Traditional NSCLC staging is based primarily on history, fiberoptic 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 refined anatomical level, with a superior sensitivity and specificity 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 defined 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 benefits 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 significant 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 first 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 significantly 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 et al. published the results of their latest long-term clinical study in 2019 and successfully confirmed that PFS (median, 14.2 months [95% CI, 7.4 to 23.1 months] with LCT vs. 4.4 months [ 95% CI, 2.2 to 8.3 months] with maintenance therapy or observation; P=0.022) and overall survival (median, 41.2 months [95% CI, 18.9 months to not reached] with LCT vs. 17.0 months [95% CI, 10.1 to 39.8 months] with maintenance therapy or observation; P=0.017) significantly improved by the early inclusion of LCT [26]. They also reported that both initial LCT before progression and delayed LCT after progression contributed to improved overall survival. In 2018, Iyengar et al. reported results from a phase II randomized trial comparing standard maintenance therapy with and without stereotactic ablative radiotherapy (SABR) in a patient population nearly identical to that of the trial reported by Gomez et al. and showed that PFS was significantly better in the SABR plus maintenance chemotherapy group than in the maintenance chemotherapy alone group (9.7 months vs. 3.5 months, p=0.01) [27]. Gomez et al. and Iyengar et al. both conducted phase II trials in patients with oligometastatic NSCLC to study the prognostic impact of aggressive local therapy. Both trials reported a significant increase in PFS by increasing aggressive local therapy. Moreover, our previous study showed that PET/CT-guided LCT was significantly efficient in patients with oligometastatic advanced lung cancer [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 efficacy of extracranial oligometastases treated with CRT and revealed that similar efficacy 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 benefits 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 influence of experience on the accuracy of tumor target area outlining can further affect the efficacy of radiotherapy. In particular, patients with advanced lung cancer often have complications such as pulmonary atelectasis, which is difficult 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 difficult to improve the prognosis of lung cancer patients. A well-defined lesion is shown in PET/CT, which can exclude the influence of subjective factors on the accuracy of target area outlining and thus improve the efficacy of radiotherapy.
Immunotherapy was not included in this study because the patient information we analyzed was first 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] first 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.