HDR brachytherapy combined with interstitial hyperthermia in locally advanced cervical cancer patients initially treated with concomitant radiochemotherapy: A phase I study

Abstract

Background and purpose: The aim of this study was to investigate whether hyperthermia (HT) combined with interstitial brachytherapy (ISBT) has any influence on acute and late side effects in patients with advanced cervical cancer. Local control (LC) and disease-free survival (DFS) were also analysed.

Materials and methods: Following the completion of radiochemotherapy, patients with cervical cancer (FIGO stages I–III) were assigned to two treatment groups, either ISBT combined with interstitial hyperthermia (ISHT) or ISBT alone as a control group. Selection criterion for the ISBT combined with HT group was advanced cervical cancer with poor response to external beam radiotherapy. A total of 76 patients were included in the statistical analysis. Once a week, HT (at a temperature above 42.5°C) was administered for 45 min before and during high dose rate (HDR) brachytherapy (BT) in 43 patients. Four HT treatments were administered.

Results: The median follow-up time was 43 months (range 4–73 months). Significant differences were not observed for the distribution of early and late complications between the HT and no HT groups. Despite this, LC was similar in both groups. The 5-year DFS for the BT and BT + HT groups was 73.6% and 65.8%, respectively. The 5-year LC for the BT and BT + HT groups was 89% and 83%, respectively. For the majority of patients the maximum temperature level of 44–45°C was achieved during the ISHT.

Conclusions: ISHT is well tolerated and does not affect treatment-related early or late complications.

• HDR brachytherapy
• interstitial hyperthermia
• cervical cancer
• side effects
• computed tomography

Introduction

Brachytherapy (BT) is an integral part of treatment for patients with locally advanced cervical cancer. Local tumour control is an important goal for primary treatment.

The results from a clinical trial involving deep hyperthermia performed during the period of external beam radiotherapy showed an improvement in overall survival (OS) for locally advanced cervical cancer patients [1]. Based on the encouraging results published in this study, we designed a phase I study evaluating the combination of interstitial hyperthermia (ISHT) and BT.

The aim of this study was to compare the effect of hyperthermia (HT) on early and late radiation-induced complications. We also investigated whether HT combined with interstitial brachytherapy (ISBT) has any effect on LC or disease free survival (DFS).

Materials and methods

Between February 2005 and September 2006, after obtaining informed consent, patients with locally advanced cervical cancer (International Federation of Gynecology and Obstetrics (FIGO) stages I–III), were assigned to ISBT combined with ISHT. Physicians tended to order HT in patients with big cervix tumour diameter. This was not a randomised trial. The second group of patients was assigned to treatment with BT alone, during the same period with informed consent to standard BT. This group was included in the analysis to compare the incidence of side effects and treatment results between the test group and the standard BT group. All data were collected prospectively.

First-line therapy for all patients involved EBRT with concomitant chemotherapy. Squamous cell cancer was confirmed histologically for all cases. The protocols and consent procedure were approved by the local medical ethics committee.

Initial locoregional staging involved a clinical examination and an abdominal and pelvic computed tomography (CT). Cystoscopy or rectoscopy with biopsy confirmation was performed in patients who had suspected tumour infiltration of the bladder or rectum.

Age, FIGO stage, haemoglobin and SCC level were also recorded.

All patients received EBRT to the pelvic ± the para-aortic region. A 4-field or 2-field treatment technique was performed using high megavoltage photons from a Varian Clinac linear accelerator (X6 and 15 MeV) (Varian Medical Systems, Inc., Palo Alto, CA, USA). EBRT was administered in a daily fraction of 1.8–2.0 Gy to a total dose of 45–50 Gy to the elective area with approximately 60 Gy administered to the enlarged lymph nodes or the parametrium. All patients also received weekly intravenous cisplatin 40 mg/m² during EBRT.

BT was initiated 2–3 weeks following EBRT. Patients underwent a clinical examination under general anaesthesia to assess the clinical response to EBRT prior to the start of BT. High dose rate (HDR) BT was delivered using an Ir-192 source from Nucletron Devices (Microselectron V2, Veenendaal, Netherlands) in four fractions of 7.5 Gy once weekly. BT was planned in 2D in accordance with Report 38 of the International Commission on Radiation Units and Measurements (ICRU). Reference points were registered on radiographs (right and left point A, ICRU bladder and rectal points). An intrauterine catheter and 2–6 interstitial metal needles were inserted into the cervix for delivery of the HDR BT. HT was administered once a week for 45 min prior to and during BT. Radiofrequency 500 kHz local hyperthermia (RFH) was performed using the same set of applicators as used for BT. The RFH system consisted of a generator, 300 W of total power, a three-channel amplifier and a temperature measurement system. As this is a capacitive device, a belt of aluminium foil (acting as a passive electrode) was wrapped around the patient's pelvis during the procedure. An additional module allowed for phase steering of the applicator's electrodes. The value of the power transmitted to the tissues was about 20 W. Patients underwent heating at a temperature above 42.5°C (up to 49°C depending upon the patient's tolerance level), which was measured by a set of three thermocouples inserted in tandem and needles. Only maximum temperatures were recorded in the process of HT. They were found manually by moving the thermocouple along each applicator in order to find the temperature peak. The hyperthermia system had no correction for self-heating of the thermocouples. Therefore, temperature measurements were also checked either in the needle which was not used for heating or in the needle which was used for heating but while the electromagnetic field was switched off for a few seconds (once to three times during the process). The temperature was always at an acceptable level of 42°C or above. After at least 30 min of heating, brachytherapy was initiated while HT continued. The total procedure time lasted for approximately 60 min. Four HT treatments were performed in each patient.

A detailed description of the RFH procedure has been published previously [2].

Patient characteristics are provided in Table I. A total of 76 patients were included in the statistical analysis.

Table I.  Patient characteristics.

Patient characteristics	Brachytherapy N (%)	Brachytherapy and hyperthermia
FIGO
I	3 (9.7)	3 (7)
II	15 (48.4)	19 (44.2)
III	13 (41.9)	21 (48.8)
Cervix diameter after EBRT
≤4 cm	23 (74.2)	21 (50)
>4 cm	8 (25.8)	21 (50)
Age
26–49 years	17 (54.8)	26 (60.5)
50–81 years	14 (45.2)	17 (39.5)
Haemoglobin level (g/dL)
≤11.3	17 (54.8)	20 (47.6)
>11.3	14 (45.2)	22 (52.4)
SCC (ng/mL)
≤2.25	14 (51.9)	15 (46.9)
>2.25	13 (48.1)	17 (53.1)

Follow-up examinations were scheduled at 6 weeks after the completion of BT, then every 3 months during the first 2 years and every 6 months in the following 3 years. When relapse was suspected, a biopsy was performed. Patients were examined for early treatment-related complications, such as perforation of the uterus or bleeding. Late complications involving the bladder, rectum and intestine were graded using the Radiation Therapy Oncology Group (RTOG/EORTC) Late Radiation Morbidity Scoring Scheme. Late complications of the vagina were graded using the subjective, objective, management and analytic (SOMA) evaluation scoring system. Failures were classified according to the first tumour relapse and were defined either as local (an area treated by BT including the cervix, fornices, proximal parametrium and proximal portion of the corpus uteri) or distant.

Statistical analysis

The main end points evaluated in this study were early tolerance of the procedure and late side effects. DFS and LC were also investigated. DFS was calculated as the length of time between the last day of treatment and the first observation of disease progression or death from any cause. LC was defined as the length of time from the end of treatment to local recurrence (additional failures were censored). When the disease did not progress or the patient survived, DFS was measured to the time of the last follow-up examination. The patients lost to the last follow-up were considered censored observations.

LC and DFS curves were derived from Kaplan-Meier estimates. Pearson's χ² and Fisher's exact tests were used to compare the distribution of variables in the study groups, and p values <0.05 were considered statistically significant.

Results

The median age of patients was 49 years, and the median follow-up time for the 76 patients included in the statistical analysis was 43 months (range 4–73 months). A total of 43 patients were treated with BT combined with HT. Significant differences were not detected for FIGO, age, haemoglobin level or SCC level between the two treatment groups. Half of the patients treated with BT combined with hyperthermia had a poor tumour response to EBRT with a cervix tumour diameter greater than 4 cm. As planned in the study, the poor-prognosis group of patients was treated with BT combined with HT. Bulky cervical tumours were confirmed only in 25% of patients treated with BT alone. All patients received four planned BT treatments.

The frequency of early complications following brachytherapy procedures was not significantly different between the groups treated with and without HT (p = 0.17). There was one perforation of the uterus observed and one severe bleeding in the group without HT. No patient required a blood transfusion. According to our experience with ISHT, it is quite easy to achieve a sufficiently high temperature in the cervix, maximum 44–45°C for the majority of patients, and the early tolerance to this method was very good.

Most patients complained of fatigue and loss of appetite. Acute grade 3–4 radiation-related toxic effects were not seen. Three patients in the BT group and three patients in the BT + HT group had grade 2 bladder early side effects. Two patients in BT and three patients in the BT + HT group had grade 2 rectum and intestine early side effects. The remaining patients during and 3 months after BT had grade 0–1 early side effects. Patients treated with HT had redness of the upper part of vaginal mucosa without dyspareunia.

There was no significant difference between the BT and BT + HT groups in late toxicity, p = 0.89. Late treatment effects are provided in Table II.

Table II.  Late complications in both treated groups.

Characteristics	HT = no N (%)	HT = yes N (%)
Rectum 0–2	29 (93.6)	42 (97.7)
Rectum 3–4	2 (6.4)	1 (2.3)
Bladder 0–2	30 (96.8)	41 (95.4)
Bladder 3–4	1 (3.2)	2 (4.6)
Vagina 0–4	31 (100)	42 (97.7)
Vagina 5	0	1 (2.3)

The 5-year DFS (95%CI) for the BT and BT + HT groups was 0.736 (0.579–0.893) and 0.658 (0.521–0.795), respectively (Figure 1).

Figure 1. Disease-free survival curves based on the treatment modality. HT = 0 (BT alone), HT = 1 (BT combined with HT). HT, hyperthermia; BT, brachytherapy.

The 5-year LC (95%CI) for the BT and BT + HT groups was 0.89 (0.775–1.00) and 0.83 (0.707–0.95), respectively (Figure 2). The 5-year DFS (95%CI) for patients with cervix tumour diameter up to 4 cm was 0.715 (0.578–0.852) and with cervix tumour diameter above 4 cm was 0.617 (0.439–0.795), respectively. The 5-year LC for small cervix tumours was 0.87 (0.765–0.975) and for bulky tumours was 0.84 (0.701–0.979), respectively.

Figure 2. Local control curves based on the treatment modality. HT = 0 (BT alone), HT = 1 (BT combined with HT). HT, hyperthermia; BT, brachytherapy.

Discussion

Half of the patients treated with BT combined with hyperthermia had a poor tumour response to EBRT, with a cervix tumour diameter above 4 cm. The group of patients with a poor prognosis after BT combined with HT achieved 83% LC at 5 years. The authors are aware that in a non-randomised study comparing two groups is inconsequential. Therefore, the results of treatment in the BT group alone should be treated as an illustration of treatment results of patients with cervical cancer in our department.

A recent analysis of six clinical trials assessing the role of hyperthermia as an adjunct to radiotherapy in the treatment of locally advanced cervix carcinoma demonstrated its effectiveness [3]. Lutgens et al. [3] concluded that the addition of hyperthermia improves local tumour control and overall survival in patients with locally advanced cervical carcinoma. In four recent clinical trials, the addition of hyperthermia to standard radiotherapy resulted in significantly improved treatment outcomes [1], [4–6], whereas in two additional studies a significant difference was not observed between the treatment groups [7], [8]. The beneficial effect of hyperthermia only occurred in studies comprised of 70–100% of patients with FIGO stage IIIB. In studies with 38–77% of FIGO stage IIIB patients, differences were not observed. Additional studies suggest that combined radiation and hyperthermia should be considered as an alternative to radiochemotherapy for patients with locally advanced cervical cancer with a contraindication to chemotherapy [9].

Proportional tumour volumes of ≥20% treated at 40–50 Gy correlated with significantly inferior 5-year LC (53% versus 97%, p < 0.001), DFS (50% versus 72%, p = 0.009) than smaller volumes [10]. The tumour regression pattern reflects the inherent radioresponsiveness of cervical cancers. Large tumours that exhibited poor shrinkage following radiochemotherapy recurred in 35.5–47% of patients [10], [11]. Local tumour control is an important goal for primary treatment. Salvage therapy for local recurrences has dismal results. In our study we observed that ISBT combined with ISHT reached the LC in patients with a poor prognosis comparable to the LC in patients with a better prognosis following initial radiochemotherapy. Hyperthermia combined with ISBT seems to be a promising option. This group of patients in particular require a combination of intracavitary and ISBT, with precise MRI-guided 3D treatment planning if possible, to achieve an effective coverage of the gross tumour volume (GTV) and high risk clinical target volume (HR-CTV). Further studies are necessary to explore these issues.

Our hyperthermia procedure results in heating the cervix only, not the entire pelvis. One advantage of using this method is that a high temperature can be obtained in a smaller volume of tissue. Insertion of thermometers into the uterine probe and into all of the needles being used provides the opportunity to better assess the temperature levels. When heating the entire pelvis, it is difficult to control the temperature [12]; this issue does not seem to apply to ISHT. According to our observations with ISHT, it is quite easy to achieve a sufficiently high temperature in the cervix, and the early tolerance for this method is very good. The limitation of the presented HT procedure was measuring only the maximum temperature during the whole process. A second issue is the timing of HT administration. While HT given during or immediately after RT gave similar enhancement ratios for tumour response and normal tissue reaction, no therapeutic gain was achieved [12]. Due to the distance of the structures from the catheter, ISHT does not heat the rectum or the bladder. We do not feel that the therapeutic effect is decreased with the concurrent heating and irradiation of the cervix.

A negative effect of HT preceding RT may be that the risk of distant metastases is increased. The maximum therapeutic gain is achieved when HT is given after RT [13].

Although 2D treatment planning was conducted, the interstitial technique of HDR BT that was used in each case resulted in effective dose coverage across the target volume. Similar to the literature data [11], [14], [15] reporting 82–89% 2- to 5-year LC, our results demonstrate an 83–89% 5-year LC in the true pelvis, indicating the effectiveness of combined intracavitary-interstitial BT applications.

Previously published data did not show significant differences between the treatment groups for acute (p = 0.99) or late grade 3 to 4 toxicity (p = 0.96) [3]. A similar conclusion can be drawn based on the data from our study. Interstitial HDR BT combined with ISHT is a relatively safe procedure, as can be observed by the similar rates of bleeding following needle removal in both arms, with no patients requiring a blood transfusion. Early morbidity for the bladder and rectum was low, probably due to prolonged treatment time. The first reason for this is the large number of patients treated in the period between 2005 and 2006 years. The second is the poor general condition of patients after chemoradiation and probably inefficient supportive care after this treatment, resulting in BT procedure delay. The frequency of late side effects of irradiation was not increased with the addition of HT. One fistula was observed in HT group.

Conclusions

Interstitial hyperthermia is well tolerated and does not affect acute and late toxicity.

Further research is necessary to assess the impact of ISBT combined with ISHT on LC in the cervical cancer patients who are poor responders to radiotherapy.

Declaration of interest: The authors state that the research presented in this manuscript is free of conflicts of interest. The correspondence author has had full access to all the data, warrants that the manuscript has been reviewed by all participants, and is responsible for the decision to submit this manuscript for publication. The authors alone are responsible for the content and writing of the paper.