18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography-Guided Chest Radiotherapy Improves Survival in Patients with Extracranial Oligometastatic Non-small Cell Lung Cancer

Tianlu Wang (  wangtianlu126@126.com ) Liaoning Cancer Institute and Hospital Chengsen Liu Cancer Hospital of China Medical University: Liaoning Cancer Institute and Hospital Yingqiu Song Cancer Hospital of China Medical University: Liaoning Cancer Institute and Hospital Zheng Wang Cancer Hospital of China Medical University: Liaoning Cancer Institute and Hospital Lei He Cancer Hospital of China Medical University: Liaoning Cancer Institute and Hospital Chenyu Wang Cancer Hospital of China Medical University: Liaoning Cancer Institute and Hospital Yu Wu Liaoning Cancer Institute and Hospital Ye Wang Liaoning Cancer Institute and Hospital Xiaofang Zhang Cancer Hospital of China Medical University: Liaoning Cancer Institute and Hospital Guang Li The First Hospital of China Medical University: The First A liated Hospital of China Medical University


Introduction
Oligometastasis is a distant metastasis with a limited number and distribution of tumors. Patients with oligometastasis usually have a maximum of 3-5 metastatic sites, excluding the primary site, and no more than 3 different organs that can be treated locally using surgery, radiation therapy, and other treatments to improve survival [1]. Currently, oligometastasis is considered to be the transitional stage of advanced tumors from inducing limited to extensive metastases, with the former metastases having a signi cantly different biology and treatment options than the latter metastases [2]. This is a shift from the conventional oncological thinking, which considers metastasis as an end-stage disease with limited treatment options. In patients with non-small-cell lung cancer (NSCLC) receiving systemic therapy, such as chemotherapy, the most common progression site is the original disease site [3][4][5][6]. Our previous studies have shown that aggressive local consolidation therapy may destroy lesions, slow disease progression, and even improve patient survival [7].
Radiation therapy is a local NSCLC treatment. The clinical outline of the gross tumor volume (GTV) is based on morphological information, such as tissue density and anatomical structure, as provided by computed tomography (CT), but not on corresponding metabolic information. Consequently, potential occult metastases are often not detected, and the information provided is not su cient to allow clinical radiation therapy [8]. 18 F-uorodeoxyglucose positron emission tomography-CT ( 18 FDG-PET /CT) is of great value for early lung cancer detection, differential diagnoses of isolated nodules in lungs and mediastinum lymph nodes, clinical staging and detection of distant metastases, treatment e cacy determination, recurrence and metastasis follow-ups, and prognosis [9,10]. 18 FDG, the most widely used PET imaging agent in clinical practice, is brought into the cell, and then 18 FDG-PET imaging distinguishes between benign and malignant lesions based on glucose metabolism, which is signi cantly correlated with tumor pathological response [11]. Most lung cancers are highly metabolic in nature, and abnormal cancer cell proliferation requires glucose overutilization. Accordingly, 18 FDG-PET/CT has the advantages of both functional and anatomical structure imaging. 18 FDG-PET/CT is better than traditional imaging methods and is increasingly recognized by clinicians for the diagnosis, treatment, and treatment e cacy evaluation of lung cancer and other tumors [12][13][14].
We demonstrated that local consolidation therapy (LCT) is superior to maintenance therapy in patients with oligometastatic NSCLC receiving PET/CT guidance [7]. However, we did not directly compare lung cancer patients who underwent PET/CT to those who underwent conventional CT, and there is no direct evidence to con rm a signi cant difference in the prognostic bene t between these two screening methods in patients with oligometastatic NSCLC. Undertreatment may signi cantly contribute to treatment failure or tumor recurrence, but overtreatment can cause serious side effects and physical damage. Minimizing unnecessary treatment while ensuring e cacy is important for the survival and quality of life of patients with advanced lung cancer. To further improve the diagnosis and treatment of oligometastatic NSCLC, we retrospectively studied the medical records of patients with oligometastatic NSCLC who underwent PET/CT and conventional CT at two centers to investigate the differences between both examination methods and the impact of radiation therapy to the primary lung cancer site on patient prognosis.

Study population
We retrospectively analyzed Chinese patients with stage IV extracranial oligometastatic NSCLC who had underwent PET/CT or CT scans at the First Hospital of China Medical University and Liaoning Cancer Hospital from February 2013 to November 2019. From patient medical records, we assessed age, gender, smoking history, patient status, tumor size, lymphatic metastases, histologic type, primary tumor site, treatment choice, and date of death. Inclusion criteria were patients with extracranial oligometastatic NSCLC with complete medical records who received chest radiotherapy (CRT) with maintenance or only maintenance therapy. PET/CT or CT was conducted on selected patients within one month before treatment. Patients with major organ dysfunction, more than one primary tumor, unknown metastatic status, or multiple metastases (number of transferring stoves >5), malignant pleural effusion, or underwent targeted therapy or immunotherapy were excluded. Propensity score matching (PSM, The PSM was performed using age and sex) was used to create a maintenance chemotherapy alone and a chest radiotherapy (CRT) plus maintenance chemotherapy groups to reduce the effects of selection bias and confounding variables. The PSM function of the IBM SPSS software (IBM Co., Armonk, NY, USA) was used to estimate the propensity score, and 1:1 nearest neighbor matching was used with a caliper width of 0.02 for PSM. A chi-square test was used to check the covariate balance of each subgroup before and after PSM.

Statistical analysis
The number and clinical characteristics of all eligible patients were counted, and the chi-square test was used. The time from each patient's rst oligometastatic diagnosis to the last follow-up or death was recorded as overall survival time. The survival curves of different variables were determined using the kaplan-meier method and then checked by a log-rank test. Results were reported as hazard ratios (HRs) and 95% con dence intervals (CIs). Forest plots were used to describe the subgroup analysis of all data. According to the univariate analysis results, signi cant variables ( p < 0.1 ) were selected and put into a Cox regression analysis and then a multivariate analysis to ensure that signi cant variables ( p < 0.05 ) were remarkably associated with the prognosis of patients with extracranial oligometastatic NSCLC. IBM SPSS was used for statistical analysis, and GraphPad Prism8 was used to draw the survival curve and forest plots.

Patient Characteristics
From analyses, 192 of a total of 532 patients with advanced lung cancer at two medical centers were selected; 113 patients were male, and 79 were female, with a median age of 60 years. We used PSM to select 178 eligible patients of 192 patients with extracranial oligometastatic NSCLC and divided them into maintenance chemotherapy alone and CRT plus maintenance chemotherapy groups ( Figure 1). Among all patients, the one-year and two-year overall survival rates were 41.7% and 15.1%, respectively, and the median survival time was 10.5 months. Patient demographic and clinical characteristics are presented in Table 1.

Univariate analysis
Considering tumor heterogeneity, we did not examine the relationship between different chemotherapy regimens and survival time. Important variables included in the univariate analysis before and after PSM, including T and N classi cations, PET/CT and CRT are presented in Table 2 and 3 (all p <0.1). The median survival time was better in patients who received PET/CT than in those who only received CT (before PSM: 16 months vs 6 months; and after PSM: 17 months vs 7 months, both, p<0.001). The median survival time was signi cantly better in the CRT plus maintenance group than in the chemotherapy alone group (before PSM: 13 months vs 8 months, p<0.001; and after PSM: 13 months vs 8 months, both, p =0.001). Figure 2 and Figure 3 showed that PET/CT and CRT were signi cantly associated with improved survival times. A subgroup analysis showed no statistical difference in survival between the chemotherapy alone and CRT plus maintenance groups for those underwent CT examination (before PSM: 8 months vs 5 months, p = 0.180 ; and after PSM: 8 months vs 5 months, p = 0.185). However, for those underwent PET/CT examination, there was a signi cant difference between the aforementioned groups (before PSM:25 months vs 11 months; and after PSM: 25 months vs 11 months, both, p <0.001).

Discussion
Traditional NSCLC staging is based primarily on history, beroptic bronchoscopy, CT, magnetic resonance imaging, and other routine imaging examinations. If the lung cancer stage is inaccurate, an inappropriate treatment regimen will inevitably have an adverse impact on patient survival. PET/CT is an advanced diagnostic medical imaging technique that shows local metabolic function at a re ned anatomical level, with a superior sensitivity and speci city than other examination methods, and allows a more effective detection of asymptomatic metastatic foci and metastatic lymph nodes [15]. Staging is more accurate when both metabolic function and anatomical information are assessed [16]. PET/CT can also improve the accuracy of depicting the target area for radiotherapy, avoiding missed target areas or increased exposure. Using PET/CT during an NSCLC radiotherapy program improves target volume delineation reliability and allows higher radiation doses without increasing side effect risks [17]. Accordingly, the volume of the scheduled irradiation target can be more accurately limited to morphologically and functionally de ned tumor areas. Fewer normal tissues can be irradiated and higher total tumor doses can be used to seek optimal therapeutic effects and develop more rational treatments. Studies report that occult extrathoracic metastases can be found in up to 37% of patients with advanced NSCLC, altering 14%-26% of NSCLC treatment decisions [18]. Although PET/CT bene ts on NSCLC diagnosis have been widely reported, we compared the prognosis of patients who underwent PET/CT and CT and found that PET/CT-localized CRT improved survival, while CT imaging-guided radiotherapy did not, indicating a signi cant PET/CT advantage in extracranial oligometastatic NSCLC diagnosis. PET/CT has become the standard imaging tool for characterizing lung nodules [19], initial staging [20,21], treatment planning, treatment response assessment [22], recurrence staging [23,24], and lung cancer monitoring. The widespread clinical use of FDG-PET/CT in patients with lung cancer has improved staging and restaging accuracies, allowing for better treatment planning and treatment response assessments.
Local consolidation therapy is a common treatment for oligometastatic NSCLC. In 2016, Gomez et al. was the rst to report the results of a phase II randomized trial that compared standard maintenance therapy (n=24) to local consolidation therapy (n=25) [25]. The median patient follow-up was 12.39 months, and the progression-free survival (PFS) was signi cantly better in the maintenance treatment group than in the local consolidation group (11.9 months vs. 3.9 months, p=0.0054). Adverse events were similar between both groups, with no treatment-induced grade 4 adverse events or deaths. Gomez [7]. Overall survival rates were extremely higher in the LCT group than in the chemotherapy alone group (13 months vs. 7 months, p=0.002). Side effects incidence was similar between LCT and chemotherapy alone groups, and there were no treatment-related adverse outcomes or deaths. To explore more effective and personalized treatment options for oligometastatic lung cancer, we focused on evaluating the e cacy of extracranial oligometastases treated with CRT and revealed that similar e cacy was achieved with radiation therapy to the primary lung site alone compared to LCT, meaning that it is possible to achieve satisfactory outcomes with treatments that cause less damage to patients with extracranial oligometastatic NSCLC than maintenance treatments. There are several possible mechanisms that could explain the survival bene ts of lung radiotherapy. First, after systemic treatment, hard-to-treat malignant cells, which are unlikely to be eliminated by subsequent maintenance therapy and can serve as a source of following metastatic spread, are left behind. However, in such cases, CRT may reduce the number of such cells. Second, CRT may enhance the effects of systemic therapy by possibly making residual lesions more sensitive to subsequent maintenance therapy. A third possibility is that radiotherapy kills tumor cells by modulating the immune system. Radiotherapists are often subjective in the process of outlining tumor target areas based on CT images, and the in uence of experience on the accuracy of tumor target area outlining can further affect the e cacy of radiotherapy. In particular, patients with advanced lung cancer often have complications such as pulmonary atelectasis, which is di cult to identify with the tumor lesions. Therefore, we believe that CT plays a limited role in the process of target area outlining, and it is di cult to improve the prognosis of lung cancer patients. A well-de ned lesion is shown in PET/CT, which can exclude the in uence of subjective factors on the accuracy of target area outlining and thus improve the e cacy of radiotherapy.
Immunotherapy was not included in this study because the patient information we analyzed was rst obtained in 2013. As research progresses, it is increasingly recognized that there are complex interactions between radiotherapy and the immune system. In addition to producing a local therapeutic effect at the irradiated tumor site, radiotherapy can also cause spontaneous tumor regression in non-irradiated lesions; this is known as the abscopal effect [28]. Although the abscopal effect was studied for decades, the exact mechanism of this phenomenon is still unclear, and Demaria et al. [29] rst linked the distal effect of radiotherapy to an immune-mediated mechanism. Preclinical studies suggest that radiotherapy is equivalent to an "agonist" in immunotherapy, making tumor cells more susceptible to T-cell-mediated immune attacks by modulating the immune system. Radiotherapy can enhance anti-tumor immune effects by inducing the release of more neoantigens from damaged tumor cells, enhancing the expression of major histocompatibility complex (MHC) class I molecules, and upregulating chemokines, cell adhesion molecules, and other immunomodulatory cell surface molecules, thereby inducing immunogenic cell death [30]. In terms of increasing attention to immunotherapy, the possibility of combining radiotherapy with immunotherapy is worth exploring, and this combination to produce synergistic antitumor activity shows great application prospects and development potential in the future.

Conclusions
PET/CT-guided chest radiation therapy is associated with improved clinical outcomes in patients with stage IV extracranial oligometastatic NSCLC. Advances in radiotherapy technology improved radiotherapy precision and ensured treatment safety, while improving radiotherapy effectiveness. Undoubtedly, the continuous optimization and innovation of radiotherapy technology in positioning, target area outlining, planning, and beam projection will continue to be a strong driving force for applying and developing radiotherapy in patients with lung cancer in the future. Future basic researches and largesample randomized clinical trials on how to further optimize combinations of radiotherapy and systemic therapy, speci cally in terms of targeted therapy and immunotherapy, in patients with lung cancer will be conducted. Informed Consent Statement: The requirement for informed consent was waived due to the retrospective nature of this study.

Declarations
Data Availability Statement: All data in this study are true and reliable. Figure 1 Flowchart depicting selection of the study population. Figure 2 a.&b. Kaplan-Meier curve of overall survival for patients who did and did not receive PET/CT in the overall population ( before PSM n=192,after PSM n=178 ).

Figures
c.&d. Kaplan-Meier curve of overall survival for patients who did and did not receive CRT in the overall population ( before PSM n=192,after PSM n=178 ).