Intracranial response to capmatinib after progression on crizotinib in a patient with MET exon 14 skipping non-small cell lung cancer-a case report.

Background: Capmatinib, a potent and selective MET tyrosine kinase inhibitor (TKI), holds promise as a therapeutic agent due to its potentially elevated intracranial efficacy in metastatic non-small cell lung cancer (NSCLC) patients harboring exon 14 skipping alterations in MET (MET Proto-Oncogene). This study aims to evaluate a targeted therapeutic approach to an MET exon 14 skipping (METex14) advanced NSCLC patient that progressed on Crizotinib and developed off target resistance alteration in PIK3CA. Case Discription: We present a case of advanced METex14 NSCLC patient wherein central nervous system (CNS) relapse occurred post complete surgical resection and remission of the lung tumor under first-line crizotinib treatment. Subsequent disease monitoring demonstrated a profound intracranial response to capmatinib in a crizotinib-resistant brain lesion. Molecular analysis unveiled the original METex14 D1028N driver mutation and a newly arisen PIK3CA bypass mutation, potentially contributing to off-target resistance. Conclusions: Before capmatinib was approved as a first line treatment option for metastatic NSCLC harboring somatic METex14 mutations, crizotinib conferred a potential option for targeted treatment. Switching to a selective MET-TKI like capmatinib with a better CNS penetration, it appears to be a promising approach for CNS metastasized NSCLC patients with METex14 mutations that failed on crizotinib. Further research is needed to more effectively understand and monitor resistance mechanisms using advanced diagnostic techniques such as DNA-based hybrid-capture (HC) next generation sequencing (NGS) to guide molecularly stratified therapy beyond the first line setting.

Evaluation of the Prognostic Impact of SP263-Evaluated PD-L1 Expression in Patients with Stage III Non-Small Cell Lung Cancer (NSLC) Treated with Radio-Chemotherapy.

BACKGROUND: The PACIFIC study showed that after radio-chemotherapy, patients with NSCLC derived a benefit in PFS and OS when treated with durvalumab. This effect was limited to patients with a PD-L1 expression of >1%, partly because the outcome in the observational control arm was surprisingly favorable. Thus, it could be speculated that a lack of PD-L1 expression confers a favorable outcome for patients with stage III NSCLC. METHODS: Clinical data, PD-L1 expression, predictive blood markers, and the outcomes of 99 homogeneously treated patients with stage III NSCLC were retrospectively captured. Statistical analyses using the log rank test were performed. RESULTS: The median OS of patients with an expression of PD-L1 < 1% was 20 months (CI 10.5-29.5) and the median OS of patients with an expression of PD-L1 ≥ 1% was 28 months (CI 16.5-39.2) (p = 0.734). The median PFS of patients with an expression of PD-L1 < 1% was 9 months (CI 6.3-11.6) and the median PFS of patients with an expression of PD-L1 ≥ 1% was 12 months (CI 9.8-14.2) (p = 0.112). CONCLUSIONS: The assumption that the lack of PD-L1 expression represents a favorable prognostic factor after radio-chemotherapy vs. PD-L1 expression > 1% was not confirmed.

Lessons learned after one year of COVID-19 from a urologist and radiotherapist view: A German survey on prostate cancer diagnosis and treatment.

INTRODUCTION: Since the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines. MATERIALS AND METHODS: To longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses. RESULTS: A total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate. CONCLUSION: While the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.

Long-term remissions in patients with early relapse of diffuse large B-cell lymphoma following high-dose chemotherapy, autologous stem cell transplantation, and radiotherapy of residual disease.

PURPOSE: The prognosis of an early relapse of diffuse large B-cell lymphoma (DLBCL) appears to be poor following autologous stem cell transplantation (ASCT). The aim of this study is to contribute data to the open question on whether additional radiotherapy can improve the outcome. PATIENTS AND METHODS: Forty-eight patients with an early relapse (median 4 months after the end of initial immunochemotherapy, range 1-11) of DLBCL have been treated in our institution with high-dose therapy (usually the BEAM protocol) and ASCT since 2008 (median age 61 years, range 28-73). Twenty-three patients received ASCT in a second treatment line, 25 in a third line (19 refractory to second-line salvage therapy, 5 after second relapse). Fifteen of these 48 patients received radiotherapy (36-50 Gy, median 40) of residual masses after ASCT. RESULTS: Three-year overall survival (OS) and progression-free survival (PFS) after second-line ASCT were 61 and 57%, after third-line ASCT 47 and 44%, respectively, without significant differences. A prognostic factor was the International Prognostic Index (IPI) at the start of salvage therapy. Three-year OS and PFS in low-risk patients were 69 and 69%, in low-intermediate-risk 63 and 53%, and in high-intermediate-risk 23 and 23%, respectively (p = 0.033). Twenty-three patients achieved a sustained complete remission (13-146 months, median 62). CONCLUSION: Sustained long-term remissions can be achieved in patients with early relapse of DLBCL following ASCT in a second or third treatment line, particularly in patients with low- and low-intermediate-risk IPI, following radiotherapy of residual disease after ASCT. Further investigations are required to clarify which patients need an alternative therapy (potentially CAR T­cells or allogeneic transplantation).

Region-specific Risk Factors for Pelvic Lymph Node Metastasis in Patients with Stage IB1 Cervical Cancer.

Objectives: We aimed to identify the risk factors associated with pelvic lymph node metastasis (LNM) at each anatomic location in patients with stage IB1 cervical cancer. Methods: A primary cohort of 728 patients with stage IB1 cervical cancer who underwent radical hysterectomy and systematic pelvic lymphadenectomy were retrospectively studied. All removed pelvic nodes (N=20,134) were pathologically examined. The risk factors for LNM in different anatomic regions (obturator, internal iliac, external iliac, and common iliac) were evaluated by multivariate logistic regression analyses. Nomograms were generated from the primary cohort and validated in another external cohort (N=242). The performance of the nomogram was assessed by its calibration and discrimination. Overall survival and progression-free survival in patients with different LNM patterns were compared. Results: LNM was found in 266 (1.3%) removed nodes and 106 (14.6%) patients. The incidences of LNM at the obturator, internal iliac, external iliac, common iliac, and parametrial regions were 8.5%, 5.4%, 4.7%, 1.9% and 1.8%, respectively. Among others, tumour size and lymph-vascular space invasion (LVSI), which are preoperatively assessable, were identified as independent risk factors of LNM in the common iliac region and the lower pelvis, respectively, and age was an additional independent risk factor of obturator LNM. The negative predictive values of tumour size <2 cm for common iliac LNM and negative LVSI combined with older age (> 50 years) for obturator LNM were 100% and 98.7%, respectively. A nomogram of these two factors showed good calibration and discrimination (concordance index, 0.761 in the primary cohort and 0.830 in validation cohort). The patients with common iliac LNM had poorer survival than those with LNM confined to the lower pelvis, while the differences in survival between patients with LNM confined to one node, one region or single side and those with more widely spreading LNM were not statistically significant. Conclusions: Tumour size, LVSI and age are region-specific risk factors for pelvic LNM in IB1 cervical cancer, which could be used to allocate the appropriate extent of pelvic lymphadenectomy.

Topographic distribution of lymph node metastasis in patients with stage IB1 cervical cancer: an analysis of 8314 lymph nodes.

BACKGROUND: Systematic pelvic lymphadenectomy or whole pelvic irradiation is recommended for the patients with stage IB1 cervical cancer. However, the precise pattern of lymphatic tumor spread in cervical cancer is unknown. In the present study we evaluated the distribution of nodal metastases in stage IB1 cervical cancer to explore the possibilities for tailoring cancer treatment. METHODS: A total of 289 patients with cervical cancer of stage IB1, according to FIGO 2009, were retrospectively analyzed. All patients underwent laparoscopic radical hysterectomy (Querleu and Morrow type C2) and systematic pelvic lymphadenectomy with or without para-aortic lymphadenectomy (level 2 or level 3 according to Querleu and Morrow) from October 2014 to December 2017. Lymph nodes removed from 7 well-defined anatomical locations as well as other tissues were examined histopathologically, and typed, graded, and staged according to the WHO/IARC classification. RESULTS: Totally 8314 lymph nodes were analyzed with the average number of 31.88 ± 10.34 (Mean ± SD) lymph nodes per patient. Nodal metastases were present in 44 patients (15.22%). The incidence of lymphatic spread to different anatomic sites ranged from 0% (presacral) to 30.92% (obturator nodes). Tumor size above 2 cm, histologically proven lymphovascular space involvement (LVSI) and parametrial invasion were shown to be significantly correlated with the higher risk of lymphatic metastasis, while obesity (BMI ≥ 25) was independently negatively associated with lymphatic metastases. CONCLUSIONS: The incidence of lymph node metastasis in patients with stage IB1 cervical cancer is low but prognostically relevant. Individual treatment could be considered for the selected low-risk patients who have smaller tumors and obesity and lack of the parametrial invasion or LVSI.

Analysis of the applicability of two-dimensional detector arrays in terms of sampling rate and detector size to verify scanned intensity-modulated proton therapy plans.

PURPOSE: The introduction of advanced treatment techniques in proton therapy, such as intensity-modulated proton therapy, leads to an increased need for patient-specific quality assurance, especially an accurate treatment plan verification becomes inevitable. In this study, signal theoretical analysis of dose distributions in scanned proton therapy is performed to investigate the feasibility and limits of two-dimensional (2D) detector arrays for treatment plan verification. METHODS: 2D detector arrays are characterized by two main aspects: the distance between the single detectors on the array or the sampling frequency; and the lateral response functions of a single detector. The analysis is based on single spots, reference fields and on measured and calculated dose distributions of typical intensity-modulated proton therapy treatment plans with and without range shifter. Measurements were performed with Gafchromic EBT3 films (Ashland Speciality Ingredients G.P., Bridgewater, NJ, USA), the MatriXX PT detector array (IBA Dosimetry, Schwarzenbruck, Germany) and the OCTAVIUS detector array 1500XDR (PTW-Freiburg, Germany) at an IBA Proteus PLUS proton therapy system (Ion Beam Applications, Louvain-la-Neuve, Belgium). Dose calculations were performed with the treatment planning system RayStation 6 or 8 (RaySearch Laboratories, Sweden). RESULTS: The Fourier analysis of the data of the treatment planning system and film measurements show maximum frequencies of 0.06/mm for the plan with range shifter and 0.083/mm for the plan without range shifter. According to the Nyquist theorem, this corresponds to minimum required sampling distances of 8.3 and 6 mm, respectively. By comparison, the sampling distances of the arrays of 7.6 mm (MatriXX PT) and 7.1 mm (OD1500XDR) are sufficient to reconstruct the dose distributions adequately from measurements if range shifters are used, whereas some fields of the plans without range shifter violated the Nyquist requirement. The lateral dose response functions of the single detectors within the arrays have clearly higher frequencies than the treatment plans and thus the volume effect only slightly influences the measurements. Consequently, the array measurements show high gamma passing rates with at least 96 % and a good agreement between the investigated line profiles. CONCLUSION: The results indicate that the detector dimensions and sampling distances of the arrays are in most studied cases adequate not to substantially influence the measurement process when they are used for analyzing typical intensity-modulated proton therapy treatment plans. Nevertheless, clinical conditions have been identified, for instance treatment plans without range shifter, under which the Nyquist theorem is violated such that a full representation of the dose distributions with the measurements is not feasible. In these cases, analysis of measurements is limited to pointwise comparisons.

Renaissance of Radiotherapy in Intestinal Lymphoma? 10-Year Efficacy and Tolerance in Multimodal Treatment of 134 Patients: Follow-up of Two German Multicenter Consecutive Prospective Phase II Trials.

PURPOSE: This article reports on the long-term impact of radiotherapy adapted to stage, histology, and previous resection in a large cohort of patients with intestinal lymphoma (iL) treated with definitive or adjuvant curative-intent radiation therapy (RT) ± chemotherapy (CHOP, MCP, or COP). PATIENTS AND METHODS: In two consecutive prospective study designs, 134 patients with indolent (stage IE-IIE) or aggressive (stage IE-IVE) iL were referred to 61 radiotherapeutic institutions between 1992 and 2003. Patients with indolent iL received extended field (EF) 30 Gy (+10 Gy boost in definitive treatment); patients with aggressive iL received involved field (IF) (EF) 40 Gy by means of stage-, histology-, and operation-adapted radiation fields. RESULTS: The patients had median age 58 years and were predominantly male (2:1). Histology showed aggressive prevalence (1.6:1), stage IE-to-stage IIE ratio of iL 1.04:1, and localized stages-to-advanced stages ratio of aggressive lymphoma 23:1. Median follow-up was in total 11.7 years: 10.0 years in the first study, GIT (GastroIntestinal-Tract) 1992, and 11.8 years in the second study, GIT 1996. Lymphoma involvement was predominantly a single intestinal lesion (82.1%). Decrease of radiation field size from EF to IF in stage I aggressive iL from GIT 1992 to GIT 1996 resulted in a nonsignificant partial reduction of chronic toxicity while maintaining comparable survival rates (5-year overall survival 87.9 vs. 86.7%, 10-year overall survival 77.4 vs. 71.5%) with nonsignificant difference in event-free survival (5-year event-free survival 82.6 vs. 86.7%, 10-year event-free survival 69.7 vs. 71.5%) and lymphoma-specific survival (5-year lymphoma-specific survival 90.1 vs. 91.9%, 10-year lymphoma-specific survival 87.6% vs. 91.9%). Comparative dose calculation of two still available indolent duodenal lymphoma computed tomography scans revealed lower radiation exposure to normal tissues from applying current standard involved site RT (ISRT) 30 Gy in both cases. CONCLUSION: RT adapted to stage, histology, and resection in multimodal treatment of iL, despite partially decreasing field size (EF to IF), achieves excellent local tumor control and survival rates. The use of modern RT technique and target volume with ISRT offers the option of further reduction of normal tissue complication probability. IMPLICATIONS FOR PRACTICE: Although patients with intestinal lymphoma (iL) are heterogeneous according to histology and subtype, they benefit from radiotherapy. Prospective study data from 134 patients with indolent iL (stage IE-IIE) or aggressive iL (stage IE-IVE) show 100% tumor control after definitive or adjuvant curative-intent radiation therapy ± chemotherapy. Radiation treatment was applied between 1992 and 2003. Median follow-up in total was 11.7 years. No radiotherapy-associated death occurred. Relapse developed in 15.7% of the entire cohort; distant failure was more frequent than local (4:1). Normal tissue complication probability can be further improved using modern involved site radiation therapy techniques.

Technical Note: Characterization of the new microSilicon diode detector.

PURPOSE: Dosimetric properties of the new microSilicon diode detector (60023) have been studied with focus on application in small-field dosimetry. The influences of the dimensions of the sensitive volume and the density of the epoxy layer surrounding the silicon chip of microSilicon have been quantified and compared to its predecessor (Diode E 60017) and the microDiamond (60019, all PTW-Freiburg, Germany). METHODS: Dose linearity has been studied in the range from 0.01 to 8.55 Gy and dose-per-pulse dependence from 0.13 to 0.86 mGy/pulse. The effective point of measurement (EPOM) was determined by comparing measured percentage depth dose curves with a reference curve (Roos chamber). Output ratios were measured for nominal field sizes from 0.5 × 0.5  cm2 to 4 × 4 cm2 . The corresponding small-field output correction factors, k, were derived with a plastic scintillation detector as reference. The lateral dose-response function, K(x), was determined using a slit beam geometry. RESULTS: MicroSilicon shows linear dose response (R2  = 1.000) in both low and high dose range up to 8.55 Gy with deviations of only up to 1% within the dose-per-pulse values investigated. The EPOM was found to lie (0.7 ± 0.2) mm below the front detector's surface. The derived k for microSilicon (0.960 at seff  = 0.55 cm) is similar to that of microDiamond (0.956), while Diode E requires larger corrections (0.929). This improved behavior of microSilicon in small-fields is reflected in the slightly wider K(x) compared to Diode E. Furthermore, the amplitude of the negative values in K(x) at the borders of the sensitive volume has been reduced. CONCLUSIONS: Compared to its predecessor, microSilicon shows improved dosimetric behavior with higher sensitivity and smaller dose-per-pulse dependence. Profile measurements demonstrated that microSilicon causes less perturbation in off-axis measurements. It is especially suitable for the applications in small-field output factors and profile measurements.

Favorable radiation field decrease in gastric marginal zone lymphoma : Experience of the German Study Group on Gastrointestinal Lymphoma (DSGL).

PURPOSE: Long-term impact of stage-adapted field reduction in a large cohort of gastric marginal zone lymphoma (gMZL) patients treated conservatively with curative radiation therapy (RT). PATIENTS AND METHODS: Prospective analysis of paper records of 290 patients with stage IE-IIE gMZL, treated in 78 radiotherapeutic institutions in Germany from 1992-2013. Stage-adapted radiation fields decreased from extended field (EF) to involved field (IF) over the course of three consecutive prospective trials of the German Study Group on Gastrointestinal Lymphoma (DSGL). Treatment results were compared between the three cohorts. RESULTS: Overall collective with median age of 60 years, slight male predominance (m:f = 1.1:1) and ratio of disease stage I:stage II = 2.1:1. Median follow-up 6.4 years in total: 13.0 years in the first gastrointestinal study (GIT 1992), 8.2 years in the second (GIT 1996) and 4.7 years in the third study (DSGL 01/2003). Stage-adapted radiation field decrease together with further technological development led to reduced relative frequencies of acute/chronic adverse effects and until now was accompanied by lower disease recurrence. The third study design with smallest field size (IF in stage I, locoregional EF in stage II) achieved the best survival outcome at the 5­year follow-up (overall survival 92.7%, event-free survival 89.5% and lymphoma-specific survival 100.0%). Disease relapse observed in 10 patients. Cumulative incidence of disease-specific death was 1.7% of the followed patients. Primary disease stage associated with lymphoma-specific survival. CONCLUSION: Stage-adapted reduction towards IF in gMZL resulted in favorable adverse effects, local control and survival rates. These results support further decreases in modern RT of gMZL.

Brain metastases in ALK-positive NSCLC - time to adjust current treatment algorithms.

The progress in molecular biology has revolutionized systemic treatment of advanced non-small-cell lung cancer (NSCLC) from conventional chemotherapy to a treatment stratified by histology and genetic aberrations. Tumors harboring a translocation of the anaplastic-lymphoma-kinase (ALK) gene constitute a distinct genetic and clinico-pathologic NSCLC subtype with patients with ALK-positive disease being at a higher risk for developing brain metastases. Due to the introduction of effective targeted therapy with ALK-inhibitors, today, patients with advanced ALK-positive NSCLC achieve high overall response rates and remain progression-free for long time intervals. Moreover, ALK-inhibitors seem to exhibit efficacy in the treatment of brain metastases. In the light of this, it needs to be discussed how treatment algorithms for managing patients with brain metastases should be modified. By integrating systemic ALK-inhibitor therapy, radiotherapy, in particular whole brain radiotherapy might be postponed deferring potential long-term impairment by neurocognitive deficits to a later time point in the course of the disease. An early treatment of asymptomatic brain metastases might offer patients a longer time without impairment of cerebral symptoms or radiotherapeutic interventions. Based on an updated extensive review of the literature this article provides an overview on the epidemiology and the treatment of patients' brain metastases. It describes the specifics of ALK-positive disease and proposes an algorithm for the treatment of patients with advanced ALK-positive NSCLC and brain metastases.

Reference conditions for ion-chamber based HDR brachytherapy dosimetry and for the calibration of high-resolution solid detectors.

The aim of this study has been to develop a two-step method of in-phantom dosimetry around a brachytherapy 192Ir photon source. The first step is to measure the absorbed dose rate to water with a calibrated ionization chamber under reference conditions, the second to cross-calibrate, under these conditions, small solid-state detectors such as silicon diodes, synthetic diamond or scintillation detectors suited for spatially resolved dose rate measurements at other, particularly at smaller source axis distances in the water phantom. This two-step approach constitutes a method for in-phantom dosimetry in brachytherapy, analogous to the "small calibration field" commonly used in teletherapy to provide the reference conditions for the cross-calibration of high-resolution detectors. Under reference conditions, all known corrections for radiation quality, volume averaging and position of the chamber's effective point of measurement (EPOM) have to be applied. The study is therefore particularly devoted to (1) the experimental determination of the position of the source axis, (2) a general formulation for the volume averaging correction factor of small ionization chambers and (3) the experimental determination of the EPOM positions for the PinPoint chamber 31014 and the 3D-PinPoint chamber PTW 31022 (both PTW Freiburg, Germany). The distance of 30mm from the source axis was chosen as the reference condition for cross calibrations. This concept is realized with the instrumentation available in a hospital, a scanning-type water phantom, a software package for small field dosimetry and detectors typically used in clinical routine dosimetry. The present development of a method of in-phantom dose measurement under 192Ir brachytherapy conditions was performed in recognition of the primary role of dose calculations, e.g. according to the AAPM TG43 recommendations. But in addition, the methodology tested here is paving a practicable way for the experimental check of typical dose values under clinical conditions, should the need arise.

The dose response functions of ionization chambers in photon dosimetry - Gaussian or non-Gaussian?

This study is concerned with the spatial resolution of air-filled ionization chambers in photon-beam dosimetry, i.e. with their dose response functions. These act as convolution kernels K(x,y), transforming true dose profiles D(x,y) into the measured signal profiles M(x,y). One-dimensional dose response functions have been experimentally determined for nine types of cylindrical ionization chambers both in their lateral and longitudinal directions, as well as across two plane-parallel chambers and for the single chambers of two 2D arrays. All these 1D dose response functions are closely described by Gaussian functions. The associated energy-dependent values of the standard deviations σ have been measured for 6 and 15 MV photons with an uncertainty of 0.02mm. At depths beyond secondary electron fluence build-up, there was no detectable depth dependence of the σ values. The general occurrence of Gaussian dose response functions, their extension beyond the geometrical boundaries of the chambers, and the energy dependence of their standard deviations can be understood by considering the underlying system of convolutions, which is the origin of the influences of secondary electron transport. Monte-Carlo simulations of the convolution kernels for a cylindrical, a square, and a flat ionization chamber and their Fourier analysis have been employed to show that the Gaussian convolution kernels are approximations to the true dose response functions, valid in the clinically relevant domain of the spatial frequency. This paper is conceived as the starting point for the deconvolution methods to be described in a further publication.

Internal scatter, the unavoidable major component of the peripheral dose in photon-beam radiotherapy.

In clinical photon beams, the dose outside the geometrical field limits is produced by photons originating from (i) head leakage, (ii) scattering at the beam collimators and the flattening filter (head scatter) and (iii) scattering from the directly irradiated region of the patient or phantom (internal scatter). While the first two components can be modified, e.g. by reinforcement of shielding components or by re-modeling the filter system, internal scatter remains an unavoidable contributor to the peripheral dose. Its relative magnitude compared to the other components, its numerical variation with beam energy, field size and off-axis distance as well as its spectral distribution are evaluated in this study. We applied a detailed Monte Carlo (MC) model of our 6/15 MV Siemens Primus linear accelerator beam head, provided with ideal head leakage shielding conditions (multi-leaf collimator without gaps) to assess the head scatter contribution. Experimental values obtained under real shielding conditions were used to evaluate the head leakage contribution. It was found that the MC-computed internal scatter doses agree with the results of our previous measurements, that internal scatter is the major contributor to the peripheral dose in the near periphery while head leakage prevails in the far periphery, and that the lateral decline of the internal scatter dose can be represented by the sum of two exponentials, with an asymptotic tenth value of 18 to 19 cm. Internal scatter peripheral doses from various elementary beams are additive, so that their sum increases approximately in proportion with field size. The ratio between normalized internal scatter doses at 6 and 15 MV is approximately 2:1. The energy fluence spectra of the internal scatter component at all points of interest outside the field have peaks near 500 keV. The fact that the energy-shifted internal scatter constitutes the major contributor to the dose in the near periphery has a general bearing for dosimetry, i.e. for energy-dependent detector responses and dose conversion factors, for the relative biological effectiveness and for second primary malignancy risk estimates in the peripheral region.

A direction-selective flattening filter for clinical photon beams. Monte Carlo evaluation of a new concept.

A new concept for the design of flattening filters applied in the generation of 6 and 15 MV photon beams by clinical linear accelerators is evaluated by Monte Carlo simulation. The beam head of the Siemens Primus accelerator has been taken as the starting point for the study of the conceived beam head modifications. The direction-selective filter (DSF) system developed in this work is midway between the classical flattening filter (FF) by which homogeneous transversal dose profiles have been established, and the flattening filter-free (FFF) design, by which advantages such as increased dose rate and reduced production of leakage photons and photoneutrons per Gy in the irradiated region have been achieved, whereas dose profile flatness was abandoned. The DSF concept is based on the selective attenuation of bremsstrahlung photons depending on their direction of emission from the bremsstrahlung target, accomplished by means of newly designed small conical filters arranged close to the target. This results in the capture of large-angle scattered Compton photons from the filter in the primary collimator. Beam flatness has been obtained up to any field cross section which does not exceed a circle of 15 cm diameter at 100 cm focal distance, such as 10 × 10 cm(2), 4 × 14.5 cm(2) or less. This flatness offers simplicity of dosimetric verifications, online controls and plausibility estimates of the dose to the target volume. The concept can be utilized when the application of small- and medium-sized homogeneous fields is sufficient, e.g. in the treatment of prostate, brain, salivary gland, larynx and pharynx as well as pediatric tumors and for cranial or extracranial stereotactic treatments. Significant dose rate enhancement has been achieved compared with the FF system, with enhancement factors 1.67 (DSF) and 2.08 (FFF) for 6 MV, and 2.54 (DSF) and 3.96 (FFF) for 15 MV. Shortening the delivery time per fraction matters with regard to workflow in a radiotherapy department, patient comfort, reduction of errors due to patient movement and a slight, probably just noticable improvement of the treatment outcome due to radiobiological reasons. In comparison with the FF system, the number of head leakage photons per Gy in the irradiated region has been reduced at 15 MV by factors 1/2.54 (DSF) and 1/3.96 (FFF), and the source strength of photoneutrons was reduced by factors 1/2.81 (DSF) and 1/3.49 (FFF).

Low-energy photons in high-energy photon fields--Monte Carlo generated spectra and a new descriptive parameter.

The varying low-energy contribution to the photon spectra at points within and around radiotherapy photon fields is associated with variations in the responses of non-water equivalent dosimeters and in the water-to-material dose conversion factors for tissues such as the red bone marrow. In addition, the presence of low-energy photons in the photon spectrum enhances the RBE in general and in particular for the induction of second malignancies. The present study discusses the general rules valid for the low-energy spectral component of radiotherapeutic photon beams at points within and in the periphery of the treatment field, taking as an example the Siemens Primus linear accelerator at 6 MV and 15 MV. The photon spectra at these points and their typical variations due to the target system, attenuation, single and multiple Compton scattering, are described by the Monte Carlo method, using the code BEAMnrc/EGSnrc. A survey of the role of low energy photons in the spectra within and around radiotherapy fields is presented. In addition to the spectra, some data compression has proven useful to support the overview of the behaviour of the low-energy component. A characteristic indicator of the presence of low-energy photons is the dose fraction attributable to photons with energies not exceeding 200 keV, termed P(D)(200 keV). Its values are calculated for different depths and lateral positions within a water phantom. For a pencil beam of 6 or 15 MV primary photons in water, the radial distribution of P(D)(200 keV) is bellshaped, with a wide-ranging exponential tail of half value 6 to 7 cm. The P(D)(200 keV) value obtained on the central axis of a photon field shows an approximately proportional increase with field size. Out-of-field P(D)(200 keV) values are up to an order of magnitude higher than on the central axis for the same irradiation depth. The 2D pattern of P(D)(200 keV) for a radiotherapy field visualizes the regions, e.g. at the field margin, where changes of detector responses and dose conversion factors, as well as increases of the RBE have to be anticipated. Parameter P(D)(200 keV) can also be used as a guidance supporting the selection of a calibration geometry suitable for radiation dosimeters to be used in small radiation fields.

Iterative 2D deconvolution of portal imaging radiographs.

Portal imaging has become an integral part of modern radiotherapy techniques such as IMRT and IGRT. It serves to verify the accuracy of day-to-day patient positioning, a prerequisite for treatment success. However, image blurring attributable to different physical and geometrical effects, analysed in this work, impairs the image quality of the portal images, and anatomical structures cannot always be clearly outlined. A 2D iterative deconvolution method was developed to reduce this image blurring. The affiliated data basis was generated by the separate measurement of the components contributing to image blurring. Secondary electron transport and pixel size within the EPID, as well as geometrical penumbra due to the finite photon source size were found to be the major contributors, whereas photon scattering in the patient is less important. The underlying line-spread kernels of these components were shown to be Lorentz functions. This implies that each of these convolution kernels and also their combination can be characterized by a single characteristic, the width parameter λ of the Lorentz function. The overall resulting λ values were 0.5mm for 6 MV and 0.65 mm for 15 MV. Portal images were deconvolved using the point-spread function derived from the Lorentz function together with the experimentally determined λ values. The improvement of the portal images was quantified in terms of the modulation transfer function of a bar pattern. The resulting clinical images show a clear enhancement of sharpness and contrast.

Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma.

BACKGROUND: Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkin's lymphoma with a favorable prognosis remains unclear. We therefore conducted a multicenter, randomized trial comparing four treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels. METHODS: We randomly assigned 1370 patients with newly diagnosed early-stage Hodgkin's lymphoma with a favorable prognosis to one of four treatment groups: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of radiation therapy (group 1), four cycles of ABVD followed by 20 Gy of radiation therapy (group 2), two cycles of ABVD followed by 30 Gy of radiation therapy (group 3), or two cycles of ABVD followed by 20 Gy of radiation therapy (group 4). The primary end point was freedom from treatment failure; secondary end points included efficacy and toxicity of treatment. RESULTS: The two chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P=0.39) or overall survival (P=0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% confidence interval [CI], 90.5 to 94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the two-cycle regimen. When the effects of 20-Gy and 30-Gy doses of radiation therapy were compared, there were also no significant differences in freedom from treatment failure (P=1.00) or overall survival (P=0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received four cycles of ABVD and 30 Gy of radiation therapy (group 1). CONCLUSIONS: In patients with early-stage Hodgkin's lymphoma and a favorable prognosis, treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy. Long-term effects of these treatments have not yet been fully assessed. (Funded by the Deutsche Krebshilfe and the Swiss Federal Government; ClinicalTrials.gov number, NCT00265018.)

Experimental study on photon-beam peripheral doses, their components and some possibilities for their reduction.

The component analysis of the peripheral doses produced at typical accelerators such as the Siemens Primus 6/15 is regarded as an approach enabling technical strategies towards the reduction of second malignancies associated with photon beam radiotherapy. Suitable phantom and detector arrangements have been applied to show that the unavoidable peripheral dose contribution due to photon scattering from the directly irradiated part of the body or phantom does not constitute the entirety of the peripheral doses. Rather, there are peripheral dose contributions due to beam head leakage and to extrafocal radiation which can be regarded as partly avoidable. Simple methods of reducing beam head leakage from the Siemens Primus 6/15 linac are, for the crossplane direction, to install a pair of adjustable shielding blocks in the accessory holder and, for the inplane direction, to close all out-of-field leaf pairs of the multileaf collimator via the treatment planning system software. The relative efficiency of these shielding measures is largest in the case of small unavoidable dose contributions, i.e. for small fields and small depths. Methods of avoiding doses coming from extrafocal radiation are also envisaged for future research.

Clinical performance of a transmission detector array for the permanent supervision of IMRT deliveries.

BACKGROUND AND PURPOSE: Clinical evaluation of a novel dosimetric accessory serving the permanent supervision of MLC function. MATERIALS AND METHODS: The DAVID system (PTW-Freiburg, Germany) is a transparent, multi-wire transmission ionization chamber, placed in the accessory holder of the treatment head. Since each of the 37 individual wires is positioned exactly below the associated leaf pair of the MLC, its signal records the opening of this leaf pair during patient treatment. RESULTS: The DAVID system closes a gap in the quality assurance program, permitting the permanent in-vivo verification of IMRT plans. During dosimetric plan verification with the 2D-ARRAY (PTW-Freiburg, Germany), reference values of the 37 DAVID signals are collected, with which the DAVID readings recorded during daily patient treatment are compared. This comparison is visually displayed in the control room, and warning and alarm levels of any discrepancies can be defined. The properties of the DAVID system as a transmission device, its sensitivity to beam delivery and leaflet errors as well as its stability have been analyzed for clinically relevant examples. In a recent version, the DAVID system has been equipped with 80 wires. CONCLUSIONS: The DAVID system permits the on-line detection of clinically relevant MLC discrepancies in IMRT deliveries.