The Role of Intraperitoneal Therapy in Advanced Ovarian Cancer
The Role of Intraperitoneal Therapy in Advanced Ovarian Cancer
In January 2006, the Gynecologic Oncology Group (GOG) published findings from GOG-172, the third phase III randomized trial of intraperitoneal (IP) cisplatin for the treatment of newly diagnosed, stage III ovarian cancer. The study compared an IP regimen (intravenous [IV] paclitaxel at 135 mg/m2 over 24 hours on day 1 + cisplatin at 100 mg/m2 IP on day 2 + paclitaxel at 60 mg/m2 IP on day 8) to an IV regimen (paclitaxel at 135 mg/m2 over 24 hours IV on day 1 + cisplatin at 75 mg/m2 IV on day 2) administered every 3 weeks for six cycles. The results of GOG-172 demonstrated a median 65.6-month overall survival associated with intraperitoneal chemotherapy, compared to 49.7 months associated with intravenous therapy (P = .03). These results were consistent with the previous two GOG randomized trials,[2,3] which also demonstrated significantly improved survival associated with intraperitoneal cisplatin-containing treatment regimens.
Concurrent with the publication of GOG-172, the National Cancer Institute issued a clinical announcementa document that is published only when an intervention that is available to the general public has been found to "substantially improve the survival outcome for a significant number of people with reasonable certainty." Furthermore, this announcement emphasized that the discussion about this procedure should begin with the surgeon prior to debulking surgery, as women should be aware of how surgery may be tailored for subsequent IP therapy.
Following the publication of the GOG-172 trial and the NCI clinical announcement, the oncology and scientific communities have been highly prolific in terms of editorials and commentaries on IP therapy.[6-16] Associated with the publication of GOG-172 were two additional studies related to quality of life and catheter outcomes in that trial.[17,18]
On January 19, 2006, the GOG sponsored a workshop in which the results from the three GOG randomized trials that demonstrated improved survival among patients treated with IP cisplatin (Southwest Oncology Group [SWOG]-8501/GOG-104, GOG-114, and GOG-172) were discussed in detail. Information was also presented on practical issues, such as toxicity management, patient quality of life, controversies about IP therapy, surgical and administrative guidelines, catheter placement, and nursing issues. The GOG website contains the workshop recording, surgical training videos, and other educational materials to facilitate the implementation of IP therapy.
Similarly, the SWOG issued a press release and sponsored a training workshop during their October semiannual meeting to further educate the oncology community about IP therapy. The reports of these workshops provide further details about the history, rationale for, and implementation of IP therapy.[5,21] The details of this body of knowledge will not be repeated here, but readers are encouraged to refer to the GOG and SWOG training and workshop materials.
Overall, these resources demonstrate the following key points: The scientific evidence supports the use of IP therapy, and opportunities for education and training are available to ensure its safe administration. IP therapy has been evaluated since the 1970s, and it has reached a point in its development where there is sufficient scientific evidence for it to be safely offered.
Despite the data demonstrating improved survival outcomes and a manageable toxicity profile, IP therapy is not routinely offered as a treatment option to all patients for the front-line treatment of optimally debulked stage III ovarian cancer. Although institutions and providers develop practice patterns and favored treatment regimens for a variety of reasons, substantial evidence supports two primary reasons why IP therapy is a treatment regimen that must be offered to all patients with optimally debulked, stage III disease: the data demonstrating improved survival and the patient's right to informed choice. These should be balanced by providing patients with the toxicity profile and practical considerations of IP therapy.
The GOG-172 IP regimen demonstrated the longest median survival65.6 months, compared to 49.7 months in the IV control groupof any randomized study of primary chemotherapy for advanced ovarian cancer to date. The relative risk of death was 0.75 (95% confidence interval [CI] = 0.58-0.97, P = .03) for IP therapy compared to those treated with IV paclitaxel (135 mg/m2 over 24 hours) plus IV cisplatin (75 mg/m2), which translates to a 25% reduction in the risk of death among those treated via IP administration in this study. This 16-month improvement in survival is impressive, particularly considering the fact that only 42% of patients enrolled in the IP treatment arm received all six courses of planned IP therapy. Progression-free survival was 18.3 months in the IV treatment group and 23.8 months in the IP treatment group (P = .05).
The magnitude of the improvement in survival has been surrounded by controversy, primarily related to the fact that the GOG-172 IP regimen was not directly compared with the current standard IV carboplatin-plus-paclitaxel regimen. However, GOG-158 demonstrated nonsignificant differences in survival between IV carboplatin plus paclitaxel and IV cisplatin plus paclitaxel. Compared to the GOG-158 IV carboplatin-plus-paclitaxel regimen, the GOG-172 IP regimen demonstrated approximately a 9-month median survival improvement (or a 19% improvement in the risk of death). Although such cross-comparisons with historical controls lack the validity of a prospective trial, these do represent the two viable front-line treatment options that should be presented to stage III ovarian cancer patients. Furthermore, GOG-158 and GOG-172 were contemporary trials, conducted among similar populations and with similar study designs through the GOG.
Toxicity of IP vs IV Therapy
The significant improvement in overall survival associated with IP therapy is not without cost. Although patient-reported quality of life was equivalent among patients treated with IV vs IP therapy 1 year following completion of treatment, the GOG-172 IP regimen does produce a short-term impact on quality of life and a greater chance that the patient will experience toxicity. Specifically, patients randomized to receive IP therapy experienced greater grade 3/4 pain (11% vs 1%), fatigue (18% vs 4%), leukopenia (76% vs 64%), infection (16% vs 6%), and platelet (12% vs 4%), gastrointestinal (46% vs 24%), metabolic (27% vs 7%), and neurologic toxicities (19% vs 9%) than those randomized to IV therapy. However, the study showed no differences in treatment-related deaths between groupsfour deaths occurred in the IV group and five in the IP group, all of which were related to infection. However, a recent meta-analysis demonstrated that across IP cisplatin trials, only fever and gastrointestinal toxicity were significantly higher among those treated IP, whereas ototoxicity was significantly higher among those treated IV.
IP therapy also produces a different toxicity profile than the current IV carboplatin-plus-paclitaxel regimen (Table 1). Each of these toxicities is manageable and short-term in nature. Current and planned research is largely focused on reducing the toxicities associated with the GOG-172 IP treatment regimen to improve acceptability and to increase the proportion of patients who are able to complete the full course of treatment.
It is now standard practice to reduce the 24-hour infusion of paclitaxel to 3 hours to reduce the myelosuppressive activity of the agent[21,24] and to allow for administration in an outpatient setting. The rationale for reducing the IV paclitaxel infusion time is based on the regimen used in GOG-158, which tested a 24-hour infusion of paclitaxel (plus carboplatin), but which is now used in practice as a 3-hour infusion of paclitaxel (plus carboplatin), with no evidence of an impact on outcome.