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BCSH Classical Hodgkins Lymphoma Guidelines Final Accepted Version Feb 2014 PDF
BCSH Classical Hodgkins Lymphoma Guidelines Final Accepted Version Feb 2014 PDF
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
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, Hodgkin’s, lymphoma, treatment, chemotherapy, radiotherapy
1
Department of Haematology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, UK
2 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:
KEY RECOMMENDATIONS
2. PRE-TREATMENT EVALUATION
Patients require pre-treatment blood evaluation including HIV serology
1A
Staging with contrast–enhanced 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
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.
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
1. BACKGROUND
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.
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.
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
7
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’s 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.
GHSG
EORTC
Age ≤ 50 No E-disease
1-3 lymph node sites involved 1-2 lymph node sites involved
EORTC GHSG
presence of one or more of the presence of one or more of the
following following
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 PET-
negative remission had a better progression-free survival (PFS) than interim PET-
positive patients. Both trials randomised 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 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).
9
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.
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 (93-
96%) for all four groups. In the arms of the study with 30 Gy of RT, there was no
difference in freedom from treatment failure (FFTF) between BEACOPP and ABVD
(P = .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.
The incidence of infradiaphragmatic early stage HL is very low and accounts for 4-
13% 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).
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 ¼ 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 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).
5 MANAGEMENT OF HL IN PREGNANCY
Staging and response assessment with MRI scanning 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.
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). Therapy-
related 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.
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
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 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
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
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).
8. RADIOTHERAPY STRATEGIES IN HL
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.
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 meta-
analyses, have confirmed the increased incidence of secondary neoplasms in long-
term 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
Pulmonary Toxicity
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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.