Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies.

BACKGROUND: Selinexor is an oral inhibitor of the nuclear export protein Exportin 1 (XPO1) with demonstrated antitumor activity in solid and hematological malignancies. We evaluated the efficacy and safety of selinexor in heavily pretreated, recurrent gynecological malignancies. METHODS: In this phase 2 trial, patients received selinexor (35 or 50 mg/m2 twice-weekly [BIW] or 50 mg/m2 once-weekly [QW]) in 4-week cycles. Primary endpoint was disease control rate (DCR) including complete response (CR), partial response (PR) or stable disease (SD) ≥12 weeks. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. RESULTS: 114 patients with ovarian (N = 66), endometrial (N = 23) or cervical (N = 25) cancer were enrolled. Median number of prior regimens for ovarian, endometrial and cervical cancer was 6 (1-11), 2 (1-5), and 3 (1-6) respectively. DCR was 30% (ovarian 30%; endometrial 35%; cervical 24%), which included confirmed PRs in 8%, 9%, and 4% of patients with ovarian, endometrial, and cervical cancer respectively. Median PFS and OS for patients with ovarian, endometrial and cervical cancer were 2.6, 2.8 and 1.4 months, and 7.3, 7.0, and 5.0 months, respectively. Common Grade 3/4 adverse events (AEs) were thrombocytopenia (17%), fatigue (14%), anemia (10%), nausea (9%) and hyponatremia (9%). Patients with ovarian cancer receiving 50 mg/m2 QW had fewer high-grade AEs with similar efficacy as BIW treatment. CONCLUSIONS: Selinexor demonstrated single-agent activity and disease control in patients with heavily pretreated ovarian and endometrial cancers. Side effects were a function of dose level and treatment frequency, similar to previous reports, reversible and mitigated with supportive care.

The rationale of opportunistic bilateral salpingectomies (OBS) during benign gynaecological and obstetric surgery: a consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG).

Ovarian cancer (OC), is a disease difficult to diagnose in an early stage implicating a poor prognosis. The 5-year overall survival in Belgium has not changed in the last 18 years and remains 44 %. There is no effective screening method (secondary prevention) to detect ovarian cancer at an early stage. Primary prevention of ovarian cancer came in the picture through the paradigm shift that the fallopian tube is often the origin of ovarian cancer and not the ovary itself. Opportunistic bilateral salpingectomy (OBS) during benign gynaecological and obstetric surgery might have the potential to reduce the risk of ovarian cancer by as much as 65 %. Bilateral risk-reducing salpingectomy during a benign procedure is feasible, safe, appears to have no impact on the ovarian function and seems to be cost effective. The key question is whether we should wait for a RCT or implement OBS directly in our daily practice. Guidelines regarding OBS within our societies are therefore urgently needed. Our recommendation is to inform all women without a child wish, undergoing a benign gynaecological or obstetrical surgical procedure about the pro's and the con's of OBS and advise a bilateral salpingectomy. Furthermore, there is an urgent need for a prospective registry of OBS. The present article is the consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG) regarding OBS.

Platinum versus platinum-combination chemotherapy in platinum-sensitive recurrent ovarian cancer: a meta-analysis using individual patient data.

BACKGROUND: The majority of women with ovarian cancer develop recurrent disease. For patients with a platinum-free interval of >6 months, platinum-based chemotherapy is a treatment of choice. The benefit of platinum-based combination chemotherapy in randomized trials varies, and a meta-analysis was carried out to gain more secure information on the size of the benefit of this treatment. MATERIALS AND METHODS: We initiated a systematic review and meta-analysis following a pre-specified protocol to determine whether combination chemotherapy is superior to single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer. RESULTS: A total of five potentially eligible randomized trials were identified that had used combination-platinum chemotherapy versus single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer. For one trial (190 patients), adequate contact with the investigators could not be established. Therefore, four trials that randomly assigned 1300 patients were included, with a median follow-up of 36.1 months. Overall survival (OS) analyses were based on 865 deaths and demonstrated evidence for the benefit of combination-platinum chemotherapy (HR = 0.80; 95% CI, 0.64-1.00; P = 0.05). Progression-free survival (PFS) analyses were based on 1167 events and demonstrated strong evidence for the benefit of combination-platinum chemotherapy (HR = 0.68; 95% CI, 0.57-0.81; P < 0.001). There was no evidence of a difference in the relative effect of combination-platinum chemotherapy on either OS or PFS in patient subgroups defined by previous paclitaxel (Taxol) treatment (OS, P = 0.49; PFS, P = 0.66), duration of treatment-free interval (OS, P = 0.86; PFS, P = 0.48) or the number of previous lines of chemotherapy (OS, P = 0.21; PFS, P = 0.27). CONCLUSIONS: In this individual patient data (IPD) meta-analysis, we have demonstrated that combination-platinum chemotherapy improves OS and PFS across all subgroups. This provides the strongest evidence to date of the benefit of combination-platinum over single-agent platinum.

Predicting the clinical behavior of ovarian cancer from gene expression profiles.

We investigated whether prognostic information is reflected in the expression patterns of ovarian carcinoma samples. RNA obtained from seven FIGO stage I without recurrence, seven platin-sensitive advanced-stage (III or IV), and six platin-resistant advanced-stage ovarian tumors was hybridized on a complementary DNA microarray with 21,372 spotted clones. The results revealed that a considerable number of genes exhibit nonaccidental differential expression between the different tumor classes. Principal component analysis reflected the differences between the three tumor classes and their order of transition. Using a leave-one-out approach together with least squares support vector machines, we obtained an estimated classification test accuracy of 100% for the distinction between stage I and advanced-stage disease and 76.92% for the distinction between platin-resistant versus platin-sensitive disease in FIGO stage III/IV. These results indicate that gene expression patterns could be useful in clinical management of ovarian cancer.

A phase III randomized trial of BAY 12-9566 (tanomastat) as maintenance therapy in patients with advanced ovarian cancer responsive to primary surgery and paclitaxel/platinum containing chemotherapy: a National Cancer Institute of Canada Clinical Trials Group Study.

OBJECTIVE: BAY 12-9566 (tanomastat) is a biphenyl matrix metalloprotease inhibitor (MMPI) with antiangiogenic and antimetastatic properties in vivo. The objective of the study was to determine whether the addition of BAY 12-9566 after optimal response to chemotherapy could improve time to progression (TTP). PATIENTS AND METHODS: Patients enrolled in the study had received 6-9 cycles of platinum/paclitaxel containing chemotherapy for stage III or IV ovarian carcinoma, with a response of no evidence of disease, or complete or partial response with residual disease < 2 cm. Patients were then randomized to BAY 12-9566 800 mg p.o. b.i.d. or placebo. The primary endpoint was progression-free survival (PFS); secondary endpoints were quality of life, toxicity, changes in CA 125 levels, response, and overall survival (OS). The total planned sample size was 730. RESULTS: The study was closed after 243 patients had been randomized because of Bayer's decision to close all ongoing trials due to negative results from other phase III trials in pancreatic and small cell lung cancer. The final analysis was performed in August 2000 after the requisite number of events for the first planned interim analysis had occurred; 54% of patients had progressed and 18% had died. PATIENT CHARACTERISTICS: performance status was ECOG 0/1/2 in 65/33/2%; median age 57 years; 79% of patients were FIGO stage III; 41% were optimally debulked; 76% had serous histology, and 67% had > or = grade 3 histology. Toxicity was generally grade 1 or 2 in severity, with the most common (BAY 12-9566 vs. placebo) being nausea (26% vs. 13%), fatigue (24% vs. 12%), diarrhea (14% vs. 10%), rash (12% vs. 7%), grade 3/4 thrombocytopenia (3% vs. 1%), and grade 3/4 anemia (5% vs. 1%). Median time to progression (TTP) was 10.4 months (8.5-11.5) for BAY 12-9566 and 9.2 months (7.2-13.9) for placebo (P = 0.67). Median overall survival (OS) was 13.9 months (12.9-infinity) for BAY 12-9566 and 11.9 months (10.5-16.5) for placebo (P = 0.53). CONCLUSION: We conclude that BAY 12-9566 was generally well tolerated and at the time of the final analysis, there was no evidence of an impact of BAY 12-9566 on PFS or OS.

Neoadjuvant chemotherapy versus primary debulking surgery in advanced ovarian cancer.

Primary surgical cytoreduction followed by chemotherapy usually is the preferred management of advanced (stage III or IV) ovarian cancer. The presence of residual disease after surgery is one of the most important adverse prognostic factors for survival. Neoadjuvant chemotherapy has been proposed as an alternative approach to conventional surgery as initial management of bulky ovarian cancer, with the goal of improving surgical quality. Since 1989, we have been treating advanced epithelial ovarian cancer with neoadjuvant chemotherapy instead of primary cytoreductive surgery in approximately half of the patients with stage III-IV disease. Selection of neoadjuvant chemotherapy was based on disease-related characteristics (eg, metastatic tumor load, stage of disease, performance status). Since 1993, open laparoscopy also has been used to aid in evaluating operability. A retrospective analysis of 338 patients was conducted to compare outcomes during 1989 to 1998, when neoadjuvant chemotherapy was used, with those observed during 1980 to 1988, when all patients underwent primary cytoreductive surgery. Crude 3-year survival rates were higher and postoperative mortality rates were lower during the second time period compared with the first. Overall, the results suggest that neoadjuvant chemotherapy results in survival rates in selected patients with advanced ovarian cancer that are comparable with those associated with primary cytoreductive surgery. Patients with stage IV disease, total metastatic tumor load greater than 1,000 g, uncountable plaque-shaped peritoneal metastases, and/or a poor performance status are probably the best candidates for this alternative approach. A prospective randomized study of neoadjuvant chemotherapy and primary cytoreductive surgery is ongoing.

Trocar implantation metastasis after laparoscopy in patients with advanced ovarian cancer: can the risk be reduced?

OBJECTIVE: The purpose of this study was to determine risk factors for trocar implantation metastasis after diagnostic laparoscopy in patients with primary or recurrent advanced ovarian cancer. STUDY DESIGN: Eighty-three women with primary advanced ovarian cancer and 21 women with recurrent ovarian cancer undergoing a laparoscopy for a tissue diagnosis and for assessment of operability were included in the study. The occurrence of implantation metastasis at the trocar incision scars was analyzed according to clinicopathologic characteristics. RESULTS: A recurrence developed at the trocar site in 7 (58%) of 12 patients undergoing a laparoscopy in which only the skin was closed at the end of the procedure and in 2 (2%) of 92 patients undergoing a laparoscopy with closure of all layers (odds ratio, 63; 95% confidence interval, 10.3-385; P <.001). The International Federation of Gynecology and Obstetrics stage at initial presentation, tumor histologic type, tumor differentiation, maximal tumor diameter at the time of diagnosis, estimated weight of the metastatic tumor, residual tumor after cytoreductive surgery, surgical characteristics, and type of chemotherapy were well balanced among both groups. Patients with implantation metastasis had significantly more ascites (median, 700 mL vs 300 mL; P =.032) and a longer interval between the start of platinum-based chemotherapy or cytoreductive surgery (median, 6 days vs 17 days; P <.01) compared with patients without abdominal wall recurrence. A palpable abdominal wall metastasis developed in none of the patients undergoing a laparoscopy with closure of all layers of the abdomen followed by cytoreductive surgery or chemotherapy within 1 week after the laparoscopy. Kaplan-Meier survival analysis showed that patients with abdominal wall implantation metastasis had a survival rate similar to that of the other patients. CONCLUSIONS: Laparoscopy with careful closure of the peritoneum, rectus sheath, and skin followed by chemotherapy or cytoreductive surgery with excision of the trocar trajectories within 1 week is safe in patients with disseminated ovarian cancer.

Malignant trophoblastic disease following a twin pregnancy consisting of a complete hydatiform mole and a normal fetus and placenta. A case report.

We report an unusual pregnancy with a complete hydatiform mole coexisting with a normal fetus and placenta. This report stresses the importance of a correct diagnosis and the dilemmas the clinician is faced with when managing such a case. Malignant trophoblastic disease occurs in 55% of complete hydatiform mole and fetus. Two-thirds require combination chemotherapy.

Cisplatin (P), vinblastine (V) and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa(-theca) cell tumours of the ovary. An EORTC Gynaecological Cancer Cooperative Group study.

The aim of this study was to investigate the clinical activity and toxicity of a modified PVB regimen (cisplatin, vinblastine and bleomycin) in patients with advanced or recurrent, pure granulosa cell tumours (GCTs) or mixed granulosa-theca cell tumours (GTCTs). The PVB regimen consisted of cisplatin (P) 20 mg/m2 intravenous (i.v.) days 1-5, vinblastine (V) 0.15 mg/kg i.v. days 1-2 and bleomycin (B) 30 mg i.v. on day 2, and 15 mg on day 15, for 28 days. 38 eligible patients were entered in this trial. Prior to PVB all patients underwent surgery and 13 received postoperative radio- or other prior chemotherapy. The median number of PVB cycles was 4 in both groups. In the group of 25 patients who had received prior surgery only, 7 and 6 patients had complete and partial responses, respectively (response rate: 52%, 95% confidence limits: 31.3-72.2%). At a median follow-up of 39 months, 6 patients were alive with no evidence of disease, 6 were alive with disease, 12 died due to malignant disease and 1 died due to intercurrent disease. The median time to progression was 13.9 months. The median survival was 25.4 months. 3-year survival was 49% (95% confidence limits: 29-69%). In the group of 13 patients who had previously received postoperative radio- or chemotherapy, 5 complete and 5 partial responses were observed on PVB (response rate: 77%, 95% confidence limit: 46.2-95.0%). At a median follow-up of 50 months, 6 patients were still alive, only 1 without evidence of disease, 6 died due to malignant disease and 1 died due to intercurrent disease. The median time to progression was 19.3 months. The median duration of survival was 41.1 months. Accompanying toxicity was distributed in a similar pattern for both groups. Severe toxicity was mainly documented as haematological toxicity, nausea/vomiting and alopecia. Furthermore cisplatin-related peripheral neurotoxicity and mild/moderate signs of bleomycin-related pulmonary toxicity were observed. The present data confirm the therapeutic activity of the PVB regimen in advanced/recurrent GCTs. The response rate was moderately high compared with previous studies, with a median duration of response of 20 months for both groups.

Ten-year results of a randomised trial comparing cisplatin with cisplatin and cyclophosphamide in advanced, suboptimally debulked ovarian cancer.

176 eligible patients with advanced suboptimally operated ovarian carcinoma were randomly allocated to receive either cisplatin 75 mg/m2 or cisplatin 50 mg/m2 and cyclophosphamide 500 mg/m2 (CP) every 28 days for six courses. The overall clinical response rates (complete response plus partial response) were 52 and 63% for CP and cisplatin, respectively (non-significant). Including results obtained by second-look laparotomy, we did not observe a statistically significant difference in response rates in the two treatment groups. Median progression-free survival was 10 and 11.9 months for CP and cisplatin, respectively (non-significant). No significant difference was observed in overall survival, with a median of 19.4 and 21.5 months for CP and cisplatin, respectively. Thirty-seven platinum-resistant and 27 platinum-sensitive tumours were treated with carboplatin or cisplatin as second-line therapy. Response rates to platinum second-line therapy were 6 and 50% for resistant and sensitive tumours, respectively (P < 0.001). This difference in response rate was also confirmed by survival analysis. Patients with platinum-sensitive tumours survived longer when they were treated with platinum-containing chemotherapy (P = 0.005). Median survival was 22.8 and 8.5 months after initiation of second-line treatment for the platinum-containing and platinum-free regimens, respectively. In summary, we observed in suboptimally operated ovarian carcinoma patients similar response rates, progression-free interval, and overall survival for equitoxic cisplatin and CP. However, the doses of cisplatin and cyclophosphamide chosen were substantially lower than current standard doses of CP. Our study demonstrates, therefore, that a suboptimal dose of CP is as effective as optimal dose monotherapy cisplatin. Patients with recurrences considered as platinum-sensitive had a significantly higher response rate and improved survival when retreated with platinum-containing therapy.

Intraperitoneal contrast material combined with CT for detection of peritoneal metastases of ovarian cancer.

OBJECTIVE: To determine the sensitivity and specificity of CT-peritoneography (CT-P) in detecting peritoneal carcinomatosis in primary or recurrent ovarian cancer. METHODS: Twenty-five patients were submitted to a standard abdominal CT (CT) as well as a computed tomography after intraperitoneal infusion of contrast material (CT-P). Twenty patients had ovarian masses clinically suspected to be malignant. In five patients with ovarian cancer who underwent prior debulking surgery, recurrent disease was suspected. RESULTS: In 21/25 patients an ovarian malignancy was histologically confirmed. During surgery peritoneal spread was found in 13 patients; only in 5 cases CT correctly suggested peritoneal metastases (sensitivity 38%). However, in 10/13 women CT-P indicated peritoneal spread, increasing the overall sensitivity from 38% to 77%. Sensitivity varied substantially according to the different abdominal areas, and was lowest in the left subphrenic space (25%). The sensitivity of CT-P was 71% and 72% in the right paracolic gutter and the pelvis, respectively. Sensitivity of CT-P was not found to be size-dependent, but was mainly related to the morphology of the lesions, with 100% sensitivity in nodular lesions, and only 21% sensitivity for flat peritoneal lesions. CT-P did not improve detection of omental metastases, and was not advantageous when ascites was present. Previous surgery reduced overall specificity from 80% to 57%. CONCLUSION: CT-P greatly improved the sensitivity of CT in the preoperative detection of peritoneal spread of ovarian malignancy. However, the technique failed to detect flat peritoneal metastases, and had a low specificity in patients with a history of prior abdominal surgery.

Exenterative surgery.

Recent progress in pelvic exenteration includes the use of continent intestinal reservoirs (e.g. Kock, Indiana and Mainz pouch) instead of the ileal conduit (Bricker), use of myocutaneous flaps to cover the vulvar or perineal defect, better knowledge of the long term side effects of intestinal reservoirs and conduits, and suggestions for new indications such as pelvic sidewall relapse of cervical carcinoma with palliative or even curative intent.

Clear cell carcinoma of the endometrium. Prognosis and metastatic pattern.

BACKGROUND: To establish the prognosis, metastatic pattern, sites of treatment failure, and effect of various treatment modalities, a large series of patients with endometrial clear cell carcinomas (ECCC) was analyzed. METHODS: Between 1970 and 1992, 181 patients with ECCC were treated. All pathologic slides and medical journals were reviewed. Clinical and histopathologic characteristics and type of treatment were analyzed with the univariate log rank test and multivariate Cox analysis. RESULTS: The 5- and 10-year actuarial disease free survival rates were 43% and 39%, respectively. Pathologic stage, clinical stage, age, and myometrial invasion were the only significant prognostic variables in the univariate analysis. In the multivariate analysis, pathologic stage and age were the sole independent prognostic factors. Two-thirds of the patients with relapse relapsed outside the pelvis. The most frequent extrapelvic sites of relapse were the upper abdomen, lungs, and liver. Four of six patients treated with platinum-containing combination chemotherapy showed response, whereas none of the patients treated with single agent alkylating chemotherapy or progestagens responded. CONCLUSIONS: Pathologic stage and age were the two most important prognostic factors in clear cell carcinoma of the endometrium. In Stage I disease, depth of myometrial invasion, age, and subtype of clear cell carcinoma were the sole independent prognostic factors. Two-thirds of the patients relapsed outside the pelvis.

A phase II study of carboplatin and hexamethylmelamine as induction chemotherapy in advanced epithelial ovarian carcinoma.

27 patients with ovarian cancer FIGO stages IIc-IV were treated with carboplatin 7 x (glomerular filtration rate + 25) mg given intravenously on day 1 and hexamethylmelamine (HMM) 150 mg/m2 orally on days 2-15, every 28 days. 3 patients were not evaluable for response. Clinical response was seen in 17 patients (71%), with six (25%) complete and 11 (46%) partial responses. The median progression-free survival was 15.6 months and the median cancer-related survival was 21.3 months. 4 patients (15%) experienced grade 3 mental depression; none had peripheral neuropathy above grade 1. The haematological toxicity was moderate, none had grade 4 leucopenia, but 4 (15%) had grade 4 thrombocytopenia. Carboplatin plus HMM had few side-effects and a high response rate with a survival comparable to other platinum-based combinations.

Alpha-particle radiotherapy with 211At-labeled monodisperse polymer particles, 211At-labeled IgG proteins, and free 211At in a murine intraperitoneal tumor model.

Four different chemical forms of the alpha-particle emitting radionuclide 211At were injected intraperitoneally in mice inoculated intraperitoneally 30 hr in advance with 10(6) cells of the K13 murine hybridoma cell line. The different 211At forms were (a) free 211At, (b) 211At-labeled TP-3 nonspecific monoclonal antibody (211At-TP-3), (c) 211At-labeled human IgG kappa (211At-hIgG kappa), and (d) 211At-labeled monodisperse polymer particles (211At-MDPP). A significantly prolonged survival (P < 0.05) was observed with injected doses down to 7 kBq for the 211At-MDPP, and down to 25 kBq for 211At-hIgG kappa. There were no significant differences in survival between 211At-MDPP, 211At-hIgG kappa, and 211At-TP-3 at the dose level of 200 kBq. The group receiving 250 kBq free 211At per animal had a shorter survival than the three other forms at 200 kBq. The groups treated with 500, 200, and 65 kBq 211At-MDPP had a similar survival. The group given the highest dose of 211At-hIgG kappa (275 kBq) had the highest fraction (50%) of long-term survivors of all groups. Biodistribution measurements and total body scintigrams in mice without tumor revealed that the free 211At was distributed all over the body within 10 min after injection while at 2 hr a high fraction of the 211At-TP-3 and 211At-hIgG kappa was still present intraperitoneally. In conclusion this study indicates that 211At-labeled MDPP and 211At-labeled IgG's may be efficient tools for treatment of intraperitoneal superficial tumor cells and malignant ascites.

Expression of c-erbB-2, c-myc, and c-ras oncoproteins, insulin-like growth factor receptor I, and epidermal growth factor receptor in ovarian carcinoma.

AIMS: To assess whether the overexpression of five dominant oncogene encoded proteins is crucial to the pathogenesis of ovarian carcinoma and whether this provides any useful prognostic information. METHODS: The expression of the insulin-like growth factor 1 receptor (ILGFR 1), epidermal growth factor receptor (EGFR), and the c-erbB-2, c-ras, and c-myc products was studied by multiparameter flow cytometry in 80 patients with epithelial ovarian cancer for whom long term follow up was available. RESULTS: Overexpression of ILGFR 1, EGFR, c-erbB-2, c-ras and c-myc was found in, respectively, nine of 80 (11%), 10 of 80 (12%), 19 of 80 (24%), 16 of 80 (20%) and 28 of 80 (35%) ovarian carcinomas. The levels of expression of ILGFR 1, EGFR, c-erbB-2 and c-ras were significantly higher in the tumours of patients with recurrent or persistent disease after chemotherapy than in the tumours of patients at initial presentation (p < 0.02). Multivariate analysis showed that residual tumour (p < 0.001), FIGO stage (p = 0.002), EGFR overexpression (p = 0.030) and previous chemotherapy (p = 0.034) were independent variables for predicting survival. CONCLUSIONS: Overexpression of these oncoproteins only occurs in a small proportion of ovarian carcinomas but may have an important role in the progression of the disease.