Authors, reference
Year of publication
Histology (no. of AC/SCC)/stage
Study design
Treatment
Effect
Hazard ratio (95 % CI)
Quality of evidence
Bedenne et al. [5]
2007
SCC(n = 239); AC(n = 29)/T3N0-1
RCT
Neoadjuvant CRT + surgery vs. dCRT
No benefit to additional surgery vs. continued CRT
0.90
High
Gebski et al. [3]
2007
SCC; AC/T0-3 N0-1
Meta-analysis
Neoadjuvant CRT-or-C + surgery vs. surgery
Survival benefit with neoadjuvant CRT
Neoadjuvant CRT: 0.84 (0.71–0.99; p = 0.04);
High
Neoadjuvant C: 0.88 (0.75–1.03; p = 0.12)
Kranzfelder et al. [2]
2011
SCC T1-4N0-1
Meta-analysis
Neoadjuvant CRT-or-C + surgery vs. surgery; dCRT vs. neoadjuvant + surgery-or- surgery
Survival benefit for neoadjuvant CRT
Neoadjuvant CRT: 0.81 (0.70–0.95; p = 0.008)
High
Neoadjuvant C: 0.93 (0.81–1.08; p = 0.368)
Sjoquist et al. [4]
2011
SCC; AC T0-3N0-1
Meta-analysis
Neoadjuvant CRT-or-C + surgery vs. surgery
Survival benefit of neoadjuvant CRT or C vs. surgery alone
CRT: 0.80 (0.68–0.93; p = 0.004)
High
C: 0.92 (0.81–1.04; p = 0.18)
Stahl et al. [6]
2005
SCC (n = 172) T3-4 N0-1
RCT
CRT + surgery vs. definitive CRT
Improved PFS in surgery arm; No difference in 2-year survival
2.1 (1.3–3.5; p = 0.003)
Moderate
Teoh et al. [7]
2013
SCC (n = 81)/T1-4N0-1
RCT
Surgery vs. dCRT
Comparable long-term survival
–
Moderate
Vallböhmer et al. [8]
2010
SCC (n = 118) AC (n = 181)/T2N1M0, T3-4N0-1M0
Observational study
Neoadjuvant CRT-or-C + surgery
–
–
Moderate
All literature was reviewed and the quality of data was classified according to the GRADE system (as outlined in Chap. 2). Specific clinical practice recommendations, based on the available evidence, were made according to the GRADE system.
Overview
While esophageal resection has been considered the standard treatment approach for patients with regionally advanced esophageal (SCC), survival following resection alone has been poor [9]. As chemotherapy with definitive dose radiation has been shown to be an effective treatment modality, it has become more difficult to determine which patients remain appropriate for surgical intervention. The initial approach to treatment strategy should be determined by the location of the primary tumor, distinguishing disease of the cervical (<5 cm from the cricopharyngeus), middle and distal esophagus. While there are no RCTs comparing resection and definitive CRT in patients with SCC of the cervical esophagus, current recommendations state that such patients should be treated with definitive CRT [10].
In patients who have regionally advanced SCC of the middle or distal esophagus, the role of surgery is more controversial. The debate regarding the role of surgery in these patients addresses whether to provide definitive dose radiation or neoadjuvant radiation therapy in anticipation of esophageal resection. Neoadjuvant radiation therapy with concurrent chemotherapy is felt to improve local control, with better rates of complete (R0) resection as well as subsequent improvement of long-term survival. It is presumed that increased rates of complete clinical response can translate to higher rates of complete pathologic response [1, 11].
Results
A multicenter observational study evaluated the outcomes of patients with complete histopathologic response, as determined at esophagectomy, following multimodal therapy for locally advanced esophageal cancer. In this multi-center cohort study, 299 patients were identified as having a complete pathologic response out of 1,673 patients who had received neoadjuvant therapy at the six participating centers. Of the 299, 118 had been diagnosed with esophageal squamous cell carcinoma. Within the cohort of “complete responders” overall 5-year survival was 68 % (95 % CI: 62–76) and disease-specific 5-year survival was 55 % (95 % CI: 48–62). Even in this population, 70 (23 %) subjects had recurrent disease, including 10 (3 %) with local recurrence and 60 (20 %) with distant recurrence [8]. Thus, as advances in CRT potentially lead to improved complete pathologic response, resection still may carry a benefit in terms of minimizing local recurrence although patients remain at risk of recurrent systemic disease. Current non-surgical staging modalities (i.e. endoscopic ultrasound (EUS), [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), computed tomography (CT) following induction therapy are not reliable in identifying patients with complete pathologic response, leading to continued focus on evaluating the potential benefits of CRT combined with surgery compared to CRT alone [12–14].
As the role of CRT as part of a multimodal approach has evolved, a comparison of neoadjuvant therapy and resection has been explored to help define the role of surgery. A meta-analysis of randomized trial data performed by Gebski and colleagues [3] evaluated randomized trials comparing neoadjuvant CRT followed by resection vs. surgery alone and neoadjuvant chemotherapy followed by resection vs. surgery alone. An update to this meta-analysis performed by Sjoquist and colleagues [4] revealed a survival benefit for patients undergoing neoadjuvant chemoradiotherapy (HR 0.80, 95 % CI 0.68–0.93; p = 0.004) or chemotherapy (HR 0.92, 95 % CI 0.81–1.04; p = 0.18) when compared to esophageal resection alone. Although these meta-analyses provide support for the benefit obtained from neoadjuvant CRT, the evaluated cohorts represented patients with heterogeneous disease stages (T0–3, N0–1), not necessarily specific for regionally advanced disease.
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