Hyperthermia classic commentary: ‘A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIB cervical carcinoma’ by Yoko Harima, International Journal of Hyperthermia 2001;17:97–105

Abstract

In our classic paper, we investigated both the clinical response and survival of patients treated with radiotherapy (RT) or thermoradiotherapy (TRT; RT plus hyperthermia [HT]) for Stage IIIB cervical carcinomas. Our study clearly demonstrated that TRT can result in beneficial effects for complete response and/or local relapse-free survival. To date, six randomized trials including our study have been published on the additive effect of HT in patients with locally advanced cervical cancer. In contrast, the combination of RT and platinum-based chemotherapy (CT) has gained wide acceptance. However, two recent meta-analyses suggested that the impact of adding CT to RT is less obvious in patients with advanced-stage tumors. Conversely, four of six randomized trials comparing the results of RT alone with TRT showed a beneficial effect for the patients with Stage IIIB tumors. From this, the patients with higher stage or bulkier tumors may benefit more from the addition of HT to RT than the addition of CT. To demonstrate the effectiveness of TRT for some cancers, including locally advanced cervical cancer, well designed randomized clinical trials are necessary.

• Hyperthermia
• cervical cancer
• randomized study

Cervical cancer is one of the most common gynecological cancers, both in incidence and mortality, with nearly 500,000 women developing the disease each year worldwide, and about half the women afflicted dying [1]. For many years, the standard treatment of advanced cervical carcinoma has been radiotherapy (RT). However, the ability of RT to cure locally advanced cervical cancer is limited by the size of the tumor, because the doses required to treat large tumors exceed the limit of toxicity of normal tissue. Locoregional failure rate of RT for advanced cervical carcinoma is 41-72% [2], [3]. If locoregional tumor control can be achieved definitively, the potential gain in survival is estimated to be 50–60% [4], [5]. Efforts to overcome this problem have included the concurrent use of chemotherapy (CT) [6] or hyperthermia (HT) [7], [8]. Thermoradiotherapy (TRT; RT plus HT) has been reported to yield higher complete and durable responses compared with RT alone in both superficial and deep-seated tumors [9], [10].

To clarify the role of TRT for the International Federation of Gynecology and Obstetrics (FIGO) stage IIIB cervical carcinomas, the present study investigated both the clinical response and survival of patients treated with radiotherapy or thermoradiotherapy [7].

To date, six randomized trials [8], [11–14], including a previous study by the present author [7], comparing the results of RT alone with TRT have been published. The majority of the patients in these studies had stage IIIB tumors. Four of these trials showed significantly better complete response, locoregional tumor control, disease-free survival, and/or overall survival rates. In one study [12], the 1.5-year pelvic control tended to be higher in the TRT group.

The previous study [7] clearly demonstrated that the addition of HT to conventional RT can result in beneficial effects for complete response (P = 0.048) and/or local relapse-free survival (P = 0.048). The Dutch study [8] showed a significant improvement in overall survival in the TRT group compared with RT alone. The study by Datta et al. [11] and the previous study [7] showed a trend of better overall survival of patients treated with TRT compared with RT alone; however, the difference was not significant. The report of Chen et al. [13] is in Chinese, which makes most of the data inaccessible. They randomized patients to four treatment groups: RT alone, RT plus HT, RT plus CT (cisplatin, 5 FU, and vincristin), and RT plus HT plus CT.

In only one trial by Vasanthan et al. [14] was no beneficial effect from TRT found. The lack of benefit from TRT in the study by Vasanthan et al. may be partly explained by an imbalance in tumor volume over the two treatment arms, the median tumor volume in the TRT arm was 60.3 cc whereas in the RT arm it was 49.5 cc. Probably the most important problem in their study is that the treatment application method may have been inadequate [15]. The HT technique used and the thermometry data obtained were considerably shorter according to published guidelines [8], [16]. An inadequate heating technique was the most plausible explanation for not finding an effect of adding HT to standard treatment with RT in several published trials [17], [18]. Vasanthan et al. [14] used a capacitive heating technique, with which it is principally possible to achieve therapeutic heating at depth, provided that the limitations of this technique are taken into account. The one center that treated half of these patients, and possibly other centres as well, were reported to have used an intra-vaginal electrode. This results in a high energy level and high temperatures in a small volume around the intra-vaginal electrode with much lower temperatures in the periphery of the tumor. In the previous study [7], using a radiofrequency capacitive heating device with 8 MHz radiofrequency electromagnetic waves, the average temperature was 40.6°± 1°C, which was in the radiosensitizing range.

Since the National Cancer Institute's clinical alert in 1999, the combination of RT and platinum-based chemotherapy (RCT) has gained wide acceptance. However, important concerns about RCT remain, because most RCT trials included relatively few patients with advanced-stage tumors (FIGO stage>II) [6]. Two recent meta-analyses suggested that the impact of adding chemotherapy to RT is less obvious in patients with advanced-stage tumors [19], [20]. Conversely, four [7], [8], [11], [12] of six randomized trials comparing the results of RT alone with TRT showed a beneficial effect for the patients with FIGO stage IIIB tumors. From this, the patients with higher stage or bulkier tumors may benefit more from the addition of HT to RT than the addition of CT.

The first results of an international multicenter phase I/II trial recently showed that a combination of RT with both CT and HT treatment is feasible [21]. To improve treatment outcomes in patients with locally advanced cervical cancer, in Japan, a randomized multicenter phase III trial comparing RT plus CT and combination of RT with both CT and HT is ongoing. To demonstrate the effectiveness of TRT for some cancers, including locally advanced cervical cancer, well designed randomized clinical trials are necessary.

On the other hand, to identify a set of genes related to thermoradiosensitivity of cervical carcinoma, the expression profiles of thermoradiosensitive and thermoradioresistant tumors were compared using a cDNA microarray analysis [22]. Details have been described in the previous report [22]. Some of these genes were already known to be associated with hypoxia-inducible genes (HIF1A) and tumor cell invasion and metastasis (the serine protease urokinase-type plasminogen activator: PLAU, uPA) in thermoradioresistant tumors. The promise of such information lies in its potential for improving clinical strategies for TRT in locally advanced cervical cancer.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.