Intraperitoneal Chemotherapy: Coming of Age?

Abstract & Commentary

By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston. Dr. Coleman is on the speaker’s bureau for GlaxoSmithKline, Bristol-Myers Squibb, and Ortho Biotech.

Synopsis: As compared with intravenous paclitaxel plus cisplatin, intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel improves survival in patients with optimally debulked stage III ovarian cancer.

Source: Armstrong DK, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.

The standard approach to adjuvant therapy in women with advanced ovarian cancer is intravenous platinum-based chemotherapy, usually in combination with a taxane. Since the disease is largely characterized by a disseminated intraperitoneal spread pattern, investigators have been interested as whether the disease may respond to therapy administered in the same route. Armstrong and colleagues from the Gynecologic Oncology Group addressed this hypothesis by conducting a randomized phase III trial of standard intravenous platinum and taxane chemotherapy vs a regimen which combined intravenous (IV) paclitaxel with intraperitoneal (IP) cisplatin and intraperitoneal paclitaxel. This latter regimen required infusion on 3 separate days each 21-day cycle. Both progression-free and overall survival were primary end points of the study. In all, 429 patients with optimally cytoreduced (defined as residual disease < 1 cm) were randomized. Grade 3 and 4 pain fatigue and hematologic, GI, metabolic and neurotoxicity were greater in the IP-therapy group. In fact, just 42% of patients randomized to receive IP therapy finished all 6 cycles via IP administration. Nonetheless, both primary end points were favorably longer in the IP arm vs IV (standard) therapy. The differences were 5.5 months gained in PFS (median, 18.3 vs 23.8 mos) and nearly 16 months in OS (median, 49.7 vs 65.6 mos). Quality of life was lower on the IP arm but the difference disappeared at 12 months post-treatment. The authors concluded that the IP regimen improved survival in optimally debulked advanced stage ovarian cancer patients.

Commentary

Advanced ovarian cancer remains the most lethal of the gynecologic malignancies because of its late stage at diagnosis and frequent relapse after primary treatment. It is commonly found at primary surgery that diffusely metastatic disease coats the intraperitoneal surfaces, sometimes with great tumor bulk, challenging the ability to completely remove the tumor. To date, that regimen of choice has been intravenously administered platinum-based and taxane chemotherapy combinations. Little has changed in the primary intravenous recommendation over the last decade although many modifications have been made; most therapeutic additions to the platinum/taxane backbone have not altered survival parameters.

The current report joins 2 previously conducted trials evaluating the merits of administering chemotherapy into the cavity where the disease is largely distributed—intraperitoneal. The concept has been under investigation for several decades and has been favorably considered, as IP drug administration is associated with superior pharmacokinetics relative to intravenous administration. In this manner high-dose drug exposure can be accomplished without the commensurate systemic toxicity. Limited surface diffusion into tumors, however, meant smaller volume residual status would be necessary. Nonetheless, in the last 10 years, there have been 3 large phase III clinical trials in ovarian cancer patients, which appear to confirm that the strategy is valid.1-3 The first trial simply compared IV cisplatin and cyclophosphamide to IP cisplatin and IV cyclophosphamide. The dosing of both agents was the same; of note, the platinum was 100 mg/m2—a dose on the upper limit of patient tolerance without marrow support. Patients were enrolled if they had 2 cm or less of residual disease from surgery. The intent was 6 courses of therapy. While PFS was not reported in the study, OS was significantly improved by approximately 8 months in the IP arm (41 vs 49 mos). Since the study appeared about the time results from a trial demonstrating the superiority of paclitaxel over cyclophosphamide in combination with platinum, the findings were not incorporated into standard care. A second trial used the IV platinum/taxane standard as a control against a regimen combining relatively high-dose carboplatin for 2 cycles followed by IP cisplatin (same dose as above) and IV paclitaxel in patients with optimal cytoreduction (defined as residual less than 1 cm). The induction chemotherapy was incorporated to help reduce the volume of post-operative residual disease but led to therapy discontinuation due to toxicity. Despite these criticisms, the IP arm was superior in both PFS and OS. For the latter variable, the gain was nearly a year and represented the first study in which overall survival in this cohort extended beyond 5 years. While the data caught the eye of many, toxicity was significant enough that the authors hesitated to recommend the regimen as “standard” for patients with optimally cytoreduced ovarian cancer.

Given the context in which the current report falls, one could conclude, “third times a charm.” On the surface, it is difficult to argue with results. Indeed the NCI has issued a statement outlining the merits of this therapy. (ctep.cancer.gov/highlights/ovarian.html) It is clear, we will need to look at this issue in further detail largely not to question the merits of the route of administration but rather how to get patients through it with acceptable toxicity. In an accompanying article from the Group, catheter-related problems were the primary reason patients were not able to complete their intended program of IP therapy. Patient selection, standardization of infusion ports and increased experience with care and symptom management will help. Alternative agents and schedules will likely also be investigated to make the treatment more user-friendly. When these goals are accomplished, we will certainly embrace this advance into our armamentarium against this lethal disease.

References

1. Walker JL, et al. Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: A Gynecologic Oncology Group Study. Gynecol Oncol. 2006;100:27-32.

2. Alberts DS, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950-1955.

3. Markman M, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003;21:2460-2465.