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Immunotherapy biomarkers
Original research
Correlation of Ktrans derived from dynamic contrast-enhanced MRI with treatment response and survival in locally advanced NSCLC patients undergoing induction immunochemotherapy and concurrent chemoradiotherapy
  1. DaQuan Wang1,
  2. SongRan Liu2,
  3. Jia Fu2,
  4. PengXin Zhang1,
  5. ShiYang Zheng1,
  6. Bo Qiu1,
  7. Hui  Liu3,
  8. YongQuan Ye4,
  9. JinYu Guo1,
  10. Yin Zhou5,
  11. HaiHang Jiang5,
  12. ShaoHan Yin6,
  13. HaoQiang He6,
  14. ChuanMiao Xie6 and
  15. Hui Liu1
  1. 1Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China
  2. 2Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China
  3. 3United Imaging Healthcare, ShangHai, China
  4. 4United Imaging of Healthcare America, Houston, Texas, USA
  5. 5SuZhou TongDiao Company, Suzhou, China
  6. 6Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China
  1. Correspondence to Hui Liu; liuhuisysucc{at}126.com; ChuanMiao Xie; xiechm{at}sysucc.org.cn; HaoQiang He; hehq{at}sysucc.org.cn

Abstract

Purpose This study aimed to investigate the prognostic significance of pretreatment dynamic contrast-enhanced (DCE)-MRI parameters concerning tumor response following induction immunochemotherapy and survival outcomes in patients with locally advanced non-small cell lung cancer (NSCLC) who underwent immunotherapy-based multimodal treatments.

Material and methods Unresectable stage III NSCLC patients treated by induction immunochemotherapy, concurrent chemoradiotherapy (CCRT) with or without consolidative immunotherapy from two prospective clinical trials were screened. Using the two-compartment Extend Tofts model, the parameters including Ktrans, Kep, Ve, and Vp were calculated from DCE-MRI data. The apparent diffusion coefficient was calculated from diffusion-weighted-MRI data. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to assess the predictive performance of MRI parameters. The Cox regression model was used for univariate and multivariate analysis.

Results 111 unresectable stage III NSCLC patients were enrolled. Patients received two cycles of induction immunochemotherapy and CCRT, with or without consolidative immunotherapy. With the median follow-up of 22.3 months, the median progression-free survival (PFS) and overall survival (OS) were 16.3 and 23.8 months. The multivariate analysis suggested that Eastern Cooperative Oncology Group score, TNM stage and the response to induction immunochemotherapy were significantly related to both PFS and OS. After induction immunochemotherapy, 67 patients (59.8%) achieved complete response or partial response and 44 patients (40.2%) had stable disease or progressive disease. The Ktrans of primary lung tumor before induction immunochemotherapy yielded the best performance in predicting the treatment response, with an AUC of 0.800. Patients were categorized into two groups: high-Ktrans group (n=67, Ktrans＞164.3×10−3/min) and low-Ktrans group (n=44, Ktrans≤164.3×10−3/min) based on the ROC analysis. The high-Ktrans group had a significantly higher objective response rate than the low-Ktrans group (85.1% (57/67) vs 22.7% (10/44), p<0.001). The high-Ktrans group also presented better PFS (median: 21.1 vs 11.3 months, p=0.002) and OS (median: 34.3 vs 15.6 months, p=0.035) than the low-Ktrans group.

Conclusions Pretreatment Ktrans value emerged as a significant predictor of the early response to induction immunochemotherapy and survival outcomes in unresectable stage III NSCLC patients who underwent immunotherapy-based multimodal treatments. Elevated Ktrans values correlated positively with enhanced treatment response, leading to extended PFS and OS durations.

  • Dynamic contrast-enhanced MRI
  • Ktrans
  • treatment response
  • immunotherapy
  • lung cancer

Data availability statement

Data are available on reasonable request. The datasets are available from the corresponding authors on reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2023-008574

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • The promising long-term outcomes of neoadjuvant immunochemotherapy in resectable non-small cell lung cancer (NSCLC) patients have been confirmed by several prospective trials, including Checkmate 816, NADIM, and Checkmate 77T trials. A recent study showed that the neoadjuvant immunochemotherapy was not only effective but also had a favorable safety profile for unresectable stage III NSCLC. The quest for a precise and sensitive biomarker capable of predicting treatment response to neoadjuvant immunochemotherapy and subsequent survival outcomes remains ongoing and unresolved.

    WHAT THIS STUDY ADDS

    • This study suggested that the Ktrans of primary lung tumor before induction immunochemotherapy, derived from dynamic contrast-enhanced (DCE)-MRI, was effective in predicting the treatment response to immunochemotherapy, with an area under the curve of 0.800. The high-Ktrans group had notably better objective response rate, prolonged progression-free survival and overall survival than the low-Ktrans group. The high-Ktrans group had higher infiltrations of CD3+/CD8+T cells and CD68+/CD86+macrophages than the low-Ktrans group.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • In future clinical practice, the DCE-MRI scan could serve as a non-invasive tool to characterize immune microenvironment and predict response to immunotherapy-based multimodal treatments and survival in unresectable stage III NSCLC.

    Introduction

    The immunotherapy targeting programmed cell death protein 1 (PD-1) and its ligand (PD-L1) has brought a breakthrough in the treatment of non-small cell lung cancer (NSCLC).1 Several prospective trials reported promising long-term outcomes of neoadjuvant immunochemotherapy in resectable NSCLC patients, including Checkmate 816, NADIM, and checkmate 77T trials.2–4 The Checkmate 816 study demonstrated that neoadjuvant nivolumab combined with chemotherapy led to prolonged event-free survival (EFS) (median: 31.6 vs 20.8 months, p=0.005) and a higher pathological complete response (pCR) rate (24.0% vs 2.2%, p<0.005) than chemotherapy alone.3 Patients who achieved a pCR or major response after immunochemotherapy had significantly longer EFS compared with those who did not.3 Because of the encouraging data, the utility of neoadjuvant immunochemotherapy in unresectable NSCLC has been started to explore. A recent study enrolled 94 unresectable NSCLC patients who received immunochemotherapy as neoadjuvant treatment.5 There were 68 patients with stage IIIA disease and 26 with stage IIIB. The surgery conversion rate was 74.4%. Of the 64 patients undergoing surgery, the major pathological response rate and pCR rate were 65.6% and 42.2%, respectively. The grade ≥3 treatment-related adverse events occurred in only 3.2% of patients. The results showed that the neoadjuvant immunochemotherapy was not only effective but also had a favorable safety profile for unresectable stage III NSCLC.5 Despite the notable response observed with neoadjuvant immunochemotherapy, as highlighted in the Checkmate 816 study, a portion of patients, accounting for 26.8%, were deemed ineligible for surgery, with 17 patients resorting to radiotherapy.3 Among the subset of patients who underwent neoadjuvant immunochemotherapy without definitive surgical intervention, the EFS rate at the 24-month mark stood at 41%, accompanied by a median time to distant metastasis of 24.8 months.3 These outcomes furnish compelling evidence advocating for the potential efficacy of neoadjuvant immunochemotherapy as a viable therapeutic avenue for individuals grappling with unresectable locally advanced NSCLC (LA-NSCLC).

    Recently, several studies have explored the biomarkers linked to the response to neoadjuvant immunochemotherapy in NSCLC. In the NADIM trial, 11 peripheral blood immune parameters and two tissue T-cell receptor (TCR) parameters were found to be associated with pCR to neoadjuvant immunochemotherapy in stage IIIA NSCLC patients.6 7 In the Checkmate 816 trial, circulating tumor DNA clearance was confirmed to be associated with both pCR and overall survival (OS) of patients.3 Nevertheless, within the subset of LA-NSCLC patients undergoing neoadjuvant immunochemotherapy without definitive surgery, the challenge arises due to the inherent difficulty in obtaining surgical samples for thorough pathological analysis. As such, the quest for a precise and sensitive biomarker capable of predicting treatment response to neoadjuvant immunochemotherapy and subsequent survival outcomes remains ongoing and unresolved.

    MRI is a widely available clinical imaging modality with the potential to address certain challenges in assessing response to immunotherapy.8 MRI employs a variety of sequences to investigate tissue anatomy, microstructure, physiology, and function, producing excellent soft tissue contrast at a high spatial resolution throughout the body.9 10 Multiple sequences can be combined in a multiparametric approach to generate a comprehensive imaging phenotype of the tumor microenvironment.11 The apparent diffusion coefficient (ADC) extracted from diffusion-weighted (DW)-MRI correlates with cellularity and has been used to predict the response of lung cancer to therapy.12–14 Dynamic contrast-enhanced MRI (DCE-MRI), as a valuable measure for studying the hemodynamic process of contrast agents entering and exiting tumors, enables the assessment of tissue perfusion and oxygenation at a macroscopic level.15 The pharmacokinetic parameters derived from DCE-MRI, such as Ktrans (the volume transfer rate), Ve (the extravascular extracellular volume fraction), Vp (the blood plasma volume fraction) and Kep (the efflux rate constant), provide quantitative information about the changes in vascular delivery and extracellular space.16 17 A recent study found that the contrast index (CI) parameters examined by DCE-MRI were associated with microvessel density and PD-L1 level in oral squamous cell carcinoma.18 Several studies showed promising role of DCE-MRI parameters to predict the efficacy of chemoradiotherapy in solid tumors.19–22 Tong et al found that the baseline Ktrans of primary rectal tumor was effective in predicting the response to neoadjuvant chemoradiotherapy, with area under the curve (AUC) of 0.92.23 The early prediction of response to immunotherapy with imaging biomarkers would be beneficial for risk stratification and treatment decision-making in unresectable LA-NSCLC. Given that MRI scan is non-invasive, identifying valid MRI parameters to assess the therapeutic effect of immunotherapy can minimize the physical burden on patients caused by biopsies and enhance its clinical applicability.

    In this study, quantitative multiparametric MRI assessments were performed on individuals diagnosed with unresectable LA-NSCLC. The primary aim was to evaluate the prognostic relevance of DCE-MRI parameters regarding tumor response postinduction immunochemotherapy and survival prognosis in LA-NSCLC patients receiving combined chemotherapy, immunotherapy, and radiotherapy. The exploration of pretreatment non-invasive functional imaging had potential value for informing clinical decision-making processes.

    Material and methods

    Patients

    The unresectable stage III NSCLC patients treated by induction immunochemotherapy, concurrent chemoradiotherapy (CCRT) with or without consolidative immunotherapy in our institution from two prospective clinical trials were screened (NCT02573506, NCT03900117).24 25 Patients were required to meet the following criteria: (1) histologically confirmed NSCLC; (2) aged 18 years or more; (3) inoperable stage III disease base on the eighth edition of the TNM (tumor, node, metastases) staging system; (4) Eastern Cooperative Oncology Group (ECOG) performance status score of 0–1; (5) receiving two cycles of induction immunochemotherapy; and (6) receiving chest DW-MRI and DCE-MRI scans before and after the induction immunochemotherapy. After screening, 116 patients were eligible for the study. Five patients were further excluded due to the limitations in making tumor measurements, including tumor atelectasis (n=1), diffuse tumor manifestation (n=1) and too small tumor size (tumor volume <1 cm3, n=3). Finally, a total of 111 patients were enrolled in the study.

    Treatment

    The enrolled patients received two cycles of induction chemotherapy combined with PD-1 inhibitor and they did not receive any prior therapies before undergoing induction immunochemotherapy. The chemotherapy regimens consisted of docetaxel (60 mg/m2 day 1) plus 75 mg/m2 of cisplatin, administered once every 3 weeks. The PD-1 inhibitors included nivolumab (360 mg, day 1) (n=106), tislelizumab (200 mg, day 1) (n=3) and camrelizumab (200 mg, day 1) (n=2), administered on day 1 of chemotherapy.

    Patients were evaluated by a multidisciplinary team after induction immunochemotherapy, those who were not eligible for surgery would receive definitive CCRT with or without consolidative immunotherapy. Hypofractionated radiotherapy was delivered with a total dose of 64–69 Gy in 16–23 fractions, using the intensity modulated radiation therapy technique and volumetric modulated arc therapy technique. The concurrent chemotherapy regimen was docetaxel (25 mg/m2) plus nedaplatin (25 mg/m2), administered once a week.

    Consolidative immunotherapy was initiated within a time frame of 4–8 weeks following CCRT. The PD-1 inhibitors used were nivolumab (360 mg, day 1), tislelizumab (200 mg, day 1), and camrelizumab (200 mg, day 1). The consolidative immunotherapy was administered in a regimen of once every 3 weeks, continuing for up to 1-year post-CCRT.

    MRI scan protocol

    The chest MRI scan was conducted at two time points: 1–7 days prior to induction immunochemotherapy and 2 weeks following induction immunochemotherapy. Patients were imaged using a 3.0T magnetic scanner (uMR 780, United Healthcare, Shanghai, China). Both DCE-MRI and DW-MRI scans were acquired for patients. The detailed parameters of the MRI sequences are shown in table 1. Before DCE-MRI acquisition, data for constructing a T1 map were obtained using an RF-spoiled 3D gradient echo multiflip angle approach. The T1 map and DCE scans shared the following parameters: the TR was 4.23 ms, the TE was 1.87 ms, and the acquisition matrix was 176×112 with a slice thickness of 3 mm. Dynamic scanning was performed over 60 phases while allowing free breathing. The temporal resolution was 6.28 s per phase, resulting in a total scan time of 6 min 17 s. The initial 10 phases were unenhanced baseline scans. Subsequently, the contrast agent, Gadobenate Dimeglumine (Bracco, Shanghai, China, 0.2 mL/kg), was administrated as an intravenous bolus injection at a flow rate of 2.5 mL/s. DW-MRI was obtained with a single-shot spin echo (SE) echo planar imaging sequence, and the parameters were as follows: TR: 4000 ms, TE: 64 ms, MATRIX: 112×112, field of view: 380×380 mm, b values: 50, 700 s/mm2. Respiratory triggering was employed during DW-MRI imaging. The average total scanning time for DW-MRI was 3 min and 8 s.

    View this table:
    Table 1

    The chest MRI scan parameters for a 3.0T magnetic scanner

    The quantitative MRI scanning and processing protocols are illustrated in figure 1. Both pretreatment and post-treatment MRI scans used identical protocol parameters. The processing pipeline included non-rigid registration to handle distortions in DWI acquisition and respiratory motion during rapid DCE acquisition. An ADC map was generated at each axial slice position and connected to the corresponding source DWI images. The primary lung tumors were collaboratively delineated by a radiation oncologist and a radiologist, both had over 10 years of professional experience. A consensus was achieved in case of any inconsistency. The delineations were performed on the last phase of DCE and then transferred to ADC images and DCE parametric images. The complete tumor volume was delineated to calculate ADC values and kinetic parameters. The tumor necrosis was regarded as part of the tumor in delineation. The arterial input function was labeled on an artery near the tumor and automatically calculated for each patient. DCE parametric metrics, including Ktrans, Kep, Ve and Vp, were calculated using two-compartment Extend Tofts model from DCE and T1 maps. The calculations were performed using the DCE analysis workstation (United-Imaging Healthcare, Shanghai, China). The study used the mean values of all parameters.

    Figure 1
    Figure 1

    (A) The treatment and imaging protocol of patients. (B) The MRI scanning and processing protocols for the measurement of kinetic parameters and apparent diffusion coefficient (ADC) values. DCE, dynamic contrast-enhanced; DWI, diffusion-weighted imaging; GRE, gradiant echo; NSCLC, non-small cell lung cancer; VOI, volume of interest.

    Tumor response evaluation

    The tumor response to induction immunochemotherapy was assessed based on the Response Evaluation Criteria in Solid Tumors (RECIST V.1.1) criteria.26 Patients were categorized as having CR, partial response (PR), stable disease (SD) or progressive disease (PD).

    Immunohistochemistry for biopsy specimens

    Histopathological biopsy specimens were obtained before induction immunochemotherapy. The formalin-fixed paraffin-embedded tissue samples of the primary lung tumors were sliced at a thickness of 3 µm. H&E stains were used for tumor area identification. Initially, the slices were deparaffinized and hydrated. Subsequently, the slices underwent antigen retrieval by exposure to EDTA (pH 8.0) and heating at 95°C in an autoclave. Afterward, the slices were allowed to cool down naturally. To block the activity of endogenous peroxidase, the slides were incubated with a 3% hydrogen peroxide solution for 10 min. Subsequently, the slides were coincubated with primary antibodies against CD3 (ZS, clone LN10), CD8 (ZS, clone SP16), CD68 (ZS, clone KP1), CD86 (CST, clone E2G8P), CD163 (ZS, clone 10D6), CD206 (CST, clone E6T5J) and Ki67 (ZS, clone MIB1) for 60 min at 37°C, using respective antibody buffers for blank controls. The next day, tissue sections were washed three times for 2 min each with PBS and then incubated with an enzyme-labeled secondary antibody (ZS) at 37°C for 20 min. Following three additional 2 min washes, tissue sections were incubated with freshly prepared enzyme substrate 3,3′-diaminobenzidine for approximately 5 min at room temperature. Finally, the slides were counterstained with hematoxylin.

    The stained slices were scanned using the Aperio Scanner (Leica Biosystem, Wetzlar, Germany). Two pathologists with more than 5 years of experience reviewed the images, and they were blinded to the patients’ clinical data. The pathologists assessed the immunohistochemistry (IHC) quality. Consensus was reached through discussion in case of any disagreements. The digital image analysis (DIA) was performed using Patholmpression software via the Evidance Platform (TongDiao Company, SuZhou, China) to quantify CD3+/CD8+ tumor-infiltrating lymphocyte (TIL), CD68+/CD86+/CD163+/CD206+ tumor-associated macrophages (TAMs) and Ki67 expression. Over the whole tissue slide, any intensity of cytoplasmic or membranous staining of mononuclear immune cells contributed to the positive percentage of tumor infiltrating lymphocytes or TAMs, and the percentage was based on the total tissue. Ki67 level was recorded as the percentage of positive invasive tumor cells with any nuclear staining regardless of intensity, and the percentage was based on total tumor cells.

    Statistical analysis

    The MRI parameters were reported in the format of “mean±SD”. The MRI parameters were compared between pretreatment and post-treatment groups with paired t-test. The receiver operating characteristic (ROC) curve and the AUC the ROC curve were applied to evaluate the predictive performance of MRI parameters. The parameter with the highest AUC value was selected for patient classification. The parameter value that maximizes (sensitivity+specificity−1) is considered as the optimal cut-off for grouping patients. The OS was calculated from the start date of immunochemotherapy to death or last follow-up if still alive. The progression-free survival (PFS) was calculated from the start date of immunochemotherapy to progression, death, or the last follow-up. Survival time was estimated using the Kaplan-Meier method and compared by the log-rank test. The Cox regression model was used to perform univariate and multivariate analyses for PFS and OS. The variables that showed a univariate relationship with outcome were included into multivariate Cox proportional-hazards regression model. The comparisons of IHC indices between different groups were performed using independent samples t-test. A p<0.05 was considered statistically significant. All statistical analyses were performed by using SPSSV. 22.0 (IBM).

    Results

    Clinical characteristics

    A total of 111 patients were enrolled in the analysis. The patients’ clinical characteristics are illustrated in table 2. The median age of all patients was 61 years (range, 33–76). There were 98 males (88.3%) and 13 females (11.7%). Of them, 19 (17.1%), 56 (50.5%) and 36 (32.4%) patients had stage IIIA, IIIB and IIIC disease, respectively. The mean volume of primary tumors was 74.0±68.1 cm3. The median forced expiratory volume at 1 s (FEV1) was 2.36 L (range, 1.0–5.38 L). After induction immunochemotherapy, 67 patients (60.4%) achieved CR or PR and 44 patients (39.6%) achieved SD or PD.

    View this table:
    Table 2

    The clinical characteristics of patients

    The univariate and multivariate analysis for survival

    With a median follow-up of 22.3 months, the median PFS and OS for all patients were 16.3 and 23.8 months, respectively. The univariate analysis showed that the ECOG score (0 vs 1), TNM stage (IIIA vs IIIB vs IIIC) and the response to immunochemotherapy (CR+PR vs SD+PD) were associated with both PFS and OS (table 3). The CR+PR patients had significantly better PFS (median: 21.1 months vs 11.1 months, p<0.001) and OS (median: not reached vs 16.1 months, p=0.01) than the SD+PD patients (figure 2). The variables of ECOG score, TNM stage and the response to immunochemotherapy were included in the multivariate analysis, and the results showed that all of them were independent factors affecting both PFS and OS (table 3).

    View this table:
    Table 3

    The univariate and multivariate analysis for progression-free survival and overall survival among 111 NSCLC patients

    Figure 2
    Figure 2

    The comparisons of progression-free survival (PFS) and overall survival (OS) between the CR+PR patients (n=67) and SD+PD patients (n=44). The CR+PR patients presented better PFS and OS than the SD+PD patients. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

    The DCE-MRI and DW-MRI data before and after induction immunochemotherapy

    The median time interval between the MRI scans of before and after induction immunochemotherapy was 45 days. The Ktrans, Kep, Ve, Vp and ADC of primary lung tumors before induction immunochemotherapy were 239.65±171.72×10−3/min, 768.26±351.24×10−3/min, 292.52±155.41×10−3, 11.48±11.0×10−3 and 1231.25±233.69×10−6 mm2/s, respectively. The Ktrans, Kep, Ve, Vp and ADC of primary lung tumors after induction immunochemotherapy were 278.77±232.38×10−3/min, 816.7±467.39×10−3/min, 331.05±188.14×10−3, 15.49±14.0×10−3 and 1608.38±335.73×10−6 mm2/s, respectively. Significant difference was observed in Ktrans (p=0.027), Vp (p<0.001) and ADC (p<0.001) values before and after induction immunochemotherapy (figure 3).

    Figure 3
    Figure 3

    The comparisons of Ktrans, Kep, Ve, Vp and ADC for primary tumors before and after induction immunochemotherapy (IC), using the paired t-test. ADC, apparent diffusion coefficient.

    The predictive value of DCE-MRI and DW-MRI parameters for tumor response to induction immunochemotherapy in LA-NSCLC patients

    Table 4 shows the ROC analysis of DCE-MRI and DW-MRI parameters to predict tumor response, including Ktrans, Kep, Ve, Vp and ADC of primary lung tumors. Figure 4 shows the ROC curves of the MRI parameters whose AUC value was more than 0.7. The Ktrans before induction immunochemotherapy yielded the best AUC, with value of 0.800 (95% CI 0.710 to 0.891). The Ve before induction immunochemotherapy, ADC and Ktrans after induction immunochemotherapy yielded moderate AUC values of 0.722, 0.772 and 0.707, respectively.

    View this table:
    Table 4

    The ROC analysis of MRI parameters for the prediction of response to induction immunochemotherapy

    Figure 4
    Figure 4

    The receiver operating characteristic (ROC) curves of Ktrans (before and after induction immunochemotherapy (IC)), Ve (before induction IC) and ADC (after induction IC) (the parameters with area under curve (AUC) being more than 0.7) on predicting tumor response to induction IC in locally advanced non-small cell lung cancer patients. The Ktrans (before induction IC) yielded the best AUC, with value of 0.800. ADC, apparent diffusion coefficient.

    Categorizing LA-NSCLC patients into high-Ktrans and low-Ktrans groups based on Ktrans value of primary lung tumors before induction immunochemotherapy

    Based on the ROC analysis of Ktrans value of primary lung tumors before induction immunochemotherapy, patients were categorized into two groups: high-Ktrans group (n=67, Ktrans>164.3×10−3/min) and low-Ktrans group (n=44, Ktrans≤164.3×10−3/min). At the baseline, the volumes of the primary lung tumors were similar between the high-Ktrans and low-Ktrans groups (70.5±65.1 cm3 vs 79.3±72.8 cm3, t=0.661, p=0.51). Following induction immunochemotherapy, the volumes of primary lung tumors in the high-Ktrans group significantly decreased compared with the low-Ktrans group (25.1±38.3 cm3 vs 65.5±78.0 cm3, t=3.64, p<0.001).

    Comparisons of treatment response to induction immunochemotherapy and survival between the high-Ktrans and low-Ktrans groups

    There were 67 patients in the high-Ktrans group and 44 patients in the low-Ktrans group.

    The objective response rate (ORR) to the induction immunochemotherapy of the High-Ktrans group was significantly higher than the low-Ktrans group (85.1% (57/67) vs 22.7% (10/44), p<0.001, figure 5). The high-Ktrans group presented better PFS (median: 21.1 vs 11.3 months, p=0.002) and OS (median: 34.3 vs 15.6 months, p=0.035) than the low-Ktrans group (figure 6).

    Figure 5
    Figure 5

    The changes in sum of unidimensional tumor dimension from baseline in individual patients.

    Figure 6
    Figure 6

    The comparisons of progression-free survival (PFS) and overall survival (OS) between the high-Ktrans group (n=67, Ktrans>164.3×10−3/min) and low-Ktrans group (n=44, Ktrans≤164.3×10−3/min). The high-Ktrans group presented better PFS and OS than the low-Ktrans group.

    The following figures illustrate the DCE image and ADC map of the primary lung tumors in a high-Ktrans patient (Ktrans=213.7×10−3/min before induction immunochemotherapy, figure 7) and in a low-Ktrans patient (Ktrans=53.9×10−3/min before induction immunochemotherapy, figure 8). The high-Ktrans patient achieved PR after two cycles of immunochemotherapy (figure 7) while the low-Ktrans patient achieved SD (figure 8).

    Figure 7
    Figure 7

    The DCE image and ADC map of primary lung tumors before and after induction immunochemotherapy (IC) of an LA-NSCLC patient in the high-Ktrans group. (A) The kinetic parameters derived from DCE image and the ADC value derived from ADC map (before induction IC (Ktrans: 213.7×10−3/min, Kep: 668.1×10−3/min, Ve: 341.0×10−3, Vp: 14.8×10−3, ADC: 1264×10−6 mm2/s); After induction IC (Ktrans: 210.5×10−3/min, Kep: 434.0×10−3/min, Ve: 388.8×10−3, Vp: 9.9×10−3, ADC: 1772×10−6 mm2/s)). (B) The coronal T1C-MRI and CT image of primary tumor. (C) The volume change of primary lung tumor. ADC, apparent diffusion coefficient; DCE, dynamic contrast-enhanced; LA-NSCLC, locally advanced NSCLC; NSCLC, non-small cell lung cancer.

    Figure 8
    Figure 8

    The DCE image and ADC map of primary lung tumors before and after induction immunochemotherapy (IC) of an LA-NSCLC patient in the low-Ktrans group. (A) the Kinetic parameters derived from DCE image and the ADC value derived from ADC map (before induction IC (Ktrans: 53.9×10−3/min, Kep: 1473.9×10−3/min, Ve: 83.8×10−3, Vp: 2.4×10−3, ADC: 1633×10−6 mm2/s); after induction IC (Ktrans: 51.8×10−3/min, Kep: 950.6×10−3/min, Ve: 154.5×10−3, Vp: 2.4×10−3, ADC: 1686×10−6 mm2/s)). (B) The coronal T1C-MRI image and CT image of primary tumor. (C) The volume change of primary lung tumor. ADC, apparent diffusion coefficient; DCE, dynamic contrast-enhanced; LA-NSCLC, locally advanced NSCLC; NSCLC, non-small cell lung cancer.

    IHC staining for the high-Ktrans and low-Ktrans groups

    The IHC staining of CD3+/CD8+ T cells, CD68+/CD86+/CD163+ CD206+ macrophages and Ki67 were performed in the primary lung tumors of 23 patients, including 11 patients in High-Ktrans group and 12 patients in low-Ktrans group. The results are shown in figures 9 and 10. The high-Ktrans group had higher infiltrations of CD3+T cells (63.3%±22.6% vs 18.1%±16.1%, p<0.001), CD8+T cells (51.6%±27.1% vs 14.5%±14.4%, p=0.001), CD68+macrophages (35.9%±25.6% vs 16.5%±9.7%, p=0.035) and CD86+macrphages (10.1%±5.1% vs 4.3%±3.8%, p=0.005) than the low-Ktrans group. No significant difference was observed in CD163+macrophage, CD206+macrophage and Ki67 between the two groups.

    Figure 9
    Figure 9

    The high-Ktrans group had higher expressions of CD3+ T cells, CD8+ T cells, CD68+macrophages and CD86+macrophages than the low-Ktrans group while CD163+macrophages, CD206+macrophages and Ki67 were comparable between the two groups.

    Figure 10
    Figure 10

    The comparisons of immune cells determined by immunohistochemistry between the high-Ktrans and low-Ktrans groups. The high-Ktrans group had higher expression of CD3+T cells, CD8+T cells, CD68+macrophages and CD86+macrophages.

    Discussion

    The current study showcased a significant correlation between the pretreatment Ktrans values derived from DCE-MRI of primary lung tumors and the response to induction immunochemotherapy, as well as survival outcomes in patients with LA-NSCLC undergoing combined treatment comprising immunotherapy, chemotherapy, and radiotherapy. Following ROC analysis of Ktrans levels prior to induction immunochemotherapy, patients were stratified into high-Ktrans and low-Ktrans groups. Notably, LA-NSCLC patients in the high-Ktrans group exhibited better treatment response to induction immunochemotherapy alongside prolonged survival compared with those in the low-Ktrans group. Furthermore, the high-Ktrans group displayed heightened infiltration of CD3+/CD8+ T cells and CD68+/CD86+ macrophages within primary lung tumors. The incorporation of DCE-MRI held promise in identifying potential markers for predicting the efficacy of induction immunochemotherapy and unraveling the heterogeneous nature of the tumor microenvironment (TME) in LA-NSCLC.

    The RECIST criteria have long served as the gold standard for evaluating tumor response to treatment, providing a standardized approach for both clinicians and researchers.27 As our understanding of tumor biology and treatment modalities deepens, it has become increasingly apparent that RECIST possesses certain limitations, particularly in capturing early treatment effects and predicting long-term outcomes. The advent of immunotherapy has revolutionized the treatment landscape for lung cancer, offering new hope and improved outcomes for patients. The RECIST criteria, primarily designed for cytotoxic chemotherapy, may not fully reflect the unique response patterns elicited by immunotherapy. Consequently, there is a growing need for alternative imaging response criteria that better predict treatment effects and correlate with meaningful clinical endpoints such as pathological response and survival in lung cancer patients undergoing immunotherapy. One such alternative criterion that has gained traction is immune-related response criteria (irRC), which considers the complex interplay between tumor, immune system, and therapy.28 Another promising approach is the use of immune-related RECIST (iRECIST), which builds on the foundation of RECIST but incorporates immune-related modifications.29 In addition to irRC and iRECIST, functional imaging modalities such as positron emission tomography (PET) hold promise in predicting treatment response and patient outcomes in lung cancer immunotherapy.30 By showing changes in tumor metabolism and metabolic activity, PET provides valuable insights into treatment response beyond anatomical size-based criteria. Furthermore, radiomic signatures derived from CT or MRI scans also have shown promise in stratifying patients based on their likelihood of response to immunotherapy and predicting survival outcomes.12 31 32

    One favorable avenue that has garnered attention in overcoming these limitations is the utilization of DCE-MRI, which has been incorporated RECIST including the immune-related guidelines iRECIST,29 33 as well as the Immunotherapy Response Assessment in Neuro-Oncology, designed for monitoring tumor response in the central nervous system, such as in the case of glioblastoma.34–36 DCE-MRI provides more quantitative measurements of vascular permeability and is often used for evaluating treatment response to angiogenesis inhibitors. Numerous published studies have indicated that DCE-MRI provides important predictive and prognostic biomarkers and allows early non-invasive treatment monitoring in solid carcinomas.37–40 It proves to be a valuable tool for investing tumor microvascular structure and heterogeneity, enhancing sensitivity to subtle drug effects, and facilitating a deeper understanding of tumor biology.15 41 42 However, this technique was not fully explored in lung cancer due to respiratory motion and difficulty of MRI of lung tissue. In the current study, we integrated a fast DCE imaging technique with motion correction and enrolled patients with relatively large lesion size (mean volume: 74.0 cm3) to enhance the accuracy of parameters.

    The derived parameter Ktrans from DCE-MRI represents the volume transfer constant of contrast agent between blood plasma and the extravascular extracellular space within tissue, serving as a surrogate marker for tumor perfusion and vascular permeability. By providing quantitative information on tumor microenvironmental characteristics, Ktrans offers a valuable complement to RECIST in assessing treatment response. The Ktrans describes the transfer rate of contrast material from the intravascular space into the tumor interstitial space.15 Ciolina et al reported that a higher pretreatment Ktrans of primary tumor was associated with a better response to neoadjuvant chemoradiotherapy in LA rectal cancer.43 A retrospective study of hypopharyngeal cancer revealed that pretreatment Ktrans of 0.202/min is the most optimal cut-off in predicting response to chemotherapy, resulting in an AUC of 0.837 and corresponding sensitivity and specificity of 76.7%, and 81.1%, respectively.44 In another study involving metastatic melanoma patients treated by immune checkpoint blockade, the responders also achieved higher pretreatment Ktrans of primary tumor than the non-responders.45 Our study found that pretreatment Ktrans of primary tumor had the best predictive performance for the response to immumochemotherapy in LA-NSCLC, with sensitivity and specificity of 85.1% and 77.3%, respectively (AUC=0.800). The high-Ktrans group demonstrated markedly elevated ORR, improved PFS and OS in contrast to the low-Ktrans group. This divergence could potentially be attributed to the observation that lung tumors with elevated Ktrans values were associated with a more permeable vascular network when compared with tumors with lower Ktrans values. The heightened vascular permeability could facilitate enhanced drug delivery, thereby affording improved accessibility to immunochemotherapy agents.

    In a recent clinical study, it was found that patients with previously irradiated melanoma brain metastases exhibited reduced Ktrans and Vp values in the pseudoprogressive lesions after 9 weeks of ipilimumab treatment.46 Another study involving treatment-naïve patients observed a progressive decline in Ktrans, Ve, and Vp in both responding and pseudoprogressive melanoma metastases over 12 weeks of pembrolizumab or combined ipilimumab and nivolumab therapy.45 Nevertheless, a notable decrease in tumor vascular permeability could only be observed after a decline in tumor volume and loss of tumor cell, indicating that vascular normalization is a relatively delayed process that occurs during immunotherapy treatment and after the initiation of cell death.45 This is contrasted with the antiangiogenic therapy in human melanoma, which specifically targets the vascular network without causing significant cell toxicity. These studies suggested that the use of DCE-MRI to analyze microstructural and functional aspects of the tumor vasculature could be valuable in identifying positive treatment response to immunotherapy.

    The ADC represents the quantitative measurement of water diffusion in tissue. Tumors with higher cell density restrict water diffusion, resulting in a decreased ADC value. Effective antitumor therapy reduced cell density by inducing tumor cell death and apoptosis, leading to a significant increase in ADC value.47 Xu et al identified that the ADC values during and after chemoradiotherapy (CCRT) could predict the response to CCRT in LA-NSCLC.48 Additionally, our previous study demonstrated a significant correlation between post-CCRT ADC value and the prognosis of LA-NSCLC.12 Patients exhibiting higher post-CCRT ADCmean values displayed improved PFS and OS rates.12 Likewise, this study found a correlation between ADC value after induction immunochemotherapy and treatment efficacy in patients. This parameter yielded a moderate AUC value of 0.772 in predicting the response of tumors to immunochemotherapy, ranking second only to the preinduction immunochemotherapy Ktrans measurement. Obtaining the Ktrans value before induction immunochemotherapy was feasible at the initial patient diagnosis, aiding in the customization of individualized treatment plans. Conversely, the ADC value following induction immunochemotherapy was only attainable postcompletion of the induction treatment. Considering these factors, the preinduction immunochemotherapy Ktrans measurement surpassed the postinduction immunochemotherapy ADC value in guiding treatment decision-making, thus serving as the primary focal point of this study.

    Both preclinical and clinical studies have investigated the potential of DCE-MRI to provide valuable information on the TME. Several studies have reported the correlations between DCE-MRI Kinetic parameters and microvascular density, interstitial fluid pressure and hypoxic fraction of tumor.42 49 50 The tumor vasculature plays diverse roles in regulating tumor growth, metastasis, and immune cells trafficking in and out of the tumor microenvironment. Several radiomics-models based on MRI have been reported to predict the infiltrations of tumor infiltrating lymphocytes (TILs) and TAMs in breast cancer.51 52 Migration and infiltration of immune cells into tumors rely on transportation through hematological and lymphatic routes, chemokine signaling, and the expression of specific cell adhesion molecules (eg, selectins, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)) on endothelial cells.53 It has been demonstrated that the combined treatment of anti-VEGFR2 and anti-PD-L1 can stimulate T cell activation and infiltration in responsive tumors through the promotion of blood vessel normalization in preclinical studies.54 The current study showed that the high-Ktrans group had higher expression of CD3+/CD8+ T cells, which suggested high-Ktrans might be vital for the T cells trafficking and the better response to the induction immunochemotherapy in LA-NSCLC patients. Macrophages play a crucial role in orchestrating the tumor microenvironment, in addition to their involvement in various physiological and pathological processes.55–57 TAMs are a significant cellular component in cancer-related inflammation and can have either beneficial or detrimental effects on cancer depending on their activation.58 59 Classically polarized macrophages (M1) exhibit antitumoral functions while alternatively polarized macrophages (M2) exhibit protumoral functions.59 More and more studies have shown that macrophage typing presents a continuous lineage, which is difficult to characterize with a single indicator or even a set of markers. Traditional markers related to macrophage polarization are often coexpressed in M1 and M2 types. For example, CD68 marker was universally expressed in both M1 and M2 groups.60 61 M2b macrophages tend to express CD86,62 but some M1 macrophages also share this marker.63 CD163 and CD206 were commonly linked to M2 polarization.63 64 The current study showed that the high-Ktrans group had intensive CD68+/CD86+ macrophages infiltrations. The higher level of CD68+/CD86+ macrophages might contribute to the improved tumor response and survival of LA-NSCLC patients in the high-Ktrans group, but the related mechanism remained unclear. The IHC staining in current study was the preliminary analysis of the relationship between the tumor environment and parameters of DCE-MRI. Further investigations such as spatial transcriptomics in larger cohort/surgical samples are warranted.

    Several limitations of this study warranted acknowledgment: (1) The exclusion of five patients was necessary due to challenges in tumor measurements, including instances of tumor atelectasis (n=1), diffuse tumor manifestation (n=1), or small tumor size (tumor volume <1 cm³, n=3). (2) Solely primary lung tumors were assessed, with locoregional metastatic lymph nodes remaining unanalyzed. (3) ROIs were delineated on MRI scans while tumor response evaluations adhered to the RECIST 1.1 criteria, which entail measuring the largest diameter on CT scans. (4) Only 23 patients had biopsy samples available for immunohistochemical (IHC) analysis, potentially introducing bias into the study findings. Although the outcomes suggested a correlation between higher Ktrans values and increased infiltration of CD3+/CD8+ T cells and CD68+/CD86+ macrophages, the limited patient cohort and biopsy sample size might have compromised result adequacy. Future studies would benefit from a larger patient cohort and inclusion of surgical samples for enhanced validation.

    Conclusions

    In conclusion, our initial findings indicated that the pretreatment Ktrans value of the primary lung tumors, as determined by DCE-MRI, held substantial predictive significance concerning early response to induction immunochemotherapy and survival in patients with unresectable stage III NSCLC who underwent immunotherapy-based multimodal treatments. Our study revealed a positive correlation between higher Ktrans value and improved treatment response, leading to prolonged PFS and OS. We advocated for further validation of these results through meticulously designed prospective studies.

    Data availability statement

    Data are available on reasonable request. The datasets are available from the corresponding authors on reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (No. B2020-296-01). Participants gave informed consent to participate in the study before taking part.

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    Footnotes

    • DW, SL and JF contributed equally.

    • Contributors HL, DW and CX contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by DW, SL, JF, PZ, SZ, BQ, HL, YY, JG, YZ, HJ, SY, HH, CX and HL. The first draft of the manuscript was written by HL, DW and SL, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. HL was the guarantor of this work.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.