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ACR Appropriateness Criteria® onHodgkin’s Lymphoma-Unfavorable

Clinical Stage I and IIPrajnan Das, MD, MPHa, Andrea Ng, MDb, Louis S. Constine, MDc,

Ranjana Advani, MDd,e, Christopher Flowers, MD, MSe,f, Jonathan Friedberg, MDg,h,David C. Hodgson, MDi, Cindy L. Schwartz, MDe,j, Richard B. Wilder, MDk,

Lynn D. Wilson, MD, MPHl, Michael J. Yunes, MDm

Combined-modality therapy, consisting of chemotherapy followed by radiation therapy (RT), represents thestandard of care for most patients with unfavorable-prognosis early-stage Hodgkin’s lymphoma. The mostwidely accepted chemotherapy regimen is ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine);however, recent trials have evaluated other regimens such as BEACOPP (bleomycin, etoposide, doxorubicin,cyclophosphamide, vincristine, procarbazine, and prednisone) and Stanford V. After chemotherapy, the stan-dard radiation field is involved-field RT, although there is increasing interest now in involved-node RT. Theauthors review recent trials on chemotherapy and RT for unfavorable-prognosis early-stage Hodgkin’s lym-phoma. This article presents illustrative clinical cases, with treatment recommendations from an expert panel ofradiation oncologists and medical oncologists.

Key Words: Appropriateness Criteria®, Hodgkin’s lymphoma, unfavorable prognosis, radiation therapy,chemotherapy

J Am Coll Radiol 2011;8:302-308. Copyright © 2011 American College of Radiology

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aThe University of Texas MD Anderson Cancer Center, Houston, Texas.bHarvard University, Boston, Massachusetts.cUniversity of Rochester Medical Center, Rochester, New York.dStanford Cancer Center, Stanford, California.eAmerican Society of Clinical Oncology, Alexandria, Virginia.fEmory University, Atlanta, Georgia.gJames P. Wilmot Cancer Center, University of Rochester, Rochester, New

ork.hAmerican Society of Hematology, Washington, District of Columbia.iPrincess Margaret Hospital, Toronto, Ontario, Canada.jRhode Island Hospital/Hasbro Children’s Hospital, Providence, Rhode Island.kMoffitt Cancer Center, Tampa, Florida.lYale University School of Medicine, New Haven, Connecticut.mBaystate Medical Center and Tufts University School of Medicine, Spring-field, Massachusetts.

Correspondence and reprints: Prajnan Das, American College of Radi-ology, 1891 Preston White Drive, Reston, VA 20191; e-mail: prajdas@mdanderson.org.

The ACR seeks and encourages collaboration with other organizations onthe development of the ACR Appropriateness Criteria® through society rep-esentation on expert panels. Participation by representatives from collaborat-ng societies on the expert panel does not necessarily imply society endorse-

tent of the final document.

302

UMMARY OF LITERATURE REVIEW

umerous studies have evaluated the impact of prognos-ic factors in stage I and II Hodgkin’s lymphoma todentify patients who benefit from more intensive ther-py [1-4]. Prognostic factors identified in these analysesnclude the number of involved lymphoid regions, theize of individual nodes, the extent of mediastinal disease,atient gender and age, the presence of B symptomsr pruritus, histology, erythrocyte sedimentation rateESR), and overall tumor burden as measured by numberf sites and disease bulk.

In the United States, there has been general consensushat two of these factors in stage I and II Hodgkin’symphoma should influence management decisions. Therst is constitutional (B) symptoms: unexplained fevers,renching night sweats, or significant weight loss aslearly defined in the Ann Arbor staging classificationystem [5]. The presence of B symptoms is correlatedith a higher likelihood of systemic disease, includingccult subdiaphragmatic disease. Evidence suggests thatevers and weight loss have more prognostic significancehan night sweats alone [6].

The second prognostic factor that should influence

reatment selection is the presence of large mediastinal

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adenopathy or bulky disease in nonmediastinal sites. Avariety of definitions of large mediastinal adenopathyhave been reported in the literature [7]. The most com-monly used definition is based on a measurement of themaximum width of the mediastinal mass on standingposteroanterior chest radiography, compared with themaximum intrathoracic diameter. A ratio greater thanone third is defined as “bulky.” Other reports have used aratio with the intrathoracic width at T5 to T6 as thedenominator [8], while still others use absolute measure-ments [9], surface area calculations, or volume measure-ments. Bulky disease in nonmediastinal sites has similarlybeen classified with varying definitions. Some protocolsdefine bulky as �10 cm, while others use �5 or �6 cm.

In interpreting the results of trials, it is important tonote that the definition of unfavorable-prognosis early-stage disease varies among cooperative groups. The Eu-ropean Organisation for Research and Treatment ofCancer (EORTC) and Groupe d’Études des Lym-phomes de l’Adulte (GELA) specify the following as un-favorable factors: age � 50 years, ESR � 50 mm/h in theabsence of B symptoms, ESR � 30 mm/h with B symp-toms, �4 sites of involvement, and bulky mediastinalinvolvement [10]. For the German Hodgkin’s Lym-phoma Study Group (GHSG), the following are consid-ered unfavorable factors: ESR � 50 mm/h in the absenceof B symptoms, ESR � 30 mm/h with B symptoms, �3sites of involvement, extranodal involvement, and bulkymediastinal mass [11].

Combined-modality therapy, consisting of chemo-therapy followed by radiation therapy (RT), representsthe standard of care for most patients with unfavorable-prognosis stage I and II Hodgkin’s lymphoma. In theUnited States, the most widely accepted systemic therapyas part of combined modality therapy is ABVD (Adria-mycin [Pharmacia SpA, Milan, Italy], bleomycin, vin-blastine, and dacarbazine). Stanford V, a 12-week,7-drug regimen that is administered on a weekly basis,contains lower cumulative doses of mechlorethamine,Adriamycin, and bleomycin than MOPP (mechloreth-amine, vincristine, procarbazine, and prednisone) andABVD. Patients with initial disease of �5 cm or macro-scopic splenic disease receive 36 Gy of involved-field RT(IFRT) 2 weeks after the chemotherapy.

In a report on 142 patients with stage III or IV orlocally extensive mediastinal stage I or II Hodgkin’s lym-phoma, 5-year freedom from progression and overall sur-vival of 89% and 96%, respectively, were achieved [12].The EORTC H7U trial explored the use of a less inten-sive regimen, EBVP II (epirubicin, bleomycin, vinblas-tine, and prednisone) in unfavorable-prognosis early-stage patients and found that it was significantly inferiorto MOPP/ABV (10-year event-free survival [EFS] rate,

68% vs 88%; P � .0001) [10]. i

Other trials examined whether unfavorable-prognosisatients may benefit from the BEACOPP (bleomycin,toposide, doxorubicin, cyclophosphamide, vincristine,rocarbazine, and prednisone) regimen, originally devel-ped for patients with advanced-stage disease. Both theORTC H9U and the GHSG HD11 studies comparedto 6 cycles of ABVD with 4 cycles of BEACOPP as

aseline, followed by IFRT to 20 to 30 Gy. No signifi-ant differences in 4-year EFS rate or overall survival rateere observed between BEACOPP and ABVD in theORTC H9U trial [13]. Recently updated results of theHSG HD11 trial showed significantly higher 5-year

reedom from treatment failure (FFTF) in the BEA-OPP arm over the ABVD arm, if followed by 20 Gy of

FRT (5-year FFTF difference, 5.7%; 95% confidencenterval, 0.1%-11.3%) [11]. However, there was no sig-ificant difference between BEACOPP and ABVD with0 Gy of IFRT.The GHSG HD14 trial tested increasing dose inten-

ity using dose-escalated BEACOPP in this population.his trial randomized patients with unfavorable clinical

tage I or II disease to 4 cycles of ABVD versus 2 cycles ofose-escalated BEACOPP and 2 cycles of ABVD, fol-

owed by IFRT to 30 Gy. Preliminary results showed aignificantly superior 3-year FFTF in the dose-escalatedEACOPP-containing arm (96% vs 90%) but no differ-nces in overall survival [14]. Of note, these differenthemotherapy regimens could be associated with differ-nt rates of acute and late toxicity, such as higher rates ofnfertility with BEACOPP. Hence, long-term follow-upill be required to evaluate the rates of late toxicity, such

s cardiovascular effects and second malignancies, withhese chemotherapy regimens.

Two trials addressed the optimal number of cycles ofhemotherapy in patients with unfavorable-prognosisarly-stage Hodgkin’s lymphoma. In the EORTC-H8Urial, patients were randomized to 6 cycles of MOPP/BV followed by IFRT, 4 cycles of MOPP/ABV fol-

owed by IFRT, or 4 cycles of MOPP/ABV followed byxtended-field irradiation [15]. At a median follow-up of2 months, there was no significant difference in 5-yearFS rates among the 3 treatment groups (84%, 88%, and7%, respectively). The overall survival rates at 10 yearsere also not significantly different (88%, 85%, and4%, respectively). In the EORTC H9U trial describedbove, there was also no significant difference between 4nd 6 cycles of ABVD at a median follow-up of 57onths [13].The role of consolidative RT after chemotherapy has

een explored in a variety of randomized trials usingifferent criteria for risk stratification. These studies haveonsistently demonstrated a benefit for freedom fromisease progression with the addition of consolidative

rradiation.

304 Journal of the American College of Radiology/Vol. 8 No. 5 May 2011

The Grupo Argentino de Tratamiento de la LeucemiaAguda conducted a trial with 277 patients with stage I orII favorable-prognosis or unfavorable-prognosis Hodg-kin’s lymphoma who were randomized to receive either 6cycles of CVPP (cyclophosphamide, vinblastine, procar-bazine, and prednisone) or CVPP followed by IFRT[16]. Overall, the disease-free survival rate was signifi-cantly higher in the combined-modality arm comparedwith the chemotherapy-alone arm (7-year rate, 71% vs62%; P � .01). Among the unfavorable-prognosis pa-tients, the disease-free survival rate (75% vs 34%, P �.001) and the overall survival rate (84% vs 66%) werehigher in the combined-modality arm compared with thechemotherapy alone arm. The use of the CVPP regimenand the inclusion of pediatric patients (45% of subjects)limit the generalizability of this trial. Moreover, the out-comes in this trial were poorer compared with otherstudies with similar patients.

In a trial from the Tata Memorial Hospital in India,179 patients who achieved complete responses to 6 cyclesof ABVD were randomized to receive either IFRT or noradiotherapy [17]. In this trial, 55% of patients had stage

Variant 1. A 26-year-old man with stage IIB nodulasupradiaphragmatic, no bulky disease; fevers �38°

Treatment RatingOverall plan

Combined-modality therapy 8Chemotherapy alone 5 Und

favRT alone 1

Type of chemotherapyABVD 8Stanford V 7 Inclu

spBEACOPP (or variants) 6 Varia

esfolBEas

Duration of chemotherapy(chemotherapy alone)

4 mo 3 Thefro

6 mo 8Duration of chemotherapy

(combined-modalitytherapy)

4 mo 8 If St6 mo 7

Note: Rating scale: 1, 2, and 3 � usually not appropriate; 4, 5, anAdriamycin, bleomycin, vinblastine, and dacarbazine; BEACOPPtine, procarbazine, and prednisone; ECOG � Eastern Cooperati

radiation therapy.

I or II disease, 15% had bulky disease, and 54% had Bsymptoms; hence, a large proportion had early-stage un-favorable-prognosis disease. The overall survival rate wassignificantly higher in the RT arm than in the no-RT arm(8-year rate, 100% vs 89%; P � .002). The EFS rate wasalso significantly higher in the RT arm (8-year rate, 88%vs 76%; P � .01). However, the high proportion ofpediatric, stage III and IV, and mixed-cellularity patientsin this trial limit its generalizability as well.

The National Cancer Institute of Canada-Eastern Co-operative Oncology Group trial enrolled 405 patientswith nonbulky stage I or IIA Hodgkin lymphoma [18].Favorable-prognosis patients were randomized to receiveeither 4 to 6 cycles of ABVD or subtotal nodal irradia-tion. Unfavorable-prognosis patients (age � 40 years orESR � 50 mm/h, mixed cellularity, lymphocyte-de-pleted histology, or �4 sites of disease) were randomizedto receive either 4 to 6 cycles of ABVD or combined-modality therapy with 2 cycles of ABVD followed bysubtotal nodal irradiation. Among the unfavorable-prog-nosis patients, the rate of freedom from disease progres-sion was significantly higher in the combined-modality

clerosis Hodgkin’s lymphoma;nd drenching night sweats

Comments

investigation. Rapid response may predictable outcome. See text.

s IFRT to sites �5 cm or to spleen if macroscopicic involvement, to 36 Gy. Awaiting ECOG results.s with supporting data include 2 cycles of dose-ated BEACOPP, followed by 2 cycles of ABVD,ed by IFRT to 30 Gy, or 4 cycles of baselineOPP followed by IFRT to 20 Gy. May beiated with increased toxicity; see text.

dition of RT to chemotherapy improves freedomdisease progression.

ord V is used, duration is 12 wk (3 mo).

� may be appropriate; 7, 8, and 9 � usually appropriate. ABVD �bleomycin, etoposide, doxorubicin, cyclophosphamide, vincris-Oncology Group; IFRT � involved-field radiation therapy; RT �

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arm compared with the chemotherapy alone arm (95%vs 88%, P � .004), but there was no significant differ-ence in overall survival. Of note, the use of subtotal nodalirradiation in this trial may eventually lead to an in-creased rate of late effects from RT, thereby diminishingthe benefits from RT. Although the National CancerInstitute of Canada Eastern Cooperative OncologyGroup trial and the other trials discussed above had var-ious limitations, it can still be concluded that the addi-tion of RT to chemotherapy improves freedom fromdisease progression in patients with unfavorable-progno-sis Hodgkin’s lymphoma (see Variant 1).

Several randomized trials have evaluated the appropri-ate extent of RT field in patients with unfavorable-prog-nosis Hodgkin’s lymphoma after chemotherapy. In theGHSG HD8 trial, 1,204 unfavorable-prognosis patientswere treated with two cycles of COPP (cyclophosph-amide, vincristine, procarbazine, and prednisone) andABVD, followed by either extended-field RT or IFRT[19]. There were no significant differences in the rates ofFFTF or overall survival between the two groups,whereas acute side effects were less frequent in the IFRTgroup. In the EORTC-H8U trial described above, therewere no significant differences in the EFS or overall sur-vival rates between the IFRT arms and extended-fieldarm [15].

Similarly, an Italian study with favorable-prognosisand unfavorable-prognosis patients showed no differencein freedom from progression or overall survival rates be-tween patients treated with subtotal nodal and splenicradiation, or IFRT, after 4 cycles of ABVD [20]. In-volved-field RT is therefore considered the standard ra-diation treatment field after chemotherapy. The defini-tion of IFRT has been detailed elsewhere [21].

After chemotherapy, the superior-inferior extent ofthe radiation field typically encompasses the prechemo-therapy extent of disease, while the lateral extent can belimited to the postchemotherapy extent of disease. Theinitial lateral extent of mediastinal disease should not betreated, unless there is known extranodal disease exten-sion into bone or chest wall.

In recent years, there has been growing interest infurther limiting the radiation treatment field to involved-node RT (INRT) [22]. The definition of INRT variesfrom group to group. In the EORTC/GELA H11 trialfor early-stage unfavorable-prognosis Hodgkin’s lym-phoma (discussed below), INRT was adopted in both thestandard and experimental arms. The GHSG is planninga randomized trial in patients with unfavorable-progno-sis early-stage disease (HD17) comparing IFRT withINRT. The results of these trials, including details onpatterns of failure, will clarify the role of INRT in early-

stage patients.

The appropriate radiation dose in patients with unfa-orable-prognosis early-stage disease after chemotherapyas addressed by the GHSG HD11 trial described above

11]. After 4 cycles of BEACOPP, a significant differencen 5-year FFTF between 20 and 30 Gy was not observed.

owever after 4 cycles of ABVD, an inferiority of the0-Gy arm could not be excluded, with a 4% lower-year FFTF in the 20-Gy arm. This led to the conclu-ion that a reduction of radiation dose from 30 to 20 Gyf IFRT in unfavorable-prognosis patients may be justi-ed only after BEACOPP, but not after ABVD (seeariants 2 and 3).Positron emission tomography has emerged as a useful

ool in the staging and follow-up of patients with Hodg-in’s lymphoma. Additionally, PET response duringhemotherapy has been shown to be a powerful prognos-ic factor [23].

A recent randomized trial evaluated whether RT cane omitted in patients who show complete responsesy PET after chemotherapy [24]. One hundred sixtyatients, who had complete responses to inductionhemotherapy but residual masses and PET-negativecans, were randomized to undergo either observationr consolidative RT. The EFS rate was significantlyower in the observation arm compared with the RTrm (86% vs 96%, P � .03). The ongoing EORTC/

Variant 2. A 26-year-old man with stage IIBnodular sclerosis Hodgkin’s lymphoma;supradiaphragmatic, bulky disease 10 cm in theneck; fevers �38°C and drenching night sweats;partial response by CT (�50% reduction) after 6cycles of ABVD

Treatment Rating CommentsRadiation field

IFRT to neck 8INRT to neck 5 Long-term data

not available.INRT definitionis still inevolution.

Mantle 3Subtotal nodalirradiation

1

Radiation dose20 to �30 Gy IFRT 630 to 36 Gy IFRT 8�36 to 40 Gy IFRT 4�40 Gy IFRT 2

Note: Rating scale: 1, 2, and 3 � usually not appropriate; 4, 5,and 6 � may be appropriate; 7, 8, and 9 � usually appropriate.ABVD � Adriamycin, bleomycin, vinblastine, and dacarbazine;IFRT � involved-field radiation therapy; INRT � involved-node

radiation therapy.

febr

lved

306 Journal of the American College of Radiology/Vol. 8 No. 5 May 2011

GELA H11 trial also explored the use of PET responseto identify patients with unfavorable-prognosis early-stage disease in whom RT may be omitted. The stan-dard arm of this trial consisted of 4 cycles of ABVD

Variant 3. A 26-year-old male, clinical stage IIA nomediastinal mass (11 cm) and bilateral neck diseasecycles of ABVD

Treatment RatiRadiation field

IFRT to mediastinum and bilateral neck 8INRT to mediastinum and bilateral neck 5

Mantle 4Subtotal nodal irradiation 2

Radiation dose20 to �30 Gy IFRT 630 to 36 Gy IFRT 8�36 to 40 Gy IFRT 4Boost mediastinum dose to 36 Gy 7Boost mediastinum dose to 40 Gy 2

Note: Rating scale: 1, 2, and 3 � usually not appropriate; 4, 5, aAdriamycin, bleomycin, vinblastine, and dacarbazine; IFRT � invo

Variant 4. A 26-year-old woman, clinical stage IIBmediastinal (13 cm) and left supraclavicular diseaseon PET after 6 months of chemotherapy

TreatmentRadiation dose

No further RT

20 to �30 Gy IFRT30 to 36 Gy IFRT�36 to 40 Gy IFRTBoost mediastinum dose to 36 GyBoost mediastinum dose to 40 Gy

Mediastinal volumeTreat postchemotherapy volume only (laterally)

Inferior margin 2 cm below prechemotherapy voluTreat prechemotherapy volume to 10 to 15 Gy, th

shrinkInferior margin 2 cm below postchemotherapy voInferior margin 5 cm below postchemotherapy voInferior margin approximately at diaphragmInferior margin 5 cm below prechemotherapy volu

Note: Rating scale: 1, 2, and 3 � usually not appropriate; 4, 5, a

involved-field radiation therapy; RT � radiation therapy.

ollowed by INRT to 30 Gy, while patients on thexperimental arm received 2 cycles of ABVD followedy PET. If the results of PET were negative, patientseceived 4 additional cycles of ABVD and then no

ar sclerosis Hodgkin’s lymphoma with bulkyartial response by CT (�50% reduction) after 6

Comments

Long-term data not available. INRT definitionis still in evolution.

6 � may be appropriate; 7, 8, and 9 � usually appropriate. ABVD �-field radiation therapy; INRT � involved-node radiation therapy.

ular sclerosis Hodgkin’s lymphoma with bulky75% reduction of mass by CT and negative results

Rating Comments

3 The addition of RT to chemotherapyimproves freedom from diseaseprogression.

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8 If there is no bone or chest wallextension, the width of thepostchemotherapy RT field maycorrespond to the postchemotherapyextent of disease.

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Das et al/Hodgkin’s Lymphoma-Unfavorable Clinical Stage I and II 307

further treatment. If the results were positive, patientsreceived 2 cycles of dose-escalated BEACOPP, fol-lowed by INRT to 30 Gy. The results of this trial arepending. It therefore seems that at the current time, thereare no available data to support the omission of RT onthe basis of PET response or early PET response in pa-tients with early-stage Hodgkin’s lymphoma, an ap-proach that should be reserved in the context of a clinicaltrial (see Variant 4).

SUMMARY

● The standard of care for unfavorable-prognosis stage Iand II Hodgkin’s lymphoma is combined-modalitytherapy, consisting of chemotherapy followed by RT.

● The most widely accepted chemotherapy regimenis ABVD. Other options, such as Stanford V andBEACOPP, may also be appropriate.

● The recommended radiation dose is 30 to 36 Gyafter ABVD, and the recommended radiation field isIFRT.

Disclaimer: The ACR Committee on AppropriatenessCriteria® and its expert panels have developed criteria foretermining appropriate imaging examinations for the di-gnosis and treatment of specified medical conditions. Theseriteria are intended to guide radiologists, radiation oncol-gists, and referring physicians in making decisions regard-ng radiologic imaging and treatment. Generally, the com-lexity and severity of a patient’s clinical condition shouldictate the selection of appropriate imaging procedures orreatments. Only those examinations generally used for thevaluation of a patient’s condition are ranked. Other imag-ng studies necessary to evaluate other coexistent diseases orther medical consequences of this condition are not consid-red in this document. The availability of equipment orersonnel may influence the selection of appropriate imagingrocedures or treatments. Imaging techniques classified asnvestigational by the FDA have not been considered ineveloping these criteria, but the study of new equipmentnd applications should be encouraged. The ultimate deci-ion regarding the appropriateness of any specific radiologicxamination or treatment must be made by the referringhysician and radiologist in light of all the circumstancesresented in an individual examination.

For additional information on ACR Appropriatenessriteria®, refer to www.acr.org/ac.

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