Clinical Investigation
Long-Term Improvement in Treatment Outcome After Radiotherapy and Hyperthermia in Locoregionally Advanced Cervix Cancer: An Update of the Dutch Deep Hyperthermia Trial

https://doi.org/10.1016/j.ijrobp.2007.07.2348Get rights and content

Purpose

The local failure rate in patients with locoregionally advanced cervical cancer is 41–72% after radiotherapy (RT) alone, whereas local control is a prerequisite for cure. The Dutch Deep Hyperthermia Trial showed that combining RT with hyperthermia (HT) improved 3-year local control rates of 41–61%, as we reported earlier. In this study, we evaluate long-term results of the Dutch Deep Hyperthermia Trial after 12 years of follow-up.

Methods and Materials

From 1990 to 1996, a total of 114 women with locoregionally advanced cervical carcinoma were randomly assigned to RT or RT + HT. The RT was applied to a median total dose of 68 Gy. The HT was given once weekly. The primary end point was local control. Secondary end points were overall survival and late toxicity.

Results

At the 12-year follow-up, local control remained better in the RT + HT group (37% vs. 56%; p = 0.01). Survival was persistently better after 12 years: 20% (RT) and 37% (RT + HT; p = 0.03). World Health Organization (WHO) performance status was a significant prognostic factor for local control. The WHO performance status, International Federation of Gynaecology and Obstetrics (FIGO) stage, and tumor diameter were significant for survival. The benefit of HT remained significant after correction for these factors. European Organization for Research and Treatment of Cancer Grade 3 or higher radiation-induced late toxicities were similar in both groups.

Conclusions

For locoregionally advanced cervical cancer, the addition of HT to RT resulted in long-term major improvement in local control and survival without increasing late toxicity. This combined treatment should be considered for patients who are unfit to receive chemotherapy. For other patients, the optimal treatment strategy is the subject of ongoing research.

Introduction

Radiotherapy (RT) is the mainstay in the management of patients with locoregionally advanced cervix carcinoma. After RT alone, locoregional failure rates for the more advanced stages ranged from 41–72% 1, 2. Local control is a prerequisite for cure, and locoregional failure generally indicates a fatal course of the disease. If locoregional tumor control can be achieved definitively, the potential gain in survival is estimated to be 50–60% 3, 4.

Several large trials showed an advantage of combining RT with chemotherapy (CT) in terms of both improved local tumor control and better overall survival. Similar advantages were found in trials that combined RT with hyperthermia (HT) (5).

Hyperthermia, the artificial increase in tissue temperature to 40°C – 44°C, is an effective cytotoxic agent, especially in cells that are in a hypoxic nutrient-deprived low-pH environment. These conditions are commonly found in malignant tumors and make cells relatively resistant to RT (6). In addition to directly killing cells at temperatures of 40°C – 44°C, HT also increases the cytotoxic effect of RT. Experimental studies showed that it interfered with the cellular repair of radiation-induced DNA damage, thereby enhancing the cytotoxic effect of RT (7). Hyperthermia also increased blood flow, which may improve tissue oxygenation and make cells more sensitive to RT (8). Several randomized studies showed an increase in response rate and tumor control in various tumor sites when RT was combined with HT 9, 10, 11, 12.

In 1990, the Dutch Deep Hyperthermia Trial (DDHT) started investigating the effect of the addition of HT to standard RT in patients with locally advanced rectal, bladder, and cervical cancer. The first results were published in 2000 13, 14. A significant improvement in response rate and local control was found with the addition of HT. Overall survival also significantly improved after adjustment for prognostic factors. For patients with primary or recurrent rectal cancer, no improvement in local control or survival could be shown, and for patients with bladder cancer, the initial gain in local control disappeared during follow-up. Although there were no significant interactions between treatment group and tumor site for complete response, local control, and overall survival, the subgroup of patients with locally advanced cervical cancer appeared to benefit most from the addition of HT. However, at a median of 43 months, follow-up time was relatively short. In this study, we report on long-term pelvic control, overall survival, and toxic effects in patients with locally advanced cervical cancer who were treated in the DDHT.

Section snippets

Patients

Patients were eligible for the trial if they required primary standard RT for cervical cancer International Federation of Gynaecology and Obstetrics (FIGO) Stages IIB (with extension to the lateral parametrium), IIIB (fixation to the pelvic wall or ureter obstruction causing hydronephrosis), or IVA (invasion of the bladder or rectum). In all patients, diagnosis was confirmed by means of histopathologic examination. Patients needed to be in reasonable general condition, defined as World Health

Results

Response rate, acute toxicity, and 3-year pelvic tumor control and overall survival rates were reported previously 13, 14. The most important information is summarized here and extended with new data.

From 1990 to 1996, 114 patients with locally advanced cervical cancer were randomized. Characteristics of patients and tumors are listed in Table 1. Nodal status was assessed in 50 of 114 patients by means of a computed tomographic (CT) scan done for RT purposes. Eighty percent of patients had FIGO

Discussion

Long-term follow-up in the DDHT showed sustained improvement in local control and overall survival after 12 years by combining RT and HT. Hyperthermia did not significantly add to radiation-induced toxicity compared with RT alone.

The DDHT was the first randomized trial that showed a survival advantage of RT with HT in women with locoregionally advanced cervical carcinoma. This advantage was similar to studies that combined RT with CT (5). The DDHT was criticized for the poor overall outcome

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      Citation Excerpt :

      The cornerstones of current treatment options include surgery for tumors limited to the cervix and radiotherapy (RT) for tumors extending locally or regionally [2]. RT is often combined with concurrent chemotherapy, or with hyperthermia (i.e. artificial increase of tissue temperature to cytotoxic levels of 40–44 °C) as an alternative in patients unfit for chemotherapy [3]. In The Netherlands, oncological guidelines deem a maximum waiting time from diagnosis to treatment of 5–7 weeks acceptable [4,5], but in practice this maximum time is sometimes exceeded for various reasons including pretreatment fertility preservation or advanced imaging procedures in the standard work-up (e.g. MRI and 18F-FDG PET/CT) [6].

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    Conflict of interest: none.

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