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Cytoreductive Surgery for Advanced Ovarian Cancer: Quo Vadis?

Cytoreductive Surgery for Advanced Ovarian Cancer: Quo Vadis?

Two-thirds of women who are newly diagnosed with invasive epithelial ovarian cancer present with stage III or IV disease. The preferred initial treatment has traditionally consisted of primary surgical debulking followed by platinum-based chemotherapy. However, recent data suggesting comparable efficacy for neoadjuvant chemotherapy and interval debulking have challenged this conventional dogma. Most patients with advanced ovarian cancer will achieve remission regardless of initial treatment, but 80% to 90% of patients will ultimately relapse. The timing and clinical benefit of a second debulking operation for recurrent disease is even more contentious. This article focuses on the recent debate regarding when—or whether—patients with ovarian cancer should undergo aggressive surgical resection.

The Latin phrase quo vadis, meaning "whither goest thou?" or "where are you going?," aptly reflects the current uncertainty in the gynecologic oncology community about how best to care for women with advanced ovarian cancer. The controversy is especially relevant since ovarian cancer mortality exceeds the combined mortality of all other gynecologic malignancies in the United States. Currently, it is the ninth leading cause of cancer in women but the fifth leading cause of all cancer-related deaths. In 2010, there were an estimated 21,880 new cases and 13,850 deaths.[1] One in 78 women (1.3%) in the US will be diagnosed with this highly lethal disease during their lifetime. Worldwide each year, approximately 225,000 women are diagnosed with ovarian cancer and more than 140,000 die.[2]

TABLE 1

Symptoms of Ovarian Cancer

Ovarian cancer is often portrayed as the disease that "whispers" because it does not present with dramatic bleeding, excruciating pain, or an obvious lump. Instead, the typical symptoms (Table 1) tend to be indolent. Patients and their healthcare providers often attribute such nonspecific changes to menopause, aging, dietary indiscretions, stress, depression, or functional bowel problems. Frequently, women are medically managed for indigestion or other presumed ailments without having a pelvic examination.[3] As a result, substantial delays prior to diagnosis are very common.

FIGURE 1

Omental Caking

Unfortunately, there is no effective screening test. Routine checks of serum CA125 markers or transvaginal sonograms do not result in early detection or reduced mortality in either the general or high-risk populations.[4] Two-thirds of women still present, as they always have, with advanced disease typically characterized by ascites, carcinomatosis, and omental caking (Figure 1).

In the United States, less than half of such patients will be cared for by a gynecologic oncologist.[5] Instead, the majority are managed by physicians not necessarily familiar with the expected, often dramatic, response of ovarian cancer to aggressive treatment even in the setting of widespread disease. For example, a consulting general surgeon may perform a diverting colostomy for obstructive symptoms and afterwards the patient might be treated with a limited duration of single-agent palliative chemotherapy—or worse, directed to hospice. When a gynecologic oncologist is involved, survival is demonstrably improved. Patients are more likely to undergo both a comprehensive de-bulking procedure and postoperative combination chemotherapy.[6]

Removal of bulky tumors as part of cancer treatment is an easy concept for patients and their families to understand. When ovarian cancer is initially suspected, they are usually anticipating an operation and are often greatly relieved when their gynecologic oncologist declares that "more than 90% of the tumor was removed" at the time of surgery. While sounding impressive, the actual benefits usually do not match up with patient expectations. In theory, fewer cancer cells at the start of chemotherapy should lead to a higher likelihood of cure. However, by the time advanced ovarian cancers are diagnosed, approximately 1010 to 1011 malignant cells are present. Optimal debulking that removes an estimated 90% of the aggregate tumor represents 1 log cell kill. In contrast, one course of chemotherapy may produce up to a 2 to 3 log cell kill, representing a 99.0% to 99.9% reduction in tumor cells. Still, despite the often pronounced chemosensitivity, some tumor cells almost invariably persist.

Recent evidence suggests that metastatic ovarian cancers, like other solid tumors, contain a small subpopulation of highly specialized stem cells that escape cytoreductive procedures and have the capacity to also evade current chemotherapeutic strategies. This "cancer stem cell hypothesis" postulates that tumors contain phenotypically distinct populations of stem-like cells with self-renewal capacity and the potential to reconstitute the entire cellular heterogeneity of a tumor. Ovarian cancer stem cells are thought to be responsible for tumor initiation, maintenance, and growth.[7] Ineffective targeting of this cell population is responsible for the therapeutic failures and tumor recurrences currently observed.[8]

TABLE 2

Theoretical Arguments for Debulking Surgery

Owing to the comparable level of chemosensitivity and the likely existence of ovarian cancer stem cells, the actual clinical benefits of debulking have been harder to prove. Several supportive, but mostly theoretical, additional arguments have been proposed to justify the biological plausibility of debulking (Table 2).[9] Within the broader field of oncology, the aggressive surgical approach to widely metastatic disease is rather specific to ovarian cancer. Patients definitely do appear to benefit from one maximal debulking attempt, but the timing of the procedure and what defines a success have become increasingly controversial.

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