Guidelines for the first line management of classical Hodgkin lymphoma

Abstract

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 of ABVD two of ABVD of four of ABVD of RT and four of ABVD of a no difference was observed in from or between the four et al, 2010). the of two of ABVD by RT to be in favourable Stage I–II HL. The trial with the follow-up in early stage HL is the and Group trial ABVD alone with treatment including et al, 2012). of this trial et al, it that RT the risk of early but with follow-up not to It is to the of this trial as is no used in and there were a small number of in the that the interpretation of of the of the However, this trial has shown that HL patients with ABVD alone long-term of from the UK trial and the EORTC trial were at the annual of in et al, 2012; et al, 2012). In patients who an early a patients. trials randomized the patients who an early with ABVD chemotherapy to receive or there was an early with the of but no been shown within the follow-up of patients with mediastinal bulk disease were from the In the patients who were ABVD 1 ABVD and This a of and of et al, 2012). the available the of for treatment of patients with early stage favourable HL defined by GHSG remains ABVD However, as there are risks for patients treated with it is in some and patients may to as the majority of patients be with chemotherapy a between the German and patients who a CT and then a ABVD with no have the excellent as ABVD RT et al, 2012). However, the to early stage risk patients RT should a and the patient be aware that a number of trials that RT the risk of early by approximately et al, 2012; et al, 2012; et al, 2012). patients are treated then the number of of ABVD is The trial, using of has the but initial data from ABVD for patients in the trial are to be between long-term of RT and the of the ABVD (Swerdlow et al, 2011). from of the UK trial and the EORTC trial et al, 2012; et al, randomized trials using PET/CT to in early stage HL have to be from all trials is that early stage patients with disease chemotherapy should receive this it remains uncertain an two of ABVD is as for long-term and as a by CT In the trial, the GHSG patients with early unfavourable HL to four of ABVD four of ABVD four of BEACOPP RT and four of BEACOPP RT et al, 2010). years no difference was observed in for all four In the of the study with of there was no difference in from treatment between BEACOPP and ABVD but a difference in of BEACOPP was seen for when RT was used et al, 2010). The German Hodgkin study Group early unfavourable HL patients to either four of ABVD or an treatment of two of escalated BEACOPP by two of ABVD et al, 2012). Chemotherapy was by RT in years the resulted in tumour control with a in compared with treatment with four of However, were in the and with no difference in this would be considered a treatment a of for the majority of patients. four of ABVD by RT is widely considered the of for unfavourable early stage HL. There is no evidence to the of RT from patients who present with bulky and of such patients were from the and 6 The incidence of early stage HL is very and accounts for of cases of Stage I–II disease et al, results are for risk factors to have a prognosis to patients with disease. Stage involvement of and is more in patients with disease and the may be by the unfavourable of the patients. this group of patients are in there is currently no evidence to that should be treated differently from their et al, et al, treatment for patients with stage 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 this is not practice & 2012). There is in the use of RT to of initial bulk disease or chemotherapy. the of randomized trials in HL, ABVD and escalated BEACOPP have of for advanced HL in & ABVD has outcomes in of procarbazine, doxorubicin, bleomycin, and vinblastine, procarbazine, bleomycin, and and but the doxorubicin, vinblastine, vincristine, bleomycin, et al, et al, et al, et al, a number of advanced HL with ABVD is with in the of et al, et al, et al, et al, et al, 2011). ABVD should be on with given of factor is only for patients with et al, 2007; et al, 2008). HL study have different for RT chemotherapy. Patients with bulky advanced stage disease who a CT can RT in with patients in who from RT et al, It remains as to RT to of initial bulk disease or tissue can be in patients treated with In the trial, of patients RT ABVD or and, with a follow-up of these patients a and compared with patients treated RT et al, the ABVD trials with the have used RT for a large of patients et al, et al, et al, BEACOPP was been by the German HL study group In with and escalated BEACOPP has and et al, from patients randomized from in the trial have shown a and of and for patients of escalated BEACOPP et al, 2012). Patients in this trial who a by conventional were not treated with RT in with the The number of patients RT from in to in with no loss in treatment et al, 2012). this is not randomized it is to that patients who escalated BEACOPP therapy not RT to of tissue et al, 2012). the outcomes for patients treated with escalated BEACOPP 6 or BEACOPP were and may to be treated on the if appropriate. have also results in HL et al, but have shown in patients years et al, and the no this for patients over years of age. ABVD with escalated BEACOPP are The EORTC trial ABVD with BEACOPP for risk HL patients has been in only et al, 2012). was found for escalated but no has been with a follow-up of trial randomized patients to either ABVD or escalated BEACOPP by treatment with RT of initial bulk and then salvage for all patients failing to a et al, 2011). treatment with escalated BEACOPP resulted in a compared with ABVD but the was no at and the strategy given to approximately a of the patients and with to this trial et al, 2011; et al, 2011; et al, it is to the results in the of UK However, the data the consensus compared with escalated BEACOPP provides a for while to the as to escalated BEACOPP provides a for advanced HL patients. ABVD has a escalated BEACOPP in of of blood fertility preservation and et al, 2008; Engert et al, The data that the and long-term of escalated BEACOPP is by treatment to 6 et al, 2012). The of and are for patients treated with escalated BEACOPP compared with 6 ABVD and 000 compared with and 000 a follow-up of the incidence of is in patients treated with 6 of escalated BEACOPP et al, 2012). the EORTC trial found no difference in between ABVD and escalated BEACOPP et al, 2012). of female are by the chemotherapy and at treatment (Behringer et al, et al, 2008). of ABVD within the trial, of women aged years and aged years chemotherapy. from patients treated with of ABVD are more but there not to be loss of fertility with the of treatment et al, et al, 2008). of escalated BEACOPP within the were of women aged compared with aged (Behringer et al, et al, 2008). PET/CT scan two of PET has been shown to be of treatment for patients who with ABVD therapy et al, 2007). number of recently and trials are assessing in with treatment for patients with escalated BEACOPP can patient outcomes et al, 2012). The UK trial to therapy with either escalated BEACOPP or with no RT while the has been to use of BEACOPP escalated and and RT to of initial bulk disease. from the group et al, 2012). There is no consensus on patients are by therapy with either ABVD or escalated BEACOPP and for patient this There are no data to a when between escalated BEACOPP and Patients for ABVD have clear in of but have a risk of and need for salvage there is also with to the need for RT to of initial bulky tissue and lack of as to the role of when treated a Patients for escalated BEACOPP have clear with to and the that RT be in only of patients. however, more There are no data on the use of escalated BEACOPP in HL, where management remains ABVD combined with therapy et al, 2012). There are no trials for the management of HL in but a number of and were reviewed by and The 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 HL treatment in excellent et al, 2011). and with scans and may the need for and, in cases, delaying therapy may be possible, this be with therapy is in the consensus is that ABVD is the of if chemotherapy is to be used & 2008). ABVD has been used to patients in all et al, & the risk to from chemotherapy is to be in the and most would and to chemotherapy at this possible, RT should be data that the group for approximately of cases of HL et al, and a number of have that their is that of especially for with advanced stage disease et al, et al, patients are more to from including which was in of patients over years treated within the North trial et al, 2013). the ABVD and especially in the and the randomized trials only small of patients. a number of at lymphoma in the early it was to a of of alternative in HL. The GHSG have trials with and and vincristine, doxorubicin, et al, 2010; et al, 2011). (bleomycin, cyclophosphamide, vincristine, procarbazine, was used to patients aged a of but with a and of patients aged years were treated for advanced stage a and of and The GHSG have also the outcomes for early stage patients treated with ABVD within the HD10 and trials et al, 2013). observed excellent of but a of months the was at the UK the for early stage patients treated with two or more of ABVD and RT was for advanced stage ABVD the was only and there were 18% et al, 2012). within this no patients who were classified as on a treatment or a The high death with ABVD is to that in the ABVD trial for patients et al, 2013). In the German to BEACOPP compared with for et al, UK and have a treatment strategy with cyclophosphamide, procarbazine, etoposide, In patients were treated with as of the et al, including early stage patients by with a of and and of and For advanced stage patients treated with 6 a of was with and of and However, patients classified as were from the UK trial and this the data with have been from an trial et al, It also remains common practice to patients with such as outcomes for this in the are generally Treatment Hodgkin Lymphoma is in of cases et al, 2010). patients with is more CT alone et al, and the of a baseline scan the of subsequent et al, 2010; et al, 2011). CT may be as of the or at a on The also to as the has been used for in trials and has high et al, 2010; et al, 2011; et al, and et al, when compared with et al, 2007). The scan is compared with the baseline scan and to the of uptake using the as of bone marrow may result in uptake that is The uptake in of initial marrow involvement should then be compared with uptake within marrow to the of disease. The can be used to treatment an and at the of treatment. the risk of 1 and were used to define a scan in the study et al, 2012). The was also used as the for in the study for patients treated with BEACOPP who subsequently not receive RT et al, 2012). It is recommended that a of 1 or is used to define a if of RT treatment is considered in with patients. the risk of and were used to define a scan in the study et al, and in the study and defined a scan with initial for patients treated on trial et al, 2012; et al, 2013). the trials in it to using or to define an to ABVD at if therapy to escalated BEACOPP is to be scans should be as the chemotherapy as to the of or an however, biopsy is recommended to treatment to uptake of including disease and are also & Patients with which was to as et al, are have outcomes with treatment et al, et al, et al, but more is of therapy trials in these patients is not for PET and control have been the of trials and are recommended for The of and on patient and of if management are considered on PET for tumour with should be to et al, 2010). and scans should be as the chemotherapy as possible, to uptake to by treatment et al, et al, 2010). scans should be as to the of the of chemotherapy as the of a of factor treatment and months RT is recommended to to et al, 2010). chemotherapy has more the role of RT in HL has but it is an of chemotherapy and chemotherapy in The evidence for RT in early and advanced HL is on However, the late of have to new protocols using treatment. An EORTC consensus by is now in of RT et al, 2008). However, this on obtaining and of the patient in the treatment et al, 2008; et al, 2013). An alternative RT which a and the et al, et al, 2013). are in cases where RT alone is The of RT is now defined from the GHSG trials HD10 and which that is for favourable early HL, and should be given to all patients with early or advanced stage where RT is There is in follow-up practice with evidence to a Clinicians patients in follow-up for years before with but follow-up varies on patient may early from follow-up of therapy. CT or PET/CT scans and with no clear evidence of for patients et al, 2012; et al, 2013). CT or PET/CT for patients is not the high long-term of HL have compared to the et al, et al, & 2010). the years of the of risk of remains HL, especially in with unfavourable However, the for remains more years treatment et al, The of morbidity and are and but also include disease and who have can and to fertility and may of HL patients have also been shown to have long-term and in & The of this of disease have been et al, all HL patients are recommended to receive blood There are no data to the of in patients who have treatment for HL. including a large and have confirmed the incidence of in long-term of HL et al, et al, 2006; et al, et al, et al, et al, large British study HL patients treated with chemotherapy between and (Swerdlow et al, 2011). modality treatment a risk for chemotherapy alone The to non-Hodgkin and However, was with for a of including and on the at treatment and the of the the risk of in women treated in or early with RT is approximately compared with a risk in the UK of et al, 2007; & 2008). with HL is that et al, 2010). this risk has been managed by a the UK et al, disease is the most important of long-term of HL, et al, & 2010). the risk and this has been to mediastinal The British Study patients treated between and and identified from (Swerdlow et al, 2007). This an risk of per 000 and the risk remains high for at and risk of was identified for and The risk was high for the ABVD and the combination of RT and of is by as as of patients treated for and late stage are all is in of patients et al, et al, et al, et al, from HL and cell tumour patients have a of factors including renal and the use of et al, et al, However, only and to be and the risk should be considered from a in and to with to stage symptoms and are and that months treatment and should to of the has been that the and in these is to be and at the of to the the British for Haematology the any for the of these This is in at the of It be reviewed at and any be on the BCSH in the initial and has the The have no of to are when there is that the or not and 1 can be to most patients. as the of or not is a grade is to individual patients. as of evidence The of evidence is as high or this in it is to the of and further or