Guidelines for the first line management of classical Hodgkin lymphoma

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. 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. 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. 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. 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. 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. 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 (Darabi et al, 2005; Vassilakopoulos et al, 2006). Standard treatment for patients with stage III/IV HL is combination chemotherapy. In the UK, patients with early stage disease but B symptoms or bulky disease have usually been managed with advanced HL protocols, although this is not universal international practice (Townsend & Linch, 2012). There is significant international variation in the use of RT to sites of initial bulk disease or residual masses following chemotherapy. Over the past three decades of comparative randomized clinical trials in HL, ABVD and escalated BEACOPP have become established international standards of care for advanced HL [reviewed in (Townsend & Linch, 2012)]. ABVD has better outcomes in terms of efficacy and/or toxicity than MOPP (mechlorethamine, vinristine, procarbazine, predisone), MOPP–ABV (MOPP, doxorubicin, bleomycin, vinblastine) hybrid and ChlVPP/PABLOE (chlorambucil, vinblastine, procarbazine, prednisone/doxorubicin, bleomycin, vincristine and etoposide), and similar efficacy, but lower toxicity, than the Stanford V regimen (mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, bleomycin, etoposide) (Canellos et al, 1992; Duggan et al, 2003; Johnson et al, 2005; Hoskin et al, 2009). From a number of advanced HL trials, failure-free/PFS with ABVD is around 73–78% with OS in the range of 82–90% (Duggan et al, 2003; Johnson et al, 2005; Federico et al, 2009; Hoskin et al, 2009; Viviani et al, 2011). ABVD should be delivered on schedule with infusions given every 14 d irrespective of neutrophil count. Granulocyte colony-stimulating factor (G-CSF) is only required for patients with infectious complications (Evens et al, 2007; Nangalia et al, 2008). Different HL study groups have followed different strategies for RT following chemotherapy. Patients with bulky advanced stage disease who achieve a CT CR after MOPP/AVD can avoid RT in contrast with patients in partial remission (PR), who did derive benefit from RT (Aleman et al, 2003). It remains unclear as to whether RT to sites of initial bulk disease or residual tissue can be safely omitted in patients treated with ABVD. In the LY09 trial, 43% of patients received RT following ABVD or ChlVPP/PABLOE and, with a median follow-up of 6·9 years, these patients had a PFS and OS advantage compared with patients treated without RT (Johnson et al, 2005). Of note, the ABVD trials with the highest OS rates have used RT for a large proportion of patients (Duggan et al, 2003; Johnson et al, 2005; Hoskin et al, 2009). Escalated BEACOPP was been developed by the German HL study group (GHLSG). In comparison with COPP–ABVD and standard dose BEACOPP, escalated BEACOPP has demonstrated improved PFS and OS (Engert et al, 2009). Data from 2182 patients randomized from 408 centres in the GHLSG HD15 trial have shown a 5-year failure-free and OS of 89% and 95% respectively, for patients receiving six cycles of escalated BEACOPP (Engert et al, 2012). Patients in this trial who achieved a PET-negative remission (but PR by conventional CT) were not treated with RT consolidation, in contrast with the HD9 trial. The number of patients receiving RT fell from 71% in HD9 to 11% in HD15, with no apparent loss in treatment efficacy (Engert et al, 2012). Although this is not randomized data, it is to that patients who achieve PET-negative remission following escalated BEACOPP therapy not RT to sites of residual tissue (Engert et al, 2012). From HD15, the outcomes for patients treated with escalated BEACOPP × 6 or BEACOPP 14 × were similar and may prefer to be treated on the regimen if appropriate. Escalated strategies have also delivered results in HL survival et al, but have shown toxicity in patients years (Engert et al, and the GHLSG no longer this for patients over years of age. Data comparing ABVD with escalated BEACOPP are The EORTC trial comparing ABVD with BEACOPP for higher risk HL patients has been presented in abstract only 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 A trial randomized patients to either ABVD or escalated BEACOPP followed by treatment with RT sites of initial bulk and residual then salvage for all patients failing to achieve a CR et al, 2011). treatment with escalated BEACOPP resulted in a progression advantage compared with ABVD = but the OS was no at 89% and (P = the strategy given to approximately a of the patients and significant with to this trial et al, 2011; et al, 2011; et al, it is difficult to interpret the results in the of standard UK However, the data support the consensus that, compared with ABVD, escalated BEACOPP provides a PFS advantage for while to the as to whether escalated BEACOPP provides a survival advantage for advanced HL patients. ABVD has a better toxicity profile than escalated BEACOPP in terms of of infectious blood fertility preservation and et al, 2008; Engert et al, 2009). The HD15 data that the and long-term toxicity profile of escalated BEACOPP is improved significantly by treatment to 6 cycles (Engert et al, 2012). The total of and are lower for patients treated with escalated BEACOPP compared with 6 × ABVD and 000 compared with and 000 With a median follow-up of 4 years, the incidence of is in patients treated with 6 cycles of escalated BEACOPP (Engert et al, 2012). the EORTC trial found no difference in rates between ABVD and escalated BEACOPP et al, 2012). of female are by the chemotherapy and at treatment (Behringer et al, 2005, et al, 2008). With 4 cycles of ABVD within the GHLSG HD14 trial, of women aged years and aged years cycles following chemotherapy. Data from patients treated with cycles of ABVD are more but there does not appear to be additional loss of fertility with the additional cycles of treatment et al, et al, 2008). With cycles of escalated BEACOPP within HD15, the were of women aged cycles compared with aged (Behringer et al, 2005, et al, 2008). A PET/CT scan after two cycles of ABVD, interim PET has been shown to be predictive of treatment failure for patients who with ABVD therapy et al, 2007). A number of recently and trials are assessing in comparison with treatment for patients with escalated BEACOPP can patient outcomes et al, 2012). The UK trial to therapy with either escalated BEACOPP or 4 × with no RT while the approach has been to use cycles of BEACOPP escalated and and RT to sites of initial bulk disease. from the group appear et al, 2012). There is no international consensus on whether patients are by therapy with either ABVD or escalated BEACOPP and for patient will this There are no data to support a IPS when between escalated BEACOPP and ABVD. Patients for ABVD will have clear in terms of toxicity, but will have a higher risk of relapse and need for salvage With there is also with to the need for RT to sites of initial bulky tissue and lack of as to the role of when treated a clinical trial. Patients for escalated BEACOPP have clear with to and the that RT will be in only of patients. however, more There are no data on the use of escalated BEACOPP in HL, where standard management remains ABVD combined with therapy et al, 2012). There are no trials for the management of HL in but a number of published and were reviewed by and The must be the of the and, management should be in with an in of may be the most appropriate of for for cases, the and outcomes following HL treatment in appear excellent (Evens et al, 2011). and with scans and may avoid the need for and, in cases, delaying therapy may be possible, although this must be with If therapy is required in the consensus is that ABVD is the regimen of if chemotherapy is to be used & 2008). Although ABVD has been used to treat patients in all 3 et al, & the risk to from chemotherapy is to be higher in the and most clinicians would and avoid to chemotherapy at this possible, RT should be data suggest that the group for approximately of cases of HL et al, and a number of have suggested that their outcome is good than that of especially for with advanced stage disease (Evens et al, et al, 2009). Older patients are more to from including toxicity, which was reported in of patients over years treated within the North American trial (Evens et al, 2013). toxicity made the ABVD and BEACOPP, especially in the and the randomized trials only small of patients. a number of at international lymphoma in the early it was to a of II of alternative in HL. The GHSG have developed 2 trials with and and vincristine, doxorubicin, et al, 2010; et al, 2011). (bleomycin, cyclophosphamide, vincristine, procarbazine, was used to treat patients aged years, a CR of but with a and OS of With patients aged years were treated for advanced stage disease, a 3-year PFS and OS of and The GHSG have also the outcomes for early stage patients treated with ABVD within the HD10 and HD11 trials et al, 2013). observed excellent rates of but a of With months median follow-up, the 5-year PFS was at With the UK study, the CR for early stage patients treated with two or more cycles of ABVD and RT was for advanced stage ABVD the CR was only and there were 18% et al, 2012). Of note, within this study, no patients who were classified as on a treatment or achieved a The high death with ABVD is similar to that in the ABVD V trial for patients (Evens et al, 2013). In the German HD9 acute toxicity to after BEACOPP compared with for et al, 2005). UK and groups have both a treatment strategy with cyclophosphamide, procarbazine, etoposide, In patients were treated with as of the et al, 2012), including early stage patients × 3 followed by with a CR of and 3-year PFS and OS of and For advanced stage patients treated with × 6 a CR of was achieved with 3-year PFS and OS of and However, patients classified as were excluded from the UK trial and this probably improved the similar data with have been reported from an trial et al, It also remains common practice to treat patients with such as although published outcomes for this regimen in the are generally Treatment Hodgkin Lymphoma is in of cases et al, 2010). patients with is more than CT alone et al, and the of a baseline scan increases the of subsequent et al, 2010; et al, 2011). CT may be as of the or at a separate on The also to as the has been used for in trials and has published high et al, 2010; et al, 2011; et al, and improved predictive et al, when compared with et a

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