Introduction Intraperitoneal Chemotherapy for Advanced Ovarian Cancer Finally a Standard of Care

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Key Words: Intraperitoneal chemotherapy, ovarian cancer, IP cisplatin, IP paclitaxel, cancer survival

Epithelial ovarian cancer is the fourth leading cause of cancer death in women in the United States, with an estimated incidence of 20,180 and 15,310 deaths in 2006 (1). According to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program, the five-year relative survival rates for women with "localized" ovarian cancer is 93.6%, whereas for those with "distant" disease it is 29.1% (2). Unfortunately, these data have changed minimally over the past decade.

In comparison to all other common solid cancers (including lung and pancreatic cancers), ovarian cancer is diagnosed far more frequently with "regional" or "distant" disease (i.e., approximately 80% of all new diagnoses) (1). These late diagnoses occur because there are no ovarian cancer specific symptoms and because of the propensity for tumor cells that invade through the capsule of the ovary to be swept into the upper abdomen where they can grow in a rich "culture media" of macrophages and lymphocytes (3).

Although bioimaging and biomarker technologies have failed to lead to the diagnosis of early stage ovarian cancers (i.e., only about 20% of ovarian cancers are diagnosed in a localized stage), the natural history of distant or advanced disease involves the metastases from ovarian cancer progressing mainly within the intraperitoneal space. Thus, regional approaches to therapy of advanced disease must be considered both rational and vital; however, regional therapy can only be successful in this setting if attention to aggressive cytoreductive surgery is preserved as a centerpiece of ovarian cancer management.

Systemic therapy (i.e., intravenously administered cytotoxic and biologic agents) has always been the favored approach for drug delivery for advanced ovarian cancer. In relation to high-impact progress in the lengthening of survival for women with ovarian cancer, there have been three hallmark developments in systemic therapy over the past 20 years, including (1) the development of intravenously administered cisplatin and carboplatin in the 1970s and 1980s (4,5); (2) the addition of paclitaxel to cisplatin and carboplatin in the 1990s (6-8); and (3) the administration of cisplatin and paclitaxel by the intraperitoneal routes in the 1990s and early 2000s (Table 1) (9-11).

In the United States over the past decade, the combination of intravenously administered carboplatin and paclitaxel has been the standard treatment of women with stages III and IV ovarian cancer, regardless of disease characteristics or success of surgical debulking (8). This combination of carboplatin plus paclitaxel was tested by both the AGO Ovarian Cancer Study Group (Germany) and by the Gynecologic Oncology Group (GOG-15 8) comparing it with a cisplatin plus paclitaxel combination (7,8). The outcome of the large phase III trial in the GOG documented better patient toler-ability and a non-significant trend toward a higher negative "second-look" exploratory laparotomy rate and longer survival duration associated with the carboplatin/paclitaxel study arm (8). Of considerable interest is that virtually all subsequent trials of this combination in first-line therapy have utilized a carboplatin dose calculated with an AUC (area under plasma concentration ■ time curve) of no more than 6 |g.hr/mL in contrast to the AUC of 7.5 |g.hr/mL used in GOG-158, mainly to cut down on relatively high rates of grade 4 neutropenia, chronic thrombocytopenia, and moderately severe peripheral neuropathy (8).

Even with the use of a carboplatin AUC calculated dose of 7.5 |g.hr/mL in combination with paclitaxel in GOG-158, the median survival duration of 57 months achieved with this intravenous regimen is considerably lower than the median survivals of 63 and 66 months achieved with the intraperitoneal cisplatin or intraperitoneal cisplatin/paclitaxel arms of GOG-114 and GOG-172, respectively (Table 1) (10,11).

With the publication of GOG-172 in January 2006, the National Cancer Institute issued a "Clinical Announcement," suggesting that women with stage III, optimally debulked (>1 cm individual sized intraperitoneal tumor plaques) be informed of the positive results of the three large, phase III intraperitoneal cisplatin-based trials stating that, "the benefit appears to be approximately a 12-month improvement in median overall survival (range 0-16 months) (9-12). The "Clinical Announcement" goes on to state "of note, the magnitude of improvement in survival is similar to that observed with the introductions of cisplatin and paclitaxel in the treatment of women with ovarian cancer" (12).

As stated in a 2002 editorial in the Journal of Clinical Oncology, "we cannot think of any other setting in oncology where the results of three positive phase III trials have not led to widespread adoption of the superior therapy. The time has come for intraperitoneal (IP) chemotherapy to move beyond the setting of clinical trials and into the standard treatment armamentarium for women with

Table 1

Survival Data Related to Gynecologic Oncology Group Trials of Intravenous or Intraperitoneal Platinum Plus Taxane Regimens in Women with Stage III, Optimally Debulked Ovarian Cancer

Group Study #

First author

Control Arm

Experimental Arm

Median Survival <months) Control Experimental

P value

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