Claudia Frank

NONINVASIVE PATIENT FIXATION FOR EXTRACRANIAL STEREOTACTIC RADIOTHERAPY

PURPOSE To evaluate the setup accuracy that can be achieved with a novel noninvasive patient fixation technique based on a body cast attached to a recently developed stereotactic body frame during fractionated extracranial stereotactic radiotherapy. METHODS AND MATERIALS Thirty-one CT studies (> or = 20 slices, thickness: 3 mm) from 5 patients who were immobilized in a body cast attached to a stereotactic body frame for treatment of paramedullary tumors in the thoracic or lumbar spine were evaluated with respect to setup accuracy. The immobilization device consisted of a custom-made wrap-around body cast that extended from the neck to the thighs and a separate head mask, both made from Scotchcast. Each CT study was performed immediately before or after every second or third actual treatment fraction without repositioning the patient between CT and treatment. The stereotactic localization system was mounted and the isocenter as initially located stereotactically was marked with fiducials for each CT study. Deviation of the treated isocenter as compared to the planned position was measured in all three dimensions. RESULTS The immobilization device can be easily handled, attached to and removed from the stereotactic frame and thus enables treatment of multiple patients with the same stereotactic frame each day. Mean patient movements of 1.6 mm+/-1.2 mm (laterolateral [LL]), 1.4 mm+/-1.0 mm (anterior-posterior [AP]), 2.3 mm+/-1.3 mm (transversal vectorial error [VE]) and < slice thickness = 3 mm (craniocaudal [CC]) were recorded for the targets in the thoracic spine and 1.4 mm+/-1.0 mm (LL), 1.2 mm+/-0.7 mm (AP), 1.8 mm+/-1.2 mm (VE), and < 3 mm (CC) for the lumbar spine. The worst case deviation was 3.9 mm for the first patient with the target in the thoracic spine (in the LL direction). Combining those numbers (mean transversal VE for both locations and maximum CC error of 3 mm), the mean three-dimensional vectorial patient movement and thus the mean overall accuracy can be safely estimated to be < or = 3.6 mm. CONCLUSION The presented combination of a body cast and head mask system in a rigid stereotactic body frame ensures reliable noninvasive patient fixation for fractionated extracranial stereotactic radiotherapy and may enable dose escalation for less radioresponsive tumors that are near the spinal cord or otherwise critically located while minimizing the risk of late sequelae.

Fractionated stereotactic radiotherapy for craniopharyngiomas

PURPOSE To investigate outcome and toxicity after fractionated stereotactic radiation therapy (FSRT) in patients with craniopharyngiomas. METHODS AND MATERIALS Twenty-six patients with craniopharyngiomas were treated with FSRT between May 1989 and February 2001. Median age was 33.5 years (range: 5-57 years). Nine patients received FSRT after surgery as primary treatment, and 17 patients were irradiated for recurrent tumor or progressive growth after initial surgery. Median target dose was 52.2 Gy (range: 50.0-57.6 Gy) with conventional fractionation. Follow-up included MRI and neurologic, ophthalmologic, and endocrinologic examinations. RESULTS The median follow-up was 43 months (range: 7-143 months). The actuarial local control rate and actuarial overall survival rates were 100% and 100%, respectively, at 5 years and 100% and 83%, respectively, at 10 years. Four patients showed complete response, 14 patients showed partial response, and 8 patients remained stable. In 5 patients, vision improved after radiation therapy. Acute toxicity was mild. One patient required cyst drainage 3 months after radiotherapy. Late toxicity after radiotherapy included impairment of hormone function in 3 out of 18 patients at risk. We did not observe any vision impairment, radionecrosis, or secondary malignancies. CONCLUSIONS FSRT is effective and safe in the treatment of cystic craniopharyngiomas. Toxicity is extremely low using this conformal technique.

Fractionated stereotactic conformal radiation therapy of brain stem gliomas: outcome and prognostic factors

BACKGROUND AND PURPOSE Evaluation of outcome and prognostic factors in patients with brain stem glioma (BSG) following fractionated stereotactic radiotherapy (FSRT). MATERIALS AND METHODS Between 1990 and 1997, we treated 41 patients with FSRT in a phase I/II trial. Median age was 24 years. Out of 36 patients with histologically proven glioma, ten had a partial tumour resection. Histology revealed low grade gliomas in 30 patients and anaplastic gliomas in six patients. A mean total dose of 54 Gy was given in daily fractions of 1.8 Gy. Median follow-up was 12 months. RESULTS Three patients died during FSRT. Neurological improvement was achieved in 19/38 patients. Reduction of tumour size was reported in 12/38, in 16 patients the lesion was unchanged, ten showed progression. Median time to progression was 23 months, median overall survival 40 months with an actuarial survival of 83% at 1 year, 55% at 3 years and 33% at 5 years. In 20 of 22 patients with recurrence progression was inside the target volume. Significant prognostic factors for survival were clinical and radiological response 6 weeks after FSRT. Treatment toxicity was mild. Ototoxicity occurred in one patient. CONCLUSIONS FSRT is a feasible treatment modality for BSG with tolerable toxicity. The risk of marginal failure is low.

Differential effects of dose rate and superfractionation on survival and cell cycle of V79 cells from spheroid and monolayer culture

Recent developments concerning brachytherapy suggest conditions for an equivalence between the common continuous low dose rate (CLDR) exposure and pulsed irradiation regimens (PDR), provided that total dose is administered in the same overall time. The respective theoretical considerations have been based solely on the phenomenon of sublethal damage recovery. The present study, therefore, aimed to assess a possible influence of growth state/cell cycle progression when CLDR and different super fractionation protocols are compared. The respective experiments were performed with V79 cells that can be grown as a rapidly proliferating monolayer culture or as small spheroids (without hypoxia) where most of the cells are out of cycle. Differential changes in cell cycle distribution occurring during the compared exposure schemes and their impact on cell survival were expected to be expressed most clearly with this model system because of the short G1 phase. Cell irradiations were performed with brachytherapy sources either continuously (137Cs) or with high dose rate pulses (192Ir) at different (1 h and 4 h) pulse repetitions whereby the overall dose rate was kept constant to approximately 1 Gy/h. Cell survival curves were generated by sampling cells at different exposure times or number of pulses, respectively. For spheroid cells an unequivocal decrease of effectivity was demonstrated with decreasing dose per pulse, and the dose effect relation obtained with hourly pulses of 1 Gy was indistinguishable from the CLDR response. For monolayer cells, on the contrary, the scheme of hourly pulses was significantly more effective than the CLDR irradiation. As measured by flow cytometry, this different behaviour could be attributed to the accumulation of cycling cells in the radiosensitive G2/M phase (G2 block) during protracted exposure which was drastically more pronounced for the pulsed scheme compared to the CLDR condition. The observed principle phenomenon of a block to cell cycle progression from high dose rate pulses (at low overall dose rate) may be less expressed in (human) cells having a long G1 period, but if applicable to a clinical situation, an increase of acute effectiveness of a superfractionated brachytherapy protocol has to be considered.

Conservative treatment of breast cancer: modified irradiation technique for women with large breasts

Seven patients with large, pendulous breasts received external beam irradiation to the whole breast (50 Gy in 25 fractions plus boost) after lumpectomy. A special breast holding mask was shaped for each patient. Three-dimensional treatment plans and dose-volume histograms of the same patient with and without a mask were compared. Day-to-day variance was checked. This technique provides improvements in dose homogeneity, reproducibility, and sparing of normal tissues. Cosmetic outcome at present is good.

Erste Erfahrungen mit einem nichtinvasiven Patientenfixieungssystem für die stereotaktische Strahlentherapie der Prostata

Hintergrund: Tumorkonforme Bestrahlungsverfahren erfordern die präzise, reproduzierbare Positionierung der Zielstrukturen. Wir stellen ein neues Fixierungssystem für die stereotaktisch geführte, intensitätsmodulierte Strahlentherapie (IMRT) im Beckenbereich im Hinblick auf die Positionierungsgenauigkeit der Prostata vor. Material und Methode: Das neue Fixierungssystem besteht aus einer umschließenden Körpermaske aus Scotchcast®, die vom Abdomen bis zu den distalen Abschnitten der Oberschenkel reicht, sowie einer Kopfmaske aus dem gleichen Material. Beide Masken sind fest mit einem Basissystem für die extrakranielle Stereotaxie verbunden. Zur Bestimmung der Lagerungspräzision wurden bei zwei Patienten insgesamt 16 CT-Untersuchungen (≥ 25 Schichten, 3 mm Schichtdicke) jeweils unmittelbar vor oder nach einer Bestrahlung mit Markierung des bestrahlten Isozentrums durchgeführt. Die Abweichungen von knöchernen Strukturen sowie von anatomischen Strukturen innerhalb des Zielvolumens wurden dann in allen drei Dimensionen gemessen. Ergebnisse: Mittlere Positionierungsfehler von 0,15 ± 0,3 mm (laterolateral), 0,9 ± 1mm (anterior-posterior), 1 ± 1mm (transversaler vektorieller Fehler) und < 3mm Schichtdicke (kraniokaudal) wurden unter Bezug auf knöcherne Orientierungspunkte ermittelt; während 0,9 ± 0,9 mm (laterolateral), 1,8 ± 1,5 mm (anterior-posterior), 2,2 ± 1,5 mm (transversaler vektorieller Fehler) und < 3mm (kraniokaudal) für die Abweichungen von Prostatabegrenzungen oder in der Prostata gelegenen Orientierungspunkten festgestellt wurden. Die häufig als Maßzahl für den Positionierungsfehler verwendete Standardabweichung der absoluten Patientenbewegung lag in der Transversalebene zwischen 0,3 und 1,7 mm. Die transversale vektorielle Maximalabweichung der Prostata lag bei 4,4 mm. Schlussfolgerung Das vorgestellte Fixierungssystem ermöglicht eine sehr genaue und zuverlässige Patientenpositionierung für die Behandlung von extrakraniellen Tumoren. Die präzise Patientenlagerung gewährleistet neben der stereotaktischen Bestrahlung von wirbelsäulennahen Tumoren auch die stereotaktische Bestrahlung in Beckenbereich. Da die Relativpositionierungsgenauigkeit der Zielstruktur gegenüber dem knöchernen Skelett variabler ist als die Positionsgenauigkeit des Skeletts, ist durch reine externe Immobilisierungsmaßnahmen keine weitere Verbesserung möglich.Purpose: Highly conformal radiotherapy techniques require precise patient positioning. We report our first experience with a new cast system for fixation of the pelvis during stereotactically guided intensity modulated radiotherapy (IMRT) of the prostate with respect to positioning accuracy of the prostate. Material and Methods The immobilization device consists of a custom-made wrap-around body cast that extends from the abdomen to the thighs and a seperate head mask, both made from Scotchcast®, and attaches to a frame for extracranial stereotaxy. Sixteen CT-studies (≥ 25 slices, thickness: 3 mm) of 2 patients who were immobilized for IMRT of prostate tumors were evaluated with respect to set-up accuracy of bony structures and the prostate itself. CT-studies were performed immediately before or after a treatment fraction. Deviations of bony landmarks and anatomical landmarks inside the planning target volume were measured in all 3 dimensions. Results: Mean patient movements of 0.15 ± 0,3 mm (latero-lateral), 0,9 ± 1mm (anterior-posterior), 1 ± 1 mm (transversal vectorial error) and < 3 mm slice thickness (craniacaudal) were recorded using bony landmarks and 0,9 ± 0,9 mm (latero-lateral), 1,8 ± 1,5 mm (anterior-posterior), 2,2 ± 1,5 mm (transversal vectorial error) and < 3 mm (craniocaudal) using the confines of, or landmarks within the prostate. Standard deviations of absolute positioning error as an often used metric for positioning accuracy ranged between 0,3 and 1,7 mm in the transversal plane. The worst case transversal vectorial deviation for the prostate was 4,4 mm. Figure 4 summarizes the set-up accuracy of bony landmarks and the prostate. Conclusion The presented combination of a body cast and head mask system in a rigid stereotictic body frame ensures reliable noninvasive patient fixation for fractionated extrcranial stereotactic radiotherapy. It provides precise and reliable positioning of the prostate and meets the requirements for highly conformal radiotherapy such as IMRT. No further improvement of reprositioning can be achieved with external immobilization devices since the positioning error of the target relative to the skeleton exceeds the accuracy of the positioning of the skeleton itself.

In-vitro-Untersuchungen zur PDR-Brachytherapie

ZusammenfassungHintergrundStrahlenbiologische Berechnungen anhand des LQ-Modells lassen Rahmenbedingungen für die Isoeffektivität einer kontinuierlichen Bestrahlung mit niedriger Dosisleistung (CLDR=continuous low dose rate) und einer superfraktionierten Bestrahlung (PDR=plused dose rate) vermuten, sofern die gleiche Gesamtdosis in der jeweils gleichen Gesamtbehandlungszeit appliziert wird. Ein für die Brachytherapie klinisch einsetzbares Fraktionierungsschema wurde erstmals von Brenner u. Hall empfohlen und soll die klassische CLDR-Bestrahlung mit Linienquellen strahlenbiologisch äquivalent mit einer schrittbewegten Afterloading-Quelle ablösen. Die Hypothese, daß LDR-Äquivalenz durch Superfraktionierung erreicht werden kann, wurde mittels In-vitro-Untersuchungen an V79-Zellen in Monolayer-und Sphäroldkulturen sowie an HeLa-Monolayern überprüft.Material und Methode nIn Anlehnung an die klinischen Verhältnisse der PDR-Brachytherapie wurden Fraktionierungsexperimente im Dosis-Leistungs-Gradienten von Afterloading-Quellen durchgeführt. Unterschiedliche Strahlendosen wurden mit der jeweils gleichen Anzahl von Fraktionen und in der jeweils gleichen „Gesamtinkubationszeit” erzeugt. Folgende Fraktionierungen wurden mit einer CLDR-Referenzkurve verglichen: 40×0,47 Gy, 20×0,94 Gy, 10×1,88 Gy, 5×3,76 Gy, 2×9,4 Gy in jeweils 20 Stunden und einmal 18,8 Gy als „Single-dose”-Exposition. Zusätzlich wurden an V79-Zellen der Einfluß der Dosisleistung im Plus auf das akute Zellüberleben und Zellzykluseffekte unter Superfraktionierung untersucht.ErgebnisseV79-Sphäroide als Modell für einen gering proliferierenden Tumor verhielten sich entsprechend den strahlenbiologischen Vorhersagen, indem mit zunehmender Fraktonierung CLDR-Äquivalenz erreicht wurde. Rasch proliferierende V79-Monolayer-Zellen zeigten einen inversen Fraktionierungseffekt. Eine superfraktionierte Bestrahlung mit Pulsen von 0,94 Gy pro Stunde bzw. 0,47 Gy pro 0,5 Stunde fürte zu einer stärkeren Zellabtötung als eine vergleichbare CLDR-Bestrahlung. Der inverse Fraktionierungseffekt bei log-Phase-V79-Zellen konnte durch dosis-leistungsabhängige Zellzyklusblockaden unter gepulster Bestrahlung erklärt werden. HeLa-Zellen verhielten sich auf Änderungen der Fraktionierung unempfindlich. Sowohl hyper- als auch hypofraktionierte Bestrahlungen waren CLDR-äquivalent.Schlußfolgerung enDie aus der PDr-Theorie abgeleitete Fraktionierungsvorschrift zur Erzielung CLDR-äquivalenter Wirkungen gilt wohl für viele, aber nicht für alle Zellinien. Proliferationskinetik und dosisleistungsabhägige Zellzykluseffekte modifizieren die aus dem „Sublethal-damage-recovery”-Modell ableitbaren Dosis-Wirkungs-Beziehungen und können die akute Strahlenwirkung signifikant beeinflussen. Dosisleistungsempfindlichkeit und rasch Proliferation begünstigen Zellzykluseffekte und begründen, übertragen auf die klinische Situation, die Möglichkeit der höheren Effektivität der gepulsten Bestrahlung bei rasch wachsenden Tumoren.AbstractBackgroundCalculations on the basis on the LQ-model have been focussed on the possible radiobiological equivalence between common continuous low dose rate irradiation (CLDR) and a superfractionated irradiation (PDR=pulsed dose rate) provided that the same total dose will be prescribed in the same overall time as with the low doserate. A clinically usable fractionation scheme for brachytherapy was recommended by Brenner and Hall and should replace the classical CLDR brachytherapy with line sources with an afterloading technique using a stepping source. The hypothesis that LDR equivalency can be achieved by superfractionation was tested by means of in vitro experiments on V79 cells in monolayer and spheroid cultures as well as on HeLa monolayers.Materials and MethodsSimulating the clinical situation in PDR brachytherapy, fractionation experiments were carried out in the dose rate gradient of afterloading sources. Different dose levels were produced with the same number of fractions in the same overall incubation time. The fractionation schedules which were to be compared with a CLDR reference curve were: 40×0.47 Gy, 20×0.94 Gy, 10×1.88 Gy, 5×3.76 Gy, 2×9.4 Gy given in a period of 20 h and 1×18.8 Gy as a “single dose” exposition. As measured by flow cytometry, the influence of the dose rate in the pulse on cell survival and on cell cycle distribution under superfractionation was examined on V79 cells.ResultsV79 spheroids as a model for a slowly growing tumor, reacted according to the radiobiological calculations, as a CLDR equivalency was achieved with increasing fractionation. Rapidly growing V79 monolayer cells showed an inverse fractionation effect. A superfractionated irradiation with pulses of 0.94 Gy/h respectively 0.47 Gy/0.5 h was significantly more effective than the CLDR irradiation. This inverse fractionation effect in log-phase V79 cells could be attributed to the accumulation of cycling cells in the radiosensitive G2/M phase (G2 block) during protected exposure which was drastically more pronounced for the pulsed scheme. HeLa cells were rather insensitive to changes of fractionation. Superfractionation as well as hypofractionation yielded CLDR equivalent survival curves.ConclusionsThe fractionation scheme, derived from the PDR theory to achieve CLDR equivalent effects, is valid for many cell lines, however not for all. Proliferation and dose rate dependend cell cycle effects modify predictions derived from the sublethal damage recovery model and can influence acute irradiation effects significantly. Dose rate sensitivity and rapid proliferation favour cell cycle effects and substantiate, applied to the clinical situation, the possibility of a higher effectiveness of the pulsed irradiation on rapidly growing tumors.

Increased dose-rate effect in V79-multicellular aggregates (spheroids). Relation to initial DNA lesions and repair

Survival of exponentially growing V79 monolayer cells was measured after irradiation at low dose-rate (up to 1.1 Gy/h) and at high dose-rate (2.5 Gy/min) and compared to corresponding survival data of V79 spheroid cells. The so-called contact effect, the increased radioresistance of cells irradiated in spheroids, was expressed to a greater extent with low dose-rate exposure. Lesion fixation by hypertonic treatment was more pronounced in spheroid versus monolayer cells and abolished the contact effect. The reduced radiosensitivity of V79 spheroid cells could not be related to a reduced number of initial DNA lesions or a higher capacity to rejoin DNA breaks (measured by neutral elution). These findings suggest that the ratio of lesion repair to fixation/misrepair may differ between cells from spheroids and monolayer culture thus influencing the response of cells to dose-rate changes differentially.

Centroblastic-centrocytic non-Hodgkin's lymphoma Stage I-III: patterns of failure following radiotherapy

Aim: To investigate the patterns of failure and survival after involved-field or more extensive radiotherapy for centroblastic-centrocytic non-Hodgkins lymphoma (NHL) as well as the impact of radiotherapy dose on local control. Patients and Methods: 47 patients with Stage I–III centroblastic-centrocytic NHL were treated with involved-field (IF), extended-field radiotherapy (EF-RT) or total lymphatic irradiation (TLI). The involved regions received 25.5–50 Gy, non-involved regions were treated with a dose of 26 Gy in most cases. Results: In Stage I/II, the majority of relapses (64%) were nodal and were located adjacent or distant to the former radiation portals. 79% of relapses occurred after IF-RT, 21% after EF-RT or TLI. 5-year overall survival (OAS) after EF-RT/TLI and IF-RT for Stages I/II was 85% and 83%, respectively (n. s.); relapse free survival (RFS) was 73% and 61%, respectively (n. s.). A tendency for better overall survival was found for patients who relapses at one or two sites (5-year overall survival 100%) compared to patients with three or more relapse sites (5-year overall survival 0%). For Stage III overall survival was 72%, freedom from progression (FFP) was 27% at 5 years. We found a dose-effect correlation for local control with a relapse rate of 31% after 26–34 Gy and 4% after application of 36 Gy; no relapses occurred after doses of 40 Gy or more. Conclusion: In involved lymph node regions a relatively small number of relapses was observed after application of a minimal dose of 36 Gy. In Stages I/II most relapses were located outside the radiation portals, yet EF-RT was not superior to IF-RT in terms of overall survival and relapse free survival. Prospective randomized trials are necessary to prove a potentially favorable effect of more extended radiotherapy protals (TLI or TNI [total nodal irradiation]) and to evaluate the optimal radiotherapy dose.Ziel: Analyse der lokalen Kontrolle, des Rezidivmusters und des Überlebens bei zentroblastisch-zentrozytischen Non-Hodgkin-Lymphomen (NHL) nach lokoregionärer Strahlentherapie oder zusätzlicher, adjuvanter Strahlentherapie der nicht befallenen Regionen. Patienten und Methode: 47 Patienten mit zentrozytisch-zentroblastischen NHL in den Stadien I–III erhielten eine Bestrahlung im Sinne einer Involved-Field- (IF-RT), Extended-Field- (EF-RT) oder einer total lymphatischen Strahlentherapie (TLI). In den befallenen Regionen wurden 25,5–50 Gy appliziert, in den adjuvant bestrahlten, nicht befallenen Regionen meist eine Dosis von 26 Gy. Ergebnisse: In den Stadien I und II war die Mehrzahl der Rezidive (64%) nodal und distant zu den ehemaligen Bestrahlungsfeldern bzw. in den angrenzenden Lymphknotenregionen gelegen. 79% der Rezidive traten nach IF-RT auf, 21% nach EF-RT oder TLI. Das 5-Jahres-Gesamtüberleben in den Stadien I/II betrug 85% für die EF-RT/TLI und 83% für die IF-RT (n. s.); das rezidivfreie Überleben betrug entsprechend 73% und 61% (n. s.). Bei Patienten, die an ein oder zwei Lokalisationen Rezidive aufwiesen, zeigte sich die Tendenz zu einem besseren Überleben (5-Jahres-Gesamtüberleben 100%) im Vergleich zu Patienten mit Rezidiven in drei oder mehr Lymphknotenregionen (5-Jahres-Gesamtüberleben 0%). Im Stadium III betrugen das 5-Jahres-Gesamtüberleben 72% und das progressionsfreie Überleben 27%. Es zeigte sich eine Dosis-Wirkungs-Beziehung für die lokale Kontrolle: Die Rezidivrate nach Applikation von 26–34 Gy betrug 31% und 4% nach einer dosis von 36 Gy; nach einer Dosis von 40 Gy oder mehr traten keine Rezidive auf. Schlussfolgerung: In befallenen Lymphknotenregionen war die Anzahl der Rezidive nach Applikation von mindestens 36 Gy relativ gering. In den Stadien I/II war die Mehrzahl der Rezidive außerhalb der Bestrahlungsfelder gelegen, die EF-RT war der IF-RT bezüglich Gesamtüberleben und rezidivfreiem Überleben jedoch nicht überlegen. Zur Überprüfung eines evtl. vorteilhaften Effekts einer ausgedehnteren Strahlentherapie (TLI oder TNI [total nodale Bestrahlung]) und zur Evaluierung der optimalen Dosis sind prospektiv randomisierte Studien erforderlich.