Esophageal Adenocarcinoma Methods and Protocols

25

patients with adenocarcinoma of the gastroesophageal junction

should be exercised with caution, since only 2–3% of these patients

were included in the CLASSIC study while ACTS GC study did

not include them. Nevertheless, for patients who have pathologic

advanced disease after upfront surgery, adjuvant chemotherapy

remains a reasonable option while chemoradiotherapy should be

reserved for those with incomplete or suboptimal surgery.

Advanced unresectable or metastatic disease carries a dismal prog-

nosis. Palliative gastrectomy may improve survival and symptom

control in highly selected patients but reported studies are largely

of retrospective nature [ 25 ]. Thus, chemotherapy remains the

standard of care for these patients. The initial meta-analysis of pal-

liative chemotherapy in advanced gastric and esophagogastric junc-

tion carcinoma by Wagner et al. in 2006 has shown a clear clinical

benefit of chemotherapy over best supportive care and the benefit

is more pronounced with combination therapy [ 26 ]. The subse-

quent Cochrane study in 2010 that included 35 trials and 5726

patients also demonstrated consistent benefit of chemotherapy

over best supportive care as well as combination therapy over

monotherapy. There was survival benefit in favor of triplet over

double chemotherapy but at the price of increasing treatment tox-

icity [ 27 ]. Table 2. summarizes the landmark chemotherapy stud-

ies in the palliative setting.

Fluoropyrimidine: 5FU, Capecitabine, and S-1: 5FU has been the

backbone of chemotherapy for advanced and metastatic disease but

prolonged hospitalization, frequent hospital visit and insertion of

central catheter have urged for more convenient oral formulation.

Most studies have shown equivalence, if not better, clinical out-

comes with oral fluoropyrimidines. Capecitabine is an oral fluoro-

pyrimidine prodrug that is activated via a three-step enzymatic

pathway. The final step of conversion requires thymidine phos-

phorylase which is more active in tumor than normal tissue thus

resulting in a preferential conversion of capecitabine to active

metabolite at the tumor site [ 28 ]. In the phase III multicenter

randomized REAL-2 study, 1002 patients were enrolled to receive

one of the four triplet regimens (ECF: epirubicin, cisplatin, 5FU;

EOF: epirubicin, oxaliplatin, 5FU; ECX: epirubicin, cisplatin,

capecitabine; EOX: epirubicin, oxaliplatin, capecitabine) [ 29 ].

Noninferiority of EOF, ECX and EOX when compared to ECF

was demonstrated and median overall survival was 9.3, 9.9, 11.2

and 9.9 months, respectively. With respect to the comparison of

fluoropyrimidines, the hazard ratio for death was in favor of

capecitabine over 5FU (HR 0.86, 95% CI, 0.80–0.99) and EOX

was superior to ECF in the secondary analysis (HR 0.80, 95% CI

0.66–0.097; p = 0.02). The toxicity profile of capecitabine was

similar to 5FU. Cisplatin with 5FU or capecitabine were tested for

noninferiority in the Korean ML17032 study [ 30 ]. Three hundred

1.2 Chemotherapy
in Palliative Setting

1.2.1 First-Line
Treatment

Chemotherapy