jurnal hodgkin lymphoma

8/11/2019 Jurnal Hodgkin Lymphoma

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original article

T he n e w e n g l a n d j o u r n a l o f medicine

n engl j med 363;7 nejm.org august 12, 2010640

Reduced Treatment Intensity in Patients

with Early-Stage Hodgkins LymphomaAndreas Engert, M.D., Annette Pltschow, Ph.D., Hans Theodor Eich, M.D.,

Andreas Lohri, M.D., Bernd Drken, M.D., Peter Borchmann, M.D.,Bernhard Berger, M.D., Richard Greil, M.D., Kay C. Willborn, M.D.,Martin Wilhelm, M.D., Jrgen Debus, M.D., Michael J. Eble, M.D.,

Martin Skler, M.D., Antony Ho, M.D., Andreas Rank, M.D.,Arnold Ganser, M.D., Lorenz Trmper, M.D., Carsten Bokemeyer, M.D.,

Hartmut Kirchner, M.D., Jrg Schubert, M.D., Zdenek Krl, M.D.,Michael Fuchs, M.D., Hans-Konrad Mller-Hermelink, M.D.,

Rolf-Peter Mller, M.D., and Volker Diehl, M.D.*

The authors affiliations are listed in theappendix. Address reprint requests toDr. Engert at Kerpenerstr. 62, 50937 Kln,Germany, or [email protected].

*Additional investigators in the HD10study are listed in the SupplementaryAppendix, available with the full text ofthis article at NEJM.org.

N Engl J Med 2010;363:640-52.Copyright 2010 Massachusetts Medical Society.

A B S T RA C T

BACKGROUND

Whether it is possible to reduce the intensity of treatment in early (stage I or II)Hodgkins lymphoma with a favorable prognosis remains unclear. We therefore con-ducted a multicenter, randomized trial comparing four treatment groups consistingof a combination chemotherapy regimen of two different intensities followed byinvolved-field radiation therapy at two different dose levels.

METHODS

We randomly assigned 1370 patients with newly diagnosed early-stage Hodgkins lym-phoma with a favorable prognosis to one of four treatment groups: four cycles ofdoxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of

radiation therapy (group 1), four cycles of ABVD followed by 20 Gy of radiationtherapy (group 2), two cycles of ABVD followed by 30 Gy of radiation therapy (group 3),or two cycles of ABVD followed by 20 Gy of radiation therapy (group 4). The primaryend point was freedom from treatment failure; secondary end points included effi-cacy and toxicity of treatment.

RESULTS

The two chemotherapy regimens did not differ significantly with respect to freedomfrom treatment failure (P = 0.39) or overall survival (P = 0.61). At 5 years, the rates offreedom from treatment failure were 93.0% (95% confidence interval [CI], 90.5 to94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with thetwo-cycle regimen. When the effects of 20-Gy and 30-Gy doses of radiation therapy

were compared, there were also no significant differences in freedom from treat-ment failure (P = 1.00) or overall survival (P = 0.61). Adverse events and acute toxiceffects of treatment were most common in the patients who received four cycles ofABVD and 30 Gy of radiation therapy (group 1).

CONCLUSIONS

In patients with early-stage Hodgkins lymphoma and a favorable prognosis, treat-ment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapyis as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of in-volved-field radiation therapy. Long-term effects of these treatments have not yetbeen fully assessed. (Funded by the Deutsche Krebshilfe and the Swiss FederalGovernment; ClinicalTrials.gov number, NCT00265018.)

The New England Journal of Medicine

Downloaded from nejm.org on September 21, 2014. For personal use only. No other uses without permission.

Copyright 2010 Massachusetts Medical Society. All rights reserved.


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Th e n e w e n g l a n d j o u r n a l o f medicine


uted to the interpretation of the results and vouchfor the accuracy and completeness of the data. TheGHSG chair wrote the first draft of the manuscriptand was supported by the lead statistician. Therewas no commercial involvement in this study and

no financial support from industry.

Chemotherapy

ABVD was administered on days 1 and 15 inmonthly cycles, at the following standard doses:doxorubicin, 25 mg per square meter of body-surface area; bleomycin, 10 mg per square meter;vinblastine, 6 mg per square meter; and dacarba-zine, 375 mg per square meter. If the white-cellcount was less than 2500 per cubic millimeter or

the platelet count was less than 80,000 per cubicmillimeter on a day when chemotherapy was sched-uled to be administered, treatment was postponeduntil normal levels were achieved. Granulocytecolony-stimulating factor was given if clinically

indicated.

Radiation therapy

Before treatment, all sites of disease were definedand documented by the treating medical oncolo-gist and radiation oncologist. A central panel ofexperts in radiation oncology then planned in-volved-field radiation therapy as defined in thestudy protocol according to treatment group and,if necessary, revised the initial staging. The rec-

1370 Patients underwent randomization

346 Were assignedto group 1

(4ABVD + 30 Gy IFRT)

180 Were excluded30 Did not have histologic

features of Hodgkinslymphoma

133 Had wrong initial staging16 Did not meet other inclusion

criteria1 Withdrew before start of

therapy

298 in group 1 wereincluded in analysis






596 in groups 1 and 2 were included inanalysis for CT comparison (4ABVD)

575 in groups 1 and 3 were included inanalysis for RT comparison (30 Gy)

594 in groups 3 and 4 were included inanalysis for CT comparison (2ABVD)

588 in groups 2 and 4 were included inanalysis for RT comparison (20 Gy)



343 Were assigned togroup 4


1190 Were included in analysis for 4-group comparison

1190 Were included in analysis for ABVD comparison

27 Withdrew before RT12 Were in group 16 Were in group 26 Were in group 33 Were in group 4

1163 Were included in analysis for IFRT comparison

Figure 1.Numbers of Patients Randomly Assigned to Treatment Groups and Included in Analyses.

ABVD denotes doxorubicin, bleomycin, vinblastine, and dacarbazine, and IFRT involved-field radiation therapy.





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Treatment intensity in ear ly-stage Hodgkins Lymphoma

n engl j med 363;7 nejm.org august 12, 2010 643

Table1.

BaselineCharacteristicsofthePatientsAccordingtoTreatmentGr

oup.*

Characteristic

T

reatmentGroup

ChemotherapyComparison

Radiatio

nTherapyComparison

AllPatients

(N=1190)

Group1:

4ABVD

+30GyIFRT

(N=298)

Group2:

4AB

VD

+20Gy

IFRT

(N=2

98)

Group3:

2ABVD

+30GyIFRT

(N=295)

Group4:

2ABVD

+20GyIFRT

(N=299)

Groups

1and2

(N=596)

Groups

3and4

(N=594)

Gro

ups

1and3

(N=

575)

Groups

2and4

(N=588)

Agey

r

38.814.3

39.514.2

38.6

14.5

38.314.3

38.714.4

39.014.3

38.514.3

38.613.9

38.614.4

Femalesexn

o.(

%)

465(39.1)

116(38.9)

121(4

0.6)

106(35.9)

122(40.8)

236(39.6

)

228(38.4

)

215(37.4

)

239(40.6

)

AnnArborstagen

o.(

%)

IA

361(30.3)

94(31.5)

92(3

0.9)

99(33.6)

76(25.4)

186(31.2

)

175(29.5

)

188(32.7)

166(28.2

)

IB

24(2.0

)

5(1.7

)

6(2

.0)

7(2.4

)

6(2.0

)

11(1.8

)

13(2.2

)

12(2.1

)

12(2.0

)

IIA

738(62.0)

182(61.1)

184(6

1.7)

175(59.3)

197(65.9)

366(61.4

)

372(62.6

)

346(60.2

)

375(63.8

)

IIB

66(5.5

)

17(5.7

)

15(5

.0)

14(4.7

)

20(6.7

)

32(5.4

)

34(5.7

)

29(5.0

)

35(6.0

)

Infradiaphragmaticdisease

n

o.(

%)

97(8.2

)

25(8.4

)

26(8

.7)

21(7.1

)

25(8.4

)

50(8.4

)

46(7.7

)

44(7.7

)

49(8.3

)

HistologictypeofHodgkins

lymphomano.o

f

patients/totalno.(

%)

Nodularlymphocyte-

predominant

81/1080(7.5

)

20/273(7.3

)

17/263

(6.5

)

24/272(8.8

)

20/272(7.4)

37/535(6.9

)

44/544(8.1

)

43/528

(8.1

)

35/526(6.7

)

Lymphocyte-richclassic

98/1080(9.1

)

23/273(8.4

)

19/263

(7.2

)

35/272(12.9)

21/272(7.7)

42/535(7.9

)

56/544(10.3

)

58/528

(11.0)

40/526(7.6

)

Nodularsclerosing

420/1080(38.9)

101/273(37.0)

112/263

(42.6)

98/272(36.0)

109/272(40.1)213/535(39.8)207/544(38.1

)197/528

(37.3

)

219/526(41.6)

Mixedcellularity

435/1080(40.3)

118/273(43.2)

103/263

(39.2)

99/272(36.4)

115/272(42.3)220/535(41.1)214/544(39.3

)206/528

(39.0)

213/526(40.5)

Lymphocyte-depleted

1/1080(0.1

)

0

0

1/272(0.4

)

0

0

1/544(0.2

)

1/528

(0.2

)

0

Notclassified

45/1080(4.2

)

11/273(4.0

)

12/263

(4.6

)

15/272(5.5

)

7/272(2.6)

23/535(4.3

)

22/544(4.0

)

23/528

(4.4

)

19/526(3.6

)

*PlusminussignsaremeansS

D.

ABVDdenotesdoxorubicin,

bleomycin,vinblastine,anddacarbazine,andIFRTinvolved-fieldradiationtherapy.

Thesegroupsincludealleligiblepatients.

Informationonstageofdisease

wasmissingfor1patientingroup2.

Informationonhistologicsubtypewasavailablefor1080patients(90.7%).





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Table2.

AdverseEventsAccordingtoTreatmentGroup.

Event

TreatmentGrou

p*

Chem

otherapyComparison

RadiationTherapyComparison

Group1:

4ABVD

+30GyIFRT

(N=298)

Group2:

4ABVD

+20GyIFRT

(N=298)

G

roup3:

2ABVD

+30GyIFRT

(N

=295)

Group4:

2ABVD

+20GyIFRT

(N=299)

Groups1and2

(N=5

96)

Groups3and4

(N=594)

Groups1and3

(N=575)

Groups2and4

(N=588)

numberofpatients(p

ercent)

no.ofpatients/totalno.(%)

Acutetoxicity(gradeIIIorIV)

Atleastoneevent

304/588

(51.7)

194/585(33.2

)

46/528

(8.7

)

16/553(2.9

)

Anemia

7/588

(1.2

)

1/585(0.2

)

0

0

Thrombopenia

3/588

(0.5

)

0

0

0

Leukopenia

138/588

(23.5)

87/585(14.9

)

0

0

Nauseaorvomiting

79/588

(13.4)

51/585(8.7

)

3/528

(0.6

)

6/553(1.1

)

Mucositis

7/588

(1.2

)

2/585(0.3

)

18/528

(3.4

)

4/553(0.7

)

Gastrointestinaltractdis-

orderordysphagia

11/588

(1.9

)

6/585(1.0

)

30/528

(5.7

)

16/553(2.9

)

Respiratorytractdisorder

12/588

(2.0

)

2/585(0.3

)

2/528

(0.4

)

0

Hairloss

165/588

(28.1)

89/585(15.2

)

6/528

(1.1

)

3/553(0.5

)

Infection

30/588

(5.1

)

10/585(1.7

)

1/528

(0.2

)

0

Pain

9/588

(1.5

)

14/585(2.4

)

3/528

(0.6

)

1/553(0.2

)

Nervoussystemdisorder

12/588

(2.0

)

7/585(1.2

)

2/528

(0.4

)

0

Secondaryneoplasia

Total

17(5.7

)

10(3.4

)

1

4(4.7

)

14(4.7

)

27

(4.5

)

28(4.7

)

31

(5.4

)

24(4.1

)

Acutemyelocyticleuke-

miaormyelodysplastic

syndrome

2(0.7

)

0

0

0

2

(0.3

)

0

2

(0.3

)

0

NonHodgkinslym-

phoma

4(1.3

)

3(1.0

)

3(1.0

)

5(1.7

)

7

(1.2

)

8(1.3

)

7

(1.2

)

8(1.4

)

Solidtumor

11(3.7

)

7(2.3

)

1

1(3.7

)

9(3.0

)

18

(3.0

)

20(3.4

)

22

(3.8

)

16(2.7

)





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ommended interval between completion of the ABVDregimen and the start of radiation therapy was 4 to6 weeks. Patients received either 30 Gy or 20 Gy ofinvolved-field radiation therapy in single fractionsof 1.8 to 2.0 Gy administered five times weekly.

Study End Points

The primary eff icacy end point was freedom fromtreatment failure. Overall survival, progression-freesurvival, complete response, and treatment toxicitywere secondary end points. Definitions of the studyend points are provided in the Supplementary Ap-pendix.

Statistical Analysis

Proof of the noninferiority of the less intensive treat-ment, as compared with the standard treatment offour cycles of ABVD plus 30 Gy of involved-fieldradiation therapy, with respect to freedom from

treatment failure at 5 years was the goal for bothchemotherapy and radiation therapy. The noninfe-riority margin was defined as 7% in the study pro-tocol. This led to the following two hypotheses: forchemotherapy, the 5-year rate of freedom from treat-ment failure in the two pooled groups assigned totwo cycles of ABVD would be less than 7% belowthe rate in the two pooled groups assigned to fourcycles, and for radiation therapy, the 5-year rate offreedom from treatment failure in the two pooledgroups assigned to 20 Gy of involved-field radiationtherapy would be less than 7% below the rate in thetwo pooled groups assigned to 30 Gy.

Survival rates for the four groups were comparedwith the use of the KaplanMeier method as well asstratif ied Cox regression analyses for hazard ratios(i.e., the chemotherapy comparison was stratifiedaccording to the radiation therapy assignment andvice versa), whereas outcomes and toxicity rates werecompared with the use of Fishers exact test. Testsof the hypotheses were performed according to theintention-to-treat principle and also on the basis ofthe treatment actually received. Subgroup analyses

were not prespecified in the statistical-analysisplan, but we performed post hoc sensitivity analy-ses that excluded patients with nodular lympho-cyte-predominant Hodgkins lymphoma. The resultsof these sensitivity analyses are presented in theSupplementary Appendix.

In addition, to estimate the combined effect ofreduced chemotherapy and reduced radiation ther-apy, we compared group 1, which received the mostintensive therapy, with group 4, which received the

Death

Totalno.o

fdeaths

15(5.0

)

13(4.4

)

1

6(5.4

)

13(4.3

)

28(4

.7)

29(4.9

)

25(4.3)

22(3.7

)

Causeofdeath

Hodgkinslymphoma

3(1.0

)

2(0.7

)

3(1.0

)

2(0.7

)

5(0

.8)

5(0.8

)

5(0.9)

3(0.5

)

Toxicityofprimary

therapy

3(1.0

)

3(1.0

)

1(0.3

)

0

6(1

.0)

1(0.2

)

1(0.2)

0

Toxicityofsalvage

therapy

0

0

4(1.4

)

1(0.3

)

0

5(0.8

)

3(0.5)

0

Secondaryneoplasia

3(1.0

)

0

5(1.7

)

3(1.0

)

3(0

.5)

8(1.3

)

8(1.4)

3(0.5

)

Cardiovasculardis-

order

3(1.0

)

3(1.0

)

0

3(1.0

)

6(1

.0)

3(0.5

)

3(0.5)

6(1.0

)

*Thesegroupsincludealleligiblepatients.

Informationonthetoxicityofprimarychemotherapy(WorldHealthOrgan

izationgradeIIIorIV)wasavailablefor11

73of1190patients(98.6

%).Informationonthetoxicityofprimary

involved-fieldradiationtherapy

(IFRT)(CommonToxicityCriteriagradeIII

orIV)wasavailablefor1081of1163patie

nts(92.9%).

Atotalof57of1190patientsdied(4.8

%),and55of1190patientshadas

econdaryneoplasm(4.6

%).Medianobservationtimeswere91monthsforoverallsu

rvivaland79monthsfor

freedomfromtreatmentfailure

andprogression-freesurvival;884patients

(74.3%)werefollowedforatleast5years

aftertheendoftherapy.

Causesoftreatment-relateddea

thswerepulmonaryfibrosis,probablybleo

mycin-induced(intwopatientsassignedt

ofourcyclesofABVDandoneassignedto

twocycles);sepsis(in

twopatientsassignedtofourcyclesofABVD);pneumonia(inonepatient

assignedtofourcyclesofABVD);andnot

specified(inonepatientassignedtofour

cyclesofABVD).





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least intensive therapy. To detect a possible in-fluence of prognostic factors or interactions be-tween the effects of chemotherapy and those ofradiation therapy, multivariate Cox regressionanalyses were specified in the protocol and per-formed as sensitivity analyses on the same datasets for comparing the two chemotherapy regi-

mens and the two radiation therapy regimens.

Results

Patients

From May 1998 through January 2003, a total of1370 patients were recruited and randomly as-signed to treatment centrally. A total of 180 pa-tients were excluded from all analyses: 30 becausethe reference histologic findings did not confirmHodgkins lymphoma, 133 because of incorrectinitial staging, 16 because they did not meet oth-

er inclusion criteria, and 1 who met the inclusioncriteria but could not subsequently be contacted(Fig. 1).

The baseline characteristics of the study pa-tients are shown in Table 1. No significant dif-ferences were noted among the treatment groupsfor any of the characteristics shown. The medianage of patients at randomization was 36 years(range, 16 to 75), and 61.0% were male; 30.3%had stage IA disease, 2.0% had stage IB, 62.0%had stage IIA, and 5.5% had stage IIB. (Informa-tion on stage of disease was missing for one pa-tient in group 2.) The most frequent subtypediagnosed by the pathology reference panel wasmixed cellularity (40.2%), and 8.1% of patientshad infradiaphragmatic disease.

The main (intention-to-treat) analysis set forthe initial chemotherapy comparison (CT1) com-prised 1190 patients: 596 patients were randomlyassigned to four cycles of ABVD and 594 to twocycles. Of these patients, 36 changed chemother-apy group or had major protocol violations; che-motherapy was not documented for 10 patients.

The per-protocol analysis set for the chemothera-py comparison (CT2) therefore comprised 1144patients (571 randomly assigned to four cycles ofABVD and 573 to two cycles). The main (inten-tion-to-treat) analysis set for the radiation ther-apy comparison (RT1) included 1163 patients:575 patients were randomly assigned to 30 Gy ofinvolved-field radiation therapy and 588 to 20 Gyof involved-field radiation therapy. Of these pa-

tients, 33 had a change in the radiation therapydose or had major protocol violations; radiationtherapy documentation was missing for 17 pa-tients. The per-protocol analysis set for the radia-tion therapy comparison included 1113 patients(557 in the 30-Gy groups and 556 in the 20-Gygroups). There were more protocol violations

and group changes in the groups that received20 Gy of involved-field radiation therapy than inthose that received 30 Gy (P = 0.05). However,since the per protocol analysis and the intention-to-treat analysis had similar results, these im-balances did not affect the f inal conclusions.

Adverse Events

Toxicity of Treatment

Acute toxicity during chemotherapy was more fre-quent in patients who received four cycles ofABVD than in those who received two cycles (Ta-

ble 2). Overall, 51.7% of the patients who receivedfour cycles of ABVD had at least one instance ofsevere toxicity (grade III or IV) as compared with33.2% of those who received two cycles (P


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Deaths

A total of 57 patients (4.8%) died during the fol-low-up period. The most frequent causes of deathwere secondary neoplasia (in 11), Hodgkins lym-phoma (in 10), cardiovascular events (in 9), toxic-ity of primary therapy (in 7), and toxicity of sal-vage therapy (in 5, all after having received two

cycles of ABVD). No difference in mortality wasnoted among the four groups or between the com-bined chemotherapy groups and the combinedradiation therapy groups (Table 2).

Disease Control and Survival

Final treatment outcomes were as follows: 1150of 1190 patients (96.6%) had a complete remission,8 (0.7%) had a partial remission, and 8 (0.7%) didnot have a response (2 had no change and 6 hadprogression of disease during treatment). (Re-sponse criteria are described in the Supplemen-

tary Appendix.) For 24 patients (2.0%), the treat-ment outcome was unclear. The relapse rate was6.0% (71 of 1190 patients). No significant differ-ences were seen in rates of remission, progres-sion, or relapse among the four treatment groupsor between the combined chemotherapy groupsand the combined radiation therapy groups.

The rates of freedom from treatment failure inthe whole intention-to-treat analysis set of 1190patients were estimated to be 92.0% (95% confi-dence interval [CI], 90.2 to 93.5) at 5 years and87.1% (95% CI, 84.5 to 89.3) at 8 years. The over-all survival rates for all 1190 patients were esti-mated to be 96.8% (95% CI, 95.7 to 97.7) at 5 yearsand 94.5% (95% CI, 92.8 to 95.8) at 8 years(Table 3). For the same patients, the rate of pro-gression-free survival was estimated to be 92.4%(95% CI, 90.6 to 93.8) at 5 years and 87.6% (95%CI, 85.0 to 89.7) at 8 years.

Chemotherapy Comparison

In the intention-to-treat analysis, the median ob-servation time for the primary end point, freedom

from treatment failure, was identical in the twochemotherapy groups (79 months). The rate of free-dom from treatment failure at 5 years was 93.0%with four cycles of ABVD (95% CI, 90.5 to 94.8)and 91.1% with two cycles (95% CI, 88.3 to 93.2)(Table 3). On the basis of the stratified Cox re-gression analysis, the hazard ratio for treatmentfailure with two cycles of ABVD as comparedwith four cycles was 1.17 (95% CI, 0.82 to 1.67).The 5-year estimated group difference (two cy-cles vs. four cycles) was 1.9 percentage points

(95% CI, 5.2 to 1.4). The sensitivity analysis,based on treatment received per protocol, showeda 5-year estimated group difference of 2.3 per-centage points (95% CI, 5.6 to 2.9). On the basisof these results, the predefined 7% inferiority oftwo cycles of ABVD plus radiation therapy can beexcluded for the primary end point, freedomfrom treatment failure. The intention-to-treatanalysis showed no significant differences be-tween the two chemotherapy groups for the sec-ondary end points of overall survival (P = 0.93;hazard ratio for death, 1.02 [95% CI, 0.61 to

1.72]) and progression-free survival (P = 0.28;hazard ratio for progression, relapse, or deathfrom any cause, 1.22 [95% CI, 0.85 to 1.77]).

Radiation therapy Comparison

In the intention-to-treat analysis of radiation ther-apy, the median observation time for the primaryend point, freedom from treatment failure, wassimilar in the two groups: 77 months with 20 Gyand 80 months with 30 Gy. The rate of freedomfrom treatment failure at 5 years was 93.4% (95%

Figure 2 (facing page).Freedom from Treatment Failureand Overall Survival.

Two pooled treatment groups were compared with re-spect to chemotherapy regimens (groups 1 and 2 vs.

groups 3 and 4) (Panel A) and radiation therapy doses

(groups 1 and 3 vs. groups 2 and 4) (Panel B). Groups1 and 4 were also compared (Panel C). Group differ-

ences with respect to freedom from treatment failureand overall survival at 5 years were estimated on the

basis of KaplanMeier analyses, and hazard ratios werecalculated with the use of Cox regression analysis (i.e.,

the comparison of the chemotherapy groups was strati-fied according to radiation therapy group, and vice ver-

sa). (For definitions of study end points, see the Sup-plementary Appendix, available with the full text of this

article at NEJM.org.) Data for all patients were analyzedon the basis of the randomly assigned treatment

groups (intention-to-treat principle). Data for overall

survival were censored on the date when the informa-tion was last obtained; when the information lag ex-

ceeded 2 years, data on survival were obtained fromregistries, whenever possible. The median observation

period for freedom from treatment failure was 79months and that for overall survival was 91 months.

The main analysis for the chemotherapy comparisonincluded 1190 eligible patients who received at least

1 dose of the assigned study treatment. According tothe protocol, 27 patients whose disease progressed or

whose chemotherapy was discontinued before the start

of radiation therapy were excluded from the main analy-sis for the radiation therapy comparison. (For methods

and results of the sensitivity analyses, see the Supple-mentary Appendix.)





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CI, 91.0 to 95.2) in the 30-Gy group and 92.9%(95% CI, 90.4 to 94.8) in the 20-Gy group (Table 3).The hazard ratio for treatment failure with 20 Gy

as compared with 30 Gy was 1.00 (95% CI, 0.68 to1.47). The 5-year estimated group difference (20 Gyvs. 30 Gy) was 0.5 percentage points (95% CI,

FreedomfromT

reatment

Failure(%)

100

80

90

70

60

4030

10

50

20

00 12 24 36 48 120

Months

B Radiation Therapy Comparison

A Chemotherapy Comparison

No. ofPatientsat Risk

4ABVD2ABVD

596594

554555

532530

506498

479473

60

430410

72

330314

84

226225

96

131131

108

5754

69

OverallSurvival(%)

100

80

90

70

60

4030

10

50

20

00 12 24 36 48 120

MonthsNo. of

Patientsat Risk

4ABVD2ABVD

596594

583589

575578

569572

562567

60

541549

72

471482

84

348361

96

227239

108

130126

2436

Difference at 5 yr, 1.9 percentage points (95% CI, 5.2 to 1.4)Hazard ratio, 1.17 (95% CI, 0.82 to 1.67)


Freedomf

romT

reatment

Failure(%)

100

8090

70

60

40

30

10

50

20

00 12 24 36 48 120

MonthsNo. of

Patientsat Risk

30 Gy IFRT20 Gy IFRT 575588 553550 526531 499502 471478

60

426411

72

328314

84

235215

96

139123

108

6150 87

OverallSurvival(%)

100

8090

70

60

40

30

10

50

20

00 12 24 36 48 120

MonthsNo. of

Patientsat Risk

30 Gy IFRT20 Gy IFRT 575588 570583 561575 556568 552560

60

535539

72

469468

84

352346

96

228232

108

125131 3228



C Comparison of Groups 1 and 4

Freedomf

romT

reatment

Failure(%)

100

80

90

70

60

40

30

10

50

20

0 0 12 24 36 48 120

MonthsNo. of

Patientsat Risk

Group 1Group 4

298299

277275

264265

255252

239239

60

217199

72

167151

84

121110

96

7466

108

3528

34

OverallSurvival(%)

100

80

90

70

60

40

30

10

50

20

0 0 12 24 36 48 120

MonthsNo. of

Patientsat Risk

Group 1Group 4

298299

293298

289293

286289

283285

60

271273

72

240241

84

182182

96

116122

108

6364

1216

Difference at 5 yr, 1.6 percentage points (95% CI, 6.3 to 3.1)Hazard ratio, 1.07 (95% CI, 0.65 to 1. 77)

Difference at 5 yr, 0.4 percentage points (95% CI, 3.4 to 2.7)Hazard ratio, 0.85 (95% CI, 0.41 to 1. 79)

4ABVD (groups 1 and 2)


30 Gy IFRT (groups 1 and 3)






Group 1

Group 4

Group 1

Group 4





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3.6 to 2.6). The sensitivity analysis based on ther-apy received showed a 5-year estimated group dif-ference of 0.2 percentage points (95% CI, 3.3 to2.8). Thus, the predefined 7% inferiority of che-motherapy plus 20 Gy of radiation therapy can beexcluded for the primary end point (freedom fromtreatment failure). The intention-to-treat analysis

showed no significant differences between theradiation therapy groups for the secondary endpoints of overall survival (P = 0.61; hazard ratiofor death, 0.86 [95% CI, 0.49 to 1.53]) and pro-gression-free survival (P = 0.98; hazard ratio forprogression, relapse, or death from any cause, 1.01[95% CI, 0.68 to 1.48]). Overall, the rates of free-dom from treatment failure might appear to behigher than those in a pure intention-to-treatanalysis, since patients who dropped out beforeradiation therapy were excluded from this analy-sis. However, this was unlikely to affect between-

group comparisons.

Prespecified Regression Analyses

Prespecified factors included in the multivariatemodel were age above 50 years (P


12/13



follow-up is needed to identify differences in long-term toxicity, such as secondary neoplasia andsevere organ damage, among different treatmentapproaches. Given that many of the late, fatal com-plications of radiation therapy do not emerge untilthe second decade after treatment, our data can-not speak to the effect of treatment on overall

survival.Since radiation therapy is associated with the

development of secondary solid tumors 5 to 25years after initial treatment,4-8some groups ad-vocate the use of chemotherapy alone for patientswith early-stage Hodgkins lymphoma. Usually, sixcycles of ABVD are given, and there has been somecontroversy on this issue.15-19For this group ofpatients, combined-approach treatment programshave provided superior tumor control when com-pared directly with chemotherapy alone in somestudies20-24but not in others.15,19Currently, com-

bined-approach treatment programs are widelyused as the treatment of choice in early-stageHodgkins lymphoma, and our study suggests thata shorter chemotherapy regimen with a lowerradiation dose preserves a high level of diseasecontrol. With an overall survival rate of 95.1% at8 years, some patients may still be overtreated.

However, the established clinical risk factors,which are based on measures such as the Inter-national Prognostic Score,25currently do not allowidentification of patients who can be cured witheven less treatment. The use of positron-emission

tomography (PET) might help to discriminate be-tween patients at low risk and those at high risk,both early in the course of chemotherapy26andafter its completion.27The potential effect of PETin patients with Hodgkins lymphoma has alsobeen suggested in a number of retrospective, non-randomized studies.28-30Several ongoing trials

are evaluating the role of PET in identifying pa-tients with early Hodgkins lymphoma and a fa-vorable prognosis who might not need additionalradiation therapy after two cycles of ABVD (theGerman Hodgkin Study Group Hodgkin Disease16 [the current GHSG HD16] trial [ClinicalTrials.gov number, NCT00736320]) or after three cy-cles of ABVD (the European Organization for Re-search and Treatment of Cancer [EORTC H10F]trial [ClinicalTrials.gov number, NCT00433433]and others).

In summary, the HD10 trial showed that in

patients with early-stage Hodgkins lymphoma anda favorable prognosis, treatment with two cyclesof ABVD followed by 20 Gy of involved-field ra-diation therapy is as effective as, and less toxicthan, four cycles of ABVD followed by 30 Gy ofinvolved-field radiation therapy.

Supported by grants from the Deutsche Krebshilfe and theSwiss Federal Government.

Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.

We thank Hiltrud Nisters-Backes, Bettina Koch, HannoloreOssadnik, Dagmar Bhmer, Thomas Schober, and Marina Schu-macher for their technical support and Dr. Joachim Yahalom forhis critical review of the draft manuscript.

appendix

The authors affiliations are as follows: the Department of Internal Medicine (A.E., P.B.), the German Hodgkin Study Group, Departmentof Internal Medicine I (A.E., A.P., P.B., M.F., V.D.), and the Department of Radiation Oncology (H.T.E., R.-P.M.), University of Cologne,Cologne; the Department of Hematology and Oncology, Charit-Universittsmedizin Berlin, Berlin (B.D.); the Departments of RadiationOncology (B.B.) and Internal Medicine II (M.S.), University of Tbingen, Tbingen; Pius-Hospital Oldenburg, Klinik fr Strahlenthera-pie und internistische Onkologie, Oldenburg (K.C.W.); Klinikum Nrnberg Nord, Medizinische Klinik 5, Schwerpunkt HmatologieOnkologie, Nrnberg (M.W.); the Departments of Radiation Oncology (J.D.) and Internal Medicine V (A.H.), University of Heidelberg,Heidelberg; the Department of Radiotherapy, Rheinisch-Westflische Technische Hochschule Aachen, Aachen (M.J.E.); Ludwig-Maxi-milians University, University Hospital Grosshadern, Department of Internal Medicine III, Munich (A.R.); the Department of Hematol-ogy, Hemostasis, Oncology, and Stem-Cell Transplantation, Hannover Medical School, Hannover (A.G.); the Department of Hematol-ogy and Oncology, Georg-August University Gttingen, Gttingen (L.T.); the Department of Oncology, Hematology, and Bone MarrowTransplantation, University Medical Center Hamburg, Hamburg (C.B.); the Department of HematologyOncology, Siloah Clinic, Han-nover (H.K.); Evangelische Krankenhaus Hamm, Medizinische Klinik, Abteilung fr Hmato-Onkologie, Hamm (J.S.); and the Institute

of Pathology, University of Wrzburg, Wrzburg (H.-K.M.-H.) all in Germany; Swiss Group for Clinical Cancer Research, Bern,Switzerland (A.L.); Medical Department III, University of Salzburg, Salzburg, Austria (R.G.); and the Department of Internal MedicineHematooncology, University Hospital and Faculty of Medicine of Masaryk University, Brno, Czech Republic (Z.K.).

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