Ovarian carcinoma is the second most common gynecologic cancer and the leading cause of death from gynecologic malignancy. Epithelial ovarian cancer represents the primary cause of death from gynecological cancer in Western countries, with approximately 26000 new cases diagnosed in the United States each year [[14–17]]. More than two-thirds of patients with epithelial ovarian cancer are diagnosed in an advanced stage of disease at presentation because of the absence of specific signs and symptoms. The 5-year overall survival ranges from 89% for stage IA to 13% for stage IV disease, according to the annual report from FIGO . About 40-85% of patients who have stage II to IV disease will relapse after primary therapy and develop abdominal or pelvic recurrence; these tumors are also characterized by a low response rate to further chemotherapy and subsequent poor prognosis (5-year survival rate < 25%) [19, 20]. Invasion of the ovarian capsule and dissemination in the peritoneal cavity is the main route by which ovarian carcinoma spreads , accounting for about 82% of cases; in contrast, only 12% of ovarian metastatic events involve the retroperitoneal lymph nodes .
Platinum/paclitaxel-based chemotherapy is the current standard of treatment after surgical staging and resection of abdominal and pelvic cancers. Despite the significant advances in treatment, however, the prognosis remains poor since the standard therapy does not lead to a sufficient reduction of tumor cells and fails to cure. Abdominal radiotherapy offers the possibility of improved tumor control; moreover, the potential role of radiotherapy for improving disease control in the abdomen and pelvis may increase the disease-free interval and survival . To date, however, there has been no proven benefit and there is significant toxicity associated with this treatment. Thus, an alternative effective therapy is urgently needed.
IOERT improves the therapeutic ratio by decreasing the toxicity in dose-limiting normal tissues that can be displaced or protected. It can be administered as an upfront radiation boost, simultaneously with surgical resection, which might allow total electron beam radiation therapy (EBRT) dose to be decreased without jeopardizing local control or survival. Another possible advantage of IOERT is that it might indirectly improve the quality of therapy by decreasing the overall treatment time as a secondary endpoint . IOERT clinical trials have also been mainly conducted on patients with locally advanced malignancies in the abdomen and pelvis [8, 24]. In this study, we observed that it was especially effective in patients who had an adequate resection of their localized extraperitoneal recurrence and a significant survival benefit whether the patients had primary disease or not. The 5-year overall survival rates were 64% in the PD group and 60% in the ILR group. Non-IORT approaches have been reported in the literature as producing OS rates of 20.6% for primary ovarian patients (stage III) and < 25% for recurrent cases [[19, 20, 25]].
Among the 14 patients with local failures in our study, a significant proportion (10/14) of the relapse sites were found outside of the IOERT targeted region. In addition, with the low toxicity associated with IOERT, the quality of life was considered an important endpoint in these patients, which is particularly dependent on strategies providing high local control rates and organ preservation, such as bladder, intestines, sigmoid colon, and the pelvic portion of the obturator nerve). Moreover, in this series we have shown that disease limited to the local and regional areas can be successfully treated with significant overall survival and disease-free survival. Even though ovarian cancer is known to have high incidence of widespread metastases, this is not always the case.
Our regimen also exhibited a favorable survival time, even in cases of abnormal CA-125 levels at pre-treatment and obvious decline in CA-125 serum level following tumor resection, IOERT, and IP chemotherapy. A study by Krivak et al. found that patients with an abnormal CA-125 (> 35 U/mL) prior to treatment were 2.45 times more likely to experience disease progression and 2.78 times more likely to die of disease, as compared to patients with CA-125 < 35 U/mL .
Although the absolute number of toxicities was lower in the present study, the incidence rate of neurotoxicity seems high. Neuropathy is a dose-limiting toxicity in IOERT and other anatomic sites treated with this modality. Animal studies have shown that the tolerance of nerve structures to IOERT may be lower than 15 Gy . In the present series, 11% of the patients developed symptoms associated with peripheral neuropathy. In four of these patients, substantial improvement was observed over time, with successful recovery noted at prolonged follow-up. Peripheral nerves in the IOERT field are dose-limiting structures requiring a dose compromise or the activation of the nerve protection policies in the IOERT component to avoid severe neurological damage.
In addition, the findings from this study suggested that subsequent IP chemotherapy may have improved the local control rates. This is consistent with a report by Chin et al. . Combined treatment modalities increase the effect of radiation significantly. IP chemotherapy was first proposed in the 1970s as a way to maximize drug delivery to the tumor while avoiding systemic toxicities associated with IV administration of the same agents [[28–30]]. The results of the Gynecologic Oncology Group (GOG-172) phase III trial demonstrated that bidirectional chemotherapy using IV paclitaxel plus IP cisplatin and paclitaxel significantly improved survival in patients with optimally debulked stage III disease . Based on these results, the National Cancer Institute and GOG have issued a clinical announcement recommending that patients with stage III ovarian cancer should be considered for IP chemotherapy after undergoing optimal surgical cytoreduction . Owing to the unique properties of the peritoneum, IP chemotherapy affords the opportunity to use higher concentrations of drugs for prolonged periods of time, directly bathing resected tumor beds, lymph node basins, and residual tumor nodules in the therapeutic agent. Unfortunately, IP chemotherapy is still limited by the fact that it cannot penetrate into large tumor nodules, essentially 3 mm or greater; IOERT may be able to do this, however . Our retrospective study suggests that IOERT plus IP chemotherapy may be a useful treatment for selected patients with EOC. Therefore, with the encouraging results of this report, IOERT plus IP chemotherapy should be further studied for its utility in chemoresistant patients with recurrent ovarian cancer.
Although IOERT has been recommended for recurrent cervical cancer by the National Cancer Institute , to our knowledge, the present report represents the first systematic review of the activity of IOERT plus IP chemotherapy against EOC. The limitations of this report are those associated with any retrospective study, including potential referral bias, other types of selection bias, and a variety of treatments, doses, and schedules. In addition, IOERT in ovarian carcinoma has not been investigated in detail, and this research did not reach statistical significance because of the small numbers in this series; nonetheless, we did observe a marked advantage in overall survival and disease-free survival. We have also demonstrated that the involved field of radiation therapy was relatively unaffected in this heavily pretreated population.
The findings of this study confirm our clinical impressions and provide important information with which to move forward in developing better therapies for advanced and recurrent carcinoma of the ovary. Additionally, the current systemic therapy options are all associated with toxicities that are potentially detrimental to a patient's overall quality of life or well-being. The IOERT treatment provided good prognosis of EOC, and in some cases with postoperative IP chemotherapy. A prospective randomized control trial comparing IOERT with various chemotherapies, established or candidates for EOC, should be considered. Our findings also suggest the need for larger studies to determine the role of IOERT in local and regional control and to evaluate its impact on distant metastasis and overall survival in advanced and recurrent ovarian cancers.