Treatment of platinum-resistant ovarian cancer

In the United States, almost 70% of the 23,000 women diagnosed annually with epithelial ovarian cancer present with advanced disease (FIGO stages III-IV). Primary therapy for these patients includes surgical cytoreduction and 6 - 8 courses of platinum- and taxane-based chemotherapy. Although 90% of patients will respond to this multi-modality combination regimen, most patients will experience recurrences. The 5 year survival for women with stage III disease is 15 - 30% and 0 - 20% for those with stage IV disease. Medical and gynecological oncologists, therefore, must be prepared to treat many women with recurrent ovarian cancer.     

Review of dose-intense platinum and/or paclitaxel containing chemotherapy in advanced and recurrent epithelial ovarian cancer

Ovarian cancer is the most lethal gynecological cancer in women in the western world with a 5-year survival of 49.7%. Advanced stage ovarian cancer is treated both surgically and with chemotherapy, but despite initial high response rates of 60- 75%, many women experience disease recurrence with a dismal prognosis, 5 year overall survival for FIGO stage IIIc and IV disease being only 32 and 18%. In an attempt to improve outcome for both primary and recurrent disease, dose-intense and dose-dense chemotherapy regimens have been investigated. This overview summarizes these results in first and second-line treatment. In first-line treatment, no benefit was found of dose-intense regimes in the majority of the studies, only toxicity was increased. However, results are conflicting with the recent Japanese Gynecologic Oncology Group (JGOG) trial showing an improved progression free and overall survival in patients treated with dose-dense weekly paclitaxel combined with standard 3-weekly carboplatin. For recurrent disease dose-dense weekly combination chemotherapy seems to be very effective in patients with platinum-resistant ovarian cancer. Several phase II studies showed an increase in response rate, progression free survival and overall survival for dose-dense paclitaxel and carboplatin, compared to results of nonplatinum chemotherapy. In platinum-sensitive ovarian cancer, on contrary, the results of weekly paclitaxel and carboplatin seem to be comparable with standard 3-weekly regimens.     

Pharmaceutical management of ovarian cancer : current status

Over recent decades, truly impressive progress has been made in the outcome associated with the pharmacological antineoplastic management of women with advanced ovarian cancer. Following initial surgery, the large majority of patients with this malignancy will receive a chemotherapy regimen that includes a platinum drug (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel). Currently, objective responses are observed in approximately 60-80% of patients treated in the front-line setting, with documented improvements in overall survival compared with prior non-platinum and taxane programmes. Unfortunately, despite the high response rate to initial chemotherapy, the majority of women with advanced disease will experience recurrence of the malignant process and be candidates for a variety of possible second-line therapeutic options. It is well recognized that ovarian cancer patients who are documented to experience an initial response to platinum-based chemotherapy but where the disease recurs approximately 6 or more months following the completion of primary therapy, may have another clinically meaningful response (both objective and subjective) to a second platinum-based strategy. However, an optimal management approach in this setting remains to be defined. Furthermore, the malignant cell populations in all ovarian cancer patients who experience an initial relapse of the disease process will eventually be resistant to the platinum agents. In this setting, multiple drugs have been shown to be biologically active. Again, an optimal strategy to be employed in the platinum-resistant setting has yet to be demonstrated through the conduct of evidence-based trials. Reasonable goals of therapy in women with recurrent or resistant ovarian cancer are to improve overall survival, reduce the severity (and delay the occurrence) of symptoms and optimize overall quality of life.     

Recurrent epithelial ovarian cancer: pharmacotherapy and novel therapeutics

Epithelial ovarian cancer will strike between 1 - 2% of women in developed countries and, unfortunately, it largely remains a lethal disease due to late-stage at diagnosis and the eventual development of chemotherapy resistance. Ovarian cancer is initially treated with surgical resection and chemotherapy (primarily platinum/taxane combinations) and remission can be attained for the majority of patients. Despite this, most women will recur and require multiple further therapies. The purpose of this paper is to review the existing treatment options, including surgery, traditional chemotherapy as well as upcoming novel and targeted therapies that may one day improve outcomes in this disease.     

MMPs in Ovarian Cancer as Therapeutic Targets

In the United States, about 22,000 women will be diagnosed with ovarian cancer in 2011, and an estimated 14,000 patients will succumb to the disease [1]. Surgery and chemotherapy present the main treatment modalities, but despite the development of novel therapies, the overall 5 years survival for ovarian cancer patients with advanced disease at diagnosis remains at only about 30%. Novel therapeutic strategies are needed to prolong survival and achieve greater cure rates. Matrix metalloproteinases (MMPs) are frequently expressed in ovarian cancer, and play an important role in the metastatic process. MMPs mediate degradation of the basement membrane as a crucial step in epithelial transformation, ovarian tumorigenesis and intraperitoneal metastasis [2]. Various preclinical and clinical studies have demonstrated that MMPs might provide a suitable therapeutic target. This review summarizes important observations regarding the expression of MMPs in ovarian cancer, their biological role, and data from clinical trials targeting MMPs in ovarian cancer patients.     

Pharmacoeconomic considerations in treating ovarian cancer

Ovarian cancer is the leading cause of death in women with gynaecological cancers. The most common type of ovarian cancer is epithelial ovarian cancer. Referred to as the 'silent' killer, this disease is difficult to detect because of the lack of specific symptoms. The majority of women who have ovarian cancer are diagnosed in the advanced stages. While the exact cause of ovarian cancer remains elusive, it is believed that the events relating to incessant ovulatory function play a major role in the development of this disease. Long term prognosis of women with ovarian cancer remains grim. Although ovarian cancer is highly responsive to chemotherapy, most women will develop persistent or recurrent disease after primary treatment. The standard front-line treatment is paclitaxel in combination with a platinum-based agent; however, toxicities associated with paclitaxel must be weighed against the clinical benefit. The economic issues associated with the treatment of ovarian cancer involve costs of chemotherapy agents and management of supportive care. Patient preferences and quality-of-life issues are also of major importance because of the short survival benefit for most patients. Therefore, quality of life must be maximised alongside efforts to prolong survival. More research is necessary to determine what trade-offs (e.g. adverse effects of treatment) patients are willing to make for modest gains in survival.     

PARP inhibition and synthetic lethality in ovarian cancer

Ovarian cancer is the leading cause of gynecologic cancer death in women. Our understanding of the treatment of ovarian cancer has evolved over the last decade, with the use neo-adjuvant chemotherapy, combined intravenous-intraperitoneal (IV-IP) chemotherapy, as well as dose dense paclitaxel. Despite significant improvements in overall survival, the majority of patients succumb to recurrent chemotherapy resistant disease. Given the above, an emphasis has been placed on exploring alternate therapeutics. Recent research efforts have improved our understanding of the molecular biology of ovarian cancer and novel targeted treatment strategies have emerged. With the discovery of BRCA1 and BRCA2 gene mutations, and a more comprehensive assessment of heredity ovarian cancer syndrome, targeted interventions exploiting this biologic susceptibility have emerged. To date, the most studied of these have been PARP inhibitors. The purpose of this review will be to discuss PARP inhibition in advanced stage ovarian cancer, highlighting recent scientific advancements.     

Recurrent epithelial ovarian cancer: pharmacotherapy and novel therapeutics

Epithelial ovarian cancer will strike between 1 – 2% of women in developed countries and, unfortunately, it largely remains a lethal disease due to late-stage at diagnosis and the eventual development of chemotherapy resistance. Ovarian cancer is initially treated with surgical resection and chemotherapy (primarily platinum/taxane combinations) and remission can be attained for the majority of patients. Despite this, most women will recur and require multiple further therapies. The purpose of this paper is to review the existing treatment options, including surgery, traditional chemotherapy as well as upcoming novel and targeted therapies that may one day improve outcomes in this disease.     

Prevention of ovarian cancer

Chemoprevention trials with OCP and retinoids will be important to determine if these drugs are effective in selected populations. Further work will be critical to understanding the mechanism of action of OCP in preventing ovarian cancer and if this protective effect will be upheld in the high-risk population. Initial results in the Milan study are promising for the retinoids in prevention of ovarian cancer and will be used in chemoprevention trials both alone and in combination with OCP's to determine if there might be an additive effect with these drugs. As yet, little is known about preinvasive changes in the ovary to predict which women are at risk for developing ovarian cancer. We can now identify high-risk women by genetic counseling and testing, yet ultrasound and serum markers are the only modality available to evaluate these women. Research is focusing on developing ways of evaluating women, particularly those at high risk for ovarian cancer, to better understand the neoplastic process in the ovary and thus identify these women prior to their developing advanced ovarian cancer. Research is also focusing on understanding chemoprevention for ovarian cancer so that women can receive the optimal chemopreventive agent when diagnosed as high risk. Prognosis with advanced disease is so poor that early diagnosis and chemoprevention are the only methods at the current time to significantly improve survival in epithelial ovarian cancer.     

Current treatment for ovarian cancer

Ovarian cancer is the most lethal gynaecologic malignancy. Epithelial ovarian cancer (EOC) constitutes approximately 90% of cases of ovarian cancer and 70% of the patients with EOC present in advanced stage. Treatment of EOC usually consists of cytoreductive surgery which includes total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), omentectomy and lymphadenectomy followed by adjuvant chemotherapy. Current adjuvant chemotherapy includes paclitaxel and either cisplatin or carboplatin given every 3 weeks for six cycles. The combination paclitaxel and platinum chemotherapy achieves clinical response in approximately 80% of patients. However, most patients will have tumour recurrence within 3 years following treatment. Patients with platinum-sensitive tumours can be re-treated with platinum and/or paclitaxel. Those with platinum-resistant tumours have poor prognosis and treatment is palliative. Options of treatment in these patients include topotecan, doxil, gemcitabine, etoposide, or enrolment in clinical trials. Future research needs to focus on the role of cytoreductive surgery, second-look surgery, consolidation chemotherapy, development of new chemotherapeutic agents, chemoresistance modulators, as well as new approaches to the treatment of women with ovarian cancer.     

Optimal therapy for platinum-resistant recurrent ovarian cancer: doxorubicin, gemcitabine or topotecan?

Ovarian cancer is more fatal than all the other gynaecological malignancies combined. Although most patients respond to first-line combination chemotherapy, the vast majority (50-75%) of patients with advanced disease will relapse. The management of patients with recurrent ovarian cancer is based on their response profile to platinum: patients with platinum-sensitive disease can be rechallenged with platinum-based chemotherapy, whereas the management of patients with platinum-resistant or -refractory disease remains an area of active investigation. In this review, the data for second-line therapy in this latter group of patients will be summarised and recommendations for their optimal management will be made.     

铂耐药卵巢癌的免疫治疗研究进展

卵巢癌是女性生殖系统疾病中死亡率最高的恶性肿瘤,大多数患者发现时已处于晚期。虽然经过满意的肿瘤细胞减灭术联合以铂类为基础的化疗可以达到临床缓解,但大多数患者会在最初治疗后数年内复发,继而死亡。化疗耐药和免疫逃逸可能是导致卵巢癌治疗失败的重要原因之一,因此迫切需要新的治疗策略来改善患者的临床结局。本文阐述了免疫治疗在铂耐药卵巢癌治疗中的研究进展。     

上皮性卵巢癌术后辅以腹腔和静脉联合化疗患者生存率观察

目的探讨上皮性卵巢癌术后辅以腹腔和静脉联合化疗的疗效。方法对60例上皮性卵巢癌患者术后给予腹腔和静脉联合化疗：平均疗程6～8个,化疗方案：TP方案（紫杉醇＋顺铂）或PC方案（环磷酰胺＋顺铂）,观察其化疗药物不良反应,3年和5年生存率。结果60例中Ⅰ期7例,Ⅱ期8例,Ⅲ～Ⅳ期45例;共化疗443个疗程;人均7．4个疗程,3年及5年生存率分别为68．3％、36．7％,药物不良反应主要为恶心呕吐及全身乏力感。结论卵巢上皮性癌在理想的肿瘤细胞减灭术后辅以腹腔和静脉联合化疗不良反应较轻、方法简便,患者易于接受,是卵巢癌患者较为理想的术后辅助治疗方法。     

Goserelin as ovarian protection in the adjuvant treatment of premenopausal breast cancer: a phase II pilot study

The aim of the present trial was to investigate the protective effects on ovarian function, and the efficacy and tolerability of goserelin added to adjuvant chemotherapy for early breast cancer. Following surgical treatment, 64 premenopausal patients with early breast cancer received goserelin 3.6 mg (every 28 days for 1 year) and an adjuvant treatment which was chosen according to the patient's prognosis. Median age was 42 years (range 27-50). ECOG performance status was 0-1 in all patients. Twenty-eight patients (44%) had estrogen receptor (ER)+ tumors and 36 (56%) patients had ER- tumors. Fifty-two (81%) patients had stage II disease and 12 (19%) had stage III disease. Eighteen patients received cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy, 46 patients received an anthracycline-based regimen, and nine of them received high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation. Fifty-one patients (80%) were irradiated. ER+ patients also received tamoxifen for 5 years. Serum estradiol was suppressed to values below 40 pg/ml in all patients. After a median follow-up of 55 months, 86% of patients had resumed normal menses, 84% of patients were disease-free and 94% were alive. The 1-, 3- and 5-year projected recurrence-free survival rates were 100, 81 and 75%, respectively. Five years after treatment one patient had a pregnancy that ended with a normal childbirth. No unexpected adverse events were reported. These data show that the addition of goserelin to adjuvant therapy of premenopausal patients with early breast cancer is well tolerated and protects long-term ovarian function.     

D-二聚体在卵巢癌诊断与病情监测中的价值

目的:研究D-二聚体(D-dimer)在卵巢癌诊断和病情监测方面的应用及其临床意义。方法:采用免疫比浊法测定45例卵巢癌患者及34例卵巢良性肿瘤患者的D-二聚体浓度,并与42例正常健康体检女性进行比较。结果:卵巢癌患者血浆中D-二聚体水平分别与卵巢良性肿瘤患者和正常对照组比较有显著增高(P<0.01),而卵巢良性肿瘤D-二聚体水平与对照组比较无明显差异(P>0.05),不同病理类型卵巢癌患者的D-二聚体水平无显著差异(P>0.05),不同病理类型卵巢良性瘤患者的D-二聚体水平无显著差异(P>0.05);卵巢癌Ⅱ～Ⅳ期患者的D-二聚体浓度明显高于Ⅰ期患者(P<0.01);不同病理分级卵巢癌患者的D-二聚体,由G1～G3级依次增加,差异有统计学意义(P<0.01)。结论:D-二聚体检测对卵巢良恶性肿瘤的判断及肿瘤的进展与分期有着重要的意义,D-二聚体对卵巢癌的实验室诊断有着特别的作用。     

Cellular therapy for ovarian cancer: experimental and clinical perspectives

Ovarian cancer is the leading cause of death among gynecologic malignancies and the 5th leading cause of cancer deaths for women in the United States. Two-thirds of patients present with advanced-stage disease (Stage III and IV) and the majority will suffer recurrence of disease, require ongoing treatment, and eventually succumb to chemotherapy-resistant disease. To potentially circumvent chemo-resistance in recurrent ovarian cancer, immunotherapy is being explored as a novel treatment option. Our laboratory findings demonstrate that immune effector cells from healthy donors elicit a significant cytotoxic response in the presence of IL-2 and IFN alpha- 2b against ovarian cancer in vitro; however, peripheral blood mononuclear cells (PBMC) isolated from ovarian cancer patients fail to elicit a similar response. A major obstacle to immunotherapy is the immunosuppressive environment supported by tumors, which limits the immune system's ability to fight the tumor. Myeloid-derived suppressor cells are an immature population of myeloid cells, which have recently been implicated to play a major role in immunosuppression and tumor evasion. In addition to novel immunotherapies, new diagnostic and prognostic markers are being identified through applying molecular tools/approaches in clinical and pathological analyses of this malignancy, which will provide additional therapeutic targets. To test these experimental therapeutic options, pre-clinical murine models of ovarian cancer are being developed. Ultimately, treatment of ovarian cancer will benefit from the careful alignment of appropriate target, drug, patient, and trial design. This article provides an objective overview of cellular therapy (the use of immune cells to elicit an anti-tumor response) for ovarian cancer highlighting both experimental and clinical perspectives.     

Multicenter phase II study of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer

Gemcitabine has activity in advanced ovarian cancer, with responses in platinum-resistant disease. This study assessed the activity of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer. All patients had histologically verified invasive epithelial ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV disease and no prior chemotherapy. Patients received gemcitabine 1250 mg/m(2) on days 1, 8 and 15 of a 28-day cycle. Radiological response was assessed after two cycles. Between December 1992 and October 1995, 35 patients were enrolled. Of 33 evaluable patients, there was one complete response and five partial responses, for an overall response rate of 18% (95% confidence interval 7-36%). Forty-two percent of patients had a greater than 50% decrease in their CA-125 levels. Of the 25 patients who received platinum-based chemotherapy following treatment with gemcitabine, 12 achieved an overall response rate of 48%. Toxicity was mild, with two episodes of WHO grade 4 neutropenia (not associated with fever) and two episodes of grade 4 thrombocytopenia (not associated with bleeding). Gemcitabine has single-agent activity for poor-prognosis patients with advanced ovarian cancer. Similar results with subsequent platinum-based therapy indicate a lack of cross-resistance. This, combined with gemcitabine's favorable toxicity profile, warrants testing in comparative trials.     

Antiangiogenic drugs in the treatment of advanced epithelial ovarian cancer

Epithelial ovarian cancer (EOC) accounts for approximately 80-90% of all ovarian cancers, and 75% of the patients are diagnosed with advanced disease (stage III and IV). Front-line systemic chemotherapy improves survival in women with advanced EOC; however, tumor recurrence occurs in almost all advanced EOC patients at a median of 15 months from diagnosis, and 5-year survival is estimated at 10 to 30%. Additionally, around 20% of patients do not respond to standard front-line therapy. Tumoral angiogenesis plays an important role in the pathogenesis of EOC, and its inhibition might improve survival in patients with advanced EOC. High-grade EOC is characterized by overexpression of vascular endothelial growth factor (VEGF), which drives dysfunctional tumor-associated angiogenesis, contributing to high interstitial pressure and increased vascular permeability. Diverse anti-angiogenic drugs are under investigation, and direct targeting of this pathway can be achieved by sequestration of VEGF protein using monoclonal antibodies (bevacizumab) or engineered binding site molecules (aflibercept), blockade of the VEGF receptor-2 with monoclonal antibodies or inhibition of receptor associated tyrosine kinase with low molecular weight inhibitors (cediranib, pazopanib, sorafenib or BIBF-1120).     

卵巢癌患者血清CAl53的表达及与临床病理特征的关系

目的探讨血清糖类抗原153（carbohydrate antigen153,CA153）在卵巢癌患者中的表达及临床意义。方法回顾性分析49例卵巢癌（A组）及62例卵巢良性病变患者（B组）术前血清CA153及血清糖类抗原125（CA125）的检测水平,并与术后病理结果等临床资料进行临床对比分析。结果卵巢癌患者术前血清CA153水平显著高于卵巢良性病变患者;血清CA153诊断卵巢癌的敏感度为40．82％,特异度为96．77％,其特异性显著高于血清CA125（P〈0．05）。卵巢癌患者分期越晚、组织分化愈差,其血清CA153检测水平越高;早期（I、II期）卵巢癌患者血清CA153的表达阳性率显著低于血清CA125（P〈0．05）。结论术前检测血清CA153有助于卵巢癌的筛查而协助诊断,术前血清CA153的表达水平越高提示卵巢癌不良预后的风险越高。