BY THOMAS HERZOG, MD
Unfortunately, nearly three-quarters of ovarian cancer patients present with disease that has spread to the upper abdomen at the time of diagnosis (Stage III). Ovarian cancer ranks as the fifth most common cancer in women and is the most mortal of all gynecologic malignancies.
Adjuvant treatment of this disease is actually straightforward in the sense that all patients receive a platinum combined with a taxane as has been the standard for the last 15 years; however, recent developments have offered some additional options that warrant consideration.
Epithelial cancers are the most frequent type of ovarian cancer, and the treatment discussion herein relates to this tumor type rather than germ cell or stromal tumors.
The predominant histology in epithelial cancer is papillary serous. High-grade serous tumors, the most frequent variant of advanced staged tumors, are more likely to express CA-125 as well as to respond to conventional chemotherapeutics.
Endometrioid tumors also respond well whereas clear-cell and mucinous tumors have a worse response to conventional adjuvant treatment. In fact, alternative treatment strategies are being explored for these latter histologic subtypes.
Initial Approach: The Role of Cytoreduction and Staging
The first issue is to establish the diagnosis, and this is generally accomplished at the time of the initial surgery.
Needle biopsy of a pelvic mass is usually discouraged as this may actually result in rupture of the mass and upstaging via spread from the pelvis to the upper abdomen.
The type of surgery needs to be decided based upon the skills of the surgeon and the distribution of disease. I prefer open exploratory laparotomy for patients with obvious clinical or radiographic evidence of disseminated disease. For management of isolated pelvic masses, I prefer minimally invasive surgery, as removal and even full staging can be accomplished laparoscopically.
A primary goal of surgery in epithelial ovarian cancer treatment is to remove as much tumor as possible. While no prospective randomized trials have been performed, multiple publications have highlighted the importance of achieving an optimal cytoreductive status in patients with advanced ovarian cancer in terms of improved survival.
The current definition of optimal cytoreduction is predicated upon no single tumor implant being greater than one centimeter following initial surgery. More recent studies have suggested that the goal should really be to remove all visible tumor implants.
To achieve this status, patients may require extended ancillary procedures such as bowel or liver resections, splenectomy, diaphragm and peritoneal stripping or resections.
A second goal of surgery is to determine the extent of spread or stage of the disease. Comprehensive staging including lymphadenectomy provides not only valuable prognostic information, but also guides treatment, especially in apparent early-stage disease.
Surgery also offers the opportunity to procure tissue. While there may be value for assay-directed therapy for recurrent disease, the role of assays in front-line therapy is limited in that, for example, it is difficult for me to omit platinum initially without prospective data to support such an intervention.
Novel molecular data and multi-gene predictors may have a role but require prospective validation for use, and thus I do not currently send tissue to decide front-line therapy outside of a clinical trial construct.
Standard Front-line Adjuvant Therapy
Adjuvant therapy consists of a platinum and a taxane. Generally the choice is carboplatin (AUC of 5-7.5) and paclitaxel (175 mg/m2 administered every three weeks for usually six cycles, although treatment may be extended by one to two cycles if the patient is normalizing her CA-125.
Alternative taxanes may offer some advantages from the standpoint of toxicities -- especially neuropathy -- and ease of administration, but their significantly increased costs do not justify routine use at this time. Further studies are needed to establish any efficacy advantage to either novel platinums or taxanes.
When Should Neoadjuvant Therapy be Administered?
One alternative consideration prior to performance of primary definitive cytoreductive surgery is neoadjuvant chemotherapy. A recent randomized European trial has shown that survival is not impaired with the administration of chemotherapy prior to surgery, and in fact the morbidity of the surgery is reduced with this approach. Thus, some experts would recommend that almost all patients should receive neoadjuvant chemotherapy as the standard.
Other data has challenged this concept, however. Currently for patients with advanced stage III and IV tumors, I prefer to perform initial cytoreduction, as this approach definitively establishes the diagnoses, permits consideration of intraperitoneal (IP) chemotherapy, and theoretically reduces the likelihood of the emergence of resistant clones.
Neoadjuvant is preferred when patients are poor surgical candidates and are likely to suffer from significant surgical morbidity or even mortality, or if they had a recent exploration with limited resection, yet a definitive diagnosis was established.
Adjuvant Options for Advanced Stage Ovarian Cancer
While the platinum/taxane backbone remains the current standard of therapy, several issues require consideration that may alter the route, schedule, duration, and composition of therapy.
The first issue to consider is the route of therapy. If a patient has a good performance status and is optimally cytoreduced, IP therapy is an excellent choice, and in fact for me is preferred, based on the strength of three phase III trials that show a significant survival advantage.
Toxicity is generally manageable in patients without significant comorbidities. Numerous regimens have been proposed to reduce toxicity that deviate from the Gynecologic Oncology Group (GOG) 172 schema. However, the degree of modification, in terms of maintaining efficacy with dose reductions and alternative platinum and taxane substitutions, requires further efficacy validation.
What is the Role of Dose-Dense Therapy?
Currently two GOG trials are attempting to establish the role of administering platinum with paclitaxel in a fractionated weekly schedule at 80 mg/m2 on days 1, 8, and 15 versus standard paclitaxel at 175 mg/m2 every three weeks.
The enthusiasm for this strategy was derived from the results of a Japanese GOG study that demonstrated a survival advantage for the dose-dense schedule. Until confirmatory data in a heterogeneous population are available, I do not standardly employ this approach in the front-line setting as therapeutic cost and toxicity are increased.
What is the Role of Maintenance Therapy?
The third issue to consider is the duration of therapy. The concept of extending the treatment of chemotherapy beyond the standard of approximately six cycles remains controversial in the management of patients with solid tumors.
The rationale for this approach is predicated by the existence of nonresistant, slowly dividing tumor cells which have been inadequately exposed to cycle-dependent cytotoxic agents during the initial treatment period and may be eliminated with further therapy.
In addition, certain antineoplastic agents, including paclitaxel, have demonstrated schedule-dependent anti-angiogenic effects. As a result, continuation of chemotherapy might delay tumor growth by targeting both residual cancer cells and associated tumor vasculature.
GOG 178 compared three extra months following standard chemotherapy versus 12 extra months of monthly paclitaxel maintenance therapy in patients with a complete clinical response to primary therapy. The results of GOG 178 demonstrated an advantage of seven months in median progression-free survival (PFS) for the group who received an additional 12 months of monthly paclitaxel (PFS: 28 months vs 21 months, HR: 2.31, 99% confidence interval 1.08 to 4.94, P= 0.0035).
While this study clearly demonstrated a prolonged PFS for patients receiving paclitaxel maintenance therapy, the merits of this strategy have been debated extensively, and practicing oncologists have not widely embraced its use.
Enthusiasm for maintenance therapy has been tempered by the fact that no trial to date including GOG 178 was able to demonstrate an overall survival advantage. I discuss the option of maintenance therapy with patients who demonstrate a complete clinical response, but I do not encourage its use outside a clinical trial (currently GOG 212). This trial includes overall survival as a primary endpoint unlike GOG 178 that was powered only for PFS as the primary endpoint. Pending maintenance trials are examining the efficacy of multi-targeted kinases/anti-angiogenics such as pazopanib and sorafinib.
Should We Add a Biologic Agent?
Lastly, the composition of front-line therapy needs to be considered. Specifically, should a targeted biologic be added?
One class of targeted compounds that has received a significant amount of attention for the potential treatment of ovarian cancer has been the anti-angiogenics.
Two recent phase III trials have examined the role of adding bevacizumab to standard platinum and taxane therapy. Both trials were positive in meeting their respective PFS endpoints. One trial GOG 218, was a placebo-controlled, double-blinded, three-arm trial that examined standard chemotherapy alone versus bevacizumab with chemotherapy versus bevacizumab with chemotherapy followed by prolonged bevacizumab treatment.
The latter cohort of bevacizumab with chemotherapy and then prolonged bevacizumab demonstrated a 3.8-month improvement in PFS over standard chemotherapy alone (10.3 vs 14.1 months median PFS).
This data, along with the results from the ICON7 trial, using a lower dose of bevacizumab, have presented clinicians with another option for patients requiring front-line adjuvant treatment for epithelial ovarian cancer.
This class of compounds may cause significant side effects including bowel perforation and renal toxicity, but these appear to be rare based upon phase III data in the front-line setting.
Nonetheless, most clinicians are awaiting longer-term safety and survival data including overall survival prior to routine use. Additionally, cost is a significant deterrent for many patients, especially based upon the observed magnitude of PFS effect, and approval in ovarian cancer is pending.
Treatment for most patients with stage IIIC epithelial ovarian cancer consists of aggressive surgical cytoreduction followed by chemotherapy with carboplatin and paclitaxel. IP chemotherapy with cisplatin and paclitaxel is an excellent choice in those who are optimally cytoreduced and have a good performance status.
Maintenance taxane therapy remains best utilized within the context of a clinical trial. Addition of bevacizumab appears promising, but the subgroup that benefits the most from this evolving novel approach requires further study.
Future enrollment on clinical trials is necessary to optimize the care of women with this difficult disease as a myriad of promising novel agents await confirmation of clinical benefit.
THOMAS HERZOG, MD, is P & S Alumni Professor of Clinical Obstetrics and Gynecology and Director of Gynecologic Oncology at NewYork-Presbyterian Hospital/Columbia University Medical Center.