Automatic collimation of radiation beams in real space with the aid of computer simulation in virtual space has enabled physicians to create complex dose distributions in real space and crystallized as 3-D conformal radiotherapy and intensity-modulated radiotherapy.(1) Consequently, the need for precise registration of virtual space to real space in daily treatment has become critically important. For the precise registration of static virtual space to real space, stereotactic body radiotherapy (SBRT), using a rigid external fixation device on the body, and image-guided radiotherapy, using online imaging of internal structures, have been established.(2,3) Real-time tumor-tracking radiotherapy (RTRT) was developed in 1999 to amplify the precision of irradiation of moving lung tumors.(4) We are now entering a real-time 4-D radiotherapy (4DRT) era, where the temporal changes in anatomy during the delivery of radiotherapy are explicitly considered in real time by the precise registration of dynamic virtual space to dynamic real space, for the purpose of achieving the optimal dose distribution in dynamic real space.
Respiratory motion considerably influences dose distribution, and thus clinical outcomes in radiotherapy for lung cancer. Breath holding, breath coaching, respiratory gating with external surrogates, and mathematical predicting models all have inevitable uncertainty due to the unpredictable variations of internal tumor motion. The amplitude of the same tumor can vary with standard deviations >5 mm occurring in 23% of T1–2N0M0 non-small cell lung cancers. Residual motion varied 1–6 mm (95th percentile) for the 40% duty cycle of respiratory gating with external surrogates. The 4-D computed tomography is vulnerable to problems relating to the external surrogates. Real-time 4-D radiotherapy (4DRT), where the temporal changes in anatomy during the delivery of radiotherapy are explicitly considered in real time, is emerging as a new method to reduce these known sources of uncertainty. Fluoroscopic, real-time tumor-tracking technology using internal fiducial markers near the tumor has ±2 mm accuracy, and has achieved promising clinical results when used with X-ray therapy. Instantaneous irradiation based on real-time verification of internal fiducial markers is considered the minimal requisite for real-time 4DRT of lung cancers at present. Real-time tracking radiotherapy using gamma rays from positron emitters in tumors is in the preclinical research stage, but has been successful in experiments in small animals. Real-time tumor tracking via spot-scanning proton beam therapy has the capability to cure large lung cancers in motion, and is expected to be the next-generation real-time 4DRT. (Cancer Sci 2012; 103: 1–6)
Stereotactic body radiotherapy
The peripheral lung parenchyma consists of many independent functional subunits. Radiation-induced pneumonitis (RP) can be avoided if we concentrate the radiation dose to the small volume, while keeping the mean lung dose (MLD) lower than its tolerance level. Using thin-slice computed tomography (CT) for planning, and a sufficient margin for the organ motion, with the aid of a body frame or imaging devices, the interfractional setup error can be 5 mm or less in SBRT of lung cancer.(5–9) Clinical studies have shown that SBRT alone can cure T1N0M0 non-small cell lung cancers, with little adverse reaction.(5–7) For 65 T1N0M0 tumors, the local control rate at 5 years was 92%, and the RP (≥grade III) rate was 1%, with a median follow-up period of 55 months.(6) The 5-year overall survival rate for Stage IA was 72%. Correcting the effect of dose per fraction, the biologically-effective dose (BED) to the tumor was 116 Gy (range: 100–141 Gy).
Considering that conventional fractionated radiotherapy (CFRT) can deliver a BED of only 72–80 Gy (60–66 Gy using 2 Gy/fraction) to the tumor, SBRT has been successful at delivering a much higher tumor dose, by taking advantage of the structure of the peripheral lung parenchyma. However, tumors having large organ motion, large volume, or are located near the trachea, main bronchus, and main vascular trunk, are not suitable for high-dose SBRT.(10,11) The risk of RP has recently been shown to increase with MLD, with a normalized total dose corrected using α/β ratio of 3 Gy(12). The relationship of RP with single nucleotide polymorphisms is also suggested.(13)
Internal motion of lung cancer
In accordance with the clinical success of SBRT for lung cancers, the control of respiratory motion is emerging as important for reducing the unnecessary irradiation of normal tissue. Treatment planning of lung cancer using CT images is subject to individual differences in respiratory motion.(14) The concept of 4DRT, where the temporal changes in anatomy are explicitly considered during the imaging, planning, and delivery of radiotherapy, was introduced in 2000.(15) Since then, fiducial gold markers have emerged as the most reliable means of tracking the motion of lung cancer in real time during radiotherapy.(16,17) The concept of 4DRT has been improved further and integrated into other systems.(18–20)
Since 3-D coordinates of the gold markers are recorded every 0.033 s using an RTRT system, the marker motion can be regarded as a surrogate of tumor motion, as long as the marker does not migrate. In general, the amplitude of the lung tumor motion is the largest in the craniocaudal direction, followed by the anteroposterior direction, and finally the right–left direction, and it is larger in the lower and outer lung fields, although this pattern can change considerably in diseased lungs.(21,22) The average amplitudes were larger than 10 mm in approximately 33% of lung cancers.(23) The amplitude and speed can vary considerably among treatment days for the same patient; the SD of the absolute amplitude was larger than 5 mm in 23% of lung cancer cases. Tumor position in the exhalation phase was shown to be more stable than that in the inhalation phase, so that tumor position upon exhalation was suggested to be more appropriate as the baseline for gated radiotherapy. However, the tumor position, even at the exhale phase, often shifts more than 2 mm during treatment. On average, four readjustments of the table position were necessary during each treatment session (30–40 min) due to baseline shifts of the tumor position of more than 2 mm.(23) Furthermore, there is a “hysteresis”; the trajectory of the marker during inhalation is often different than that at exhalation, so we need to monitor the hysteresis in gating and scanning of the beam for moving tumors.(16) Therefore, among the treatment techniques in which a narrow therapeutic beam is moved or scanned along the predicted trajectory of the tumor, there can be serious discrepancy between the planning and motion of the beam. The probability density of the trajectory of the marker detected before radiotherapy is expected to be useful for treatment planning of real-time 4DRT (Fig. 1). A dynamic internal margin based on the probability density is expected to improve the efficiency of beam usage.(24)
Instead of implantation of internal fiducial markers, external surrogates are expected to be useful for respiratory gating. The combination of external surrogates and internal observation with simple prediction models was suggested to reduce the residual motion of the tumor in a simulation study.(25) However, a lack of correlation between external signals and internal tumor positions during breathing and breath-hold periods have been reported.(26–28) The residual motion varied between 0.9 and 6.2 mm (95th percentile) for 40% duty-cycle windows, and large fluctuations (>300%) were seen in the residual motion between some beams in respiration gating with an external surrogate.(29) When tumor position was predicted based on the external surrogates, the baseline shift of tumor position was the major source of targeting error.(30) The absolute change in mean tumor position from the first 10-min block to the third 10-min block was >5 mm in 13% of 55 treatment fractions in lung cancer treatment.(31)
4-D CT (4DCT) with a respiration-gating system using external surrogates has been reported to be effective in reducing uncertainty in treatment planning for lung tumors.(32) However, the 4DCT images are all vulnerable to problems relating to the lack of correlation between external surrogates and internal tumor positions during breathing.
Breath coaching and holding
Audiovisual biofeedback is often used to help individuals maintain a regular breathing rhythm or to hold their breath during treatment.(33–35) However, the effectiveness of visual coaching for tumor localization is still debatable, given variations in observers, lengths of observation times, and different research methods.(28,36–38) Neicu et al.(37) pointed out that biofeedback is not useful coaching for patients with medical or respiratory difficulty, while in fact, those patients actually need to be coached more than anyone else. The registration between virtual dynamic space in CT plan and real dynamic space in actual treatment has uncertainty, because CT is studied in a limited time period (<5 min) compared to the treatment delivery (10–40 min). Differences in tumor positions exceeding 5 mm between coached and uncoached 4DCT scans were detected in up to 56% of mobile tumors.(39) It is still uncertain whether breath coaching is reliable enough to reduce the internal residual motion of the tumor during the beam-on period.
Prediction of organ motion
The prediction of internal motion is expected to be useful for 4DRT to reduce intrafractional error, but it is not so simple. The instantaneous maximum speed of lung cancer can be more than 33 mm/s in 29% of patients, and variable in the same patient.(23) The latency period can be <100 ms in electronic gating, but might be longer in mechanical tracking systems, such as robotics and multileaf collimators.(40,41) The respiratory patterns are not simple sine curves, and can be categorized into several types: regular breathing, frequency changes, baseline shifts, amplitude changes, cardiac motion, or combination patterns.(42) In terms of overall error in predicting respiratory motion, the adaptive filter model-based prediction algorithm performs better than the sinusoidal model.(43) Linear filtering, Kalman filtering, neural networks, local regression, autoregressive-moving average model, and others have been reported to reduce error in prediction.(44–48) These models are usable for a regular breathing pattern, but are not yet clinically reliable enough for other respiratory patterns.
Real-time tumor-tracking radiotherapy
Real-time tumor-tracking radiotherapy consists of two parts: (i) real-time monitoring of tumor position using tracking technology in computer science; and (ii) instantaneous irradiation technology. There have been two instantaneous irradiation methods: (i) pursuing irradiation, where the therapeutic beam changes its direction during treatment; and (ii) interrupting irradiation, where the therapeutic beam does not change its direction.(40) By definition, pursuing irradiation without real-time monitoring, but with some prediction models, is not included in RTRT. The prototype RTRT system used the interrupting irradiation method. The system recognizes the 3-D coordinates of a gold marker (1.5 mm) in or around the tumor 30 times/s using the two fluoroscopic X-ray systems. The linear accelerator is gated to irradiate the tumor only when the marker is within ±1–2 mm from its planned coordinates relative to the isocenter. The geometric accuracy of the system is not deteriorated by the unpredictable respiratory motion up to a speed of 40 mm/s. Debates regarding the uncertainty of the migration of markers have been clarified by the clinical studies of RTRT with strict quality control, which showed excellent results for lung cancers, liver cancers, and others.(49–51) Real-time tumor monitoring without fiducial markers for peripheral radio-dense tumors is appealing, but is still unreliable for the majority of patients.(52) At present, instantaneous irradiation based on real-time verification of internal fiducial markers is appreciated as the minimal requisite for real-time 4DRT of lung cancers.
Molecular tracking radiotherapy
Positron emission tomography can improve the precision of determinations of the extent of lung cancer, and positron emission markers have been proposed as fiducial markers, instead of metallic markers, in RTRT.(53–56) Positron-sensitive detectors are used to record coincident annihilation gamma rays from fiducial positron emission markers implanted in or around the tumor. Cancers in small animals have been cured using a positron emitter as the surrogate of tumor motion (Fig. 2).(54) A parallel-plane PET system has been developed to be attached to a linear accelerator for molecular-base patient setup verification.(57) If we can detect the real-time distribution of hypoxic cells during radiotherapy using the parallel-plane PET system, a real-time boost of the dose to the radio-resistant cancer cells will be realized, even when temporal change in the hypoxic region in the tumor is apparent.(58,59)
Real-time tumor-tracking, spot-scanning proton beam therapy
Proton beam therapy (PBT) has physical advantages over X-ray therapy, especially for large cancers, because of the Bragg peak.(60–63) The clinical outcome of lung cancers is expected to be improved with PBT.(64–68) Although debates exist about the requirement of randomized, clinical trials to confirm the benefit of expensive PBT systems, PBT technology is improving rapidly, and hospital-based PBT systems are now increasing in number (Fig. 3).(66–68) Active spot-scanning PBT is known as a new-generation PBT, whose advantages include a large field size (maximum 30 × 40 cm), little contamination by neutrons (lower carcinogenesis), flexibility in the number of beams (better dose distribution), and the capability for intensity-modulated PBT.(69–72) The size of the machine and building can be reduced, and the total cost-effectiveness improved if the PBT machine is dedicated to active spot scanning.
Large cancers in moving organs, such as T3N1M0 non-small cell lung cancers and large hepatocellular carcinomas, are problems than can be overcome by the new-generation PBT.(73) Real-time tumor-tracking, spot-scanning PBT, that is, real-time 4-D PBT, might be a solution.
Carbon beam therapy, which has a Bragg peak as a proton beam and sharper lateral dose distribution than a proton beam, achieved an excellent local control rate for rare malignant tumors resistant to CFRT.(74) However, the advantage of carbon beam therapy compared to PBT has yet to be determined for many cancers. Its distinct characteristics of a sharp lateral penumbra might be more useful for spot-scanning technology.(75)
The risk of second malignancies after radiotherapy strongly depends on the organ, age of the patient, dose, and the characteristics of the beam.(76) Novel risk-visualization methods are needed to facilitate routine risk-adapted, personalized clinical decision-making.
Conclusions and future remarks
The control of organ motion is emerging as a crucial objective in reducing unnecessary irradiation to normal tissue. External surrogates, breath coaching, and prediction models all require attention because of their lack of reliability in accurately localizing internal lung cancer lesions. Instantaneous irradiation based on real-time verification of internal fiducial markers is appreciated as the minimal requisite for real-time 4DRT of lung cancers at present. Molecular imaging for tumor tracking is a key area for investigation in the next decade. Real-time tumor-tracking, spot-scanning PBT is expected to open the door to the next stage of curing large tumors in moving organs.
This review is partly based on the research grant by the Japan Society for the Promotion of Science (JSPS) through the “Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program),” initiated by the Council for Science and Technology Policy (CSTP).
Hiroki Shirato has received research funding from Hitachi Co. Ltd. and Mitsubishi Heavy Industries Co. Ltd.