous PCA for postoperative pain. The PCA was programmed to deliver morphine 1 mg or hydromorphone 0.1-0.2 mg, with a lockout interval of 10 and 6 minutes for 80% and 20% of the patients, respectively. MEASUREMENTS AND MAIN RESULTS: Patients were asked, up to 4 times during PCA use and once within 4 hours after PCA use, to describe and rate their intensity of pain at rest and after activity. During the first 12 hours of intravenous PCA use, 75% of the patients reported moderate-to-severe pain > or = 5 on a verbal numeric rating scale) at rest, 80% after activity. Corresponding values, respectively, were 33% and 72% for the 12-24-hour period, 43% and 76% for the 24-36-hour period, and 36% and 64% for the 36-48-hour period of intravenous PCA use. Within 4 hours of stopping PCA, 30% and 58% of the patients had moderate-to-severe pain at rest and after activity, respectively. In approximately 50% of patients, presence of pain was described with words signifying sensory and affective dimensions of pain. Pain control was rated as good or very good by 54% of patients during the first 12 hours of intravenous PCA. Ratings of pain control tended to improve with time. CONCLUSION: Successful postoperative pain management using PCA is difficult to achieve on a consistent basis unless treatment is individualized. Our data support the hypothesis that small fixed doses fail to achieve adequate relief in many patients.

Analgesic and hemodynamic effects of a single 7.5-mg intravenous dose of morphine in patients with moderate-to-severe postoperative pain.

STUDY OBJECTIVES: To evaluate the analgesic and hemodynamic effects of a single dose of intravenous morphine 7.5 mg in patients experiencing moderate-to-severe postoperative pain, and to determine any gender differences in analgesic response. DESIGN: Randomized, double-blind, parallel-group, multicenter study. SETTING: Postanesthesia care unit of a university teaching hospital. PATIENTS: Eighty-eight patients who underwent total abdominal hysterectomy or prostatectomy. INTERVENTION: Thirty-seven patients received a single dose of morphine sulfate 7.5 mg and 51 patients received placebo, both administered intravenously for 1 minute. MEASUREMENTS AND MAIN RESULTS: Overall, morphine had no significant effect on systolic or diastolic blood pressure, heart rate, oxygen saturation, or respiratory rate. Compared with baseline, morphine significantly reduced pain intensity at 2, 5, and 10 minutes after administration (p<0.05). The difference in pain intensity between patients who received morphine and those who received placebo, however, was significant only at the 5-minute time point (p<0.02). Patients receiving morphine also reported mild pain relief at 2 and 5 minutes after its administration. Peak analgesic effect was reported 2 minutes after its administration in three quarters of the patients. Significant gender differences also were observed in response to analgesic effect. In women, no significant differences in pain intensity were seen at any time between the morphine and placebo groups, whereas in men receiving morphine, pain intensity was significantly less at 2, 5, and 10 minutes compared with baseline and that seen in the placebo group. Women were generally more satisfied with their pain treatment than were men. CONCLUSION: A single 7.5-mg intravenous bolus dose of morphine did not appear to provide adequate reduction in perceived pain intensity in patients with moderate-to-severe postoperative pain. In addition, in contrast to the findings of other experimental pain studies, our data suggest that women are more tolerant of postoperative pain than are men.

Prevalence and predictors of psychological distress among women with ovarian cancer.

PURPOSE: To identify the prevalence of psychological distress among women with ovarian cancer and to examine the association between these symptoms of distress and demographic and medical variables. PATIENTS AND METHODS: Participants were 143 women with ovarian cancer. Forty-eight percent of participants had been diagnosed with advanced-stage disease (stage III or IV) and most (80%) were currently receiving treatment. Psychological distress was assessed with the following measures: the Beck Depression Inventory, the Mental Health Inventory, the Impact of Events Scale, and a questionnaire regarding mental health service use. RESULTS: Approximately one fifth of women reported moderate to severe levels of distress, and more than half reported high stress responses to their cancer and its treatment. Most participants (60%) were not using any mental health services or psychotropic medications. There was also evidence to suggest that younger patients, patients with more advanced or recurrent disease, and patients who had more recently been diagnosed with ovarian cancer experienced greater psychological distress. CONCLUSION: These findings indicate that psychological distress and high stress responses to cancer are prevalent among women with ovarian cancer, suggesting they should be carefully evaluated to determine whether treatment for these symptoms is warranted.

A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study.

OBJECTIVES: Docetaxel is an inhibitor of microtubule depolymerization and has demonstrated activity in paclitaxel-resistant breast cancer and gynecologic cancer. The Gynecologic Oncology Group (GOG) conducted a study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma to determine its activity, and nature and degree of toxicity, in this cohort of patients. METHODS: Patients with platinum- and paclitaxel-resistant ovarian or peritoneal carcinoma, defined as progression while on or within 6 months of therapy, were eligible if they had measurable disease and had not received more than one chemotherapy regimen. Docetaxel at a dose of 100 mg/m(2) was administered iv over 1 h every 21 days. A prophylactic regimen of oral dexamethasone 8 mg bid was begun 24 h before docetaxel administration and continued for 48 h thereafter. Hepatic function was strictly monitored. RESULTS: Sixty patients were entered and treated with a total of 256 courses, with all 60 evaluable for toxicity and 58 evaluable for response. Responses were observed in 22.4% of patients, with 5.2% achieving complete response and 17.2% achieving partial response (95% CI, 12.5-35.3%). The median duration of response was 2.5 months. The likelihood of observing a response did not appear to be related to the length of the prior paclitaxel-free interval or duration of prior paclitaxel infusions. The principal adverse effect of grade 4 neutropenia occurred in 75% of patients. There was one treatment-related death. Dose reductions were required in 36% of patients. CONCLUSIONS: Docetaxel is active in paclitaxel-resistant ovarian and peritoneal cancer but, in view of significant hematologic toxicity, further study is warranted to ascertain its optimal dose and schedule.