Annals of Oncology Advance Access published online on August 25, 2008
Annals of Oncology, doi:10.1093/annonc/mdn591
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The role of secondary cytoreduction in the management of the first relapse in epithelial ovarian cancer
1 Department of Gynaecological Oncology, The Norwegian Radium Hospital
2 Clinical Trials Unit, The Norwegian Radium Hospital and The Norwegian Cancer Association
3 University of Oslo, Oslo, Norway
* Correspondence to: H. Oksefjell MD, Department of Gynaecological Oncology, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway. Tel: +47 22934000, Fax: +47 22934469; E-mail: halldis.oksefjell{at}radiumhospitalet.no
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Background: The aim of this study was to investigate the benefit of secondary cytoreduction (SCR) in the first relapse in epithelial ovarian cancer and to attempt to define selection criteria for SCR.
Patients and methods: A retrospective population-based study on recorded information from 789 patients treated at the Norwegian Radium Hospital during 1985–2000 for their initial recurrence. In all, 217 had SCR and 572 were treated with chemotherapy alone.
Results: Median survival time (MST) was 1.1 years for the chemotherapy group. Complete optimal cytoreduction (COC) was achieved in 35% of all 217 patients, in 49% of the patients operated with debulking intent and in 52% if bowel surgery was done with debulking intent. MST was 4.5 versus 0.7 years for 0 versus>2 cm residual disease, respectively. Residual disease after SCR, treatment-free interval (TFI) and age were found to be prognostic factors for overall survival (OS) in multivariate analysis. Localised tumour was found to be the only significant factor to predict COC.
Conclusions: SCR followed by chemotherapy gives a clear survival benefit compared with chemotherapy and should be offered when the tumour is localised. The combination of COC, TFI >24 months and age 
39 years identifies a group of patients with the best OS.
first relapse, ovarian cancer, secondary cytoreduction
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Epithelial ovarian carcinoma (EOC) accounts for the majority of deaths from gynaecologic malignancies. To date no good screening methods to detect the cancer at an early stage have been developed. Thus,
70% of women with newly discovered ovarian cancer have advanced disease at the time of diagnosis [1]. Nevertheless, a complete clinical remission can be achieved in 80% of these patients with the use of maximal surgical cytoreduction and platinum-based combination chemotherapy [2]. Today carboplatin and a taxane combined is standard primary chemotherapy. Unfortunately, upwards of 75% of those clinical complete responders develop recurrent disease. Recent studies have reported superior results in women with platinum-sensitive relapsed ovarian cancer [platinum-free interval or progression-free interval (PFI) >6 months] treated with paclitaxel [3] or gemcitabine [4] in combination with carboplatin as compared with platinum monotherapy. For patients with platinum-resistant relapsed ovarian cancer, there are many drugs available but most commonly used are pegylated liposomal doxorubicin [5], topotecan [6] or gemcitabine [6] each used as monotherapy. Unlike the high complete response (removal of all visible tumour) rates achieved after aggressive front-line therapy, it is the minority of patients who attain complete clinical response with second-line therapy and many studies have shown that the chance of complete clinical response is directly correlated with the PFI. Harrison et al. [7] have also shown that subsequent remissions are shorter than the previous one in 94% of cases. In situations of recurrent disease it may be possible to improve the chance of complete response and/or duration of second remission by adding secondary cytoreductive (SCR) surgery to chemotherapy. Berek et al. [8] initially defined SCR as a surgical procedure carried out on patients with persistent or recurrent disease after completion of a full planned course of chemotherapy. Morris et al. [9] demonstrated that patients not responding to chemotherapy during the primary treatment benefit little from SCR.
Many reports have, with the exception of the study of Munkarah et al. [10], demonstrated a clear survival benefit for patients undergoing optimal SCR [11–23]. Most are retrospective studies but two recent ones are prospective [13, 16]. Optimal cytoreduction (OC) (1cm tumour residuum) was achieved in varying proportions of patients (38%–100%) [10, 11–13, 16–22]. Outcomes were, however, directly related to volume of relapsed disease [13, 14], and three of the studies reported on patients with localised recurrences only [10, 17, 18]. Residual disease following SCR was most often reported as a strong predictor for survival. The definition of OC, however, varies across these reports [11–21]. It has also been suggested that the amount of residual disease following primary surgery predicts the patient most likely to benefit from SCR [8, 11, 19, 21–24]. Disease-free interval, PFI and diagnosis-to-recurrence intervals were found to be independent prognostic factors in three of the studies [11, 14, 18]. Other factors with significant influence on survival were ascites, performance status, International Federation of Gynecology and Obstetrics (FIGO) stage (stage), number of cycles and type of salvage chemotherapy and CA 125 values [11, 13, 16, 19, 20]. Harter et al. [19] found good performance status, lower stage, minimal residual tumour after primary surgery and absence of ascites associated with complete optimal cytoreduction (COC) at relapse [19, 20].
Selection of surgical candidates to relieve gastrointestinal obstruction is often difficult. In a Cochrane Database Review, Feuer et al. [25] found no conclusive criteria on which to base selection after reviewing many retrospective case series on intestinal obstruction in gynaecological cancers.
The Norwegian Radium Hospital (NRH) serves as a referring hospital for south-eastern parts of the country including 60% of the Norwegian population.
The aim of this study was to investigate the benefit of SCR and attempt to define criteria for selecting patients most likely to benefit from SCR.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Data were retrospectively collected from patient records found via the hospital code registry for diagnosis and operation. A total of 789 patients treated for the first recurrence EOC were identified. Recurrences are registered up to and including 2001 only. Overall survival (OS) time is counted from start of treatment of relapse until death or the time of data lock which was 1 January 2007.
We identified 217 patients from 1985 to 2000 with EOC who had any surgical procedure following primary debulking and chemotherapy and 572 who got only chemotherapy at first relapse. Surgery for bowel obstruction or cytoreduction was included. Non-responders to chemotherapy during primary treatment are also included. Patients with borderline tumours are excluded.
Time to first recurrence was defined as the time from completion of initial treatment to the diagnosis of progressive or recurrent disease and called treatment-free interval (TFI). This interval was divided according to NRH TFI definitions into quartiles: 0–5, 6–11, 12–23 and 24 or more months. Other registered parameters were age at the time of recurrence, stage, histology and grade of differentiation (grade) at the initial diagnosis. Residual disease after the primary surgery and SCR was assessed from operative notes and defined as no macroscopic tumour, macroscopic 2 cm and macroscopic >2 cm.
Types of chemotherapy, either as chemotherapy alone or as post-SCR therapy, were subdivided into five groups: 1 = single-agent platinum; 2 = platinum in combination with non-taxane chemotherapy; 3 = regimens with taxane monotherapy; 4 = regimens with taxanes in combination and 5 = others such as anthracyclines, cyclophosphamide, thiotepa and fluorouracil.
Treatment of the first relapse was registered in three groups as no surgery versus surgery for local or disseminated disease in the pelvis or abdominal cavity. Local disease means one or two lesions in abdomen or pelvis and refers to what is found during the operation. Ascites was variably noted in the records and is therefore not registered. We mean that the characteristic of disseminated disease can, however, serve as a surrogate for ascites here. Performance status was not always evaluable and was therefore not registered.
It was noted whether surgery was chosen with the intent of carrying out SCR before chemotherapy or because of bowel obstruction. Surgery on the bowel was scored as resection with anastomosis or bypass with ostomy. Before determining who would benefit from SCR, a thorough clinical examination of the patient supported by computed tomography scan, ultrasound and CA 125 was done. The decision to attempt SCR was then discussed in a tumour board among the gynaecological oncologists in every case. Our selection criteria for SCR were if the tumour was relatively localised in pelvis or upper abdomen, age, good performance status and TFI >6 months.
statistical analysis
The association between prognostic factors in treatment groups were evaluated by the chi-square test. OS was estimated using Kaplan–Meier methods and groups were compared with log-rank tests. The expected important prognostic factors were included in the Cox proportional hazards regression model and the analysis was done with backward, stepwise elimination. Binary stepwise logistic regression was used to try to find factors predictive of OC. P values 0.05 were regarded as significant. Data analysis was carried out using SPSS 15.0.
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The clinicopathologic characteristics of the entire patient cohort (789) and median survival times (MSTs) for the three treatment groups are listed in Tables 1 and 2. Differences in prognostic factors between the operated patients and those who got chemotherapy alone are shown in Table 1. At the primary treatment significantly more patients had serous, poorly differentiated tumours, >0 to <2 cm residual tumour and stage IV in the chemotherapy group. At relapse significantly more patients with TFI >24 months had SCR compared with significantly more patients >70 years who had chemotherapy. Table 2 also shows the P values for the univariate analyses for possible prognostic factors for outcome after treatment. The number of patients for the different characteristics varies because of missing data elements from the chart review. Twenty-one patients operated for bowel obstruction were excluded from statistical analysis because the residual tumour after SCR was not registered. SCR was chosen for 217 (27%) of the 789 patients with 68 (35%) being without macroscopic tumour and 33 (17%) having individual tumour nodules
2 cm after SCR (Table 1). MST was 4.5 years in patients who were SCR to no residuum compared with 0.7 years in patients left with residual disease >2 cm, and 2.3 years when 2 cm macroscopic disease was left (Table 2). The difference was highly significant in univariate analysis (P < 0.001) (Figure 1), and it was significant both for local and disseminated tumour relapse (Table 2).
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Also stage, grade and residual tumour following primary surgery affected survival after surgery for the first recurrence as shown in Table 2.
In all, 84 of the 217 patients who were operated on had localised disease. Figure 2 shows a significant difference in survival (P < 0.01) in favour of localised disease with an MST of 3.4 versus 1.0 and 1.1 years for patients who were operated for disseminated disease or got chemotherapy without surgery, respectively (Table 2). Unfortunately, it was not registered which of the patients who received chemotherapy without SCR had localised disease.
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When surgery was carried out with the intent to SCR, whether or not bowel surgery was carried out, the survival was significantly better than those operated on for bowel obstruction without debulking intent (MST 2.5 versus 0.5 years) (P < 0.01). COC was achieved in 49% of the patients operated with SCR intentions. Only seven of the 66 patients operated for bowel obstruction had localised tumour versus 59 with disseminated disease (Table 1). For these patients MST was 0.7 and 0.5 years, respectively (P = 0.06) and significantly inferior to those who underwent operation with intent of SCR (P < 0.01) (Table 2). When bowel surgery in general was necessary, survival was significantly worse as compared with cases when no bowel surgery was required (1.1 versus 2.1 years) (P < 0.01) (Table 2), but comparing those who did or did not get bowel surgery when operated on with SCR intent and not because of bowel obstruction, there was no difference in OS (MST 1.9 and 2.0) (data not shown).
When carrying out bowel surgery with SCR intent, 23 of 44 were maximally debulked (52%) while when doing it for bowel obstruction only three of 61 had no macroscopic residuum (5%) (data not shown).
For the five different groups of chemotherapy given following SCR, there was a significant difference in survival benefit based upon type of postoperative therapy: paclitaxel combination therapy MST 3.7 years; platinum combinations 3.3 years; single-agent platinum 2.0 years; paclitaxel single agent 0.9 years and others 0.8 years. For patients who received only chemotherapy, paclitaxel-based combinations had the best MST of 3.3 years compared with 1.5 years for platinum combination (P = 0.01) (Table 2). Patients with localised tumour relapse who got paclitaxel-based combination postoperatively had an MST that has not been reached after 7 years (Table 2). There were no differences between platinum combination and paclitaxel combination in the two SCR groups (P = 0.5).
Survival curves for patients with different TFI from end of primary treatment to relapse are shown in Figure 3. There is also a clear survival benefit for patients with the longest TFI between completion of primary therapy and development of recurrence irrespective of the treatment given for that recurrence. When that interval is at least 24 months, MST is 4.5 years compared with 1.6 years for 12–23 months and even shorter survival with TFI <12 months. The patients operated for local recurrences had overall good survival so that TFI was of less importance.
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Most of the patients were between 50 and 69 years. Thirteen patients were 39 years or younger and had 10 years MST after surgery compared with the women aged >70 years with an MST of only a little more than 1 year (P = 0.02) (Table 2).
The operated patients with highly differentiated tumours showed a significantly superior survival to those with moderate and poorly differentiated tumours (5.1 versus 1.2 and 1.4 years median survival) (P < 0.01) (Table 2). The difference is not significant for the local tumour relapses probably because of few patients and more of these patients had highly differentiated tumours (20% versus 12% for disseminated disease and 5% for non-operated), whereas as mentioned above, survival is generally good whatever therapy is chosen (last data not shown).
The majority of the patients had serous tumours (Table 2).
A majority of the 789 patients had stage III tumours. We found the best MST for SCR in those patients with FIGO stages I and II cancer 5.1 and 2.5 years, respectively (P < 0.01). The MST for stages III and IV are 1.2 and 1.4 years, respectively.
The following factors at first relapse were evaluated in a multivariate regression model: stage, grade, residual tumour after SCR, residual tumour after primary surgery, TFI, chemotherapy group, age and surgery or no surgery in multivariate analysis. We found residual tumour after SCR, TFI and age as independent prognostic factors for survival (Table 3). We also evaluated age, stage, TFI, residual disease after primary surgery and surgery for localised versus disseminated disease as predictors for the ability of SCR to remove all visible disease. Only localised tumour remained as prognostic factor in binary logistic regression.
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The optimal mode of treatment of relapses of ovarian cancer is still debated and may vary depending on a number of intrinsic biologic factors [6]. Chi et al. [14] and Harter et al. [19] reviewed the literature and showed a survival advantage for SCR for patients with recurrent ovarian cancer. In the retrospective study reported here of patients who underwent SCR from 1985 to 2001, the largest population-based single institution study to date, a survival benefit from SCR for recurrent ovarian cancer was found for COC patients who appreciated an MST of 4.5 years as compared with a 1.1-year MST for patients who were managed without SCR (Figures 1 and 2 and Table 2). This is comparable to earlier reports taking into account different definitions of OC coupled with the fact that we did not de facto exclude patients operated for bowel obstruction and those who were resistant to primary therapy [10–13, 16–19]. COC was achieved in 49% of the patients operated with SCR intention, and for those patients undergoing bowel surgery with SCR intention, 52% were maximal debulked. We are aware of the selection bias in a report of this retrospective character but in multivariate analysis of the listed prognostic factors at primary treatment in Table 1 no one remained independent prognostic factor. At relapse, two prognostic factors were significantly independent among the operated patients and the ‘control group’ patients >70 years in the chemotherapy group and >24 months TFI in the surgery group. These two prognostic factors were included in our selection criteria procedure for SCR.
Compared with patients undergoing surgery where COC was not possible, the difference in OS was highly significant in univariate analysis and the strongest prognostic factor for OS in multivariate analysis. This same finding has been reported by other authors [10–19]. It remains to be determined if there is some way to preoperatively determine which patients are most amenable to COC so that the surgical experience can be reserved for those patients most likely to benefit. In our experience there was a relatively good correlation between the findings pre- and peroperatively. Only 20% of the patients operated on with SCR intent were found to be ineligible for resection, but explorative laparotomy or laparoscopy is better than imaging according to Munkarah et al. [10].
Like others we also found TFI following primary therapy to be a significant prognostic factor for OS in multivariate analysis [11, 14, 18, 21, 23]. The lack of a survival difference for patients with localised disease based on TFI indicates that these patients may benefit from SCR even if it is carried out shortly following primary treatment. An alternate explanation is that patients who recur locally have a different intrinsic biology than those who recur systemically as our results are indicating as well.
Age as a prognostic factor for OS at SCR as shown in this study is seldom reported, although young age, overall, has been shown by others to be prognostically favourable [26].
Residual tumour after primary surgery was also a prognostic factor for OS after SCR in univariate analysis in our study and has been shown by others [8, 11, 19, 21, 22]. After adjusting for other prognostic factors, however, we found no significant difference (Table 3). One possible explanation for this could be that we did not exclude primary chemotherapy non-responders from SCR. It can also be due to small patient numbers in the operated groups with lack of statistical power.
We also found extent of disease to play an important role in OS as shown by others [13, 14]. Patients operated for localised disease lived significantly longer than those with disseminated disease as previously reported by other authors [10, 17, 18].
We also found that grade was important for disseminated disease but not for localised tumour at SCR. Highly differentiated tumours in the disseminated groups had better survival than the poorly differentiated tumours. For postoperative adjuvant chemotherapy, we found paclitaxel-based combinations to give the best OS of the five different chemotherapy groupings defined in the study (P < 0.01). In the local disease group, the MST has not yet been reached after 7 years (Table 2). However, there were no differences between platinum combination and paclitaxel combination in the two SCR groups (P = 0.5). Phase III studies in platinum-sensitive recurrence have shown that platinum in combination with paclitaxel or gemcitabine is better than platinum monotherapy [3–4]. As far as we know the relative efficacies of different platinum combinations following SCR have not yet been established. In our department we at present use carboplatin and paclitaxel as the standard regimen for sensitive tumours at first recurrence according to the recommendation of the International Collaborative Ovarian Neoplasm 4 study.
Although stage and grade were significant prognostic factors for survival in univariate analysis, the significance disappeared in multivariate analysis.
That surgery with SCR intention led to better OS than surgery for bowel obstruction is quite clear, expected and reflects our selection of patients for SCR. Some, albeit few of the patients operated for bowel obstruction, can also be optimal debulked [23].
More important is that 52% of the patients who underwent bowel surgery with SCR intent were maximal debulked.
We have shown a clear survival benefit for patients who undergo a secondary COC followed by chemotherapy compared with chemotherapy alone at the time of first recurrence. Further, we have shown a significant difference in survival for SCR used in patients with local and disseminated disease.
Other conclusions from this study are that residual disease, TFI and age are independent prognostic factors for OS after SCR at the first relapse. COC was possible in a significant percentage of patients properly selected for SCR.
Localised tumour was found to be the only significant factor remaining when trying to predict COC in stepwise logistic regression. Therefore, selection of patients for SCR is crucial and all techniques including imaging should be utilised to select those patients with localised disease and the greatest chance of COC and the largest benefit from SCR [14].
This is a retrospective study, however, with known limitations. While a prospective randomised study is awaited to determine specific treatment recommendations [19], we recommend SCR independent of TFI for localised tumours and consider SCR for TFI >24 months for disseminated disease (Table 4).
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Inger and John Fredriksens's Foundation for Ovarian Cancer Research.
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We thank the scientific secretary, Mrs. Gry Seppola for technical and organisational help. We also thank Anne Birgitte Jacobsen at the Clinical Trials Unit, NRH, for supporting the construction of the electronic database and we thank our specialised pathologists for reviewing all the histological sections.
Received for publication May 28, 2008. Revision received July 24, 2008. Accepted for publication July 25, 2008.
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