Maria E. L. van der Burg

Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer

BACKGROUND Primary debulking surgery before initiation of chemotherapy has been the standard of care for patients with advanced ovarian cancer. METHODS We randomly assigned patients with stage IIIC or IV epithelial ovarian carcinoma, fallopian-tube carcinoma, or primary peritoneal carcinoma to primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant platinum-based chemotherapy followed by debulking surgery (so-called interval debulking surgery). RESULTS Of the 670 patients randomly assigned to a study treatment, 632 (94.3%) were eligible and started the treatment. The majority of these patients had extensive stage IIIC or IV disease at primary debulking surgery (metastatic lesions that were larger than 5 cm in diameter in 74.5% of patients and larger than 10 cm in 61.6%). The largest residual tumor was 1 cm or less in diameter in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. Postoperative rates of adverse effects and mortality tended to be higher after primary debulking than after interval debulking. The hazard ratio for death (intention-to-treat analysis) in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 0.84 to 1.13; P=0.01 for noninferiority), and the hazard ratio for progressive disease was 1.01 (90% CI, 0.89 to 1.15). Complete resection of all macroscopic disease (at primary or interval surgery) was the strongest independent variable in predicting overall survival. CONCLUSIONS Neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary debulking surgery followed by chemotherapy as a treatment option for patients with bulky stage IIIC or IV ovarian carcinoma in this study. Complete resection of all macroscopic disease, whether performed as primary treatment or after neoadjuvant chemotherapy, remains the objective whenever cytoreductive surgery is performed. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003636.)

The Effect of Debulking Surgery after Induction Chemotherapy on the Prognosis in Advanced Epithelial Ovarian Cancer

BACKGROUND Although the value of primary cytoreductive surgery for epithelial ovarian cancer is beyond doubt, the value of debulking surgery after induction chemotherapy has not yet been defined. In this randomized study we investigated the effect on survival of debulking surgery. METHODS Eligible patients had residual lesions measuring more than 1 cm in diameter after primary surgery. After three cycles of cyclophosphamide and cisplatin, these patients were randomly assigned to undergo either debulking surgery or no surgery, followed by further cycles of cyclophosphamide and cisplatin. The study end points were progression-free and overall survival. At surgery 65 percent of the patients had lesions measuring more than 1 cm. In 45 percent of this group, the lesions were reduced surgically to less than 1 cm. RESULTS Of the 319 patients who underwent randomization, 278 could be evaluated (140 patients who underwent surgery and 138 patients who did not). Progression-free and overall survival were both significantly longer in the group that underwent surgery (P = 0.01). The difference in median survival was six months. The survival rate at two years was 56 percent for the group that underwent surgery and 46 percent for the group that did not. In the multivariate analysis, debulking surgery was an independent prognostic factor (P = 0.012). Overall, after adjustment for all other prognostic factors, surgery reduced the risk of death by 33 percent (95 percent confidence interval, 10 to 50 percent; P = 0.008). Surgery was not associated with death or severe morbidity. CONCLUSIONS Debulking surgery significantly lengthened progression-free and overall survival. The risk of death was reduced by one third, after adjustment for a variety of prognostic factors.

Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial

BACKGROUND Serum CA125 concentration often rises several months before clinical or symptomatic relapse in women with ovarian cancer. In the MRC OV05/EORTC 55955 collaborative trial, we aimed to establish the benefits of early treatment on the basis of increased CA125 concentrations compared with delayed treatment on the basis of clinical recurrence. METHODS Women with ovarian cancer in complete remission after first-line platinum-based chemotherapy and a normal CA125 concentration were registered for this randomised controlled trial. Clinical examination and CA125 measurement were done every 3 months. Patients and investigators were masked to CA125 results, which were monitored by coordinating centres. If CA125 concentration exceeded twice the upper limit of normal, patients were randomly assigned (1:1) by minimisation to early or delayed chemotherapy. Patients and clinical sites were informed of allocation to early treatment, and treatment was started as soon as possible within 28 days of the increased CA125 measurement. Patients assigned to delayed treatment continued masked CA125 measurements, with treatment commencing at clinical or symptomatic relapse. All patients were treated according to standard local practice. The primary outcome was overall survival. Analysis was by intention to treat. This study is registered, ISRCTN87786644. FINDINGS 1442 patients were registered for the trial, of whom 529 were randomly assigned to treatment groups and were included in our analysis (265 early, 264 delayed). With a median follow-up of 56·9 months (IQR 37·4-81·8) from randomisation and 370 deaths (186 early, 184 delayed), there was no evidence of a difference in overall survival between early and delayed treatment (HR 0·98, 95% CI 0·80-1·20, p=0·85). Median survival from randomisation was 25·7 months (95% CI 23·0-27·9) for patients on early treatment and 27·1 months (22·8-30·9) for those on delayed treatment. INTERPRETATION Our findings showed no evidence of a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration alone, and therefore the value of routine measurement of CA125 in the follow-up of patients with ovarian cancer who attain a complete response after first-line treatment is not proven. FUNDING UK Medical Research Council and the European Organisation for Research and Treatment of Cancer.

Molecular profiling of platinum resistant ovarian cancer

The aim of this study is to discover a gene set that can predict resistance to platinum‐based chemotherapy in ovarian cancer. The study was performed on 96 primary ovarian adenocarcinoma specimens from 2 hospitals all treated with platinum‐based chemotherapy. In our search for genes, 24 specimens of the discovery set (5 nonresponders and 19 responders) were profiled in duplicate with 18K cDNA microarrays. Confirmation was done using quantitative RT‐PCR on 72 independent specimens (9 nonresponders and 63 responders). Sixty‐nine genes were differentially expressed between the nonresponders (n = 5) and the responders (n = 19) in the discovery phase. An algorithm was constructed to identify predictive genes in this discovery set. This resulted in 9 genes (FN1, TOP2A, LBR, ASS, COL3A1, STK6, SGPP1, ITGAE, PCNA), which were confirmed with qRT‐PCR. This gene set predicted platinum resistance in an independent validation set of 72 tumours with a sensitivity of 89% (95% CI: 0.68–1.09) and a specificity of 59% (95% CI: 0.47–0.71)(OR = 0.09, p = 0.026). Multivariable analysis including patient and tumour characteristics demonstrated that this set of 9 genes is independent for the prediction of resistance (p < 0.01). The findings of this study are the discovery of a gene signature that classifies the tumours, according to their response, and a 9‐gene set that determines resistance in an independent validation set that outperforms patient and tumour characteristics. A larger independent multicentre study should further confirm whether this 9‐gene set can identify the patients who will not respond to platinum‐based chemotherapy and could benefit from other therapies.

Clinical pharmacokinetics of doxorubicin in combination with Gf120918, a potent inhibitor of Mdr1 P-glycoprotein

Previous clinical investigations with doxorubicin indicated that modulators of P-glycoprotein dramatically decrease the systemic clearance of the drug, which complicates the interpretation of toxicity and response data. In the present study, we examined the pharmacokinetics of doxorubicin and GF120918, a novel potent P-glycoprotein inhibitor, in cancer patients in a search for more selective modulation of multidrug resistance (MDR). Seven cohorts (46 patients) received sequential treatments with doxorubicin alone by a 5 min i.v. bolus (50-75 mg/m2), oral GF120918 alone (50 mg q.d.-400 mg b.i.d.), and the combination of doxorubicin and GF120918. Serial blood and urine samples were taken during both treatment courses and analyzed for doxorubicin and its metabolite doxorubicinol by a liquid chromatographic assay. The pharmacokinetic characteristics of doxorubicin in the presence or absence of GF120918 indicate a very minor overall effect of the modulator, except at the highest combined dose level (i.e. 75 mg/m2 plus 400 mg b.i.d.). A limited number of patients experienced significantly increased exposure to doxorubicinol upon combined treatment, which was associated with concomitantly higher plasma levels of GF120918. Sigmoidal maximum-effect models revealed significant correlations (p<0.02) between the area under the curve of doxorubicinol and the percent decrease in neutrophils and platelets. Sigmoidicity factors in the fitted Hill equation were similar between both treatment courses, suggesting no pharmacodynamic potentiation of doxorubicinol myelotoxicity by GF120918. Our data indicate that GF120918 at the tested doses of combination treatment achieves plasma concentrations that reverse MDR in experimental models and it lacks the significant kinetic interaction with doxorubicin observed previously with other modulators. Hence, it may be possible in future trials to assess the contribution of a potent inhibitor of P-glycoprotein activity to the toxicity and activity of doxorubicin with the knowledge that profound plasma pharmacokinetic interactions are unlikely.

Surgical Staging and Treatment of Early Ovarian Cancer: Long-term Analysis From a Randomized Trial

A long-term follow-up analysis of the randomized clinical trial Adjuvant Chemotherapy in Ovarian Neoplasm (ACTION) from the European Organization for Research and Treatment of Cancer was undertaken to determine whether the original results with a median follow-up of 5.5 years could be verified after longer follow-up with more events. In the ACTION trial, 448 patients with early ovarian cancer were randomly assigned, after surgery, to adjuvant chemotherapy or to observation (no further treatment). The original analysis found that adjuvant chemotherapy improved recurrence-free survival but not overall survival and found in a subgroup analysis that completeness of surgical staging was an independent prognostic factor, with better recurrence-free and overall survival among those with complete (optimal) surgical staging. After a median follow-up of 10.1 years, we analyzed the more mature data from the ACTION trial and found support for most of the main conclusions of the original analysis, except that overall survival after optimal surgical staging was improved, even among patients who received adjuvant chemotherapy (hazard ratio of death = 1.89, 95% confidence interval = 0.99 to 3.60; overall two-sided log-rank test P = .05). More cancer-specific deaths were observed among nonoptimally staged patients (40 [27%] of the 147 deaths in the observation arm and 11 [14%] of the 76 deaths in the adjuvant chemotherapy arm) than among optimally staged patients (seven [9%] of the 75 deaths in the observation arm and 11 [14%] of the 76 deaths in the adjuvant chemotherapy arm) (two-sided chi(2) test for heterogeneity, P = .06). Thus, completeness of surgical staging in patients with early ovarian cancer was found to be statistically significantly associated with better outcomes, and the benefit from adjuvant chemotherapy appeared to be restricted to patients with nonoptimal surgical staging.

Phase I Pharmacologic Study of Oral Topotecan and Intravenous Cisplatin: Sequence-Dependent Hematologic Side Effects

PURPOSE In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. PATIENTS AND METHODS Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m(2) either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. RESULTS Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m(2)/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m(2)/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence. CONCLUSION The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m(2)/d PO x 5 preceded by cisplatin 75 mg/m(2) IV day 1 once every 3 weeks, and topotecan 2.0 mg/m(2)/d PO followed by cisplatin 75 mg/m(2) IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.

Mismatch repair and treatment resistance in ovarian cancer

BackgroundThe treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy.MethodsWe determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell linesResultsMSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines.Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation.ConclusionNo MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation.

A phase II study of epidoxorubicin in colorectal cancer and the use of cyclosporin-A in an attempt to reverse multidrug resistance

We determined the ability of the multidrug resistance (MDR) reversal agent cyclosporin-A to increase anthracycline drug accumulation in colorectal tumour cells in vitro, using the technique of on-line flow cytometry. Data of four previously untreated patients showed that cyclosporin-A can increase intracellular net-uptake of daunorubicin. A phase II study was initiated in 24 colorectal cancer patients. They received cyclosporin-A at a dose of 3 mg kg-1 over 1 h as i.v. infusion, at 7 h and at 1 h preceding cytotoxic drug administration. At the end of the second cyclosporin-A administration epidoxorubicin 90 mg m-2 was administered as i.v. bolus. Cycles were repeated every 3 weeks. Median cyclosporin-A peak blood levels and levels at 18 h after cytotoxic drug administration appeared to be 6248 ng ml-1 and 1012 ng ml-1 respectively. Only one partial response was observed, despite these high cyclosporin-A levels. Cyclosporin-A did not cause major toxicity, only a 29% incidence of hot flushes was observed. Epidoxorubicin toxicities were as expected but the frequency of severe leucocytopenia was striking. This treatment schedule can not be considered active in colorectal cancer.

Expression of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in benign, borderline, malignant primary and metastatic ovarian tumors

Elevated levels of expression of the urokinase‐type plasminogen activator (uPA) and its inhibitor PAI‐1 have shown to be related to poor prognosis in a variety of cancer types. In the present study, cytosolic levels of uPA and PAI‐1 were determined with enzyme‐linked immunosorbent assays in cytosols prepared from 244 human ovarian tissues of different histological sub‐types. Both uPA and PAI‐1 were significantly associated with the malignant progression of ovarian tissues; the levels were increased going from normal tissue, via benign and borderline adenomas, to primary and metastatic adenocarcinomas. For the 90 patients (34 early‐stage and 56 patients with advanced disease) from whom the primary adenocarcinoma tissues were examined, uPA and PAI‐1 levels were evaluated for their association with clinicopathological parameters and with progression‐free and overall survival. Neither uPA nor PAI‐1 were significantly associated with the age of the patient, FIGO stage, tumor grade, tumor rest, the presence of ascites, or with progression‐free or overall survival. On the other hand, age, FIGO stage/tumor rest and the presence of ascites, were significantly related to the length of both progression‐free and overall survival in univariate analyses. Tumor grade was of prognostic significance in the analysis for progression‐free survival, but not for overall survival. After adjustment for FIGO stage/tumor rest, only age retained its prognostic significance, in the analysis for progression‐free survival and in that for overall survival.