Sven Clausen

Second cancer risk after 3D-CRT, IMRT and VMAT for breast cancer

PURPOSE Second cancer risk after breast conserving therapy is becoming more important due to improved long term survival rates. In this study, we estimate the risks for developing a solid second cancer after radiotherapy of breast cancer using the concept of organ equivalent dose (OED). MATERIALS AND METHODS Computer-tomography scans of 10 representative breast cancer patients were selected for this study. Three-dimensional conformal radiotherapy (3D-CRT), tangential intensity modulated radiotherapy (t-IMRT), multibeam intensity modulated radiotherapy (m-IMRT), and volumetric modulated arc therapy (VMAT) were planned to deliver a total dose of 50 Gy in 2 Gy fractions. Differential dose volume histograms (dDVHs) were created and the OEDs calculated. Second cancer risks of ipsilateral, contralateral lung and contralateral breast cancer were estimated using linear, linear-exponential and plateau models for second cancer risk. RESULTS Compared to 3D-CRT, cumulative excess absolute risks (EAR) for t-IMRT, m-IMRT and VMAT were increased by 2 ± 15%, 131 ± 85%, 123 ± 66% for the linear-exponential risk model, 9 ± 22%, 82 ± 96%, 71 ± 82% for the linear and 3 ± 14%, 123 ± 78%, 113 ± 61% for the plateau model, respectively. CONCLUSION Second cancer risk after 3D-CRT or t-IMRT is lower than for m-IMRT or VMAT by about 34% for the linear model and 50% for the linear-exponential and plateau models, respectively.

Development of a Novel Method for Intraoperative Radiotherapy During Kyphoplasty for Spinal Metastases (Kypho-IORT)

PURPOSE Approximately 30% of patients with cancer receive bone metastases, of which 50% are in the spine. Approximately 20% present with unstable lesions requiring surgical intervention, followed by fractionated radiotherapy over 2-4 weeks to prevent early regrowth. Because of the limited survival time of patients with metastatic cancer, novel treatment concepts shortening the overall treatment time or hospitalization are desirable. In this study, we established a novel approach for intraoperative radiotherapy during kyphoplasty (Kypho-IORT), a method that combines stabilizing surgery and radiotherapy within one visit, after estimating the percentage of eligible patients for this treatment. METHODS AND MATERIALS To estimate the percentage of eligible patients, 53 planning CTs (897 vertebrae) of patients with spinal metastases were evaluated. The number of infiltrated vertebrae were counted and classified in groups eligible or not eligible for Kypho-IORT. The Kypho-IORT was performed in a donated body during a standard balloon kyphoplasty using the INTRABEAM system and specially designed applicators. A single dose of 10 Gy (in 10 mm) was delivered over 4 min to the vertebra. This was verified using two ionization chambers and a Monte Carlo simulation. RESULTS The estimation of eligible patients resulted in 34% of the evaluated patients, and thus 34% of patients with instable spinal metastases are suitable for Kypho-IORT. This study shows also that, using the approach presented here, it is possible to perform an IORT during kyphoplasty with an additional 15 min operation time. The measurement in the donated body resulted in a maximum dose of 3.8 Gy in the spinal cord. However, the Monte Carlo depth dose simulation in bone tissue showed 68% less dose to the prescription depth. CONCLUSION We present for the first time a system using an x-ray source that can be used for single-dose IORT during kyphoplasty. The described Kypho-IORT can decrease the overall treatment time for up to 34% of patients who usually receive radiotherapy for spinal metastases.

Clinical Implementation of Volumetric Intensity-Modulated Arc Therapy (VMAT) with ERGO++

Background and Purpose:Volumetric modulated arc therapy (VMAT) has the potential to deliver dose distributions comparable to the established intensity-modulated radiotherapy techniques for a multitude of target paradigms. Prior to implementing VMAT into their clinical routine in December 2008, the authors evaluated the dose calculation/delivery accuracy of 24 sample VMAT plans (prostate and anal cancer target paradigms) with film and ionization dosimetry. After the start of the clinical program, in vivo measurements with a rectal probe were performed.Material and Methods:The VMAT plans were generated by the treatment-planning system (TPS) ERGO++ (Elekta, Crawley, UK) and transferred to a phantom. Film dosimetry was performed with Kodak EDR2 films, and evaluated with dose profiles and γ-index analysis. Appropriate ionization chambers were used for absolute dose measurements in the phantom and for in vivo measurements. The ionization chamber was used with localization of the measurement volume based on positioning cone-beam computed tomography.Results:Plans were transferred from ERGO++ to the record and verify (R&V) system/linear accelerator (linac). The absolute dose deviations recorded with the ionization chamber were 1.74% ± 1.62% across both indications. The γ-index analysis of the film dosimetry showed no deviation > 3%/3 mm in the high-dose region. On in vivo measurements, a deviation between calculation and measurement of 2.09% ± 2.4% was recorded, when the chamber was successfully positioned in the high-dose region.Conclusion:VMAT plans can be planned and treated reproducibly in high quality after the commissioning of the complete delivery chain consisting of TPS, R&V system and linac. The results of the individual plan verification meet the commonly accepted requirements. The first in vivo measurements confirm the reproducible precision of the delivered dose during clinical treatments.ZusammenfassungHintergrund und Ziel:Die volumetrisch modulierte Arc-Therapie (VMAT) bietet die Möglichkeit, für einige Planparadigmata zur bisher etablierten intensitätsmodulierten Strahlentherapie vergleichbare Dosisverteilungen zu generieren. Vor der im Dezember 2008 erfolgten Einführung von VMAT in die eigene klinische Routine überprüften die Autoren Dosisberechnung und Bestrahlungsgenauigkeit anhand von 24 VMAT-Plänen (Anal- und Prostatakarzinomplanungsparadigmata) mittels Film- und Ionisationsdosimetrie. Erste Patientenbestrahlungen wurden mittels rektaler In-vivo-Dosimetrie verifiziert.Material und Methodik:Die VMAT-Pläne wurden mit dem Planungssystem ERGO++ (Elekta, Crawley, UK) generiert und in einem Phantom verifiziert. Filmdosimetrie wurde mittels Kodak-EDR2-Film, Dosisprofilen und der γ-Analyse realisiert. Geeignete Ionisationskammern wurden für absolute Dosismessungen im Phantom und für die In-vivo-Dosimetrie verwendet. Ein Cone-Beam-Computertomogramm wurde für die Lokalisation des Messvolumens der Ionisationskammer im Rektum verwendet.Ergebnisse:Die Pläne wurden durchgängig fehlerfrei von ERGO++ an das „record and verify“-(R&V-)System und an den Beschleuniger übertragen. Die mittlere Abweichung der Absolutdosimetrie betrug 1,74% ± 1,62%. Die γ-Index-Analyse der Filmdosimetrie zeigte keine Abweichung > 3%/3 mm im Hochdosisbereich. Die In-vivo-Messungen ergaben nach erfolgreicher Positionierung im Hochdosisbereich eine mittlere Abweichung zwischen berechneter und applizierter Dosis von 2,09% ± 2,4%.Schlussfolgerung:VMAT-Pläne können auf Basis der klinisch zugelassenen Kette aus Planungs-, R&V- und Bestrahlungssystem nach adäquater Kommissionierung reproduzierbar erzeugt und zuverlässig bestrahlt werden. Die Ergebnisse der Individualplanverifikation erfüllen die allgemein akzeptierten Bedingungen. Erste in vivo ermittelte Dosen bestätigen die Präzision der Dosisapplikation im klinischen Einsatz.

A novel approach for superficial intraoperative radiotherapy (IORT) using a 50 kV X-ray source: a technical and case report.

The use of IORT as a treatment modality for patients with close or positive margins has increased over the past decade. For situations where a flat area (up to 6 cm in diameter) has to be treated intraoperatively, new applicators for superficial treatment with a miniature X‐ray source (INTRABEAM system) were developed. Here we report our evaluation of the dosimetric characteristics of these new applicators and their first clinical use. Each of these flat and surface applicators consists of a radiation protective metal tube and a flattening filter, which converts the spherical dose distribution of the X‐ray source into a flat one. The homogeneity of each dose distribution and depth‐dose measurements were evaluated using film dosimetry in a solid water phantom and a soft X‐ray ionization chamber in a water tank. The first patient was treated with 5 Gy delivered in 5 mm using a 4 cm FLAT applicator over 21 minutes. The flat applicators show the maximum homogeneity, with a uniformity ratio of 1.02‐1.08 in certain depths. In 1 mm depth surface applicators show a uniformity ratio of 1.15‐1.28. They also show a higher dose rate and a steeper dose gradient compared to the flat applicators. The results of this investigation demonstrated that the flat and surface applicators have unique dosimetric characteristics that need to be considered during the treatment planning stages. This work also showed that it is possible to perform a superficial localized IORT which provides new application possibilities for use of the INTRABEAM system. PACS number: 87.55.ne

Can the risk of secondary cancer induction after breast conserving therapy be reduced using intraoperative radiotherapy (IORT) with low- energy x-rays?

BackgroundRadiation induced secondary cancers are a rare but severe late effect after breast conserving therapy. Intraoperative radiotherapy (IORT) is increasingly used during breast conserving surgery. The purpose of this analysis was to estimate secondary cancer risks after IORT compared to other modalities of breast radiotherapy (APBI - accelerated partial breast irradiation, EBRT - external beam radiotherapy).MethodsComputer-tomography scans of an anthropomorphic phantom were acquired with an INTRABEAM IORT applicator (diameter 4 cm) in the outer quadrant of the breast and transferred via DICOM to the treatment planning system. Ipsilateral breast, contralateral breast, ipsilateral lung, contralateral lung, spine and heart were contoured. An INTRABEAM source (50 kV) was defined with the tip of the drift tube at the center of the spherical applicator. A dose of 20 Gy at 0 mm depth from the applicator surface was prescribed for IORT and 34 Gy (5 days × 2 × 3.4 Gy) at 10 mm depth for APBI. For EBRT a total dose of 50 Gy in 2 Gy fractions was planned using two tangential fields with wedges. The mean and maximal doses, DVHs and volumes receiving more than 0.1 Gy and 4 Gy of organs at risk (OAR) were calculated and compared. The life time risk for secondary cancers was estimated according to NCRP report 116.ResultsIORT delivered the lowest maximal doses to contralateral breast (< 0.3 Gy), ipsilateral (1.8 Gy) and contralateral lung (< 0.3 Gy), heart (1 Gy) and spine (< 0.3 Gy). In comparison, maximal doses for APBI were 2-5 times higher. EBRT delivered a maximal dose of 10.4 Gy to the contralateral breast and 53 Gy to the ipsilateral lung. OAR volumes receiving more than 4 Gy were 0% for IORT, < 2% for APBI and up to 10% for EBRT (ipsilateral lung). The estimated risk for secondary cancer in the respective OAR is considerably lower after IORT and/or APBI as compared to EBRT.ConclusionsThe calculations for maximal doses and volumes of OAR suggest that the risk of secondary cancer induction after IORT is lower than compared to APBI and EBRT.

A Monte Carlo based source model for dose calculation of endovaginal TARGIT brachytherapy with INTRABEAM and a cylindrical applicator

PURPOSE To generate and validate a source model of a miniature X-ray generator (INTRABEAM, Carl Zeiss Surgical, Oberkochen, Germany) for endovaginal TARGeted Intra-operative radioTherapy (TARGIT) brachytherapy a Geant4-based Monte Carlo (MC) tool was developed. The model was used to calculate the accurate relative dose distribution for the source combined with a cylindrical applicator which was developed for endovaginal treatment. METHODS AND MATERIALS Geometries with given materials of the X-ray source and applicator were implemented in a Geant4-based dose calculation framework. To reduce the calculation time, phase space files for a set of circular electron beam foci and different beam radii were precalculated. Different beam radii had to be considered because the exact electron beam path on the target is not known in advance. To estimate the electron beam radius distribution of the system, a least squares minimization between the EBT film measured relative dose distribution and the simulation was performed. RESULTS Relative dose distributions were calculated and compared with Gafchromic EBT film measurements to validate the MC method. In a region of interest around the source, the 2%/2mm gamma criterion matched with 98%. Profiles showed excellent agreement between measurement and simulation. The calculation time to simulate an entire treatment was twelve minutes. CONCLUSIONS The method was able to predict the radius and width of the trajectory where the electrons impact on the target. This enables the complete simulation. The developed method allows calculating relative dose distributions for endovaginal TARGIT brachytherapy matching measured relative dose distributions within clinically acceptable limits.

Radiation protection for an intraoperative x-ray source compared to C-arm fluoroscopy

BACKGROUND Intraoperative radiotherapy (IORT) using the INTRABEAM(®) system promises a flexible use regarding radiation protection compared to other approaches such as electron treatment or HDR brachytherapy with (192)Ir or (60)Co. In this study we compared dose rate measurements of breast- and Kypho-IORT with C-arm fluoroscopy which is needed to estimate radiation protection areas. MATERIALS AND METHODS C-arm fluoroscopy, breast- and Kypho-IORTs were performed using phantoms (silicon breast or bucket of water). Dose rates were measured at the phantoms surface, at 30 cm, 100 cm and 200 cm distance. Those measurements were confirmed during 10 Kypho-IORT and 10 breast-IORT patient treatments. RESULTS The measured dose rates were in the same magnitude for all three paradigms and ranges from 20 μSv/h during a simulated breast-IORT at two meter distance up to 64 mSv/h directly at the surface of a simulated Kypho-IORT. Those measurements result in a circle of controlled area (yearly doses >6 mSv) for each paradigm of about 4 m±2 m. DISCUSSION/CONCLUSIONS All three paradigms show comparable dose rates which implies that the radiation protection is straight forward and confirms the flexible use of the INTRABEAM(®) system.

Intraoperative radiotherapy (IORT)—a resurrected option for treating glioblastoma?

Despite surgical resection, radiochemotherapy and adjuvant chemotherapy, glioblastoma multiforme (GBM) is still associated with an extremely poor prognosis. As almost all tumors recur locally and evidence for a radiation dose-dependent effect on survival exists, intraoperative radiotherapy (IORT) could be an approach to avoid tumor cell proliferation between surgery and radiochemotherapy while sparing healthy tissue. The majority of previous studies used forward-scattering electron tubes (resembling intraoperative electron radiotherapy, IOERT) and suffered from technical and geometrical limitations. Consequently, the outcomes in previous studies range from highly beneficial to merely effective. This review shall give an overview on past, present and future applications of IORT for GBM and shall discuss what prospective steps are to be taken to thoroughly assess whether the approach has the ability to prolong patient survival.

Quality Assurance and Commissioning

The X-ray source (XRS 4) of the INTRABEAM® system accelerates electrons with a maximum voltage of 50 kV. These are steered down a 10-cm-long drift tube (probe) to strike a thin gold target at the end, and generate bremsstrahlung photon radiation in an approximately isotropic distribution (Wenz and Kraus-Tiefenbacher 2011). The probe tip consists of beryllium, transparent to X-rays above an energy of 10 keV, coated with nickel and titanium nitride, to give a durable and biocompatible surface. All of these materials will affect the characteristic spectrum of the source, to give an effective energy of approximately 20 kV for the probe only (Beatty et al. 1996; Dinsmore et al. 1996). With a spherical breast applicator attached, the beam will be hardened due to the additional material in the path of the radiation, which preferentially absorbs lower energy photons. The applicators are made from a biocompatible polyetherimide material (Ultem®), with an additional aluminium layer inside the smaller sizes (≤3.0 cm diameter) to give similar levels of hardening and shield the shaft from excess leakage.

Phase I/II trial of combined kyphoplasty and intraoperative radiotherapy in spinal metastases

BACKGROUND CONTEXT Spinal metastases occur in 30%-50% of patients with systemic cancer. The primary goals of palliation are pain control and prevention of local recurrence. PURPOSE This study aimed to test the safety and efficacy of a combined modality approach consisting of kyphoplasty and intraoperative radiotherapy (Kypho-IORT). STUDY DESIGN/SETTING Kyphoplasty and intraoperative radiotherapy was a prospective, single-center phase I/II trial. Patients were enrolled in a classical 3+3 scheme within the initial phase I, where Kypho-IORT was applied using a needle-shaped 50 kV X-ray source at three radiation dose levels (8 Gy in 8-mm, 8 Gy in 11-mm, and 8 Gy in 13-mm depth). Thereafter, cohort expansion was performed as phase II of the trial. The trial is registered with clinicaltrials.gov, number NCT01280032. PATIENT SAMPLE Patients aged 50 years and older with a Karnofsky Performance Status of at least 60% and with one to three painful vertebral metastases confined to the vertebral body were eligible to participate. OUTCOME MEASURES The primary end point was safety as per the occurrence of dose-limiting toxicities. The secondary end points were pain reduction, local progression-free survival (L-PFS), and overall survival (OS). METHODS Pain was measured using the visual analog scale (VAS) and local control was assessed in serial computed tomography or magnetic resonance imaging scans. RESULTS None of the nine patients enrolled in the phase I showed dose-limiting toxicities at any level and thus, 52 patients were subsequently enrolled into a phase II, where Kypho-IORT was performed at various dose levels. The median pain score significantly dropped from 5 preoperatively to 2 at the first postoperative day (p<.001). Of 43 patients who reported a pre-interventional pain level of 3 or more, 30 (69.8%) reported a reduction of ≥3 points on the first postoperative day. A persistent pain reduction beyond the first postoperative day of ≥3 points was seen in 34 (79.1%) patients. The 3, 6, and 12 month L-PFS was excellent with 97.5%, 93.8%, and 93.8%. The 3, 6, and 12 months OS was 76.9%, 64.0%, and 48.4%. CONCLUSION Kyphoplasty and intraoperative radiotherapy is safe and immediately provided sustained pain relief with excellent local control rates in patients with painful vertebral metastases.