Phase Ib/II study of weekly topotecan and daily gefitinib in patients with platinum resistant ovarian, peritoneal, or fallopian tube cancer.

INTRODUCTION: 50-70% of epithelial ovarian cancers overexpress epidermal growth factor receptor, and its expression has been correlated with poor prognosis. We conducted a phase Ib/II trial to examine the efficacy, safety, and toxicity of gefitinib, a tyrosine kinase inhibitor, combined with topotecan in women with recurrent ovarian cancer with epidermal growth factor receptor positivity. METHODS: Patients with measurable recurrent or persistent cancer after treatment with a platinum containing regimen with positive epidermal growth factor receptor expression, as determined by immunohistochemistry, were eligible for the study. Initial treatment was 250 mg/day gefitinib (oral) and 2.0 mg/m2 topotecan (intravenous) on days 1, 8, and 15, on a 28 day cycle. Dose escalations were planned for topotecan (dose levels 1-3: 2, 3, and 4 mg/m2) until the maximum tolerated dose was reached. RESULTS: 19 patients received a total of 61 cycles. Median age was 59.8 years (range 42-76 years). Histologic types in treated patients included 74% serous (n=14), 11% mixed (n=2), 11% transitional (n=2), and 5% clear cell (n=1). For phase Ib, three patients were treated at dose level 1, three at dose level 2, and three at dose level 3 for topotecan. The maximum tolerated dose was 4.0 mg/m2 (days 1, 8, and 15) for topotecan and 250 mg (daily) for gefitinib. Therefore, dose level 3 was used for phase II. Among the 19 patients, 63.2% (n=12) had progressive disease, 15.8% (n=3) had stable disease, 10.5% (n=2) had a partial response, and 10.5% (n=2) were not evaluable. The most serious adverse events of any grade attributed to the therapy were anemia (89.4%), neutropenia (68.4%), abdominal pain (84%), constipation (78.9%), and diarrhea (78.9%). CONCLUSION: Although the drug combination was relatively well tolerated, this prospective phase Ib/II clinical trial did not show sufficient clinical activity of topotecan combined with gefitinib in patients with epidermal growth factor receptor positive recurrent ovarian, fallopian tube, or peritoneal cancers.

Corrigendum: Enhanced Cytotoxic Effects of Combined Valproic Acid and the Aurora Kinase Inhibitor VE465 on Gynecologic Cancer Cells.

[This corrects the article on p. 58 in vol. 3, PMID: 23519775.].

Sustained complete response after maintenance therapy with topotecan and erlotinib for recurrent cervical cancer with distant metastases.

INTRODUCTION: Recurrent cervical cancer is associated with a poor prognosis. Most treatment responses are partial and of short duration. The development of new therapies is vital to improve treatment for recurrent disease. Epidermal growth factor receptor (EGFR) inhibitors may have a role in this setting. CASE DESCRIPTION: A 53-year-old woman with stage IB2 squamous cell carcinoma of the cervix was initially treated with chemoradiation. Six months after completing treatment, she developed a recurrence in the common iliac and para-aortic lymph nodes above the previous radiation field and was treated with additional radiation therapy. Two years later, she developed recurrent disease in the left supraclavicular lymph nodes and was treated with chemoradiation followed by 3 cycles of adjuvant cisplatin and topotecan. She had a complete response and was placed on maintenance therapy with topotecan and erlotinib, which was well tolerated and produced minimal side effects. After 20 months of maintenance therapy, it was discontinued given the long interval without evidence of disease. The patient is currently without evidence of disease 5 years after completing the topotecan-erlotinib treatment. CONCLUSION: We noted a sustained response in a patient with recurrent metastatic cervical cancer treated with radiotherapy, cisplatin, and topotecan followed by maintenance therapy with topotecan and erlotinib. Further evaluation of the role of EGFR inhibitors in this setting should be considered given their favorable toxicity profile and biological relevance.

Enhanced Cytotoxic Effects of Combined Valproic Acid and the Aurora Kinase Inhibitor VE465 on Gynecologic Cancer Cells.

Increasing evidence shows that targeting epigenetic changes including acetylation and deacetylation of core nucleosomal histones as well as Aurora kinases hold promise for improving the treatment of human cancers including ovarian cancer. We investigated whether the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), and the Aurora kinase inhibitor VE465 can have additive or synergistic effects on gynecologic cancer cells. We tested the in vitro antitumor activity of VPA and VE465, alone and in combination, in gynecologic cancer cells and assessed potential mechanisms of action. 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) analysis revealed that 72 h of treatment with VPA or VE465 alone induced dose-dependent cytotoxic effects in nine gynecologic cancer cell lines (ovarian: 2008/C13, OVCAR3, SKOV3, and A2780; cervical: ME180 and CaSki; endometrial: HEC-1B; and uterine sarcoma: MES-SA and MES-SA/D×5). Co-treatment with VPA and VE465 enhanced cytotoxic effects on five of these cell lines: ovarian: 2008/C13, A2780, and OVCAR3; endometrial: HEC-1B; and cervical: ME180. In ovarian 2008/C13 cells, co-treatment with VPA (2 mM) and VE465 (1 µM) induced more apoptosis than either VPA or VE465 alone. Western blot analysis showed that VPA alone increased the expression of cleaved PARP and p21 in a dose-dependent manner in 2008/C13 cells, while co-treatment with VPA and VE465 induced more cleaved PARP than treatment with VPA or VE465 alone did. The combined use of VPA and VE465 enhanced cytotoxic effects in some ovarian cancer cells, via enhanced induction of apoptosis. Targeting epigenetics with the HDAC inhibitor, in combination with Aurora kinase inhibitors, holds promise for more effective therapy of ovarian cancer.

Aurora kinase inhibitor VE 465 synergistically enhances cytotoxicity of carboplatin in ovarian cancer cells through induction of apoptosis and downregulation of histone 3.

Aurora kinases are essential for regulation of chromosome segregation and cytokinesis during mitosis and play a role in growth and progression of human tumors, including ovarian cancer. Aurora A and Aurora B are frequently overexpressed in high-grade and low-grade ovarian cancers. Targeting Aurora kinases has great potential for improving the efficacy of chemotherapies of ovarian cancer. In this study, we investigated whether the Aurora kinase inhibitor, VE 465, can enhance the anti-tumor activity of carboplatin in human ovarian cancer cells. The antitumor activity of VE 465 was tested by MTT proliferative assay in multiple established human epithelial ovarian cancer cell lines of varying p53 status. VE 465 and carboplatin had a synergistic effect on cell viability in both platinum-sensitive and -resistant ovarian cancers. The growth-inhibitory effect was accompanied by reduction in expression of histone 3 and an increase in apoptosis. We conclude that VE 465 enhances the efficacy of carboplatin agents in ovarian carcinoma.

Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer.

OBJECTIVES: On the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer. METHODS: Patients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n=10; taxane refractory, n=11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and (18)F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies. RESULTS: Patients received a total of 42 treatment cycles. No dose-limiting toxicity was observed. The median progression-free survival and overall survival were 1.9 months and 4.5 months, respectively. One patient with a PTEN mutation achieved a partial remission (PR) for 7.5 months, and another patient with a PIK3CA mutation had stable disease (SD) for 4 months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with KRAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with (18)F-FDG-PET responses. CONCLUSIONS: Patients tolerated perifosine 150 mg PO daily plus docetaxel at 75 mg/m(2) every 4 weeks. Further clinical evaluation of effects of perifosine with docetaxel on biological markers and efficacy in patients with ovarian cancer with defined PI3K pathway mutational status is warranted.

Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum.

OBJECTIVE: To determine whether hormonal therapies have efficacy in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. METHODS: We searched departmental databases for patients with histologically-confirmed, evaluable, recurrent low-grade serous ovarian or peritoneal carcinoma who received hormonal therapy at our institution between 1989 and 2009. We retrospectively reviewed patients' medical records for demographic, disease, hormonal therapy, and estrogen receptor and progesterone receptor expression data. We used the Response Evaluation Criteria in Solid Tumors version 1.1 to determine patients' responses to hormonal therapy. Because patients could have received more than one evaluable hormonal therapy regimen, we chose to define the outcome metric as "patient-regimens." Median time to disease progression (TTP) and overall survival (OS) were also calculated. Regression analysis was also performed. RESULTS: We identified 64 patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Patients' median TTP and median OS were 7.4 and 78.2 months, respectively. Patients received 89 separate hormonal patient-regimens, which produced an overall response rate of 9% (6 complete responses and 2 partial responses). Sixty-one percent of the patient-regimens resulted in a progression-free survival duration of at least 6 months. Patient-regimens involving ER+/PR+ disease produced a longer median TTP (8.9 months) than patient-regimens involving ER+/PR- disease did (6.2 months; p=0.053). This difference approached but did not reach statistical significance. CONCLUSIONS: Hormonal therapies have moderate anti-tumor activity in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Further study to determine whether ER/PR expression status is a predictive biomarker for this rare cancer subtype is warranted.

Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.

BACKGROUND: Sequential treatment with azacitidine can induce re-expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. A phase 1b-2a clinical trial of this sequential combination of azacitidine and carboplatin was initiated in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. METHODS: Patients with pathologically confirmed intermediate-grade or high-grade epithelial ovarian cancer who developed disease progression within 6 months (resistant disease, n = 18 patients) or during a platinum-based therapy (refractory disease, n = 12 patients) were eligible. All patients had measurable disease. RESULTS: Thirty patients received a total of 163 cycles of treatment. This regimen produced 1 complete response, 3 partial responses (overall response rate [ORR], 13.8%), and 10 cases of stable disease among 29 evaluable patients. For those patients who achieved clinical benefits, the median duration of the treatment was 7.5 months. The median progression-free survival (PFS) and overall survival (OS) for all patients were 3.7 months and 14 months, respectively. Patients with platinum-resistant disease achieved an ORR of 22%, with a median PFS of 5.6 months and a median OS of 23 months. The predominant toxicities were fatigue and myelosuppression. Correlative studies indicated that DR4 methylation in peripheral blood leukocytes was decreased during treatment in 3 of 4 objective responders (75%), but in only 5 of 13 nonresponders (38%). CONCLUSIONS: To the authors' knowledge, the results of the current study provide the first clinical evidence that a hypomethylating agent may partially reverse platinum resistance in patients with ovarian cancer. Further clinical evaluation of hypomethylating agents in combination with carboplatin is warranted.

Targeted therapies for rare gynaecological cancers.

Some gynaecological cancers are uncommon, such as sex cord-stromal tumours, malignant germ-cell tumours, vulvar carcinoma, melanoma of the female genital tract, clear-cell carcinoma of the ovary and endometrium, neuroendocrine tumours of the cervix, and gestational trophoblastic neoplasia. All these cancers have different clinicopathological characteristics, suggesting different molecular biological pathogeneses. Despite aggressive treatment, some cancers recur or respond poorly to therapy. Comprehensive knowledge of the molecular biology of each cancer might help with development of novel treatments that maximise efficacy and minimise toxic effects. Targeted therapy is a new treatment strategy that has been investigated in various tumours in clinical and laboratory settings. Since these cancers are rare and large clinical trials are difficult to do, molecular biological techniques might allow rapid proof-of-principle experiments in few patients. Novel targeted agents either alone or in combination with other treatments offer promising therapeutic options.

Phase 2 study of canfosfamide in combination with pegylated liposomal doxorubicin in platinum and paclitaxel refractory or resistant epithelial ovarian cancer.

BACKGROUND: Canfosfamide is a novel glutathione analog activated by glutathione S-transferase P1-1. This study evaluated the safety and efficacy of canfosfamide in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum resistant ovarian cancer. Patients with platinum resistant ovarian carcinoma and measurable disease received canfosfamide at 960 mg/m2 in combination with PLD at 50 mg/m2, intravenously day 1 in every 28 day cycles until tumor progression or unacceptable toxicities. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). RESULTS: Canfosfamide plus PLD combination therapy was administered at 960/50 mg/m2, respectively. Thirty-nine patients received a median number of 4 cycles (range 1.0-18.0). The ORR was 27.8% (95% CI, 14.2-45.2) with a disease stabilization rate of 80.6% (95% CI, 64.0-91.8) in the evaluable population. The CA-125 marker responses correlated with the radiological findings of complete response or partial response. The median PFS was 6.0 months (95% CI, 4.2-7.9) and median survival was 17.8 months. The combination was well tolerated. Myelosuppression was managed with dose reductions and growth factor support. Grade 3 febrile neutropenia was observed in 2 patients (5.1%). Non-hematologic adverse events occurred at the expected frequency and grade for each drug alone, with no unexpected or cumulative toxicities. CONCLUSIONS: Canfosfamide in combination with PLD is well tolerated and active in platinum and paclitaxel refractory or resistant ovarian cancer. A randomized phase 3 study was conducted based on this supportive phase 2 study.

Nuclear cyclin B1 is overexpressed in low-malignant-potential ovarian tumors but not in epithelial ovarian cancer.

OBJECTIVE: To investigate the role of cyclin G1 and cyclin B1 in ovarian tumorigenesis. STUDY DESIGN: We examined cyclin B1 and G1 expression in 58 epithelial ovarian cancer, 18 low-malignant-potential ovarian tumors, and 6 normal ovarian epithelium samples using immunohistochemistry. We also examined cyclin G1 and p53 expression in 7 epithelial ovarian cancer cell lines using Western blot analysis. RESULTS: Nuclear cyclin B1 expression was significantly higher in low-malignant-potential tumors than in normal ovarian epithelium. There was no difference in nuclear or cytoplasmic cyclin B1 or cyclin G1 expression between epithelial ovarian cancer and normal ovarian epithelium. Cyclin G1 and B1 expression was not associated with p53 expression or clinicopathologic features in patients with epithelial ovarian cancer or low-malignant-potential tumors. CONCLUSION: Our data demonstrated that nuclear cyclin B1 is overexpressed in low-malignant-potential tumors, which may contribute to the development of low-malignant-potential tumors. Cyclin B1 and G1 may not be suitable targets for epithelial ovarian cancer treatment.

Poor survival outcome with moderate and severe hypercalcemia in gynecologic malignancy patients.

OBJECTIVE: Determine the incidence of hypercalcemia in gynecologic malignancy patients and their survival outcome. DESIGN: Single-institution retrospective clinical study. PATIENTS AND METHODS: We used Fisher exact test, Kaplan-Meier survival curves, and Cox proportional hazards model to analyze demographic and clinical data from gynecologic malignancy patients with hypercalcemia who had been treated at The University of Texas M.D. Anderson Cancer Center from September 1997 to August 2006. RESULTS: Of the 5260 gynecologic malignancy patients, 268 had hypercalcemia (5%). Of the 268, 12 were excluded because of hyperparathyroidism or coexisting malignancies; thus, 256 patients were included in the study. Most patients (82%) had mild hypercalcemia. Severity of hypercalcemia was associated with disease stage (P = 0.0019), use of hypercalcemia treatment (P < 0.0001), and survival duration (P < 0.0001). The median survival duration of patients who had not been treated for hypercalcemia was 432 days compared with 106 days in patients who had been treated. The shorter survival duration of treated patients seems to result from their disease status and hypercalcemia severity rather than whether they were treated for hypercalcemia. CONCLUSIONS: Moderate and severe hypercalcemia is associated with poorer survival duration in gynecologic malignancy patients. Early detection and treatment of hypercalcemia in these patients may prolong survival. To our knowledge, this is the first study of hypercalcemia in patients with general gynecologic malignancy.

Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant.

PURPOSE: Previous studies have suggested that low-grade serous ovarian carcinoma is more chemoresistant to first-line or neoadjuvant chemotherapy than high-grade serous carcinoma. The purpose of this study was to further characterize this chemoresistance in recurrent low-grade serous ovarian carcinoma. METHODS: From a 1990-2007 search of the departmental databases at our institution, we identified recurrent low-grade serous ovarian carcinoma patients; abstracted chemotherapy response information from the medical records of those whose disease was: 1) histologically-confirmed, 2) measurable or evaluable, and 3) treated with chemotherapy; and retrospectively reviewed these data. Response was determined based on modified RECIST. Time to progression and overall survival were also calculated. RESULTS: We identified 58 evaluable patients with recurrent low-grade serous ovarian carcinoma who received 108 separate chemotherapy regimens ("patient-regimens"), which produced 4 responses-(1 complete and 3 partial; overall response rate, 3.7%). The overall response rate for the platinum-sensitive cohort was 4.9%, and for the platinum-resistant cohort, 2.1%. Stable disease was observed in 65 (60.2%) of 108 patient-regimens. Median overall survival was 87.1 months. The median time to progression was 29.0 weeks (34.7, platinum-sensitive cohort; 26.4, platinum-resistant cohort) (P=0.32). CONCLUSIONS: Compared with high-grade ovarian cancers, recurrent low-grade serous ovarian carcinoma appears relatively chemoresistant. Whether the latter's high rate of stable disease owes more to the tumor's biology or the influence of chemotherapy remains unclear. Based on these findings, phase II trials of novel targeted agents in recurrent low-grade serous ovarian carcinoma are warranted.

Azacitidine enhances sensitivity of platinum-resistant ovarian cancer cells to carboplatin through induction of apoptosis.

OBJECTIVE: The objective of the study was to investigate whether azacitidine sensitizes platinum-resistant ovarian cancer cells to carboplatin and the possible mechanisms involved. STUDY DESIGN: We tested the in vitro antitumor activity of azacitidine both alone and combined with carboplatin in the ovarian cancer cell line 2008/C13 and Hey by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assays and investigated the potential mechanisms by flow cytometry, terminal transferase deoxyuridine 5-triphosphate nick-end labeling assay, Western blot, reverse transcriptase-polymerase chain reaction (PCR), and promoter methylation-specific PCR. RESULTS: Sequential treatment (ie, 24-hour azacitidine pretreatment followed by 48-hour cotreatment with azacitidine and carboplatin) significantly inhibited growth in 2008/C13 and Hey cells. More apoptotic cells were induced in 2008/C13 cells by sequential treatment than by a single drug. Increased cleaved caspase-3 and -8 were seen in 2008/C13 cells after sequential treatment with azacitidine and carboplatin. DR4 was demethylated, and DR4 messenger ribonucleic acid expression was increased in 2008/C13 cells after the 24-hour azacitidine treatment. CONCLUSION: Azacitidine enhanced the sensitivity of platinum-resistant ovarian cancer cells to carboplatin associated with caspase-3- and -8-dependent apoptosis pathway and reexpression of DR4.

Update on aurora kinase inhibitors in gynecologic malignancies.

Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis and play a role in tumorigenesis and tumor progression in humans. Aurora kinase A and Aurora kinase B are overexpressed in some gynecologic cancers, and their overexpression is associated with poor prognosis. Thus, targeting of Aurora kinases has become an attractive strategy for pharmaceutical companies, who have developed more than 30 Aurora kinase inhibitors for treatment of cancers. Some of these inhibitors have been shown to be effective in targeted therapies for human cancer, and others are currently being investigated. In this review, we summarize the most recent advances in preclinical studies and clinical trials of patented Aurora kinase inhibitors for gynecologic tumors.

Chemotherapy for recurrent and metastatic cervical cancer.

OBJECTIVES: Our purpose is to review the chemotherapy for recurrent and metastatic cervical cancer. METHODS: We reviewed the phase II and III clinical trials of chemotherapy regimens and recent advances of targeted therapy for treatment of recurrent and metastatic cervical cancer. We also reviewed chemotherapy for rare histological subtypes of cervical cancer. RESULTS: Recent data has shown that the combination of cisplatinum and topotecan is the only regimen to demonstrate a progression-free survival and overall survival advantage over single agent cisplatin in the setting of recurrent cervical cancer. Preliminary study results indicate that targeted therapies may have an important role in the management of recurrent or metastatic cervical cancer. CONCLUSION: There remains a need for novel agents and further research focusing on the management of recurrent and metastatic cervical cancer. Future goals of therapy are to increase efficacy of treatment options while decreasing toxicity.

Efficacy of letrozole in the treatment of recurrent platinum- and taxane-resistant high-grade cancer of the ovary or peritoneum.

OBJECTIVE: To evaluate the efficacy and safety of letrozole in patients with recurrent platinum- and taxane-resistant estrogen receptor-positive (ER+) high-grade cancer of the ovary or peritoneum. METHODS: A single-institution, phase II study was performed in women with recurrent ER+ epithelial carcinoma of the ovary or peritoneum. All patients had measurable disease. Letrozole was administered at a dose of 2.5 mg orally once daily until disease progression or toxicity occurred. RESULTS: Thirty-three patients were enrolled. The median age was 63 years (range, 38 to 83 years). Twenty-three patients (74%) had received three or more prior chemotherapy regimens. The 31 patients evaluable for response received a total of 81 cycles (4 weeks/cycle) of therapy (range, 1 to 14 cycles/patient). The median treatment duration was 8 weeks (range, 4 to 52 weeks). None of the patients had a complete response (CR), 1 (3%) had a partial response (PR), and 7 (23%) had stable disease (SD). The median duration of clinical benefit (SD and PR) was 9 weeks (range, 7 to 46 weeks). The median follow-up for all patients was 25 weeks. All patients were evaluable for toxicity. The most common adverse effects were fatigue (36%) and diaphoresis (21%). No grade 3 or 4 toxicities were reported, and no patients discontinued treatment owing to adverse effects. Eighteen patients (58%) went on to receive additional therapy with other agents. CONCLUSION: In patients with ER-positive, platinum- and taxane-resistant high-grade ovarian and primary peritoneal cancer treated with letrozole, 26% derived a clinical benefit (SD and PR).

Diammine dicarboxylic acid platinum enhances cytotoxicity in platinum-resistant ovarian cancer cells through induction of apoptosis and S-phase cell arrest.

PURPOSE: Polysaccharides such as chondroitin play a potent role in tumor growth, tissue repair and angiogenesis. These properties make chondroitin a good candidate for novel drug delivery systems. Diammine dicarboxylic acid platinum (DDAP), a novel polymeric platinum compound, was developed by conjugating the platinum analogue to aspartate-chondroitin for drug delivery to tumor cells. DDAP improves platinum solubility which may reduce systemic toxicity and be more efficacious than cisplatin in killing tumor cells. METHODS: We tested and compared the cytotoxic effects of DDAP and CDDP on the platinum-sensitive 2008 and A2780 ovarian cancer cell lines and their platinum-resistant sublines 2008.C13 and A2780cis; we also investigated DDAP's mechanism of action. RESULTS: In the platinum-sensitive cell lines, the cytotoxic effects of DDAP and CDDP were comparable. However, in the platinum-resistant sublines, significantly greater cell-growth inhibition was induced by DDAP than by CDDP, especially at lower doses. DDAP also induced more apoptosis than CDDP did in the 2008.C13 subline, which was partially mediated by the caspase 3-dependent pathway. In addition, lower (but not higher) doses of DDAP arrested 90% of S-phase 2008.C13 cells, which might be associated with up-regulation of p21 and maintenance of low cyclin A expression. Furthermore, greater cellular uptake of DDAP was seen in platinum-resistant than in platinum-sensitive ovarian cancer cells. CONCLUSIONS: Low-dose DDAP enhances drug delivery to platinum-resistant ovarian cancer cells and substantially inhibits their growth by inducting apoptosis and arresting cells in the S-phase, suggesting that DDAP may overcome platinum resistance in ovarian cancer.

Hormone replacement therapy after treatment of endometrial cancer.

Hormone replacement therapy (HRT) after endometrial cancer (EMC) treatment is an uncertain subject with limited exploration among gynecologic cancer research. Because estrogen is a well-recognized etiologic factor of EMC, most physicians are probably reluctant to provide a replacement therapy, or limit its use to only a selected group of patients. In order to give an overview on this subject, we searched the English-language literature to identify relevant studies or reports. We found that HRT did not appear to increase the recurrence or death rates in EMC. However, most information came from retrospective studies with selection bias, or from a small prospective non-randomized study. The only randomized controlled trial of the Gynecologic Oncology Group could also not provide a definite answer regarding its safety and recommendation. In conclusion, on the basis of the currently available studies, HRT after EMC treatment does not appear to have an adverse effect on EMC. Nevertheless, because of a limitation of data, the physician should thoroughly consider all possible benefits and theoretical risks of recurrence or mortality in each individual to provide the best of care for their patients.