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Intraperitoneal Therapy for Ovarian Cancer: A Sacrifice Bunt

Co-Chairman, Ovarian Cancer CommitteeThe Gynecologic Oncology GroupUniversity of Mississippi School of MedicineJackson, MSCancer CenterFranklin Square HospitalBaltimore, MD

FOR OVER TWO decades investigators have explored the role of chemotherapy administered directly into the peritoneal cavity for patients with ovarian cancer and other malignancies.¹ The concept has been evaluated most extensively in ovarian cancer, which remains confined to the peritoneal cavity for much of its natural history. There has been and remains controversy over the role of this approach, and clinical investigators reviewing the same data set have been quite polarized either for or against this therapeutic approach.^2-4 Supporters of the concept argue that the regional therapeutic advantage varies from 20-fold for cisplatin to nearly a 3 log concentration gradient for paclitaxel when peritoneal to plasma levels are compared.⁵ Additionally, supporters cite the clear activity of regionally administered drugs in a series of phase II trials particularly in those patients with drug-sensitive and small-volume disease. Conversely, detractors argue that ovarian cancer is not really an intraperitoneal disease, since early dissemination to retroperitoneal nodes is common, pharmacologic advantage in the peritoneal compartment does not reflect the level attained by tumor, which receives drug by passive diffusion, typically only a few millimeters, and the majority of studies of systemic dose-intense chemotherapy have not demonstrated a clear outcome advantage.⁶

BATTING PRACTICE

Two decades of studies of intraperitoneal therapy for persistent or recurrent ovarian carcinoma have clearly shown that the procedure is generally safe, particularly in experienced users. Further, these studies have demonstrated that the technique is most active in patients who have drug-sensitive (prior response to systemic therapy lasting for 6 months) disease and small-volume (minimal macroscopic or microscopic) disease. If one chooses patients who meet these two criteria and verifies response by reassessment laparotomy, some 35% to 50% of patients can be expected to have no residual disease after intraperitoneal chemotherapy. Median time to clinical progression after attainment of this no-evidence-of-disease status can be many months.⁵ Whether this long disease-free interval could occur with systemically administered agents is unknown, since no prospective, randomized trials have been conducted. In any event, it has become clear that intraperitoneal therapy should be used as salvage treatment only in patients with microscopic disease who have demonstrated a prior response to platinum-based systemic therapy. There are precious few patients who meet these two stringent criteria, since recurrence is usually determined at the time of palpable, imageable, or symptomatic disease when intraperitoneal salvage is not operational because of disease volume.⁴

ON DECK

The use of intraperitoneal therapy as part of primary treatment has been explored in nonrandomized trials. Studies from Memorial Sloan-Kettering Cancer Center have suggested a survival benefit for patients treated with three cycles of intraperitoneal cisplatin and etoposide who had a surgically documented complete response to systemic platinum-based therapy.⁷ Patients treated in this manner had a survival that was superior to a "similar" group of patients with similar prognostic factors who had not been so treated, but this was based on comparison to a nonrandomized cohort and lacks the conviction that a randomized study would give. This approach, however, is being evaluated in patients at high risk for recurrence after a complete surgical response to systemically administered therapy in two separate trials using either interferon alfa-2a or cisplatin compared with no additional therapy. The results of these trials should be forthcoming in the next several years and are anxiously awaited. These studies explore the use of intraperitoneal therapy in patients who meet the criteria described above who are most likely to benefit from the intraperitoneal approach. Negative results for these studies will certainly call into serious question the value of this approach as primary or consolidation therapy in ovarian cancer. Positive results, however, will lend support to further studies to validate this approach or possibly make it a standard of care if the intraperitoneal approach is better enough to overcome the resistance of many clinicians to use of this methodology because of perceived or real technical difficulties.

BATTER UP AND HIT BY A WILD PITCH

The first randomized trial to explore the value of intraperitoneal chemotherapy as part of primary treatment in advanced disease was reported nearly 5 years ago.⁸ In that trial, 546 eligible patients with postoperative disease bulk 2 cm were treated with intravenous cyclophosphamide (600 mg/m²) and cisplatin (100 mg/m²) given to half intravenously and the other half intraperitoneally. Results from that study showed surgically defined complete responses of 47% and 36% in the intraperitoneal and intravenous groups, respectively. Median survival times were 49 and 41 months for the intraperitoneal and intravenous groups, respectively, and the survival differences were statistically significant (P < .02). There was also less toxicity in the intraperitoneal group. This study has been criticized by some for several reasons: (1) the accrual was extended after an "interim" analysis to accrue more patients with low-volume residual disease ( 0.5 cm), a cohort in which there was no statistical benefit to intraperitoneal therapy; (2) the survival hazard ratio planned (0.67) was not reached in this study (0.76); and (3) the surgically documented complete response rate in the intravenous group was lower than that in previous studies using a similar therapeutic regimen. Nevertheless, this study did accomplish the goal of demonstrating that intraperitoneal therapy was superior to intravenous therapy. A smaller study from Italy, however, was unable to show any advantage for intraperitoneal versus intravenous cisplatin (50 mg/m²) in conjunction with intravenous epidoxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²).⁹

SACRIFICE BUNT

In this issue of the Journal of Clinical Oncology, the results of another moderately large randomized trial are reported.¹⁰ In this trial, 462 assessable patients with optimally cytoreduced ovarian cancer (residual mass 1 cm) were randomly allocated to receive either intravenous or intraperitoneal therapy consisting of a platinum and a taxane, which had become the standard of care in the United States shortly after this trial was activated. Paclitaxel was administered to both groups intravenously (135 mg/m² over 24 hours). Cisplatin was administered either intravenously or intraperitoneally (75 mg/m²). In an attempt to further reduce intraperitoneal tumor volumes before initiation of the intraperitoneal cisplatin and improve its distribution and diffusion into tumor tissue, two cycles of moderate-dose carboplatin (dosed to an area under the concentration curve of 9) were given first with the intent of administering six cycles of the platinum and taxane doublet to each group. The moderate-dose carboplatin had the effect of preventing the planned full treatment in the experimental arm, with 18% of patients actually receiving two cycles of intraperitoneal cisplatin, in large part due to chronic thrombocytopenia from the prior carboplatin therapy. Other toxicities, including neutropenia and gastrointestinal and metabolic toxicities, also predominated to a significant degree in the experimental arm. On the positive side, there were some outcome advantages in the experimental arm; progression-free survival favored the intraperitoneal arm (28 v 22 months; relative risk, 0.78; P = .01, one-tailed), as did survival (63 v 52 months; relative risk, 0.81; P = .05, one-tailed). This was the first study to ever break the 5-year median survival barrier. The overall benefit of this or any therapy, however, is the ability to control disease long term or even cure the patient. It is unfortunate in this trial that the surgical definition of complete response (a likely surrogate for protracted disease control) was not adhered to by the investigators Survival end points were likely influenced by salvage therapies, which were uncontrolled in this study. Progression-free survival may also have been influenced if salvage therapies were administered before clinical progression (marker-only relapse); how frequently this occurred in this trial is not divulged by the authors.

Appropriately, the authors do not suggest that the experimental regimen used in this study should become a standard of care, nor even used in "standard clinical practice." They do suggest that the outcomes of this trial lend support to the concept of regional therapy and that lessons learned here have led to a more rational approach for the future. This trial has been replaced by another recently completed trial in which the same patient population was randomized to intravenous cisplatin and paclitaxel or intravenous paclitaxel on day 1, intraperitoneal cisplatin on day 2, and intraperitoneal paclitaxel on day 8 of a 21-day cycle. Thus, this sacrifice bunt may have moved the runner from first to second and into scoring position, even though this batter was thrown out at first. If the recently completed trial, however, does not show a significant advantage in therapeutic index for the regional therapy approach, most will logically conclude that the batter who is up simply hit into a 6-5-3 double play.

It is important to be cognizant that when paclitaxel was initially brought into primary therapy and the results initially reported in abstract form in 1993 and again in 1995, and before their publication in 1996,¹¹ most clinicians in the United States rapidly adopted this new doublet as the standard of care. The hazard ratios in that study were on the order of 0.70 for both progression-free and overall survival, not dissimilar from the hazard ratios reported in this and the previous randomized trials of intraperitoneal and intravenous therapies. Yet intraperitoneal therapy has certainly not become the standard of care, which may be in large part due to a perceived lack of therapeutic efficacy or significant toxicity associated with the therapy, in effect a perception regarding the therapeutic index of the therapy. So even after this sacrifice bunt, the next hit will have to be solid enough to bring the man on second home. That trial has now reached its accrual goals, and the results will be forthcoming in some 3 years. We all await the results of this "correct" approach to regional therapy. In the interim, there are many new cytotoxic drugs already on the market with clear activity in ovarian cancer (gemcitabine, oral etoposide, pegylated liposomal doxorubicin, and topotecan). We no longer have the luxury of utilization of precious patient resources to further explore high-dose or regional approaches with current therapies, just as we no longer have the luxury of exploring issues of dose, schedule, or sequence of administration of current drugs¹² when these new agents deserve incorporation into primary therapy. It is for that reason that the Gynecologic Oncology Group has decided to combine all patients with advanced ovarian cancer into a single study that will explore the role, if any, of three of these agents as part of primary therapy. Several international consortia will likely join in this effort over the ensuing years in what will hopefully become an efficient mechanism to rapidly evaluate the plethora of new drugs that are entering the clinical arena. Our European colleagues have performed trials in stage IIB to IV ovarian cancer for many years. It is now an appropriate time for investigators in the United States to follow suit. The value of regional therapy can be visited in the future if the batter who is up gets the necessary RBI.

REFERENCES

1. Jones RB, Myers CE, Guarino AM, et al: High volume intraperitoneal chemotherapy ("belly bath") for ovarian cancer: Pharmacologic basis and early results. Cancer Chemother Pharmacol 1: 161-166, 1978[Medline]

2. Ozols RF: Intraperitoneal therapy in ovarian cancer: Time’s up. J Clin Oncol 9: 197-199, 1991[Medline]

3. Muggia FM, Alberts DS: Intraperitoneal chemotherapy in ovarian cancer: Time’s not up. J Clin Oncol 9: 1510-1511, 1991[Medline]

4. Ozols RF: Intraperitoneal salvage chemotherapy in ovarian cancer: Who’s left to treat? Gynecol Oncol 45: 1-2, 1992[Medline]

5. Markman M: Intraperitoneal therapy of ovarian cancer. Semin Oncol 25: 256-260, 1998

6. McGuire WP: How many more nails to seal the coffin of dose intensity? Ann Oncol 8: 311-313, 1997[Free Full Text]

7. Barakat R, Almadrones L, Venkatraman E, et al: A phase II trial of intraperitoneal cisplatin and etoposide as consolidation therapy in patients with stage II-IV epithelial ovarian cancer following negative surgical assessment. Gynecol Oncol 69: 17-22, 1998[Medline]

8. Alberts DS, Liu PY, Hannigan EV, et al: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335: 1950-1955, 1996[Abstract/Free Full Text]

9. Gadducci A, Carnino F, Chiara S, et al: Intraperitoneal versus intravenous cisplatin in combination with intravenous cyclophosphamide and epidoxorubicin in optimally cytoreduced advanced epithelial ovarian cancer: A randomized trial of the Gruppo Oncologico Nord-Ovest. Gynecol Oncol 76: 157-162, 2000[Medline]

10. Markman M, Bundy BN, Alberts DS, et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: An intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19: 1001-1007, 2001[Abstract/Free Full Text]

11. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and IV ovarian cancer. N Engl J Med 334: 1-6, 1996[Abstract/Free Full Text]

12. McGuire WP: Confirmation of the "old" standard of care for ovarian cancer and a challenge. J Natl Cancer Inst 92: 674-675, 2000[Free Full Text]

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