Prognosis for local radical treatment in patients with esophageal squamous cell carcinoma with low-risk oligometastatic recurrence after curative resection: a retrospective cohort study

Introduction

The International Agency for Research on Cancer recently estimated that there were 544,000 new deaths from esophageal carcinoma (EC) and 60,400 new EC cases reported worldwide in 2020. Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of EC in Southern Asia and Eastern Africa, and esophageal adenocarcinoma is the predominant subtype in Northern Europe and the United States (1). Despite the wide application of radical esophagectomy and 3-field lymph node (LN) dissection, as well as significant improvements in radiotherapy and systemic therapy in EC in recent years, the recurrence rate of advanced EC after curative treatment remains high at approximately 45% (2,3). Patients with EC with recurrent disease, including locoregional recurrence, distant metastasis, or both, have a poor prognosis with many patients dying within 4–10 months (4,5). Thus, identifying an effective treatment regimen for EC recurrence is crucial to improving survival.

In 1995, Hellman et al. initially proposed the concept of ‘oligometastases’, and suggested that it represents an optimistic situation for metastatic disease (6), in contrast to that of widespread systemic recurrence. Oligometastatic disease (OMD) is defined as an intermediate phase in which systemic metastatic tumors with indolent biological behavior are limited in number and location and may theoretically be eradicated by definitive local treatment.

OMD is often encountered at the initial diagnosis or after curative treatment in clinical practice. Limited numbers of safely treatable metastases diagnosed after curative esophagectomy was defined as oligometastatic recurrence (OLR). In a retrospective study, patients with ≤5 metastases located in a single organ were defined as having OLR (4). Yamaguchi et al. defined EC patients with ≤3 metastases located in a single organ as OLR (7). In another study, ESCC patients with <5 recurrences in 1 organ had longer overall survival (OS) after recurrence than those with 6 or more recurrences in 1 organ, or metastases located in multiple organs (21 vs. 9.8 months, P=0.003) (8). There was wide variation in the number of metastases and metastatic organs involved. Radical treatment methods for primary EC have not been inconsistent. And multicenter, prospective randomized controlled trials (RCTs) are lacking. To date, there has been no consistent definition of OLR after curative esophagectomy. Moreover, the role of local therapy, including radiation, radiofrequency ablation, and resection, in OLR after radical esophagectomy remains unknown (9-12).

Thus, the primary aims of the current study were to precisely define low-risk OLR and identify independent prognostic factors in patients with ESCC with low-risk OLR after radical esophagectomy. The secondary aim was to investigate the role of chemotherapy combined with local treatment (CCLT) in patients with low-risk OLR. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-205/rc).

Methods

Patients

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This retrospective study was approved by the Ethics Committee of Fujian Cancer Hospital (No. YKT2021-005-01), and informed consent was taken from all the patients. We reviewed patients with ESCC who had previously undergone radical esophagectomy and 2- or 3-field lymphadenectomy and had newly diagnosed recurrence at Fujian Cancer Hospital between January 2010 and May 2019. The inclusion criteria were as follows: (I) Eastern Cooperative Oncology Group performance status score ≤2; (II) histologically confirmed oligometastatic ESCC after radical esophagectomy and 2- or 3-field lymphadenectomy; (III) total number of metastases ≤5 and located in ≤3 organ systems with or without regional recurrence and/or regional LN metastases; (IV) no regional recurrence and/or regional LN metastases only; (V) ability to tolerate chemotherapy (CT) and local treatment; and (VI) no other history of malignant disease. The staging was re-determined according to the 8^th American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system based on the clinical data (13).

Definition of low-risk and high-risk OLR

A clear consensus regarding OLR has not yet been reached. The most common definition of OLR used in clinical practice and trials is the presence of ≤5 metastases safely treatable with curative intent. However, clinical outcomes vary greatly. In this study, low-risk OLR was defined as ≤5 metastases safely treatable with curative intent located in a single organ. The presence of ≤5 metastases safely treatable with curative intent located in 2–3 organs with or without regional recurrence and/or regional LN metastases was defined as high-risk OLR.

Treatment of low-risk and high-risk OLR

OLR treatment was classified as (I) CT alone and (II) CCLT. Patients with OLR who received the best supportive care, local therapy only, or no treatment were excluded from this study. All patients with OLR were treated with 2 or more cycles of CT. The CT regimens included: (I) paclitaxel 135 mg/m² by intravenous (i.v.) infusion on day 1 + cisplatin 80 mg/m² i.v. infusion on day 2; (II) capecitabine 1,000 mg/m² orally twice a day on day 1–14 + cisplatin 80 mg/m² i.v. infusion on day 1; (III) 5-fluorouracil 750 mg/m² i.v. bolus on days 1–4 + oxaliplatin 75 mg/m² i.v. infusion on day 1; and (IV) S-1 40–60 mg orally twice a day on days 1–14 + cisplatin 80 mg/m² i.v. infusion on day 1. Local treatment included surgical resection, stereotactic body radiotherapy (SBRT), fractionated stereotactic radiation therapy (FSRT), conventional radiotherapy, and radiofrequency ablation. Due to the heterogeneity in tumor sites and metastatic organs, there was a variety of SBRT/FSRT schemes and conventional radiotherapy schedules applied. The range of SBRT/FSRT doses were 25–60 Gy, with 5–10 Gy per fraction in 5–10 fractions. Conventional radiotherapy was administered using medical linear accelerator with prescription radiation dose ranging from 30 to 63 Gy with 2–2.1 Gy per fraction in 10–30 fractions.

Follow-up

Regular follow-up examinations were typically performed every 3 months in the first year, every 6 months over the next 2 years, and yearly thereafter. Routine evaluations included physical examination, blood tests, tumor markers, biochemical investigations, thoracic and upper abdominal CT scanning, and magnetic resonance imaging when recurrences in the liver, brain, or bone with suspected spinal cord compression were found. November 2022 was the last censoring date for the evaluation of survival time. The disease-free interval (DFI) was defined as the interval between the date of surgery and the date of diagnosis of recurrence. OS after recurrence was defined as the interval between the radiologic/clinical diagnosis of recurrence and death or the last follow-up. The main clinical endpoint of interest was OS after recurrence.

Statistical analysis

All recorded data were analyzed using the software SPSS 23.0 (IBM Corp., Armonk, NY, USA).

The OS curves after recurrence were analyzed using the Kaplan-Meier method, and a log-rank test was used to assess differences in OS between the groups. Cox proportional hazards regression analysis was performed to identify independent factors predictive of OS for patients with ESCC and low-risk OLR. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for each factor. All tests were 2-sided, and a P value <0.05 was considered statistically significant.

Results

Patient characteristics

We reviewed the clinical data of 990 consecutive EC patients treated with radical esophagectomy who experienced a disease recurrence. Ultimately, 83 patients with ESCC (71 males and 12 females) who met the inclusion criteria were included. Out of the entire cohort of 83 ESCC patients with OLR after curative resection, 35 patients with ≤5 metastases located in a single organ were categorized as the low-risk OLR group and 48 patients with ≤5 metastases located in 2–3 organs with or without regional recurrence and/or regional LN metastases were categorized as the high-risk OLR group. The median follow-up time was 15 months (range, 1–147 months). The median age of the patients was 56 years (range, 37–79 years). The basic characteristics of all patients are summarized in the Table 1.

Recurrence pattern of low- and high-risk OLR

The sites of recurrence in the low-risk OLR group (n=35; 42.2%) were the lungs (n=18; 51.5%), liver (n=6; 17.1%), bones (n=4; 11.4%), and brain (n=7; 20%). The median survival times (MSTs) after recurrence for metastases located in the lung only, liver only, bone only, and brain only were 30, 13, 15, and 16 months, respectively. The 2-year OS rates after recurrence for the lung, liver, bone, and brain only were 61.1%, 0%, 50.0%, and 42.9%, respectively. The MST and 2-year OS of patients with low-risk OLR with liver oligometastases were significantly worse than those of patients with lung oligometastases (P=0.009). Statistical analysis showed no significant difference in MST and 2-year OS for brain oligometastases (P=0.056) and bone oligometastases (P=0.64) compared with lung oligometastases (Table 2).

Conversely, 30 patients (36.1%) in the high-risk OLR group had a recurrence in 23 organs with regional recurrence and/or regional LN metastases and 18 (21.7%) without regional recurrence and/or regional LN metastases. The MST after recurrence for patients with ESCC in the high-risk OLR group with and without regional recurrence and/or regional LN metastases was 11 and 16 months, respectively. The survival curves after recurrence in patients with ESCC with high-risk OLR according to regional recurrence and/or regional LN metastases are shown in Figure 1A (1- and 2-year OS of 46.3% and 14.6%, vs. 57.1% and 14.3%, respectively; P=0.83). In this study, regional recurrence and/or regional LN metastasis in the high-risk OLR group were not associated with long-term survival after recurrence.

Figure 1 Kaplan-Meier survival curve for OS after recurrence for 48 patients with EC with high-risk OLR according to regional recurrence and/or regional lymph node disease (A) and 83 patients with EC according to the recurrence pattern (B). OS, overall survival; EC, esophageal carcinoma; OLR, oligometastatic recurrence; RR, regional recurrence.

OS after the recurrence of low- and high-risk OLR

The MST after recurrence for patients with ESCC in the low- and high-risk OLR groups was 19 and 11 months, respectively. For patients with ESCC in the low-risk OLR group (n=35), the 1- and 2-year OS rates after recurrence were 71.4% and 42.9%, respectively. For patients with ESCC in the high-risk OLR group (n=48), the 1- and 2-year OS rates after recurrence were 47.9% and14.6%, respectively. Based on these results, OS after recurrence was significantly better for patients with ESCC in the low-risk OLR group than in those in the high-risk OLR group (P=0.03) (Figure 1B).

To identify the factors affecting long-term survival after recurrence in the entire cohort, we performed univariate analysis and demonstrated that a lower third tumor location (P=0.005), lower pathological LN (pN) stage (P<0.001), and low-risk OLR (P=0.03) were significantly associated with improved OS after recurrence. Multivariable analysis confirmed that the lower pN stage (P=0.003), low-risk OLR (P=0.003), and longer DFI (P=0.01) were independent prognostic factors for improved OS (Table 3).

OS after recurrence in patients with low- or high-risk OLR according to the treatment method

A total of 57 patients received ≥2 cycles of CT alone after recurrence, and 26 patients received CCLT after recurrence. The local treatment for patients with ESCC after recurrence was surgical resection (n=2, 7.7%), SBRT/FSRT or conventional radiotherapy (n=20, 76.9%), or radiofrequency ablation (n=4, 15.4%). The MST after recurrence for patients with ESCC in the low-risk OLR group treated with CT and CCLT was 17 and 32 months, respectively. For patients with ESCC in the low-risk OLR group treated with CT (n=23) vs. CCLT (n=12), the 1- and 2-year OS rates after recurrence were 60.9% and 30.4% versus 91.7% and 66.7%, respectively. Based on these results, OS after recurrence was significantly better for patients with ESCC in the low-risk OLR group treated with CCLT than in those treated with CT (P=0.003) (Figure 2A). For patients with ESCC in the high-risk OLR group treated with CT (n=34) or CCLT (n=14), the 1- and 2-year OS rates after recurrence were 38.2% and 11.8% versus 71.4% and 21.4%, respectively. From these results, the OS after recurrence was not significantly different between patients with ESCC in the high-risk OLR group treated with CT and those treated with CCLT (P=0.23) (Figure 2B).

Figure 2 Kaplan-Meier survival curve for OS after recurrence in 35 patients with low-risk OLR (A) and 48 patients with high-risk OLR (B) according to treatment type. OS, overall survival; OLR, oligometastatic recurrence; CCLT, chemotherapy combined with local treatment; CT, chemotherapy.

To identify the factors affecting OS after recurrence in patients with low-risk OLR, we performed univariate analysis and demonstrated that treatment method with CCLT (P=0.003) and lower pN stage (P<0.001) were significantly associated with improved OS after recurrence. Multivariable analysis confirmed that a higher degree of differentiation (lower grade) (P=0.01), CCLT treatment (P=0.02), and lower pN stage (P=0.006) were independent prognostic factors for improved OS (Table 4).

Discussion

In this study, 83 patients with ESCC who underwent radical esophagectomy and newly diagnosed OLR were analyzed. Patients with ≤5 metastases safely treatable with curative intent located in 2–3 organs with or without regional recurrence and/or regional LN metastases had worse 2-year OS after recurrence than those with ≤5 metastases safely treatable with curative intent located in a single organ (2-year OS, 14.6% vs. 42.9%, P=0.03). Multivariable analysis confirmed that ESCC with ≤5 metastases safely treatable with curative intent located in a single organ was an independent prognostic factor. Thus, low-risk OLR was defined as ≤5 metastases safely treatable with curative intent located in a single organ in our study. We also established that CCLT with local treatment, including surgical resection, SBRT/FSRT, conventional radiotherapy, and radiofrequency ablation, was the main prognostic factor for patients with ESCC with low-risk OLR after radical esophagectomy and 2- or 3-field LN dissection. For patients with ESCC in the low-risk OLR group treated with CT and CCLT, the 2-year OS rates after recurrence were 30.4% versus 66.7% (P=0.003), respectively. Further multivariable analysis demonstrated that treatment method was an independent prognostic factor affecting OS after recurrence in patients with low-risk OLR. These findings suggest that CCLT is a promising treatment option for patients with ESCC and low-risk OLR.

It remains unclear whether patients with OLR benefit from local treatment. For breast cancer patients with OMD, the role of local treatment was not formally recommended by guidelines and clear-cut reference literature. However, some selecting patients with OMD would increase the chance of long-term local control by appropriate local treatments (14). In a review article by Saeed et al., locally ablative therapies (LAT) including primarily surgery and SBRT had a positive impact on oligometastatic breast cancer compared with standard of care treatments. A recent study demonstrates the local treatments play crucial roles in ESCC with OLR (15). A multicenter cohort study by Kroese et al. retrospectively evaluated 205 patients with esophagogastric cancer with synchronous and metachronous OMD who underwent (I) systemic therapy, (II) local treatment, (III) CCLT, or (IV) best supportive care and found that the median OS was significantly increased for local plus systemic therapy compared with systemic therapy alone (35 vs. 13 months, P<0.001). Moreover, CCLT was an independent factor for improved OS. The local treatment performed in the study included SBRT and metastasectomy (16). In another study by Morinaga et al. with 97 ESCC patients with OLR, systemic therapy combined with local therapy after recurrence was the only prognostic factor for OS after recurrence (8). Kanamori et al. retrospectively analyzed 33 patients with EC who had undergone metastasectomy for lung metastases after definitive treatment and found that the 5-year OS and MST were 43% and 17.9 months, respectively. Surgical resection is safe and effective in patients with EC with metastatic pulmonary tumors (17). In a prospective, single-arm phase II trial by Liu et al., 34 patients with ESCC and ≤3 metastases were enrolled to receive radical treatment with SBRT to all metastatic lesions and at least 4 cycles of CT. The results showed that the median disease-free interval was 13.3 months. The 2-year progression-free survival (PFS) and OS rates were 33.8% and 58%, respectively. SBRT with systemic therapy was well-tolerated and effective for patients with lung metastases (18). In a retrospective analysis of real-world data, Duan et al. investigated 86 oligometastatic ESCCs treated with local radiotherapy plus programmed cell death protein 1 (PD-L1) inhibitors and found that the 1- and 2-year PFS rates were 61.4% and 26.7%, respectively. The objective response rate and disease control rate were 91.3% and 57.3%, respectively. Only 1 patient was observed as having a grade 5 treatment-related adverse event. Local therapy plus PD-L1 was shown to be a safe and effective treatment option (19). Our study focused on OS after ESCC recurrence in patients with low-risk OLR and found that CCLT was associated with a better 2-year OS after recurrence than CT (66.7% vs. 30.4%, P=0.003). Moreover, CCLT was a significant independent predictor of a favorable OS after recurrence. A select subgroup of patients with ESCC with low-risk OLR benefited from CCLT.

The lack of consensus regarding the definition of OLR and OMD makes identification of prognostic factors in patients with EC more challenging. Several studies have investigated the factors that could be utilized in daily clinical practice for better patient selection. DFI, defined as the phase between the date of surgery and the date of diagnosis of recurrence, has been treated as a prognostic factor in many studies. Ohkura et al. studied 206 patients with EC with recurrence after radical therapy and found that a DFI ≥12 months had a better OS than a DFI <12 months (4). Ghaly et al. (20) found that DFI was an independent prognostic factor for isolated recurrence in patients with EC treated with definitive treatment, which is similar to the findings of Shiono who found that in 57 patients with EC with pulmonary metastases who underwent resection, patients with a DFI ≤12 months had a worse OS than those with a DFI >12 months. Moreover, the DFI is an independent factor for OS (21). In our study, a DFI >12 months was also a clinical factor significantly related to 2-year OS in patients with ESCC with recurrence.

In some studies, the location of the metastasis was treated as a prognostic factor for EC recurrence. Nobel et al. studied 104 EC cases with isolated solid organ recurrence in the liver, lung, and brain and found that patients with lung oligometastases had longer median OS than those with brain or liver oligometastases (P<0.001) (22). Depypere et al. studied 766 patients with EC with recurrence and found that patients with solitary LN recurrence located in one region had a superior OS than those with metastasis in single organs, including the liver, brain, lung, and adrenal glands (16.8 vs. 9.9 months, P=0.0074) (23). Grou-Boileau et al. studied 755 esophageal cancer patients and found that 27 patients (3.6%) exhibited locoregional recurrence after esophagectomy following neoadjuvant therapy. Locoregional recurrence in that study was defined as pathologically confirmed recurrences at the anastomosis or radiologically confirmed mediastinal and celiac LN metastasis. Local therapy including radiotherapy and surgery were the main modality used in this study and the 2- and 5-year OS were 61.1% and 22.2%, respectively (24). In our study, the 2-year OS rates after recurrence in patients with EC with isolated solid organ recurrence in the lung, liver, bone, and brain were 61.1%, 0%, 50%, and 42.9%, respectively. The OS rate of patients with low-risk OLR with liver oligometastases was significantly worse than that of those with lung oligometastases (P=0.009). Yokoyama et al. found that rectal cancer patients with isolated lung metastases had a more indolent course and should be treated with surgery, which leads to a better prognosis compared with that of patients with liver and brain metastases. Moreover, the wide application of magnetic resonance imaging could enable the earlier detection of small lesions in the brain and liver to achieve better results (25). The OS after EC recurrence in patients with high-risk OLR according to the presence of regional recurrence and/or regional LN metastases was not statistically significant in the current study (2-year OS 14.6% vs. 14.3%; P=0.83).

The strengths of our study include that we precisely defined low-risk OLR and reported that CCLT is a particularly promising treatment method for EC with low-risk OLR according to our data. In addition, our study further analyzed the OS difference among patients with low-risk OLR with isolated solid organ recurrence in the lung, liver, bone, and brain and demonstrated that patients with lung oligometastases had longer OS than those with liver oligometastases. These results will help oncologists to define low-risk OLR and select optimal treatment methods for ESCC patients with low-risk OLR after curative resection in real-world settings. However, this study had some limitations. First, the number of low and high-risk OLR cases included was limited to a single institution, and more data will be required to verify our results. Additionally, the number of patients with low-risk OLR treated with CCLT was also limited, and the role of CCLT in these patients needs to be elucidated in further studies. Second, selection bias inherent in retrospective studies may have reduced the overall validity of our results. Third, owing to the lack of data on progression-free survival and cause-specific survival, these factors were not included in the assessment.

Conclusions

Our results showed that low-risk OLR is reasonably defined as ≤5 metastases safely treatable with curative intent in a single organ. Patients with ESCC who experience low-risk OLR after curative resection treated with CCLT had a favorable OS compared to those treated with CT alone in multivariable analysis. Thus, CCLT is a promising treatment option for patients with ESCC and low-risk OLR. Prospective randomized studies to verify our results are warranted.

Acknowledgments

The authors thank all patients who participated in the study.

Funding: This research was funded by the National Clinical Key Specialty Construction Program, 2021 and Fujian Provincial Clinical Research Center for Cancer Radiotherapy and Immunotherapy (No. 2020Y2012).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-205/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-205/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-205/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-205/coif). The 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 (as revised in 2013). This retrospective study was approved by the Ethics Committee of Fujian Cancer Hospital (No. YKT2021-005-01), and informed consent was taken from all the patients.

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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