Long-term significance of urinary neopterin in ovarian cancer: a study by the Austrian Association for Gynecologic Oncology (AGO).

BACKGROUND: Neopterin is produced by activated macrophages upon stimulation with interferon-γ (IFN-γ) and thus, elevated neopterin concentrations in patients indicate cellular inate immune response. Most studies in patients with malignant diseases found an association between higher neopterin concentrations and reduced survival and impaired prognosis. Nevertheless, neopterin is not a classical tumor marker since it is not produced by the cancer cells themselves. PATIENTS AND METHODS: In a study conducted by the Austrian Gynecologic Oncology Group (AGO) in 114 patients with ovarian cystadenomas and 223 patients with invasive ovarian cancer, patients' urinary neopterin was determined before and after primary therapy. The relevance of neopterin in long-term median follow-up was assessed. RESULTS: Elevated levels (cut-off 250 µmol/mol creatinine) were found less frequently in women with benign ovarian cystadenomas (24%) than in patients with malignant disease (58%). After 10 years, only 57% of ovarian cancer patients with elevated urinary neopterin levels survived without disease progression following primary therapy when compared with 86% of women with normal levels (P < 0.001). Along with residual tumor, FIGO stage, age and histological type, neopterin was significantly associated with overall survival (OS) and progression-free survival (PFS). The median PFS was 52 and 12 months and the median OS was 81 and 24 months for patients with normal and elevated neopterin, respectively, P < 0.001. In a multivariate Cox regression analysis, only residual tumor, neopterin and age were independently associated with OS, while only residual tumor was predictive for PFS. Thirty patients with early-stage invasive ovarian cancer (FIGO I and II) were analyzed separately. Of 3 patients with elevated neopterin, 2 died of disease in contrast to 2 out of 27 patients with normal neopterin (P = 0.004). CONCLUSION: In ovarian cancer, the negative impact of elevated urinary neopterin levels indicates a detrimental effect of cancer-associated inflammatory reaction.

Interferon-gamma in combination with carboplatin and paclitaxel as a safe and effective first-line treatment option for advanced ovarian cancer: results of a phase I/II study.

We have previously shown that interferon-gamma 1b (IFN-gamma) in combination with cyclophosphamide and cisplatin significantly prolongs progression-free survival in ovarian cancer. In this phase I/II study, we examined if administration of IFN-gamma is also safe in combination with the current standard treatment, paclitaxel and carboplatin. Thirty-four patients with newly diagnosed advanced epithelial ovarian cancer, FIGO stage III/IV, were treated for six to nine cycles with paclitaxel (175 mg/m(2)) and carboplatin (area under the curve [AUC] 5) every 3 weeks. IFN-gamma was administered in an escalating dose from 6 days/cycle with 0.025 mg sc up to 9 days/cycle with 0.1 mg sc. As expected, administration of IFN-gamma was associated with flu-like symptoms. Grade 3/4 neutropenia was observed in 74% (25 out of 34) of patients. Other side effects, in particular peripheral neuropathies, were within the previously observed ranges for the paclitaxel plus carboplatin combination. Overall response rate (complete or partial response) in patients who received either six or nine doses (0.1 mg) of IFN-gamma/cycle (n = 28) was 71%. IFN-gamma is safe in combination with carboplatin and paclitaxel for first-line treatment of patients with advanced ovarian cancer. This combination should be further evaluated as an immunotherapeutic treatment option for ovarian cancer.

Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial.

Intraperitoneal treatment with interferon-gamma (IFN-gamma) has been shown to achieve surgically documented responses in the second-line therapy of ovarian cancer. To assess its efficacy in the first-line therapy, we conducted a randomized controlled trial with 148 patients who had undergone primary surgery for FIGO stage Ic-Illc ovarian cancer. In the control arm women received 100 mg/m(-2) cisplatin and 600 mg/m(-2) cyclophosphamide, the experimental arm included the above regimen with IFN-gamma 0.1 mg subcutaneously on days 1, 3, 5, 15, 17 and 19 of each 28-day cycle. Progression-free survival at 3 years was improved from 38% in controls to 51% in the treatment group corresponding to median times to progression of 17 and 48 months (P= 0.031, relative risk of progression 0.48, confidence interval 0.28-0.82). Three-year overall survival was 58% and 74% accordingly (n.s., median not yet reached). Complete clinical responses were observed in 68% with IFN-gamma versus 56% in controls (n.s.). Toxicity was comparable in both groups except for a mild flu-like syndrome, experienced by most patients after administration of IFN-gamma. Thus, with acceptable toxicity, the inclusion of IFN-gamm in the first-line chemotherapy of ovarian cancer yielded a benefit in prolonging progression-free survival.

Ovarian preservation in the surgical treatment of cervical carcinoma.

OBJECTIVES: In the surgical treatment of cervical carcinoma the conservation of ovaries in premenopausal women is a common procedure. To date, however, there have been no controlled studies to prove that the risk of recurrence or death from disease is not elevated among women who do not undergo oophorectomy. STUDY DESIGN: We performed a matched pairs analysis according to the tumor volume, comparing the outcomes of patients with in situ conservation of >/=1 ovary with those of control subjects who underwent bilateral oophorectomy. From among 658 patients, 150 pairs with International Federation of Gynecology and Obstetrics stage I disease were matched. Kaplan-Meier survival curves were compared with the log rank test. RESULTS: Among patients who retained their ovaries 5- and 10-year overall survival rates were 98% and 96%, respectively, versus 97% and 97% for the oophorectomy control group. The corresponding figures for progression-free survival were 95% and 94%, respectively, versus 97% and 93%. Outcomes were equal with sufficient power to detect a 10% difference. Three of 214 patients with conservation of ovaries (1.3%) subsequently required oophorectomy, all because of benign ovarian diseases. CONCLUSIONS: Our results confirm that ovarian conservation is safe in International Federation of Gynecology and Obstetrics stage I disease and that the occurrence of subsequent complications in ovaries retained in situ is rare.

Increased radiosensitivity by a combination of 9-cis-retinoic acid and interferon-y in breast cancer cells.

Interferons (IFNs) and retinoic acid (RA) are known to possess antiproliferative effects in various human cancer cell lines, including squamous cervix carcinoma and breast cancer cell lines. Frequently synergistic effects could be observed by the combination of both, and in clinical trials high response rates could be achieved by IFN-alpha in combination with 13-cis-RA in patients with squamous carcinoma of the uterine cervix. Since radiation-potentiating effects of IFNs and RA were described, we evaluated the additional impact of irradiation on three human breast cancer cell lines and investigated the antiproliferative effects of single, double, or triple treatments with IFN-gamma, 9-cis-RA, and irradiation. Antiproliferative effects were observed in all cell lines by any single treatment. When combining IFN-gamma with 9-cis-RA, synergism could be observed in all experiments. The combination of either IFN-gamma or 9-cis-RA with irradiation resulted mostly in additive effects. Irradiation contributed additive or further synergistic effects to the already synergistic effects of the combination of these two drugs. Thus synergism of IFN-gamma and 9-cis-RA always at least persisted fully. These results suggest that a regimen of IFN, RA, and radiotherapy (RT) might be a promising combination in the therapy of solid tumors, where RT is part of the conventional treatment.