A novel molecular mechanism for anticancer drug-induced ovarian failure: Irinotecan HCl, an anticancer topoisomerase I inhibitor, induces specific FasL expression in granulosa cells of large ovarian follicles to enhance follicular apoptosis

Clinical use of CPT-11 combination chemotherapy frequently induces ovarian dysfunction in premenopausal and perimenopausal cancer patients, but its mechanism remains unclear. Mouse experiments were performed to clarify the molecular mechanism of CPT-11-induced ovarian dysfunction. Clinically therapeutic doses of CPT-11 were injected intraperitoneally into 8-week-old female MCH mice, and their ovaries were examined by the TUNEL assay to detect dead cells. Immunohistochemical examinations were simultaneously performed to detect the expression of activated caspase 3, Fas antigen and Fas ligand (FasL). Furthermore, normal murine ovarian tissue fragments were incubated with recombinant soluble FasL in organ cultures and stained by the TUNEL assay to detect apoptotic cells. Intraperitoneal CPT-11 injections induced specific TUNEL-positive cells and cell death with cleaved caspase 3 expression among large ovarian follicular granulosa cells. Apoptotic follicles (follicles containing >/=10 TUNEL-positive cells per ovarian section) were only found among large follicles. The final apoptotic follicle ratios were approximately 30% of the total follicles independent of the CPT-11 dose, while CPT-11 dose-dependently enhanced apoptotic processes in murine ovarian follicles. Fas antigen was expressed in most ovarian cells, with extremely high expression levels detected in luteal cells. CPT-11 injections did not significantly increase the Fas expression levels in ovarian cells. Although no FasL expression was detected in normal ovarian tissues, CPT-11 injections significantly induced specific FasL expression in granulosa cells. Incubation of organ-cultured normal murine ovarian tissue fragments with recombinant mouse soluble FasL significantly increased the numbers of TUNEL-positive granulosa and luteal cells. In conclusion, CPT-11 dose-dependently induced specific FasL expression in granulosa cells of developing ovarian follicles. The induced FasL reacted with the Fas antigen constitutively expressed on granulosa cells, such that apoptosis can only be enhanced and induced in granulosa cells in an autocrine and/or paracrine manner. This cell lineage-specific and differentiation stage-specific apoptosis in granulosa cells is thought to be the main molecular mechanism of the ovarian dysfunction induced by CPT-11 combination chemotherapy.     

Pituitary-ovarian function in breast cancer patients on adjuvant chemoimmunotherapy.

One hundred thirty-one patients with operable breast cancer were treated with adjuvant chemoimmunotherapy consisting of 5-fluorouracil, adriamycin, cyclophosphamide, and BCG (FAC-BCG). Fifty-five of 131 patients were premenopausal of which 71% (38/55) became amenorrheic. To determine the mechanism of amenorrhea, we measured the immunoreactive serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and plasma estradiol (E2) before and after intravenous administration of luteinizing hormone-releasing hormone (LH-RH) in 11 unselected premenopausal patients who developed amenorrhea and 11 unselected patients who did not. Serum prolactin (PRL) levels were also measured before and after iv administration of thyrotropin-releasing hormone (TRH). Our results showed that patients who developed amenorrhea had abnormally high serum LH and FSH levels at basal and after LH-RH stimulation and low plasma estradiol. Serum PRL levels were normal. Patients who developed amenorrhea were older than those who did not, but their serum LH and FSH levels were also significantly higher and plasma estrogens were significantly lower than that found in 11 normal women with regular menses of the same age range. These results indicate that amenorrhea that develops in some patients with breast cancer after FAC-BCG therapy is a result of primary ovarian failure.     

化疗对乳腺癌患者性激素及月经的影响

目的：研究术后辅助化疗对乳腺癌患者性激素的影响及与月经的关系。方法：对60例乳腺癌患者术后行6个周期的CAF方案辅助化疗,观察化疗期间患者月经和血浆雌二醇（E2）、孕酮（P）、黄体生成素（LH）、促卵泡素（FSH）的变化及其影响因素。结果：40例患者化疗期间发生闭经（闭经组）,20例化疗结束时仍有月经（未闭经组）。其中闭经组8例化疗后可恢复,32例不可恢复。闭经组患者血浆E2、P水平下降（P〈0．05）。闭经发生率与年龄、化疗药物强度和化疗进程呈正相关（P〈0．05）,其中黄体生成素（LH）、促卵泡素（FSH）下降组月经不可再恢复。结论：化疗可抑制乳腺癌患者性激素的分泌,导致闭经的发生。     

抗苗勒管激素用于评价戈舍瑞林对年轻乳腺癌患者卵巢功能抑制作用的前瞻性临床研究

目的:探讨抗苗勒管激素用于评价戈舍瑞林对年轻乳腺癌患者卵巢功能抑制的可行性.方法:选取激素受体阳性的术后、化/放疗后年轻乳腺癌患者40例,随机分为戈舍瑞林+他莫昔芬组(简称戈舍瑞林组)20例,他莫昔芬组20例(对照组).戈舍瑞林组在戈舍瑞林注射前1 d及注射戈舍瑞林3、6、12针后测定血清雌二醇(E2)、卵泡刺激素(FSH)、黄体生成素(LH)及抗苗勒管激素(AMH)水平.对照组在相应时间段内进行检测.并对比两组不良反应发生率.结果:治疗前两组血清E 2、FSH、LH及AMH水平差异无统计学意义(P均>0.05).治疗后戈舍瑞林组的3个不同时间段血清E 2、FSH、LH及AMH水平均低于对照组水平(P均<0.05).戈舍瑞林组发生不良反应10例(50.0%),对照组6例(30.0%),主要不良反应为恶心、潮热、盗汗、性欲减退、阴道干涩、关节痛、骨质疏松等,均为Ⅰ-Ⅱ级.两组不良反应发生率差异无统计学意义(P>0.05).结论:抗苗勒管激素可以用于评价戈舍瑞林对年轻乳腺癌患者卵巢功能的抑制作用.     

A case of advanced gastric cancer with lymphangitis carcinomatosa after operation of Krukenberg tumor treated by TS-1 plus CPT-11 as third-line chemotherapy

Chemotherapies for recurrent gastric cancer have not yet been established. Here we report a case of type 4 gastric cancer associated with lymphangitis carcinomatosis which became refractory to the previous chemotherapies. The case was a 40-year-old woman. She had been diagnosed with gastric cancer after a Krukenberg tumor operation. Chemotherapies (TS-1 plus CDDP as first-line, and TS-1 plus taxanes as second-line) were performed, and a partial response was achieved. Disease activity has been well controlled until this time. Since recurrence of left pleural effusion and lymphangitis carcinomatosis was recognized, we changed the chemotherapy TS-1 plus CPT-11. Pleural effusion decreased and lymphangitis carcinomatosis improved. The serum CA 19-9 level rose transiently after CPT-11 administration, and tended to fall at the second week of chemotherapy. However, the patient died 2 years 4 months after the onset. TS-1 plus CPT-11 combination chemotherapy would be effective for lymphangitis carcinomatosis and also useful as third-line chemotherapy for recurrent gastric cancer.     

抗米勒管激素用于年轻乳腺癌患者卵巢功能抑制个体化治疗的评价

背景与目的：年轻乳腺癌患者应用促黄体生成素释放激素类似物戈舍瑞林治疗没有个体化用药方案,并缺乏临床可用的指导依据。该研究皆在探讨抗米勒管激素(anti-Müllerian hormone,AMH)在年轻乳腺癌患者卵巢功能抑制个体化治疗的评价作用。方法：选取2012年5月—2014年1月在上海交通大学附属仁济医院因雌激素受体(estrogen receptor,ER)和孕激素受体(progesterone receptor,PR)阳性的乳腺癌41例患者,术前随机分为戈舍瑞林6个疗程+化疗组(简称戈舍瑞林组)20例,化疗组21例,30例同年龄组健康妇女为正常对照组,随访(17.4±6.2)个月。观察两组治疗后的停经时间与复潮时间,于术前1个月、戈舍瑞林组或化疗组术后月经复潮后3、6个月检测AMH、促卵泡激素(follicle-stimulating hormone,FSH)和E₂水平。正常对照组在相应时间段内检测AMH、FSH和E₂水平。结果：3组患者的术前临床资料及术前FSH、E2水平差异均无统计学意义(P>0.05),乳腺癌患者术前AMH水平较正常对照组降低,差异有统计学意义(P=0.04);戈舍瑞林组较化疗组停经时间更短,差异有统计学意义(P=0.00);戈舍瑞林组较化疗组复潮时间更短,差异有统计学意义(P=0.00);与正常对照组及术前比较,戈舍瑞林组及化疗组FSH、E₂水平在5个测定时间的差异均无统计学意义(P>0.05);戈舍瑞林组及化疗组在5个测定时间的AMH水平均显著降低,差异均有统计学意义(P=0.00),两组在复潮后3、6个月AMH水平逐渐上升,差异均有统计学意义(P<0.05);与化疗组相比,戈舍瑞林组的AMH水平下降明显,戈舍瑞林组的AMH水平在复潮6个月后比化疗组升高,差异均有统计学意义(P<0.05)。结论：年轻乳腺患者在卵巢功能抑制治疗+化疗过程中,AMH较其他评价卵巢储备的指标明显下降,在其他指标恢复术前水平后仍提示卵巢受损,提示AMH可以作为评价年轻乳腺癌患者卵巢功能的指标,亦有可能成为戈舍瑞林个体化治疗的评价指标。     

A case of papillary adenocarcinoma of the ovary that responded favorably to irinotecan hydrochloride and cisplatin after the administration of paclitaxel and carboplatin]

Recently, the standard treatment for advanced ovarian cancer has changed from CP therapy (cyclophosphamide, cisplatin (CDDP)) to TJ therapy (paclitaxel (TXL), carboplatin (CBDCA)). Irinotecan (CPT-11) is one of the derivatives of camptotecin and has been reported to have a high efficacy for ovarian cancer. In one case of ovarian cancer, chemotherapy was applied with CBDCA and TXL. However, after 2 months of six courses of the chemotherapy, CA-125 was elevated. The elevation of tumor marker levels in serum without the recurrent focus forced us to treat the patient with CPT-11 and CDDP for the second line chemotherapy. Tumor marker levels improved at the beginning of the therapy. In conclusion, CPT-11 and CDDP was effective against the recurrence of ovarian cancer treated with TJ therapy.     

Three cases of liver metastasis of colon cancer responding to systemic combination chemotherapy utilizing CPT-11

Though the first choice of treatment for liver metastasis in colon cancer is surgical resection of liver, 30-60% of such patients experience a recurrence of liver metastasis. Even if reoperation is done optimally, the surgical resection of liver metastasis may not be a definitely curative treatment. For cases of liver metastasis from colon cancer that are non-resectable due to multiple liver metastases, other organ metastases (lung, bone, brain etc.), the advanced age of the patient, or other complications (cerebrovascular disease, diabetes mellitus, heart disease etc.), hepatic arterial infusion or systemic combination chemotherapies are selected. In the present paper, we report 3 cases of effective systemic chemotherapy utilizing CPT-11 for liver metastases from colon cancers. The method was UFT + irinotecan (CPT-11), cisplatin (CDDP) + tegafur + CPT-11, UFT + CPT-11 + etoposide (ETP) + pirarubicin (THP). The result obtained was a partial response (PR) in each case. As there were few adverse effects, we could provide treatment during a short-term admission or an outpatient basis. We thus obtained good post-chemotherapeutic QOL, and these regimens may be effective forms of chemotherapies in the future.     

宫颈癌患者卵巢移位手术后放射治疗对卵巢功能的作用分析

目的探讨卵巢移位术对宫颈癌患者放射治疗后卵巢功能的作用。方法选取2008年5月至2012年5月收治的40例宫颈癌患者为研究对象,行卵巢移位术治疗,并按照患者放射治疗指征在手术后进行放射性治疗,观察其手术前、手术后和放射治疗结束1个月后和放射治疗结束6个月后血清中性激素水平以及随访情况。结果手术后患者血清性激素水平无明显变化,化疗结束1个月后垂体分泌卵泡刺激素（FSH）和促黄体生成素（LH）水平明显上升,雌二醇（E2）和孕酮（P）水平明显下降（P〈0．05）,并于化疗结束6个月后恢复手术前水平。放射治疗结束6个月后,25例患者出现潮热、盗汗、烦躁、失眠等围绝经期症状,性生活满意度为37．5％,且复发1例,手术后生活质量（QOL）满意度为51．2％,无死亡病例。放射治疗结束1年后围绝经期症状自行消失,仅3例患者存在围绝经期症状,性生活满意度为95．0％,QOL满意度96．4％,2例复发,患者全部生存。放射治疗结束6个月与1年后两组在围绝经期症状、性生活满意度和QOL满意度差异均具有统计学意义（P〈0．05）。结论卵巢移位术能够有效保护宫颈癌患者放射治疗后卵巢功能,操作方便、疗效可靠,且明显降低了复发率,对患者手术后生活质量的提高具有重要意义,值得临床广泛推广。     

Combination chemotherapy with irinotecan hydrochloride (CPT-11) and mitomycin C in platinum-refractory ovarian cancer

The aim of this study was to examine the level of activity of irinotecan hydrochloride (CPT-11) and mitomycin-C (MMC) combination chemotherapy in a patient population with platinum-refractory ovarian cancer. Patients received CPT-11 (140 mg/m2) in combination with MMC (7 mg/m2) on days 1, 15, 29 until disease progression, unacceptable toxicity developed, or they elected to discontinue treatment. Overall, 61 cycles of CPT-11/MMC chemotherapy were delivered to 13 patients. The major toxicity with this regimen was neutropenia, which was brief and reversible. The incidences of grade 3 and 4 neutropenia were 46% (6/13) and 15% (2/13), respectively. The nonhematological toxicities were generally mild and well tolerated. Of the 13 patients, 4 (31%) experienced an objective response (1 CR, 3 PRs). Among responders, the median duration of response was 30 weeks (range, 12 to 292+ weeks). The median time to progression for the 13 patients who received treatment on this trial was 24 weeks (range, 8 to 292+ weeks), with a median survival of 36 weeks (range, 20 to 292+ weeks). This preliminary study shows that the combination of CPT-11 and MMC appears to be an active regimen in patients with refractory ovarian cancer.     

Multiple hepatic metastases and ovarian metastases of colon cancer responding to combined therapy with S-1 and CPT-11--a case report

We report a patient with multiple hepatic metastases and ovarian metastases of transverse colon cancer treated by combination of S-1 and CPT-11. The patient was a 51-year-old woman with cancer of the transverse colon and multiple hepatic metastases. She had undergone surgery. Resection of the transverse colon and left ovary was performed because left ovarian metastases were found during the operation. After the operation, the patient was given chemotherapy with S-1 (120 mg/body on days 1-14) and CPT-11 (150 mg/body on day 1). After completion of 11 courses of chemotherapy, abdominal CT scans revealed that the LDAs of the liver had disappeared, so the patient was judged to have achieved CR. No adverse event was observed. This case suggests that the combination of S-1 and CPT-11 may be an effective regimen for advanced colon cancer with multiple hepatic metastases.     

Combination of CPT-11 with cisplatin as first-line chemotherapy in advanced epithelial ovarian cancer

As CPT-11 was shown to be efficacious in recurrent ovarian cancer, a phase II trial has been undertaken at a recommended dose determined in the phase I trials of combination therapy of CPT-11 with cisplatin (CDDP). As first-line chemotherapy, 60 mg/m(2) of CPT-11 (on days 1, 8, and 15) and 60 mg/m(2) of CDDP (on day 1) were intravenously administered to patients with epithelial ovarian cancer with residual lesions larger than 2 cm, and patients who underwent exploratory laparotomy. Case 1 and 2 achieved CR and PR after completion of the first and second courses, respectively. After the third course when CA125 values turned negative, secondary cytoreductive surgery was performed in both cases, and the tumor was completely extirpated. Dose limiting toxicity was neutropenia, which was managed by administration of granulocyte stimulating factor or by skipping the administration of CPT-11. In Case 2, the number of platelets decreased with repetition of the courses. Grade 3 or worse diarrhea was not observed. The combination therapy of CPT-11 with CDDP is considered to be safe and efficacious in treatment of epithelial ovarian cancer.     

A case of drug-induced interstitial pneumonia caused by S-1 and CPT-11 combination therapy for advanced colon cancer

The patient was a 77-year-old woman admitted for nausea and abdominal pain. Computed tomography (CT) revealed advanced ascending colon cancer with liver metastasis. After operation, we started combination chemotherapy of S-1 and irinotecan (CPT-11); S-1(80 mg/m2) administered orally for consecutive days followed by 14 days rest.CPT -11 (100 mg/m2) was given as a 2-hour infusion on day 1 and 15. The patient complained of high fever and subsequent dyspnea with severe hypoxemia after the first course of combination chemotherapy of S-1 and CPT-11.CT scan showed diffuse interstitial lesions with ground glass opacity on both lungs. Steroid pulse therapy with oxygen therapy remarkably improved her symptoms, and abnormal findings on CT scan also resolved. Drug lymphocyte stimulation test was positive against S-1 and negative against CPT-11. These findings were consistent with S-1-induced lung injury. Drug -induced pneumonia needs to be considered in the differential diagnosis when patients treated with S-1 and CPT-11 combination therapy present high fever and dyspnea.     

A case of advanced ovarian carcinosarcoma that responded remarkably to neoadjuvant chemotherapy of combined CPT-11 and CDDP

Carcinosarcoma of the ovary is a very rare and highly malignant neoplasm that accounts for less than 1% of ovarian neoplasms. Survival of patients with advanced stage cancer is poor and the best treatment is not clear. We report the case of a 60-year-old woman who had Stage IV advanced heterogeneous ovarian carcinosarcoma with lung and liver metastases. The lesions were considered surgically incurable, so she was placed on neoadjuvant chemotherapy of combination CPT-11 (60 mg/m2, day 1, 15) and CDDP (60 mg/m2, day 1). Tumor markers of CA125 and LDH decreased remarkably to the normal level after 3 and 4 courses of chemotherapy, respectively. After 7 courses of chemotherapy, the ovarian tumor was obviously reduced, and the lung and liver metastases had disappeared. The patient was then able to undergo surgery. The current case suggests that combination CPT-11 and CDDP is effective against advanced ovarian carcinosarcoma.     

宫颈鳞癌行卵巢移位患者卵巢状况的研究

目的：探讨宫颈鳞癌患者行卵巢移位术对卵巢功能变化的影响,及患者接受放疗后对移位卵巢内分泌功能的影响。方法选取宫颈鳞癌患者80例,均先行卵巢移位手术,医生依据患者自身恢复情况选择不同放疗方案,30例术后未进行放疗,另50例后续采用放疗方案。分析手术前后及放疗后3个月、6个月、12个月患者卵巢功能变化,并观察促卵泡成熟激素（ FSH）,促黄体激素（ LH）,雌二醇（ E2）和潮热、多汗、阴道干涩等围绝经期症状指标。结果卵巢移位术并未影响宫颈鳞癌患者血清中FSH、LH和E2表达水平。与未放疗患者相比,术后放疗降低了宫颈鳞癌患者血清中FSH和LH表达水平,而上调了E2表达水平;对放疗患者进行周期性分析,结果显示,放疗3个月后,患者体内FSH和LH水平显著升高,E2表达水平显著下降,差异均具有统计学意义;放疗6个月后,FSH和LH水平高于术前而低于放疗3个月时表达水平,E2表达水平低于术前而高于放疗3个月表达水平;放疗12个月后,FSH和LH表达水平高于术前而低于放疗3个月和6个月,E2表达水平低于术前而高于放疗3个月和6个月。此外,放疗后3个月时,23例患者卵巢功能失调;随着放疗方案的进行,6个月时,失调人数下降为11例;12个月后,降为7例,其他43例患者卵巢功能均恢复正常。结论卵巢移位术结合放疗可以作为1种临床治疗宫颈鳞癌患者的策略。     

化疗对乳腺癌患者性激素及月经的影响

目的:研究术后辅助化疗对乳腺癌患者性激素的影响及与月经的关系.方法:对60例乳腺癌患者术后行6个周期的CAF方案辅助化疗,观察化疗期间患者月经和血浆雌二醇( E2) 、孕酮( P) 、黄体生成素(LH)、促卵泡素(FSH)的变化及其影响因素.结果:40 例患者化疗期间发生闭经(闭经组) ,20 例化疗结束时仍有月经(未闭经组) .其中闭经组8例化疗后可恢复,32例不可恢复.闭经组患者血浆E2 、P 水平下降( P＜0.05) .闭经发生率与年龄、化疗药物强度和化疗进程呈正相关( P＜0.05) ,其中黄体生成素(LH)、促卵泡素(FSH)下降组月经不可再恢复.结论:化疗可抑制乳腺癌患者性激素的分泌,导致闭经的发生.     

Menstrual abnormality in patients with breast cancer receiving adjuvant endocrine-chemotherapy

Menstrual status and ovarian function were studied in 24 premenopausal breast cancer patients receiving adjuvant therapy with chemotherapy and tamoxifen or chemotherapy alone. In 13 of 24 patients (54.1%), abnormal menses, including amenorrhea in 12 cases and oligomenorrhea in 1 case, developed during adjuvant therapy. In patients with abnormal menses, serum estradiol was significantly lower, and the levels of gonadotropins were significantly higher than in patients with normal menses. Among 13 patients with abnormal menses, 4 patients treated with cyclophosphamide revealed persistent amenorrhea during the whole period with adjuvant therapy, and the levels of serum estradiol and progesterone were extremely low. Furthermore, in these patients normal menses has not recovered and the levels of serum estradiol and progesterone remained low 4 to 5 months after cessation of cyclophosphamide administration. Thus, adjuvant chemotherapy caused depression of ovarian function, and cyclophosphamide induced ovarian failure, resulting in complete amenorrhea.     

A case of AFP-producing gastric cancer responding to low-dose CPT-11 and low-dose cisplatin combination chemotherapy

Gastric cancers that produce alpha feto protein (AFP) usually have a poor prognosis. We report an AFP-producing gastric cancer that showed a partial response to low-dose CPT-11 and low-dose cisplatin combination chemotherapy. AFP-producing gastric cancers successfully treated with chemotherapy have been reported, but to our knowledge this is the first report of successful treatment with low-dose CPT-11 and low-dose cisplatin combination chemotherapy. Case: A 49 year-old woman who had gastric cardiac cancer with esophageal invasion was admitted to our institution. Since AFP-positive cells were demonstrated immunohistochemically in biopsy specimens and levels of AFP in serum were high, AFP-producing cancer was diagnosed. Because of metastasis to Virchow's node and the paraaortic lymph nodes, the tumor was considered unresectable. The patient's poor general condition necessitated chemotherapy with low toxicity and high efficacy. She was treated with low-dose CPT-11 and low-dose cisplatin combination chemotherapy. After two cycles of this treatment, the tumor volume and the serum levels of AFP had decreased markedly. The only side effect of the treatment was leukopenia.     

Molecular determinants of irinotecan efficacy

Molecular markers predicting the efficacy of CPT-11 based chemotherapies in patients with colorectal cancer (CRC) are unknown. Therefore, we investigated whether mRNA levels of drug targets (Topoisomerase I, TS), enzymes involved in 5-FU metabolism (DPD), in angiogenesis (EGFR, IL-8, VEGF) and in DNA-repair/drug detoxification (ERCC1, GST-P1) are associated with the clinical outcome of patients with CRC treated with first-line CPT-11 based chemotherapy. Thirty three patients with metastatic CRC were included in the study. Intratumoral gene expression levels were assessed from paraffin-embedded tissue samples, using laser capture microdissection and quantitative Real-Time PCR. Complete response was observed in 1 patient, partial response in 12 patients, stable disease in 13 patients and progressive disease in 6 patients. Response was inevaluable for 1 patient. Patients with complete response or partial response were classified as responders, while patients with stable disease or progressive disease were classified as nonresponders. High intratumoral mRNA levels of EGFR, ERCC1 and GSPT-P1 were each significantly associated with response to CPT-11 based chemotherapy. Recursive partitioning analysis showed that mRNA levels of EGFR and ERCC1 are primarily responsible for delineating responders from nonresponders. Also, the combination of high intratumoral gene expression levels of both EGFR and ERCC1 was significantly associated with progression-free survival. The mRNA levels of EGFR had a significant correlation with expression levels of ERCC1, GST-P1 and VEGF. This small retrospective study suggests that gene expression levels of EGFR, ERCC1 and GST-P1 may be useful in predicting the clinical outcome of patients with metastatic CRC treated with first-line CPT-11 based chemotherapy.     

Primär- und Rezidivtherapie des Ovarialkarzinoms

In most cases, ovarian cancer is diagnosed at an advanced stage because effective screening procedures are lacking. After adequate surgery and chemotherapy, cure is often possible in early ovarian cancer. In advanced ovarian cancer, most patients will relapse despite maximum surgery and chemotherapy. Combination chemotherapy has no advantage compared with monotherapy in so-called platinum-refractory ovarian cancer. In platinum-sensitive recurrent ovarian cancer, secondary surgery with the aim of complete resection could be beneficial in selected patients. Platinum-based combination chemotherapies are superior to monotherapy in such patients. Different toxicity profiles must be considered.