See related article, page 763
In this month’s American Journal of Obstetrics & Gynecology , Rowland et al found that, compared with primary debulking, neoadjuvant chemotherapy produced a cost savings in women with advanced-stage epithelial cancer at ≥65 years. This result, based on a model developed from randomized trial results, raises the question: What are the most important factors in prescribing the ideal treatment?
To consider this, let us start with a little background. It is important to know that the combination of surgery and chemotherapy is the cornerstone of management for newly diagnosed ovarian cancer; however, the order of these treatments has been less clear. In general, the typical treatment for advanced ovarian cancer consists of primary debulking surgery with the intention to achieve optimal (no residual disease >1 cm) or, ideally, complete (removal of all visible disease) resection. This is then followed by 6 cycles of chemotherapy with a platinum-taxane–based regimen. Neoadjuvant chemotherapy emerged to address cases in which the disease burden was too extensive, the location of disease prohibited optimal resection, or the patients were not medically suitable to undergo an extensive surgical primary debulking procedure. Although referred to as neoadjuvant chemotherapy, this strategy also includes surgery. However, the patients undergo a platinum-taxane–based chemotherapy regimen, typically for 3 cycles, followed by an interval debulking procedure with the intent of complete resection, followed by additional chemotherapy.
Although the use of neoadjuvant chemotherapy is often based on the aforementioned factors, there are, of course, institutional and physician biases. Predicting which patients with ovarian cancer would benefit from the neoadjuvant chemotherapy approach has been less successful. Studies that have used CA-125 levels and radiographic imaging to identify appropriate candidates for neoadjuvant treatment have not been reproducible. More recently, laparoscopy has been demonstrated to be a useful tool to evaluate whether a patient can be debulked optimally without the morbidity of laparotomy.
Approach
Originally, the neoadjuvant chemotherapy approach was limited to women who were unlikely to be resected optimally; however, more recently the use of neoadjuvant chemotherapy has been studied in the setting of primary therapy. In 2010, the European Organisation for Research and Treatment of Cancer (EORTC) conducted a randomized trial that compared neoadjuvant chemotherapy to primary debulking surgery for women with advanced stage IIIc and IV ovarian cancer and demonstrated that the overall survival between the 2 approaches were equivalent. After release of these data, the debate regarding the selection of approach has escalated, particularly in the United States. Although the gold standard for studies is a randomized clinical trial, there are some specific concerns with the outcomes of this EORTC study. One major issue was that only 41.6% of the patients underwent optimal debulking at the time of primary surgery compared with 80.6% in the neoadjuvant arm. This low rate of optimal/complete debulking rates in the primary surgery arm likely contributed to a low overall median survival of approximately 30 months.
One of the pitfalls we face in oncologic studies is the comparison of outcomes from study to study. This is a dangerous practice because it assumes that the studies have the same eligibility criteria and that similar factors contribute to the outcomes of both studies. For example, antagonists of the EORTC study noted the aforementioned argue that the 30-month median survival is inferior to the 66-month median survival that was seen in the Gynecologic Oncology Group (GOG) study (protocol 172) that used intraperitoneal chemotherapy. However, the EORTC trial included women with bulky stage IIIC and IV disease, both with suboptimal and optimal resection; the GOG study evaluated women with optimally resected stage III disease. Further, the median age in the EORTC study of 62-63 years was higher than that in the GOG intraperitoneal study. Therefore, directly comparing studies is generally invalid.
Age
The median age of women with ovarian cancer is approximately 65 years. Higher age is associated with poorer outcomes in ovarian cancer survival. This may be because elderly patients are more likely to experience a higher number of comorbidities, which makes a longer surgical effort more challenging. Therefore, determination of the appropriate treatment for women based on age alone, independent of performance status, is questionable. It would be short-sighted to state, based on results of the cost analysis of Rowland et al, that all women >65 years old with advanced ovarian cancer should be treated with neoadjuvant chemotherapy. Women with advanced ovarian cancer should be assessed by a gynecologic oncologist before the selection of management approach, especially given that nearly two-thirds of women with ovarian cancer do not receive care adherent with the National Comprehensive Cancer Network guidelines. Because of the possible initiation of chemotherapy by a medical oncologist (without surgical training) or curbed surgical effort, elderly patients may be at higher risk of substandard care. The EORTC trial, along with other prospective and retrospective studies, noted that women who were able to undergo complete cytoreduction at the time of surgery (primary or interval debulking) had the best outcomes. Therefore, the approach that allows for this outcome in women who are ≥65 years old should be emphasized.
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