Anthony Lomax

Intensity modulation in radiotherapy: photons versus protons in the paranasal sinus.

PURPOSEnThe purpose of this study is to investigate whether successive tightening of normal tissue constraints on an intensity modulated X-ray therapy plan might be able to improve it to the point of clinical comparability with the corresponding intensity modulated proton therapy plan.nnnMATERIALS AND METHODSnPhoton and proton intensity modulated plans were calculated for a paranasal sinus case using nominal dose constraints. Additional photon plans were then calculated in an effort to match the dose-volume histograms of the critical structures to those of the proton plan.nnnRESULTSnOn reducing the low dose contribution to both orbits in the photon plan by tightening the constraints on these structures, an increased dose heterogeneity across the target resulted. When all critical structures were more strictly constrained, target dose homogeneity and conformity was further compromised. An increased integral dose to the non-critical normal tissues was observed for the photon plans as dose was progressively removed from the critical structures.nnnCONCLUSIONSnBoth modalities were found to provide comparable target volume conformation and sparing of critical structures, when the nominal dose constraints were applied. However, the use of intensity modulated protons provided the only method by which critical structures could be spared at all dose levels, whilst simultaneously providing acceptable dose homogeneity within the target volume.

Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuro-ectodermal tumors: Spinal theca irradiation

PURPOSEnConventional postoperative photon-beam radiotherapy to the spine in children with medulloblastoma/PNET is associated with severe late effects. This morbidity (growth and developmental) is related to the exit dose of the beams and is particularly severe in young children. With the purpose of reducing this toxicity, a dosimetric study was undertaken in which proton therapy was compared to standard megavoltage photon treatment.nnnMETHODS AND MATERIALSnThe results of a comparative dosimetric study are presented in such a way that the dose distribution achievable with a posterior modulated 100 MeV proton beam (spot scanning method) is compared with that of a standard set of posterior 6 MV x-ray fields. The potential improvements with protons are evaluated, using dose-volume histograms to examine the coverage of the target as well as the dose to the vertebral bodies (growth plates), lungs, heart, and liver.nnnRESULTSnThe target (i.e., the spinal dural sac) received the full prescribed dose in both treatment plans. However, the proportions of the vertebral body volume receiving > or = 50% of the prescribed dose were 100 and 20% for 6 MV x-rays and protons, respectively. For 6 MV x-rays > 60% of the dose prescribed to the target was delivered to 44% of the heart volume, while the proton beam was able to completely avoid the heart, the liver, and in all likelihood the thyroid and gonads as well.nnnCONCLUSIONnThe present study demonstrates a potential role of proton therapy in decreasing the dose (and toxicity) to the critical structures in the irradiation of the spinal neuraxis in medulloblastoma/PNET. The potential bone marrow and growth arrest sparing effects make this approach specially attractive for intensive chemotherapy protocols and for very young children. Sparing the thyroid gland, the posterior heart wall, and the gonads may be additional advantages in assuring a long-term posttreatment morbidity-free survival.

Variations in linear energy transfer within clinical proton therapy fields and the potential for biological treatment planning

PURPOSEnTo calculate the linear energy transfer (LET) distributions in patients undergoing proton therapy. These distributions can be used to identify areas of elevated or diminished biological effect. The location of such areas might be influenced in intensity-modulated proton therapy (IMPT) optimization.nnnMETHODS AND MATERIALSnBecause Monte Carlo studies to investigate the LET distribution in patients have not been undertaken so far, the code is first validated with simulations in water. The code was used in five patients, for each of them three planning and delivery techniques were simulated: passive scattering, three-dimensional modulation IMPT (3D-IMPT), and distal edge tracking IMPT (DET-IMPT).nnnRESULTSnThe inclusion of secondary particles led to significant differences compared with analytical techniques. In addition, passive scattering and 3D-IMPT led to largely comparable LET distributions, whereas the DET-IMPT plans resulted in considerably increased LET values in normal tissues and critical structures. In the brainstem, dose-averaged LET values exceeding 5 keV/μm were observed in areas with significant dose (>70% of prescribed dose). In noncritical normal tissues, even values >8 keV/μm occurred.nnnCONCLUSIONnThis work demonstrates that active scanning offers the possibility of influencing the distribution of dose-averaged LET (i.e., the biological effect) without significantly altering the distribution of physical dose. On the basis of this finding, we propose a method to alter deliberately the LET distribution of a treatment plan in such a manner that the LET is maximized within certain target areas and minimized in normal tissues, while maintaining the prescribed target dose and dose constraints for organs at risk.

Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuroectodermal tumors: Reduction of the supratentorial target volume

PURPOSEnOne of the components of radiotherapy (RT) in medulloblastoma/primitive neuroectodermal tumors is the prophylactic irradiation of the whole brain (WBI). With the aim of reducing late neuropsychologic morbidity a CT-scan-based dosimetric study was undertaken in which treatment was confined mainly or exclusively to supratentorial sites considered at high risk for disease recurrence.nnnMETHODS AND MATERIALSnA comparative dosimetric study is presented in which a three field (two laterals and one posterior) proton plan (spot scanning method) is compared with a two-field conventional WBI 6 MV x-ray plan, to a 6-field hand-made 6 MV x-ray plan, and to a computer-optimized 9-field inverse 15 MV x-ray plan. For favorable patients, 30 Gy were delivered to the ventricles and main cisterns, the subfrontal and subtemporal regions, and the posterior fossa. For the unfavorable patients, 10 Gy WBI preceeded a boost to 30 Gy to the same treatment volume chosen for favorable patients. The dose distribution was evaluated with dose-volume histograms to examine the coverage of the targets as well as the dose to the nontarget brain and optical structures. In addition, the risks of radiation-related late neuropsychologic effects after WBI were collected from the literature and used to predict normal tissue complication probabilities (NTCPs) for an intelligence quotient deficit after treatment with photon or proton beams.nnnRESULTSnProton beams succeeded better in reducing the dose to the brain hemispheres and eye than any of the photon plans. A 25.1% risk of an IQ score <90 was predicted after 30 Gy WBI. Almost a 10% drop in the predicted risk was observed when using proton beams in both favorable and unfavorable patients. However, predicted NTCPs for both optimized photon plans (hand made and inverse) were only slightly higher (0.3-2.5%) than those of proton beams. An age-modifying factor was introduced in the predictive NTCP model to assess for IQ differences in relation with age at irradiation. Children with ages between age 4 to 8 benefitted most from the dose reduction in this exercise (similar NTCP predictions for both proton and inverse plans).nnnCONCLUSIONnModulated proton beams may help to significantly reduce the irradiation of normal brain while optimally treating the supratentorial subsites at higher risk for relapse. A decrease in morbidity can be expected from protons and both optimized proton plans compared to WBI.

PROTON THERAPY FOR MALIGNANT PLEURAL MESOTHELIOMA AFTER EXTRAPLEURAL PLEUROPNEUMONECTOMY

PURPOSEnTo perform comparative planning for intensity-modulated radiotherapy (IMRT) and proton therapy (PT) for malignant pleural mesothelioma after radical surgery.nnnMETHODS AND MATERIALSnEight patients treated with IMRT after extrapleural pleuropneumonectomy (EPP) were replanned for PT, comparing dose homogeneity, target volume coverage, and mean and maximal dose to organs at risk. Feasibility of PT was evaluated regarding the dose distribution with respect to air cavities after EPP.nnnRESULTSnDose coverage and dose homogeneity of the planning target volume (PTV) were significantly better for PT than for IMRT regarding the volume covered by >95% (V95) for the high-dose PTV. The mean dose to the contralateral kidney, ipsilateral kidney, contralateral lung, liver, and heart and spinal cord dose were significantly reduced with PT compared with IMRT. After EPP, air cavities were common (range, 0-850 cm(3)), decreasing from 0 to 18.5 cm(3)/day. In 2 patients, air cavity changes during RT decreased the generalized equivalent uniform dose (gEUD) in the case of using an a value of < - 10 to the PTV2 to <2 Gy in the presence of changing cavities for PT, and to 40 Gy for IMRT. Small changes were observed for gEUD of PTV1 because PTV1 was reached by the beams before air.nnnCONCLUSIONnBoth PT and IMRT achieved good target coverage and dose homogeneity. Proton therapy accomplished additional dose sparing of most organs at risk compared with IMRT. Proton therapy dose distributions were more susceptible to changing air cavities, emphasizing the need for adaptive RT and replanning.

Differential DNA repair pathway choice in cancer cells after proton- and photon-irradiation

BACKGROUND AND PURPOSEnNon-homologous end-joining (NHEJ) and homologous recombination (HR) contribute to the repair of irradiation-induced DNA double-strand breaks (DSBs). We investigated the impact of the two major DSB repair machineries for cellular survival of human tumor cells in response to proton- and photon-irradiation.nnnMATERIALS AND METHODSnDNA damage repair and cell survival were analyzed in wildtype, HR- and NHEJ-repair-compromised and pharmacologically DNA-PKcs-inhibited human tumor cells in response to clinically relevant, low-linear energy transfer proton- and 200-keV photon-irradiation.nnnRESULTSnPharmacological inhibition of DNA-PKcs strongly radiosensitized lung adenocarcinoma and glioblastoma cells to photon- but to a much lower extent to proton-irradiation. Enhanced radiosensitization correlated with strongly delayed repair kinetics with elevated amounts of γH2AX foci after photon-irradiation. Interestingly, we observed reduced phosphorylation of DNA-PKcs at Ser-2056 and Thr-2609 clusters after proton-irradiation compared to photon-irradiation. In contrast, A549 cells depleted of the RAD51 recombinase were markedly hypersensitive to proton-irradiation in comparison with control cells. Likewise, human BRCA2-deficient ovarian carcinoma cells were hypersensitive toward proton- in comparison with photon-irradiation.nnnCONCLUSIONnA differential DNA damage response with enhanced susceptibility of HR-deficient tumor cells to proton-irradiation and increased sensitivity of photon-irradiated tumor cells to NHEJ inhibitors were demonstrated.

Characterizing a proton beam scanning system for Monte Carlo dose calculation in patients

The presented work has two goals. First, to demonstrate the feasibility of accurately characterizing a proton radiation field at treatment head exit for Monte Carlo dose calculation of active scanning patient treatments. Second, to show that this characterization can be done based on measured depth dose curves and spot size alone, without consideration of the exact treatment head delivery system. This is demonstrated through calibration of a Monte Carlo code to the specific beam lines of two institutions, Massachusetts General Hospital (MGH) and Paul Scherrer Institute (PSI). Comparison of simulations modeling the full treatment head at MGH to ones employing a parameterized phase space of protons at treatment head exit reveals the adequacy of the method for patient simulations. The secondary particle production in the treatment head is typically below 0.2% of primary fluence, except for low-energy electrons (<0.6u2009MeV for 230u2009MeV protons), whose contribution to skin dose is negligible. However, there is significant difference between the two methods in the low-dose penumbra, making full treatment head simulations necessary to study out-of-field effects such as secondary cancer induction. To calibrate the Monte Carlo code to measurements in a water phantom, we use an analytical Bragg peak model to extract the range-dependent energy spread at the two institutions, as this quantity is usually not available through measurements. Comparison of the measured with the simulated depth dose curves demonstrates agreement within 0.5u2009mm over the entire energy range. Subsequently, we simulate three patient treatments with varying anatomical complexity (liver, head and neck and lung) to give an example how this approach can be employed to investigate site-specific discrepancies between treatment planning system and Monte Carlo simulations.

An Analysis of Plan Robustness for Esophageal Tumors: Comparing Volumetric Modulated Arc Therapy Plans and Spot Scanning Proton Planning

Purpose Planning studies to compare x-ray and proton techniques and to select the most suitable technique for each patient have been hampered by the nonequivalence of several aspects of treatment planning and delivery. A fair comparison should compare similarly advanced delivery techniques from current clinical practice and also assess the robustness of each technique. The present study therefore compared volumetric modulated arc therapy (VMAT) and single-field optimization (SFO) spot scanning proton therapy plans created using a simultaneous integrated boost (SIB) for dose escalation in midesophageal cancer and analyzed the effect of setup and range uncertainties on these plans. Methods and Materials For 21 patients, SIB plans with a physical dose prescription of 2 Gy or 2.5 Gy/fraction in 25 fractions to planning target volume (PTV)50Gy or PTV62.5Gy (primary tumor with 0.5 cm margins) were created and evaluated for robustness to random setup errors and proton range errors. Dose–volume metrics were compared for the optimal and uncertainty plans, with P<.05 (Wilcoxon) considered significant. Results SFO reduced the mean lung dose by 51.4% (range 35.1%-76.1%) and the mean heart dose by 40.9% (range 15.0%-57.4%) compared with VMAT. Proton plan robustness to a 3.5% range error was acceptable. For all patients, the clinical target volume D98 was 95.0% to 100.4% of the prescribed dose and gross tumor volume (GTV) D98 was 98.8% to 101%. Setup error robustness was patient anatomy dependent, and the potential minimum dose per fraction was always lower with SFO than with VMAT. The clinical target volume D98 was lower by 0.6% to 7.8% of the prescribed dose, and the GTV D98 was lower by 0.3% to 2.2% of the prescribed GTV dose. Conclusions The SFO plans achieved significant sparing of normal tissue compared with the VMAT plans for midesophageal cancer. The target dose coverage in the SIB proton plans was less robust to random setup errors and might be unacceptable for certain patients. Robust optimization to ensure adequate target coverage of SIB proton plans might be beneficial.

Protonentherapie mit „Spot-Scanning“ bei Rhabdomyosarkomen im frühen Kindesalter

Ziel:Die Durchführbarkeit und Verträglichkeit der Spot-Scanning-Protonentherapie in tiefer Sedierung bei Kindern mit Rhabdomyosarkomen (RMS) sollten geprüft werden.Patienten und Methodik:Seit 2004 werden junge Kinder am Paul Scherrer Institut (PSI), Villigen, Schweiz, auch in tiefer Sedierung mit Protonen bestrahlt. Ausgewertet wurden Kinder unter 5 Jahren mit RMS im Bereich des Kopfes und Körperstamms. Alle Kinder waren in eine Therapieoptimierungsstudie eingeschlossen und wurden prospektiv hinsichtlich der Verträglichkeit der Bestrahlung untersucht.Ergebnisse:Neun Kinder im medianen Alter von 1,9 Jahren wurden untersucht (sechs embryonale RMS und je ein alveoläres, undifferenziertes und nicht klassifizierbares RMS). Die Lokalisationen waren parameningeal (n = 4), orbital (n = 3), Kopf-Hals-Bereich (n = 1) und Prostata (n = 1). Bei allen Kindern lag ein IRS-Stadium III vor. Die Bestrahlung erfolgte ausschließlich mit Protonen (Gesamtdosen 46–54 CGE [Cobalt-Gray-Äquivalent]). Akuttoxizitäten Grad 3 oder 4 nach RTOG/EORTC traten ausschließlich im Bereich des Knochenmarks auf.Schlussfolgerung:Die Protonentherapie bei RMS im frühen Kindesalter war problemlos durchführbar und hervorragend verträglich. Prospektive, standardisierte Erhebungen von Spättoxizität und Lebensqualität sind essentiell.Purpose:To evaluate the feasibility and acute toxicity of spot-scanning proton therapy under deep sedation in young children with rhabdomyosarcomas (RMS).Patients and Methods:Since 2004, children requiring sedation can be admitted for proton therapy at Paul Scherrer Institute (PSI), Villigen, Switzerland. Children under 5 years of age with RMS of the head and the trunk were analyzed. All children were enrolled in a multidisciplinary treatment protocol and prospective, standardized evaluation of side effects was performed.Results:Nine children were included aged 0.9–3.8 years (embryonal RMS in six, and alveolar, undifferentiated or nonclassified in one each). The tumor site was parameningeal (n = 4), orbital (n = 3), head and neck (n = 1), and prostate (n = 1). All children were in IRS group III. Total proton dose was 46–54 CGE (cobalt-gray equivalent). Only the myelotoxicity exceeded grade 3 or 4 (RTOG/EORTC).Conclusion:Proton therapy for RMS in early children is feasible and well tolerated. The prospective standardized evaluation of toxicity and quality of life needs to be continued.

Protonentherapie mit „Spot-Scanning“ bei Rhabdomyosarkomen im frühen Kindesalter@@@“Spot-Scanning” Proton Therapy for Rhabdomyosarcomas of Early Childhood. First Experiences at PSI: Erste Erfahrungen am PSI

Ziel:Die Durchführbarkeit und Verträglichkeit der Spot-Scanning-Protonentherapie in tiefer Sedierung bei Kindern mit Rhabdomyosarkomen (RMS) sollten geprüft werden.Patienten und Methodik:Seit 2004 werden junge Kinder am Paul Scherrer Institut (PSI), Villigen, Schweiz, auch in tiefer Sedierung mit Protonen bestrahlt. Ausgewertet wurden Kinder unter 5 Jahren mit RMS im Bereich des Kopfes und Körperstamms. Alle Kinder waren in eine Therapieoptimierungsstudie eingeschlossen und wurden prospektiv hinsichtlich der Verträglichkeit der Bestrahlung untersucht.Ergebnisse:Neun Kinder im medianen Alter von 1,9 Jahren wurden untersucht (sechs embryonale RMS und je ein alveoläres, undifferenziertes und nicht klassifizierbares RMS). Die Lokalisationen waren parameningeal (n = 4), orbital (n = 3), Kopf-Hals-Bereich (n = 1) und Prostata (n = 1). Bei allen Kindern lag ein IRS-Stadium III vor. Die Bestrahlung erfolgte ausschließlich mit Protonen (Gesamtdosen 46–54 CGE [Cobalt-Gray-Äquivalent]). Akuttoxizitäten Grad 3 oder 4 nach RTOG/EORTC traten ausschließlich im Bereich des Knochenmarks auf.Schlussfolgerung:Die Protonentherapie bei RMS im frühen Kindesalter war problemlos durchführbar und hervorragend verträglich. Prospektive, standardisierte Erhebungen von Spättoxizität und Lebensqualität sind essentiell.Purpose:To evaluate the feasibility and acute toxicity of spot-scanning proton therapy under deep sedation in young children with rhabdomyosarcomas (RMS).Patients and Methods:Since 2004, children requiring sedation can be admitted for proton therapy at Paul Scherrer Institute (PSI), Villigen, Switzerland. Children under 5 years of age with RMS of the head and the trunk were analyzed. All children were enrolled in a multidisciplinary treatment protocol and prospective, standardized evaluation of side effects was performed.Results:Nine children were included aged 0.9–3.8 years (embryonal RMS in six, and alveolar, undifferentiated or nonclassified in one each). The tumor site was parameningeal (n = 4), orbital (n = 3), head and neck (n = 1), and prostate (n = 1). All children were in IRS group III. Total proton dose was 46–54 CGE (cobalt-gray equivalent). Only the myelotoxicity exceeded grade 3 or 4 (RTOG/EORTC).Conclusion:Proton therapy for RMS in early children is feasible and well tolerated. The prospective standardized evaluation of toxicity and quality of life needs to be continued.