Trial Information

Olympia-MITO13-validation of a Laparoscopic Score to Predict the Chance of Optimal Cytoreduction in Advanced Ovarian Cancer Patients: an Open-label Prospective Multicentric-trial.

Results from large but retrospective studies clearly demonstrated that RT after primary
surgery is the most important prognostic factor in AOC patients. Subsequently, several
studies have shown a complete cytoreduction (RT=0) is associated with a statistically
significant longer survival rate than minimal residual disease (RT=1-2 cm). As a
consequence, a maximal surgical effort is considered the main goal to pursue in these
patients.

However, data from the literature have shown that a certain percentage of AOC patients,
variable between 10 and 80%, are still considered inoperable at time of primary surgery, and
they are submitted to an unnecessary xipho-pubic laparotomy. This approach, beside affecting
QoL, can be related to some complications and delay in starting chemotherapy. This result
can be related to a series of variables, including patient's performance status, philosophy
of the centre and skillness of the surgeon. Finally, the anatomic diffusion of the disease
is described as one of the most limiting factor to an optimal cytoreduction.

In order to preoperatively identify patients with unresectable tumors, which can be spared
an unnecessary exploratory laparotomy, several approaches have been attempted, including CA
125 serum levels and CT-scan. However, the accuracy of those parameters has been
unsatisfactory, and limited by the retrospective nature of the studies and the highly
variable rates of optimal cytoreduction in different series.

Laparoscopy is well-known to offer a direct and magnified vision of the peritoneal cavity
and a better view of the upper abdomen. It allows the pathological assessment of the disease
without an open surgical procedure, with a shorter operating time and better results in
terms of post-operative morbidity. We first demonstrated in a pilot study that laparoscopy
alone is able to provide the same information regarding the chance of optimal cytoreduction
(RT<= 1cm) than standard laparotomy in clinically AOC patients. Since then, other
investigators have confirmed the role of laparoscopy in the evaluation of the possibility of
achieving optimal residual disease in the same clinical subset.

However, one of the major criticism to these studies was represented by the surgeon
subjectivity in evaluating optimal debulking in relation to surgical team and operating room
performances. Consequently, on the basis of previous published papers, we set up a
quantitative predictive model, which provides each patient with a score, taking into account
several laparoscopically-assessed sites of disease to objectively predict the chance of
achieving optimal cytoreduction. This model gives each parameter (omental cake,
diaphragmatic carcinosis, peritoneal carcinosis, superficial liver metastases, stomach
infiltration, bowel infiltration and mesenteric retraction) a value of 2 (see "Statistical
considerations").

Finally, we undertook a study to validate the performance of the model in a larger
prospective series of AOC patients. For each laparoscopic parameter we have discussed and
agreed the characteristics able to define a positive evaluation, especially those
identifying the critical areas of surgical resection. This study confirmed that with a PI
cut-off > 8, the percentage of inappropriate "no exploration" is 0, while the percentage of
unnecessary exploration equals to 40.5%. In conclusion the laparoscopic subjective ability
to predict optimal cytoreduction was definitively turned into an objective score.

Moreover, the laparoscopic score (Fagotti's score) has been validated externally in a centre
different from the one where it was developed [19,20], demonstrating that predictive
qualities of PI remain unchanged even if applied on a different population centre, with own
surgical background. This report suggests that the limit of subjectiveness, characterizing
the evaluation of ovarian cancer spread, tend to a solution.

Study design Phase I

1. Patients with a clinical/radiological suspicious primary advanced ovarian/peritoneal
cancer should undergo the following pre-operative staging examinations: haematological
and chemical parameters, including CA 125 serum levels, thorax-abdomen-pelvis CT-scan.

2. If inclusion criteria will be satisfied, an informed consent has to be signed before
any surgical procedure.

3. Patients will be then submitted to an open laparoscopy with at least one ancillary
trocar to evaluate the seven parameters previously described, assigning each one a
score to obtain a global predictive index. PI score is calculated based on. A video
has to be registered.

4. Patients'characteristics, including histological diagnosis, should be reported in the
enclosed summarizing schedule. On the other hand, no additional information regarding
the following treatment of the patient, i.e. abandoned vs. upfront surgery, RT or
follow up are required during the preliminary phase 1.

5. Send Laproscopic form, pre-operative documents and Video to the coordinating centre.

For preliminary phase 1, a minimum number of 10 patients has to be enrolled in one year.
Time and number of cases can be increased to reach the established accuracy rate > 80%.

The fairness of the laparoscopic PI value obtained in each specific centre will be
established through the revision of film material by the coordinating centre and the
accuracy will be calculated after realizing 10 cases. The centres achieving an accuracy rate
> 80% can enter in the second phase of the study. Other centres will require further cases
until the achievement of the objective.

All enrolled patients who receive the expected treatment will be considered
intention-to-treat-population (ITT).

Participation to preliminary Phase I of the study is a necessary but not sufficient
pre-requisite to adhere to Phase II. A new approval from the Ethical Committee is needed to
enter into the Phase II.

Centres can withdraw from the study in any time, but a written explanation is required.

Phase II Only centres participating to Phase I can enter into Phase II trial, after
achieving an accuracy rate >75%. A new approval from the Ethical Committee is needed to
enter into the Phase II.

1. Patients with a clinical/radiological suspicious primary advanced ovarian/peritoneal
cancer should undergo the following pre-operative staging examinations: haematological
and chemical parameters, including CA 125 serum levels, thorax-abdomen-pelvis CT-scan.

2. If inclusion criteria will be satisfied, an informed consent has to be signed before
any surgical procedure (Appendix 1).

3. Patients will be then submitted to an open laparoscopy with at least one ancillary
trocar to evaluate the seven parameters previously described, assigning each one a
score to obtain a global predictive index. PI score is calculated based on Appendix 2.
No videos need to be registered.

4. Patients'characteristics, including histological diagnosis, should be reported in the
enclosed summarizing schedule (Appendix 3). In this case additional information
regarding the following treatment of the patient, i.e. abandoned vs. upfront surgery,
RT and site, type of surgical procedures needed to obtain optimal cytoreduction, and
follow up data are required (Appendix 4).

5. Send Appendices 2 and 3 to the coordinating centre. For phase 2 study, a minimum number
of 100 patients should be enrolled in two years, overall.

Results regarding the primary objective of the study can be obtained immediately after the
enrolment of all the patients. Secondary objectives of the study need at least a minimum
follow-up of 3 years.