Cytoreductive Surgery Is the Best Way to Affect Survival Outcomes
Historically, cytoreductive or debulking surgery has been the cornerstone of treatment for advanced ovarian cancer. Initially proposed by Meigs in 1934, primary debulking surgery (PDS) has repeatedly been associated with improved overall survival (OS).[1-4] However, this approach is the subject of much debate. Some providers question the value of extensive debulking surgery as the first step in the treatment of advanced ovarian cancer, arguing instead for the use of neoadjuvant chemotherapy (NACT). The only two published prospective randomized studies comparing PDS and NACT are the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial and the CHORUS trial. These have served as the foundation for those advocating the NACT approach.
The EORTC 55971 study was conducted by the EORTC’s Gynecological Cancer Group and the National Cancer Institute of Canada Clinical Trials Group. From 1998 to 2006, EORTC 55971 enrolled more than 600 women with bulky stage III or IV advanced ovarian cancer. The investigators reported no significant difference in progression-free survival (PFS) or OS between the two treatment arms, concluding that NACT with interval debulking surgery (IDS) was not inferior to, and was possibly safer than, PDS.[5,7]
The CHORUS trial, which enrolled and randomized over 550 women with advanced ovarian cancer, supported these results, concluding that NACT/IDS yielded comparable survival and decreased surgical morbidity, compared with PDS.[6,8]
In 2016, the Society of Gynecologic Oncology and the American Society of Clinical Oncology published clinical practice guidelines for the use of NACT in the setting of newly diagnosed advanced ovarian cancer. Included was a recommendation that women with resectable disease who were fit for PDS could be offered either NACT or PDS. This recommendation was based, in large part, on the conclusions of the aforementioned randomized trials.
We argue that PDS is the best treatment option for women with resectable disease who are medically fit for surgery, and that NACT is not equivalent to PDS in this population.
Generalizability of the EORTC and CHORUS Trials
Ovarian cancer surgery is different from other cancer surgeries in that the goal is to resect all macroscopic tumor implants, rather than leave a microscopic margin. In 1975, Griffiths reported an association between survival and maximum diameter of residual disease after PDS. Since then, numerous studies have demonstrated that maximal surgical efficacy, as demonstrated by the amount of residual disease, is the one and only significant modifiable prognostic factor (factors such as age, tumor grade, stage, etc, are not modifiable) for survival, other than the type of postoperative chemotherapy administered.[2,3,11-17] However, resectability was not part of the preoperative inclusion criteria in either the EORTC or the CHORUS trial. Thus, only 41% of patients were left with residual disease of less than 1 cm (ie, were optimally debulked). This means that the majority of patients in whom PDS was attempted had a suboptimal surgical outcome; even the most ardent supporters of PDS would admit that suboptimal surgery does not improve survival. Reported optimal cytoreduction rates in the literature range from 15% to greater than 85%.[4,18] Centers experienced in ovarian tumor cytoreductive surgery usually achieve optimal resection rates of 75% or greater. These findings raise two questions:
1) Were the primary debulking surgeries attempted in EORTC 55971 and the CHORUS trials equivalent to those one would find in high-volume, specialized, more experienced tertiary care centers?
2) Was the patient population skewed towards cases that were more difficult to resect?
Value of maximum surgical effort
In the EORTC trial, residual tumor was most frequently documented on the diaphragm, abdominal peritoneum, and pelvis. Ultimately, the decision to debulk depends on the training and expertise of the surgeon. Surgical paradigms have shifted since these trials began recruiting patients over a decade ago. Many gynecologic oncologists have moved toward more extensive and radical surgeries in an attempt to decrease residual disease at the time of PDS. Debulking surgeries now include more extensive upper abdominal procedures, such as diaphragm stripping and/or resection, splenectomy, distal pancreatectomy, partial liver resection, cholecystectomy, and resection of tumor from the porta hepatis. These extensive procedures require utilization of all the surgical resources at an institution. The patient deserves whatever treatment is necessary to safely achieve maximal cytoreduction. Safe resection of diaphragmatic and peritoneal disease may be beyond the capacity of a general gynecologic or gynecologic oncology surgeon; however, these procedures are well within the capabilities of a hepatobiliary surgeon or general surgical oncologist. Contemporary approaches that enhance the surgical armamentarium in advanced ovarian cancer have resulted in higher rates of complete gross resection and optimal resection (residual disease ≤ 1 cm), and, consequently, longer OS.[13,14,19,20] Multiple US and international studies have demonstrated the feasibility and safety of a more radical surgical approach in specialty centers, with morbidity, mortality, and the timing of chemotherapy not statistically different from what are seen with surgery limited to the pelvis.[21-25]
While randomized controlled trials (RCTs) are the gold standard for determining the best treatment option, they are not without limitations. Most notably, the results cannot be generalized to populations that are not represented in the study. RCTs usually represent a very distinct subset of a population. The EORTC and CHORUS trials are prime examples of this potential for selection bias.
The PFS and OS for the NACT arms of the EORTC and CHORUS trials are consistent with those described in other NACT studies; however, the median survival times of 23 to 30 months in the PDS arms are dismally low.[7,8,26] Other RCTs in this population of primary surgery recipients report median survival times of 45 to 66 months.[9,27,28] Moreover, a retrospective review of an identical sample population of patients treated during the same time period at Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated a median survival of 50 months for all patients treated with PDS, and a more recent publication from MSKCC reported a median survival of 72 months for all patients who had undergone PDS, regardless of residual disease status (including both those who had optimal cytoreduction and those who had suboptimal reduction). The large survival differences between EORTC 55971 and CHORUS and the MSKCC series lead us to infer that there may have been a selection bias in the EORTC and CHORUS trials. There were likely some unique characteristics in those patients whom the providers chose to recruit and/or those willing to be randomized. For example, the women in the CHORUS trial were older, had a higher proportion of poorly differentiated tumors, and had a poorer performance status than patients in other comparable studies. Moreover, both trials had surprisingly low recruitment rates. The shorter-than-expected median operative time of 165 minutes in the PDS arm also is an indication of the surgical commitment, expertise, and comprehensiveness of the operative teams. Despite the inclusion of some very-high-volume centers, each large institution recruited only 1 to 2 patients per year on average. Who were these patients, and how were the remaining nonrecruited patients managed? We cannot extrapolate data from this population of patients, who may have already had a poorer prognosis compared with the average patient with advanced ovarian cancer.
At the time of diagnosis and initiation of treatment, a patient presents with tumor composed of both chemosensitive and chemoresistant cells. Surgical debulking removes the vast majority of tumor cells of both types and decreases the quantity of cells that can spontaneously mutate into drug-resistant phenotypes. NACT is essentially a form of “chemical tumor debulking.” However, if chemotherapy is a patient’s first treatment, more tumor cells are present, and they have a longer time in which to build increased chemoresistance. Also, interrupting the chemotherapy by introducing IDS in the middle of the 6 to 8 cycles of chemotherapy may give the tumor cells still present additional time in which to build chemoresistance. This poses a significant risk because almost all patients whose disease recurs eventually develop chemoresistance, and 1 in 4 present with platinum-resistant disease at the time of their first recurrence. The risk of developing chemoresistance is higher in patients treated with NACT even if complete gross resection is achieved at the time of their surgery.[34,35] Additionally, patients who have been treated with NACT are less likely to respond to a platinum combination at the time of recurrence.[35,36]
Patient Selection for NACT
The rates of NACT utilization in stage IIIC and IV disease have been increasing over the past decade.[30,37] This is not necessarily a bad thing, since PDS is not appropriate for every patient diagnosed with advanced ovarian cancer. However, it is imperative that this increase in the use of NACT occur in the appropriate patient population. The goal is to personalize medical care such that each patient receives the best treatment for her specific tumor burden—one that will provide her with the longest OS and the highest quality of life possible. Data suggest that patients over age 75 with poor performance and nutritional status, who would require extensive surgery to attain optimal cytoreduction, may be best served by a neoadjuvant approach. Patients who cannot be optimally debulked are also best treated with NACT. Recently, Makar et al published an analysis of five phase III trials, three Cochrane reviews, and four meta-analyses. The authors proposed stratifying patients with advanced ovarian cancer into five categories based on patterns of tumor spread, response to chemotherapy, and prognosis, in order to better determine which patients to select for PDS and which for NACT. They concluded that NACT is preferable only in cases in which the main tumor bulk is restricted to the upper abdomen, and is associated with massive ascites or the presence of miliary spread and/or massive mesenteric metastases, which would require multiple intestinal resections at the time of PDS. They also noted that NACT is preferable in stage IV ovarian cancer with multiple intrahepatic and/or lung metastases, or with massive ascites with miliary spread. In 2014, Suidan et al published an algorithm identifying three clinical and six radiologic findings associated with an increased risk of suboptimal outcome at time of PDS. Once validated, this algorithm may prove to be a beneficial tool for patient selection. Laparoscopy for patients with questionable resectability may also be useful in patient selection. It affords the surgeon the opportunity to assess the peritoneal cavity and collect tissue without subjecting the patient to the morbidity of a laparotomy that will not improve survival.
PDS followed by platinum-based chemotherapy affords patients with advanced ovarian cancer the best chance at the longest survival. If a patient is fit for surgery and has potentially resectable disease, she should be offered PDS. NACT does have its benefits, but should be reserved for women who are deemed inappropriate for surgical management or who have preoperative or laparoscopic findings indicative of unresectable disease.
Because primary cytoreductive surgeries can be complex, preoperative preparation is crucial. This sometimes requires consultation with general surgeons, surgical oncologists, or hepatobiliary surgeons, as well as the readiness of these colleagues to assist, in the event that disease encountered at PDS is difficult or impossible for the gynecologic oncologist to remove. This type of preparation may be difficult at medical centers with less experience in these types of surgeries and may influence the provider’s choice of NACT over PDS. Whenever possible, patients with advanced ovarian cancer should be treated by experienced gynecologic oncologists at specialized institutions that offer the infrastructural support necessary to accommodate these complex cases. As it stands, the issue of PDS vs NACT for advanced ovarian cancer has yet to be appropriately resolved. The international Trial on Radical Upfront Surgery in Advanced Ovarian Cancer (TRUST) is currently recruiting patients to centers with proven, robust surgical programs with physicians who are willing to randomize all eligible participants. Hopefully, results from this study will contribute to our understanding of this issue. Until then, we must rely on sound clinical judgment to appropriately select patients for primary surgery or primary chemotherapy.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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