Johanna Gellermann

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.

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.

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.

Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness.

Cancer is sporadic in nature, characterized by an initial clonal oncogenic event and usually a long latency. When and how it subverts the immune system is unknown. We show, in a model of sporadic immunogenic cancer, that tumor-specific tolerance closely coincides with the first tumor antigen recognition by B cells. During the subsequent latency period until tumors progress, the mice acquire general cytotoxic T lymphocyte (CTL) unresponsiveness, which is associated with high transforming growth factor (TGF) β1 levels and expansion of immature myeloid cells (iMCs). In mice with large nonimmunogenic tumors, iMCs expand but TGF-β1 serum levels are normal, and unrelated CTL responses are undiminished. We conclude that (a) tolerance to the tumor antigen occurs at the premalignant stage, (b) tumor latency is unlikely caused by CTL control, and (c) a persistent immunogenic tumor antigen causes general CTL unresponsiveness but tumor burden and iMCs per se do not.

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.

Local hyperthermia combined with radiotherapy and-/or chemotherapy: Recent advances and promises for the future

Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tissues to temperatures ranging between 39 and 45°C. Recent developments based on the thermoradiobiological rationale of hyperthermia indicate it to be a potent radio- and chemosensitizer. This has been further corroborated through positive clinical outcomes in various tumor sites using thermoradiotherapy or thermoradiochemotherapy approaches. Moreover, being devoid of any additional significant toxicity, hyperthermia has been safely used with low or moderate doses of reirradiation for retreatment of previously treated and recurrent tumors, resulting in significant tumor regression. Recent in vitro and in vivo studies also indicate a unique immunomodulating prospect of hyperthermia, especially when combined with radiotherapy. In addition, the technological advances over the last decade both in hardware and software have led to potent and even safer loco-regional hyperthermia treatment delivery, thermal treatment planning, thermal dose monitoring through noninvasive thermometry and online adaptive temperature modulation. The review summarizes the outcomes from various clinical studies (both randomized and nonrandomized) where hyperthermia is used as a thermal sensitizer of radiotherapy and-/or chemotherapy in various solid tumors and presents an overview of the progresses in loco-regional hyperthermia. These recent developments, supported by positive clinical outcomes should merit hyperthermia to be incorporated in the therapeutic armamentarium as a safe and an effective addendum to the existing oncological treatment modalities.

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.

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.