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836 www.thelancet.com Vol 380 September 1, 2012

Lancet 2012; 380: 83647

Published Online

July 25, 2012

http://dx.doi.org/10.1016/

S0140-6736(12)60035-X

Department of Haematology,

University College London

Medical School, Cancer

Institute, London, UK

(W Townsend MBChB,

Prof D Linch F Med Sci)

Correspondence to:

Prof David Linch, Department of

Haematology, University College

London Medical School, Cancer

Institute, 72 Huntley Street,

London WC1E 6BT, UK

[email protected]

Hodgkins lymphoma in adults

William Townsend, David Linch

Management of Hodgkins lymphoma continues to develop. Outcomes for patients with favourable-risk, early-stagedisease are excellent, and serial reductions in intensity of treatment have been made to retain the excellent prognosiswhile reducing the late effects of treatment. Prognosis is also very good in advanced-stage disease but the rate ofrelapse is higher than in early-stage disease, and the optimum first-line treatment is unclear. Workers are investigatingthe role of functional imaging to assess whether treatment can be tailored according to response, with the mostintensive therapies reserved for patients predicted to have poor outcomes. In this Seminar we critically appraise themanagement of Hodgkins lymphoma in early-stage disease, advanced-stage disease, and at relapse, with a focus onlate effects of treatment.

IntroductionMost patients with Hodgkins lymphoma are cured withfirst-line therapy. The main challenges are to reduce the

toxic effects of treatment while maintaining excellentoutcomes, and to improve survival for patients withpoor-risk, refractory, or relapsed disease. Since ourprevious Seminar,1 there have been important advancesin the management of Hodgkins lymphoma, mostnotably in the use of PET, deintensification of treatmentin selected patients, and the management of relapseddisease.

EpidemiologyIncidence of Hodgkins lymphoma in the UK and USA is2728 per 100 000 per year, with roughly 1700 newcases diagnosed in the UK every year.2,3 The disease ismore frequent in men than in women, and peaks in

incidence are noted in young adults and in peopleolder than 60 years.4,5 Incidence has remained mostlyunchanged during the past two decades.6,7 Hodgkinslymphoma is classified as either classical or nodularlymphocyte-predominant.8 Four subtypes of classicalHodgkins lymphoma exist, which differ in presentation,sites of involvement, epidemiology, and association withEpstein-Barr virus (table 1); management, however, isbroadly similar in all subtypes.8 Nodular lymphocyte-predominant Hodgkins lymphoma has a distincthistological appearance, immunophenotype, and clinicalcourse. Understanding of the pathophysiology ofHodgkins lymphoma continues to develop.911

Diagnosis and stagingHodgkins lymphoma typically presents as painlesslymphadenopathy, which is frequently cervical or supra-

clavicular. More than 50% of patients have a mediastinalmass, which can be asymptomatic or can present asdyspnoea, cough, or obstruction of the superior venacava.12 Systemic symptoms are reported in 25% ofpatients. Fever, drenching night sweats, and loss of morethan 10% of bodyweight over 6 months are termedB symptoms and have prognostic importance. Othersymptoms such as pruritis, fatigue, and alcohol-relatedpain do not have prognostic importance and are thusnot regarded as B symptoms. Diagnosis of Hodgkinslymphoma should be confirmed histologically. Contrast-enhanced CT of the neck, chest, abdomen, and pelvisshould be done for staging. Functional imaging withF-fluorodeoxyglucose (F-FDG) PET is increasingly

used to stage disease accurately, delineate margins ofradiotherapy, and provide a baseline for subsequentresponse assessment.

Bone-marrow involvement is identified in 58% ofpatients with Hodgkins lymphoma, but in apparentlyearly-stage disease the rate of involvement is less than 1%and is generally judged too low to justify taking of a bonemarrow biopsy.1315 In advanced disease, discovery of bone-marrow involvement will not change treatment, but willaffect the restaging procedures done at the end of treat-ment. F-FDG PET is sensitive for focal bone-marrowinfiltration,16 and its increasing use will reduce the numberof staging trephine biopsies done. Staging of Hodgkinslymphoma is based on modifications of the Ann Arbor

system (panel 1), and is useful for prognostication andtreatment planning.

Prognosis and risk stratificationThe outlook for patients with early-stage disease (stageIIIA) is excellent, with overall survival exceeding 90% inmany trials. In advanced-stage disease, overall survival is7590%. In both early-stage and advanced-stage disease,further stratification according to risk factors is oftendone. Early-stage disease is stratified into favourable andunfavourable (sometimes referred to as intermediatestage) by some groups according to the presence orabsence of risk factors. The definition of early-stage

Search strategy and selection criteria

We systematically searched Medline and PubMed for

articles published between January, 2000 and July, 2012 for

the term Hodgkins lymphoma and the related terms

early stage, advanced stage, and relapsed or

refractory. We did not restrict references by language of

publication, and relevant references published before the

search period were also included. References from relevant

articles were also searched. Conference reports and

abstracts are included when relevant.

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unfavourable disease varies (table 2), but the mostconsistently used determinants are disease bulk and thepresence of B symptoms. In the UK and the USA,subdivision of early-stage disease is not commonpractice; instead patients with B symptoms are judged tohave advanced disease. However, evidence shows thatprofound treatment reductions can be made in favourableearly-stage disease,17 and thus identification of this groupof patients should be mandatory.

For advanced stage disease, the international prog-nostic score (also known as the Hasenclever score) isused to predict prognosis.18 The score is calculatedaccording to seven clinical and laboratory factors(panel 2); the presence of each factor reduces 5 yearoverall survival on average by 8% (table 3). Riskstratification according to response assessment by

interim F-FDG PET in both early-stage and advanced-stage disease will probably supplement or replacepresent methods of assigning risk.

PET in Hodgkins lymphomaF-FDG PET can be used in combination with CT forstaging, end-of-treatment and interim assessments, andfollow-up surveillance, although its precise role has notbeen defined. In prospective studies, F-FDG PET atdiagnosis upstaged 1324% more patients than did CT.1921When upstaging moves a patient from early-stage toadvanced-stage disease (as happened in 715% ofpatients), a change in management is warranted.1921There is no evidence that this change in management

affects long-term survival, however, partly because of thesuccess of salvage therapy. Staging F-FDG PET alsoprovides a baseline scan against which subsequent scanscan be compared.22

End-of-treatment F-FDG PET can be used todistinguish between fibrotic tissue and residual activedisease. In a prospective study,23 negative end-of-treatment F-FDG PET had a 96% (95% CI 9197)negative predictive value for progression or early relapsein advanced-stage disease. Thus, in advanced-stage

patients with a residual mass but a negative end-of-treatment F-FDG PET scan, radiotherapy couldpotentially be omitted. F-FDG PET has been adoptedin the revised response criteria for lymphoma, whichrequire a negative scan to classify a patient as incomplete remission and allows residual masses as longas they are not F-FDG avidso-called metaboliccomplete remission.22 Although the negative predictivevalue of F-FDG PET is very high, the positive predictivevalue is less reliable, with false-positives occurringbecause of infection, inflammation, increased uptake ofF-FDG in brown fat, and reactive changes aftertreatment. Thus, to ascertain whether relapse hasoccurred, histological evidence is preferable to F-FDGPET alone.24

The greatest interest is in the potential use of F-FDG

PET for interim assessment after initial cycles ofchemotherapy, with the aim of identification of whichpatients are cured and which need escalation oftreatment. Response after two cycles of chemotherapy ismore predictive of outcome than traditional riskstratification based on results of clinical and laboratorytests.2527 Data suggest that interim assessment can beeven more predictive if done after the first cycle ofchemotherapy.28 Results of prospective clinical trialsassessing the escalation or de-escalation of treatment onthe basis of interim F-FDG PET are awaited. Untilconclusive results are available, treatment decisionsshould not be made by interim assessment. SurveillanceF-FDG PET has been assessed in routine follow-up, but

data do not support such an approach.29

There are several unresolved questions relating to thereproducibility and quality control of F-FDG PET andthe standardised interpretation of minimum uptake.Quantification of F-FDG uptake can be assessed as astandard uptake value or by visual assessment. For thepurposes of clinical trials, a five-point scale (Deauvillescale) that compares the standard uptake value of a lesionwith that of the mediastinum or liver is recommended(panel 3).30

EBV association Epidemiology Clinical features

Nodular lymphocyte-predominant

Hodgkins lymphoma

No association Accounts for 5% of all Hodgkins lymphoma; more

common in male than in female patients

75% of patients are early stage; risk of transformation to

high-grade non-Hodgkin lymphoma

Classical Hodgkins lymphoma

Nodular sclerosis classicalHodgkins lymphoma

Intermediate association;1040% of patients EBV positive

Accounts for 70% of classical Hodgkins lymphoma inEurope and North America

Mediastinal mass present in 80% of patients; prognosisbetter than in other subtypes of classical disease

Mixed-cellularity classicalHodgkins lymphoma

Strong association; up to 75% ofpatients EBV positive

Accounts for 25% of classical disease; prevalent inpatients with HIV infection and developing countries

Peripheral and abdominal lymphadenopathy common;splenic infiltration in 30% of patients

Lymphocyte-rich classical

Hodgkins lymphoma

Intermediate association Accounts for 5% of classical Hodgkins lymphoma Peripheral lymphadenopathy common; mediastinal mass rare

Lymphocyte-depleted classical

Hodgkins lymphoma

Strong association; up to 75% of

patients EBV positive

Rarest subtype, accounts for

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ManagementEarly-stage favourable diseaseCombined modality therapy (chemotherapy and radio-therapy) has replaced radiotherapy alone in localisedHodgkins lymphoma because it substantially reducesrelapse rate through the chemotherapeutic eradication ofoccult disease outside the radiation field and allows forsmaller radiation fields.3134 A meta-analysis35 confirmed areduction in relapse rate with combined modality therapy,

and although it did not report a survival benefit, a separateretrospective study36 identified mantle field radiotherapyalone as an independent risk factor for death.

The gold-standard treatment for favourable early-stage disease was thought to be four cycles of ABVD(doxorubicin, bleomycin, vinblastine, and dacarbazine)followed by 36 Gy involved-field radiotherapy (IFRT),37

but this approach now represents over-treatment. TheEuropean Organisation for Research and Treatment ofCancer (EORTC) H9 trial38 suggested that the radiationdose could be reduced to 20 Gy in patients who achievedcomplete remission or complete remission unconfirmedafter chemotherapy. The German Hodgkin LymphomaStudy Group (GHSG) HD10 trial17 randomly assignedpatients with favourable early-stage disease to two or fourcycles of ABVD chemotherapy followed by either 20 Gy

or 30 Gy IFRT. At 5 year follow-up, investigators reportedno significant difference in freedom from treatmentfailure or overall survival between the study groups, andmore toxic effects in the groups that received four cyclesof chemotherapy or 30 Gy IFRT, or both. Two cycles ofABVD and 20 Gy IFRT should therefore be regarded asthe standard of care in favourable early-stage disease asdefined by the GHSG (ie, 10 cm in diameter)

E Involvement of one contiguous or proximal extranodal site

Risk factors Stratification

GHSG (Germany) 3 nodal areas involved, mediastinal bulk*,

ESR 50 or ESR 30 if B symptoms present,extranodal disease

Favourable=stage III with no risk factors;unfavourable (intermediate)=stage IIIA

with 1 risk factor, or stage IIB with no

mediastinal bulk or extranodal disease

E ORTC Ag e 50,me dia stin al b ulk, E SR 50 or E SR

30 if B symptoms present, 4 nodal sites

Favourable=stage III supradiaphragmatic

disease with no adverse factors;unfavourable=stage III supradiaphragmatic

disease with 1 risk factor

GELA (France) Any increase in ESR, age 45 years,

extranodal disease, haemoglobin 105 g/L,lymphocyte count 0610/L, male sex

Favourable=stage III with no risk factors;unfavourable=stage IIIA with 1 risk factor

ECOG/NCI (USA) Bulky d ise as e , B s ymp toms E ar ly stag e= no a dvers e f ac tors; a dvanc ed

stage=1 risk factor

NCRI (UK) Bulky disease, B symptoms Early stage=no adverse factors; advanced

stage=1 risk factor

The country in which the research group is based is shown in parentheses. GHSG=German Hodgkin Study Group.

EORTC=European Organisation for Research and Treatment of Cancer. GELA=Groupe dEtudes des Lymphomes

de lAdulte. ECOG=Eastern Cooperative Oncology Group. NCI=National Cancer Institute. NCRI=National Cancer

Research Institute. *Mediastinal bulk is defined as a mediastinal mass with a diameter greater than 035 times the

maximum thoracic diameter. B Symptoms are unexplained f ever, night sweats, or documented unexplained weight

loss (>10% bodyweight over 6 months). EORTC early-stage favourable trials do not include very favourable patients

ie, patients with stage IAdisease, patients younger than 40 years, or female patients with nodular sclerosing histology.

Bulky disease includes mediastinal mass larger than 035 times the transthoracic diameter, and other sites of disease

measuring 10 cm or larger.

Table 2: Risk stratification of early-stage Hodgkins lymphoma, by research group

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be advantageous in view of the drugs association withpulmonary fibrosis.

Early-stage unfavourable diseaseCombined modality therapy is the standard treatment forunfavourable early-stage disease in most of Europe,although most patients with B symptoms or bulkydisease in the UK have been treated with protocols usedfor advanced disease. In the EORTC H8 trial,32 IFRT wasas effective as extended-field radiotherapy (EFRT) in earlyunfavourable disease and no difference in outcome wasreported between four and six cycles of MOPPABV(mechlorethamine, vincristine, procarbazine, prednis-olone, doxorubicin, bleomycin, and vinblastine).32 TheGHSG HD8 trial showed that after four cycles ofalternating COPP (cyclophosphamide, vincristine, pro-

carbazine, and prednisolone) and ABVD, relapse rate orsurvival did not differ between the IFRT (30 Gy and anadditional 10 Gy to sites of bulk) and EFRT (30 Gy and anadditional 10 Gy to sites of bulk) groups, although acutetoxic effects were significantly higher in the latter. 48Although these protocols resulted in high rates ofcomplete remission, relapse rates of up to 1520% haveled to searches for more effective initial chemotherapy.49

The EORTC H9 trial50 randomly assigned patients withearly unfavourable disease to four cycles of ABVD, sixcycles of ABVD, or four cycles of baseline BEACOPP(bleomycin, etoposide, doxorubicin, cyclophosphamide,vincristine, procarbazine, and prednisolone) followed by30 Gy IFRT in all groups. Investigators noted more toxic

effects in patients in the BEACOPP group than in theABVD groups, but outcome did not differ. The GHSGHD11 trial49 randomised patients to get four cycles of eitherABVD or baseline BEACOPPand either 20 Gy or 30 GyIFRT. The outcome was inferior after ABVD and 20 Gyradiotherapy, but other treatment groups had similaroutcomes, indicating that baseline BEACOPP and 20 GyIFRT is as effective as ABVD and 30 Gy IFRT. However,because more toxic effects were associated with BEACOPPthan with ABVD, most clinicians have concluded that fourcycles of ABVD followed by 30 Gy IFRT should remainstandard practice. To investigate further whether intensivechemotherapy can improve outcome in this group, theGHSG HD14 trial51 randomly assigned patients to receive

either four cycles of ABVD or two cycles of escalatedBEACOPP, followed by two cycles of ABVD with 30 GyIFRT in both treatment groups. A small but significantimprovement in freedom from treatment failure wasidentified in patients who received escalated BEACOPPand two cycles of ABVD compared with those who receivedsix cycles of ABVD (948% vs 877%, p45 years

Male sex

Serum albumin concentration

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standard comparator than COPP alternated with ABVD).Escalated BEACOPP results in increased haematological

toxic effects, infections, secondary malignancies, and ratesof infertility compared with both BEACOPP and alter-nating COPPABVD,60,61 but the improvement in overallsurvival at 10 years is impressive (overall survival at 10years was 75% with COPPABVD, 80% with baselineBEACOPP, and 86% with esclated BEACOPP).

The GHSG HD12 trial62 assessed whether the toxiceffects of BEACOPP can be reduced; four cycles of escal-ated BEACOPP were followed by four cycles of baselineBEACOPP and preliminary results suggest that thisregimen is not associated with a significant loss ineffi cacy. Meanwhile the GHSG HD15 trial63 reportedbetter results and fewer toxic effects and secondarymalignancies with six cycles of escalated BEACOPP

followed by PET-guided radiotherapy than with eithereight cycles of escalated BEACOPP or eight cycles ofBEACOPP-14.

Findings from a small Italian trial56 confirmed thatevent-free survival was better with escalated BEACOPPthan with ABVD. However, salvage was inferior inpatients who did not respond to BEACOPP, and thus theoverall survival benefit at 7 years was not significant (89%with BEACOPP vs 84% with ABVD). The power of thistrial was low, but a Cochrane analysis64 of four trials ofescalated BEACOPP (including the Italian study) showedthat although progression-free survival increasessignificantly with escalated BEACOPP (HR 053, 95% CI044064), this improvement does not translate to a

significant benefit in overall survival (08, 059109).Some centres previously reserved escalated BEACOPPfor patients with high international prognostic scores,65but long-term follow-up of the GHSG HD9 trial suggeststhat the regimen has an equivalent benefit in patients ofany score.60

The role of radiotherapy in advanced-stage diseaseis unclear. IFRT to sites of initial disease bulk waspreviously given to all patients after chemotherapy, andfindings from a retrospective analysis66 of data from theUK suggested that this strategy improved progression-freeand overall survival. An EORTC trial67 randomly assignedpatients in complete remission after MOPPABV to IFRT

or no radiotherapy, and showed no significant differencesin event-free or overall survival between the two groups.67In the same study, patients in partial remission afterchemotherapy benefited from consolidation radiotherapy,leading the investigators to recommend consolidationIFRT only to such patients.68 However, the findings of theGHSG HD15 trial showed that radiotherapy can beomitted for patients with residual masses if they are PETnegative after BEACOPP chemotherapy.23 Thus, theproportion of patients benefiting from consolidationradiotherapy is probably small.

Randomised trials have established that consolidationof first complete remission with high-dose therapy andautologous stem-cell transplantation has no benefit inprogression-free or overall survival, even in patientswith high-risk disease.6971 Thus, this approach is

not recommended.

Response-adapted therapyInterim F-FDG PET in advanced-stage disease has highsensitivity and specificity,72 and is better than theinternational prognostic score in prediction of out-come.2527 Treatment can be tailored according to theresults of interim PET scans in advanced disease. Avigdorand colleagues65 gave 45 patients two cycles of escalatedBEACOPP and then did a PETCT scan. 72% of patientshad a negative scan, and de-escalation to ABVD for asubsequent four cycles led to 4 year progression-freesurvival of 87%. The GHSG HD18 trial73 is testingwhether the number of cycles of escalated BEACOPP can

be reduced from eight to four in patients with a negativeinterim scan. An alternative approach is to start treatmentwith ABVD and escalate to BEACOPP if the interim scanis positive.74,75 This strategy is being prospectively exploredin the UK National Cancer Research Institute ResponseAdapted Therapy using FDG-PET Imaging in AdvancedHodgkin Lymphoma (RATHL) trial.76 This trial is alsoassessing the randomised omission of further bleomycinin patients with a negative F-FDG PET scan after twocycles of ABVD.

Relapsed or refractory disease and salvagechemotherapyRoughly 10% of patients with early-stage disease and

2030% with advanced disease will be refractory to,or relapse after, initial treatment. The strategy formanagement of relapsed or refractory disease is to deliversalvage chemotherapy, followed by high-dose chem-otherapy and autologous stem-cell transplantation inresponding patients.77,78 The outlook of patients withrelapsed disease depends on time to relapse, stage at timeof relapse, and performance status. Patients withrefractory diseaseincluding those who relapse lessthan 3 months after completion of treatmenthavesignificantly worse outcomes than do those who relapsehaving previously been in remission.79 In large Germanretrospective studies, 5 year overall survival for primary

Panel 3: Deauville criteria for interim

F-fluorodeoxyglucose PET29

1 No uptake

2 Uptake mediastinum

3 Uptake >mediastinum but liver*

4 Uptake moderately increased at any site compared with

the liver

5 Uptake substantially increased at any site compared with

the liver, or any new sites of disease

*Score 3 could be judged positive in trials investigating a reduction in therapy, or

negative in trials investigating intensification of treatment.

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refractory patients was 26%,80 compared with 46% forthose relapsing 312 months after chemotherapy and 71%for those relapsing more than 1 year after treatment.81

No trials have directly compared salvage regimens orinvestigated the optimum number of cycles. Salvagechemotherapy should ideally introduce drugs that werenot used in the original treatment, should be reasonablynon-toxic, and should not impair subsequent harvestof haemopoietic stem cells.79 ESHAP (etoposide,methylprednisolone, cytarabine, and cisplatin), DHAP(dexamethasone, cytarabine, and cisplatin), IVE(ifosphamide, etoposide, and epirubicin), and ICE(ifosphamide, carboplatin, and etoposide) are the mostwidely used, with response rates of 6080%. 79 BEACOPPhas also been successfully used in this setting.82Radiotherapy alone could have a role in selected patients

with localised late relapse, but the criteria for thissituation are hard to define.83

For patients not responding to first-line salvagechemotherapy, an alternative salvage regimen such asmini-BEAM (carmustine, etoposide, cytarabine, andmelphalan) can be effective as a bridge to transplantationin many patients. The new drug brentuximab vedotincould be useful in this context. A UK prospective trial84 isinvestigating the role of allogeneic haemopoietic stem-celltransplantation in the primary refractory setting.

Stem-cell transplantationAutologous stem-cell transplantationData from randomised trials77,78 show improved

progression-free survival with salvage chemotherapyfollowed by autologous stem-cell transplantation com-pared with salvage chemotherapy alone. Refinements intechniques, including use of peripheral-blood stem cellsand growth factors and improved patient selection andsupportive care, have led to a reduction in transplantation-related mortality to less than 3%. The depth of response(ie, complete response vs partial response) to salvagechemotherapy before autologous stem-cell transplantationis important, with improved progression-free and overallsurvival for patients in complete remission,85 and evidenceshows that a negative F-FDG PET scan after salvagechemotherapy predicts outcome after autologous stem-cell transplantation.86 Overall survival in patients with

relapsed disease treated with this technique is greaterthan 65%, compared with 30% in refractory disease.87

Use of sequential high-dose therapy to increase theintensity of conditioning before autologous stem-celltransplantation has no obvious benefit compared withthe standard BEAM (carmustine, etoposide, cytarabine,and melphalan) regimen and autologous stem-celltransplantation, and is associated with increased toxiceffects.88 Similarly, intensification with tandem autolo-gous stem-cell transplantation has been investigatedand could have a role in patients with adverse riskfactors, although any potential benefit should beweighed against the increased toxic effects.89

Allogeneic haemopoietic stem-cell transplantationEvidence of a graft-versus-disease effect in Hodgkinslymphoma90 has resulted in increased use of reduced-intensity conditioning allogeneic transplantation inpatients who did not respond to standard salvagetherapy; treatment-related mortality of this procedure inexpert centres is roughly 20%.91,92 Use of donorlymphocyte infusions to harness the graft-versus-diseaseeffect and treat relapse after transplantation has alsobeen shown.91 In a donor versus no-donor analysis ofpatients who relapsed after autologous stem-celltransplantation, both progression-free (393% vs 142%)and overall survival (66% vs 42%) were significantlyhigher in the donor group than in the no-donor group(p

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Nodular lymphocyte-predominant HodgkinslymphomaNodular lymphocyte-predominant Hodgkins lymphomaaccounts for 5% of all Hodgkins lymphoma diagnosesand is distinguished from classical disease by theabsence of Hodgkin and ReedSternberg cells and thepresence of characteristic lymphocyte-predominantcells, which are sometimes called popcorn cells.8Lymphocyte-predominant cells are clonal B cells thathave retained the B-cell phenotype and are classicallyCD30 negative.8 Most patients (70%) are male andmedian age at presentation is 3040 years. Early-stagedisease is identified in 75% of patients.103 Nodularlymphocyte-predominant Hodgkins lymphoma has anexcellent prognosis, but late relapses are frequentlyrecorded.104 Transformation to diffuse large B-cell

lymphoma is reported in 814% of patients 48 yearsafter diagnosis,104106 and the risk of transformationincreases with time.105

Because of the rarity of nodular lymphocyte-predominant Hodgkins lymphoma, few prospectivetrial data are available, and the best treatment isunknown. In view of the excellent long-term survivaland young age at presentation, the late effects oftreatment should be carefully considered. For patientswho have had an excision biopsy taken and haveno evidence of residual disease, some clinicianshave previously used observation alone, but this strategycould be unacceptable because of the high rate ofrelapse.106,107 Early-stage disease can be treated with

radiotherapy alone, leading to 10 year progression-freesurvival of 89% and overall survival of 96%; the rate ofrelapse is higher in stage 2 than in stage 1 disease, butoverall survival does not differ.108 IFRT is as effective asmore extensive radiotherapy and has lower rates oflate complications. In advanced disease, combinationchemotherapy is needed, but little evidence is availableto support a particular regimen. ABVD is often used, butregimens with fewer toxic effects such as CVP (cyclo-phosphamide, vincristine, and prednisolone) are recom-mended by some groups.43 Rituximab has been used as asingle agent in phase 2 trials in both front-line andrelapsed settings, with response rates of up to 100% butfrequent relapses.109,110 The incorporation of rituximab

into chemotherapy regimens might be reasonable, andrituximab maintenance might also be beneficial,although this practice is not proven.

Special situationsElderlyElderly patients have poorer survival than do youngerpatients because of comorbidities, toxic effects of treat-ment, and reduced treatment intensity. In the absence ofcomorbidities precluding anthracycline use, standardtreatment is recommended in patients younger than70 years. For elderly patients or those with noteworthycomorbidities, ABVD is thought to be too toxic, and

alternative regimens such as VEPEMB (vinblastine,cyclophosphamide, procarbazine, prednisolone, etopo-side, mitoxantrone, and bleomycin) are used.111,112 Newdrugs with few toxic effects will probably have a role in thetreatment of elderly patients with Hodgkins lymphoma.

PregnancyHodgkins lymphoma is one of the most common cancersreported in pregnancy.113 To avoid radiation exposure,staging should be with ultrasonography or whole-bodyMRI.114 Radiotherapy should generally be avoided becauseof the risk of teratogenicity. On the basis of data fromsmall case series, treatment with ABVD seems to be safe,especially in the second and third trimesters.115 Othertreatment options include observation or symptomcontrol with steroids or vinblastine alone until delivery.

However, the potential increased risk of relapse orrefractory disease with this approach should be considered.

HIV/AIDSIn the era of highly active antiretroviral therapy, themanagement and disease-specific prognosis of patientswith coexisting HIV/AIDS and Hodgkins lymphoma arethe same as for patients with Hodgkins lymphomawithout HIV/AIDS.116,117

Late effects of treatment and survivorshipThe late effects of treatment are key determinants ofthe long-term morbidity, mortality, and quality of life ofpatients treated for Hodgkins lymphoma and necessitates

long-term follow-up. In the first 10 years after treatmentmost deaths are due to relapse, but after this time deathsdue to late effects predominate.118 Secondary malignanciescan be solid organ (most commonly lung, skin, breast, andgastrointestinal) or haematological (leukaemia, myelo-dysplasia, and secondary lymphomas).119 Risk of secondarymalignancies is highest after treatment in childhood.120,121Radiotherapy is associated with increased cancer risk atmost irradiated sites, whereas after chemotherapy secon-dary malignancies are restricted to acute leukaemia, non-Hodgkin lymphoma, and lung cancer.122 Initial treatmentwith radiotherapy alone has the highest risk of secondarymalignancies because of treatment failures and exposureto subsequent salvage therapy.123,124 The risk of development

of malignant disease in people treated for Hodgkinslymphoma before adulthood has been estimated to be185 times greater than the general population, with a30 year cumulative risk of 18% for male patients and 26%for female patients.121

The most common secondary malignancy in femalepatients is breast cancer. Age of younger than 20 yearsat time of treatment and EFRT incorporating themediastinum are the most important risk factors.124,125 Therisk of breast cancer was estimated to be 29% (95% CI202401%) in patients who received 40 Gy mediastinalirradiation before age 25 years in one study.126 UKguidelines recommend that female patients given

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supradiaphragmatic radiotherapy are offered screeningwith yearly mammography or MRI from 8 years aftertreatment or at age 25 years (whichever is later). 127 USguidelines recommend yearly screening from 10 yearsafter treatment or at 40 years of age (whichever is earlier).43

Chemotherapy drugs, especially alkylating agents,contribute to secondary malignancy risk; however, theincrease in risk associated with ABVD seems negligible.Small increases in the incidence of myelodysplasia andacute myeloid leukaemia were reported in the BEACOPPgroups of the GHSG HD9 trial, although the overall rateof secondary malignant disease was not increasedcompared with other chemotherapy regimens.60

Increases in incidence (noted from 1 to more than25 years after therapy) of myocardial infarction, con-gestive cardiac failure, asymptomatic coronary disease,

valvular dysfunction, and stroke have all been recordedafter treatment for Hodgkins lymphoma, and the risk ofcardiac mortality persists for many years after treatment.128The risk is related to supradiaphragmatic radiotherapy,anthracycline-containing chemotherapy, and possibly theuse of vinca alkaloids. Traditional cardiovascular riskfactors are additive and adjustment of modifiable riskfactors is important.

Other late effects include subfertility, endocrine dys-function, peripheral neuropathy, and local effects fromradiotherapy. Fertility is an important consideration inview of the young age of many people diagnosed withHodgkins lymphoma. Rates of amenorrhoea arehigher, whereas recovery of antimllerian hormone

concentrations and birth rates are lower, in womengiven BEACOPP than in those given ABVD; being olderthan 30 years at time of treatment was an importantrisk factor for subfertility.129 In one study,130 50% of womengiven escalated BEACOPP did not recover normalmenstruation compared with less than 5% after ABVD.Attempts to protect female fertility during BEACOPPtreatment by hormonal manipulation have beenunsuccessful.131 Pregnancy is frequently possible afterautologous stem-cell transplantation if menstruation wasnormal before high-dose therapy. In men, the rate ofazoospermia after treatment with BEACOPP is 8793%,whereas ABVD induces permanent azoosepermia in lessthan 5% of patients.61,132,133 For male patients, sperm storage

can usually be offered before treatment, whereas fertility-sparing measures in female patients are time consumingand, because of treatment delays, not always advisable.

ConclusionToday most patients with Hodgkins lymphoma are curedand current developments are likely to lead to further, ifsmall, improvements in overall survival because of bothimproved tumour eradication and reduction of lateeffects. Because of the success of the treatment ofHodgkins lymphoma, proof of further advances willrequire very large trials with long-term follow-up, andinternational collaboration will be essential.

Contributors

Both authors contributed equally to the writing of this Seminar.

Conflicts of interest

DL has served on advisory boards for Roche and MillenniumPharmaceuticals, and has received travel grants from Roche and Chugai.WT declares that he has no conflicts of interest.

Acknowledgments

WT is a clinical lymphoma fellow at the Cancer Research UK and UCLCancer Trials Centre and is funded by the Lymphoma Research Trust.DL is a National Institute for Health Research senior clinical fellow andreceives funding from Cancer Research UK, the Lymphoma ResearchTrust, Leukaemia and Lymphoma Research, and the National Institutefor Health Research Biomedical Research Centre at University CollegeLondon Hospitals.

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123 Franklin JG, Paus MD, Pluetschow A, Specht L. Chemotherapy,radiotherapy and combined modality for Hodgkins disease, withemphasis on second cancer risk. Cochrane Database Syst Rev2005;4: CD003187.

124 Franklin J, Pluetschow A, Paus M, et al. Second malignancy riskassociated with treatment of Hodgkins lymphoma: meta-analysis ofthe randomised trials. Ann Oncol2006; 17: 174960.

125 Baxi SS, Matasar MJ. State-of-the-art issues in Hodgkins lymphomasurvivorship. Curr Oncol Rep 2010; 12: 36673.

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126 Travis LB, Hill D, Dores GM, et al. Cumulative absolute breastcancer risk for young women treated for Hodgkin lymphoma.

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127 Howell SJ, Searle C, Goode V, et al. The UK national breast cancerscreening programme for survivors of Hodgkin lymphoma detectsbreast cancer at an early stage. Br J Cancer2009; 101: 58288.

128 Swerdlow AJ, Higgins CD, Smith P, et al. Myocardial infarctionmortality risk after treatment for Hodgkin disease: a collaborativeBritish cohort study.J Natl Cancer Inst2007; 99: 20614.

129 Harel S, Ferm C, Poirot C. Management of fertility in patientstreated for Hodgkins lymphoma. Haematologica 2011; 96: 169299.

130 Behringer K, Breuer K, Reineke T, et al, and the German HodgkinsLymphoma Study Group. Secondary amenorrhea after Hodgkinslymphoma is influenced by age at treatment, stage of disease,chemotherapy regimen, and the use of oral contraceptives duringtherapy: a report from the German Hodgkins Lymphoma StudyGroup.J Clin Oncol2005; 23: 755564.

131 Behringer K, Wildt L, Mueller H, et al, and the German HodgkinStudy Group. No protection of the ovarian follicle pool with the useof GnRH-analogues or oral contraceptives in young women treatedwith escalated BEACOPP for advanced-stage Hodgkin lymphoma.Final results of a phase II trial from the German Hodgkin StudyGroup. Ann Oncol2010; 21: 205260.

132 Viviani S, Santoro A, Ragni G, Bonfante V, Bestetti O,Bonadonna G. Gonadal toxicity after combination chemotherapy forHodgkins disease. Comparative results of MOPP vs ABVD.

Eur J Cancer Clin Oncol1985; 21: 60105.133 van der Kaaij MA, Heutte N, Le Stang N, et al, and the EuropeanOrganisation for Research and Treatment of Cancer: EORTCLymphoma Group, and the Groupe dEtude des Lymphomes delAdulte. Gonadal function in males after chemotherapy forearly-stage Hodgkins lymphoma treated in four subsequent trialsby the European Organisation for Research and Treatment ofCancer: EORTC Lymphoma Group and the Groupe dEtude desLymphomes de lAdulte.J Clin Oncol2007; 25: 282532.

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