Fewer than 30% of women presenting with ovarian cancer are assigned as early stage.1 Although the overall prognosis for these cases is expected to be good, ovarian cancer is considered to be a heterogeneous disease, with varied histological subtypes, differing biological behaviour, and a tendency to spread via the peritoneal cavity and lymphatic routes.
The classification of the disease to early stage is based on: (1) an assumption of the absence of spread at surgery or (2) the absence of histological evidence of spread following surgicopathological assessment (surgical staging). The former will contain a higher proportion of cases that are understaged, which are therefore more likely to benefit from chemotherapy. It is also clear that in the second category, the proportion of cases that are judged to be early stage will be dependent upon the quality of the surgicopathological assessment.2 However, even after extensive surgicopathological assessment, stage-I ovarian cancer may recur because of inherent biological high-risk factors.3
Additionally, the surgical management of apparently localised disease may not be straightforward, as in many cases it may be unclear whether an ovarian mass is malignant or not. This raises questions about how best to perform surgical staging. As a result, several unanswered questions remain: should these patients undergo a second ‘staging’ operation, and if so should this be a laparoscopic procedure to reduce morbidity? Can intraoperative frozen section analysis at the time of the initial surgery avoid the need for a second surgical procedure? How reliable is frozen section analysis?
These questions need to be considered in relation to the knowledge regarding the value of adjuvant chemotherapy. How strong is the evidence of benefit, and which patients are best suited to receive adjuvant chemotherapy? Where there is uncertainty about the stage, should a more liberal approach be taken offering chemotherapy rather than subjecting patients to a second surgical procedure? If patients are given chemotherapy should they receive single-agent carboplatin or combination therapy with paclitaxel, and if so, should this be for six or three cycles?
This edition of BJOG presents two articles highlighting the controversies in the surgical and medical management of early-stage ovarian cancer. In the first article, Rouzier et al.4 describe their analyses of 49 783 women diagnosed with early-stage ovarian cancer registered in the US SEERS Database over a 17-year period. They present the case for comprehensive surgical staging, including the performance of systematic retroperitoneal lymphadenectomy, and suggest that this is associated with an improvement in outcome survival by providing therapeutic benefit, either through direct surgical removal of disease or by guiding adjuvant chemotherapy.
The most significant shortcoming in their analysis is the effect of the ‘Will Rodgers phenomenon’, where survival statistics are improved in lower and higher stage cases simply by the accurate categorisation of cases. Removing cases with confirmed positive lymph nodes from the early-stage category, and placing them in the higher stage category, will in effect improve the survival outcomes for both groups. This is otherwise described as stage migration.
In the second article, Adams et al.5 provide a retrospective review of their experiences of adjuvant chemotherapy following surgery in the management of early-stage ovarian cancer in the North-West of England over a 4-year period, using carboplatin alone or in combination with paclitaxel chemotherapy. Although showing that the combination chemotherapy was offered to more women of younger age and better performance status, they were unable to identify any beneficial effect with the combined regimen. The conclusions of this study are restricted by selection bias and the small number of patients studied.
Both studies4,5 however, highlight the variations that exist in clinical management and the deficiencies in knowledge about early-stage ovarian cancer.
What do we know so far from previous prospective studies about the use of chemotherapy in early-stage ovarian cancer?
The two largest studies, analysed both individually and jointly, have provided limited information.6–8 Recruitment to both trials was stopped prematurely after many years of accrual, and during this time surgical practices changed, with greater emphasis on more comprehensive staging. Two-thirds of patients in the European Organization For Research and Treatment of Cancer (EORTC) ACTION trial, where staging procedures were more precisely defined, were under-staged.9 In the International Collaborative Ovarian Neoplasm 1 (ICON1) trial, the entry criteria were relatively broad, and simply required the clinician to be uncertain whether adjuvant chemotherapy was indicated. This trial included a number of stage-II cases, which today would not be considered an area of uncertainty. Adequate surgical staging was not a prerequisite for entry to this study.
When data from the EORTC ACTION and ICON1 trials were combined, postoperative (adjuvant) chemotherapy produced a small improvement in overall survival rates. Furthermore, long-term follow-up of the ICON1 trial reported that a small significant benefit in survival remains.10 However, in the subgroup analysis of the EORTC ACTION trial, the benefit of chemotherapy was confined to patients with known suboptimal staging. This was confirmed in a long-term follow-up analysis of the ACTION trial data (median follow-up of 10.1 years) showing better outcomes (recurrence-free and overall survival) with complete (optimal) surgical staging, with no additional benefit of adjuvant chemotherapy in this group. There was no difference in results when the poorly differentiated tumours were analysed separately.11 This result is supported by information from a single institution series where thorough staging resulted in more than 92% of women with stage-IA or -IB disease surviving without adjuvant chemotherapy.12
A recent Cochrane Review by Winter-Roach et al.,13 supports these findings. There is an effect of chemotherapy on survival, and its impact is in patients who have not undergone thorough staging.
Despite this, considerable uncertainty remains about the value of chemotherapy in early-stage disease, and many clinicians are deciding without clear evidence to offer some patients combination therapy. A trial from the Gynecologic Oncology Group showed that three cycles of carboplatin and paclitaxel are as effective as six cycles, and that toxicity is reduced.14 However, this trial does not address the question of whether treatment with carboplatin alone is adequate for these patients. One could argue that for inadequately staged patients potentially with stage-III disease, combination chemotherapy is worthwhile based on the evidence of advanced disease trials.15,16 However, without substantial evidence to support the addition of paclitaxel to carboplatin in early-stage disease, a case could be made for using single-agent carboplatin in all patients who require chemotherapy. The counter-argument to this is that because ovarian cancer is a heterogeneous disease, we should pay more attention to biology than stage, and consider combination chemotherapy for ‘high-risk’ stage-IC disease. Defining risk is not easy. We currently use crude morphological data,3 and urgently need to find other biomarkers that define a higher risk of recurrence. In the interim, perhaps surrogate measures such as DNA ploidy are able to provide valuable contributions in differentiating high- and low-risk groups.17
The authors of the ACTION trial, and a subsequent commentary in the International Journal of Gynecologic Oncology,18 recommended the need for further trials in early-stage ovarian cancer, and that the design of these trials should be to compare standard surgery followed by chemotherapy with standard surgery followed by comprehensive surgical staging, with selective chemotherapy reserved for cases up-staged by the staging procedure, i.e. avoiding chemotherapy where the disease appeared to be confined to the ovary. Is such a study feasible?19
There are no current plans to develop trials in the surgical or medical management of early-stage ovarian cancer, with most research efforts being concentrated on the more frequently occurring higher stage cases, and the investigation of newer chemotherapeutic drugs or novel biological agents. The National Cancer Research Network in the UK, formed after the ICON1 trial, has an excellent opportunity to undertake research into the less frequent conditions described here. However, these studies require a large number of patients and international collaboration would be needed. The Gynecological Cancer InterGroup (GCIG) provides an established forum to conduct collaborative studies, but before these take place there would need to be a better understanding of biological determinants of risk of recurrence to reduce the number of patients required for a study evaluating the appropriate use of chemotherapy in this group.
Also, if these proposed studies are to be supported, the Gynaecological Oncology community would need to agree on a definition of comprehensive surgical staging. With such wide variations in surgical practice, it is not clear that this would be possible at the moment.9,11,19 Also, there would need to be greater clarity about the reliability of frozen section analysis to provide accurate information, and it would need to be more widely available.20
Data from the Northern Gynaecological Oncology Centre and the Department of Pathology, Queen Elizabeth Hospital, Gateshead, UK, of over 1200 cases of frozen section analysis in the management of suspected ‘early-stage’ ovarian cancer performed over a 10-year period reveals a false-negative rate of 4.1% and a false-positive rate of 2.6%. The mean time from receipt of results to reporting was 18 minutes (pers. comm; A. P Cross, B. R Naik). These statistics have allowed the surgical team to correctly identify at the time of the primary laparotomy the great majority of ovarian cancer cases that can be managed by a comprehensive staging procedure. In the few remaining cases, a second staging procedure can be considered.
The use of frozen section analysis for intraoperative diagnosis does present some difficulties (largely as a result of histological sampling and interpretation), but if sufficient training and experience is gained, and the outcomes are regularly audited, it can play a powerful role in patient management.20 However, the use of frozen section pathology is relatively limited in the UK, in contrast with other countries, and pathologist training (and the desire to offer the service) is key to its introduction.
The many unanswered questions relating to early-stage ovarian cancer are likely to impact on the National Institute of Health and Clinical Excellence (NICE) current preparation of guidance for the recognition and initial management of ovarian cancer. It is unlikely that its recommendation for the use of chemotherapy and type of drugs will be prescriptive. However, its recommendation on the quality of surgical staging and the strategy of dealing with suspected early-stage ovarian disease is likely to be more clear-cut, and could help introduce comprehensive guidelines on surgical staging and the use of intraoperative frozen section analysis to the UK. Further work is required to identify more precisely the biological characteristics of tumours that differentiate those requiring chemotherapy and those that respond to drugs from those that do not. Prospective studies that reduce the need for postoperative chemotherapy and its associated morbidities is something that all would agree are urgently required.