The role of surgical treatment in isolated organ recurrence of esophageal cancer—a systematic review of the literature

The review was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [5]. A study protocol was agreed by all authors. Identification of eligible studies was performed through search of PubMed (MEDLINE) database until 10 August 2017. The following algorithm was applied: “(surgery OR (surgical treatment) OR metastasectomy) AND ((esophageal or oesophageal) AND (cancer OR carcinoma)) AND (metastasis OR metastases OR recurrence).” Two independent reviewers (DS, IIL) screened the available literature, and discrepancies were resolved by team consensus. Finally, reference lists of eligible studies were manually assessed in order to detect any potential relevant article (“snowball” procedure).

Eligible were considered those studies reporting on patients undergoing surgery for metachronous, solitary organ recurrence following primary surgical treatment of esophageal cancer. Neither language nor study sample size restriction was applied. Exclusion criteria were as follows: (1) irrelevant studies, (2) studies reporting on synchronous metastases, (3) reviews and meta-analyses, and (4) editorials and letters to the editors.

Two independent authors (DS, IIL) extracted the data. Results were cross-checked by a third reviewer (DIT), and any discrepancies were resolved by team consensus. Variables of interest included general study characteristics (e.g., author, year of publication, number of patients), number of lesions, disease-free interval (DFI) following esophagectomy, type of operation, and survival following resection of recurrence. DFI was defined as the time from primary surgery for esophageal cancer to disease recurrence. Data were tabulated when possible. Due to the nature of the included studies (i.e., case reports) and the high heterogeneity in reporting of outcomes among eligible studies, no cumulative statistical analysis or meta-analysis was attempted. Ultimately, a purely descriptive presentation of available data was adopted.

The results yielded by the initial algorithm and the successive steps of the selection process are depicted in Fig. 1. Following screening of titles and abstracts, 120 studies were retrieved for full-text evaluation. Thirty-three studies were deemed eligible, while two were identified from their reference lists for a total of 35 studies included in the analytic cohort. Overall, studies reported on isolated liver recurrences undergoing surgical resection (n = 87 patients), isolated lung (n = 163 patients), brain (n = 30), and other recurrences (n = 10 patients), encompassing a total of 290 patients included in this review.

Liver represents a common organ for metastasis for a wide range of tumors. The benefit of liver resection for colorectal and neuroendocrine metastases has been proven and is considered as a standard treatment with curative intention when feasible. Few retrospective studies with > 50 highly selected patients aimed to show the benefit of liver resection for non-colorectal and non-neuroendocrine tumors. In most of them, however, the operative management for metachronous metastases of esophageal cancer represents only a very small part of the mentioned series. Adam et al. reviewed 1452 patients operated for non-colorectal and non-neuroendocrine liver metastases. Among them, 20 patients with liver metastases from esophageal cancer and 25 patients with liver metastases from gastroesophageal junction cancer underwent liver resection, reporting a 3-year survival of 32% and 12%, respectively and a median survival of 16 and 14 months, respectively [6].

Other studies focus on the outcomes of surgical management of liver recurrence after esophageal resection for both types of squamous cell carcinoma (SCC) and adenocarcinoma. The largest series is reported from Liu et al. in which 26 patients with solitary hepatic metastasis after esophagectomy for SCC underwent liver resection. The surgical group presents 1- and 2-year cumulative survival rates of 50.8 and 21.2%, respectively, which were significantly higher than the 31.0 and 7.1% survival rates of those patients in the non-surgical group (n = 43). In both groups, a DFI of more than 12 months after esophagectomy was connected to better outcomes [7]. Ichida et al. [8] reported also a group of 5 patients undergoing hepatectomy for liver metastases of esophageal cancer, who showed a median survival of 13 months following recurrence detection, compared to a median survival time of 5 months of the non-surgical group [8]. In a case series of 4 patients, Huddy et al. included two young patients of 44 and 47 years old, presenting with one and two liver metastases, respectively, 9 months after esophagectomy for adenocarcinoma. Both were treated with systematic chemotherapy and subsequent liver resection; the first one remained free of disease during the 23 months of follow-up, and the second one had an overall survival of 21 months following liver resection [9]. The outcomes of the abovementioned studies as well as of case reports of patients undergoing liver resection for the treatment of liver metastases from esophageal primaries described in the literature are summarized in Table 1 [6‐16].

Surgical resection is accepted as a treatment modality for resectable pulmonary metastases arising from various solid tumors, in the absence of other extrapulmonary metastasis. Several retrospective studies have intended to investigate its benefit in the case of metachronous, pulmonary metastasis after surgical treatment of esophageal cancer. Ichikawa et al. reported a retrospective series of 23 patients with pulmonary oligometastatic disease after curative treatment of esophageal cancer (esophagectomy ± neoadjuvant or adjuvant chemotherapy or definitive chemoradiotherapy). The lungs were the initial recurrence site in 19 patients. All patients underwent surgical resection, including wedge resection, segmentectomy, and lobectomy, and the predicted overall 5-year survival rate was 43.5% with a median survival time of 28.7 months (range 4.9–214.5 months). The authors suggested that the group of patients with pulmonary metastasis as initial recurrence had a significantly longer survival (median survival 63 months) in comparison to the patients with antecedent extrapulmonary metastasis (11 months, p = 0.0411) [17]. Kobayashi et al. reviewed 30 pulmonary metastasectomies of 23 patients who presented pulmonary recurrence after definitive treatment of SCC (17 patients underwent esophagectomy, 5 patients definitive chemoradiotherapy, and 1 patient endoscopic submucosal dissection). Among these surgical resections, 26 concerned solitary metastasis including recurring metastases, 2 were undertaken at patients with two metastatic lesions, and 2 at patients with three metastases. The cumulative survival for patients without a history of extrapulmonary metastasis between initial treatment and pulmonal recurrence was 40.7% at 5 years, while the patients with well and moderately differentiated SCC had significantly prolonged survival compared to those with poor differentiated primaries (p < 0.01). DFI of > 12 months was showed as another favorable prognostic factor (median survival with DFI > 12 months and DFI < 12 months was 43.7 and 24.7 months, respectively, p = 0.02) [18]. The largest published series is the one reported by Shiono et al., including 49 patients who underwent metastasectomy (48 cases with SCC, 1 case with adenocarcinoma), 39 of whom with solitary metastases. The authors identified DFI of less than 12 months to be an independent prognostic factor (p = 0.04) for significantly worse prognosis, thus concluding that pulmonary metastasectomy for esophageal cancer should be considered for selected patients with a DFI of 12 months or more [19]. Kanamori et al. published recently a series of 33 patients undergoing pulmonary metastasectomy, 27 of whom with single pulmonary lesions and 22 of them having the lungs as first recurrence site. The overall median survival time was 17.9 months. Significant unfavorable prognostic factors identified with univariate analysis were DFI < 16 months and nodal status of esophageal carcinoma, but multivariate analysis failed to identify these factors to be significant. Again, in this study, most primary tumors histology was SCC [20].

The differential diagnosis between metachronous metastasis of esophageal SCC and second primary lung SCC based only on histologic features can be a diagnostic challenge. Kozu et al. excluded in their retrospective study patients with DFI longer than 24 months, solitary lung lesions, and no signs of esophageal cancer recurrence after pulmonary resection because these clinical criteria may imply a second primary lung SCC. Based on these exclusion criteria, they included 15 patients who underwent pulmonary metastasectomy for pulmonary recurrence of esophageal cancer in their institution. The results showed a 3-year overall survival of 44%. The diameter of the pulmonary metastasis (more or less than 20 mm) was marginally associated with the overall survival (OS) (p = 0.087), but none of the parameters examined (age, tumor stage, DFI, CEA levels, surgical approach, and procedure) was found to be a significant prognostic factor [21]. Table 2 shows the results of studies concerning lung metastasectomy for esophageal carcinoma [8, 10, 17‐24].

The incidence of brain metastasis from esophageal carcinoma reported in the literature is 0–2% [25].The prognosis of these patients is poor, and a median survival of 3.8 months after the diagnosis of brain metastases has been reported [26]. Brain recurrences tend to occur in patients with large primary tumors and findings of local invasion and lymph node metastasis by CT scan and/or microscopic examination [27]. Moreover, in contrary to other primary tumors, a low incidence of lung metastasis at the time brain metastasis appears has been reported in patients with brain metastases from esophageal carcinoma [28]. In a single-center retrospective study, the outcome of surgical resection followed by whole-brain radiotherapy (WBRT) for brain metastases from esophageal carcinoma has been compared to radiation or palliative treatment. Five out of 26 patients with brain metastases from esophageal carcinoma underwent surgery followed by WBRT. Three patients presented a single cerebral lesion and 2 patients had 2 lesions. The median survival of these patients was 7.0 months, while patients who underwent radiation therapy and chemotherapy survived for 4.0 and 1.8 months, respectively. The authors concluded that surgical intervention, the presence of a single lesion, Karnofsky Performance Status (KPS), and extracranial disease status had a statistically significant impact on survival. However, the median time from the diagnosis of esophageal carcinoma to the diagnosis of brain metastasis was 10.2 months (0.0–39.2 months), indicating that patients with synchronous metastases undergoing palliative therapy have been included. Furthermore, no data about the initial treatment of the primary tumor are mentioned [29]. Ogawa et al. reported the outcomes of 36 patients with brain metastases from esophageal cancer treated in a single institution, 8 of whom had no active extracranial disease and controlled primary tumor (primary tumor in complete remission after surgical resection, radical radiotherapy/radiochemotherapy, or a combination therapy). Seventeen patients had a single cerebral metastasis. The median survival was 9.6 months for patients who underwent surgery and radiotherapy and 1.8 months for patients treated only with radiotherapy. Treatment modality, KPS, and extracranial disease status had a statistically significant impact on survival [28]. In another series of 27 patients with brain metastases (13 patients had a single brain lesion), the longest survival was seen in patients with single brain lesions who underwent resection followed by WBRT (median survival, 9.6 months; P = 0.02 compared with all other treatments). The median time from diagnosis of primary tumor was 5.6 months (range 0.0–36.5 months), and 19 patients suffered from systemic metastasis as well [26]. The most recent case series was reported in 2007. Out of 17 patients treated for brain metastasis (median time from diagnosis of primary tumor 12.3 months, range 2.1–36.2 months), 3 patients treated with resection and WBRT had a median survival of 65.6 months (range 2.3–90.6 months), and in all treatment categories, patients with single cerebral metastasis had a better outcome than those with multiple metastases (median survival 38.2 and 16.4 months, respectively). Again, in that case, authors do not mention what kind of therapeutic regime was followed for the primary tumor, but as authors of previous studies, they conclude that an aggressive strategy with neurosurgery followed by radiation offers favorable results in patients with good KPS [30].

The adrenal glands are a frequent site of recurrence of esophageal neoplasms: esophagus is the third most frequent site of origin of adrenal metastases. Although adrenalectomy is a clear indication for the treatment of adrenal metastases from some cancers (lung cancer, renal cell cancer, and melanoma), there are very few case reports of adrenalectomy for recurrence of esophageal cancer following esophagectomy in the literature and thus there are no clear indications on how to treat patients with adrenal metastases from esophageal cancers. In a case series of 5 patients, only one 79-year-old patient presented with no signs of other metastasis and was treated, 13 months after esophagectomy for a Siewert type 2 carcinoma of the esophagogastric junction, with a laparoscopic left adrenalectomy. He died with progressive disease 28 months later [31]. O’Sullivan et al. reported a case of a 50-year-old man who was submitted to an open right adrenalectomy 4 years after a two-stage esophagectomy for a Siewert type 1 cancer of the esophagogastric junction and remained disease-free for over 4 years postadrenalectomy [32]. In another case, a 71-year-old patient underwent a right adrenalectomy for a solitary adrenal metastasis that appeared 22 months after a subtotal esophagectomy with two-field lymphadenectomy for esophageal adenocarcinoma. The patient was free of recurrence for the next 5 years and 11 months [33].

The kidney is the fourth or fifth most common visceral metastatic site for a primary esophageal carcinoma, but a solitary, unilateral metastasis is rare and often found accidentally, since the patients are mostly asymptomatic. There are only very few case reports of surgical resection of renal recurrence of esophageal cancer after primary surgical treatment. Lim et al. reported a case of solitary recurrence 2 years after an esophagectomy for a SCC, which was treated with radical nephrectomy. The follow-up revealed suspicious paraaortic lymphadenopathy that decreased in extent after admission of palliative chemotherapy, but no data concerning the survival are mentioned [34]. A 57-year-old patient, treated with radiation therapy for esophageal cancer, showed a recurrence in the right kidney accompanied with a tumor thrombus in the inferior vena cava 1 year after. He was treated with right nephrectomy with thrombus resection and died 2 months later [35]. Sun et al. reported also a case of nephrectomy for a solitary renal metastasis 9 months after an esophagectomy for a SCC (stage pT2N0M0), and the patient died 3 months later [36].

Esophageal carcinoma is a rare cause of splenic metastasis, with only five reported cases of isolated splenic secondaries. Sanyal et al. reported the unusual case of a 25-year-old female patient who underwent splenectomy, distal pancreatectomy, and resection of the splenic colonic flexure for a 6 × 6 cm symptomatic solitary splenic recurrence 15 months after a transhiatal esophagectomy and adjuvant chemoradiotherapy for a SCC of the lower third of esophagus. She remained free of disease 7 months postsplenectomy [37]. Table 3 summarizes all case reports of the literature for metastasectomies undertaken for adrenal, renal, and splenic recurrences of esophageal cancer [31‐40].