This study presented the analysis of free-breathing lung tumor motion characteristics using GE 4DCT and Varian RPM systems. Tumor respiratory movement was found to be associated with GTV size, the superior-inferior tumor location in the lung, and the attachment degree to rigid structure (e.g., chest wall, vertebrae, or mediastinum), with tumor location being the most important factor among the other two. Improved outcomes in survival and local control of 43 lung cancer patients were also reported. Consideration of respiration-induced motion based on 4DCT for lung cancer yields individualized margin and more accurate and safe target coverage and thus can potentially improve treatment outcome.
Respiration-induced tumor motion is a significant source of geometric uncertainty in radiotherapy for thoracic malignancies [
Adding the fourth dimension, time, to three-dimensional CT is termed four-dimensional CT (4DCT) [
Studies on the assessment of lung tumor motion using different approaches, which ranged from fluoroscopy [
The 4DCT is proven to be more effective and objective for the evaluation of breathing motion. This is still of great interest for more comprehensive understanding on factors associated with respiration-induced tumor motion and on its impact of treatment outcome. The main purpose of this work is, then, to determining these factors and the impact by analyzing the respiration motion and outcome data collected for 4DCT-based radiotherapy in our clinic.
This retrospective research was conducted according to the principle described in the
After a review of medical records in our hospital, we identified 43 patients with 44 lung tumors who underwent 4DCT scans during quiet respiration between September 2005 and January 2008. Each patient had at least one pulmonary lesion with distinct boundary. Tumor staging was done by contrast-agent CT chest and abdomen, magnetic resonance imaging (MRI) of the brain, and bone scintigraphy whereas positron-emission tomography and CT were not mandatory. All patients who had local and/or regional disease, received a curative intent radiotherapy with or without chemotherapy. Karnofsky Performance Status (KPS) ≥70 and weight loss <5% in half a year were required. Exclusion criteria included previous thoracic surgery, previous radiation treatment, clinically significant pleural effusion limiting delineation of the total extent of the primary tumor, lobar atelectasis, and an inability to breathe in a reproducible manner (breath variability was more than 5%). Patients were excluded from the study in survival analysis section if their total dose was <60 Gy.
At SYSUCC, a 16 slice 4DCT scanner (GE Lightspeed, GE) with a respiration management system (RPM, Varian) was used to acquire respiration correlated CT. Retrospective 4DCT scanning entailed the generation of multiple slices at each relevant table position, during at least the length of a full respiration cycle (oversampling). The acquired data (about 1000 images) were sorted into 10 datasets correlating with 10 phases of the respiratory cycle. The phase 0% represents the end of inspiration, with the phase 50% for the end of expiration. The spatial resolution along the superior-inferior direction was limited by the 2.5 mm slice thickness.
The gross tumor volumes (GTVs) on ten respiratory phases were delineated using a treatment planning system (Pinnacle3, version 7.6c, Philips). All GTVs were delineated with an autosegmentation tool using threshold −750 to 4096 Hu first then manually modified by a single radiation oncologist. All contours were checked by two other radiation oncologists for consistency.
The GTV volumes for the ten phases were recorded as GTV-0%, GTV-20%, …, and GTV-90%. The mean GTV volume was calculated from the average GTVs of ten respiratory phases as mean GTV = 1/10 (GTV-0% + GTV-10% +
The centriods of GTVs in ten phases were determined by the planning system and were used to calculate the magnitudes of motions in three directions termed as dLR, dAP, and dSI, the distance between the two extreme positions in left-right (LR), anterior-posterior (AP), and superior-inferior (SI) direction during the respiratory cycle phases, respectively. The 3D vector was calculated as follows: 3D vector =
The CT set at 20% phase was chosen as reference CT to determine the relative GTV location in the lung. The location parameter consisted of three directional components, fLR, fAP, and fSI, corresponding to the relative fractional location in the lung in LR, AP, and SI directions, respectively. For example, fSI was the distance between the apex of the lung and the GTV centroid divided by the distance between the apex and the diaphragm point passing through the GTV centroid in the SI direction. For the LR and AP directions, the same method was applied except that the distance was defined from the centriod to the carina (for LR) or to the anterior boundary of the lung (for AP), and the divisor was defined as ipsilateral lung LR or AP diameter. The attachment degree to rigid structure (e.g., chest wall, vertebrae, or mediastinum, which all minimal respiratory motion) was defined as the ratio of the longest diameter attached to the rigid structure divided by longest diameter of the tumor in transversal plane.
In the clinic, GTVs included the primary tumor (GTV-T), positive lymph nodes (GTV-N) with lymph nodes in the mediastinum with a short diameter >1 cm, or lymph nodes with positive tumor cell sampling, or clusters of small lymph nodes of short diameter <1 cm within 1 region, or 18F-FDG standard uptake value >2.5 on PET/CT at initial staging. IGTV was obtained on 4DCT maximal intensity projection or ten phases. For patients who had squamous cell carcinoma, the clinical target volume tumor (CTV-T) included IGTV-T with a margin of 0.6 cm. For patients who had adenocarcinoma or histology not otherwise specified nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC), the CTV-T was created by IGTV-T with a margin of 0.8 cm. The clinical target volume node (CTV-N) included the positive lymph nodes region only. A 5 mm expansion uniformly around the CTV created the planning target volumes (PTV).
6–8 MV X-rays were used. All NSCLC patients underwent radiotherapy with conventional fractionation schemes. Tumors were prescribed as high as possible (not lower than 60 Gy) based on normal tissue dose-volume constraint. For locally advanced NSCLC (T3-4NxM0 or TxN2-3M0) patients, concurrent chemotherapy consisted of weekly or 2 cycles of monthly cisplatin and taxane-based regimens. For limited-stage SCLC patients, thoracic radiotherapy was administrated with a total dose of 45 Gy and at hyperfractionated technique of 1.5 Gy/fraction twice daily. The minimal interval between fractions was 6 hours. Patients received thoracic radiotherapy within the first 2 cycles of cisplatin and etoposide (EP). Patients who achieved complete remission (CR) or partial remission (PR) of tumor after the completion of chemoradiotherapy (4–6 cycles of EP plus concurrent thoracic radiotherapy) were offered prophylactic cranial irradiation (PCI), which was delivered daily to a total dose of 30 Gy over a period of 3 weeks or 25 Gy over 2 weeks.
After completion of treatment, patients were reviewed within 4–6 weeks, then every 3 months in the first 2 years, and every 4 months in the third year, every 6 months thereafter. Physical examination and CT scans of the thorax and upper abdomen were performed routinely.
SPSS 13.0 statistical software was used (SPSS Inc., Chicago, IL). To understand what factors could be associated with and predictive of tumor motion, logistic regression (backward stepwise method) was used to test the relationship between GTV motion and clinical or anatomic factors, which were either continuous or categoric variables (e.g
Patient characteristics are listed in Table
Patient and treatment characteristics of the 43 patients.
Factors | Characteristic | Number of cases | Percentage |
---|---|---|---|
Gender | Male | 38 | 88.4% |
Female | 5 | 11.6% | |
Age (years old) | Median | 56 | |
Range | 35–78 | ||
NSCLC | 27 | 62.8% | |
Histology | SCLC | 15 | 34.9% |
Metastases | 1 | 2.3% | |
I-II | 2 | 7.4% | |
Stage of NSCLC |
IIIA | 5 | 18.5% |
IIIB | 15 | 55.6% | |
IV | 5 | 18.5% | |
Stage of SCLC |
Limited stage | 15 | 100% |
T1 | 10 | 23.8% | |
T status* | T2 | 7 | 16.7% |
T3 | 7 | 16.7% | |
T4 | 18 | 42.8% | |
N0-1 | 5 | 11.9% | |
N status* | N2 | 16 | 38.1% |
N3 | 21 | 50% | |
Left upper lobe | 16 | 36.4% | |
Left lower lobe | 1 | 2.3% | |
Tumor location† | Right upper lobe | 17 | 38.6% |
Right middle lobe | 4 | 9.1% | |
Right lower lobe | 6 | 13.6% | |
GTV volume |
Median | 45 | |
Range | 0.5–454 | ||
Tumor attachment status† | Solitary tumor | 14 | 31.8% |
Attached tumor | 30 | 68.2% | |
Median | 62 | ||
Treatment dose of NSCLC (Gy) ( |
Range | 54–70 | |
<60 | 6 | 22.2% | |
60–65 | 13 | 48.1% | |
66–70 | 8 | 29.6% | |
Treatment dose of SCLC ( |
45 | 15 | 100% |
Concurrent |
NSCLC | 24‡ | 88.9% |
SCLC | 15 | 100% |
†One NSCLC patient had two lung lesions.
‡Two early patients received radiation alone. One locally advanced patient canceled chemotherapy for active tuberculosis.
NSCLC: nonsmall cell lung cancer; SCLC: small cell lung cancer; GTV: gross tumor volume.
GTV centroid motion exceeding 5 mm was seen in 10 of 43 patients (23%), while 61% of lung tumors moving less than 3 mm (Figure
The 3D point trajectories of GTV centroid. Green plots represent the movement of tumor center of mass is more than 5 mm in any directions (10/44), yellow points mean whose movement is less than 3 mm in three directions (27/44), and red plots represent whose is movement between 3–5 mm (7/44). (a) anterior-posterior view; (b) lateral view.
Analysis of all data revealed that the variations in GTV centroid 3D vector movement was associated with GTV size, the SI tumor location in the lung, and the attachment degree to a rigid structure, such as chest wall, vertebrae, or mediastinum (Table
Relationship of GTV centroid 3D vector with clinical and anatomic factors by logistic regression.
Clinical and anatomic factors |
|
---|---|
Gender | 0.198 |
Age | 0.095 |
Histology | 0.114 |
fLR | 0.073 |
fAP | 0.111 |
fSI | 0.001 |
GTV volume (cm3) | 0.046 |
Attachment degree to rigid structure | 0.008 |
Logistic regression suggested that the tumor centriod 3D vector was associated with GTV volume, fSI (the superior-inferior tumor location in the lung) and the attachment degree to rigid structure (e.g., chest wall, vertebrae, or mediastinum).
NSCLC: nonsmall cell lung cancer; SCLC: small cell lung cancer; fLR, fAP, fSI: fractional left-right, anterior-posterior, and superior-inferior location, respectively; GTV: gross tumor volume; attachment degree to rigid structure: the ratio of the longest diameter attached to the rigid structure divided by longest diameter of the tumor in transversal plane.
Relationship between vector and fSI, filtered out attachment degree to rigid structure >0.6,
The peripheral lung tumor located near the diaphragm showed the greatest degree of motion, followed by upper-lobe posterior-segment solitary tumors. Detailed characteristics of high-mobility tumors are summarized in Table
The characteristics of high-mobility tumors (movement more than 5 mm).
Case | Tumor location | GTV (cm3) | Longest diameter (cm) | Attachment degree | fAP | fSI | dLR (mm) | dAP (mm) | dSI (mm) | Vector (mm) |
---|---|---|---|---|---|---|---|---|---|---|
A | RUL (apicoposterior segmental) | 24.9 | 4.6 | 0.5 | 0.56 | 0.37 | 0.8 | 1 | 5.1 | 5.3 |
B | RUL (posterior basal segmental) | 31.6 | 5.9 | 0.47 | 0.68 | 0.47 | 2.5 | 2.3 | 5.8 | 6.7 |
C | RUL (posterior basal segmental) | 2.2 | 1.6 | 0 | 0.46 | 0.54 | 1.4 | 1 | 5.2 | 5.5 |
D | RUL (posterior basal segmental) | 2.4 | 1.9 | 0 | 0.61 | 0.57 | 0.7 | 1.9 | 6.3 | 6.6 |
E | RLL (lateral posterior basal segmental) | 165.3 | 6.2 | 0.92 | 0.78 | 0.82 | 2.5 | 2.1 | 5.1 | 6.1 |
F | RLL (dorsal segmental) | 0.55 | 1.2 | 0 | 0.76 | 0.51 | 1.4 | 2 | 6 | 6.5 |
G | LLL (lingular bronchus) | 12.5 | 2.9 | 0 | 0.42 | 0.74 | 2.6 | 5.2 | 11.7 | 13.1 |
H | RLL (anteriorbasal segmental) | 2.2 | 1.4 | Attach to diaphragm | 0.12 | 0.9 | 5.3 | 1.7 | 5.6 | 7.9 |
I | LLL (lateral posterior basal segmental) | 59.6 | 4.9 | Attach to diaphragm | 0.83 | 0.89 | 1.3 | 1.3 | 13.5 | 14 |
J | RLL (lateral basal segmental) | 17.0 | 3.7 | Attach to diaphragm | 0.58 | 0.92 | 1.9 | 4.9 | 14.4 | 15.3 |
GTV: gross tumor volume; RUL: right upper lobe; RLL: right lower lobe; LLL: left lower lobe; fAP, fSI: fractional anterior-posterior, superior-inferior location, respectively; dLR, dAP, and dSI: the magnitude of motion in lateral, anterior-posterior (AP), and superior-inferior (SI) direction of ten respiratory phases, respectively.
GTV centriod movement by different positional and attachment status.
Tumor location | Magnitude of solitary tumor (mean ± SD mm) |
Magnitude of attached tumor (mean ± SD mm) |
||||||
---|---|---|---|---|---|---|---|---|
|
Later | AP | SI |
|
Later | AP | SI | |
Upper level | 9 | 0.9 |
1.5 |
2.3 |
20 | 0.9 |
1.2 |
1.5 |
Middle level | 1 | 2.6 | 5.2 | 11.7 | 7 | 1.5 |
2.1 |
2.2 |
Lower level | 4* | 2.5 |
2.7 |
10 |
3 | 1.5 |
1.5 |
3.0 |
Upper level included right upper lobe, anterior, and apicoposterior segment in left upper lobe. Middle level included right middle lobe and lingular bronchus in left lobe. Lower level included left and right lower lobes.
SD: standard deviation; AP: anterior-posterior direction, and SI: superior-inferior direction.
The more attached to the rigid structure, the less mobile of tumor was. For those tumors located to the mediastinum, movement in AP direction was a major contributor to the GTV motion, with the magnitude less than 3.5, 4, and 3.5 mm in LR, AP, and SI direction. These movements were probably associated with cardiac contraction and/or aortic pulsation.
In all 20 patients with an attachment degree to rigid structure of being more than 0.6, the magnitude was small, with 1.0 ± 0.6, 1.5 ± 0.9, and 1.5 ± 1.5 mm in the LR, AP, and SI directions, respectively. For this tumor group, there were 2 outliers with large motion in SI direction, with the magnitude of 5.1 mm and 4.5 mm. One located in lower lobe, the other in upper lobe but posterior segment. When filtered out the outliers, maximum movement observed in the LR, AP, and SI directions were 2 mm, 3.7 mm, and 2.8 mm.
For big tumor (GTV ≥45cm3) located upper 1/3 and middle 1/3, the magnitude in AP direction was dominant. For small tumor (GTV <45cm3), the largest motion was in SI direction.
Up to February 2013, the median follow-up duration was 32.6 months (range, 1.9–89.8 months) in all patients; 80.4 months (range: 65.6–89.8 months) in the survivors: and 20.6 months (range: 3.0–75.0 months) in patients who had died. Four NSCLC patients (Stage I in 1, IIIB in 2, and IV in 1) and four limited-stage SCLC patients are alive and free of disease. One SCLC patients is alive with local disease recurrence underwent salvage treatment. Twelve patients have died of distant metastases (NSCLC in 8, SCLC in 4). Eight patients have died of locoregional progression inside the thorax and metastases both (NSCLC in 5, SCLC in 3). One SCLC patient died of local progression inside the radiation field. Two NSCLC patients have died of treatment-related toxicity. One NSCLC patient has died with the metastases for secondary cancer in rectum. Two patients have died as a result of other medical conditions, one for the cause of sputum jams and other for severe pneumonia. For NSCLC subgroup (Stage IIIA in 15 and IIIB in 5), the median survival time was 41.6 months. At 1-, 3- and 5-year actuarial survival was 75%, 55%, and 36.7%, whereas SCLC patients (limited-stage in 15) have a 1-, 3, and 5-year survival of 73.3%, 52.5%, and 37.5%, respectively, with the median survival time of 47.6 month (Figure
Overall survival (a) and progression-free survival curves (b) of local advanced NSCLC and limited-stage SCLC.
The median progression-free survival time was 17.1 months for NSCLC group and 34.4 months for SCLC group; 1, 3-year progression-free survival were 62.7% versus 60% and 28.5% versus 45.7% for NSCLC group and SCLC group (Figure
The local progression-free survival (a) and metastasis-free survival curve (b).
Of the 25 patients who experienced treatment failure or died, 4 patients (NSCLC in 1, SCLC in 3) developed local and/or regional tumor progression without distant metastases; 14 patients (NSCLC in 10, SCLC in 4) developed metastatic disease without locoregional progression; and 7 patients (NSCLC in 4, SCLC in 3) showed concurrent thoracic and distant metastatic progression during the follow-up phase.
The reliability of motion results in this work was dependent on two factors, regularity in patient breathing and consistency in GTV delineation. Data from both phantoms and clinical practice demonstrated that respiratory regularity was of most importance to reduce motion artifacts during 4DCT scan [
It was found that tumor centroids vector movement was associated with GTV size, the SI tumor location (fSI), and the attachment degree to rigid structure. This result was intuitive but contrasted to the studies by Stevens et al. [
Similar to the previously published studies [
Of the three related factors, tumor location probably weighted more than GTV size and attachment degree to rigid structure. This is supported by our original findings as follows. Firstly, the peripheral lung tumors located near the diaphragm showed the greatest degree of motion, followed by upper-lobe posterior-segment solitary tumors. Even in the tumors with an attachment degree to rigid structure of more than 0.6, which estimated very small magnitude, still can be seen cases in these two location moved more than 5 mm. Secondly, when excluding all the cases with attachment degree more than 0.6, the linear correlation between centroid vector mobility and fSI would enhance, regardless of tumor size. Thirdly, regardless of tumor attachment status, for big tumors (volume ≥45 cm3) located upper 1/3 and middle 1/3 and those close to the mediastinum, magnitude in AP direction was dominant. Those results indicated that more consideration should focus on tumor location when determining internal margin for target mobility.
Compared with our study, Liu et al. [
4DCT simulation can provide benefits in selected patients. Similar to that reported by Rietzel et al. [
The predominant cause of deaths for lung cancer is believed to be distant metastases and local recurrence. Local failure remains a major challenge when treating lung cancer with radiotherapy, as high as 30%–50% recurrence rate at 5 years in NSCLC [
In this work, we observed unexpected and promising local control and survival rate with the use of 4DCT for both NSCLC and SCLC. The 5-year overall survival rates of 36.7% for NSCLC and 37.5% for SCLC were encouraging undoubtedly, as compared to the 5-year overall survival rate of around 20% from conventional treatments for locally advanced NSCLC and limited-stage SCLC as reported in the literature and in our own clinical experience [
Liao et al. [
Although with the use of 4DCT, we can safely reduce the margin to account for intrafractional respiration motion, other components contributing to PTV margin, such as interfractional variations, set-up margin, need to be considered. While every effort was made to keep breath regular and ensure target delineation accurate, some artifacts and inconsistency were hard to eliminate. The limited number of cases analyzed is the major drawback of the current study. Our ongoing research is to increase number of the cases and to update the results in the future.
The 4DCT data in this work indicate that the peripheral lung tumors located near the diaphragm show the greatest degree of respiration motion, followed by upper-lobe posterior-segment solitary tumors. Tumor respiration motion was found to be associated with tumor location, volume, and attachment to rigid structures, with tumor location being the most important factor among the other two. The use of 4DCT resulted in the use of individualized margin to account for patient-specific breathing motion, improving the accuracy for tumor targeting during radiotherapy. This may contribute to the improved local control and overall survival as observed presently for both NSCLC and SCLC.
All authors have no conflict of interests.
Y. Wang and Y. Bao contributed equally to this paper.
The authors thank their patients and their families for their willingness to take part in this study. They thank the Chief of Medical Physics Professor X. Allen Li from Medical College of Wisconsin for reviewing the paper and offering helpful comments. No external funding was received for this study.