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Hodgkins lymphoma is a rare malignancy, with anincidence of about 24 per 100000 per year.1 Prevalencein women peaks in the third decade and then falls, but inmen it remains fairly constant after this time.1 Diagnosisof Hodgkins lymphoma is based on the finding ofHodgkin/Reed-Sternberg cells in an appropriate cellularbackground of reactive leucocytes and, in some cases,fibrosis. The disorder is classified into two distinctentities: nodular lymphocyte-predominant Hodgkinslymphoma; and classical Hodgkins lymphoma.2

Nodular lymphocyte-predominant Hodgkins lym-phoma represents about 5% of all cases of the disease. It ismost common in males, and typically presents with

limited nodal disease of the neck without constitutionalsymptoms.3

Classical Hodgkins lymphoma is divided into foursubtypes (panel 1). In the developed world, nodularsclerosing classical Hodgkins lymphoma accounts forover two-thirds of all cases. Lymphocyte-rich classicalHodgkins lymphoma is a newly defined entity, and isclosely similar to the disorder previously classified asdiffuse lymphocyte-predominant Hodgkins disease.Lymphocyte-depleted Hodgkins lymphoma is now rarelydiagnosed; most patients diagnosed with this entity wouldnow be classified as having nodular sclerosing disease oranaplastic large-cell lymphomas. All subtypes of classicalHodgkins lymphoma are at present treated in the sameway.

PathogenesisIn nodular and classical lymphocyte-predominantsubtypes of Hodgkins lymphoma, the malignant cellis derived from a B lymphocyte, with clonal immuno-globulin gene rearrangements in most patients.46

Malignant cells in nodular lymphocyte-predominantHodgkins lymphoma have the immunophenotype and

Lancet 2003; 361: 94351

Royal Free and University College Medical School, London

WC1E 6HX, UK (L Yung MRCP, Prof D Linch FRCP)

Correspondence to: Prof D Linch, Department of Haematology, Royal

Free and University College Medical School, University College

London, 98 Chenies Mews, London, WC1E 6HX, UK

(e-mail: [email protected])

genotype of post-germinal-centre B cells, whereas inclassical Hodgkins lymphoma, mature B-cell antigenexpression can be low or absent, and no immunoglobulin

is produced despite immunoglobulin gene rearrangementsand subsequent somatic mutations (panel 2). In somecases of the disease, absence of immunoglobulinproduction is attributable to mutations in theimmunoglobulin gene (eg, creation of stop codons),7,8 butin others, dysregulation of transcriptional machineryentailed in immunoglobulin gene expression takes place.8

The immunoglobulin receptor complex providesimportant survival signals to developing B cells, andabsence of immunoglobulin expression could putHodgkin/Reed-Sternberg cells at a survival disadvantageunless other antiapoptotic events had happened.

Epstein-Barr virus infection is one such possibleevent.911 Nuclear proteins of this virus, such as EBNA andLMP1 (latent membrane protein 1), have been detected

in about 40% of cases of classical Hodgkins lymphoma,with the highest frequency in mixed cellularity disease.12

LMP1 is known to have oncogenic potential by triggeringBCL2 expression and acting via the CD40 cell-signallingpathway, allowing cells to evade cellular apoptoticmechanisms.13 Association with Epstein-Barr virus varieswith age; childhood Hodgkins lymphoma is almostinvariably associated, as are most cases in elderly people.The lowest rates of Epstein-Barr virus-associatedHodgkins lymphoma are reported in young adults (age

Hodgkins lymphoma

Lynny Yung, David Linch

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THE LANCET Vol 361 March 15, 2003 www.thelancet.com 943

Hodgkins lymphoma was first described in 1832, but the nature of the pathognomic Reed-Sternberg cell, on whichdiagnosis of the disease is based, has only been elucidated in the past few years. Radiotherapy has been used to treatlocalised disease since the 1940s, and in the 1960s, effective combination chemotherapy regimens were introducedfor anatomically advanced disease. The past three decades have witnessed continued improvement in outcome tosuch an extent that Hodgkins lymphoma is now one of the most curable of all non-cutaneous malignancies. Withimproved survival and extended follow-up, relevance of treatment-induced late effects has become apparent, andmodern therapeutic strategies must fully account for these effects. We review the pathology of Hodgkins lymphoma,and its clinical presentation, investigation, present management, and natural history, including late effects oftreatment.

Search strategy and selection criteria

We systematically searched Medline with terminology relating

to the aspects of Hodgkins lymphoma discussed in this

Seminar. Articles were retrieved up to October, 2002, andstudies reported in full and abstract form have been included.

Panel 1: WHO classification of Hodgkins lymphoma

q Nodular lymphocyte-predominant Hodgkins lymphoma

q Classical Hodgkins lymphoma

Nodular sclerosis classical Hodgkins lymphoma

Mixed cellularity classical Hodgkins lymphoma

Lymphocyte-rich classical Hodgkins lymphoma

Lymphocyte-depleted classical Hodgkins lymphoma


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1534 years),9 raising the possibility that alternativelymphotropic viruses are implicated in the pathogenesis ofcases negative for Epstein-Barr virus.13 Hodgkinslymphoma associated with immunosuppressed states suchas HIV-1 infection, post-solid organ and bone-marrow

transplantation, and congenital immunodeficiency statesis also usually associated with this virus.14

A further mechanism by which Hodgkin/Reed-Sternberg cells might escape apoptosis is via the NFBpathway (figure 1).1518 NFB belongs to a family oftranscription factors implicated in regulation of manyprocesses, including apoptosis and oncogenesis. It isupregulated in Reed-Sternberg cells in most patients withclassical Hodgkins lymphoma, and is regulated by severalupstream elements, including CD40 ligand and tumournecrosis factor-receptor-associated factors, though theexact mechanism is still unclear.17 NFB is present in thecytosol of the resting cell attached to its inhibitor IB.Activation of the cell by various routes, such as via CD40ligand or LMP1, leads to activation of Ikinase (IKK) and

phosphorylation of IB and subsequent ubiquitinationwith degradation by the 26S proteasome.16 LiberatedNFB is then able to move into the nucleus in which itactivates transcription of several target genes implicated inprevention of apoptosis. Furthermore, the C-FLIPprotein, which inhibits apoptosis and has been implicatedin germinal-centre cell survival, was expressed inmalignant cells of 18 of 19 patients with Hodgkinslymphoma.19

Clinical presentationThe presenting features of Hodgkins lymphoma aremany. Most patients present with an enlarged butotherwise asymptomatic lump, typically in the lower neckor supraclavicular region. Mediastinal masses are frequentand are sometimes discovered after routine chestradiography. Patients might complain of chest discomfortwith a cough or dyspnoea. About 25% of patients will havesystemic symptoms at presentation, typically fatigue, fever,weight loss, and night sweats. Pruritus and intermittentfevers usually associated with night sweats are classic

symptoms of Hodgkins lymphoma.

StagingThe Ann Arbor staging system was developed more than30 years ago to define patients who could be treated byradiotherapy, and it is still valuable in defining treatmenteven though radiation alone is not generally used. Thesystem was modified in 1989 (Cotswold modifications;panel 3),20 taking into account the importance of bulkydisease and the fact that laparotomy and splenectomywere no longer recommended as staging procedures,because they have no effect on overall survival and are

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944 THE LANCET Vol 361 March 15, 2003 www.thelancet.com

Panel 2: Comparison of phenotypes of classical andlymphocyte-predominant Hodgkins lymphoma

Antigen Classical Hodgkins Nodular lymphocyte-

lymphoma predominant Hodgkins

(Reed-Sternberg lymphoma (L&H

cells) cells)

CD20 Occasionally positive Usually positiveOther B-cell Usually negative Usually positive

antigens

CD30 Positive Negative

CD15 Usually positive Negative

Immunoglobulin Absent Present

expression

L&H=atypical and lymphocytic and histiocytic.

IB

p65

IB

p65

p65

PP

IB

P

Ikinase

LMP CD40

Cytokines, eg,

TNF

Proteasomal

degradation

Target gene

transcription

p50

p50

p50

P

Figure 1: NFB activationTNF=tumour necrosis factor; P=phosphate. p50 and p65 are

heterodimers of NFB.

Panel 3: Ann Arbor staging system with Cotswoldmodifications for Hodgkins lymphoma

Stage

1 Involvement of one lymph-node region or lymphoid

structure (eg, spleen, thymus, Waldeyers ring)

2 Two or more lymph-node regions on the same side of the

diaphragm3 Lymph nodes on both sides of the diaphragm

31: with splenic hilar, coeliac, or portal nodes

32: with para-aortic, iliac, or mesenteric nodes

4 Involvement of extranodal site(s) beyond that

designated E

Modifying features

A No symptoms

B Fever, drenching night sweats, weight loss greater than

10% in 6 months

X Bulky disease: greater than a third widening of

mediastinum

greater than 10 cm maximum diameter of

nodal mass

E Involvement of single, contiguous, or proximal extranodal

siteCS Clinical stage

PS Pathological stage

Panel 4: EORTC risk factors in localised disease25

FavourablePatients must have all features:

q Clinical stage 1 and 2

q Maximum of three nodal areas involved

q Age younger than 50 years

q Erythrocyte sedimentation rate (ESR) less than 50 mm/h

without B symptoms or ESR less than 30 mm/h with B

symptoms

q Mediastinal/thoracic ratio less than 035

Unfavourable

Patients have any features:

q Clinical stage 2 with involvement of at least four nodal areas

q Age older than 50 years

q ESR greater than 50 mm/h if asymptomatic or ESR

greater than 30 mm/h if B symptomsq Mediastinal/thoracic ratio greater than 035


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associated with significant morbidity and occasionallymortality.21

Lymphangiography is also now rarely done, and CT isthe major means of staging intrathoracic and intra-abdominal disease. MRI is largely restricted to assessmentof specific situations such as bony involvement andspinal-cord compression. Fluorodeoxyglucose-positronemission tomography (FDG-PET), relying on the uptakeof 2-fluoro-2-deoxy-D-glucose by metabolically active

tissues, might provide more accurate staging informationthan CT,2224 but is not yet standard practice.

Prognostic factorsThe British National Lymphoma Investigation (BNLI)published a prognostic index in localised Hodgkinslymphoma in 1985 based on analysis of more than2000 patients.21 This index was complex and not widelyadopted, though the principle of determining treatmenton the basis of risk factors has become well established.The EORTC (European Organisation for the Researchand Treatment of Cancer) have identified several featuresindicative of a worse prognosis in stage 1 and 2 diseaseand have used them to stratify treatment (panel 4).25 Inadvanced disease, the international prognostic score (or

Hasenclever index) was developed (panel 5)26 on the basisof analysis of 5141 patients treated initially with ananthracycline-containing chemotherapy regimen. Sevenfactors were identified, which individually reducedpredicted 5-year freedom from progression rate byaround 8%.

Response assessmentResidual masses after treatment are very frequent inHodgkins lymphoma, creating problems in establishingwhich patients have had a complete response. The entityof unconfirmed or uncertain complete response has beenintroduced,27 which refers to patients in whom there isuncertainty about remission status because of persistentradiological abnormalities, especially in the mediastinum.

Planar and single-photon emission CT (SPECT) galliumscanning have been used to assess residual masses. 28

Gallium is predominantly excreted via the gastrointestinaltract, which could limit its use in assessment ofabdominal disease.29 Comparative studies betweengallium scanning and PET are underway.30

PET scanning is likely to have an important role inclarification of remission status in patients with anuncertain or unconfirmed complete response since2-fluoro-2-deoxyglucose is taken up by residualmetabolically active tumour cells and not fibrotic tissue.31

FDG-PET has been shown to have significantly highersensitivity, specificity, and positive and negativepredictive values for disease-free survival than CT.31,32

Our practice is to do PET no earlier than 3 weeks aftercompletion of treatment in patients who have suspicioussymptoms or a residual mass on end-of-treatment CT.

On the basis of clinical findings and results of PET,patients can be closely monitored with repeat PET if

necessary, or might be offered further treatment.However, PET cannot reliably assess extranodal orinflammatory disease well,32 and at present, biopsy ofunusual lesions is recommended.

TreatmentBoth localised and advanced Hodgkins lymphoma can becured in most patients, and outcome has improved overthe past three decades (figure 2). Unlike many otherforms of cancer, it is often possible to cure Hodgkinslymphoma even if first-line treatment fails. This factcreates the dilemma of whether it is better to use a moreextensive treatment initially, to cure as many individualsas possible, or whether a less intensive treatment shouldbe used first, followed by aggressive salvage therapy in

more patients.

Nodular lymphocyte-predominant Hodgkins lymphoma

No prospective randomised trials have been undertakenspecifically in patients with nodular lymphocyte-predominant Hodgkins lymphoma. Disease is usuallylocalised, and is often treated with surgical excision andinvolved-field radiotherapy, though if excision iscomplete then radiotherapy might be unnecessary. TheEuropean Task Force on Lymphoma reported a 96%complete response rate to primary treatment, with a 99%and 94% 8-year disease-specific survival for stage 1 and2 disease, respectively.3 Patients with advanced-stage orrelapsed disease are generally treated in the same way aspatients with classical Hodgkins lymphoma (see below).

Researchers from Germany and Stanford, USA, havereported use of the CD20 monoclonal antibodyrituximab in patients with nodular lymphocyte-predominant Hodgkins lymphoma. Treatment is well-tolerated, and results have been encouraging, with a veryhigh response rate.33,34 These data are preliminary, andneed longer follow-up, but rituximab should certainly beconsidered in patients failing combination chemo-therapy.

Classical Hodgkins lymphoma

All forms of classical Hodgkins lymphoma are usuallytreated in the same way, although in some centresspecific histological subtypes are used as prognosticfactors, and could therefore modify the risk group andtreatment prescribed. Therapy is mainly based onanatomical stage.

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Panel 5: Hasenclever index26

1 Age older than 45 years

2 Male sex

3 Serum albumin less than 40 g/L

4 Haemoglobin concentration less than 105 g/dL

5 Stage 4 disease

6 Leucocytosis (white-cell count greater than or equal to15109/L

7 Lymphopenia (less than 06109/L or less than 8% of the

total white-cell count)

100

80

60

40

20

0Cumulative

proportionsurviving

(%)

0 10

p


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Localised disease

Many trials have been done in localised Hodgkinslymphoma, but to directly compare results from differenttrials is difficult. Entry criteria vary, and some groupsstratify localised disease into several different risk groups.The EORTC, for instance, has divided localised diseaseinto two risk groups (panel 4). In the UK, usual practice

has been to have only one category of localised disease,and patients with stage 2B or 3A disease are automaticallyregarded as advanced disease.

Traditionally, treatment for localised disease wasradiotherapy alone. Complete remission rates were veryhigh, but relapse was frequent. The more extensive theradiation fields, the lower the relapse rate, and in arandomised trial done by the BNLI, mantle or inverted-Yfields resulted in a roughly 11% higher time-to-treatment-failure value than involved-field radiotherapy.35 In Europe,even more extended radiation fields have been usedroutinely, but even so, 2030% of patients still relapse.More extensive radiation fields have not translated intoimproved survival, attesting to the success ofchemotherapy in radiation failures.36 Nonetheless, such

high relapse rates are now deemed unacceptable.Relapse risk can be reduced by use of combined

treatment with chemotherapy and radiotherapy. Littleevidence exists that this combined modality treatmentimproves survival;36 however, with this therapy, shortercourses of chemotherapy than are used in advanceddisease and more restricted radiation fields can be used.

In the EORTC H7 combined modality treatment trialfor unfavourable-risk disease, four cycles of chemotherapywere as effective as six, and involved-field radiation was aseffective as subtotal nodal irradiation.37 Even in this poor-risk group of patients, failure-free survival and overallsurvival at 6 years were 89% and 90%, respectively. Bycontrast, in patients with better-risk disease, shortercourses of chemotherapy are adequate. For example, in

the EORTC/GELA H8 trial for favourable-risk disease,three cycles of a MOPP (chlormethine, vincristine,procarbazine, and prednisolone)/ABV (doxorubicin,bleomycin, and vinblastine) hybrid regimen plus involved-field radiotherapy were more effective than subtotal nodalirradiation, and gave a 4-year event-free survival of 99%.38

Three cycles of combination chemotherapy (usuallyABVD [doxorubicin, bleomycin, vinblastine, anddacarbazine]) plus involved-field radiotherapy should thusbe judged the standard for treatment in favourable-risklocalised disease. Various even shorter chemotherapyregimens have been combined with involved-fieldradiotherapy,39 and although they might be less efficaciousthan three cycles of ABVD or equivalent, they probablyhave fewer short-term and long-term toxic effects.

As well as reducing the amount of chemotherapy, itmight also be possible to reduce the radiation field anddose in combined modality treatment. In the GermanHD8 trial, patients with stage 1 or 2 disease and at leastone risk factor were treated with four courses ofalternating COPP (cyclophosphamide, vincristine,procarbazine, and prednisone) and ABVD. Rates ofsurvival or freedom from treatment failure did not differbetween patients receiving consolidation involved-fieldradiotherapy and those receiving extended-fieldradiation.40 The present HD10 trial is designed toinvestigate use of reduced doses of radiation and restrictedfields.41

Concern over radiation-induced second malignancieshas raised the issue of whether localised disease should betreated with chemotherapy alone, and this issue is thesubject of ongoing trials.

Advanced disease

Introduction of the MOPP chemotherapy regimen in the1960s was a major landmark in treatment of advancedHodgkins lymphoma.42 Over the next few years, severalmodifications to this regimen were made, whichmaintained efficacy but reduced associated toxiceffects.4346 The ABVD regimen was introduced in the1970s as non-crossresistant salvage for patients failingMOPP,4347 and was later used as first-line treatment,particularly because the drugs in ABVD were far less likely

to induce infertility and secondary leukaemia than werethose in MOPP. ABVD was also combined with MOPP orMOPP-like therapy in either an alternating or hybridregimen to introduce many drugs over a short period in thehope of reducing development of tumour resistance. Aseries of randomised trials4851 subsequently establishedABVD as the gold standard (table) on the basis of itsefficacy and reduced long-term toxic effects.

Encouraging results have been reported with somealternative regimens. The Stanford V regimen is a12-week course of seven active drugs with radiotherapy tosites of initial bulk disease. Data for 142 patients showed a5-year failure-free survival of 89% and a 5-year overallsurvival of 96%.52 A small randomised Italian study,however, noted the Stanford V regimen to be inferior to

ABVD;53 randomised trials of Stanford V versus ABVD arecontinuing in several countries.

The German Hodgkin Study Group54 compared theirstandard alternating regimen (COPP and ABVD) with ahybrid regimen (BEACOPP [bleomycin, etoposide,doxorubicin, cyclophosphamide, vincristine, procar-bazine, and prednisone]) and a dose-intensified version ofthis regimen (escalated BEACOPP). Escalated BEACOPPneeds routine administration of granulocyte-colonystimulating factor. Results of the final analysis showedsignificant improvement in freedom from treatment failureat 5 years in the BEACOPP arm compared with the COPPand ABVD arm (76% vs 69%); a further substantialimprovement was seen in the escalated BEACOPP arm, inwhich freedom from treatment failure at 5 years was87%.54 Both BEACOPP arms showed an advantage inoverall survival at 5 years over the standard COPP and

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Trial Disease Number Treatment FFS OS Time

name stage of (%) (%) (years)

patients

CALGB48 3, 4 361 5

MOPP 50* 66

MOPP/ABVD 65* 75

ABVD 61* 76

INT Milan49 1A4 427 10

(415 MOPP/ABVD 67 74

evaluable) alternating

MOPP/ABV 69 72

hybrid (radio-

therapy to initial

bulk in both

arms)

NCIC50 3B4 or 301 5

after wide MOPP/ABV 71 81

field radio- hybrid

therapy MOPP/ABVD 67 83

alternating

CALGB 34 or after 856 3

895251 radiotherapy MOPP/ABV 67 85

failure ABVD 65 87

CALGB=Cancer and Leukaemia Group B; NCIC=National Cancer Institute of

Canada; FFS=failure-free survival; OS=overall survival. *p


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ABVD arm; however, no significant difference betweenbaseline BEACOPP and escalated BEACOPP was noted.Nine cases of acute myeloid leukaemia/myelodysplasticsyndrome were reported in the escalated dose armcompared with four in the baseline BEACOPP arm andone in the COPP and ABVD arm.54 This findingemphasises the fact that longer follow-up will be needed

before final conclusions can be drawn. Furthermore,patients have considerably more chance of infertility with aprocarbazine-containing regimen than with ABVD.55 Atthe very least, results of this study show there is a cleardose-response relation within the dose range possiblewithout haemopoietic stem-cell support.

A further issue is whether intensive regimens, such asescalated BEACOPP, should be reserved for high-riskpatients. In the UK, the ChlVPP alternating withPABLOE regimen56 has been widely used, and analysis of326 patients showed not only a reduced failure-freesurvival in poor-risk patients (IPS 47) but also a reducedsalvage rate with alternative therapies.57 Thus, regimenssuch as escalated BEACOPP might be most beneficial inhigh-risk patients. Researchers have suggested that high-

risk patients might benefit from high-dose therapy andstem-cell transplantation in first remission,58 but results ofa randomised trial did not substantiate this.59 It isnoteworthy in this trial that patients receiving continuedconventional dose therapy had good 5-year failure-freesurvival of 83%, showing the difficulty in defining a poor-prognosis group once a good response to initial therapy hasbeen obtained.

Radiotherapy in advanced Hodgkins lymphoma

Consolidation radiotherapy has frequently been used inpatients with advanced Hodgkins lymphoma, especially inpatients achieving an unconfirmed or uncertain completeresponse or in those with bulky disease at presentation.Evidence for this practice is not strong. The Groupe

dEtude des Lymphomes de LAdulte H89 trial indicatedno benefit to radiotherapy consolidation compared withtwo extra cycles of a doxorubicin-containing regimen.60

Results of the EORTC 20884 trial similarly showed noadvantage of consolidation radiotherapy in remission afterMOPP/ABV hybrid therapy.61 Furthermore, a meta-analysis comparing chemotherapy with combined modalitytherapy suggested that the addition of radiotherapy mightbe associated with a reduced survival attributable to long-term effects of treatment.62 Despite these negativeconclusions about consolidation radiotherapy, tworegimens with good results both use radiotherapyconsolidation in most patients. In Stanford V,52 85% ofpatients received radiotherapy, and in escalatedBEACOPP,54 radiotherapy was given to most patients.

Treatment of childhood Hodgkins lymphoma

Hodgkins lymphoma in children and adolescents iscurable in over 90% of cases.63 Several specific childhoodtreatment regimens have been developed, whichencompass the same general principles, namely, avoidanceof laparotomy staging, risk-adjusted therapy, combinedmodality treatment at all stages of disease, avoidance ofprocarbazine in boys to protect future fertility, and keepingradiation dose and field and anthracycline dose to aminimum.64 Many of these same principles are now beingapplied in adults with Hodgkins lymphoma.

Relapsed disease

Some patients receiving chemotherapyeither de novo orafter radiation failurewill have refractory disease or willrelapse. Occasionally, patients can be cured by

radiotherapy if persistent or relapsed disease is localised,but most patients will need systemic treatment. Manypatients with long first remissions can be cured by furtherstandard dose chemotherapy, but results of suchapproaches are poor if remission has been short or diseasewas refractory to initial chemotherapy.65,66

High-dose chemotherapy and autologous stem-cell

transplantation was pioneered in patients with relapsedHodgkins lymphoma more than 40 years ago, but it hasonly become an established modality of treatment in thepast two decades.67 Procedure-related mortality has fallenover recent years because of better selection of patientsand improved supportive care68 and more rapidengraftment associated with peripheral-blood stem cells,which have now largely replaced bone marrow as thesource of haemopoietic stem cells.69 In large single-centreseries,68 and in Registry reviews,70 about 4050% oftransplanted patients with relapsed or resistant disease arealive after 5 years. Several different conditioning regimenshave been used, and high-dose chemotherapy is generallypreferred to total-body irradiation. This preference isbecause chemotherapy is logistically easier to administer,

is as effective as total body irradiation, and might beassociated with less pneumonitis, although high-dosechemotherapy is undoubtedly also associated withpneumonitis, especially in patients who have receivedmediastinal radiation in the preceding year.71,72 After high-dose therapy, irradiation of persistent masses or sites ofprevious large volume disease is common practice,although no trial data to substantiate this practice areavailable.

Before high-dose therapy, standard-dose chemotherapyis usually given to reduce disease bulk and determinechemosensitivity. In patients who have disease thatprogresses through standard-dose salvage therapy, or havepersistent B symptoms or a raised concentration of lactatedehydrogenase, results of high-dose therapy are probably

too poor to justify proceeding to this course of action.However, in some cases, a mass will not immediatelyreduce in size, and failure to achieve a formal response(complete or partial remission) should not exclude apatient from receiving an autograft.

The BNLI did a small randomised trial of BEAM(carmustine, etoposide, cytarabine, and melphalan)followed by autologous stem-cell transplantation or mini-BEAM (the same drugs at reduced doses) in patients withrefractory or relapsed disease. A highly significantprogression-free survival advantage was noted in the high-dose treatment arm,73 and similar results havesubsequently been reported from a larger German study.74

Neither study showed an overall survival benefit, whichmight, in part, be attributable to the small size of these

trials, or might be because some patients failing standard-dose salvage therapy can still be rescued by high-dosetherapy at a later time. When therefore is the optimumtime to consider an autograft procedure? This procedureis widely recommended for all patients younger than age65 years who fail first-line chemotherapy, although thistreatment might not be appropriate if first completeremission lasted more than 3 years.

The value of allogeneic transplantation in patients withHodgkins lymphoma is unclear. In large published series,high rates of transplant-related mortality have beenreported.7578 Nonetheless, patients surviving an allogeneictransplant may have a reduced relapse rate,7779 suggestinga graft-versus-lymphoma effect. There is interest in use ofless toxic non-myeloablative allogeneic transplants inHodgkins lymphoma, especially in patients who havefailed a previous autograft. In a UK study of 24 patients

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with relapsed or refractory disease, only two procedure-related deaths were reported. Several patients whosubsequently relapsed responded to donor lymphocyteinfusions. Further follow-up and larger trials will beneeded to ascertain the role of this modality oftreatment.80

Late effects of Hodgkins lymphoma and itstreatmentBecause the cure rate for Hodgkins lymphoma has risen,

and longer-term follow-up data have become available,the importance of late effects of treatment have becomemore apparent (panel 6). In a study of young adultpatients aged younger than 29 years at diagnosis, whoachieved continuing complete remission after first-lineor second-line treatment, actuarial overall survival at20 years was 93% and 85%, respectively, compared wth985% in the age-matched general population.81 Furtherreview of patients treated for favourable-risk diseaseindicated that treatment-related mortality exceeded thatfrom Hodgkins lymphoma by 1215 years after initialtherapy.82 The two most frequent causes of excess deathsare second malignancies and ischaemic heart disease.

The most common second malignancy in patients withHodgkins lymphoma is lung cancer. This disease is

mainly attributable to radiotherapy, althoughchemotherapy also contributes to the risk.83,84 It isimperative that all patients who have had thoracicradiation are strongly encouraged never to smoke. Risk ofdeveloping secondary myeloid leukaemia is related to thecumulative dose of alkylating agents received, andtherefore, arises predominantly in patients who have hadremitting and relapsing disease. Secondary breast cancermainly occurs after irradiation to the mediastinum oraxillae, especially when given to adolescent females oryoung women. A dose-response relation exists, whichunderscores use of the minimum radiation dose neededfor tumour control.85 Risk in such patients of everdeveloping breast cancer is about 2050%,86 and patientsat such high risk need to be aware of this fact and offered a

screening programme. Other malignancies that arise inexcess in patients treated for Hodgkins lymphomainclude non-Hodgkin lymphomas, head and necktumours, cancers of the colon, stomach, and thyroid, andmalignant melanoma.84,86,87 Patients should be advised toconsult their doctor if they have any suspicious symptoms,and they should be strongly advised to use effectivemeasures to avoid sunburn.

The Stanford group reported about a three-foldincrease in relative risk of cardiac death in patients whodid not die from Hodgkins lymphoma,88 which is a majorrisk because prevalence of cardiac disease in the generalpopulation is so high. The major contributing factor ismediastinal irradiation when a dose in excess of 30 Gy isused.88 Whether or not the increasing use ofanthracyclines will have a long-term effect on cardiacdisease is not yet clear.

The most common endocrine disorders arehypothyroidism after radiation to the lower neck andinfertility. Around 50% of patients receiving neckirradiation will develop hypothyroidism, and theseindividuals should have their thyroid function assessedevery year.89 Recipients of neck irradiation are also athigher risk of development of dental caries and other oral

diseases.90

The importance of regular dental attentionshould be emphasised to patients.

Infertility arises after irradiation of the gonads and afteruse of drugs such as procarbazine and alkylating agents.Repeated use is most damaging, and young femalepatients receiving an autologous transplant will oftenremain fertile if they are still menstruating before receivinghigh-dose therapy.68 Sperm cryopreservation beforechemotherapy is standard practice for men who have notcompleted their families. Artificial insemination has a lowsuccess rate per cycle; however, intracytoplasmic sperminjection may improve the success rate.91 Hodgkinslymphoma can typically be slow-growing, which mightpermit harvesting of eggs, in-vitro fertilisation, andembryo storage in those young women who have an

established partner.92 Oocyte cryopreservation and ovariantissue banking are presently in development.93

Psychological trauma associated with contracting amalignant disease, receiving radiotherapy andchemotherapy, and coping with risk or eventuality ofrelapse is great. In one survey,94 many patients reported alower perceived level of overall health and dissatisfactionin their personal relationships as a result of disease, itstreatment, or both. Many also had difficulties in obtaininglife assurance and financial loans.

Present treatment strategies must therefore aim to giveminimum therapy without jeopardising the high rates ofcure that are now possible with front-line therapy.

Novel treatments

Cytotoxic drugsGemcitabine, an analogue of cytarabine, has antitumouractivity in Hodgkins lymphoma.95 It is well tolerated witha favourable toxicity profile, and given at a dose of1250 mg/m2, it has been reported to have a response ratein excess of 35% in heavily pretreated patients.96

In view of the fact that NFB is frequently activated inHodgkin/Reed-Sternberg cells, this pathway is animportant target for new drug development. Particularattention is focused on proteasome inhibitors, whichprevent degradation of IB and thus keep the liberation ofactive NFB to a minimum.17,97

Immunotherapy

Ex-vivo generation of Epstein-Barr virus-specific cytotoxic

T lymphocytes for reinfusion into patients with Hodgkinslymphoma has had limited success.98 However, strategiesaimed at generation of LMP-selective cytotoxic T lympho-cytes with autologous dendritic cells could prove moreefficacious.99

One of the most promising antigens for targetedimmunotherapy is the CD30 antigen, which is highlyexpressed on Hodgkin/Reed-Sternberg cells. Severalgroups of researchers have shown that antiCD30monoclonal antibodies chemically linked to active toxinshave antitumour activity in Hodgkin cell lines and alsoin SCID mice inoculated with tumour.100103 Studiesinvestigating radioimmunotherapy with 131I-labelledantiCD30 are also underway.104

Internalisation of an antibody-conjugated toxin can beamplified by use of antibodies with specificity for both atumour-associated antigen and a cell-surface antigen,

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Panel 6: Late effects of Hodgkins lymphoma andits treatment

q Second malignancies

q Cardiac disease

q Endocrine dysfunction

q Psychological trauma

q Lung damage (usually subclinical)q Hyposplenism (after splenectomy or splenic irradiation)

q Dental caries


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which facilitates internalisation of the formed complex.CD25 is the interleukin 2 receptor. An antiCD30 andCD25 immunotoxin was tested in SCID mice inoculatedwith Hodgkins lymphoma and achieved a substantiallyhigher cure rate than that achieved with single agentalone.105 Phase 1 and 2 trials have been done in patientswith refractory disease, and moderate responses have been

reported.106

An alternative use of bispecific antibodies is to augmentcell-mediated tumour killing by target-killer cellinteraction. Bispecific antibodies recognising CD30 andCD3 or CD28 on T cells have been developed and areactive in animals.107,108 Bispecific antibodies recognisingCD30 and either CD16, which is expressed on naturalkiller cells, granulocytes, and macrophages, or CD64,which is expressed on monocytes, macrophages, andactivated neutrophils, have also been developed.109,110

ConclusionThe nature of the malignant cell in Hodgkins lymphomais now understood, but the mechanism of tumorigenesishas not been fully elucidated. Results of treatment

continue to improve, and with such high cure rates, lateeffects become more important. In many situations, thesame ultimate survival can be achieved with differenttherapeutic approaches. Less intensive initial therapycures fewer patients, but many failures can be rescued bysubsequent more intensive treatment. Choice of approachis thus dependent on an appreciation of short-term andlong-term side-effects, and increasingly the patient mustbe involved in an informed decision-making process.

Conflict of interest statementNone declared.

AcknowledgmentsLY is funded by the Lymphoma Research Trust and DL receives funding

from the Medical Research Council, Cancer Research UK, the Leukaemia

Research Fund, and the Lymphoma Research Trust. DL sits on the

Roche Oncology Advisory Board. The funding sources had no role in the

writing of this Seminar.

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