Originally published as JCO Early Release 10.1200/JCO.2007.11.8992 on August 27 2007

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Concept of Optimal Surgical Cytoreduction in Advanced Ovarian Cancer: A Brief Critique and a Call for Action

Maurie Markman

Department of Gynecologic Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

It would not be an exaggeration to state that the goal of attempting to surgically maximally cytoreduce diffuse intraperitoneal ovarian cancer represents one of the most unique standard-of-care management strategies in oncology.¹ One can only imagine the response of a hospital quality committee upon learning a general surgeon had performed over the past year a dozen such procedures, including removal of multiple metastatic peritoneal implants and retroperitoneal lymph nodes of varying size, along with masses adherent to the diaphragm and within the liver, in patients with pancreatic cancer.

Thus, the first question to be answered in this article relates to the fundamental justification for this approach in disease management. It has been known for more than 30 years that women with advanced ovarian cancer who initiate systemic therapy with an apparent small total quantity of residual disease after surgical cytoreduction experience a superior outcome compared with patients with larger amounts of macroscopic cancer.² In fact, such retrospective data are so strong that randomized clinical trials in ovarian cancer will either include this feature as one important stratification factor, or will simply restrict entry of patients into the study based on a perceived objective measure of this parameter (for example, largest single residual malignant mass 1 cm in maximum diameter).^3,4

Yet, despite the overwhelming evidence that the size of residual tumor masses after surgery is a highly relevant prognostic feature of advanced ovarian cancer, there remain profoundly limited evidence-based data to support the conclusion that it is the surgical procedure itself that is actually responsible for the superior outcome associated with smaller disease,^5,6 or if the technical ability to cytoreduce the cancer simply identifies a biologically more favorable patient subgroup.^1,5-7 It is reasonable to speculate that the multiple factors (both currently defined and still unknown) that likely determine the manner in which a cancer progresses throughout the peritoneal cavity and that might substantially influence a surgeon's ability to remove the majority of visible tumor may also define such critically important features as the presence of de novo, or development of acquired, cytotoxic drug resistance.

In fact, to the best of my knowledge, of the three completed phase III trials that have at least attempted to partially address the issue of the relevance of a surgical cytoreductive procedure, compared with the cancer's inherent biology in defining outcome in advanced ovarian cancer, one study suggested a role for surgery,⁸ while two trials (one with an inadequate sample size) failed to reveal a survival advantage from the procedure.^9,10 It must be noted that these randomized trials were conducted to define a role for an interval cytoreductive surgery.^8-10 To date, the benefits of primary surgical cytoreduction in ovarian cancer have not been defined through a well-designed and conducted prospective phase III trial.¹

However, in the absence of such definitive data, it is possible to provide a rational hypothesis for why surgical cytoreduction in advanced ovarian cancer might at least be partially (even if not exclusively) responsible for the superior outcome associated with the presence of small volumes of intraperitoneal metastatic cancer. By decreasing the total quantity of disease, or removing cancer in specific locations (such as a lesion causing bowel obstruction) before the initiation of systemic therapy there may be an improvement in the patient's nutritional and immunological status, which might enhance still poorly defined internal mechanisms to fight the cancer, as well as to permit the individual to successfully tolerate the adverse effects of subsequently delivered cytotoxic therapy.

Further, the removal of large malignant masses may substantially increase the probability that optimal concentrations of highly active cytotoxic antineoplastic agents will be delivered to the residual cancer cell population. In addition, to the extent that the effectiveness of chemotherapy depends on the presence of well-oxygenated tissue that will permit more effective killing by drugs most active against cycling cells, surgical cytoreduction may be a clinically relevant management approach.

Thus, assuming the overall morbidity associated with primary surgery is limited, it is not difficult to make a strong argument that the potential (but not definitively proven) survival benefits associated with primary surgical cytoreduction outweigh the risks of the performance of this procedure in the majority of women with advanced ovarian cancer.

However, one must now deal with the question of what it means to achieve an optimal surgical cytoreduction,¹¹ and the level of evidence required to suggest it is appropriate in routine clinical practice to subject patients to a risk of added morbidity to achieve a particular clinical state.

While the Gynecologic Oncology Group, for the purpose of determining eligibility for clinical trial entry, currently defines optimal residual disease in advanced ovarian cancer as being 1 cm in largest tumor diameter,⁴ several groups have strongly argued that the legitimate goal of primary surgery should be considered as leaving no visible macroscopic tumor at the completion of the procedure.^12-15 Not surprisingly, justification for changing this definition, and fundamental surgical philosophy, comes solely from retrospective data suggesting the superior survival of patients who achieved this clinical state, compared with women with any degree of residual macroscopic cancer.

What is wrong with simply accepting these retrospective data regarding the utility of removal of all visible disease in advanced ovarian cancer, and (as noted above) agreeing with a theoretical rationale this might benefit patients?

Two major arguments can be advanced that this aggressive management strategy differs substantially from the more modest goal associated with defining optimal cytoreduction as being a reasonable attempt to leave the patient with small volume residual cancer.

First, it will be anticipated that the time, effort, blood loss, morbidity, and cost of surgery will be increased with more aggressive attempts at resection even by highly experienced gynecologic cancer surgeons, raising the critically important issue of the relative risks versus benefits, especially when considering the complete lack of evidence-based data supporting benefits of the management philosophy.^1,5,16 Second, it is likely that the required surgical expertise, at the level of both the individual surgeon and the institution where such procedures are undertaken, will be far more limited in availability than that associated with the current definition of optimal cytoreduction.¹⁷

Therefore, it logically follows that if it is truly necessary to declare there should be a change in the current concept of ovarian cancer surgical management to enhance the survival of women with advanced disease, this will require: (a) focused training, or retraining, of surgical oncologists (gynecologic or general) and additional institutional resources and expertise to permit the more aggressive cytoreduction; and/or (b) referral of patients to centers able to undertake these procedures.^18,19 If either (a) or (b), or both, do not occur, one would be legitimately concerned that such surgery ultimately will be performed by individuals at institutions, who do not have adequate knowledge, preparation, and experience to provide what is required to safely and effectively employ this approach. In this regard, it is relevant to note available data for high risk and complex oncologic surgical procedures that reveal that treatment-related morbidity and mortality are directly related to the overall experience of the provider and institution with management of the condition.^20-23

Thus, considering both the important conceptual and pragmatic concerns associated with concluding that the current paradigm of a reasonable attempt at surgical cytoreduction to leave the ovarian cancer patient with small volume residual macroscopic cancer before the initiation of chemotherapy should be changed to a management strategy that strongly urges surgeons to do whatever is necessary to remove all visible disease to enhance outcome, it is rational to argue that evidence-based data is required to make, or even suggest, such a definitive statement.

I call on the gynecologic oncology clinical research community to seriously consider how such a phase III randomized trial might be conducted. For example, if a consensus can be developed among gynecologic oncologists as to what is considered to fall within the domain of a reasonable standard approach to surgical cytoreduction, and what enters the realm of a more aggressive strategy, it might be possible to provide an acceptable working definition of the two different surgeries that can be employed within the confines of a well-considered phase III randomized trial. Patients agreeing to participate in such a study could be randomly assigned to one of the two approaches before initial surgery, or perhaps in the intraoperative setting, once it is determined that an attempt at optimal cytoreduction is feasible. The end point of the trial will be both survival and serious treatment-related morbidity.

Clearly, development of an acceptable trial design will be difficult, complex, and will necessitate compromise. Further, it will require the input of multiple individuals and, ultimately, the cooperation of the gynecologic surgical community. For the good of our patients, hopefully, these major hurdles can be overcome.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

NOTES

published online ahead of print at www.jco.org on August 27, 2007.

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