Quality of life of advanced ovarian cancer patients in the randomized phase III study comparing primary debulking surgery versus neo-adjuvant chemotherapy.

OBJECTIVE: The EORTC 55971 trial compared primary debulking surgery (PDS) versus neo-adjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). The impact of both treatment arms on quality of life (QOL) is reported. METHODS: Patients with stages IIIc or IV ovarian cancer completed the EORTC QLQ-C30 before treatment, at the third and sixth cycle of chemotherapy, and at 6- and 12-month follow-up. RESULTS: Data of 404 patients (N=201 PDS arm; N=203 IDS arm) were included in the QOL analysis. Between treatment arms no statistically significant differences were found in any of the QOL functioning scales. Patients showed a clinically relevant improvement (>10 points) on the global health/QOL, role functioning, emotional functioning and social functioning scales during and after treatment independent of the type of treatment. Clinically relevant differences from baseline to the follow-up assessments were noted for fatigue, pain, insomnia, appetite loss, constipation, diarrhea indicating symptom control in both treatment arms. Institutions with good QOL compliance were associated with better outcomes. There was a statistical significant difference in the overall debulking status with 39.9% optimal debulking surgery in institutions with good QOL compliance compared to 19.9% in institutions with poor QOL compliance (p=0.0011). Overall survival (median 32.30 versus 23.29 months; p=0.0006) and progression free survival (median 12.35 versus 9.92 months; p=0.0002) were also significantly better. CONCLUSIONS: Survival and QOL after NACT followed by surgery was similar to survival and QOL after PDS followed by chemotherapy. However, institutions with good QOL compliance had better survival outcomes.

Review of dose-intense platinum and/or paclitaxel containing chemotherapy in advanced and recurrent epithelial ovarian cancer.

Ovarian cancer is the most lethal gynecological cancer in women in the western world with a 5-year survival of 49.7%. Advanced stage ovarian cancer is treated both surgically and with chemotherapy, but despite initial high response rates of 60- 75%, many women experience disease recurrence with a dismal prognosis, 5 year overall survival for FIGO stage IIIc and IV disease being only 32 and 18%. In an attempt to improve outcome for both primary and recurrent disease, dose-intense and dose-dense chemotherapy regimens have been investigated. This overview summarizes these results in first and second-line treatment. In first-line treatment, no benefit was found of dose-intense regimes in the majority of the studies, only toxicity was increased. However, results are conflicting with the recent Japanese Gynecologic Oncology Group (JGOG) trial showing an improved progression free and overall survival in patients treated with dose-dense weekly paclitaxel combined with standard 3-weekly carboplatin. For recurrent disease dose-dense weekly combination chemotherapy seems to be very effective in patients with platinum-resistant ovarian cancer. Several phase II studies showed an increase in response rate, progression free survival and overall survival for dose-dense paclitaxel and carboplatin, compared to results of nonplatinum chemotherapy. In platinum-sensitive ovarian cancer, on contrary, the results of weekly paclitaxel and carboplatin seem to be comparable with standard 3-weekly regimens.

Genomic aberrations relate early and advanced stage ovarian cancer.

BACKGROUND: Because of the distinct clinical presentation of early and advanced stage ovarian cancer, we aim to clarify whether these disease entities are solely separated by time of diagnosis or whether they arise from distinct molecular events. METHODS: Sixteen early and sixteen advanced stage ovarian carcinomas, matched for histological subtype and differentiation grade, were included. Genomic aberrations were compared for each early and advanced stage ovarian cancer by array comparative genomic hybridization. To study how the aberrations correlate to the clinical characteristics of the tumors we clustered tumors based on the genomic aberrations. RESULTS: The genomic aberration patterns in advanced stage cancer equalled those in early stage, but were more frequent in advanced stage (p = 0.012). Unsupervised clustering based on genomic aberrations yielded two clusters that significantly discriminated early from advanced stage (p = 0.001), and that did differ significantly in survival (p = 0.002). These clusters however did give a more accurate prognosis than histological subtype or differentiation grade. CONCLUSION: This study indicates that advanced stage ovarian cancer either progresses from early stage or from a common precursor lesion but that they do not arise from distinct carcinogenic molecular events. Furthermore, we show that array comparative genomic hybridization has the potential to identify clinically distinct patients.

Nomogram for suboptimal cytoreduction at primary surgery for advanced stage ovarian cancer.

AIM: Maximal cytoreduction to minimal residual tumor is the most important determinant of prognosis in patients with advanced stage epithelial ovarian cancer (EOC). Preoperative prediction of suboptimal cytoreduction, defined as residual tumor >1 cm, could guide treatment decisions and improve counseling. The objective of this study was to identify predictive computed tomographic (CT) scan and clinical parameters for suboptimal cytoreduction at primary cytoreductive surgery for advanced stage EOC and to generate a nomogram with the identified parameters, which would be easy to use in daily clinical practice. MATERIALS AND METHODS: Between October 2005 and December 2008, all patients with primary surgery for suspected advanced stage EOC at six participating teaching hospitals in the South Western part of the Netherlands entered the study protocol. To investigate independent predictors of suboptimal cytoreduction, a Cox proportional hazard model with backward stepwise elimination was utilized. RESULTS: One hundred and fifteen patients with FIGO stage III/IV EOC entered the study protocol. Optimal cytoreduction was achieved in 52 (45%) patients. A suboptimal cytoreduction was predicted by preoperative blood platelet count (p=0.1990; odds ratio (OR)=1.002), diffuse peritoneal thickening (DPT) (p=0.0074; OR=3.021), and presence of ascites on at least two thirds of CT scan slices (p=0.0385; OR=2.294) with a for-optimism corrected c-statistic of 0.67. CONCLUSION: Suboptimal cytoreduction was predicted by preoperative platelet count, DPT and presence of ascites. The generated nomogram can, after external validation, be used to estimate surgical outcome and to identify those patients, who might benefit from alternative treatment approaches.

Quality of pathology reports for advanced ovarian cancer: are we missing essential information? An audit of 479 pathology reports from the EORTC-GCG 55971/NCIC-CTG OV13 neoadjuvant trial.

OBJECTIVE: To assess the quality of surgical pathology reports of advanced stage ovarian, fallopian tube and primary peritoneal cancer. This quality assurance project was performed within the EORTC-GCG 55971/NCIC-CTG OV13 study comparing primary debulking surgery followed by chemotherapy with neoadjuvant chemotherapy and interval debulking surgery. METHODS: Four hundred and seventy nine pathology reports from 40 institutions in 11 different countries were checked for the following quality indicators: macroscopic description of all specimens, measuring and weighing of major specimens, description of tumour origin and differentiation. RESULTS: All specimens were macroscopically described in 92.3% of the reports. All major samples were measured and weighed in 59.9% of the reports. A description of the origin of the tumour was missing in 20.5% of reports of the primary debulking group and in 23.4% of the interval debulking group. Assessment of tumour differentiation was missing in 10% of the reports after primary debulking and in 20.8% of the reports after interval debulking. Completeness of reports is positively correlated with accrual volume and adversely with hospital volume or type of hospital (academic versus non-academic). Quality of reports differs significantly by country. CONCLUSION: This audit of ovarian cancer pathology reports reveals that in a substantial number of reports basic pathologic data are missing, with possible adverse consequences for the quality of cancer care. Specialisation by pathologists and the use of standardised synoptic reports can lead to improved quality of reporting. Further research is needed to better define pre- and post-operative diagnostic criteria for ovarian cancer treated with neoadjuvant chemotherapy.

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.

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.)

Pathway analysis of gene lists associated with platinum-based chemotherapy resistance in ovarian cancer: the big picture.

OBJECTIVE: Ovarian cancer is the leading cause of death from gynecological cancers in the Western world (Parkin et al., 2005). The overall 5-year survival is only 30% (Moss and Kaye, 2002), which is for a significant part due to platinum-based chemotherapy resistance. In this study, we performed a pathway analysis on nine published gene sets associated with platinum resistance in ovarian cancer, including a study by us. With this exploratory study, we aim to identify overlapping pathways associated with platinum-based chemotherapy resistance mechanisms in ovarian cancer. METHODS: Gene Ontology (GO) analysis and Ingenuity Pathway Analysis (IPA) were performed to determine which functional processes were differentially represented in the combined gene lists of nine studies (457 genes) compared to all Unigene identifiers or the Ingenuity knowledge base. RESULTS: The GO and IPA analysis resulted in the generation of 23 gene networks, and showed that 13 GO processes (>or=2 times enriched), 71 canonical pathways (p<0.05,), eight toxicity pathways (p<0.05) and 74 biological functions (p<0.005) are significantly associated with the 9-study gene set. CONCLUSION AND RECOMMENDATIONS: Several pathways identified have previously been shown to be associated with therapy resistance: these include 'oxidative stress response mediated by Nrf2,' 'TP53 signaling' and 'TGFbeta signaling.' The role of TGFbeta signaling and related miRNAs identified in the network analysis in epithelial-to-mesenchymal transition (EMT) and stemness as well as the possible relation with platin-based chemotherapy resistance are further discussed in detail. We propose that future international cooperation should aim at a uniform pooled analysis of the wealth of ovarian cancer array data already available. This will enhance the power of each separate ovarian cancer study and can lead to promising results.

Integrated genomics of chemotherapy resistant ovarian cancer: a role for extracellular matrix, TGFbeta and regulating microRNAs.

Epithelial ovarian cancer is the sixth most common cancer in women worldwide and the most important cause of death from gynaecological cancers in the Western world. Our explorative pathway analysis on seven published gene-sets associated with platinum resistance in ovarian cancer reveals TP53 and transforming growth factor beta as key genes. Furthermore, the extracellular matrix was associated with chemotherapy resistance in ovarian cancer as well as endocrine resistance in breast cancer. Pathway analysis again revealed transforming growth factor beta as a key gene regulating extracellular matrix gene expression. A model is presented based on literature linking transforming growth factor beta, extracellular matrix, integrin signalling, epithelial to mesenchymal transition and regulating microRNAs with a (bivalent) role in chemotherapy response.

Clinical management of ovarian small-cell carcinoma of the hypercalcemic type: a proposal for conservative surgery in an advanced stage of disease.

Ovarian small-cell carcinoma of the hypercalcemic type is a rare and highly malignant tumor. In two thirds of the patients, the tumor is associated with asymptomatic paraneoplastic hypercalcemia. The diagnosis may be impeded; the tumor must be distinguished from other tumors with similar features.This tumor occurs predominantly in young women and is merely lethal. The 1-year survival is solely 50%, with an overall 5-year survival rate of approximately 10%. It is believed that the empirical treatment characterized by combination of radical surgery, chemotherapy, and radiotherapy results in the most favorable outcome in terms of survival. However, the outcome remains extremely poor despite this aggressive approach.Alternatively, these poor survival rates may justify a less aggressive fertility sparing approach without compromising the outcome. Such an approach is illustrated by a case report involving a patient with ovarian small-cell carcinoma of the hypercalcemic type, FIGO stage IIIC. A fertility-sparing approach was used, consisting of conservative surgery followed by induction chemotherapy, interval debulking surgery, and local radiotherapy. During follow-up of 60 months, there was no evidence of disease and the normal menstrual cycle resumed.In addition to this case report, histopathological features, different therapeutic modalities, and outcome of ovarian small-cell carcinoma of the hypercalcemic type is reviewed. This report suggests that a fertility-sparing approach may be just as feasible as the generally applied aggressive approach.

Continuous ambulatory peritoneal dialysis: pharmacokinetics and clinical outcome of paclitaxel and carboplatin treatment.

PURPOSE: Administration of chemotherapy in patients with renal failure, treated with hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) is still a challenge and literature data is scarce. Here we present a case study of a patient on CAPD, treated with weekly and three-weekly paclitaxel/carboplatin for recurrent ovarian cancer. EXPERIMENTAL: During the first, second and ninth cycle of treatment, blood, urine and CAPD samples were collected for pharmacokinetic analysis of paclitaxel and total and unbound carboplatin-derived platinum. RESULTS: Treatment was well tolerated by the patient. No excessive toxicity was observed and at the end of treatment she was in a complete remission. The plasma pharmacokinetics of paclitaxel were unaltered compared to historical data, with neglectable urinary and CAPD clearance. In contrast, the pharmacokinetics of carboplatin were altered, with doubled half-lives compared to patients with normal renal function. Of the administered carboplatin dose, up to 20% was cleared via the dialysate, while only up to 8% was cleared via the urine. CONCLUSION: Paclitaxel and carboplatin can be safely administered to patients with chronic renal failure on CAPD. For paclitaxel the generally applied dose can be administered, and although for carboplatin dose-adjustment is required due to the diminished renal function, the dose can be calculated using Calvert's formula.

Mismatch repair and treatment resistance in ovarian cancer.

BACKGROUND: The 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. METHODS: We 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 lines RESULTS: MSI 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. CONCLUSION: No 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.

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.

The role of interval debulking surgery in ovarian cancer.

The mainstay of treatment for advanced ovarian cancer is the multimodality approach of debulking surgery and paclitaxel--platinum chemotherapy. The size of residual lesions after primary surgery remains the most important prognostic factor for survival. Optimal primary debulking surgery can be performed in approximately 40% of patients and up to 80% if it is done by gynecologic oncologists, but sometimes at the cost of considerable morbidity and even mortality. Based on a trial conducted by the European Organization for Research and Treatment of Cancer, optimal as well as suboptimal interval debulking surgery increases overall (P=0.0032) and progression-free survival (P=0.0055). However, not all patients who have undergone suboptimal primary debulking surgery seem to benefit from interval debulking surgery. Preliminary data from the Gynecologic Oncology Group interval debulking study (GOG-152) indicate that, if the gynecologic oncologist makes a maximal effort to resect the tumor, patients who have undergone suboptimal debulking surgery probably gain little benefit from interval debulking surgery.

Clinical importance of molecular determinations in gynecologic patients with multiple tumors.

BACKGROUND: The prognosis and treatment of patients with multiple tumors may depend on the correlation between tumors: multiple primary tumors, or recurrent tumors, and metastatic disease. The authors investigated whether the detection of molecular aberrations in multiple gynecologic tumors in individual patients provided clinically useful information on the correlation between the tumors. METHODS: Between 1999 and 2001, molecular analyses were performed on tissue from 15 gynecologic patients, all with multiple tumors. The molecular analyses included loss of heterozygosity determinations at eight DNA loci and mutation analyses of p53 exons 5-8 using the single-strand conformation polymorphism method. Previously, it was not possible to use routine diagnostic histopathology to determine accurately the correlation between multiple lesions in patients with gynecologic malignancies, information that may have an impact on clinical decision-making and prognosis. RESULTS: Molecular results were obtained from all tumors from each of the 15 patients. The DNA alterations detected provided evidence that two patients had second primary tumors, nine patients had a single tumor with metastases, and four patients had two independent primary tumors as well as metastatic disease. The results provided additional diagnostic information and contributed to clinical decision-making. CONCLUSIONS: The authors demonstrated that, by comparing DNA alterations in multiple tumors within an individual patient, evidence about correlations between the tumors can be obtained. These investigations can be performed on routinely processed tissues, and the results may be of clinical importance in helping to determine the management or prognosis of patients with gynecologic malignancies.