卵巢癌的诊断和治疗(医大讲课)

Diagnosis and Treatment of Ovarian Cancer Shen Keng Department of OB/GYNPeking Union Medical College HospitalEpidemiology and Genetic FactorsOvarian cancer is the second most common gynecological malignancy,but the commonest malignancy of the female genital tract to result in deathIncidence:In general population lifetime risk for ovarian cancer in a women is roughly 1/70 or 1.4%.Epidemiology 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年龄危险因素危险因素与子宫内膜、结肠、乳腺癌的关系与子宫内膜、结肠、乳腺癌的关系家庭史家庭史生产史和激素水平生产史和激素水平Epidemiology 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 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 HOCSEpidemiology 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.MultiparityHistopathologyEpithelial ovarian cancer,usually classed simply as adenocarcinoma,include a number of specific histological types:Serous adenocarcinomaMuconous adenocarcinomaEndometrioid adenocarcinomaMalignant Brenner tumor(transitional cell)Clear cell adenocarcinomaHistopathologyMalignant Germ Cell Tumor of the Ovary include a number of specific histological types:DysgerminomaYolk-Sac Tumor(endodermal sinus tumor)TeratomasChoriocarcinomaMixed germ cell tumorHistopathologyMalignant Tumor of the Gonadal stroma:Granulosal-cell tumors Adult type Juvenile typeSertoli-cell tumorsLeydig-cell tumorsSertoli-Leydig-cell tumorsSex cord tumor with annular tubulesSpread of ovarian cancerLocal spreadIntra-abdominal spreadlymphatic spreadhemtogenous spreadSymptomsSymptoms are most often absent with early stage ovarian cancer.When present,symptoms tend to be nonspecificGI 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 cavityAbdominal distention:big mass,omental cake,ascites intestinal obstruction SymptomsPostmenopausal 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 examinationFixed,bilateral pelvic massesAbdominal mass:omental cake,big ovarian tumorAbdominal percussion:ascitesA nodular tumor in PODPleural effusion Meiges syndrome consists of ascites and hydrothorax associated with fibroma and thecoma.Preoperative workupPap smear(f)D&CTumor makers:CA125,CEA,HCG,AFP,LDHChest film to look for lung metastasis and pleural effusionPreoperative workupBarium enema to evaluate the lower GI tractPlain film of the abdomen to identify intestinal obstruction IVP to assess the urinary systemUSG,CT scan or MRI to determinate the anatomy relationship between the ovarian cancer and pelvic organs 卵巢癌的卵巢癌的MRIMRICourtesy of Barry N.Courtesy of Barry N.Siskind Siskind,MD,The Graduate Hospital Imaging Center,Philadelphia,PA,USA,MD,The Graduate Hospital Imaging Center,Philadelphia,PA,USA子宫子宫子宫子宫卵巢卵巢卵巢卵巢 肿块肿块肿块肿块直肠直肠直肠直肠Preoperative 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 cancerDiagnostic Establish diagnosis and determine histology and grade of the tumor Surgical staging Reassessment Laparotomy Therapeutic Primary cytoredution Secondary cytoreduction Provision of intravenous and intraperitonel accessPalliative Reduction of tumor bulk,Relieve gastrointestinal obstructionSurgeries for ovarian cancerComprehensive staging laparotomyRestaging laparotomyPrimary cytoreductive surgeryInterval debulkingSecond-look laparotomySecond debulking (Recytoreductive surgery)Standard procedure of cytoreductive surgery for Standard procedure of cytoreductive surgery for ovarian cancerovarian cancerLongitudinal incisionAbdominal fluid for cytology ExplorationOmentectomyTotal hysterectomyBilateral salpingo-oohporectomyPara-aortic and pelvic lymphadenectomyLow anterior resection of colonAppendectomy卵巢癌的临床分期卵巢癌的临床分期卵巢癌卵巢癌I I期和期和IIII期期IaIaIaIa期期期期 Ic Ic Ic Ic 期期期期腹水腹水腹水腹水阳性阳性阳性阳性 或或IbIbIbIb期期期期I I期期IIII期期 IIa IIa IIa IIa 期期期期 IIb IIb IIb IIb 期期期期 IIc IIc IIc IIc 期期期期卵巢癌卵巢癌IIIIII期和期和IVIV期期BeechamBeecham Sevigne Sevigne,MM閙閙閙閙entoento de de Stadification Stadification des des Principales Tumeurs Solides Principales Tumeurs SolidesIIIIII期期种植性肝转移种植性肝转移腹腔腹膜转移腹腔腹膜转移腹腔腹膜转移腹腔腹膜转移肝实质性转移肝实质性转移恶性胸膜细胞恶性胸膜细胞前锁骨淋巴结前锁骨淋巴结IVIV期期卵巢癌的治疗卵巢癌的治疗:手术手术(I)(I)DeVita et al.Cancer:Principles&Practice of Oncology.1993全腹腔探查全腹腔探查全腹腔探查全腹腔探查和活检和活检和活检和活检网膜网膜几乎所有的病人进几乎所有的病人进行全子宫、双侧输行全子宫、双侧输卵管及网膜切除术卵管及网膜切除术Lymph 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%Intestinal metastasis and operation in ovarian cancerRectosigmoid 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 monthsConservative surgery in ovarian cancerGerm cell tumor(any stage)Stage I grade I granulosal cell tumor For epithelial cancer:1.Young patient and desire of reproduction1.Young patient and desire of reproduction 2 Stage Ia,2 Stage Ia,3.Grade 1 3.Grade 1 4.Capsule intake 4.Capsule intake 5.No adhesion 5.No adhesion 6.Peritoneal cytology negative 6.Peritoneal cytology negative 7.Multiple biopsies of high risk negative 7.Multiple biopsies of high risk negative 8.Follow up available 8.Follow up availableManagement of Ovarian CancerEarly diseaseStage IA/B grade I/IIexploratory operation;conservative resectionpreserve fertility in bilateral borderline tumours adjuvant therapy unprovenUnfavourable typepoorly differentiated clear cell tumourscapsule penetrationruptured capsulepositive washingsstage II:standard operation+adjuvant therapy早期卵巢癌的化疗早期卵巢癌的化疗FIGO IFIGO I，IIII期卵巢癌期卵巢癌“预后好预后好”的患者的患者90%90%以上可长期无瘤存活，而且不需以上可长期无瘤存活，而且不需要辅助化疗。要辅助化疗。有高危因素的患者，有高危因素的患者，30%-40%30%-40%有复发的危险，有复发的危险，25%-30%25%-30%在首次手术后在首次手术后5 5年内死亡。年内死亡。与复发有关的高危因素与复发有关的高危因素：（1 1）包膜破裂）包膜破裂 （2 2）肿瘤表面生长）肿瘤表面生长 （3 3）低分化（）低分化（G3G3）（）（4 4）与周围组织粘连与周围组织粘连 （5 5）透明细胞癌）透明细胞癌 （6 6）腹腔冲洗液阳性）腹腔冲洗液阳性 （7 7）卵巢癌外转移）卵巢癌外转移Management of Ovarian Cancer Advanced stage diseaseStage III/IV Primary cytoreductive surgery/interval debulking Obtained optimal debulkung(residual tumor 6 months)-secondary debunking following chemotherapy Palliative treatment(Radiotherapy,immunotherapy)unprovenChemotherapy 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 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 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 cisplatinOther important side effect include alopecia and mucositis.Combination ChemotherapyPaclitaxel acts as a mitotic spindle poison.Paclitaxel is also a very effective drug for ovarian cancer at the present timeSome 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铂基础治疗方案通常联合:紫杉醇紫杉醇紫杉醇紫杉醇环磷酰胺环磷酰胺环磷酰胺环磷酰胺 阿霉素阿霉素阿霉素阿霉素 通常需要间隔通常需要间隔3-43-4周至少周至少6 6个周期的治疗个周期的治疗晚期卵巢癌的化疗晚期卵巢癌的化疗*一线治疗一线治疗*国内国内顺铂顺铂+环磷酰胺环磷酰胺(PC)PC)顺铂顺铂+阿霉素阿霉素+环磷酰胺环磷酰胺(PAC)PAC)*国外国外泰素顺铂泰素顺铂泰素卡铂泰素卡铂泰素每周疗法泰素每周疗法Combination 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 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 cancerFor this reason there remains significant controversy as to what constitutes optimal posttherapy surveillance.Post-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)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规范化治疗首次的规范化治疗(理想的肿瘤细胞减灭术加上以足理想的肿瘤细胞减灭术加上以足够疗程的铂类和够疗程的铂类和/或紫杉醇为基础的联合化疗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的患者可获得临床完全缓解.60%-70%的患者最终还会复发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怎样合理处理复发性卵巢癌意见尚不统一卵巢癌的复发卵巢癌的复发类型类型(1)化疗敏感型卵巢癌化疗敏感型卵巢癌:定义为对初期以铂类药物为基础的治疗定义为对初期以铂类药物为基础的治疗有明确反应有明确反应,且已经达到临床缓解且已经达到临床缓解,停用化停用化疗疗6个月以上个月以上,病灶复发病灶复发.卵巢癌的复发卵巢癌的复发类型类型(2)化疗耐药型卵巢癌化疗耐药型卵巢癌:定义为患者对初期的化疗有反应定义为患者对初期的化疗有反应,但在完但在完成化疗相对短的时间内证实复发成化疗相对短的时间内证实复发,一般认一般认为为,完成化疗后完成化疗后6个月内的复发个月内的复发,应考虑为应考虑为铂类药物耐药铂类药物耐药卵巢癌的复发卵巢癌的复发类型类型(3)顽固性卵巢癌顽固性卵巢癌:是指在初期化疗时对化疗有反应是指在初期化疗时对化疗有反应或或明显明显反应的患者中发现有残余病灶反应的患者中发现有残余病灶,例如例如:“二二探探”阳阳性者性者.卵巢癌的复发卵巢癌的复发类型类型(4)难治性卵巢癌难治性卵巢癌:是指对化疗没有产生最小有效反应的患者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包括在初始化疗期间,肿瘤稳定或肿瘤进肿瘤稳定或肿瘤进展者展者,大约发生于大约发生于20%的患者的患者.这类患者对这类患者对二线化疗的有效反应率最低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治疗前的准备:详细复习病史包括详细复习病史包括详细复习病史包括详细复习病史包括:(1)(1)手术分期手术分期手术分期手术分期.(2).(2)组织学类型和分级组织学类型和分级组织学类型和分级组织学类型和分级.(3).(3)手术的彻底手术的彻底手术的彻底手术的彻底性性性性.(4).(4)和残余瘤的大小及部位和残余瘤的大小及部位和残余瘤的大小及部位和残余瘤的大小及部位.(5).(5)术后化疗的方案术后化疗的方案术后化疗的方案术后化疗的方案,途径途径途径途径,疗程疗程疗程疗程,疗效疗效疗效疗效.(6).(6)停用化疗的时间停用化疗的时间停用化疗的时间停用化疗的时间.(7).(7)出现复发的出现复发的出现复发的出现复发的时间等时间等时间等时间等.对复发性卵巢癌进行定性、分型、定位分析对复发性卵巢癌进行定性、分型、定位分析对复发性卵巢癌进行定性、分型、定位分析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对患者的生活状态对患者的生活状态对患者的生活状态(PS)PS)进行评分进行评分进行评分进行评分,对患者重要对患者重要对患者重要对患者重要器官的功能进行评估器官的功能进行评估器官的功能进行评估器官的功能进行评估.目前观点认为目前观点认为:对于复发性卵巢对于复发性卵巢癌的治疗目的一般是趋于保守性的癌的治疗目的一般是趋于保守性的,因因此在选择此在选择复发复发性性卵巢癌卵巢癌治治疗方案时疗方案时,对对所选择方案的预期毒性作用及其对整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个生活质量的影响都应该加以重点考虑虑.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对复发性卵巢癌的治疗价值尚未确定手术对复发性卵巢癌的治疗价值尚未确定手术对复发性卵巢癌的治疗价值尚未确定,手术手术手术手术的指征和时机还存在一些争论的指征和时机还存在一些争论的指征和时机还存在一些争论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复发性卵巢癌的手术治疗主要用于三个方面复发性卵巢癌的手术治疗主要用于三个方面复发性卵巢癌的手术治疗主要用于三个方面:1.解除肠梗阻解除肠梗阻 2.12个月复发灶的减灭个月复发灶的减灭.3.切除孤立的复发灶切除孤立的复发灶.对晚期复发卵巢癌是先手术还是先化疗仍有争议对晚期复发卵巢癌是先手术还是先化疗仍有争议对晚期复发卵巢癌是先手术还是先化疗仍有争议对晚期复发卵巢癌是先手术还是先化疗仍有争议.Chemotherapy 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.Second line chemotherapy for epithelial ovarian cancer Depending on the initial chemotherapy,second line chemotherapy may include:Topotecan Paclitaxel Platinum Ifosfamide Taxotere HexamethylmelamineCombination Chemotherapy对复发卵巢癌有效的新药对复发卵巢癌有效的新药SurvivalEarly-stage diseaseFive year survival rate for patients with stage I or stage II disease are 80%to 100,depending on the tumor gradeAdvanced 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 diseaseFive 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 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 malignantGerm cell tumors are quite rare after the third decades of life.1.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 ovaryMalignant Germ Cell Tumor of the OvaryManagement 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 postoperativelyCourses of chemotherapy are depending on the high risk factors of the tumor and tumor maker levelsSex 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 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 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 factorsPrognostic factorsStage(extraovary metastasis)Tumor sizeHistologic typeMitotic countAtypiaDNA ploidy (associated with other adverse histolopathologic parameters)High stage,vascular invasion,nuclear atypia,high mitotic activity plus aneuploidy poor prognosis