The Many Challenges of Neoadjuvant Chemotherapy for Ovarian Cancer

Ovarian cancer is a unique malignancy. While the disease can spread hematogenously or via the lymphatic system, the bulk of the tumor is found on peritoneal surfaces. This peritoneal disease results from shedding of ovarian tumor cells into the peritoneal cavity, circulation of these cells throughout the abdomen and pelvis, and eventual implantation onto peritoneal surfaces. Viability and growth of these cells and successful tumor formation is further dependent upon the development of sufficient neovasculature to support cell survival and tumor growth.

This unique pattern of spread within the relatively accessible peritoneal cavity has led to attempts at surgical cytoreduction before administration of systemic chemotherapy. Dating back to pivotal studies from Griffiths in 1975,[1] nearly every study has demonstrated an inverse correlation between volume of tumor remaining at the completion of initial surgery and overall survival for patients with ovarian cancer.[2] Thus, the goal for patients today is to have “optimal” tumor cytoreduction to no macroscopic visible disease with their initial diagnostic surgery.

Benefits of a Neoadjuvant Approach

The recognition that not all patients can be optimally debulked at initial surgery has led to alternative approaches to achieving optimal surgical status. One of these is the administration of chemotherapy before definitive surgery, an approach referred to as neoadjuvant chemotherapy. In this edition of ONCOLOGY, Dr. Peter Schwartz, a long time advocate of this approach, reviews the issue of neoadjuvant chemotherapy in ovarian cancer. The strategy has clear benefits for ovarian cancer patients, including a higher rate of optimal cytoreduction; improved nutritional, medical, and emotional status prior to surgery; decreased operative time; decreased blood loss; shorter stays in the surgical intensive care unit; and decreased total hospitalization time. The pivotal question is whether disease outcome is worsened by this approach.

Ideal Trial Design

The hypothesis underlying the neoadjuvant approach is that optimal debulking after administration of chemotherapy will have the same survival benefit as a similar degree of debulking achieved before chemotherapy. The ideal trial to address this issue would randomize patients who are able to undergo optimal surgical cytoreduction to either such surgery followed by chemotherapy, or to chemotherapy before surgery. This approach would require a metric for reliably predicting which patients can undergo optimal surgery. Unfortunately, no such metric exists,[3] and even Dr. Schwartz acknowledges that “at present, there is no absolute way to identify which patients with advanced-stage ovarian cancer will or will not be able to be optimally cytoreduced at the time of their initial operation.”

Advocates of the neoadjuvant approach might argue that the above trial design is not the ideal strategy; that it uses the wrong patient population; that they are trying to identify patients who cannot be optimally cytoreduced and provide them with the potential to have the survival benefits of optimal cytoreduction after chemotherapy. However, if we cannot reliably identify patients able to have successful surgery, then we also cannot reliably identify patients who can’t.

Role of Surgical Expertise

Surgical outcome for ovarian cancer is highly variable. Success depends on patient and tumor characteristics but is, in fact, more highly dependent on the skill, experience, and dedication of the surgeon.[4] Whether one is an advocate of neoadjuvant chemotherapy or aggressive initial surgery, there is consensus that all ovarian cancer patients should have surgery performed by a qualified gynecologic oncologist. It is unfortunate that even today fewer than half of women with ovarian cancer have the benefit of this surgical expertise in their care.[5]

Could the use of neoadjuvant chemotherapy worsen disease prognosis? Disease resistance is due to the emergence of treatment-resistant clones. These clones arise from individual cells that either had de novo resistance or developed such resistance under the selective pressure of chemotherapy. Surgical debulking will be beneficial in either scenario: It will remove more cells with intrinsic resistance or will reduce the pool of cells available to develop resistance. Since optimal surgical cytoreduction can remove many logs of cells, the development of chemotherapy resistance may be minimized with aggressive initial chemotherapy.

Patient Selection

There are multiple challenges facing those doing research on neoadjuvant chemotherapy for ovarian cancer. The most critical are developing selection criteria to identify surgically unresectable patients-what Dr. Schwartz refers to as “estimating surgical cytoreducibility” and determining optimal neoadjuvant therapies. This will ensure that women who are good surgical candidates are not denied the survival advantage associated with optimal primary surgery and that those women in whom aggressive initial surgery is not viable will have the best opportunity to derive the maximal benefit from therapy.

-Deborah K. Armstrong, MD

The main article can be found here.

Disclosures:

Financial Disclosure: 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:

References

1. Griffiths CT: Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 42:101-104, 1975.

2. Bristow RE, Tomacruz RS, Armstrong DK, et al: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 20:1248-1259, 2002.

3. Salani R, Axtell A, Gerardi M, et al: Limited utility of conventional criteria for predicting unresectable disease in patients with advanced stage epithelial ovarian cancer. Gynecol Oncol 108:271-275, 2008.

4. Goff BA, Matthews BJ, Larson EH, et al: Predictors of comprehensive surgical treatment in patients with ovarian cancer. Cancer 109:2031-2042, 2007.

5. Bristow RE, Zahurak ML, del Carmen MG, et al: Ovarian cancer surgery in Maryland: Volume-based access to care. Gynecol Oncol 93:353-360, 2004.