Immunotherapy in Ovarian Cancer

The use of intravenous or subcutaneous immunostimulants in addition to chemotherapy has not improved the response rate or survival of ovarian cancer patients. The GOG used melphalan with or without subcutaneous administration of Corynebacterium parvum in a randomized trial, and there was no difference between the two groups. Another trial used combination chemotherapy with cisplatin, doxorubicin, and cyclophosphamide with or without BCG (Bacillus Calmette-Guerin) by scarification in patients with suboptimal ovarian cancer, and there was no difference between the two groups. This finding was confirmed in a study by SWOG. The intraperitoneal administration of C. parvum did produce complete responses in some patients with minimal residual disease at second-look laparotomy, suggesting that the regional administration of an immunostimulant, similar to the intralesional injection of melanoma with BCG, might be an effective way to control small amounts of residual cancer confined to the peritoneal cavity.

Based on the response seen with regional nonspecific immunotherapy, several trials of intraperitoneal cytokines have been performed. In a GOG study, recombinant human IFN-α exhibited activity when administered i.p. to patients with minimal residual ovarian cancer. Administration of 25-50 million units three times a week was not tolerated because of persistent general malaise, fever, and gastrointestinal toxicity. Treatment with the same dose once a week was tolerated for 8-16 consecutive weeks. Notably, there was an absence of significant neurotoxicity and renal toxicity. While most of the side effects of single agent recombinant IFN-α seem to complement those of cisplatin, the general malaise and gastrointestinal toxicity produced by both could potentially be additive when these agents are combined. Similar results were reported in another trial of IP IFN-α in the Netherlands. The toxicity encountered in this trial was similar to that seen in the Phase I GOG trial. In a follow-up Phase II trial conducted by the GOG, there was a 28% surgically-documented response rate in 25 patients with platinum-sensitive minimal residual tumors. Overall, 53 surgically evaluated patients have been treated in three trials, with 40% responses and 25% complete responses. All of the responding patients had microscopic or small macroscopic residual disease. Thus, the use of high-dose IP recombinant IFN-α given frequently can result in the regional control of very small-volume disease confined to the peritoneal cavity. Whether survival is affected is not known. Other cytokines have been evaluated. A Phase I-II trial of intraperitoneal interferon-γ also yielded a 30% response rate. Another phase I trial with intraperitoneal IL-2 has been performed, and the optimal dose was defined.

Preclinical studies have examined the interaction of cytokines, such as IFN-a, tumor necrosis factor, and IL-2, with various cytotoxic agents, including cisplatin and doxorubicin Even low doses of cytokines can induce synergistic activity with standard cytotoxic drugs against fresh ovarian cancer cells in vitro. Italian investigators reported a surgically-documented complete response rate of 50% when ovarian cancer patients received weekly treatment IP with cisplatin, alternating with human IFN-α (50 x 10 units). Responses were confined to those patients who started their treatment with minimum residual disease. Toxicity was similar to that seen with IFN-α alone. Therefore, the combination of IP cisplatin and IFN-α appeared to be tolerated and resulted in an appreciable response rate. Since response rates were similar to those reported in other studies of single-agent IP cisplatin, it was unclear whether the addition of IFN-α to the cisplatin had any significant benefit. When the GOG conducted a study of combined IP IFN-α and cisplatin, a very low partial response rate of 7% was seen, contrary to the results of other Phase I-II trials of IP cisplatin and IFN-α in patients with residual small-volume ovarian cancer, in which response rates of 20% to 40% have been noted. In the GOG study, however, most evaluable patients had extensive carcinomatosis that was cisplatin-resistant and the maximum tumor diameters were > 1 cm. In a follow-up Phase II study of IFN-α alternating with cisplatin in patients with platinum-sensitive minimal residual disease, the surgically-documented response rate was 28%. In a randomized Phase III trial, Windbichler and colleagues have demonstrated that the use of subcutaneous interferon-γ in women receiving first-line platinum-based chemotherapy in ovarian cancer was well-tolerated. A higher complete clinical response rate (68% vs 56%) and longer disease progression-free survival (48 months vs 17 months, p = .031) was observed in women receiving the interferon-γ plus chemotherapy than in women who were treated with chemotherapy alone. Improved progression-free survival was seen in patients with residual disease greater than 2 cm, as well as in those with optimal resection.