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.

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.

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.

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.

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.

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.

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.

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.