Weekly administration of bevacizumab, gemcitabine, and oxaliplatin in patients with recurrent and refractory ovarian cancer: a preliminary result of 19 cases.

OBJECTIVE: Combination therapy using gemcitabine with oxaliplatin (GEMOX) showed moderate activity in recurrent ovarian cancers. However, severe toxicities have been observed in patients who received full-dose therapy of GEMOX. On the other hand, bevacizumab enhances chemotherapeutic efficacy in various cancers. Here, we evaluated the effect of weekly low-dose administration of GEMOX in combination with bevacizumab (B-GEMOX) for patients with recurrent and refractory ovarian cancers (ROCs). METHODS: A total of 19 patients with ROC were treated with B-GEMOX: 2 mg/kg of bevacizumab, 300 mg/m(2) of gemcitabine, and 30 mg/m(2) of oxaliplatin, 3 weeks on and 1 week off, q4weeks. The treatment was continued until development of severe toxicities or progressive disease. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors and Gynecologic Cancer Intergroup criteria. RESULTS: Median number of the B-GEMOX therapy was 5 cycles. Response was observed in 4 (34%) cases by Response Evaluation Criteria in Solid Tumors, and in 2 (29%) cases by Gynecologic Cancer Intergroup criteria, resulting in overall response rate of 32%. Clinical benefit excluding progressive disease was obtained in 79% of the patients. Median progression-free survival was 4.5 months (range, 2-16+ months). Toxicities were mild and mainly consisted of hematologic, gastrointestinal, and neuropathy; however, there were no nonhematologic toxicities more than grade 1. CONCLUSIONS: Weekly administration of B-GEMOX was active for patients with ROC and showed mild toxicities. These results warrant further prospective studies for patients with ROC.

Complete remission of recurrent ovarian clear cell carcinoma by chemotherapy with bevacizumab, trabectedin and oxaliplatin.

Clear cell carcinoma of the ovary has shown an exceedingly chemo-resistant phenotype, especially in cases that are recurrent or refractory to previous therapy. Also, progression-free survival was less than 6 months, even in the patients that achieved response when they were treated with conventional anti-cancer cytotoxic agents. We present a case with recurrent and refractory ovarian clear cell carcinoma that achieved complete remission using a combination of bevacizumab, trabectedin and oxaliplatin. The progression-free interval of the patient is over 30 months, and she is still receiving the combination therapy without toxicities of more than grade 2.

Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers.

OBJECTIVES: Currently, pegylated liposomal doxorubicin (PLD) is regarded as one of the standard treatment options in recurrent ovarian cancers (ROC). Bevacizumab has shown significant antitumor activity for ROC in single-agent or in combination with cytotoxic agents. We have conducted a preliminary study to investigate effects of combination of bevacizumab and PLD for heavily pretreated patients with ROC. METHODS: Thirty patients with ROC were treated with combination therapy with weekly bevacizumab and PLD, 2 mg/kg of continuous weekly bevacizumab and 10 mg/m(2) of PLD (3 weeks on, 1 week off). The treatment was continued until development of disease progression, or unmanageable adverse effects. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and Gynecologic Cancer Intergroup (GCIG) CA125 response criteria. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. RESULTS: Overall response rate was 33%, and clinical benefit rate (CR+PD+SD) was 73%. Median progression-free survival was 6 months (range: 2-20 months), and a 6-months progression-free survival was 47%. Any hematological toxicities more than grade 3 were not observed. Two cases developed non-hematologic toxicities more than grade 2; a case with grade 3 hand-foot syndrome, another with grade 3 gastrointestinal perforation (GIP). The case with GIP was conservatively treated and recovered after 2 months, and there was no case with treatment-related death. CONCLUSION: The present investigation suggested that combination therapy with bevacizumab and PLD was active and well tolerated for patients with ROC. We recommend the regimen be evaluated in further clinical studies.

Weekly administration of temsirolimus for heavily pretreated patients with clear cell carcinoma of the ovary: a report of six cases.

Clear cell carcinoma (CCC) of the ovary is well-known to be chemotherapy resistant compared with other histologic subtypes. An inhibitor against the mammalian target of rapamycin, temsirolimus (TEM) has been reported to be effective in renal CCC. Therefore, we investigated the effects of TEM in patients with CCC of the ovary. Six patients with CCC of the ovary who had been heavily pretreated by more than 4 regimens were given TEM: the cycle consisted of weekly TEM (10 mg/m(2)) for 3 weeks followed by 1 week off. The treatment was continued until development of either progressive disease, or unmanageable adverse effects. Response evaluation was based upon the Response Evaluation Criteria in Solid Tumors version 1.0. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events version 3.0. The median cycle of weekly TEM was 3 (range 2-14). Among five cases in which responses could be evaluated, partial response was observed in one case (20%) and stabilized disease was seen in another case (20%). There were no toxicities greater than grade 3, and no case developed severe toxicity requiring discontinuation of weekly TEM. The patient who showed a partial response obtained a progression-free period of 14 months. In conclusion, weekly TEM shows a potential therapeutic benefit for patients with CCC of the ovary. Further studies including a translational approach are needed to select candidates for whom TEM therapy would be beneficial.

Interaction of the regulatory subunit of the cAMP-dependent protein kinase with PATZ1 (ZNF278).

The effects of cAMP in cell are predominantly mediated by the cAMP-dependent protein kinase (PKA), which is composed of two genetically distinct subunits, catalytic (C) and regulatory (R), forming a tetrameric holoenzyme R(2)C(2). The only known function for the R subunit is that of inhibiting the activity of the C subunit kinase. It has been shown that overexpression of RIalpha, but not the C subunit kinase, is associated with neoplastic transformation. In addition, it has also been demonstrated that mutation in the RIalpha, but not the C subunit is associated with increased resistance to the DNA-damaging anticancer drug cisplatin, thus suggesting that the RIalpha subunit of PKA may have functions independent of the kinase. We show here that the RIalpha subunit interacts with a BTB/POZ domain zinc-finger transcription factor, PATZ1 (ZNF278), and co-expression with RIalpha results in its sequestration in the cytoplasm. The cytoplasmic/nuclear translocation is inducible by cAMP. C-terminus deletion abolishes PATZ1 interaction with RIalpha and results in its localization in the nucleus. PATZ1 transactivates the cMyc promoter and the presence of cAMP and co-expression with RIalpha modulates its transactivation. Moreover, PATZ1 is aberrantly expressed in cancer. Taken together, our results showed a potentially novel mechanism of cAMP signaling mediated through the interaction of RIalpha with PATZ1 that is independent of the kinase activity of PKA, and the aberrant expression of PATZ1 in cancer point to its role in cell growth regulation.

Massive intra-abdominal undifferentiated carcinoma derived from an endometrioid adenocarcinoma in a "normal-sized" ovary.

We report a case of massive intra-abdominal undifferentiated carcinoma derived from a tiny well-differentiated endometrioid adenocarcinoma of the ovary. The patient, a 56-year-old woman, who presented with a large intra-abdominal mass, underwent cytoreductive surgery with hysterectomy and bilateral salpingo-oophorectomy. Macroscopically, the intra-abdominal mass was composed of fragile and solid tumor components with extensive necro-hemorrhagic areas, mimicking a primary peritoneal tumor. Both ovaries were apparently normal in size, but a cut section of the right ovary revealed a 2-cm solid and cystic tumor showing focal rupture to the peritoneal surface. The intra-abdominal tumor consisted of pleomorphic cells without specific differentiation, showing diffuse sheet-like proliferation. The right ovarian tumor was a histologically well-differentiated endometrioid adenocarcinoma. Both the intra-abdominal undifferentiated tumor and the ovarian adenocarcinoma cells were immunohistochemically positive for keratin AE1/3, Ber-EP4, and CD10. Epithelial membrane antigen was positive only in the ovarian adenocarcinoma component, and vimentin was diffusely positive only in the intra-abdominal undifferentiated tumor component. Calretinin was negative in both tumor components. Allelotype analysis using 24 polymorphic markers located on 12 chromosomal arms showed that the intra-abdominal undifferentiated carcinoma and ovarian adenocarcinoma components had a high concordance rate (88%) of allelic patterns including identical allelic loss patterns at 7 chromosomal loci, suggesting a common genetic lineage. These data suggest that ovarian endometrioid adenocarcinoma, even when small in size, can give rise to a massive undifferentiated carcinoma filling the peritoneal cavity.

Survival analysis of ovarian clear cell carcinoma confined to the ovary with or without comprehensive surgical staging.

Pure-type clear cell carcinoma (CCC) has been recognized as a distinct subtype of ovarian cancer, showing a resistance to chemotherapy and resulting in poor prognosis. Our aim was to evaluate the effects of complete surgical procedures followed by adjuvant chemotherapy for CCC patients whose tumors were confined to the ovary (pT1M0). During the period of 1987-2005, 56 patients with stage I CCC were identified and two cases were excluded due to retroperitoneal lymph node metastasis. A total of 54 patients were enrolled in the study and divided into two groups: Group A (n=38, 1993-2005) underwent complete surgical staging including pelvic and para-aortic lymphadenectomy. Group B (n=16, 1987-1992) underwent a hysterectomy, bilateral salpingo-oopherectomy, omentectomy without comprehensive lymphadenectomy. Every patient received six courses of adjuvant chemotherapy using a platinum agent. Survival analysis was estimated by the Kaplan-Meier method and prognostic factors were evaluated using a Cox regression model. The clinical characteristics of the two groups were similar, except for the rate of conventional platinum-based chemotherapy (p=0.02). Multiple regression survival analysis revealed that the completion of a comprehensive staging operation was the only independent factor for progression-free survival of stage I CCC patients (p=0.03) and that the chemotherapeutic regimen was not a prognostic factor (p=0.43). The present study indicates that we should accomplish complete surgical staging procedures for CCC confined to the ovary.

Clear cell adenocarcinoma associated with clear cell adenofibromatous components: a subgroup of ovarian clear cell adenocarcinoma with distinct clinicopathologic characteristics.

We occasionally encountered clear cell adenofibromatous (CCAF) components coexisting in the ovarian clear cell adenocarcinoma (CCA). To reveal the clinicopathologic significance of CCAF components in CCA, we classified 67 cases of surgically resected CCA into CCA with and without CCAF components [CCAF(+) and (-) groups], and compared clinicopathologic parameters, that is, patient age, clinical stage, the degree of optimal cytoreduction, patient outcome, histologic grade and Ki-67 labeling index of the CCA, and the presence of endometriosis, between these 2 groups. Fourteen cases (21%) and 53 cases were classified as CCAF(+) and CCAF(-) groups, respectively. Of these 14 CCAF(+) cases, the CCAF components with atypia were observed adjacent to the CCAF components without atypia in 10, and adjacent to the obvious CCAs in 13 cases. In comparison with the CCAF(-) group, the CCAF(+) group showed a higher frequency of histologically low-grade tumors [93% (13 of 14) vs. 43% (23 of 53), P=0.0027], a lower Ki-67 labeling index (mean 35.9% vs. 44.0%, P=0.0492), and better patient prognosis (5-year survival 78.8% vs. 49.3%, P=0.0277). Endometriosis was much less frequent in the CCAF(+) group than in the CCAF(-) group [14.7% (2 of 14) vs. 67.9% (36 of 53), P=0.00096]. Multivariate analysis identified only optimal cytoreduction as independent favorable prognostic factor. These results suggest that CCAF besides endometriosis is associated with the development of CCA, and that the CCAF(+) group may be a distinct subgroup of CCA with less aggressive biologic behavior.

Clinicopathological significance of WT1 expression in ovarian cancer: a possible accelerator of tumor progression in serous adenocarcinoma.

Recently, oncogenic potential of the WT1 gene has been proposed in some human solid tumors and leukemias. Although previous studies have shown the frequent expression of the WT1 protein in ovarian serous adenocarcinomas (OSAs), its clinicopathologic significance is still unclear. We immunohistochemically examined the expression status of WT1 in 119 OSAs and analyzed the correlation of the intensity of WT1 immunoreactivity with the level of WT1 mRNA expression by quantitative real-time polymerase chain reaction, clinicopathologic variables, expression of p53, Bcl-2, and Ki-67 labeling index (LI). Of 119 OSAs, nuclear WT1 immunoreactivity was positive in 99 (83%), of which 44 (44%) and 55 (56%) exhibited high and low WT1 immunoreactivities, respectively. The quantitative WT1 mRNA levels were significantly correlated with the intensity of WT1 immunoreactivity (P < 0.05). In comparison with WT1-negative OSAs, the WT1-positive OSAs showed a higher grade (P = 0.007), advanced stage (P = 0.018), and higher Ki-67 LI (P < 0.001). Additionally, high WT1 immunoreactivity was correlated with a higher grade (P = 0.003), Ki-67 LI (P = 0.012), Bcl-2 expression (P = 0.003), and poorer patient outcome (5-year survival, 36.5 vs 63.8%, P = 0.008 by log-rank test). The WT1 protein may be an accelerator of the progression of OSA.

Inhibitory effects of bisphosphonates on the proliferation of human ovarian cancer cell lines and the mechanism.

Bisphosphonates are now well established as successful agents for the prevention and treatment of postmenopausal osteoporosis and corticosteroid-induced bone loss. Bisphosphonates have also recently become important in the management of cancer-induced bone disease, and they now have a widely recognized role for patients with multiple myeloma and bone metastases secondary to breast cancer and prostate cancer. Recent studies suggest that, besides the strong antiosteoclastic activity, the efficacy of such compounds in the oncological setting could also be due to direct anti-tumor effect. However, the effect of bisphosphonates to ovarian and endometrial cancers has not been elucidated. Thus, we examined the direct effect of bisphosphonates on the various ovarian cancer cell lines. Except for etidronate, all of bisphosphonates examined had the direct inhibitory effects on proliferation of all ovarian cancer cell lines used. Especially, pamidronate had the most marked inhibitory effect and inhibited dose-dependently the proliferation of ovarian cancer cell lines. KFr 13 cells among ovarian cancer cell lines used was the most sensitive to pamidronate and the caspase 3 activity was markedly stimulated by treatment with pamidronate, suggesting induction of apoptosis.

Application of expression genomics for predicting treatment response in cancer.

During tumor progression, multiple genetic changes in the genome vastly alter the transcriptomes of cancers. Some of these changes, including the mutations of various growth regulatory genes as well as alterations in the transcription of a large number of genes, may lead to resistance to treatment. Therefore, capturing such genomic information of the tumors would enable a physician to decide on the course of treatment options clinically available. Currently, it is still not feasible to identify all the genetic mutations that have occurred in a patient's cancer genome. However, the advent of DNA microarray coupled with the completion of the human genome sequence and the identification of all its genes, have made possible genome-wide gene expression profiling of the cancer genome. In this review, we will focus on the application of expression genomics for identifying signature gene expression profiles in primary cancers to predict response to either radio- or chemotherapy. We envision that transcription profiling of the cancer genomes ultimately will not only reveal how altered gene expression results in resistance to treatment, but also be exploited for predicting and personalizing cancer therapy.

Chronic administration of single weekly paclitaxel in heavily pretreated ovarian cancer patients.

Ovarian cancer patients with paclitaxel-resistance have been reported to respond to a weekly schedule of the same drug. In this report, two cases with long progression free interval by weekly paclitaxel (T) are presented. Case 1. A 41-year-old Japanese woman, gravida 2, para 0, was referred to our hospital in September 16, 1998, because of abdominal mass accompanying large amount of ascites with elevated CA125 (8400 U/ml) and CA19-9 (770 U/ml). Exploratory laparotomy (tumor biopsy plus partial omentectomy) was performed September 21, 1998. After the surgery, the tumor was diagnosed as serous cystadenocarcinoma of the ovary (stage IV) and 6 cycles of treatment consisting of cyclophosphamide, adriamycin and cisplatin (CAP) were performed. The CA 125 level (8400 U/ml) rapidly declined to 150 U/ml by this CAP therapy. After second cytoreductive surgery (SRS) (total hysterectomy and bilateral salpingo-oophorectomy), residual tumor was less than 2 cm. Although 7 cycles of CAP was added, ascites and elevation of CA 125 (5100 U/ml) were observed. Therefore, treatment with single weekly T was performed and CA 125 levels remained between 70-90 U/ml during 13 cycles of this therapy (progression free interval; more than 1 year). Thereafter, she is alive with disease and followed-up. Case 2. A 48-year-old Japanese woman, gravida 3, para 2, was referred to our hospital in July 22, 1998, because of abdominal swelling and pain. Computing tomography (CT) and magnetic resonance imaging (MRI) revealed large amount of ascite and pelvic mass (9 x 7 x 7 cm), and low density area (3 x 3 cm) suggesting metastasis in right lobe of liver. Serum CA 125 level elevated to 5100 U/ml. Bilateral salpingo-oophorectomy and infracolic omentectomy were performed on August 5, 1998. The tumor was diagnosed as endometrioid adenocarcinoma of the ovary, stage IV and chemotherapy with CAP was initiated on September 5, 1998. After 6 cycles of CAP, SRS was performed. After SRS, 3 cycles of CAP were added and changed to weekly T because of damage of renal function. The CA 125 level returned within normal range during weekly T. Total 13 cycles of weekly T were performed and progression free interval was about 18 months. Thereafter, she received treatments with gamma knife and CAP for brain metastasis. She is alive without disease and followed-up. Side effects by weekly T were mild and tolerable despite of long term treatment. In addition, weekly T can be safely used in outpatient setting and even in patients with poor performance status (PS), and warrant long time to progression.

[The efficacy of Shakuyaku-Kanzo-to for peripheral nerve dysfunction in paclitaxel combination chemotherapy for epithelial ovarian carcinoma].

Shakuyaku-Kanzo-to was first medicated for muscular pain which was called Komuragaeri, and it has been reported that it is effective for peripheral nerve dysfunction such as arthralgia and numbness. Recently, Paclitaxel (T) and Carboplatin (J) combination chemotherapy (TJ chemotherapy) has been a standard first-line chemotherapy for epithelial ovarian carcinoma. For the arthralgia and muscular pain occurring in TJ chemotherapy, non-steroid-anti-inflammatory drugs (NSAIDs), Vitamin B12 (VB12) and Shakuyaku-Kanzo-to are the major medications. In this study, we examined twenty-one cases in which arthralgia and muscular pain occurred in TJ chemotherapy (including 16 cases as first-line chemotherapy). In all cases, patients took 7.5 g of Shakuyaku-Kanzo-to orally per day for eight days. We investigated the efficacy of Shakuyaku-Kanzo-to retrospectively with the following results. In nine cases (43%), Shakuyaku-Kanzo-to was effective in reducing pain. Especially in TJ chemotherapy as first-line chemotherapy, Shakuyaku-Kanzo-to was even more effective in reducing pain. We suggested that Paclitaxel combination chemotherapy with Shakuyaku-Kanzo-to taken orally is a more safe and tolerable way to reduce pain in epithelial ovarian carcinoma.

Altered phospholipid transfer protein gene expression and serum lipid profile by topotecan.

Camptothecin (CPT) and its structural analogues including topotecan and irinotecan, are inhibitors of topoisomerase I. These drugs are clinically active against a broad spectrum of cancers. To understand the genesis of chemotherapeutic resistance to the CPT family of anticancer drugs, we examined by gene expression profiling the pharmacological response to topotecan in the human hepatoma HepG2 cells and found a striking induction of the phospholipid transfer protein (PLTP) gene expression by topotecan. We showed that activation of PLTP gene expression is specific to CPT and its analogues including specific enantiomers that inhibit topoisomerase I. PLTP-mediated lipid transfer to high-density lipoprotein (HDL) is thought to be important for shuttling and redistribution of lipids between lipoproteins, which are normally returned to the liver for metabolism via the reverse cholesterol transport pathway. Hence, we asked whether elevated PLTP levels might increase the transfer of drugs into HDL. We observed that CPT was not accumulated in HDL and other lipoproteins. In addition, topotecan treatment in mice caused a marked reduction in serum HDL that was accompanied by an increase in triglyceride and cholesterol levels. These results showed that PLTP does not mediate the transfer of topoisomerase I inhibitors to serum lipoproteins. However, elevated serum PLTP levels following treatment with topoisomerase I inhibitors in cancer patients may serve as a biomarker for monitoring the development of hypertriglyceridemia and acute pancreatitis.

Identification of potential serum markers for endometrial cancer using protein expression profiling.

OBJECTIVES: Screening method of endometrial cancer (EC) has not been established yet. Our study was to explore serum biomarkers of EC patients using surface-enhanced laser desorption and ionization-time-of-flight mass spectrometry (SELDI-TOF MS). METHODS: Serum samples from 65 EC patients and 40 controls were analyzed by SELDI-TOF MS (training set). Single- and multi-variant analyses were performed to compare protein profiles in serum of EC patients and healthy controls. Subsequently, blind test set including 40 EC patients and 40 controls were analyzed for validation. RESULTS: A panel of four biomarker candidates were selected in training set analysis. These markers could also distinguish stage I patients from controls. Among them, two biomarkers were purified and identified as apolipoprotein A1 and a modified form of apolipoprotein C1. Screening for blind test set using dual-biomarker analysis yielded a sensitivity of 82% and a specificity of 86%. CONCLUSIONS: Involvement of apolipoproteins with EC is first suggested in this study. In addition to possibility of screening method for EC, findings of these new biomarkers might be related with carcinogenesis or predisposition to EC.

Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors.

Recent studies have shown that platelet-derived growth factors and their receptors are frequently co-expressed in ovarian cancers. Herein, we investigated the role of the platelet-derived growth factor pathway in the development of ovarian clear-cell adenocarcinoma, a highly chemoresistant form of ovarian cancer. Immunohistochemical expression of platelet-derived growth factor receptor-alpha and receptor-beta, platelet-derived growth factor A-chain and B-chain was examined in 31 cases of clear-cell adenocarcinoma and 56 coexisting putative precursor lesions: 17 non-atypical and 19 atypical endometrioses, and 10 non-atypical and 10 atypical clear-cell adenofibroma components. Twenty-one solitary endometrioses were also examined. Vascular endothelial cells were always positive for all the markers examined, and were used as positive controls. The frequencies of positivity for platelet-derived growth factor receptor-alpha and receptor-beta, and platelet-derived growth factor A-chain increased in accordance with higher cytologic atypia in the putative precursors: 71, 47, and 59% in the 17 non-atypical endometrioses, 84, 73, and 84% in the 19 atypical endometrioses, 0% each in the 10 non-atypical clear-cell adenofibromas, 100, 90, and 90% in the 10 atypical clear-cell adenofibromas, and 97, 97, and 100% in the 31 clear-cell adenocarcinomas, respectively. Positivity for platelet-derived growth factor B-chain increased in accordance with increased atypia in clear-cell adenofibroma: 0% in non-atypical clear-cell adenofibromas, 30% in atypical clear-cell adenofibromas, and 60% in coexisting carcinomas. However, in contrast, positivity for platelet-derived growth factor B-chain decreased in accordance with increased atypia in endometriosis coexisting with clear-cell adenocarcinomas: 35% in non-atypical endometrioses, 11% in atypical endometrioses, and 5% in coexisting carcinomas. Platelet-derived growth factor receptor-alpha and receptor-beta, and their ligands A-chain and B-chain were positive in 14, 29, 19, and 62% of the solitary endometrioses, respectively. These results indicate activation of the platelet-derived growth factor pathway in ovarian clear-cell adenocarcinomas and suggest biological differences between carcinomas that arise in association with clear-cell adenofibroma vs endometriosis.

Effect of HER-2/neu overexpression on chemoresistance and prognosis in ovarian carcinoma.

AIM: To investigate the effect of HER-2/neu protein overexpression on chemoresistance and prognosis in patients with epithelial ovarian carcinoma. METHODS: A total of 141 ovarian carcinoma tissues surgically resected between 1987 and 2003 were assessed by immunohistochemistry (IHC). The characteristic of the patients and immunohistochemical results were compared by chi2-test. Survival analysis was performed by the Kaplan-Meier method and the log-rank test. RESULTS: HER-2/neu overexpression was detected in 18 cases (12.8%). There were no significant differences in histopathological subtypes (P = 0.3550), FIGO stages (P = 0.8858), or residual tumor size at first surgery (P = 0.6607) between the cases with HER-2/neu overexpression and the cases without HER-2/neu overexpression. Among the 58 cases which responded to chemotherapy, only five cases (8.6%) showed HER-2/neu overexpression. However, among the 38 cases which did not respond to chemotherapy, eight cases (21.1%) showed HER-2/neu overexpression. Overexpression of HER-2/neu had a tendency to relate with chemoresistance of epithelial ovarian carcinoma, but there were no statistically significant differences (P = 0.0817). No association was observed between HER-2/neu overexpression and cumulative survival rate (P = 0.4970). CONCLUSIONS: The results of the current study show that although HER-2/neu overexpression has a tendency to be associated with chemoresistance, it can not be a prognostic factor for the patients with epithelial ovarian carcinoma.

Treatment options in the management of ovarian cancer.

The standard regimen used as primary chemotherapy of ovarian cancer is combination chemotherapy using paclitaxel and carboplatin. The main objective of first-line chemotherapy is to induce complete response. Although most cases respond to the initial chemotherapy, many cases relapse within 3 years. Such relapsed and persistent cases become resistant to first-line chemotherapy and require second-line chemotherapy. Objectives of such a second-line chemotherapy are to obtain disease palliation to cease disease progression. Meanwhile, consolidation or maintenance chemotherapy may be added to prevent or inhibit disease relapse for patients with advanced disease after induction of complete remission by a primary chemotherapy. When the unresectable tumour is presumed by primary surgery, neoadjuvant chemotherapy may be selected. Recently, conventional cytotoxic anticancer drugs containing paclitaxel have been shown to be capable of inhibiting angiogenesis. The notion of 'redefining' chemotherapeutic drugs has been recognised; thus, continuous low-dose chemotherapy -- so-called metronomic chemotherapy -- has been approved as a new concept. Many new molecular-targeted therapies became available for clinical cancer therapy. The explosion of new molecular targets and the development and application of many powerful technologies should accelerate the discovery of innovative molecular therapeutics. Understanding the molecular mechanisms will help to clarify the pathways in ovarian cancer development and help to identify new therapeutic and diagnostic targets. These are exciting times for new drug development and the treatment of cancer. Cautious optimism should prevail for all investigators involved in translating these exciting new biological findings into new pharmacological agents for treatment of cancer.