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).

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.

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.

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.

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.)

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.

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.

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.

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.

Fourier deconvolution reveals the role of the Lorentz function as the convolution kernel of narrow photon beams.

The two-dimensional lateral dose profiles D(x, y) of narrow photon beams, typically used for beamlet-based IMRT, stereotactic radiosurgery and tomotherapy, can be regarded as resulting from the convolution of a two-dimensional rectangular function R(x, y), which represents the photon fluence profile within the field borders, with a rotation-symmetric convolution kernel K(r). This kernel accounts not only for the lateral transport of secondary electrons and small-angle scattered photons in the absorber, but also for the 'geometrical spread' of each pencil beam due to the phase-space distribution of the photon source. The present investigation of the convolution kernel was based on an experimental study of the associated line-spread function K(x). Systematic cross-plane scans of rectangular and quadratic fields of variable side lengths were made by utilizing the linear current versus dose rate relationship and small energy dependence of the unshielded Si diode PTW 60012 as well as its narrow spatial resolution function. By application of the Fourier convolution theorem, it was observed that the values of the Fourier transform of K(x) could be closely fitted by an exponential function exp(-2pilambdanu(x)) of the spatial frequency nu(x). Thereby, the line-spread function K(x) was identified as the Lorentz function K(x) = (lambda/pi)[1/(x(2) + lambda(2))], a single-parameter, bell-shaped but non-Gaussian function with a narrow core, wide curve tail, full half-width 2lambda and convenient convolution properties. The variation of the 'kernel width parameter' lambda with the photon energy, field size and thickness of a water-equivalent absorber was systematically studied. The convolution of a rectangular fluence profile with K(x) in the local space results in a simple equation accurately reproducing the measured lateral dose profiles. The underlying 2D convolution kernel (point-spread function) was identified as K(r) = (lambda/2pi)[1/(r(2) + lambda(2))](3/2), fitting experimental results as well. These results are discussed in terms of their use for narrow-beam treatment planning.

Mapping radiation quality inside photon-irradiated absorbers by means of a twin-chamber method.

In photon-beam radiotherapy, the absorbed dose in an irradiated object contains a contribution by energy-degraded photons originating from Compton scatter processes at parts of the treatment head and within the absorber itself. These low-energy spectral components may lead to changes in the response of non-ideally water-equivalent radiation detectors, such as Si diodes and radiographic films, in the water/tissue dose conversion factors and in the relative biological effectiveness (RBE). As a simple means of accounting for these changes in spectral quality, the Monte Carlo calculated fraction of the kerma or absorbed dose contributed by scattered photons with energies not exceeding a certain cut-off value has previously been proposed as a useful parameter. In this paper, we present an equivalent experimental approach, providing a means for the spatial mapping of radiation quality. Its applicability will be demonstrated for the case of (60)Co and 6 MV photons. A twin-chamber combination of a Farmer type ionization chamber, equipped with a graphited PMMA outer electrode, and a chamber of the same design, but with an outer electrode made from copper, has been developed. The measured quantity is the signal ratio (SR) of the copper wall and graphited wall chambers. A correlation between the SR and the fraction of the air kerma respectively of the absorbed dose to water, contributed by photons with energies not exceeding 200 keV, has been established at a Theratron 780-C (60)Co teletherapy unit and at a Siemens Primus 6 MV linear accelerator. We also describe a two-dimensional version of the twin-chamber method using the PTW 2D-Array 256. Typical trends of parameter SR with depth and off-axis distance in water-equivalent phantoms have been observed. Thereby, a simple experimental method for the space-resolved assessment of the dose fraction attributable to low-energy Compton scattered photons can be presented as an innovative instrument of describing radiation quality in radiotherapy.

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.

Dosimetric characteristics of an unshielded p-type Si diode: linearity, photon energy dependence and spatial resolution.

The unshielded Si diode PTW 60012, used for accurate measurements of the transversal dose profiles of narrow photon beams, has been investigated with regard to its linearity, photon energy dependence and spatial resolution. The diode shows a slight supralinearity, i.e., increase of the response with pulse dose, by 3% over the pulse dose range 0.1 to 0.8 mGy. In p-type silicon, supralinearity results from the increased chance for radiation-induced electrons to escape recombination when the pulse dose increases. Over the energy range from 6 to 15 MV, the response decreases by about 4%. This small variation of the response results from partial compensation between the influences of the secondary electron energy on the mass stopping power ratio silicon/water and on electron backscattering from the silicon chip. The lateral response function of the examined diode has a full half width of 1.3 mm. Dose profiles of 5 mm half-width can still be recorded with negligible error.

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 effect of a carbon-fiber couch on the depth-dose curves and transmission properties for megavoltage photon beams.

PURPOSE: To investigate the attenuation of a carbon-fiber tabletop and a combiboard, alongside with the depth-dose profile in a solid-water phantom. MATERIAL AND METHODS: Depth-dose measurements were performed with a Roos chamber for 6- and 10-MV beams for a typical field size (15 cm x 15 cm, SSD [source-surface distance] 100 cm). A rigid-stem ionization chamber was used to measure transmission factors. RESULTS: Transmission factors varied between 93.6% and 97.3% for the 6-MV beam, and 95.1% and 97.7% for the 10-MV photon beam. The lowest transmission factors were observed for the oblique gantry angle of 150 degrees with the table-combiboard combination. The surface dose normalized to a depth of 5 cm increased from 59.4% (without table, 0 degrees gantry), to 108.6% (tabletop present, 180 degrees gantry), and further to 120% (table-combiboard combination) for 6-MV photon beam. For 10 MV, the increase was from 39.6% (without table), to 88.9% (with table), and to 105.6% (table-combiboard combination). For the 150 degrees angle (tablecombiboard combination), the dose increased from 59.4% to 120% (6 MV) and from 39% to 108.1% (10 MV). CONCLUSION: Transmission factors for tabletops and accessories directly interfering with the treatment beam should be measured and implemented into the treatment-planning process. The increased surface dose to the skin should be considered.

Spatial resolution of 2D ionization chamber arrays for IMRT dose verification: single-detector size and sampling step width.

The spatial resolution of 2D detector arrays equipped with ionization chambers or diodes, used for the dose verification of IMRT treatment plans, is limited by the size of the single detector and the centre-to-centre distance between the detectors. Optimization criteria with regard to these parameters have been developed by combining concepts of dosimetry and pattern analysis. The 2D-ARRAY Type 10024 (PTW-Freiburg, Germany), single-chamber cross section 5 x 5 mm(2), centre-to-centre distance between chambers in each row and column 10 mm, served as an example. Additional frames of given dose distributions can be taken by shifting the whole array parallel or perpendicular to the MLC leaves by, e.g., 5 mm. The size of the single detector is characterized by its lateral response function, a trapezoid with 5 mm top width and 9 mm base width. Therefore, values measured with the 2D array are regarded as sample values from the convolution product of the accelerator generated dose distribution and this lateral response function. Consequently, the dose verification, e.g., by means of the gamma index, is performed by comparing the measured values of the 2D array with the values of the convolution product of the treatment planning system (TPS) calculated dose distribution and the single-detector lateral response function. Sufficiently small misalignments of the measured dose distributions in comparison with the calculated ones can be detected since the lateral response function is symmetric with respect to the centre of the chamber, and the change of dose gradients due to the convolution is sufficiently small. The sampling step width of the 2D array should provide a set of sample values representative of the sampled distribution, which is achieved if the highest spatial frequency contained in this function does not exceed the 'Nyquist frequency', one half of the sampling frequency. Since the convolution products of IMRT-typical dose distributions and the single-detector lateral response function have no or very small frequency contributions beyond 0.1 mm(-1), the mathematical approach introduced by Nyquist and Shannon shows that the sampling frequency of 0.2 mm(-1) is appropriate. Overall it is shown that the spatial resolution of the 2D-ARRAY Type 10024 is appropriate for the dose verification of IMRT plans. The insights obtained are also applied in the discussion of other available two-dimensional detector arrays.

Two-dimensional ionization chamber arrays for IMRT plan verification.

In this paper we describe a concept for dosimetric treatment plan verification using two-dimensional ionization chamber arrays. Two different versions of the 2D-ARRAY (PTW-Freiburg, Germany) will be presented, a matrix of 16 x 16 chambers (chamber cross section 8 mm x 8 mm; the distance between chamber centers, 16 mm) and a matrix of 27 x 27 chambers (chamber cross section 5 mm x 5 mm; the distance between chamber centers is 10 mm). The two-dimensional response function of a single chamber is experimentally determined by scanning it with a slit beam. For dosimetric plan verification, the expected two-dimensional distribution of the array signals is calculated via convolution of the planned dose distribution, obtained from the treatment planning system, with the two-dimensional response function of a single chamber. By comparing the measured two-dimensional distribution of the array signals with the expected one, a distribution of deviations is obtained that can be subjected to verification criteria, such as the gamma index criterion. As an example, this verification method is discussed for one sequence of an IMRT plan. The error detection capability is demonstrated in a case study. Both versions of two-dimensional ionization chamber arrays, together with the developed treatment plan verification strategy, have been found to provide a suitable and easy-to-handle quality assurance instrument for IMRT.

The dose-area product, a new parameter for the dosimetry of narrow photon beams.

In the dosimetry of narrow photon fields with side lengths of the order of 1 cm, the traditional parametrisation via the absolute dose on the beam axis and the relative lateral dose distribution has to deal with the difficulty to find sufficiently small detectors and to adjust them accurately on the narrow-beam axis. This can be avoided by reconsidering the parametrisation, using as normalization factor the surface integral of the dose in the plane perpendicular to the beam axis, abbreviated as the "dose-area product" (DAP). We investigated and confirmed the ability of a large-area parallel-plate ionisation chamber, with a sensitive volume shaped as a flat cylinder of 81.6 mm diameter and 2 mm thickness, to perform the integration over the full lateral dose profile of narrow photon beams with side lengths up to 5 cm. The lateral adjustment of this large-area detector relative to a narrow photon beam is not critical. The large-area ionisation chamber was calibrated in terms of the DAP by reference to a 0.3 cm3 ionisation chamber. A field-size dependent "modified output factor" was defined as the ratio of the DAP measured at 5 cm phantom depth for 100 cm SSD, and the monitor reading. A prominent phenomenon of narrow photon fields is the field-size and source-distance independence of the relative axial profile of the DAP as function of the thickness of a pre-absorber or of the depth in a phantom. For narrow-beam treatment planning in IMRT, the DAP is combined with the energy- and field size-dependent relative lateral dose distribution which is represented, for example, by a Gaussian convolution kernel. Another useful feature of the DAP is the possibility of its direct control during patient irradiation by means of an on-line monitor with spatial resolution, arranged in the accessory holder.

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.