Surgery for ovarian cancer.

Surgery is a critical component of the multimodality approach to ovarian cancer. Surgery confirms the diagnosis and establishes the stage of disease, especially important when the tumor appears to be limited to the ovaries. In advanced disease, surgical cytoreduction improves response to chemotherapy and survival. Second-look laparotomy provides a means for assessing response to therapy, predicting prognosis, and determining the need for further therapy. Surgery can also provide palliation of intestinal obstruction.     

First-line chemotherapy for advanced ovarian cancer: paclitaxel, cisplatin and the evidence.

As of June 1998, four randomized trials have been completed comparing the combination of paclitaxel and cisplatin with a cisplatin-based control arm. The results of three of these trials are available; one has been published as a full paper, the other two in abstract form only. Two of the reported trials (GOG-111 and the Intergroup trial) provide clear evidence that cisplatin combined with paclitaxel is a more effective regimen than one using the same dose of cisplatin combined with cyclophosphamide. The results of the third reported trial (GOG-132) are rather different, suggesting that a higher dose of single-agent cisplatin may be as effective as the paclitaxel/cisplatin combination tested in the other two trials. A number of explanations for these unexpected results have been proposed: false-positive results in GOG-111 and the Intergroup trial; false-negative results in GOG-132; high crossover in GOG-132 (including crossover before progression); the cyclophosphamide in the control arm of GOG-111 and the Intergroup trial had a negative impact on outcome in the control group in these trials; the higher dose of cisplatin when used as a single agent in GOG-132 had a positive impact on outcome for the control group in this trial. These explanations are discussed in detail, and their implications explored.     

High frequency of chromosome 9 deletion in ovarian cancer: evidence for three tumour-suppressor loci.

We have screened 33 ovarian tumours of various grades and stages for the loss of heterozygosity (LOH) of markers on chromosome 9. LOH was detected in 26 cases (79%). Eleven tumours (33%) showed LOH of all informative markers. The remaining 15 cases had partial deletions. Of these, six (18%) had losses on 9p only, three (9%) had LOH confined to 9q and six (18%) had losses on both chromosome arms, four of which had a retention of hetereozygosity in between. There was no association between tumour grade stage or histopathology and any losses. High-density deletion mapping was carried out in 12 selected cases that had partial deletions of 9p and/or 9q. The deleted region on 9p included the cyclin-dependent kinase inhibitor 2 (CDKN2) locus and one tumour was found to have a homozygous deletion of CDKN2. LOH on 9q extended over a larger region. We found evidence for two regions of deletion on 9q, one at 9q34 and the other encompassing the nevoid basal cell carcinoma (Gorlin) syndrome locus on proximal 9q.     

Cytoreductive surgery for ovarian cancer.

AIM: The aim of this study is to describe the technique of managing peritoneal dissemination in patients with ovarian cancer, based on radical surgical excision and, later, perioperative chemotherapy. METHOD:Treatments included complete surgical resection of the peritoneal disease, and intraperitoneal intraoperative and postoperative chemotherapy, using Adriamycin intraoperatively, and Cis-platinol next 1-5 postoperative days. RESULTS: Eleven cytoreductive procedures were performed between 1996 and 2002. Eight patients with primary ovarian cancer underwent total hysterectomy with bilateral adnexectomy, omentectomy and peritonectomy of the pelvic cavity. In 3 cases with recurrent ovarian cancer, peritonectomy alone was performed. Bowel resection was performed in all patients. The median operation time was 279 min (range 190-500min). Median total blood loss was 919 mL (range 450-1330 mL). The median survival time was 22 months. CONCLUSION: Cytoreductive procedure offers satisfactory results in peritoneal carcinomatosis in patients with advanced primary ovarian cancer.     

Primary surgery for ovarian cancer.

AIM: Review studies on survival outcomes for all survival treatment methods of primary ovarian cancer. METHODS: This presentation is based on systematic literature search in Pubmed, Medline, Cochrane and Internet addresses for treatment protocols. RESULTS: Major controversies still exist on what constitutes optimal surgical staging in a patient with early-stage ovarian cancer and what is optimal surgical management for high-risk patients. Several large retrospective studies consistently identify the size of the largest residual disease after primary cytoreductive surgery as an independent determinant of prognosis, but the size limit of residual disease that needs to be fulfilled for cytoreduction to have effect on survival is not identified. The effect of neoadjuvant chemotherapy in advanced ovarian cancer is uncertain. A large prospective randomized study is initiated for assessing the role of neoadjuvant chemotherapy. The survival rate is better for patients treated at teaching hospitals compared with non-teaching hospitals. CONCLUSION: This systematic review demonstrates the need for more studies on survival outcomes for all surgical treatment methods of primary ovarian cancer assessed in this report.     

Molecular genetic evidence for unifocal origin of advanced epithelial ovarian cancer and for minor clonal divergence.

Detection of loss of heterozygosity (LOH) and DNA flow cytometry (FCM) were used to trace the origin of bilateral ovarian cancer from 16 patients. From each tumour the DNA index (DI) and LOH patterns for chromosomes 1, 3, 6, 11, 17, 18, 22 and X were determined with 36 microsatellite markers. Formalin-fixed, paraffin-embedded as well as frozen specimens were used. Flow cytometric cell sorting was used to enrich tumour cells for polymerase chain reaction (PCR)-driven LOH analysis. Analysis of the LOH data showed that in 12 of the 16 cases concordance was observed for all informative markers, namely retention of heterozygosity (ROH) or loss of identical alleles in both tumour samples. In four cases discordant LOH patterns were observed. In two cases the discordant LOH was found for one of the chromosomes tested while other LOH patterns clearly indicated a unifocal origin. This suggests limited clonal divergence. In the other two cases all LOH patterns were discordant, most likely indicating an independent origin. The number of chromosomes showing LOH ranged from 0 to 6. Comparison of DNA FCM and the LOH data showed that the latter technique has a higher sensitivity for the detection of a unifocal origin. In 14/16 cases evidence was found for a unifocal origin, while in two cases clonal divergence was found at LOH level and in two other cases clonal divergence at DNA ploidy level. In 12 cases the complete observed allelotype had developed before the formation of metastases, including the two cases showing a large DNA ploidy difference.     

Clinical significance of neopterin for prognosis and follow-up in ovarian cancer

Neopterin, a pyrazinopyrimidine compound, is a marker of activation of cell-mediated immunity. The prognostic value of pretherapeutically and of serially measured urinary neopterin levels in patients with ovarian cancer was assessed, in a blinded manner, by analysis of 658 urine specimens from 74 women. The specimens were collected during a 5-year period (January 1981 to January 1986). Thirty-one deaths due to cancer were observed during the study period. By statistical analysis, a significant predictive value of pretherapeutic neopterin levels was found and compared with that of other possible prognostic clinical and laboratory findings. Multivariate analysis, using stratification by tumor stage, demonstrated that this predictive information was independent of other variables. A significant association was found between serial neopterin measurements and the current risk of death during follow-up (P less than 0.0001). In addition, current death risk was correlated with neopterin levels measured 6 months previously (P = 0.026). The histological outcome at surgical reexamination was correlated with the current neopterin levels (P = 0.016). Further, normal neopterin levels in women with evidence of tumor at surgical reexamination were shown to be a sign of better prognosis than elevated levels. Measurement of urinary neopterin levels during follow-up of women with ovarian cancer appears to be a valuable adjunct to conventional techniques, particularly in patients refusing explorative surgery.     

Oncogenes in ovarian cancer.

The discovery of cancer-causing genes has provided us with the exciting opportunity to begin to understand the molecular pathology of ovarian cancer. Activation of several of these genes including HER-2/neu, myc, ras, and p53 has been described in some ovarian cancers (Table 2). In addition, some proto-oncogenes such as the EGF receptor (erbB) and the M-CSF receptor (fms) are expressed along with their respective ligands in some ovarian cancers. Finally, for every oncogene that has been studied in ovarian cancer, there are at least a half-dozen that remain unexplored. In the future, when we have a better understanding of the molecular pathology involved in the development of ovarian cancer, this may allow us to better diagnose and treat, and eventually prevent, ovarian cancer.     

Lack of evidence for CDK12 as an ovarian cancer predisposing gene

Familial Cancer - CDK12 variants were investigated as a genetic susceptibility to ovarian cancer in a series of 416 unrelated and consecutive patients with ovarian carcinoma and who carry neither...     

Clinical applications of hormonal therapy in ovarian cancer

Opinion statement The ovary is an endocrine organ and an end organ. Hormones and their receptors have been associated with ovarian cancer and may be related to its causation. Some data suggest that hormonal therapies may have some effect on ovarian cancer in palliative settings. No hormonal therapy is approved by the US Food and Drug Administration (FDA) for the treatment of any type of ovarian malignancy nor is it listed as an active agent by any of the authoritative compendia. Because of the endocrine associations with ovarian cancer, the minimal side effects, and demonstrated activity of hormonal therapies in other endocrine-associated malignancies, further study is needed.     

Chemotherapy for advanced epithelial ovarian cancer.

In the past decade there have been significant improvements in chemotherapy for advanced ovarian cancer. Platinum-based chemotherapy has improved response rates and, to a lesser degree, prolonged survival. Taxol and its combination with platinum drugs holds the promise for even further improvements in survival. Clinical trials are evaluating issues such as dose-intensity, new combinations, and drug resistance.     

腹腔镜下根治术治疗早期卵巢癌的疗效观察

目的探讨腹腔镜下根治术在早期卵巢癌治疗中的价值。方法选取80例早期卵巢癌患者,根据手术方式的不同将其分为对照组40例(采取传统开腹手术治疗)和观察组40例(采取腹腔镜下根治术治疗)。比较两组患者的手术相关指标(包括手术时间、术中出血量、切口长度、淋巴结清扫数量、淋巴结阳性率)、术后疼痛程度[视觉模拟评分法(VAS)]和术后恢复指标(包括术后排气时间、术后恢复进食时间、术后下床活动时间、术后住院时间)、临床疗效指标(包括中转开腹率、术后1年内复发率、术后化疗率)和术后并发症发生情况。结果观察组患者的术中出血量明显少于对照组患者,切口长度明显短于对照组患者(P﹤0.01)。观察组患者的VAS评分明显低于对照组患者,术后排气时间、术后恢复进食时间、术后下床活动时间、术后住院时间均明显短于对照组患者(P﹤0.01)。两组患者的术后化疗率比较,差异无统计学意义(P﹥0.05)。观察组患者的术后1年内复发率、术后并发症的总发生率均低于对照组患者(P﹤0.05)。结论腹腔镜下根治术治疗早期卵巢癌具有术中出血量少、手术创口小、术后恢复快、术后复发率低和并发症少的优势,并能够减轻早期卵巢癌患者的疼痛程度,且与传统开腹手术的术后化疗率相当,值得临床推广应用。     

Prognostic factors in ovarian cancer: current evidence and future prospects

In ovarian cancer, translational research on the prognostic impact of molecular biological factors has until now not led to clinical implementation of any of these factors. This is partly due to the often conflicting results of different prognostic factor studies on the same molecular biological factor. We have performed meta-analyses on studies in ovarian cancer on four putative prognostic molecular biological factors, epidermal growth factor-receptor (EGFR), HER-2/neu, glutathione-S-transferase (GST)-pi and p53. Odds ratios were estimated for the increase in death at 1 and 5 years for patients with ovarian cancer, harbouring aberrant EGFR, HER-2/neu, GST-pi and p53, respectively. Patients with aberrant Her2/neu or p53 in their tumours had significantly worse odds of surviving 1 and 5 years, respectively. Patients with aberrant EGFR in their tumours only had a significantly greater risk of mortality at 5 years, while there seemed to be a trend for a decreased probability of 5-year survival for patients with aberrant GST-pi in their tumours. Despite inevitable flaws (such as small individual study sizes, publication bias, etc.) our meta-analysis confirms that therapeutic drugs targeted at EGFR, HER-2/neu, GSTpi and p53 may have therapeutic potential. Since ovarian cancer is a relatively rare disease, international collaboration to increase the number of patients to be analysed is critical for progress in translational research on the prognostic impact of molecular biological factors and on innovative treatment in ovarian cancer. In addition it is important to reach a consensus about guidelines for the design, conduct and analysis of translational studies in ovarian cancer.     

First-line treatment for advanced ovarian cancer: paclitaxel,platinum and the evidence

Four large randomised trials of paclitaxel in combination with platinum against a platinum-based control treatment have now been published in full, representing around 88% (3588 out of 4057) of patients randomised into the eight known trials of this question. There is substantial heterogeneity in the results of these four trials. Four main explanations for this heterogeneity have been proposed: differences in the extent and timing of 'crossover' to taxanes in the control groups; differences in the types of patient included; differences in the effectiveness of the research regimens used; differences in the effectiveness of the control regimens used. In this study we examine whether any of these explanations is consistent with the pattern of results seen in these trials. Each explanation suggests that a particular characteristic of each trial was responsible for the results observed. For each explanation the trials were split into groups according to that characteristic, in order to partition the total heterogeneity into that seen 'within' and 'between' groups of trials. If a particular explanation was consistent with the pattern of results, we would expect to see relatively little heterogeneity within each group of trial results viewed in this way, with most of the heterogeneity being between groups which are dissimilar with respect to the key characteristic. Heterogeneity 'within' and 'between' groups was formally compared using the F-ratio. If any explanation appeared to be consistent with the results of the trials, it was considered whether the explanation was also consistent with other evidence available about these regimens. Only one explanation appeared to be consistent with the pattern of results seen in these trials, and that was differences in effectiveness of the control arms used in these trials. This suggests that the very positive results in favour of paclitaxel/cisplatin seen in two of the trials may have been due to the use of a suboptimal control arm. There is no direct evidence about the relative effectiveness of the control arms used in these trials, but indirect evidence is consistent with the conclusion that the cyclophosphamide/cisplatin regimen used in two of the trials may be less effective than the control regimens used in the other trials. Specific concerns about the choice of a cyclophosphamide/cisplatin control arm in the first of these trials to report were raised before the results of the other trials were known, i.e. before any heterogeneity had been observed. Further investigation of this question would be useful. In the meantime, given all of the randomised evidence on the efficacy and toxicity associated with the regimens used in these trials, we conclude that single agent carboplatin is a safe and effective first-line treatment for women with advanced ovarian cancer.