Guidelines for the first line management of classical Hodgkinlymphoma

George A. Follows,1 Kirit M. Ardeshna,2 Sally F. Barrington,3 Dominic J. Culligan,4 Peter J. Hoskin,5 David Linch,2,6 Shalal

Sadullah,7 Michael V. Williams8 and Jennifer Z. Wimperis9 for the British Committee for Standards in Haematology

1Department of Haematology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, Cambridge, 2Department of Haema-

tology, University College Hospital London Hospitals NHS Trust, 3St Thomas’ Division of Imaging, PET Imaging Centre, Kings Col-

lege London, London, 4Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, 5Mount Vernon Cancer Centre,

Northwood, 6Department of Haematology, UCL Cancer Institute, University College Centre of Imaging, London, 7Department of Hae-

matology, James Paget University Hospital, Great Yarmouth, 8Department of Oncology, Addenbrookes Hospital, Cambridge University

Teaching Hospitals, London, and 9Department of Haematology, Norfolk and Norwich University Hospital, Norwich, UK

Keywords: Hodgkin, Hodgkin lymphoma, treatment, chemo-

therapy, radiotherapy.

The guideline group was selected to be representative of

UK-based medical experts and patients’ representatives.

MEDLINE and EMBASE were searched systematically for

publications in English from January 1990 to June 2013

using the key words Hodgkin, Lymphoma, Treatment, Che-

motherapy and Radiotherapy. References from relevant pub-

lications were also searched. The writing group produced the

draft guideline, which was subsequently revised by consensus

by members of the Haemato-Oncology Task Force of the

British Committee for Standards in Haematology (BCSH).

The guideline was then reviewed by a sounding board of

approximately 50 UK haematologists and the BCSH and

comments incorporated where appropriate. The ‘GRADE’

system was used to quote levels and grades of evidence,

details of which can be found in Appendix I. The objective

of this guideline is to provide healthcare professionals with

clear guidance on the management of patients with classical

Hodgkin Lymphoma (HL). The guidance may not be appro-

priate for all patients with HL and in all cases individual

patient circumstances may dictate an alternative approach.

Key recommendations

Pre-treatment evaluation

● Patients require pre-treatment blood evaluation including

human immunodeficiency virus (HIV) serology (1A).

● Staging with contrast–enhanced computerized tomogra-

phy (CT) of the neck to pelvis is required (1A), although

positron-emission tomography (PET)/CT is preferable if

clinically feasible (1B).

● Early stage patients should be classified as favourable or

unfavourable (1A).

● Advanced stage patients should be assessed to define the

Hasenclever/International Prognostic Score (IPS) (1A).

● For male patients, pre-treatment semen cryopreserva-

tion should be offered where possible (1A).

● For female patients, pre-treatment review of options

with a fertility specialist should be considered (1A).

Management of early stage disease

● Prognostic factors should be determined to allocate

patients to favourable and unfavourable sub-groups (1A).

● Standard of care for patients with favourable early stage

HL is 2 3 ABVD (doxorubicin, bleomycin, vinblastine,

dacarbazine) and 20 Gy radiotherapy (RT) (1A).

● Standard of care for unfavourable early stage HL is

4 3 ABVD and 30 Gy RT (1A).

● A treatment option for unfavourable early stage HL is

23 escalated BEACOPP (bleomycin, etoposide, doxoru-

bicin, cyclophosphamide, vincristine, procarbazine,

prednisone) + 2 3 ABVD and 30 Gy RT (1A).

● The decision to omit RT from the management of stage

IA/IIA non-bulky patients should involve discussion

with a radiation oncologist (1B) and patients choosing

to omit RT need to be aware of the balance of risks

between RT and additional cycles of chemotherapy (1B).

● RT should not normally be omitted in patients present-

ing with bulky disease (1B).

● Early stage patients treated without RT should receive

at least 3 3 ABVD (1B).

● Patients receiving bleomycin should be assessed carefully

for signs and symptoms of pulmonary toxicity before

each dose. A history of new or worsening dyspnoea or

Correspondence: Department of Haematology, Addenbrookes

Hospital, Cambridge University Teaching Hospitals, Cambridge, UK.

E-mails: bcsh@b-s-h.org.uk; george.follows@addenbrookes.nhs.uk

guideline

First published online 9 April 2014doi: 10.1111/bjh.12878

ª 2014 John Wiley & Sons LtdBritish Journal of Haematology, 2014, 166, 34–49

pulmonary crackles should lead to stopping of bleomycin

until an alternative cause is identified (1B).

Management of advanced stage disease

● Patients aged 16–60 years old with advanced stage HL

should receive either 6–8 cycles of ABVD or six cycles

of escalated BEACOPP (1A).

● The choice between ABVD and escalated BEACOPP will

depend on a range of factors, particularly the patient’s

opinion on the toxicity/efficacy balance between the reg-

imens (2B).

● Patients with a higher IPS are at higher risk of relapse,

potentially supporting the use of escalated BEACOPP in

this higher risk group, although there are no prospec-

tive trial data to support a specific IPS cut-off at which

escalated BEACOPP may be advantageous (2B).

● Patients treated with escalated BEACOPP who achieve

an end-of-treatment PET-negative remission do not

require consolidation RT to residual tissue (1A).

● Patients treated with ABVD should be considered for

RT to sites of original bulk or residual tissue >1�5 cm.

It remains unclear whether RT can be safely omitted in

ABVD patients who have residual tissue >1�5 cm on CT

that is PET-negative (1A).

● Interim PET (iPET2) is highly predictive of outcome in

patients treated with ABVD (1A).

● It remains unclear how iPET2-positive patients are opti-

mally managed in routine practice. Accepting the

limitations of small, published datasets, treatment

intensification to escalated BEACOPP � RT appears

reasonable (2B).

● Patients who remain PET-positive on completion of

therapy require biopsy assessment or close clinical/

radiological surveillance for early progression (1B).

● Patients who develop progressive disease on therapy

should be considered for treatment intensification with

transplantation (see separate guidelines) (1A).

Management of HL in pregnancy

● Patients should be closely co-managed with a speciald

obstetric/fetal medicine unit (1B).

● Staging investigations and response evaluation should

be tailored to the clinical presentation with radiology

input to minimize fetal radiation exposure (1C).

● Delaying commencement of chemotherapy until post-

delivery would not be standard practice and should be

done with caution (1C).

● ABVD is the regimen of choice unless specifically con-

traindicated (1B).

● Wherever possible, RT should be delayed until post-

delivery (1B).

Management of HL in elderly patients

● Elderly patients should be formally assessed for fitness

to receive combination chemotherapy with a co-morbid-

ity assessment tool, which should distinguish ‘frail’

from ‘non-frail’ patients (2B).

● Patients considered ‘frail’ should not usually be offered

conventional combination chemotherapy (2B).

● ‘Non-frail’ patients should be offered combination che-

motherapy and RT with the aim of achieving complete

remission (CR), which is associated with better survival

(1B).

● Older patients receiving bleomycin must be followed

very closely for symptoms and signs of bleomycin lung

toxicity (1A).

● Guidance on therapy choice for non-frail patients is

hampered by the lack of randomized trial data. Treat-

ment with VEPEMB (vinblastine, cyclophosphamide,

prednisolone, procarbazine, etoposide, mitoxantrone) or

COPP (cyclophosphamide, vincristin, procarbazine,

prednisone)/ABVD appears to have lower treatment-

related mortality than ABVD or BEACOPP (2B).

PET/CT in HL

● PET/CT should be reported by PET/CT imaging special-

ists (1C).

● As pre-treatment staging with PET/CT will upstage a

minority of patients and aid the interpretation of subse-

quent PET/CT, it is recommended when clinically feasi-

ble (1B).

● PET/CT response should be reported according to

Deauville criteria (2B).

● By Deauville criteria, a score of 1 or 2 should be consid-

ered ‘negative’ and 4 or 5 considered ‘positive’. Deau-

ville score 3 should be interpreted according to the

clinical context but in many HL patients indicates a

good prognosis with standard treatment (1B).

● Biopsy is advised prior to second-line therapy to con-

firm residual disease with a score of 4 or 5 where possi-

ble to exclude false-positive uptake with

fluorodeoxyglucose (FDG) (1B).

● The optimal management of iPET2-positive patients

remains uncertain. Therefore, at this time, iPET2

remains desirable for ABVD-treated patients but cannot

be mandated as a standard of care (2B).

● If a pre-treatment decision has been made to treat an

early stage patient with RT following ABVD, then there

is no clear role for interim PET/CT (1A).

● End-of-treatment PET/CT is recommended for all

patients who have not achieved an interim PET-negative

remission as this may directly affect RT planning,

biopsy considerations and follow-up strategy (1B).

Guideline

ª 2014 John Wiley & Sons Ltd 35British Journal of Haematology, 2014, 166, 34–49

Radiotherapy strategies in HL

● The evidence for the role of RT in HL is based on

involved field RT (IFRT) (1A).

● Reduced volume approaches, involved node (INRT) or

involved site (ISRT) are under evaluation in current

protocols (2B).

● The dose for favourable early stage disease should be

20 Gy, and 30 Gy for all other patients (1A).

Follow-up, late effects and survivorship

● Patients are usually followed with intermittent outpa-

tient clinical review for 2–5 years following first line

therapy (2C).

● There is no proven role for routine surveillance CT or

PET/CT imaging in patients who are otherwise well fol-

lowing first line therapy (2B).

● HL patients should be made aware that they are at an

increased lifetime risk of second neoplasms, cardiovas-

cular and pulmonary disease and infertility (1A).

● Apart from the current breast cancer-screening pro-

gramme, there are no national cancer screening pro-

grammes tailored for HL survivors. Women treated with

mediastinal RT before the age of 35 years should be

offered entry into the breast cancer National Notification

Risk Assessment and Screening programme (NRASP)

(1A).

● Regular lifestyle advice should be offered to reduce sec-

ondary neoplasms and cardiovascular risk. There should

be complete avoidance of smoking and careful manage-

ment of cardiovascular risks, such as hypertension, dia-

betes mellitus and hyperlipidaemia (1B).

● Patients who have had RT to the neck and upper medi-

astinum should have regular thyroid function checks.

Hypothyroidism can occur up to 30 years after RT (1A).

● Patients should receive irradiated blood products for

life (1B).

Background

The annual incidence of Hodgkin Lymphoma (HL) in the

UK is 2�7/100 000 with approximately 1700 new cases per

annum with a slight male predominance (Cancer Research

UK, 2010). There is a peak in incidence in young adults aged

20–34 years with a further peak observed >70 years of age.

The incidence is currently stable (Morton et al, 2006; Cancer

Research UK, 2010; Shenoy et al, 2011).

Hodgkin Lymphoma is characterized by the presence of

Hodgkin and Reed-Sternberg (HRS) cells within a cellular

infiltrate of non-malignant inflammatory cells that make up

the majority of the tumour tissue (Swerdlow et al, 2008). HRS

cells have only recently been identified as clonal B cells that

lack typical B-cell surface antigens. B cells failing to express

surface immunoglobulin usually undergo apoptosis but HRS

cells evade cell death through a number of mechanisms,

including incorporation of Epstein-Barr virus (EBV) latent

membrane proteins (LMP1 and 2), constitutive activation of

the transcription factor nuclear factor jB (NFjB), and inter-

action with components of the microenvironment (Swerdlow

et al, 2008; Steidl et al, 2011; Kuppers et al, 2012).

Hodgkin Lymphoma is classified as either nodular lym-

phocyte predominant (NLPHL) or classical HL. There are

four sub-types of classical HL: nodular sclerosis, mixed cellu-

larity, lymphocyte-rich and lymphocyte-depleted; there is no

difference in the prognosis or management of the different

sub-types of classical HL. In Europe and North America,

nodular sclerosis classical HL accounts for 70% of all classical

HL. Lymphocyte-depleted classical HL is more prevalent in

immunocompromised patients and is seen more commonly

in developing countries, where it has a strong association

with EBV infection. NLPHL is distinct histologically and

HRS cells are not present, it has a risk of transformation to

high grade non-Hodgkin lymphoma and is managed differ-

ently from classical HL (Swerdlow et al, 2008).

Clinical presentation of classical HL is usually with painless

lymphadenopathy, which is most commonly cervical or supra-

clavicular. Mediastinal disease is identified in 80% of patients

and is more common in nodular sclerosing HL, whilst periph-

eral or sub-diaphragmatic lymphadenopathy is more common

in mixed-cellularity classical HL. Bone marrow involvement is

detected in only 5–8% of patients with conventional staging

(Mauch et al, 1993; Levis et al, 2004a; Swerdlow et al, 2008),

but in up to 18% with positron emission tomography (PET)/

computerized tomography (CT) staging (El-Galaly et al, 2012).

Systemic symptoms of drenching night sweats, unexplained

fever >38°C, and weight loss of >10% over 6 months are termed

B symptoms and are identified in approximately 25% of

patients.

Pretreatment evaluation

Blood evaluation should include full blood count, erythrocyte

sedimentation rate, renal function, liver function, bone pro-

file, lactate dehydrogenase and testing for human immunode-

ficiency virus (HIV).

Patients should be staged with a contrast-enhanced CT scan

covering the neck, chest, abdomen and pelvis. An initial PET/

CT scan is highly recommended as this provides a baseline for

interpretation of subsequent scans and, in a minority of cases, it

can upstage patients and alter the planned therapy. It is appreci-

ated that a minority of patients may present with very advanced

disease and if obtaining a PET/CT scan would result in a treat-

ment delay this may not be clinically appropriate.

It was common practice to limit bone marrow evaluation

to patients with advanced stage disease or B symptoms, how-

ever, it is now generally accepted that PET/CT can accurately

detect marrow involvement and evaluation by biopsy is often

unnecessary (El-Galaly et al, 2012). Clinicians should be

Guideline

36 ª 2014 John Wiley & Sons LtdBritish Journal of Haematology, 2014, 166, 34–49

aware that diffuse bone marrow uptake on PET may just

reflect a reactive process.

Patients with early stage disease should be categorized as

having favourable or unfavourable characteristics. Patients

with advanced stage disease should have their Hasenclever/

International Prognostic Score (IPS) determined (Hasenclev-

er & Diehl, 1998).

Consideration should be given to fertility preservation and

semen cryopreservation should be offered routinely before

therapy with combination chemotherapy. There is increasing

evidence for the effectiveness of oocyte preservation as a fer-

tility-sparing strategy and referral to a fertility specialist

should be considered, if treatment delays are acceptable. This

is especially important if the plan is to administer escalated

BEACOPP (bleomycin, etoposide, doxorubicin, cyclophos-

phamide, vincristine, procarbazine, prednisone). ABVD

(doxorubicin, bleomycin, vinblastine, dacarbazine) is gener-

ally considered to be fertility-sparing, but some patients may

need to receive salvage chemotherapy and stem cell trans-

plantation, which can result in a reduction of fertility. The

role for prophylactic use of gonadotropin-releasing hormone

(GnRH) analogues to preserve female fertility remains uncer-

tain (Behringer et al, 2012; Wong et al, 2013). For women

with a stable partner, and in whom a delay of treatment is

possible, in vitro fertilization for embryo cryopreservation

may be appropriate. However, this may not be widely avail-

able at short notice. Ovarian tissue cryopreservation remains

experimental and so far has resulted in only a small number

of pregnancies and births (Loren et al, 2013). Generally, fer-

tility preservation techniques can only be discussed on a

case-by-case basis, involving fertility experts and oncologists

who can judge the appropriateness of the techniques and the

risks of delaying treatment.

Key recommendations for pre-treatment evaluation

● Patients require pre-treatment blood evaluation includ-

ing HIV serology (1A).

● Staging with contrast–enhanced CT of the neck to pelvis

is required (1A), although PET/CT is preferable if clini-

cally feasible (1B).

● Early stage patients should be classified as favourable or

unfavourable (1A).

● Advanced stage patients should be assessed to define the

Hasenclever/IPS (1A).

● For male patients, pre-treatment semen cryopreserva-

tion should be offered where possible (1A).

● For female patients, pre-treatment review of options

with a fertility specialist should be considered (1A).

Management of early stage disease

Randomized trials have shown that combined modality treat-

ment with chemotherapy and radiotherapy (RT) results in

superior tumour control compared with RT alone (Noordijk

et al, 2006; Engert et al, 2007; Ferme et al, 2007). Clinical

trials in patients with Stage I–II disease have increasingly

evaluated treatment reduction as a strategy to reduce late

morbidity and mortality. These trials have defined and

refined prognostic factors for favourable and unfavourable

prognosis Stage I–II HL. Traditionally in the UK, patients

with early stage HL with B symptoms or bulk disease have

been managed with protocols for advanced stage disease.

However, long-term follow-up of large trial data sets, such as

the German Hodgkin Study Group (GHSG) HD10 trial, have

confirmed that these patients generally have excellent out-

comes when treated with early stage unfavourable risk proto-

cols. Definition of ‘large mediastinal mass’/bulky disease

varies slightly between study groups: The European Organi-

zation for the Research and Treatment of Cancer (EORTC)

defines bulk as a mediastinal thoracic ratio >0�35 at T5/6.

The UK National Cancer Research Institute (NCRI) and

GHSG define a mediastinal mass ratio >0�33 as ‘large’, while

the US National Comprehensive Cancer Network (NCCN)

and National Cancer Institute of Canada (NCIC) define

bulky as a mediastinal mass ratio>0�33 or any mass with

maximal diameter >10 cm. Prognostic factors for the EORTC

and GHSG are listed in Tables I and II.

Favourable early stage disease

Recent trials have focussed on abbreviating chemotherapy

and RT dosages, and assessing RT-free treatment strategies.

The GHSG HD10 trial randomized 1190 patients into four

treatment arms, which included two cycles of ABVD plus

30 Gy RT, two cycles of ABVD plus 20 Gy of RT, four cycles

of ABVD plus 30 Gy of RT and four cycles of ABVD plus

20 Gy of RT. With a 7�6-year median follow up, no differ-

ence was observed in freedom from progression (97%) or

overall survival (OS, 98%) between the four groups (Engert

et al, 2010). Thus, the least toxic approach consisting of two

cycles of ABVD followed by 20 Gy RT appears to be suffi-

cient in favourable Stage I–II HL.

The trial with the longest published median follow-up

(11�3 years) in early stage HL is the IA/IIA non-bulky NCIC

and Eastern Cooperative Oncology Group (ECOG) trial

comparing ABVD alone (4–6 cycles) with treatment includ-

Table I. Favourable prognosis Stage I–II Hodgkin Lymphoma.

EORTC GHSG

No large mediastinal adenopathy No large mediastinal adenopathy

ESR <50 without B symptoms ESR <50 without B symptoms

ESR <30 with B symptoms ESR <30 with B symptoms

Age ≤ 50 years No extranodal disease

1–3 lymph node sites involved 1–2 lymph node sites involved

EORTC, European Organization for the Research and Treatment of

Cancer; GHSG, German Hodgkin Study Group; ESR, erythrocyte

sedimentation rate.

Guideline

ª 2014 John Wiley & Sons Ltd 37British Journal of Haematology, 2014, 166, 34–49

ing subtotal nodal irradiation (STNI) (Meyer et al, 2012).

From separate sequential analysis of this trial (Meyer et al,

2005, 2012), it appears that omitting RT increases the risk of

early relapse, but with longer follow-up does not appear to

compromise OS. It is difficult to interpret the comparative

aspects of this trial as STNI is no longer used in routine

practice, and there were a small number of unusual events in

the STNI arm that complicated the interpretation of OS of

the RT-arm of the study. However, this trial has shown that

treating IA/IIA non-bulky HL patients with ABVD alone

delivers long-term OS of 94%.

Data from the UK NCRI trial (RAPID) and the EORTC

H10 trial were presented at the annual American Society of

Hematology meeting in 2012 (Andre et al, 2012; Radford

et al, 2012). In both trials, patients who achieved an early

PET-negative remission had a better progression-free survival

(PFS) than interim PET-positive patients. Both trials ran-

domized the patients who achieved an early PET-negative

remission with ABVD chemotherapy to receive or omit RT.

With both trials, there was an early PFS advantage with the

inclusion of RT, but no OS advantage had been shown

within the limited follow-up periods of both trials. Of note,

patients with mediastinal bulk disease were excluded from

the RAPID trial. In the RAPID study, patients who were

PET-positive after three ABVD cycles received 1 9 additional

ABVD and RT. This achieved a 3-year PFS of 85�9% and OS

of 93�9% (Radford et al, 2012).

With the current available data, the standard of care for treat-

ment of patients with early stage favourable HL (as defined by

GHSG criteria) therefore remains ABVD 9 2 + RT. However,

as there are longer term risks for patients treated with RT, it is

recognized that, in some circumstances, clinicians and patients

may prefer to treat without RT, particularly as the majority of

IA/IIA non-bulky patients will be cured with chemotherapy

alone. Indeed, a cross-trial comparative analysis between the

German HD10/11 and NCIC HD6, suggested patients who

achieve a CT complete remission (CR) after 2 9 ABVD, and

then complete a total 4 9 ABVD with no RT, have the same

excellent outcome as 2 9 ABVD + RT (Hay et al, 2012). How-

ever, the decision to treat early stage good risk patients without

RT should involve a radiation oncologist and the patient must

be made aware that a number of trials indicate that removing

RT probably increases the risk of early relapse by approximately

3–7% (Meyer et al, 2005, 2012; Andre et al, 2012; Radford et al,

2012). If patients are treated without RT, then choosing the

optimum number of cycles of ABVD is difficult. The NCIC/

ECOG trial, using 4–6 cycles of ABVD, has the longest follow-

up, but initial data from 3 9 ABVD for PET-negative patients

in the RAPID trial are encouraging. A balance therefore needs

to be struck between long-term toxicity of RT and the toxicity

of the additional ABVD cycles (Swerdlow et al, 2011).

Apart from abstract presentations of the UK NCRI trial

(RAPID) and the EORTC H10 trial (Andre et al, 2012; Rad-

ford et al, 2012), larger randomized trials using PET/CT to

guide decision-making in early stage HL have yet to be for-

mally reported. Consensus opinion from all trials groups is

that early stage patients with persisting PET-avid disease after

chemotherapy should receive RT. At this stage, it remains

uncertain whether achieving an interim PET-negative remis-

sion after two cycles of ABVD is as predictive for long-term

PFS and OS as achieving a CR by established CT criteria.

Unfavourable early stage disease

In the HD11 trial, the GHSG randomly assigned 1395 patients

with early unfavourable HL to four cycles of ABVD plus 30 Gy

RT, four cycles of ABVD plus 20 Gy RT, four cycles of BEA-

COPP plus 30 Gy RT and four cycles of BEACOPP plus 20 Gy

RT (Eich et al, 2010). With 6�8 years median follow-up, no dif-

ference was observed in OS (93–96%) for all four groups. In the

arms of the study with 30 Gy of RT, there was no difference in

freedom from treatment failure (FFTF) between BEACOPP and

ABVD (P = 0�65), but a significant difference in favour of BEA-

COPP was seen for FFTF when 20 Gy RT was used (P = 0�02)(Eich et al, 2010). The German Hodgkin study Group HD14

Trial randomly assigned early unfavourable HL patients to

either four cycles of ABVD or an intensified treatment of two

cycles of escalated BEACOPP followed by two cycles of ABVD

(2 + 2) (von Tresckow et al, 2012). Chemotherapy was fol-

lowed by 30 Gy RT in both arms. At 5 years follow-up, the

dose-intensified regime resulted in better tumour control with a

6�2% improvement in PFS compared with standard treatment

with four cycles of ABVD. However, acute toxicities were signif-

icantly higher in the 2 + 2 arm and with no difference in OS,

this regimen would be considered a treatment option rather

than a standard of care for the majority of patients.

Currently, four cycles of ABVD followed by 30 Gy RT is

widely considered the standard of care for unfavourable early

stage HL. There is no evidence to support the removal of RT

from patients who present with bulky disease, and of note,

such patients were excluded from the RAPID and NCIC/

ECOG 6 trials.

Infradiaphragmatic early stage disease

The incidence of infradiaphragmatic early stage HL is very

low and accounts for 4–13% of cases of Stage I–II disease

Table II. Unfavourable prognosis Stage I–II Hodgkin lymphoma.

EORTC presence of one or

more of the following

GHSG presence of one or more

of the following

Large mediastinal adenopathy Large mediastinal adenopathy

ESR ≥50 without B symptoms ESR ≥50 without B symptoms

ESR ≥30 with B symptoms ESR ≥30 with B symptoms

Age >50 years Extranodal disease

≥4 lymph node sites involved ≥3 lymph node sites involved

EORTC, European Organization for the Research and Treatment of

Cancer; GHSG, German Hodgkin Study Group; ESR, erythrocyte

sedimentation rate.

Guideline

38 ª 2014 John Wiley & Sons LtdBritish Journal of Haematology, 2014, 166, 34–49

(Vassilakopoulos et al, 2006). When results are adjusted for

risk factors they appear to have a similar prognosis to

patients with supradiaphragmatic disease. Older age, clinical

Stage II (borderline), involvement of ≥3 sites and higher IPS

is more frequent in patients with infradiaphragmatic disease

and the previously reported poorer outcome may be

explained by the unfavourable profile of the patients.

Although this group of patients are under-represented in

clinical trials, there is currently no evidence to suggest that

they should be treated differently from their supradiaphrag-

matic counterparts (Darabi et al, 2005; Vassilakopoulos et al,

2006).

KEY recommendations for management of early stagedisease

● Prognostic factors should be determined to allocate

patients to favourable and unfavourable sub-groups

(1A).

● Standard of care for patients with favourable early stage

HL is 2 3 ABVD and 20 Gy RT (1A).

● Standard of care for unfavourable early stage HL is

4 3 ABVD and 30 Gy RT (1A).

● A treatment option for unfavourable early stage HL is 23

escalated BEACOPP + 2 3 ABVD and 30 Gy RT (1A).

● The decision to omit RT from the management of stage

IA/IIA non-bulky patients should involve discussion

with a radiation oncologist (1B) and patients choosing

to omit RT need to be aware of the balance of risks

between RT and additional cycles of chemotherapy (1B).

● RT should not normally be omitted in patients present-

ing with bulky disease (1B).

● Early stage patients treated without RT should receive

at least 3 3 ABVD (1B).

● Patients receiving bleomycin should be assessed care-

fully for signs and symptoms of pulmonary toxicity

before each dose. A history of new or worsening dysp-

noea or pulmonary crackles should lead to stopping of

bleomycin until an alternative cause is identified (1B).

Advanced stage disease

Standard treatment for patients with stage III/IV HL is com-

bination chemotherapy. In the UK, patients with early stage

disease but B symptoms or bulky disease have usually been

managed with advanced HL protocols, although this is not

universal international practice (Townsend & Linch, 2012).

There is significant international variation in the use of RT

to sites of initial bulk disease or residual masses following

chemotherapy.

Over the past three decades of comparative randomized

clinical trials in HL, ABVD and escalated BEACOPP have

become established international standards of care for

advanced HL [reviewed in (Townsend & Linch, 2012)].

ABVD has better outcomes in terms of efficacy and/or toxic-

ity than MOPP (mechlorethamine, vinristine, procarbazine,

predisone), MOPP–ABV (MOPP, doxorubicin, bleomycin,

vinblastine) hybrid and ChlVPP/PABLOE (chlorambucil, vin-

blastine, procarbazine, prednisone/doxorubicin, bleomycin,

vincristine and etoposide), and similar efficacy, but lower

toxicity, than the Stanford V regimen (mechlorethamine,

doxorubicin, vinblastine, prednisone, vincristine, bleomycin,

etoposide) (Canellos et al, 1992; Duggan et al, 2003; Johnson

et al, 2005; Hoskin et al, 2009). From a number of advanced

HL trials, failure-free/PFS with ABVD is around 73–78%

with OS in the range of 82–90% (Duggan et al, 2003; John-

son et al, 2005; Federico et al, 2009; Hoskin et al, 2009; Vivi-

ani et al, 2011). ABVD should be delivered on schedule with

infusions given every 14 d irrespective of neutrophil

count. Granulocyte colony-stimulating factor (G-CSF) is only

required for patients with infectious complications (Evens

et al, 2007; Nangalia et al, 2008).

Different HL study groups have followed different strate-

gies for RT following chemotherapy. Patients with bulky

advanced stage disease who achieve a CT CR after MOPP/

AVD can avoid RT in contrast with patients in partial remis-

sion (PR), who did derive benefit from RT (Aleman et al,

2003). It remains unclear as to whether RT to sites of initial

bulk disease or residual tissue can be safely omitted in

patients treated with ABVD. In the LY09 trial, 43% of

patients received RT following ABVD or ChlVPP/PABLOE

and, with a median follow-up of 6�9 years, these patients had

a PFS and OS advantage compared with patients treated

without RT (Johnson et al, 2005). Of note, the ABVD trials

with the highest OS rates have used RT for a large propor-

tion of patients (Duggan et al, 2003; Johnson et al, 2005;

Hoskin et al, 2009).

Escalated BEACOPP was been developed by the German

HL study group (GHLSG). In comparison with COPP–

ABVD and standard dose BEACOPP, escalated BEACOPP

has demonstrated improved PFS and OS (Engert et al, 2009).

Data from 2182 patients randomized from 408 centres in the

GHLSG HD15 trial have shown a 5-year failure-free and OS

of 89% and 95% respectively, for patients receiving six cycles

of escalated BEACOPP (Engert et al, 2012). Patients in this

trial who achieved a PET-negative remission (but PR by con-

ventional CT) were not treated with RT consolidation, in

contrast with the HD9 trial. The number of patients receiv-

ing RT fell from 71% in HD9 to 11% in HD15, with no

apparent loss in treatment efficacy (Engert et al, 2012).

Although this is not prospective randomized data, it is rea-

sonable to conclude that patients who achieve PET-negative

remission following escalated BEACOPP therapy do not

require RT to sites of residual tissue (Engert et al, 2012).

From HD15, the outcomes for patients treated with escalated

BEACOPP 9 6 or BEACOPP 14 9 8 were similar and

clinicians/patients may prefer to be treated on the latter

regimen if appropriate. Escalated BEACOPP-based strategies

have also delivered impressive results in high-risk childhood/

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ª 2014 John Wiley & Sons Ltd 39British Journal of Haematology, 2014, 166, 34–49

adolescent HL [5-year event-free survival (EFS)/OS: 94%/

97%] (Kelly et al, 2011), but have shown unacceptable treat-

ment-related toxicity in patients >60 years old (Engert et al,

2009) and the GHLSG no longer recommends this protocol

for patients over 60 years of age.

Data directly comparing ABVD with escalated BEACOPP

are limited. The EORTC 20012 trial comparing ABVD with

BEACOPP (49 escalated, 49 standard) for higher risk HL

patients has been presented in abstract form only (Carde

et al, 2012). A PFS advantage was found for escalated BEA-

COPP, but no survival advantage has yet been demonstrated

with a median follow-up of 3�8 years. A smaller Italian trial

randomized patients to either ABVD or escalated BEACOPP

followed by treatment intensification with RT (to sites of

initial bulk and residual tissue) then salvage chemotherapy/

autologous transplant for all patients failing to achieve a CR

(Viviani et al, 2011). Initial treatment with escalated BEA-

COPP resulted in a 7-year freedom-from-first progression

advantage compared with ABVD (85% vs. 73%; P = 0�004),but the 7-year OS was no different, at 89% and 84%,

respectively (P = 0�32). Considering the first line intensifica-

tion strategy given to approximately a quarter of the

patients and significant criticisms raised with regards to this

trial (Borchmann et al, 2011; Corazzelli et al, 2011; Tam

et al, 2011), it is difficult to interpret the results in the con-

text of standard UK practice. However, the data support the

consensus view that, compared with ABVD, escalated BEA-

COPP provides a PFS advantage for patients, while adding

to the intense debate as to whether first line escalated BEA-

COPP provides a true survival advantage for advanced HL

patients.

ABVD has a better toxicity profile than escalated BEA-

COPP in terms of direct side effects of chemotherapy,

infectious complications, blood product requirements, fertil-

ity preservation and secondary myelodysplastic syndrome

(MDS)/acute myeloid leukaemia (AML) (Sieniawski et al,

2008; Engert et al, 2009). The HD15 data confirm that the

short- and long-term toxicity profile of escalated BEACOPP

is improved significantly by limiting treatment to 6 cycles

(Engert et al, 2012). The cumulative total doses of doxorubi-

cin and bleomycin are lower for patients treated with 69

escalated BEACOPP compared with 6 9 ABVD (210 mg/m2

and 60 000 iu/m2 compared with 300 mg/m2 and 120 000

iu/m2, respectively). With a median follow-up of 4 years, the

cumulative incidence of MDS/AML is 0�3% in patients trea-

ted with 6 cycles of escalated BEACOPP (Engert et al, 2012).

Interestingly the EORTC 20012 trial found no difference in

second cancer/MDS rates between ABVD and escalated BEA-

COPP (Carde et al, 2012).

Rates of female infertility are strongly influenced by the

chemotherapy choice and age at treatment (Behringer et al,

2005, 2013; De Bruin et al, 2008). With 4 cycles of ABVD

within the GHLSG HD14 trial, 100% of women aged

<30 years and 94% aged >30 years regained regular

menstrual cycles following chemotherapy. Data from patients

treated with 6–8 cycles of ABVD are more limited, but there

does not appear to be additional loss of fertility with the

additional cycles of treatment (Hodgson et al, 2007a; De

Bruin et al, 2008). With 6–8 cycles of escalated BEACOPP

within HD15, the corresponding figures were 82% of women

aged <30 regained regular menstrual cycles compared with

45% aged >30 (Behringer et al, 2005, 2013; De Bruin et al,

2008).

A positive PET/CT scan after two cycles of ABVD,

interim PET (iPET), has been shown to be strongly predic-

tive of treatment failure for patients who continue with

ABVD therapy (Gallamini et al, 2007). A number of

recently closed and ongoing therapeutic trials are assessing

whether, in comparison with historical controls, treatment

intensification for iPET2 positive patients with escalated

BEACOPP can improve patient outcomes (Gallamini et al,

2011, 2012). The UK RATHL trial (http://public.ukcrn.org.

uk/search/StudyDetail.aspx?StudyID=4488) chose to intensify

therapy with either 49 escalated BEACOPP or 4 9 BEA-

COPP-14 with no RT requirement, while the Italian

approach has been to use 8 cycles of BEACOPP (49 esca-

lated and 49 standard) and RT to sites of initial bulk dis-

ease. Initial reports from the Italian group appear

encouraging (Gallamini et al, 2011, 2012).

There is no international consensus on whether patients

are best served by starting therapy with either ABVD or esca-

lated BEACOPP and personal priorities for each patient will

clearly influence this decision. There are no prospective data

to support a specific IPS cut-off when deciding between esca-

lated BEACOPP and ABVD. Patients opting for ABVD will

have clear benefits in terms of toxicity, but will have a higher

risk of relapse and need for salvage therapy/autologous trans-

plant. With ABVD-treated patients, there is also uncertainty

with regards to the need for RT to sites of initial bulky dis-

ease/residual tissue and lack of clarity as to the role of iPET2

when treated outside a clinical trial. Patients opting for esca-

lated BEACOPP have clear benefits with regards to EFS and

the clarity that RT will be needed in only 10% of patients.

They will, however, potentially experience more treatment-

related toxicity.

There are no data on the use of escalated BEACOPP in

HIV-related HL, where standard management remains

ABVD combined with anti-retroviral therapy (Montoto et al,

2012).

Key recommendations for management of advancedstage disease

● Patients aged 16–60 years with advanced stage HL

should receive either 6–8 cycles of ABVD or 6 cycles of

escalated BEACOPP (1A).

● The choice between ABVD and escalated BEACOPP will

depend on a range of factors, particularly the patient’s

opinion on the toxicity/efficacy balance between the

regimens (2B).

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40 ª 2014 John Wiley & Sons LtdBritish Journal of Haematology, 2014, 166, 34–49

● Patients with a higher IPS are at higher risk of relapse,

potentially supporting the use of escalated BEACOPP in

this higher risk group, although there are no prospec-

tive trial data to support a specific IPS cut-off at which

escalated BEACOPP may be advantageous (2B).

● Patients treated with escalated BEACOPP who achieve

an end of treatment PET-negative remission do not

require consolidation RT to residual tissue (1A).

● Patients treated with ABVD should be considered for

RT to sites of original bulk or residual tissue >1�5 cm.

It remains unclear whether RT can be safely omitted in

ABVD patients who have residual tissue >1�5 cm on CT

that is PET-negative (1A).

● Interim PET (iPET2) is highly predictive of outcome in

patients treated with ABVD (1A).

● It remains unclear how iPET2-positive patients are opti-

mally managed in routine practice. Accepting the limi-

tations of small, published datasets, treatment

intensification to escalated BEACOPP � RT appears

reasonable (2B).

● Patients who remain PET-positive on completion of

therapy require biopsy assessment or close clinical/

radiological surveillance for early progression (1B).

● Patients who develop progressive disease on therapy

should be considered for treatment intensification with

transplantation (see separate guidelines) (1A).

Management of HL in pregnancy

There are no prospective trials for the management of HL in

pregnancy, but a number of published case reports, case ser-

ies and case cohorts were reviewed by Bachanova and Con-

nors (2008). The priority must be the health of the mother

and, ideally, management should be in conjunction with an

obstetrician experienced in high-risk pregnancy. While termi-

nation of pregnancy may be the most appropriate course of

action for certain patients, for many cases, the fetal and

maternal outcomes following HL treatment in pregnancy

appear excellent (Evens et al, 2011).

Staging and response assessment with magnetic resonance

imaging scans and ultrasound may avoid the need for radia-

tion-based imaging and, in certain cases, delaying therapy

until post-partum may be possible, although this must be

done with caution.

If therapy is required in pregnancy, the general consensus

is that ABVD is the regimen of choice if multi-agent chemo-

therapy is to be used (Bachanova & Connors, 2008).

Although ABVD has been used to treat patients in all 3 tri-

mesters (Anselmo et al, 1999; Cardonick & Iacobucci, 2004),

the potential risk to fetal development from chemotherapy

is likely to be higher in the first trimester and most clini-

cians would try and avoid exposure to chemotherapy at

this time. Wherever possible, RT should be delayed until

post-delivery.

Key recommendations for HL in pregnancy

● Patients should be closely co-managed with a special-

ized obstetric/fetal medicine unit (1B).

● Staging investigations and response evaluation should

be tailored to the clinical presentation with radiology

input to minimize fetal radiation exposure (1C).

● Delaying commencement of chemotherapy until post-

delivery would not be standard practice and should be

done with caution (1C).

● ABVD is the regimen of choice unless specifically con-

traindicated (1B).

● Wherever possible, RT should be delayed until post

delivery (1B).

Management of HL in elderly patients

Population based data suggest that the over-60s age group

account for approximately 20% of cases of HL (Stark et al,

2002) and a number of studies have suggested that their out-

come is consistently less good than that of younger patients,

especially for those with advanced stage disease (Evens et al,

2008, 2012, 2013; Proctor et al, 2009). Older patients are

more likely to die from non-HL causes, including bleomycin

lung toxicity, which was reported in 24% of patients over

60 years old treated within the North American Intergroup

trial E2496 (Evens et al, 2013). Therapy-related toxicity has,

therefore, made delivering the ‘gold standard’ chemothera-

pies, ABVD and BEACOPP, challenging, especially in the

over-70s and the major randomized trials contain only small

numbers of elderly patients.

Following a number of workshops at international lym-

phoma meetings in the early 2000s it was decided to pursue a

series of non-randomized phase II studies of alternative thera-

pies in elderly HL. The GHSG have developed phase 2 trials

with BACOPP (modified and dose-reduced BEACOPP) and

PVAG (prednisolone, vincristine, doxorubicin, gemcitabine)

(Halbsguth et al, 2010; Boll et al, 2011). BACOPP (bleomy-

cin, adriamycin, cyclophosphamide, vincristine, procarbazine,

prednisone) was used to treat 65 patients aged 65–70 years,

producing a CR rate of 85% but with a 12% treatment-related

mortality and 33 month OS of 70%. With PVAG, 59 patients

aged 60–75 years were treated for mainly advanced stage dis-

ease, producing a 3-year PFS and OS of 58% and 66%.

The GHSG have also analysed the outcomes for early stage

elderly patients treated with ABVD within the HD10 and

HD11 trials (Boll et al, 2013). They observed excellent

response rates (CR of 89%), but a treatment-related mortality

of 5%. With 92 months median follow-up, the 5-year PFS

was estimated at 75%. With the UK Shield registration study,

the CR rate for early stage patients treated with two or more

cycles of ABVD and involved field RT (IFRT) was 62% but,

for advanced stage ABVD patients, the CR rate was only 46%,

and there were 18% treatment-related deaths (Proctor et al,

2012). Of note, within this registration study, no patients

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who were classified as ‘frail’ based on a scoring system, com-

pleted treatment or achieved a CR. The high treatment-

related death rate with ABVD is similar to that described in

the ABVD versus Stamford V trial for older patients (Evens

et al, 2013). In the German HD9 elderly analysis, acute toxic-

ity led to 21% treatment-related deaths after BEACOPP com-

pared with 8% for COPP/ABVD (Ballova et al, 2005).

UK and Italian groups have both explored a treatment strat-

egy with VEPEMB (vinblastine, cyclophosphamide, predniso-

lone, procarbazine, etoposide, mitoxantrone). In total, 103

patients were treated with VEPEMB as part of the Shield pro-

gramme (Proctor et al, 2012), including 31 early stage patients

(VEPEMB 9 3 followed by involved field RT) with a CR rate

of 74% and 3-year PFS and OS of 74% and 81%, respectively.

For 72 advanced stage patients treated with VEPEMB 9 6 a

CR rate of 61% was achieved with 3-year PFS and OS of 58%

and 66%, respectively. However, patients classified as ‘frail’

were excluded from the UK VEPEMB trial and this probably

improved the results. Nevertheless, similar encouraging data

with VEPEMB have been reported from an Italian trial (Levis

et al, 2004b). It also remains common practice to treat less fit

elderly patients with older non-anthracycline containing regi-

mens, such as ChlVPP, although published outcomes for this

regimen in the elderly are generally poor (The International

ChlVPP Treatment Group, 1995).

Key recommendations for management of elderlypatients

● Elderly patients should be formally assessed for fitness

to receive combination chemotherapy with a co-morbid-

ity assessment tool, which should identify ‘frail’ from

‘non-frail’ patients (2B).

● Patients considered ‘frail’ should not usually be offered

conventional combination chemotherapy (2B).

● ‘Non-frail’ patients should be offered combination che-

motherapy and RT with the aim of achieving CR, which

is associated with better survival (1B).

● Older patients receiving bleomycin must be followed

very closely for symptoms and signs of bleomycin lung

toxicity (1A).

● Guidance on therapy choice for non-frail patients is

hampered by the lack of randomized trial data. Treat-

ment with VEPEMB or COPP/ABVD appears to have

lower treatment-related mortality than ABVD or BEA-

COPP (2B).

The use of PET/CT in HL

Hodgkin Lymphoma is 18FFDG avid in 97–100% of cases

(Weiler-Sagie et al, 2010). Staging patients with FDG PET-CT

is more accurate than CT alone (Cheson et al, 2007) and the

availability of a baseline scan increases the reliability of subse-

quent response assessment (Quarles van Ufford et al, 2010;

Barrington et al, 2011). Contrast-enhanced CT may be done

as part of the PET-CT examination or at a separate visit,

depending on local imaging arrangements.

The five-point scale (5-PS) also referred to as the ‘Deau-

ville criteria’ has been used for reporting in response guided

trials and has published high inter-observer agreement (Bar-

rington et al, 2010; Furth et al, 2011; Biggi et al, 2013) and

improved predictive value (Le Roux et al, 2011) when com-

pared with earlier International Harmonization criteria

(Juweid et al, 2007). The response scan is compared with the

baseline scan and scored according to the level of highest

residual FDG uptake using the 5-PS as follows:

Score 1: No uptake.

Score 2: Uptake less than or equal to the mediastinum.

Score 3: Uptake greater than the mediastinum but less

than the liver.

Score 4: Uptake moderately higher than the liver.

Score 5: Uptake markedly higher than the liver.

After chemotherapy, stimulation of normal bone marrow

may result in diffusely increased uptake that is higher than

normal liver. The uptake in sites of initial marrow involve-

ment should then be compared with uptake within normal

marrow to assess the presence/absence of residual disease.

The 5-PS can be used to assess response during treatment

(with an interim scan) and at the end of treatment. To avoid

the risk of under-treatment, scores 1 and 2 were used to

define a ‘negative’ scan in the RAPID study (Radford et al,

2012). The mediastinum was also used as the threshold for

satisfactory response in the HD15 study for patients treated

with BEACOPP who subsequently did not receive RT (Engert

et al, 2012). It is recommended therefore that a score of 1 or

2 is used to define a complete metabolic response (CMR) if

omission of ‘standard’ RT treatment is being considered in

discussion with patients.

To avoid the risk of over-treatment, scores 4 and 5 were

used to define a ‘positive’ scan in the NCRI RATHL study

(Barrington et al, 2010) and in the Italian HD0607 study and

scores 1, 2, 3 defined a ‘negative’ scan (http://www.clinicaltri-

als.gov/ct2/show/NCT00795613) with initial reports suggest-

ing satisfactory responses for patients treated on trial

(Gallamini et al, 2012; Johnson et al, 2013). Until the trials

report in full, it seems prudent to recommend using score 4

or 5 to define an inadequate response to ABVD at interim, if

therapy intensification to escalated BEACOPP is to be con-

sidered. Interim scans should ideally be performed as long

after the last chemotherapy administration as possible to

avoid potential false-positive uptake.

At the end of treatment, score 4 or 5 probably represents

an inadequate response, however, biopsy is recommended

prior to second line treatment to exclude false-positive

uptake reflecting treatment-related inflammation. Other

causes of false-positive uptake, including infection, granu-

lomatous disease and sarcoid-like reactions, are also recog-

nized (Barrington & O’Doherty, 2003). Patients with score 3,

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which was previously referred to as ‘minimal residual

uptake’, (Hutchings et al, 2005) are likely have good out-

comes with standard treatment (Hutchings et al, 2005; Biggi

et al, 2013; Johnson et al, 2013), but until more information

is available, de-escalation of therapy outside trials in these

patients is not advised.

Standardized methods for PET acquisition and quality con-

trol have been developed during the conduct of response-

guided trials and are recommended for best clinical practice.

The reliability of visual and quantitative assessments depends

on correct patient preparation, image acquisition and quality

assessment of imaging equipment. Therefore, if management

changes are considered based on PET findings, guidelines for

tumour imaging with FDG standards should be adhered to

(Boellaard et al, 2010). Both interim and end-of-treatment

scans should be performed as long after the last chemotherapy

administration as possible, to avoid false-positive uptake due

to inflammation induced by treatment (Spaepen et al, 2003;

Boellaard et al, 2010). Therefore, interim scans should be per-

formed as close to the start of the next cycle of chemotherapy

as practical. At the end of treatment, a minimum of 10 d

following chemotherapy, 2 weeks after granulocyte colony-

stimulating factor (G-CSF) treatment and 3 months after RT is

recommended to elapse prior to scanning (Boellaard et al,

2010).

Key recommendations for PET/CT in HL

● PET/CT should be reported by PET/CT imaging special-

ists (1C).

● As pre-treatment staging with PET/CT will upstage a

minority of patients and aid the interpretation of subse-

quent PET/CT, it is recommended when clinically feasi-

ble (1A).

● PET/CT response should be reported according to

Deauville criteria (2B).

● By Deauville criteria, a score of 1 or 2 should be consid-

ered ‘negative’ and 4 or 5 considered ‘positive’. Deau-

ville score 3 should be interpreted according to the

clinical context but in many HL patients indicates a

good prognosis with standard treatment (1B).

● Biopsy is advised prior to second-line therapy to con-

firm residual disease with a score of 4 or 5 where possi-

ble to exclude false-positive uptake with FDG (1B).

● The optimal management of iPET2 positive patients

remains uncertain. Therefore, at this time, iPET2

remains desirable for ABVD-treated patients but cannot

be mandated as a standard of care (2B).

● If a pre-treatment decision has been made to treat an

early stage patient with RT following ABVD, then there

is no clear role for interim PET/CT (1A).

● End-of-treatment PET/CT is recommended for all

patients who have not achieved an interim PET negative

remission as this may directly affect RT planning,

biopsy considerations and follow-up strategy 1B.

Radiotherapy strategies in HL

As chemotherapy has become more effective, the role of RT

in HL has diminished, but it is still an essential tool, maxi-

mizing local control, allowing fewer cycles of chemotherapy

and avoiding intensive chemotherapy in relapse.

The evidence base for RT in both early and advanced HL

is based on IFRT. However, concerns regarding the late

effects of radiation have led to new protocols using reduced

volume treatment. An EORTC consensus led by Groupe d’

Etude des Lymphomes de l’ Adulte (GELA) is now in favour

of involved node RT (INRT) (Girinsky et al, 2008). However,

this depends on obtaining pre- and post-treatment PET-CT

imaging of the patient in the treatment position (Girinsky

et al, 2008; Specht et al, 2013). An alternative approach uses

involved site RT (ISRT), which adds a 15 mm safety margin

above and below the involved node (Hoskin et al, 2013;

Specht et al, 2013). Larger volumes are still preferred in

those rare cases where RT alone is recommended.

The dose of RT is now well defined from the GHSG trials

HD10 and HD11, which show that 20 Gy is sufficient for

favourable early HL, and 30 Gy should be given to all other

patients with early or advanced stage disease, where RT is

indicated.

Key recommendations for radiotherapy strategies in HL

● The evidence for the role of RT in HL is based on IFRT

(1A).

● Reduced volume approaches, INRT or ISRT are under

evaluation in current protocols (2B).

● The dose for favourable early stage disease should be

20 Gy, and 30 Gy for all other patients (1A).

Follow-up, late effects and survivorship issues

There is significant variation in follow-up practice with little

evidence to support a particular strategy. Clinicians typically

keep patients in follow-up clinics for 5 years before discharge

with intermittent outpatient review, but follow-up frequency

inevitably varies depending on patient requirements. Some

patients/clinicians may prefer early discharge from formal

follow-up after completion of first line therapy.

Routine CT or PET/CT scans significantly increase radia-

tion exposure and health care costs with no clear evidence of

benefit for patients (Voss et al, 2012; Patel et al, 2013). As

such, routine CT or PET/CT scanning for otherwise well

patients is not normally required.

Despite the high cure rates, long-term survivors of HL have

increased mortality compared to the general population (Ng

et al, 2002; Favier et al, 2009; Baxi & Matasar, 2010). During

the first 5–10 years of follow-up, the lead cause of absolute

excess risk (AER) of mortality remains HL, especially in those

with unfavourable prognosis. However, the AER for all-cause

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mortality remains significantly elevated more than 20 years

after treatment (Ng et al, 2002). The major causes of long

term, non-relapse morbidity and mortality are second neo-

plasms and cardiac disease, but also include pulmonary dis-

ease and infections. Patients, who have received neck RT, can

become hypothyroid and issues relating to reduced fertility

and psychosocial problems may significantly affect quality of

life. HL patients have also been shown to have long-term

anergic immunological responses and measurable defects in

T-cell function (Levy & Kaplan, 1974). The clinical implica-

tions of this remain unclear. Cases of transfusion-associated

graft-versus-host disease have been reported (Baglin et al,

1992). Consequently, all HL patients are recommended to

receive lifelong irradiated blood products. There are no data

to support the life-long avoidance of live vaccines in patients

who have completed treatment for HL.

Second neoplasms

Several studies, including a Cochrane review, large cohort

studies and meta-analyses, have confirmed the increased inci-

dence of secondary neoplasms in long-term survivors of HL

(Bhatia et al, 2003; Franklin et al, 2005, 2006; Travis et al,

2005; Hodgson et al, 2007b; Favier et al, 2009; Meadows

et al, 2009). A recent large collaborative British Cohort study

followed 5798 HL patients treated with chemotherapy

between 1963 and 2001 (Swerdlow et al, 2011). Combined

modality treatment (CMT) carried a greater relative risk

(RR) for secondary neoplasms than chemotherapy alone

(CA) [RR CMT 3�9; 95% confidence interval (CI), 3�5–4�4;RR CA 2�0; 95% CI, 1�7–2�4]. The largest AERs related to

lung cancer, CMT 14�0, CA 10�7, non-Hodgkin lymphoma,

CMT 13�9, CA 11�6 and leukaemia, CMT 11�7, CA 12�8.However, CMT was associated with AERs for a range of

additional secondary neoplasms including breast, bowel, non-

melanoma skin cancer and unspecified primary.

Depending on the age at treatment and the extent of the

radiation field, the 25-year cumulative risk of breast cancer

in women treated in childhood or early adulthood with RT

is approximately 10–33%, compared with a lifetime risk in

the UK of 11% (Taylor et al, 2007; Westlake & Cooper,

2008). Furthermore, survival stage-for-stage with breast can-

cer after HL is worse than that following de novo breast can-

cer (Milano et al, 2010). Since 2003, this breast cancer risk

has been prospectively managed by a screening programme

throughout the UK (Howell et al, 2009).

Cardiovascular disease

Cardiovascular disease is the second most important cause

of excess mortality amongst long-term survivors of HL, after

secondary neoplasms (Ng et al, 2002; Baxi & Matasar,

2010). Myocardial infarction (MI) carries the greatest risk

and this has been particularly linked to mediastinal RT. The

Collaborative British Cohort Study followed 7033 patients

treated between 1967 and 2000 and identified 166 deaths

from MI (Swerdlow et al, 2007). This represented an abso-

lute excess risk of 126 per 100 000 person-years, and the

risk remains high for at least 25 years. Significant and inde-

pendent increased risk of MI was identified for supradia-

phragmatic RT, anthracyclines and vinca-alkaloids. The risk

was particularly high for the ABVD regimen and the combi-

nation of supradiagphragmatic RT and vincristine without

anthracyclines.

Pulmonary toxicity

Shortness of breath is described by as many as 30% of

patients treated for HL; bleomycin pulmonary toxicity, acute

radiation pneumonitis and late stage pulmonary fibrosis are

all implicated. Fatal pulmonary fibrosis following bleomycin

is described in 1–2% of bleomycin-treated patients (Williams

et al, 1987; Kaye et al, 1998; Nichols et al, 1998; O’Sullivan

et al, 2003). Data from HL and germ cell tumour patients

have suggested a range of contributing factors including older

age, higher doses, pre-existing lung disease, renal impairment

and the concomitant use of G-CSF (O’Sullivan et al, 2003;

Martin et al, 2005). However, only dose and older age seem

to be reliably associated and the risk should be largely consid-

ered idiosyncratic. Bleomycin toxicity ranges from a measured

decrease in diffusion capacity, lung volumes and vital capac-

ity, to pneumonitis with nonspecific patchy opacities to end

stage pulmonary fibrosis (http://www.drugs.com). Early

symptoms and signs are dyspnoea/dry cough and crackles that

occur 1–9 months after starting treatment and should lead to

immediate cessation of the drug until another cause has been

identified. Anecdotal case reports suggest that steroids might

help pre-fibrotic stages (Sleijfer, 2001).

KEY recommendations for follow-up, late effects andsurvivorship

● Patients are usually followed with intermittent outpa-

tient clinical review for 2–5 years following first line

therapy (2C).

● There is no proven role for routine surveillance CT or

PET/CT imaging in patients who are otherwise well fol-

lowing first line therapy (2B).

● HL patients should be made aware that they are at an

increased lifetime risk of second neoplasms, cardiovas-

cular and pulmonary disease and infertility (1A).

● Apart from the current breast cancer-screening pro-

gramme, there are no national cancer screening pro-

grammes tailored for HL survivors. Women treated with

mediastinal RT before the age of 35 years should be

offered entry into the breast cancer National Notification

Risk Assessment and Screening programme (NRASP)

(1A).

● Regular lifestyle advice should be offered to reduce sec-

ondary neoplasms and cardiovascular risk. There should

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44 ª 2014 John Wiley & Sons LtdBritish Journal of Haematology, 2014, 166, 34–49

be complete avoidance of smoking and careful manage-

ment of cardiovascular risks such as hypertension, dia-

betes mellitus and hyperlipidaemia (1B).

● Patients who have had RT to the neck and upper

mediastinum should have regular thyroid function

checks. Hypothyroidism can occur up to 30 years after

RT (1A).

● Patients should receive irradiated blood products for

life (1B).

Disclaimer

While the advice and information in these guidelines is

believed to be true and accurate at the time of going to

press, neither the authors, the British Society for Haematolo-

gy nor the publishers accept any legal responsibility for the

content of these guidelines. This Guideline is in date at the

time of publishing. It will be reviewed at least annually and

any updates will be posted on the BCSH website http://www.

bcshguidelines.com.

Acknowledgement

Dr William Townsend, senior trainee in Haematology, UCH,

London, performed the initial literature search and has

helped assemble the final document.

Conflicts of interest

The authors have no conflicts of interest to declare.

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Appendix IGrade nomenclature

Strength of recommendations

Strong (grade 1): Strong recommendations (grade 1) are made

when there is confidence that the benefits do or do not out-

weigh harm and burden. Grade 1 recommendations can be

applied uniformly to most patients. Regard as ‘recommend’.

Weak (grade 2): Where the magnitude of benefit or not is

less certain a weaker grade 2 recommendation is made.

Grade 2 recommendations require judicious application to

individual patients. Regard as ‘suggest’.

Quality of evidence

The quality of evidence is graded as high (A), moderate

(B) or low (C). To put this in context it is useful to consider

the uncertainty of knowledge and whether further research

could change what we know or our certainty.

(A) High: Further research is very unlikely to change confi-

dence in the estimate of effect. Current evidence derived from

randomised clinical trials without important limitations.

(B) Moderate: Further research may well have an important

impact on confidence in the estimate of effect and may

change the estimate. Current evidence derived from rando-

mised clinical trials with important limitations (e.g. inconsis-

tent results, imprecision – wide confidence intervals or

methodological flaws – e.g. lack of blinding, large losses to

follow up, failure to adhere to intention to treat analysis), or

very strong evidence from observational studies or case series

(e.g. large or very large and consistent estimates of the mag-

nitude of a treatment effect or demonstration of a dose-

response gradient).

(C) Low: Further research is likely to have an important

impact on confidence in the estimate of effect and is likely to

change the estimate. Current evidence from observational

studies, case series or just opinion.

Guideline

ª 2014 John Wiley & Sons Ltd 49British Journal of Haematology, 2014, 166, 34–49