晚期卵巢癌新辅助化疗的研究进展

摘 要：卵巢癌是死亡率最高的妇科恶性肿瘤之一,约70%患者确诊时已属Ⅲ~Ⅳ期,预后较差。目前标准的治疗方式是理想初始肿瘤细胞减灭术,术后辅以铂类联合紫杉醇类化疗。对于病灶难以切除的晚期卵巢癌患者而言,可以选择术前新辅助化疗以提高满意减瘤术的手术机率。本文对晚期卵巢癌新辅助化疗的研究进展进行综述。     

晚期卵巢癌肿瘤细胞减灭术术前选择新辅助化疗的评估

卵巢癌是妇科三大肿瘤之一。因卵巢位于盆腔深部，卵巢癌患者多无明显症状，察觉时已是晚期。晚期卵巢癌恶性程度高，预后差，手术辅以化疗是目前主要治疗手段，手术中尽可能切除肿瘤、缩小残留病灶达到理想肿瘤细胞减灭术以延长生存期、改善预后。对于无法手术的晚期卵巢癌患者，新辅助化疗能够改善手术条件．增加手术满意度，是可行的治疗方案。因此，术前对晚期卵巢癌患者手术可行性进行评估，予以患者正确的首选治疗方案，提高手术满意度，避免不必要的剖腹探查。目前用以晚期卵巢癌肿瘤细胞减灭术术前评估的方法有1）影像学检查．如CT、PET，MRI等；2）CA125值，根据CA125值的高低评估手术可行性；3）腹腔镜探查，根据术中所见评估开腹手术可行性；4）其他各种肿瘤标记物如p53。各研究中探讨的手术评估手段大多局限于某一个方面。未能将有意义的预测因素全部纳入进行综合分析，准确性尚存在不足。探索新的方式方法．或是交叉应用两种或两种以上评估手段对晚期卵巢癌肿瘤细胞减灭术可行性进行综合评估，提高手术满意程度，缩小残留病灶，达到延长晚期卵巢癌患者生存时间和改善晚期预后的目的。本文就晚期卵巢癌肿瘤细胞减灭术可行性的评估和新辅助化疗的选择进行综述．     

血清白蛋白对晚期卵巢癌

新辅助化疗联合中间性肿瘤细胞减灭术给不适合初次肿瘤细胞减灭术的晚期卵巢癌患者带来新的希望,但术前筛选恰当的患者予以新辅助化疗是妇科肿瘤医生的一大挑战。低白蛋白血症是卵巢癌初次肿瘤细胞减灭术术后并发症高发的独立危险因素之一。本文将就低白蛋白血症对卵巢癌新辅助化疗加中间性肿瘤细胞减灭术（neoadjuvant chemotherapy & interval debulking surgery,NACT IDS）治疗模式的影响进行综述。     

PDS或NACT——晚期卵巢癌患者的初始治疗该如何选择

卵巢癌肿瘤细胞减灭术（primay debulking sugery,PDS）是晚期卵巢癌患者的首选治疗方法。对于不能达到理想肿瘤减灭水平或/和有围手术期高风险的患者,新辅助化疗（neoadjuvant chemotherapy,NACT）及间数性肿瘤细胞减灭术（interyal debulking sugery,IDS）是另一替代选择。如何抉择 PDS 与NACT,目前临床实践中还存在一些争议,困惑甚至滥用的现象。本文对此进行了评述,旨在帮助大家正确选择适合的治疗方法。强调应根据患者肿瘤病变的程度和围手术期的危险因素,合理平衡治疗获益与风险,规范化,个体化地选择对患者最有利的治疗方式才是最重要的。     

30例晚期卵巢癌术前介入化疗疗效分析

选择晚期卵巢癌患者 30例 ,行肿瘤细胞减灭术前 ,给予髂内动脉插管介入治疗。介入化疗后 ,所有患者症状缓解率达 90 0 % ,盆腔包块有效消退率为 5 6.67% ,其中 2 3例成功实施有效肿瘤细胞减灭术 ,减灭术成功率为 76.67%。研究结果提示 ,晚期卵巢癌术前行介入化疗可提高手术切除率 ,为进一步治疗创造条件。     

晚期卵巢癌新辅助化疗疗效分析

目的 探讨新辅助化疗在治疗晚期卵巢癌中的作用和意义.方法 对45例晚期卵巢癌患者,20例采用新辅助化疗,然后进行肿瘤减灭术(新辅助化疗组);25例首先行肿瘤减灭术(先期手术组).所有患者术后均化疗.结果 新辅助化疗组满意肿瘤减灭率70.0%,先期手术组为36.0%,两组比较有明显差异(P＜0.05);新辅助化疗组术中出血量及手术时间较先期手术组少,两组比较均有明显差异(P＜0.05);新辅助化疗组的中位生存时间(34个月)较先期手术组(28个月)长.结论 对于初次手术不能达到满意减瘤或不能进行手术的晚期卵巢癌患者,新辅助化疗能提高减瘤术的成功率,有延长患者生存时间的趋势.     

PDS或NACT——晚期卵巢癌患者的初始治疗该如何选择

卵巢癌肿瘤细胞减灭术（primay debulking sugery,PDS）是晚期卵巢癌患者的首选治疗方法。对于不能达到理想肿瘤减灭水平或/和有围手术期高风险的患者,新辅助化疗（neoadjuvant chemotherapy,NACT）及间数性肿瘤细胞减灭术（interyal debulking sugery,IDS）是另一替代选择。如何抉择 PDS 与NACT,目前临床实践中还存在一些争议,困惑甚至滥用的现象。本文对此进行了评述,旨在帮助大家正确选择适合的治疗方法。强调应根据患者肿瘤病变的程度和围手术期的危险因素,合理平衡治疗获益与风险,规范化,个体化地选择对患者最有利的治疗方式才是最重要的。     

30例晚期卵巢癌术前介入化疗疗效分析

选择晚期卵巢癌患者30例,行肿瘤细胞减灭术前,给予髂内动脉插管介入治疗。介入化疗后,所有患者症状缓解率达90．0％,盆腔包块有效消退率为56．67％,其中23例成功实施有效肿瘤细胞减灭术,减灭术成功率为76．67％。研究结果提示,晚期卵巢癌术前行介入化疗可提高手术切除率,为进一步治疗创造条件。     

双路径先期化疗对Ⅲ期卵巢癌疗效和预后的影响

目的 探讨双路径先期化疗对Ⅲ期卵巢癌肿瘤细胞减灭术加术后化疗疗效和预后的影响.方法 将36例Ⅲ期卵巢癌分为A、B两组,A组行双路径先期化疗加中间肿瘤细胞减灭术加术后化疗(22例);B组行初次肿瘤细胞减灭术加术后化疗(14例).比较两组肿瘤细胞减灭术的彻底性、病情缓解率和生存率.结果 A、B组达到理想肿瘤细胞减灭术者分别占86.4%和35.7%;手术时间分别为(190±20)min和(270±30)min;术中出血分别为(400±100)ml和(800±200)ml;病情缓解率分别为77.3%和35.7%;1,3年生存率分别为90.9%、64.3%和68.2%、35.7%(P＜0.05),5年生存率分别为31.8%和21.4%(P＞0.05).结论 双路径先期化疗用于Ⅲ期卵巢癌治疗,可以降低肿瘤细胞减灭术风险,提高理想肿瘤细胞减灭术比例和术后化疗反应率,对生存率有益.     

新辅助化疗联合肿瘤细胞减灭术治疗Ⅲ～Ⅳ期卵巢癌的疗效分析

目的 探讨新辅助化疗联合肿瘤细胞减灭术治疗Ⅲ～Ⅳ期卵巢癌的疗效.方法 回顾性分析60例Ⅲ～Ⅳ期卵巢癌的临床治疗相关资料,根据采用的治疗方法不同分为对照组30例和化疗组30例,其中对照组患者仅行肿瘤细胞减灭术,观察组患者术前进行新辅助化疗后再行肿瘤细胞减灭术.比较分析两组患者的肿瘤体积、腹腔积液量、术中出血量、手术时间和住院时间等相关指标,并观察疗效.结果 观察组患者的肿瘤体积、腹腔积液量、术中出血量、手术时间和住院时间等指标与对照组相比均显著降低(P＜0.05);观察组患者的临床疗效显优于对照组,观察组的总有效率为73.3％,显著高于对照组(43.4％).结论 Ⅲ～Ⅳ期卵巢癌患者肿瘤细胞减灭术之前,进行2～3个疗程的化疗可减少腹腔积液量和术中出血量,缩短手术时间和住院时间,提高临床疗效.     

Systematic review of adjuvant care for women with Stage I ovarian carcinoma

BACKGROUND: Several adjuvant care interventions to treat women with Stage I ovarian carcinoma have been studied. The aim of the current systematic review was to determine the optimal strategy for adjuvant care for women with Stage I ovarian carcinoma. METHODS: A systematic search was conducted to find randomized controlled trials published between 1965 and April 2004 that examined adjuvant therapy (e.g., chemotherapy and radiotherapy) for women with Stage I ovarian carcinoma. RESULTS: Thirteen randomized controlled trials were identified that compared adjuvant therapies for women with Stage I ovarian carcinoma. Eight of these trials reported results only for patients with Stage I disease. The majority of patients in the five randomized trials that compared adjuvant chemotherapy with no chemotherapy did not receive lymphadenectomy as part of their surgical staging. The pooled results for Stage I patients indicated a survival benefit (relative risk [RR], 0.74; 95% confidence interval [CI], 0.58-0.94; P = 0.01), and a benefit in terms of a reduced risk of developing disease recurrence (RR, 0.70; 95% CI, 0.58-0.86; P = 0.0004) favoring adjuvant chemotherapy. Platinum-based adjuvant chemotherapy was reported to improve overall 5-year survival (absolute survival difference 8%; 95% CI, 2-12%; hazard ratio, 0.67; 95% CI, 0.50-0.90; P = 0.008). CONCLUSIONS: Adjuvant platinum-based chemotherapy for women with Stage I ovarian carcinoma improved survival and reduced the risk of recurrent disease. The optimally staged group accounted for approximately 10% of women with Stage I disease. The role of adjuvant chemotherapy in optimally staged patients (especially those with good prognostic factors) has not been assessed adequately.     

Secondary acute myelocytic leukemia after adjuvant therapy for early-stage breast carcinoma. A new complication of cyclophosphamide, methotrexate, and 5-fluorouracil therapy

The occurrence of treatment-related hematologic malignancies after adjuvant therapy with alkylating agents for gastrointestinal cancers, ovarian carcinoma, and breast cancer and after treatment for Hodgkin's disease, non-Hodgkin's lymphoma, germ-cell tumors, and multiple myeloma has been well documented. Adjuvant chemotherapy is frequently used for the treatment of early stage breast cancer, and to date there has been no increase in the incidence of secondary myelodysplastic syndromes or acute leukemia after cyclophosphamide-based regimens when compared with surgical controls. This report describes two patients who developed acute myelocytic leukemia only after exposure to cyclophosphamide, methotrexate, and 5-fluorouracil adjuvant therapy. These two cases of acute leukemia, which developed 3 years after diagnosis of breast cancer and initiation of chemotherapy, were characterized by trilineage dysplasia and pancytopenia, and had abnormalities of chromosomes 5 and 7: characteristics consistent with treatment-related leukemia. Many women are diagnosed with early stage breast cancer each year who are potential candidates for adjuvant therapy. Although certain subgroups of patients have been shown to benefit from adjuvant therapy, continued efforts must be directed at identifying responders so that others will not be exposed to the additional risks of chemotherapy.     

Adjuvant endocrine therapies for premenopausal women

Adjuvant endocrine treatment for premenopausal woman remains a controversial area in the therapeutical approach of early stages of breast cancer. Metaanalysis show that ovarian ablation and suppression produce, in a global way, significant benefits in terms of reduction of the risk of recurrence and death. Nevertheless, in the presence of adjuvant chemotherapy, the benefits of ovarian suppression or ablation are clearly reduced, probably in relation to the impact that amenorrhoea induced by chemotherapy. On the other hand, in premenopausal patients, the same metaanalysis show that the use of adjuvant tamoxifen produces benefits in disease-free survival and overall survival very similar to those observed in postmenopausal women. Additionally, the benefits from tamoxifen persist independently of whether or not adjuvant chemotherapy is being received. Thus, some of the questions to answer are: first, is there, in premenopausal women, an additional benefit when ovarian suppression is associated to tamoxifen? Second, it remains controversial if ovarian suppression must be indicated for all patients who receive chemotherapy or only those that have not reached amenorrhoea when adjuvant chemotherapy is completed. Moreover, although in the last decades more than 15,000 premenopausal patients have been included in specific trials of adjuvant endocrine therapy with ovarian suppression or ablation, the best modality of treatment has not been established, and what is more important, the role of its association with tamoxifen has not been completely defined. Many of these aspects remain controversial and the decision about the best therapeutical approach must be individualised in each patient.     

Ovarian metastases from primary gastrointestinal malignancies: the Royal Marsden Hospital experience and implications for adjuvant treatment.

We investigated the pattern and frequency of ovarian metastases in patients with primary gastrointestinal malignancies and evaluated the response to surgery, chemotherapy and in three cases radiotherapy. The literature reports that this group of patients have a poor prognosis, but no report has specifically addressed the response to chemotherapy. Using a database which is generated prospectively, we analysed 51 patients with primary gastrointestinal malignancies and ovarian metastases. All patients received chemotherapy but only 36 were evaluable for response; five had adjuvant treatment and ten had non-measurable disease. Seventeen patients had surgical oophorectomy and three patients received radiotherapy. The overall response rate to chemotherapy was 22%; eight partial responses and no complete responses. When stratified according to site of response, 11 (31%) patients had a partial response at sites of extraovarian metastases and only five (14%) had a partial response in the ovaries. Seven patients with primary colorectal cancer had a differential response in favour of extraovarian sites. The median survival was 9 months for the 51 patients. Three premenopausal women with resected gastric carcinoma received adjuvant chemotherapy and relapsed only in the ovaries. In primary colorectal tumours the response of ovarian metastases to chemotherapy is less than that for other sites. Therefore, the ovary may be a sanctuary site for metastases which has important implications for adjuvant chemotherapy in women. These women could be followed up regularly by transvaginal ultrasonography to detect such metastases at an early stage when they would be amenable to surgical resection. Surgery should be considered for selected patients who develop metachronous metastases, as patients may be rendered disease free for several months.     

Treatment of brain metastasis from ovarian cancer]

Systemic metastases from ovarian carcinoma are frequent, but they seldom affect the central nervous system. We present here the case of a patient treated for an ovarian cancer by surgery and chemotherapy. Three months after the end of chemotherapy, the patient developed cerebral metastases from ovarian carcinoma (CMOC) treated by iterative surgery and and whole brain irradiation. As the frequency of solitary cerebral metastasis of ovarian cancer is higher than with other cancers, it is likely that they behave slightly differently. Literature analysis reveals an increase in the incidence of CMOC since the middle of the nineties. CMOC can occur during or after adjuvant chemotherapy and the best management strategies to better define determinants of survival for patients are not well known. It appears that a better outcome of CMOC may be obtained by an aggressive treatment, if possible, including surgery, radiotherapy, and chemotherapy. Taking into account the increase in the incidence of the CMOC and their early occurrence, some authors have proposed a prophylactic brain radiotherapy in patients who receive adjuvant chemotherapy.     

Neoadjuvant chemotherapy for advanced epithelial ovarian cancer]

Primary surgical cytoreduction followed by paclitaxel/carboplatin combination chemotherapy currently is the treatment of choice for advanced epithelial ovarian cancer. Aggressive surgery is widely accepted as a valid approach to initial cytoreduction of stage III disease, but suboptimal residual disease following primary surgical resection is one of the most important adverse prognostic factors in these patients. Neoadjuvant chemotherapy has been proposed as an alternative approach to conventional surgery for initial management of bulky ovarian cancer, with the goal of improving surgical quality. General acceptance of neoadjuvant chemotherapy as an alternative to primary surgery for patients who are not ideal surgical candidates remains limited, because equivalent or superior survival has not yet been demonstrated in a prospective randomized study. A large-scale, prospective, randomized study is being conducted by the European Organization for Research and Treatment of Cancer (EORTC) Gynecologic Cancer Cooperative Group and Gynecologic Oncology Group (GOG) to compare outcomes (overall and progression-free survival, quality of life, treatment complications) of neoadjuvant chemotherapy/interval debulking surgery versus primary cytoreductive surgery/adjuvant chemotherapy in patients with advanced epithelial ovarian carcinoma.     

Complete response to irinotecan hydrochloride and nedaplatin in a patient with advanced ovarian clear cell carcinoma

A 55-year-old multiparous woman was diagnosed with stage IIIc ovarian clear cell carcinoma. Three years after the first surgery and adjuvant chemotherapy with irinotecan hydrochloride and mitomycin C, she developed common iliac lymph node recurrence. Two cycles of chemotherapy with irinotecan hydrochloride and nedaplatin led to a complete response. Surgical resection revealed pathological complete response. The chemosensitivity of ovarian clear cell carcinoma has been reported to be very poor. No standard chemotherapeutic regimens for this carcinoma have been established. The present study is the first report of a pathological complete response in a patient with advanced ovarian clear cell carcinoma. Future studies are needed to confirm the efficacy of this regimen for this carcinoma.     

Treatment of patients with early epithelial ovarian cancer

PURPOSE OF REVIEW: During 2003, the first randomized trials were published comparing adjuvant platin-based chemotherapy versus no treatment in early epithelial ovarian cancer. RECENT FINDINGS: Recent findings of the European Organisation for Research and Treatment of Cancer Adjuvant ChemoTherapy In Ovarian Neoplasm and International Collaborative Ovarian Neoplasm-1 trials showed an improvement of overall survival of 8% in patients treated with adjuvant platin-based chemotherapy compared with observation. In a subgroup analysis, in 150 optimally surgically staged patients of the European Organisation for Research and Treatment of Cancer Adjuvant ChemoTherapy In Ovarian Neoplasm trial, there appears to be no benefit of adjuvant chemotherapy. In past years, it has been shown that degree of differentiation is a much stronger predictor of recurrence in early ovarian cancer than International Federation of Gynaecology and Obstetrics subclassification (Ia, Ib, Ic). It has also been shown that patients with bilateral tumors (Ib) have the same prognosis as International Federation of Gynaecology and Obstetrics stage Ic patients. SUMMARY: During the past year, it has been shown that platin-based adjuvant chemotherapy improves recurrence-free and overall survival in early epithelial ovarian cancer. It should be emphasized, however, that this was demonstrated in patients in whom the true nature of early stage disease was doubtful in many patients due to incomplete surgical staging. In a subgroup of patients who are optimally surgically staged, adjuvant chemotherapy may be less effective. Theoretically, only a future trial randomizing optimal surgical staging versus adjuvant chemotherapy may be able to provide definitive conclusions, but such a trial would be almost impossible to conduct. In the meantime, optimal staging is advocated in all patients who are fit enough to undergo this procedure. Degree of differentiation should be incorporated in a new International Federation of Gynaecology and Obstetrics classification for stage I disease and in clinical decision making.     

Second-line and subsequent therapy for ovarian carcinoma

Ovarian carcinoma continues to be the leading cause of death among gynecologic malignancies. Paclitaxel and platinum chemotherapy is still the treatment of choice after primary debulking surgery. Salvage chemotherapy with several single agents has only modest activity and does not prolong survival of patients with relapsed ovarian carcinoma. An intense search has been made for novel approaches to treatment of ovarian cancer, and several new treatments, such as immunotherapy and gene therapy, show promise. Newer combination chemotherapy regimens and molecularly targeted therapy need to be developed. High-dose chemotherapy with autologous stem-cell transplantation appears to benefit selected groups of patients and is still investigational. Whole abdominal radiotherapy for relapsed microscopic disease should be studied in prospective randomized trials. Women with advanced ovarian carcinoma should continue to be encouraged to participate in welldesigned clinical trials.     

Latest information in the diagnoses of ovarian carcinoma

Despite improvements in median and overall survival from a combination of improved operation techniques and chemotherapy with platinum-compounds and paclitaxel, long-term survival rates for patients with epithelial ovarian carcinoma remain disappointing, and ongoing efforts are aimed at developing more effective primary therapies. In early ovarian carcinoma, conservative management is used to denote surgery that preserves reproductive potential without compromising curability. With some exceptions, such a strategy may be applicable for women younger than 40, who wish to bear children. A major dilemma facing gynecologic oncologists is to determine whether the accurate staging laparotomy is needed for apparent low-risk stage I ovarian carcinoma and how many cycles of chemotherapy will be needed for high-risk stage I ovarian carcinoma. In advanced ovarian carcinoma, main objectives of salvage therapy include: a improvement in quality of life and symptoms; b. tumor load reduction and survival advantage; c. evaluation of potentially active new drugs to be included in first-line treatment. We need to evaluate the potential benefit on survival of systematic pelvic and para-aortic lymphadenectomy during primary or secondary cytoreductive surgery in patients with advanced ovarian carcinoma. Paclitaxel/cisplatin is considered to be the international standard treatment based on the data of GOG 111 trial showing that paclitaxel/cisplatin has provided a survival benefit better than that of cyclophosphamide/cisplatin. This choice of standard therapy might, however, be questioned based on the results of the largest randomised study, ICON3. There were no statistically significant differences in progression-free or overall survival among paclitaxel/carboplatin and carboplatin only or a platinum combination (cyclophosphamide/doxorubicin/cisplatin). The best selection for adjuvant chemotherapy is still controversial and a large number of studies are now ongoing.