Reirradiation combined with hyperthermia in breast cancer recurrences: overview of experience in Erasmus MC.

For superficial hyperthermia a custom-built multi-applicator multi-amplifier superficial hyperthermia system operating at 433 MHz is utilised. Up to 6 Lucite Cone applicators can be used simultaneously to treat an area of 600 cm2. Temperatures are measured continuously with fibre optic multi-sensor probes. For patients with non-standard clinical problems, hyperthermia treatment planning is used to support decision making with regard to treatment strategy. In 74% of our patients with recurrent breast cancer treated with a reirradiation scheme of 8 fractions of 4 Gy in 4 weeks, combined with 4 or 8 hyperthermia treatments, a complete response is achieved, approximately twice as high as the CR rate following the same reirradation alone. The CR rate in tumours smaller than 30 mm is 80-90%, for larger tumours it is 65%. Hyperthermia appears beneficial for patients with microscopic residual tumour as well. To achieve high CR rates it is important to heat the whole radiotherapy field, and to use an adequate heating technique.

Intraspinal temperatures during regional deep hyperthermia induced by electromagnetic radiation in the Macaca mulatta.

A capacitive ring system operating at 27 MHz was tested for temperature distribution in the abdominal cavity of the living Rhesus monkey. Catheters were introduced through the abdomen and their location checked after the experiment. During two of these experiments a catheter was also introduced into the intraspinal canal. Temperature distribution was rather homogeneous within the abdominal cavity. Core temperature remained 3-5 degrees C below intra-abdominal temperatures. The intraspinal temperature increase was of the same magnitude compared with intra-abdominal temperature increase. Similar findings in other species have been reported by others. It is concluded that during non-invasive induction of regional hyperthermia by electromagnetic radiation, where a high level of energy is directed close to the spine, the intraspinal temperatures may be increased as high as the temperatures within the surrounding tissues. The central nervous system may be relatively sensitive to hyperthermia and hyperthermia may sensitize the spinal cord to radiation. Therefore, when hyperthermia is targeted at areas near the spine, either alone or in combination with radiotherapy applied to the tolerance limit of the spinal cord, these findings will have to be taken into consideration.

Physiological implications of hyperbaric oxygen tensions in isolated limb perfusion using melphalan: a pilot study.

Controversy exists concerning the optimal pO2 of the perfusate during isolated limb perfusion (ILP) with melphalan. Therefore we studied the implications of hyperbaric oxygen tensions in the perfusate. In 12 consecutive patients, subcutaneous pO2 (Continucath 1000), tissue and tumor pH, and blood gas values were monitored throughout the ILP procedure. ILP started with an oxygen flow through the bubble oxygenator which was set routinely at one half of the flow of the perfusate; 30 min before the end of ILP, the oxygen flow was tripled. Mean arterial pO2 before and during ILP (before and after increasing the oxygen supply) was 19.4, 25.5 and 49.4 kPa, respectively. Mean subcutaneous pO2 values before, during (before and after increasing the oxygen supply), and post-ILP, were 7.4, 10.1, 16.3, and 9.1 kPa, respectively. Tissue pH values in the subcutis and muscle decreased during routine oxygen supply (p = 0.001); muscle pH moved towards starting values after increase of the oxygen supply (p = 0.011). In 4 patients, tumor pH was recorded showing a rise after increasing the oxygen supply (from 7.10 to 7.22; p = 0.11). In conclusion, high pO2 in the perfusate improves muscle pH during ILP. However, a concomitant rise in tumor pH may unfavorably influence the therapeutic effect of ILP, as it has been shown that low pH increases the cytotoxicity of melphalan.

Radiofrequency capacitive heating of deep-seated tumours using pre-cooling of the subcutaneous tissues: results on thermometry in Dutch patients.

The capacity of a radiofrequency, 13.56 MHz, capacitive hyperthermia system using extensive pre-cooling of the subcutaneous tissue to induce locoregional deep heating has been investigated in 11 patients. Tumour location was presacral in nine--and eccentric towards the lateral side of the pelvis in two patients. For thermometry multiple catheters (mean 2.7) were inserted into the treatment volume. The mean numbers of temperature measuring points per treatment were 9.4 in tumour, 5.5 in muscle and 7.2 in subcutaneous fat. RF energy was applied after 30 min of cooling through two flexible boli perfused with saline water at 5-10 degrees C. Patient tolerance to pre-cooling was very good and after some initial discomfort the patient became rapidly accustomed to the cold water boli. For some patients better temperatures were achieved when the conventional anterior-posterior applicator set-up was replaced by a set-up with an applicator on each lateral side of the patient. As patients can tolerate temperatures within the fat tissue as high as 45.5 degrees C without complaining it appears important to monitor the temperature at the transition of fat to muscle tissue to prevent subcutaneous burns. The study shows that pre-cooling cannot avoid preferential heating at the interface from fat to muscle tissue. In this patient group the quality of the hyperthermia treatment appeared to be rather poor: 60% of the measured tumour temperatures were below 40 degrees D.

Some practical notes on documentation of superficial hyperthermia treatment.

A detailed and accurate documentation of the treatment setup of each individual hyperthermia session is extremely important for retrospective data analysis as well as treatment quality control. In this paper the relatively simple and cheap documentation system developed by the Hyperthermia Department of the Dr Daniel den Hoed Cancer Center, is presented.

Temperature distribution and pH changes during hyperthermic regional isolation perfusion.

Hyperthermic perfusion was given as a palliative treatment in three patients with a bulky tumour in the leg. During the treatment, temperature and pH data were collected in both tumour and normal tissues. The hyperthermia dose administered was 2 h at 41.9-42.7 degrees C. It was found that the temperature distribution was far from homogeneous. In one case tumour pH could be monitored throughout the whole treatment procedure. The tumour pH showed a steep decrease during the initial phase of the perfusion, from a mean value of 7.11 to 5.94 at the start of the hyperthermic phase. Subcutis pH decreased only 0.29 units during the whole procedure. In all three patients considerable tumour regression was observed, without severe toxicity. Hyperthermic perfusion appeared to be an effective debulking treatment. The pH decrease in tumour tissue, immediately before hyperthermia, may be responsible for the remarkable effectiveness of the hyperthermic treatment.

The relationship between the unmodified initial tissue pH of human tumours and the response to combined radiotherapy and local hyperthermia treatment.

The relationship between unmodified tumour pH before treatment and tumour response was investigated in patients receiving combined radiotherapy and local hyperthermia treatment. Tumour pH showed a statistically significant positive correlation with the response rate (Spearman correlation coefficient 0.31, n = 50, 2P less than 0.05). The mean pH of tumours showing a complete response (CR) was significantly higher than that of tumours showing a partial response (PR) as well as those showing no change (NC). As the means of the PR and NC groups were not significantly different from each other, these groups were combined for further analysis. The pH of the CR group was also significantly different from that of the NC + PR group (CR: 7.36 +/- 0.05, median 7.36, n = 18, NC + PR: 7.16 +/- 0.06, median 7.21, n = 32); Mann-Whitney test: 2P less than 0.05). Stratification of the data with respect to radiotherapy dose, hyperthermia dose or tumour volume showed that these factors were not associated with tumour pH to such a degree that they might have seriously biased the results. The results suggest that enhancement of the cytotoxic effects of hyperthermia by low pH known from experiments with cell cultures is not observed in tumours which are treated with radiotherapy and hyperthermia, and that even the converse may occur. The reasons for this are discussed at length and it is suggested that sudden modification of the tumour pH directly prior to or during treatment is imperative to obtain any sensitizing effect.

Low dose reirradiation in combination with hyperthermia: a palliative treatment for patients with breast cancer recurring in previously irradiated areas.

Ninety-seven patients with breast cancer recurring in a previously irradiated area (mean dose 44 Gy) were reirradiated in combination with hyperthermia and had evaluable tumor responses. In the reirradiation series, radiotherapy was given twice weekly in most patients, with a fraction size varying from 200 to 400 cGy, the total dose varying from 8 to 32 Gy. Hyperthermia was given following the radiotherapy fractions. The combined treatment resulted in 35% complete and 55% partial responses. Duration of response was median 4 months for partial response and 26 months for complete response, respectively. The median survival time for all patients was 12 months. Acute skin reaction was mild, with more than moderate erythema in only 14/97 patients. Thermal burns occurred in 44/97 patients, generally at sites where pain sensation was decreased, and therefore they did not cause much inconvenience. In the 19 patients who survived more than 2 years, no late radiation damage was observed. When patients who received a "high dose" (greater than 29 Gy and hyperthermia) were compared with those who received a "low dose" (less than 29 Gy and hyperthermia), a higher complete response rate was observed in the high dose group (58% vs. 24%), whereas no difference in acute toxicity was found. We conclude that reirradiation with 8 x 4 Gy in combination with hyperthermia twice weekly is a safe, effective and well tolerated method for palliative treatment of patients with breast cancer recurring in previously irradiated areas.

Retrospective analysis of the response of tumours in patients treated with a combination of radiotherapy and hyperthermia.

One hundred and twelve patients with various carcinomas were treated on 112 fields with radiotherapy and hyperthermia, using non-invasive techniques. Radiotherapy dose ranged from 13-70 Gy (except for one patient receiving hyperthermia alone) with a mean of 28.6 Gy. The combined treatment was primarily aimed at giving palliation; 79 per cent of the patients had received previous irradiation on the same area. Hyperthermia was given twice weekly following radiotherapy. From the temperature data collected, 12 different parameters expressing the hyperthermia 'dose' were derived. The various parameters for both treatment modalities, i.e. radiotherapy and hyperthermia, and some of the tumour parameters were statistically evaluated with respect to their influence on tumour response. The overall response rate was 87 per cent including 33 per cent complete response. The complete response rate increased with increasing radiotherapy total dose, i.e. from 23 per cent (14-25 Gy) and 38 per cent (28-36 Gy) to 60 per cent (greater than 38 Gy). A positive correlation between the tumour temperature parameter representative of the coldest spot in the tumour, and the level of response was found. Achievement of complete response appeared also to be determined to a considerable extent by radiotherapy total dose as well as tumour volume. The correlation between response level and the minimum hyperthermia dose parameters persisted, however, after correction for the influence of tumour volume and radiotherapy total dose. These results support the opinion that higher tumour response rates can be achieved by increasing the hyperthermia treatment level at the coldest spot in the tumour.