The changing face of brain metastasis in esophageal cancer in the current era of multi-modality therapy—literature review

Introduction

Background

According to the 2020 Global Cancer Statistics, esophageal cancer ranks sixth in terms of causes of death worldwide and is the seventh most common malignant tumor. In 2020, there were an anticipated 604,000 new cases of esophageal cancer and 544,000 deaths from the disease worldwide (1). Twenty to thirty percent of patients with esophageal cancer have distant metastasis at the time of diagnosis, and significant proportion relapse with distant metastasis after potentially curative treatment. Therefore, esophageal cancer is often deemed to be a systemic disease.

Brain metastasis from esophageal cancer are rarely present at the outset (less than 25% of cases) and their development is usually delayed phenomenon with latency ranging between 6–12 months from diagnosis or completion of curative therapy. In the latter case the latency may be even longer approaching up to 18–24 months.

The development of brain metastasis represents a critical step in the evolution of metastatic disease and reflects on disruption of blood brain barriers and seeding of tumor cells in the central nervous system. These changes are likely to be associated with transformation into more aggressive phenotype and significant alteration of survival dynamics.

The development of brain metastasis from esophago-gastric cancer (BMEC) was supposedly a rare phenomenon. In two separate Surveillance, Epidemiology, and End Results (SEER) studies the incidence of BMEC ranged from 1.6% to 5% (2,3). However, more recent studies have reported much higher incidence of brain metastasis ranging from 13% to 23.4% (4,5).

Rationale and knowledge gap

It remains unclear if the increased reporting of BMEC relates to shift in histopathological patterns [e.g., increasing incidence of adenocarcinoma (AC) vs. squamous cell carcinoma (SqCC)], or optimization of adjuvant strategies and more frequent use of multi-modality therapy. The optimization of therapeutic strategies including the more frequent adoption of multi-modality therapy has been associated with an improvement in survival with patients living longer and therefore more likely to develop brain metastasis compared to in the past. In addition, the improvement in diagnostic technology may be indirectly responsible for more frequent detection of BMEC and contributing to the increased rates observed in more recent studies. Moreover, the effects of these new emerging patterns on prognosis and outcomes remains poorly defined.

Objective

We performed a review of literature to interrogate above parameters and report on the current state of diagnosis and management of BMEC. The rationale of such a review is strengthened by the changing therapeutic landscape of metastatic esophageal cancer with more frequent use of potent systemic strategies including immunomodulation [e.g., programmed death ligand-1 (PDL-1) directed systemic therapy] and the advent and wider availability of focused stereotactic ablative strategies for management of individual brain metastasis. We present this article in accordance with the Narrative Review reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-7/rc).

Methods

We searched the PubMed database using different permutations and combinations of the following key words: esophageal cancer OR gastro-esophageal cancer OR gastric cancer AND brain metastasis. The following filters were applied: study type: case reports, clinical study, clinical trial, clinical trial protocol, clinical trial, Phase I, clinical trial, Phase II, clinical trial, Phase III, clinical trial, Phase IV, controlled clinical trial, observational study, randomized controlled trial; language: English; species: humans; publication date: custom range: start date from 01/01/2005.

The available data was mainly limited to case reports or single institute studies. We selected case reports and studies which had reported clearly on the presenting features of BMEC and also the treatment options and outcomes. We interrogated the studies to identify the following parameters: patient demographics, histopathological characteristics, disease background (previous curative therapy for localized disease or metastatic disease at outset), solitary versus multiple brain metastasis, presence of extra cranial disease, treatment options including surgery, stereotactic radiosurgery (SRS), radiotherapy, systemic anti-cancer therapy (SACT), and outcomes (response, survival). Studies which failed to report on the treatment options and outcomes were excluded from the analysis. The search strategy is summarized in Table 1.

Key content and findings

We identified 15 case reports from 16 studies describing 20 cases with BMEC that are summarized in Table 2 (6-21). There was male preponderance with 13 males and 7 females. The median age was 60 years (range, 28–69 years). There were 12 cases of SqCC and 8 cases of AC. Thirteen patients underwent previous curative therapy and the reported latency for development of BMEC ranged from 8–96 months. Seven patients had evidence of metastatic disease at presentation. Eleven patients had solitary BMEC. Eight patients had surgical resection. Nine patients had SRS, six patients had whole brain radiotherapy (WBRT), one patient had combined WBRT and SRS and one patient had involved-field radiotherapy. Eight patients received systemic chemotherapy, two patients received immunotherapy. Two patients received local instillation of 5-fluorouracil pellets, and one received concurrent temozolomide. The median survival in case reports was 11 months (range, 1.5–78 months) from detection of brain metastasis. The longest survival (>2 years) was observed in patients who had solitary metastasis and were treated with surgical resection and SRS. Indeed, there were four patients who survived in excess of 35 months with the longest reported survival of 78 months. Two patients with multiple lesions survived for 21 and 24 months without surgical resection but were treated with SRS or WBRT combined with systemic chemotherapy and immunotherapy.

We identified nine single institutional cohorts that had reported on BMEC which are summarized in Table 3 (22-30). Welch et al. [2017] reported on 22 (3.8%) patients with BMEC from an original cohort of 495 patients. AC was the predominant histology in 21 patients, while SqCC was seen in one patient. Ten stage IV patients with distant metastases and twelve patients who were first treated for locally advanced disease subsequently developed brain metastases.

Overall survival (OS) after brain metastases diagnosis was 18% at 1 year (median, 4 months). No difference in OS after brain metastases diagnosis was observed in patients initially treated for localized disease compared to patients who presented with stage IV disease. The OS was superior for patients who initially had surgical resection compared to patients treated with WBRT or SRS alone (1-year OS, 67% vs. 0%; median OS, 13.5 vs. 3 months; P=0.003) (22).

Zhang et al. [2020] reported on cohort of 31 patients with BMEC with SqCC as predominant histology (n=26). Most lesions were solitary (n=18) and only six patients underwent surgical resection. The rest were treated with combination of radiotherapy and/or systemic chemotherapy. Patients with BMEC had a median survival time of 16.7 (range, 2.33–163.30) months after being diagnosed with a primary esophageal tumor, and 6.47 (range, 0.43–148.13) months after being diagnosed with brain metastases. The 1-year survival was 70.8% for solitary lesions compared with 30.8% for multiple lesions (P=0.943). Surgery and chemotherapy were independent predictors of OS (23).

Zheng et al. [2021] reported on 21 patients with BMEC who were treated with SRS. Six patients had AC (28.6%) and 15 patients had SqCC (71.4%). The median age was 66 (range, 58–73) years. Ten patients (47.6%) presented with a single metastasis and 11 patients (52.4%) presented with multiple metastases (range, 2–11). The median tumor volume was 0.55 (range, 0.004–44.64) cm³. The local tumor control rate after SRS was 94.2%. The median survival time from the diagnosis of esophageal cancer was 22 months and the median survival from SRS was 16 months. Four patients had subsequent SRS (one for boost therapy, three for new metastatic deposits), and one patient underwent craniotomy due to tumor progression. Seventeen (89.5%) of the 19 patients who died, succumbed to systemic disease progression. The study demonstrated effective role of SRS in treating BMEC (24).

Bowden et al. [2014] reported on single institution retrospective analysis of 30 patients with BMEC—median age of 59 (range, 37–86) years—who underwent Gamma knife^® SRS. The histopathological origin was AC in 26 patients (87%), and SqCC in three patients (10%), and mixed neuroendocrine carcinoma in one patient (3%). Fifteen patients were treated for a single metastasis and 15 patients were treated for multiple metastases for a total of 87 tumors. The median tumor volume was 5.7 (range, 0.5–44) cm³ with a median marginal dose of 17 (range, 12–20) Gy. The median survival following brain metastasis diagnosis was 8 months, while the median survival following SRS was 4.2 months, with a 19% 12-month survival rate following SRS. A higher Karnofsky performance status (KPS) at the time of procedure was associated with an increase in survival (P=0.023). The local tumor control rate in this group was 92%. SRS proved an effective means of providing local control for esophageal metastases to the brain. The presence of systemic disease progression at the time of brain metastasis resulted in poor long-term survival (30).

Wang and Xu [2020] reported on 21 patients (AC =19; SqCC =2) with BMEC with median age 65 years. The median survival from diagnosis to development of BM was 11.8 (range, 0–249.2) months. The 1-year survival rate was 20% with median OS of 4.8 (range, 1.13–23.3) months. The presence of KPS score of ≥70 was associated with a significantly better OS than those with KPS score <70 (8.4 vs. 3.9 months, P=0.033). Patients treated with brain radiotherapy showed better outcomes in both median OS (8.4 vs. 2.9 months) and 1-year survival rate (23.1% vs. 14.3%, P=0.043). The median OS of patients treated with radiotherapy combined with chemotherapy and/or targeted therapy or radiotherapy alone was similar [9.7 (range, 3.4–23.3) vs. 7.2 (range, 1.7–18.4) months, P=0.215] (31).

Vanstraelen et al. [2023] reported on 2,131 patients who underwent esophagectomy with curative intent, from which 70 patients (3.3%) developed likely BMEC. Twenty four patients had pathological confirmation of brain metastasis. Median OS was 7.4 months [95% confidence interval (CI): 4.80–9.96]. BMEC treated with curative intent (surgery or stereotactic radiation) had a significantly better median OS (16 months; 95% CI: 11.3–20.7) compared to those without (3.7 months; 95% CI: 0.9–6.6, P<0.001) (26).

Stuart et al. [2023] reported on 339 patients undergoing minimally invasive esophagectomy from which 15 (4.4%) developed BMEC and 9/15 (60.0%) had isolated brain metastasis (iBM). Most patients were diagnosed with SqCC (55.6%), localized in the middle third of the esophagus (66.7%), and had a pathologic complete response (66.7%) after initial treatment. The treatment options included SRS (44.4%), surgical resection (22.2%), SRS and surgical resection (11.1%), and best supportive care (22.2%). The median time to development of iBM was 8.4 (range, 0.2–37.5) months and survival after detection of iBM was 14.3 months (95% CI: 0–45.9). The 2-year survival rate after detection of iBM was 44.4% (27).

The interpretation of data from these studies is limited by their significant heterogeneity and assessment and reporting of different parameters. However, there is an indication of probable changing patterns of BMEC in patients treated with previous curative therapy particularly in the context of multi-modality adjunctive treatment. In such patients BMEC may be often the first and often isolated site of relapse. These studies also demonstrate that solitary or iBM may have more favorable prognosis compared to those with multiple metastasis. Active treatment should be considered with surgery and/or SRS particularly for solitary lesions. In patients not suitable for surgery/SRS WBRT combined with systemic chemotherapy ± targeted therapies may be considered and also associated with improved survival.

Discussion

Brain metastasis develop in approximately 25–35% of malignancies and predominantly from lung (48%) and breast (15%) cancer (32,33). The incidence of brain metastasis from esophageal cancer is relatively rare but the reported incidence has been gradually increasing (4). It remains unclear whether this represents a true increase in incidence or is an indirect result of patients living longer due to improvement in therapeutic strategies or more frequent detection due to better use of diagnostic technology. The development of brain metastasis is often a late event of disease progression and usually not present at initial diagnosis even if metastases may be already present in other organs. There is usually latency of more than 9 months after initial diagnosis prior to development of BMEC. However, the timing of detection of brain metastasis may be confounded by lack of consistent diagnostic protocols for performing imaging to detect brain metastasis. There is significant male preponderance and previous series have shown that more than two-thirds of patients developing BMEC are males (34,35). In addition, BMEC usually affect younger patients (usually <70 years) as has shown by multiple case reports and previous studies (18,19,23,24). Barz and associates postulated on possible mechanisms for differences in brain metastases due to age and hypothesised on probable sclerosis of capillaries of elderly people preventing dissemination and seeding of tumour cells (36).

There is conflicting data in terms of histopathological correlation with development of BMEC. Brunner et al. [2022] reported a significantly higher risk of BMEC in patients with AC compared to SqCC [risk ratio (RR), 2.883; 95% CI: 1.213–6.971] (34). Welch et al. [2017] reported on large cohort of 583 patients and reported on BMEC developing in 22 patients from which 21 patients had AC (22). In contrast to above, series from Japan and China have shown similar incidence of BMEC but with preponderance of SqCC (24,25,37).

The production of neuroserpin and serpin (inhibitors of plasminogen activators) by AC (including those from breast and lung) has been hypothesized to promote the development of brain metastasis by inhibiting apoptosis by astrocytes (38). Another mechanism behind the increased risk of BMEC in AC may also be related to the overexpression of HER2 (39,40). However, other studies have failed to show an association between HER2 overexpression and development of brain metastasis. Feilchenfeldt et al. [2015] reported on 100 patients with gastro-oesophageal AC with median age of 59 years of which 85 (85%) were males. HER2 status was positive in 36% (95% CI: 26.6–46.2) of cases. The median OS from diagnosis was 16.9 months (95% CI: 14.0–20.7) and was not related to the HER2 status. E-cadherin loss (9%) and loss of expression of at least one DNA MMR proteins in 6% were other molecular abnormalities reported that may be associated with the development of brain metastasis (41).

In our series, the institutional cohorts failed to report on outcomes based on histological subtype, and due to the small number of individual cases it is not possible to perform detailed survival analysis based on histology. Therefore, it remains unclear how the survival in BMEC may be influenced by histological subtype.

The development of BMEC after curative therapy is an intriguing phenomenon and cause of much interest and debate. Nobel and colleagues have shown that in patients after curative therapy brain metastasis may often be the first site of relapse and often isolated in nature and without any extracranial disease (42). Abu Hejleh et al. [2012] retrospectively reviewed 142 patients with esophageal cancer who underwent esophagectomy. Cancer relapsed in 43/142 (30%) patients. The brain was the first site of relapse in 9/43 patients (21%) and HER2 over-expression was observed in 5/9 (56%) cases (43).

Rice et al. [2006] first proposed the hypothesis that the adjunctive treatment of esophageal cancer promotes development of BMEC. In their study, they included 403 patients with esophagectomy alone and 369 patients who had adjuvant therapy combined with esophagectomy. The types of adjuvant therapies included preoperative (n=118), postoperative (n=124) and both pre- and post-operative (n=127). Six patients in the control group and 23 patients in the adjuvant group developed BMEC, 20 of whom relapsed within 1 year. The risk of BMEC occurrence was 2.5%, 4%, 7.0%, and 18.4% in the control, preoperative intervention, postoperative intervention, and preoperative and postoperative adjuvant groups, respectively (44). Brunner et al. [2022] reported that BMEC occurred more frequently in patients receiving peri-operative chemotherapy or neoadjuvant chemoradiotherapy (CRT) with a longer latency to the development of brain metastasis approaching 21 months (34). Kawabata et al. [2007] reported on a retrospective study of 254 esophageal cancer patients who received either surgery alone or surgery and adjuvant chemotherapy. They showed that of the 73% of patients who received chemotherapy, 11 patients developed BMEC (45). The probable mechanisms determining the more frequent development of BMEC in patients receiving optimal adjunctive treatment include the possibility of brain acting as tumor ‘sanctuary’ for cancer cells in presence of effective systemic therapies dictated by the presence of potential blood brain barrier (34).

The higher than expected incidence of BMEC in patients after potentially curative treatment has been highlighted in several contemporary series. Smith et al. [2023] analyzed prospectively collected data on 85 patients combined from three phase II preoperative CRT trials and showed that the brain was the first site of disease recurrence in 7% of patients after esophagectomy, median time to brain metastasis was 9.6 months with a median survival of only 5.4 months (46). Stuart et al. [2023] found recurrent disease isolated to the brain in 4.4% of patients at a median time of 8.4 months after surgery. Nearly all of the patients in their institutional cohort received neoadjuvant CRT before having a minimally invasive esophagectomy (27).

The brain was the only site of recurrence in most patient with brain metastases, which confirms previous studies demonstrating that esophageal cancer recurrence after esophagectomy may be isolated to the brain in 60–78% of patients (27,42,47). In the largest study of 1,760 patients by Nobel and colleagues the development of isolated BMEC was associated with the presence of complete pathological response and diabetes mellitus although the exact mechanisms remain poorly defined (42).

The prognosis of BMEC depends on the number of metastasis (solitary vs. multiple), and presence of extracranial disease. Kothari et al. [2016] reported on retrospective study of 49 patients and on multivariate analysis patients with one (median survival, 10.7 months) or two (median survival, 4.7 months) brain metastases had significantly improved OS compared to patients with three or more brain metastases (median survival, 0.3 months, P<0.01) (48). Harada et al. [2020] reported on 68 patients with BMEC and showed that those with solitary lesion, absence of extra cranial disease, and who underwent surgery or SRS had best survival (49).

The local treatment options for management of BMEC include surgery, SRS or radiotherapy (involved-field or whole brain). Stuart and colleagues showed patients who recurred in the brain were amenable to surgery, SRS, or a combination of both. The survival rate in this cohort reached 44% at 2 years after the detection of brain disease recurrence (27).

Brunner et al. [2022] reported on significantly prolonged median survival after brain surgery (34). Welch and colleagues observed that survival was superior for patients who initially had surgical resection of brain lesions compared to patients treated with WBRT or SRS alone (1-year OS, 67% vs. 0%; median OS, 13.5 vs. 3 months; P=0.003) (22).

Early diagnosis and intervention in patients with brain metastases could improve survival. However, National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines for staging do not recommend performing routine brain imaging in asymptomatic esophageal patients. Nobel et al. [2020] postulated that in patients developing pathological complete response after neoadjuvant therapy, BMEC may represent true isolated recurrence, whereas in those with residual nodal disease, BMEC may actually be the first observed site of widespread metastasis (42). They further suggested that patients who receive neoadjuvant therapy and achieve a complete pathologic response would benefit most from brain imaging, both preoperatively and with routine surveillance, due to the increased likelihood of iBM. There is further guidance needed on patients who would be suitable for screening for BMEC.

The present review provides summary of emerging evidence regarding management of BMEC in the current era of multi-modality therapy. However, the robustness of the review is limited due to significant heterogeneity of the data and lack of consistent reporting in different studies. Most importantly, there is lack of any data to suggest any variability of outcomes based on underlying histology.

Conclusions

The incidence of BMEC has been rising in contemporary modern series particularly in patients who have received previous curative therapy with multi-modality treatment. In such patients BMEC may represent the first and often isolated site of relapse. This may be particularly relevant to patients developing complete pathological response to multi-modality treatments. Early diagnosis and treatment of BMEC in these patients is likely to be associated with better prognosis raising the argument for incorporation of BMEC screening protocols in their follow-up algorithms. The prognosis of solitary lesions is favorable compared to multiple lesions with 2-year survival of approximately 50% reported in some series (27). Surgical resection and/or SRS are standard therapeutic options especially for solitary lesions. Patients not suitable for surgery/SRS may be treated with WBRT ± SRS which in some series has been shown to associated with improved survival. Further research should be directed at identifying selected group of patients who may benefit from adoption of screening protocols and also for defining the optimal screening strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-7/rc

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-7/prf

Funding: None.

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