Post on 16-May-2023
Survival After Hodgkin Lymphoma
Causes of Death and Excess Mortality in Patients Treatedin 8 Consecutive Trials
Olav Favier, MD1, Natacha Heutte, PhD1,2, Aspasia Stamatoullas-Bastard, MD3, Patrice Carde, MD, PhD4,
Mars B. van’t Veer, MD, PhD5, Berthe M. P. Aleman, MD, PhD6, Evert M. Noordijk, MD, PhD7,
Jose Thomas, MD8, Christophe Ferme, MD4, and Michel Henry-Amar, MD, PhD1,2, for the European
Organization for Research and Treatment of Cancer (EORTC) Lymphoma Group and the Groupe
d’Etudes des Lymphomes de l’Adulte (GELA)
BACKGROUND: The objective of this study was to analyze cause-specific excess mortality in adult patients
with Hodgkin lymphoma (HL) with respect to treatment modality. METHODS: The study population con-
sisted of 4401 Belgian, Dutch, and French patients aged 15 to 69, in all stages of disease, who were treated
between 1964 and 2000. Excess mortality was expressed by using a standardized mortality ratio (SMR)
and calculating the absolute excess risk (AER). Relative survival was calculated and analyzed using a previ-
ously described regression model. RESULTS: At a median follow-up of 7.8 years, 725 of 4401 patients
(16.5%) had died, 51% of HL, 10% of treatment-related toxicity, 18% of second cancer, 5% of cardiovascular
diseases, 2% of infections, 8% of other causes, and 6% of an unspecified cause. Overall, the SMR was 7.4
(95% confidence limits [CL], 6.9-8.0), and the AER was 182.8 (95% CL, 167.7-198.8). These indicators were
3.8 (95% CL, 3.2-4.5) and 27.9, respectively, for deaths from a second cancer and 4.0 (95% CL, 2.3-6.7) and
3.3, respectively for deaths from infection. After 15 years, the observed survival rate was 75%, and the rela-
tive survival rate was 80%. In patients with early-stage disease, the overall excess mortality was associated
with age �40 years (P ¼ .007), men (P < .001), unfavorable prognosis features (P < .001), and 2 treat-
ments: combined nonstandard nonalkylating chemotherapy plus involved-field radiotherapy (P ¼ .002) and
mantle-field irradiation alone (P ¼ .003). With follow-up censored at the first recurrence, no treatment
modalities were associated with excess mortality. CONCLUSIONS: Progressive disease remained the pri-
mary cause of death in patients with HL in the first decades after treatment. Excess mortality in patients
with early-stage disease was linked significantly to treatment modalities that were associated with poor
treatment failure-free survival. Cancer 2009;115:1680–91. VC 2009 American Cancer Society.
KEY WORDS: Hodgkin lymphoma, long-term survival, causes of death, relative survival.
Received: August 7, 2008; Revised: September 30, 2008; Accepted: October 16, 2008
Published online: February 10, 2009 VC 2009 American Cancer Society
DOI: 10.1002/cncr.24178, www.interscience.wiley.com
Corresponding author: Michel Henry-Amar, MD, PhD, Centre Francois Baclesse, 3 Avenue General Harris, F-14076 Caen Cedex 05, France; Fax: (011)
33 231455097; m.henry.amar@baclesse.fr
1Clinical Research Unit, Francois Baclesse Cancer Center, Caen, France; 2GRECAN EA-1772, University of Caen Basse-Normandy, Caen, France; 3Hema-
tology Department, Henri Becquerel Cancer Center, Rouen, France; 4Hematology Department, Gustave Roussy Cancer Institute, Villejuif, France;5Radiotherapy Department, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; 6Radiotherapy Department, The Netherlands Cancer Insti-
tute, Amsterdam, the Netherlands; 7Radiotherapy Department, Leiden University Medical Center, Leiden, the Netherlands; 8Hematology Department,
Gasthuisberg University Hospital, Leuven, Belgium
We acknowledge the following individuals for their participation in the study: Umberto Tirelli, MD, PhD, Division of Medical Oncology A, National
Cancer Institute, Aviano, Italy; John M. M. Raemaekers, MD, PhD, St. Radboud University Medical Center, Nijmegen, the Netherlands; Houchingue
Eghbali, MD, Bergonie Cancer Institute, Bordeaux, France; Pieternella J. Lugtenburg, MD, PhD, University Medical Center, Rotterdam, the Netherlands
(European Organization for Research and Treatment of Cancer Lymphoma Group); and Pauline Brice, MD, PhD, Saint-Louis University Hospital, Paris,
France; Catherine Sebban, MD, Leon-Berard Cancer Center, Lyon, France; Laurent Voillat, MD, Besancon University Hospital, Besancon, France; Rene-
Olivier Casasnovas, MD, PhD, Dijon University Hospital, Dijon, France (Adult Lymphoma Study Group).
1680 Cancer April 15, 2009
Original Article
Hodgkin lymphoma (HL) has become a highlycurable cancer.1,2 Patients have a relatively long sur-vival, although a few studies have concluded that thedeath rate of patients with HL still is greater than thatof the general population.3,4 This may relate to variouscomplications, such as second malignancies,5-9 cardiactoxicity,10-12 and infections.4 Twenty years after theirtreatment, more patients have died from other causesthan from HL.4,13 Because treatment efficiency hasimproved dramatically, 1 way to improve long-termsurvival is to reduce mortality from causes other thanHL.
Several studies have examined excess mortality from
major causes in large cohorts of patients with HL,3-5,8,13
but few have analyzed excess mortality by detailed treat-
ment categories.12 However, Swerdlow et al failed to iden-
tify treatment categories (with detailed chemotherapy
dose or dose and field of radiation used) linked to an
excess risk of death from myocardial infarction.12 By
using data from randomized clinical trials of the European
Organization for Research and Treatment (EORTC)
Lymphoma Group and the Adult Lymphoma Study
Group (GELA), we conducted a retrospective study with
the objectives of estimating excess mortality from causes
other than HL and examining mortality with respect to
patient and clinical characteristics and treatment
modality.
MATERIALS AND METHODS
Patients and Data Collection
The cohort was composed of patients who were included
in 8 consecutive clinical trials conducted from 1964 to
2000 in 10 European countries. The selection of patients
and methods of data collection were published previ-
ously.14-17 The data used concerned nationality, date of
birth, sex, clinical stage according to the Ann Arbor classi-
fication, date of randomization, treatment, date of first re-
currence, date of last examination and vital status, date of
death, and primary cause of death. Causes of death were
reported as follows: progressive disease, treatment-related
toxicity without evidence of active disease, second cancer,
cardiovascular disease, infection, other causes, and death
from cause unspecified. Overall, 5015 patients were
included. Data were stored under the responsibility of the
same researcher (M.H.-A.).
General Population Data
To estimate excess mortality, survival data from the stud-
ied population and mortality data from the general popu-
lation were needed. Death rates were calculated using the
numbers of deaths and individuals at risk obtained from
the World Health Organization Mortality Database.18
Causes of deaths were specified using the International
Classification for Diseases (revisions 7-10).19 Death rates
were derived for each combination of 5-year age group,
sex, country, and calendar year, by dividing the numbers
of deaths from given causes (all causes, cancer, cardiovas-
cular diseases, infections, and other causes) by the mid-
year number of individuals at risk. Only patients who ori-
ginated from countries where >5% of all patients in the
database resided were selected (Fig. 1). Population data
were available until 2004 for the Netherlands, until 2003
FIGURE 1. Flow chart of patients who were randomized in 8
European Organization for Research and Treatment of Can-
cer Lymphoma Group and the Adult Lymphoma Study Group
clinical trials from 1964 to 2000 conducted in 10 European
countries.
Survival After Hodgkin Lymphoma/Favier et al
Cancer April 15, 2009 1681
for France, and until 1997 for Belgium. Therefore, 23
Belgian patients who enrolled on trials in 1998 or later
were excluded from the current analysis, and 4401
patients (88%) were available for analysis.
Statistical Analysis
Time at risk was computed from the date of randomiza-
tion to the date of death or the date of the last examina-
tion. Time at risk was limited to 15 years to prevent the
possibility that older trials would overweight the last fol-
low-up periods, and this lead to the censoring of 477
patients (ie, 1684 person-years), including 142 patients
from the H1 trial, 83 patients from the H2 trial, 133
patients from the H5 trial, and 119 patients from the H6
trial. Time at risk also was censored when last vital status
date exceeded the year for which general mortality data
were available.
The standardized mortality ratio (SMR) was calcu-
lated as the ratio of observed deaths to expected deaths. The
expected numbers of deaths, overall and for main causes,
were calculated by multiplying the numbers of person-years
by sex, 5-year age group, nationality, and calendar year by
the corresponding mortality rates from general population
data. The absolute excess risk (AER) of death was computed
as the difference between observed and expected numbers of
deaths divided by the number of person-years at risk and
multiplied by 10,000. The SMR and AER 95% confidence
limits (CL) were obtained assuming the Poisson distribu-
tion of the observed numbers.
Survival analysis was performed using the method of
Kaplan and Meier. The relative survival method was used
to correct observed survival from background mortality.
Two approaches were used: the first compared observed
survival with relative survival, and the second aimed at
analyzing factors that may influence excess risk of death.18
In the latter approach, the relative excess risks of death
from baseline characteristics were quantified based on the
exponential of the estimates derived from the model
described by Dickman et al.20 Baseline characteristics
included age (ages 15-39 years, 40-49 years, and 50-69
years), sex, prognostic group, splenectomy, and treat-
ment. Radiotherapy (RT) was subgrouped into involved-
field (IF-RT), mantle-field RT and (sub)total lymph node
irradiation. Chemotherapy was categorized into nonalky-
lating therapy, alkylating agent-containing therapy, 3 or 4
cycles, and 6 cycles. Nonalkylating chemotherapy
included vinblastine (associated with mantle-field RT in
the H1 trial and [sub]total lymph node irradiation in the
H2 trial); combined doxorubicin, bleomycin, vinblastine,
and dacarbazine (ABVD) (associated with mantle-field
RT in the H6 trial); and combined epirubicin, bleomycin,
vinblastine, and prednisone (EBVP) (associated with
involved-field RT in the H7 trial). Alkylating chemother-
apy consisted of procarbazine (associated with vinblastine
in the H2 trial); combined mechlorethamine, vincristine,
procarbazine, and prednisone (MOPP) (alone or com-
bined with ABVD and iceberg RT in the H3B4 trial;
MOPP alone and mantle-field RT in the H5 and H6 tri-
als; and MOPP combined with doxorubicin, bleomycin,
vinblastine [ABV] with or without RT in the H7, H8,
and H34 trials). RT and chemotherapy categories were
pooled into 1 variable (Table 1) in which the combination
of IF-RT and 3 or 4 cycles of alkylating chemotherapy
was considered the reference category. The definitions for
prognostic groups were derived from those used in the
design of the H7 and H8 trials.14,17 An unfavorable prog-
nosis was defined either as supradiaphragmatic clinical
stage II disease with �4 lymph node areas involved, or as
no B symptoms and an erythrocyte sedimentation rate
(ESR) �50 mm in the first hour, or as B symptoms and
an ESR �30 mm in the first hour, or a mediastinum/
thorax ratio �0.35. Data were available for 2451 of the
2630 patients who were included in the H6, H7, and H8
trials (Table 2). To analyze the impact of first-line treat-
ment, the same model was used with the time at risk cen-
sored at the date of first recurrence. Risk factor analyses
were limited to patients who had early-stage disease,
because the treatments used depended greatly on disease
stage, and only 17% of all patients and 26% of all deaths
involved advanced-stage disease (Table 3). A backward
selection procedure was used. All statistical tests were 2-
sided, and P < .01 indicated statistical significance. The
SAS statistical software (release 9.1.3; SAS Institute, Cary,
NC) was used.
RESULTS
Observed Deaths
Overall, 725 of 4401 patients (16.5%) who were treated
for HL died (Table 3). Among the patients with early-
Original Article
1682 Cancer April 15, 2009
Table
1.Treatm
entGivenbyTrial
EarlyStageDiseaseTrials
H1
(1964-1971)
H2
(1971-1977)
H5
(1977-1982)
H6
(1982-1988)
H7
(1988-1993)
H8
(1993-1999)
H1to
H8
Trials
(1964-1999)
Variable
No.
%No.
%No.
%No.
%No.
%No.
%No.
%
No.ofpatients
accrued
267
264
490
550
710
1370
3651
Treatm
ent
Splenectomy
00
124
47
233
48
125
23
00
00
482
13
IF-R
Tafter
NonalkylatingCT*
00
00
00
00
311
44
00
311
9
MOPP-A
BV33or34
00
00
00
00
00
528
39
528
14
MOPP-A
BV36
00
00
00
00
230
32
288
21
518
14
Mantle-field
irradiationand
Nochemotherapy
139
52
00
97
20
92
17
36
532
2396
11
NonalkylatingCT
128
48
00
00
162
29
00
00
290
8
MOPP36
00
00
144
29
177
32
00
00
321
9
(S)TLIafter
Nochemotherapy
00
176
66
249
51
119
22
133
19
235
17
912
25
NonalkylatingCT
00
44
17
00
00
00
00
44
1
VLB
andPCZ
00
44
17
00
00
00
00
44
1
MOPP-A
BV34
00
00
00
00
00
287
21
287
8
IF-R
Tindicatesinvolved-field
radiotherapy;CT,
chemotherapy;MOPP-A
BV,combined
mechlorethamine,vincristine,procarbazine,and
prednisoneplusdoxorubicin,bleomycin,and
vinblastine;MOPP,
com-
binedmechlorethamine,vincristine,procarbazine,andprednisone;(S)TLI,subtotalortotallymphnodeirradiation;VLB,vinblastine;PCZ,procarbazine
*NonalkylatingCTdenoteschemotherapywithoutalkylatingagents:vinblastine(associatedwithmantle-field
irradiationin
theH1trialorsubtotallymphnodeirradiationin
theH2trial);
combineddoxorubicin,
bleomycin,vinblastine,anddacarbazine(associatedwithmantle-field
irradiationin
theH6trial);
andcombinedepirubicin,bleomycin,vinblastine,andprednisone(associatedwithinvolved-field
irradiationin
the
H7trial).
Survival After Hodgkin Lymphoma/Favier et al
Cancer April 15, 2009 1683
stage disease, the 10-year survival rate increased from 70%
in the H1 trial to 90% in the H8 trial. Among the patients
with advanced-stage disease, the 10-year survival rate was
62% in the H3B4 trial and 73% in the H34 trial. Of the
725 deaths, 366 deaths (51%) were from disease progres-
sion, 74 deaths (10%) were from treatment-related toxic-
ity, 130 deaths (18%) were from second cancer, 33 deaths
(5%) were from cardiovascular disease, 15 deaths (2%)
were caused by infection, 61 deaths (8%) were from other
causes, and 46 deaths (6%) were from an unspecified
cause. Of the 366 disease progression-related deaths, 82%
occurred from 0 to 4 years after randomization, 15%
occurred from 5 to 9 years after randomization, and 3%
occurred from 10 to 14 years after randomization. The
rates were 37%, 42%, and 21%, for deaths from second
cancers, respectively; and 60%, 28%, and 12% for deaths
from other causes, respectively.
Excess Mortality by All Causes
Overall, the SMR was 7.4 (95% CL, 6.9-8.0), correspond-
ing to 182.8 excess deaths (95% CL, 167.7-198.8 excess
deaths) for 10,000 person-years (Table 4). The SMR
decreased by 2-fold between 0 to 4 years after randomiza-
tion and 5 to 9 years after randomization and remained sta-
ble thereafter. Overall, the SMR was higher in women than
in men (9.1 vs 6.8), whereas the AER was 2 times higher in
men (225.3 vs 133). SMR changes with time also differed
according to sex: Among women, the SMR decreased by 3-
fold and then increased; whereas, among men, it constantly
decreased. This also was true for the AER. However, the
AER was similar in the last 5 years after randomization in
both men and women. The SMR and AER also varied with
age. The SMR decreased with increasing age: It was 14.0
(95% CL, 12.7-15.5) in patients ages 15 to 39 years, 7.1
(95% CL, 6.0-8.4) in patients ages 40 to 49 years, and 3.6
(95% CL, 3.1-4.2) in patients ages 50 to 69 years. In con-
trast, the AER increased with age: It was 145.8 (95% CL,
131.0-161.8) in patients ages 15 to 39 years, 250.6 (95%
CL, 204.3-303.0) in patients ages 40 to 49 years, and 370.2
(95%CL, 297.1-451.9) in patients ages 50 to 69 years.
Excess Mortality by Cause of Death
Although deaths from second cancer represented 18% of
all deaths (Table 3), they accounted for 15% of excess
Table 2. Baseline Patient Characteristics
No. of Patients (%)
Characteristic Early-StageDisease
Advanced-StageDisease
AllPatients
No. of patients accrued 3651 750 4401
CountryBelgium 378 (10) 131 (17) 509 (12)
France 1749 (48) 233 (31) 1982 (45)
Netherlands 1524 (42) 386 (52) 1910 (43)
Mean age [range], y 33 [15-70] 36 [15-70] 34 [15-70]15-39 2723 (75) 490 (65) 3213 (73)
40-49 531 (14) 118 (16) 649 (15)
50-69 397 (11) 142 (19) 539 (12)
Male/female ratio 1.14 1.84 1.23
Clinical stageI 1171 (32) 2 (<1) 1173 (27)
II 2480 (68) 5 (1) 2485 (56)
III 0 (0) 409 (55) 409 (9)
IV 0 (0) 334 (44) 334 (8)
PY, uncensored data 30,052 4282 34,334
PY, censored data at recurrence* 26,119 3828 29,947
Median FU for uncensored data [range], y 8.1 [0-25] 6.2 [0-15] 7.8 [0-25]
Median FU for censored data at recurrence [range], y* 7.2 [0-25] 5.3 [0-15] 6.9 [0-25]
PY indicates person-years at risk; FU, follow-up
*Censored data were censored at the date of first recurrence.
Original Article
1684 Cancer April 15, 2009
deaths overall (AER, 27.9 vs 182.8) (Table 4). This pro-
portion increased with time from 7% in the period 0 to 4
years after randomization, to 31% in the period 5 to 9
years after randomization, and to 42% in the period 10 to
14 years after randomization. The increase was more pro-
nounced in men than in women, ie, 5%, 33%, and 45%
versus 10%, 24% and 38%, respectively. The SMR
decreased with increasing age: It was 7.5 (95% CL, 5.5-
9.9) in patients ages 15 to 39 years, 3.6 (95% CL, 2.4-
5.1) in patients ages 40 to 49 years, and 2.7 (95% CL,
2.0-3.5) in patients ages 50 to 69 years; whereas the AER
increased with age: It was 15.9 (95% CL, 11.1-21.9) in
patients ages 15 to 39 years, 41.9 (95% CL, 22.3-67.9) in
patients ages 40 to 49 years, and 99.6 (95% CL, 60.3-
147.7) in patients ages 50 to 69 years.
Cardiovascular diseases represented the third most
common cause of death but were not associated with
excess mortality. Infections were responsible for excess
mortality both overall and by sex. However, significant
excess mortality was observed only in the period from 0 to
4 years after randomization.
Among the 15 deaths from infection, 3 deaths
occurred in splenectomized patients (SMR, 9.1; 95% CL,
1.9-26.6), and 12 deaths occurred in nonsplenectomized
patients (SMR, 3.6; 95% CL, 1.8-6.2). Of these 12
deaths, 10 were observed in patients who received �4
cycles of MOPP with or without RT, corresponding to an
SMR of 27.1 (95%CL, 13.0-49.9).
Survival
Overall, the observed 15-year survival estimate was 74.5%
(95% CL, 72.3%-76.6%) compared with an expected
rate of 94.1% and leading to a relative survival estimate of
79.7% (Fig. 2A). For patients with early-stage disease,
these rates were 76.6% (95% CL, 74.4%-78.8%), 94.4%,
and 81.8%, respectively; and for patients with advanced-
stage disease, these rates were 69.3% (95% CL, 65.1%-
73.6%), 95.6%, and 73.8%, respectively.
The impact of age on survival is illustrated in Figure
2B-D. The differences between relative and observed 15-
year survival estimates were 1.8%, 5.9%, and 17.6% in
patients ages 15 to 39 years, 40 to 49 years, and 50 to 69
years, respectively. These differences were 2.2% (83.8%
vs 81.6%) in women and 5.9% (75.9% vs 70%) in men.
In Figure 3, the improvement in treatment efficacyTable
3.DistributionofDeath
sbyTrials
Trial
CauseofDeath
H1
H2
H5
H6
H7
H8
H3B4
H34
AllPatients
No.ofpatients
atrisk
267
264
490
550
710
1370
190
560
4401
Allcauses
14/101*[5/38]
42/71[16/27]
50/106[10/22]
27/67[5/12]
30/83[4/12]
49/110[4/8]
31/71[16/37]
65/116[12/21]
308/725[7/16.5]
Hodgkin
lymphoma
0/75(0/74)
3/27(7/38)
3/31(6/29)
1/35(4/53)
2/40(7/48)
5/55(10/50)
18/51(58/72)
16/52(25/45)
48/366(16/51)
Treatm
ent-relatedtoxicity
0/1
(0/1)
3/3
(7/4)
6/10(12/9)
5/6
(18/9)
2/6
(7/7)
13/17(27/16)
5/8
(16/11)
17/23(26/20)
51/74(16/10)
Secondcancer
2/10(14/10)
11/14(26/20)
16/31(32/29)
7/10(26/15)
12/17(40/21)
17/18(35/16)
4/5
(13/7)
19/25(29/21)
88/130(29/18)
Cardiovasculardiseases
4/6
(29/6)
10/10(24/14)
7/8
(14/8)
5/7
(19/10)
1/1
(3/1)
0/0
(0/0)
0/1
(0/2)
0/0
(0/0)
27/33(9/5)
Infections
0/0
(0/0)
0/1
(0/1)
4/9
(8/9)
0/0
(0/0)
0/0
(0/0)
0/0
(0/0)
3/5
(10/7)
0/0
(0/0)
7/15(2/2)
Othercauses
3/4
(21/4)
7/7
(17/10)
4/5
(8/5)
7/7
(26/10)
6/10(20/12)
11/13(22/12)
1/1
(3/1)
11/14(17/12)
50/61(16/8)
Unknowncauses
5/5
(36/5)
8/9
(19/13)
10/12(20/11)
2/2
(7/3)
7/9
(23/11)
3/7
(6/6)
0/0
(0/0)
2/2
(3/2)
37/46(12/6)
*Deathsin
patients
whowere
censored
atrecurrence/alldeaths.Numbers
insquare
brackets
indicate
theproportionofpatients
thatdied
ofanycausein
agiventrial;numbers
inparenthesesdenote
the
proportionofpatients
thatdiedofagivencauseamongalldeathsforagiventrial.
Survival After Hodgkin Lymphoma/Favier et al
Cancer April 15, 2009 1685
Table
4.Standard
izedMortality
RatioandAbsolute
ExcessRiskbyCausesofDeath
,Tim
eatRisk,andSex(N
¼4401)
AllCausesofDeath
SecondCancer
Infection
Age,y
No.ofPY
atRisk
Obs/Exp
SMR
(95%
CL)
AER
(95%
CL)
Obs/Exp
SMR
(95%
CL)
AER*
(95%
CL)
Obs/Exp
SMR
(95%
CL)
AER
(95%
CL)
Allpatients
0-14
34,334
725/97.3
7.4
(6.9-8.0)
182.8
(167.7-198.8)
130/34.3
3.8
(3.2-4.5)
27.9
(21.7-35)
15/3.7
4(2.3-6.7)
3.3
(1.4-6.1)
0-4
19,531
485/50
9.7
(8.9-10.6)
222.7
(201.1-245.8)
48/17.2
2.8
(2.1-3.7)
15.8
(9.3-23.8)
12/1.9
6.3
(3.3-11.1)
5.2
(2.2-9.8)
5-9
11,325
174/35.1
5(4.2-5.8)
122.6
(100.7-147.2)
55/12.7
4.3
(3.3-5.7)
37.4
(25.4-52)
1/1.4
0.7
(0-4.1)
�0.3
(�1.2-3.7)
10-14
3478
66/12.2
5.4
(4.2-6.9)
154.7
(111.7-206.4)
27/4.4
6.1
(4-8.9)
65(38.5-100.3)
2/0.4
4.5
(0.5-16.1)
4.5
(�0.6-19.5)
Girls 0-14
15,798
236/25.9
9.1
(8-10.4)
133(114.6-153.3)
43/10.6
4.1
(2.9-5.5)
20.5
(13-30)
7/0.9
7.5
(3-15.4)
3.8
(1.2-8.5)
0-4
8908
167/12
13.5
(11.5-15.7)
173.6
(146.2-204.2)
21/5
4.2
(2.6-6.4)
18(9-30.4)
5/0.4
11.1
(3.6-25.8)
5.1
(1.3-12.6)
5-9
5318
43/10.2
4.2
(3.1-5.7)
61.8
(39.4-89.8)
12/4.2
2.9
(1.5-5)
14.7
(3.8-31.5)
1/0.4
2.6
(0.1-14.7)
1.2
(�0.7-9.8)
10-14
1572
26/3.3
7.8
(5.1-11.5)
144.3
(86.9-221.2)
10/1.4
7.2
(3.4-13.2)
54.7
(21.6-108.1)
1/0.1
9.4
(0.2-52.3)
5.7
(�0.5-34.8)
Boys
0-14
18,536
489/71.4
6.8
(6.3-7.5)
225.3
(202.4-249.7)
87/23.7
3.7
(2.9-4.5)
34.2
(24.8-45.1)
8/2.8
2.9
(1.2-5.7)
2.8
(0.4-7)
0-4
10,623
318/37.6
8.4
(7.5-9.4)
263.9
(231.9-298.7)
27/12.2
2.2
(1.5-3.2)
13.9
(5.3-25.5)
7/1.5
4.8
(1.9-10)
5.2
(1.3-12.2)
5-9
6007
131/24.9
5.3
(4.4-6.2)
176.5
(140.8-217.2)
43/8.5
5.1
(3.7-6.8)
57.5
(37.7-82.3)
0/1
0(0-3)
�1.6
(�1.6-3.3)
10-14
1906
40/8.9
4.5
(3.2-6.1)
163.3
(103.3-239.2)
17/3
5.7
(3.3-9.1)
73.4
(36.2-127)
1/0.3
2.9
(0.1-16.3)
3.5
(�1.7-27.4)
PYindicatespatient-years;Obs,observednumberofdeaths,Exp,expectednumberofdeaths;SMR,standardizedmortalityratio;CL,confidencelim
its;AER,absolute
excessrisk.
TheAER
per10,000PY.
Original Article
1686 Cancer April 15, 2009
between trials is illustrated for patients with early-stage
disease (Fig. 3A,B) and patients with advanced-stage dis-
ease (Fig. 3C,D). In patients with early-stage disease, the
differences between relative and observed 10-year survival
estimates were 2.8%, 3.4%, 3.6%, 2%, 3.3%, and 2.6%
FIGURE 2. Expected, relative, and observed survival overall
(A) and by age group (B-D). Data in parentheses correspond
to 15-year survival estimates. The 5-year, 10-year, and 15-year
relative survival estimates were 90%, 85.4%, and 79.7%,
respectively (A).
FIGURE 3. Relative and observed survival by trial in patients
with early-stage disease (A,B) or advanced-stage disease
(C,D). Data in parentheses correspond to 10-year survival
estimates except for trials H8 and H3B4, for which data
(asterisks) correspond to 9-year and 8-year estimates,
respectively.
Survival After Hodgkin Lymphoma/Favier et al
Cancer April 15, 2009 1687
Table
5.Multiple
RegressionModels
ofRelativeSurvivalfo
rRiskFacto
rsofExcessMortality
(AllCausesofDeath
)fo
rPatients
WithEarly-S
tageDisease
Randomizedin
theH6,H7,
orH8Euro
peanOrg
anizationfo
rResearchandTreatm
entofCancer-AdultLymphomaStu
dyGro
up
Trials
(N¼2541)
ModelWithAllTreatm
ent
Classes
FinalModel
Variable
No.of
Patients
atRisk
Median
FU,y
No.of
Deaths
Observed
RER
95%
CL
PRER
95%
CL
P10-y
RS
Estimate,%
Age,y
15-39
1868
7.65
144
1.0
1.0
1.14-2.22
.007
92
40-69
673
7.27
106
1.67
1.20-2.34
.003
1.59
87.7
Sex Women
1222
7.66
88
1.0
1.0
93.6
Men
1319
7.46
162
1.76
1.28-2.41
<.001
1.85
1.35-2.54
<.001
88.6
Prognosticgroup
Favorable
1239
7.74
94
1.0
1.0
93.9
Unfavorable
1302
7.38
156
3.25
2.03-5.19
<.001
2.74
1.90-3.94
<.001
89
Splenectomy
No
2416
7.51
230
1.0
Yes
125
8.52
20
2.2
0.86-5.61
.099
Treatm
ent
IF-R
Tafter
NonalkylatingCT*
309
8.62
47
2.66
1.51-4.70
<.001
1.81
1.23-2.65
.002
85.9
MOPP-A
BV33or34
503
7.03
28
1.0
1.0y
92.2
MOPP-A
BV36
494
7.41
56
1.44
0.82-2.55
.205
Mantle-field
irradiationand
Nochemotherapy
158
8.52
19
2.38
0.84-6.72
.102
2.62
1.40-4.92
.003
89.8
NonalkylatingCT
162
8.28
16
1.35
0.64-2.85
.427
MOPP36
177
8.05
24
1.97
1.02-3.81
.043
(S)TLIafter
Nochemotherapy
470
8.12
33
2.25
1.13-4.50
.021
MOPP-A
BV34
268
6.79
27
1.27
0.64-2.51
.492
FU
indicatesfollo
w-up;RER,relativeexcessrisk;CL,confidencelim
its;RS,relativesurvival;IF-R
T,involved-field
radiotherapy;CT,
chemotherapy;MOPP-A
BV,
combinedmechlorethamine,vincristine,procar-
bazine,andprednisoneplusdoxorubicin,bleomycin,andvinblastine;MOPP,
combinedmechlorethamine,vincristine,procarbazine,andprednisone;(S)TLI,subtotalortotallymphnodeirradiation.
*NonalkylatingCTdenotesCTwithoutalkylatingagents:combineddoxorubicin,bleomycin,vinblastine,anddacarbazine(associatedwithmantle-field
irradiationin
theH6trial);
combinedepirubicin,bleomycin,
vinblastine,andprednisone(associatedwithinvolved-field
irradiationin
theH7trial).
yThereferencetreatm
entcategory
correspondsto
alltreatm
enttypesexceptIF-R
TwithnoalkylatingCTandmantle-field
irradiationalone.
Original Article
1688 Cancer April 15, 2009
for the H1, H2, H5, H6, H7, and H8 trials, respectively.
In patients with advanced-stage disease, the estimates
were 1.1% for the H3B4 trial and 5.6% for the H34 trial.
Risk Factor Analysis in Patients
With Early-Stage Disease
Characteristics that were included in the relative survival
model were age group (ages 15-39 years vs 40-49 years vs
50-69 years), sex, prognosis (unfavorable; no vs yes), and
treatment. Treatment included splenectomy and an 8-
item list of various combinations of chemotherapy and
RT (see Table 5). After backward selection, the age group
40 to 69 years, men, an unfavorable prognosis, and 2
treatment modalities (combined EBVP chemotherapy
plus IF-RT and mantle-field RT alone) were associated
with a significant excess risk of death (P< .01) (see Table
5, Final Model). When censoring the time at risk at first
recurrence to analyze the potential impact of initial treat-
ment on excess mortality, no treatment types were associ-
ated with a significant excess risk.
DISCUSSION
Almost 66% of deaths that occur in the first 2 decades af-
ter treatment for HL are related to disease progression or
early recurrence (51%) or to acute treatment-related tox-
icity (10%), which mainly occurs during the first 5 years
after diagnosis. Other frequent causes of death that occur
later are second cancers, cardiovascular diseases, and infec-
tions; and, of these, only deaths from second cancers and
infections are significantly in excess. The data also indicate
that the AER is higher in men than in women, although
the SMR is systematically lower in men because of higher
background mortality. Excess mortality from infections is
significant only in patients who have undergone splenec-
tomy or who receivedMOPP chemotherapy.
In a series of 1080 patients with early-stage HL
aged �50 years, Ng et al reported an SMR (all
causes) of 6.4 and an AER of 104.2.3 In our series,
the SMR was comparable although slightly higher
(7.4) (Table 4). According to time period, Ng et al
reported SMRs of 9.9, 6.2, and 4.8 in the follow-up
periods at 0 to 4 years, 5 to 9 years, and 10 to 14
years, respectively, which were very similar to our
findings. In contrast, their AERs were much lower
(116.7, 89.3, and 87.3, respectively) compared with
the AERs in our series (222.7, 122.6, and 154.7,
respectively). These differences probably account for
age, because our patients were almost 9 years older.
Aleman et al reported on 1261 patients aged �40
years in all disease stages, including 534 patients who
died.4 In their series, the AER decreased by 5-year
periods from >350 to 150 until Year 15 and then
increased to 330 until Year 30 after diagnosis. In both
series, deaths from HL represented the major cause of
death during the period from 0 to 10 years after diag-
nosis. Among deaths that were not related to HL, sig-
nificant excess risk was observed for second cancers
and cardiovascular diseases, mainly �15 years after di-
agnosis and treatment initiation. In our series, no sig-
nificant excess in deaths from cardiovascular disease
was observed despite chest RT, probably because the
time at risk was limited to 15 years and because our
patients were older.21 Nevertheless, deaths from myo-
cardial infarction can occur in excess even a short
time after treatment initiation, as demonstrated
recently12: In a study of 7033 patients who were
treated between 1979 and 1999, a significant excess
risk of myocardial infarction was observed from the
first year after diagnosis and for 25 years. The SMR
ranged between 1.7 and 4.2, and the AER ranged
between 4.6 and 28.9. The risk associated with supra-
diaphragmatic irradiation is always significant (SMR,
>2.0; P < .01) as well as the risk associated with
anthracyclines alone or in combination with supra-
diaphragmatic irradiation. However, both the SMR
and the AER decreased with increasing calendar year
of first treatment, suggesting that modern therapy is
associated with a lower risk.
In our study, we used the relative survival model
because it estimates net survival (ie, survival corrected for
background mortality). This model avoids the problem of
inaccuracy in death certificates. The 5-year relative sur-
vival estimate (90%) (Fig. 2A) is similar to that published
recently by the French Cancer Registry Network (88%)
and the American Cancer Society (86% for the period
1996-2003),2,22 although lower rates also have been
reported.1,23 The 10-year relative survival estimate
(85.4%) also was higher than the observed survival in the
United States during 2000 to 2004 (80.1%).24 These
studies indicate that no significant improvement has been
Survival After Hodgkin Lymphoma/Favier et al
Cancer April 15, 2009 1689
made in survival rates since the 1980s. With longer fol-
low-up, the British National Lymphoma Investigation
has reported an estimated 15-year relative survival rate of
74.2% for patients with early-stage disease, an estimate
that is lower than ours.25
In our current series, the 10-year expected survival is
almost 97%, leading to a difference between relative and
crude survival estimates ranging from 2% to 3.5% in
patients with early-stage HL and from 1.1% to 5.6% in
patients with advanced-stage HL without heterogeneity
between trials. These limited differences suggest that
deaths unrelated to HL and its treatment do not account
for much in patient life expectancy at least during the 15
years after diagnosis. However, the difference is more pro-
nounced with increasing age (Fig. 2B-D) probably
because comorbidities are present more often in older
patients.25,26
Prognostic analysis applied to relative survival indi-
cates that being a man, age �40 years, unfavorable fea-
tures at diagnosis, and 2 treatment modalities are
associated with a significant (P < .01) excess mortality
from all causes (Table 5). Variables that are used to deter-
mine patient prognosis, including age, were used in the
design of the H6, H7 and H8 trials to predict the risk of
early progression/recurrence. However, the current results
indicate that the same model also may be useful for pre-
dicting excess mortality. We also confirmed in part the
results reported by Roy et al, who used the same model
from British National Lymphoma Investigation data to
demonstrate that being a man and age �25 years (with
risk increasing with increasing age) both are associated
with excess mortality from all causes, like what was
reported by Allemani et al.25,27 Similar results also were
reported by Janssen-Heijnen et al based on cancer registry
data.28 Of the 2 treatment modalities that were associated
with an excess risk of death, 1 concerned the nonstandard
nonalkylating EBVP chemotherapy regimen followed by
IF-RT, which was used in the H7 trial.17 Therefore, in
addition to the excess risk of mortality overall, this treat-
ment was associated with a low survival rate in patients
who had early-stage HL with unfavorable features. In con-
trast, no excess risk of death was associated with the com-
bination of ABVD and IF-RT. The second treatment
modality that was associated with a significant excess mor-
tality was mantle-field irradiation alone. This treatment
led to very low event-free survival in patients who had a
very favorable prognosis29: Now, it has been abandoned
even for these patients. The same model applied to
patients who were continuously disease-free (ie, with time
at risk censored at first recurrence) was unable to identify
a treatment modality that was associated with an increased
risk of death, suggesting that the excess risk of death asso-
ciated with the 2 treatments described above probably was
caused by disease progression or recurrence and its treat-
ment. Finally, no impact of treatment on excess mortality
from second cancer was observed, whereas alkylating
chemotherapy and extensive RT were included in the
treatment administered to these patients. However, most
deaths from second cancers (with the exception of deaths
from leukemia) occur �10 years after treatment,3-5 and
the limited time at risk as well as the limited number of
events probably jeopardize the statistical power of the
analysis.
Despite the high survival rates, even after modern
treatment strategies, long-term complications can be re-
sponsible for excess mortality decades after patients have
been cured of the disease. In patients with early-stage HL,
excess mortality is linked significantly to treatments asso-
ciated with poor treatment failure-free survival. However,
it is probable that not all risk factors of fatal complications
have been brought to light; the possible roles of the host
and HL per se outline the need for prospective studies and
careful long-term follow-up, including a meticulous
search for treatment-related complications. Patients also
should be offered regular screening programs for relevant
second cancers and cardiovascular diseases.
Conflict of Interest Disclosures
Supported by research grants from the Foundation for MedicalResearch.
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