Key points

Introduction

Esophageal cancer, an uncommon but highly virulent malignancy in the United States, will be diagnosed in 16,910 patients in 2016, with 15,690 deaths. It is the seventh leading cause of death in men in the United States. In comparison with its relative rarity in the United States, esophageal cancer (predominantly squamous cell carcinoma [SCC]) is endemic in parts of East Asia, which accounts for more than one-half of the approximately 500,000 cases that develop per year (this number does not fully take into account gastroesophageal or gastroesophageal junction (GEJ) tumors, which may variously be categorized as gastric cancers).

SCC and adenocarcinoma account for 98% of all cases of esophageal cancer. SCCs typically occur in the proximal two-thirds of the esophagus, whereas adenocarcinomas are found in the distal one-third and at the GEJ. Although cases of SCC have declined steadily, the incidence of adenocarcinoma of the distal esophagus, GEJ and gastric cardia has increased 4% to 10% per year among US men since 1976, so that it now comprises 75% of all tumors.

For locally advanced esophageal cancer, surgery remains the mainstay of treatment. Numerous studies—that have included both adenocarcinoma and SCC histologies and focused on tumors from the esophagus/GEJ and/or stomach—have evaluated preoperative and postoperative strategies for locally advanced disease, including chemotherapy or chemoradiation. As a whole, these studies show that some treatment in addition to surgery clearly improves outcomes. This review article discusses these studies; where relevant, we note whether these studies primarily enrolled patients with esophageal/GEJ or gastric tumors.

Introduction

Esophageal cancer, an uncommon but highly virulent malignancy in the United States, will be diagnosed in 16,910 patients in 2016, with 15,690 deaths. It is the seventh leading cause of death in men in the United States. In comparison with its relative rarity in the United States, esophageal cancer (predominantly squamous cell carcinoma [SCC]) is endemic in parts of East Asia, which accounts for more than one-half of the approximately 500,000 cases that develop per year (this number does not fully take into account gastroesophageal or gastroesophageal junction (GEJ) tumors, which may variously be categorized as gastric cancers).

SCC and adenocarcinoma account for 98% of all cases of esophageal cancer. SCCs typically occur in the proximal two-thirds of the esophagus, whereas adenocarcinomas are found in the distal one-third and at the GEJ. Although cases of SCC have declined steadily, the incidence of adenocarcinoma of the distal esophagus, GEJ and gastric cardia has increased 4% to 10% per year among US men since 1976, so that it now comprises 75% of all tumors.

For locally advanced esophageal cancer, surgery remains the mainstay of treatment. Numerous studies—that have included both adenocarcinoma and SCC histologies and focused on tumors from the esophagus/GEJ and/or stomach—have evaluated preoperative and postoperative strategies for locally advanced disease, including chemotherapy or chemoradiation. As a whole, these studies show that some treatment in addition to surgery clearly improves outcomes. This review article discusses these studies; where relevant, we note whether these studies primarily enrolled patients with esophageal/GEJ or gastric tumors.

Preoperative chemotherapy

A strategy of perioperative chemotherapy is the predominant approach in Europe, based primarily on the phase III MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial performed in the UK. This trial randomized 503 patients with gastric cancer (26% of whom had tumors in the lower esophagus/GEJ) to 3 cycles (9 weeks) each of preoperative and postoperative ECF (epirubicin/cisplatin/5-fluorouracil [5-FU]) and surgery or surgery alone. Perioperative chemotherapy resulted in significant improvement in 5-year overall survival (OS; 36% vs 23%; P = .009), establishing this regimen as a standard of care.

A similar degree of benefit was also noted in the contemporaneous French FFCD 9703 trial of 224 patients with esophagogastric adenocarcinoma. Patients were randomized to 6 cycles (18 weeks) of perioperative 5-FU/cisplatin followed by surgery versus surgery alone. Perioperative chemotherapy on this trial was associated with a significant improvement in 5-year disease-free survival (DFS; 34% vs 19%; P = .003) and OS (38% vs 24%; P = .02). Although comparisons between different clinical trials must be made cautiously, the survival benefit seen with 5-FU/cisplatin on this trial seems to be nearly identical to that seen with ECF in the MAGIC trial.

The benefit of the anthracycline—and the duration of preoperative therapy—has now been disputed definitively by the MRC OEO-5 study which has so far only been presented in abstract form. This study randomized 897 patients with esophageal/GEJ adenocarcinomas to preoperative chemotherapy with either 6 weeks of 5-FU/cisplatin or 12 weeks of ECX (epirubicin/cisplatin/capecitabine) chemotherapy. Although the pathologic response rate was improved in the ECX group versus the 5-FU/cisplatin group (including a pathologic complete response [pCR] rate of 11% vs 3% in the patients who underwent surgery), there was no difference in median progression-free survival between the groups (PFS; 1.78 vs 1.53 years; P = .058) or OS (2.15 vs 2.02 years; P = .86).

The OEO-5 study has therefore also raised the provocative suggestion that as little as 6 weeks of preoperative chemotherapy conveys the same OS benefit as 12 weeks of chemotherapy. Although this may be counterintuitive based on the MAGIC and FFCD studies, as well as other studies in gastric cancer that have administered 6 to 12 months of adjuvant chemotherapy, these results are not without precedent. As will be discussed elsewhere in this article, the CROSS study (ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study) found benefit for preoperative chemoradiation, where patients received only 5 weekly treatments of carboplatin/paclitaxel as the entirety of their systemic chemotherapy. The absolute improvement in OS seen in the CROSS study is also very much in the range of 10% to 15% seen in other positive phase III studies discussed herein.

It is also important to remember that, although the MAGIC and FFCD studies aimed to deliver 18 weeks of perioperative chemotherapy, only 50% of patients who underwent preoperative chemotherapy and surgery were able to receive or complete adjuvant chemotherapy on both studies, further suggesting that most patients derived the survival benefit of chemotherapy from receiving significantly less than 18 weeks of treatment. The generally poor ability to deliver therapy after surgery was also seen in the recently presented Dutch CRITICS study and would suggest, especially given the absence of a biological rationale to split up the same systemic treatment with surgery, that future experimental strategies should focus on exclusively preoperative approaches.

Aside from the MAGIC and FFCD studies, other phase III evaluations of preoperative or perioperative chemotherapy in esophagogastric adenocarcinomas have either been negative or had more marginal benefit. The North American Intergroup 113 trial failed to show a survival benefit for perioperative 5-FU/cisplatin in 440 patients with esophageal cancer (approximately one-half of whom had adenocarcinomas; eligibility was limited to extension of the tumor to 2 cm beyond the GEJ into the stomach). The MRC OEO-2 trial, which randomized 802 patients to surgery alone versus 2 cycles of preoperative 5-FU/cisplatin, reported a modest improvement in 5-year OS with chemotherapy (23% vs 17%; P = .03). Two-thirds of patients had adenocarcinomas and three-quarters of tumors were in the lower esophagus or gastric cardia. Most recently, the European EORTC (Europrean Organization for Research and Treatment of Cancer) 40954 trial evaluated a strategy of preoperative 5-FU/leucovorin/cisplatin in 144 patients with GE and gastric adenocarcinoma. The trial was stopped because of poor accrual, which limited the power of the study, and no differences in survival were detected.

These data are summarized in Table 1 . An updated metaanalysis by Sjoquist and colleagues of 10 randomized trials involving preoperative chemotherapy for esophageal and GEJ cancers suggested a 13% decreased risk of all-cause mortality for this approach in patients with adenocarcinomas versus surgery alone (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79–0.96; P <.005). In this metaanalysis, both the MAGIC and EORTC 40954 trials were excluded because their outcomes were not stratified based on gastric versus GEJ tumors.

Preoperative chemoradiation

The seminal phase III RTOG trial (US Radiation Therapy Oncology Group 85-01) demonstrated the superiority of chemoradiation over radiation alone. This nonoperative study compared standard fractionation radiation (64 Gy) versus radiation (50 Gy) plus concurrent 5-FU/cisplatin. The trial was stopped when data from 121 patients showed an improved median OS in favor of chemoradiation (12.5 vs 8.9 months). The 2-year survival was also improved in the chemoradiation group (38% vs 10%), as was 5-year survival (21% vs 0%). Although the majority of patients treated on this trial had SCC, long-term survival was also seen in the small number of adenocarcinoma patients on the trial, with 13% of patients alive at 5 years. Based on this study, chemoradiation was established as the standard of care in the nonsurgical management of locally advanced esophageal SCC.

Since then, preoperative chemoradiation has been evaluated extensively in trials of esophageal cancer. Six contemporary randomized trials have compared preoperative chemoradiation followed by surgery versus surgery alone. Of these, 3 have been positive and revealed a survival benefit for this approach. These results are summarized in Table 2 .

Table 2

Results of phase III preoperative chemoradiation trials in esophageal and gastroesophageal junction cancer

Treatment	Histology	No. of Patients	R0 Resection Rate (%)	Pathologic CR Rate (%)	Survival		Local Failure (%)	Reference
					Median	Overall
Preoperative CRT	Adeno (76%) + SCC	50	45	24	16.9 mo	3-y 30%	19	Urba et al, 2001
Surgery		50	45	N/A	17.6 mo	3-y 16%	42
Preoperative CRT	Adeno	58	NS	25	16 mo	3-y 32%	NS	Walsh et al, 1996
Surgery		55		N/A	11 mo	3-y 6%
Preoperative CRT	SCC	143	81	26	18.6 mo	5-y 26%	NS	Bosset et al, 1997
Surgery		139	69	N/A	18.6 mo	5-y 26%
Preoperative CRT	Adeno (63%) + SCC + other	128	80	9	22.2 mo	NS	15	Burmeister et al, 2005
Surgery		128	59	N/A	19.3 mo		26
Preoperative CRT	Adeno (75%) + SCC	30	NS	40	4.5 y	5-y 39%	NS	Tepper et al, 2008
Surgery		26		N/A	1.8 y	5-y 16%
Preoperative CRT	Adeno (74%) + SCC	178	92	29	49.4 mo	3-y 58%	NS	Van Hagen et al, 2012
Surgery		188	69	N/A	24.0 mo	3-y 44%

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