Cytoreductive Surgery in the Management of Ovarian Cancer

August 1, 2008
Peter E. Schwartz, MD
Peter E. Schwartz, MD

Volume 22, Issue 9

The standard management for advanced-stage ovarian cancer was established in the mid-1970s. At a 1974 National Cancer Institute Consensus Conference on Ovarian Cancer, Griffiths presented data supporting the role for aggressive cytoreductive surgery as the first step in the management of this disease, followed by cytotoxic chemotherapy.

ABSTRACT: The standard management for previously untreated advanced-stage epithelial ovarian cancer is optimum cytoreductive surgery followed by aggressive cytotoxic chemotherapy. This approach is based on a retrospective review of a single-institution experience published more than 30 years ago and has yet to be confirmed in a prospective randomized trial. Many subsequent studies have supported the observation that advanced ovarian cancer patients who have the longest survival invariably have no macroscopic disease left at the completion of the initial surgery. The combination of a platinum- and taxane-based chemotherapy regimen is now well established as the most active one for treating women with advanced ovarian cancer. However, the overwhelming majority of patients with advanced ovarian cancer will eventually experience disease recurrence and develop resistance to cytotoxic chemotherapy. Selected patients with recurrent ovarian cancer-ie, those with an isolated recurrence identified more than 6 months following completion of initial chemotherapy and who have an excellent performance status-are managed with cytoreductive surgery followed by a platinum-based regimen. As in previously untreated patients, patients who have no macroscopic residual tumor left after secondary debulking for recurrent ovarian cancer have a significantly better survival than those left with any gross tumor. This article will review the role of surgery in the initial management of advanced-stage and recurrent ovarian cancer, focusing on the definition of optimum surgical cytoreduction.

The standard management for advanced-stage ovarian cancer was established in the mid-1970s. At a 1974 National Cancer Institute Consensus Conference on Ovarian Cancer, Griffiths presented data supporting the role for aggressive cytoreductive surgery as the first step in the management of this disease, followed by cytotoxic chemotherapy.[1]

In a retrospective review, Griffiths demonstrated that women with advanced-stage disease who had no residual disease at the completion of the initial surgery had a 39-month average survival, whereas those with less than a 5-mm maximum diameter of residual disease had a 29-month average survival. Patients with 6- to 15-mm residual disease had an 18-month mean survival, and those with more than 1.5 cm residual disease had an 11-month mean survival.

Griffiths et al subsequently demonstrated that if one cytoreduced patients with advanced-stage tumors to less than a 1.5-cm maximum diameter of residual disease, those patients had the same survival as patients who at the time of beginning the initial surgery had metastatic implants with less than a 1.5-cm diameter.[2] The 5-year survival for both those cytoreduced to < 1.5 cm and those with only miliary disease < 1.5 cm initially present was approximately 20%. Thus, for at least 80% of the patients, the surgery and chemotherapy proved to be palliative, not curative.

Other Available Data

Numerous institutional series have confirmed that patients with the least residual disease at completion of their initial cytoreductive surgery experienced the longest survivals.[3-8] However, no prospective randomized American trials have been performed to confirm cytoreductive surgery as the most effective initial step in the treatment of advanced ovarian cancer, and few reports have used a definition of no macroscopic residual disease to define optimal surgical cytoreduction.[5,9,10]

In 1992, Hoskins et al attempted to confirm Griffiths’ observation that cytoreduction to 1 cm or less residual disease would achieve the same survival results as those accrued to patients who initially had less than 1-cm implants in the upper abdomen.[11] Hoskins et al retrospectively reviewed the results of the Gynecologic Oncology Group (GOG) trial 52, a study confined to optimally cytoreduced stage III ovarian cancers, all of which were treated with postoperative platinum-based chemotherapy. Optimal surgical cytoreduction was defined by the GOG as residual disease ≤ 1 cm in maximum diameter at the completion of the initial surgery.

Figure 1: Survival After Surgical Cytoreduction in Ovarian Cancer, First GOG Trial-(A) Progression-free survival (PFS) for patients with stage III ovarian cancer treated with intravenous cisplatin and paclitaxel. (B) Overall survival (OS) for patients with stage III ovarian cancer treated with intravenous cisplatin and paclitaxel. NP = no progression; P = progression. Reprinted, with permission, from Winter WE 3rd et al.[18] Copyright © 2007 by the American Society of Clinical Oncology. All rights reserved.


The study included patients with stage IIIA (ie, only microscopic disease in the upper abdomen), stage IIIB (disease ≤ 2 cm in the upper abdomen at the beginning of surgery), and stage IIIC (disease that was present in the upper abdomen > 2 cm at the initiation of the surgery). While patients who had stage IIIA or IIIB disease did well following surgery and postoperative chemotherapy, 90% of the optimally surgically cytoreduced patients who had stage IIIC disease-based on gross omental disease > 1 cm and gross disease anywhere else in the abdominal cavity prior to initiating cytoreduction-died within 5 years following the initial diagnosis.

Hoskins et al noted that the patients with the worst survival were those with gross omental disease in addition to visible disease elsewhere in the abdominal cavity and those who had clear cell or mucinous histologic types of cancer. Further, the authors noted that younger women were more likely to have stage IIIA or IIIB disease with histologically lower-grade tumors. Older women tended to have high-grade cancer. The study failed to confirm Griffiths’ observation that stage III patients who were optimally surgically cytoreduced achieved the same survival as those who initially had only miliary disease in the upper abdomen at the beginning of their laparotomy.[1]

Role of Disease Biology

An unanswered question in this setting concerns whether the inherent biology of the disease or the surgical skills of the physician are most important in determining the outcome of initial cytoreductive surgery. In an attempt to answer this question, Crawford et al reviewed the Scottish Randomized Trial in Ovarian Cancer (SCOTROC-1) data on 1,011 patients participating in a prospective randomized trial for International Federation of Gynecology and Obstetrics (FIGO) stage IC–IV patients who were to receive cytotoxic chemotherapy following surgery.[12] All patients were treated with carboplatin and randomized to also receive either paclitaxel or docetaxel (Taxotere). There was no difference in survival for the women receiving paclitaxel or docetaxel. Essentially all patients participating in either of the treatment groups had the same survival outcomes.

Data were collected prospectively on the surgical findings, and a prognostic score was created based on the following four significant patient characteristics: (1) FIGO stage, (2) preoperative serum CA-125 level, (3) presence or absence of an omental cake, and (4) clear cell histology vs other. (Gross omental disease and histology were also significant in the GOG study.[12]) The patients were then placed into one of four quartiles based on their prognostic score. The survival of patients in each quartile was determined based on whether there was no macroscopic residual disease, ≤ 2 cm residual disease, or > 2 cm residual disease at completion of the initial surgery. Residual disease was confirmed by postoperative, prechemotherapy computed tomography (CT) scans.

Figure 2: Survival After Surgical Cytoreduction in Ovarian Cancer, Second GOG Trial-(A) Progression-free survival (PFS) for patients with stage IV ovarian cancer treated with intravenous cisplatin and paclitaxel. (B) Overall survival (OS) for patients with stage IV ovarian cancer treated with intravenous cisplatin and paclitaxel. Reprinted, with permission, from Winter WE 3rd et al.[19] Copyright © 2008 by the American Society of Clinical Oncology. All rights reserved.

The patients who benefited most from surgical cytoreduction to no residual disease were those in the first two quartiles.[13] The patients in the third or fourth quartile experienced no apparent survival benefit from having no macroscopic residual disease at the end of cytoreductive surgery, as there was no statistical difference in progression-free survival (PFS) for those with no residual disease compared to those with residual disease either less than or greater than 2 cm. These findings supported the view that the inherent biology of the disease is key in determining outcomes.

Optimal Cytoreduction

Definitions of optimal surgical cytoreduction following completion of the initial surgery have varied in the literature from no macroscopic residual disease to 3 cm gross residual disease.[3-8] In the United States, the GOG has settled on 1 cm or less residual disease as a criterion for optimum cytoreductive surgery. Using this definition, “ultraradical surgery” is now being recommended by several centers in the United States. Ultraradical surgery incorporates splenectomies, partial pancreatectomies, diaphragm resections, and multiple bowel resections into the surgical treatment for patients with advanced-stage (FIGO stage IIIC–IV) ovarian cancer.[14,15]

Reports by advocates for this approach reveal that they have accomplished at least 70% optimum surgical cytoreduction in one series and up to 92% optimum surgical cytoreduction in another series.[14,15] However, when one evaluates these series based on no macroscopic residual disease at the completion of the initial surgery, both series report only a 22% incidence of patients left with no macroscopic residual disease. It would appear that the ultraradical surgery has been most effective in surgically cytoreducing patients who might have > 1 cm residual disease in the past into the ≤ 1 cm disease category, but not into the no macroscopic residual disease category.[14-16]

CT Scan vs Surgical Assessment

Recently, a prospective study of 78 women with advanced ovarian cancer who were optimally cytoreduced to ≤ 1 cm macroscopic residual disease compared postoperative, prechemotherapy CT findings with the surgeon’s assessment of residual disease left at completion of the initial surgical cytoreduction.[17] In 20 (26%) of the 78 cases, residual “definitely malignant disease” > 1 cm was identified by CT scan. In 10 additional cases (13%) findings of “probably malignant residual disease” > 1 cm was identified by CT scan. “Indeterminate findings” were identified in 7 cases (9%). In 41 cases (52%), no disease > 1 cm was identified.

Statistical analysis found that no macroscopic disease left at the completion of the initial surgery was the only factor associated with postoperative, prechemotherapy CT scans showing < 1-cm lesions. Residual disease on postoperative CT scans was significantly more likely to be found in patients with 0.6 to 1 cm residual disease at completion of the initial “optimal” cytoreductive surgery. The authors could not state whether these findings reflect underestimation of residual disease by surgeons, overestimation of residual disease by radiologists, or rapid regrowth of cancer. Regardless of the cause, it supports the importance of cytoreduction to no gross residual disease at the initial surgery.

GOG Studies


Two recent GOG studies have been reported that cause us to reflect on what is being accomplished with surgical cytoreduction in the management of advanced ovarian cancer.[18,19] The first series included 1,895 stage III disease patients, the largest series of stage III patients reported to date.[18] It involved patients participating in one arm of six different prospective, randomized GOG trials. All of the patients in these treatment arms had received cisplatin and paclitaxel chemotherapy in standard intravenous regimens. The GOG studies are significant for being rigidly controlled regarding type and dosage of chemotherapy administered and for treating a rather homogeneous group of patients.

Among patients with stage III disease, 23% were optimally cytoreduced to no macroscopic residual disease-a similar percentage to that achieved by those proposing ultraradical surgical techniques to optimally cytoreduce patients with advanced ovarian cancer.[14,15] A major impact on both progression-free and overall survival (OS) was seen in these optimally cytoreduced patients (Figure 1). PFS was 33.0 months for those with no macroscopic residual disease and OS was 71.9 months, a survival status significantly better (P < .001) than the PFS and OS for those with 0.1 to 1 cm residual disease (16.8 and 42.4 months, respectively) and for those with > 1 cm residual disease (PFS = 14.1 months; OS = 35.0 months).

The GOG subsequently reported on 360 stage IV patients participating in one of four prospective, randomized GOG trials, all of whom received the same regimen of intravenous cisplatin and paclitaxel.[19] Only 8% of the patients with stage IV disease were cytoreduced to no macroscopic residual tumor. PFS for those with no macroscopic residual disease was 20.1 months and OS for this group was 64.1 months (Figure 2). Surprisingly, there was no difference in survival for patients with ≤ 1 cm macroscopic residual disease (PFS = 13.0 months; OS = 28.7 months) and those with 1.1 to 5 cm macroscopic residual disease (PFS = 13.0 months; OS = 31 months). The only difference in survival when macroscopic residual disease was encountered was for the group of patients who had more than 5 cm macroscopic residual disease; their PFS was 8.9 months and their OS, 22.5 months.

Once again, the major benefit of cytoreduction surgery accrued to the few patients (8%) with no macroscopic residual disease. Patients with metastases to the supraclavicular, axillary, and mediastinal lymph nodes and those with subcutaneous metastases had a better survival than those with malignant pleural effusions, multiple hepatic metastases, or metastases to multiple sites. Approximately 48% of the patients in this series had stage IV disease by virtue of a malignant pleural effusion. The operative results of this report were consistent with the recent report in which ultraradical surgical cytoreduction for stage IV patients resulted in only 6% who were surgically cytoreduced to no macroscopic residual disease.[16]

Best Cytoreduction Results With Initial Surgery


Ideally, surgical cytoreduction to no macroscopic residual disease should approach 100% in patients undergoing initial surgery for advanced ovarian cancer. Only two groups of investigators have reported a greater than 80% initial surgical cytoreduction rate to no macroscopic residual disease when treating patients with advanced ovarian cancer (Table 1).[5,9,10]

Table 1

Complete Surgical Cytoreduction in Advanced Ovarian Cancer

Parameter

Eisenkop
et al,[5] 1998

Eisenkop
et al,[9] 2003

Scholz
et al,[10] 2007

Disease stage

IIIC, IV

IIIC

IIIC, IV

Number of patients

160

213

55

Mean operative
time

254 min
(75–435 min)

180 min
(70–380 min)

372 min
(160–590 min)

Mean estimated
blood loss

1,190 mL
(100–6,000 mL)

980 mL
(30–7,000 mL)

-

Mean number of
transfusions

4 (0–22)

4 (0–24)

9 (2–22)

Median hospital stay

12 d (2–61 d)

12 d (3–64 d)

35 d (13–73 d)

Deaths ≤ 30 d

3

4

0

No visible
residual tumor

85.3%

87.7%

83%

Median survival

54 mo

75.8 mo

47 mo

 

Eisenkop and colleagues’ most recent report on their success in applying ultraradical cytoreduction to remove all gross disease was approximately 85% no macroscopic residual disease in stage IIIC patients, with ≤ 1 cm residual disease achieved in 12%, and > 1 cm residual disease in the very few remaining patients.[9] These investigators believed that patients cytoreduced to no macroscopic residual disease did well regardless of which agents were combined with platinum as adjuvant therapy. Their median overall survival for stage IIIC disease was 75.8 months.[9] Survival was statistically influenced only by the extent of peritoneal metastatic implants that had to be removed. Mean operative time was 180 minutes (range = 90–380 minutes), estimated blood loss was 980 mL (30–7,000 mL), mean number of transfusions was 4 units (0–24 units), and median hospital stay 12 days (2–61 days). The authors reported four deaths within 30 days of surgery.

Scholz et al recently reported their success in treating 55 patients with stage IIIC and IV disease, in whom 83% were surgical cytoreduced to no residual tumor (Table 1).[10] Mean operative time was 372 minutes (160–590 minutes). Patients participating in this series received an average of 9 units of blood (2–22 units), 8 units of fresh frozen plasma intraoperatively (0–24 units), and 2 units of blood postoperatively (0–9 units). Five patients required reoperation (two for leakage of anastamosis, one for bleeding, one for bowel leakage, and one for a stomach lesion). Mean hospital stay was 35 days (13–73 days). No deaths occurred within the first 30 days postoperatively. The authors reported a 28-month PFS, but their patients’ overall survival was only 48 months.


Interval Cytoreduction Surgery


Interval cytoreductive surgery was popularized in Europe in nonrandomized trials, which suggested that women who underwent initial surgery but were suboptimally cytoreduced should receive three cycles of chemotherapy, and if they responded to the chemotherapy, they should then be optimally surgically cytoreduced.[20-23] Patients who responded to chemotherapy and were then optimally cytoreduced to 1 cm or less residual disease had a prolonged survival compared to those who either could not be optimally cytoreduced at the interval cytoreductive surgery or had not undergone interval cytoreductive surgery. Patients who were reoperated on and had less than 1 cm disease on entry into the abdominal cavity did not appear to benefit from the second operation. However, the overall survival with this approach was not as good as the survival for patients who were optimally cytoreduced to ≤ 1 cm macroscopic disease at the initial surgery.[21]

Figure 3: Residual Disease and Survival in Patients With Ovarian Cancer-Influence of residual disease after cytoreductive surgery for recurrence on overall survival. CI = confidence interval; HR = hazard ratio; OS = overall survival; RD = residual disease after surgery for recurrence. Reprinted, with permission, from Harter P et al.[28]

EORTC Trial

A prospective randomized trial published in 1995 by the European Organization for the Research and Treatment of Cancer (EORTC) demonstrated an increase in both progression-free survival and overall survival for patients who were initially suboptimally cytoreduced to > 1 cm macroscopic residual disease but were then given three cycles of platinum-based chemotherapy and, if they responded, underwent interval cytoreduction to ≤ 1 cm residual disease.[24] Those who underwent interval cytoreduction received three additional cycles of chemotherapy. Patients in the control arm had undergone suboptimal cytoreduction (> 1 cm residual disease) followed by six cycles of the same chemotherapy (Table 2).

 

Table 2

Interval Cytoreductive Surgery in Advanced Ovarian Cancer

Features

EORTC Study[24]

GOG Study[25]

Eligible patients

319

424

Serous cancer

59%

76%

Stage IV

22%

6%

Chemotherapy

Cisplatin/cyclophosphamide

Cisplatin/paclitaxel

Median PFS
Secondary surgery
Chemotherapy only


18 mo
13 mo


12.5 mo
12.7 mo

Median overall survival
Secondary surgery
Chemotherapy only


26 mo
20 mo


36.2 mo
35.7 mo

EORTC = European Organisation for Research and Treatment of Cancer; GOG = Gynecologic Oncology Group; PFS = progression-free survival.


Once again, the patients who benefitted from interval surgical cytoreduction were those who initially responded to the chemotherapy but still had > 1 cm residual disease prior to the interval cytoreduction. No benefit was demonstrated if the patients failed to initially respond to the chemotherapy or if the disease found at the time of reexploration was > 1 cm maximum tumor diameter and could not be cytoreduced to < 1 cm residual disease.

GOG Trial


A subsequent GOG prospective randomized trial revealed no survival advantage when American gynecologic oncologists performed the initial suboptimal cytoreduction surgery and then, following three cycles of carboplatin and paclitaxel, attempted a second surgical cytoreduction followed by three additional cycles of chemotherapy.[25] The median overall survival for both the control arm (patients who underwent surgery followed by six cycles of chemotherapy) and the interval surgical cytoreduction arm was 36 months (Table 2). The GOG findings were consistent with GOG 111, which demonstrated that suboptimally cytoreduced patients have a median OS of 37 months.[26]

In contrast, the EORTC interval cytoreduction trial demonstrated a PFS survival of 18 months and an OS of 26 months.[24] The reason for the discrepancy in survival between the GOG and EORTC trials was that the GOG trial used carboplatin and paclitaxel as its standard therapy whereas the EORTC trial used carboplatin and cyclophosphamide-a regimen that is now recognized as inferior.[26]

Cytoreduction for Recurrent Disease


The role of cytoreductive surgery in the treatment of recurrent ovarian cancer is still being developed. Consensus in the literature supports aggressive cytoreduction for patients who have a prolonged disease-free survival following their initial diagnosis (12–18 months), solitary or a limited number of sites of recurrence identified by diagnostic imaging (2–5), and a good performance status (GOG 0–2).[27-36] When operating for recurrent ovarian cancer, complete tumor resection almost invariably is associated with a prolonged survival compared to leaving any residual disease (Table 3).


Table 3

Surgical Cytoreduction for Recurrent Ovarian Cancer: Median Survivals Based on Complete vs Incomplete Tumor Resection

   

Median Survival

Number of Patients

Complete Tumor Resection

Complete
Tumor
Resection

Incomplete Tumor
Resection

Gronlund et al,[33] 2004

38

16 (42%)

51.8 mo

19.9 mo

Eisenkop et al,[31] 2000

106

87 (82.1%)

44.4 mo

19.3 mo

Zang et al,[32] 2004

117

11 (9.4%)

Not reached

26.0 mo (≤ 1 cm)
14.5 mo (>10)

Benedetti Panici et al,[36] 2007

47

37 (78.7)

61

19

Salani et al,[27] 2007

55

41 (74.5)

50

7.2

Harter et al,[28] 2006

267

124 (46.4)

45.2

19.7


One recent retrospective study of 57 patients with recurrent ovarian cancer reported that the three most important factors for overall survival by multivariate analysis were (1) a diagnosis-to-recurrence interval of ≤ 18 months (OS = 49 vs 3 months; P = .0013), (2) no microscopic tumor left after secondary cytoreduction (OS = 50 vs 7.2 months; P = .0001), and (3) one or two recurrence sites on diagnostic imaging studies (OS = 50 vs 12 months; P = .026).[27] The factors that make a patient most likely to benefit from secondary surgical cytoreduction are also the factors that make the patient most likely to benefit from secondary chemotherapy.

AGO Study



A large, retrospective review of cytoreductive surgery in 267 women with recurrent ovarian cancer treated in 25 European centers from 2000 to 2003 was recently reported by the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO).[28] This study included patients with stage I (46, 18.0%), stage II (33, 12.9%), stage III (165; 64.7%), and stage IV (11, 4.3%) disease. Patients had had treatment-free intervals of < 6 months (36, 13.5%), 6 to 12 months (63, 23.6%), and > 12 months (168, 62.9%). Ages ranged from 24 to 84 years (median = 60 years), and 91.9% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Patients with no macroscopic disease following secondary surgical cytoreduction had a median survival of 45.2 months, while those with macroscopic disease had a median survival of 19.7 months (hazard ratio [HR] = 3.71; 95% confidence interval [CI] = 2.27–6.05; P < .0001; see Figure 3). Interestingly, the size of the macroscopic residual tumor had no impact on survival. The median survival of patients with a residual tumor of 0.1 to 1.0 cm was 19.6 months, and for those with macroscopic residual disease > 1 cm, it was 19.7 months (HR = 0.84, 95% CI = 0.51–1.40, P = .502). In a multivariate analysis, the three factors that affected survival after secondary cytoreduction were complete resection (residual tumor 0 vs > 0 mm: HR = 2.94; 95% CI = 1.68–5.17; P < .001), ascites (< 500 vs ≤ 500 mL: HR = 2.30, 95% CI = 1.31–4.04; P = .004), and platinum-containing chemotherapy (yes vs no: HR = 1.84; 95% CI = 1.13–3.01; P = .015).


Table 4

Univariate Analysis of Significant Factors for Achieving Complete Resection in Ovarian Cancer Patients

Status

N

P Value

OR

95% CI

ECOG performance status

0

> 0 a

118
149

< .0001

1
2.74

1.66–4.51

FIGO stage

I/II
III/IV a

79
188

.01

1

1.18–3.46

Residual disease after primary surgery

0 mm
> 0 mm

124
143

.0005

1
2.39

1.46–3.91

Preoperative serum CA-125 b

0-70 U/mL
71–350 U/mL
> 350 U/mL

100
102
47

.001

1
1.23
3.76


0.70–2.15
1.77–7.99

Ascites in preoperative diagnostic imaging

< 500 mL
≥ 500 mL

231
36

< .001

1
6.11

2.45–15.23

Localization of recurrence in preoperative diagnostic imaging

Pelvis
Others a

71
196

.017

1
1.96


1.12–3.41

Peritoneal carcinomatosis in preoperative diagnostic imaging b

No a
Yes

209
58

.0001

1
3.34


1.77–6.31

Intraoperative peritoneal carcinomatosis

No
Yes

125
125

< .0001

1
6.87

4.00–11.76

a Missing data were added to this group.

b Cancer antigen (CA)-125 and peritoneal carcinomatosis in preoperative diagnostics not calculated in multivariate analysis because of correlation with ascites.

CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; FIGO = International Federation of Gynecology and Obstetrics; HR = hazard ratio; OR = odds ratio.

Source: Harter P et al.[28]


Thus, as with surgery for previously untreated ovarian cancer, leaving no macroscopic residual disease was the most important factor in prolonging survival for women with recurrent disease. A univariate analysis of significant factors for achieving complete resection are presented in Table 4. A multivariate analysis for achieving complete resection of recurrent disease is presented in Table 5.


Table 5

Multivariate Analysis of Factors for Achieving Complete Resection

Parameter

Estimatea

OR

95% CI

P Value

ECOG performance status

0.98 vs 0.27

2.65

1.56–4.52

< .001

Residual disease after primary surgery b

0.90 vs 0.27

2.46

1.45–4.20

< .001

Ascites

1.63 vs 0.48

5.08

1.97–13.16

< .001

Localization of recurrence in
preoperative diagnostic imaging

0.44 vs 0.31

1.55

0.85–2.82

.155

a See Table 4 for comparison groups.

b Alternatively, FIGO stage if residual disease after primary surgery is unknown (HR = 1.87;
95% CI = 1.04–3.37; P = .036).

CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; FIGO = International Federation of Gynecology and Obstetrics; HR = hazard ratio; OR = odds ratio.

Source: Harter P et al.[28]


The AGO investigators created a predictive model for complete surgical cytoreduction in patients with recurrent disease, which will be investigated prospectively in the AGO-DESKTOP OVAR II clinical trial. In brief, patients with recurrent ovarian cancer who have a disease-free interval > 6 months, an ECOG performance status of 0, no residual disease left after primary surgery, and ascites estimated by diagnostic imaging to be < 500 mL will undergo a laparotomy for surgical cytoreduction, followed by platinum-based chemotherapy. Patients who do not meet all these criteria but for whom surgery is still desired, will undergo an open laparoscopy first to attempt to determine whether a surgical resection is possible. If carcinomatosis is present, they will receive platinum-based chemotherapy. If cytoreductive surgery is possible, they will undergo a laparotomy.

Other Trials in Recurrent Disease



Several institutions recently reported their results in cases where a preoperative assessment identified recurrent ovarian cancer seemingly limited to lymph nodes.[29,30] Benedetti Panici et al reported their approach in 48 such women, 40 of whom initially underwent open laparoscopy to determine surgical cytoreducibility.[29] A laparotomy was performed in 31 patients, 29 of whom were able to undergo a systematic lymphadenectomy. All of the latter patients were cytoreduced to no macroscopic disease. Only 6 of the 40 patients had previously undergone a systematic lymphadenectomy. At the surgery for recurrent disease, the cancer was limited to retroperitoneal lymph nodes in 17 patients, while 12 also had intraperitoneal disease. All 29 patients were cytoreduced to no macroscopic disease.

At a median follow-up of 26 months, for the 29 patients undergoing systematic lymphadenectomy, 18 women were alive and free of disease, 9 were alive with disease, and 2 had died from their disease. Among the patients who were not cytoreducible, 5 were alive with disease and 6 were dead of disease at a median follow-up of 18 months. An important observation in this study was the finding of positive nonbulky lymph nodes in 15 patients (52%) undergoing systematic lymphadenectomy, 8 of whom had lymph nodes that were only microscopically positive. The latter finding supports the role for a systematic lymphadenectomy at the time of surgery for recurrence rather than a resection limited to removal of a bulky lymph node.

Prospective randomized trials are necessary to determine the value of cytoreductive surgery in the treatment of recurrent ovarian cancer. To this end, the EORTC is currently accruing patients to protocol 55963. The goal of this protocol is to compare progression-free and overall survival in patients with platinum-sensitive recurrent ovarian cancer, who will be randomized to chemotherapy with or without secondary surgical cytoreduction. Toxicities of treatment, complications related to surgery, and quality of life will be also evaluated.

Summary



Aggressive cytoreductive surgery is a vital part of the initial treatment of patients with advanced-stage ovarian cancer and selected patients with recurrent ovarian cancer. The recent GOG reports of PFS and OS for stage III and IV patients reveal dramatic survival differences for those who are optimally cytoreduced to no macroscopic disease compared to those with any residual disease.[18,19] Patients with stage III disease who were cytoreduced to macroscopic disease ≤ 1 cm had a modest improvement in PFS and OS compared to those with > 1 cm residual disease. However, there was no survival difference for stage IV patients who were cytoreduced to ≤ 1 cm compared to those with 1.1 to 5.0 cm of macroscopic disease. The AGO data support cytoreduction to macroscopic residual disease as the most important prognostic factor for survival in patients with recurrent ovarian cancers.[28]

These recent large studies support the definition of optimum cytoreductive surgery for previously untreated advanced ovarian cancer or selected patients with recurrent disease to be a procedure that leaves no macroscopic disease at its completion.[18,19,28] Alternative treatment approaches must be developed for those patients who initially present with advanced ovarian cancer and cannot be surgically cytoreduced to no residual disease, as these patients will almost always develop recurrent disease that will become resistant to chemotherapy.

 

This article is reviewed here:

Surgical Cytoreduction for Ovarian Cancer: Issues Awaiting Formal Clarification

Primary Cytoreduction in Advanced Ovarian Cancer: ‘Biologic and Surgical Aggressiveness'

References:

References


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