The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer.

BACKGROUND: BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms. PATIENTS AND METHODS: Patients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemar's test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan-Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups. RESULTS: Inter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemar's test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92). CONCLUSIONS: BRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further development of BRCA1 IHC as a potential biomarker for BRCA1 loss in high-grade serous ovarian cancer.

Medical service redesign shares the load saving 6000 bed days and improving morale.

BACKGROUND AND AIMS: In 2010, demand on the Auckland City Hospital general medical service exceeded capacity. A review by the Royal Australasian College of Physicians was critical of training offered to registered medical officers, and low morale was a problem across the service. Management offered support for an improved model that would solve these problems. METHODS: A project to redesign the general medical service was undertaken. Baseline analysis found uneven workload and insufficient capacity at peak times for patient presentations. Workshops involving the entire service led to a new model that splits workload and teams into patients likely to have a short stay from those requiring longer, ward-based care. Admissions are now distributed over 12 teams on weekdays and 4 on the weekends. There was an increase of approximately 2.5 in consultant full time equivalents but no change in registrar or house officer staffing. RESULTS: Since the introduction of the new model, the average length of stay has fallen from 3.7 to 3.2 days (14%) and the median length of stay by 28%, resulting in a saving of 6000 bed days per year. Readmission, inpatient and 30-day mortality rates are unchanged. These results have been sustained over 18 months with signs of continuing improvement. CONCLUSION: This project owes its success to the following factors - management support; iterative engagement of a range of staff; provision of timely data analysis; increases in senior medical officer staffing and reorganisation leading to more predictable and fair work practices. One challenge is discontinuity, whether between doctors and patients or within the medical team.

Quality of resuscitation orders in general medical patients.

BACKGROUND: Documentation of resuscitation status in hospitalized patients has relevance in the management of cardiopulmonary arrest. Its association with mortality, Length Of hospital Stay (LOS) and the patients' primary diagnosis has not been established in general medical inpatients in hospitals in Australia and New Zealand. AIM: To investigate the association of resuscitation orders with in-hospital mortality and LOS in a range of diagnoses, adjusting for severity of illness and other covariates. DESIGN: Retrospective study. METHODS: The admission notes of 1681 medical admissions to four tertiary care teaching hospitals across Australia and New Zealand were reviewed retrospectively for frequency and nature of resuscitation documentation and its association with mortality, LOS and primary diagnosis. RESULTS: Resuscitation orders were documented in 741 patients (44.7%). For the 232 patients with a Not For Resuscitation (NFR) order, the in-hospital mortality rate was higher than in control patients (14% vs. 1.2%, P<0.005). The mortality rate remained significantly higher in the NFR group after propensity matching of the controls for age and co-morbidity (14% vs. 5%, P<0.005). The death-adjusted LOS for the NFR group was also significantly higher compared to the control patients (9.7 days vs. 4.7 days, P<0.005) and this difference remained after propensity matching (9.7 days vs. 7.7 days, P<0.05). Those patients with a primary diagnosis of respiratory tract infection or cardiac failure were more likely to be documented NFR compared to those with cellulitis or urinary tract infection. CONCLUSIONS: The documentation of NFR in a patient's admission notes is associated with increased in-hospital mortality and LOS. This is only partly explicable in terms of these patients' greater age and co-morbidity.

Survival in epithelial ovarian cancer: a multivariate analysis incorporating BRCA mutation status and platinum sensitivity.

BACKGROUND: Patients with BRCA-associated ovarian cancer (OC) have a survival advantage over those with sporadic OC. To further explore this, we examined the impact of prognostic factors on disease-free survival (DFS) and overall survival (OS) in patients with known BRCA mutation status. PATIENTS AND METHODS: We reviewed stage III-IV OC patients treated at our institution between 1 December 1996 and 30 September 2006 and also tested on protocol for BRCA mutations. Impact on DFS and OS was determined by Kaplan-Meier analysis and a Cox proportional hazards model. RESULTS: Of the 110 patients, 36 had deleterious BRCA mutations [BRCA (+)] and 74 were BRCA wild type [BRCA(-)]. Thirty-one of 36 (86%) BRCA (+) and 60 of 74 (81%) BRCA (-) patients were platinum sensitive (P = 0.60). Median OS was longer for BRCA (+) patients (not reached versus 67.8 months; P = 0.02), but DFS was similar (26.9 versus 24.0, P = 0.3). On multivariate analysis, OS correlated with primary platinum sensitivity [HR = 0.15; 95% CI (confidence interval) 0.06-0.34] and BRCA (+) mutation status (HR = 0.33; 95% CI 0.12-0.86). CONCLUSIONS: BRCA mutation status predicted OS independent of primary platinum sensitivity, suggesting that underlying tumor biology contributes to disease outcome and may be worthy of consideration in future clinical trial design.

A phase I study evaluating the safety and pharmacokinetics of weekly paclitaxel and carboplatin in relapsed ovarian cancer.

This phase I study sought to determine the toxicity profile, pharmacokinetics, and antitumor activity of giving carboplatin every 3 weeks and paclitaxel weekly in patients with relapsed ovarian cancer. Eligible patients with relapsed epithelial ovarian cancer and prior treatment with platinum- and paclitaxel-based therapy were treated with an escalating regimen of carboplatin (day 1) at an area under the curve (AUC) of 4-6 and 1-h infusions of paclitaxel (days 1, 8, and 15) at 50-80 mg/m(2) cycled at 3-week intervals. Pharmacokinetic studies were performed on the first day of cycles 1 and 2. All patients had a platinum-free interval of greater than 6 months from the most recent platinum treatment. A total of 77 cycles were administered to 16 patients, with a similar median number of cycles per patient at each dose level varying from 4.6 to 5.3. Febrile neutropenia and grade 4 thrombocytopenia were the dose-limiting toxicities at dose levels 3 and 4 after the third cycle, with no mucositis, nausea, vomiting, or peripheral neuropathy observed greater than grade 2. The maximum tolerated dose of carboplatin was an AUC of 5 and 80 mg/m(2) for paclitaxel. Pharmacokinetic analysis showed a marginal statistical difference with regard to reduced systemic paclitaxel concentration after cycle 2 compared with cycle 1 (P= 0.06). Of nine patients evaluable for a radiographic response, the response rate was 66.6% with a complete response of 33.3%. All five patients with nonmeasurable disease achieved a biochemical response. The combination of carboplatin given every 3 weeks at an AUC of 5 and 1-h weekly paclitaxel at 80 mg/m(2) is a feasible and reasonably well-tolerated regimen and may have significant antitumor activity in relapsed ovarian cancer patients.

Early CA-125 fluctuations in patients with recurrent ovarian cancer receiving chemotherapy.

The objective of this study was to analyze retrospective populations with recurrent ovarian cancer to assess differences in CA-125 patterns during chemotherapy. The populations included all patients treated between January 1994 and January 2004, who received liposomal doxorubicin and topotecan, and all patients treated between July 1997 and June 2001, who received carboplatin. Prognostic variables were abstracted from the medical records. Eighty-nine patients received liposomal doxorubicin and topotecan therapy and 21 received carboplatin; of these, 59 (liposomal doxorubicin), 60 (topotecan), and 17 (carboplatin) patients had evaluable CA-125 patterns. Patients given liposomal doxorubicin were more likely to have received only one or two cycles of therapy (37/89 [42%]) than patients receiving either carboplatin (5/21 [24%]) or topotecan (20/89[22%]). In cycle 1, CA-125 increases in patients were carboplatin, 4/17 (24%); liposomal doxorubicin, 41/59 (69%); and topotecan, 11/60 (18%). In cycle 2, CA-125 increases were carboplatin, 2/16 (13%); liposomal doxorubicin, 19/37 (51%); and topotecan, 9/50 (18%). In cycle 3, CA-125 increases were carboplatin, 0/12 (0%); liposomal doxorubicin, 7/23 (30%); and topotecan, 6/38 (16%). Of patients having any CA-125 decrease and given two or more cycles, fewer declines were seen in those given liposomal doxorubicin precycle 2 (18/35[51%]) than in those given carboplatin (13/16[81%]) or topotecan (49/56[88%]). The most prominent delay in CA-125 decline was in patients given liposomal doxorubicin compared with those given topotecan or carboplatin. In the entire population, only 3 of 107 (2.8%) patients demonstrated first CA-125 decline precycle 4. Discontinuation of therapy solely on the basis of early CA-125 increase (precycle 3), particularly with liposomal doxorubicin chemotherapy, may exclude some patients who will benefit from continued therapy.

Paclitaxel and carboplatin in the treatment of advanced or recurrent endometrial cancer: a large retrospective study.

The aim of this study was to assess the efficacy and tolerability of paclitaxel and carboplatin (TC) in the treatment of patients with advanced or recurrent endometrial cancer. Patients eligible for this retrospective analysis had endometrial cancer with either advanced or recurrent measurable disease (untreated primary stage III/IV or stage III/IV patients with persistent, measurable disease [> or =2 cm] after surgery), Eastern Cooperative Oncology Group (ECOG) performance status > or =3, and received at least one cycle of TC. Response rates were determined using Response Evaluation Criteria in Solid Tumors criteria. Institutional Review Board approval was obtained prior to the initiation of this study. Eighty-five eligible patients, with a median age of 62 years (range 36-80) were identified. Fifty-seven (67%) of patients were treated at the time of recurrence. Prior radiation therapy had been used in the treatment of 36 (42%) patients, while 13 (15%) patients had received prior chemotherapy. Median follow-up time was 11.7 months (range 1.1-96.7 months), and the median number of cycles of therapy received was six (range 1-18). The overall response rate (ORR) was 43%, with a complete response rate of 5% and a partial response rate of 38%. Chemotherapy-naive patients had an ORR of 47%. Only seven (8%) patients had to discontinue therapy due to toxicity. Median progression-free survival was 5.3 months (95% CI, 4.6-7.4), with a median overall survival of 13.2 months (95% CI, 11.7-18.2). We conclude that TC is an active and tolerable regimen in the treatment of patients with advanced or recurrent endometrial cancer.

Phase II study of tirapazamine plus cisplatin in patients with advanced or recurrent cervical cancer.

The aim of this study was to evaluate the activity and toxicity of a tirapazamine (TPZ)/cisplatin drug combination in patients with stage IV or recurrent cervical cancer. The chemotherapy was administered for a maximum of eight cycles every 21 days. TPZ was administered intravenously at 330 mg/m(2) over a 2-h infusion, followed 1 h later by cisplatin intravenously at 75 mg/m(2) over 1 h on day 1. All patients received antiemetics including dexamethasone, ondansetron, and lorazepam. Subsequent doses were unchanged, reduced, or omitted according to observed toxicity and protocol guidelines. Response evaluation was performed every two cycles. Thirty-six patients with stage IV or recurrent cervical cancer were treated. Ninety-four percent of patients had prior radiotherapy. Two patients had prior chemotherapy. There were two complete responses and eight partial responses (27.8%). An additional 11 patients (30.6%) had stable disease as their best response. Response rate was greater in tumors outside of the previously radiated field (44.4% vs 11.1%). The median time to progression was 32.7 weeks. The most frequent grade 3 or 4 adverse events were nausea, vomiting, and fatigue, which occurred in 30.6%, 25%, and 22% of subjects, respectively. Anemia was the most frequent grade 3 or 4 hematologic toxicity at 8.3%. We conclude that the combination of cisplatin and TPZ was reasonably well tolerated in patients with recurrent or advanced cervical cancer. Further evaluation of this drug combination may be warranted.

Changing attitudes to the management of ischaemic stroke between 1997 and 2004: a survey of New Zealand physicians.

AIM: In 1997, a survey of New Zealand physicians' opinions on the management of stroke was carried out. Since then, there have been a number of advances in stroke therapy. We have repeated the 1997 survey to assess changes in physicians' opinions on stroke management. METHODS: A questionnaire was sent to 293 physicians responsible for patients admitted with acute stroke to hospitals throughout New Zealand. It included questions on the management of acute stroke and secondary prevention and was based on the 1997 questionnaire. RESULTS: Responses were received from 211 physicians of whom 174 (82%) managed patients with an acute stroke. The number of respondents who thought that stroke units were efficacious has increased (57% in 1997 to 89%, P < 0.001). The use of aspirin acutely (P < 0.001) and intravenous tissue plasminogen activator (P = 0.006) has also increased. In 2004, antihypertensive therapy for secondary stroke prevention would be commenced if the blood pressure was 150/90 by 98% of respondents and 140/90 by 70% of respondents. In 2004, a statin would be commenced if the total cholesterol level was 4.0 mmol/L by 56% of respondents and 5.0 mmol/L by 91% of respondents. CONCLUSIONS: This survey has shown important changes in the management of ischaemic stroke over the past 7 years.

Topotecan and liposomal doxorubicin in recurrent ovarian cancer: is sequence important?

A variety of agents have emerged to treat patients with recurrent epithelial ovarian cancer (EOC). Most patients receive both topotecan (T) and liposomal doxorubicin (D); however, there are no data regarding the benefit of a sequence-D followed by T (DT) or T followed by D (TD). We identified 89 consecutive patients with recurrent EOC, who received both D and T from January 1994 to January 2004 at Memorial Hospital. We compared the duration of treatment, toxicity, and overall survival (OS) for patients who received either DT or TD. Sixty-four patients received DT, and 25 patients received TD. The groups were balanced regarding age, stage, surgical debulking, platinum sensitivity, prior therapy, and intervening drugs between D and T. Median numbers of cycles on DT and TD were seven and six, respectively (P= 0.61); there was no difference in duration based on platinum sensitivity. Removal from therapy for toxicity was similar, DT (22%) and TD (36%) (P= 0.18). Finally, there was no difference in median OS based on sequence, DT (18.28 months) and TD (17.75 months) (P= NS). Platinum sensitivity did not affect median OS based on sequence. Based on duration, toxicity, and OS there is no advantage of one sequence of D and T when treating patients with recurrent EOC.

New agents for the treatment of ovarian cancer: the next generation.

Ovarian cancer shares many important characteristics with more common malignancies including breast, lung, and colon cancer. The relative chemosensitivity of ovarian cancer and other aspects of its unique biology provide opportunities for novel interventions. In this brief summary, some of the potential targets in ovarian cancer are discussed, including the HER kinases, heat shock protein, the 26S proteasome, and the angiogenesis pathway. The opportunities to change the treatment of ovarian cancer will require creative clinical trial design but the next decade promises to be filled the therapeutic advances for patients with ovarian cancer.

Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer.

PURPOSE: To determine the maximum-tolerated dose, pharmacodynamics, and safety of the combination of bortezomib and carboplatin in recurrent ovarian cancer. PATIENTS AND METHODS: Fifteen patients were treated with a fixed dose of carboplatin (area under the curve [AUC] 5) and increasing doses of bortezomib (0.75, 1, 1.3, and 1.5 mg/m2/dose). Patients must have received upfront chemotherapy and up to two prior chemotherapy regimens for recurrent disease. Neurologic evaluation was performed at baseline and after every two cycles by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire and examination by an attending neurologist. All patients received carboplatin alone in cycle 1 to establish baseline pharmacodynamics for nuclear factor-kappa B (NF-kB). Starting with cycle 2, patients were treated with carboplatin on day 1 and bortezomib on days 1, 4, 8, and 11. RESULTS: Diarrhea, rash, neuropathy, and constipation (with colonic wall thickening on computed tomography) were dose-limiting toxicities, occurring in the two patients treated at the 1.5 mg/m2/dose level. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire was helpful in guiding the need for dose reductions. Neurotoxicity was manageable through six cycles, with appropriate dose reductions. Carboplatin had no effect on bortezomib pharmacodynamics as measured by percent inhibition of the 20S proteasome. Bortezomib decreased carboplatin-induced NF-kB. The overall response rate to this combination was 47%, with two complete responses (CR) and five partial responses, including one CR in a patient with platinum-resistant disease. CONCLUSION: The recommended phase II dose of bortezomib administered in combination with carboplatin (AUC 5) is 1.3 mg/m2/dose.

Multi-institutional phase 2 study of TLK286 (TELCYTA, a glutathione S-transferase P1-1 activated glutathione analog prodrug) in patients with platinum and paclitaxel refractory or resistant ovarian cancer.

The purpose of this study was to determine the safety and efficacy of TLK286 (TELCYTA(TM)), a glutathione analog prodrug, in patients with platinum and paclitaxel refractory or resistant ovarian carcinoma. Thirty-six patients with measurable disease were enrolled. TLK286 was administered at 1000 mg/m2 intravenously every 3 weeks. The endpoints were objective response rate assessed by Response Evaluation Criteria in Solid Tumors (RECIST) and survival. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria. Thirty-four platinum refractory or resistant patients (94%) were evaluable for objective tumor response. Five patients (15%) had objective tumor responses, including one durable complete response (CR) of greater than 3 years and continuing. The disease stabilization rate was 50%, including one CR (3%), four partial responses (12%), and 12 durable disease stabilizations (35%). Responses were accompanied by improvement in clinical symptoms and Eastern Cooperative Oncology Group Performance Status (ECOG PS) and decline in CA125 levels. Median survival was 423 days with survival of 60% at 1 year and 40% at 18 months. TLK286 was well tolerated in this population. TLK286 is an active agent in chemotherapy-resistant ovarian cancer. Further studies of TLK286 in platinum and paclitaxel refractory or resistant ovarian cancer are in progress.

Anthracyclines in the treatment of gynecologic malignancies.

OBJECTIVE: The purpose of this article is to present a summary of the pharmacology of anthracyclines as well as to review the results of clinical trials including patients with gynecologic malignancies treated with anthracycline-based therapy. METHODS: We performed a MEDLINE literature search of relevant clinical trials for the scope of this review that evaluated anthracycline-based therapy in gynecologic malignancies. RESULTS: Doxorubicin has established activity in carcinomas that arise in the ovary, uterine cervix, and endometrium as well as in uterine sarcomas. However, doxorubicin has structural characteristics that limit its efficacy and safety. Newer anthracyclines with distinct structure, pharmacokinetics, pharmacodynamics, and toxicity profiles have been developed to overcome the limitations of doxorubicin and to further exploit the activity of anthracyclines. Epirubicin is characterized by a structural formula that confers similar cytotoxic antitumor activity with fewer associated side effects than its analogue. Most recently, pegylated liposomal formulations, with distinct pharmacokinetic properties and a favorable toxicity profile, have shown antitumor activity as salvage therapy in ovarian cancer. Intraperitoneal mitoxantrone is also associated with activity in ovarian cancer; however, its clinical use is limited by the severity of local adverse effects. CONCLUSIONS: The role of anthracyclines in the management of advanced gynecologic malignancies is important as part of first-line therapy or as a salvage approach. Newer anthracycline agents such as epirubicin and pegylated liposomal doxorubicin are associated with a more favorable toxicity profile. Clinical trials are under way to further explore the role of newer anthracycline-based regimens as first-line or salvage treatment in gynecologic malignancies.

A phase I and pharmacological study of the farnesyl protein transferase inhibitor L-778,123 in patients with solid malignancies.

This Phase I study was performed to assess the feasibility of administering L-778,123, a peptidomimetic farnesyl protein transferase (FPTase) inhibitor, as a continuous i.v. infusion for 7 days every 3 weeks and to determine the recommended dose for subsequent disease-directed trials. This study also sought to characterize the pharmacological behavior of L-778,123 and to determine whether the desired biological effect, inhibition of protein farnesylation, could be detected and assessed during treatment. Patients with advanced solid malignancies were treated with L-778,123 as a continuous i.v. infusion for 7 days every 3 weeks at doses ranging from 35 to 1120 mg/m(2)/day. On the basis of preclinical studies, toxicity assessments included cardiac telemetry, electrocardiograms, and electroretinograms in addition to more routine safety monitoring laboratory tests. Plasma sampling was performed to characterize the pharmacokinetics of L-778,123, and peripheral blood mononuclear cells (PBMCs) were sampled to detect and monitor the inhibitory effects of L-778,123 on the prenylation of HDJ2, a chaperone protein that undergoes farnesylation. Twenty-five patients received 51 complete courses of L-778,123. An unacceptably high incidence of dose-limiting toxicities, consisting of grade 4 thrombocytopenia, significant prolongation of the QT(c) interval, and profound fatigue, was observed at the 1120 mg/m(2)/day dose level. At the next lower L-778,123 dose level, 560 mg/m(2)/day, seven new patients had no unacceptable toxicity. Instead, myelosuppression was mild to moderate and QT(c) prolongation was negligible. Pharmacokinetics were linear, and L-778,123 plasma concentrations at steady-state (mean, 8.09 +/- 3.11 microM at 560 mg/m(2)/day) exceeded IC(50) values (range, 0.07-5.35 microM) required for growth inhibition and cytotoxicity in preclinical studies. The systemic clearance of L-778,123 averaged 106.4 +/- 45.6 ml/min/m(2), and the terminal half-life of elimination was 2.8 +/- 1.0 h. L-778,123 inhibited HDJ2 prenylation for the duration of the drug infusion in a dose-dependent manner, but seemed to plateau above 560 mg/m(2)/day. At the 560 mg/m(2)/day dose level, the mean percentage of HDJ2 protein in its unprenylated form increased from 1.41% +/- 1.71% (pretreatment) to 28.76% +/- 6.10% (day 4) and 30.86 +/- 4.96 (day 8) and declined to 2.28% +/- 2.11% one week after drug discontinuation (day 16). L-778,123 administered as a continuous 7-day i.v. infusion for 7 days every 21 days is well tolerated at doses of 560 mg/m(2)/day and results in biologically relevant concentrations and consistent inhibition of HDJ2 prenylation in PBMCs. Although the relationship between drug-related inhibition of HDJ2 prenylation in PBMCs and both prenylation of relevant proteins and growth inhibition in tumor cells is unknown, serial analyses of HDJ2 prenylation provide a pharmacodynamic marker of protein prenylation that may be useful in optimizing the development of drugs targeting FPTase.

The costs and efficacy of liposomal doxorubicin in platinum-refractory ovarian cancer in heavily pretreated patients.

OBJECTIVE: In clinical practice, chemotherapy agents demonstrating modest second-line activity against platinum-refractory epithelial ovarian cancer (PROC) are frequently used in patients who have received multiple prior chemotherapy agents. Whether the response rates reported in selected patients can be expected in heavily pretreated patients is not known. Similarly, the costs of palliative chemotherapy are not known. We sought to determine the response, survival, and predictors of response in an unselected cohort of PROC patients receiving liposomal doxorubicin (LD) for relapsed disease, and the overall costs of delivering liposomal doxorubicin in this setting. METHODS: In a cohort of 62 consecutive patients who initiated LD as second- or greater-line therapy for PROC, the following variables were examined: age, number of prior regimens for relapse disease, duration of first clinical remission, time from last prior treatment, dose intensity of LD received, response/clinical benefit, time to progression, toxic effects, and survival. Multivariate analyses were used to identify predictors of clinical benefit and overall survival. Direct medical charges were calculated and converted to costs, and major cost drivers determined. RESULTS: Sixty-two patients received a total of 174 cycles of LD. The mean number of cycles per patient was 2 (range, 1-8); the median number of prior regimens for recurrent PROC was 2 (range, 0-8); and the median duration of the first clinical remission was 6 months. Median dose intensity of LD delivered was 11.4 mg/m(2)/week (range, 2.8-16.7 mg/m(2)/week). Nine of sixty-two patients (14.5%) had an objective clinical response by CA-125 and/or CT scan (95% confidence interval, 6-23%). Grade 3/4 toxicity occurred in 11% of patients. In the full cohort, median time to progression was 2.2 months, and median overall survival, 9.6 months (range, 0.2-26 months). Dose intensity was the only independent predictor of overall response. Duration of first clinical remission and number of prior salvage regimens were associated with longer overall survival. The mean total direct medical cost per cycle of LD was $5763, and the major cost drivers were hospitalizations and drug acquisition/delivery costs. CONCLUSION: LD is an active agent in PROC, even when used as greater-than-second-line therapy. Among heavily pretreated patients, delivering a dose intensity of at least 9.0 mg/m(2)/week was associated with a higher probability of response. The cost per cycle of LD is driven by hospitalizations and drug acquisition/delivery costs.