Survival after Hodgkin lymphoma

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; [email protected]

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


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).



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


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.



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


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.



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


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



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.

References

1. Verdecchia A, Francisci S, Brenner H, et al. Recent cancersurvival in Europe: a 2000-02 period analysis of EURO-CARE-4 data. Lancet Oncol. 2007;8:784-796.

2. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008.CA Cancer J Clin. 2008;58:71-96.

3. Ng AK, Bernardo MP, Weller E, et al. Long-term survivaland competing causes of death in patients with early-stageHodgkin’s disease treated at age 50 or younger. J ClinOncol. 2002;20:2101-2108.

Original Article


4. Aleman BM, van den Belt-Dusebout AW, Klokman WJ,et al. Long-term cause-specific mortality of patients treatedfor Hodgkin’s disease. J Clin Oncol. 2003;21:3431-3439.

5. Van Leeuwen FE, Swerdlow AJ, Travis LB. Second cancersafter treatment of Hodgkin lymphoma. In: Hoppe RT,Mauch PT, Armitage JO, Diehl V, Weiss LM, eds. Hodg-kin Lymphoma, 2nd ed. Philadelphia, Pa: Lippincott Wil-liams & Wilkins; 2007:347-370.

6. Hill DA, Gilbert E, Dores GM, et al. Breast cancer riskfollowing radiotherapy for Hodgkin lymphoma: modifica-tion by other risk factors. Blood. 2005;106:3358-3365.

7. Franklin J, Pluetschow A, Paus M, et al. Second malig-nancy risk associated with treatment of Hodgkin’s lym-phoma: meta-analysis of the randomised trials. Ann Oncol.2006;17:1749-1760.

8. Henry-Amar M, Hayat M, Meerwaldt JH, et al. Causes ofdeath after therapy for early stage Hodgkin’s disease enteredon EORTC protocols. EORTC Lymphoma CooperativeGroup. Int J Radiat Oncol Biol Phys. 1990;19:1155-1157.

9. Hodgson DC, Gilbert ES, Dores GM, et al. Long-termsolid cancer risk among 5-year survivors of Hodgkin’s lym-phoma. J Clin Oncol. 2007;25:1489-1497.

10. Hancock SL, Tucker MA, Hoppe RT. Factors affecting latemortality from heart disease after treatment of Hodgkin’sdisease. JAMA. 1993;270:1949-1955.

11. Aleman BM, van den Belt-Dusebout AW, De Bruin ML,et al. Late cardiotoxicity after treatment for Hodgkin lym-phoma. Blood. 2007;109:1878-1886.

12. Swerdlow AJ, Higgins CD, Smith P, et al. Myocardial in-farction mortality risk after treatment for Hodgkin disease:a collaborative British cohort study. J Natl Cancer Inst.2007;99:206-214.

13. Henry-Amar M, Somers R. Survival outcome after Hodg-kin’s disease: a report from the international data base onHodgkin’s disease. Semin Oncol. 1990;17:758-768.

14. Ferme C, Eghbali H, Meerwaldt JH, et al. Treatment ofearly stages Hodgkin lymphoma: the EORTC-GELA H8trials. N Engl J Med. 2007;357:1916-1927.

15. Aleman BM, Raemaekers JM, Tirelli U, et al. Involved-field radiotherapy for advanced Hodgkin’s lymphoma. NEngl J Med. 2003;348:2396-2406.

16. Raemaekers J, Kluin-Nelemans H, Teodorovic I, et al. Theachievements of the EORTC Lymphoma Group. Eur JCancer. 2002;38(suppl 4):S107-S113.

17. Noordijk EM, Carde P, Dupouy N, et al. Combined-mo-dality therapy for clinical stage I or II Hodgkin’s lym-phoma: long-term results of the European Organisation forResearch and Treatment of Cancer H7 randomized con-trolled trials. J Clin Oncol. 2006;24:3128-3135.

18. World Health Organizatoin. WHO Statistical InformationSystem (WHOSIS), 17 November 2006 update. Availableat: http://www.who.int/whosis/mort/download/en/index.html.Accessed January 10, 2007.

19. World Health Organization. International Statistical Classi-fication of Diseases and Health Related Problems. (The)ICD-10, 2nd ed. Geneva, Switzerland: World Health Orga-nization; 2005.

20. Dickman PW, Sloggett A, Hills M, et al. Regression mod-els for relative survival. Stat Med. 2004;23:51-64.

21. Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascularstatus in long-term survivors of Hodgkin’s disease treatedwith chest radiotherapy. J Clin Oncol. 2004;22:3139-3148.

22. Bossard N, Velten M, Remontet L, et al. Survival of cancerpatients in France: a population-based study from the Asso-ciation of the French Cancer Registries (FRANCIM). Eur JCancer. 2007;43:149-160.

23. Yu XQ, O’Connell DL, Gibberd RW, et al. Trends in sur-vival and excess risk of death after diagnosis of cancer in1980-1996 in New South Wales, Australia. Int J Cancer.2006;119:894-900.

24. Brenner H, Gondos A, Pulte D. Ongoing improvement inlong-term survival of patients with Hodgkin disease at allages and recent catch-up of older patients. Blood.2008;111:2977-2983.

25. Roy P, Vaughan HG, Vaughan HB, et al. Long-term sur-vival in Hodgkin’s disease patients. A comparison of rela-tive survival in patients in trials and those recorded inpopulation-based cancer registries. Eur J Cancer. 2000;36:384-389.

26. van Spronsen DJ, Janssen-Heijnen MLG, Lemmens VEPP,et al. Independent prognostic effect of co-morbidity in lym-phoma patients: results of the population-based EindhovenCancer Registry. Eur J Cancer. 2005;41:1051-1057.

27. Allemani C, Sant M, De Angelis R, Marcos-Gragera R,Coebergh JW, and the EUROCARE Working Group.Hodgkin disease survival in Europe and the US. Prognosticsignificance of morphologic groups. Cancer. 2006;107:352-360.

28. Janssen-Heijnen MLG, Houterman S, Lemmens VEPP,Brenner H, Steyerberg EW, Coebergh JWW. Prognosis forlong-term survivors of cancer. Ann Oncol. 2007;18:1408-1413.

29. Noordijk E, Carde P, Hagenbeek A, et al. Combination ofradiotherapy and chemotherapy is advisable in all patientswith clinical stage I-II Hodgkin’s disease. Six-year results ofthe EORTC-GPMC controlled clinical trials H7-VF, H7-Fand H7-U [abstract]. Int J Radiat Oncol Biol Phys. 1997;39(suppl 2):173.



Survival after Hodgkin lymphoma

Documents

Transcript of Survival after Hodgkin lymphoma