Commentary (Markman): Neoadjuvant Chemotherapy for Ovarian Cancer

Few would question the statement that the role of surgery in the management of epithelial ovarian cancer is unique in solid tumor oncology. It is currently "standard practice" for physicians confronted with a patient with a "solid tumor" to search for evidence of spread of the malignancy beyond the local area of involvement before undertaking an aggressive attempt to produce a "surgical cure." For example, while a female patient shown to have multiple peritoneal implants from a documented stomach cancer may still have the primary cancer removed in a reasonable effort to prevent, treat, or avoid bleeding, perforation, or pain, there should be no realistic expectation that the metastatic disease can be resected in an attempt to "cure" the malignancy. Yet, if this same patient presented with an advanced ovarian cancer, and similar surgical findings in the peritoneal cavity, every reasonable effort would be made to remove all visible tumor deposits, as "standard management," prior to the initiation of chemotherapy.[ 1] Thus, in addition to the common use of surgical exploration to define the extent of disease, and to "cure" the small percentage of patients with an apparently localized cancer, aggressive surgery is considered to play a central role in optimizing survival in the large majority of women with advanced ovarian cancer. Unanswered Questions
The justifications-both extensive retrospective and far more limited prospective data-for what might reasonably be considered a most unusual management paradigm for a "solid tumor" are nicely outlined in the review by Vergote and his colleagues. This body of evidence can be very briefly summarized as follows: Patients with advanced ovarian cancer who initiate chemotherapy with the smallest possible residual tumor volume (preferably no gross residual disease) experience the greatest opportunity for prolonged survival and possible "cure." Unfortunately, despite the conclusiveness of this observation, it currently remains unknown if patients who initiate cytotoxic therapy with less (or no) gross disease live longer because they underwent successful surgical cytoreduction, or if they live longer because of currently poorly characterized but favorable biologic characteristics of their disease process. Stated slightly differently, are the biologic features of a particular ovarian malignancy that permit or prevent removal of macroscopic cancer (eg, absence or presence of diffuse peritoneal carcinomatosis, or extensive lymph node involvement) the same factors that define a tumor's inherent chemosensitivity or propensity to develop "acquired" drug resistance? If biology is the major factor, "successful surgical cytoreduction" can appropriately be viewed merely as a "clinical indicator of that favorable biology," rather than as the reason for the favorable outcome. Aggressive Surgical Approach
Finally, it is possible, or perhaps even likely, that both biology and surgical skill are critically important issues in defining the success of subsequently administered chemotherapy, and in determining an individualpatient's ultimate survival. In fact, a reasonable argument can be advanced that an aggressive surgical management philosophy will become even more clinically relevant in the future as increasingly effective chemotherapeutic agents are developed. At least conceptually, it will be critically important that all viable malignant cells are exposed to the concentrations of these drugs required to achieve the desired cytotoxic or cytostatic effect. An example of the favorable impact of a successful attempt at removing all or most gross residual disease in women with advanced ovarian cancer is the survival advantage associated with cisplatin-based intraperitoneal chemotherapy.[2-4] Existing evidence supports the conclusion that the ovarian cancer patient most likely to benefit from regional treatment is one with the smallest possible residual volume when treatment is initiated (eg, a maximum tumor diameter < 1 cm). Neoadjuvant Chemotherapy
In those individuals who are unable to undergo primary surgical cytoreduction, either due to extensive intra- or extra-abdominal disease, or where comorbid medical conditions would argue against employing this strategy, the concept of neoadjuvant chemotherapy has been advanced by a number of investigators over the past decade (references included in the Vergote review). Researchers have used a variety of methods to determine whether a patient is a candidate for such an approach, including physical and radiographic findings (eg, extensive carcinomatosis), or an initial laparoscopic assessment to determine resectability of the cancer. As discussed by Vergote, the results of an important European/Canadian prospective phase III randomized trial may provide (a) critical supportfor the statement that the ultimate survival outcome in advanced ovarian cancer is equivalent if chemotherapy follows, or precedes, an attempt at maximal surgical cytoreduction; or (b) the first proof that primary cytoreductive surgery before the administration of cytotoxic chemotherapy is a crucial factor in optimizing the chances for the most favorable outcome in this malignancy. Conclusions
For the present, however, it is reasonable to conclude, as have Vergote and his colleagues, that if a patient with advanced ovarian cancer is able to undergo an attempt at complete tumor removal performed by an appropriately skilled surgeon, this should be the preferred management option. Additional justification for this statement comes from the knowledge that cytoreductive procedures performed in ovarian cancer patients by experiencedgynecologic cancer surgeons currently are associated with highly acceptable risks of both short- and long-term morbidity, and very low mortality. Conversely, it is also legitimate to offer patients the realistic hope for a satisfactory outcome if chemotherapy (platinum/taxane-based) is the initial treatment approach, following histologic confirmation of a malignancy consistent with either ovarian or primary peritoneal cancer. Depending on the extent and rapidity of response, as well as the patient's overall medical status, it may be reasonable to consider an interval surgical cytoreductive procedure (following three to fours courses of chemotherapy), or to complete the treatment program without additional surgery. For a specific individual undergoing treatment, optimal management will depend on particular clinical circumstances and patient choice.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Ozols RF, Rubin SC, Thomas GM, et al: Epithelial ovarian cancer, in Hoskins WJ, Perez CA, Young RC, et al (eds): Principles and Practice of Gynecologic Oncology, 4th ed, pp 895-989. Philadelphia, Lippincott Williams & Wilkins, 2005.
2. Alberts DS, Liu PY, Hannigan EV, et al: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335:1950-1955, 1996.
3. Markman M, Bundy BN, Alberts DS, et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in smallvolume stage III ovarian carcinoma: An Intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19:1001-1007, 2001.
4. Armstrong DK, Bundy BN, Baergen R, et al: Randomized phase III study of intravenous paclitaxel and cisplatin versus intravenous paclitaxel, intraperitoneal cisplatin and intraperitoneal paclitaxel in optimal stage III epithelial ovarian cancer: A Gynecologic Oncology Group trial (abstract 803). Proc Am Soc Clin Oncol 21:201a, 2002.