Combination of 4-HPR and oral contraceptive in monkey model of chemoprevention of ovarian cancer.

4-(N-hydroxyphenyl) retinamide (4-HPR) and the oral contraceptives (OCP) are currently being used alone, and in combination, for the prevention of ovarian cancer. However, the mechanism of their effects has not been studied. Non-human primate models are ideal for studying the role of these and other drugs for cancer chemoprevention because of the genetic similarity between primates and humans in respect to hormone regulation and menstrual cycle. 4-HPR and OCP were administered to sixteen female adult Macacca mulatta (Rhesus macaques) for three months alone and in combination. Laparotomy was performed before and after treatment, and ovarian biopsies were obtained to evaluate the expression of retinoid and hormone receptors, and apoptosis. ER alpha was undetectable, but ER beta, PR, RXR alpha, and RXR gamma were constitutively expressed in the ovaries. 4-HPR induced RXR alpha and RXR gamma expression at a low level and, OCP induced expression of ER beta. However, the combination of 4-HPR with OCP had a larger effect on expression of retinoid receptors. Apoptosis was detected in the 4-HPR group (equivalent dose: 200 mg/day).

Quality of life and sexual functioning in cervical cancer survivors.

PURPOSE: To compare quality of life and sexual functioning in cervical cancer survivors treated with either radical hysterectomy and lymph node dissection or radiotherapy. METHODS: Women were interviewed at least 5 years after initial treatment for cervical cancer. Eligible women had squamous cell tumors smaller than 6 cm at diagnosis, were currently disease-free, and had either undergone surgery or radiotherapy, but not both. The two treatment groups were then compared using univariate analysis and multivariate linear regression with a control group of age- and race-matched women with no history of cancer. RESULTS: One hundred fourteen patients (37 surgery, 37 radiotherapy, 40 controls) were included for analysis. When compared with surgery patients and controls using univariate analysis, radiation patients had significantly poorer scores on standardized questionnaires measuring health-related quality of life (physical and mental health), psychosocial distress and sexual functioning. The disparity in sexual function remained significant in a multivariate analysis. Univariate and multivariate analyses did not show significant differences between radical hysterectomy patients and controls on any of the outcome measures. CONCLUSION: Cervical cancer survivors treated with radiotherapy had worse sexual functioning than did those treated with radical hysterectomy and lymph node dissection. In contrast, these data suggest that cervical cancer survivors treated with surgery alone can expect overall quality of life and sexual function not unlike that of peers without a history of cancer.

Phase II trial of irinotecan in patients with metastatic epithelial ovarian cancer or peritoneal cancer.

PURPOSE: To evaluate the efficacy and toxicity of irinotecan in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian cancer or primary peritoneal cancer. PATIENTS AND METHODS: Thirty-one patients with measurable disease were enrolled in our study at The University of Texas M.D. Anderson Cancer Center. Twenty-five of these patients were treated with irinotecan at a dose of 300 mg/m2 intravenously for 90 minutes every 3 weeks; the remaining six patients were treated with 250 mg/m2 because their age was greater than 65 years. Median age was 57 years (range, 38 to 74 years). The majority (84%) had a Zubrod performance status of 0. All patients were evaluated for irinotecan toxicity, and 29 (94%) were evaluable for response. RESULTS: The overall response rate was 17.2%. One patient (3%) had a complete response, four (14%) had partial responses, 14 (48%) had stable disease, and 10 had (35%) disease progression. Median progression-free survival was 2.8 months (range, 1.1 to 16 months), median duration of response was 1.4 months (range, 0.7 to 10.1 months); median survival from primary diagnosis was 24.3 months (range, 6.5 to 85.7 months); and median survival from initiation of irinotecan was 10.1 months (range, 2.3 to 34 months). Major toxicities included fatigue (16 patients), neutropenia (11 patients), diarrhea (nine patients), nausea (10 patients), and anorexia (seven patients). Eleven patients required dose reductions because of these toxicities. No treatment-related deaths occurred. CONCLUSION: Irinotecan has moderate efficacy and substantial toxicity in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian or primary peritoneal cancer.

4-HPR modulates gene expression in ovarian cells.

Ovarian cancer has a high rate of recurrence and subsequent mortality following chemotherapy despite intense efforts to improve treatment outcomes. Recent trials have suggested that retinoids, especially 4-(N-hydroxyphenyl) retinamide (4-HPR), play an important role as a chemopreventive agent and are currently being used in clinical trials for ovarian cancer chemoprevention as well as treatment. This study examines the mechanism of its activity in premalignant and cancer cells. We investigated the modulation of gene expression by 4-HPR in immortalized ovarian surface epithelial (IOSE) cells and ovarian cancer (OVCA433) cells with DNA microarray. Real time RT-PCR and western blotting were used to confirm the microarray results and metabolic changes were examined with optical fluorescence spectroscopy. 4-HPR resulted in an up-regulation of expression of proapoptotic genes and mitochondrial uncoupling protein in OVCA433 cells and modulation of the RXR receptors in IOSE cells, and down-regulation of mutant BRCA genes in both IOSE and OVCA433 cells. 4-HPR had a larger effect on the redox in the 433 cells compared to IOSE. These findings suggest that 4-HPR acts through different mechanisms in premalignant ovarian surface cells and cancer cells, with a preventive effect in premalignant cells and a treatment effect in cancer cells.

In vitro model of normal, immortalized ovarian surface epithelial and ovarian cancer cells for chemoprevention of ovarian cancer.

BACKGROUND: Epithelial ovarian cancer has the highest mortality rate among the gynecologic cancers. The synthetic retinoid, N-(4-hydroxyphenyl) retinamide (4-HPR), has been used in the chemoprevention of ovarian cancer. However, the effectiveness of its application for different populations has been questioned because of the genetic differences among normal, high risk, and women with cancer. OBJECTIVE: To explore the similarities and the differences in 4-HPR effects on different ovarian epithelial cells which mimic different populations of women, normal ovarian surface epithelium to represent the normal population of women, immortalized ovarian surface epithelium to represent premalignant changes, and cells derived from ovarian cancer cells to represent malignant changes were used as in vitro models. METHODS: Normal ovarian surface epithelial cells, immortalized ovarian surface epithelial cells, and ovarian cancer cells were incubated for different intervals with increasing concentrations of 4-HPR. Growth inhibition, the fraction of apoptotic cells, the expression of apoptosis-related genes, including p53, p16, p21, and caspase-3, and mitochondrial permeability transition were measured before and after 4-HPR treatment. RESULTS: Treatment with 4-HPR produced growth inhibition and apoptosis in a dose-dependent manner for all 3 cell types. 4-HPR produced the strongest activation of the p53 pathway in normal ovarian epithelial (NOE) cells, while it caused the largest increase in MPT in the cancer cells, suggesting a different mechanism for growth inhibition and/or apoptosis in these cell lines. 4-HPR, at a concentration of 10 muM, had a maximal effect on caspase-3 activity at 72 h in normal cells and at 48 h in immortalized and cancer cells, although the effects were modest. CONCLUSIONS: Normal ovarian surface epithelial cells, immortalized ovarian surface epithelial cells, and ovarian cancer cells showed a differential response to 4-HPR. Although the same endpoints of growth inhibition and apoptosis induction were present in response to 4-HPR, these endpoints may be regulated through different pathways. IMPLICATIONS: Clinical trials with higher concentrations of 4-HPR should prove beneficial.

Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer.

GOALS OF WORK: Although many patients with ovarian cancer achieve favorable responses to primary chemotherapy, the majority of women will experience recurrence of their cancer. Selection of second- or third-line chemotherapy ultimately depends on patient preferences for different side effects. To better understand this process, we evaluated preferences and symptom distress in patients with ovarian cancer. PATIENTS AND METHODS: A total of 70 women with ovarian cancer who had previously received at least three cycles of platinum-based chemotherapy and currently undergoing chemotherapy for newly diagnosed or recurrent disease were interviewed in an outpatient chemotherapy clinic. The patients were asked to rank order 27 health states using a modified visual analog scale and to complete the Memorial Symptom Assessment Scale (MSAS). MAIN RESULTS: Most favorable health states included perfect health, clinical remission and complete control of chemotherapy-induced nausea and vomiting (CINV). Least favorable health states included more severe CINV health states and death. Patients on first-line chemotherapy had less symptom distress, and rated sexual dysfunction, fatigue and memory loss more favorably than patients on second- or third-line chemotherapy (P<0.05). Married patients generally had less symptom distress compared to patients who were not married, but married patients indicated more distress with sexual dysfunction (P=0.04). Married patients rated alopecia less favorably than unmarried patients (P=0.03), but married patients viewed certain CINV health states more favorably (P=0.02-0.04). CONCLUSIONS: CINV remains one of the most dreaded side effects of chemotherapy. Separate preference profiles exist for patients with newly diagnosed and recurrent disease, as well as for married versus unmarried patients. While MSAS scores and VAS rankings showed consistency across some health states, this was not true for CINV, suggesting that current symptom status may only influence patient preferences for selected side effects.

Innovations in the treatment of invasive cervical cancer.

Invasive cervical cancer is characterized by basement membrane-invading lesions capable of metastasizing through the lymphatic and vascular systems. Treatment methods were reviewed by panelists at the Second International Conference on Cervical Cancer (Houston, TX, April 11-14, 2002), and new opportunities for translational research were discussed. Reviews encompassed hysterectomy with or without lymph node dissection or cervical conization in cases with microinvasion and radical trachelectomy with or without lymph node dissection as fertility-sparing surgery. Chemoradiation is used to treat advanced cervical malignancies, and the risks and benefits of radiotherapy are significant. Pelvic exenteration is used to treat certain types of recurrences. Use of the Miami pouch for continent urinary diversion was highlighted. Gynecologic oncologists expect novel in vivo imaging techniques currently being developed to help guide therapy choices within the next decade. The most significant research priorities are large group-randomized trials involving fertility-sparing procedures and the management of microinvasive carcinoma (MICA); better identification of candidates for chemoradiation; and the development of innovative approaches to exenteration. Improving diagnostic technologies, refining the criteria by which therapies are chosen, and preserving fertility remain challenges in selecting the most appropriate treatment for invasive cervical cancer. Research advances in both diagnosis and treatment are expected to improve therapy and outcomes.

Functional outcomes and complications of continent urinary diversions in patients with gynecologic malignancies.

OBJECTIVE: The purpose of this study was to review our experience with continent urinary diversions in patients with gynecologic malignancies and evaluate the presentation and management of early and late complications. METHODS: A retrospective chart review was performed of all patients who underwent a continent urinary diversion on the Gynecologic Oncology Service at The University of Texas M. D. Anderson Cancer Center during the period January 1988 to March 2001. We analyzed our data to evaluate potential risk factors for complications. Renal status, conduit integrity, and overall patient outcomes were also studied. RESULTS: We identified 40 patients who underwent a continent urinary diversion using an ileocolonic segment (Miami pouch technique). All patients had a history of gynecologic malignancies. The median age at the time of the procedure was 50 years (range 24 to 76 years), and the median weight was 69.6 kg (range 47 to 125 kg). A total of 39 patients (98%) had a history of radiotherapy. Continent urinary diversion was performed as part of an anterior pelvic exenteration in 12 patients (30%), in conjunction with a total pelvic exenteration in 18 patients (45%), and as the main procedure in 10 patients (25%). The median estimated blood loss was 2100 ml (range 200 to 8500 ml). The median length of hospitalization was 19.5 days (range 7 to 56 days). A total of 24 patients (60.0%) had a postoperative complications unrelated to the reservoir. Complications directly related to the continent urinary diversion were seen in 26 (65.0%) of 40 patients. None of the patients in this study group developed chronic renal failure, and there were no perioperative deaths. At last evaluation, 36 (90%) of 40 patients reported normal continent conduit function. CONCLUSIONS: Continent urinary diversion using an ileocolonic segment is a reasonable alternative to the ileal and transverse colon conduit in bladder reconstruction in patients undergoing radical pelvic surgery. The routine use of postoperative total parenteral nutrition, the chronic use of antibiotics after discharge from the hospital, and the routine use of imaging studies remain controversial. In this group of patients, the majority of complications may be successfully managed conservatively.