AJR:203, November 2014 W497

Many studies have shown that perfusion CT findings can reflect the vascular physiolog-ic features of a tumor. Perfusion CT has been used for the assessment of response to ther-apy for tumors of the head, liver, lung, pan-creas, kidney, rectum, and other organs [4–9]. However, in most studies, the perfusion pa-rameters were calculated on the basis of a re-stricted area of interest inside the large lesion rather than in the whole tumor area. There-fore, the accuracy of the parameters is under-mined by the heterogeneity of the lesion, and the perfusion parameters do not adequately reflect the complete picture of the entire tu-mor [10]. The introduction of faster scanners makes possible reliable volumetric evaluation of perfusion parameters within a large area, such as a whole-tumor region, because of wid-er z-axis coverage [11, 12]. However, to our knowledge, there has been no study on the use of whole-tumor perfusion CT for monitoring the response of non–small cell lung cancer to multiarterial infusion chemotherapy.

Value of Whole-Tumor Dual-Input Perfusion CT in Predicting the Effect of Multiarterial Infusion Chemotherapy on Advanced Non–Small Cell Lung Cancer

Xiang Sheng Li1 Hong Xia Fan1 Hong Fang1 He Huang2 Yun Long Song1 Chun Wu Zhou3

Li XS, Fan HX, Fang H, Huang H, Song YL, Zhou CW

1Department of CT, Air Force General Hospital, People’s Liberation Army, Haidian District, Beijing, China.

2Department of Interventional Radiology, Air Force General Hospital, People’s Liberation Army, Haidian District, Beijing, China.

3Department of Radiology, Cancer Hospital, Chinese Academy of Medical Sciences, 17 Panjiayuannanli Rd, Chaoyang District, Beijing, China 100021. Address correspondence to C. W. Zhou (zhouchw88@163.com).

Cardiopulmonar y Imaging • Or ig ina l Research

WEB This is a web exclusive article.

AJR 2014; 203:W497–W505

0361–803X/14/2035–W497

© American Roentgen Ray Society

For patients with advanced non–small cell lung cancer who can-not undergo surgery or do not tolerate radiotherapy or conven-

tional chemotherapy, multiarterial infusion chemotherapy is an important conservative treatment that is valuable for reducing tumor size and symptoms and the incidence of ad-verse effects of anticancer drugs [1]. The ef-fect of multiarterial infusion chemotherapy closely correlates with the blood supply of malignant lung tumors. In addition to the bronchial artery, systemic arteries, such as the internal thoracic artery, intercostal arter-ies, and inferior phrenic artery, are frequent-ly the feeding arteries of malignant lung tu-mors, and sometimes the pulmonary arteries are involved [2, 3]. Quantitative evaluation of these feeding arteries with noninvasive imaging before treatment is helpful for pre-dicting the effect of multiarterial infusion chemotherapy and for selecting patients who are sensitive to this therapy.

Keywords: lung cancer, multiarterial infusion chemotherapy, perfusion CT

DOI:10.2214/AJR.13.11621

Received July 27, 2013; accepted after revision February 28, 2014.

OBJECTIVE. The purposes of this study were to prospectively evaluate tumor perfusion using whole-tumor dual-input perfusion CT in advanced non–small cell lung cancer treated with multiarterial infusion chemotherapy and to determine whether treatment effect can be predicted in light of perfusion parameters.

SUBJECTS AND METHODS. Forty-two patients with advanced non–small cell lung cancer were enrolled in this study. Whole-tumor dual-input perfusion CT was performed for all these patients, who subsequently received multiarterial infusion chemotherapy. The patients were divided into responders and nonresponders according to response to treatment. The rela-tion between baseline perfusion parameters and prognosis after therapy was analyzed.

RESULTS. The responder group had higher bronchial flow than the nonresponder group (p = 0.02). The AUC for bronchial flow was 0.83; pulmonary flow, 0.71; and perfusion index, 0.66. The higher bronchial flow group (≥ 65.34 mL/min/100 mL) and lower pulmonary flow group (< 23.05 mL/min/100 mL) had longer median progression-free survival periods (p = 0.01, p = 0.03) and overall survival periods (p = 0.04, p = 0.04). Multivariate analysis showed that bronchial flow was a significant prognostic factor for progression-free survival and over-all survival (p = 0.01, p = 0.02) and that pulmonary flow may be helpful for predicting pro-gression-free survival (p = 0.04) and overall survival (p = 0.03).

CONCLUSION. Whole-tumor dual-input perfusion CT can provide information on the dual blood supply of tumors, which is helpful for predicting the treatment effect of multiarte-rial infusion chemotherapy for advanced non–small cell lung cancer.

Li et al.CT of Non–Small Cell Lung Cancer

Cardiopulmonary ImagingOriginal Research

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The purposes of this study were to prospec-tively evaluate the characteristics of the dual blood supply of advanced non–small cell lung cancer by use of whole-tumor dual-input per-fusion CT and to determine whether the effect of multiarterial infusion chemotherapy can be predicted in light of perfusion parameters.

Subjects and MethodsPatient Population and Informed Consent

From March 3, 2009, to July 21, 2013, all pa-tients with suspected advanced lung cancer at our hospital were offered the opportunity to undergo perfusion CT if they met the following inclusion criteria: the lesion was pathologically proved to be

non–small cell lung carcinoma after bronchosco-py or biopsy; the tumor was believed to be a T3 or T4 lesion with or without nodal involvement or distant metastasis when the patient was enrolled in this study; the patient had never undergone an-titumor therapy and would undergo multiarterial infusion chemotherapy after admission; and there

E

Fig. 1—65-year-old man with stage III squamous carcinoma of lung.A, Routine contrast-enhanced CT image before therapy shows mass in left lung hilum. Largest diameter of mass is 3.5 cm. Multiple mediastinal lymphadenectases are evident.B, Perfusion CT image shows mean value of bronchial flow (or arterial flow) is 88.80 mL/min/100 mL, which is much higher than cutoff value (65.34 mL/min/100 mL).C, Perfusion CT image shows that mean value of pulmonary flow is 25.80 mL/min/100 mL.D, Perfusion CT image shows that mean value of perfusion index is 22.71%.E, Routine contrast-enhanced CT image 2 months after multiarterial infusion chemotherapy shows that tumor has had partial response to therapy. Mass has shrunk to 2.6 cm, and mediastinal lymph node had decreased greatly.

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was no contraindication to administration of con-trast medium.

Of 54 patients who underwent multiarterial in-fusion chemotherapy, 12 patients were excluded from this study for the following reasons: injec-tion or imaging failure (n = 3), patient noncom-pliance (n = 3), discontinuation of multiarteri-al infusion chemotherapy or transfer to another treatment (n = 4), and loss to follow-up (n = 2). Eventually, 42 patients were included in this study.

Of the 42 patients (26 men [mean age, 52 years; range, 47–72 years], 16 women [mean age, 56 years; range, 49–75 years]), 14 had disease that stayed at an operable clinical stage (≤ IIIA), but their medical condition did not allow surgery owing to advanced age (> 70 years) (n = 6), liv-er dysfunction (Child-Pugh score > 10) (n = 4), or progression of respiratory failure (Pao2 < 60 mm Hg) (n = 4). Nineteen patients could not un-dergo surgery but could not tolerate radiotherapy or standard chemotherapy for the following rea-sons: poor performance status (≥ 2) (n = 6), old age (> 70 years) (n = 8), or respiratory failure (Pao2 < 60 mm Hg) (n = 5). Nine patients could not undergo surgery but refused radiotherapy or standard chemotherapy and asked for multiarte-rial infusion chemotherapy. This study was ap-proved by the local ethics committee, and each patient gave written informed consent, which included information on the radiation exposure during the CT examinations.

Perfusion CT TechniquePerfusion CT was performed with a 320-

MDCT scanner (Aquilion One, Toshiba Medical Systems). All the patients were trained to perform a breath-hold during perfusion CT scanning (≈ 30 seconds). Shallow abdominal breathing was per-mitted at the end stage of acquisition if the patient was unable to perform a breath-hold for the entire period of CT scanning.

A preliminary unenhanced CT scan was ob-tained to localize the tumor at a slice thickness of 5 mm. Dynamic perfusion CT scanning was per-formed with the following parameters: 0.5-sec-ond gantry rotation time; 80 kVp; 80 mA; 512 × 512 matrix; 300- to 350-mm FOV; and 30-second acquisition time. The imaging range was a 16-cm area covering the mass and pulmonary hilum. Nonionic iodinated contrast medium (50 mL io-promide, 370 mg I/mL, Ultravist, Bayer Schering Pharma) was injected at a rate of 7 mL/s through the antecubital vein and followed by a 20-mL sa-line flush. The contrast agent and saline flush were administered through a dual-head power injector (Injektron CT2, Medtron). The first two volumes were acquired before contrast agent arrived in the heart and served as the baseline. Two seconds af-

ter the bolus injection, 15 intermittent low-dose volume acquisitions were made with 2-second in-tervals and without table movement. After the dy-namic study, another 50 mL of contrast medium was injected at a rate of 3 mL/s for contrast-en-hanced chest CT at 5-mm slice thickness and no scan delay. The time interval between perfusion CT scanning and the start of chemotherapy ranged from 1 to 3 days.

The radiation dose for dynamic perfusion CT and the total radiation dose were calculated from the dose-length product (DLP) listed in the expo-sure summary sheet generated by the CT equip-ment and multiplied by a factor of 0.014 [13].

Image AnalysisImaging postprocessing was performed with

the perfusion software (off-label use) of the CT equipment (Body Perfusion, Toshiba Medical Systems). The first step was volume registration to correct for motion between the dynamic vol-umes and create a registered volume series. The nonrigid volume registration was performed auto-matically when we pressed the Body Registration button of the autoanalysis software for perfusion CT. The registered volumes were then loaded into the body perfusion analysis software.

The images were computed with dual-input maximum slope mode. The pulmonary arteri-al input was measured by placement of a circu-lar ROI within the pulmonary artery trunk on a selected image. The bronchial arterial input was measured by placement of an ROI within the aor-ta. The peak time of the left atrial time-intensity curve was used to differentiate pulmonary circu-lation (before the peak time point) and bronchial circulation (after the peak time point).

The whole volume of interest was isolated by manual segmentation by two chest radiologists with more than 3 years’ experience using this analysis software. The two readers were blinded to each other’s results to allow measurement of in-terobserver variability. The volume of interest en-compassed the profiles of the mass and avoided lymphangitis and peritumoral fibrosis described as nonsolid irregularities of surrounding paren-chyma. The following settings were adopted for segmentation: The tissue upper and lower lim-its were 0 and 150 HU. The unenhanced attenu-ation was subtracted from the attenuation-time curves to obtain quantities proportional to the av-erage contrast medium concentration in the tis-sue region considered. A time-attenuation curve was produced by automatic least-squares fitting at the workstation. The initial maximum slope was also calculated automatically. With the assump-tion that venous outflow from the tumor can be ne-glected during the measurement period, perfusion

was calculated according to the following equa-tion: perfusion equals maximum initial slope of tissue curve divided by maximum attenuation of the arterial input function. Finally, perfusion im-ages with color scales and perfusion parameters, including arterial flow, pulmonary flow, and per-fusion index were calculated automatically. In this study, the perfusion parameter arterial flow was expressed as bronchial flow, which reflects the systemic blood supply of malignant lung tumors; pulmonary flow reflected the pulmonary blood supply of the tumor; and perfusion index was cal-culated according to the following equation [14]: PF / (PF + BF), where PF is pulmonary flow and BF is bronchial flow.

Stage and Grade of TumorStage IIB was defined as T2N1M0 or T3N0M0;

IIIA as T1N2M0, T2N2M0, T3N1M0, T3N1M0, or T3N2M0; IIIB as N3M0 regardless of T cate-gory or T4M0 regardless of N category; and IV as M1 regardless of T or N category [15]. Histologic grading encompassed two groups. One group in-cluded grades 1 and 2, and the other grades 3 and 4. Grade 1 was defined as good differentiation of tumor cells, grade 2 as moderate differentiation of tumor cells, grade 3 as poor differentiation of tu-mor cells, and grade 4 as lack of differentiation of tumor cells [15, 16].

Multiarterial Infusion ChemotherapyThe femoral artery was punctured by means of

the Seldinger technique. Intraarterial digital sub-traction angiography was performed to detect the feeding arteries, such as the bronchial artery, in-ternal thoracic artery, intercostal artery, and in-ferior phrenic artery. Infusion chemotherapy was performed through these feeding arteries. To avoid occluding the corresponding feeding ar-teries with the catheter, we manually performed angiography and infusion. Carboplatin (230–260 mg) and epirubicin (60–90 mg, Pharmorubicin, Pharmacia) were administered as first-line ther-apy. We generally administered the treatment at least twice at an interval of 2–4 weeks.

Evaluation Criteria of Therapeutic EffectA follow-up contrast-enhanced CT examination

was performed 4–6 weeks after treatment and once every 3 months after that. However, if the patient had relevant clinical symptoms or if other imag-ing examinations showed that the situation of the patient was suspicious, the follow-up examination was performed immediately. The median follow-up time was 16 months (range, 7.5–25.4 months).

The treatment response to therapy was deter-mined by a radiologist who had 5 years of experience in evaluation of the treatment effects of multiarte-

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rial chemotherapy and was blinded to the informa-tion on pulmonary flow, bronchial flow, and per-fusion index for every tumor. Response to treatment was classified as follows: complete response, disap-pearance of a lesion; partial response, the largest di-ameter had decreased more than 30% 12 months after treatment; progressive disease, an increase of at least 20% of the largest diameter; stable disease, neither sufficient shrinkage to qualify for partial re-sponse nor sufficient increase in the largest diameter to qualify for progressive disease [17]. The largest diameter of the lesion was measured with electronic calipers on the contrast-enhanced image that showed the largest cross-sectional area of the mass.

The patients were classified into two groups: re-sponders and nonresponders. The responders were defined as having a complete or a partial response, and the nonresponders had stable or progressive disease. Progression-free survival was measured from the baseline perfusion CT scan to the date of progression or death of any cause. Overall surviv-al was measured from the date of the baseline per-fusion CT scan to the date of death. Patients who were alive on the closeout date had their survival date censored to that date.

Statistical AnalysisStatistical analysis was performed with the SPSS

statistical package (version 13.0, IBM SPSS). The Kolmogorov-Smirnov test was used to determine whether the data fit a normal distribution. In this study, the perfusion parameters for most subgroups did not fit a normal distribution, and the sample size of some subgroups was small. Consequently, the comparison of perfusion parameters between two groups was performed with the Mann-Whitney U test. A value of p < 0.05 was considered significant.

Interobserver agreement on perfusion CT anal-ysis was assessed with the Bland-Altman method. The mean difference, SD, 95% limits of agree-ment, and interclass correlation coefficient were calculated for each of three perfusion parameters [18]. For the perfusion parameters bronchial flow, pulmonary flow, and perfusion index, ROC analy-ses were performed. The cutoff point, sensitivity, and specificity were calculated automatically with the statistical software. The cutoff point was de-fined as having the shortest distance to the left up-per corner of the ROC coordinate system.

The patients were classified into two groups on the basis of cutoff points of perfusion parameters, and the Kaplan-Meier survival curves were com-pared between the two groups. The perfusion param-eters that had prognostic value, together with tumor characteristics, were assessed by multivariate analy-sis in a Cox proportional hazards regression model. The Cox regression model was constructed by for-ward selection (introduction = 0.05; removal = 0.1).

ResultsExposure Dose to Patients

The mean DLP for the dynamic perfusion protocol was 314.3 ± 89.7 (SD) mGy · cm, or 4.4 ± 1.1 mSv (κ = 0.014). The mean DLP for the entire CT examination of each patient was 598.7 ± 120.7 mGy · cm, or 8.4 ± 3.3 mSv (κ = 0.014).

Clinical Characteristics of the PatientsAmong the 42 patients who underwent

infusion chemotherapy, seven patients re-ceived only transbronchial infusion che-motherapy because no other feeding vessel was found; 35 patients received multiarte-rial infusion chemotherapy. The clinical characteristics of these patients were sum-marized in Table 1. During the follow-up period, 23 patients had partial response to treatment, 12 patients continued to have stable disease, and seven patients contin-ued to have progressive disease.

Interobserver Agreement for CT Perfusion Analysis

Table 2 summarizes the mean value, SD, mean difference, and 95% limits of agree-ment for the two paired sets of tumor mea-surements. Good agreement was found be-tween the two observers in terms of CT perfusion analysis.

Correlation Between Baseline Perfusion Parameters and Tumor Type, Tumor Size, Tumor Stage, and Tumor Grade and Metastasis

The perfusion parameters are summarized in Table 3. There was no difference in bron-chial flow (p = 0.13), pulmonary flow (p = 0.12), or perfusion (p = 0.16) index between squamous carcinoma and adenocarcinoma.

The large-tumor group had lower bronchial flow (p = 0.03) and perfusion index (p = 0.04) than the small-tumor group, but there was no difference in pulmonary flow between the

TABLE 1: Tumor Characteristics and Clinical Tumor Response Assessment

CharacteristicNo.

(n = 42)

Pathologic type

Squamous carcinoma 25 (59.5)

Adenocarcinoma 17 (40.5)

Tumor size

< 4 cm 27 (64.3)

≥ 4 cm 15 (35.7)

Tumor stage

IIB 1 (2.4)

IIIA 13 (31.0)

IIIB 16 (38.1)

IV 12 (28.6)

Tumor grade

Well differentiated 21 (50.0)

Poorly differentiated 21 (50.0)

Lymphatic or distant metastasis

Present 23 (54.8)

Absent 19 (45.2)

Responders

Complete response 0

Partial response 23 (54.8)

Nonresponders

Stable disease 12 (28.6)

Progressive disease 7 (16.7)

Note—Values in parentheses are percentages.

TABLE 2: Interobserver Agreement on CT Perfusion Analysis (n = 42)

Perfusion Measurement MeanMean

Difference95% Limits of Agreement

Intraclass Correlation Coefficient

Pulmonary flow (mL/min/100 mL) 0.43 −1.897, 2.065 0.9975–0.9994

Observer 1 22.80 ± 7.90

Observer 2 23.23 ± 7.94

Bronchial flow (mL/min/100 mL) 1.03 −2.024, 3.245 0.9967–0.9990

Observer 1 65.44 ± 12.34

Observer 2 66.47 ± 12.58

Perfusion index (%) 0.89 −1.213, 1.465 0.9982–0.9995

Observer 1 26.21 ± 14.30

Observer 2 25.32 ± 15.41

Note—Perfusion index is defined as pulmonary flow / (bronchial flow + pulmonary flow).

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large-tumor group and the small-tumor group (p = 0.08). Tumors at a stage higher than IIIA had lower bronchial flow and pulmonary flow than tumors at stage IIIA (p = 0.02) or lower than IIIA (p = 0.03), and there was no dif-ference in perfusion index between the two groups (p = 0.09). Poorly differentiated tu-mors had higher bronchial flow (p = 0.03) and a lower perfusion index (p = 0.04) than well-differentiated tumors, and there was no dif-ference in pulmonary flow between the two groups (p = 0.11). There was no difference in bronchial flow (p = 0.11), pulmonary flow (p = 0.12), or perfusion index (p = 0.11) be-tween the group that had lymphatic or distant metastasis and the group that did not.

Baseline Perfusion Parameters and Tumor Characteristics in Responders and Nonresponders

As shown in Table 4, the responder group had higher bronchial flow than the nonresponder group (p = 0.02) (Fig. 1). The mean value of bronchial flow was 71.23 ± 17.87 mL/min/100 mL in the responder group and 59.65 ± 11.96 mL/min/100 mL in the nonresponder group. There was no difference between the two groups with respect to pulmonary flow (p = 0.07) or perfusion index (p = 0.09). There was no difference in tumor type (p = 0.14) or metas-tasis (p = 0.10) between the responder and the nonresponder groups. Response to treatment correlated with the tumor characteristics, in-cluding tumor size (p = 0.03), tumor stage (p = 0.04), and histologic grade (p = 0.04).

ROC Curves of Perfusion ParametersThe ROC curves for the perfusion param-

eters are shown in Figure 2. There was a sig-nificant difference between the area under the reference line and the AUCs for bron-

chial flow (p < 0.0001), pulmonary flow (p = 0.0002), and perfusion index (p = 0.0003). The AUC for bronchial flow was 0.83, and the cutoff value was 65.34 mL/min/100 mL, which yielded 86.1% sensitivity and 74.3%

TABLE 3: Correlation Between Baseline Perfusion Parameters and Tumor Characteristics

Characteristics No. of TumorsPulmonary Flow (mL/min/100 mL) p

Bronchial Flow (mL/min/100 mL) p

Perfusion Index (%) p

Pathologic type 0.12 0.13 0.16

Squamous carcinoma 25 21.45 ± 7.13 64.67 ± 14.34 25.21 ± 14.12

Adenocarcinoma 17 23.53 ± 8.32 67.45 ± 15.67 26.22 ± 15.21

Tumor size 0.08 0.03 0.04

< 4 cm 27 25.45 ± 9.03 60.67 ± 12.34 30.22 ± 19.13

≥ 4 cm 15 20.53 ± 6.98 71.45 ± 16.67 22.21 ± 12.33

Tumor stage 0.03 0.02 0.09

IIIA or lower 14 26.34 ± 10.23 70.76 ± 16.12 27.23 ± 18.42

Higher than IIIA 28 19.23 ± 6.12 60.89 ± 12.57 24.36 ± 14.23

Histologic grade 0.11 0.03 0.04

Well differentiated 21 24.75 ± 8.87 61.17 ± 13.86 29.27 ± 19.45

Poorly differentiated 21 20.97 ± 7.03 70.56 ± 17.09 23.26 ± 13.14

Metastasis 0.12 0.11 0.11

Present 23 23.21 ± 8.03 64.78 ± 14.89 26.43 ± 15.21

Absent 19 22.34 ± 7.76 66.46 ± 15.34 25.35 ± 14.23

Note—Data are mean ± SD. Perfusion index is defined as pulmonary flow / (bronchial flow + pulmonary flow).

TABLE 4: Difference in Baseline Perfusion Parameters and Tumor Characteristics Between Responders and Nonresponders

Perfusion Parameter Responders (n = 23) Nonresponders (n = 19) p

Bronchial flow (mL/min/100 mL) 71.23 ± 17.87 (64.32–79.12) 59.65 ± 11.96 (50.32–67.25) 0.02

Pulmonary flow (mL/min/100 mL) 20.67 ± 6.94 (15.15–28.97) 24.94 ± 8.93 (17.46–30.01) 0.07

Perfusion index (%) 24.23 ± 12.32 (16.33–29.32) 28.34 ± 19.32 (22.01–37.23) 0.09

Pathologic type (no.) 0.14

Squamous carcinoma 14/25 11/25

Adenocarcinoma 9/17 8/17

Tumor size (no.) 0.03

< 4 cm 17/27 10/27

≥ 4 cm 6/15 9/15

Tumor stage (no.) 0.04

IIIA or less 10/14 4/14

Greater than IIIA 13/28 15/28

Histologic grade (no.) 0.04

Well differentiated 8/21 13/21

Poorly differentiated 15/21 6/21

Metastasis (no.) 0.10

Present 12/23 11/23

Absent 11/19 8/19

Note—Data are mean ± SD. Values in parentheses are 95% CI. Perfusion index is defined as pulmonary flow / (bronchial flow + pulmonary flow).

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specificity. The AUC for pulmonary flow was 0.71, and the cutoff value was 23.05 mL/min/100 mL, which yielded 80.2% sensitiv-ity and 70.3% specificity. The AUC for per-fusion index was 0.66, and the cutoff value was 25.32%, which yielded 78.5% sensitivity and 65.4% specificity.

Prediction of Survival With Perfusion ParametersThe patients were classified into two groups

when the cutoff value of bronchial flow was set at 65.34 mL/min/100 mL. The median progression-free survival period for the high bronchial flow group (≥ 65.34 mL/min/100 mL) was 12.7 months, and that for the low bronchial flow group (< 65.34 mL/min/100 mL) was 7.9 months (p = 0.01) (Fig. 3A). The median overall survival periods were 19.9 and 10.8 months (p = 0.03) (Fig. 3B).

The patients were classified into two groups when the cutoff value of pulmonary flow was set at 23.05 mL/min/100 mL. The median progression-free survival period for the high pulmonary flow group (≥ 23.05 mL/min/100 mL) was 8.9 months, and that for the low pul-monary flow group (< 23.05 mL/min/100 mL) was 11.3 months (p = 0.04) (Fig. 4A). The me-dian overall survival periods were 12.6 and 17.3 months (Fig. 4B) (p = 0.04).

The patients were classified into two groups when the cutoff value of perfusion index was set at 25.32%. The median pro-gression-free survival period for the high perfusion index group (≥ 25.32%) was 9.5 months, and that for the low perfusion in-dex group (< 25.32%) was 10.6 months (p = 0.10). The median overall survival periods were 13.9 and 15.7 months (p = 0.12).

Multivariate analysis with a proportional hazards regression model showed that bron-chial flow and tumor characteristics, includ-ing tumor stage, tumor grade, and lymphatic (or distant) metastasis, were significant predic-tors of progression-free survival and overall survival. Pulmonary flow and tumor size were helpful for predicting progression-free surviv-al and overall survival. The hazard ratios for these factors are shown in Tables 5 and 6.

DiscussionTo our knowledge, this is the first study of

the correlation between CT perfusion parame-ters and the effect of multiarterial infusion che-motherapy on advanced non–small cell lung cancer. The study showed that the perfusion parameter bronchial flow was a significant fac-tor influencing a successful outcome of multi-arterial infusion chemotherapy for advanced

non–small cell lung cancer. The tumors with higher bronchial flow were more sensitive to infusion chemotherapy. In addition, baseline bronchial flow may be a significant predictor of

progression-free survival or overall survival af-ter therapy, and baseline pulmonary flow might be helpful for predicting length of progression-free or overall survival.

TABLE 5: Results of Multivariate Analysis of Progression-Free Survival Using Cox Proportional Hazards Model

Variable Hazard Ratio 95% CI p

Bronchial flow (mL/min/100 mL) 9.54 1.42–25.51 0.01

< 65.34

≥ 65.34

Pulmonary flow (mL/min/100 mL) 3.44 1.12–5.32 0.04

< 23.05

≥ 23.05

Tumor size (cm) 3.45 2.13–8.34 0.04

< 4

≥ 4

Histologic grade 6.31 1.25–30.54 0.03

1 and 2

3 and 4

Tumor stage 8.97 2.54–55.67 0.02

IIIA or lower

Higher than IIIA

Metastasis 10.25 1.29–37.34 0.01

Yes

No

TABLE 6: Results of Multivariate Analysis for Overall Survival Using Cox Proportional Hazards Model

Variable Hazard Ratio 95% CI p

Bronchial flow (mL/min/100 mL) 8.47 1.12–65.51 0.02

< 65.34

≥ 65.34

Pulmonary flow (mL/min/100 mL) 3.98 0.78–23.32 0.03

< 23.05

≥ 23.05

Tumor size (cm) 4.47 1.13–12.34 0.04

< 4

≥ 4

Histologic grade 9.57 2.02–41.58 0.02

1 and 2

3 and 4

Tumor stage 10.67 3.59–67.87 0.01

IIIA or lower

Higher than IIIA

Metastasis 12.34 1.45–75.43 0.01

Yes

No

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In this study, the dual-input CT perfusion technique, performed with two feeding ves-sels as the input function, was based on the maximum slope method, which is used for simultaneous evaluation of the pulmonary and systemic circulation of lung cancer [14, 19, 20]. The peak enhancement time point of the left atrium was used to separate the pul-monary artery and bronchial artery circula-tions because the left atrium lies functional-ly between the pulmonary circulation and the bronchial circulation [14]. In contrast, the sin-gle-input CT perfusion technique takes into account only the dominant circulation of lung cancer, and secondary circulation is ignored, which may result in underestimation of the pulmonary circulation of lung cancer [14].

The scanning duration was short, set at 30 seconds, in this study because the CT per-fusion technique with the maximum slope method is based only on the initial upslope of the time-attenuation curve [20]. In addi-tion, the injection rate of contrast medium must be high because the perfusion param-eters are more accurate only when the tumor maximum slope enhancement is reached be-fore venous drainage begins [14, 19]. There-fore, use of a short injection time resulting in a flow rate of 7 mL/s is mandatory because the requirements for this application are markedly higher than for the liver because the pulmonary transit time is considerably shorter than the mesenteric transit time.

Respiratory motion has an adverse influ-ence on perfusion CT of the chest and can re-

duce image quality and examination reliabil-ity. For example, the incidence of perfusion CT failure due to respiratory motion was 15.5% in the study by Wang et al. [21]. In con-trast, only three patients were excluded from this study because of respiratory motion. The noise of CT images caused by use of low volt-age was resolved with an application for mo-tion correction and noise reduction. The new perfusion software used in our study enabled motion correction and thus reduced misregis-tration respiratory artifacts. In addition, short scan duration contributed to reducing imag-ing failure caused by respiratory motion.

This study showed that perfusion parame-ters were influenced by tumor size. Larger tu-mors had lower bronchial flow and pulmonary flow values than smaller tumors, possibly be-cause the larger tumors may be prone to ne-crosis and thus become more heterogeneous, which might have led to the decrease in mea-surements of bronchial flow and pulmonary flow [22]. In addition, the larger tumor had lower perfusion index than smaller tumor. This phenomenon implies that the systemic circu-lation increases and eventually becomes the dominant blood supply to the tumor when tu-mor size increases, which is consistent with the results in the study by Yuan et al. [14]. Spira et al. [23] measured perfusion parameters in different lung cancer subtypes and found that blood volume and blood flow (bronchial flow) did not differ significantly between adeno-carcinoma, squamous cell carcinoma, and small cell lung cancer. Similarly, in our study,

we found no significant differences in the per-fusion parameters bronchial flow, pulmonary flow, and perfusion index between adeno-carcinoma and squamous cell lung cancer.

Li et al. [24] analyzed the variation of CT perfusion parameters in different stages and found that the perfusion values peak en-hancement and blood volume of T2 tumors were significantly lower than those of T1 tu-mors, but they found no statistically significant difference between other stages of tumors. In contrast, we compared the perfusion parame-ters among the tumors at different stages and found that tumor in higher stages had lower bronchial flow and pulmonary flow than tu-mors at lower stages. The disparity between the two studies may be due to differences in evaluation methods and stages of disease in different patients. Poorly differentiated tumors had higher bronchial flow or a lower perfusion index than well-differentiated tumors. We also found that the perfusion parameters of lung cancer were not associated with lymphatic or distant metastasis, which implies that lymph node or distant metastasis depends not only on angiogenesis but also on other factors, such as angiolymphatic invasion, adhesion molecules, and the immunologic mechanism [25].

There is a disagreement on the proportion of pulmonary circulation in the total blood sup-ply of lung carcinoma. Kiessling et al. [22] in-vestigated tumor vasculature and angiogenesis using dynamic perfusion CT with a single-in-put maximum slope mode and found that in ap-proximately 29% of tumors, pulmonary vessels

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AFig. 3—Correlation between baseline bronchial flow (BF) and survival after multiarterial infusion chemotherapy.A, Kaplan-Meier plot shows median progression-free survival period is 12.7 months for high bronchial flow group (≥ 65.34 mL/min/100 mL) and 7.9 months for low bronchial flow group (< 65.34 mL/min/100 mL) (p = 0.01).B, Kaplan-Meier plot shows median overall survival period is 19.9 months for high bronchial flow group (≥ 65.34 mL/min/100 mL) and 10.8 months for low bronchial flow group (< 65.34 mL/min/100 mL) (p = 0.03).

BFig. 2—ROC curves for three perfusion parameters show that AUCs of bronchial flow (BF), pulmonary flow (PF), and perfusion index (PI) are 0.83, 0.71, and 0.66, and cutoff values are 65.34 and 23.05 mL/min/100 mL and 25.32%. There is significant difference between area under reference line and AUCs for bronchial flow (p < 0.0001), pulmonary flow (p = 0.0002), and perfusion index (p = 0.0003).

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also served as the feeding artery of the tumor. Nakano et al. [26] investigated the feasibility of separately evaluating bronchial arterial and pulmonary arterial perfusion of lung cancer us-ing dual-input perfusion CT and found that the mean bronchial arterial perfusion was 26.8 ± 26.4 mL/min/100 mL, mean pulmonary arte-rial perfusion was 25.1 ± 19.12 mL/min/100 mL, and the mean total blood perfusion (de-fined as the percentage of pulmonary arteri-al perfusion in the sum of pulmonary arterial perfusion and bronchial arterial perfusion) was 48.8% ± 31.9%.

The mean perfusion index in our study is similar to that in a study by Yuan et al. [27], who evaluated the dual blood supply of lung carcinoma using the same instrument and eval-uation as we used and found that the mean per-fusion index was approximately 30%. In an-other study, however, Yuan et al. [14] found that the mean value of perfusion index was approx-imately 21%. The possible reasons for the dis-crepancy between these studies are as follows: First, the difference in method of perfusion CT may contribute to the disparity between stud-ies. In the study by Kiessling et al. [22], single-input maximum slope mode was used, and the thoracic aorta was selected to determine the ar-terial input function. Therefore, pulmonary flow may be underestimated because the effect of the pulmonary artery as the input function was not considered. Second, dual blood supply depends on tumor characteristics, including size, location, and stage [26]. We believe that the differences in tumor characteristics among these studies may be an important reason for the disparity in percentage of pulmonary flow in the blood supply of lung cancers.

It is notable that not only the bronchial ar-tery but also other arteries of the systemic cir-culation, such as intercostal arteries, the in-ternal thoracic artery, and the inferior phrenic artery, contribute to the measurement of bron-chial flow when the time-attenuation curve of the aorta is used as the input function for sys-temic circulation [14]. Therefore, the perfusion parameter bronchial flow reflects all the feed-ing arteries of the systemic circulation rath-er than only the bronchial artery. This study showed that the perfusion parameter bronchi-al flow may be a predictor of treatment effect of multiarterial infusion chemotherapy, which is helpful for guiding treatment of lung cancer. If bronchial flow is high, a more satisfactory treatment effect and longer survival may be ob-tained; in contrast, if bronchial flow is low, the patient may have poor response to treatment, and another conservative therapy should be

considered. When the cutoff point of bronchi-al flow was set at 65.34 mL/min/100 mL, sen-sitivity was 86.1% and specificity was 74.3%. In addition, the high bronchial flow group had longer median progression-free survival and overall survival periods. The possible reason is that if bronchial flow is higher, more chemo-therapeutic agent may be prone to pass through the incomplete tumor vessels and to have anti-tumor function, which leads to good response to multiarterial infusion chemotherapy [10, 21].

Wang et al. [21] in our department investi-gated the feasibility of perfusion CT using de-convolution mode for prediction of early re-sponse after chemoradiotherapy for non–small cell lung cancer. They found that perfusion CT could serve as a significant predictor of early tumor response and overall survival. Similar-ly, in our study, we had comparable results us-ing perfusion CT with maximum slope mode and confirmed the value of perfusion CT in predicting the treatment effect of multiarteri-al chemotherapy. Compared with the study by Wang et al., our study had the following advan-tages. First, perfusion CT performed with du-al-input perfusion mode provided information on the value of both systemic circulation and pulmonary circulation in making a prognosis about lung carcinoma. The study by Wang et al. did not provide this information. Second, in their study, only four slices were selected, so the perfusion parameters did not adequately re-flect perfusion of the whole tumor. In contrast, in our study, whole-tumor perfusion CT was used, and the perfusion parameters reflected perfusion of the whole tumor.

This study showed that there was no statis-tical difference in pulmonary flow values be-tween responders and nonresponders. This re-sult might have been due to small sample size or other, unclear reasons. The ROC curve for pulmonary flow showed that the AUC was 0.71.

Kaplan-Meier plots showed that the higher pul-monary flow group had a shorter progression-free survival period and overall survival period, which is helpful for predicting the prognosis of lung carcinoma. This phenomenon may have occurred because infusion chemotherapy was performed through the bronchial artery or mul-tiple systemic arteries but not through the pul-monary artery. Therefore, if pulmonary flow is high, the treatment effect may be undermined [3, 28]. There is a discrepancy between the lack of pulmonary flow difference between re-sponders and nonresponders and the weakly significant predictive difference in the survival data. The possible reasons are as follows: First, the tumor response to treatment mainly reflects a short-term treatment effect, but survival data mainly reflect the long-term treatment effect. Second, the proportion of pulmonary circula-tion may change over time after therapy owing to the change in bronchial circulation caused by infusion chemotherapy, and thus the pulmo-nary flow values at different stages after thera-py may be varied [2, 3].

The perfusion index reflects the ratio of the pulmonary blood supply to the to-tal blood supply of a malignant lung tumor, which varies from person to person. This study showed that there was no significant difference in perfusion index values between the responder and nonresponder groups. The AUC for perfusion index was 0.66. There were no differences in progression-free sur-vival and overall survival rates between the low perfusion index group and the high per-fusion index group. Whether the absence of significant difference in perfusion index was due to small sample size or other, unclear factors needs further research.

There were several limitations to this study. First, perfusion was calculated by maximum slope method rather than deconvolution meth-

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AFig. 4—Correlation between baseline pulmonary flow (PF) and survival after multiarterial infusion chemotherapy.A, Kaplan-Meier plot shows median progression-free survival period is 8.9 months for high PF group (≥ 23.05 mL/min/100 mL) and 11.3 months for low PF group (< 23.05 mL/min/100 mL) (p = 0.04).B, Kaplan-Meier plot shows median overall survival period is 12.6 months for high pulmonary flow group (≥ 23.05 mL/min/100 mL) and 17.3 months for low pulmonary flow group (< 23.05 mL/min/100 mL) (p = 0.04).

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od, and the parameters were based on the maximum slope of the time-intensity curve and the enhancement peak of the input ves-sel. Therefore, blood volume, mean transit time, and permeability–surface area product could not be generated directly [19, 20]. Sec-ond, most cases stayed at stage III or IV and some tumors were accompanied by obstruc-tive pneumonia or atelectasis, which resulted in uncertainty of the tumor margins. There-fore, it was difficult to accurately evaluate tu-mor size. Third, although we tried to decrease the radiation exposure of patients by reducing the kilovoltage and tube current for CT, and the shorter scanning time would additional-ly decrease the radiation exposure, perfusion CT scanning still increased the additional ra-diation exposure of patients. Fourth, the bias in parameter mean values might have been caused by noisy pixel data resulting from the low dose used in this study, and only four time points were available for calculating the slope of a voxel for the pulmonary enhancement part. Finally, after chemotherapy, the blood supply of lung tumors frequently changed, which might have influenced prognosis. We did not investigate the influence of this change in blood supply on treatment effect.

ConclusionWhole-tumor dual-input perfusion CT can

provide useful information about the dual blood supply of tumors. This information is helpful for predicting the effect of treatment of advanced non–small cell lung cancer with multiarterial infusion chemotherapy. Tumors with higher bronchial flow value may have a good response to multiarterial infusion che-motherapy. Bronchial flow is a significant prognostic factor for progression-free sur-vival and overall survival, and pulmonary flow may be helpful for predicting progres-sion-free and overall survival.

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