Omission of staging PET/CT linked to reduced survival in stage III non-small cell lung cancer: insights from the LUCAS project real-world data

Introduction

Background

Lung cancer is the world’s leading cancer in incidence and mortality in both men and women. Around 6,500 new lung cancer cases are diagnosed annually in the Czech Republic. Three-quarters of these cases are non-small cell lung cancer (NSCLC), and the rest are small cell lung cancer (SCLC) (1). Stage III NSCLC is an advanced stage of lung cancer, with different subgroups according to the extent of the primary tumor (T) and affliction of regional lymph nodes (N). Stage III (8th edition) comprises both resectable and unresectable tumors. For instance, we can meet resectable large tumors with invasion to the chest wall (T4) but without lymph node involvement (N0), and on the other hand relatively small tumors (3–4 cm, T2a) with unresectable lymph nodes involvement (namely invasive N2). Stage III NSCLC often requires a multimodal approach with the combination of treatments—local treatment (surgery or radiotherapy) plus systemic treatment (perioperative, neoadjuvant, adjuvant, or concurrent). Tumors unsuitable for local treatment (usually IIIC) are treated like stage IV. Positron emission tomography (PET), ideally combined with computed tomography (PET/CT) of the whole body in extent of torso, is an essential diagnostic method for stage III NSCLC. It is crucial for excluding metastatic stages and determining the optimal treatment plan for patients with potentially curative intent, such as surgery, radical radiotherapy, chemoradiotherapy. Accurate staging with PET/CT is more effective than CT of the chest and abdomen in detecting distant metastases, particularly in unexpected locations (5–29% more) (2-5). PET/CT changes the choice of therapeutic approach in up to 30–40% of NSCLC cases (6). PET/CT is also of prognostic importance (7,8).

Rationale and knowledge gap

Initial PET/CT of the trunk is recommended for diagnosing both early and advanced lung cancer in European and American guidelines (5,9). European Society for Medical Oncology (ESMO) guidelines recommend PET/CT for all patients considered for curative treatment. However, National Comprehensive Cancer Network (NCCN) guidelines do not recommend PET/CT for tumors smaller than 3 cm, without hilar node involvement, where the risk of unexpected mediastinal metastases and distant metastases is minimal. A systematic review that included 18 studies from ten countries on PET/CT in lung tumors and solitary lung lesions, despite the heterogeneity of the studies, documented the cost-effectiveness of PET/CT over conventional CT staging (10,11). Yet, there are still significant differences in using PET/CT for staging in real-world practice. Even in such groundbreaking study, phase 3 trial PACIFIC (NCT02125461) investigating the efficacy of durvalumab as consolidation therapy in patients with stage III NSCLC PET/CT was not mandatory (12,13).

Numerous studies have documented the sensitivity, specificity, and accuracy of PET/CT in lung cancer staging (14,15). It must be emphasized repeatedly that both more accurate M and N staging by PET/CT increases the chances of selecting the correct treatment for patients and for high-quality treatment. It has been reported that up to 35% of NSCLC cases staged with CT experience a change in staging when evaluated with PET. In the majority of cases, this results in upstaging leading to a change in treatment approach. The impact of PET on staging has shown an up-stage in 33–41%, and down-stage in 9.5–10% of cases (16-18). A meta-analysis showed that PET/CT has a sensitivity and specificity of 84% and 89%, respectively, compared to conventional staging with CT, which has 57% and 84%, respectively. Some studies have demonstrated that 17–24% of patients with stage III disease were upstaged to stage IV due to unexpected metastases detected by PET/CT (19).

However, publications demonstrating the benefit of PET/CT in terms of prolonged overall survival (OS) compared to conventional chest and abdominal CT staging are limited. Most research focuses on early-stage patients, consistently showing about a 20% reduction in unnecessary thoracotomy. Some studies showed no differences in stages I, II, but significant differences were noted in resectable stage III (20,21). In radiotherapy, PET/CT is invaluable for radiotherapy planning. It allows for better delineation of the extent of the disease gross tumor volume (GTV) and functional tumor volume (FTV), especially in areas of atelectasis or inflammation behind tumor stenosis. This accuracy is crucial for the quality of radiation treatment and its effects, including OS (22). A pivotal paper evaluating the benefit of PET/CT vs. CT staging in the context of survival among a broad population of lung cancer patients was published. It was found that PET/CT use was correlated with higher levels of care and resulted in lower mortality in patients with NSCLC. The study has several limitations. The primary concern is that therapeutic options improved over those 13 years (23).

Objective

The aim of our study was to evaluate the use of whole-body PET/CT as an initial staging modality for patients enrolled in the LUCAS project, diagnosed with clinical stage III NSCLC. Additionally, we aimed to assess whether the performance of PET/CT correlates with OS. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-108/rc).

Methods

LUCAS registry

The data source for the presented study is the national registry—LUCAS. The LUCAS registry is a joint project of the Czech Pneumological and Phthisiological Society, Czech Medical Association of J. E. Purkyně. LUCAS registry focuses on monitoring and continuously evaluating the extent, structure, and quality of care for lung cancer patients in the Czech Republic [code C34 according to the International Classification of Diseases, version 10 (ICD-10)] from establishing the diagnosis through their entire lifespan. Established on June 1, 2018, the LUCAS registry prospectively follows lung cancer patients across 11 pneumo-oncology centers in the Czech Republic, of which seven are included in the current analysis. The project is registered at ClinicalTrials.gov under registration number NCT04228237. All participants were required to sign an informed consent form as a prerequisite to their participation in the registry. The study had been approved by the Ethics Committee of University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University (No. 63/18 MEK 13). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

In the LUCAS registry, basic demographic and clinical characteristics, performance status (PS) assessment according to the Eastern Cooperative Oncology Group (ECOG), morphological, immunohistochemical, immunochemical, and molecular genetic characteristics, data about pharmacotherapy (including types, combinations and sequences), data about other interventions (including surgery, radiotherapy and endobronchial therapy), are recorded.

All the data and results published in this article were processed in cooperation with OAKS Consulting s.r.o., responsible for project management and output processing.

Study population

Eligible patients had histologically or cytologically confirmed locally advanced NSCLC, stage III, and met the study conditions based on the inclusion and exclusion criteria.

Inclusion criteria were: age ≥18 years, histologically or cytologically confirmed diagnosis of locally advanced NSCLC stage III, complete data of monitored parameters: ECOG score for PS (ECOG PS), smoking status, morphological diagnosis, tissue collection method, date of diagnosis, and Tumor Nodes Metastasis (TNM) Classification of Malignant Tumors.

Exclusion criteria were: SCLC, neuroendocrine type of tumor, unknown tumor type, staging CT done in the center prior to PET/CT, and incomplete data of monitored parameters: ECOG PS, smoking status, morphological diagnosis, tissue collection method, date of diagnosis establishment, and TNM. A patient with NSCLC was defined as having the following tumor types: adenocarcinoma; adenosquamous carcinoma; carcinoma NOS (not otherwise specified); squamous cell carcinoma; large cell carcinoma, and large cell carcinoma referred to as “other non-squamous”. A non-smoker is defined as a patient who has never smoked in their life. A former smoker is defined as a patient who has not smoked for at least 1 year. Tumor location was determined according to the ICD-10 diagnosis code: C34.0—main bronchus; C34.1—upper lobe bronchus or lung; C34.2—middle lobe bronchus or lung; C34.3—lower lobe bronchus or lung; C34.8—overlapping lesion of bronchus and lung; C34.9—bronchus or lung, unspecified.

Methods of staging

Methods of staging were as follows: in the PET/CT group—whole-body PET/CT (in extent of torso), bronchoscopy, endobronchial ultrasound (EBUS)/endoscopic ultrasonography (EUS) if indicated (for surgery candidates with positive mediastinal lymph nodes on PET/CT), and optional brain magnetic resonance imaging (MRI). In the CT group: chest and abdomen CT, bronchoscopy, EBUS/EUS if indicated (for surgery candidates with positive mediastinal lymph nodes on CT) and optional brain CT or MRI.

PET/CT and CT imaging

PET/CT examinations were performed on devices of different manufacturers and using local examination protocols. Despite variations, all centers followed standard procedures generally recommended for lung cancer staging. All examinations utilized ¹⁸F-fluorodeoxyglucose [¹⁸F]-2-fluoro-2-deoxy-D-glucose (FDG) after a fasting period of at least 6 hours and with glycemic control maintained. The blood glucose cut-off for PET/CT was set at 180 mg/dL. The radiopharmaceutical activity was adjusted based on the patient’s weight as per recommendations, and examinations were performed approximately 60 minutes post-application. PET/CT was conducted in the extent of the whole-body, respectively “torso”, typically including the brain. Most centers employed full-dose CT during PET/CT imaging. PET/CT and CT protocol parameters (kV, mA, time for one bed position, slice thickness, etc.) were used according to the local standard of each center.

Statistical analysis

Kaplan-Meier method was used to estimate the OS. The date of death was obtained from the Czech Statistical Office on 31 March 2022. These data were supplemented with death information from the “Reimbursement payment (K-batch)” and the CLADE information system for manual data entry into the LUCAS registry. Subsequently, duplicates were removed. Living patients were censored at the last date they were known to be alive. Moreover, a few patients were censored at the date of loss to follow-up. Basic statistics such as the proportion of patients with a recorded event and median OS with a 95% confidence interval (CI) were presented. The log-rank test (Mantel-Cox) and Cox regression model were used to compare survival between the study groups. The influence of a given variable on OS is then quantified using hazard ratios (HRs). For a categorical variable, for instance, patients have a 2-fold higher risk of an event at an HR =2 for a given category than patients in the reference category if the values of the other variables remain unchanged. Continuous variables were tested using the Mann-Whitney test; either Pearson’s χ² test or Fisher’s exact test was used for categorical variables. Hypothesis testing was performed at a 5% significance level. P values lower than this level correspond to statistically significant differences. The analysis was performed using IBM SPSS Statistics 29, and R software was utilized to plot the survival curves.

Results

The primary parameter for evaluation was the presence or absence of PET/CT.

The LUCAS registry was established in June 2018. At the date of data export up to February 9, 2022, 703 patients were eligible for the assessment based on inclusion and exclusion criteria (first patient included in the register on June 1, 2018). Baseline characteristics can be seen in Table 1. The median age of all patients was 69 years, the majority were men (66.6%) and current or former smokers (88.1%). The percentage of IIIA, IIIB, IIIC were 40.4%, 40.8% and 18.8% respectively. Most of the patients had ECOG PS score 1 (56.2%). Fifty-five point five percent of patients had squamous cell carcinoma.

A total of 354 (50.4%) patients underwent whole-body PET/CT as an initial staging method and 349 (49.6%) patients underwent conventional staging using CT of the thorax and abdomen. Differences are present between the two arms (Table S1), resulting from retrospective patient evaluation. There were significant differences in the PET/CT use across the centers. The use of PET/CT as an initial imaging ranged between 2.8–96.6% (Table S2). The most common reason for omitting PET/CT was limited local and time availability of the examination. No statistically significant changes of the PET/CT use were found in the centers over the course of time (Table S3).

Since there was a difference in some parameters (age, smoking status, PS, type of tumor, stage, T classification of tumor, and treatment regimens), a Cox regression model was performed to account for the influence of these variables on PET/CT performance and its effect on OS.

The median OS was statistically significantly higher in patients with PET/CT than with only CT—20.9 (95% CI: 18.1–23.7) vs. 9.0 (95% CI: 7.3–10.6) months, P<0.001. The statistically significant difference was observed for various stages (IIIA, IIIB, IIIC) as presented in Table 2. The median OS in PET/CT group vs. CT group in stage IIIA, IIIB and IIIC was 34.2 vs. 11.0, 20.4 vs. 9.3 and 13.4, vs. 6.1 months, respectively. Differences in OS between groups are illustrated using Kaplan-Meier curves in Figure 1.

Figure 1 Survival analysis using the Kaplan-Meier curve—comparison of a group of patients according to PET/CT status. (A) Overall survival in patients with stage III; (B) overall survival in patients with stage IIIA; (C) overall survival in patients with stage IIIB; (D) overall survival in patients with stage IIIC. PET/CT, positron emission tomography and computed tomography.

Multivariate analysis using Cox regression model

Cox regression model showed that a statistically significant difference in OS according to the PET/CT status was independent prognostic factor when adjusted for basic clinical and demographic characteristics. The results of Cox regression model are presented in Table 3.

Discussion

Our aims were to evaluate the use of staging whole-body PET/CT in the LUCAS registry project and determine whether performing PET/CT correlates with the survival. In our study, there are significant differences between the centers in the use of PET/CT as an initial staging method. We found that survival of patients who underwent staging using PET/CT of the trunk was more than twice that of those with conventional staging using CT of the thorax and abdomen (20.9 vs. 9.0 months). The most pronounced difference was seen in stage IIIA disease. The use of staging whole-body PET/CT was identified as an independent prognostic factor for survival in stage III NSCLC patients when adjusted for basic clinical and demographic characteristics (age, sex, stage, histology, PS, smoking, type of treatment). Our 4-year retrospective study showed no significant differences in the indication for PET/CT within individual years, suggesting that time does not play a crucial role in our findings.

In the literature, there is limited data evaluating the benefit of staging with PET/CT vs. CT in terms of OS. Most research focuses on early-stage patients, with consistent evidence of approximately a 20% reduction in unnecessary thoracotomy and survival benefits only in stage III patients (20,24). In our study, the greatest difference in survival was found in stage IIIA patients, who are potentially resectable, with survival being more than three times higher compared to the CT group (34.2 vs. 11.0 months). The reason for better survival in the PET/CT group is more accurate staging and the establishment of appropriate treatment. Some data indicate that around 20% of stage III patients are upstaged to stage IV by PET/CT (19). Despite the fact that PET/CT is routinely recommended in the guidelines for NSCLC patients, it was not mandated in the landmark and practice-changing PACIFIC study. This study in stage III patients demonstrated the benefit of adjuvant durvalumab following successful chemoradiotherapy (12,25). EBUS/EUS is another basic diagnostic procedure in stage III. According to the current recommendations, PET/CT-positive lymph nodules should be verified by invasive mediastinal staging, with EBUS/EUS being the first available option, followed by mediastinoscopy. Mediastinal staging with EBUS/EUS was standard for potential surgery candidates across all centers. However, the majority of patients in our study were not candidates for surgery and precise data on biopsy confirmation are not available in our analysis. All centers involved in our study required to meet the quality standards of a Complex Oncology Center in the Czech Republic. It can be assumed that they all adhere to modern diagnostic practices, have access to novel treatments, and employ qualified and experienced pulmonologists, oncologists, surgeons and radiotherapists. However, it should be further investigated in future studies why, despite the availability of modern methods and qualified doctors, there is limited access to PET/CT in some centers. In NSCLC, adherence to guidelines varies and has a negative impact on patient survival (26,27). We must identify and overcome barriers to adherence.

Our study has several limitations. It relied exclusively on the LUCAS registry. Therefore, the main limitation was the retrospective study design. Potential biases include differences in smoking status, age, PS, type of tumor, stage (IIIA–IIIC) between CT and PET/CT subgroups. We have yet to determine the exact impact of treatment regimens across centers. However, given that the study was conducted within one country, we can rule out differences in the availability of treatment regimens between centers. We believe that the sufficient number of patients in this study largely mitigates this potential bias.

Conclusions

Omission of PET/CT can mean a significant decrement in survival for the patient in stage III NSCLC, likely due to poor staging and suboptimal treatment. Routine use of PET/CT is strictly recommended for the optimal management of stage III NSCLC patients even outside the high-income countries.

Acknowledgments

Funding: This work was supported by Czech Pneumological and Phthiseological Society, Czech Medical Association of J. E. Purkyně.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-108/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-108/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-108/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-108/coif). G.K. receives payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and support for attending meetings and/or travel from AstraZeneca, and participates on a Data Safety Monitoring Board or Advisory Board for AstraZeneca. P.D. receives consulting fees from LUCAS Project. M.H. participates on a Data Safety Monitoring Board or Advisory Board for AstraZeneca. A.M. receives payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing from AstraZeneca. J.D. receives consulting fees from LUCAS Project. M.S. receives consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, support for attending meetings and/or travel from AstraZeneca, and participated on a Data Safety Monitoring Board or Advisory Board for AstraZeneca. 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. All participants were required to sign an informed consent form. The study had been approved by the Ethics Committee of University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University (No. 63/18 MEK 13). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

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/.

References

1. SVOD. SVOD Report - Diagnóza C34 – ZN průdušky - bronchu a plíce [Internet]. [cited 2023 Aug 8]. Available online: https://www.svod.cz/report.php?diag=C34
2. Sahiner I, Vural GU. Positron emission tomography/computerized tomography in lung cancer. Quant Imaging Med Surg 2014;4:195-206. [PubMed]
3. Owens C, Hindocha S, Lee R, et al. The lung cancers: staging and response, CT, (18)F-FDG PET/CT, MRI, DWI: review and new perspectives. Br J Radiol 2023;96:20220339. [Crossref] [PubMed]
4. Farsad M. FDG PET/CT in the Staging of Lung Cancer. Curr Radiopharm 2020;13:195-203. [Crossref] [PubMed]
5. National Comprehensive Cancer Network. NSCLC and SCLC guideline (version 3.2023). [Internet]. 2005 [cited 2023 Aug 8]. Available online: https://www.nccn.org/guidelines/category_1
6. Vilstrup MH, Torigian DA. [18F]Fluorodeoxyglucose PET in Thoracic Malignancies. PET Clin 2014;9:391-420. v. [Crossref] [PubMed]
7. Volpi S, Ali JM, Tasker A, et al. The role of positron emission tomography in the diagnosis, staging and response assessment of non-small cell lung cancer. Ann Transl Med 2018;6:95. [Crossref] [PubMed]
8. Dondi F, Albano D, Bellini P, et al. Prognostic role of baseline (18)F-FDG pet/CT in stage I and stage ii non-small cell lung cancer. Clin Imaging 2023;94:71-8. [Crossref] [PubMed]
9. Remon J, Soria JC, Peters S, et al. Early and locally advanced non-small-cell lung cancer: an update of the ESMO Clinical Practice Guidelines focusing on diagnosis, staging, systemic and local therapy. Ann Oncol 2021;32:1637-42. [Crossref] [PubMed]
10. Cao JQ, Rodrigues GB, Louie AV, et al. Systematic review of the cost-effectiveness of positron-emission tomography in staging of non--small-cell lung cancer and management of solitary pulmonary nodules. Clin Lung Cancer 2012;13:161-70. [Crossref] [PubMed]
11. Kukava S, Baramia M. Place and Role of PET/CT in the Diagnosis and Staging of Lung Cancer. In: Jeremić B. editor. Advances in Radiation Oncology in Lung Cancer. Cham: Springer International Publishing; 2022:85-111.
12. Mielgo-Rubio X, Rojo F, Mezquita-Pérez L, et al. Deep diving in the PACIFIC: Practical issues in stage III non-small cell lung cancer to avoid shipwreck. World J Clin Oncol 2020;11:898-917. [Crossref] [PubMed]
13. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:1919-29. [Crossref] [PubMed]
14. McLoud TC. The role of PET scanning in the evaluation of lung carcinoma. Cancer Imaging 2003;3:83-4.
15. Hadique S, Jain P, Hadi Y, et al. Utility of FDG PET/CT for assessment of lung nodules identified during low dose computed tomography screening. BMC Med Imaging 2020;20:69. [Crossref] [PubMed]
16. Hicks RJ, Kalff V, MacManus MP, et al. (18)F-FDG PET provides high-impact and powerful prognostic stratification in staging newly diagnosed non-small cell lung cancer. J Nucl Med 2001;42:1596-604. [PubMed]
17. Gregory DL, Hicks RJ, Hogg A, et al. Effect of PET/CT on management of patients with non-small cell lung cancer: results of a prospective study with 5-year survival data. J Nucl Med 2012;53:1007-15. [Crossref] [PubMed]
18. Bissonnette JP, Sun A, Grills IS, et al. Non-small cell lung cancer stage migration as a function of wait times from diagnostic imaging: A pooled analysis from five international centres. Lung Cancer 2021;155:136-43. [Crossref] [PubMed]
19. Sharma R, Tripathi M, D'Souza M, et al. The importance of 18F-FDG PET/CT, CT and X-rays in detecting primary stage III A lung cancer and the incidence of extra thoracic metastases. Hell J Nucl Med 2009;12:22-5. [PubMed]
20. Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med 2009;361:32-9. [Crossref] [PubMed]
21. Chen WM, Chen M, Hsu JG, et al. Use of Preoperative FDG PET/CT and Survival of Patients with Resectable Non-Small Cell Lung Cancer. Radiology 2022;305:219-27. [Crossref] [PubMed]
22. Greenspan BS. Role of PET/CT for precision medicine in lung cancer: perspective of the Society of Nuclear Medicine and Molecular Imaging. Transl Lung Cancer Res 2017;6:617-20. [Crossref] [PubMed]
23. Vella M, Meyer CS, Zhang N, et al. Association of Receipt of Positron Emission Tomography-Computed Tomography With Non-Small Cell Lung Cancer Mortality in the Veterans Affairs Health Care System. JAMA Netw Open 2019;2:e1915828. [Crossref] [PubMed]
24. van Tinteren H, Hoekstra OS, Smit EF, et al. Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet 2002;359:1388-93. [Crossref] [PubMed]
25. Krákorová G. Diagnostic and therapeutic guidelines for stage III non-small-cell lung cancer. Onkologie 2016;10:11-4. [Crossref]
26. John A, Yang B, Shah R. Clinical Impact of Adherence to NCCN Guidelines for Biomarker Testing and First-Line Treatment in Advanced Non-Small Cell Lung Cancer (aNSCLC) Using Real-World Electronic Health Record Data. Adv Ther 2021;38:1552-66. [Crossref] [PubMed]
27. Sterbis E, Liang R, Trivedi P, et al. Lack of Adherence to Guideline-Based Imaging Before Subsequent Radiation in Patients with Non-Small Cell Lung Cancer: Impact on Patient Outcomes. J Nucl Med 2023;64:75-81. [Crossref] [PubMed]