Alterations of intratumoral pharmacokinetics of 5-fluorouracil in head and neck carcinoma during simultaneous radiochemotherapy.

The kinetics of local drug uptake and metabolism of the anticancer drug 5-fluorouracil (5-FU) has been monitored by means of 19F nuclear magnetic resonance spectroscopy in 17 patients with neck tumors during concurrent radiochemotherapy. All of the patients underwent an accelerated hyperfractionated, concomitant-boost radiochemotherapy with 5-FU [600 or 1000 mg/m2 of body surface (b.s.)] and carboplatin (70 mg/m2 of b.s.). Serial 19F nuclear magnetic resonance spectra were obtained during and after the administration of 5-FU in a 15-T scanner with the use of a 5-cm diameter surface coil positioned on a cervical lymph node metastasis. Examinations were performed at day 1 of therapy and, in 13 patients, also after 43.5 Gy of irradiation at day 1 of the second chemotherapy cycle. Resonances of 5-FU and the catabolites 5,6-dihydro-5-fluorouracil (DHFU) and alpha-fluoro-beta-alanine (FBAL) were resolved in the tumor spectra. The median of the 5-FU and FBAL levels was significantly higher (more than 2-fold) at the second compared with the first examination, whereas the level of DHFU did not change. This effect could indicate an increased delivery of 5-FU into the interstitial space of the tumor in the course of the combined treatment, which would result in an enhanced exposure of the tumor cells to the drug. A potential mechanism for synergy between radio- and chemotherapy is discussed, but alternative mechanisms are also being considered. The findings indicate that a method is available to rationally address the design of dosing schedules in concurrent therapy regimens.

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.

Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases.

PURPOSE: Evaluation of the treatment outcome after radiosurgery (RS) alone or in combination with whole-brain radiotherapy (WBRT) with special attention to prescribed dose and its influence on local control and survival. PATIENTS AND METHODS: Between September 1984 and January 1997, 236 patients with 311 brain metastases treated with radiosurgery met the following inclusion criteria: one to three brain metastases per patient; no previous WBRT; and Kamofsky performance status (KPS) > or = 50%. One hundred fifty-eight patients treated only with RS received a median dose of 20 Gy prescribed to the 80% isodose line; 78 patients received RS with a median dose of 15 Gy/80% and an additional course of WBRT. RESULTS: For the entire series, overall median survival was 5.5 months, with control of CNS disease achieved in 92% of the treated brain metastases; the results were not significantly different between patients treated by RS with or without WBRT. However, in patients without evidence of extracranial disease, median survival was increased for patients who received WBRT (15.4 vs 8.3 months; P=.08). Additionally, there was a suggestion that increased doses for patients treated with RS only resulted in improved outcome. Four lesions were suspicious for radiation necrosis by magnetic resonance imaging (MRI); in one of the four lesions, radiation necrosis was confirmed histologically. The incidence of transient low-grade toxicity was 18%; symptoms could be treated by the temporary administration of steroids. CONCLUSION: RS is an effective, noninvasive means of controlling brain metastases when used alone or in combination with WBRT. There is a trend for superior local control and especially in patients without extracranial disease for superior survival when RS is used in conjunction with WBRT. Randomized trials would seem to be warranted, comparing the benefit of RS with or without additional WBRT.

High efficacy of fractionated stereotactic radiotherapy of large base-of-skull meningiomas: long-term results.

PURPOSE: Large skull-base meningiomas are difficult to treat due to their proximity or adherence to critical structures. We analyzed the long-term results of patients with skull-base meningiomas treated by a new approach with high-precision fractionated stereotactic radiotherapy. PATIENTS AND METHODS: One hundred eighty-nine patients with benign meningiomas were treated with conformal fractionated stereotactic radiotherapy between 1985 and 1998. Patients were undergoing a course of radiotherapy either as primary treatment, following subtotal resection, or for recurrent disease. The median target volume was 52.5 mL (range, 5.2 to 370 mL). The mean radiation dose was 56.8 Gy (+/- 4.4 Gy). Follow-up examinations, including magnetic resonance imaging, were performed at 6-month intervals thereafter. RESULTS: The median follow-up period was 35 months (range, 3 months to 12 years). Overall actuarial survival for patients with World Health Organization (WHO) grade I meningiomas was 97% after 5 years and 96% after 10 years. Local tumor failure was observed in three of 180 patients with WHO grade I tumors and was significantly higher in two of nine patients with WHO grade II tumors. A volume reduction of more than 50% was observed in 26 patients (14%). Preexisting cranial nerve symptoms resolved completely in 28% of the patients. Clinically significant treatment-induced toxicity was seen in 1.6% of the patients. No treatment-related deaths occurred. CONCLUSION: The results of this study demonstrate that fractionated stereotactic radiotherapy is safe and effective in the therapy of subtotally resected or unresectable meningiomas. The overall morbidity and incidence subacute and late side effects of this conformal radiotherapy approach were low.

Sequential high-dose therapy with peripheral-blood progenitor-cell support in low-grade non-Hodgkin's lymphoma.

PURPOSE: To evaluate the feasibility of a sequential high-dose therapy with peripheral-blood progenitor-cell (PBPC) support in patients with follicular lymphoma. PATIENTS AND METHODS: Since July 1991, we have included 30 patients (17 men and 13 women) with a median age of 41 years (range, 26 to 55) in the study. At the time of study entry, 17 patients were in first and six in second or higher remission. Another six patients had relapse of disease and one had tumor progression. PBPC were collected during filgrastim-supported leukocyte recovery following high-dose cytarabine (ara-C)/mitoxantrone (HAM). RESULTS: A median of two leukaphereses (range, one to seven) resulted in a median of 5.7 x 10(6) CD34+ cells/kg (range, 2.9 to 23.7 x 10(6). A distinct population of B-lymphoid progenitors (CD34+/CD19+) was not detectable in the autografts, and the content of CD19+ B cells was remarkably low, comprising a median of 0.07% of the mononuclear cells. Using the polymerase chain reaction (PCR) assay for the major breakpoint regions (MBR) of the bcl-2/immunoglobulin H (IgH) translocation, 22 patients had autografts positive for the t(14;18) translocation, whereas seven patients had PCR-negative transplants. The autograft of one patient could not be assessed. Following myeloablative therapy, hematologic recovery was rapid without cytokine support. The median times to reach a platelet count > or = 20 x 10(9)/L and neutrophil count > or = 0.5 x 10(9)/L were 11 and 13 days, respectively. Nonhematologic toxicity was moderate. Twenty-nine patients were alive in remission after a median follow-up duration of 6 months (range, 1 to 18). Of 22 patients autografted with t(14;18)-positive harvests, 11 had PCR-detectable cells in bone marrow and/or peripheral blood as long as 16 months posttransplantation. In contrast, six patients became PCR-negative between 3 and 16 months after reinfusion. Follow-up examinations with PCR data for the remaining five patients are not yet available. CONCLUSION: Conversion to PCR negativity in patients autografted with PCR-positive harvests suggests that the myeloablative regimen is effective and that any reinfused t(14;18)-positive cells may not be sustained. Because conventional chemotherapy provides no cure, we believe that high-dose therapy including total-body irradiation (TBI) should be explored in these particularly radiosensitive lymphomas.

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.

Myeloablative therapy with blood stem cell transplantation is effective in mantle cell lymphoma.

Long-term disease-free survival following conventional cytotoxic therapy is extremely rare in patients with advanced-stage mantle cell lymphoma (MCL). High-dose conditioning therapy consisting of hyperfractionated total body irradiation (TBI, 14.4 Gy) and cyclophosphamide (200 mg/kg) was therefore offered to 13 patients (four females/nine males) with advanced-stage MCL. The patients were relatively young with a median age of 49 years (range 30-60). High-dose cytarabine and mitoxantrone with granulocyte colony-stimulating factor (G-CSF) support were given for second-line therapy and mobilization of peripheral blood stem cells (PBSC). During cytokine-stimulated marrow recovery, a median of two leukaphereses (range 1-4) were performed. Using direct immunofluorescence analysis including two-color staining, the proportion of CD19+ B cells and CD34+/CD19+ B lymphoid progenitor cells was found to be extremely low with quantities below detection limit in approximately 50% of the autografts. At the time of autografting, nine patients (pts) were in first partial (five pts) or complete (four pts) remission, while four patients had achieved a second complete remission. Following myeloablative therapy a median number of 7.5 x 10(6) CD34+ cells/kg were autografted. The median time for neutrophil (> or = 0.5 x 10(9)/l) and platelet recovery (> or = 20 x 10(9)/l) was 13 and 10 days, respectively. Hematological recovery was delayed in a patient who received 5.8 x 10(6) positively selected CD34+ cells/kg. There was one toxic death 17 days post-transplantation because of overwhelming interstitial pneumonia. Two patients with a history of previous treatment failure relapsed 10 and 11 months post-transplantation, respectively, at sites of previous disease. Ten patients are disease-free with a median follow-up time of 18 months (range 10-47). The results presented here suggest that PBSC-supported high-dose therapy including TBI may provide long-term disease-free survival for patients with advanced-stage mantle cell lymphoma.

Tandem high-dose therapy with ifosfamide, epirubicin, carboplatin and peripheral blood stem cell support is an effective adjuvant treatment for high-risk primary breast cancer.

We evaluated the therapeutic efficacy and toxicity of a tandem high-dose therapy with peripheral blood stem cell (PBSC) support in 40 patients with high-risk, primary breast cancer (stage II-III) and involvement of ten or more positive axillary lymph nodes. Their median age was 44 years (range 23-56). Two cycles of cytotoxic chemotherapy with ifosfamide (10000 mg/m2) and epirubicin (100 mg/m2) were administered. Granulocyte colony-stimulating factor (G-CSF) was given to hasten neutrophil reconstitution and to mobilise PBSC during marrow recovery. Leukaphereses were performed following the first and/or second cycle. Tandem high-dose therapy consisted of two cycles with ifosfamide (15 or 12 g/m2) and epirubicin (150 mg/m2), while carboplatin (900 mg/m2) was added for the last 24 patients included. Using an immunocytochemical method, two of 11 patients had cytokeratin-positive tumour cells in three leukapheresis products that were collected following the first G-CSF-supported cycle with ifosfamide and epirubicin, whereas only two harvests obtained following the second cycle in 26 patients contained cytokeratin-positive tumour cells. The number of CD34+ cells/kg re-infused following both high-dose cycles was similar (4.20 +/- 0.29 x 10(6), first cycle and 5.25 +/- 0.63 x 10(6), second cycle), and no notable difference was noted in the speed of haematological reconstitution. An absolute neutrophil count (ANC) of 0.5 x 10(9)/1 was reached after a median time of 13 days, while an unsupported platelet count of 20.0 x 10(9)/1 was achieved after a median time of 8 (first cycle) and 9 (second cycle) days post-transplantation. Patients autografted with more than 7.5 x 10(6) CD34+ cells/kg had platelet counts above 20 x 10(9)/1 within less than 10 days. 6 patients relapsed between 7 and 11 months (median 8 months) post-transplantation. 37 patients are alive and in remission with a median follow-up time of 11 months (range 1-38). This translates into a probability of disease-free survival (DFS) of 77% (95% CI 32-95%) at 38 months. The probability of overall survival is 85%, since 3 patients with local relapse achieved a second complete remission following surgery and involved-field radiotherapy. In conclusion, a sequential high-dose therapy including ifosfamide, epirubicin, carboplatin and PBSC support is well tolerated and effective in patients with high-risk primary breast cancer. Involved-field irradiation should be performed post-transplantation to reduce the risk of local relapse.

Charged particle therapy to pediatric tumors of the retroperitoneal region: a possible indication.

Despite a very successful interdisciplinary therapy regimen for pediatric solid tumors dominated by surgery and chemotherapy, the role of radiotherapy might become again more important if new techniques will allow a better dose localization to the target volume combined with a better protection of the normal tissue. This characteristic is known for charged particle beams. In a field study based on German cooperative trials, the possibility of a charged particle radiotherapy to retroperitoneal tumors of childhood will be discussed regarding indications in risk groups and recurrences. Absolute patient numbers are estimated from the clinical experiences and the incidences of the diseases. A stepwise introduction of this new therapy modality is proposed.

Seed loss in interstitial radiotherapy of prostatic carcinoma with I-125.

Incidence, extent, and time of seed loss after retropubic I-125 implantation was assessed in 52 patients treated for prostatic carcinoma. Radiographic controls up to 62 months were done to evaluate losses. Ninety percent of all patients lost seeds, averaging 8% of total implant number. Loss most frequently occurred within the first month by transurethral routes. Monitoring for seed loss is mandatory to assess dose deficit or inhomogeneous dose distribution, and to avoid environmental radiation hazards.

Renal tolerance to nonhomogenous irradiation: comparison of observed effects to predictions of normal tissue complication probability from different biophysical models.

PURPOSE: A patient series was analyzed retrospectively as an example of whole organ kidney irradiation with an inhomogenous dose distribution to test the validity of biophysical models predicting normal tissue tolerance to radiotherapy. METHODS AND MATERIAL: From 1969 to 1984, 142 patients with seminoma were irradiated to the paraaortic region using predominantly rotational techniques which led to variable but partly substantial exposure of the kidneys. Median follow up was 8.2 (2.1-21) years and actuarial 10-year survival (Kaplan-Meier estimate) 82.8%. For all patients 3-dimensional dose distributions were reconstructed and normal tissue complication probabilities for the kidneys were generated from the individual dose volume histograms. To this respect different published biophysical algorithms had been introduced in a 3-dimensional-treatment planning system. RESULTS: In seven patients clinical manifest renal impairment was observed (interval 10-84 months). An excellent agreement between predicted and observed effects was seen for two volume-oriented models, whereas complications were overestimated by an algorithm based on critical element assumptions. CONCLUSIONS: Should these observations be confirmed and extended to different types of organs corresponding algorithms could easily be integrated into 3-dimensional-treatment planning programs and be used for comparing and judging different plans on a more biologically oriented basis.

Consequences of optimization in PDR brachytherapy--is a routine geometrical optimization recommendable?

PURPOSE: On the basis of clinical examples for interstitial volume implants and surface molds the benefit and disadvantage of optimization in pulsed dose rate (PDR) brachytherapy using a stepping source was investigated. Geometrically optimized PDR dose distributions were compared with nonoptimized ones as produced by Ir wires. METHODS AND MATERIALS: In 25 patients who were treated with a double-plane interstitial breast implant with flexible catheters the first smoothly surrounding isodose, the reference volume and the uniformity and quality index derived from natural dose-volume histograms (Anderson) were considered. The effect of geometrical optimization on surface molds, which were used to irradiate chest wall relapses from breast cancer, was investigated by analyzing the reference surface, dose profiles, and depth-dose curves of a source arrangement covering an area of 10 x 10 cm2. RESULTS: Only in 3 of 25 patients the dose distribution of the volume implant was worsened by geometrical volume optimization regarding the homogeneity or the first smoothly surrounding isodose. Predominantly geometrical volume optimization reduced underdosage at the edges of the implants and improved the dose uniformity. The reference volume was increased. The geometrical distance optimization of surface mold dose distributions resulted in an enhancement of the reference surface and an improvement of the dose homogeneity on the skin surface. CONCLUSIONS: Geometrical optimization substantially changes the dose distribution. Only in a minority of cases the dose distributions of volume implants were worsened by geometrical volume optimization. Nevertheless, a close look at the results has to be recommended, especially if an overdosage in the lateral regions of the dose distribution and a dose falloff near the middle catheters is observed. The enhancement of the reference volume by geometrical volume optimization must be considered when choosing the active lengths. In surface mold treatment planning geometrical distance optimization is necessary to achieve homogeneous dose distributions for irradiation fields of different size and shape.

First experiences with superfractionated skin irradiations using large afterloading molds.

PURPOSE: Radiotherapy of cutaneous metastases of breast cancer requires large radiation fields and high doses. This report examines the effectiveness and sequelae of superfractionated irradiation of cutaneous metastases of breast cancer with afterloading molds on preirradiated and nonirradiated skin. METHODS AND MATERIALS: A flexible reusable skin mold was developed for use with a pulsed (PDR) afterloader. An array of 18 parallel catheters was sewn between two foam rubber slabs 5 mm in thickness to provide a defined constant distance to the skin. By selection of appropriate dwell positions, arbitrarily shaped skin areas can be irradiated up to a maximal field size of 17 x 23.5 cm2. Irradiations are performed with a nominal 37 GBq 192Ir stepping source in pulses of 1 Gy/h at the skin surface. The dose distribution is geometrically optimized. The 80 and 50% dose levels lie 5 and 27 mm below the skin surface. Sixteen patients suffering from metastases at the thoracic wall were treated with 18 fields (78-798 cm2) and total doses of 40-50 Gy applying two PDR split courses with a pause of 4-6 weeks. Eleven of the fields had been previously irradiated with external beam therapy to doses of 50-60 Gy at 7-22 months in advance. RESULTS: For preirradiated fields (n = 10) the results were as follows: follow-up 4.5-28.5 months (median 17); local control (LC): 8 of 10; acute skin reactions: Grade 2 (moist desquamation) 2 of 10; intermediate/late skin reactions after minimum follow-up of 3 months: Grade 1 (atrophy/pigmentation): 2 of 10, Grade 2-3a (minimal/marked teleangiectasia): 7 of 10, Grade 4 (ulcer): 1 of 10; recurrencies: 2 of 10. For newly irradiated fields (n = 7) results were: follow-up: 2-20 months (median 5); LC: 6 of 7; acute reactions: Grade 1: 4 of 7, Grade 2: 3 of 7; intermediate/late skin reactions after minimum follow-up of 3 months (n = 5): Grade 2-3a: 2 of 5; recurrencies: 0 of 7. Local control could be achieved in 82% of the mold fields. Geometric optimization was mandatory to achieve a homogeneous dose distribution on the skin. CONCLUSION: Superfractionated brachytherapy with skin molds is an effective alternative for the treatment of skin metastases of breast cancer even if the skin is preirradiated. This method is economically advantageous compared to external beam therapy, which would require several weeks. At the curved chest wall, optimized molds can provide better dose homogeneity than abutted electron fields. Skin reactions are comparable to the sequelae of orthovolt irradiation. In preirradiated areas, PDR doses should be restricted to 40-45 Gy. PDR doses of 50 Gy seem to be the limit for tolerance even in previously unirradiated fields.

Acute central nervous system (CNS) toxicity of total body irradiation (TBI) measured using neuropsychological testing of attention functions.

PURPOSE: The purpose of this study was to investigate acute normal tissue damage of low irradiation doses to the healthy, adult central nervous system (CNS) using neuropsychological testing of attention functions. METHODS AND MATERIALS: Neuropsychological testing (IQ, attention [modified Trail-Making Test A, Digit Symbol Test, D2 Test, Wiener Determination Machine]) was used to examine 40 patients (43 +/- 10 years) before and immediately after the first fraction (1.2 Gy) of hyperfractionated total body irradiation (TBI) at the University of Heidelberg. The patients received antiemetic premedication. Test results are given as mean percentiles +/- standard deviation, with 50 +/- 34 being normal. Thirty-eight control patients (53 +/- 15 years) were studied to quantify the influence of hospitalization, stress, and repeated testing. RESULTS: The patients showed normal baseline test results (IQ = 101 +/- 14, attention = 54 +/- 28) and no decrease in test results after 1.2 Gy TBI. Attention functions improved (66 +/- 25) corresponding to a practice effect of repeated testing that was seen in the control group, although alternate versions of the tests were used (IQ = 104 +/- 10, attention before = 42 +/- 29, attention after = 52 +/- 31). CONCLUSION: Our data show no deterioration of neuropsychologic test results acutely after 1.2 Gy whole body exposure in adult patients without CNS disease receiving antiemetic medication.

Fractionated stereotactic radiotherapy (FSRT) for optic glioma.

PURPOSE: To determine efficacy and toxicity of fractionated stereotactic radiotherapy (FSRT) in patients with optic glioma. METHODS AND MATERIALS: Ten patients suffering from optic glioma were treated by FSRT between December 1990 and December 1995 at the German Cancer Research Center (DKFZ) in Heidelberg. Eight patients were treated for progressive recurrent tumor following partial tumor resection and 2 patients were treated postoperatively. Dose distributions were calculated by a 3D treatment planning system (Voxelplan, Heidelberg). Patients were treated with a noninvasive repeatable stereotactic fixation system using a manually driven midsize multileaf collimator attached to a linear accelerator. We applied a median prescribed total dose to the isocenter of 52.4 Gy with a median daily fraction size of 1.8 Gy. RESULTS: All patients treated by definitive radiotherapy remained free from local tumor progression during the follow-up period (range 12-72 months) except the 1 patient treated for recurrence after previous radiotherapy. A complete remission was achieved in 3 patients with subsequent improvement of visual acuity. None of the patients with locally controlled tumor experienced any further impairment of vision. One patient developed new ACTH deficiency. No other clinically significant late effects attributable to radiotherapy were observed. CONCLUSION: FSRT permits treatment of optic glioma with excellent tumor control and without clinically relevant morbidity. Compared to conventional techniques there is the potential of sparing the pituitary gland in chiasmatic lesions.

Fractionated stereotactically guided radiotherapy and radiosurgery in the treatment of functional and nonfunctional adenomas of the pituitary gland.

PURPOSE: We evaluated survival rates and side effects after fractionated stereotactically guided radiotherapy (SCRT) and radiosurgery in patients with pituitary adenoma. METHODS AND MATERIALS: Between 1989 and 1998, 68 patients were treated with FSRT (n = 63) or radiosurgery (n = 5) for pituitary adenomas. Twenty-six had functional and 42 had nonfunctional adenomas. Follow-up included CT/MRI, endocrinologic, and ophthalmologic examinations. Mean follow-up was 38.7 months. Seven patients received radiotherapy as primary treatment and 39 patients received it postoperatively for residual disease. Twenty-two patients were treated for recurrent disease after surgery. Mean total dose was 52.2 Gy for SCRT, and 15 Gy for radiosurgery. RESULTS: Overall local tumor control was 93% (60/65 patients). Forty-three patients had stable disease based on CT/MRI, while 15 had a reduction of tumor volume. After FSRT, 26% with a functional adenoma had a complete remission and 19% had a reduction of hormonal overproduction after 34 months' mean. Two patients with STH-secreting adenomas had an endocrinologic recurrence, one with an ACTH-secreting adenoma radiologic recurrence, within 54 months. Reduction of visual acuity was seen in 4 patients and partial hypopituitarism in 3 patients. None of the patients developed brain radionecrosis or radiation-induced gliomas. CONCLUSION: Stereotactically guided radiotherapy is effective and safe in the treatment of pituitary adenomas to improve local control and reduce hormonal overproduction.

Radiation-induced regional cerebral blood volume (rCBV) changes in normal brain and low-grade astrocytomas: quantification and time and dose-dependent occurrence.

PURPOSE: New tumor-conformal radiation-treatment modalities have been established with the intention to spare normal tissue while maintaining or improving local tumor control. To document radiation-induced changes in normal brain and low-grade astrocytoma we measured regional cerebral blood volumes (rCBV) using a dynamic susceptibility-weighted contrast-enhanced MR technique (DSC-MRI). We attempted to assess pretherapeutic rCBV values and time- and dose-dependent changes following radiotherapy. METHODS AND MATERIALS: For prospective and longitudinal assessment of rCBV in normal brain and low-grade astrocytoma, 25 patients with histologically proven fibrillary astrocytoma (WHO Grade II) were examined before radiotherapy and during follow-up. Based on CT- and MR-data sets in a stereotactic setup, three-dimensional (3D) treatment planning was done. Radiotherapy was delivered using fractionated stereotactic radiotherapy (FSRT) to mean and median total doses of 60.9 and 60 Gy, respectively (range, 55.8-66 Gy). During MR imaging for treatment planning and follow-up examinations, 55 T2-weighted gradient echo images were acquired before, during, and after intravenous contrast bolus injection. The acquired signal-time curves were converted into concentration-time curves. The area under the tissue concentration-time curve was calculated and normalized to an integrated arterial input function. Thus, absolute rCBV values could be calculated. RESULTS: Pretherapeutic mean rCBV for normal gray (GM) and white brain matter (WM) were 7.2 +/- 2.7 and 3.6 +/- 1.5 mL/100 g tissue, respectively. Mean rCBV for astrocytoma was 6.5 +/- 3.7 mL/100 g tissue. After radiotherapy, rCBV for GM and WM was significantly reduced (p < 0.01) in high-dose areas (40-100% of total dose). A nonsignificant reduction was measured in low-dose areas (up to 40% of total dose). Reduction of rCBV in astrocytomas to a plateau level of 4.6 +/- 0.4 mL/100 g tissue was measured at 6 months after radiotherapy and remained stable in locally controlled tumors. CONCLUSION: Monitoring of rCBV changes in normal brain and low-grade astrocytoma was feasible using a DSC-MRI technique. The method was able to document radiation effects in low-grade astrocytoma, even if the majority of tumors showed no change in diagnostic MR-imaging. Radiation induced decrease of rCBV in GM and WM was correlated to total dose delivered to a tissue area, with high doses causing a significant decrease. Minor decline of rCBV in GM and WM outside high-dose areas after stereotactic radiotherapy confirms the efficacy to spare normal brain tissue by the use of modern conformal radiotherapy techniques. Nonetheless, a critical minimal dose initiating rCBV changes is yet unknown.

Conformal radiotherapy of challenging paraspinal tumors using a multiple arc segment technique.

PURPOSE: Target volumes that wrap around the spinal cord are difficult to treat. We present and evaluate a refined multiple arc segment (MAS) technique that is applicable with standard three-dimensional (3D) radiotherapy equipment and may be a solution for facilities that do not yet have full access to intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: The presented technique consisted of 13 isocentric coplanar beam's eye view shaped fields, delivered as 20 degrees or 10 degrees arc segments with an integrated multileaf collimator (MLC) using automatic sequential field delivery. Dose-volume histograms (DVH) for this technique were compared to a modified bar-arc technique (MBA) modeled as 30 static fields and to an inverse planned IMRT technique using 7 coplanar, equispaced beams delivered with the same MLC. RESULTS: Compared to the MBA technique, maximum dose and target coverage were similar when using 80% of the maximum dose as the reference dose. However, the MAS technique reduced the maximum doses (to > or = 1% of the organs at risk [OAR]) by 9% for the spinal cord, 17% for the esophagus, and 25% for the trachea, as well as the mean doses. Although inverse planned IMRT could further reduce exposure of OAR except for the spinal cord and improve target coverage, our forward planned MAS technique seems to achieve clinically comparable results. CONCLUSION: Substituting a series of small split-field arc segments for large static fields and using additional narrow paraspinal segments significantly improves the sparing of organs at risk for paraspinal targets. Although these results are not quite as good as those achieved with IMRT, for facilities not yet equipped with inverse treatment planning capability, the presented technique enables dose escalation for primary paraspinal tumors and retreatment of recurrent lesions.

Comparison of intensity-modulated radiotherapy with conventional conformal radiotherapy for complex-shaped tumors.

PURPOSE: Conformal and intensity-modulated radiotherapy (IMRT) plans for 9 patients were compared based on characterization of plan quality and effects on the oncology department. METHODS AND MATERIALS: These clinical cases, treated originally with conformal radiotherapy (CRT), required extraordinary effort to produce conformal treatment plans using nonmodulated, shaped noncoplanar fields with multileaf collimators (MLCs). IMRT plans created for comparison included rotational treatments with slit collimator, and fixed-field MLC treatments using equispaced coplanar, and noncoplanar fields. Plans were compared based upon target coverage, target conformality, dose homogeneity, monitor units (MU), user-interactive planning time, and treatment delivery time. The results were subjected to a statistical analysis. RESULTS: IMRT increased target coverage an average of 36% and conformality by 10%. Where dose escalation was a goal, IMRT increased mean dose by 4-6 Gy and target coverage by 19% with the same degree of conformality. Rotational IMRT was slightly superior to fixed-field IMRT. All IMRT techniques increased integral dose and target dose heterogeneity. IMRT planning times were significantly less, whereas MU increased significantly; estimated delivery times were similar. CONCLUSION: IMRT techniques increase dose and target coverage while continuing to spare organs-at-risk, and can be delivered in a time frame comparable to other sophisticated techniques.

Conventionally fractionated stereotactic radiotherapy (FSRT) for acoustic neuromas.

PURPOSE: Analysis of local tumor control and functional outcome following conventionally fractionated stereotactic radiotherapy (FSRT) for acoustic neuromas. PATIENTS AND METHODS: From 11/1989 to 9/1999 51 patients with acoustic neuromas have been treated by FSRT. Mean total dose was 57.6 +/- 2.5 Gy. Forty-two patients have been followed for at least 12 months and were subject of an outcome analysis. Mean follow-up was 42 months. We analyzed local control, hearing preservation, and facial and trigeminal nerve functional preservation. We evaluated influences of tumor size, age, and association with neurofibromatosis Type 2 (NF2) on outcome and treatment related toxicity. RESULTS: Actuarial 2- and 5-year tumor control rates were 100% and 97.7%, respectively. Actuarial useful hearing preservation rate was 85% at 2 and 5 years. New hearing loss was diagnosed in 4 NF2 patients. Pretreatment normal facial nerve function was preserved in all cases. Two cases of new or impaired trigeminal nerve dysesthesia required medication. No other cranial nerve deficit was observed. In Patients without NF2 tumor size or age had no influence on tumor control and cranial nerve toxicity. Diagnosis of NF2 was associated with higher risk of hearing impairment (p = 0.0002), the hearing preservation rate in this subgroup was 60%. CONCLUSION: FSRT has been shown to be an effective means of local tumor control. Excellent hearing preservation rates and 5th and 7th nerve functional preservation rates were achieved. The results support the conclusion that FSRT can be recommended to patients with acoustic neuromas where special attention has to be taken to preserve useful hearing and normal cranial nerve function. For NF2 patients, FSRT may be the treatment of choice with superior functional outcome compared to treatment alternatives.