[en] Purpose: Radiosurgical treatment (RS) of acoustic neuromas is a well established treatment. However, few data are available concerning conformal fractionated radiotherapy (FT) of this tumor entity. We evaluated treatment outcome and toxicity for both treatment modalities in 41 patients treated at our institution between 1984 and 1997. Material and Methods: All treatments were performed using a specially adapted linear accelerator and circular collimators for convergent beam RS or multi-leaf collimators (leaf thickness 1 or 3mm) for multi-field RS or fractionated treatment. 22 patients (7 male, 15 female, median age 60 years, range 20-83 years) were treated radiosurgically with single doses between 7 and 28 Gray (median 15 Gy) prescribed to the 80% isodose line. Tumor volumes ranged from 0.7 to 10.5 ccm with a median volume of 3.4 ccm. The median number of isocenters was 2 (1-4 isocenters). One patient was treated by a multi-field technique (14 isocentric irregularly shaped noncoplanar fields). 19 patients (5 male, 14 female, median age 55 years, range 20-81 years) were treated with stereotactic conformal radiotherapy. Median dose was 60 Gray with a median daily fraction size of 2 Gy and a median of 3 (1-4) irregularly shaped isocentric fields. Tumor volumes ranged from 0.7 to 32.4 ccm (median 15 ccm). Median follow-up was 30 months (7-149 months) for radiosurgical and 30 months (2-88 months) for fractionated treatment. Seven patients who underwent fractionated treatment had previously undergone neurosurgical resection on the contralateral side. One had undergone radiosurgery on the opposite side before. Results: All tumors were locally controlled. A volume reduction of more than 20% was seen in 16% after RS and 18% following FT. Typical posttherapeutic central reduction of contrast media enhancement was found in 73% following RS after a median of 8 (3-12) months and in 63% following FT after a median of 6 (1-12) months. Temporary brainstem edema was diagnosed in 4 patients (18%) in the RS group, none of them requiring therapy, but none in the FT group. Hearing impairment improved in 1 case (RS) and 4 cases (FT). Complete hearing loss was diagnosed in 1 case in the FT group but in 3 cases in the RS group (all these patients were treated with 16 Gy or more). One temporary facial nerve weakness was found after FT. Among the RS group treated with ≥16 Gy, 4 permanent facial nerve lesions were observed with complete facial nerve paresis in 2 patients. Improvement of vertigo or tinnitus was found in 1 patient after FT and in 3 patients treated with RS. If radiosurgical doses were <15 Gy, no severe side effects were observed. Among this group, 6 patients (54%) showed a significant reduction of preexisting neurological dysfunction. Conclusion: Radiosurgical treatment of small acoustic neuromas with doses <15 Gy prescribed to a volume <10 ccm results in excellent tumor control with no relevant toxicity. For fractionated therapy, results are comparable, even if the tumor volume exceeded 10 ccm. Single dose treatment with doses >15 Gy may cause higher toxicity. Fractionated conformal radiotherapy offers effective tumor control and low morbidity especially after contralateral neurosurgical resection of an acoustic neuroma with consecutive hearing loss and/or facial paresis

[en] The authors are using Dunning rat prostate tumor sublines to study tumor growth kinetics and response to radiation therapy and/or local tumor phyperthermia (43.5 degrees, 30 minutes). After radiation therapy (0-40 Gy, one fraction), the anaplastic AT1 tumors (volume doubling, 5.2 days) increased in volume during the 1st week, whereas the volume of the differentiated H1 tumors HI tumors (volume doubling, 10 days) did not change appreciably for 3-6 weeks. Based on regrowth kinetics, the AT1 appears to be more radioresistant than the HI subline. TERs of approximately 1.3 were found for both tumor sublines. The volume response after radiation therapy and hyperthermia and the rather low TER values are different from those seen with faster-growing rodent tumors

[en] Purpose/Objective: Proliferation of surviving tumor cells during fractionated radiotherapy may limit tumor control, especially in rapidly proliferating tumors. It has been widely accepted, that this may play a major role in head and neck tumors. Several methods for the assessment of tumor proliferation have been developed, however, most of them are either laborious, invasive or potentially toxic. Today, the gold standard is the flow cytometric BrdUrd assay. We present a flow cytometric method for detection of PCNA, which is an intranuclear proliferation associated protein, in solid human head and neck tumors and how these data correlate with outcome. Materials and Methods: Pretherapeutic biopsies of 20 inoperable patients with squamous cell carcinoma of the head and neck (T3-4N2M0) were examined. The tissue was disaggregated with pepsin/HCl, antibody staining was performed using the clone PC10. Biparametric flow cytometry was performed after a FITC conjugated secondary antibody and propidiumjodine staining was applied. The PCNA-index (i.e. percentage PCNA-positive cells), the DNA-index and the S-phase fraction (SPF, euploid tumors only) were determined. The therapy consisted of combined accelerated-hyperfractionated radiochemotherapy (66 Gy in 5 wks, concomittant boost of 1.6 Gy/d in wks 4+5, Carboplatin in wks 1+5). The median follow-up time was 14 mths (5 - 28), the clinical partners (V.R., A.D.) were 'blinded' towards the PCNA-values. Results: 13 patients suffered from disease progession and 11 died. The actuarial median survival and disease free survival (DFS) were 14.4 and 10.7 mths, respectively. The PCNA-values ranged from 3.2 to 70% (median 9%), there were 7 aneuploid and 13 euploid tumors. SFP in the euploid tumors ranged from 4 to 14.5% (median 10.5%). Neither SFP nor ploidy had a significant influence on the outcome. The patients were divided according to their PCNA-value in higher (n=10) and lower (n=10) than the median. The survival and DFS were 13.1 and 7.6 mths for the group > 9% and both values were greater than 15 mths for the group <9%. The difference in DFS was significant (p = 0.03, log rank test). Conclusion: These results fall in line with other studies showing the influence of the pretherapeutic proliferation on the outcome after radiotherapy. However, there are several points to mention. This study was performed during a clinical trial of the efficacy of a moderately accelerated therapy regimen. This therapy certainly reduces the influence of the proliferation on the outcome, but as our results show, the patients with faster proliferating tumors still have a worse outcome. They have a shorter survival and DFS. The DFS, i.e. the time until progression, is the more relevant parameter in this study, because of various salvage therapies, which may influence overall survival. However, it is unlikely that one single parameter, in this case proliferation, will adequately predict the response to radiotherapy, although our patients represent a clinically homogeneous sample and received identical therapy

[en] Purpose/Objective: Cerebral AVM are inborn malformations which may become symptomatic in young adult patients by hemorrhage, seizures or steal syndromes. Depending on size, location and drainage, there is a risk for rupture with potentially devastating consequences. Treatment options include neurosurgery, embolization or radiosurgery. The radiosensitivity of normal brain tissue is the main limitation for radiotherapy of CNS tumors. Improved treatment planning and irradiation techniques, however, minimize the dose to unaffected brain tissue. The purpose of this study was to investigate the neuropsychological effects of radiosurgical treatment in patients with cerebral AVM. Materials and Methods: Forty-four patients with cerebral arterio-venous malformations were included into the study. Patients with hemiparesis, aphasia or hemianopia were excluded from testing. The patients were examined the day before (n=44), acutely after radiosurgery (n=23) and during the regular follow-up (subacute phase n=21, chronic phase n=12). Radiosurgery was performed using a modified linear accelerator and either rotations of 9 non-coplanar arcs or 15 individually collimated, isocentric, non-coplanar fields. Doses of 15 - 22 Gy (median 20 Gy) were prescribed to the 80% isodose (minimum dose to the target volume). The dose to the total brain was calculated as 0.5 to 2 Gy depending on dose, location and size of the target volume. The neuropsychological testing was done using a computer assisted testing facility allowing standardized testing conditions. The extensive testing battery included assessment of general intelligence (shortened version Wechsler Adult Intelligence Scale), attention (Digit Symbol Test (DST), D2 test (D2), a letter cancellation test, a modified Trail Making Test A (ZVT), and the WDG measuring the reaction time in a complex signal-reaction-situation) and memory (Benton Visual Retention Test (BVRT), Rey Auditory Verbal Learning Test (RAVLT), Cube test). Testing during the follow-up period included reassessment of attention and memory using parallel versions of the tests. Patients were classified as having neuropsychological deficits, when their test results were one standard deviation (z ≤ -1.0) below the mean (z = 0) of the normal distribution. Results: The pretherapeutic evaluation revealed already significant deviations from the normal population in this patient group. Twenty-four percent of the patients had deficits in general intelligence (18 - 38% in the different subtests), in attention (25 - 31%) and memory (42 - 61%). The table shows the percentage of patients with deficits in attention and memory during the acute, subacute and chronic phase after radiosurgery. The numbers give the range for 4 subtest of attention and memory, respectively: Conclusion: The acute tolerance of radiosurgery seems to be very good in these patients showing no relevant increase in number of patients with neuropsychological deficits. Although the long term follow-up needs to be further increased, our data indicate a tendency of slight improvement in the overall performance of AVM patients in the chronic phase after radiosurgey. This would mean that the benefit for the patient by irradiation of the AVM outweights the irradiation induced normal tissue effects

[en] Purpose: Retrospective evaluation of treatment outcome after radiosurgery (RS) alone or in combination with whole brain radiotherapy (WBRT). Aim of our analysis was to examine dose-effect-relationship and prognostic factors in our series. Material and Methods: Between 1984 and 1996, 260 patients with a total of 389 brain metastases were treated radiosurgically. In 181 patients, RS was the only treatment, for 79 patients RS was combined with WBRT. A median dose of 20 Gy was prescribed to the 80% isodose for RS alone. Patients with additional WBRT received a median dose of 15 Gy. Median follow-up was 4,2 months for all radiosurgically treated patients. Results: Median survival was 5,5 months and local tumor control was 92 %. These results were not significantly different between the patients without or with a course of WBRT. 1- and 2-year-survival-rates were 19,2% / 8,3% in the patientgroup treated by RS alone and 30,4% / 13,9% in combined treatment modality. Neurological symptoms were stable or improved in 88% of patients with locally controlled brain metastases, thus preventing impaired quality of life secondary to progressive CNS-disease. The incidence of temporary lowgrade toxicity was 18%, symptoms were always effectively treated with temporary administration of steroids. Favorable prognostic factors were identified: age < 60 years; solitary brain metastasis; no extracerebral tumor progression, karnofsky performance ≥ 80 %. 37 patients with all these favorable prognostic factors had a median survival of 13,4 months. (10(37)) are still alive with a median of 28,3 months after therapy. The 1- and 2-year-survival-rates were 56,8% and 27 % respectively. RS was performed alone in 17 and combined in 20 of these cases with no difference in survival. Regarding to dose-effect-relationship we evaluated patients who were alive 1 year after RS. In case of RS alone with 20 Gy prescribed to the 80 % isodoseline all tumors were locally controlled 3 months after RS, however 21 % ((6(29))) of these patients showed a local progression later in the course (between 10 and 52 months after RS). All of them died due to progressive cerebral disease. As opposed to this, 9 patients treated with a prescribed dose of 25 Gy/80 % isodose developed no local progression and no therapy related morbidity. Median survival for this group was 8,5 months. For combined RS and WBRT local control at 1 year after therapy was 92 % independent from prescription of 12 or 15 Gy / 80 % isodose. Conclusion: RS as single therapy or combined with WBRT is an effective, non-invasive therapy in the interdisciplinary management of cerebral metastases. Treatment related morbidity is low. There is no higher rate of side effects after combined therapy. Considering excellent local control, short hospitalization and low treatment related morbidity, RS is an important modality for palliative treatment of CNS-metastases. Further randomized trials in patients with prognostic favorable factors should evaluate treatment outcome after a prescribed dose of 25 Gy / 80% isodose in RS alone

[en] Clinically, certain categories of tumors respond well to fast neutrons. To understand the action of neutrons on tumor tissues, the authors are studying the Dunning rat prostate tumor system. The authors report the treatment response of the anaplastic AT-1 subline (volume doubling, 5.2 days) to 10 fraction of neutrons (0-1.6 Gy per fraction) versus Co-60 (2.4-4.8 Gy per fraction). As with one fraction, the tumors continued to increase in volume for 2 weeks after radiation, followed by a regrowth with no local control. Based on regrowth kinetics, a radiobiologic effectiveness (RBE) of about 3.3 was found, compared with an RBE of 3 for one fraction found in an earlier study

[en] Purpose: Aim of this retrospective study was to evaluate cataract incidence in a homogeneous group of patients after total-body irradiation followed by autologous bone marrow transplantation or peripheral blood stem cell transplantation. Method and Materials: Between 11/1982 and 6/1994 in total 260 patients received in our hospital total-body irradiation for treatment of haematological malignancy. In 1996-96 patients out of these 260 patients were still alive. 85 from these still living patients (52 men, 33 women) answered evaluable on a questionnaire and could be examined ophthalmologically. Median age of these patients was 38,5 years (15 - 59 years) at time of total-body irradiation. Radiotherapy was applied as hyperfractionated total-body irradiation with a median dose of 14,4 Gy in 12 fractions over 4 days. Minimum time between fractions was 4 hours, photons with a energy of 23 MeV were used, and the dose rate was 7 - 18 cGy/min. Results: Median follow-up is now 5,8 years (1,7 - 13 years). Cataract occurred in (28(85)) patients after a median time of 47 months (1 - 104 months). In 6 out of these 28 patients who developed a cataract, surgery of the cataract was performed. Whole-brain irradiation prior to total-body irradiation was more often in the group of patients developing a cataract (14,3%) vs. 10,7% in the group of patients without cataract. Conclusion: Cataract is a common side effect of total-body irradiation. Cataract incidence found in our patients is comparable to results of other centres using a fractionated regimen for total-body irradiation. The hyperfractionated regimen used in our hospital does obviously not result in a even lower cataract incidence. In contrast to acute and late toxicity in other organ/organsystems, hyperfractionation of total-body irradiation does not further reduce toxicity for the eye-lens. Dose rate may have more influence on cataract incidence

[en] To better understand the role of PCNA after photon irradiation in vivo, using flow cytometry, we studied the immunochemical PCNA-staining in V79 cells after irradiation with 6-MeV photons with and without serum depletion and with and without low-dose pre-irradiation under different growth conditions. Material and methods: Using V79 hamster cells, BrdUrd incorporation, total and DNA-bound PCNA were measured for exponential cells and for confluent cells at different times (up to 14 days) after reaching confluence. Cells were either grown with medium containing 10% fetal calf serum (FCS) or 0.5% FCS. Six days after reaching confluence, cells were irradiated with 1 Gy (and 8 Gy for non-serum-depleted cells) (6-MV photons, 2 Gy/min). Then, immunochemical PCNA-staining was measured by flow cytometry at 0, 30, 60 and 120 min after irradiation. For studying the adaptive response, exponentially growing cells and cells that were 6 days in confluence were pretreated with 0.01 Gy, reincubated for 5 h and then definitively treated with 1 Gy and harvested and processed as described above. Results: Four days after reaching confluence, DNA-bound PCNA and BrdUrd content were reduced to a minimum of <15% positive cells while total PCNA remained essentially unchanged. After irradiation with 1 Gy 6 days after reaching confluence, cells grown with 10% FCS showed a moderate but distinct transient increase in DNA-bound PCNA at 30 min after irradiation. After irradiation with 8 Gy, there was no clear increase at 30 min but a more distinct decrease at 60 min, implying that the increase might occur earlier in the time course at higher doses. Total cellular PCNA and BrdUrd uptake were constant during the first 2 hours after irradiation. In cells that were kept with serum depleted medium for 6 days after reaching confluence, total PCNA was reduced and no changes in either DNA-bound PCNA or BrdUrd-uptake were observed after irradiation. When cells were primed with a dose of 0.01 Gy 5 h before subsequent treatment with 1 Gy, neither for exponentially growing cells nor for those in confluence a significant difference in the detected amount of PCNA (total and DNA-bound) or BrdUrd was observed when compared to cells treated without a priming dose. Conclusions: The moderate X-ray induced DNA association of PCNA is indicative for ongoing DNA repair but appears to require serum stimuli. However, this p53-independent pathway involving PCNA does not seem to be the most relevant for survival in these rodent cells that tolerate much residual damage. Furthermore, no adaptive response for DNA-association of PCNA could be detected in V79 cells. (orig./MG)

[en] Purpose/Objectives Interstitial pneumonia (IP) is a severe complication after allogenic bone marrow transplantation (BMT) with incidence rates between 10 % and 40 % in different series. It is a polyetiologic disease that occurs depending on age, graft vs. host disease (GvHD), CMV-status, total body irradiation (TBI) and immunosuppressive therapy after BMT. The effects of fractionation and dose rate are not entirely clear. This study evaluates the incidence of lethal IP after hyperfractionated TBI for autologous BMT or stem cell transplantation. Materials and Methods Between 1982 and 1992, 182 patients (60 % male, 40 % female) were treated with hyperfractionated total body irradiation (TBI) before autologous bone marrow transplantation. Main indications were leukemias and lymphomas (53 % AML, 21 % ALL, 22 % NHL, 4 % others) Median age was 30 ys (15 - 55 ys). A total dose of 14.4 Gy was applied using lung blocks (12 fractions of 1.2 Gy in 4 days, dose rate 7-18 cGy/min, lung dose 9 - 9.5 Gy). TBI was followed by cyclophosphamide (200 mg/kg). 72 % were treated with bone marrow transplantation, 28 % were treated with stem cell transplantation. Interstitial pneumonia was diagnosed clinically, radiologically and by autopsy. Results 4 patients died most likely of interstitial pneumonia. For another 12 patients interstitial pneumonia was not the most likely cause of death but could not be excluded. Thus, the incidence of lethal IP was at least 2.2 % but certainly below 8.8 %. Conclusion Lethal interstitial pneumonia is a rare complication after total body irradiation before autologous bone marrow transplantation in this large, homogeously treated series. In the autologous setting, total doses of 14.4 Gy can be applied with a low risk for developing interstitial pneumonia if hyperfractionation and lung blocks are used. This falls in line with data from series with identical twins or t-cell depleted marrow and smaller, less homogeneous autologous transplant studies. Thus, Graft versus host disease seems to be a major determinant of the incidence of interstitial pneumonia

No abstract available