Anna Simeonova

Intensity modulated radiosurgery of brain metastases with flattening filter-free beams

PURPOSEnFlattening filter free (FFF) irradiation potentially reduces treatment delivery time in radiosurgery thus eliminating intrafraction motion and increasing patient comfort. We compared plan quality and efficiency of VMAT and IMRT plans for FFF- and standard delivery for brain metastases with single fraction doses of 20 Gy and validated the dosimetric accuracy of the FFF delivery.nnnMATERIAL AND METHODSnCT data of 15 patients with brain metastases were included in this study. For every patient, 2 IMRT- and 2 VMAT-plans were created using a high-resolution MLC with two different delivery modes (6MV standard vs. 6MV FFF). Plan quality and efficiency was assessed by analysis of conformity, homogeneity, dose gradients, treatment delivery time and number of monitor units (MU). Dosimetric evaluation was performed for 10 FFF plans with radiochromic film and ion chamber.nnnRESULTSnPlan quality was similar for both approaches. FFF provided a mean treatment time reduction of 51.5% with similar MU for VMAT and IMRT for this low-modulation paradigm. The dosimetric validations showed an absolute dose deviation of +0.93 ± 0.99% and γ-index analysis (3%/3mm and 3%/1mm) resulted in agreement of 99.08 ± 1.58% respectively 93.46 ± 2.41%.nnnCONCLUSIONnFFF radiosurgery is an efficient technique for intensity modulated hypofractionated or single fraction treatments with similar plan quality when compared to flattened beams at reduced treatment time.

Flattening-filter-free intensity modulated breath-hold image-guided SABR (Stereotactic ABlative Radiotherapy) can be applied in a 15-min treatment slot

Hypofractionated image-guided stereotactic ablative radiotherapy (igSABR) is effective in small lung/liver lesions. Computer-assisted breath-hold reduces intrafraction motion but, as every gating/triggering strategy, reduces the duty cycle, resulting in long fraction times if combined with intensity-modulated radiotherapy (IMRT). 10 MV flattening-filter-free IMRT reduces daily fraction duration to <10 min for single doses of 5-20 Gy.

Factors of influence on acute skin toxicity of breast cancer patients treated with standard three-dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery (BCS)

Purpose/ObjectivesStandard 3D-CRT after BCS may cause skin toxicity with a wide range of intensity including acute effects like erythema or late effects. In order to reduce these side effects it is mandatory to identify potential factors of influence in breast cancer patients undergoing standard three-dimensional conformal radiation therapy (3D-CRT) of the breast and modern systemic therapy.Materials/MethodsBetween 2006 and 2010 a total of 211 breast cancer patients (median age 52,4 years, range 24–77) after BCS consecutively treated in our institution with 3D-CRT (50 Gy whole breast photon radiotherapy followed by 16 Gy electron boost to the tumorbed) were evaluated with special focus on documented skin toxicity at the end of the 50 Gy-course. Standardized photodocumentation of the treated breast was done in each patient lying on the linac table with arms elevated. Skin toxicity was documented according to the common toxicity criteria (CTC)-score. Potential influencing factors were classified in three groups: patient-specific (smoking, age, breast size, body mass index = BMI, allergies), tumor-specific (tumorsize) and treatment-specific factors (antihormonal therapy with tamoxifen or aromatase inhibitors, chemotherapy). Uni- and multivariate statistical analyses were done using IBM SPSS version 19.ResultsAfter 50 Gy 3D-CRT to the whole breast 28.9% of all 211 patients had no erythema, 62.2% showed erythema grade 1 (G1) and 8.5% erythema grade 2. None of the patients had grade 3/4 (G3/4) erythema.In univariate analyses a significant influence or trend on the development of acute skin toxicities (erythema G0 versus G1 versus G2) was observed for larger breast volumes (p=0,004), smoking during radiation therapy (p=0,064) and absence of allergies (p=0,014) as well as larger tumorsize (p=0,009) and antihormonal therapy (p=0.005).Neither patient age, BMI nor choice of chemotherapy showed any significant effect on higher grade toxicity. In the multivariate analysis, factors associated with higher grade skin toxicity were larger breast target volume (p=0,003), smoking (p=0,034) and absence of allergies (p=0,002).ConclusionPatients treated in this study showed less objectively documented skin toxicity after 50 Gy 3D-CRT compared to similar patient cohorts. Factors associated with higher grade skin toxicity were smoking during 3D-CRT, absence of allergies and larger breast volumes.

Clinical outcome of hypofractionated breath-hold image-guided SABR of primary lung tumors and lung metastases.

BackgroundStereotactic Ablative RadioTherapy (SABR) of lung tumors/metastases has been shown to be an effective treatment modality with low toxicity. Outcome and toxicity were retrospectively evaluated in a unique single-institution cohort treated with intensity-modulated image-guided breath-hold SABR (igSABR) without external immobilization. The dose–response relationship is analyzed based on Biologically Equivalent Dose (BED).Patients and methods50 lesions in 43 patients with primary NSCLC (nu2009=u200927) or lung-metastases of various primaries (nu2009=u200916) were consecutively treated with igSABR with Active-Breathing-Coordinator (ABC®) and repeat-breath-hold cone-beam-CT. After an initial dose-finding/-escalation period, 5x12u2009Gy for peripheral lesions and single doses of 5u2009Gy to varying dose levels for central lesions were applied. Overall-survival (OS), progression-free-survival (PFS), progression pattern, local control (LC) and toxicity were analyzed.ResultsThe median BED2 was 83u2009Gy. 12 lesions were treated with a BED2 of <80u2009Gy, and 38 lesions with a BED2 of >80u2009Gy. Median follow-up was 15 months. Actuarial 1- and 2-year OS were 67% and 43%; respectively. Cause of death was non-disease-related in 27%. Actuarial 1- and 2-year PFS was 42% and 28%. Progression site was predominantly distant. Actuarial 1- and 2u2009year LC was 90% and 85%. LC showed a trend for a correlation to BED2 (pu2009=u20090.1167). Pneumonitis requiring conservative treatment occurred in 23%.ConclusionIntensity-modulated breath-hold igSABR results in high LC-rates and low toxicity in this unfavorable patient cohort with inoperable lung tumors or metastases. A BED2 of <80u2009Gy was associated with reduced local control.

Combined Radiation Therapy and Sunitinib for Preoperative Treatment of Soft Tissue Sarcoma

AbstractBackgroundAntiangiogenic substances and radiation therapy (RT) may have synergistic effects and improve irradiation efficacy. We present a cohort study evaluating the toxicity of combined sunitinib and RT as neoadjuvant treatment of extremity and retroperitoneal soft tissue sarcoma (STS).nMethodsSixteen patients with locally advanced extremity (6/16) or retroperitoneal (10/16) STS were treated with continuous-dosing sunitinib (15/16: 37.5xa0mg daily; 1/16: 25xa0mg daily) and standard RT (45–50.4xa0Gy) preoperatively. Surgery was scheduled 5–9xa0weeks following neoadjuvant treatment. The primary goal of the study was to determine combined treatment toxicity according to the Common Terminology Criteria for Adverse Events. Secondary goals were the evaluation of postoperative morbidity and treatment response.ResultsEight of 16 patients developed grade 3, and one patient developed grade 4, hematological toxicity. One patient experienced grade 3 hand–foot syndrome. The most frequent treatment toxicities of any grade were hematological (15/16) or dermatological (9/16). Three patients had partial response, 11 had stable disease, and 2 had progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST).n Fourteen of 16 patients underwent surgery; tumors were not removed in two patients because of patient refusal or intercurrent metastatic disease. The proportion of tumor necrosis exceeded 90xa0% in 5 of 14 patients, and 4 patients had postoperative complications requiring reintervention.ConclusionsPreoperative treatment with concurrent sunitinib and RT was tolerable, and postoperative morbidity did not increase. Combined treatment with RT and sunitinib was also feasible in patients with retroperitoneal STS, and warrants further investigation.

Are three doses of SABR (stereotactic ablative radiotherapy) more effective than 30 doses of conventional radiotherapy

In early stage non-small cell lung cancer (NSCLC) definitive radiation therapy is an appropriate alternative to surgery. Recent studies show, that in such patients hypofractionation schedules (for example 3 times 18 Gy or 5 times 12 Gy), can be safely applied, without causing severe toxicities and achieving high local control rates of up to 90% and more. In the last couple of years a lot of knowledge about the cancer biology, technical aspects, clinical outcomes and toxicities has been accumulated from different clinical trials. The purpose of this review is to summarize recent outcomes and developments in stereotactic radiation therapy for patients with early stage NSCLC.

Impact of flattening-filter-free radiation on the clonogenic survival of astrocytic cell lines

Background and purposeFlattening-filter-free (FFF) beams are increasingly used in radiotherapy as delivery times can be substantially reduced. However, the relative biologic effectiveness (RBE) of FFF may be increased relative to conventional flattened (FLAT) beams due to differences in energy spectra. Therefore, we investigated the effects of FFF and FLAT beams on the clonogenic survival of astrocytoma cells.Material and methodsThree cell lines (U251, U251-MGMT, and U87) were irradiated with 6-MV and 10-MV X-rays from a linear accelerator in FFF- or FLAT-beam modes at dose rates in the range of 0.5–24xa0Gy/min. The surviving fraction (SF) as function of dose (2–12xa0Gy) was determined by the colony formation assay and fitted by the linear-quadratic model. For both beams (FFF or FLAT), the cells were pelleted in conical 15-ml centrifuge tubes and irradiated at 2-cm depth in a 1u2009×u20091-cm2 area on the central axis of a 30u2009×u200930-cm2 field. Dosimetry was performed with a 0.3-cm3 rigid ionization chamber. RBE was determined for FFF versus FLAT irradiation.ResultsThe RBE of FFF at 7.3–11.3xa0Gy was 1.027u2009±u20090.013 and 1.063u2009±u20090.018 relative to FLAT beams for 6- and 10-MV beams, respectively, and was only significantly higher than 1 for 10xa0MV. Significantly increased survival rates were seen for lower dose rates (0.5xa0Gy/min FLAT vs. 5xa0Gy/min FLAT) at higher doses (11.9xa0Gy), while no differences were seen at dose rates u2009≥u20091.4xa0Gy/min (1.4xa0Gy/min FFF vs. 14xa0Gy/min FFF and 2.4xa0Gy/min FFF vs. 24xa0Gy/min FFF).ConclusionsFFF beams showed only a slightly increased RBE relative to FLAT beams in this experimental set-up, which is unlikely to result in clinically relevant differences in outcome.ZusammenfassungHintergrundDie Flattening-Filter-freie (FFF) Bestrahlungstechnik findet zunehmend Verwendung, da sich die Applikationsdauer der einzelnen Fraktionen deutlich verkürzen lässt. Aufgrund der Unterschiede im Spektrum könnte die relative biologische Wirksamkeit (RBW) von FFF jedoch höher sein als bei konventioneller Technik (d.h. bei Bestrahlung mit Flattening-Filter; FLAT). Wir untersuchten daher die Effekte von FFF und FLAT auf das klonogene Überleben von Astrozytomzelllinien.MethodenDrei Zelllinien (U251, U251-MGMT und U87) wurden mit konventioneller (FLAT) und FFF-Technik mit Photonen zweier Energien (6 und 10xa0MV) in Einzeldosen von 2–12xa0Gy und mit Dosisleistungen von 0,5–24xa0Gy/min bestrahlt. Die Überlebensraten wurden mittels Colony-Assay nach dem linear-quadratischen Modell errechnet. Für alle Bestrahlungen wurde ein spezieller Versuchsaufbau mit Positionierung der Zellen auf einem 1u2009×u20091u202fcm2 Areal in der Zentralachse eines 30u2009×u200930xa0cm2 Feldes gewählt. Die applizierten Dosen und Dosisraten wurden mit einer PTW 0,3xa0cm3 Ionisationskammer gemessen. Die RBW wurde für FFF in Bezug auf FLAT berechnet.ErgebnisseVerglichen mit FLAT lag die RBW von FFF bei Dosen von 7.3–11.3xa0Gy für 6 und 10xa0MV bei 1,027u2009±u20090,013 und 1,063u2009±u20090,018 und war nur signifikant höher als 1 für 10xa0MV. Bei niedrigeren Dosisraten (0,5xa0Gy/min FLAT vs. 5xa0Gy/min FLAT) und hohen Einzeldosen (11.9xa0Gy) wurden signifikant erhöhte Überlebensraten gesehen. Im Gegensatz dazu waren keine statistisch signifikanten Unterschiede mehr nachweisbar, wenn die Dosisraten bei 1.4xa0Gy/min und höher lagen (1,4xa0Gy/min FFF vs. 14xa0Gy/min FFF und 2,4xa0Gy/min FFF vs. 24xa0Gy/min FFF).SchlussfolgerungVerglichen mit FLAT zeigte FFF in unserem Modell eine nur marginal erhöhte RBW. Die Technik wird daher sehr wahrscheinlich keinen klinisch relevanten Einfluss auf das Outcome haben.

Combined sunitinib and radiation therapy for preoperative treatment of soft tissue sarcoma: results of a phase I trial of the German interdisciplinary sarcoma group (GISG-03)

BackgroundExperimental data demonstrated that concurrent anti-angiogenic treatment with sunitinib may improve the efficacy of radiation therapy (RT). Here we report the results of a phase I trial performed within the German Interdisciplinary Sarcoma Group (GISG-03) of combined sunitinib and RT for neoadjuvant treatment of locally advanced soft tissue sarcoma (STS).MethodsThe primary endpoint of the study was to explore the recommended dose of sunitinib combined with RT for subsequent trials. Treatment response, postoperative complications after tumor resection and toxicity according to CTCAE 4.0 were secondary endpoints. The study used a 3u2009+u20093 design. Patients received either 25xa0mg (dose level 1) or 37.5xa0mg (dose level 2) sunitinib two weeks prior to and throughout RT (28 × 1.8xa0Gy). Surgery was scheduled 5–8 weeks after completion of neoadjuvant treatment. Study registration: NCT01498835.ResultsSix patients were enrolled in dose level 1 and three patients in dose level 2. Median tumor size was 11xa0cm. Tumors were located in the retroperitoneum (4/9), lower leg (3/9) or trunk (2/9). At dose level 1, 1/6 patients developed dose limiting lymphopenia. At dose level 2, no patient developed dose limiting toxicity. Most frequent toxicities were hematological (8/9) and oral (5/9). Dose adjustments of sunitinib were necessary in 5/9 patients. All patients received full dose RT and underwent tumor resection (8/9 R0 and 1/9 R1). Local toxicity of RT did not exceed Grade 2. 2/9 patients had postoperative complications requiring re-intervention. Treatment response according to RECIST was as follows: partial response 1/9, stable disease 7/9, and progressive disease 1/9. Pathological examination revealedu2009≥u200995xa0% tumor necrosis in 3/9 resected specimens.ConclusionsCombined sunitinib and RT was tolerable as neoadjuvant treatment for locally advanced STS patients regardless of tumor localization. The recommended sunitinib dose for subsequent trials is 37.5xa0mg.

Comparison of anisotropic aperture based intensity modulated radiotherapy with 3D-conformal radiotherapy for the treatment of large lung tumors.

PURPOSE/OBJECTIVE(S)nIMRT allows dose escalation for large lung tumors, but respiratory motion may compromise delivery. A treatment plan that modulates fluence predominantly in the transversal direction and leaves the fluence identical in the direction of the breathing motion may reduce this problem.nnnMATERIALS/METHODSnPlanning-CT-datasets of 20 patients with Stage I-IV non small cell lung cancer (NSCLC) formed the basis of this study. A total of two IMRT plans and one 3D plan were created for each patient. Prescription dose was 60 Gy to the CTV and 70 Gy to the GTV. For the 3D plans an energy of 18 MV photons was used. IMRT plans were calculated for 6 MV photons with 13 coplanar and with 17 noncoplanar beams. Robustness of the used method of anisotropic modulation toward breathing motion was tested in a 13-field IMRT plan.nnnRESULTSnAs a consequence of identical prescription doses, mean target doses were similar for 3D and IMRT. Differences between 3D and 13- and 17-field IMRT were significant for CTV Dmin (43 Gy vs. 49.1 Gy vs. 48.6 Gy; p<0.001) and CTV D(95) (53.2 Gy vs. 55.0 Gy vs. 55.4 Gy; p=0.001). The D(mean) of the contralateral lung was significantly lower in the 17-field plans (17-field IMRT vs. 13- vs. 3D: 12.5 Gy vs. 14.8 Gy vs. 15.8 Gy: p<0.05). The spinal cord dose limit of 50 Gy was always respected in IMRT plans and only in 17 of 20 3D-plans. Heart D(max) was only marginally reduced with IMRT (3D vs. 13- vs. 17-field IMRT: 38.2 Gy vs. 36.8 Gy vs. 37.8 Gy). Simulated breathing motion caused only minor changes in the IMRT dose distribution (~0.5-1 Gy).nnnCONCLUSIONSnAnisotropic modulation of IMRT improves dose delivery over 3D-RT and renders IMRT plans robust toward breathing induced organ motion, effectively preventing interplay effects.

Überlegenheit der IMRT gegenüber der konventionellen 3D-EBRT auch bei der lokalen Kontrolle von Extremitätensarkomen

ven Resektionsrandern (p = 0,04), wurden ofter praoperativ bestrahlt (p < 0,001) und es mussten ofter Nerven manipuliert werden (p = 0,04). Die mediane Nachbeobachtungszeit der mit konventioneller EBRT behandelten Patienten betrug 90 Monate, die der mit IMRT behandelten 42 Monate. In der multivariaten Analyse blieb die IMRT nach Korrektur fur Patientenalter und Tumorgrose ein unabhangiger Pradiktor fur eine geringere Lokalrezidivrate (Hazard Ratio 0,46; 95 %-KI 0,24–0,89; p = 0,02).