ovarian cancer represents the sixth most commonly diagnosed cancer among women in the world and causes more deaths per year than any other cancer of the female reproductive system . in advanced disease which constitutes about 75% of women at presentation ,
this has been the approach for some decades , though the 5-year survival remains poor at about 40% .
epithelial ovarian cancer constitutes the majority of disease types , and this review will focus on reports relating to advanced epithelial ovarian carcinoma .
a medline database search ( january 1966 to april 2009 ) was undertaken using key words : epithelial ovarian cancer , debulking surgery , and interval debulking surgery resulting in 80 articles with 14 relevant papers .
the articles in full were obtained for each of the papers and reviewed by the authors .
results in terms of overall survival ( os ) and progression free survival ( pfs ) were evaluated in each study .
the 80 resulting articles were screened and 14 relevant papers were retained : 3 meta - analysis [ 24 ] , 3 randomized control trials ( rtc ) [ 57 ] ( table 1 )   2 cochrane reviews ( crs ) [ 8 , 9 ] , and 6 case / control ( cc ) reports enrolling more than 50 patients [ 1015 ] ( table 2 ) .
the initial studies supporting the concept of debulking surgery were published in the 1970s by griffiths et al . .
the premise for considering the potential impact of reducing intra - abdominal tumour burden was based on the findings of work by magrath et al . , which reported enhanced survival outcome by reducing intra - abdominal disease , in patients with hodgkin 's disease .
griffiths undertook a retrospective analysis of just over 100 women and noted that those with residual disease masses < 1.6 cms in largest diameter had an improved survival outcome compared with patients left with a greater disease volume .
a subsequent small prospective study   on a heterogeneous population of patients , who underwent aggressive radical surgery , also revealed the better survival pattern associated with less tumour burden .
thus , the concept of debulking surgery in ovarian cancer became the normal approach to this disease .
the use of adjuvant chemotherapy , which is platinum based , is also the accepted norm in care .  
the question as to whether the surgical ability of the operator or the inherent tumour biology of the disease is the main factor impacting on survival remains a debate .
indeed , the benefit of radical debulking has already come under criticism   while some have advocated that tumour biology rather than the surgical effort might determine prognosis . in a study of 213 patients with stage iiic epithelial ovarian cancer who underwent complete cytoreduction before initiation of systemic platinum - based combination chemotherapy , eisenkop and spirtos   came to the conclusion that the need to remove a large number of peritoneal implants correlates with biological aggressiveness and diminished survival , but not significantly enough to preclude long - term survival or justify abbreviation of the operative effort .
regarding primary surgery , there is a plethora of published papers , all of which support the findings of griffiths , though none are randomized controlled trials , and hence , all with similar inherent biases .
it is also important to note that various definitions of optimal cytoreduction have been proposed [ 2224 ] .
the gynaecologic oncology group ( gog ) currently defines optimal cytoreduction as leaving residual disease less than 1 cm in maximum tumour diameter .
there are 3 systematic reviews on residual disease and outcome , which have conflicting conclusions . in an analysis of 81 cohorts of patients ( over 6000 women ) with advanced - stage ovarian carcinoma treated with platinum - based chemotherapy bristow et al .   found a 5.5-percent increase in median survival for every 10-percent increase in the proportion of patients achieving maximal cytoreduction .
, ( again over 6000 women ) whereby the administration of platinum was deemed more important in influencing survival rather than the achievement of optimum debulking surgery .
the main difference between these papers is that in bristow 's study , all patients were exposed to adjuvant platinum therapy , which was not the case in hunters study .
the third and smaller study also concluded that optimum debulking was associated with improved survival patterns , though further prospective trials were necessary . at the beginning of the eighties , berek et al .   noticed that secondary cytoreduction could also improve survival
subsequently , the role of interval debulking surgery ( ids ) has been investigated in three prospective randomized controlled trials ( rcts ) [ 57 ] where conclusions are different .
interval debulking surgery is defined as a second operation performed after 3 or 4 cycles of platinum chemotherapy in woman who had suboptimal debulking primary surgery .
the trials by redman et al .   and the gog by rose et al .   failed to show any advantage of ids .
the study by redman was closed prematurely , as no survival benefit was noted at interim analysis , and of note , optimum debulking was defined as < 2 cms residium compared with < 1 cms in the other studies .   in the gog study ,
550 women with suboptimally debulked stage iii / iv ovarian cancer received three cycles of paclitaxel / cisplatin and then were randomly assigned to interval cytoreduction or no surgery .
a secondary attempt at cytoreduction was not associated with an improvement in progression free survival ( pfs ) ( 12.5 versus 12.7 months ) or overall survival ( os ) ( 36.2 versus 35.7 months ) .
this was not the case with the eortc trial carried out by van de burg et al . , which showed that the ids group had a significantly increased median survival of 6 months compared to those who had not undergone this procedure .
indeed this is still the only prospective rct showing a survival benefit with  debulking  surgery .
nevertheless , it is important to point out some differences between these trials . at the time of the eortc trial , chemotherapy consisted of cisplatin / cyclophosphamide as paclitaxel was not available , unlike the gog trial .
another major difference was that in the eortc trial , primary surgery was not necessarily performed by a trained gynaecological oncologist , resulting in different extents of debulking .
the number of patients with less than 5 cm of residual tumour following primary cytoreduction in the eortc trial was less than a third , compared to 55 percent in the gog trial .
surgery performed by a trained gynaecological oncologist has been shown to increase survival , and the gog study therefore concludes that with appropriate persons undertaking primary surgery , ids is not required .
the term ids should be confined to patients who have had primary surgical debulking , but it has been used in situations whereby a primary surgical attempt is delayed until during chemotherapy .
six large case - control studies [ 1015 ] relating to  delayed  primary surgery were identified , and are summarized in table 2 .
one of the studies [ 10 , colombo et al . ] divided patients into 2 groups to evaluate the place of surgery in the therapeutic sequence of care : group 1 receiving upfront surgery and group 2 where first debulking was undertaken after chemotherapy . in group 1
the os was 38 months and 3 factors significantly predicted suboptimal upfront surgery : poor performance status , extensive mesenteric involvemen , and stage iv disease .
the second group showed os of 26 months , and despite a response to nact in 90% of cases , there was no long - term survivors in the patients whose interval cytoreduction was suboptimal .
generally , os was stated to be influenced by three main factors : the extent of the disease at the time of diagnosis , the biology of the tumour , and its chemosensitivity , and the authors concluded that optimal surgery with limited morbidity ( 14% in their case ) can be achieved in many cases at primary surgery setting .
hegazy et al .   found , in a population of patients with advanced ovarian carcinoma where resectability was not possible , that neoadjuvant chemotherapy helped to select patients for feasible and relatively less aggressive ids , thus preventing initial surgical failure , in terms of optimal debulking .
however , morris et al .   in 1989 demonstrated that patients resistant to chemotherapy during primary treatment had little benefit from ids .
this was also concluded by rafii et al .   as well as the selection effect of nact for the second intention surgery .
in another recent study , the complete response rates after three cycles of platinum / taxane chemotherapy was 36.1% . after ids , 80% of all patients were left with optimal residuals ( < 2 cms ) . the response rate to chemotherapy given in a neoadjuvant
setting was comparable to those published in literature in patients who were treated with conventional upfront tumour reduction surgery followed by adjuvant chemotherapy .
they also found that residual decease after ids is the only significant predictive factor associated with prolonged pfs ( p = .003 ) .
to date , there is very little good quality evidence to either support or refute the use of neoadjuvant chemotherapy in the treatment of ovarian cancer .
a retrospective study between 1980 and 1997 from vergote et al .   included 285 patients with stages iii and iv ovarian cancer . in the period from 1980 to 1988 ,
optimal primary cytoreduction ( 0.5 cm residual disease ) was achieved in 82% of cases , but patients with stage iv disease or a metastatic tumour load of > 1 kg prior to this procedure had poorer survival with high postoperative mortality ( 6% ) . between 1989 and 1997
patients received either upfront surgery or chemotherapy depending on the extent of the disease and the performance status .
this subsequent management improved overall survival , despite a reduction of 25% in the rate of primary debulking . a large norwegian retrospective study ( n = 789 )   carried out at the radium hospital looked at treatment model for 1st relapse of ovarian cancer of any stage .
they found that treatment free interval ( tfi ) following primary therapy is a significant prognostic factor for os in multivariate analysis .
they also report age as prognostic factor for os at the time of secondary cytoreductive surgery .
survival benefit was clear for patients with optimum secondary cytoreductive surgery followed by chemotherapy compared with chemotherapy alone at the time of recurrence .
complete secondary cytoreductive surgery was found possible in a significant percentage of patients properly selected for this secondary surgery .
guidelines at relapse   for local and disseminated disease have been set up , where secondary cytoreductive surgery is recommended as independent of tfi for localized tumours and should be considered for tfi > 24 months in case of disseminated disease ( table 3 ) . selecting the right patients for the right treatment sequence
has been studied [ 28 , 29 ] with one model having an 85% specificity or ability to identify patients undergoing optimal surgery . in certain situations
laparoscopy is recommended as the most valuable tool for evaluating the operability in upfront or second line debulking surgery .
this paper has reviewed only rcts and large series , which do reflect the findings of many other reports on the specific debates surrounding the role and timing of surgery in ovarian carcinoma .
there is agreement that one of the most important prognostic factors for survival in the treatment of ovarian cancer is the amount of residual tumour after cytoreduction [ 4 , 16 ] .
it is welcome to note that in more recent times surgical approaches have undergone scrutiny in rcts .
indeed there is evidence of a shift from debulking for all to debulking for a select group , or put another way increased individualisation of therapy . unlike in previous decades the use of neoadjuvant chemotherapy seems to have gained some popularity , though the real impact requires the formal publication of the randomized trials eortc 55971 and chorus .
the eortc study has been presented at the igcs in bangkok and generated a lot of debate , as to the role of neoadjuvant chemotherapy .
another factor which can not be ignored in the debate is the inherent tumour biology where the question , raised by some   and still requiring an answer , is to know if it is the surgeon 's skills or tumour biology which determines survival outcome . in this respect , opinions vary regarding its impact on the ability to surgically debulk . on the other hand ,
others have put forward the strong expression of the p53 tumour suppressor gene correlating with reduced likelihood of achieving complete cytoreduction .
the progress and accessibility to novel technologies applied to biology will make possible in the future the assessment of new prognostic profilesbased on genetic and/or proteomic tumour characteristics .
 initial surgical management is commonly accepted to date as paramount in the treatment of women presenting with epithelial ovarian cancer and permits the assessment of the disease ( staging ) , the histological confirmation of disease type and grade , and the practice of maximal debulking preceding platinum - based chemotherapy . 
 many studies have shown that the volume of residual disease after initial surgical cytoreduction inversely correlates with survival . 
 thus , women with optimal debulking performed by a trained specialist have improved median survival . in this review , we will focus on the answers gleaned from clinical trials on primary and interval surgery , which prompts the question on the timing of surgery in respect to chemotherapy . 
 interval debulking surgery ( ids ) is secondary cytoreduction following primary debulking and is carried out in between the courses of chemotherapy . 
 the major clinical trials and the latest systematic reviews seem unable to give any definitive guidance or recommendation for clinical practice . 
 the choice of aggressive primary cytoreduction or upfront chemotherapy followed by second line surgical cytoreduction seems among others to have to be individualized according to tumour load , prediction of its resectability , and response to chemotherapy . 
 the role of tumour biology must also be kept in mind . 
 finally , concrete answers are awaited on the timing of surgery from the ongoing prospective randomized control trials ( chorus and eortc 55971 ) though preliminary data from the latter have already been presented at major meetings ( igcs 2008 ; sgo 2009 ) and ignited strong debate . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusions