Intraoperative radiation therapy in recurrent ovarian cancer

Purpose: To evaluate disease outcomes and complications in patients with recurrent ovarian cancer treated with cytoreductive surgery and intraoperative radiation therapy (IORT).

Methods and Materials: A retrospective study of 24 consecutive patients with ovarian carcinoma who underwent secondary cytoreduction and intraoperative radiation therapy at our institution between 1994 and 2002 was conducted. After optimal cytoreductive surgery, IORT was delivered with orthovoltage X-rays (200 kVp) using individually sized and beveled cone applications. Outcomes measures were local control of disease, progression-free interval, overall survival, and treatment-related complications.

Results: Of these 24 patients, 22 were available for follow-up analysis. Additional treatment at the time of and after IORT included whole abdominopelvic radiation, 9; pelvic or locoregional radiation, 5; chemotherapy, 6; and no adjuvant treatment, 2. IORT doses ranged from 9–14 Gy (median, 12 Gy). The anatomic sites treated were pelvis (sidewalls, vaginal cuff, presacral area, anterior pubis), para-aortic and paracaval lymph node beds, inguinal region, or porta hepatitis. At a median follow-up of 24 months, 5 patients remain free of disease, whereas 17 patients have recurred, of whom 4 are alive with disease and 13 died from disease. Five patients recurred within the radiation fields for a locoregional relapse rate of 32% and 12 patients recurred at distant sites with a median time to recurrence of 13.7 months. Five-year overall survival was 22% with a median survival of 26 months from time of IORT. Nine patients (41%) experienced Grade 3 toxicities from their treatments.

Conclusion: In carefully selected patients with locally recurrent ovarian cancer, combined IORT and tumor reductive surgery is reasonably tolerated and may contribute to achieving local control and disease palliation.

Introduction

Notwithstanding the improvement in the relative survival of women diagnosed with invasive epithelial ovarian cancer from 37% to 43% over the past three decades, ovarian cancer survival rate remains much lower compared with the 61.5% overall cancer survival statistic for women (1). A major issue is tumor recurrence within the first 3 years despite an initially promising tumor response (2, 3, 4). Recurrence of chemoresistant ovarian cancer is usually a fatal occurrence because the salvage rate with current treatment modalities is very low. The median disease-free survival is approximately 20–25 months with a median overall survival of 50 months in optimally debulked advanced-stage patients (5, 6, 7). Attempts at improving outcomes for these patients with additional systemic treatments using intravenous and intraperitoneal chemotherapy, regional radiotherapy, and high-dose chemotherapy with autologous stem cell transplantation have been described in the literature (8, 9, 10, 11, 12, 13, 14, 15, 16). Response rates to these various treatment modalities have varied, with some studies showing potential benefit of some type of therapy compared with no further treatment. Few studies definitively prove prolongation of life, with room remaining for treatment improvements with respect to efficacy, safety, and toxicity.

The disappointing median overall survival rates have therefore prompted studies of numerous multimodality treatments in adjunctive, sequential, or consolidative settings. In fact, the role of radiotherapy as an adjuvant or salvage therapeutic modality in recurrent, chemoresistant ovarian cancer has been extensively investigated with curative potential demonstrated in a selected subgroup of patients (17, 18, 19, 20, 21, 22). In this radiosensitive tumor, adjuvant whole abdominopelvic radiation therapy (WAPRT) has been reported to be effective and be of benefit for patients with minimal residual ovarian cancer (17, 18, 19, 20, 21, 22, 23, 24). Recently, two well-designed prospective randomized trials showed a survival benefit in patients with epithelial ovarian cancer randomized to receive postchemotherapy whole-abdominal radiation vs. no additional treatment (13) and in patients with pathologic complete response after chemotherapy randomized to whole-abdominal radiation vs. additional chemotherapy vs. no further treatment (14). However, well-documented toxicities related to WAPRT, including acute hematologic and delayed intestinal side effects (17, 24) constrain the amount of tolerable external beam radiation therapy (EBRT) that can be delivered. Although the EBRT dose to the whole abdomen is limited by the radiation tolerance of the small intestine, liver, and kidney to approximately 20–25 Gy, the optimal EBRT dose necessary to control microscopic upper abdominal disease is in the range of 22.5–30 Gy. Macroscopic tumor deposits would require even higher doses of EBRT—around 50–60 Gy—for disease control (25, 26). These factors, along with the advent of new chemotherapeutic agents, have, therefore, led to a decline in the use of WAPRT in ovarian cancer.

Intraoperative radiation therapy (IORT), which delivers a single high dose of radiation to the tumor bed directly, is an important treatment modality in the management of gynecologic malignancies. A single-dose IORT has been reported to have two to three times the biologic effect of fractionated EBRT, with an IORT dose of 15 Gy being equivalent to 30–45 Gy of fractionated EBRT (27). IORT, therefore, can deliver sufficiently high doses of radiation to residual tumor cells following cytoreductive surgery with minimal exposure to surrounding tissues because radiation-sensitive structures can be displaced away from the treatment fields. Indeed, review of the available literature suggests that use of IORT in patients undergoing salvage surgery for recurrent gynecologic cancer may improve long-term local control and overall survival (27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38).

The present study reports specifically on the outcomes of a cohort of 22 patients with recurrent ovarian carcinoma in whom IORT was added to the treatment armamentarium in an attempt to potentially improve local control and disease-specific survival.