Annals of Oncology 16 (Supplement 8) viii36–viii38, 2005
3rd International Ovarian Cancer Consensus Conference:outstanding issues for future consideration
G. Stuart1, E. Avall-Lundqvist2, A. du Bois3, M. Bookman4, D. Bowtell5, M. Brady4, A. Casado6,A. Cervantes7, E. Eisenhauer1, M. Friedlaender5, K. Fujiwara8, S. Grenman2, J. P. Guastalla9,P. Harper10, T. Hogberg2, S. Kaye11, H. Kitchener10, G. Kristensen2, R. Mannel4, W. Meier3,B. Miller12, A. Oza1, R. Ozols4, M. Parmar10, J. Pfisterer3, A. Poveda7, D. Provencher1,E. Pujade-Lauraine9, M. Quinn5, M. Randall4, J. Rochon3, G. Rustin10, S. Sagae8, F. Stehman4,E. Trimble13, T. Thigpen4, P. Vasey11, I. Vergote6, R. Verheijen6, J. Vermorken6 & U. Wagner3
1NCIC-CTG (Canada); 2NSGO (Scandinavia); 3AGO-OVAR (Germany); 4GOG (USA); 5ANZGOG (Australia–New Zealand); 6EORTC (Europe); 7GEICO (Spain);8JGOG (Japan); 9GINECO (France); 10MRC/NCRI (UK); 11SGCTG (Scotland, UK); 12RTOG (USA); 13NCI-US
The process of consensus reflects an agreement upon one or
cooperative group and a timeframe for action. It is expected that
more statements about a topic at a particular point in time. Sub-
these items would be completed before a subsequent Conference.
sequent to that time, the level of consensus and the nature of
The second component of this manuscript will seek to collate
consensus may change. In this context, it is noted that this
those new questions that emanated from this Conference and
requires a dynamic process to remain current. The first Consen-
may be considered for future consensus statements. This is best
sus Workshop on Ovarian Cancer was held in 1993 and the
considered in the context of a cancer control model.
second in 1998. There has been a period of some 6 years sincethe last event. It is anticipated that as knowledge about ovarian
cancer evolves, so will the need to realign consensus statementsabout the management of the disease process.
This topic was recognized as an area of intense interest during
It is also acknowledged that any such process is unlikely to
this Conference. This included the concept of identification of
satisfactorily address all aspects of knowledge about the man-
risk through molecular markers as well as the need for techno-
agement of ovarian cancer. The 3rd International Ovarian Can-
logical and genetic imaging techniques for early detection. The
cer Consensus Conference (OCCC) successfully focused on
ability to conduct rapid proteomics screening for the purposes
aspects of treatment relevant to the conduct of clinical trials.
of early diagnosis is viewed as a critical issue for subsequent
Although this was intended and appropriate, it was noted that
this precluded appropriate consideration of the research andclinical elements of etiology, prevention, screening, early de-tection, diagnosis, supportive care and palliative care for those
persons affected by ovarian cancer. Therefore, the framework
There is a need to conduct randomized prospective trials to
for any subsequent conferences will have to consider these areas
validate biologic markers of disease and the impact on out-
and define the scope of the process.
comes. This includes both known subpopulations at significant
Thus, this manuscript will first summarize those specific
hereditary risk as well as less well-known groups. Molecular
questions that were generated through this OCCC which require
profiling through increased utilization of cooperative tumor
further action before the next Conference. Secondly, there will
banks has generated a considerable body of knowledge, but it
be an identification of those new questions that emanated from
is still not clear whether this is able to correlate with improved
this OCCC and may be considered for future consensus state-
outcomes. Although much is known about the conventional his-
ments. Thirdly, there is a proposed agenda for a subsequent
topathology of ovarian cancer, the specific entity of micropapil-
Conference subject to the ongoing changes in knowledge and
lary ovarian tumors will require further study.
practice. Finally, there is a brief discussion as to how this andearlier consensus workshops have affected current practice.
First, during the course of the OCCC it was recognized that
there were a number of critical issues in the management ofwomen with ovarian carcinoma that could and should be
Undoubtedly, the definition of end points in clinical trials that
addressed prior to any subsequent consensus process. These pro-
produce conclusions in a definitive but timely manner will re-
posed steps reflect discussion in the plenary sessions about spe-
main of great interest. This is particularly relevant if one con-
cific questions. These steps are summarized in tabular format
siders prevention, diagnostic and maintenance trials where
(Table 1). These items are identified with a specific responsible
traditional end points may not suffice. Even in therapeutic trials,
Ó 2005 European Society for Medical Oncology
Table 1. Summary of proposed action steps
To undertake a systematic review of ovarian cancer treatment trials to
assess shifts in progression-free relative to overall survival
To confirm definition of terminology in ovarian cancer treatment trials
To conduct a literature review of patient perception of preferencesfor outcomes
To review the characteristics of long-term survivors (i.e. >5 years) of
prior ovarian cancer trials in advanced ovarian cancer
To conduct a meta-analysis of actual carboplatin dose using appropriate trials
To establish a ‘bank’ of questions for consideration at next Ovarian Cancer
To establish a GCIG Working Group on the levels of evidence required to
change the standard arm of clinical trials
To provide a ddefinition and a validation tool of symptom control as a trial
To conduct a meta-analysis of outcomes in the subset of clear cell and
To identify the ‘new’ standard radiation therapy regimen for the treatment of
women with advanced epithelial ovarian cancer
To define the role of PET scanning in future ovarian cancer clinical trials
stabilization of disease and control of symptoms could be con-
directly, but also for more effective accrual into phase II and
sidered as desirable primary outcomes for specific interventions
It is very positive that outcomes in the population of women
The present OCCC did not intend to evaluate the role of surgery
with ovarian cancer have improved in the past few decades.
in the management of women with ovarian cancer. Yet, signif-
However, this has created a number of new issues that require
icant questions remain about the timing and extent of primary
consideration. It is possible that much is to be learned from
cytoreductive surgery and the specific role of secondary cytor-
profiling those women who have long-term survivals following
eductive surgery. It is still not clear how best to apply detailed
a diagnosis of ovarian cancer to better understand the disease.
molecular pathology data including drug resistance/prognostic
Furthermore, there are numerous issues to be considered
factors/molecular genetics to intelligently inform molecular tar-
amongst this population including quality of life, risk of second
geted therapy amongst women with a diagnosis of ovarian can-
malignancies and next generation risk analysis.
cer. There is increasing clinical adoption of neo-adjuvanttherapy regimens without the supporting high quality evidence. This requires evaluation in a randomized trial setting. It is also
apparent that there remains an asymmetry between availabledata, inferred knowledge and subsequent practice in the appli-
In addition to the clinical issues there are a number of related
cation of both dose-dense therapies and alternative administra-
issues that must be given future consideration in the manage-
ment of women with a diagnosis of ovarian cancer and theconduct of clinical trials. This includes regulatory issues withinthe Food and Drug Administration USA, pharmacoeconomic
issues and the broader economic analysis. The need to harmo-nize regulatory issues around tumor banks is evident.
The scheduling and nature of regular follow-up after completionof primary therapy for ovarian cancer has not been objectivelydetermined. The duration of surveillance has been affected by
therapies unable to allow long-term survivals. Furthermore,there is significant consideration about the establishment of
With the rapid accumulation of new knowledge, the answers to
standard second-line therapy regimens for those women who
many of these questions may quickly become apparent. Other
develop recurrent disease. This would impact front-line trials
areas may remain unresolved until after a subsequent workshop.
The third area for consideration is to identify those questions
cooperative clinical trials group. In aggregate form, these trials
and issues that are anticipated to be of high priority at subse-
and others have confirmed the role of a platinum compound with
quent workshops and thus, provide a framework for an agenda.
a taxane as standard therapy for women with ovarian cancer,
This futuristic consideration must allow for significant shifts
recognized the option of single-agent carboplatin as a standard
in the knowledge about ovarian cancer. However, it expected
therapy and demonstrated the lack of benefit of an anthracycline
that subsequent workshops will still wish to consider four spe-
to the above-mentioned regimens [2–6]. This may be viewed as
a marker of positive impact on the global consensus process. However, it is important that future consensus workshops have
1. Early diagnosis. The benefit of early diagnosis has been
included a process of evaluation in order to effectively measure
identified but the specific mechanism to do so remains sub-
the impact of this process on the burden of ovarian cancer.
ject to investigation. This will include consideration of the
Additionally, in considering the consensus process, it is ap-
role of proteomics as well as molecular markers. There
parent that the generation of new data so frequently presented in
should also be an assessment of the role of diagnostic imag-
the setting of publications and/or meetings does not necessarily
ing including PET scanning in women with ovarian cancer.
lead to better information. Furthermore, it is even less often that
2. First-line therapies. This will likely remain as a focus of
better information promotes new knowledge or practices. As
interest over the next decade and require ongoing review.
new data become available, they must be considered in the
This should include a consideration of the role of optimal
context of how this might be effectively adopted into practice.
radiation therapy both in first-line and salvage therapy.
Future international consensus workshops on the treatment of
3. Maintenance/consolidation. The question will likely remain
women with ovarian cancer should consider the impact of pre-
as to whether one should consider novel therapies in this
vious workshops on the outcome of women affected by ovarian
regard and what should the valid end points be in this setting.
cancer. The relevant questions must be derived from a direct
4. Post-recurrence/progression therapy. This area will undoubt-
correlation of the issues with the desired outcomes and an
edly remain as a major issue. The question should consider
opportunity created for discussion and consensus.
treatment selection (as relates to prediction of responseand resistance), appropriate surgery, measures of symptomcontrol/quality of life, survivorship, end points. The issue of
whether there should be a standard protocol for women with
1. Heintz APM, Odicino F, Maisonneuve P et al. Carcinoma of the Ovary.
progressive disease after first-line therapy merits consideration.
Volume 25 of the FIGO Annual Report on the Results of Treatment in
The final area to be addressed is the impact that this and earlier
Gynecologic Cancer. Int J Gynecol Obstet 2003; 83 (Suppl 1): 135–156.
consensus workshops have had on current practice. Although
2. Piccart MJ, Bertelsen K, James K et al. Randomized intergroup trial of
this issue is important to understand, it is one that is very diffi-
cisplatin–paclitaxel versus cisplatincyclophosphamide in women with
advanced epithelial ovarian cancer: three year results. J Natl Cancer Inst
cult to quantify. If the intent is to influence the standard of
practice, then one could consider that the shifts in 5-year sur-
3. McGuire WP, Hoskins WJ, Brady MF et al. Cyclophosphamide and
vival rates as documented by FIGO are markers of this impact.
cisplatin compared with paclitaxel and cisplatin in patients with stage
During the period from 1988–2003, the 5-year survival rate for
III and stage IV ovarian cancer. N Engl J Med 1996; 334: 1–6.
women diagnosed with stage III ovarian cancer has increased
4. International Collaborative Ovarian Neoplasm Group. Paclitaxel plus
from 22.9% to a high of 49.2% (range 28.9% to 49.2%) .
carboplatin versus standard chemotherapy with either single-agent
Although numerically modest, this is a significant gain at
carboplatin or cyclophosphamide, doxorubicin and cisplatin in women
a global level. However, there are multiple confounding factors
with ovarian cancer: the ICON3 randomized trial. Lancet 2002; 360:
in this correlation that may consider the relationship only as
coincidental. If the intent of the consensus process is to provide
5. du Bois A, Combe M, Rochon J et al. Epirubicin/paclitaxel/carboplatin
support to the effective conduct of clinical trials, then the impact
(TEC) vs paclitaxel/carboplatin (TC) in first-line treatment of ovarian
cancer (OC) FIGO stages IIB–IV. An AGO-GINECO Intergroup phase
may be evaluated by a record of successful completion of in-
III trial. J Clin Oncol 2004; 22 (Suppl 14): (Abstr 5007).
ternational phase III trials in the population of women with
6. Kristensen GB, Vergote I, Eisenhaeur E et al. First line treatment of
a diagnosis of ovarian cancer. This is more readily quantified
ovarian/tubal/peritoneal cancer FIGO stage IIB–IV with paclitaxel/
as since the previous consensus conference, there have been at
carboplatin with or wihout epirubicin (TEC vs TC). A Gynecologic
least four randomized clinical trials completed assessing the
Cancer Intergroup study of NSGO, EORTC GCG and NCIC CTG.
first-line treatment of women with a diagnosis of advanced ovar-
Results on progression free survival. J Clin Oncol 2004; 22 (Suppl 14):
ian cancer that include accrual from more than one national
Universitätsklinikum Jena – Zentrale Notfallaufnahme Arbeitsanweisung Risikostratifizierung – ambulant oder stationär? efinition Vorübergehender Bewusstseinsverlust im Rahmen einer generalisierten cerebralen Hypoperfusion und zügiges Erwachen nach maximal 1-3 Minuten (meist aber nur Sekunden) ohne medizinische Intervention. Die Definition der Synkope ist übrigens je nach Fachdis