215 / 220
inhibit the production of gastric acid and are commonly
and chronically used in patients with HNSCC for the
management of their gastroesophageal reflux disease. How-
ever, the potential effects of antacid medications and any
potential mechanisms for altering HNSCC progression and
outcome are unknown. Identifying molecular mechanisms
associated withHNSCC progression andmetastasis is key to
improving clinical outcomes.
HNSCC are marked by their aggressiveness and invasive-
ness (5). HNSCC are known for poor clinical outcomes with
mortality among the highest of all carcinomas mainly due
to the development of metastatic disease (11, 12). The
ability for cancer to metastasize seems to associate with the
expression of endothelial adhesion molecules ligands by
circulating tumor cells that allow them to bind to the
endothelium lining the vasculature initiating extravasation
(13, 14). Sialyl Lewis X (sLeX) is an endothelial adhesion
molecule known to play the key role in the initiation of the
metastatic spread in gastrointestinal cancers by initiating
dissemination through direct interaction with E-selectin
expressing endothelium (15). In agreement with findings
fromother types of human cancer (e.g. gastric, breast, colon;
refs. 15–18), our previous studies have shown that cimet-
idine, the prototypical drug of the H2RAs, may have an
effect on E-selectin, a molecule with critical roles in cancer
dissemination (19). In addition, cimetidine seems to affect
other players with important roles in tumor growth and
progression (e.g. epithelial growth factor signaling path-
way), and to prevent metastasis (20, 21, 22). Our
in vitro
analysis of a well-characterized set of human cell lines
derived from the most common locations of the HNSCC
indicates that oral squamous cell carcinomas expressed
higher sLeX, which increases with advanced stage (23). Our
current study has identified the highest H2RA usage in
patients with oral carcinomas. It is interesting to note that
in contrast to cimetidine, the most frequently prescribed
H2RA drug in our cohort, ranitidine, has not proven to have
similar effects as cimetidine (22); it is also known that the
two also differ in molecular structure. In our patient cohort,
cimetidine alone was used by only a few patients (16/596)
compared with ranitidine (215/596). When analyzed per
individual drug, despite the significant number of ranitidine
users, our analysis failed to demonstrate the same benefit on
patient survival as the entire H2RA class. Therefore, we
postulate that H2RA drugs may differ in their mechanisms
of action and may alter expression of other factors besides
key endothelial adhesionmolecules that could explain their
clinical benefits in patients with HNSCC.
Remarkably, our analysis identified H2RA class usage as
significant prognostic factor for recurrence-free survival
only in patients with oropharyngeal tumors positive for
HPV16. HPV has recently emerged as the primary etiologic
factor for patients with tumors in the oropharynx that are
also associated with younger age at diagnosis; 65% to 85%
of the oropharyngeal cancers diagnosed this year in the
United States are HPV-related with 3-year failure rates of
30% to 36% (24–31). Consequently, unique pathologic
profiles have emerged that are consistent with the changing
incidence of HNSCC (32–34). Patients withHPV
þ
head and
neck cancer have a distinct risk profile, associated with a less
remarkable history of tobacco and alcohol use (35, 36), a
more beneficial micronutrient profile (37), improved cel-
lular immunity (38), and improved survival compared to
those with HPV tumors (39–42). Notably, a significant
subset (20% 30%) of HPV
þ
tumors fails to respond to
therapy and recur principally as distant metastases. Studies
1:H2RA only
3: PPI and H2RA
PPI_H2RA
4: PPI only
2: Neither
Product-limit survival estimates
With number of subjects at risk
A
B
C
Product-limit survival estimates
With number of subjects at risk
Product-limit survival estimates
With number of subjects at risk
1.0
0.8
0.6
0.4
0.2
0.0
Survival probability
336
204
0
20
40
Days from baseline survey to death
60
80
100
NO
YES
263
183
203
146
153
106
H2RA
No
+ Censored
Log-rank
P
= 0.0479
Yes
116
76
94
50
45
24
14
11
2
1
1.0
0.8
0.6
0.4
0.2
0.0
Survival probability
237
303
0
20
40
Days from baseline survey to death
60
80
100
NO
YES
184
262
126
223
87
172
PPI
No
+ Censored
Log-rank
P
< 0.0001
+ Censored
Log-rank
P
< 0.0001
Yes
64
128
51
93
23
46
9
16
2
1
1.0
0.8
0.6
0.4
0.2
0.0
Survival probability
79
158
125
178
0
20
40
Days from baseline survey to death
60
80
100
1
2
3
4
67
117
116
146
48
78
98
125
34
53
72
100
20
44
56
72
15
36
35
58
7
16
17
29
4
5
7
9
1
1
0
1
Figure 1.
Survival bene
fi
ts according with intake of antacids in patients
with HNSCC. A, unadjusted OS in relation with usage of H2RA (A) and
PPIs (B). C, each antacid class alone and in combination versus nonusers.
Median follow-up
¼
55 months; 95% CI, 50
–
60 months.
PPIs and H2RAs Usage and Survival in HNSCC Patients
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195