Wolfgang Tilly

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).

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.

Scanning E-field sensor device for online measurements in annular phased-array systems.

PURPOSE A measurement device for noninvasive and simultaneous control of antennas during regional radiofrequency (rf) hyperthermia and, subsequently, the estimation of the power distribution in the interior of patients are essential preconditions for further technological progress. Aiming at this, the feasibility of an electro-optical electric field sensor was investigated during clinical rf hyperthermia. MATERIAL AND METHODS The electro-optical electric field (E-field) sensor is based on lithiumniobate crystals and the Mach-Zehnder interferometer structure, and was tested in an earlier phantom study. For this study, a mechanical scanning device was developed allowing the registration of the E-field during clinical application. Data were recorded along a curve in the water bolus of the SIGMA 60 applicator of the annular phased-array system BSD-2000 (BSD Medical Corp., Salt Lake City, UT) close to the base points of the flat biconical dipole antennas. The results were compared with modeling calculations using the finite-difference time-domain (FDTD) method. For the latter, different antenna models were assumed. For systematic registration of the E-field curves in amplitude and phase, we employed an elliptical lamp phantom with fat-equivalent ring (filled with saline solution) and an elliptical polyacrylamide phantom with acrylic glass wall. Further measurements were carried out during the treatment of 5 patients with 20 hyperthermia treatments. RESULTS Data of both phantom and patient measurements can be satisfactorily described by the FDTD method, if the antenna model is refined by taking into account the conical form of the dipoles and the special dielectric environment of the feeding point. Phase deviations can be entered ex posteriori for correction in the calculation algorithm. A comparison of amplifier power measurement (forward and backward power) and bolus E-field scans near the antenna base points demonstrates that E-field measurements between antennas and patient are a necessity for the appropriate characterization of antenna radiation properties. These measurements are sensitive to variations of the lossy medium in position and shape, and can be correctly predicted with current models. However, the differences between different patients are moderate and unspecific in both calculations and measurements, with fluctuations at maximum of 30 degrees in phases and 40% in amplitudes. CONCLUSIONS The measurement method presented here turned out to be a practical tool for online registration of E-fields in phases and amplitudes along arbitrary curves in a water bolus or phantom. It can be utilized to evaluate antenna design and modeling calculations and leads, thus, to a better understanding of complicated multiantenna systems. In clinical routine, it can be employed as input for patient-specific hyperthermia planning and, finally, for the realization of online control with subsequent optimization of the power distribution in the patient.

Dose-Escalated Conformal Radiotherapy of Glioblastomas – Results of a Retrospective Comparison Applying Radiation Doses of 60 and 70 Gy

Background: Dose escalated three-dimensional conformal radiotherapy with 70 Gy against glioblastomas was compared retrospectively with the standard scheme of 60 Gy using 2-D-planning. Patients and Methods: In the period from 1994 to 1998, a series of 135 patients with glioblastomas was treated by surgery and postoperative radiotherapy. A conversion from 2-D into 3-D-planning was carried out in 4/1996. The prescribed total dose for the first 65 patients was 60 Gy (group 60). A boost up to 70 Gy was added for the remaining 70 patients (group 70). Results: The median survival time was 8.0 months for group 60 and 8.3 months for group 70. A dependency on the applied dose range was found. The median survival time was 3 months for patients who received a radiation dose of 55 Gy or less, 8.6 months for doses between 56 and 65 Gy, and 9.6 months for patients with a dose between 66 and 75 Gy (p < 0.01). In a multivariate analysis only the performance status maintained significance (p = 0.02) as a prognostic factor, while the dose range reached borderline significance (p = 0.09). Conclusion: No statistically significant survival prolongation was reached despite a dose escalation to 70 Gy.

A non-randomised, single-centre comparison of induction chemotherapy followed by radiochemotherapy versus concomitant chemotherapy with hyperfractionated radiotherapy in inoperable head and neck carcinomas.

BackgroundThe application of induction chemotherapy failed to provide a consistent benefit for local control in primary treatment of advanced head and neck (H&N) cancers. The aim of this study was to compare the results of concomitant application of radiochemotherapy for treating locally advanced head-and-neck carcinoma in comparison with the former standard of sequential radiochemotherapy.MethodsBetween 1987 and 1995 we treated 122 patients with unresectable (stage IV head and neck) cancer by two different protocols. The sequential protocol (SEQ; 1987–1992) started with two courses of neoadjuvant chemotherapy (cisplatin [CDDP] + 120-h continuous infusions (c.i.) of folinic acid [FA] and 5-fluorouracil [5-FU]), followed by a course of radiochemotherapy using conventional fractionation up to 70 Gy. The concomitant protocol (CON; since 1993) combined two courses of FA/5-FU c.i. plus mitomycin (MMC) concomitantly with a course of radiotherapy up to 30 Gy in conventional fractionation, followed by a hyperfractionated course up to 72 Gy. Results from the two groups were compared.ResultsPatient and tumor characteristics were balanced (SEQ = 70, CON = 52 pts.). Mean radiation dose achieved (65.3 Gy vs. 71.6 Gy, p = 0.00), response rates (67 vs. 90 % for primary, p = 0.02), and local control (LC; 17.6% vs. 41%, p = 0.03), were significantly lower in the SEQ group, revealing a trend towards lower disease-specific (DSS; 19.8% vs. 31.4%, p = 0.08) and overall (14.7% vs. 23.7%, p = 0.11) survival rates after 5 years. Mucositis grades III and IV prevailed in the CON group (54% versus 44%). Late toxicity was similar in both groups.ConclusionConcurrent chemotherapy seemed more effective in treating head and neck tumors than induction chemotherapy followed by chemoradiation, resulting in better local control and a trend towards improved survival.

Das pT4-Rektumkarzinom

ZusammenfassungGrundlagen: Beim in die Umgebung infiltrierenden Rektumkarzinom (uT4) sind nicht nur die Resektabilität eingeschränkt, sondern auch die Überlebensdaten inklusive der lokalen Rezidivrate schlecht. Aufgrund der Datenlage wurden neue Therapiekonzepte entwickelt, wobei gerade präoperative Konzepte hinsichtlich Resektabilität und Lokalrezidivrate überzeugend gute Resultate zeigten.Methodik: Verschiedene Therapieregime in der Behandlung des lokal weit fortgeschrittenen Rektumkarzinoms mit Infiltration in Nachbarorgane (uT4) werden dargestellt und diskutiert. Die therapieinduzierten Nebenwirkungen werden in Abhängigkeit der Therapiestrategien kritisch aufgezeigt.Ergebnisse: Prinzipiell ist die Nebenwirkungsrate im präoperativen gegenüber dem postoperativen Behandlungskonzept niedriger und ist daher vorzuziehen. Beim uT4-Rektumkarzinom erreicht man durch eine präoperative Therapie ohne wesentliche Erhöhung der postoperativen Morbidität nicht nur die Verbesserung der Resektabilität, sondern damit konsequenterweise auch eine Verbesserung der Überlebensraten.Schlußfolgerungen: Eine präoperative kombinierte Behandlung mit einer Radio-Chemotherapie beim uT4-Rektumkarzinom erzielt eine Tumorrückbildung, eine verbesserte lokale Kontrolle und eine Überlebensverlängerung und ist damit empfehlenswert.SummaryBackground: The rate of resectability and local recurrence in locally advanced rectal cancer infiltrating neighbouring organs (uT4) has led to reevaluation of treatment concepts. Preoperative combined radio-chemotherapy demonstrated favourable results in both: resectability and local recurrence.Methods: Different therapeutical strategies in the treatment of locally advanced primary rectal cancer infiltrating neighbouring organs (uT4) are demonstrated and discussed. Therapeutic induced toxicity depending on treatment regimen is critically elucidated.Results: Therapeutic induced toxicity in the preoperative setting is lower than in the postoperative treatment concept. Toxicity depends on the kind of chemotherapy and the application form (bolus, continuous). Preoperative treatment regimens increase the resectability of T4-tumors and in consequence improve the survival data without increasing postoperative complications.Conclusions: Preoperative combined treatment of locally advanced uT4 rectal cancer revealed encouraging downstaging, local control, and survival rates.