Martin Fuss

Proton radiation therapy (prt) for pediatric optic pathway gliomas: comparison with 3d planned conventional photons and a standard photon technique

PURPOSE Following adequate therapy, excellent long-term survival rates can be achieved for patients with optic pathway gliomas. Therefore, avoidance of treatment-related functional long-term sequelae is of utmost importance. Optimized sparing of normal tissue is of primary concern in the development of new treatment modalities. The present study compares proton radiation therapy (PRT) with a three-dimensional (3D)-planned multiport photon and a lateral beam photon technique for localized and extensive optic pathway tumors. METHODS AND MATERIALS Between February 1992 and November 1997, seven children with optic pathway gliomas underwent PRT. For this study, we computed proton, 3D photon, and lateral photon plans based on the same CT data sets, and using the same treatment planning software for all plans. Radiation exposure for normal tissue and discrete organs at risk was quantified based on dose-volume histograms. RESULTS Gross tumor volume (GTV) ranged from 3.9 cm3 to 127.2 cm3. Conformity index (relation of encompassing isodose to GTV volume) was 2.3 for protons, 2.9 for 3D photons, and 7.3 for lateral photons. The relative increase of normal tissue (NT) encompassed at several isodose levels in relation to NT encompassed by the 95% proton isodose volume was computed. Relative NT volume of proton plan isodoses at the 95%, 90%, 80%, 50%, and 25% isodose level increased from 1 to 1.6, 2.8, 6.4, to a maximum of 13.3. Relative volumes for 3D photons were 1.6, 2.4, 3.8, 11.5, and 34.8. Lateral plan relative values were 6, 8.3, 11.5, 19.2, and 26.8. Analysis for small (<20 cm3) and larger (> 80 cm3) tumors showed that protons encompassed the smallest volumes of NT at all isodose levels. Comparable conformity and high-dose gradient were achieved for proton and 3D photon plans in small tumors. However, with increasing tumor volume and complexity, differences became larger. At the 50% isodose level, 3D photons were superior to lateral photons for small tumors; this advantage was equalized for larger tumors. At the lowest isodose level, 3D photons encompassed the highest amount of NT. Analysis of organs at risk showed that PRT reduced doses to the contralateral optic nerve by 47% and 77% compared to 3D photons and lateral photons, respectively. Reductions were also seen for the chiasm (11% and 16%) and pituitary gland (13% and 16%), with differences at clinically relevant tolerance levels. Furthermore, reduced dose exposure of both temporal lobes (sparing 39% and 54%) and frontal lobes was achieved with PRT. CONCLUSION PRT offered a high degree of conformity to target volumes and steep dose gradients, thus leading to substantial normal tissue sparing in high- and low-dose areas. It is expected that this will result in decreased long-term toxicity in the maturing child. Advantages of proton versus 3D photon plans became increasingly apparent with increasing target size and tumor complexity. Even in small tumors, conformity of 3D photon irradiation came at the expense of a larger amount of NT receiving moderate to low radiation doses. Lateral photons resulted in inferior dose distribution with high radiation exposure of clinically relevant normal tissues.

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.

Proton radiation therapy for medium and large choroidal melanoma: preservation of the eye and its functionality

PURPOSE Evaluation of efficacy and safety of proton radiation therapy (PRT) for medium- and large-size choroidal melanoma with focus on preservation of the eye and its function. METHODS Retrospective review of 78 patients with 60 medium and 18 large-size choroidal melanomas at a median follow-up of 34 months. RESULTS The 5-year data for local control, metastases-free survival, and disease-specific survival were estimated to be 90.5 +/- 3.7%, 76.2 +/- 6.7%, and 75.6 +/- 7.6%, respectively. Eye preservation was achieved in 75.3% of patients, with useful (better than 20/200) visual acuity (VA) in 49.1% of surviving patients. Both local failure and complications led to enucleation. Prognosticators were tumor close to the optic disc (p = 0.003), large tumors involving the ciliary body (p = 0.041), and local failure (p < 0.001). Prognostic factors for VA following PRT were initial VA (p = 0.001), doses to optic disc (p = 0.001) and fovea (p = 0.022) higher than 35 CGE (Cobalt Gray equivalent), tumor close to the optic disc (p = 0.034), and retinal detachment (p < 0.001). Tumor basis diameter was significantly related to metastases free survival (p = 0.02), overall survival (p = 0.033), and disease specific survival (p = 0.017), but did not impair local tumor control, rate of enucleation, and VA. CONCLUSION The present data suggest that PRT is an effective and safe treatment for medium and large size choroidal melanoma. PRT can preserve the eye and its function in a reasonable percentage of patients. Further evaluation in controlled clinical trials comparing PRT to plaque radiotherapy and enucleation is required.

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.

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.

Full Scale IQ (FSIQ) changes in children treated with whole brain and partial brain irradiation. A review and analysis.

Purpose: Neuropsychological impairment has been reported following whole brain and partial brain irradiation in children. The purpose of this analysis was to assess current knowledge, with focus on correlation with radiation dose, irradiated volume and age. Method: Full Scale IQ (FSIQ) data, representing 1,938 children, were derived from 36 publications and analyzed as to radiation dose, irradiation volume, and age. Results: FSIQ after whole brain irradiation showed a non-linear decline as dosage increased. The dose-effect relationship was age-related, with more pronounced FSIQ decline at younger age. FSIQ test results below the normal level (< 85) were found at doses higher than 24 and 36 Gy in children under age 3, and older than age 6, respectively. Mean FSIQ test result after 18 Gy was 100, thus at the mean standard value; a minor decline was detectable only when compared to test results of a control group. Young children scored at this dose in the low normal range. Partial brain irradiation caused minor FSIQ decline, with measurable effects at dose levels > 50 Gy. Conclusion: The collected data suggest that whole brain irradiation doses of 18 and 24 Gy have no major impact on intellectual outcome in children older than age 6, but may cause impairment in younger children. Doses > 24 Gy comprise a substantial risk for FSIQ decline, even in older children. At equal dose levels, partial brain irradiation is less damaging than whole brain irradiation. The authors are well aware of limitations in the interpretation of data collected for the current review. Thus, further research is required to evaluate the effect of low-dose whole brain irradiation as well as partial brain irradiation on FSIQ development.Hintergrund: Störungen der neurokognitiven Entwicklung sind nach Ganz- und Teilhirnbestrahlung kindlicher zerebraler Tumoren berichtet worden. Diese Arbeit bestimmt den momentanen Wissensstand und analysiert kausale Zusammenhänge von Bestrahlungsdosis, bestrahltem Volumen und dem Alter der Kinder zur Zeit der Behandlung. Methode: Aus 36 englischsprachigen Publikationen wurden Full-Scale-IQ-(FSIQ-)Daten von 1 936 Kindern gewonnen und bezüglich Bestrahlungsdosis, bestrahltem Volumen und dem Alter der Kinder analysiert. Ergebnisse: Die FSIQ-Werte fielen nicht linear mit steigenden Bestrahlungsdosen ab (Abbildungen 1 und 2). Die Dosisbeziehung war altersbezogen, wobei jüngere Kinder einen ausgeprägteren Abfall der Testwerte zeigten. Bei Kindern unter drei Jahren lagen die Testergebnisse nach 24 Gy Ganzhirnbestrahlung unterhalb des Normalwertbereichs (FSIY 90 bis 110), wohingegen die Werte bei Kindern über sechs Jahren erst nach 36 Gy im selben Maße abfielen. Der mittlere Testwert nach 18 Gy Ganzhirnbestrahlung lag bei 100; das bedeutet, auf dem standardisierten Mittelwert der FSIQ-Tests war nur ein geringer Abfall der Testwerte im Vergleich zur ebenfalls getesteten Kontrollgruppe (Mittelwert 104) zu erheben (Tabelle 1). Kleine Kinder wurden nach 18 Gy Ganzhirnbestrahlung im niedrig normalen Bereich getestet. Teilhirnbestrahlungen verursachten geringe Abfälle der FSIQ-Testwerte nach Gesamtdosen > 50 Gy. Schlussfolgerung: Die gesammelten Daten zeigen, dass Ganzhirndosen von 18 und 24 Gy keinen oder nur einen geringen Einfluss auf die intellektuelle Entwicklung von Kindern über sechs Jahren haben. Bei jüngeren Kindern wird nach diesen Dosen jedoch bereits eine Schädigung nachweisbar (Tabelle 2). Dosen 24 Gy können die kognitive Leistungsfähigkeit auch bei älteren Kindern erheblich beeinträchtigen. Die Dosis-Wirkungs-Beziehung ist nicht linear mit stärkerer Schädigung bei höheren Dosen in allen Altersgruppen. In vergleichbaren Dosen ist die Teilhirnbestrahlung weniger schädigend als eine Ganzhirnbestrahlung. Datensammlung und Auswertungsmethode zeigen bestehende Limitationen auf und weisen auf mögliche Interpretationsfehler hin. Weitere Testungen und prospektive Studien sind erforderlich, um den Einfluss niedriger Dosen in der Ganzhirnbestrahlung sicherer bestimmen zu können. Der erwartete normalgewebsschonende Effekt zunehmend eingesetzter 3-D-geplanter Teilhirnbestrahlungen sollte bezüglich der Entwicklung der kognitiven Leistungsfähigkeit dokumentiert werden.

Stereotactic radiation therapy for malignant choroidal tumors: preliminary, short-term results.

PURPOSE To evaluate the role of stereotactic radiation therapy (SRT) in the treatment of malignant choroidal tumors. DESIGN Prospective, noncomparative case series. PARTICIPANTS Ten patients with unifocal choroidal metastasis (three lung carcinoma, three breast carcinoma, three colon carcinoma, one cutaneous melanoma) and five patients with primary choroidal melanoma underwent single-dose or fractionated SRT. METHODS Before treatment, computed tomography (CT) scans of the orbit were obtained with the patient wearing an individualized immobilization mask. An integrated macro-CCD-camera system viewed the eye for detection of movements. Three-dimensional computer-based treatment planning was carried out. Dose distribution was calculated and displayed in isodose lines on the CT data set. For SRT, a dedicated stereotactic linear accelerator (6 MV) was used. Total doses for choroidal metastases were 12 to 20 Gy in a single dose or 30 Gy over 10 days (3 Gy each session), and total doses for choroidal melanoma were 50 Gy over 5 or 10 days (10 or 5 Gy each session). MAIN OUTCOME MEASURES Best corrected visual acuity (ETDRS-chart), biomicroscopy, ultrasound examination, fluorescein angiography, and magnetic resonance imaging (MRI) were performed before treatment and at regular intervals after completion of SRT. RESULTS During a follow-up period from 1 to 34 months (median, 6.5 months), local tumor control was achieved in all eyes. A decrease in tumor size on ultrasonography or MRI was noted in eight patients. No persistent side effects were observed during follow-up. CONCLUSIONS Stereotactic radiation therapy allows steep dose gradients outside the target volume by minimizing the field of exposure. Thus only low radiation doses affect surrounding radiosensitive ocular structures. Our initial findings suggest that this technique may be effective in controlling tumor growth. Further studies are needed to compare treatment efficacy and safety with conventional treatment methods.

Assessment of neuropsychological changes in patients with arteriovenous malformation (AVM) after radiosurgery

PURPOSE The purpose of this study was to investigate neuropsychological effects of radiosurgery in patients with cerebral arteriovenous malformation (AVM), with special focus on attention and memory. This report describes the study setup and presents the first results during a follow-up of up to 1 year. MATERIALS AND METHODS Seventy-nine patients were studied before, acutely after radiosurgery, and during the regular follow-up (subacute phase: Weeks 6-12, chronic phase: Months 6-12). Radiosurgery was performed using a modified linear accelerator (minimum doses to the target volume: 15-22 Gy, median 20 Gy). Estimated whole brain dose was 0.5 to 2 Gy. Neuropsychological testing included assessment of general intelligence (Wechsler Adult Intelligence Scale), attention (modified Trail-Making Test A, Digit Symbol Test, D2 Test, Wiener Determination Machine) and memory (Rey Auditory Verbal Learning Test, Benton Visual Retention Test). During follow-up, alternate test versions were used. Neuropsychological deficits were defined as a test score of at least one standard deviation (SD) below the mean of the normal distribution. RESULTS The pretherapeutic evaluation revealed marked deviations from the normal population; 24% had deficits in intelligence (range 23-31% in different subtests), attention (35%, 23-59%) and memory (48%, 31-61%). The overall percentage of aberrant results was reduced by 12% (memory) to 14% (attention) in the chronic phase up to 12 months after therapy. The improvement in test scores was significant (p < 0.05) in 3 of 4 subtests of attention functions. CONCLUSIONS 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 to slight improvement in the overall neuropsychological performance of AVM patients in the chronic phase after radiosurgery.

Normal tissue complication probability (NTCP) calculations as a means to compare proton and photon plans and evaluation of clinical appropriateness of calculated values

Calculation of normal tissue complication probabilities (NTCP) for proton radiation therapy (PRT) and two photon radiation therapy techniques for cranial irradiation of childhood optic nerve gliomas was made. Evaluation of usefulness of calculated NTCP values for comparison of treatment plans and clinical appropriateness of computed data was used. Three radiation plans were calculated on datasets of children treated previously for optic nerve gliomas with PRT. Dose–volume histograms (DVH) were computed and used to calculate NTCP. Evaluated complication endpoints were necrosis, blindness, and cognitive impairment. Calculated NTCP depended strongly on tumor volume and the normal tissue volume exposed to high radiation doses. Dose conformity and steeper dose‐gradient correlated with reduced NTCP. Regarding the chosen complication endpoints, PRT was superior to 3D photons; conventional photons were calculated to have the highest NTCPs. Differences might reach clinical significance for cognitive impairment, a frequently observed toxicity. Calculated NTCP values were highly dependent on implemented clinical data. Calculation of NTCP can be used for ranking of treatment plans and modalities. Highly dependent on implemented clinical data, the calculated percentage of NTCP might be more of a figure of merit than a real predictive value and requires comparison to clinical experience. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 351–358 (2000).