Chie Hee Cho

Liver Malignancies: CT-Guided Interstitial Brachytherapy in Patients with Unfavorable Lesions for Thermal Ablation

PURPOSE To evaluate computed tomography (CT)-guided brachytherapy in patients with very large liver malignancies or with liver tumors located adjacent to the liver hilum. MATERIALS AND METHODS In this prospective nonrandomized phase II trial, we treated 20 patients (19 liver metastases and one cholangiocarcinoma) with CT-guided high-dose-rate (HDR) brachytherapy using a (192) Iridium source. All patients demonstrated no functional liver degradation prior to irradiation. Entry criteria were liver tumors > 5 cm (group A, n = 11, no upper limit) or liver tumors < or = 5 cm adjacent to the liver hilum (group B, n = 9). Dose planning for brachytherapy was performed with three dimensional (3D) CT data acquired after percutaneous applicator positioning. Magnetic resonance (MR) imaging follow-up was performed 6 weeks and every 3 months post intervention. Primary endpoints were complications, local tumor control (absence of tumor growth after treatment followed by shrinkage of the lesion starting at 6 months) and progression-free survival. RESULTS The mean tumor diameter was 7.7 cm (range, 5.5-10.8 cm) in group A, 3.6 cm (range, 2.2-4.9 cm) in group B. On average, a minimal dose of 17 Gy in the target volume was applied (range, 12-25 Gy). Severe side effects were recorded in two patients (10%). One patient demonstrated an obstructive jaundice caused by tumor edema after irradiation of a metastasis adjacent to the bile duct bifurcation. One patient developed intra-abdominal hemorrhage that was treated by a single blood transfusion and has ceased. We frequently encountered moderate increases of liver enzymes (70% of patients) and bilirubin (50% of patients) without clinical symptoms and thus considered to be insignificant. The median follow-up was 13 months. In group A (tumors > 5 cm), primary local tumor control after 6 and 12 months was 74% and 40%, respectively; in group B, it was 100% and 71%, respectively. All but one local recurrence (in a patient with diffuse tumor progression) were successfully treated during another CT-guided brachytherapy leading to a primary assisted local control of 93% after 12 months. CONCLUSION CT-guided brachytherapy based on individual dose plans and 3D CT data sets generated encouraging results in large liver malignancies as well as in tumors located adjacent to the liver hilum.

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.

Simulation of different applicator positions for treatment of a presacral tumour

Introduction: Proximally located presacral recurrences of rectal carcinomas are known to be difficult to heat due to the complex anatomy of the pelvis, which reflect, shield and diffract the power. This study is to clarify whether a change of position of the Sigma-Eye applicator in this region can improve the heating. Material and methods: Finite element (FE) planning calculations were made for a phantom model with a proximal presacral tumour using a fixed 100 MHz radiofrequency radiation. Shifts of the applicator were simulated in 1 cm steps in x-(lateral), y-(posterior) and z-(longitudinal) direction. Computations also considered the network effects of the Sigma-Eye applicator. Optimisation of the phases and amplitudes for all positions were performed after solving the bioheat-transfer-equation. The parameters T90, T50, sensitivity, hot spot volume and total deposited power have been sampled for every applicator position with optimised plans and a standard plan. Results: The ability to heat a presacral tumour clearly depends on the applicator position, for standard antenna adjustment and also for optimised steering of the Sigma-Eye applicator. The y-direction (anterior-posterior) is very sensitive. Using optimised steering for each position, in z-direction (longitudinal), we found an unexpected additional optimum at 8 cm cranial from the middle position of the phantom. The x-direction (lateral) is in a clinical setting less important and shows only smaller changes of T90 with an expected optimum in the central position. A positioning of the applicator in the axial and anterior position of the mid-pubic symphysis should be avoided for treatment of the presacral region, regardless of the used adjustment. Use of amplitude and phase optimisation yields better T90 values than plans optimised only by phases, but they are much more sensitive for small variations of phases and amplitudes during a treatment, and the total power of the Sigma-Eye applicator can be restricted by the treatment software. Conclusions: Complex geometry of the human pelvis seems to be the reason for the difficulties to warm up the proximal presacral region. The assumption that every position can be balanced by a proper phase adaption, is true only in a small range. A centring of the applicator on the mid-pubic symphysis to heat this region should be avoided. From the practical point of view improved warming should be performed by optimisation of phases only.

Comparison of MR-thermography and planning calculations in phantoms

A systematic comparison of three-dimensional MR (magnetic resonance) thermography and planning calculations in phantoms for the hyperthermia (HT) SIGMA-Eye applicator. We performed 2 x 6 experiments in a homogeneous cylindrical and a heterogeneous elliptical phantom by adjusting 82 different patterns with different phase control inside an MR tomograph (Siemens Magnetom Symphony, 1.5 Tesla). For MR thermography, we employed the proton resonance frequency shift method with a drift correction based on silicon tubes. For the planning calculations, we used the finite-difference time-domain (FDTD) method and, in addition, modeled the antennas and the transforming network. We generated regions according to a segmentation of bones and tissue, and used an interpolation technique with a subgrid of 0.5 cm size at the interfaces. A Gauss-Newton solver has been developed to adapt phases and amplitudes. A qualitative agreement between the planning program and measurements was obtained, including a correct prediction of hot spot locations. The final deviation between planning and measurement is in the range of 2-3 W/kg, i.e., below 10%. Additional HT phase and amplitude adaptation, as well as position correction of the phantom in the SIGMA-Eye, further improve the results. HT phase corrections in the range of 30-40 degrees and HT amplitude corrections of +/- 20-30% are required for the best agreement. The deviation /MR-FDTD/, and the HT phase/amplitude corrections depend on the type of phantom, certain channel groups, pattern steering, and the positioning error. Appropriate agreement between three-dimensional specific absorption rate distributions measured by MR-thermography and planning calculations is achieved, if the correct position and adapted feed point parameters are considered. As long as feed-point parameters are uncertain (i.e., cannot be directly measured during therapy), a prospective planning will remain difficult. However, we can use the information of MR thermography to better predict the patterns in the future even without the knowledge of feed-point parameters.

Regional hyperthermia of the abdomen in conjunction with chemotherapy for peritoneal carcinomatosis : Evaluation of two annular-phased-array applicators

Background. Peritoneal carcinomatosis is a stage of gynecological and gastrointestinal malignancies with poor prognosis. Options for enhancing the effect of standard chemotherapy, such as aggressive surgery and intraperitoneal chemotherapy, have limitations. In this phase I/II study, we evaluated regional hyperthermia of the pelvis and abdomen using the annular-phased-array technique as an adjunct to chemotherapy. Methods. Forty-five patients with peritoneal carcinomatosis (with or without liver metastases) in colorectal cancer (CRC) (n = 16), ovarian cancer (OC) (n = 17), or gastric/pancreatic/biliary cancer (n = 12) underwent standard chemotherapy and regional hyperthermia. Most CRC patients received second-line chemotherapy. All OC patients were platinum resistant. Regional hyperthermia was applied using a SIGMA-60 applicator (OC), a SIGMA-Eye/MR applicator (CRC), or various ring applicators (gastric/pancreatic/biliary cancer). Results. Abdominal regional hyperthermia was well tolerated, with acceptable acute discomfort and no long-term morbidity. The SIGMA-Eye/MR applicator achieved higher systemic temperatures (associated with higher systemic stress) and more effective heating of the upper abdomen; the SIGMA-60 applicator achieved higher temperatures (and power densities) in the pelvis. Three-year overall survival was encouraging for patients with CRC (22%) and OC (29%) but not gastric/pancreatic/biliary cancer. For the SIGMA-60 applicator (patients with OC), higher measured temperatures at the vaginal stump correlated with better outcome. Conclusions. The SIGMA-60 and SIGMA-Eye/MR applicators are feasible for abdominal heating and have low toxicity. The SIGMA-60 applicator is specifically suitable for malignancies with high pelvic burden; the SIGMA-Eye/MR applicator better heats the upper abdomen, including the liver. Further randomized investigations are warranted.

Image artifacts during MRT hybrid hyperthermia – Causes and Elimination

Purpose: Online MR-thermometry during hyperthermia can improve treatment control. It needs excellent image quality during hyperthermia treatment to get information from subtracted images. Materials and methods: For hybrid hyperthermia two high-frequency devices were used in combination working with different frequencies. The imaging was performed on a 1.5 T MR tomograph (Siemens Symphony, Quantum Gradienten, Maestro Class, Firma Siemens, Erlangen, Germany) at 64 MHz whereas hyperthermia was administered with a BSD 2000 3D unit utilizing a Sigma Eye applicator and a 12 channel DODECK transistor amplifier (BSD 2000, BSD-MC, Salt Lake City, Utah, USA) operating at 100 MHz. For analysing image artifacts a spectrum analyser (Hewlett Packard HP8591E) was used. Results: Two different image artifacts, occurring during the use of this hybrid system, are described. The artifacts result from introduction of additional frequencies into the imager. Here we demonstrated the detection and elimination of these spurious frequencies in the context of two case studies. Conclusion: Hybrid hyperthermia requires excellent imaging for optimal operation. Additional frequencies causing image artifacts can be identified by use of a spectrum analyser. Once identified, these interfering frequencies can be eliminated with appropriate RF filters. With MRI quality control for hyperthermia systems with different treatment frequencies is possible.

Termoterapia en cáncer de próstata mediante el uso de nanopartículas magnéticas

A novel method of interstitial heating using magnetic nanoparticles and a direct injection technique has been evaluated in human cancers in recent clinical trials. In prostate cancer, this approach was investigated in two separate phase-I-studies, employing magnetic nanoparticle thermotherapy alone and in combination with permanent seed brachytherapy. The feasibility and good tolerability was shown in both trials, using the first prototype of a magnetic field applicator. As with any other heating technique, this novel approach requires specific tools for planning, quality control and thermal monitoring, based on appropriate imaging and modelling techniques. In these first clinical trials, a newly developed method for planning and non-invasive calculations of the 3-dimensional temperature distribution based on computed tomography could be validated. Limiting factors of this approach at present are patient discomfort at high magnetic field strengths and suboptimal intratumoral distribution of nanoparticles. Until these limitations will be overcome and thermal ablation can safely be applied as a monotherapy, this treatment modality is being evaluated in combination with irradiation in patients with localized prostate cancer.

Regional abdominal hyperthermia combined with systemic chemotherapy for the treatment of patients with ovarian cancer relapse: Results of a pilot study

Purpose: Due to the poor prognosis of patients with ovarian cancer relapse (OCR), newer strategies are warranted to improve the therapeutic index. We performed a prospective phase I/II-study of regional abdominal hyperthermia (RHT) combined with systemic chemotherapy in OCR patients in order to evaluate outcome, efficacy and tolerance. Materials and methods: OCR patients with an Eastern Cooperative Oncology Group status <2, without any thromboembolic disease or severe cardiovascular co-morbidities, and pre-treated with at least one systemic chemotherapy regimen due to epithelial ovarian cancer were enrolled into the present study. RHT was applied using a SIGMA 60 applicator and a Hybrid-System SIGMA-Eye/MRT composed of a 1.5T-MRT and a Sigma-Eye-applicator. Results: Overall, 36 OCR patients were enrolled. The majority of the patients (>80%) were classified as platinum resistant. The most common chemotherapeutic agent applied was pegylated-liposomal-doxorubicin (47.2%) followed by carboplatin (16.6%) and topotecan (13.9%). One patient (2.8%) achieved a complete remission (CR), 12 patients (33.3%) yielded a partial remission (PR) and 16 patients (44.4%) developed a progressive disease (PD). In platinum-sensitive patients we observed higher response (57.1% versus 31%) and lower progression rates (28.6% versus 48.3%) than in platinum-resistant patients. Eleven patients (30.5%) discontinued treatment due to toxicity. The main toxicity was a haematological one with grade 3/4 anaemia, leucopenia and thrombocytopenia occurring in 13.9%, 5.6% and 8.3%, respectively. Median overall survival was 12 months (range: 1–48), while median progression-free survival was 5 months (range: 0.5–34). Conclusions: Our results demonstrate the feasibility of RHT combined with systemic treatment. Prospective phase III trials are warranted to evaluate the benefit and efficacy in heavily pre-treated patients with OCR.

Neue Behandlungsansätze mit Hyperthermie bei Zervixkarzinomen

ZusammenfassungDie Hyperthermie (Wärmetherapie) hat bisher keinen Eingang in die onkologische Standardtherapie gefunden. Sie bietet jedoch große onkologische Potenziale, da sie gut verträglich ist und sowohl die Radiotherapie als auch die Chemotherapie bei vielen Ausbreitungsstadien verstärken kann. Für das lokal fortgeschrittene Zervixkarzinom (im Stadium ≥FIGO IIB) wurden mehrere randomisierte Studien durchgeführt, in denen die höhere lokale Wirksamkeit der hyperthermen Radiotherapie im Vergleich zur Standardradiotherapie belegt werden konnte. Der Einfluss der Hyperthermie auf die Radiochemotherapie wird nun in einer internationalen prospektiven Studie geprüft. Auch die präoperative trimodale Anwendung wurde in einer Phase-II-Studie evaluiert. Darüber hinaus gibt es neuere technologische Entwicklungen in der Hyperthermie (Hybridhyperthermie, Nanotherapie und Teilkörperhyperthermie), die insbesondere eine Anwendung in der Behandlung des rezidivierenden Zervixkarzinoms ermöglichen (Beckenwandrezidiv und/oder peritoneale Ausbreitung).AbstractHyperthermia has not yet been established as a standard procedure in oncological practice. However, patients tolerate this modality very well, and the effects of radiation therapy as well as chemotherapy were demonstrated to get enhanced in various stages of oncological diseases. Therefore, a high potential benefit can be expected. A number of randomised studies have been performed for locally advanced cervical cancer (stages ≥FIGO IIB) demonstrating an increased local efficacy for hyperthermic radiation therapy compared to radiation alone. The impact of hyperthermia in conjunction with radio-chemotherapy is currently examined in an international prospective study. In addition, a trimodal therapy was evaluated in a neoadjuvant approach as phase II study. Furthermore, hyperthermia is undergoing great technological advances (e.g. hybrid hyperthermia, nanotherapy, and part-body hyperthermia), which enables its use in recurrent cervical cancer, in particular with pelvic wall infiltration and peritoneal involvement.

CT-gesteuerte Brachytherapie@@@CT-Guided Brachytherapy. A Novel Percutaneous Technique for Interstitial Ablation of Liver Malignancies: Eine neue perkutane Technik zur interstitiellen Ablation von Lebermetastasen

Ziel:Analyse der Sicherheit und Effektivität CT-gesteuerter Brachytherapie zur Ablation von Lebermalignomen.Patienten und Methodik:21 Patienten mit 21 Lebermalignomen (19 Metastasen, zwei primäre Lebermalignome) wurden mit perkutaner, CT-gesteuerter interstitieller Brachytherapie mit 192Ir behandelt. Alle Patienten wiesen Umstände auf, die eine bildgeführte thermische Ablation mit Radiofrequenz oder laserinduzierter Thermotherapie (LITT) einschränkten: Tumordurchmesser ≥ 5 cm bei sieben, enge Lagebeziehung zu Pfortader oder großen Lebervenen bei zehn, enge Lagebeziehung zur Hepatikusgabel bei vier Patienten. Die Dosimetrie erfolgte über unmittelbar nach CT-geführter Applikatorpositionierung akquirierte dreidimensionale CT-Datensätze.Ergebnisse:Die mittlere Tumorgröße betrug 4,6 cm (2,5–11 cm). Die minimale Dosis innerhalb des Tumorvolumens lag im Mittel bei 17 Gy (12–20 Gy). Der Volumenanteil gesunden Leberparenchyms mit einer Exposition > 5 Gy betrug 18% (5–39%) vom Lebergesamtvolumen abzüglich Tumorlast. Übelkeit und Erbrechen traten bei sechs Patienten auf (28%). Ein Patient entwickelte eine Obstruktion des Ductus choledochus durch ein strahleninduziertes Tumorödem in unmittelbarer Nachbarschaft. Leberenzymparameter und Bilirubinwerte zeigten regelhaft diskrete Anstiege ohne klinisches Korrelat. Die lokale Tumorkontrolle betrug 87% nach 6 Monaten und 70% nach 12 Monaten.Schlussfolgerung:CT-gesteuerte Brachytherapie ist sicher und effektiv. Die Technik ermöglicht gegenüber thermischen Ablationsverfahren eine breitere Indikationsstellung hinsichtlich Tumorgröße und Tumorlokalisation.Purpose:To assess safety and efficacy of CT-guided brachytherapy of liver malignancies.Patients and Methods:21 patients with 21 liver malignancies (19 metastases, two primary liver tumors) were treated with interstitial CT-guided brachytherapy applying a 192Ir source. In all patients, the use of image-guided thermal tumor ablation such as by radiofrequency or laser-induced thermotherapy (LITT) was impeded either by tumor size ≥ 5 cm in seven, adjacent portal or hepatic vein in ten, or adjacent bile duct bifurcation in four patients. Dosimetry was performed using three-dimensional CT data sets acquired after CT-guided positioning of the brachytherapy catheters.Results:The mean tumor diameter was 4.6 cm (2.5–11 cm). The mean minimal tumor dose inside the tumor margin amounted to 17 Gy (12–20 Gy). The proportion of the liver parenchyma exposed to > 5 Gy was 18% (5–39%) of total liver parenchyma minus tumor volume. Nausea and vomiting were observed in six patients after brachytherapy (28%). One patient demonstrated obstructive jaundice due to tumor edema after irradiation of a metastasis adjacent to the bile duct bifurcation. We commonly encountered asymptomatic increases of liver enzymes. Local control rates after 6 and 12 months were 87% and 70%, respectively.Conclusion:CT-guided brachytherapy is safe and effective. This technique displays broader indications compared to image-guided thermal ablation by radiofrequency or LITT with respect to tumor size or localization.