ABSTRACT: 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. 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.
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. As a result, substantial delays prior to diagnosis are very common.
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. 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. 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.
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. Ineffective targeting of this cell population is responsible for the therapeutic failures and tumor recurrences currently observed.
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). 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.
Primary Debulking Surgery
Joe V. Meigs, a gynecologic surgeon at Massachusetts General Hospital, initially described ovarian tumor debulking in 1934. The concept did not gain traction until the mid 1970s, when C. Thomas Griffiths published his seminal paper on the subject. Case series and other retrospective data accrued rapidly thereafter to further establish primary cytoreductive surgery as the de facto standard of care.[12,13]
The success of the operation depends on numerous factors, including patient selection, tumor location, and surgeon expertise. To achieve a survival benefit, an optimal result was initially defined as no residual tumors that individually measure more than 2 cm in size. For purposes of uniformity, the Gynecologic Oncology Group (GOG) re-defined "optimal" debulking as residual implants ≤ 1 cm. For the past few decades, this criterion has served as the benchmark of success. Patients undergoing optimal primary cytoreductive surgery (≤ 1 cm residual disease), followed by intraperitoneal platinum-based chemotherapy, have a median overall survival of 66 months —the longest survival duration ever reported in a phase III study of ovarian cancer. The level of success achieved in this GOG trial (protocol #172) is currently the gold standard for comparisons of any other treatment sequence.
Despite the accumulated evidence supporting the importance of primary debulking, it remains controversial whether the better outcome is due to the surgeon's technical proficiency or some ill-defined, intrinsic feature of the cancer that makes the tumor implants easier to remove.[16,17] In general, extensive upper abdominal disease is strongly indicative of an aggressive tumor biology. Although this is a common location of unresectable disease, optimal debulking may still be achieved in many of these patients by performing "ultra-radical" procedures, such as splenectomy (Figure 2) or diaphragmatic resection.[19,20] However, it is still unclear what impact ultra-radical techniques have on quality of life and morbidity. In addition, the cost-effectiveness of this intervention has not been investigated. Regardless, survival rates have been shown to improve when the surgical paradigm is revised to a more aggressive philosophy incorporating these and other radical techniques (Figure 3).[22,23] Patients referred to specialized centers where such radical procedures are commonly performed may anticipate higher rates of optimal debulking and improved survival without additional major morbidity.
One valid criticism of cytoreductive surgery is that the assessment of gross residual disease by the surgeon at the completion of the operation he or she performed is biased and subjective. Due to tissue induration, inadequate exploration, or other factors, inaccuracies in the assessment of residual tumor size are commonplace. Perhaps because of the inability to reliably quantify the remaining disease, a recent subanalysis of accumulated data from several prospective GOG trials demonstrated that patients with 0.1 to 1.0 cm residual disease had marginally improved overall survival compared with patients who had > 1 cm residual disease if they had stage III ovarian cancer and no improvement if they had stage IV disease. In fact, a dramatic survival benefit was only achieved with complete resection to microscopic residual disease (Table 3).[26,27] Based on these findings and other similar reports, there is a growing consensus that optimal cytoreduction should be defined using a more stringent criterion. Raising the bar for debulking success accordingly decreases the proportion of patients with stage III-IV ovarian cancer in whom complete resection can be accomplished (Table 4). Although complete resection is often not feasible, cytoreduction to as little residual tumor as possible should always be the focus of aggressive surgical efforts, since each incremental decrease in residual disease below 1 cm may be associated with an incremental improvement in overall survival.
Even when successful, the obvious disadvantage of radical cytoreductive surgery is that it may result in a prolonged postoperative recovery that is fraught with complications. The initiation of chemotherapy may be delayed—or worse, postponed indefinitely.[29,30] When an optimal result is not possible, the surgical approach should be limited in scope to avoid unnecessary postoperative morbidity.