1. Population characteristics
A total of 1008 patients were preselected from hospital databases, of whom 215 met the inclusion criteria for the study. A flowchart is shown in Figure 1.
Of these 215 patients, 25 (11.6%) took a PPI, and 130 (60.5%) did not during CRT. Drug status was unknown in 60 patients (27.9%). In patients with known drug status, the frequency of PPI use was 16.1%. The most commonly used PPI was esomeprazole (Supplementary Table S1), and the median daily dose was 20 mg. The main indications were treatment of GERD, ulcers, and hiatal hernia.
The details of patient demographics are presented in Table 1. The two groups were balanced for sex distribution, age, stage, and location of the primary tumor. Of the 215 patients, 135 (62.8%) were men. The median age at diagnosis was 61 (range, 54–69 years). Rectal tumors were located in the middle rectum and lower rectum in 94 (43.7%) and 107 (49.8%) patients, respectively. They were mostly locally advanced stages: T3, T4, and N1 or N2 in 165 (77%), 17 (8%), and 181 (84.2%) patients, respectively, leading to 26 patients with stage II and 181 patients with stage III according to the Thésaurus National de Cancérologie Digestive classification [1].
Table 1: Baseline characteristics of selected patients, overall and according to proton pump inhibitor (PPI) intake.
Characteristics
|
Overall
(N=215)
|
Yes (N=25)
|
PPI intake
No (N=130)
|
Unknown (N=60)
|
P-value (1)
|
sex, n (%)
|
|
|
|
|
0.54
|
Male
|
135 (62.8)
|
17 (68)
|
80 (61.5)
|
38 (63.3)
|
|
Female
|
80 (37.2)
|
8 (32)
|
50 (38.5)
|
22 (36.7)
|
|
Age in years, median (range)
|
61 (54–69)
|
61 (56–71)
|
62 (54–69)
|
61 (53.5–65.5)
|
0.52
|
Rectal cancer location, n (%)
|
|
|
|
|
0.67
|
High
|
14 (6.5)
|
2 (8)
|
7 (5.4)
|
5 (8.3)
|
|
Middle
|
94 (43.7)
|
13 (52)
|
61 (46.9)
|
20 (33.3)
|
|
Lower
|
107 (49.8)
|
10 (40)
|
62 (47.7)
|
35 (58.3)
|
|
Stage of cancer according to TNCD(2), (MD=2) n (%)
|
|
|
|
|
0.11
|
I
|
7 (3.3)
|
0 (0)
|
4 (3.1)
|
3 (5.2)
|
|
II
|
25 (11.7)
|
7 (28)
|
16 (12.3)
|
2 (3.4)
|
|
III
|
181 (85)
|
18 (72)
|
110 (84.6)
|
53 (91.4)
|
|
MD: number of missing data
(1)Tests comparing PPI intake vs. no PPI intake
(2)TNCD: Thésaurus National de Cancérologie Digestive [1]
Treatment characteristics are summarized in Table 2. The characteristics of CRT were well balanced between patients with and without PPI intake. CRT combined a median RT dose of 50 Gy and a median capecitabine dose of 1600 mg/m2.
Table 2: Treatment characteristics and complications according to proton pump inhibitor (PPI) intake.
Treatment characteristics and safety data
|
Overall (N=215)
|
Yes (N=25)
|
PPI INTAKE
No (N=130)
|
Unknown (N=60)
|
P-value(1)
|
Radiotherapy
|
|
Dose (Gray)
|
50
|
50
|
50
|
50
|
|
Fractions
|
25
|
25
|
25
|
25
|
Duration (days)
|
36
|
36
|
36
|
36
|
Chemotherapy
|
|
Capecitabine (dose in mg/m2)
|
1600
|
1600
|
1600
|
1600
|
|
Oxaliplatine combination (MD=5) n (%)
|
1
|
Yes
|
40 (19)
|
3 (12.5)
|
18 (13.8)
|
19 (33.9)
|
|
No
|
170 (81)
|
21 (87.5)
|
112 (86.2)
|
37 (66.1)
|
Safety of chemoradiotherapy
|
|
Severe toxicity, (MD=3) n (%)
|
0.58
|
Yes
|
36 (17)
|
6 (24)
|
23 (17.8)
|
7 (12.1)
|
|
No
|
176 (83)
|
19 (76)
|
106 (82.2)
|
51 (87.9)
|
Toxicities, n
|
|
Diarrhea
|
19
|
12
|
3
|
4
|
|
Radiodermitis
|
5
|
0
|
5
|
0
|
|
Rectal syndrome
|
3
|
0
|
2
|
1
|
Hematologic
|
3
|
1
|
2
|
0
|
Others(2)
|
5
|
2
|
2
|
1
|
Toxicity leading to treatment interruption, (MD=3) n (%)
|
0.54
|
Yes (CESSATION of RT)
|
2 (0.9)
|
0 (0)
|
1 (0.8)
|
1 (1.7)
|
|
Yes (CESSATION of CT)
|
16 (7.5)
|
5 (20)
|
10 (7.8)
|
1 (1.7)
|
Yes (CRT)
|
9 (4.2)
|
0 (0)
|
6 (4.7)
|
3 (5.2)
|
No
|
185 (87.3)
|
20 (80)
|
112 (86.8)
|
53 (91.4)
|
Surgery
|
|
|
|
Time interval from RT (days), median (range)
|
56 (48-68)
|
55 (47–64)
|
57 (50–69)
|
55 (46–67)
|
|
Surgical procedure, (MD=3) n (%)
|
|
Colorectal exerisis
|
104 (49.1)
|
8 (33.3)
|
64 (49.6)
|
32 (54.2)
|
|
Proctectomy
|
55 (25.9)
|
9 (37.5)
|
36 (27.9)
|
10 (16.9)
|
Abdominal amputation
|
48 (22.6)
|
5 (20.8)
|
28 (21.7)
|
15 (25.4)
|
Local excision
|
4 (1.9)
|
2 (8.3)
|
0 (0)
|
2 (3.4)
|
Total pelvectomy
|
1 (0.5)
|
0 (0)
|
1 (0.8)
|
0 (0)
|
Postoperative complications, (MD=7) n(%)
|
0.18
|
Yes
|
58 (27.9)
|
10 (41.7)
|
36 (28.1)
|
12 (21.4)
|
|
No
|
150 (72.1)
|
14 (58.3)
|
92 (71.9)
|
44 (78.6)
|
Type of complications, n
|
0.94
|
Parietal
|
4
|
1
|
2
|
1
|
|
Infection
|
15
|
2
|
9
|
4
|
Fistula
|
6
|
2
|
4
|
0
|
Bowel obstruction
|
21
|
3
|
13
|
5
|
Others(3)
|
12
|
2
|
8
|
2
|
Adjuvant chemotherapy, (MD=4) n (%)
|
0.69
|
Yes
|
87 (41.2)
|
11 (45.8)
|
53 (41.4)
|
23 (39)
|
|
No
|
124 (58.8)
|
13 (54.2)
|
75 (58.6)
|
36 (61)
|
Chemotherapy(4), (MD=4) n (%)
|
0.62
|
5-FU
|
1 (1.1)
|
0 (0)
|
1 (1.9)
|
0 (0)
|
|
Capecitabine
|
21 (24.1)
|
4 (36.3)
|
12 (22.6)
|
5 (21.7)
|
CAPOX
|
13 (14.9)
|
0 (0)
|
8 (15.1)
|
5 (21.7)
|
|
FOLFOX
|
51 (58.6)
|
7 (63.6)
|
31 (58.5)
|
13 (56.5)
|
|
FOLFOX-bevacizumab
|
1 (1.1)
|
0 (0)
|
1 (1.9)
|
0 (0)
|
|
CRT: chemoradiotherapy
CT: chemotherapy
MD: number of missing data
RT: radiotherapy
(1)Tests comparing PPI intake vs. no-PPI intake
(2)Others: acute urinary retention, allergy, and hand-foot syndrome
(3)Others: colic necrosis, acute urinary retention, and delayed healing
(4)Chemotherapy protocols according to Thésaurus National de Cancérologie Digestive [1]:
- 5-FU or LV5FU2 (day [D] 1 equal to day 14): folinic acid 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU 2400 mg/m2 over 46 hours
- Capecitabine (D1 equal to D21): 1250 mg/m2 twice daily from D1 to D14
-
CAPOX (D1 equal to D21): on D1 oxaliplatin 130 mg/m2, and from D1 to D14, capecitabine 1000 mg/m2 twice daily
-
FOLFOX (D1 equal to D14): folinic acid 400 mg/m2, oxaliplatin 85 mg/m2, 5-FU bolus 400 mg/m2, 5-FU 2400 mg/m2 over 46 hours
- FOLFOX-bevacizumab (D1 equal to D14): bevacizumab 5 mg/kg, folinic acid 400 mg/m2, oxaliplatin 85 mg/m2, 5-FU bolus 400 mg/m2, 5-FU 2400 mg/m2 over 46 hours
The median time between surgery and the end of RT was 56 days (8 weeks). A total of 194 (95.6%) surgical resections were complete (R0 resection). Fifty-eight patients (27.9%) had postoperative complications, mainly occlusive syndrome (n=21) or infectious complications (n=15). The rate of postoperative complications was higher in the PPI group than in the non-PPI group (41.7% vs. 28.1%, p=0.18), but the difference was not significant.
2. Pathological features
Overall, among the 204 patients evaluated for this criterion, the proportion of complete pathological response (ypT0N0) was 18% (Table 3). It seems lower in the PPI group than in the non-PPI group (8.7% vs. 19%), but the difference was not significant (p=0.36).
Table 3
Pathological features of patients taking proton pump inhibitors (PPIs) vs no PPIs.
|
TOTAL
|
|
PPI USE
NO
|
|
P-VALUE
|
|
YES
|
UNKNOWN
|
|
COMPLETE RESPONSE (YPT0N0), (MD=11) N (%)
|
0.36
|
YES
|
37 (18.1)
|
2 (8.7)
|
24 (19)
|
11 (20)
|
|
NO
|
167 (81.9)
|
21 (91.3)
|
102 (81)
|
44 (80)
|
|
COMPLETE RESECTION (R0), (MD=12) N (%)
|
0.59
|
YES
|
194 (95.6)
|
23 (100)
|
119 (95.2)
|
52 (94.5)
|
|
NO
|
9 (4.4)
|
0 (0)
|
6 (4.8)
|
3 (5.5)
|
|
3. Recurrence-free survival
The survival analysis results are presented in Table 4. Relapse was reported in seven patients in the PPI group and in 33 patients in the non-PPI group.
Table 4
Survival outcome
|
Overall
|
Yes
|
PPI intake
No
|
Unknown
|
P-value
|
Relapse-free survival
|
|
|
|
|
|
Numbers of events, n
|
|
Relapse
|
61
|
7
|
33
|
21
|
|
Local
|
6
|
0
|
5
|
1
|
|
Metastatic
|
37
|
6
|
21
|
15
|
|
Combined
|
18
|
1
|
7
|
5
|
|
Death without prior relapse
|
9
|
2
|
5
|
2
|
|
Recurrence-free survival, (95% CI)
|
|
36-month RFS
|
71.1 (64.2–76.8)
|
61.5 (38.9-77.8)
|
71.6 (62.5–78.8)
|
74.0 (60.5–83.4)
|
|
60-month RFS
|
63.4 (56.0–69.9)
|
61.5 (38.9-77.8)
|
66.9 (57.3–74.9)
|
58.7 (44.6–70.4)
|
|
Hazard ratio (relapse or death), (95% CI)
|
|
HR (PPI/no PPI)
|
-
|
1.26 (0.61–2.60)
|
Ref [1]
|
-
|
0.54
|
HR (PPI/no PPI or unknown)
|
-
|
1.20 (0.60–2.42)
|
Ref [1]
|
0.60
|
Overall survival
|
|
|
|
|
|
Number of deaths, n
|
|
Death
|
35
|
4
|
22
|
9
|
|
Related to disease progression
|
20
|
3
|
13
|
6
|
|
Unrelated to disease progression
|
15
|
1
|
9
|
3
|
|
Overall survival, (95% CI)
|
|
36-month OS
|
91.9 (87.2–95.0)
|
87.4 (65.9–95.8)
|
90.6 (83.7–94.7)
|
96.5 (86.7–99.1)
|
|
60-month OS
|
80.3 (73.5–85.5)
|
81.2 (56.5–92.7)
|
79.0 (69.7–85.8)
|
82.7 (69.3–90.6)
|
|
Hazard ratio (death), (95% CI)
|
|
HR (PPI/no PPI)
|
-
|
0.95 (0.33–2.76)
|
Ref [1]
|
-
|
0.93
|
HR (PPI/no PPI or unknown)
|
-
|
1.05 (0.37–2.97)
|
Ref [1]
|
0.93
|
Patients who took a PPI while on CRT did not have a statistically significant decrease in RFS over the first 5 years compared to patients who did not take a PPI. Indeed, 5-year RFS rates were 61.5% vs. 66.9% (HR=1.26, 95% CI, 0.61–2.60, p=0.54) (Figure 2). The results were stable when comparing patients with PPI intake to patients with no PPI intake or unknown treatment (HR=1.20, 95% CI, 0.60–2.42, p=0.60).
Overall, the 3-year RFS rate was 71.1% (95% CI 64.2–76.8), with 61.5% (95% CI 38.9–77.8) in the PPI group and 71.6% (95% CI 62.5–78.8) in the non-PPI group.
4. Overall survival
The 3-year OS rate was 91.9% (95% CI 87.2–95): 87.4% (95% CI 65.9–95.8) in the PPI group and 90.6% (95% CI 83.7–94.7) in the non-PPI group (Table 4, Figure 3, and Supplementary Figure S2). Co-medication with PPIs was not associated with a decrease in 5-year OS (81.2 vs. 79% [HR=0.95, 95% CI 0.33–2.76, p=0.93]).
5. Safety
Of the 215 patients included in the study, 36 experienced severe toxicity (the most common was diarrhea). The addition of oxaliplatin was associated with a significant increase in the risk of severe toxicity (13/40 [33%] vs. 23/170 [14%], p=0.004). Treatment was discontinued in 27 patients (12.7%), mostly chemotherapy (n=16) and mainly due to diarrhea (41% of reasons for discontinuation). The rate of severe toxicities during CRT was similar in both groups (24% in the PPI group vs. 17.8% in the non-PPI group, p=0.58), but gastrointestinal toxicities such as diarrhea were more frequent in the PPI group than in the non-PPI group (12/25 and 48% vs. 3/130 and 2.3%, p<10-5). The rate of chemotherapy discontinuation during treatment was higher in patients on PPIs than in patients not on PPIs (20% vs. 7.8%, p=0.07). On the contrary, PPI use did not affect the safety of RT. In the PPI group, interruption of RT and/or CRT and severe RT-related toxicities were not observed.