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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 1Department of Haematology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, UK

2Department of Haematology, University College Hospital London Hospitals NHS Trust, London,

3PET

Imaging Centre, St Thomas Division of Imaging, Kings College London 4 Department of

Haematology, Aberdeen Royal Infirmary, Aberdeen, 5Mount Vernon Cancer Centre, Northwood,

Middlesex 6Department of Haematology, UCL Cancer Institute, University College Centre of Imaging ,

London 7Department of Haematology James Paget University Hospital, Great Yarmouth

8Department

of Oncology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, UK, 9Department of

Haematology Norfolk and Norwich University Hospital, Norwich

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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

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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-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

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

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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

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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

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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 gonadotropin-releasing 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 case-by-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

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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 EORTC

GHSG

No large mediastinal adenopathy

No large mediastinal adenopathy

ESR

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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 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).

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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 (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. 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 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). 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).

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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 (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

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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 post-partum may be possible, although this must be done with caution. If therapy is required in pregnancy, the general consensus is that ABVD is the regimen of choice if multi-agent chemotherapy is to be used (Bachanova 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.

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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). 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. 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).

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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 no uptake Score 2 uptake less than or equal to the mediastinum Score 3 uptake greater than the mediastinum but less than the liver Score 4 uptake moderately higher than the liver Score 5 uptake markedly higher than the liver After chemotherapy, stimulation of normal bone marrow may result in diffusely increased uptake 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.

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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

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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

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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 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 vinca-alkaloids. 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.