Maximum standardized uptake value significance in clinical stage IB–IIIB non-small cell lung cancer

Introduction

Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers (1,2). Of patients with resected NSCLC, 30–55% develop recurrence (3,4). Over the past few decades, the main standard of care for resectable stage II–IIIB NSCLC has been surgery combined with adjuvant chemotherapy (5). The National Comprehensive Cancer Network guidelines suggest that adjuvant chemotherapy may also be required for high-risk stage IB NSCLC (6). Recently, several studies have shown that neoadjuvant chemotherapy with immune checkpoint inhibitors (ICIs) improves the prognosis of locally advanced NSCLC (7-9). Recent clinical trials, including those of neoadjuvant therapy, have expanded the criteria for eligibility of patients from clinical stage IB to IIIB (10). As treatment options increase for patients with these stages of NSCLC, in addition to tumor, node, metastasis (TNM) classification, other preoperative predictors for accurately assessing the malignant potential of the tumor will become increasingly important in planning therapeutic strategies.

The introduction of positron-emission tomography (PET)/computed tomography (CT) has enhanced the precision of diagnosis in the preoperative staging of NSCLC (11,12). Furthermore, several studies have also demonstrated that the maximum standardized uptake value (SUVmax) of primary tumors plays a significant role as a preoperative tool for the assessment of the malignant potential in clinical stage IA NSCLC (13,14). However, it remains debated whether SUVmax can be used to predict the prognosis of patients with clinical stage IB to IIIB NSCLC, which are patients who would potentially have been eligible for recent studies involving neoadjuvant therapy.

Thus, we conducted this study to elucidate factors associated with recurrence-free survival (RFS) and overall survival (OS) of patients with clinical stage IB to IIIB NSCLC, and to investigate the prognostic and clinicopathological impact of various preoperative factors, including SUVmax. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2283/rc).

Methods

Study population

Overall, 585 consecutive patients underwent complete resection with lobectomy for primary NSCLC with clinical stage IB–IIIB at Kanagawa Cancer Hospital between January 2012 and December 2021 All patients underwent PET/CT at our institution. Patients with EGFR mutations (n=73), ALK rearrangements (n=18) were excluded because their prognosis and post-recurrence survival are distinct due to the high efficacy of molecular targeted therapies. Patients receiving neoadjuvant therapy (n=46) and those with no numerical value of SUVmax (n=52) were excluded from this retrospective observational study. The patient selection process is summarized in the flow diagram (Figure S1). Thus, we enrolled 396 patients with resected stage IB–IIIB NSCLC. Clinical and pathological data for each patient were retrospectively collected through of a review of the medical records. The collected variables included age, sex, smoking history, carcinoembryonic antigen (CEA) titer, primary tumor SUVmax, clinical and pathological stage, evidence of invasiveness, and histological type. Histological classification was performed according to the World Health Organization criteria (15). TNM staging followed the Union for International Cancer Control and American Joint Committee on Cancer staging system (8th edition) (16). Preoperative nodal staging was based on PET/CT, chest CT, and invasive procedures. Mediastinal nodes (N2) suspected of metastasis were histologically confirmed using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). For hilar nodes (N1), malignancy was diagnosed radiologically based on a short-axis diameter ≥10 mm or a high fluorodeoxyglucose uptake comparable to that of the primary tumor. The final staging was determined at the surgeon’s discretion based on integrated clinical findings. All patients underwent lobectomy or greater with systematic mediastinal lymph node dissection (ND2a or greater). The extent of lymphadenectomy did not differ by SUVmax. The surgical approach (minimally invasive vs. open) showed no significant impact on oncologic outcomes. Recurrence and death information of the patients in the present study were collected from the medical records of our hospital.

Patient follow-up

After complete resection, the patients were followed-up at 3–6 months intervals for the first 2 years, 6–12 months intervals for the next 3 years, and 1-year intervals thereafter. Patients underwent routine follow-up evaluations, including a physical examination, chest radiography, blood tests, and periodic CT scans of the chest and abdomen. If symptoms or signs indicative of recurrence were detected, further evaluations were conducted including brain magnetic resonance imaging and PET/CT scans. Recurrence was diagnosed based on the physical examination and diagnostic imaging results. Histological and cytological confirmation of recurrence was made when clinically feasible, such as by transbronchial lung biopsy of the newly appearing lung tumor or EBUS-TBNA of enlarged mediastinal lymph nodes during follow-up.

Statistical analysis

Categorical variables were compared using the chi-squared test. To determine the optimal cut off value for SUVmax in predicting pathological tumor invasiveness, receiver operating characteristic (ROC) curves were generated, maximizing both sensitivity and specificity. RFS and OS for both groups were estimated using the Kaplan-Meier method, and statistical differences between the survival curves were evaluated by the log-rank test. OS was defined as the time from surgery to the date of death from any cause or to last follow-up. RFS was defined as the time from surgery to the date of the first postoperative recurrence, death, or the last follow-up. The date of recurrence was defined as the date of histological confirmation or identification based on clinicoradiological findings by a physician. The last follow-up was censored if the patient was alive or lost to follow-up. To determine factors associated with RFS and OS, Cox proportional hazards regression models were used for univariate and multivariate analyses. In these analyses, we included age, sex, smoking history, CEA titer, primary tumor SUVmax, clinical invasive size, clinical nodal metastasis, histological type, adenocarcinoma grading system, vascular invasion, lymphatic permeation, pleural visceral invasion, and adjuvant therapy.

All tests were 2-sided and P values <0.05 were considered to indicate a statistically significant difference between groups. All statistical calculations were performed using the SPSS statistical software package (version 28.0; SPSS Inc., Chicago, IL, USA).

Ethics approval

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Kanagawa Cancer Center Review Board (No. 2023 EKI-93). Informed consent was waived in this retrospective study.

Results

The total number of patients with clinical stage IB to IIIB was 396. The median follow-up period for all patients after surgery was 42 months. Table 1 shows the clinicopathological characteristics of patients. Most patients were men and had a history of smoking. The number of patients with stages IB, II and IIIA/B was 107 (27%), 180 (45%), and 109 (28%), respectively. The optimal SUVmax cutoff value was determined to be 6.0 using ROC curve analysis (Figure S2). At this cutoff, the sensitivity was 0.79 and the specificity was 0.66, with an area under the curve of 0.79. Almost three-quarters of patients had an SUVmax above this threshold. About one-third of patients underwent surgery without preoperative pathological confirmation. Histologically, adenocarcinoma was the most common type, followed by squamous cell carcinoma (SqCC). About one-third of patients underwent adjuvant chemotherapy after surgery.

Multivariable analysis revealed that SUVmax [hazard ratio (HR), 1.8; 95% confidence interval (CI), 1.0–3.3; P=0.04], and visceral pleural invasion (HR, 1.8; 95% CI: 1.1–2.9; P=0.02) were statistically significant factors associated with RFS (Table 2). Age (HR, 2.2; 95% CI: 1.1–4.1; P=0.02), SUVmax (HR, 2.3; 95% CI: 1.1–4.9; P=0.03), and blood vessel invasion (HR, 2.0; 95% CI: 1.1–3.9; P=0.03) were statistically significant factors associated with worse OS (Table 3). Notably, SUVmax remained independently associated with RFS and OS comparable to histologic aggression.

Figure 1 shows the survival analysis using the Kaplan-Meier method stratified by SUVmax of patients with clinical stage IB to IIIB NSCLC. The log-rank test revealed significant differences in RFS and OS between the clinical stage IB to IIIB patients with SUVmax >6.0 and SUVmax ≤6.0 of the primary tumor [5-year RFS rate, 48.4% (95% CI: 42.1–54.7%) and 73.1% (95% CI: 64.1–82.1%), P<0.001; 5-year OS rate, 59.0% (95% CI: 52.5–65.5%) and 84.6% (95% CI: 76.8–92.4%), P<0.001].

Figure 1 (A) RFS and (B) OS curves of patients with non-small cell lung cancer at clinical stage IB to IIIB, according to their SUVmax. The differences in RFS and OS between clinical stage IB to IIIB with SUVmax ≤6.0 and SUVmax >6.0 (RFS and OS, P<0.001) were statistically significant. OS, overall survival; RFS, recurrence-free survival; SUVmax, maximum standardized uptake value.

Figure 2 shows a classified survival analysis stratified by SUVmax of patients with each clinical stage, IB, II, and IIIA/B NSCLC. The log-rank test showed significant differences in RFS and OS between the clinical stage IB patients with SUVmax >6.0 and SUVmax ≤6.0 of the primary tumor (n=107; 5-year RFS rate, 59.7% (95% CI: 46.8–72.6%) and 86.8% (95% CI: 75.6–98.0%), P=0.003; 5-year OS rate, 73.0% (95% CI: 60.9–85.2%) and 91.9% (95% CI: 82.9–100%), P=0.04). Moreover, clinical stage II patients with SUVmax >6.0 and SUVmax ≤6.0 of the primary tumor also showed significant differences in RFS and OS [n =180; 5-year RFS rate, 54.2% (95% CI: 45.0–63.4%) and 76.6% (95% CI: 63.9–89.3%), P=0.03;5-year OS rate, 60.9% (95% CI: 51.3–70.5%) and 90.5% (95% CI: 81.7–99.3%), P=0.004]. On the other hand, no significant differences in RFS and OS were found between the clinical stage IIIA/B patients with SUVmax >6.0 and SUVmax ≤6.0 of the primary tumor [n=109; 5-year RFS rate, 31.3% (95% CI: 20.5–42.1%) and 25.0% (95% CI: 2.3–47.7%), P=0.76; 5-year OS rate, 46.6% (95% CI: 34.8–58.4%) and 49.4% (95% CI: 19.8–79.0%), P=0.71].

Figure 2 (A,C,E) RFS and (B,D,F) OS curves of patients with non-small cell lung cancer at clinical stage IB, II and IIIA/B, according to their SUVmax. The differences in RFS and OS between clinical stage IB and II with SUVmax ≤6.0 and SUVmax >6.0 (both RFS and OS, P<0.05) were statistically significant, whereas no significant differences in RFS and OS were found in clinical stage IIIA/B. OS, overall survival; RFS, recurrence-free survival; SUVmax, maximum standardized uptake value.

Based on the results of the multivariable analysis, we compared clinicopathological characteristics between patients with clinical stage IB to IIIB NSCLC with SUVmax <6.0 and SUVmax ≥6.0 (Table 4). We found significant differences in sex, smoking history, CEA titer, histological types, pathological stage, blood vascular invasion, pleural visceral invasion, and grading system of adenocarcinoma between these groups. Pathological upstaging and distant recurrence were more commonly found in patients with clinical stage IB to IIIB NSCLC with SUVmax ≥6.0 than in those with SUVmax <6.0.

Discussion

The focus of this study was to examine the clinicopathological factors associated with RFS and OS in patients with clinical stage IB to IIIB NSCLC. We showed that SUVmax of >6.0 of the primary tumor was significantly associated with RFS and OS. In the present study, SUVmax could be used to stratified the prognosis after surgery in patients with clinical stage IB to IIIB NSCLC, and particularly in those with clinical stage IB to IIB. Furthermore, the rates of pathological upstaging and distant recurrence were higher in patients with a SUVmax >6.0 than in those with a SUVmax ≤6.0 of the primary tumor.

Patients with clinical stage IB to IIIB NSCLC are at a high risk of postoperative recurrence (3,4). These patients are therefore generally considered to require not surgery alone, but multimodal treatment, including neoadjuvant or adjuvant chemotherapy (5). Recent clinical trials involving neoadjuvant therapy have yielded positive results due to the emergence of ICIs (7-10). In these patients, in addition to TNM classification, accurate prognosis prediction by using preoperative factors, including SUVmax of the primary tumor, can assist in planning of therapeutic strategies. SUVmax of the primary tumor has been reported to be an important tool for staging as well as a prognostic factor in patients with NSCLC. In a systematic review and meta-analysis of 13 eligible studies, Berghmans et al. concluded that the SUV of the primary tumor is a prognostic indicator in NSCLC (11). Paesmans et al. reported that the SUVmax of the primary tumor is an independent prognostic marker in patients with pathological stage I to III NSCLC, based on multivariate pooled analysis of individuals’ data (17). Although these studies analyzed all stages of NSCLC, the SUVmax of the primary tumor has been reported to be biased by stage. Sun et al. showed significant differences in the SUVmax between pathological T1 and T2–4, but the differences among stages T2 to T4 were not significant in cases of lung adenocarcinoma (18). Conversely, several studies have evaluated the SUVmax in early-stage lung cancer. Okada et al. demonstrated a significant difference in the 3-year disease-free survival rate for patients with clinical state IA lung adenocarcinoma, based on whether SUVmax of the primary tumor was ≤2.5 or >2.5 (13). Tsutani et al. revealed that the SUVmax of the primary tumor enabled the prediction of pathological tumor invasiveness and the prognosis of clinical stage IA lung adenocarcinoma (14). However, reports on the role of the SUVmax in primary tumors of locally advanced NSCLC have been limited. In the current study, we investigated the RFS and OS of patients with clinical stage IB to IIIB based on the AJCC 8th edition TNM classification. Multivariate analysis showed that SUVmax was associated with RFS and OS. SUVmax also enabled the stratification of prognosis in patients with clinical stage IB to IIIB disease, and particularly in those with clinical stage IIB disease.

The poor prognosis in the high-SUVmax group in this study may be explained as follows. First, the rate of pathological upstaging between the high- and low-SUVmax groups (27% vs. 17%) was significantly different. Pathological downstaging was more common in the low-SUVmax group, at a rate of 45% (P=0.002). Ghaly et al. reported that the SUVmax of the primary tumor was associated with an elevated risk of nodal disease for peripheral T1a N0 NSCLC of the 449 patients (19). In a study involving 189 cases, Li et al. concluded that a high SUVmax for primary tumors predicted nodal upstaging in patients with clinical N0 NSCLC (20). In the current study, among patients with clinical stage IB to IIIB NSCLC, the high-SUVmax group had more pathological N1 or N2 cases than did the low-SUVmax group (P<0.001). Thus, not only early-stage NSCLC, but also locally advanced NSCLC with a high preoperative SUVmax may represent an advanced stage. Second, we found a significant difference in the histological features between the high- and low-SUVmax groups in this study. Non-adenocarcinomas, including SqCC, large-cell neuroendocrine carcinoma (LCNEC), and pleomorphic carcinoma, were more common in the high-SUVmax group. Hao et al. reported that, in a population-based propensity-score matched analysis, patients with lung SqCC were at a significantly greater risk of having a shorter OS and lung cancer-specific survival, and stated that the prognoses of patients with SqCC and adenocarcinoma were very different (21). Patients with LCNEC were more likely to develop recurrences and to exhibit poor survival. In their multivariable analysis, Lee et al. revealed that a higher SUVmax was associated with a shorter disease-free survival in patients with LCNEC (22). Ito et al. concluded that pulmonary pleomorphic carcinoma had strong malignant potential with frequent distant metastases and that the SUVmax in these cases tended to be high (23). Conversely, in the patients with adenocarcinoma in the present study, the solid- or micropapillary-predominant type was more frequently seen in the high-SUVmax group, and we found a significant difference in the rate of grade 3 according to the grading system for invasive lung adenocarcinoma between the high- and low-SUVmax groups (30% vs. 18%; P<0.001). Grade 3 tumors are poorly differentiated, and have 20% or more high-grade patterns (solid, micropapillary, or complex glands). Moreira et al. reported that this grading system allowed prognostic grouping for lung adenocarcinoma that is reproducible in multiple datasets from different institutions, and should allow a comprehensive comparison of prognostic or predictive markers in adenocarcinoma (24). Third, the high-SUVmax group experienced more distant recurrences, and the main initial distant recurrence sites were the bone or brain. The prognosis of patients with lung cancer with distant recurrence after surgery has been reported: those with bone and brain metastases have poor prognoses (25,26). These metastases decrease the patient’s quality of life or performance status, making treatment after recurrence more difficult. Yoshino et al. revealed that bone metastasis was marginally associated with a poor prognosis after surgery in patients with pathological stage I to III (25). Isaka et al. reported that the prognosis of patients who developed brain or bone metastasis after surgery was significantly worse among 727 patients with postoperative recurrent pathological stage 0 to IIIA NSCLC (26).

In recent years, the field of neoadjuvant therapy for locally advanced NSCLC has evolved rapidly with the advent of ICIs. TNM classification is the main system for classifying malignancy and is used in the selection of neoadjuvant therapy. In this study, we showed that SUVmax differed according to the prognosis and pathological features of patients with clinical stage IB to IIIB NSCLC. While neoadjuvant therapy indications are expanding, patients with clinical stage IB–IIB and a low SUVmax (≤6.0) in this study showed excellent 5-year OS (>90%) with surgery and/or standard adjuvant therapy. For these low-metabolic tumors, intensive neoadjuvant therapy may not be necessary, considering its potential toxicities and high costs. Preoperative SUVmax can help clinicians avoid overtreatment and select the most appropriate candidates for intensive multimodal strategies. Thus, we suggest that the combination of clinical stage and SUVmax can help in the accurate evaluation of the malignant potential of locally advanced NSCLC. This may facilitate decision-making on the use of neoadjuvant therapy for those patients with NSCLC. Additionally, while lobectomy is the standard for stage IB–IIIB NSCLC, the relationship between SUVmax and tumor aggressiveness might also help in selecting patients for different surgical extents in future clinical trials.

There are several limitations in this study. First, its retrospective nature and execution at a single institution introduce the potential for selection bias among the patient cohort. Second, preoperative nodal staging was primarily based on PET/CT and chest CT. While we performed invasive staging (EBUS-TBNA) for radiologically suspicious nodes, most patients staged as clinical N0 or N1 did not undergo systematic histological confirmation. This may introduce a potential diagnostic bias, as radiological staging is known to have an occult metastasis rate of approximately 10–15%. Third, the SUVmax cutoff value was derived from our institutional data. Therefore, the generalizability of this specific threshold may be limited. The lack of uniformity in SUVmax measurement across institutions is a known issue, which means the reported values are likely influenced by technical factors such as imaging protocols and data processing. PET procedures and SUVmax determination may need to be standardized to overcome these issues. Further investigations involving multiple institutions would be required to verify our findings. Forth, SUVmax represents only the highest point of metabolic activity and does not reflect the total volume or heterogeneity of the tumor. Future studies using volumetric parameters may provide further insights into the prognostic impact of metabolic activity. Fifth, there is the lack of evaluation regarding the impact of post-recurrence interventions, including local and systemic therapies. These variables have the potential to influence the clinical course and affect overall long-term survival.

Conclusions

This study revealed that SUVmax was strongly associated with RFS and OS in patients with clinical stage IB–IIIB NSCLC. The SUVmax of the primary tumor is valuable for accurately evaluating the malignant potential of preoperative locally advanced NSCLC.

Acknowledgments

The authors are indebted to the medical editors from Editage for the language editing of the manuscript. We also thank Mami Murakami for assistance with the statistical analyses in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2283/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2283/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2283/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2283/coif). N.I. reports receiving speaking and lecture fees from Astra Zeneca, Chugai pharma, Pfeizer, Taiho pharma, MSD, Boehringer Ingelheim, Eli Lilly, Ono pharma, Teijin, Nihon Mediphysics, Fuji film, Johnson & Johnson, Bristol-Meyers, Olympus, and Medtronics. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Kanagawa Cancer Center Review Board (No. 2023 EKI-93). Informed consent was waived in this retrospective study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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