International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationLong-Term Improvement in Treatment Outcome After Radiotherapy and Hyperthermia in Locoregionally Advanced Cervix Cancer: An Update of the Dutch Deep Hyperthermia Trial
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
References (37)
- et al.
Carcinoma of the intact uterine cervix with radiotherapy alone: A French cooperative study: Update and multivariate analysis of prognostic factors
Int J Radiat Oncol Biol Phys
(1997) - et al.
Tumor size, irradiation dose and long-term outcome of carcinoma of the uterine cervix
Int J Radiat Oncol Biol Phys
(1998) - et al.
Radical radiation alone versus radical radiation plus microwave hyperthermia for N3 (TNM-UICC) neck nodes: A prospective randomized clinical trial
Int J Radiat Oncol Biol Phys
(1988) - et al.
Report of long-term follow-up in a randomized trial comparing radiation and radiation therapy plus hyperthermia to metastatic lymph nodes in Stage IV head and neck patients
Int J Radiat Oncol Biol Phys
(1994) - et al.
Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma
Lancet
(1995) - et al.
Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: Results from five randomized controlled trials
Int J Radiat Oncol Biol Phys
(1996) - et al.
Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: A prospective randomized, multicentre trial
Lancet
(2000) - et al.
Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC)
Int J Radiat Oncol Biol Phys
(1995) - et al.
Radiotherapy for cervical cancer with high-dose rate brachytherapy—Correlation between tumor size, dose and failure
Radiother Oncol
(1994) - et al.
Prognostic factors in patients with carcinoma of the uterine cervix treated with external beam irradiation and IR-192 high-dose-rate brachytherapy
Int J Radiat Oncol Biol Phys
(1998)
Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systemic review and meta-analysis
Lancet
The adverse effects of treatment prolongation in cervical carcinoma
Int J Radiat Oncol Biol Phys
A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer
Radiother Oncol
The correlation of acute toxicity and late rectal injury in radiotherapy for cervical carcinoma: Evidence suggestive of consequential late effect (CQLE)
Int J Radiat Oncol Biol Phys
Regional hyperthermia combined with radiotherapy for uterine cervical cancers: A multi-institutional prospective randomized trial of the Atomic Energy Agency
Int J Radiat Oncol Biol Phys
Innovative techniques in radiation oncology. Clinical research programs to improve local and regional control in cancer
Cancer
The American Society of Therapeutic Radiologists Presidential Address: October 1981. Potential for improving survival rates for the cancer patient by increasing the efficacy of treatment of the primary lesion
Cancer
Point-counterpoint: What is the optimal trial design to test hyperthermia for carcinoma of the cervix?
Int J Hyperthermia
Cited by (159)
Radiosensitization by Hyperthermia Critically Depends on the Time Interval
2024, International Journal of Radiation Oncology Biology PhysicsAssessment of the thermal tissue models for the head and neck hyperthermia treatment planning
2023, Journal of Thermal BiologySample forms and templates
2023, Translational Interventional RadiologyThe Emerging Evidence Supporting Integration of Deep Regional Hyperthermia With Chemoradiation in Bladder Cancer
2023, Seminars in Radiation OncologyPrognostic impact of waiting time between diagnosis and treatment in patients with cervical cancer: A nationwide population-based study
2022, Gynecologic OncologyCitation 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].
Conflict of interest: none.