Four-dimensional Radiotherapy Research Articles

Biomedical advances and future prospects of high-precision three-dimensional radiotherapy and four-dimensional radiotherapy.

Biomedical advances of external-beam radiotherapy (EBRT) with improvements in physical accuracy are reviewed. High-precision (±1 mm) three-dimensional radiotherapy (3DRT) can utilize respective therapeutic open doors in the tumor control probability curve and in the normal tissue complication probability curve instead of the one single therapeutic window in two-dimensional EBRT. High-precision 3DRT achieved higher tumor control and probable survival rates for patients with small peripheral lung and liver cancers. Four-dimensional radiotherapy (4DRT), which can reduce uncertainties in 3DRT due to organ motion by real-time (every 0.1-1 s) tumor-tracking and immediate (0.1-1 s) irradiation, have achieved reduced adverse effects for prostate and pancreatic tumors near the digestive tract and with similar or better tumor control. Particle beam therapy improved tumor control and probable survival for patients with large liver tumors. The clinical outcomes of locally advanced or multiple tumors located near serial-type organs can theoretically be improved further by integrating the 4DRT concept with particle beams.

Clinical applicability of deep learning-based respiratory signal prediction models for four-dimensional radiation therapy.

For accurate respiration gated radiation therapy, compensation for the beam latency of the beam control system is necessary. Therefore, we evaluate deep learning models for predicting patient respiration signals and investigate their clinical feasibility. Herein, long short-term memory (LSTM), bidirectional LSTM (Bi-LSTM), and the Transformer are evaluated. Among the 540 respiration signals, 60 signals are used as test data. Each of the remaining 480 signals was spilt into training and validation data in a 7:3 ratio. A total of 1000 ms of the signal sequence (Ts) is entered to the models, and the signal at 500 ms afterward (Pt) is predicted (standard training condition). The accuracy measures are: (1) root mean square error (RMSE) and Pearson correlation coefficient (CC), (2) accuracy dependency on Ts and Pt, (3) respiratory pattern dependency, and (4) error for 30% and 70% of the respiration gating for a 5 mm tumor motion for latencies of 300, 500, and 700 ms. Under standard conditions, the Transformer model exhibits the highest accuracy with an RMSE and CC of 0.1554 and 0.9768, respectively. An increase in Ts improves accuracy, whereas an increase in Pt decreases accuracy. An evaluation of the regularity of the respiratory signals reveals that the lowest predictive accuracy is achieved with irregular amplitude patterns. For 30% and 70% of the phases, the average error of the three models is <1.4 mm for a latency of 500 ms and >2.0 mm for a latency of 700 ms. The prediction accuracy of the Transformer is superior to LSTM and Bi-LSTM. Thus, the three models have clinically applicable accuracies for a latency <500 ms for 10 mm of regular tumor motion. The clinical acceptability of the deep learning models depends on the inherent latency and the strategy for reducing the irregularity of respiration.

Analysis of a Parallel Manipulator Implemented in Four-Dimensional Radiotherapy for Physiological Motion of Human Tissues

Analysis of a Parallel Manipulator Implemented in Four-Dimensional Radiotherapy for Physiological Motion of Human Tissues

Tumor motion in lung cancers: An overview of four-dimensional radiotherapy treatment of lung cancers

AbstractMost modern radiotherapy centers have adopted contouring based treatment. Sparing of the normal structures has been made more achievable than ever before by use of technologies such as Intensity Modulated Radiotherapy (IMRT) and Image guided radiotherapy (IGRT). However, unlike, sites such as brain or head neck, thorax is a site in active motion, mostly contributed by patient's respiratory movement. 4 D radiotherapy, that addresses the issues of motion in thoracic tumours answers this critical question. The present article outlines the scope of need for 4 D radiotherapy and discusses the options available for 4 D treatments of cancer patients.

Development and Analysis of a Novel Parallel Manipulator Used in Four-Dimensional Radiotherapy

Radiotherapy (RT) enables a selective destruction of tumor cells, although the treatment area is limited to the irradiated volume. Any RT technique comes along with multiple sources of error, which can lead to a deviation of the dose that is applied to the patient. Phantoms—structures that replicate a human and include measurement technology to assess the applied dosage—are used to make such errors observable. Past RT-technologies assumed static tumors. Correspondingly, most existing phantoms comprise only static components. Nowadays, RT is at a transition stage toward techniques which explicitly account for physiological motion. These techniques require phantoms generating such motion. Consequentially, a demand for new kinds of manipulators, which operate with a RT-phantom, has come up and will further increase in the future. Key demands of such manipulators are among others, the generation of full rigid body motion, high acceleration, high stiffness, compactness, little weight, and easy portability. Another indispensable feature is the spatial separation of mechatronic components and phantom structure to ensure human equivalency of the latter. In this work, a new kind of parallel kinematic manipulator (PKM), which is tailored to the requirements of RT-phantom technology, is presented. The PKM consists of low cost standardized mechanical components and sets the target structures, which are located inside a human-equivalent area, into translational and rotational motion in three degrees-of-freedom (DOFs). Only a part of the end-effector is located within the human-equivalent area. All the remaining parts of the PKM are located outside that area. Two versions of the manipulator are presented in detail: their kinematics are derived and their kinetostatic properties are compared. This includes a workspace analysis and the analysis of the transmission behavior in general, meaning the influence of the most important design parameters on the performance. It can be shown that practical differences of both kinematics are negligible, while the modified version provides significant mechanical advantages. In conclusion, a first special purpose manipulator for application in the evolving field of RT-phantom technology is presented. The PKM, which employs a novel kinematic structure, provides higher suitability for its purpose than any other robotic system employed so far for the same purpose.

Magnetic Resonance Compatibility of a Transponder Aimed for Radiotherapy Positioning - A Phantom Study.

Electromagnetic Positioning Systems (EMP) is a new position-ing technique in four-dimensional radiotherapy. Patients with implanted transponders may be referred for magnetic resonance imaging (MRI) making it important to establish the MR safety. Oranges were prepared with transponders and imaged on a 3T MR scanner with different sequences. Computed tomography (CT) was performed as comparison. MR artifacts were assessed. An estimation of the maximum transponder de-flection force and heating was made. The mean measured displacement of transponders was 0.1 mm (range=0.03-0.3 mm). Artifacts were observed adjacent to transponders using all sequences. The deflection force on the transponder in the gantry was less than 38 mN. No heating was observed. The absence of any substantial movement, the weak measured deflection force and absence of observed heating speaks for the safe use of MR imaging with transponder 3T. Local artefacts makes evaluation impossible adjacent to transponders.

Quality assurance for dynamic tumor tracking using the Vero4DRT system

Purpose: We perform quality assurance (QA) for indirect dynamic tumor tracking (DTT) using four-dimensional radiation therapy (the Vero4DRT™ system). Methods: A single photon beam was set with a 40 × 40 mm 2 field size at a gantry angle of zero degrees and a low monitor unit setting of 200. Doses were measured using a 0.016 cm 3 ionization chamber inserted in a phantom under stationary, DTT, and non-DTT conditions for sinusoidal (peak-to-peak) amplitude [ A ] and breathing period [ T ] (20 mm, 2 s; 20 mm, 4 s; and 40 mm, 4 s). The stationary condition was measured for comparison. Dose profiles were measured using Gafchromic EBT3 films in the phantom under the same conditions. Results: For chamber measurement, the relative doses were as follows: 0.99 with non-DTT and 1.00 with DTT at A = 20 mm and T = 2 s; 0.99 with non-DTT and 1.00 with DTT at A = 20 mm and T = 4 s; and 0.84 with non-DTT and 1.00 with DTT at A = 40 mm and T = 4 s. For film measurement, the spatial distances between the 90% dose of the dose profiles were as follows: 6.53 mm for non-DTT and 0.40 mm for DTT at A = 20 mm and T = 2 s; 6.33 mm for non-DTT and 0.15 mm for DTT at A = 20 mm and T = 4 s; and 10.61 mm for non-DTT and 0.17 mm with DTT at A = 40 mm and T = 4 s. Conclusion: Our results showed high dosimetric and geometric accuracy for DTT using four-dimensional modeling and marked reduction of the blurring effects on dose distribution. We recommend the use of a QA procedure for DTT performed using the Vero4DRT™ system.

Radiotherapy dosimetry audit: three decades of improving standards and accuracy in UK clinical practice and trials.

Dosimetry audit plays an important role in the development and safety of radiotherapy. National and large scale audits are able to set, maintain and improve standards, as well as having the potential to identify issues which may cause harm to patients. They can support implementation of complex techniques and can facilitate awareness and understanding of any issues which may exist by benchmarking centres with similar equipment. This review examines the development of dosimetry audit in the UK over the past 30 years, including the involvement of the UK in international audits. A summary of audit results is given, with an overview of methodologies employed and lessons learnt. Recent and forthcoming more complex audits are considered, with a focus on future needs including the arrival of proton therapy in the UK and other advanced techniques such as four-dimensional radiotherapy delivery and verification, stereotactic radiotherapy and MR linear accelerators. The work of the main quality assurance and auditing bodies is discussed, including how they are working together to streamline audit and to ensure that all radiotherapy centres are involved. Undertaking regular external audit motivates centres to modernize and develop techniques and provides assurance, not only that radiotherapy is planned and delivered accurately but also that the patient dose delivered is as prescribed.

Comparison between audio-only and audiovisual biofeedback for regulating patients' respiration during four-dimensional radiotherapy.

PurposeTo compare audio-only biofeedback to conventional audiovisual biofeedback for regulating patients' respiration during four-dimensional radiotherapy, limiting damage to healthy surrounding tissues caused by organ movement.Materials and MethodsSix healthy volunteers were assisted by audiovisual or audio-only biofeedback systems to regulate their respirations. Volunteers breathed through a mask developed for this study by following computer-generated guiding curves displayed on a screen, combined with instructional sounds. They then performed breathing following instructional sounds only. The guiding signals and the volunteers' respiratory signals were logged at 20 samples per second.ResultsThe standard deviations between the guiding and respiratory curves for the audiovisual and audio-only biofeedback systems were 21.55% and 23.19%, respectively; the average correlation coefficients were 0.9778 and 0.9756, respectively. The regularities between audiovisual and audio-only biofeedback for six volunteers' respirations were same statistically from the paired t-test.ConclusionThe difference between the audiovisual and audio-only biofeedback methods was not significant. Audio-only biofeedback has many advantages, as patients do not require a mask and can quickly adapt to this method in the clinic.

SU-E-J-266: A Pitfall of a Deformable Image Registration in Lung Cancer

Purpose: For four-dimensional (4D) planning and adaptive radiotherapy, deformable image registration (DIR) is needed and the accuracy is essential. We evaluated the accuracy of one free-downloadable DIR software library package (NiftyReg) and one commercial DIR software (MIM) in lung SBRT cancer patients. Methods: A rigid and non-rigid registrations were implemented to our in-house software. The non-rigid registration algorithm of the NiftyReg and MIM was based on the free-form deformation. The accuracy of the two software was evaluated when contoured structures to peak-inhale and peak-exhale 4DCT image data sets were measured using the dice similarity coefficient (DSC). The evaluation was performed in 20 lung SBRT patients. Results: In our visual evaluation, the eighteen cases show good agreement between the deformed structures for the peak-inhale phase and the peak-exhale phase structures (more than 0.8 DSC value). In the evaluation of the DSC in-house software, averaged DSC values of GTV and lung, heart, spinal cord, stomach and body were 0.862 and 0.979, 0.932, 0.974, 0.860, 0.998, respectively. As the Resultof the registration using the MIM program in the two cases which had less than 0.7 DSC value when analyzed using the in-house software, the DSC value were improved to 0.8. The CT images in a case with low DSC value shows the tumor was surrounded by the structure with the similar CT values, which were the chest wall or the diaphragm. Conclusion: Not only a free-downloadable DIR software but also a commercial software may provide unexpected results and there is a possibility that the results would make us misjudge the treatment planning. Therefore, we recommend that a commissioning test of any DIR software should be performed before clinical use and we should understand the characteristics of the software.

A study on the reproducibility by computed tomography (CT) using a phantom

In general, computed tomography (CT) scanning methods for CT image acquisition include axial scanning methods, helical scanning methods and cine scanning methods. Many studies have reported the usefulness of four-dimensional computed tomography (4D CT) scanning for the planning of four-dimensional radiation therapy. On the contrary, no study has reported the reproducibility of 4D CT images for the above-mentioned scanning methods. Therefore, in this study, a phantom that could be moved independently was manufactured, and this manufactured phantom was applied in the same way as in the 4D CT method. Scanning was then performed using the three methods so that the reproducibility of the image could be compared and analyzed. The study used a self-manufactured drive phantom and a respiration-gated drive motor to reproduce movements in the upward/downward directions and in the top/bottom directions. Markers were placed on the drive motor, and a radiopaque material (localizer) was attached to allow positional marking on the marker for the differentiation of movement when performing CT. The top/bottom movement when using the self-manufactured drive phantom was fixed at 1.3 cm (16 times/1 min), and the upward/downward movement was fixed at 0.2 cm (8 rot/1 min) by using a respiration-gated drive motor. After each movement had been fixed, images were taken with axial, helical and cine scanning for the three methods of CT. A radio-opaque material attached to the marker to indicate movement was compared and analyzed by using radiation treatment planning (RTP) equipment to ensure volume reproducibility. The study results revealed that the total volume of the marker was 88.2 cm3, and when a 3-cm shift in the top/bottom directions and a 0.3-cm shift in the upward/downward directions were taken into account, the total volume was 184.3 cm3. By CT scan type, the total volume was 135 cm3 for axial scanning, 164.9 cm3 for helical scanning and 181.7 cm3 for cine scanning. Regarding the reproducibility of movement, the cine scan depicted the marker much better than the other scans did. In addition, the reproducibility of the radiopaque material attached to the marker was better for the cine scan.

A novel four-dimensional radiotherapy planning strategy from a tumor-tracking beam's eye view

To investigate the feasibility of four-dimensional radiotherapy (4DRT) planning from a tumor-tracking beam's eye view (ttBEV) with reliable gross tumor volume (GTV) delineation, realistic normal tissue representation, high planning accuracy and low clinical workload, we propose and validate a novel 4D conformal planning strategy based on a synthesized 3.5D computed tomographic (3.5DCT) image with a motion-compensated tumor. To recreate patient anatomy from a ttBEV in the moving tumor coordinate system for 4DRT planning (or 4D planning), the centers of delineated GTVs in all phase CT images of 4DCT were aligned, and then the aligned CTs were averaged to produce a new 3.5DCT image. This GTV-motion-compensated CT contains a motionless target (with motion artifacts minimized) and motion-blurred normal tissues (with a realistic temporal density average). Semi-automatic threshold-based segmentation of the tumor, lung and body was applied, while manual delineation was used for other organs at risk (OARs). To validate this 3.5DCT-based 4D planning strategy, five patients with peripheral lung lesions of small size (<5 cm3) and large motion range (1.2–3.5 cm) were retrospectively studied for stereotactic body radiotherapy (SBRT) using 3D conformal radiotherapy planning tools. The 3.5DCT-based 4D plan (3.5DCT plan) with 9–10 conformal beams was compared with the 4DCT-based 4D plan (4DCT plan). The 4DCT plan was derived from multiple 3D plans based on all phase CT images, each of which used the same conformal beam configuration but with an isocenter shift to aim at the moving tumor and a minor beam aperture and weighting adjustment to maintain plan conformality. The dose–volume histogram (DVH) of the 4DCT plan was created with two methods: one is an integrated DVH (iDVH4D), which is defined as the temporal average of all 3D-phase-plan DVHs, and the other (DVH4D) is based on the dose distribution in a reference phase CT image by dose warping from all phase plans using the displacement vector field (DVF) from a free-form deformable image registration (DIR). The DVH3.5D (for the 3.5DCT plan) was compared with both iDVH4D and DVH4D. To quantify the DVH difference between the 3.5DCT plan and the 4DCT plan, two methods were used: relative difference (%) of the areas underneath the DVH curves and the volumes receiving more than 20% (V20) and 50% (V50) of prescribed dose of these 4D plans. The volume of the delineated GTV from different phase CTs varied dramatically from 24% to 112% among the five patients, whereas the GTV from 3.5DCT deviated from the averaged GTV in 4DCT by only −6%±6%. For planning tumor volume (PTV) coverage, the difference between the DVH3.5D and iDVH4D was negligible (<1% area), whereas the DVH3.5D and DVH4D were quite different, due to DIR uncertainty (∼2 mm), which propagates to PTV dose coverage with a pronounced uncertainty for small tumors (0.3–4.0 cm3) in stereotactic plans with sharp dose falloff around PTV. For OARs, such as the lung, heart, cord and esophagus, the three DVH curves (DVH3.5D, DVH4D and iDVH4D) were found to be almost identical for the same patients, especially in high-dose regions. For the tumor-containing lung, the relative difference of the areas underneath the DVH curves was found to be small (5.3% area on average), of which 65% resulted from the low-dose region (D < 20%). The averaged V20 difference between the two 4D plans was 1.2% ± 0.8%. For the mean lung dose (MLD), the 3.5DCT plan differed from the 4DCT plan by −1.1%±1.3%. GTV-motion-compensated CT (3.5DCT) produces an accurate and reliable GTV delineation, which is close to the mean GTV from 4DCT. The 3.5DCT plan is equivalent to the 4DCT plan with <1% dose difference to the PTV and negligible dose difference in OARs. The 3.5DCT approach simplifies 4D planning and provides accurate dose calculation without a substantial increase of clinical workload for motion-tracking delivery to treat small peripheral lung tumors with large motion.

SU‐E‐J‐121: A New 4D Radiotherapy Planning Strategy Using Synthesized Tumor‐Motion‐Compensated Computed Tomography

To validate a four-dimensional radiotherapy (4DRT) planning based on a synthesized CT image compensating for tumor motion, accounting for tumor rotation, deformation and distortion due to motion artifacts, and producing realistic normal tissue density in motion-tracking beam eye view. 4D computed tomography (4DCT) images of six patients with peripheral lung lesions in mid or lower lobs (motion range: 0.5-3.5cm and size: 1.5±2.0 cm3 ) were used. A customized program was used for simulating the patient anatomy with a motion-compensated tumor using 4DCT by aligning the tumor and averaging the 4DCT into a static 3.5DCT image. The gross tumor volume (GTV) was delineated semiautomatically using a threshold algorithm. Variation of GTV in each phase CT was assessed across all phases. 3DRT plans were generated using 3.5DCT and 4DCT and compared for validation. An integrated dose volume histogram (iDVH) from all phase plans and dose warping using deformable image registration (DIR) were used for evaluating 4D plans and comparing with 3.5D plans. The range of tumor volume variation over the mean within a breathing cycle was 87%±46%. The 3.5DCT produced an 'averaged' GTV, more reliable than that from any phase CT. The results show that the 3.5D plan is equivalent to the 4D plan, except for low dose area, using the iDVH evaluation. On average, the percentage difference for the areas under the DVH and iDVH is 4.3%±2.7%, while 2/3 of the difference results from low dose region blow D20%. Using DIR-based dose warping, PTV coverage varies due to DIR uncertainty for the small lesions. The 3.5D plan is equivalent to the 4D plan for peripheral lung lesions, yet requires much less clinical workload. The 3.5D plan accounts for tumor motion and tumor variation for a more reliable delineation, and for realistic normal tissue representation for motion tracking.

SU-E-J-164: Verification of Commercial Respiratory Tracking System Using Scintillation Screen.

The accuracy of the tracking system is critical for the result of four-dimensional radiation therapy. The objective of this study is to propose the method of verifying the accuracy of respiratory tracking system. The scintillation screen and the light marker between the transparent acrylic plates were designed to move according to the prerecorded respiratory organ motion of volunteers. A vertical circle photon beam with 3 cm diameters from the cyberknife unit was planned to track the motion of the scintillation screen with the plates. In dark room, the CCD camera outside of the phantom captured the scintillation from the screen and the light marker in 30 frames per second when the photon beam was incident. The pictures were captured by the CCD camera were analyzed frame by frame, and the discrepancy between the scintillating circle on the scintillation screen and the light marker depending on the time was measured. The discrepancy of the motions of the delivered photon beam and the light marker was analyzed. In the preliminary study, the maximum discrepancy was measured less than 1.5 mm in normal breathing pattern as the manufacturer specified it. As the speed of the motion was increased, the discrepancy between the position of the beam and internal marker increased. However, the error was clinically acceptable. The further study will be performed for the irregular respiratory motion patterns. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (20110004848).

4次元照射と呼吸同期照射

4次元照射と呼吸同期照射

A 4DRT simulation study using a synthetic 3.5D CT image with motion-free target of lung cancer based on 4DCT

Four-Dimensional Radiotherapy (4DRT) planning based on 4D Computed Tomography (4DCT) is limited by drastically increased planning workload and unavoidably needed new software. We introduced a new concept of 3.5DCT for a simplified 4DRT planning. This 3.5DCT is synthesised from 4DCT by aligning the tumour centres in each phase, simulating a motion-compensated tumour from the beam eye’s view. Four patients’ 4DCTs were used for the 4DRT planning, which were compared with motion-trajectory-based and respiratory-gated plans. This simplified 4DRT plan shows dosimetric advantage of significant reduction of V95 and V20. This suggests that the static 3.5DCT image is sufficient for 4DRT planning.

Development of Monte Carlo Dose Verification System for MHI-TM2000 in Step-and-shoot Cases

MHI-TM2000 (Mitsubishi Heavy Industries, Ltd., Japan) is an innovative image-guide radiotherapy (IGRT) system employing a C-band X-ray head with gimbal mechanics, two sets of kV X-ray tubes and flat panel detectors mounted on an O-ring shaped gantry, an electronic portal imaging device, an infrared camera system, and a robotic treatment couch with five degrees of freedom. This IGRT system has a capability of pursuing irradiation for a moving target using real-time imaging and real-time active beam adaptation, this is, four-dimensional radiotherapy.

Stereotactic Body Radiation Therapy for Lung Cancer: Achievements and Perspectives

Stereotactic body radiation therapy is a new treatment modality where narrow beams from several directions focus on the target while sparing the adjacent normal tissues with high accuracy. This technique basically derived from that of radiosurgery for intracranial lesions allows us to deliver high dose to the target leading to high control of the tumor without causing significant cytotoxicities associated with the treatment. Early-stage non-small cell lung cancers are regarded as most appropriate malignancies for this modality and accordingly have most intensively been investigated. With many encouraging outcomes in retrospective studies, several prospective clinical trials have been started world-wide. Japan Clinical Oncology Group protocol 0403 is a phase II trial of stereotactic body radiation therapy for T1N0M0 non-small cell lung cancer including both inoperable and operable patients. The results for operable patients are to be disclosed this year after 3 years of follow-up. It is highly probable that stereotactic body radiation therapy can be a standard treatment modality for inoperable patients for early-stage non-small cell lung cancer. The role of stereotactic body radiation therapy for operable patients is expected to be clarified by the outcomes of coming clinical trials. Tremendous advance in stereotactic body radiation therapy is expected when four-dimensional radiation therapy coping with tumor movement is realized. Among several approaches, tumor tracking appears most ideal. The new image-guided radiotherapy system which has the capability of tumor tracking has been developed in Japan.

Synchronous monitoring of external/internal respiratory motion: validity of respiration-gated radiotherapy for liver tumors

Four-dimensional (4D) radiotherapy, in particular respiration gating for the treatment of lung tumors, is gaining popularity. Its utility for other sites, however, has not been investigated fully. The purpose of this study was to see whether 4D therapy is feasible for liver tumors. Six patients (five with hepatomas and one with metastatic liver tumor) had a fiducial, gold marker 1.5 mm in diameter implanted in the vicinity of their liver tumors. The inner and external (i.e., upper abdominal wall) respiratory movements were simultaneously recorded using a real-time tumor-tracking radiotherapy system and respiration monitor equipment applied to the mid to upper abdomen. The fluctuations from the baseline position of liver tumors were small; the mean absolute value was 3.92 +/- 1.94 mm. The mean right-left, anteroposterior, and craniocaudal total movements were 4.19 +/- 2.46, 7.23 +/- 2.96, and 15.98 +/- 6.02 mm, respectively. The phase shift was negligible. Liver tumors may be suitable for respiration-gated radiotherapy, and they may become curable with 4D radiotherapy.

Assessing Four-dimensional Radiotherapy Planning and Respiratory Motion-induced Dose Difference Based on Biologically Effective Uniform Dose

Four-dimensional (4D) radiotherapy is considered as a feasible and ideal solution to accommodate intra-fractional respiratory motion during conformal radiation therapy. With explicit inclusion of the temporal changes in anatomy during the imaging, planning, and delivery of radiotherapy, 4D treatment planning in principle provides better dose conformity. However, the clinical benefits of developing 4D treatment plans in terms of tumor control rate and normal tissue complication probability as compared to other treatment plans based on CT images of a fixed respiratory phase remains mostly unproven. The aim of our study is to comprehensively evaluate 4D treatment planning for nine lung tumor cases with both physical and biological measures using biologically effective uniform dose (D =) together with complication-free tumor control probability, P+. Based on the examined lung cancer patients and PTV margin applied, we found similar but not identical curves of DVH, and slightly different mean doses in tumor (up to 1.5%) and normal tissue in all cases when comparing 4D, P0%, and P50% plans. When it comes to biological evaluations, we did not observe definitively PTV size dependence in P+ among these nine lung cancer patients with various sizes of PTV. Moreover, it is not necessary that 4D plans would have better target coverage or higher P+ as compared to a fixed phase IMRT plan. However, on the contrary to significant deviations in P+ (up to 14.7%) observed if delivering the IMRT plan made at end-inhalation incorrectly at end-exhalation phase, we estimated the overall P+, PB, and PI for 4D composite plans that have accounted for intra-fractional respiratory motion.