Radiotherapy combined with hyperthermia for primary malignant melanomas of the esophagus.

Primary malignant melanoma of the esophagus (PMME) forms about 0.1% of all primary esophageal cancers. Treatment options are very limited for patients unfit for surgery. This is the first report describing the results of external radiotherapy combined with regional hyperthermia for two inoperable PMME patients. Two patients with a T2-3N0M0 PMME were considered unfit for surgery based on age and general condition. External radiotherapy of a total dose of 35 Gy was given in a scheme of seven times 5 Gy, two times per week, and once weekly combined with external and intraluminal hyperthermia (aim 43°C). Toxicity was mild and both patients completed treatment according to protocol. Adequate temperatures at the intraluminal border of the tumor were achieved. In both patients, a complete remission was achieved with complete relief of obstructive symptoms and without signs of locoregional tumor progression until the end of follow-up at 11 and 15 months. External radiation combined with regional hyperthermia could be a good alternative to resection in patients unfit for surgery with a malignant melanoma of the esophagus.

Improving locoregional hyperthermia delivery using the 3-D controlled AMC-8 phased array hyperthermia system: a preclinical study.

BACKGROUND: The aim of this study is preclinical evaluation of our newly developed regional hyperthermia system providing 3-D SAR control: the AMC-8 phased array consisting of two rings, each with four 70 MHz waveguides. It was designed to achieve higher tumour temperatures and improve the clinical effectiveness of locoregional hyperthermia. METHODS: The performance of the AMC-8 system was evaluated with simulations and measurements aiming at heating a centrally located target region in rectangular (30 x 30 x 110 cm) and elliptical (36 x 24 x 80 cm) homogeneous tissue equivalent phantoms. Three properties were evaluated and compared to its predecessor, the 2-D AMC-4 single ring four waveguide array: (1) spatial control and (2) size of the SAR focus, (3) the ratio between maximum SAR outside the target region and SAR in the focus. Distance and phase difference between the two rings were varied. RESULTS: (1) Phase steering provides 3-D SAR control for the AMC-8 system. (2) The SAR focus is more elongated compared to the AMC-4 system, yielding a lower SAR level in the focus when using the same total power. This is counter-balanced by (3) a superficial SAR deposition which is half of that in the AMC-4 system, yielding a more favourable ratio between normal tissue and target SAR and allowing higher total power and up to 30% more SAR in the focus for 3 cm ring distance. CONCLUSION: The AMC-8 system is capable of 3-D SAR control and its SAR distribution is more favourable than for the 2-D AMC-4 system. This result promises improvement in clinical tumour temperatures.

On verification of hyperthermia treatment planning for cervical carcinoma patients.

PURPOSE: The aim of this study was to verify hyperthermia treatment planning calculations by means of measurements performed during hyperthermia treatments. The calculated specific absorption rate (SAR(calc)) was compared with clinically measured SAR values, during 11 treatments in seven cervical carcinoma patients. METHODS: Hyperthermia treatments were performed using the 70 MHz AMC-4 waveguide system. Temperatures were measured using multisensor thermocouple probes. One invasive thermometry catheter in the cervical tumour and two non-invasive catheters in the vagina were used. For optimal tissue contact and fixation of the catheters, a gynaecological tampon was inserted, moisturized with distilled water (4 treatments), or saline (6 treatments) for better thermal contact. During one treatment no tampon was used. At the start of treatment the temperature rise (DeltaT(meas)) after a short power pulse was measured, which is proportional to SAR(meas). The SAR(calc) along the catheter tracks was extracted from the calculated SAR distribution and compared with the DeltaT(meas)-profiles. RESULTS: The correlation between DeltaT(meas) and SAR(calc) was on average R = 0.56 +/- 0.28, but appeared highly dependent on the wetness of the tampon (preferably with saline) and the tissue contact of the catheters. Correlations were strong (R approximately 0.85-0.93) when thermal contact was good, but much weaker (R approximately 0.14-0.48) for cases with poor thermal contact. CONCLUSION: Good correlations between measurements and calculations were found when tissue contact of the catheters was good. The main difficulties for accurate verification were of clinical nature, arising from improper use of the gynaecological tampon. Poor thermal contact between thermocouples and tissue caused measurement artefacts that were difficult to correlate with calculations.

Reliability of temperature and SAR measurements at oesophageal tumour locations.

INTRODUCTION: For treatment of oesophageal cancer, neo-adjuvant locoregional hyperthermia (HT) has been applied in combination with chemotherapy (ChT) +/- radiotherapy (RT) at the institute. Until now, 26 patients were treated within a completed phase I study combining HT with ChT and 29 patients within an ongoing phase II study combining HT with ChT + RT. METHODS: HT was given with the 70 MHz AMC-4 waveguide system. Initially, oesophageal temperatures were measured using multi-sensor thermocouple probes (TCs) inside a nasogastric tube (NT), but the question arose whether these measurements were reliable enough to quantify the achieved tumour temperatures accurately. Presently, TCs are mounted on the outside of an inflatable balloon catheter (BC) for better intra-luminal fixation and better contact with the tumour. During 14 treatment sessions in four patients TCs inside a NT and mounted on a BC were used simultaneously. Data from these 14 treatment sessions were used to compare temperature and Specific Absorption Rate (SAR) measurements ('DeltaT-measurements') using NTs or BCs. To determine the predictive value of the local SAR for the tumour temperatures achieved during treatment, the relation between the initial DeltaT and steady state temperature (SST) was evaluated. RESULTS: There was a strong correlation between the temperature measured in the NT (Ttube) and the temperature measured with a BC (Tballoon): R = 0.88 +/- 0.13. However, Ttube was on average approximately 1 degrees C higher than Tballoon and there was a large variation between the different treatments in the relation between both measurements, rendering Ttube a probably unreliable measure for tumour temperatures. The correlation between the DeltaT measured in the NT (DeltaTtube) and with a BC (DeltaTballoon) was rather weak: R = 0.46 +/- 0.25. The correlation between the initial DeltaT and the SST was much stronger for the BC measurements, R = 0.78 +/- 0.19, than for the NT measurements, R = 0.61 +/- 0.23. Thus, DeltaTballoon has a higher predictive value for the achieved tumour temperatures than DeltaTtube. Both DeltaT and SST were generally higher for the NT measurements than for the BC measurements, suggesting an over-estimation of tumour temperatures. Averaged over all treatments in the phase I trial using a NT (20 treatments) or a BC (45 treatments), T90 was significantly higher when measured with a NT. CONCLUSION: Oesophageal temperature and SAR (DeltaT) measurements inside a NT are less reliable than BC measurements. These artefacts are due to bad thermal contact with the tumour tissue and are, therefore, not specific for thermocouple thermometry. For reliable temperature or SAR measurements inside lumina or cavities good thermal contact must be assured, e.g. by using a balloon catheter.

Prospective treatment planning to improve locoregional hyperthermia for oesophageal cancer.

BACKGROUND: In the Academic Medical Center (AMC) Amsterdam, locoregional hyperthermia for oesophageal tumours is applied using the 70 MHz AMC-4 phased array system. Due to the occurrence of treatment-limiting hot spots in normal tissue and systemic stress at high power, the thermal dose achieved in the tumour can be sub-optimal. The large number of degrees of freedom of the heating device, i.e. the amplitudes and phases of the antennae, makes it difficult to avoid treatment-limiting hot spots by intuitive amplitude/phase steering. AIM: Prospective hyperthermia treatment planning combined with high resolution temperature-based optimization was applied to improve hyperthermia treatment of patients with oesophageal cancer. METHODS: All hyperthermia treatments were performed with 'standard' clinical settings. Temperatures were measured systemically, at the location of the tumour and near the spinal cord, which is an organ at risk. For 16 patients numerically optimized settings were obtained from treatment planning with temperature-based optimization. Steady state tumour temperatures were maximized, subject to constraints to normal tissue temperatures. At the start of 48 hyperthermia treatments in these 16 patients temperature rise (DeltaT) measurements were performed by applying a short power pulse with the numerically optimized amplitude/phase settings, with the clinical settings and with mixed settings, i.e. numerically optimized amplitudes combined with clinical phases. The heating efficiency of the three settings was determined by the measured DeltaT values and the DeltaT-ratio between the DeltaT in the tumour (DeltaToes) and near the spinal cord (DeltaTcord). For a single patient the steady state temperature distribution was computed retrospectively for all three settings, since the temperature distributions may be quite different. To illustrate that the choice of the optimization strategy is decisive for the obtained settings, a numerical optimization on DeltaT-ratio was performed for this patient and the steady state temperature distribution for the obtained settings was computed. RESULTS: A higher DeltaToes was measured with the mixed settings compared to the calculated and clinical settings; DeltaTcord was higher with the mixed settings compared to the clinical settings. The DeltaT-ratio was approximately 1.5 for all three settings. These results indicate that the most effective tumour heating can be achieved with the mixed settings. DeltaT is proportional to the Specific Absorption Rate (SAR) and a higher SAR results in a higher steady state temperature, which implies that mixed settings are likely to provide the most effective heating at steady state as well. The steady state temperature distributions for the clinical and mixed settings, computed for the single patient, showed some locations where temperatures exceeded the normal tissue constraints used in the optimization. This demonstrates that the numerical optimization did not prescribe the mixed settings, because it had to comply with the constraints set to the normal tissue temperatures. However, the predicted hot spots are not necessarily clinically relevant. Numerical optimization on DeltaT-ratio for this patient yielded a very high DeltaT-ratio ( approximately 380), albeit at the cost of excessive heating of normal tissue and lower steady state tumour temperatures compared to the conventional optimization. CONCLUSION: Treatment planning can be valuable to improve hyperthermia treatments. A thorough discussion on clinically relevant objectives and constraints is essential.

Phase II study of carboplatin and whole body hyperthermia (WBH) in recurrent and metastatic cervical cancer.

OBJECTIVE: Hyperthermia enhances carboplatin cytotoxicity preclinically, and clinical studies have shown radiant heat Whole Body Hyperthermia (WBH) to be safe. In this study, the efficacy and toxicity of the combination of 41.8 degrees C WBH and carboplatin in recurrent and/or metastatic cervical cancer were explored. METHODS: Recurrent and/or metastatic cervical cancer patients were treated with 41.8 degrees C WBH and concurrent carboplatin, cycled every 28 days (max. 6 cycles). RESULTS: Twenty-one of 25 participants were evaluable for response: one complete remission, six partial responses, stable disease in nine patients and progression in five, leading to a response rate of 33%. Three of four evaluable chemotherapy pre-treated patients progressed, while this was seen in only 2 of 17 chemotherapy-naive patients. The median survival is 7.8 months (range 1.3 to 43+) and no patients were lost to follow up. Grades 3/4 toxicities were common: leukopenia in 35%, thrombopenia in 61% and anemia in 22% of all treatments. Excessive, partly reversible renal toxicity was seen in two patients (grades 3 and 4). CONCLUSION: The efficacy of WBH and carboplatin in recurrent and/or metastatic cervical cancer seems comparable to that of other palliative chemotherapy regimens in this disease. The considerable toxicity, though largely manageable, includes unexpected and severe unacceptable renal toxicity. This regimen seems less suitable for palliative care.

A feasibility study in oesophageal carcinoma using deep loco-regional hyperthermia combined with concurrent chemotherapy followed by surgery.

This phase I-II study investigated the feasibility of external deep loco-regional hyperthermia in localized primarily operable carcinoma of the thoracic oesophagus and gastro-oesophageal junction. Toxicity when combining neo-adjuvant hyperthermia with concurrent chemotherapy (CDDP and etoposide) was evaluated. Hyperthermia was given with a four antenna array, operating at 70 MHz arranged around the thorax. Temperatures were monitored rectally, intra-oesophageal at tumour level and intramuscular near the spine. In four steps, a thermal dose escalation was performed from 15-60 min of heating to 41 degrees C with two patients in each step. The combined treatment courses were repeated every 3 weeks for a maximum of four courses. From January 1999-February 2002, 31 patients were included. Pre-treatment tumour stage mainly consisted of T3N1 (stage III) tumours, with a mean length of 6 cm. The maximum tumour temperature failed to reach at least 41 degrees C in five patients during the test session of hyperthermia alone. Combined hyperthermia and chemotherapy was given 55 times in 26 patients. The amplitude was set at a ratio between top:bottom:left:right = 1:3:3:3, with a power range of 800-1000 W. Thermal data showed that is was technically feasible to heat the oesophagus; the median results were T(90) = 39.3 degrees C, T(50) = 40 degrees C, T(10) = 40.7 degrees C and a median T(max) = 41.9 degrees C. In more distally located tumours higher temperatures were reached. In one patient, a transient grade 2 sensory neuropathy was seen. Further toxicity was mainly of haematological origin. Blisters or fat necrosis were not observed. Twenty-two patients underwent oesophageal-cardia resection with gastric tube reconstruction. There was no report of complications in the post-operative phase, which could be contributed to either the prior chemotherapy or the hyperthermia.

A pilot study of whole body hyperthermia and carboplatin in platinum-resistant ovarian cancer.

The aim of this study was to determine whether the addition of whole body hyperthermia (WBH) to carboplatin (CBDCA) can induce responses in patients with platinum-resistant ovarian cancer. 16 pretreated patients with platinum-resistant ovarian cancer were entered on a Systemic Hyperthermia Oncological Working Group (SHOWG) study; (14 patients were eligible with 14 evaluable for toxicity and 12 for response). The patients were treated with WBH (Aquatherm) 41.8 degrees C x 60 min in combination with carboplatin (CBDCA) (area under the curve (AUC) of 8) every 4 weeks. Disease status was evaluated every two cycles. Patients were treated for a maximum of six cycles. One patient had a complete response (CR) and 4 had a partial response (PR). 4 patients had stable disease (SD). 3 patients had progressive disease (PD). 2 patients were unevaluable: 1 had a bowel obstruction shortly after her first treatment; the second patient achieved a CR, but only had one treatment secondary to an idiosyncratic reaction to sedative drugs. 2 patients entered on study were ineligible, as they did not meet criteria for platinum resistance; 1 entered a CR and 1 had SD. Dose-limiting toxicity, which required CBDCA dose reductions, was grade 4 thrombocytopenia. Other toxicities included neutropenia (grade 3/4), and nausea and/or vomiting. Consistent with preclinical modelling, these results suggests that 41.8 degrees C WBH can overcome platinum resistance in ovarian cancer. These observations suggest further investigation of the therapeutic potential of WBH in a group of patients who historically fail to respond to salvage therapies is warranted.

Feasibility, toxicity, and preliminary results of weekly loco-regional hyperthermia and cisplatin in patients with previously irradiated recurrent cervical carcinoma or locally advanced bladder cancer.

PURPOSE: The biological rationale for combining locoregional hyperthermia (HT) with cisplatin (CDDP) is the potentiating effect of HT on CDDP uptake and cytotoxicity. Feasibility, toxicity, and preliminary results of a clinical trial of weekly loco-regional HT in combination with cisplatin are described in this article. METHODS AND MATERIALS: Patients with previously irradiated unresectable local recurrent cervical carcinoma or locally advanced bladder carcinoma were treated with weekly cycles of locoregional HT (70 MHz four antenna phased array system) for 1 h and CDDP 50 mg/m(2) IV for a maximum of 12 courses. RESULTS: Fourteen patients, 10 patients with recurrent cervical carcinoma and 4 with locally advanced bladder carcinoma, were entered in this study. A total of 100 cycles were given. Overall toxicity was acceptable; Grade 3 (WHO) toxicity (gastrointestinal, hematological, and neurotoxicity) was observed in 5 out of 14 patients. No Grade 4 toxicity was seen. Subcutaneously fatty necrosis due to HT occurred in 11% of the cycles, while two patients developed skin burns. Two out of 10 patients with recurrent cervical carcinoma were not evaluable for response. Four out of eight evaluable cervical carcinoma patients responded (two pathologic complete responses, one pathologic confirmed partial response, one partial response): response rate 50% (95% confidence interval 15.7-84.3%). Salvage surgery became possible in three out of four responding patients, whose tumors were previously considered unresectable. Two out of the four evaluable patients with locally advanced bladder carcinoma responded (two partial responses). CONCLUSIONS: Weekly loco-regional HT and CDDP 50 mg/m(2)/week for a maximum of 12 courses is feasible with an acceptable toxicity, which seems not to be enhanced by the addition of loco-regional HT. The encouraging preliminary results of this treatment schedule warrant further study, especially in patients with previously irradiated recurrent cervical carcinomas.