British Journal of HaematologyVolume 166, Issue 1 p. 34-49 GuidelineFree Access Guidelines for the first line management of classical Hodgkin lymphoma George A. Follows, Corresponding Author George A. Follows Department of Haematology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, Cambridge, UK Correspondence: Department of Haematology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, Cambridge, UK. E-mails: bcsh@b-s-h.org.uk; george.follows@addenbrookes.nhs.ukSearch for more papers by this authorKirit M. Ardeshna, Kirit M. Ardeshna Department of Haematology, University College Hospital London Hospitals NHS Trust, London, UKSearch for more papers by this authorSally F. Barrington, Sally F. Barrington St Thomas' Division of Imaging, PET Imaging Centre, Kings College London, London, UKSearch for more papers by this authorDominic J. Culligan, Dominic J. Culligan Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, UKSearch for more papers by this authorPeter J. Hoskin, Peter J. Hoskin Mount Vernon Cancer Centre, Northwood, UKSearch for more papers by this authorDavid Linch, David Linch Department of Haematology, University College Hospital London Hospitals NHS Trust, London, UK Department of Haematology, UCL Cancer Institute, University College Centre of Imaging, London, UKSearch for more papers by this authorShalal Sadullah, Shalal Sadullah Department of Haematology, James Paget University Hospital, Great Yarmouth, UKSearch for more papers by this authorMichael V. Williams, Michael V. Williams Department of Oncology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, London, UKSearch for more papers by this authorJennifer Z. Wimperis, Jennifer Z. Wimperis Department of Haematology, Norfolk and Norwich University Hospital, Norwich, UKSearch for more papers by this author for The British Committee for Standards in Haematology, Corresponding Author The British Committee for Standards in Haematology Correspondence: Department of Haematology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, Cambridge, UK. E-mails: bcsh@b-s-h.org.uk; george.follows@addenbrookes.nhs.ukSearch for more papers by this author George A. Follows, Corresponding Author George A. Follows Department of Haematology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, Cambridge, UK Correspondence: Department of Haematology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, Cambridge, UK. E-mails: bcsh@b-s-h.org.uk; george.follows@addenbrookes.nhs.ukSearch for more papers by this authorKirit M. Ardeshna, Kirit M. Ardeshna Department of Haematology, University College Hospital London Hospitals NHS Trust, London, UKSearch for more papers by this authorSally F. Barrington, Sally F. Barrington St Thomas' Division of Imaging, PET Imaging Centre, Kings College London, London, UKSearch for more papers by this authorDominic J. Culligan, Dominic J. Culligan Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, UKSearch for more papers by this authorPeter J. Hoskin, Peter J. Hoskin Mount Vernon Cancer Centre, Northwood, UKSearch for more papers by this authorDavid Linch, David Linch Department of Haematology, University College Hospital London Hospitals NHS Trust, London, UK Department of Haematology, UCL Cancer Institute, University College Centre of Imaging, London, UKSearch for more papers by this authorShalal Sadullah, Shalal Sadullah Department of Haematology, James Paget University Hospital, Great Yarmouth, UKSearch for more papers by this authorMichael V. Williams, Michael V. Williams Department of Oncology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, London, UKSearch for more papers by this authorJennifer Z. Wimperis, Jennifer Z. Wimperis Department of Haematology, Norfolk and Norwich University Hospital, Norwich, UKSearch for more papers by this author for The British Committee for Standards in Haematology, Corresponding Author The British Committee for Standards in Haematology Correspondence: Department of Haematology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, Cambridge, UK. E-mails: bcsh@b-s-h.org.uk; george.follows@addenbrookes.nhs.ukSearch for more papers by this author First published: 09 April 2014 https://doi.org/10.1111/bjh.12878Citations: 54AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat The guideline group was selected to be representative of UK-based medical experts and patients' representatives. MEDLINE and EMBASE were searched systematically for publications in English from January 1990 to June 2013 using the key words Hodgkin, Lymphoma, Treatment, Chemotherapy and Radiotherapy. References from relevant publications were also searched. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-Oncology Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of approximately 50 UK haematologists and the BCSH and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with classical Hodgkin Lymphoma (HL). The guidance may not be appropriate for all patients with HL and in all cases individual patient circumstances may dictate an alternative approach. Key recommendations Pre-treatment evaluation Patients require pre-treatment blood evaluation including human immunodeficiency virus (HIV) serology (1A). Staging with contrast–enhanced computerized tomography (CT) of the neck to pelvis is required (1A), although positron-emission tomography (PET)/CT is preferable if clinically feasible (1B). Early stage patients should be classified as favourable or unfavourable (1A). Advanced stage patients should be assessed to define the Hasenclever/International Prognostic Score (IPS) (1A). For male patients, pre-treatment semen cryopreservation should be offered where possible (1A). For female patients, pre-treatment review of options with a fertility specialist should be considered (1A). Management of early stage disease Prognostic factors should be determined to allocate patients to favourable and unfavourable sub-groups (1A). Standard of care for patients with favourable early stage HL is 2 × ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and 20 Gy radiotherapy (RT) (1A). Standard of care for unfavourable early stage HL is 4 × ABVD and 30 Gy RT (1A). A treatment option for unfavourable early stage HL is 2× escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) + 2 × ABVD and 30 Gy RT (1A). The decision to omit RT from the management of stage IA/IIA non-bulky patients should involve discussion with a radiation oncologist (1B) and patients choosing to omit RT need to be aware of the balance of risks between RT and additional cycles of chemotherapy (1B). RT should not normally be omitted in patients presenting with bulky disease (1B). Early stage patients treated without RT should receive at least 3 × 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). Management of advanced stage disease Patients aged 16–60 years old with advanced stage HL should receive either 6–8 cycles of ABVD or six cycles of escalated BEACOPP (1A). The choice between ABVD and escalated BEACOPP will depend on a range of factors, particularly the patient's opinion on the toxicity/efficacy balance between the regimens (2B). Patients with a higher IPS are at higher risk of relapse, potentially supporting the use of escalated BEACOPP in this higher risk group, although there are no prospective trial data to support a specific IPS cut-off at which escalated BEACOPP may be advantageous (2B). Patients treated with escalated BEACOPP who achieve an end-of-treatment PET-negative remission do not require consolidation RT to residual tissue (1A). Patients treated with ABVD should be considered for RT to sites of original bulk or residual tissue >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). Management of HL in pregnancy Patients should be closely co-managed with a speciald obstetric/fetal medicine unit (1B). Staging investigations and response evaluation should be tailored to the clinical presentation with radiology input to minimize fetal radiation exposure (1C). Delaying commencement of chemotherapy until post-delivery would not be standard practice and should be done with caution (1C). ABVD is the regimen of choice unless specifically contraindicated (1B). Wherever possible, RT should be delayed until post-delivery (1B). Management of HL in elderly patients Elderly patients should be formally assessed for fitness to receive combination chemotherapy with a co-morbidity assessment tool, which should distinguish ‘frail’ from ‘non-frail’ patients (2B). Patients considered ‘frail’ should not usually be offered conventional combination chemotherapy (2B). ‘Non-frail’ patients should be offered combination chemotherapy and RT with the aim of achieving complete remission (CR), which is associated with better survival (1B). Older patients receiving bleomycin must be followed very closely for symptoms and signs of bleomycin lung toxicity (1A). Guidance on therapy choice for non-frail patients is hampered by the lack of randomized trial data. Treatment with VEPEMB (vinblastine, cyclophosphamide, prednisolone, procarbazine, etoposide, mitoxantrone) or COPP (cyclophosphamide, vincristin, procarbazine, prednisone)/ABVD appears to have lower treatment-related mortality than ABVD or BEACOPP (2B). PET/CT in HL PET/CT should be reported by PET/CT imaging specialists (1C). As pre-treatment staging with PET/CT will upstage a minority of patients and aid the interpretation of subsequent PET/CT, it is recommended when clinically feasible (1B). PET/CT response should be reported according to Deauville criteria (2B). By Deauville criteria, a score of 1 or 2 should be considered ‘negative’ and 4 or 5 considered ‘positive’. Deauville score 3 should be interpreted according to the clinical context but in many HL patients indicates a good prognosis with standard treatment (1B). Biopsy is advised prior to second-line therapy to confirm residual disease with a score of 4 or 5 where possible to exclude false-positive uptake with fluorodeoxyglucose (FDG) (1B). The optimal management of iPET2-positive patients remains uncertain. Therefore, at this time, iPET2 remains desirable for ABVD-treated patients but cannot be mandated as a standard of care (2B). If a pre-treatment decision has been made to treat an early stage patient with RT following ABVD, then there is no clear role for interim PET/CT (1A). End-of-treatment PET/CT is recommended for all patients who have not achieved an interim PET-negative remission as this may directly affect RT planning, biopsy considerations and follow-up strategy (1B). Radiotherapy strategies in HL The evidence for the role of RT in HL is based on involved field RT (IFRT) (1A). Reduced volume approaches, involved node (INRT) or involved site (ISRT) are under evaluation in current protocols (2B). The dose for favourable early stage disease should be 20 Gy, and 30 Gy for all other patients (1A). Follow-up, late effects and survivorship Patients are usually followed with intermittent outpatient clinical review for 2–5 years following first line therapy (2C). There is no proven role for routine surveillance CT or PET/CT imaging in patients who are otherwise well following first line therapy (2B). HL patients should be made aware that they are at an increased lifetime risk of second neoplasms, cardiovascular and pulmonary disease and infertility (1A). Apart from the current breast cancer-screening programme, there are no national cancer screening programmes tailored for HL survivors. Women treated with mediastinal RT before the age of 35 years should be offered entry into the breast cancer National Notification Risk Assessment and Screening programme (NRASP) (1A). Regular lifestyle advice should be offered to reduce secondary neoplasms and cardiovascular risk. There should be complete avoidance of smoking and careful management of cardiovascular risks, such as hypertension, diabetes mellitus and hyperlipidaemia (1B). Patients who have had RT to the neck and upper mediastinum should have regular thyroid function checks. Hypothyroidism can occur up to 30 years after RT (1A). Patients should receive irradiated blood products for life (1B). Background The annual incidence of Hodgkin Lymphoma (HL) in the UK is 2·7/100 000 with approximately 1700 new cases per annum with a slight male predominance (Cancer Research UK, 2010). There is a peak in incidence in young adults aged 20–34 years with a further peak observed >70 years of age. The incidence is currently stable (Morton et al, 2006; Cancer Research UK, 2010; Shenoy et al, 2011). Hodgkin Lymphoma is characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells within a cellular infiltrate of non-malignant inflammatory cells that make up the majority of the tumour tissue (Swerdlow et al, 2008). HRS cells have only recently been identified as clonal B cells that lack typical B-cell surface antigens. B cells failing to express surface immunoglobulin usually undergo apoptosis but HRS cells evade cell death through a number of mechanisms, including incorporation of Epstein-Barr virus (EBV) latent membrane proteins (LMP1 and 2), constitutive activation of the transcription factor nuclear factor κB (NFκB), and interaction with components of the microenvironment (Swerdlow et al, 2008; Steidl et al, 2011; Kuppers et al, 2012). Hodgkin Lymphoma is classified as either nodular lymphocyte predominant (NLPHL) or classical HL. There are four sub-types of classical HL: nodular sclerosis, mixed cellularity, lymphocyte-rich and lymphocyte-depleted; there is no difference in the prognosis or management of the different sub-types of classical HL. In Europe and North America, nodular sclerosis classical HL accounts for 70% of all classical HL. Lymphocyte-depleted classical HL is more prevalent in immunocompromised patients and is seen more commonly in developing countries, where it has a strong association with EBV infection. NLPHL is distinct histologically and HRS cells are not present, it has a risk of transformation to high grade non-Hodgkin lymphoma and is managed differently from classical HL (Swerdlow et al, 2008). Clinical presentation of classical HL is usually with painless lymphadenopathy, which is most commonly cervical or supraclavicular. Mediastinal disease is identified in 80% of patients and is more common in nodular sclerosing HL, whilst peripheral or sub-diaphragmatic lymphadenopathy is more common in mixed-cellularity classical HL. Bone marrow involvement is detected in only 5–8% of patients with conventional staging (Mauch et al, 1993; Levis et al, 2004a; Swerdlow et al, 2008), but in up to 18% with positron emission tomography (PET)/computerized tomography (CT) staging (El-Galaly et al, 2012). Systemic symptoms of drenching night sweats, unexplained fever >38°C, and weight loss of >10% over 6 months are termed B symptoms and are identified in approximately 25% of patients. Pretreatment evaluation Blood evaluation should include full blood count, erythrocyte sedimentation rate, renal function, liver function, bone profile, lactate dehydrogenase and testing for human immunodeficiency virus (HIV). Patients should be staged with a contrast-enhanced CT scan covering the neck, chest, abdomen and pelvis. An initial PET/CT scan is highly recommended as this provides a baseline for interpretation of subsequent scans and, in a minority of cases, it can upstage patients and alter the planned therapy. It is appreciated that a minority of patients may present with very advanced disease and if obtaining a PET/CT scan would result in a treatment delay this may not be clinically appropriate. It was common practice to limit bone marrow evaluation to patients with advanced stage disease or B symptoms, however, it is now generally accepted that PET/CT can accurately detect marrow involvement and evaluation by biopsy is often unnecessary (El-Galaly et al, 2012). Clinicians should be aware that diffuse bone marrow uptake on PET may just reflect a reactive process. Patients with early stage disease should be categorized as having favourable or unfavourable characteristics. Patients with advanced stage disease should have their Hasenclever/International Prognostic Score (IPS) determined (Hasenclever & Diehl, 1998). Consideration should be given to fertility preservation and semen cryopreservation should be offered routinely before therapy with combination chemotherapy. There is increasing evidence for the effectiveness of oocyte preservation as a fertility-sparing strategy and referral to a fertility specialist should be considered, if treatment delays are acceptable. This is especially important if the plan is to administer escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is generally considered to be fertility-sparing, but some patients may need to receive salvage chemotherapy and stem cell transplantation, which can result in a reduction of fertility. The role for prophylactic use of gonadotropin-releasing hormone (GnRH) analogues to preserve female fertility remains uncertain (Behringer et al, 2012; Wong et al, 2013). For women with a stable partner, and in whom a delay of treatment is possible, in vitro fertilization for embryo cryopreservation may be appropriate. However, this may not be widely available at short notice. Ovarian tissue cryopreservation remains experimental and so far has resulted in only a small number of pregnancies and births (Loren et al, 2013). Generally, fertility preservation techniques can only be discussed on a case-by-case basis, involving fertility experts and oncologists who can judge the appropriateness of the techniques and the risks of delaying treatment. Key recommendations for pre-treatment evaluation Patients require pre-treatment blood evaluation including HIV serology (1A). Staging with contrast–enhanced CT of the neck to pelvis is required (1A), although PET/CT is preferable if clinically feasible (1B). Early stage patients should be classified as favourable or unfavourable (1A). Advanced stage patients should be assessed to define the Hasenclever/IPS (1A). For male patients, pre-treatment semen cryopreservation should be offered where possible (1A). For female patients, pre-treatment review of options with a fertility specialist should be considered (1A). Management of early stage disease Randomized trials have shown that combined modality treatment with chemotherapy and radiotherapy (RT) results in superior tumour control compared with RT alone (Noordijk et al, 2006; Engert et al, 2007; Ferme et al, 2007). Clinical trials in patients with Stage I–II disease have increasingly evaluated treatment reduction as a strategy to reduce late morbidity and mortality. These trials have defined and refined prognostic factors for favourable and unfavourable prognosis Stage I–II HL. Traditionally in the UK, patients with early stage HL with B symptoms or bulk disease have been managed with protocols for advanced stage disease. However, long-term follow-up of large trial data sets, such as the German Hodgkin Study Group (GHSG) HD10 trial, have confirmed that these patients generally have excellent outcomes when treated with early stage unfavourable risk protocols. Definition of ‘large mediastinal mass’/bulky disease varies slightly between study groups: The European Organization for the Research and Treatment of Cancer (EORTC) defines bulk as a mediastinal thoracic ratio >0·35 at T5/6. The UK National Cancer Research Institute (NCRI) and GHSG define a mediastinal mass ratio >0·33 as ‘large’, while the US National Comprehensive Cancer Network (NCCN) and National Cancer Institute of Canada (NCIC) define bulky as a mediastinal mass ratio>0·33 or any mass with maximal diameter >10 cm. Prognostic factors for the EORTC and GHSG are listed in Tables 1 and 2. Table 1. Favourable prognosis Stage I–II Hodgkin Lymphoma. EORTC GHSG No large mediastinal adenopathy No large mediastinal adenopathy ESR <50 without B symptoms ESR <50 without B symptoms ESR <30 with B symptoms ESR <30 with B symptoms Age ≤ 50 years No extranodal disease 1–3 lymph node sites involved 1–2 lymph node sites involved EORTC, European Organization for the Research and Treatment of Cancer; GHSG, German Hodgkin Study Group; ESR, erythrocyte sedimentation rate. Table 2. Unfavourable prognosis Stage I–II Hodgkin lymphoma. EORTC presence of one or more of the following GHSG presence of one or more of the following Large mediastinal adenopathy Large mediastinal adenopathy ESR ≥50 without B symptoms ESR ≥50 without B symptoms ESR ≥30 with B symptoms ESR ≥30 with B symptoms Age >50 years Extranodal disease ≥4 lymph node sites involved ≥3 lymph node sites involved EORTC, European Organization for the Research and Treatment of Cancer; GHSG, German Hodgkin Study Group; ESR, erythrocyte sedimentation rate. Favourable early stage disease Recent trials have focussed on abbreviating chemotherapy and RT dosages, and assessing RT-free treatment strategies. The GHSG HD10 trial randomized 1190 patients into four treatment arms, which included two cycles of ABVD plus 30 Gy RT, two cycles of ABVD plus 20 Gy of RT, four cycles of ABVD plus 30 Gy of RT and four cycles of ABVD plus 20 Gy of RT. With a 7·6-year median follow up, no difference was observed in freedom from progression (97%) or overall survival (OS, 98%) between the four groups (Engert et al, 2010). Thus, the least toxic approach consisting of two cycles of ABVD followed by 20 Gy RT appears to be sufficient in favourable Stage I–II HL. The trial with the longest published median follow-up (11·3 years) in early stage HL is the IA/IIA non-bulky NCIC and Eastern Cooperative Oncology Group (ECOG) trial comparing ABVD alone (4–6 cycles) with treatment including subtotal nodal irradiation (STNI) (Meyer et al, 2012). From separate sequential analysis of this trial (Meyer et al, 2005, 2012), it appears that omitting RT increases the risk of early relapse, but with longer follow-up does not appear to compromise OS. It is difficult to interpret the comparative aspects of this trial as STNI is no longer used in routine practice, and there were a small number of unusual events in the STNI arm that complicated the interpretation of OS of the RT-arm of the study. However, this trial has shown that treating IA/IIA non-bulky HL patients with ABVD alone delivers long-term OS of 94%. Data from the UK NCRI trial (RAPID) and the EORTC H10 trial were presented at the annual American Society of Hematology meeting in 2012 (Andre et al, 2012; Radford et al, 2012). In both trials, patients who achieved an early PET-negative remission had a better progression-free survival (PFS) than interim PET-positive patients. Both trials randomized the patients who achieved an early PET-negative remission with ABVD chemotherapy to receive or omit RT. With both trials, there was an early PFS advantage with the inclusion of RT, but no OS advantage had been shown within the limited follow-up periods of both trials. Of note, patients with mediastinal bulk disease were excluded from the RAPID trial. In the RAPID study, patients who were PET-positive after three ABVD cycles received 1 × additional ABVD and RT. This achieved a 3-year PFS of 85·9% and OS of 93·9% (Radford et al, 2012). With the current available data, the standard of care for treatment of patients with early stage favourable HL (as defined by GHSG criteria) therefore remains ABVD × 2 + RT. However, as there are longer term risks for patients treated with RT, it is recognized that, in some circumstances, clinicians and patients may prefer to treat without RT, particularly as the majority of IA/IIA non-bulky patients will be cured with chemotherapy alone. Indeed, a cross-trial comparative analysis between the German HD10/11 and NCIC HD6, suggested patients who achieve a CT complete remission (CR) after 2 × ABVD, and then complete a total 4 × ABVD with no RT, have the same excellent outcome as 2 × ABVD + RT (Hay et al, 2012). However, the decision to treat early stage good risk patients without RT should involve a radiation oncologist and the patient must be made aware that a number of trials indicate that removing RT probably increases the risk of early relapse by approximately 3–7% (Meyer et al, 2005, 2012; Andre et al, 2012; Radford et al, 2012). If patients are treated without RT, then choosing the optimum number of cycles of ABVD is difficult. The NCIC/ECOG trial, using 4–6 cycles of ABVD, has the longest follow-up, but initial data from 3 × ABVD for PET-negative patients in the RAPID trial are encouraging. A balance therefore needs to be struck between long-term toxicity of RT and the toxicity of the additional ABVD cycles (Swerdlow et al, 2011). Apart from abstract presentations of the UK NCRI trial (RAPID) and the EORTC H10 trial (Andre et al, 2012; Radford et al, 2012), larger randomized trials using PET/CT to guide decision-making in early stage HL have yet to be formally reported. Consensus opinion from all trials groups is that early stage patients with persisting PET-avid disease after chemotherapy should receive RT. At this stage, it remains uncertain whether achieving an interim PET-negative remission after two cycles of ABVD is as predictive for long-term PFS and OS as achieving a CR by established CT criteria. Unfavourable early stage disease In the HD11 trial, the GHSG randomly assigned 1395 patients with early unfavourable HL to four cycles of ABVD plus 30 Gy RT, four cycles of ABVD plus 20 Gy RT, four cycles of BEACOPP plus 30 Gy RT and four cycles of BEACOPP plus 20 Gy RT (Eich et al, 2010). With 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 = 0·65), but a significant difference in favour of BEACOPP was seen for FFTF when 20 Gy RT was used (P = 0·02) (Eich et al, 2010). The German Hodgkin study Group HD14 Trial randomly assigned early unfavourable HL patients to either four cycles of ABVD or an intensified treatment of two cycles of escalated BEACOPP followed by two cycles of ABVD (2 + 2) (von Tresckow et al, 2012). Chemotherapy was 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 OS, this regimen would be considered a treatment option rather than a standard of care for the majority of patients. Currently, four cycles of ABVD followed by 30 Gy RT is widely considered the standard of care for unfavourable early stage HL. There is no evidence to support the removal of RT from patients who present with bulky disease, and of note, such patients were excluded from the RAPID and NCIC/ECOG 6 trials. Infradiaphragmatic early stage disease The incidence of infradiaphragmatic early stage HL is very low and accounts for 4–13% of cases of Stage I–II disease (Vassilakopoulos et al, 2006). When results are adjusted for risk factors they appear to have a similar prognosis to patients with supradiaphragmatic disease. Older age, clinical Stage II (borderline), involvement of ≥3 sites and higher IPS is more frequent in patients with infradiaphragmatic disease and the previously reported poorer outcome may be explained by the unfavourable profile of the patients. Although this group of patients are under-represented in clinical trials, there is currently no evidence to suggest that they should be treated differently from their supradiaphragmatic counterparts