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.
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 [
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 [
RCTs investigating the role of IDS.
Name of Study & year | Rose PG et al. [ | Van der Burg et al. [ | Redman et al. |
---|---|---|---|
N | 550 with 448 randomized 226 IDS versus 222 no IDS | 425 with 319 randomized 278 evaluated: 138 IDS versus 140 no IDS | 86 randomized with 7 |
FIGO stage | II-IV | IIB-IV | II-IV |
Trial characteristics | RD > 1 cm after primary surgery and responding/stable after 3 cycles of Cisplatin/pacitaxelStage IV only pleural effusion | RD > 1 cm & maximum primary debulking not attempted in all cases with high proportion of RD >5 cm Randomization after 3 cycles of CP | Primary surgery and RD > 2 cm 1–4 CP Or 3 PAB followed by |
PFS for IDS versus No IDS | 12.5 versus 12.7 | 18 versus 13 | |
OS for IDS versus No IDS | 36.2 versus 35.7 | 26 versus 20 | 15 versus 12 months |
CP: cisplatin/cyclophosphamide; overall survival in months; PAB
Nonrandomized case control studies evaluating delayed primary debulking surgery.
Name of Study | Colombo et al. [ | Oksefjell et al. [ | Hegazy et al. [ | Le T et al. [ | Rafii et al. [ | Vergote [ |
---|---|---|---|---|---|---|
N | 203 | 789(217 IDS 572 non IDS) | 59 all submitted to prior surgical exploration | 61 | 109 | 285 |
FIGO stage | IIc-IV | All stages treated for 1st relapse | II-IV | IV without bowel obstruction | IV | III-IV |
Important study data | Gr 1 conventional OS = 38 m Gr 2 with NACT OS = 26 m | Platinum single or combination/taxol single or combinationor other | NACT platinum-taxol OS = 41.7 m | NACT platinum- taxol + IDSOS = 45.5 m (under 20% of patients in study) | ||
Main conclusions | Benefit of IDS versus chemotherapy alone when tumour is localised. | Response rate to NACT comparable to that of upfront surgery stated in literature | Benefit of IDS in patient responding to NACT | OS was higher for patients with high tumour load treated with NACT than with upfront surgery | ||
Best OS (48 m) with radical primary cytoreduction, TFI >24 m & ≤ 39 years | Importance of maximal secondary cytoreduction in IDS | NACT can select patients for surgery |
IDS: interval debulking surgery; m = months; NACT: neoadjuvant chemotherapy; OS: overall survival; PFS: progression free survival; PPS: patient performance status; TFI: treatment free interval.
The initial studies supporting the concept of debulking surgery were published in the 1970s by Griffiths et al. [
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 [
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. [
At the beginning of the eighties, Berek et al. [
The trials by Redman et al. [
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 [
One of the studies [
In another recent study [
A retrospective study between 1980 and 1997 from Vergote et al. [
A large Norwegian retrospective study (
Radium hospital guidelines for IDS based on TFI and number of recurrence sites, taken from Oksefjell et al. 2009 [
TFI, months | Local disease | Disseminated disease |
---|---|---|
0–5 | Consider SCR | No SCR |
6–11 | Offer SCR | No SCR |
12–23 | Offer SCR | No SCR |
>24 | Offer SCR | Consider SCR |
SCR: secondary cytoreduction; TFI: treatment-free interval.
Selecting the right patients for the right treatment sequence is challenging. Predicting the possibility to perform successful surgery has been studied [
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 [
Another factor which cannot be ignored in the debate is the inherent tumour biology where the question, raised by some [