Bert Hildebrandt

Hyperthermia in combined treatment of cancer

Hyperthermia, the procedure of raising the temperature of tumour-loaded tissue to 40-43 degrees C, is applied as an adjunctive therapy with various established cancer treatments such as radiotherapy and chemotherapy. The potential to control power distributions in vivo has been significantly improved lately by the development of planning systems and other modelling tools. This increased understanding has led to the design of multiantenna applicators (including their transforming networks) and implementation of systems for monitoring of E-fields (eg, electro-optical sensors) and temperature (particularly, on-line magnetic resonance tomography). Several phase III trials comparing radiotherapy alone or with hyperthermia have shown a beneficial effect of hyperthermia (with existing standard equipment) in terms of local control (eg, recurrent breast cancer and malignant melanoma) and survival (eg, head and neck lymph-node metastases, glioblastoma, cervical carcinoma). Therefore, further development of existing technology and elucidation of molecular mechanisms are justified. In recent molecular and biological investigations there have been novel applications such as gene therapy or immunotherapy (vaccination) with temperature acting as an enhancer, to trigger or to switch mechanisms on and off. However, for every particular temperature-dependent interaction exploited for clinical purposes, sophisticated control of temperature, spatially as well as temporally, in deep body regions will further improve the potential.

Description and characterization of the novel hyperthermia- and thermoablation-system MFH 300F for clinical magnetic fluid hyperthermia.

Magnetic fluid hyperthermia (MFH) is a new approach to deposit heat power in deep tissues by overcoming limitations of conventional heat treatments. After infiltration of the target tissue with nanosized magnetic particles, the power of an alternating magnetic field is transformed into heat. The combination of the 100 kHz magnetic field applicator MFH 300F and the magnetofluid (MF), which both are designed for medical use, is investigated with respect to its dosage recommendations and clinical applicability. We found a magnetic field strength of up to 18 kA/m in a cylindrical treatment area of 20 cm diameter and aperture height up to 300 mm. The specific absorption rate (SAR) can be controlled directly by the magnetic field strength during the treatment. The relationship between magnetic field strength and the iron normalized SAR (SAR(Fe)) is only slightly depending on the concentration of the MF and can be used for planning the target SAR. The achievable energy absorption rates of the MF distributed in the tissue is sufficient for either hyperthermia or thermoablation. The fluid has a visible contrast in therapeutic concentrations on a CT scanner and can be detected down to 0.01 g/l Fe in the MRI. The system has proved its capability and practicability for heat treatment in deep regions of the human body.

Noninvasive magnetic resonance thermography of soft tissue sarcomas during regional hyperthermia : Correlation with response and direct thermometry

The objective of this study was to evaluate noninvasive magnetic resonance (MR) thermography for the monitoring of regional hyperthermia (RHT) in patients with soft tissue sarcomas of the lower extremities and pelvis.

Methods and potentials of magnetic resonance imaging for monitoring radiofrequency hyperthermia in a hybrid system.

Introduction: Non-invasive thermometry (NIT) is a valuable and probably indispensable tool for further development of radiofrequency (RF) hyperthermia. A hybridization of an MRI scanner with a hyperthermia system is necessary for a real-time NIT. The selection of the best thermographic method is difficult, because many parameters and attributes have to be considered. Methods: In the hybrid system (Siemens Symphony/BSD-2000-3D) the standard methods for NIT were tested such as T1, diffusion (ADC: apparent diffusion coefficient) and proton-resonance-frequency shift (PFS) method. A series of three-dimensional datasets was acquired with different gradient-echo sequences, diffusion-weighted EPI spin-echo sequences and calculated MR-temperatures in the software platform AMIRA-HyperPlan. In particular for the PFS-method, corrective methods were developed and tested with respect to drift and other disturbances. Experiments were performed in phantoms and the results compared with direct temperature measurements. Then the procedures were transferred to clinical applications in patients with larger tumours of the lower extremity or the pelvis. Results: Heating experiments and MR-thermography in a homogeneous cylindrical phantom give an excellent survey over the potentials of the methods. Under clinical conditions all these methods have difficulties due to motion, physiological changes, inhomogeneous composition and susceptibility variations in human tissues. The PFS-method is most stable in patients yielding reasonable MR temperature distributions and time curves for pelvic and lower extremity tumours over realistic treatment times of 60–90 min. Pooled data exist for rectal tumour recurrencies and soft tissue sarcomas. The fat tissue can be used for drift correction in these patients. T1 and diffusion-dependent methods appear less suitable for these patients. The standard methods have different sensitivities with respect to the various error sources. The advantages and pitfalls of every method are discussed with respect to the literature and illustrated by the phantom and patient measurements. Conclusions: MR-controlled RF hyperthermia in a hybrid system is well established in phantoms and already feasible for patients in the pelvic and lower extremity region. Under optimal conditions the temperature accuracy might be in the range of 0.5°C. However a variety of developments, especially sequences and post-processing modules, are still required for the clinical routine.

Impact of Overall Treatment Time on Local Control of Anal Cancer Treated with Radiochemotherapy

Between 1987 and 2000, 111 patients with epidermoid anal cancer (T1–T4 Nx M0) were assigned to primary simultaneous radiochemotherapy (RCT) with a radiation dose of 45 Gy, performed either as a split course with 2-Gy single fractions (schedule A, 1987–1996, n = 65 patients) or continuously with fractions of 1.8 Gy (schedule B, 1996–2000; n = 38 patients). The chemotherapy consisted of continuous infusions of 5-fluorouracil (5-FU; 800/1,000 mg/m2/day, on 4/5 consecutive days, during weeks 1 and 5) together with one (schedule A) or two (schedule B) short infusions of mitomycin C (10 mg/m2) during the first course of 5-FU. Associations between clinical outcome and various prognostic factors were assessed in 103 patients who completed these schedules. For both patient groups combined, 5-year local control rate was 67% and 5-year survival rate 71%. Advanced tumor stage, size, and nodal status significantly decreased the 5-year local control rate as well as the overall treatment time (OTT) >41 days (58% for OTT >41 days vs. 79% for OTT ≤41 days; p = 0.04). However, we did not find a correlation with the prescribed radiotherapy schedule (A or B). In conclusion, in patients with anal carcinomas treated with RCT with a radiation dose of 45 Gy, the predominant determinant of local control is the resulting OTT and not the administration schedule (split course or continuous radiotherapy).

Regional Hyperthermia in Conjunction with Definitive Radiotherapy against Recurrent or Locally Advanced Prostate Cancer T3 pN0 M0

Background and Purpose:Since long-term results of the standard treatment of locally advanced or recurrent prostatic carcinoma are unsatisfactory, the role for additional regional hyperthermia was evaluated in a phase I/II study.Patients and Methods:From 08/1996 to 03/2000, 22 patients were treated by a standard irradiation regimen (68.4 Gy) in combination with regional hyperthermia (weekly, five to six times), and five of 22 patients received short-term (neoadjuvant) hormonal treatment. Of these, 15 patients had primary prostatic carcinoma T3 pN0 M0 and seven a histologically confirmed local recurrence after radical prostatectomy. Feasibility of hyperthermia, and acute/late toxicity as well as long-term follow-up (prostate- specific antigen [PSA] control, overall survival) were analyzed. Clinical endpoints were correlated with thermal parameters.Results:Mean maximum temperatures along the urethra of 41.4 °C (41.0 °C for the recurrences), and mean T90 values of 40.7 °C could be achieved. Severe acute toxicity of grade 3 occurred at the rectum in three, at the urethra in four, at the intestine in one, and a burn induced by hyperthermia in one of 22 patients. Late toxicity was only observed rectally in one patient (grade 3) and at the urethra in two patients (grade 2). There was no correlation between thermal parameters and any toxicity. The survival curves showed a PSA control for primary prostatic carcinoma > 50% after 6 years, but no long-term PSA control for the recurrences. Overall survival after 6 years was 95% for primary carcinoma, and 60% for the recurrences. There was a clear correlation between higher temperatures or thermal doses with long-term PSA control.Conclusion:Regional hyperthermia might be a low-toxicity approach to increase PSA control of common treatment schedules. Further evaluation, in particular employing improved hyperthermia technology, is worthwhile.Hintergrund und Ziel:Die Langzeitergebnisse der Standardtherapie beim lokal fortgeschrittenen oder rezidivierten Prostatakarzinom sind unbefriedigend. Daher wurde eine zusätzliche regionale Hyperthermie in einer Phase-I/II-Studie evaluiert.Patienten und Methodik:Von 08/1996 bis 03/2000 wurden 22 Patienten mit einer Standardradiotherapie von 68,4 Gy in Kombination mit regionaler Hyperthermie (wöchentlich, fünf bis sechs Sitzungen) behandelt. Bei fünf von 22 Patienten wurde eine neoadjuvante Hormonbehandlung durchgeführt. Bei 15 Patienten lag ein primäres Prostatakarzinom T3pN0M0 vor; sieben Patienten hatten ein histologisch bestätigtes Lokalrezidiv nach radikaler Prostatektomie. Geprüft wurden die Durchführbarkeit der Hyperthermie, die akute und späte Toxizität sowie die Langzeitkontrolle (PSA-Kontrolle [prostataspezifisches Antigen], Gesamtüberleben). Die klinischen Endpunkte wurden mit thermischen Parametern korreliert.Ergebnisse:Es konnten mittlere Maximaltemperaturen entlang der Urethra von 41,4 °C (41,0 °C für die Rezidive) sowie mittlere T90 von 40,7 °C erreicht werden. Schwere akute Nebenwirkungen vom Grad 3 traten am Rektum bei drei, an der Urethra bei vier, am Dünndarm bei einem sowie durch Hyperthermie bedingt (Verbrennung) bei einem von 22 Patienten auf. Spätfolgen wurden nur bei einem Patienten am Rektum (Grad 3) und bei zwei Patienten an der Urethra (Grad 2) festgestellt. Es bestand keine Korrelation zwischen thermischen Parametern und irgendeiner Toxizität. Die Überlebenskurven zeigten eine PSA-Kontrolle von > 50% beim primären Prostatakarzinom nach 6 Jahren, jedoch keine Langzeit-PSA-Kontrolle bei den Rezidiven. Das Gesamtüberleben betrug nach 6 Jahren 95% für die primären Prostatakarzinome und 60% für die Rezidive. Es fand sich eine deutliche Korrelation zwischen hohen Temperaturen bzw. thermischen Dosen und der langfristigen PSA-Kontrolle.Schlussfolgerung:Die regionale Hyperthermie könnte eine gut verträgliche Zusatztherapie sein, um die PSA-Kontrolle von üblichen Therapieschemata zu verbessern. Hier ist eine weitere Evaluation sinnvoll, insbesondere auch unter Anwendung verbesserter Hyperthermietechnologien.

Noninvasive magnetic resonance thermography of recurrent rectal carcinoma in a 1.5 Tesla hybrid system.

To implement noninvasive thermometry, we installed a hybrid system consisting of a radiofrequency multiantenna applicator (SIGMA-Eye) for deep hyperthermia (BSD-2000/3D) integrated into the gantry of a 1.5 Tesla magnetic resonance (MR) tomograph Symphony. This system can record MR data during radiofrequency heating and is suitable for application and evaluation of methods for MR thermography. In 15 patients with preirradiated pelvic rectal recurrences, we acquired phase data sets (25 slices) every 10 to 15 minutes over the treatment time (60-90 minutes) using gradient echo sequences (echo time = 20 ms), transformed the phase differences to MR temperatures, and fused the color-coded MR-temperature distributions with anatomic T1-weighted MR data sets. We could generate one complete series of MR data sets per patient with satisfactory quality for further analysis. In fat, muscle, water bolus, prostate, bladder, and tumor, we delineated regions of interest (ROI), used the fat ROI for drift correction by transforming these regions to a phase shift zero, and evaluated the MR-temperature frequency distributions. Mean MR temperatures (T(MR)), maximum T(MR), full width half maximum (FWHM), and other descriptors of tumors and normal tissues were noninvasively derived and their dependencies outlined. In 8 of 15 patients, direct temperature measurements in reference points were available. We correlated the tumor MR temperatures with direct measurements, clinical response, and tumor features (volume and location), and found reasonable trends and correlations. Therefore, the mean T(MR) of the tumor might be useful as a variable to evaluate the quality and effectivity of heat treatments, and consequently as optimization variable. Feasibility of noninvasive MR thermography for regional hyperthermia has been shown and should be further investigated.

Thermal monitoring: invasive, minimal-invasive and non-invasive approaches.

Background: Thermal treatments need verification of effectiveness. Invasive intra-tumoural thermometry was established as a standard method several years ago. However, in deep heating, invasive techniques have disadvantages. Therefore, alternatives have been suggested and are under development. Methods: In three phase II studies treating rectal cancer, cervical cancer and prostate cancer, this study replaced invasive (intra-tumoural) thermometry by tumour-related reference points or catheter sections in the rectum, vagina or urethra. Index temperatures and thermal dose parameters were determined. Two recent studies treated patients with recurrent rectal cancer and soft tissue sarcoma using non-invasive MR-thermometry employing the SIGMA-Eye applicator. The proton resonance frequency shift (PRFS) method was employed to generate MR-temperature distributions during the entire heat treatment in 10 min intervals (via phase differences). Fat correction (nulling specified regions in the fat tissue) was utilized to calibrate the method, in particular with respect to the B0-drift. Results: Statistically significant correlations were found between response (downstaging, WHO) and thermal parameters in rectal cancer (37 patients, rectum measurement, T90, cum min T90 ≥ 40.5°C) and cervical cancer (30 patients, vagina, mean temperature and equ min 43°C in a reference point). In prostate cancer (14 patients), a clear correlation was verified between long-term PSA control (≤1 ng ml−1) and urethral temperatures (T90, Tmax cum min T90 ≥ 40.5°C). The mean MR-temperature in the tumour at steady-state as well as the mean T90 were significantly correlated with response for recurrent rectal carcinoma regarding palliation and analgesia (15 patients) and with pathohistological regression rate in soft tissue sarcoma (nine patients). Conclusions: For tumours in the pelvis and in the lower extremities, invasive measurements can be replaced by minimally-invasive or non-invasive techniques, which provide equivalent or even more complete information. Extending the application of these surveillance methods to abdominal tumours or liver metastases is a challenge, but strongly desirable for clinical reasons.

Planning transarterial radioembolization of colorectal liver metastases with Yttrium 90 microspheres: evaluation of a sequential diagnostic approach using radiologic and nuclear medicine imaging techniques

The purpose of the study was to establish a diagnostic approach to the preparation of patients with colorectal liver metastases considered for transarterial radioembolization (RE). Twenty-two patients sequentially underwent computed tomography (CT; thorax/abdomen), magnetic resonance imaging (MRI; liver; hepatocyte-specific contrast), positron emission tomography (PET/PET-CT; F18-fluoro-desoxy-glucose), and angiography with perfusion scintigraphy [planar imaging; tomography with integrated CT (SPECT-CT)]. The algorithm was continued when no contraindication or alternative treatment option was found. The impact of each test on the therapy decision and RE management was recorded. Patient evaluation using CT revealed contraindications for RE in 4/22 patients (18%). Of the remaining 18 patients, 2 were excluded and 3 were assigned to locally ablative treatment based on MRI and PET results (28%). The remaining 13 patients entered the planning algorithm: SPECT-CT revealed gastrointestinal tracer accumulations in 4 (31%) patients [SPECT, 2 (15%)], making a modified application necessary. In five patients (38%), planar scintigraphy revealed relevant hepatopulmonary shunting. Therapy was finally administered to all 13 patients without therapy-related pulmonary or gastrointestinal morbidity. Each part of the diagnostic algorithm showed a relevant impact on patient management. The sequential approach appears to be suitable and keeps the number of unnecessary treatments and therapy risks to a minimum.

The Biologic Rationale of Hyperthermia

The clinical efficacy of various of hyperthermia approaches has been demonstrated in the scope of various randomised trials. In addition, a large body of preclinical data on alterations of cellular and molecular pathways under the circumstance of elevated temperatures is available. However, there is still uncertainty about the mechanisms which are acutally responsible for the beneficial effect of clinical hyperthermia when applied as an adjunt to radiotherapy, chemotherapy, or radiochemotherapy. This chapter gives a clinically orientated overview on the cytotoxic effect of heat alone and in conjunction with radiation and drugs, heat-induced alterations of the tumour microenvironment, and the immunological targets of hyperthermia.