Introduction
Carcinoma of the uterine cervix is the fourth most common female malignancy globally, following breast, colorectal and lung cancers (1). In developed countries, including the USA, ~12,900 women are diagnosed with cervical cancer and ~4,100 mortalities per year are attributed to this disease (2). The 5-year overall survival rate is 68% for all stages of cervical cancer; however, the survival rate is 91% when the disease is diagnosed in an early phase. Patients with metastases in regional lymph nodes only have a 57% 5-year survival rate, and those with distant metastases only have a 16% 5-year survival rate. The overall 5-year survival rate is relatively high in Korea (80–81.2% over the last 15-year period) (3). Increased cancer screening and updated treatment strategies are key factors that have produced improved results (4). Specifically, the survival of women with recurrent cervical cancer or para-aortic lymph node (PAN) metastasis remains poor. More effective treatment methods and regimens are therefore needed. Cisplatin is an effective single therapeutic regimen for first-line therapy, but single-agent regimens for recurrent cervical cancer have a poor response rate (only 13%) (5). The recurrence rate is lower for patients with a pelvic recurrence within previously irradiated areas than for those with extra-pelvic sites of disease. In addition, the responsiveness of pelvic recurrences is partial at best and has a brief (median 4–6 months) duration (6). To enhance the therapeutic response, chemotherapy was combined with hyperthermia (cisplatin + hyperthermia for previously radiated cases), which has been demonstrated to be feasible (7) when used in tri-modal applications for the cervix (8–11). By using local hyperthermia and systemic administration of chemotherapy, it is possible to achieve maximum synergism without increasing the systemic side effects, which primarily affect the bone marrow and kidneys (12). Modulated electro-hyperthermia, which was used in the present study, is a type of hyperthermia used in oncological treatments that avoids the drawbacks of conventional electromagnetic heating (13,14). This treatment device is designed to selectively heat malignant tumors and tumor cells by modularly delivering 13.56 MHz RF (15–18). This method works by heating the malignant cells, selectively and effectively acting on the cell membrane (19), and inducing apoptotic cell death (20). This advanced treatment produces damage-associated cellular patterns and promotes immunogenic cell death (21). The heat-induced increase in the tumor response to radiotherapy is due, at least in part, to an increase in the oxygen supply via increased blood circulation in tumors. The enhanced response of tumors to chemotherapy may be due to three factors. First, mild heating increases the delivery of chemotherapy drugs to the tumors by increasing blood flow to and within the tumor. Second, mild heating increases the cellular uptake of drugs by increasing cell membrane permeability. Third, heating facilitates the reaction rate of drugs, which potentiates their cytotoxicity (21,22).
This method uses modulated radiofrequency for energy delivery and achieves selective thermal action in non-homogeneous tissue (23). It is also notably gentle, and its use on brain malignancies has been successful (24–26), even at increased doses for advanced cases (16). Modulated electro-hyperthermia does not cause pain and has fewer side effects, which results in improved patient satisfaction and quality of life (18). Patients treated with modulate electro-hyperthermia have reported pain relief (23) and, as a result, a decreased dose of analgesic is required (22). The aim of the present study was to evaluate the effect of modulated electro-hyperthermia combined with conventional chemotherapy compared with chemotherapy alone on recurrent cervical cancer previously treated with irradiation, by analyzing the outcomes of patients subjected to each treatment. The objectives of the present study were to determine the local control, treatment outcome and side effects.
Discussion
Surgery, chemotherapy, radiotherapy, or a combination of these modalities continues to be the primary treatment option for invasive cervical cancer. However, following surgery and postoperative radiotherapy, primary definitive concurrent chemo-radiation therapy or radiotherapy alone results in the development of recurrent pelvic disease in up to 40% of patients. With the exception of salvage surgery as a treatment option for certain individuals among these patients, the use of systemic chemotherapy is the only remaining treatment modality (27). Cisplatin has emerged as the most active single agent for treating patients with metastatic disease, and no other standard cytotoxic drug has been consistently associated with objective response rates of ≥25%. However, for patients who experience relapse following definitive radiation therapy, cisplatin has only a minor effect (6,28).
In a study by Potter et al (29), the complete response rate to cisplatin in patients with distant metastases was 53% with an overall response rate of 73%, whereas no complete responses and only 7 partial responses (21%) were observed among 33 patients with localized pelvic recurrence or persistent disease. Thus, the application of deep local hyperthermia along with the systemic administration of cisplatin appears to be an attractive option in patients with recurrent pelvic cervical cancer. Once initial feasibility data regarding the clinical use of cisplatin and local hyperthermia combination treatment were reported (29), Rietbroek et al (7) published a phase II study of combined weekly locoregional hyperthermia and systemic cisplatin administration in patients with previously irradiated recurrent cervical carcinoma (30). Using a regimen of 50 mg of cisplatin per week with a one-week interruption following four cycles for a total of 12 cycles, corresponding to a projected dose intensity of 40 mg per week, these authors observed an overall response in 12/23 patients (52%; 95% confidence interval, 31–73%) (7).
The expectation is that a hyperthermia-induced increase in temperature may increase blood flow in the targeted region as a homeostatic response (31,32). An elevated local temperature (≤40°C) has been demonstrated to initiate various physical and chemical processes and to ease pain in patients with cancer (27). Drug potentiation in target tissues increases the treatment response. The temperature increase induced by hyperthermia enhances the reaction rate of a given drug independent of an increase in drug delivery due to enhanced blood flow, and increases the reaction rate in target tumor cells, thereby escalating tumor cell death (18,23). The thermally increased metabolism (the so-called enhanced chemo-metabolism) associated with hyperthermia also increases the absorption of cytotoxins (27) and is expected to enhance drug absorption.
It is well known that heating tumors to mild temperatures, for example 40–43°C, kills tumor cells and increases the tumor response of radiotherapy and chemotherapy with various anti-cancer drugs (33,34). The heat-induced increase in the tumor response to radiotherapy is due, at least in part, to an increase in oxygen supply via the heat-induced enhancement of intratumoral blood circulation. The heat-induced increase in the tumor response to chemotherapy may be due to the following three factors. First, mild heating increases the delivery of chemotherapy drugs to tumors by increasing tumor blood flow. Second, mild heating elevates the cellular uptake of drugs by increasing cell membrane permeability. Third, heating facilitates the reaction rate of drugs, which potentiates their cytotoxicity (27). It must be noted that the systemic body temperature may increase when tumors are treated with regional or local hyperthermia (22). It is therefore likely that such an increase in body temperature may alter the pharmacokinetics of chemotherapy drugs when chemotherapy and regional hyperthermia are concomitantly applied (35).
In the present study, concerning cervical cancer recurrence in patients previously treated with irradiation, chemotherapy combined with modulated electro-hyperthermia significantly increased the treatment response. The overall response rate (CR+PR+SD/PD) to treatment was significantly improved among the patients who underwent chemotherapy combined with modulated electro-hyperthermia compared with those that underwent chemotherapy alone (P=0.0461). At the evaluation conducted at the last follow-up visit, the results were significantly improved in the group that underwent chemotherapy combined with modulated electro-hyperthermia compared with chemotherapy alone (P=0.0218). According to the present study, anti-cancer treatment and hyperthermia may have a synergistic effect.
Specifically, in the case of chemotherapy alone, significant recurrence was observed only when the cervix was the target of the therapeutic response (P=0.0456), but in the chemotherapy combined with modulated electro-hyperthermia group, no significant differences in abdominal lymph node and cervical recurrence were observed (P=0.6199). Hyperthermia may therefore be slightly more effective for the treatment of abdominal lymph node metastasis.
The present study demonstrated the feasibility and advantages of chemotherapy combined with hyperthermia, concurrent with the application of platinum derivatives, for patients with recurrent cervical cancer who have regional lymph node metastasis. A longer-term follow-up study is required to compare the disease-free survival rates of patients.