A new noninvasive approach in breast cancer therapy using magnetic resonance imaging-guided focused ultrasound surgery.

An ideal vision of modern medicine includes tumor surgery with the human body remaining completely intact. A noninvasive therapy could avoid infections and scar formation; it would require less anesthesia, reduce recovery time, and possibly also reduce costs. This study investigated whether human breast cancer can be effectively treated with a novel combination of image guidance and energy delivery, noninvasive magnetic resonance imaging (MRI)-guided focused ultrasound (FUS). We have developed a FUS therapy unit guided by MRI for the treatment of human breast tumors in a clinical 1.5 T MR scanner. With interactive target segmentation on MRI, defined volumes could be noninvasively treated in a single session with on-line MR temperature control. The ultrasound waves were focused through the intact skin and resulted in the localized thermal tissue ablation at a maximum temperature of 70 degrees C. The therapy principle was first demonstrated in sheep breast in vivo and was then applied in a patient with core biopsy-proven invasive breast cancer 5 days before breast-conserving surgery. MRI proved suitable to delineate the breast cancer, served as stereotactic treatment planning platform, and delineated the FUS-related tissue changes such as interruption of tumor blood flow. Furthermore, MRI localized the hot spot in the tumor and measured temperature elevation during the treatment. This allowed us to monitor the efficacy and safety of FUS therapy. Immunohistochemistry of the resected specimen demonstrated that FUS homogeneously induced lethal and sublethal tumor damage with consecutive up-regulation of p53 and loss of proliferative activity. This effect was realized without anesthesia and damage to the surrounding healthy tissue or systemic effects. Overall, our results show that noninvasive MRI-guided therapy of breast cancer is feasible and effective. Thus, MRI-guided FUS may represent a new strategy for the neoadjuvant, adjuvant, or palliative treatment in selected breast cancer patients and in patients with other soft-tissue tumors.

Transient enlargement of contrast uptake on MRI after linear accelerator (linac) stereotactic radiosurgery for brain metastases.

PURPOSE/OBJECTIVE: With the increasing number of patients successfully treated with stereotactic radiosurgery for brain metastases, decision making after therapy based on follow-up imaging findings becomes more and more important. Magnetic resonance imaging (MRI) is the most sensitive means for follow-up studies. The objective of this study was to investigate the treatment outcome of our radiosurgery program and to describe the response of brain metastases to contrast-enhanced MRI after linear accelerator (linac) stereotactic radiosurgery and identify factors to distinguish among local control and local failure. METHODS AND MATERIALS: Using serial MRI, we followed the course of 87 brain metastases in 48 consecutive patients treated between September 1996 and November 1997 with linac-based radiosurgery with 15-MV photons. Treatment planning was performed on an MR data cube. For spherical metastases, radiosurgery was delivered using a 9 noncoplanar arc technique with circular-shaped collimators. For irregularly shaped targets, radiosurgery was delivered using a manually driven multi-leaf collimator with a leaf width of 1.5 mm projected to the isocenter. Median radiosurgery dose was 20 Gy prescribed to the 80% isodose. Together with whole brain radiotherapy (20 x 2 Gy, 5/w), a median radiosurgical dose of 15 Gy was delivered. Median follow-up was 8 (range 2--36) months. Factors influencing local control and survival rates were analyzed with respect to MRI response, and Kaplan-Meier curves were calculated. RESULTS: Actuarial local tumor control was 91% at one and two years. Patient survival at one and two years was 30% and 18%. Median survival was 9 months. During follow-up in 70 (81%) of the 87 treated metastases, the contrast-enhancing volumes on T1W images were stable or disappeared partly or completely. A transient enlargement of contrast-enhancing volumes was observed in 11 (12%) of the 87 lesions treated, while a progressive enlargement due to local treatment failure was observed in 6 (7%) of the 87 treated metastases. Younger age, early contrast onset after radiosurgery, and previous chemotherapy were associated with this transient enlargement of contrast-enhancing lesion volume. CONCLUSIONS: Linac-based radiosurgery is an effective, noninvasive, and safe treatment option for patients with brain metastases. A marked enlargement of the contrast-enhancing volume on T(1)-weighted MR images after radiosurgery is a sensitive predictor for, but not equivalent with, local failure. In as many as two-thirds of the cases with contrast enlargement in MRI follow-up, the contrast enlargement is transient with no need for further treatment. While some MRI findings are more likely if transient enlargement is present, a clear decision cannot be made based on MRI, and ultimately the clinical status dictates further action.

Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial.

PURPOSE: To investigate the feasibility and the clinical response of a stereotactic single-dose radiation treatment for liver tumors. PATIENTS AND METHODS: Between April 1997 and September 1999, a stereotactic single-dose radiation treatment of 60 liver tumors (four primary tumors, 56 metastases) in 37 patients was performed. Patients were positioned in an individually shaped vacuum pillow. The applied dose was escalated from 14 to 26 Gy (reference point), with the 80% isodose surrounding the planning target volume. Median tumor size was 10 cm(3) (range, 1 to 132 cm(3)). The morbidity, clinical outcome, laboratory findings, and response as seen on computed tomography (CT) scan were evaluated. RESULTS: Follow-up data could be obtained from 55 treated tumors (35 patients). The median follow-up period was 5.7 months (range, 1.0 to 26.1 months; mean, 9.5 months). The treatment was well tolerated by all patients. There were no major side effects. Fifty-four (98%) of 55 tumors were locally controlled after 6 weeks at the initial follow-up based on the CT findings (22 cases of stable disease, 28 partial responses, and four complete responses). After a dose-escalating and learning phase, the actuarial local tumor control rate was 81% at 18 months after therapy. A total of 12 local failures were observed during follow-up. So far, the longest local tumor control is 26.1 months. CONCLUSION: Stereotactic single-dose radiation therapy is a feasible method for the treatment of singular inoperable liver metastases with the potential of a high local tumor control rate and low morbidity.

Extracranial stereotactic radiation therapy: set-up accuracy of patients treated for liver metastases.

PURPOSE: Patients with liver metastases might benefit from high-dose conformal radiation therapy. A high accuracy of repositioning and a reduction of target movement are necessary for such an approach. The set-up accuracy of patients with liver metastases treated with stereotactic single dose radiation was evaluated. METHODS AND MATERIALS: Twenty-four patients with liver metastases were treated with single dose radiation therapy on 26 occasions using a self-developed stereotactic frame. Liver movement was reduced by abdominal pressure. The effectiveness was evaluated under fluoroscopy. CT scans were performed on the planning day and directly before treatment. Representative reference marks were chosen and the coordinates were calculated. In addition, the target displacement was quantitatively evaluated after treatment. RESULTS: Diaphragmal movement was reduced to median 7 mm (range: 3-13 mm). The final set-up accuracy of the body was limited to all of median 1.8 mm in latero-lateral direction (range: 0.3-5.0 mm) and 2.0 mm in anterior-posterior direction (0.8-3.8 mm). Deviations of the body in cranio-caudal direction were always less than the thickness of one CT slice (<5 mm). However, a repositioning was necessary in 16 occasions. The final target shift was median 1.6 mm (0.2-7.0 mm) in latero-lateral and 2.3 mm in anterior-posterior direction (0.0-6.3 mm). The median shift in cranio-caudal direction was 4.4 mm (0.0-10.0 mm). CONCLUSIONS: In patients with liver metastases, a high set-up accuracy of the body and the target can be achieved. This allows a high-dose focal radiotherapy of these lesions. However, a control CT scan should be performed directly before therapy to confirm set-up accuracy and possibly prompt necessary corrections.

A comparison of shock wave and sinusoidal-focused ultrasound-induced localized transfection of HeLa cells.

Both shock waves and sinusoidal continuous wave ultrasound can mediate DNA transfer into cells. The relative transfection efficiencies of different ultrasound modalities are unclear. The purpose of this paper is to compare the transfection efficiency of lithotripter shock waves and focused sinusoidal ultrasound in vitro. HeLa cells were transfected with beta-galactosidase and luciferase plasmid DNA reporter. Shock waves were generated by an electromagnetic sound source. Sixty to 360 pulses at 1 Hz pulse frequency were administered at 13, 16 or 19 kV capacitor voltage. Sinusoidal focused ultrasound was generated by a single focus piezoceramic air-backed disk transducer at a carrier frequency of 1.18 MHz operated in a pulsed mode. Compared to cells mixed with DNA only, shock waves induced up to eightfold more transfected cells at a cell viability of 5%, while sinusoidal-focused ultrasound induced up to 80-fold more transfected cells at a cell viability of 45%. The corresponding transfection efficiencies of the HeLa cells were 0.08% for shock waves and 3% for focused ultrasound. These results may contribute to the selection of the ultrasound modality as a localized, noninvasive and safe tool to mediate gene transfer.

Invasive thymoma: treatment with postoperative radiation therapy.

PURPOSE: To assess radiation therapy and chemotherapy in the treatment of invasive thymoma and thymic carcinoma. MATERIALS AND METHODS: In 1981-1995, 43 patients received irradiation after total (n = 23) or subtotal (n = 20) resection. Tumors were thymic carcinoma (n = 10) or invasive thymoma (n = 33). Masaoka stage was II in 10 patients, III in 14, and IV in 19. Median total dose applied was 50 Gy (range, 10-72 Gy). Seventeen patients (five with stage III and 12 with stage IV) also received chemotherapy. RESULTS: Patients with thymic carcinoma had a median survival of 9.5 months, compared with 50 months for patients with invasive thymoma (P = .008). Patients' median survival and 5-year survival rates were 97 months and 90% for stage II, 65 months and 67% for stage III, and 32.5 months and 30% for stage IV tumors (P = .024). Overall control rate within the radiation field was 81% (35 patients) and overall local control rate within the thorax was 74% (32 patients). Of the 17 patients who received chemotherapy and radiation therapy, nine had thymic carcinoma and a median survival of 12 months (range, 1.4-23.0 months). CONCLUSION: With total doses of 45-50 Gy, local control is achievable after radical resection. Whether patients with completely resected stage II thymomas should receive radiation after surgery remains uncertain, as does the role of chemotherapy in the treatment of thymoma.

Combined endoluminal and external irradiation of inoperable oesophageal carcinoma.

PURPOSE: Higher radiation doses to oesophageal cancer might be possible by the steep dose gradient of an afterloading source. Structures at risk are not impaired by endoesophageal brachytherapy. Our experiences with endoesophageal afterloading in combination with external beam treatment are reported. METHODS AND MATERIALS: Fifty-four patients were treated by this technique. All patients suffered from an inoperable oesophageal carcinoma (7 adenocarcinoma, 47 squamous-cell carcinoma). Patients were scheduled by tumour stage and medical condition into a curative group (21 patients) and into a palliative group (33 patients). Mean sum doses of 60.3 Gy (range 58-70 Gy) percutaneously and an additional endoluminal dose of 13.6 Gy (range 10-20 Gy) were applied endoluminally in the curative group and 44.9 Gy (range 14-53 Gy) plus 17.5 Gy (range 5-30 Gy), respectively, in the palliative group. Overall treatment time was 10 weeks (range 4.6-14.3 weeks) for the curative group and 9.3 weeks (range 4.1-13.9 weeks) for the palliative group. RESULTS: Six weeks after the end of therapy a radiological remission could be observed in 32/33 of the palliatively treated patients (10 complete, 22 partial, 1 none). In 13 patients of this group a local progression was observed after a median time of 7.1 months. Median survival of this group was 9 months. A radiological remission occurred in 18/21 of the curatively treated patients (11 complete, 7 partial, 3 none). Median time to local progression (12 patients) was 4.5 months in this group and median survival was 7.7 months. The difference in time to progression reached a significant level (P = 0.05). The only favourable factors for survival were an incomplete or complete radiological remission (median survival 7.5 versus 11.4 months, P = 0.003) and stage I/II or III/IV (median survival 7.4 versus 12.6 months, P = 0.0024). The prior estimation of the treatment goal was not confirmed by survival data (curative, 7.7 months versus palliative, 9.0 months (not significant)). Eight of 54 minor and 8/54 (15%) major adverse events were observed. In four of these patients major complications were caused by progressive tumour. CONCLUSIONS: Endoesophageal afterloading combination with percutaneous irradiation is a feasible save treatment in inoperable cases. A good local tumour regression and functional results can be reached. The data suggest that higher endoluminal doses extend the time to local progression. In comparison with the literature survival can not be increased by this treatment technique. The best way to combine both treatment modalities has not yet been found.

Low-grade astrocytoma: treatment with conventionally fractionated stereotactic radiation therapy.

PURPOSE: To assess the efficacy of fractionated stereotactic radiation therapy for low-grade astrocytoma in terms of improvements to therapeutic ratio, patient survival, and quality of life. MATERIALS AND METHODS: Since 1987, 32 patients with inoperable grade II astrocytoma were irradiated. Stereotactic radiation therapy was given only to patients with progressive symptoms. The mean total dose applied was 59.8 Gy (range, 54.0-65.0 Gy). RESULTS: Four years after therapy, the overall survival rate calculated with Kaplan-Meier analysis was 76%. Median progression-free survival was 48 months. On the basis of clinical symptoms, 91% (29 of 32) of patients showed improvement or stable disease after stereotactic radiation therapy. Eleven local failures were observed, 10 of which were within the planning target volume; one patient had a continuously enlarging mass. Acute toxic effects of radiation did not exceed grade II of the World Health Organization classification. Two patients developed reversible contrast enhancement without clinical symptoms on MR images within 1 year after stereotactic radiation therapy. CONCLUSION: Stereotactic radiation therapy for grade II astrocytoma appears to improve patients' quality of life or stabilize disease and is not correlated with marginal misses.

[Clinical value of positron emission tomography (PET) in oncologic questions: results of an interdisciplinary consensus conference. Schirmerreschaft der Deutschen Gesellschaft for Nuklearmedizin]. / Klinische Wertigkeit der Positronen-Emissions-Tomographie (PET) bei onkologischen Fragestellungen: Ergebnisse einer interdisziplinären Konsensuskonferenz.

AIM: The purpose of the present paper is to assess clinical value of PET in oncology on the basis of published studies. METHODS: Clinical value of PET in oncology was evaluated by a panel of recognized experts in the framework of an interdisciplinary consensus conference. On the basis of PET studies, well documented in the international literature, the value of PET for solving clinical questions was classified according to the following categories (classes 1a, 1b, 2a, 2b, 3): "appropriate" (1a), "mostly acceptable" (1b), "helpful" (2a), "value as yet unknown" (2b), "useless" (3). RESULTS: 2-fluorodeoxyglucose (FDG) acts as the radiopharmaceutical of choice for PET in clinical oncology. PET is indicated (1a) for diagnosing relapse in high grade glioma (FDG) or low grade glioma (C-11 methionine or F-18 fluorotyrosine), differential diagnosis of solitary peripheral pulmonary nodules in high risk patients and for diagnosis of pancreatic carcinoma. PET may be clinically used (1b): In "low-grade" glioma, search for unknown primary in head and neck tumors, suspicion of relapse in non-small cell bronchial carcinoma (NSCBC) and colorectal carcinoma, lymphnode staging in NSCBC, pancreatic carcinoma, muscle invasive bladder carcinoma and testicular cancer. Staging of Hodgkin's disease (HD, stage I/II vs III), early therapy control in patients with a residual mass or suspicion of relapse in HD and in high grade NHL, lymph node staging and search for distant metastases in malignant melanoma (Breslow > 1.5 mm), search for lymph node or distant metastases in differentiated thyroid cancer with elevated hTG and a negative radioiodide whole body scan. Many further indications are emerging, but are not yet sufficiently well documented in the literature. For most indications beside scientific studies, an individual cost benefit utility evaluation by the responsible physician is recommended. CONCLUSION: Metabolic imaging of PET provides for many principle advantages compared to conventional anatomically based cross sectional imaging. For routine use in oncology a detailed assessment of specific efficiency of PET is indicated.

[Intraoperative radiotherapy of locally advanced and recurrent rectal cancer]. / Intraoperative Radiotherapie des lokal ausgedehnten und rezidivierten Rectumcarcinoms.

Intraoperative radiotherapy (IORT) offers a technique to increase radiation dose to the residual tumor or tumor bed while sparing neighboring radiosensitive organs. Beyond the mostly employed dedicated electron beam facilities, the afterloading--'flab'-technique was also used. In first prospective studies IORT was performed in patients with not completely resected locally advanced (T4) or recurrent tumors after complete external beam radiotherapy (50.4 Gy) as an additional boost dose, using small field sizes. This locally restricted dose escalation yielded higher local control and an increased prognosis. Nerves and ureters were dose limited. In our series IORT was performed for rectal carcinomas stages II and III. After an external beam radio- or radio-chemotherapy with 41.4 Gy, shrinking field boost irradiation was done intraoperatively with moderate doses and larger IORT field sizes. Compared to a historical control with high-dose external beam radiotherapy alone local control rate was increased. Radiogenic neuropathy or stenosis of the ureter was not observed. The impact on prognosis must awaited. Randomized studies are required to clearly describe the role of IORT in rectal carcinoma.