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Guidelines for the First Line Management of Classical Hodgkin Lymphoma


British Committee for Standards in Haematology

Corresponding author:
Dr G A Follows
c/o BCSH Administrator
British Society for Haematology
100 White Lion Street
London
N1 9PF, UK
e-mail bcsh@b-s-h.org.uk
Writing Group:
Follows GA1, Ardeshna KM2, Barrington SF3, Culligan DJ4, Hoskin PJ5, Linch
D2,6, Sadullah S7, Williams MV8, Wimperis JZ9
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
Haematology 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 least annually
basis 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
Declarations of Interest
The authors have no conflicts of interest to declare
Key words
Hodgkin, Hodgkins, lymphoma, treatment, chemotherapy, radiotherapy
1

Department of Haematology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, UK


3
Department of Haematology, University College Hospital London Hospitals NHS Trust, London, PET
4
Imaging Centre, St Thomas Division of Imaging, Kings College London Department of
5
Haematology, Aberdeen Royal Infirmary, Aberdeen, Mount Vernon Cancer Centre, Northwood,
6
Middlesex Department of Haematology, UCL Cancer Institute, University College Centre of Imaging ,
7
8
London Department of Haematology James Paget University Hospital, Great Yarmouth Department
9
of Oncology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, UK, Department of
Haematology Norfolk and Norwich University Hospital, Norwich
2

1. INTRODUCTION:
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 Jan 1990 to June 2013 using key
words Hodgkin, Lymphoma, Treatment, Chemotherapy, 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. The guideline was then reviewed by a sounding board of
approximately 50 UK haematologists, the BCSH (British Committee for Standards in
Haematology) 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 1. 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
2. PRE-TREATMENT EVALUATION
Patients require pre-treatment blood evaluation including HIV serology
1A
Staging with contrastenhanced CT 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 a 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
3 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 x ABVD
and 20 Gy RT. 1A
Standard of care for unfavourable early stage HL is 4 x ABVD and 30 Gy
RT. 1A
A treatment option for unfavourable early stage HL is 2 x escalated
BEACOPP + 2 x ABVD and 30Gy RT. 1A
The decision to omit RT from the management of 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 x 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

4 MANAGEMENT OF ADVANCED STAGE DISEASE


Patients aged 16 to 60 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 patients opinion on the toxicity /
efficacy balance between the regimens. 2B
Patients with a higher International Prognostic score 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-oftreatment 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 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
5 MANAGEMENT OF HL IN PREGNANCY
Patients should be closely co-managed with a specialised obstetric /
fetal medicine unit 1B
Staging investigations and response evaluation should be tailored to the
clinical presentation with radiology input to minimise 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 contraindicated 1B
Wherever possible, RT should be delayed until post-delivery 1B.
6 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
radiotherapy 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 randomised trial data. Treatment with VEPEMB or COPP/ABVD

appears to have lower treatment-related mortality than ABVD or


BEACOPP. 2B
7 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, score 1,2 should be considered negative and 4,5
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 score 4,5 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
radiotherapy planning, biopsy considerations and follow-up strategy 1B
8 RADIOTHERAPY STRATEGIES IN HL
The evidence for the role of radiotherapy in HL is based on involved
field radiotherapy (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 for all
other patients 30 Gy. 1A
9 FOLLOW-UP, LATE EFFECTS AND SURVIVORSHIP
Patients are usually followed with intermittent outpatient clinical review
for 2 to 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 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 radiotherapy before the age of 35 yrs
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 the 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 radiotherapy to the neck and upper mediastinum
should have regular thyroid function checks. Hypothyroidism can occur
up to 30 years after radiotherapy. 1A
Patients should receive irradiated blood products for life. 1B

1. 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 ages 20-34 years
with a further peak observed >70 years. The incidence is currently stable (Morton,
Wang et al. 2006; Cancer Research UK 2010; Shenoy, Maggioncalda et al. 2011).
HL is characterised 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, Campo 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 NFB, and interaction with components of the
microenvironment (Swerdlow, Campo et al. 2008; Steidl, Connors et al. 2011;
Kuppers, Engert et al. 2012).
HL 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, Campo 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 5-8% of patients with conventional
staging (Mauch, Kalish et al. 1993; Levis, Pietrasanta et al. 2004; Swerdlow, Campo
et al. 2008), but in up to 18% with PET/CT staging (El-Galaly, d'Amore 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.

2. PRETREATMENT EVALUATION
Blood evaluation should include full blood count, erythrocyte sedimentation rate
(ESR), renal function, liver function, bone profile, lactate dehydrogenase and testing
for HIV.

Patients should be staged with a contrast-enhanced CT scan covering 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 aware that diffuse bone
marrow uptake on PET may just reflect a reactive process.
Patients with early stage disease should be categorised as having favourable or
unfavourable characteristics. Patients with advanced stage disease should have
their Hasenclever / International Prognostic Score (IPS) determined (Hasenclever
and 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. ABVD 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 gonadotropinreleasing hormone (GnRH) analogues to preserve female fertility remains uncertain
(Behringer, Thielen et al. 2012; Wong, O'Neill et al. 2013). For women with a stable
partner, and in whom a delay of treatment is possible, in vitro fertilisation 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, Mangu et al.
2013). Generally, fertility preservation techniques can only be discussed on a caseby-case basis, involving fertility experts and oncologists who can judge the
appropriateness of the techniques and the risks of delaying treatment.
KEY RECOMMENATIONS FOR PRE-TREATMENT EVALUATION
Patients require pre-treatment blood evaluation including HIV serology
1A
Staging with contrastenhanced CT 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 a 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

3. MANAGEMENT OF EARLY STAGE DISEASE


Randomised trials have shown that combined modality treatment with chemotherapy
and radiotherapy results in superior tumour control compared with radiotherapy
alone (Noordijk, Carde et al. 2006; Engert, Franklin et al. 2007; Ferme, Eghbali 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
Hodgkins 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 Organisation 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 >10cm. Prognostic
factors for the EORTC and GHSG are listed in Table 1 and 2.

Table 1 - Favourable prognosis Stage I-II Hodgkin Lymphoma


GHSG

EORTC
No
large
adenopathy

mediastinal No
large
adenopathy

mediastinal

ESR <50 without B symptoms

ESR <50 without B symptoms

ESR <30 with B symptoms

ESR <30 with B symptoms

Age 50

No E-disease

1-3 lymph node sites involved

1-2 lymph node sites involved

EORTC, European Organisation for the Research and Treatment


of Cancer; GHSG, German Hodgkins Study Group

Table 2 - 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

E-disease

4 lymph node sites involved

3 lymph node sites involved

EORTC, European Organisation for the Research and Treatment


of Cancer; GHSG, German Hodgkins Study Group

3.1 Favourable Early Stage Disease

Recent trials have focussed on abbreviating chemotherapy and radiotherapy


dosages, and assessing radiotherapy-free treatment strategies. The GHSG HD 10
trial randomised 1,190 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 difference was observed in freedom from progression (97%) or OS
(98%) between the four groups (Engert, Plutschow 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 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 ECOG trial comparing ABVD alone (4 to 6 cycles)
with treatment including subtotal nodal irradiation (STNI) (Meyer, Gospodarowicz et
al. 2012). From separate sequential analysis of this trial (Meyer, Gospodarowicz et
al. 2005; Meyer, Gospodarowicz et al. 2012), it appears that omitting RT increases
the risk of early relapse, but with longer follow-up does not appear to compromise
overall survival. 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 which complicated the interpretation of the overall survival
(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 overall survival (OS) of
94%.
Data from the UK NCRI trial (RAPID) and the EORTC H10 trial were presented at
the annual American Society of Haematology (2012) (Andre, Reman et al. 2012;
Radford, Barrington et al. 2012). In both trials, patients who achieved an early PETnegative remission had a better progression-free survival (PFS) than interim PETpositive patients. Both trials randomised patients who achieved an early PETnegative 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 overall survival
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 3 x ABVD, received 1 x
additional ABVD and RT. This achieved a 3 yr PFS of 85.9% and OS of 93.9%
(Radford, Barrington 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 x2
+RT. However, as there are longer term risks for patients treated with RT, it is
recognised that in some circumstances, clinicians and patients may prefer to treat
without radiotherapy, 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 HD.6, suggested patients who achieve a CT CR
after 2 x ABVD, and then complete a total 4 x ABVD with no RT, have the same
excellent outcome as 2 x ABVD + RT (Hay, Klimm 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 RT probably increases the risk of early relapse by approximately 3 to 7%
(Meyer, Gospodarowicz et al. 2005; Andre, Reman et al. 2012; Meyer,
Gospodarowicz et al. 2012; Radford, Barrington 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 to 6 cycles of ABVD has the longest follow-up, but initial
data from 3 x 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, Higgins et al. 2011).

Apart from abstract presentation of the UK NCRI trial (RAPID) and the EORTC H10
trial, larger randomised 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 radiotherapy. At this stage, it remains uncertain whether achieving an interim
PET-negative remission after 2 cycles of ABVD is as predictive for long term PFS
and OS as achieving a complete remission by established CT criteria.

3.2 Unfavourable Early Stage Disease


In the HD 11 trial, the GHSG randomly assigned 1,395 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. With 6.8 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 = .65), but a significant difference in favour of BEACOPP was seen for FFTF
when 20 Gy RT was used (P = .02) (Eich, Diehl 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 2 cycles of ABVD(2+2) (von Tresckow, Plutschow 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 6.2%
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 overall survival, 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.

3.3 Infradiaphragmatic Early Stage Disease


The incidence of infradiaphragmatic early stage HL is very low and accounts for 413% of cases of Stage I - II disease (Vassilakopoulos, Angelopoulou 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 international prognostic score 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, Sieber et al. 2005; Vassilakopoulos, Angelopoulou et al. 2006).
KEY RECOMMENDATIONS FOR MANAGEMENT EARLY STAGE DISEASE

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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 x ABVD
and 20 Gy RT. 1A
Standard of care for unfavourable early stage HL is 4 x ABVD and 30 Gy
RT. 1A
A treatment option for unfavourable early stage HL is 2 x escalated
BEACOPP + 2 x ABVD and 30Gy RT. 1A
The decision to omit RT from the management of 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 x 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
4 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 and Linch 2012). There is significant international
variation in the use of radiotherapy to sites of initial bulk disease or residual masses
following chemotherapy.
Over the past 3 decades of comparative randomised clinical trials in HL, ABVD and
escalated BEACOPP have become established international standards of care for
advanced HL (reviewed in (Townsend and Linch 2012)). ABVD has better outcomes
in terms of efficacy and/or toxicity than MOPP, MOPPABV hybrid and
ChlVPP/PABLOE and similar efficacy, but lower toxicity, than the Stanford V
regimen (Canellos, Anderson et al. 1992; Duggan, Petroni et al. 2003; Johnson,
Radford et al. 2005; Hoskin, Lowry et al. 2009). From a number of advanced HL
trials, failure-free/progression-free survival with ABVD is around 73-78% with overall
survival in the range of 82-90% (Duggan, Petroni et al. 2003; Johnson, Radford et al.
2005; Federico, Luminari et al. 2009; Hoskin, Lowry et al. 2009; Viviani, Zinzani et al.
2011). ABVD should be delivered on schedule with infusions given every 14 days
irrespective of neutrophil count. G-CSF is only required for patients with infectious
complications (Evens, Cilley et al. 2007; Nangalia, Smith 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 PR, who did derive benefit
from RT (Aleman, Raemaekers 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. With LY09, 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,
Radford et al. 2005). Of note, the ABVD trials with the highest overall survival rates
have used RT for a large proportion of patients (Duggan, Petroni et al. 2003;
Johnson, Radford et al. 2005; Hoskin, Lowry et al. 2009).

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Escalated BEACOPP has been developed by the German HL study group (GHLSG).
In comparison with COPPABVD and standard dose BEACOPP, escalated
BEACOPP has demonstrated improved progression-free and overall survival
(Engert, Diehl et al. 2009). Data from 2182 patients randomised from 408 centres in
the GHLSG HD15 trial have shown a 5-year failure-free and overall survival of 89%
and 95% for patients receiving 6 cycles of escalated BEACOPP (Engert, Haverkamp
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, Haverkamp et al. 2012). Although this
is not prospective randomised 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, Haverkamp et al. 2012).From HD15,
the outcomes for patients treated with escalated BEACOPP x 6 or BEACOPP14 x 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 / adolescent HL (5 year EFS/OS: 94%/97%) (Kelly,
Sposto et al. 2011), but have shown unacceptable treatment-related toxicity in
patients >60 (Engert, Diehl et al. 2009) and the GHLSG no longer recommended this
protocol for patients over 60.
Data directly comparing ABVD with escalated BEACOPP are limited. The EORTC
20012 trial comparing ABVD with BEACOPP (4x escalated, 4 x standard) for higher
risk HL patients has been presented in abstract form only (Carde, Karrasch 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 3.8 years. A
smaller Italian trial randomised 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, Zinzani 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=0.004), but 7-year overall survival was no different at
89% and 84% respectively (p=0.32). Considering the first line intensification strategy
given to approximately patients and significant criticisms raised with regards to
this trial (Borchmann, Diehl et al. 2011; Corazzelli, Russo et al. 2011; Tam, Herschtal
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 progression-free-survival 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 MDS/AML (Sieniawski, Reineke et al. 2008;
Engert, Diehl 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, Haverkamp et al. 2012). The cumulative total doses of
doxorubicin and bleomycin are lower for patients treated with 6 x escalated
BEACOPP compared with 6 x 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 treated with 6 cycles of
escalated BEACOPP (Engert, Haverkamp et al. 2012). Interestingly the EORTC
20012 trial has found no difference in 2nd cancer / MDS rates between ABVD and
escalated BEACOPP (Carde, Karrasch et al. 2012).

12

Rates of female infertility are strongly influenced by the chemotherapy choice and
age at treatment (Behringer, Breuer et al. 2005; De Bruin, Huisbrink et al. 2008;
Behringer, Mueller et al. 2013). With 4 cycles of ABVD within the GHLSG HD14 trial,
100% of women aged < 30 and 94% aged > 30 regained regular menstrual cycles
following chemotherapy. Data from patients treated with 6 to 8 cycles of ABVD are
more limited, but there does not appear to be additional loss of fertility with the
additional cycles of treatment (De Bruin, Huisbrink et al. 2008, Hodgson, Pintilie et
al. 2007). With 6 to 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, Breuer et al. 2005; De Bruin, Huisbrink et al. 2008;
Behringer, Mueller et al. 2013).
A positive PET/CT scan after 2 cycles of ABVD, interim PET (iPET), has been shown
to be strongly predictive of treatment failure for patients who continue with ABVD
therapy (Gallamini, Hutchings 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(National Cancer Research Network 2013) (UK NCRI
Portfolio RATHL)(Gallamini, Patti et al. 2011; Gallamini, Rossi et al. 2012). The UK
RATHL trial chose to intensify therapy with either 4 x escalated BEACOPP or 4 x
BEACOPP-14 with no RT requirement, while the Italian approach has been to use 8
cycles of BEACOPP (4x escalated and 4 x standard) and RT to sites of initial bulk
disease. Initial reports from the Italian group appear encouraging (Gallamini, Patti et
al. 2011; Gallamini, Rossi et al. 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 escBEACOPP 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 event-free survival 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, Shaw et al. 2012).
KEY RECOMMENDATIONS FOR MANAGEMENT OF ADVANCED STAGE
DISEASE
Patients aged 16 to 60 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 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

13

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 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

5 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 are reviewed in
(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, Advani et
al. 2011).
Staging and response assessment with MRI scanning and ultrasound may avoid the
need for radiation-based imaging, and in certain cases, delaying therapy until postpartum 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 and
Connors 2008). Although ABVD has been used to treat patients in all 3 trimesters
(Anselmo, Cavalieri et al. 1999; Cardonick and 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 specialised obstetric/fetal
medicine unit 1B
Staging investigations and response evaluation should be tailored to the
clinical presentation with radiology input to minimise 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 contraindicated 1B
Wherever possible, RT should be delayed until post delivery 1B.

14

6. 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, Wood 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, Sweetenham et
al. 2008; Proctor, Wilkinson et al. 2009; Evens, Helenowski et al. 2012; Evens, Hong
et al. 2013). Older patients are more likely to die from non-HL causes, including
bleomycin lung toxicity, which was reported in 24% of patients over 60 treated within
the North American intergroup trial E2496 (Evens, Hong et al. 2013). Therapyrelated toxicity has, therefore, made delivering the gold standard chemotherapies,
ABVD and BEACOPP, challenging, especially in the over 70s and the major
randomised 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-randomised 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 and gemcitabine) (Halbsguth, Nogova et al. 2010; Boll,
Bredenfeld et al. 2011). With BACOPP they treated 65 patients aged 65-70 yrs
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 were treated for mainly advanced
stage disease producing a 3-yr 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, Gorgen 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 2 or
more cycles of ABVD and IFRT was 62% but with advanced stage ABVD patients,
the CR rate was only 46%, and there were 18% treatment-related deaths (Proctor,
Wilkinson et al. 2012). Of note, within this registration study, no patients classified as
frail based on a scoring system completed treatment or achieved a CR. The high
treatment-related death rate with ABVD is similar to that described in the ABVD vs.
Stamford V trial for older patients (Evens, Hong 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, Ruffer et al. 2005).
UK and Italian groups have both explored a treatment strategy with VEPEMB
(vinblastine, cyclophosphamide, prednisolone, procarbazine, etoposide and
mitoxantrone). In total, 103 patients were treated with VEPEMB as part of the Shield
programme (Proctor, Wilkinson et al. 2012), including 31 early stage patients
(VEPEMB x 3 followed by involved field radiotherapy) with a CR rate of 74% and 3 yr
PFS and OS of 74% and 81% respectively. With 72 advanced stage patients treated
with VEPEMB x 6 a CR rate of 61% was achieved with 3 yr PFS and OS of 58% and
66% respectively. However, patients classified as frail were excluded from the UK
VEPEMB trial and this likely improved the results. Nevertheless, similar encouraging
data with VEPEMB have been reported from an Italian trial (Levis, Anselmo et al.
2004). 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).

15

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
radiotherapy 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 randomised trial data. Treatment with VEPEMB or COPP/ABVD
appears to have lower treatment-related mortality than ABVD or
BEACOPP. 2B
7 THE USE OF PET/CT IN HL
HL is 18F-fluorodeoxyglucose (FDG) avid in 97-100% of cases (Weiler-Sagie,
Bushelev et al. 2010). Staging patients with FDG PET-CT is more accurate than CT
alone (Cheson, Pfistner et al. 2007) and the availability of a baseline scan increases
the reliability of subsequent response assessment (Quarles van Ufford, Hoekstra et
al. 2010; Barrington, Mackewn 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 interobserver
agreement (Barrington, Qian et al. 2010; Furth, Amthauer et al. 2011; Biggi,
Gallamini et al. 2013) and improved predictive value (Le Roux, Gastinne et al. 2011)
when compared with earlier International Harmonisation criteria (Juweid, Stroobants
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 five point score as
follows:
Score 1
Score 2
Score 3
Score 4
Score 5

no uptake
uptake less than or equal to the mediastinum
uptake greater than the mediastinum but less than the liver
uptake moderately higher than the liver
uptake markedly higher than the liver

After chemotherapy, stimulation of normal bone marrow may result in diffusely


increased uptake which 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, score 1 and score
2 were used to define a negative scan in the RAPID study (Radford, Barrington 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 radiotherapy (Engert, Haverkamp et al. 2012). It is recommended therefore
that score 1 or 2 is used to define a complete metabolic response (CMR) if omission
of standard radiotherapy treatment is being considered in discussion with patients.

16

To avoid the risk of over-treatment, scores 4 and 5 were used to define a positive
scan in the NCRI RATHL study (Barrington, Qian et al. 2010) and in the Italian
HD0607 study and scores 1,2,3 to define a negative scan (ClinicalTrials.gov 2013)
with initial reports suggesting satisfactory responses for patients treated on trial
(Gallamini, Rossi et al. 2012; Johnson 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 likely 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 recognised (Barrington and O'Doherty 2003). Patients with score 3, which
was previously referred to as minimal residual uptake, (Hutchings, Mikhaeel et al.
2005) are likely have good outcomes with standard treatment (Hutchings, Mikhaeel
et al. 2005; Biggi, Gallamini et al. 2013; Johnson 2013), but until more information is
available, de-escalation of therapy outside trials in these patients is not advised.
Standardised methods for PET acquisition and Quality Control 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,
O'Doherty 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, Stroobants et al. 2003;
Boellaard, O'Doherty 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 days following chemotherapy, 2 weeks after granulocyte
colony-stimulating factor (G-CSF) treatment and 3 months after radiotherapy is
recommended to elapse prior to scanning (Boellaard, O'Doherty et al. 2010).
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, score 1,2 should be considered negative and 4,5
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 score 4,5 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

17

End of treatment PET/CT is recommended for all patients who have not
achieved an interim PET negative remission as this may directly affect
radiotherapy planning, biopsy considerations and follow-up strategy 1B
8. RADIOTHERAPY STRATEGIES IN HL
As chemotherapy has become more effective, the role of radiotherapy 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 radiotherapy in both early and advanced HL is based on
involved field radiotherapy (IFRT). However, concerns regarding the late effects of
radiation have led to new protocols using reduced volume treatment. An EORTC
consensus led by the GELA group is now in favour of involved node radiotherapy
(INRT) (Girinsky, Specht et al. 2008). However, this depends on obtaining pre- and
post-treatment PET-CT imaging of the patient in the treatment position (Girinsky,
Specht et al. 2008; Specht, Yahalom et al. 2013). An alternative approach uses
involved site radiotherapy (ISRT) which adds a 15 mm safety margin above and
below the involved node (Hoskin, Diez et al. 2013; Specht, Yahalom et al. 2013).
Larger volumes are still preferred in those rare cases where radiotherapy alone is
recommended.
The dose of radiotherapy is now well defined from the GHSG trials HD10 and HD11,
which show that, for favourable early HL 20 Gy is sufficient, and 30 Gy should be
given to all other patients with early or advanced stage disease, where radiotherapy
is indicated.
KEY RECOMMENDATIONS FOR RADIOTHERAPY STRATEGIES IN HL
The evidence for the role of radiotherapy in HL is based on involved
field radiotherapy (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 for all
other patients 30 Gy. 1A

9. 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, Chen et al. 2012;
Patel, Buckstein 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, Bernardo et al. 2002; Favier, Heutte et al.
2009; Baxi and 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 mortality remains
significantly elevated more than 20 years after treatment (Ng, Bernardo et al. 2002).
The major causes of long term, non-relapse, morbidity and mortality are second

18

neoplasms and cardiac disease, but also include pulmonary disease and infections.
Patients, who have received neck radiotherapy, 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 and Kaplan 1974). The
clinical implications of this remain unclear. Cases of transfusion-associated graft
versus host disease have been reported (Baglin, Joysey et al. 1992). Consequently,
all Hodgkin lymphoma 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 metaanalyses, have confirmed the increased incidence of secondary neoplasms in longterm survivors of HL (Bhatia, Yasui et al. 2003; Franklin, Paus et al. 2005; Travis, Hill
et al. 2005; Franklin, Pluetschow et al. 2006; Hodgson, Gilbert et al. 2007; Favier,
Heutte et al. 2009; Meadows, Friedman et al. 2009). A recent large collaborative
British Cohort study followed 5,798 HL patients treated with chemotherapy from
1963-2001 (Swerdlow, Higgins 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% CI, 3.5 to 4.4; RR CA 2.0; 95% CI, 1.7 to 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 radiotherapy is approximately 10-33%, compared with a lifetime risk in the UK of
11% (Taylor, Winter et al. 2007; Westlake and Cooper 2008). Furthermore, survival
stage-for-stage with breast cancer after HL is worse than that following de novo
breast cancer (Milano, Li et al. 2010). Since 2003 this breast cancer risk has been
prospectively managed by a screening programme throughout the UK (Howell,
Searle 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, Bernardo et al.
2002; Baxi and Matasar 2010). Myocardial infarction (MI) carries the greatest risk
and this has been particularly linked to mediastinal radiotherapy. The Collaborative
British Cohort Study followed 7033 patients from 1967-2000 and identified 166
deaths from myocardial infarction (MI) (Swerdlow, Higgins 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 radiotherapy, anthracyclines and vincaalkaloids. The risk was particularly high for the ABVD regimen and the combination
of supradiagphragmatic radiotherapy 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

19

fibrosis are all implicated. Fatal pulmonary fibrosis following bleomycin is described
in 1-2% of bleomycin-treated patients (Williams, Birch et al. 1987; Kaye, Mead et al.
1998; Nichols, Catalano et al. 1998; O'Sullivan, Huddart 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, Huddart et al. 2003; Martin, Ristow 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
(Drugs information online, Drugs.com). Early symptoms and signs are dyspnoea/dry
cough and crackles which 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 AND


SURVIVORSHIP
Patients are usually followed with intermittent outpatient clinical review
for 2 to 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 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 radiotherapy 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 the 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 radiotherapy to the neck and upper mediastinum
should have regular thyroid function checks. Hypothyroidism can occur
up to 30 years after radiotherapy. 1A
Patients should receive irradiated blood products for life. 1B

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24

Appendix 1

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 (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 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 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.