A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens.

The objective of this study was to determine the objective response rate in patients with platinum-sensitive and platinum-resistant recurrent ovarian cancer to treatment with trabectedin (Yondelis) administered as a 3-h infusion weekly for 3 weeks of a 4-week cycle. We carried out a multicentre Phase II trial of trabectedin in patients with advanced recurrent ovarian cancer. Trabectedin (0.58 mg m(-2)) was administered via a central line, after premedication with dexamethasone, to 147 patients as a 3-h infusion weekly for 3 weeks followed by 1-week rest. Major eligibility criteria included measurable relapsed advanced ovarian cancer and not more than two prior platinum-containing regimens. Patients were stratified according to the treatment-free interval (TFI) between having either platinum-sensitive (>/=6 months TFI) or platinum-resistant disease (<6 months TFI)/platinum-refractory disease (progression during first line therapy). In the platinum-sensitive cohort, 62 evaluable patients with measurable disease had an overall response rate (ORR) of 29.0% (95% CI: 18.2-41.9%) and median progression-free survival (PFS) was 5.1 months (95% CI: 2.8-6.2). Four patients with measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) criteria had no follow-up scans at the end of treatment. In the platinum-resistant/refractory cohort, 79 patients were evaluable with an ORR of 6.3% (95% CI: 2.1-14.2%). Median PFS was 2.0 months (95% CI: 1.7-3.5 months). Two patients with measurable disease per RECIST criteria had no follow-up scans at the end of treatment. The most frequent (>/=2% of patients) drug-related treatment-emergent grade 3/4 adverse events were reversible liver alanine transferase elevation (10%), neutropaenia (8%), nausea, vomiting, and fatigue (5% each). Trabectedin is an active treatment, with documented responses in patients with platinum sensitive advanced relapsed ovarian cancer, and has a manageable toxicity profile.

Comparative analysis of methods for collection and measurement of cytokines and immunoglobulins in cervical and vaginal secretions of HIV and HPV infected women.

The goal of these studies was to distinguish which of two techniques [cervicovaginal lavage (CVL) and cervical wick (SS)] is the optimal collection method for the measurement of the local immunological response in human papillomavirus (HPV) and HIV infected women. The following parameters were measured in 24 paired samples from 15 women (9 HIV+, 6 HIV-): total protein, immunoglobulin levels, HPV-specific antibodies, and Th1-Th2 cytokines. In addition, relative mRNA levels from CVL cell pellets were compared to protein levels from CVL supernatants. The total protein (2-fold) and IgG concentration (10-fold) are higher in the SS samples, were reproducible (%CV<3) and these levels correlated (P<0.0001) with their paired CVL sample. Type-specific HPV-L1 IgG and IgA antibodies were detected in CVL and SS (r>0.28, P<0.008) with excellent reproducibility (CV<3.0%). However, SS (%CV>18) failed to yield reproducible results for the cytokine assays as compared to the CVL (%CV<5.0). Furthermore, no correlations were found between relative mRNA levels from CVL cell pellet and cytokine protein levels in CVL supernatants. The CVL sample's superior reproducibility in the cytokine assays makes this the better collection method. In addition, cytokine protein level's failure to correlate with mRNA suggests tight regulation of cytokine genes or production from a different cell population.

Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study.

PURPOSE: To assess progression-free survival (PFS) and overall survival (OS) in patients with suboptimally debulked epithelial ovarian cancer receiving cisplatin (100 mg/m(2)) or 24-hour infusion paclitaxel (200 mg/m(2)) or the combination of paclitaxel (135 mg/m(2)) followed by cisplatin (75 mg/m(2)). PATIENTS AND METHODS: After stratification for disease measurability, patients were randomized to receive six cycles of one of the treatments every 3 weeks. If measurable, complete response (CR) or partial response (PR) was determined. RESULTS: Six hundred fourteen of 648 patients who entered onto the trial were eligible. Monotherapies were discontinued more frequently (cisplatin because of toxicity or patient refusal [17%], and paclitaxel because of progression [20%]) compared with the combination therapy (7% and 6%, respectively). Neutropenia, fever, and alopecia were more severe with paclitaxel-containing regimens; whereas anemia, thrombocytopenia, neurotoxicity, nephrotoxicity, and gastrointestinal toxicity were more severe with cisplatin-containing regimens. The CR/PR rates on paclitaxel monotherapy were significantly lower compared with the cisplatin regimens (42% v 67%, respectively; P <.001). The relative hazard (RH) of first progression or death was significantly greater among those randomized to paclitaxel (RH = 1.41; 95% confidence interval [CI], 1.15 to 1.73; P <.001) when compared with cisplatin; however, RH did not differ significantly between the two cisplatin regimens (RH = 1.06; 95% CI, 0.895 to 1.30). Relative to cisplatin, the death rate on paclitaxel was 15% greater (RH = 1.15; 95% CI, 0. 929 to 1.42), and the death rate on the combination treatment was 1% less (RH = 0.99; 95% CI, 0.795 to 1.23). These differences among treatment groups were not statistically significant (P =.31). CONCLUSION: Cisplatin alone or in combination yielded superior response rates and PFS relative to paclitaxel. However, OS was similar in all three arms, and the combination therapy had a better toxicity profile. Therefore, the combination of cisplatin and paclitaxel remains the preferred initial treatment option.

Phase I and pharmacokinetic study of intraperitoneal topotecan.

OBJECTIVE: To determine the maximum tolerated dose and pharmacokinetics of topotecan when administered by the intraperitoneal route. METHODS: A dose-escalating Phase I trial was conducted in which fifteen % of the total dose was given as an intraperitoneal bolus in two litres of D5W and the remainder was given as a continuous intraperitoneal infusion over 24 hours. Treatments were given every 21 days. Pharmacokinetic analyses were performed at the recommended phase II dose. RESULTS: Seventeen patients received a total of 43 cycles at 21-day intervals. The maximum tolerated dose was 4 mg/m2 and acute dose-limiting toxicity was neutropenia. Other toxicities included leukopenia, anemia, emesis, fever, and abdominal pain. Although no objective responses were achieved, five of ten patients with ascites had a decrease in fluid accumulation with administration of intraperitoneal topotecan. The recommended phase II dose is 3 mg/m2. Pharmacokinetic analysis performed at a dose of 3 mg/m2 demonstrated that elimination from the peritoneal cavity followed second-order kinetics with k1 = 1.6 hr(-1), k2 = 0.3 hr(-1) and first and second-phase half-lives of 0.49 and 2.7 hours, respectively. Plasma pharmacokinetic behavior was best described by first-order kinetics with k = 0.5 hr(-1) and a half-life of 3.9 hours. The pharmacologic advantage, expressed as the peritoneal to plasma AUC ratio was 31.2. CONCLUSIONS: Intraperitoneal administration of topotecan at 3 mg/m2 results in a substantial increase in drug exposure for the peritoneal cavity without compromising systemic exposure; this may be beneficial for the treatment of patients with ovarian cancer or intraperitoneal carcinomatosis.

Use of ileocecal continent urinary reservoir in patients with previous pelvic irradiation.

OBJECTIVE: To assess the results of the use of ileocecal continent urinary reservoirs in patients with previous pelvic irradiation. METHODS: A retrospective analysis for morbidity and clinical outcome was undertaken for 37 female patients with prior therapeutic pelvic irradiation who underwent continent urinary diversion with a detubularized right colonic segment as the urinary reservoir, a plicated ileocecal valve as the continence mechanism, and a tapered distal ileum for efferent catheterization. RESULTS: Thirty-one patients had persistent or recurrent pelvic malignancies, 17 of whom had total pelvic exenteration and 14 had anterior exenteration. The remaining 6 patients had radiation-induced vesicovaginal fistulas without evidence of recurrence and underwent urinary diversion alone. Follow-up ranged from 2 to 33 months (median 11 months). Postoperative radiographic evaluation revealed no evidence of urinary extravasation. Of the 74 implanted ureters, 4 had reflux (5%), 2 developed stricture (3%), and 5 had mild to moderate hydronephrosis (7%). All patients achieved daytime continence with catheterization intervals of 3-8 hr (median 4 hr) and capacities of 200-1000 cc (median 500 cc). Nighttime continence was reported by 33 of 37 patients (89%). Reoperation was required in 3 patients (8%), 2 with stoma stenosis and 1 with difficulty in catheterization. CONCLUSIONS: The use of the ileocecal continent urinary reservoir in patients with previous pelvic irradiation achieves results comparable to those reported for nonirradiated patients, thus supporting its use in this select group of patients.

Intraperitoneal administration of cisplatin and 5-fluorouracil in residual ovarian cancer: a Phase II Gynecologic Oncology Group trial.

Forty-eight patients with persistent or recurrent epithelial ovarian cancer who had persistent or recurrent disease following intravenous (i.v.) cisplatin-based chemotherapy were treated with intraperitoneal (ip) cisplatin and 5-fluorouracil (5-FU) as salvage therapy. All patients had surgically documented minimal residual disease (1.0 cm or less maximum tumor diameter) at the completion of surgery and were without clinical, radiographic, or histologic evidence of extraperitoneal disease. Of the 45 patients evaluable for response, 13 had a documented partial response (PR) or complete response (CR) to previously administered i.v. cisplatin (cisplatin-sensitive) while the remaining 32 patients were noted to have stable or progressive disease on the previous i.v. cisplatin regimen (cisplatin-refractory). The median number of treatment cycles was six. At the completion of eight cycles of chemotherapy, 22 patients had no clinical or radiographic evidence of persistent disease and were thus eligible for a third-look laparotomy. Seven patients refused surgical evaluation. Three of the 15 patients who underwent a third-look laparotomy had a pathologic complete response (PCR) while 3 other patients had surgically documented partial response. All the surgically documented responses were in cisplatin-sensitive patients for a surgically documented response rate in this patient population of 66.7% (3 of 9 PCR and 3 of 9 PR). The remaining nine patients, who were all previously cisplatin-refractory, had stable or progressive disease documented at third-look laparotomy. Thirty-four patients experienced leukopenia with a median WBC nadir of 2800/microliters while 12 patients experienced thrombocytopenia with the median platelet nadir of 122,000/microliters. There was one treatment-related death secondary to sepsis. Four patients experienced catheter-related complications, ip cisplatin and 5-FU as salvage therapy is feasible in a multi-institutional cooperative group trial and, in cisplatin-sensitive patients, is an effective treatment option.

A comparison of intravenous versus intraperitoneal chemotherapy for the initial treatment of ovarian cancer.

A phase III study was conducted comparing intraperitoneal (ip) versus intravenous (iv) cisplatin-based therapy for patients with newly diagnosed ovarian cancer to determine if the pharmacologic advantage of ip delivery could be translated into an improved response and survival rate. Twenty-nine patients were randomized to receive six cycles of ip cisplatin 200 mg/m2 plus ip etoposide 350 mg/m2 with iv thiosulfate protection given every 4 weeks; thirty-three patients were randomized to receive six cycles of iv cisplatin 100 mg/m2 plus iv cyclophosphamide 600 mg/m2 administered every 3 weeks. Patients were stratified by stage (IIC-IV) and size of residual disease (> or < or = 1 cm). The study was conducted in a community-wide setting. The complete response in evaluable patients was 48% in the ip group and 52% in the iv group. The surgical complete response rate for all patients on study, underestimated because not all patients in complete clinical remission had a second-look laparotomy, was 31% in the ip group and 33% in the iv group. There was no difference in the response rates between the treatment arms as a function of residual disease < or = or > 1 cm. With a median follow-up of 46 months (range 21-70 months) there is no difference in response duration or survival. Both regimens were well tolerated with comparable hematologic and nonhematologic toxicity.

Phase I and pharmacokinetic study of intraperitoneal ormaplatin.

Ormaplatin is a cisplatin analog which has demonstrated activity against cisplatin-resistant tumors in preclinical studies. We delivered 28 cycles to 14 patients in a phase I trial of intraperitoneal ormaplatin given every 28 days. The maximum tolerated dose was 88.4 mg/m2 and acute dose-limiting toxicity was abdominal pain. Other toxicities include nausea, emisis, fever, and severe neuropathy seen in 1 patient at a cumulative dose of 399 mg/m2. No objective responses were observed. Hematologic toxicity was mild. The dose recommended for future trials of intraperitoneal ormaplatin is 66.5 mg/m2. Pharmacokinetic analysis performed at a dose of 66.5 mg/m2 demonstrated that the initial phase of elimination from the peritoneal cavity follows first-order kinetics with k = 0.69 hr-1 and half-life of 1.4 hr. Plasma pharmacokinetic behavior is best described by biexponential model with k1 = 0.369 hr-1, k2 = 0.107 hr-1, and first half-life of 2.9 hr and second half-life of 8.4 hr. Pharmacologic advantage, calculated by ratio of peritoneal to plasma AUC, is 17.1. If site-specific activity is demonstrated, then the intraperitoneal route of administration of ormaplatin at 66.5 mg/m2 may be beneficial.

Profiles of women age 30-39 and age less than 30 with epithelial ovarian cancer.

OBJECTIVE: To study a group of women diagnosed with epithelial ovarian cancer at a young age (less than 40). METHODS: Tumor registry data were analyzed with respect to age at diagnosis, stage, grade, frequency of nulligravidity, and family history of breast or ovarian cancer. Frequencies were analyzed using contingency tables, and survival distributions were analyzed according to the method of Kaplan and Meier. Multivariate survival analysis was performed with the Cox method. RESULTS: We found significantly higher frequencies of low-grade tumors (90 versus 37%; P = .0003, chi 2 test) and early-stage tumors (45 versus 17%; P = .03, Fisher exact test) in women less than 30 at the time of diagnosis (very young patients) than in those between 30-39. We also found a significant (P = .017, Breslow statistic) survival advantage for the very young women. Multivariate analysis demonstrated tumor grade as the independent variable for survival. CONCLUSION: These findings support the concept of a preclinical phase of epithelial carcinoma and show that young women may derive substantial benefit from ovarian cancer screening programs.

Flow cytometric evaluation of ovarian cancer.

BACKGROUND: Despite recent advances in the treatment of ovarian cancer, the long-term prognosis for patients with this malignancy appears to depend more on tumor prognostic factors than on treatment regimens. The traditionally used prognostic factors are often subjective and, currently, have not been sufficient to determine individual patient prognosis. METHODS: Newer techniques of quantitative cytologic testing, including flow cytometry, facilitate the objective evaluation of tumor cell heterogeneity and the identification of additional prognostic factors. RESULTS: There is good evidence, mainly from retrospective studies, that DNA ploidy is a valuable prognostic indicator in patients with both early-stage and late-stage ovarian cancer. Most of the recent flow cytometric studies have identified ploidy as an independent prognostic factor, with aneuploidy predicting a significantly shorter survival time, even in patients with borderline malignant tumors. Flow cytometric determination of cell cycle information (e.g., S-phase fraction or proliferative index) may represent additional prognostic information and may be used to predict the early tumor response to treatment. CONCLUSIONS: Although additional prospective studies are needed to establish the exact value of flow cytometric evaluation for ovarian cancer and other gynecologic malignancies, there is little doubt that the prognostic value of this information will influence clinical management of patients with these malignancies in the near future.

The current status of flow cytometry in gynecologic oncology.

In recent years, the use of flow cytometry has expanded from its initial research role to include the detection of clinically relevant abnormalities in the nuclear DNA content of tumor cells and variations in cell-growth kinetics. Retrospective studies have shown that DNA ploidy, and possibly the proliferative or S-phase fraction, is a valuable prognostic indicator in patients with gynecologic malignancies, including gestational trophoblastic disease, early- and late-stage ovarian cancer, squamous-cell cervical cancer and its precursor lesions, and endometrial adenocarcinoma. Further prospective studies are needed to establish the exact value of flow cytometry for gynecologic and other tumors. However, the prognostic value of this information certainly will influence the clinical management of patients with these malignancies in the near future.

Endometrial thickness after menopause: effect of hormone replacement.

Ultrasound (US) images of the pelvis were evaluated in 112 asymptomatic postmenopausal women to investigate the normal range of endometrial thickness (double-layer measurement) and the effect of hormone replacement on these measurements. Twenty-one patients (19%) had endometrial thickness greater than 0.8 cm. One patient, with an endometrial thickness of 2.5 cm, had endometrial carcinoma. Consideration of the known actions of estrogen and progestogen on the endometrium led the authors to believe that the clinical significance of an endometrium measuring more than 0.8 cm depends on the patient's hormonal status. Among asymptomatic postmenopausal women with an endometrial thickness between 0.8 and 1.5 cm, those receiving unopposed estrogen or continuous estrogen and progestogen need to undergo dilatation and curettage (D&C) or biopsy and those receiving no hormones or receiving sequential estrogen and progestogen should be encouraged to undergo D&C or biopsy. If a patient in one of the latter two groups is unwilling to undergo an invasive procedure, then US examination at 3-month intervals is acceptable. Any patient with endometrial thickness of at least 1.5 cm should undergo histologic diagnosis, regardless of symptoms or hormone status.

Prevalence of simple adnexal cysts in postmenopausal women.

This prospective study was performed with ultrasound (US) to determine the prevalence of unilocular, nonseptated adnexal cysts ("simple cysts") in healthy postmenopausal women and the relationship between cyst occurrence and both hormone replacement and length of time since onset of menopause. Transabdominal and transvaginal US were performed on 149 volunteers aged 50 years or older. Patients were classified according to hormone regimens (no hormones, unopposed estrogen, continuous daily estrogen and progesterone, and sequential estrogen and progesterone) and time since onset of menopause (less than 5 years, 5-10 years, and greater than 10 years). Simple adnexal cysts were found in 22 women with the aid of transvaginal and/or transabdominal US, yielding a relative frequency of 14.8% +/- 5.7% and a prevalence of 14,800 patients with cysts per 100,000 patients. No statistical relationship was found between cyst frequency and type of hormone replacement or length of time since onset of menopause.

Phase I and pharmacokinetic trial of intraperitoneal etoposide in combination with the multidrug-resistance-modulating agent dipyridamole.

Dipyridamole synergistically enhances the sensitivity of human ovarian carcinoma cells to etoposide in vitro. We conducted a phase I trial to investigate the feasibility of using dipyridamole to selectively increase the sensitivity to etoposide of tumors confined to the peritoneal cavity. Etoposide and dipyridamole were administered as a continuous 72-hour intraperitoneal infusion to 16 patients. The maximum tolerated dose of etoposide was 175 mg/m2 per day when administered with dipyridamole at a fixed dose of 24 mg/m2 per day. Dose-limiting toxic effects were leukopenia and thrombocytopenia. No other major toxic effects were observed. The free peritoneal etoposide and dipyridamole concentrations varied with the etoposide dose rate, reaching 218.9 and 25.3 microM, respectively, at an etoposide dose rate of 175 mg/m2 per day. The free etoposide and dipyridamole concentrations attained were well within the range needed for synergistic interaction.

Indiana pouch continent urinary reservoir in patients with previous pelvic irradiation.

Little information exists on the use of continent urinary reservoirs in patients with previous pelvic irradiation. We report the use of the Indiana pouch urinary reservoir in ten women with a history of pelvic irradiation for cervical cancer, of whom eight underwent a total pelvic exenteration for recurrent pelvic tumor and two had diversion for radiation-induced vesicovaginal fistula. All ten women achieved daytime continence, with a median time between catheterizations of 4.5 hours and a median pouch capacity of 500 mL. There was no evidence of leakage from the reservoir or significant ureteral reflux or obstruction on postoperative radiographic evaluation. No patient has required reoperation or had significant postoperative complications with the technique described.

Circadian gating of S phase in human ovarian cancer.

Cell proliferation in 30 patients with ovarian cancer was analyzed using flow cytometry to determine changes in the percentage of cells in S phase. By this measure, proliferation in tumor cells appears to follow a cyclical pattern of peaks and troughs that is out of phase with the circadian rhythm in proliferation of normal tissues. In round-the-clock monitoring of replication stages in tumor cells recovered from i.p. lavage fluid in postsurgery patients, peaks of tumor and nontumor cell DNA synthesis commonly occurred at different times of day. When patients were grouped so that only tumor cell proliferation was being measured, a highly significant 24-h rhythm nearly 12 h out of phase with nontumor cell proliferation was found. This peak in the percentage of S-phase cells occurs most commonly in mid- to late morning and appears to offer an opportunity for timing chemotherapy to coincide with high tumor cell vulnerability and low toxicity to normal tissue.