Jan D.P. Van Dijk

Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial

Summary Background Local-control rates after radiotherapy for locally advanced tumours of the bladder, cervix, and rectum are disappointing. We investigated the effect of adding hyperthermia to standard radiotherapy. Methods The study was a prospective, randomised, multicentre trial. 358 patients were enrolled from 1990 to 1996, in cancer centres in the Netherlands, who had bladder cancer stages T2, T3, or T4, N0, M0, cervical cancer stages IIB, IIIB, or IV, or rectal cancer stage M0–1 were assessed. Patients were randomly assigned radiotherapy (median total dose 65 Gy) alone (n=176) or radiotherapy plus hyperthermia (n=182). Our primary endpoints were complete response and duration of local control. We did the analysis by intention to treat. Findings Complete-response rates were 39% after radiotherapy and 55% after radiotherapy plus hyperthermia (p Interpretation Hyperthermia in addition to standard radiotherapy may be especially useful in locally advanced cervical tumours. Studies of larger numbers of patients are needed for other pelvic tumour sites before practical recommendations can be made.

Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: Results from five randomized controlled trials

PURPOSE Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. METHODS AND MATERIALS Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials. RESULTS We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. CONCLUSION The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.

Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: Data from a phase III trial

PURPOSE The objective of this study was to determine whether the thermal dose delivered during hyperthermia treatments and other thermal factors correlate with outcome after combined radiation and hyperthermia of breast carcinoma recurrences. Data were from the combined hyperthermia and radiation treatment arms of four Phase III trials, which when pooled together, demonstrated a positive effect of hyperthermia. METHODS AND MATERIALS Four Phase III trials addressing the question of whether hyperthermia could improve the local response of superficial recurrent breast cancer to radiation therapy were combined into a single analysis. Thermal dosimetry data were collected from 120 of the 148 breast cancer recurrence patients who received hyperthermia. The data were analyzed for correlations between thermal parameters as well as important clinical parameters and outcome (complete response rate, local disease free survival, time to local failure, and overall survival). RESULTS Five thermal parameters were tested, all associated with the low regions of the measured temperature distributions. Max(TDmin) and Sum(TDmin) were associated with complete response where TDmin is the minimum thermal dose measured by any of the tumor temperature sensors during a treatment: Max(TDmin) is the maximum of TDmin over a series of treatments. Using a categorical relationship with a cutoff of 10 min for Sum(TDmin), the complete response rate was 77% for Sum(TDmin) > 10 min and 43% for Sum(TDmin) < or = 10 min (p = 0.022, adjusted for study center and significant clinical factors). The overall complete response rate for hyperthermia and radiation was 61% compared to 41% for radiation alone. Either Max(TDmin) or Sum(TDmin) were also associated with local disease free survival, time to local failure and overall survival. CONCLUSIONS An earlier report of this trial demonstrated a significant benefit when hyperthermia was added to radiation in the treatment of breast cancer recurrences. The analysis of thermal factors demonstrates that parameters representative of the low end of the measured temperature distributions are associated with initial complete response rate, local disease-free survival, time to local failure and overall survival.

Carcinoma of the uterine cervix stage IB and IIA: Results of postoperative irradiation in patients with microscopic infiltration in the parametrium and/or lymph node metastasis

One hundred and thirty-two patients received postoperative radiation therapy following radical hysterectomy and pelvic lymphadenectomy for carcinoma of the uterine cervix Stage IB and IIA. In 43 patients with negative lymph node the 5- and 10-year survival rate was 85%. The other 89 patients with positive lymph node had 5- and 10-year survival rates of 60% and 51%, respectively. Multifactorial analysis of prognostic factors in the group of patients with lymph node metastasis disclosed pathology, microscopic infiltration in the parametrium and vascular space invasion as independent prognostic factors, that is, the 5-year survival rates were: 66% for squamous cell carcinomas versus, 25% for adenocarcinomas (p value: 0.001), 76% negative parametrium versus 39% positive parametrium (p value: 0.008), 68% no vascular space invasion versus 43% if invasion was observed (p value: 0.04). Sites of failure in 37 recurrences out of 89 patients with lymph node metastasis were pelvic alone 9, distant metastases alone 15, and combined pelvic plus distant metastasis in 12 patients. In one patient the site of failure was unknown. These data warrant more intensive local and systemic treatment, particularly in patients with poor prognostic factors. In the whole group, severe complications were observed in 11 patients.

Results of Deep Body Hyperthermia with Large Waveguide Radiators

The purpose of this report is to present results of work in progress on hyperthermia treatment planning and clinical application of a fourapplicator phased array hyperthermia system for heating of large and deepseated tumors.

Staging and prognosis using endosonography in patients with inoperable esophageal carcinoma treated with combined intraluminal and external irradiation

Brachytherapy and external irradiation combined are an alternative to surgery in the treatment of advanced esophageal cancer. Endosonography has proved to be an accurate method of staging the depth of tumor invasion of esophageal cancer. Sixty-three patients with inoperable esophageal cancer underwent endosonography followed by combined brachytherapy and external irradiation. Staging was incomplete in 31 of 63 patients because of tight stenosis or difficulty in imaging celiac lymph nodes. During follow-up of 23 patients, reduction of tumor thickness and lymph node abnormalities was observed in 16. The median survival was 10.4 months. Survival time was correlated with initial number of metastatic lymph nodes found by endosonography. Paradoxically, the survival of patients with more extensive intra-luminal tumor growth was significantly better than survival of those with less tumor growth. In summary, the response to combined brachytherapy and external irradiation could accurately be assessed with endosonography. Lymph node abnormalities and tumor thickness were closely related to survival rate.

Experimental studies on the response of growing bones to X ray and neutron irradiation

The effects of X ray and 14 MeV neutron irradiation on growing tibia of mice were studied. As reported in the literature, the age of the animal at irradiation was an important factor if the endpoint in analyzing the radiation effect is the absolute shortening, difference in length between unirradiated and irradiated tibia, achieved by the treatment. However, if the growth remaining at the moment of irradiation is taken into account no significant differences in effect were observed with aging, and the dose given appeared to be the overruling factor. This was valid for both X ray and neutron irradiation. Absorbed dose-response curves after X ray irradiation showed a shoulder in the lower range of absorbed doses, which was not the case for neutron irradiation. RBE values for 14 MeV neutrons as compared to 250 kV X rays varied from 3.6 to 2.0 depending on the single absorbed dose level. No differences in RBE were found with aging. A mathematical formula was derived which can predict the absolute shortening when the initial and final length of the tibia are known as well as the absorbed dose of irradiation to be administered.

Visualization of interfering RF-electric fields in a lossy liquid simulating a patient's body in a hyperthermia treatment by a LED-matrix

Matrices Of LED-dipoles have been constructed as a cheap and easy-to-use tool for Quality Assurance in deep body hyperthermia. Placed inside a phantom, i.e. a watertank filled with saline, one type of LED-matrix visualizes axial E-field components, the other one both radial components of the E-field. By moving of the matrix plate, the components of the E-field can be monitored in the complete inner volume of the phantom. Due to the feature of measurements in real time, LED-matrices are especially suitable to check numerous variations of set-up parameters as e.g. phase and amplitude settings as well as the performance of deep body hyerthermia systems in clinical routine.