卵巢癌的诊断和治疗(医大讲课）

nullnullDiagnosis and Treatment of Ovarian Cancer Shen Keng Department of OB/GYN Peking Union Medical College Hospital Epidemiology and Genetic FactorsEpidemiology and Genetic FactorsOvarian cancer is the second most common gynecological malignancy, but the commonest malignancy of the female genital tract to result in death Incidence: In general population lifetime risk for ovarian cancer in a women is roughly 1/70 or 1.4%.Epidemiology and Genetic FactorsEpidemiology and Genetic FactorsThe incidence in Asia, Africa and Latin America is lower than in Western countries. The most common tumor type is epithelial (85%). 卵巢癌的危险因素卵巢癌的危险因素年龄危险因素与子宫内膜、结肠、乳腺癌的关系家庭史生产史和激素水平Epidemiology and Genetic FactorsEpidemiology and Genetic FactorsHigh risk factors: 1. More than 40yrs. 2. Caucasian race (white) 3. Late menopause. 4. Infertility 5. Positive family history of CA ovary 6. BRCA geneEpidemiology and Genetic FactorsEpidemiology and Genetic FactorsFamily history is the strongest risk factor for ovarian cancer Women with one affected first class relative: risk rate for ovarian cancer is 5% Women with two affected first class relative: risk rate for ovarian cancer is 7% A member of HOCS: risk rate for ovarian cancer is 20%--50% BRCA1 &BRCA2 gene associated with HOCS Epidemiology and Genetic FactorsEpidemiology and Genetic FactorsPrevention & protective factors for ovarian cancer appear to be conditions associated with fewer lifetime ovulations 1. Use of oral contraceptive pills 2. Shorter duration of reproductive years 3. Conditions of chronic anovulation 4. History of breastfeeding 5. MultiparityHistopathologyHistopathologyEpithelial ovarian cancer, usually classed simply as adenocarcinoma, include a number of specific histological types: Serous adenocarcinoma Muconous adenocarcinoma Endometrioid adenocarcinoma Malignant Brenner tumor (transitional cell) Clear cell adenocarcinoma HistopathologyHistopathologyMalignant Germ Cell Tumor of the Ovary include a number of specific histological types: Dysgerminoma Yolk-Sac Tumor (endodermal sinus tumor) Teratomas Choriocarcinoma Mixed germ cell tumor HistopathologyHistopathologyMalignant Tumor of the Gonadal stroma: Granulosal-cell tumors Adult type Juvenile type Sertoli-cell tumors Leydig-cell tumors Sertoli-Leydig-cell tumors Sex cord tumor with annular tubules Spread of ovarian cancerSpread of ovarian cancerLocal spread Intra-abdominal spread lymphatic spread hemtogenous spreadSymptomsSymptomsSymptoms are most often absent with early stage ovarian cancer. When present, symptoms tend to be nonspecific GI tract complaints: such as nausea, abdominal cramping, or change in bowel habits,are often the early symptoms of advanced stage disease. By this time, the disease may be widely disseminated throughout the peritoneal cavity Abdominal distention: big mass, omental cake, ascites intestinal obstruction SymptomsSymptomsPostmenopausal bleeding may occur from endometrial hyperplasia stimulated by estrogen from a ovarian tumor. Virilization is found in 50% of patients who have an androgen-secreting Sertoli-Leydig-cell tumor. Colicky pain is associated with torsion of a mobile ovarian tumor. Constant pain may be experienced with the distention of hemorrhage into a tumorPhysical examinationPhysical examinationFixed, bilateral pelvic masses Abdominal mass: omental cake, big ovarian tumor Abdominal percussion: ascites A nodular tumor in POD Pleural effusion Meige’s syndrome consists of ascites and hydrothorax associated with fibroma and thecoma. Preoperative workupPreoperative workupPap smear (f) D&C Tumor makers: CA125, CEA, HCG, AFP, LDH Chest film to look for lung metastasis and pleural effusionPreoperative workupPreoperative workupBarium enema to evaluate the lower GI tract Plain film of the abdomen to identify intestinal obstruction IVP to assess the urinary system USG, CT scan or MRI to determinate the anatomy relationship between the ovarian cancer and pelvic organs 卵巢癌的MRI卵巢癌的MRICourtesy of Barry N. Siskind, MD, The Graduate Hospital Imaging Center, Philadelphia, PA, USA子宫卵巢 肿块直肠Preoperative workupPreoperative workupPeritoneocentesis for reliving abdominal distention and cytology examination. Laparoscopy can be used to obtained pathological diagnosis of ovarian cancer preoperatively The role of Surgery in the management of ovarian cancer The role of Surgery in the management of ovarian cancer Diagnostic Establish diagnosis and determine histology and grade of the tumor Surgical staging Reassessment Laparotomy Therapeutic Primary cytoredution Secondary cytoreduction Provision of intravenous and intraperitonel access Palliative Reduction of tumor bulk, Relieve gastrointestinal obstruction Surgeries for ovarian cancerSurgeries for ovarian cancerComprehensive staging laparotomy Restaging laparotomy Primary cytoreductive surgery Interval debulking Second-look laparotomy Second debulking (Recytoreductive surgery)Standard procedure of cytoreductive surgery for ovarian cancerStandard procedure of cytoreductive surgery for ovarian cancerLongitudinal incision Abdominal fluid for cytology Exploration Omentectomy Total hysterectomy Bilateral salpingo-oohporectomy Para-aortic and pelvic lymphadenectomy Low anterior resection of colon Appendectomy 卵巢癌的临床分期卵巢癌的临床分期卵巢癌I期和II期卵巢癌I期和II期卵巢癌III期和IV期卵巢癌III期和IV期Beecham Sevigne, M閙ento de Stadification des Principales Tumeurs SolidesIII期种植性肝转移腹腔腹膜转移肝实质性转移恶性胸膜细胞前锁骨淋巴结IV期nullnullnullnullnullnull卵巢癌的治疗: 手术 (I)卵巢癌的治疗: 手术 (I)DeVita et al. Cancer: Principles & Practice of Oncology.1993全腹腔探查 和活检网膜几乎所有的病人进 行全子宫、双侧输 卵管及网膜切除术nullnullnullLymph nodes metastasis and retroperitonal lymphadenectomy in ovarian cancerLymph nodes metastasis and retroperitonal lymphadenectomy in ovarian cancerLymphatic pathway is an important route of metastasis in ovarian cancer. The overall incidence of retroperitoneal positive nodes 54.3% The incidence of positive pelvic nodes 46.7% positive para-aortic nodes 37.5% Both aortic and pelvic nodes positive 48.7% nullnullnullnullIntestinal metastasis and operation in ovarian cancerIntestinal metastasis and operation in ovarian cancer Rectosigmoid involved 95.2% Metastasis to small bowel 41.9% Superficial and serosal invasion 64.5% Complete or optimal resection 74.2% resection of the bowel 31.2% Colostomy 9.8% 27.4% survival with mean survival time 30.3 months nullConservative surgery in ovarian cancer Conservative surgery in ovarian cancer Germ cell tumor (any stage) Stage I grade I granulosal cell tumor For epithelial cancer : 1. Young patient and desire of reproduction 2 Stage Ia, 3. Grade 1 4. Capsule intake 5. No adhesion 6. Peritoneal cytology negative 7. Multiple biopsies of high risk negative 8. Follow up available Management of Ovarian CancerManagement of Ovarian CancerEarly disease Stage IA/B grade I/II exploratory operation; conservative resection preserve fertility in bilateral borderline tumours adjuvant therapy unproven Unfavourable type poorly differentiated clear cell tumours capsule penetration ruptured capsule positive washings stage II: standard operation + adjuvant therapy 早期卵巢癌的化疗早期卵巢癌的化疗FIGO I，II期卵巢癌 “预后好”的患者90%以上可长期无瘤存活，而且不需要辅助化疗。 有高危因素的患者，30%-40%有复发的危险，25%-30%在首次手术后5年内死亡。 与复发有关的高危因素： （1）包膜破裂 （2）肿瘤面生长 （3）低分化（G3）（4）与周围组织粘连 （5）透明细胞癌 （6）腹腔冲洗液阳性 （7）卵巢癌外转移 Management of Ovarian CancerManagement of Ovarian Cancer Advanced stage disease Stage III/IV Primary cytoreductive surgery / interval debulking Obtained optimal debulkung (residual tumor <2cm) First line chemotherapy ( 6--9 courses) Recurrent diseases Progressive disease / resistant disease-----salvage Chemotherapy Sensitive disease ( recurrence > 6 months)---secondary debunking following chemotherapy Palliative treatment (Radiotherapy, immunotherapy) unprovenChemotherapy in ovarian cancerChemotherapy in ovarian cancerFirst line chemotherapy for epithelial ovarian cancer CHexUP and Thio-Tepa protocol ( 1982-1985) PAC or PC (1986-1990) DDP, 5-FU, Ara-c, Bleomycin, CTX. IP & IV Combination (1991-1994) Taxol, DDP/Carpa (1995-2000) Weekly taxol /Carpa(2000--) Combination ChemotherapyCombination ChemotherapyCisplatin acts by binding to DNA and producing cross-links and DNA adducts. Cisplatin is a very effective drug for ovarian cancer. Important side effects include severe nausea and vomiting, dose-related nephrotoxicity, ototoxicity, peripheral nerutoxicity and myelosuppresionCombination ChemotherapyCombination ChemotherapyThe mechanism of action of carboplatin is the same as that of cisplatin, the side effects, however, differ greatly. The most important side effect is thrombocytopenia. Leukopenia and anemia also occur but are less severe. Neurotoxicity and nephrotoxicity are less severe with carboplatin than with cisplatin Other important side effect include alopecia and mucositis. Combination ChemotherapyCombination ChemotherapyPaclitaxel acts as a mitotic spindle poison. Paclitaxel is also a very effective drug for ovarian cancer at the present time Some patients exhibit hypersensitivity to paclitaxel. Other side effect include myelosuppression , nerotoxicity, mucositis, diarrhea, alopcia nausea and vomiting卵巢上皮癌的化疗卵巢上皮癌的化疗铂基础治疗方案通常联合: 紫杉醇 环磷酰胺 阿霉素 通常需要间隔3- 4周至少6个周期的治疗晚期卵巢癌的化疗晚期卵巢癌的化疗一线治疗 国内 顺铂+环磷酰胺(PC) 顺铂+阿霉素+环磷酰胺(PAC) 国外 泰素＋顺铂 泰素＋卡铂 泰素每周疗法Combination ChemotherapyCombination ChemotherapyCombination chemotherapy most often is used as postoperative treatment for advanced epithelial ovarian cancer. Combination chemotherapy with six courses of cisplatin or carboplatin plus paclitaxel is the treatment of choice for patients with advanced disease. Courses are given every 3 to 4 weeks with monitoring of tumor status by physical examination. CA125 levels ,and imaging studies if appropriate卵巢癌病人化疗存活率卵巢癌病人化疗存活率 McGuire WP et al. N Engl J Med. 1996Post-Therapy SurveillancePost-Therapy SurveillanceFollow-up after therapy in ovarian cancer is poorly defined. At the present time there is no definitive test for detecting the presence of microscopic recurrent epithelial ovarian cancer For this reason there remains significant controversy as to what constitutes optimal posttherapy surveillance. Post-Therapy SurveillancePost-Therapy SurveillanceScreening modalities: 1. Pelvic Examination 2. CA 125 (44% sensitivity, 96% specificity, 65% accuracy) 3. Ultrasound (20%-89% sensitivity, 75%-100% specificity) 4. Second-look laparotomy 5. CT scan (44% sensitivity, 86% specificity, 63% accuracy) 6. MIR imaging. 6. Position emission tomography (PET) (83% sensitivity, 80% specificity, 82% accuracy) nullnullnull卵巢癌复发的诊断和治疗卵巢癌复发的诊断和治疗首次的化治疗(理想的肿瘤细胞减灭术加上以足够疗程的铂类和/或紫杉醇为基础的联合化疗) 70%-80%的患者可获得临床完全缓解. 60%-70%的患者最终还会复发. 对卵巢癌复发的诊断和治疗是卵巢癌治疗中最为棘手的问题. 怎样合理处理复发性卵巢癌意见尚不统一卵巢癌的复发类型 (1)卵巢癌的复发类型 (1)化疗敏感型卵巢癌: 定义为对初期以铂类药物为基础的治疗有明确反应,且已经达到临床缓解,停用化疗6个月以上,病灶复发.卵巢癌的复发类型 (2)卵巢癌的复发类型 (2)化疗耐药型卵巢癌: 定义为患者对初期的化疗有反应,但在完成化疗相对短的时间内证实复发,一般认为,完成化疗后6个月内的复发,应考虑为铂类药物耐药卵巢癌的复发类型(3)卵巢癌的复发类型(3)顽固性卵巢癌: 是指在初期化疗时对化疗有反应或明显反应的患者中发现有残余病灶,例如:“二探”阳性者.卵巢癌的复发类型 (4)卵巢癌的复发类型 (4)难治性卵巢癌: 是指对化疗没有产生最小有效反应的患者,包括在初始化疗期间,肿瘤稳定或肿瘤进展者,大约发生于20%的患者. 这类患者对二线化疗的有效反应率最低.卵巢癌复发的治疗卵巢癌复发的治疗治疗前的准备: 详细复习病史包括: (1)手术分期. (2)组织学类型和分级. (3)手术的彻底性. (4)和残余瘤的大小及部位. (5)术后化疗的方案,途径,疗程,疗效. (6)停用化疗的时间. (7)出现复发的时间等. 对复发性卵巢癌进行定性、分型、定位分析 对患者的生活状态(PS)进行评分,对患者重要器官的功能进行评估. 目前观点认为: 对于复发性卵巢癌的治疗目的一般是趋于保守性的, 因此在选择复发性卵巢癌治疗方案时,对所选择方案的预期毒性作用及其对整个生活质量的影响都应该加以重点考虑. 目前观点认为: 对于复发性卵巢癌的治疗目的一般是趋于保守性的, 因此在选择复发性卵巢癌治疗方案时,对所选择方案的预期毒性作用及其对整个生活质量的影响都应该加以重点考虑.复发性卵巢癌的手术治疗复发性卵巢癌的手术治疗手术对复发性卵巢癌的治疗价值尚未确定, 手术的指征和时机还存在一些争论. 复发性卵巢癌的手术治疗主要用于三个方面: 1.解除肠梗阻 2.>12个月复发灶的减灭. 3.切除孤立的复发灶. 对晚期复发卵巢癌是先手术还是先化疗仍有争议.Chemotherapy in Ovarian CancerChemotherapy in Ovarian CancerSecond line chemotherapy for epithelial ovarian cancer Patients with persistent or recurrent diseases should be treated with second line chemotherapy. Unfortunately, response rates for second line chemotherapy are only 10% to 30%. Regarding of the approach, second line chemotherapy for persistent or recurrent ovarian cancer is not curative. Combination ChemotherapyCombination ChemotherapySecond line chemotherapy for epithelial ovarian cancer Depending on the initial chemotherapy, second line chemotherapy may include: Topotecan Paclitaxel Platinum Ifosfamide Taxotere Hexamethylmelamine对复发卵巢癌有效的新药对复发卵巢癌有效的新药SurvivalSurvivalEarly-stage disease Five year survival rate for patients with stage I or stage II disease are 80% to 100, depending on the tumor grade Advanced disease Five year survival rate for patients with stage IIIa is 30% to 40% Five year survival rate for patients with stage IIIb is 20% Five year survival rate for patients with stage IIIc or IV is 5% Recurrent disease Five year survival rate for patients with negative SLL is 50% Five year survival rate for patients with microscopic disease is 35% Five year survival rate for patients with macroscopic disease is 5% Malignant Germ Cell Tumor of the OvaryMalignant Germ Cell Tumor of the OvaryTwenty percent to 25% of all malignant tumor of the ovary are of germ cell origin. In the first decades of life, 70% of ovarian tumors are of germ cell origin and one third are malignant Germ cell tumors are quite rare after the third decades of life.Malignant Germ Cell Tumor of the OvaryMalignant Germ Cell Tumor of the Ovary1.Malignant germ cell tumor of the ovary is very sensitive to the chemotherapy. Chemotherapy has been a very important treatment for this kind ovarian tumor. 2.Chemotherapy has improved the survival of patients with Malignant germ cell tumor of the ovary dramatically. Survival rate has been increased from 10% to 90% 3.Reproductive function can be preserved for any stage patients with malignant germ cell tumor of the ovaryManagement of malignant germ cell tumor of the ovary Management of malignant germ cell tumor of the ovary Primary treatment is surgical. Unilateral oophorectomy with preserved reproductive function is considered. PVB and PEB chemotherapy are the treatment of choice for patients with MGCT postoperatively Courses of chemotherapy are depending on the high risk factors of the tumor and tumor maker levelsSex cord stromal tumorsSex cord stromal tumorsOvarian sex cord-stromal tumor account for less than 5%. It may occur at any age, although the age of peak incidence for granular cell tumors is in the postmenopausal years. No standard therapy exists. Lower malignant potential and late recurrence Sex cord stromal tumorsSex cord stromal tumorsSurgery remains cornerstone of treatment for patients with ovarian sex cord stromal tumors. 95% of the tumor are unilateral, 95% are confined to the ovary. Unilateral salpingo-oophorectomy seems to appropriate treatment for young patients with stage Ia disease. THBSO is considered standard surgery for old patients and advanced stage diseases.Sex cord stromal tumorsSex cord stromal tumorsPVB chemotherapy is the treatment of choice for selected patient with sex cord stromal tumor after surgical treatment. Long term follow-up should be considered for this kind of tumor because of late recurrence. The 10 year survival rate is 90%, and the 20 year survival rate drop to 75%.Sex cord stromal tumors Prognostic factorsSex cord stromal tumors Prognostic factorsStage(extraovary metastasis) Tumor size Histologic type Mitotic count Atypia DNA ploidy (associated with other adverse histolopathologic parameters) High stage, vascular invasion, nuclear atypia, high mitotic activity plus aneuploidy  poor prognosisnullnull