Angelika Zabel

CLINICAL RESULTS OF RETREATMENT OF VERTEBRAL BONE METASTASES BY STEREOTACTIC CONFORMAL RADIOTHERAPY AND INTENSITY-MODULATED RADIOTHERAPY

PURPOSE Reirradiation of spinal tumors is limited by the tolerance of the spinal cord. We evaluated local control, pain relief, neurologic improvement, side effects, and survival rates after fractionated conformal radiotherapy (FCRT) and intensity-modulated RT (IMRT) of recurrent spinal metastases. METHODS AND MATERIALS Eighteen patients with 19 radiologic manifestations were retreated for recurrent spinal metastases using FCRT (n = 5) or IMRT (n = 14). All patients had previously undergone conventional RT (median dose 38 Gy). The indication for reirradiation was tumor progression associated with pain (n = 16) or neurologic symptoms (n = 12). The median time to recurrence was 17.7 months. The median total dose for reirradiation was 39.6 Gy. RESULTS The overall local control rate was 94.7% after a median follow-up of 12.3 months. Of 16 patients with pain, 13 experienced significant relief after reirradiation. Neurologic improvement was obtained in 5 of 12 patients. Tumor size remained unchanged in 84.2%. A partial response was seen in 2 of 19 patients. One patient had local tumor progression 9.5 months after reirradiation. Six patients received chemotherapy after reirradiation because of progressive distant metastases. Twelve patients died 10.5 months median after reirradiation. No clinically significant late toxicity was seen after FCRT or IMRT. CONCLUSION These data demonstrate that FCRT and IMRT are effective and safe in recurrent spinal tumors and can be offered to patients to achieve local control, as well as pain relief.

Treatment of brain metastases in patients with non-small cell lung cancer (NSCLC) by stereotactic linac-based radiosurgery: prognostic factors

A restrospective study of patients with brain metastases from non-small cell lung cancer (NSCLC) is performed to identify patients who benefit from radiosurgery and to determine prognostic factors for survival. Eighty-six consecutive patients with a total of 110 brain metastases from NSCLC were treated with linac-based radiosurgery. Six patients with eight brain metastases who received radiosurgery as a focal boost to whole brain radiotherapy where excluded. Median age at treatment was 60 years. Median dose was 20 Gy/80%-isodose. A chi(2)-test was used to identify potential prognostic factors for local control of brain metastases and survival of the patients. Median follow-up was 6 months (range 1 1/2-77 months) with 17/80 patients still alive. Median actuarial survival was significantly longer (P<0.004) in patients with metachronous onset of brain metastases in comparison to synchronous onset (8.3 vs. 3.3 months). Survival was significantly increased after radiosurgery in the absence of extracranial tumor progression (P<0.03). Eleven patients (14%) developed new brain metastases after radiosurgery after a latency of median 5 months. Actuarial local control rate was 96% after 3 months. Local control was significantly increased with a prescribed dose > or=18 Gy/80%-isodose (P<0.01). We conclude that especially patients with poor prognostic factors and a limited number of brain metastases may be palliatively treated with radiosurgery alone. This approach allows to effectively control CNS manifestation of the disease and can be integrated into chemotherapeutic protocols.

INTENSITY-MODULATED RADIOTHERAPY OF THE FEMALE BREAST

Current methods for intensity-modulated radiotherapy (IMRT) in breast cancer use forward planning based on equivalent radiological path length to design intensity modulated tangential beams. Compared to conventional tangential techniques, dose reduction of organs at risk is limited using these techniques. We developed a method for intensity modulation of multiple beams for adjuvant radiotherapy of breast cancer by application of a virtual bolus defined on CT for inverse optimization. This method enables multibeam IMRT, which provides improved sparing of lung and heart tissue. In this paper, we present the general aspects of this approach and an evaluation of the optimum beam configuration for IMRT based on inverse treatment planning. We compared this method to conventional techniques. Different clinical examples illustrate the possible indications and feasibility of this new approach. This method is superior to conventional techniques because of the reduction of high-dose area of a substantial cardiac volume in those cases where the parasternal lymph nodes are part of the target volume.

Human Glioblastoma and Carcinoma Xenograft Tumors Treated by Combined Radiation and Imatinib (Gleevec

Background and Purpose:Imatinib (Gleevec®, Glivec®) is an inhibitor of α- and β-platelet-derived growth factor receptors and other tyrosine kinases, that are also associated with the function of growth factors. Imatinib has been approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors and is under investigation for the therapy of several other malignant tumors. Since radiotherapy is an important treatment option in many tumors, combined effects of imatinib and radiation were analyzed here.Material and Methods:In vitro, U87 cells (human glioblastoma), A431 cells (human epidermoid carcinoma), and HUVECs (human umbilical venous endothelial cells) were treated with imatinib alone and in combination with radiation. Clonogenic survival and cell proliferation were determined with and without additional radiation (0–10 Gy). In vivo, U87 and A431 cells (5 × 106) were subcutaneously injected into hind limbs of balb c nu/u mice. Drug and radiation treatments started on day 0 when tumor volumes were approximately 400–500 mm3. Tumors were treated with 5 × 5 Gy (U87) or 6 × 5 Gy (A431) on consecutive days from day 0. Imatinib was administered orally via the mouse diet starting on day 0 until the end of observation. Tumor growth and microvessel density (CD31 IHC) were analyzed.Results:In vitro, imatinib increased radiosensitivity of U87 and A431 tumor cells as well as HUVECs in both clonogenic and cell number/proliferation assays. The enhancement of radiosensitivity in HUVECs was comparable to that observed in the tumor cells. In vivo, the concurrent and continuous administration of imatinib increased tumor growth delay of fractionated radiotherapy in the carcinoma and the glioblastoma models at reduced microvessel densities. No apparent additional toxicity by the combination of radiation and imatinib versus monotherapies was observed in terms of weight, skin, or general behavior.Conclusion:Imatinib (Gleevec®), a “molecular targeted” approved drug for human malignancies, can enhance the tumor growth reduction induced by fractionated radiotherapy in glioblastoma and carcinoma models. The data provides a rationale to further investigate the combination.Hintergrund und Ziel:Die Dysregulation von Zellwachstum und Zelldifferenzierung, Hauptmerkmale der malignen Tumortransformation, entsteht durch eine chronisch-aberrante Aktivierung von Wachstumsfaktoren. Imatinib (Glivec®) inhibiert spezifische Tyrosinkinasen, wie PDGF-(„platelet-derived growth factor“) und c-KIT-Rezeptoren, welche Wachstumsrezeptoren darstellen oder mit deren Funktion assoziiert sind. Imatinib wird bei der Behandlung der chronischen myeloischen Leukämie und gastrointestinaler Stromatumoren bereits eingesetzt und bei einer Reihe weiterer Tumorentitäten in klinischen Studien untersucht. Strahlentherapie ist eine Option bei einigen dieser Tumoren, so dass die Untersuchung von Kombinationseffekten relevant ist.Material und Methodik:In vitro wurden U87-Zellen (humanes Glioblastom), A431-Zellen (humanes epidermoides Karzinom) und HUVECs (humane umbilikalvenöse Endothelzellen) bestrahlt und mit Imatinib behandelt. Klonogenes Überleben und Zellproliferation wurden bestimmt. In vivo wurden U87- und A431-Tumoren auf Balb-c-nu/u-Mäusen untersucht. Die Behandlung begann bei Tumorvolumina von 400–500 mm3 mit 5 × 5 Gy (U87) bzw. 6 × 5 Gy (A431). Imatinib wurde kontinuierlich ab Therapiebeginn gleichzeitig zur Strahlentherapie bis zum Beobachtungsende verabreicht. Die Tumorgröße und die Mikrogefäßdichte (CD31 IHC) wurden analysiert.Ergebnisse:Imatinib erhöhte die Strahlensensibilität von U87-Zellen und HUVECs, weniger ausgeprägt auch von A431-Zellen, im klonogenen und Proliferations-Assay. Der Effekt unterschied sich bei Endothelzellen nicht signifikant von jenem bei den Tumorzellen. In vivo vergrößerte die zusätzliche Gabe von Imatinib die Tumorwachstumsverzögerung durch Strahlentherapie beim Glioblastom und beim Karzinom bei deutlicher Reduktion der Mikrogefäßdichte ohne erkennbare Zunahme der Toxizität.Schlussfolgerung:Imatinib (Gleevec®) als klinisch zugelassener Vertreter der „Targeted therapy“-Medikamente kann den tumorwachstumshemmenden Effekt einer fraktionierten Strahlentherapie beim Glioblastom und bei Karzinomen verstärken, was weiter untersucht werden sollte.

Invers geplante intensitätsmodulierte Strahlenbehandlung bei einer Patientin mit rechtsseitigem Mammakarzinom und Trichterbrust

Hintergrund: Eine 44-jährige Patientin mit der Indikation zur Bestrahlung bei brusterhaltender Therapie eines Mammakarzinoms war zugewiesen worden, da bei ausgeprägter Trichterbrust mit konventionellen Techniken keine zufrieden stellende Dosisverteilung erreicht werden konnte. Daher erfolgte die Bestrahlung als intensitätsmodulierte Strahlentherapie (IMRT) mit inverser Bestrahlungsplanung. Die IMRT wurde hinsichtlich der erzielten Dosisverteilung und der Durchführtbarkeit mit konventionellen Techniken verglichen. Patientin und Methoden: Bei Tumorsitz rechts unten innen beinhaltete das Zielvolumen die rechte Restbrust und den ipsilateralen parasternalen Lymphabfluss. Nach inverser Optimierung erfolgte die Bestrahlung in “Step-and-shoot”-Technik mit zwölf IMRT-Feldern mit sechs Intensitätsstufen an einem 6-MV-Linearbeschleuniger. Es wurden 50,4 Gy im Zielvolumen appliziert. Zum Vergleich wurden Bestrahlungspläne in konventioneller Technik mit zwei tangentialen irregulären 6-MV-Photonen-Feldern (Technik A) und in kombinierter Form mit zusätzlichem 15-MeV-Elektronen-Feld (Technik B) erstellt. Untersucht wurden Konformität und Homogenität im Zielvolumen und die Dosisverteilung im Normalgewebe. Ergebnisse: Die Konformität an beide Zielvolumina konnte mit IMRT erheblich verbessert werden. Die Homogenität im Zielvolumen war nur geringgradig schlechter als mit Technik A. Das Lungenvolumen, das mehr als 20 Gy erhält, konnte von 56,8% mit Technik A bzw. 40,1% mit Technik B auf 22,1% reduziert werden. Die Therapie wurde ohne nennenswerte Nebenwirkungen toleriert. Die mittlere Behandlungszeit pro Sitzung betrug 19,5 min. Schlussfolgerungen: Eine invers geplante IMRT in Vielfeldertechnik ist in der adjuvanten Situation beim Mammakarzinom einsetzbar. Im vorliegenden Fall einer Patientin mit Trichterbrust konnte im Vergleich zu konventionellen Techniken eine massive Dosisreduktion der ipsilateralen Lunge ohne Dosiseinbußen im Zielvolumen erreicht werden. Inwieweit der höhere technische Aufwand der IMRT bei der brusterhaltenden Therapie zu einem klinisch detektierbaren Vorteil führt, wird derzeit im Rahmen einer kontrollierten Studie untersucht.Background: A 44-year old woman with breast cancer was transferred to our institution for irradiation. Due to a pronounced funnel chest no satisfying dose distribution was obtained by conventional techniques. Thus an intensity-modulated radiotherapy (IMRT) based on inverse optimisation was carried out. IMRT was compared to conventional techniques regarding dose distribution and feasibility. Patient and Methods: Tumor site was in the right middle lower quadrant. Target volume included the right breast and the parasternal lymph nodes. Target dose was 50.4 Gy. Based on inverse optimisation irradiation was carried out in “step-and-shoot”-technique with twelve intensity modulated beams with six intensity steps. Additionally, treatment plans were calculated using conventional techniques (technique A with two tangential wedged 6-MV photon beams, technique B with additional oblique 15-MeV electron portal). We analysed conformality and homogeneity of target volume and dose distribution within normal tissue. Results: Dose conformality was substantially improved by IMRT. Dose homogeneity was slightly decreased compared to technique A. Lung volume irradiated with a dose higher than 20 Gy was reduced from 56.8% with technique A and 40.1% with technique B, respectively to 22.1% with IMRT. Treatment was tolerated well by the patient without relevant side effects. Mean treatment time was 19.5 min. Conclusion: The inversely planned IMRT using multiple beam directions is suitable for breast irradiation following breast conserving surgery. In the present case of a woman with funnel chest lung dose was substantially reduced without reduction of target dose. In which was the complex treatment technique leads to a clinically detectable advantage is examined at present, in the context of a study.

Number and orientation of beams in inversely planned intensity-modulated radiotherapy of the female breast and the parasternal lymph nodes.

Intensity-modulated radiotherapy (IMRT) provides better sparing of normal tissue. We evaluated the optimum beam configuration for IMRT based on inverse treatment planning in adjuvant radiotherapy for breast cancer in a case of left-sided tumor. In addition to radiotherapy planning with the conventional technique of tangential wedged 6-MV photon beams and an oblique 15-MeV electron beam, we performed inversely planned IMRT with the step-and-shoot-technique. Dose calculation was carried out using the treatment planning system Virtuos with the inverse optimization module KonRad adapted to it. IMRT plans were generated for 2 to 16 beams. The results were compared with conventional techniques. For a maximum treatment time of 20 minutes, it is shown that IMRT with 12 modulated photon beams and 7 intensity steps is best suited for treatment in the presented case. Compared with a conventional technique with photons combined with electrons, dose conformality and homogeneity of the planning target volume was increased. The mean heart dose was reduced from 9.1 Gy to 6.1 Gy. The volume of heart irradiated with a dose higher than 30 Gy was reduced from 7.6% to 1.9%, and the volume of the left lung from 13.6% to 11.5% as well. Inverse optimization for IMRT with multiple beams is feasible in the adjuvant treatment of breast cancer. Because of the reduction of the high-dose area of a substantial cardiac volume, it is superior to conventional techniques in cases where the parasternal lymph nodes should be integrated into the target volume. Here, a clinical advantage might be detectable.

Results of Three-dimensional Stereotactically-guided Radiotherapy in Recurrent Medulloblastoma

AbstractPurpose: To evaluate survival rates and side effects after stereotactically-guided radiotherapy (SRT) in patients with recurrent medulloblastoma of the brain. Methods and materials: Between 1992 and 2000, 20 patients with 29 radiological manifestations were treated with fractionated SRT (n=21) or radiosurgery (n=8). Median age was 16 years with 6 patients ≤14 years. All patients had prior cranio-spinal radiotherapy plus boost to the posterior fossa with a total dose of 54 Gy. Time to recurrence was 33 months mean. Eighteen of the 29 lesions were located within the boost volume. Chemotherapy was given according to current international study protocols (HIT) in all patients. Mean total dose for re-irradiation was 24 Gy for fractionated stereotactically-guided radiotherapy, and 15 Gy for radiosurgery. Mean follow-up was 88.5 months. Results: Overall local control was 89.7%. Thirteen recurrences showed partial or complete response in CT/MR-imaging, 13 showed stable disease. Local tumor progression was seen 5 months mean after radiotherapy in three cases. A multifocal intracranial progression was seen in 9 patients, 5 patients developed additional spinal metastases. Thirteen patients died with disseminated cranio-spinal progression, after 72.6 months median. No late toxicity >CTC II∘ especially no brain radionecrosis was seen after radiotherapy. Conclusion: SRT is effective and safe in the treatment of recurrent medulloblastoma to improve local control without evident side effects. The main problem remains the control of subclinical cranio-spinal dissemination.

The role of stereotactically guided conformal radiotherapy for Local tumor control of esthesioneuroblastoma

Background: In a retrospective analysis we compared conventional radiotherapy and stereotactically guided conformal radiotherapy (SCRT) in patients with esthesioneuroblastoma. Patients and Methods: Between 1991 and 1999 14 patients with esthesioneuroblastoma underwent radiotherapy at our institution. Median follow-up was 30 months (range 12–107 months). Treatment included adjuvant radiotherapy (9), adjuvant radiochemotherapy (3) or radiotherapy alone (2). Eight patients received SCRT with 3-D treatment planning. For comparison a standard three-field plan for these patients and dose-volume histogram analyses were performed. Median total dose was 64 Gy using SCRT and 56 Gy with standard technique. Results: Local tumor control rate was 50% with conventional radiotherapy and 75% with SCRT. Overall survival was 33.3% and 62.5%, respectively. Target coverage could be improved statistically significant (p < 0.05) and dose to critical structures was reduced using SCRT. Greatest differences were seen regarding volume above the 30%-isodose as well as mean dose of brain stem (p < 0.05). A reduction of maximum dose was seen using SCRT as consequence of a more homogeneous treatment. Conclusions: SCRT improves target coverage and sparing of organs at risk. Our clinical data although with low patient numbers suggest that the technical advantage translates into a clinical advantage. The use of SCRT appears to facilitate higher dose prescriptions without risking major acute and late side effects. Thus the risk of complications in this area is minimized. Adjuvant radiotherapy is a save and effective treatment modality for local control of esthesioneuroblastoma.Hintergrund: Ziel der vorliegenden Untersuchung war ein retrospektiver Vergleich der konventionellen Strahlentherapie und stereotaktischer Konformationsbestrahlung (SCRT) bei Patienten mit einem Ästhesioneuroblastom. Patienten und Methode: Im Zeitraum von 1991 bis 1999 wurden 14 Patienten mit histologisch gesichertem Ästhesioneuroblastom in unserer Abteilung strahlentherapiert. Die mediane Nachbeobachtungszeit lag bei 30 Monaten (12–107 Monate). Die Behandlungsmodalitäten umfassten adjuvante Strahlentherapie (9), adjuvante Radiochemotherapie (3) oder primäre Strahlentherapie (2). Acht Patienten wurden stereotaktisch konformierend geplant und bestrahlt. Zum Vergleich wurden für diese Patienten ein konventioneller Drei- Felder-Plan erstellt und Dosis-Volumen-Histogramm-Analysen durchgeführt. Die mediane Gesamtdosis betrug 64 Gy bei SCRT und 56 Gy mit konventioneller Technik. Ergebnisse: Mit konventioneller Technik lag die lokale Tumorkontrollrate bei 50% im Vergleich zu 75% mit SCRT. Das Gesamtüberleben lag bei 33,3% bzw. 62,5%. Die Zielvolumenauslastung ließ sich mit SCRT signifikant verbessern (p < 0,05) und die Dosisbelastung der Risikostrukturen reduzieren. Der größte Unterschied fand sich bezüglich des Volumens oberhalb der 30%-Isodose und der mittleren Dosisbelastung des Hirnstamms (p < 0.05). Des Weiteren fand sich eine Reduktion der Maximaldosis als Folge einer homogeneren Dosisverteilung bei SCRT. Schlussfolgerungen: SCRT verbessert die Zielvolumenauslastung und Schonung der Risikostrukturen. Unsere klinischen Daten lassen trotz niedriger Patientenzahlen vermuten, dass der technische Vorteil zu einem klinischen Vorteil führt. Mittels SCRT scheint eine Dosiseskalation ohne Erhöhung des Risikos therapiebedingter lokaler Nebenwirkungen und Spätkomplikationen möglich zu sein. Mit modernen Techniken stellt die adjuvante Strahlentherapie eine sichere und effektive Behandlungsmodalität zur lokalen Kontrolle beim Ästhesioneuroblastom dar.

Virtueller Bolus zur inversen Bestrahlungsplanung bei intensitätsmodulierter Radiotherapie des Mammakarzinoms im Rahmen der adjuvanten Therapie

Fragestellung: Die intensitätsmodulierte Strahlenbehandlung (IMRT) verspricht eine verbesserte Schonung für Risikostrukturen. Wir untersuchten, in welcher Form eine inverse Bestrahlungsplanung zur IMRT der Restbrust beim Mammakarzinom durchführbar ist. Methodik: Neben einer Bestrahlungsplanung in konventionller Technik mit tangentialen 6-MV-Keilfilter-Feldern wurde eine IMRT-Bestrahlungsplanung mit inverser Planoptimierung (KonRad®) durchgeführt. Im Planungs-CT wurde ein Bolus von 10 mm Dicke und einer Dichte von −60 HE definiert. Der Einfluss des Bolus auf die Planoptimierung wurde bestimmt, indem die Optimierung ohne Bolus, die nachfolgende Dosisberechnung ohne und mit Bolus durchgeführt wurden. Um den Einfluss des Bolus auf die Dosisberechnung zu bestimmen, erfolgte nach Optimierung mit Bolus eine Dosisberechnung ohne Bolus und mit verschiedenen Bolusdicken. Die Planungsergebnisse wurden jeweils mit der Dosisverteilung einer konventionellen Bestrahlung verglichen. Ergebnisse: Die inverse Planungsoptimierung mit einem Dosisalgorithmus, der Gewebeinhomogenitäten berücksichtigt, führt zu einer erhöhten Hautbelastung. Diese lässt sich reduzieren, indem man ausschließlich zur inversen Optimierung einen Hilfsbolus verwendet. Es lässt sich damit eine Hautschonung entsprechend der konventionellen Therapie erreichen. Die Relativdosisverteilung bleibt von der Verwendung des Bolus bei einer Dicke von 10 mm weitgehend unbeeinflusst. Die Absolutdosis unterscheidet sich bei Dosisberechnung mit und ohne Bolus um 3,4%. Daher muss der Bolus im Sinne eines virtuellen Bolus vor der abschließenden Dosisberechnung wieder entfernt werden. Schlussfolgerungen: Zur inversen Optimierung einer IMRT der Restbrust ist ein virtueller Bolus erforderlich. Damit ist eine IMRT-Bestrahlung gemäß Konsensus von EORTC, BCCG und EUSOMA (1991) möglich. Insbesondere kann die gleiche Zielvolumendefinition wie bei der konventionellen Therapie verwendet werden. Es sind hiermit IMRT-Techniken in konventioneller Feldgeometrie und in Vielfeldertechnik realisierbar.Background: Intensity modulated radiotherapy (IMRT) provides better sparing of normal tissue. We investigated the feasibility of inverse treatment planning for IMRT in adjuvant radiotherapy for breast cancer. Material and Methods: In addition to radiotherapy planning in conventional technique with tangential wedged 6-MV-photon beams we performed inversely planned IMRT (KonRad®). In the CT scans for treatment planning we defined a 10-mm bolus of − 60 HE density. The influence of this bolus on planning optimization was determined by optimization without and dose calculation with and without bolus. Dose calculation after dose optimization with bolus was performed using different bolus thickness to determine the influence of the bolus on dose calculation. The results were compared with dose distribution in conventinal technique. Results: Inverse optimization with a dose algorithm which considers tissue inhomogeneity results in unintended dose increase at the patient surface. With a virtual 10-mm bolus used for inverse optimization the dose increase was reduced. Thus, skin sparing was identical to conventional planning. The relative dose distribution was negligibly affected by the use of a 10-mm bolus. Difference in absolute dose was 3.4% compared to calculation without bolus. Therefore, the bolus must be removed before final dose calculation. Conclusion: The realization of inverse optimization for IMRT of the breast requires the use of a virtual bolus. Thereby, IMRT in accordance to the consensus recommendations of the EORTC, BCCG and EUSOMA is possible. Especially, the same target definition as in conventional technique may be used. IMRT techniques with a conventional beam arrangement of two tangential fields or multiple beam techniques can be realized.

Intensity-modulated radiotherapy of sacral chordoma--a case report and a comparison with stereotactic conformal radiotherapy.

In a case of partially resected sacral chordoma, the planning target volume (PTV) received 60 Gy and the gross target volume (GTV) 72 Gy using inversely planned, intensity-modulated, radiation therapy (IMRT). IMRT was compared with 3D-conformal radiotherapy (CRT). With IMRT, it was found that dose distribution is more homogeneous within the PTV outside the GTV and allows simultaneous dose escalation within the GTV. The volume of bowel receiving a dose higher than 40 G y was reduced from 400cc with CRT to 220cc with IMRT. If particle therapy is not available, IMRT seems to be a promising alternative in the treatment of sacral chordomas.