Interval Cytoreduction

Since complete tumor resection is achieved in only 40% to 60% of advanced ovarian cancers and in an effort to increase the proportion of patients with advanced ovarian cancer that are ultimately left with an optimal volume of residual disease, the concept of a second attempt at debulking, or interval cytoreductive, surgery following an initial suboptimal effort and several cycles of systemic chemotherapy has been proposed by some clinicians. The European Organization for Research and Treatment of Cancer evaluated interval debulking surgery in a randomized trial. They evaluated 278 patients with residual disease greater than 1 cm after primary surgery. After three cycles of cyclophosphamide and cisplatin, patients were randomized to debulking surgery and no surgery, followed by additional chemotherapy. After adjustment for other prognostic factors, surgery reduced the risk of death by 33%.35

Table 7-1. Comparison of GOG 152 and EORTC Studies of Secondary/Interval Debulking Surgery after Three Doses of Chemotherapy

GOG 152 EORTC Study

No. of eligible patients

Maximal surgical effort at initial surgery

Chemotherapy regimen

Serous cancers (%)

Stage IV disease (%)

Disease >5 cm after initial surgery (%)

Optimal at start of secondary surgery (%)

Optimal at end of secondary surgery (%)

Median progression-free survival for secondary surgery group from study entry (months)

Median survival for secondary surgery group from study entry (months)

424 Yes

Cisplatin and paclitaxel

36.2

319 No

Cisplatin and cyclophosphamide

*Surgical data not available on three in EORTC study.

EORTC, European Organization for Research and Treatment of Cancer.

From Monk BJ, Disaia PJ: What is the role of conservative primary surgical management of epithelial ovarian cancer: the United States experience and debate. Int J Gynecol Cancer 15(Suppl 3):199-205, 2005.

Another study conducted by GOG randomized 550 patients with suboptimal primary cytoreduction, and three cycles of cisplatin and paclitaxel were randomized to interval debulking surgery and chemotherapy versus chemotherapy alone. Both groups had median survivals of 33 months, and the authors concluded that the addition of secondary cytoreductive surgery did not improve progression-free survival or overall survival.36 The fact that the GOG trial involved initial "maximal surgical effort" and the use of a more active chemotherapy regimen may help explain this divergent conclusion37 (Table 7-1).

Similarly, malnourished women, in whom the risk of postoperative morbidity and mortality is high, may be better served by upfront or neoadjuvant chemotherapy and later maximal surgical cytoreduction in chemotherapy responders.16 The potential advantages of this approach include an increased rate of optimal debulking, less extensive surgery, reduced blood loss, lower morbidity, shortened hospital stay, and the avoidance of aggressive surgery in women with chemoresistant disease who have poor outcome regardless of treatment. Bristow and Chi38 recently performed a meta-analysis of the published literature pertaining to neoadjuvant chemotherapy and identified 21 studies totaling 835 patients that met their inclusion criteria. They were again able to demonstrate that for each 10% increase in the percentage of patients undergoing maximal interval cytoreductive surgery, which was variably defined, there was an associated 1.9-month increase in median survival time. It is interesting that the investigators also found that within the range of three to six median cycles of chemotherapy before interval surgery, each additional cycle of chemotherapy was associated with an incremental decrease in median survival time of 4.1 months (Fig. 7-19).

However, without prospective, randomized trials, neoadjuvant chemotherapy followed by later cytoreduction cannot be considered to provide a superior outcome over that achieved by aggressive initial surgical debulking followed by combination chemotherapy with paclitaxel.

Figure 7-19. Simple linear regression analysis: median cohort survival time plotted against percent maximum interval cytoreductive surgery. Circle size is proportional to the number of subjects in each study and does not reflect the degree of statistical variation between studies. (From Bristow RE, Chi DS: Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis. Gynecol Oncol 103:10701076, 2006, Figure 1.)

Percent maximal interval cytoreduction

• Median survival time -Predicted median survival time

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