This study demonstrated that HRS (CNS, bone, abdominal organ, and pleural) recurrence or multiple SRL (lung, intrathoracic lymph node, cervical and axillary lymph node, chest wall, eye and tongue, and skin) recurrences were vital recurrences that were associated with poor PRS. Preoperative predictors for vital recurrence were CEA ≥ 5 ng/ml, PET max SUV ≥ 3.0, and clinical stage ≥ II. Patients with all three predictors had vital recurrence at 46.7% within 5 years after surgery.
The median PRS and 5-year PRS rates were 26 months and 24.5%, respectively, which were similar to those in previous reports [3–6]. In the previous study, the frequency of recurrence to intrathoracic lymph nodes, lung, bone, pleura, brain, abdominal organ, cervical lymph node, and chest wall was 22–42% [4, 6], 37–42% [4–6], 12–18% [4–6], 7–16% [4, 6], 11–18% [4–6], 10–15% [4–6], 9% [4], and 2% [4], respectively, and those frequencies were comparable to present study. There are a limited number of reports analyzing prognosis according to initial recurrence sites. A previous study reported that poor PRS has been observed in patients with lung [15], brain [16], bone [5, 6, 16, 17], and liver recurrence [6, 18]. However, since these studies were based on small sample size, there is no consensus on the association between PRS and recurrence site. In the present study of 727 recurrent patients, the largest study using a multicenter database revealed that HRS or multiple LRS recurrences were associated with a significantly poor PRS. In contrast, PRS was significantly better in patients with single LRS recurrence.
The specific reason why PRS differs in recurrence site is as follows: first, HRS tongue including bone, brain, and pleural recurrence may decrease the patient's quality of life or lower performance status, making treatment after recurrence more difficult [19–23]. Second, recurrences in the liver and CNS have been reported to be less responsive to chemotherapy [22]. As shown in Table 2, a more aggressive tumor was observed in the HRS or multiple LRS recurrence groups than in the single SRL recurrence group, which may result in poor PRS.
Recently, it has been reported that local therapy prolongs PRS in patients with 3–5 or fewer oligo-recurrent foci [3, 24–26]. The present study suggests that local therapy may improve the prognosis of patients with a single LRS recurrence because cancer cells with a less aggressive nature are localized. Previously, Hishida et al. reported that oligo-distant recurrence (single site) has no difference in prognosis compared with oligo-locoregional recurrences (1–3 sites) [24]. Torok et al. reported oligo-distant recurrence (1–3 sites) had a significantly better PRS than diffuse distant recurrence (> 3 sites or pleural dissemination). Further investigation is necessary to determine the efficacy of local therapy for the oligo-distant recurrence of a single LRS.
Patients with HRS or multiple LRS recurrences had poor PRS and OS, suggesting that these patients had systemic cancer at the time of surgery. These patients had difficulty in controlling cancer through local therapy such as surgery and radiation therapy alone, and combination therapy with systemic therapy, such as immune checkpoint inhibitors, tyrosine kinase inhibitors, and chemotherapy was necessary during the perioperative period. In recent years, nivolumab plus platinum-based chemotherapy has demonstrated longer event-free survival for clinical stage IB-IIIA NSCLC without epidermal growth factor receptor gene mutation (EGFR) and anaplastic lymphoma kinase (ALK) translocation in CM816. The HR for death or distant metastases was 0.53 (95% CI, 0.36–0.77) and the subgroup analysis showed that greater benefit was observed in a population with a poor prognosis [14].
There are few studies on predictors of recurrence in specific organs and even fewer studies on preoperative predictors. A previous study reported that tumor grade, metastatic lymph node ratio ≥ 30% (LNR), non-squamous cell carcinoma histology, bronchial invasion, perineural invasion, and adjuvant chemotherapy were associated with brain recurrence [7, 27, 28]. Motono et al. analyzed seven postoperative patients with pleural dissemination and reported that young age and poor differentiation are risk factors for pleural dissemination [29]. Previous studies have reported that older age [8], adenocarcinoma histology [8, 30], and higher stage [8, 31] are associated with distant recurrence. Wu et al. scored the risk of distal recurrence as smoking history, additional primary malignancy, non-anatomic resections, adenocarcinoma histology, pleural invasion, and angiolymphatic invasion and reported that intermediate- or high-risk groups had a higher frequency of distal recurrence [32]. The strength of this study is the analysis of preoperative CEA values and the PET maxSUV in all patients. Furthermore, the present study is the first to show that CEA values and PET maxSUV, along with clinical stage, are preoperative predictors of HRS and multiple LRS recurrences leading to poor PRS.
Patients with CEA ≤ 5 ng/ml, PET maxSUV ≤ 3.0, and clinical stage ≤ II recur in HRS or multiple LRS at 46.7% within 5 years after surgery; therefore, these patients should receive aggressive neoadjuvant/adjuvant therapy. On the other hand, neoadjuvant therapy may not be necessary in patients with any of these predictors, as vital metastasis occurs in as low as 3.2% of cases. These preoperative predictors are important for personalized neoadjuvant/adjuvant therapy in resectable clinical stage IB-III NSCLC. Further studies are necessary to compare the effectiveness of neoadjuvant therapy and adjuvant therapy for patients who are likely to experience recurrence at HRS or multiple LRS in a large-scale clinical trial.
This study demonstrated the importance of comprehensive surveillance of all recurrence sites at the time of recurrence to predict survival after recurrence. Moreover, recognition of HRS/LRS and the risk of recurrence are useful for postoperative surveillance. Patients with symptomatic recurrence have been reported to have a poorer prognosis than those with asymptomatic recurrence detected during surveillance [33]. Detection of a single LRS before developing into multiple LRSs may result in a better PRS. Although the ASCO guidelines do not recommend routine follow-up with PET-CT or head magnetic resonance imaging (MRI) (evidence quality: low; strength of recommendation: moderate) [34], intentional follow-up, including head MRI and PET-CT, is considered necessary for patients with one or more predictors of vital recurrence. Future clinical trials of personalized surveillance based on CEA level, PET maxSUV, and clinical stage are warranted.
This study has several limitations. First, this was a retrospective study and selection bias may have been possible. No common surveillance protocol has been established at the three institutions in this study, both postoperatively and at recurrence. Second, we did not examine the effects of the treatment after recurrence. Third, this study did not examine the number of recurrent foci. Further studies on the association between the number of recurrent foci and PRS are necessary. Fourth, information on EGFR mutations, ALK translocation, and programmed cell death 1- ligand 1 status was not available in this study. The relationship between these statuses and recurrence sites needs to be further verified.