2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TREATMENT PARADIGMS FOR GASTROESOPHAGEAL ADENOCARCINOMA
the role of postoperative RT in a patient population that
underwent a standard D2 gastric dissection. 12 In this study,
458 patients were randomly assigned to receive postoperative
chemotherapy alone (capecitabine/cisplatin [XP]) or
CRT (XP 3 capecitabine/RT 3 XP), with the aim to identify
a 45% improvement in 3-year DFS. These investigators did
observe a modest improvement in the addition of RT, particularly
in the large subset of patients who were node
positive (3-year DFS, 72% vs. 77%; p � 0.0365; Table 1).
These data support the role of adjuvant RT in this disease,
as suggested initially by INT-0116, and are currently being
prospectively validated in a node-positive resected cohort.
Results of Recent Phase III Studies:
Esophageal Cancer
In esophageal carcinoma, the CROSS study was presented
at the 2011 ASCO Annual Meeting, and examined the
effects of preoperative CRTin advanced esophageal cancer.
This study found that a combination regimen of CRT before
resection is superior to surgery alone. 13 In this multicenter
phase III randomized study, 364 patients in the Netherlands
with resectable esophageal adenocarcinoma or squamous
cell carcinoma (SCC) were randomly assigned to receive
combined-modality therapy of CRTfollowed by surgery or
KEY POINTS
Table 1. Recent Phase III Studies in Patients with Localized Esophagogastric Carcinoma
Study Year Disease Type Subgroup Comparison
Esophagus cancer
Van Der Gaast
et al 13
2010 Esophageal
adenocarcinoma (74%)
and SCC (23%), stage
II/III
Mariette et al 18 2010 Esophageal
adenocarcinoma (30%)
and SCC (70%), stage
I/II
CRT (41.4 Gy) �
surgery surgery
Gastric cancer
Bang et al 3 2011 Gastric adenocarcinoma Post-op
capecitabine/oxaliplatin
vs. surgery alone
Fuchs et al 11 2011 Gastric and GEJ
adenocarcinoma
● Significant heterogeneity in treatment paradigms for
upper GI malignancies.
● Several recent studies have attempted to redefine the
standard of care.
● Global disease heterogeneity make broad applicability
somewhat questionable.
● Our challenge is to recognize differences in disease
biology to optimize treatment paradigms.
No. of
Patients Survival
Hazard
Ratio 95% CI p value
364 49 26 mo 0.67 0.49 to 0.91 0.008
Adeno CA 0.82 0.58 to 1.16
SCC 0.34 0.17 to 0.68
CRT (45 Gy) � surgery vs.
surgery alone
195 31.8 vs.44.5 months* 0.92 0.63 to 1.35 0.68
Post-op FU/LV � FU/RT vs.
post-op ECF � FU/RT
1035 74% vs.60%† 0.56 0.44 to 0.72 � 0.0001
540 36.6 vs.37.8 months* 1.03 0.80 to 1.34 0.80
Lee et al 12 2012 Gastric adenocarcinoma Post-op XP vs. XP–RT–XP 458 74% vs.78.2%† 0.6865 0.47 to 0.995 0.047
Node-positive patients 396 72% vs. 77.5%† 0.0365
Abbreviations: ECF, epirubicin, cisplatin, and fluorouracil; FU, fluourouracil; GEJ, gastroesophageal junction; LV, leucovorin; post-op, postoperative; RT,
radiotherapy; SCC, squamous cell carcinoma; XP, capecitabine/cisplatin.
* Overall survival.
† 3-year disease-free survival.
surgery alone. Preoperative CRT consisted of weekly paclitaxel
50 mg/m 2 and carboplatin dosed at area under the
curve (AUC) 2 for 5 weeks with concurrent 41.4 Gy RT
administered in 23 fractions. After CRT, patients underwent
resection within 6 weeks of completion of preoperative
therapy. This study suggests that most patients with T1N1
or T2–3Nx esophageal carcinoma should consider preoperative
CRT as a standard care option. The median survival of
patients who received CRT and surgery was 49 months,
compared with 26 months for those who received surgery
alone (HR � 0.67; p � 0.011; Table 1). With a median
follow-up of 32 months, 70 patients had died in the CRT
group compared with 97 in the surgery-alone group, and
3-year overall survival was also superior in the CRT arm.
However, although the majority of patients (74% in both
arms) had adenocarcinoma, it appears that the benefit of
CRT was primarily derived in patients with esophageal
SCC. Patients with esophageal SCC observed an HR of 0.34,
representing a dramatic 66% reduction in risk of death with
preoperative CRT, whereas in the subset of patients with
esophageal adenocarcinoma, the HR for survival in patients
receiving CRT was 0.82 (Table 1).
To place these data into context with other randomized
studies that predominantly included distal esophageal and
GEJ carcinoma as well as a recent updated metaanalysis,
9,14-17 if surgery is identified as part of the treatment
plan for a patient with localized disease, applying
preoperative therapy does confer a survival advantage. In
addition, esophageal SCC seems to be more sensitive to
CRT. There are data that support either combined preoperative
CRT or preoperative chemotherapy alone for
esophageal adenocarcinoma, and the data supporting the
superiority of trimodal therapy (CRT � surgery) over bimodal
therapy (chemotherapy � surgery) remains debatable.
A recent study by Stahl and colleagues suggested an
improved survival with trimodality therapy in adenocarcinoma
of the esophagus/GEJ, although the study was closed
257