Comparison of adverse effects of proton and X-ray chemoradiotherapy for esophageal cancer using an adaptive dose–volume histogram analysis

摘要

Consecutive patients who underwent definitive CCRT utilizing X-rays (n = 19) or protons (n = 25) between 2009 and 2011 were enrolled in the study. Patient characteristics are shown in Table?id="xref-table-wrap-1-1" class="xref-table" href="#T1">1. The staging evaluation of each patient was done with upper GI series, CT scans, esophagogastroduodenoscopy (EGD), and positron emission tomography (PET)/CT scans. Endoscopic ultrasound was also used if the depth of invasion was unclear. The X-ray group included more advanced stage cases than the proton group. The median dose of radiation was 60 Gy in both groups. Most tumor sites were in the thoracic esophagus, and all tumors were squamous cell carcinoma. The X-ray therapy system consisted of a linear accelerator (Clinac iX, Varian Medical Systems, Palo Alto, CA, USA) equipped with a 5–10 mm multileaf collimator (MLC), a rotational treatment couch, and a treatment-planning system (Xio ver. 4.8, Elekta, Stockholm, Sweden). The PBT system consisted of a 250-MeV synchrotron equipped with an isocentric rotational gantry, a 15 × 15 cm passive scattering port with a 5-mm MLC, a rotational treatment couch, a treatment-planning system (Hitachi 3D Treatment Planning System ver. 2.0, Tokyo, Japan), a treatment-planning CT scanner, and an X-ray simulator without any system modification. The gross tumor volume (GTV) was defined as all diseased tissue seen on CT images and other diagnostic imaging. To confirm the tumor location on CT, two to three metal markers were placed in the normal esophageal wall at the tumor edges during endoscopy prior to the initial treatment planning. The initial clinical target volume (CTV1) included all areas of potential disease spread, such as the esophageal wall and mediastinal lymph nodes. For cancer of the thoracic esophagus (n = 34), the whole thoracic esophagus was included in CTV1 in most patients. The second CTV (CTV2) included the GTV with 20- to 25-mm margins in the cranial and caudal directions of the tumor and 10-mm margins in other directions. The lung contour was defined as the thoracic cavity excluding the bilateral main bronchus. The heart contour was defined as described by Feng et al. [id="xref-ref-10-1" class="xref-bibr" href="#ref-10">10]. In brief, superiorly the heart starts just inferior to the left pulmonary artery. For simplification, a round structure including the great vessels was contoured. Inferiorly, the heart blends with the diaphragm. The superior vena cava was included for simplification and consistency. Experimental PBT plans were made for patients who received X-ray therapy, using the actual planning CT. Alternatively, X-ray plans were made using the planning CT for patients who received PBT. Original CTVs and PTVs used in the actual treatment were maintained in the experimental plans. To evaluate cumulative dose and volume from different planning CTs accurately, all planning CTs and doses linked to CT images were merged using deformation techniques [id="xref-ref-12-1" class="xref-bibr" href="#ref-12">12–id="xref-ref-14-1" class="xref-bibr" href="#ref-14">14]. Data conversion and translation between systems, CT–CT deformation, and dose volume studies were performed using MIM Maestro ver. 6 (Cleveland, OH, USA). The concept of dose delivery to the target and normal tissue was exactly the same in X-ray and proton planning. Coverage of PTVs was provided by 95% of prescribed doses, and the maximum spinal dose was restricted up to 44 Gy. After summation of each X-ray and proton treatment plan, dosimetric factors such as percentage volume of whole lung, heart receiving more than a certain dose (Vx), and the mean lung dose (MLD) were calculated using DVH analysis. The experimental plans were compared with the actual treatment plans. Typical dose distributions and the total DVH for X-rays and protons are shown in Fig.?id="xref-fig-1-1" class="xref-fig" href="#F1">1. NTCP was calculated using the Lyman–Kutcher–Burman (LKB) model following Emami et al. and Burman et al. [id="xref-ref-15-1" class="xref-bibr" href="#ref-15">15–id="xref-ref-17-1" class="xref-bibr" href="#ref-17">17]: class="disp-formula" id="disp-formula-1"> class="mathjax mml-math">mml:math display="block"mml:mtextNTCP/mml:mtextmml:mo=/mml:momml:mstylemml:mrowmml:mfracmml:mn1/mml:mnmml:mrowmml:msqrtmml:mn2/mml:mnmml:mrowmml:miπ/mml:mi/mml:mrow/mml:msqrt/mml:mrow/mml:mfrac/mml:mrowmml:msubsupmml:mo∫/mml:momml:mrowmml:mo?/mml:momml:mi mathvariant="normal"∞/mml:mi/mml:mrowmml:mit/mml:mi/mml:msubsupmml:mrowmml:msupmml:mie/m