Maintenance Treatment With Interferon for Advanced Ovarian Cancer: Results of the Northern and Yorkshire Gynaecology Group Randomised Phase III Study

Objectives:

* Must patients with advanced epithelial ovarian cancer ultimately relapsed even after favorahle response to chemotherapy.

* Although a variety of strategies have been tested, increased response rate has not been associated with improvement in survival.

* The maintenance therapy using low dose interferonalpha (INFa) improved survival of patients with multiple myeloma, who demonstrated no evidence of disease progression following primary chemotherapy.

* Therefore, it is hypothesized that maintenance therapy using INFa may be effective in patients with epithelial ovarian cancer following surgery and/ or chemotherapy, and radomized Phase III trial was performed.

Patients and methods:

* Patients with histologically proven epithelial ovarian cancer with no evidence of disease progression following postoperative chemotherapy were eligible.

* 300 patients were randomized either to no maintenance treatment group or INF-a 2a (4-5 mega-units subcutaneously 3 days per week).

* The INF was continued until disease progression, or in response to toxicity or patient request.

Results:

* Between 1990 and 1997, in 300 patients 151 were randomized to observation group and 149 was to interferon greoup.

* The baseline patient characteristics was similar in the two treatment arms.

* The median follow-up time for interferon group was 27.0 months (range 2.3-149.7), and for observation patients 32.2 months (range 1.7-141.7) for observation group.

* 144 received at least one injection of INFa.

* The most common adverse event for both interferon and observation patients was fatigue (72 and 46%, respectively) and dose modification of INFa was made in 18 (12.5%) patients due to toxicity.

* The median overall survival in the interferon arm was 27.0 months and in the observation arm 32.7 months.

* The median clinical event-free survival in the interferon arm was 10.3 months and 10.4 months in the observation arm.

* No benefit for interferon maintenance was seen in terms of either overall or clinical event-free survival.

* Subset analysis was made to compare the survival and clinical event free survival regarding the use of INF among disease free group and disease present group after initial surgery and /or chemotherapy, but no benefit of maintenance therapy using INFa was observed.

Discussion:

This trial was designed to determine whether the use of low-dose subcutaneous INFa could improve the overall survival of patients with epithelial ovarian cancer following primary therapy with surgery and/or chemotherapy. Patients with all stages of disease at presentation and with no evidence of disease progression after primary therapy were randomised within the trial. The overall and clinical event-free survival of ovarian cancer patients studied within this trial was typical of results obtained with platinum combination chemotherapy in the 1990s. However, survival times were not improved by the addition of maintenance low-dose subcutaneous IFNa following primary therapy.

Interferon-a has been shown to have an in vitro activity against ovarian cancer cell lines (Epstein et ai. 1980) and a limited clinical benefit in advanced ovarian cancer (Freedman et al. 1983; Einhorn et al. 1988). Clinical studies have assessed the effect of intraperitoneal INFa in a number of phase II studies both after and in combination with platinum chemotherapy (Berek et ai 1985; Nardi et al. 1990; Willemse et al. 1990; Bruzzone et al. 1997; Berek et al. 1999). These studies have confirmed that such a treatment can he delivered although its benefit over standard treatment has not been assessed. No clinical trial of subcutaneous INFa in ovarian cancer has previously been reported. However, an alternative immunoregulatory cytokine, interferon-g has been assessed in a randomised phase III trial as an addition to primary chemotherapy with cisplatin and cylophosphamide (Windbichler et al. 2000). This showed a significant improvement in progression-free survival. However, improvements in clinical response rate and overall survival did not achieve statistical significance.

Experience with biological therapy has suggested that the benefits of such therapy are often seen in patients with small volume or clinically undetectable disease. Although this effect has also been seen in previous trials of cytokine therapy in ovarian cancer (Berek et al. 1985; Pujade-Lauraine et al. 1996), the recent study of interferon-g showed equal efficacy in patients with both small and large volume disease (Windbichler et al. 2000). To mirror the initial study of interferon maintenance in myeloma, patients with no evidence of disease progression following primary therapy were randomised and therefore, many patients with residual disease were randomised. However, a subgroup analysis of the patients in complete clinical remission within this study failed to identify a significant benefit for those patients.

Compliance with interferon maintenance was poor. At 6 months, only 67% of patients with no evidence of disease progression remained on interferon maintenance. This is likely to be due to the fact that this cohort of patients had undergone both surgical intervention and chemotherapy prior to commencing interferon treatment. This is in contrast to studies in myeloma, renal cancer and melanoma in which treatment rarely follows both extensive surgery and chemotherapy. Pegylated interferon has recently been introduced into clinical trials. The half-life of these modified forms of interferon are significantly increased allowing weekly administration. It may be that the use of such treatment would improve compliance by reducing both the frequency of administration and the toxicity associated with the treatment. Despite modern chemotherapy combinations, the natural history of ovarian carcinoma remains one of relapse following initial response to chemotherapy. A potential benefit for maintenance paclitaxel chemotherapy for some patients with ovarian cancer has recently been reported although at the cost of clinically significant toxicity (Markman et al. 2003). The need for an effective nontoxic maintenance therapy is clear. This study has demonstrated that subcutaneous INF-a given following surgery and chemotherapy is not the answer to this ongoing dilemma.

However, the recent development of new, targeted molecular therapies may allow the concept of maintenance therapy to be examined further.

Conclusion:

* The maintenance therapy with INFa did not improve the survival in patients with epithelial cancer following surgery and/or chemotherapy.

Selected references:

Berek JS, Hacker NF, Lichtenstein A, et al. Intraperitoneal recombinant alpha-interferon for “salvage” immunotherapy in stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. Cancer Res 1985;45:4447-53

Berek JS, Markman M, Stonehraker B, et al. Intraperitoneal interferon-alpha in residual ovarian carcinoma: a phase II gynecologic oncology group study. (Jynecol Oncol 1999;75:10-4

Bruzzone M, Rubagotti A, Gadducci A, et al. Intraperitoneal carboplatin with or without interferon-alpha in advanced ovarian cancer patients with minimal residual disease at second look: a prospective randomized trial of 111 patients. G.O.N.O. Gruppo Oncologic Nord Ovest. Gynecol Oncol 1997;65:499-505

Einhorn N, Ling P, Einhorn S, Strander H. A phase II study on escalating interferon doses in advanced ovarian carcinoma. AmJ Clin Oncol 1988;! 1:3-6

Freedman RS, Gutterman JU, Wharton JT, et al. Leukocyte interferon (IFN alpha) in patients with epithelial ovarian carcinoma. ] Biol Response Mod 1983;2:133-8

Nardi M, Cognetti F, Pollera CF, et al. Intraperitoneal recombinant alpha-2-interferon alternating with cisplatin as salvage therapy for minimal residual-disease ovarian cancer: a phase II study. J Clin Oncol 1990;8:1036-41

Willemse PH, de Vries EG, Mulder NH, et al. Intraperitoneal human recombinant interferon alpha-2b in minimal residual ovarian cancer. Eur ] Cancer 1990;26:353-8

Windbichler GH, Hausmaninger H, Stummvoll W, et al. Interferon- gamma in the first-line therapy of ovarian cancer: a randomised phase III trial. BrJ Cancer 2000; 82:1138-44

Commentary:

Standard treatment approach for advanced epithelial cancer is the primary dehulking surgery followed by chemotherapy with paclitaxel plus carhoplatin. Although primary response of the disease to this regimen is reasonable, long term prognosis is not satisfactory. Therefore, it is necessary to seek other additional strategies such as maintenance chemotherapy.

Although Markman et al. demonstrated a significant improvement of progression-free survival by using monthly administration of paclitaxel, overall survival benefit was not tested because of early closure of the study. Nevertheless, this study was the only trial that showed survival advantage by addition of maintenance chemotherapy. However, since maintenance chemotherapy with paclitaxel produced a significant increase of toxicities, the need of less toxic regimen is obvious.

Immunological agents such as interferon may be of interest as a less toxic maintenance therapy agent. In this study prolonged use of INFa did not demonstrate survival benefit in patients with epithelial ovaria\n cancer after surgery and/or chemotherapy. This may be due to the low compliance of the use of INFa probably because of toxicity such as fatigue. The main issue in the maintenance immunotherapy is the dose determination of the agents. Recently, Fujiwara et al. reported that immunomodulator agent higher dose of Z- 100 may adversely affect on survival compared with lower dosage in patients with locally advanced cervical cancer of the uterus when treated with radiation therapy. This study clearly indicated the necessity of further investigations, such as determination of the optimal dose, to elucidate the role of immunological agents.

Further reading:

Markman M, Liu PY1 Wilczynski S, 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;21:2460-5

Fujiwara K, Ohashi Y, Nakayama H, et al. Phase III doubleblind randomized trial of radiation therapy for stage UIB cervical cancer in combination with low or high dose Z100, immunomodulator widely used in Japan. Proc Am Soc Clin Oncol 2004;Abstract #5029

Hall GD et al. Br J Cancer 2004;91:621-6

Commentary by: Keiichi Fujiwara, Kawasaki Medical School, Kurashiki City, Japan

Copyright CRC Press Dec 2004