Intrafractional Tumor Motion: Lung and Liver Hiroki Shirato, Yvette Seppenwoolde, Kei Kitamura, Rikiya Onimura, and Shinichi Shimizu Three-dimensional (3D) dose distribution has been im- proved by 3D conformation and intensity modulation in external radiotherapy. Interfractional uncertainty has been reduced by image-guided setup techniques. Re- duction of ambiguity because of intrafractional target motion is the next step forward. Respiratory organ mo- tion is known to be the largest intrafractional organ motion. Radiotherapy techniques controlling, gating, or tracking respiratory motion are under investigation to use smaller safety margins and higher doses for mov- ing tumors. However, data on intrafractional tumor mo- tion are sparse. We developed a fluoroscopic real-time tracking system and implantation techniques of fiducial markers for moving organs and have been accumulat- ing knowledge about internal tumor motion. We also found the importance of 4-dimensional treatment plan- ning to account for tumor motion in precision radio- therapy. This article reviews the current basic knowl- edge on respiratory physiology and summarizes the accumulating knowledge on internal motion of lung and liver tumors. �� 2004 Elsevier Inc. All rights reserved. Tvoluntaryrespiratory he main muscles are under both and involuntary (automatic) con- trol.1-3 Voluntary control arises from the motor and premotor cortex and passes along the corti- cospinal tract.4 Involuntary control is mediated by both rhythmic and nonrhythmic systems lo- cated in the brainstem as well as by intrasegmen- tal and intersegmental reflexes in the spinal cord (Fig 1). At rest, a healthy person breathes 12 to 15 times per minute. Possible pacemaker neurons were found in the brainstem at the pre-Botzinger complex in the ventrolateral medulla, which is supposed to act as the central respiratory pattern generator of inspiratory rhythm.5,6 Although the role of pre-Botzinger complex is still controver- sial, the central respiratory pattern generator is widely accepted to interact with the large neural network via inhibitory synaptic connections for the evolution of the respiratory rhythm.7 Two major pathways from the motor cortex are known to be involved in voluntary control of breathing: (1) the direct path, which affects mo- tor neurons controlling diaphragm movements and lung inflation, and (2) a path that leads to the respiratory center in the brainstem and af- fects the respiratory motor pattern via the mod- ulation of the respiratory network perfor- mance.3,6,8-10 There have been numerous efforts to build a computational simulation model of respira- tion.9-12 However, these models have not been able to predict actual respiratory patterns in hu- man beings. More careful analysis of available data and additional experimental studies are re- quired to build a realistic and detailed model of interactions between automatic and voluntary/ behavioral control of breathing. Physiologic Motion of Respiratory Muscles Inspiration primarily requires contraction of the diaphragm and the external intercostal muscles located between the ribs (Fig 2). Contraction of the diaphragm causes it to move downward and increases the vertical dimension of the thoracic cavity, resulting in pulmonary expansion. Con- traction of the diaphragm produces a 75% change in intra-thoracic volume during resting inspira- tion.13 The external intercostals contract to ele- vate the lower ribs and push the sternum out- ward, increasing the anteroposterior dimension of the thoracic cavity.14,15 Expiration is normally passive because of the elastic recoil. There is hysteresis in the relationship between pressure and lung volume lung volume is different be- tween inspiration and expiration at the same pressure.16 In voluntary active expiration, the in- ternal intercostal muscles contract and pull the rib cage downward, and the abdominal muscles assist by pulling the rib cage down and increasing From the Department of Radiology, Hokkaido University School of Medicine, Sapporo, Japan and Department of Radiotherapy, The Netherlands Cancer Institute/Antonivan Leeuwenhoek Hospital, Am- sterdam, The Netherlands. Supported in part by the grant from Japanese Ministry of Educa- tion, Culture, Sports, Science and Technology. Address reprint requests to Hiroki Shirato, MD, Section of Radi- ation Oncology, Department of Radiology, Hokkaido University School of Medicine, North-15 West-7, Kita-ku, Sapporo, Japan 006-8638. �� 2004 Elsevier Inc. All rights reserved. 1053-4296/04/1401-0003$30.00/0 doi:10.1053/j.semradonc.2003.10.008 10 Seminars in Radiation Oncology, Vol 14, No 1 (January), 2004: pp 10-18

abdominal pressure which forces the diaphragm up. Attempts to perform tidal inspiration with the diaphragm alone markedly reduces rib cage expansion and the upper rib cage moves paradox- ically.14 In the same individual, the tidal volume and frequency can change with the biochemical con- dition (eg, CO2 concentration, exercise), body position (standing, supine, or prone),17 abdomi- nal contents (food intake, time elapsed since eat- ing), and emotional condition (anxiety). Respira- tory motion of the internal organs depends on the body position, the position of the arms, and the type of immobilization devices used.18 Pathological Motion of Respiratory Muscles In the normal condition, total resistance of the lung is so small that the respiratory muscles need to generate low magnitude pressure or force to overcome the flow resistance of the lung. In chronic obstructive lung diseases, the lung is hy- perinflated to overcome increased flow resis- tance, so that the diaphragm operates in a posi- tion disadvantageous to proper function, and there is a larger demand on the intercostal mus- cles to assist in respiration. Patients with inter- stitial fibrosis suffer from shortness of breath and frequent breathing with small amplitudes be- cause of decreased elasticity of the lungs. The motion of the respiration muscles is also altered by pleural adhesion after pleuritis, thoracic sur- gery,19 a history of thoracic irradiation, diabetes mellitus,20 and hypothyroidism.21 The resistance of the airflow is affected by asthma, any inflam- mation of lung tissue, medication including ace- tylcholine, bronchodilators, and corticosteroids,22 and other conditions such as chest pain, malnu- trition, disuse atrophy, and muscle fatigue.23 Ra- diotherapy itself, with or without chemotherapy for lung cancer, may alter the respiratory motion by an acute inflammatory effect on bronchial mucosa and lung parenchyma and malnutrition because of esophagitis during the course of radi- ation therapy. Motion of Lung Tumors We studied lung tumor movement during tidal breathing in the supine position using a real-time tumor-tracking (RTRT) system.24,25 Three-di- mensional (3D) coordinates of a 1.5- to 2.0-mm gold marker inserted into or near the lung tumor mass were recorded 30 times a second for more than 10 continuous minutes. Bronchial fiberoptic endoscopy was used to insert the marker by wedg- ing it into the small bronchi near the tumor without injury to lung parenchyma or pleura. Using 2 sets of diagnostic fluoroscopy and image processor units, the system determines the 3D position of the gold marker using real-time pat- tern recognition and calibrated projection geom- etry. At present, this method is regarded as one of the most precise for measurement of internal tumor motion. Amplitudes of Intrafractional Lung Tumor Motion The position of the tumor as a function of time t can be defined as: S(t) S0 S cos2n( t/t- ), Figure 2. Muscle motion at inspiration and expiration. Figure 1. Respiratory neural model. Intrafractional Tumor Motion 11