Clinical and Theoretical Background of Surgical Cytoreduction

The concept of cytoreductive surgery for ovarian cancer has evolved since Meigs1 first proposed in 1934 that as much tumor as possible should be removed to enhance the effects of postoperative radiation. Forty years after Meigs' initial proposition, Griffiths2 published the landmark study that first clearly delineated the inverse relationship between postoperative residual tumor size and ovarian cancer patient survival. More contemporary studies published by Hoskins and the Gynecologic Oncology Group (GOG) demonstrated two important principles with respect to residual disease after primary surgery for advanced-stage ovarian cancer.3 First, there is a threshold effect, or a maximal diameter of residual disease above which even extensive efforts at cytoreduction will not impact survival. Second, below this threshold there is also a continuum effect—such that the smaller the residuum, the better the survival outcome—with patients who are left with no gross residual disease having the most favorable prognosis.4

Box 10-1. Benefits of Tumor Cytoreduction

• Log-kill of tumors with chemotherapy is greater in small volume tumors

• Elimination of chemotherapy-resistant cells

• Removal of large tumor masses with poor blood flow

• Improved intestinal tract function

• Higher response rate to chemotherapy

• Prolonged disease-free survival

• Improved overall survival

Tumor cytoreduction of advanced epithelial ovarian carcinoma has both theoretical and clinical benefits (Box 10-1). A key concept in understanding the potential benefits of tumor cytoreduction is the Gompertzian cell growth curve. Tumor cell numbers tend to increase exponentially over time, and the rate of growth is faster in the earlier part of the curve when tumors are relatively small.5 Chemotherapy works by killing rapidly growing and dividing cells. Log-kill of tumors with chemotherapy is therefore thought to be greater in tumors of smaller volume, which are made up of rapidly growing and dividing cells. Surgical cytoreduction of tumor volume from larger slow-growing tumors to smaller rapid-growing ones thereby offers patients a greater chance of response to chemotherapy.

The elimination of potentially chemotherapy-resistant cells is another benefit of surgical cytoreduction. The probability of spontaneous mutations and drug-resistant phenotypes increases as tumor size and cell numbers increase, according to the mathematical model of Goldie and Coldman.6 Therefore, by decreasing tumor size and cell numbers, cytoreductive surgery has the ability to remove existing resistant tumor cells and to decrease the spontaneous development of additional resistant cells. In addition, surgery has the potential to remove large tumor masses with poor blood flow, allowing better distribution of intratumoral chemotherapy. These possible benefits are supported by the numerous reports on the clinical benefits of cytoreduc-tion and theoretically hold true for both primary and secondary clinical scenarios.

Although the basic treatment paradigm of a maximum cytoreductive surgical effort before initiating platinum- and taxane-based chemotherapy is well established, the majority of patients with advanced-stage epithelial ovarian cancer ultimately experience tumor recurrence.7,8 For this reason, the therapeutic value of repeating the initial surgical treatment plan (cytoreduction) has been widely debated. Since the publication by Berek and associates9 in 1983, which first introduced the term "secondary cytoreduction," the clinical scenarios, indications for, and anticipated outcomes of repeat tumor-reductive operations for recurrent ovarian cancer have been better defined.10

By most accounts, cytoreductive surgery for recurrent ovarian cancer is defined as an operative procedure performed at some time remote (disease-free interval of more than 6 to 12 months) from the completion of primary therapy with the intended purpose of tumor reduction. Even within this narrowly defined clinical scenario, the potential usefulness of surgical cytoreduction remains controversial. Operative therapy plays only a minor role in the treatment of recurrent ovarian cancer in routine clinical practice. This might be based on the one hand on the technical complexity of secondary surgery in patients with repetitive abdominal procedures, and on the other hand on the lack of conclusive evidence and existence of several unanswered questions regarding cytoreductive surgery in this setting. The survival impact of successful tumor reduction has been difficult to quantify in relation to other relevant clinical and biologic prognostic characteristics.

Box 10-2. 1998 International Ovarian Cancer Consensus Conference Criteria for Optimal Candidates for Secondary Cytoreductive Surgery

• Disease-free interval >12 months

• Response to first-line therapy

• Potential for complete resection based on preoperative evaluation

• Good performance status

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