Beate Rau

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.

Preoperative hyperthermia combined with radiochemotherapy in locally advanced rectal cancer: a phase II clinical trial

OBJECTIVE A prospective phase II study was performed to determine the feasibility and efficacy in terms of response rate, resectability, and morbidity in patients with locally advanced rectal cancer who received preoperative regional hyperthermia combined with radiochemotherapy (HRCT). SUMMARY BACKGROUND DATA Recent studies suggest that preoperative radiochemotherapy in locally advanced rectal cancer can induce downstaging, but after resection the incidence of local recurrences remains high. Hyperthermia (HT) may add tumoricidal effects and improve the efficacy of radiochemotherapy in a trimodal approach. PATIENTS AND METHODS Thirty-seven patients with histologically proven rectal cancer and T3 or T4 lesions, as determined by endorectal ultrasound and computed tomography, entered the trial. 5-Fluorouracil (300-350 mg/m2) and leucovorin (50 mg) were administered on days 1 to 5 and 22 to 26. Regional HT using the SIGMA 60 applicator (BSD-2000) was given once a week before radiotherapy (45 Gy with 1.8-Gy fractions for 5 weeks). Surgery followed 4 to 6 weeks after completion of HRCT. RESULTS Preoperative treatment was generally well tolerated, with 16% of patients developing grade III toxicity. No grade IV complications were observed. The overall resectability rate was 32 of 36 patients (89%), and 31 resection specimens had negative margins (R0). One patient refused surgery. In 5 patients (14%), the histopathologic report confirmed no evidence of residual tumor (pCR). A partial remission (PR) was observed in 17 patients (46%). The survival rate after 38 months was 86%. In none of the patients was local recurrence detected after R0(L), but five patients developed distant metastases. CONCLUSION Preoperative HRCT is feasible and effective and may contribute to locoregional tumor control of advanced rectal cancer, which is to be proven in an ongoing phase III trial.

Prospective comparison of endorectal ultrasound, three-dimensional endorectal ultrasound, and endorectal MRI in the preoperative evaluation of rectal tumors. Preliminary results.

AbstractBackground: The aim of this study was to compare the value of endorectal ultrasound (EUS), three-dimensional (3D) EUS, and endorectal MRI in the preoperative staging of rectal neoplasms. Methods: Thirty consecutive patients with rectal tumors were assessed by EUS and endorectal MRI. Additionally, three-dimensional ultrasound was performed in a subgroup of 25 patients. EUS data were obtained with a bifocal multiplane transducer (10 MHz) and processed on a 3D ultrasound workstation. MR imaging was carried out with a 1.5 T superconducting unit using an endorectal surface coil. Results: EUS was carried out successfully in all 30 patients, whereas endorectal MRI was not feasible in two patients. Compared with the histopathological classification, EUS and endorectal MRI correctly determined the tumor infiltration depth in 25 of 30 and 28 patients, respectively. The comparative accuracy of EUS, 3D EUS, and endorectal MRI in predicting tumor invasion was 84%, 88%, and 91%, respectively. EUS, three-dimensional EUS, and endorectal MRI enabled us to assess the lymph node status correctly in 25, 25, and 24 patients, respectively. Both three-dimensional EUS and endorectal MRI combined high-resolution imaging and multiplanar display options. Assessment of additional scan planes facilitated the interpretation of the findings and improved the understanding of the three-dimensional anatomy. Conclusion: The accuracy of three-dimensional EUS and endorectal MRI in the assessment of the infiltration depth of rectal cancer is comparable to conventional EUS. One advantage of both methods is the ability to obtain multiplanar images, which may be helpful for the planning of surgery in the future.

Dynamic Expression Profile of p21WAF1/CIP1 and Ki-67 Predicts Survival in Rectal Carcinoma Treated With Preoperative Radiochemotherapy

PURPOSE We investigated p53 and its downstream effectors p21WAF1/CIP1, BAX, and hMSH2 as well as the proliferation marker Ki-67 (mki-67/MIB-1) in patients undergoing preoperative radiochemotherapy for rectal carcinoma to identify prognostic and predictive factors. The focus of this study was on the dynamics of these genetic markers in a longitudinal study-that is, before and after radiochemotherapy. PATIENTS AND METHODS Expression of p53, BAX, p21WAF1/CIP1, Ki-67, and hMSH2 was investigated by immunohistochemistry in pre- and posttherapeutic tumor samples in 66 patients. Tumor DNA was screened for p53 mutations by single-strand conformation polymorphism-polymerase chain reaction (SSCP-PCR). Paired tumor samples (pretherapy and posttherapy) were collected prospectively. RESULTS Patients with a decrease in p21 expression following radiochemotherapy had better disease-free survival (P =.03). Similarly, patients with an increase in proliferative activity as measured by increased Ki-67 expression posttherapy had better disease-free survival (P <.005). In addition, we observed a significantly better prognosis for patients with high hMSH2 expression. In contrast, pretherapeutic levels of p53, BAX, or p21 expression and p53 mutation had no prognostic value, indicating that the combination of radiotherapy and chemotherapy might override defects in these genes. CONCLUSION These findings are novel and support the clinical relevance of p21 in the suppression of both proliferation and apoptosis. Thus, the dynamic induction of p21WAF1/CIP1 was associated with a lower proliferative activity but an ultimately worse treatment outcome following neoadjuvant radiochemotherapy and tumor resection. Induction of p21, therefore, represents a novel resistance mechanism in rectal cancer undergoing preoperative radiochemotherapy.

Accuracy of endorectal ultrasound after preoperative radiochemotherapy in locally advanced rectal cancer

AbstractObjectives: Factors limiting the accuracy of endorectal ultrasound in staging, locally advanced primary rectal cancer after preoperative neoadjuvant radiochemotherapy (RCT) were evaluated. Methods: Patients (n= 84) with initial locally advanced rectal cancer (uT3/uT4) undergoing R0 resection were investigated after preoperative treatment that combined radiotherapy up to 45 Gy with two cycles of chemotherapy (5-FU and leucovorin on d 1–5 and 22–28). At 4 to 6 weeks after completion of RCT and before tumor resection, preoperative endoluminal ultrasound was performed. Results: The accuracy to predict the depth of tumor infiltration (T-category) was found to correlate with downstaging. The T-category was correctly staged before surgery in 15 of the 51 responders (29%) and in 27 of 33 nonresponders (82%), whereas misinterpretation occurred in 36 of the responders (71%) and in 6 of the nonresponders (18%) (p < 0.001). Neither tumor distance from anal verge nor tumor location correlated with the staging accuracy. Lymph node involvement was correctly assessed in 48 patients (57%). Wall invasion was correctly ascertained in 42 patients (50%), with under estimation in 11 patients (13%) and overestimation in 31 patients (37%). Conclusions: After radiochemotherapy, endosonography does not provide a satisfactory accuracy for preoperative staging of rectal cancer. New interpretation and diagnostic criteria are needed for the prediction of treatment response.

CLINICAL USE OF THE HYPERTHERMIA TREATMENT PLANNING SYSTEM HYPERPLAN TO PREDICT EFFECTIVENESS AND TOXICITY

PURPOSE The main aim is to prove the clinical practicability of the hyperthermia treatment planning system HyperPlan on a beta-test level. Data and observations obtained from clinical hyperthermia are compared with the numeric methods FE (finite element) and FDTD (finite difference time domain), respectively. METHODS AND MATERIALS The planning system HyperPlan is built on top of the modular, object-oriented platform for visualization and model generation AMIRA. This system already contains powerful algorithms for image processing, geometric modeling, and three-dimensional graphics display. A number of hyperthermia-specific modules are provided, enabling the creation of three-dimensional tetrahedral patient models suitable for treatment planning. Two numeric methods, FE and FDTD, are implemented in HyperPlan for solving Maxwells equations. Both methods base their calculations on segmented (contour based) CT or MR image data. A tetrahedral grid is generated from the segmented tissue boundaries, consisting of approximately 80,000 tetrahedrons per patient. The FE method necessitates, primarily, this tetrahedral grid for the calculation of the E-field. The FDTD method, on the other hand, calculates the E-field on a cubical grid, but also requires a tetrahedral grid for correction at electrical interfaces. In both methods, temperature distributions are calculated on the tetrahedral grid by solving the bioheat transfer equation with the FE method. Segmentation, grid generation, E-field, and temperature calculation can be carried out in clinical practice at an acceptable time expenditure of about 1-2 days. RESULTS All 30 patients we analyzed with cervical, rectal, and prostate carcinoma exhibit a good correlation between the model calculations and the attained clinical data regarding acute toxicity (hot spots), prediction of easy-to-heat or difficult-to-heat patients, and the dependency on various other individual parameters. We could show sufficient agreement between the calculations and measurements for power density (specific absorption rate) within the range of assessed precision. Tumor temperatures can only be estimated, because of the rather variable perfusion conditions. The results of the FE and FDTD methods are comparable, although slight differences exist resulting from the differences in the underlying models. There are also statistically provable differences among the tumor entities regarding the attained specific absorption rate, temperatures, and volume loads in normal tissue. However, gross fluctuations exist from patient to patient. CONCLUSION The hyperthermia planning system HyperPlan could be validated for a number of the 30 patients. Further improvements in the implemented models, FE and FDTD, are required. Even at its present state of development, hyperthermia planning for regional hyperthermia delivers valuable information, not only for clinical practice, but also for further technologic improvements.

Preoperative radiochemotherapy in locally advanced or recurrent rectal cancer: regional radiofrequency hyperthermia correlates with clinical parameters

PURPOSE Preoperative radiochemotherapy (RCT) is a widely used means of treatment for patients suffering from primary, locally advanced, or recurrent rectal cancer. We evaluated the efficacy of treatment due to additional application of regional hyperthermia (HRCT) to this conventional therapy regime in a Phase II study, employing the annular phased-array system BSD-2000 (SIGMA-60 applicator). The clinical results of the trial were encouraging. We investigated the relationship between a variety of thermal and clinical parameters in order to assess the adequacy of thermometry, the effectiveness of hyperthermia therapy, and its potential contribution to clinical endpoints. METHODS AND MATERIALS A preoperative combination of radiotherapy (1.8 Gy for 5 days a week, total dose 45 Gy applied over 5 weeks) and chemotherapy (low-dose 5-fluorouracil [5-FU] plus leucovorin in the first and fourth week) was administered to 37 patients with primary rectal cancer (PRC) and 18 patients with recurrent rectal cancer (RRC). Regional hyperthermia (RHT) was applied once a week prior to the daily irradiation fraction of 1.8 Gy. Temperatures were registered along rectal catheters using Bowman thermistors. Measurement points related to the tumor were specified after estimating the section of the catheter in near contact with the tumor. Three patients with local recurrence after abdominoperineal resection, had their catheters positioned transgluteally under CT guidance, where the section of the catheter related to the tumor was estimated from the CT scans. Index temperatures (especially T(max), T(90)) averaged over time, cumulative minutes (cum min) (here for T(90) > reference temperature 40.5 degrees C), and equivalent minutes (equ min) (with respect to 43 degrees C) were derived from repetitive temperature-position scans (5- to 10-min intervals) utilizing software specially developed for this purpose on a PC platform. Using the statistical software package SPSS a careful analysis was performed, not only of the variance of thermal parameters with respect to clinical criteria such as toxicity, response, and survival but also its dependency on tumor characteristics. RESULTS The rate of resectability (89%) and response (59%) were high for the PRC group, and a clear positive correlation existed between index temperatures (T(90)) and thermal doses (cum min T(90) >/= 40.5 degrees C). Even though the overall 5-year survival was encouraging (60%) and significantly associated with response, there was no statistically significant relationship between temperature parameters and long-term survival for this limited number of patients. However, nonresectable tumors with higher thermal parameters (especially cum min T(90) >/= 40.5 degrees C) had a tendency for better overall survival. We found even higher temperatures in patients with recurrences (T(90) = 40.7 degrees C versus T(90) = 40.2 degrees C). However, these conditions for easier heating did not involve a favorable clinical outcome, since surgical resectability (22%) and response rate (28%) for the RRC group were low. We did not notice any other dependency of thermal parameters to a specific tumor or patient characteristics. Finally, neither acute toxicity (hot spots) induced by hyperthermia or RCT nor perioperative morbidity were correlated with temperature-derived parameters. Only a higher probability for the occurrence of hot spots was found during treatment with elevated power levels. CONCLUSION In this study with two subgroups, i.e., patients with PRC (n = 37) and RRC (n = 18), there exists a positive interrelationship between thermal parameters (such as T(90), cum min T(90) >/= 40,5 degrees C) and clinical parameters concerning effectiveness. Additional hyperthermia treatment does not seem to enhance toxicity or subacute morbidity. Procedures to measure temperatures and to derive thermal parameters, as well as the hyperthermia technique itself appear adequate enough to classify heat treatments in

Restaging of Locally Advanced Carcinoma of the Rectum with MR Imaging after Preoperative Radio-Chemotherapy plus Regional Hyperthermia

Background: The restaging accuracy of MR imaging in advanced primary rectal carcinoma after preoperative radiochemotherapy and regional hyperthermia was evaluated and compared with the histopathologically verified degree of tumor remission after a course of radio-chemo-thermotherapy. Patients and Methods: 35 patients with primary rectal carcinoma (uT3/uT4) underwent MRI using a surface coil 4–6 weeks after radiochemotherapy (n = 35), regional hyperthermia (n = 23), and before curative surgery. We defined as gold standard for the remission status the comparison of pretherapeutic endosonography with the histopathology of the resected specimen. Results: T category was correctly restaged after preoperative treatment in only 19 (54%) of 35 patients. Nine of 20 responders were overstaged and seven of 15 non-responders were understaged. Concurrently, the N category was correctly restaged in 19 (54%) of 35 patients (twelve responders and seven non-responders). Overstaging occurred in four responders and two non-responders, understaging occurred in four responders and six non-responders. Conclusions: MRI proved independent of the response status as not suitable to restage locally advanced rectal carcinoma after preoperative radiochemotherapy despite optimized imaging technique and spatial resolution. Basically, imaging the morphology of a tumor cannot clearly differentiate between vital and devitalized tissue after a treatment. Functional imaging such as PET (positron emission tomography) appears more feasible for restaging after radio-chemo-thermotherapy.Hintergrund: Die Genauigkeit der Stadienbestimmung mittels MR-Bildgebung wurde bei primär fortgeschrittenen Rektumkarzinomen nach präoperativer Radiochemotherapie und regionaler Hyperthermie geprüft und mit der histopathologisch ermittelten Tumorremission nach präoperativer Behandlung verglichen. Patienten und Methode: 35 Patienten mit primären Rektumkarzinomen (uT3/uT4) wurden MR-tomographisch mittels Oberflächenspule 4–6 Wochen nach Radiochemotherapie (n = 35) plus Hyperthermie (n = 23) vor der kurativen Resektion untersucht. Als Goldstandard für die Remission wurde der Vergleich von prätherapeutischer Endosonographie mit dem histopathologischen Befund des Resektats definiert. Ergebnisse: Das T-Studium nach präoperativer Behandlung wurde nur bei 19 von 35 Patienten (54%) korrekt wiedergegeben, bei neun von 20 Respondern überbenimmt und bei sieben von 15 Nonrespondern unterschätzt. Daneben wurde auch cie N-Kategorie bei 19 von 35 Patienten (54%) korrekt bestimmt (bei zwölf Respondern und sieben Nonrespondern). Eine Überschätzung trat bei vier Respondern und zwei Nonrespondern auf, eine Unterschätzung bei vier Respondern und sechs Nonrespondern. Schlussfolgerungen: Die MR-Bildgebung erwies sich trotz optimierter Aufnahmetechnik mit erhöhter räumlicher Auflösung und unabhängig vom Remissionsstatus als ungeeignet, das Stadium lokal fortgeschrittener Rektumkarzinome nach präoperativer Radiochemotherapie exakt zu ermitteln. Grundsätzlich ist die Darstellung der Morphologie eines Tumors nicht geeignet, zwischen vitalem und devitalisiertem Tumorgewebe nach Vorbehandlung zu differenzieren. Funktionelle Verfahren (z. B. die Positronenemissionstomographie) könnten für die Verlaufskontrolle nach Radiochemothermotherapie geeigneter sein.

RATIONALE FOR USING INVASIVE THERMOMETRY FOR REGIONAL HYPERTHERMIA OF PELVIC TUMORS

PURPOSE Invasive thermometry for regional hyperthermia is time-consuming, uncomfortable, and risky for the patient. We tried to estimate the benefit/cost ratio of invasive thermometry in regional hyperthermia using the radiofrequency system BSD-2000. METHODS AND MATERIALS We evaluated 182 patients with locally advanced pelvic tumors that underwent regional hyperthermia. In every patient a tumor-related temperature measurement point was obtained either by invasive or minimally invasive catheter measurement tracks. In the earlier period for every patient an intratumoral measurement point was decided as obligatory and intratumoral catheters were implanted intraoperatively, CT guided, or under fluoroscopy. In the later period, invasive thermometry often was avoided, if a measurement point in or near the tumor was reached by an endoluminally inserted catheter (rectal, vaginal, cervical, urethral, or vesical). For every patient side effects and complications referred to thermometry were evaluated and compared with the potential benefit of the invasively achieved temperature data. The suitability of endolumimally registered temperatures is analyzed to estimate local feasibility (specific absorption rate achieved) and local effectiveness (thermal parameters correlated with response). RESULTS In 74 of 182 patients invasive thermometry was performed, at most CT-guided for soft tissue sarcomas and rectal recurrences. In 14 of 74 (19%) side effects such as local inflammation, pain, or abscess formation occurred that enforced removal of the catheter. However, local problems were strongly correlated with the dwell time of the catheter and nearly never occurred for dwell times less than 5 days. Fortunately, no fatal complications (e.g., bleeding or perforation) occurred during or after implantation which could be attributed to the invasive thermometry procedure. Endoluminal tumor-related temperature rises per time unit (to estimate power density) were correlated with intratumoral rises at the same patients (where both measurements were available). For a subgroup of patients pooled in two Phase II studies with rectal (n = 37) and cervical (n = 18) carcinomas thermal parameters derived from endoluminal measurements were correlated with response or local control, resp. CONCLUSIONS If a tumor-related endoluminal temperature measurement point is available, additional invasive thermometry gives no further information to improve the power deposition pattern. For primary rectal and cervical cancer, and probably as well for prostate, bladder and anal cancer, endoluminal measurements are suitable to estimate local feasibility and effectiveness. Therefore, invasive thermometry is dispensable in the majority of patients. In some selected cases, temperature measurement in the tumor center is required to estimate the maximum temperature. In those cases, dwell time of catheters should be minimized--and it should be considered to perform invasive thermometry at the beginning (one or two heat treatments).