Survival of gastrointestinal cancer in Hodgkin lymphoma survivors 45 3 3. Overall and disease-specific survival of Hodgkin lymphoma survivors who subsequently developed gastrointestinal cancer Submitted Lisanne Rigter Michael Schaapveld Cécile Janus Augustinus Krol Richard van der Maazen Judith Roesink Josée Zijlstra Gustaaf van Imhoff Philip Poortmans Max Beijert Pieternella Lugtenburg Otto Visser Petur Snaebjornsson Anna van Eggermond Berthe Aleman Flora van Leeuwen * Monique van Leerdam * * Both authors contributed equally
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Survival of gastrointestinal cancer in Hodgkin lymphoma survivors 45
3
3. Overall and disease-specific survival
of Hodgkin lymphoma survivors who
subsequently developed
gastrointestinal cancer
Submitted
Lisanne Rigter
Michael Schaapveld
Cécile Janus
Augustinus Krol
Richard van der Maazen
Judith Roesink
Josée Zijlstra
Gustaaf van Imhoff
Philip Poortmans
Max Beijert
Pieternella Lugtenburg
Otto Visser
Petur Snaebjornsson
Anna van Eggermond
Berthe Aleman
Flora van Leeuwen*
Monique van Leerdam*
* Both authors contributed equally
46 Chapter 3
Abstract
Background
Hodgkin lymphoma (HL) survivors have an increased risk of gastrointestinal (GI)
cancer. This study aims to evaluate whether survival of patients who survived HL
and developed GI cancer differs from survival of first primary GI cancer patients.
Patients and methods
Overall and cause-specific survival of GI cancer patients in a HL survivor cohort (GI-
HL, n=104, including esophageal, gastric, small intestinal and colorectal cancer) was
compared with survival of a first primary GI cancer patient cohort (GI-1, n=1025,
generated by case matching based on tumor site, gender, age and year of
diagnosis). Cox proportional hazards regression was used for survival analyses.
Multivariable analyses were adjusted for GI cancer stage, grade of differentiation,
surgery, radiotherapy, chemotherapy.
Results
GI-HL cancers were diagnosed at a median age of 54 years (interquartile range 45-
60). No differences in tumor stage or frequency of surgery were found. GI-HL
patients less often received radiotherapy (8% vs. 23% in GI-1 patients, P<0.001)
and chemotherapy (28% vs. 41%, P=0.01) for their GI tumor.
Compared with GI-1 patients, overall and disease-specific survival of GI-HL patients
was worse (univariable hazard ratio (HR) 1.30 (95% confidence interval (CI) 1.03-
1.65) P=0.03 and HR 1.29 (95% CI 1.00-1.67) P=0.049, respectively; multivariable
HR 1.33 (95% CI 1.05-1.68) P=0.02 and HR 1.33 (95% CI 1.03-1.72) P=0.03,
respectively). Mortality from other causes was non-significantly increased in GI-HL
patients compared with GI-1 patients (HR 1.44 (95% CI 0.81-2.56) P=0.22).
Conclusion
Long-term overall and disease-specific survival of GI cancer in HL survivors is worse
compared with first primary GI cancer patients. Differences in tumor stage, grade
of differentiation, treatment, or mortality from other causes could not explain this
worse survival. As such, this may be explained by a worse treatment response due
to HL-related comorbidities or due to a different pathogenesis of therapy-related
gastrointestinal cancer.
Survival of gastrointestinal cancer in Hodgkin lymphoma survivors 47
3
Background
Hodgkin lymphoma (HL) survivors are at increased risk of developing second
malignancies, which are a major cause for morbidity and mortality. 1-6 Compared
with the general population, the risk of developing gastrointestinal (GI) cancer is
approximately 5-fold higher in HL survivors. 1, 2, 4, 7-11 This risk remains elevated up
to 40 years after HL and is strongly related to HL treatment. 1 Both exposure to
radiotherapy and alkylating agents, such as procarbazine, have been associated
with the development of GI cancers. 1, 2, 7-9, 11-13
A few studies suggest a difference in clinical and histopathological characteristics
of GI cancer in HL survivors compared with first primary GI cancer. 14-16 To our
knowledge, only one previous study examined survival of GI cancer in HL survivors
and reported a worse overall survival in subgroups of HL survivors compared with
first primary GI cancer patients, i.e.; those diagnosed with TNM stage IIB-IV colon
cancer and a small group (n=8) of TNM stage I gastric cancer. 15 The same authors
found no differences in disease-specific survival.
The cause of the reported reduced overall survival of GI cancers in HL survivors
remained unknown. Less favorable survival might be due to differences in (HL
treatment-induced) carcinogenesis leading to differences in GI tumor
characteristics, or to adaptation of GI cancer treatment due to the previous
treatment for HL. Furthermore, increased risks of competing causes of death, such
as other malignancies or cardiovascular disease, might play a role. 5, 17, 18
In view of the reported worse overall survival of GI cancer in HL survivors and its
unknown etiology, we designed this study to evaluate overall and cause-specific
survival of GI cancer in HL survivors.
Patients and Methods
Study design This study compared overall and cause-specific survival of esophageal, gastric,
small intestinal and colorectal cancer in a HL survivor cohort (GI-HL) with survival of
a population-based cohort of first primary GI cancer patients (GI-1).
48 Chapter 3
Gastrointestinal cancer patients in a Hodgkin lymphoma survivor cohort (GI-HL) In a Dutch multicenter cohort of HL patients who survived at least 5 years after
primary treatment (n=2,996), 121 patients with carcinomas of the esophagus,
stomach, small intestine or colorectum were identified. Data on HL patients,
diagnosed in the period 1965-2000 and between 15 and 50 years of age at HL
diagnosis, were collected as previously described. 1, 5, 17 In short, data collection
comprised detailed HL treatment data and information on second cancers, using
medical records, by responses to questionnaires sent to general practitioners and
linkage with the Netherlands Cancer Registry (NCR, from 1989 onwards). 1
A total of 17/121 (13%) GI-HL patients were excluded, of whom 16 because they
were not confirmed by the NCR, most likely due to incomplete data registration as
HL was diagnosed before complete population-based cancer registration in the
Netherlands in 1989 (figure 1). In patients with more than one HL-GI cancer, only
the first (if metachronous) or highest TNM stage (if synchronous) was included in
the analyses.
First primary gastrointestinal cancer cohort (GI-1) For each GI-HL cancer, the NCR searched for 10 matched controls with a GI-1
cancer, based on the following criteria: gender, no prior diagnosis of invasive
tumors, tumor location (esophagus, stomach, small intestine or colorectum), year
of diagnosis (closest proximity, maximum of 5 years difference) and age at
diagnosis (closest proximity, maximum of 3 years difference). For three GI-HL
patients, it was not possible to obtain 10 matched GI-1 patients because of the
young age at diagnosis. Subsequently, data on GI cancer characteristics, treatment,
and follow up were collected for both GI-HL and GI-1 patients.
From Statistics Netherlands (CBS), we obtained information on the cause of death,
which was categorized into GI cancer of interest or other causes, including
unknown causes. As all data were processed and analyzed completely
anonymously, this study was exempt from review by the Institutional Review
Board.
Survival of gastrointestinal cancer in Hodgkin lymphoma survivors 49
3
Statistical analyses Patient and tumor characteristics of GI-HL and GI-1 patients were compared using
Chi-square, Fishers’ exact or Mann-Whitney U tests. Overall survival and cause-
specific survival were presented using the Kaplan-Meier method. Cause-specific
survival was divided into disease-specific survival, related to the GI cancer of
interest, and survival related to other causes of death (using GI-cancer-related
death as a censoring event).
In 12 out of 104 GI-HL patients, the HL-GI tumor was not the first diagnosis of a
malignancy after HL. Since these other primary tumors or their treatment might
affect survival, these 12 patients and their matched controls were excluded from
tumors and their 911 matched controls were included in Cox proportional hazards
regression models. As the grouping variable (GI-HL vs. GI-1) was the main
independent variable of interest, its effect on survival (e.g. HR) was primarily
evaluated in a univariable model. In addition, we evaluated the effect of patient-
related and tumor-related characteristics on the survival difference between GI-HL
and GI-1 patients, i.e. on the HR of this grouping variable. For this purpose, a
multivariable model with tumor characteristics, treatment characteristics and a
combination of tumor and treatment characteristics was created. We also assessed
disease-specific mortality while treating other causes of death as a competing risk.
Due to the relatively small number of patients in GI site-specific multivariable
models, the effect of tumor characteristics and treatment characteristics on the
survival difference between GI-HL and GI-1 patients was evaluated in models that
included the grouping variable and one other characteristic. In case of a >10%
change in the hazard ratio for the grouping variable (e.g. GI-HL vs. GI-1), a
characteristic was considered as an influencing factor on the survival difference
between groups. Analyses were performed using IBM SPSS Statistics 22 and STATA
version 14.
50 Chapter 3
Figure 1. CONSORT diagram of gastrointestinal cancer in Hodgkin lymphoma survivors (GI-HL) and first primary gastrointestinal cancer patients (GI-1).
* The Netherlands Cancer Registry (NCR) attempted to register previous cancers for all patients with incident cancer since 1989; the history of previous cancers is known to be incomplete.
Survival of gastrointestinal cancer in Hodgkin lymphoma survivors 51
3
Results
General description and comparison of GI-HL and GI-1 patients GI-HL cancers were diagnosed at a median age of 54 years (interquartile range
(IQR) 45-60). The majority occurred in males (67%). Patients were diagnosed with
HL at a median age of 30 years (interquartile range (IQR) 22-41, supplementary
table 1). Median year of HL diagnosis was 1981 (range 1966-2000). In 53/104 (51%)
patients, HL had been treated with both radiotherapy and procarbazine-containing
chemotherapy and 43/104 (41%) patients had been treated for a HL recurrence.
Due to the matching procedure, GI-HL cancers were not different from GI-1
cancers with respect to gender and age at diagnosis (table 1). In addition, TNM
stage of both groups was comparable. GI-HL patients were less frequently treated
for their GI tumor with radiotherapy (8% vs. 23% in GI-1 patients, P<0.001) or
chemotherapy (29% vs. 41%, P=0.01). GI-HL tumors were treated more frequently
with surgery alone and less frequently with combined modality treatment that
included radiotherapy or chemotherapy compared with GI-1 tumors (P=0.005,
table 1).
Gastrointestinal cancer: overall survival Median survival times of 104 GI-HL patients and 1,025 GI-1 patients were 2.4 years
and 2.5 years, respectively. Overall survival of GI-HL patients was worse than that
of GI-1 patients (hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.01-1.58,
P=0.037). HL survivors in whom the GI-HL cancer was a third primary and their
matched controls were excluded for further survival analyses, leaving 92 GI-HL
patients who also had worse overall survival compared with 911 GI-1 patients (HR
1.30, 95% CI 1.03-1.65, P=0.028, supplementary table 1). After five years, overall
survival of GI-HL and GI-1 patients was 28% and 37%, respectively, after 10 years
18% and 30%, respectively, and after fifteen years 15% and 28%, respectively
(figure 2, table 2).
Several multivariable models were evaluated for the identification of contributive
(mediating) factors (e.g. tumor characteristics or treatment characteristics) to the
overall survival difference between GI-HL and GI-1 patients.
52 Chapter 3
Table 1. Characteristics of gastrointestinal cancer in Hodgkin lymphoma survivors and first primary gastrointestinal cancer patients.
Gastrointestinal cancers include two GI-HL small intestinal cancers and their matched GI-1 controls. Abbreviations: GI-HL, gastrointestinal cancer in Hodgkin lymphoma survivors; GI-1, first primary gastrointestinal cancer patients; RT, radiotherapy; CT, chemotherapy. * defined as neuroendocrine carcinomas, large cell carcinomas, undifferentiated carcinomas, anaplastic carcinomas or unspecified carcinomas.
GI cancer characteristic Gastrointestinal cancer
GI-HL (N=104)
GI-1 (N=1025)
n (%) n (%) P value Age Median (IQR) 54 (45-60) 54 (45-60) 0.82 Gender Male 70 (67) 698 (68) 0.87 Female 34 (33) 327 (32) Morphology category Adenocarcinoma 81 (78) 900 (88) <0.001 Squamous cell carcinoma 18 (17) 117 (11) Other carcinoma* 5 (5) 8 (1) TNM Stage I 12 (12) 124 (12) 0.79 II 24 (23) 202 (20) III 26 (25) 253 (25) IV 35 (34) 387 (38) Unknown 7 (7) 59 (6) Grade of differentiation Well / low grade 8 (8) 36 (4) 0.005 Moderate / intermediate 34 (33) 340 (33) Poor / high 22 (21) 338 (33) Undifferentiated / anaplastic 4 (4) 10 (1) Unknown 36 (35) 301 (29) Surgery No 37 (36) 396 (39) 0.54 Yes 67 (64) 629 (61) Radiotherapy No 96 (92) 785 (77) <0.001 Yes 8 (8) 240 (23) Chemotherapy No 75 (72) 608 (59) 0.01 Yes 29 (28) 417 (41) Treatment category No treatment 18 (17) 153 (15) 0.005 Surgery only 51 (49) 348 (34) Surgery & RT and/or CT 16 (15) 281 (27) RT and/or CT only 19 (18) 243 (24)
Survival of gastrointestinal cancer in Hodgkin lymphoma survivors 53
3
Figure 2. Overall survival of gastrointestinal cancer in Hodgkin lymphoma survivors (GI-HL, blue) compared with first primary gastrointestinal cancer patients (GI-1, green).
* first primary gastrointestinal cancer patients, green line, number of cases at risk. † gastrointes nal cancer in Hodgkin lymphoma survivors, blue line, number of cases at risk. In the first multivariable model, adjusted for tumor characteristics (TNM stage,
grade of differentiation, tumor location), the difference between GI-HL and GI-1
patients remained present (HR 1.33 (95% CI 1.05-1.68) P=0.02).
This difference also remained present after adjustment for treatment
characteristics (surgery, radiotherapy, chemotherapy) and after adjustment for
both tumor and treatment characteristics (HR 1.32 (95% CI 1.04-1.68) P=0.02 and
HR 1.33 (95% CI 1.05-1.68) P=0.02, respectively).
54 Chapter 3
Gastrointestinal cancer: cause-specific survival Disease-specific survival was worse in GI-HL patients than in GI-1 patients (HR 1.29
(95% CI 1.00-1.67) P=0.049). Mortality from other causes appeared to be non-
significantly higher in GI-HL patients compared with GI-1 patients (HR 1.44 (95% CI
0.81-2.56) P=0.22). At five years after GI cancer diagnosis, cumulative disease-
specific mortality and cumulative mortality from other causes in GI-HL patients
were 66% and 7%, respectively, and in GI-1 patients 56% and 7%, respectively
(table 3). In a multivariable model adjusted for treatment characteristics, disease-
specific survival remained worse in GI-HL patients than in GI-1 patients (HR 1.33
(95% CI 1.03-1.72) P=0.03). After adjustment for both tumor characteristics and
treatment characteristics, this survival difference also remained present (HR 1.33
(95% CI 1.03-1.72) P=0.03).
Esophageal cancer characteristics and survival GI-HL esophageal cancers were more frequently located in the upper esophagus
than GI-1 cancers (23% vs. 7%, P=0.01, figure 3). A lower frequency of
adenocarcinomas and a higher frequency of squamous cell and other carcinomas
(including neuroendocrine carcinomas, large cell carcinomas, undifferentiated
carcinomas, anaplastic carcinomas or unspecified carcinomas) was found in the GI-
HL group compared with the GI-1 group (P=0.005, supplementary table 2). No
differences in TNM stage or grade of differentiation were observed between both
groups. GI-HL esophageal cancers were treated less frequently with radiotherapy
(20% vs. 40% in GI-1, P=0.03) and chemotherapy (13% vs. 43%, P=0.001) or
treatments that included radiotherapy and/or chemotherapy (27% vs. 57%,
P=0.002). Overall survival was not significantly different in GI-HL esophageal cancer
patients compared with GI-1 patients (HR 1.20 (95% CI 0.79-1.85) P=0.41, figure 2,
table 2). Cumulative disease-specific mortality was high (79% in GI-HL and 74% in
GI-1 patients at 5 years) and did not differ between GI-HL and GI-1 patients (HR
1.17 (95% CI 0.75-1.84) P=0.49). When tumor and treatment characteristics were
added to the model, the survival difference between GI-HL and GI-1 patients
remained (not exceeding a 10% reduction in HR, supplementary table 3, 4).
Tabl
e 2.
Ove
rall
surv
ival
of g
astr
oint
estin
al c
ance
r in
Hod
gkin
lym
phom
a su
rviv
ors
com
pare
d w
ith fi
rst p
rimar
y ga
stro
inte
stin
al
canc
er p
atie
nts.
Abbr
evia
tions
: GI-H
L, g
astr
oint
estin
al c
ance
r in
Hod
gkin
lym
phom
a su
rviv
ors;
GI-1
, firs
t prim
ary
gast
roin
test
inal
can
cer p
atie
nts;
H
R, h
azar
d ra
tio; 9
5% C
I, 95
% c
onfid
ence
inte
rval
. *
Cox
prop
ortio
nal h
azar
ds re
gres
sion
mod
el a
djus
ted
for d
icho
tom
ized
var
iabl
es T
NM
sta
ge (I
/II v
s. II
I/IV)
, gra
de o
f di
ffere
ntia
tion
(wel
l/mod
erat
e vs
. poo
r/un
diffe
rent
iate
d) a
nd tu
mor
loca
tion
(eso
phag
us/s
tom
ach
vs. s
mal
l in
test
ine/
colo
rect
um).
†
Cox
prop
ortio
nal h
azar
ds re
gres
sion
mod
el a
djus
ted
for s
urge
ry, r
adio
ther
apy,
che
mot
hera
py.
‡ Co
x pr
opor
tiona
l haz
ards
regr
essio
n m
odel
adj
uste
d fo
r dic
hoto
miz
ed v
aria
bles
TN
M s
tage
, gra
de o
f diff
eren
tiatio
n su
rger
y,
radi
othe
rapy
, che
mot
hera
py.
$ Co
x pr
opor
tiona
l haz
ards
regr
essio
n m
odel
adj
uste
d fo
r tum
or su
bsite
: eso
phag
eal c
ance
r: u
pper
vs.
oth
er, g
astr
ic:
antr
um/p
ylor
us v
s. o
ther
, col
orec
tal c
ance
r: co
lon
vs. r
ectu
m.
Cha
ract
erist
ic
Gas
troi
ntes
tinal
can
cer
Esop
hage
al c
ance
r G
astr
ic c
ance
r Co
lore
ctal
can
cer
GI-H
L (n
=92)
%
(95%
CI)
GI-1
(n=9
11)
% (9
5% C
I) G
I-HL
(n=2
5)
% (9
5% C
I) G
I-1 (n
=243
) %
(95%
CI)
GI-H
L (n
=31)
%
(95%
CI)
GI-1
(n=3
08)
% (9
5% C
I) G
I-HL
(n=3
4)
% (9
5% C
I) G
I-1 (n
=340
) %
(95%
CI)
5-ye
ar s
urvi
val
28 (1
8-37
) 37
(34-
40)
12 (0
-25)
21
(16-
27)
13 (1
-26)
26
(21-
31)
50 (3
3-67
) 57
(52-
63)
10-y
ear s
urvi
val
18 (1
0-27
) 30
(27-
33)
6 (0
-16)
18
(13-
23)
7 (0
-16)
21
(17-
26)
37 (2
0-53
) 46
(40-
51)
15-y
ear s
urvi
val
15 (7
-23)
28
(25-
31)
6 (0
-16)
16
(12-
21)
7 (0
-16)
21
(16-
26)
27 (1
0-44
) 41
(36-
47)
G
I-HL
vs. G
I-1 (r
ef)
HR (9
5% C
I) P
valu
e HR
(95%
CI)
P va
lue
HR (9
5% C
I) P
valu
e HR
(95%
CI)
P va
lue
Uni
varia
ble
1.30
(1.0
3-1.
65)
0.03
1.
20 (0
.79-
1.85
) 0.
41
1.33
(0.9
1-1.
96)
0.15
1.
36 (0
.90-
2.06
) 0.
15
Mul
tivar
iabl
e, in
clud
ing
Tum
or c
hara
cter
istic
s* 1.
39 (1
.10-
1.76
) 0.
006
Trea
tmen
t cha
ract
erist
ics†
1.32
(1.0
4-1.
68)
0.02
Tu
mor
+ tr
eatm
ent‡
1.33
(1.0
5-1.
68)
0.02
Tu
mor
sub
site$
1.15
(0.7
4-1.
79)
0.54
1.
71 (1
.14-
2.55
) 0.
009
1.29
(0.8
5-1.
96)
0.24
56 Chapter 3
Figure 3. Subsite of gastrointestinal cancer in Hodgkin lymphoma survivors and first primary gastrointestinal cancer patients.
Both mid esophagus and stomach body contain overlapping or unspecified locations. Abbreviations: GI-HL, gastrointestinal cancer in Hodgkin lymphoma survivors; GI-1, first primary gastrointestinal cancer patients. * P=0.01 ** P<0.001 † including cecum, ascending, descending, sigmoid, overlapping, colon not otherwise specified (transverse colon includes the hepatic and splenic flexure).
Tabl
e 3.
Cau
se-s
peci
fic c
umul
ativ
e m
orta
lity
from
gas
troi
ntes
tinal
can
cer i
n H
odgk
in ly
mph
oma
surv
ivor
s an
d fir
st p
rimar
y ga
stro
inte
stin
al c
ance
r pat
ient
s.
Cum
ulat
ive
mor
talit
y w
as c
alcu
late
d us
ing
com
petin
g ris
k an
alys
es. A
bbre
viat
ions
: GI-H
L, g
astr
oint
estin
al c
ance
r in
Hod
gkin
lym
phom
a su
rviv
ors;
GI-1
, firs
t pr
imar
y ga
stro
inte
stin
al c
ance
r pat
ient
s; H
R, h
azar
d ra
tio; 9
5% C
I, 95
% c
onfid
ence
inte
rval
. *
Cox
prop
ortio
nal h
azar
ds re
gres
sion
mod
el a
djus
ted
for s
urge
ry, r
adio
ther
apy,
che
mot
hera
py.
† Co
x pr
opor
tiona
l haz
ards
regr
essio
n m
odel
adj
uste
d fo
r dic
hoto
miz
ed v
aria
bles
TN
M s
tage
, gra
de o
f diff
eren
tiatio
n, su
rger
y, ra
diot
hera
py, c
hem
othe
rapy
. ‡
Cox
prop
ortio
nal h
azar
ds re
gres
sion
mod
el a
djus
ted
for t
umor
subs
ite: e
soph
agea
l can
cer:
uppe
r vs.
oth
er, g
astr
ic: a
ntru
m/p
ylor
us v
s. o
ther
, col
orec
tal
canc
er: c
olon
vs.
rect
um.
Cum
ulat
ive
mor
talit
y
G
astr
oint
estin
al c
ance
r Es
opha
geal
can
cer
Gas
tric
can
cer
Colo
rect
al c
ance
r G
I-HL
(n=9
2)
% (9
5% C
I) G
I-1 (n
=911
) %
(95%
CI)
GI-H
L (n
=25)
%
(95%
CI)
GI-1
(n=2
43)
% (9
5% C
I) G
I-HL
(n=3
1)
% (9
5% C
I) G
I-1 (n
=308
) %
(95%
CI)
GI-H
L (n
=34)
%
(95%
CI)
GI-1
(n=3
40)
% (9
5% C
I) 5-
year
mor
talit
y G
I can
cer
Oth
er c
ause
s of
dea
th
66 (5
5-75
) 7
(3-1
3)
56 (5
3-59
) 7
(6-9
) 79
(57-
91)
8 (1
-23)
74
(68-
79)
5 (3
-8)
81 (6
2-91
) 6
(1-1
9)
65 (5
9-70
) 9
(6-1
3)
44 (2
7-60
) 6
(1-1
7)
35 (3
0-41
) 7
(5-1
0)
10-y
ear
mor
talit
y G
I can
cer
Oth
er c
ause
s of
dea
th
72 (6
2-80
) 9
(4-1
7)
61 (5
7-64
) 10
(8-1
2)
85 (6
2-95
) 8
(1-2
3)
76 (7
0-81
) 7
(4-1
0)
87 (6
9-95
) 6
(1-1
9)
69 (6
3-74
) 10
(9-1
4)
50 (3
3-66
) 13
(4-2
7)
42 (3
7-48
) 12
(9-1
6)
15-y
ear
mor
talit
y G
I can
cer
Oth
er c
ause
s of
dea
th
72 (6
2-80
) 13
(7-2
2)
61 (5
8-65
) 11
(9-1
3)
85 (6
2-95
) 8
(1-2
3)
76 (7
0-81
) 8
(5-1
2)
87 (6
9-95
) 6
(1-1
9)
69 (6
3-74
) 10
(9-1
4)
50 (3
3-66
) 22
(9-4
0)
45 (3
9-50
) 14
(10-
18)
Di
seas
e-sp
ecifi
c
GI-H
L vs
. GI-1
(ref
) HR
* (9
5% C
I) P
valu
e HR
* (9
5% C
I) P
valu
e HR
* (9
5% C
I) P
valu
e HR
† (95%
CI)
P va
lue
Uni
varia
ble
1.29
(1.0
0-1.
67)
0.04
9 1.
17 (0
.75-
1.84
) 0.
49
1.43
(0.9
5-2.
13)
0.08
1.
27 (0
.77-
2.10
) 0.
35
Mul
tivar
iabl
e, in
clud
ing
Trea
tmen
t cha
ract
erist
ics*
1.33
(1.0
3-1.
72)
0.03
Tu
mor
+ tr
eatm
ent†
1.33
(1.0
3-1.
72)
0.03
Tu
mor
sub
site‡
1.11
(0.7
0-1.
76)
0.67
1.
80 (1
.19-
2.74
) 0.
006
1.11
(0.6
6-1.
86)
0.70
O
ther
cau
ses o
f dea
th
Uni
varia
ble
1.44
(0.8
1-2.
56)
0.22
1.
60 (0
.36-
7.06
) 0.
53
1.02
(0.3
1-3.
34)
0.97
1.
61 (0
.76-
3.38
) 0.
21
58 Chapter 3
Gastric cancer characteristics and survival GI-HL gastric cancers were more frequently located in the antrum or pylorus (41%
vs. 20% in GI-1) and less frequently in the cardia or fundus (18% vs. 31% in GI-1,
P=0.01, figure 3). Treatment with surgery alone was more frequent in HL-GI
patients than in GI-1 patients (59% vs. 37%, P=0.02), and treatment that included
at least radiotherapy or chemotherapy was less frequently given (24% vs. 43%,
P=0.04, supplementary table 2).
There was a trend towards worse overall and disease-specific survival in GI-HL
gastric cancer patients compared with GI-1 patients (HR 1.33 (95% CI 0.91-1.96)
P=0.15 and HR 1.43 (95% CI 0.95-2.13) P=0.08, respectively, figure 2, table 2 and
3). In multivariable models that included TNM stage, tumor subsite (cardia/body vs.
antrum/pylorus) or surgery, the overall and disease-specific survival difference
between GI-HL gastric cancer patients and GI-1 patients substantially increased
(defined as a >10% change in HR of the grouping variable GI-HL vs. GI-1 patients;
disease-specific survival adjusted for subsite, HR 1.80 (95% CI 1.19-2.74) P=0.006;
adjusted for stage, HR 1.66 (95% CI 1.11-2.49) P=0.01; adjusted for surgery, HR
2.00 (95% CI 1.33-3.01) P=0.001, supplementary table 3, 4). None of the evaluated
characteristics decreased the survival difference, so none of these characteristics
could explain the observed difference in survival.
Colorectal cancer characteristics and survival GI-HL colorectal cancers were more frequently located in the transverse colon and
less frequently in the rectum compared with GI-1 colorectal cancers (34% and 11%
vs. 9% and 32%, respectively, P<0.001, figure 3). It is likely that (partly) due to this
difference in rectal cancer frequency, a difference in treatment with radiotherapy
was present between GI-HL and GI-1 patients (5% vs. 26%, P=0.004, supplementary
table 2). No further differences in TNM stage, surgery or chemotherapy were
present between groups.
Overall and disease-specific survival were not significantly different when
comparing GI-HL patients with GI-1 patients (HR 1.36 (95% CI 0.90-2.06) P=0.15
and HR 1.27 (95% CI 0.77-2.10) P=0.35, respectively). In a multivariable model,
Survival of gastrointestinal cancer in Hodgkin lymphoma survivors 59
3
tumor location was the only characteristic that decreased any possible difference
in survival. After adjustment for location either in colon or rectum, disease-specific
survival differences between GI-HL patients and GI-1 patients became substantially
Median (interquartile range) 30 (22-41) 31 (25-39) 26 (21-36) 30 (22-45) Treatment period 1966-1979 1980-1989 1990-2000
44 33 27
11 12
7
11 11 12
22
9 7
HL radiotherapy (RT)
No RT 6 3 1 2
Mantle field only 31 14 6 10
Mantle field + infradiaphragmatic RT 51 12 24 15
Infradiaphragmatic RT only 11 0 1 9
Yes, field unknown 5 1 2 2
HL chemotherapy (CT)
No CT 43 13 17 13
CT, no procarbazine 12 4 1 7
Procarbazine-containing CT 41 10 15 14
Yes, type of CT unknown 8 3 1 4
HL recurrence 43 13 16 14 Second non-gastrointestinal cancer diagnoses in HL survivors †
Oropharynx 3 2 0 1
Lung 1 1 0 0
Breast 4 1 2 1
Lymphoma (NOS) 2 1 1 0
Cervix 1 0 0 1
Connective/soft tissue (NOS) 1 0 0 1
Abbreviations: HL, Hodgkin lymphoma; RT, radiotherapy; CT, chemotherapy; NOS, not otherwise specified. * including two HL patients with a small intestinal cancer. † GI-HL is the third cancer, excluded from extensive survival analyses.