BSCH 2014 Guidelines LH

guideline
Guidelines for the first line management of classical Hodgkin

lymphoma
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
1
Department of Haematology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, Cambridge, 2Department of Haematology, University College Hospital London Hospitals NHS Trust, 3St Thomas Division of Imaging, PET Imaging Centre, Kings College 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 Haematology, 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, chemotherapy, 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, Chemotherapy and Radiotherapy. References from relevant publications 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 appropriate 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 contrastenhanced computerized tomography (CT) of the neck to pelvis is required (1A), although
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
First published online 9 April 2014

doi: 10.1111/bjh.12878
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 cryopreservation 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, doxorubicin, 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 presenting 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
2014 John Wiley & Sons Ltd

British Journal of Haematology, 2014, 166, 3449
Guideline
pulmonary crackles should lead to stopping of bleomycin
until an alternative cause is identified (1B).
Management of advanced stage disease

Patients aged 1660 years old with advanced stage HL
should receive either 68 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 patients
opinion on the toxicity/efficacy balance between the regimens (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 prospective 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 >15 cm.
It remains unclear whether RT can be safely omitted in
ABVD patients who have residual tissue >15 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 optimally 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 postdelivery would not be standard practice and should be
done with caution (1C).
ABVD is the regimen of choice unless specifically contraindicated (1B).
Wherever possible, RT should be delayed until postdelivery (1B).
Management of HL in elderly patients

Elderly patients should be formally assessed for fitness
to receive combination chemotherapy with a co-morbidity 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 chemotherapy 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. Treatment with VEPEMB (vinblastine, cyclophosphamide,
prednisolone, procarbazine, etoposide, mitoxantrone) or
COPP (cyclophosphamide, vincristin, procarbazine,
prednisone)/ABVD appears to have lower treatmentrelated mortality than ABVD or BEACOPP (2B).
PET/CT in HL
PET/CT should be reported by PET/CT imaging specialists (1C).
As pre-treatment staging with PET/CT will upstage a
minority of patients and aid the interpretation of subsequent PET/CT, it is recommended when clinically feasible (1B).
PET/CT response should be reported according to
Deauville criteria (2B).
By Deauville criteria, a score of 1 or 2 should be considered negative and 4 or 5 considered positive. Deauville 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 confirm residual disease with a score of 4 or 5 where possible
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).
35
Guideline
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 outpatient clinical review for 25 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 following first line therapy (2B).
HL patients should be made aware that they are at an
increased lifetime risk of second neoplasms, cardiovascular and pulmonary disease and infertility (1A).
Apart from the current breast cancer-screening programme, there are no national cancer screening programmes 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 secondary neoplasms and cardiovascular risk. There should
be complete avoidance of smoking and careful management of cardiovascular risks, such as hypertension, diabetes 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).
Background
The annual incidence of Hodgkin Lymphoma (HL) in the
UK is 27/100 000 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
2034 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
36
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 interaction with components of the microenvironment (Swerdlow
et al, 2008; Steidl et al, 2011; Kuppers et al, 2012).
Hodgkin Lymphoma is classified as either nodular lymphocyte predominant (NLPHL) or classical HL. There are
four sub-types of classical HL: nodular sclerosis, mixed cellularity, 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 differently from classical HL (Swerdlow et al, 2008).
Clinical presentation of classical HL is usually with painless
lymphadenopathy, which is most commonly cervical or supraclavicular. Mediastinal disease is identified in 80% of patients
and is more common in nodular sclerosing HL, whilst peripheral or sub-diaphragmatic lymphadenopathy is more common
in mixed-cellularity classical HL. Bone marrow involvement is
detected in only 58% 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 >38C, 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 profile, lactate dehydrogenase and testing for human immunodeficiency 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 appreciated that a minority of patients may present with very advanced
disease and if obtaining a PET/CT scan would result in a treatment 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, however, 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
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 (Hasenclever & 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 fertility-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, cyclophosphamide, vincristine, procarbazine, prednisone). ABVD
(doxorubicin, bleomycin, vinblastine, dacarbazine) is generally considered to be fertility-sparing, but some patients may
need to receive salvage chemotherapy and stem cell transplantation, which can result in a reduction of fertility. The
role for prophylactic use of gonadotropin-releasing hormone
(GnRH) analogues to preserve female fertility remains uncertain (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 available 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, fertility 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 including HIV serology (1A).
Staging with contrastenhanced CT of the neck to pelvis
is required (1A), although 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/IPS (1A).
For male patients, pre-treatment semen cryopreservation should be offered where possible (1A).
For female patients, pre-treatment review of options
with a fertility specialist should be considered (1A).
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 III 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 III 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 outcomes when treated with early stage unfavourable risk protocols. Definition of large mediastinal mass/bulky disease
varies slightly between study groups: The European Organization for the Research and Treatment of Cancer (EORTC)
defines bulk as a mediastinal thoracic ratio >035 at T5/6.
The UK National Cancer Research Institute (NCRI) and
GHSG define a mediastinal mass ratio >033 as large, while
the US National Comprehensive Cancer Network (NCCN)
and National Cancer Institute of Canada (NCIC) define
bulky as a mediastinal mass ratio>033 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 76-year median follow up, no difference 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 sufficient in favourable Stage III HL.
The trial with the longest published median follow-up
(113 years) in early stage HL is the IA/IIA non-bulky NCIC
and Eastern Cooperative Oncology Group (ECOG) trial
comparing ABVD alone (46 cycles) with treatment includTable I. Favourable prognosis Stage III Hodgkin Lymphoma.
EORTC
GHSG
No large mediastinal adenopathy

ESR <50 without B symptoms
ESR <30 with B symptoms
Age 50 years
13 lymph node sites involved
No large mediastinal adenopathy

ESR <50 without B symptoms
ESR <30 with B symptoms
No extranodal disease
Management of early stage disease

Randomized trials have shown that combined modality treatment with chemotherapy and radiotherapy (RT) results in
EORTC, European Organization for the Research and Treatment of

Cancer; GHSG, German Hodgkin Study Group; ESR, erythrocyte
sedimentation rate.
37
Guideline
Table II. Unfavourable prognosis Stage III Hodgkin lymphoma.
EORTC presence of one or
more of the following
GHSG presence of one or more

of the following
Large mediastinal adenopathy

ESR 50 without B symptoms
ESR 30 with B symptoms
Age >50 years
Large mediastinal adenopathy

ESR 50 without B symptoms
ESR 30 with B symptoms
Extranodal disease
EORTC, European Organization for the Research and Treatment of

Cancer; GHSG, German Hodgkin Study Group; ESR, erythrocyte
sedimentation rate.
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 randomized 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 859% and OS
of 939% (Radford et al, 2012).
With the current available data, the standard of care for treatment 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). However, 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
38
RT probably increases the risk of early relapse by approximately

37% (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 46 cycles of ABVD, has the longest followup, 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; Radford et al, 2012), larger randomized trials using PET/CT to
guide decision-making in early stage HL have yet to be formally 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 remission 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 BEACOPP plus 30 Gy RT and four cycles of BEACOPP plus 20 Gy
RT (Eich et al, 2010). With 68 years median follow-up, no difference was observed in OS (9396%) 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 = 065), but a significant difference in favour of BEACOPP was seen for FFTF when 20 Gy RT was used (P = 002)
(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 followed by 30 Gy RT in both arms. At 5 years follow-up, the
dose-intensified regime resulted in better tumour control with a
62% improvement in PFS compared with standard treatment
with four cycles of ABVD. However, acute toxicities were significantly 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 413% of cases of Stage III disease
Guideline
(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 supradiaphragmatic counterparts (Darabi et al, 2005; Vassilakopoulos et al,
2006).
KEY recommendations for 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 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 presenting 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 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 combination 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 toxicity than MOPP (mechlorethamine, vinristine, procarbazine,
predisone), MOPPABV (MOPP, doxorubicin, bleomycin,
vinblastine) hybrid and ChlVPP/PABLOE (chlorambucil, vinblastine, 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 7378%
with OS in the range of 8290% (Duggan et al, 2003; Johnson et al, 2005; Federico et al, 2009; Hoskin et al, 2009; Viviani 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 strategies 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 remission (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 69 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 proportion 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 conventional CT) were not treated with RT consolidation, in
contrast with the HD9 trial. The number of patients receiving 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 reasonable 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/
39
Guideline
adolescent HL [5-year event-free survival (EFS)/OS: 94%/
97%] (Kelly et al, 2011), but have shown unacceptable treatment-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 BEACOPP, but no survival advantage has yet been demonstrated
with a median follow-up of 38 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 BEACOPP resulted in a 7-year freedom-from-first progression
advantage compared with ABVD (85% vs. 73%; P = 0004),
but the 7-year OS was no different, at 89% and 84%,
respectively (P = 032). Considering the first line intensification 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 context of standard UK practice. However, the data support the
consensus view that, compared with ABVD, escalated BEACOPP provides a PFS advantage for patients, while adding
to the intense debate as to whether first line escalated BEACOPP provides a true survival advantage for advanced HL
patients.
ABVD has a better toxicity profile than escalated BEACOPP in terms of direct side effects of chemotherapy,
infectious complications, blood product requirements, fertility 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 doxorubicin 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 03% in patients treated 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 BEACOPP (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
40
treated with 68 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 68 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 predictive 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 BEACOPP-14 with no RT requirement, while the Italian
approach has been to use 8 cycles of BEACOPP (49 escalated and 49 standard) and RT to sites of initial bulk disease. 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 escalated 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 escalated 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 transplant. With ABVD-treated patients, there is also uncertainty
with regards to the need for RT to sites of initial bulky disease/residual tissue and lack of clarity as to the role of iPET2
when treated outside a clinical trial. Patients opting for escalated 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 treatmentrelated 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 advanced

stage disease
Patients aged 1660 years with advanced stage HL
should receive either 68 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 patients
opinion on the toxicity/efficacy balance between the
regimens (2B).
Guideline
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 prospective 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 >15 cm.
It remains unclear whether RT can be safely omitted in
ABVD patients who have residual tissue >15 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 optimally 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
There are no prospective trials for the management of HL in
pregnancy, but a number of published case reports, case series and case cohorts were reviewed by Bachanova and Connors (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 termination 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 radiation-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 chemotherapy is to be used (Bachanova & Connors, 2008).
Although ABVD has been used to treat patients in all 3 trimesters (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 clinicians 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 specialized 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 postdelivery would not be standard practice and should be
done with caution (1C).
ABVD is the regimen of choice unless specifically contraindicated (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 outcome 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 chemotherapies, 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 lymphoma meetings in the early 2000s it was decided to pursue a
series of non-randomized phase II studies of alternative therapies 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 (bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine,
prednisone) was used to treat 65 patients aged 6570 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 6075 years were treated for mainly advanced stage disease, 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
41
Guideline
who were classified as frail based on a scoring system, completed treatment or achieved a CR. The high treatmentrelated 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 toxicity led to 21% treatment-related deaths after BEACOPP compared with 8% for COPP/ABVD (Ballova et al, 2005).
UK and Italian groups have both explored a treatment strategy with VEPEMB (vinblastine, cyclophosphamide, prednisolone, procarbazine, etoposide, mitoxantrone). In total, 103
patients were treated with VEPEMB as part of the Shield programme (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 regimens, 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 elderly

patients
Elderly patients should be formally assessed for fitness
to receive combination chemotherapy with a co-morbidity 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 chemotherapy 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. Treatment with VEPEMB or COPP/ABVD appears to have
lower treatment-related mortality than ABVD or BEACOPP (2B).
The use of PET/CT in HL

Hodgkin Lymphoma is 18FFDG avid in 97100% 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 subsequent response assessment (Quarles van Ufford et al, 2010;
42
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 Deauville criteria has been used for reporting in response guided
trials and has published high inter-observer agreement (Barrington et al, 2010; Furth et al, 2011; Biggi et al, 2013) and
improved predictive value (Le Roux et al, 2011) when compared 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 involvement 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.clinicaltrials.gov/ct2/show/NCT00795613) with initial reports suggesting 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 considered. 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, granulomatous disease and sarcoid-like reactions, are also recognized (Barrington & ODoherty, 2003). Patients with score 3,
Guideline
which was previously referred to as minimal residual
uptake, (Hutchings et al, 2005) are likely have good outcomes 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 control have been developed during the conduct of responseguided 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 performed 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 colonystimulating factor (G-CSF) treatment and 3 months after RT is
recommended to elapse prior to scanning (Boellaard et al,
2010).
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, maximizing 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

Key recommendations for PET/CT in HL
PET/CT should be reported by PET/CT imaging specialists (1C).
As pre-treatment staging with PET/CT will upstage a
minority of patients and aid the interpretation of subsequent PET/CT, it is recommended when clinically feasible (1A).
PET/CT response should be reported according to
Deauville criteria (2B).
By Deauville criteria, a score of 1 or 2 should be considered negative and 4 or 5 considered positive. Deauville 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 confirm residual disease with a score of 4 or 5 where possible 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.
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 radiation 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 510 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
43
Guideline
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 neoplasms and cardiac disease, but also include pulmonary disease 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 implications 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 incidence 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 39; 95% confidence interval (CI), 3544;
RR CA 20; 95% CI, 1724]. The largest AERs related to
lung cancer, CMT 140, CA 107, non-Hodgkin lymphoma,
CMT 139, CA 116 and leukaemia, CMT 117, CA 128.
However, CMT was associated with AERs for a range of
additional secondary neoplasms including breast, bowel, nonmelanoma 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 1033%, compared with a lifetime risk in
the UK of 11% (Taylor et al, 2007; Westlake & Cooper,
2008). Furthermore, survival stage-for-stage with breast cancer after HL is worse than that following de novo breast cancer (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
44
treated between 1967 and 2000 and identified 166 deaths

from MI (Swerdlow et al, 2007). This represented an absolute excess risk of 126 per 100 000 person-years, and the
risk remains high for at least 25 years. Significant and independent increased risk of MI was identified for supradiaphragmatic RT, anthracyclines and vinca-alkaloids. The risk
was particularly high for the ABVD regimen and the combination 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 12% of bleomycin-treated patients (Williams
et al, 1987; Kaye et al, 1998; Nichols et al, 1998; OSullivan
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 (OSullivan et al, 2003;
Martin et al, 2005). However, only dose and older age seem
to be reliably associated and the risk should be largely considered idiosyncratic. Bleomycin toxicity ranges from a measured
decrease in diffusion capacity, lung volumes and vital capacity, 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 19 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 and

survivorship
Patients are usually followed with intermittent outpatient clinical review for 25 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 following first line therapy (2B).
HL patients should be made aware that they are at an
increased lifetime risk of second neoplasms, cardiovascular and pulmonary disease and infertility (1A).
Apart from the current breast cancer-screening programme, there are no national cancer screening programmes 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 secondary neoplasms and cardiovascular risk. There should
Guideline
be complete avoidance of smoking and careful management of cardiovascular risks such as hypertension, diabetes 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).
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.
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-
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Appendix I
Grade nomenclature
Strength of recommendations
Strong (grade 1): Strong recommendations (grade 1) are made
when there is confidence that the benefits do or do not outweigh 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
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the uncertainty of knowledge and whether further research
could change what we know or our certainty.
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(A) High: Further research is very unlikely to change confidence 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 randomised clinical trials with important limitations (e.g. inconsistent 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 magnitude of a treatment effect or demonstration of a doseresponse 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.
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guideline

Guidelines for the first line management of classical Hodgkin

Keywords: Hodgkin, Hodgkin lymphoma, treatment, chemotherapy, radiotherapy.

Correspondence: Department of Haematology, Addenbrookes

First published online 9 April 2014

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

Management of early stage disease

2014 John Wiley & Sons Ltd

Management of advanced stage disease

Management of HL in elderly patients

Follow-up, late effects and survivorship

surface immunoglobulin usually undergo apoptosis but HRS

Key recommendations for pre-treatment evaluation

superior tumour control compared with RT alone (Noordijk

Favourable early stage disease

No large mediastinal adenopathy

No large mediastinal adenopathy

Management of early stage disease

EORTC, European Organization for the Research and Treatment of

GHSG presence of one or more

Large mediastinal adenopathy

Large mediastinal adenopathy

EORTC, European Organization for the Research and Treatment of

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

RT probably increases the risk of early relapse by approximately

Unfavourable early stage disease

Infradiaphragmatic early stage disease

KEY recommendations for management of early stage

Advanced stage disease

treated with 68 cycles of ABVD are more limited, but there

Key recommendations for management of advanced

Key recommendations for HL in pregnancy

Management of HL in elderly patients

Key recommendations for management of elderly

The use of PET/CT in HL

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

Key recommendations for radiotherapy strategies in HL

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

Follow-up, late effects and survivorship issues

treated between 1967 and 2000 and identified 166 deaths

KEY recommendations for follow-up, late effects and

gy nor the publishers accept any legal responsibility for the

2014 John Wiley & Sons Ltd

Behringer, K., Mueller, H., Goergen, H., Thielen,

menopause following Hodgkin lymphoma.

M., Hallek, M., Kanz, L., Dohner, H., Dorken,

2014 John Wiley & Sons Ltd

Viviani, S., Bolis, S., Trentin, L., Olivieri, A.,

2014 John Wiley & Sons Ltd

P.W. (2009) Randomized comparison of the

Meyer, R.M., Gospodarowicz, M.K., Connors,

T.A., Peny, A.M., Girinsky, T., Raemaekers, J.M.

2014 John Wiley & Sons Ltd

New England Journal of Medicine, 365, 15441545;

lymphoma. Clinical features, prognostic factor

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