Description of the condition
Hodgkin lymphoma (HL) is a cancer of the lymphatic system of the body, involving the lymph nodes, spleen, and other organs such as the liver, lung, bone or bone marrow depending on the tumour stage (Lister 1989). It is a B-cell lymphoma which accounts for less than 1% of all neoplasms throughout the world (Fraga 2007). Hodgkin lymphoma is characterised by a small proportion of tumour cells, known as Hodgkin- and Reed-Sternberg-cells. The malignant cells usually account for only about 1% of cells in the tumour tissue surrounded by a specific inflammatory microenvironment (Diaz 2011; Shenoy 2011).
In western countries HL typically shows a bimodal age distribution with a first peak around the age of 30 and a second peak after the age of 50. It accounts for 10% to 15% of all lymphoma in industrialised countries with an incidence of 2 to 3 per 100,000 inhabitants. Therefore it can be regarded as a relatively rare disease, but nevertheless, it is one of the most common malignancies in young adults (Caporaso 2009; Swerdlow 2003; Thomas 2002).
There is a distinction between two types of HL according to the Revised European-American Lymphoma/World Health Organization (REAL/WHO) classification: lymphocyte predominance HL (LP-HL) representing about 5% of all HL, and classical HL (˜95%). They differ in morphology, phenotype, molecular features and therefore in clinical behavior as well as clinical presentation (Harris 1999; Re 2005). Classical HL is further divided into four subtypes (nodular sclerosis, mixed cellularis, lymphocyte-rich classical Hodgkin lymphoma, and lymphocyte depleted Hodgkin lymphoma) all of which are treated similarly (Fraga 2007).
The disease usually develops in lymph nodes of the upper part of the body, mostly in the latero-cervical lymph nodes which results in painless swelling of the lymphatic tissue involved. Normally HL appears within certain parts of the body with peripheral extranodal involvement being rare. As a sign of large tumour size or spreading, 25% of patients present themselves with B-symptoms such as fever of unknown origin, heavy sweating during nighttime and loss of more than 10% of body weight (Connors 2009; Pileri 2002).
For staging, the Ann Arbor Classification and the International Prognostic Index (IPI) (only for advanced stages) is used. Referring to Ann Arbor, we distinguish between four different tumour stages summarised as limited (˜40% of patients) and advanced (˜60% of patients) disease. Stages one to three indicate the degree of lymph node involvement, while stage four indicates disseminated organ involvement and can be found in 20% of cases. Factors influencing the prognosis of Hodgkin lymphoma are, for example, large mediastinal mass, three or more involved lymph node areas, high erythrocyte sedimentation rate (ESR), extranodal lesion, and advanced age, and may slightly vary between different study groups. Additionally, the definition of bulky disease (largest tumour diameter greater than 10 cm), often referred to as the Cotswold modification (Lister 1989), is taken into consideration.
Generally, Hodgkin lymphoma is classified into early favourable, early unfavourable and advanced stage (Engert 2007; Klimm 2005). In Europe, the early favourable stage group usually comprises Ann Arbor stages I and II without risk factors. Early unfavourable stage includes those patients in stages I and II with risk factors, as well as selected patients with stage IIIA disease. Most stage III and IV patients are classified in the advanced-stage risk group (Diehl 2001; Engert 2003). Patients with Ann Arbor stage IIB and some specific risk factors, or stage II with bulky disease, may be included in trials for advanced stages.
With cure rates of 80 to 90%, HL is one of the most curable cancers worldwide (Engert 2010; Engert 2012; von Tresckow 2012). A combination of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) has been widely accepted as the gold-standard chemotherapy regimen in HL (Canellos 1992; Engert 2010). For treatment of limited stage disease, a combination of chemotherapy and involved field radiation (IF-RT) is performed (Engert 2010; von Tresckow 2012) whereas advanced stage disease is treated with an intensified regime such as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (Bauer 2011; Borchmann 2011; Engert 2012) or ABVD. Recently, a large randomised trial showed that two cycles of ABVD followed by 20 Gy of IF-RT is sufficient for the treatment of early favourable HL (Engert 2010), whereas patients with early unfavourable HL are usually treated with four cycles of chemotherapy followed by 30Gy IF-RT. Of late, two cycles of BEACOPPescalated (esc) followed by two cycles of ABVD have been shown to improve the progression-free survival (PFS) in comparison to four cycles of ABVD in early unfavourable patients (von Tresckow 2012).
In case of relapse or refraction to initial treatment, high dose chemotherapy followed by autologous hemapoietic stem cell transplantation is the therapy of choice (Josting 2010; Linch 1993; Schmitz 2002).
Description of the intervention
Computer tomography is an imaging tool for interim tumour staging, associated with a high radiation exposure. Another imaging tool to make a statement about the progression or non-progression of a tumour during therapy is [F-18]-fluorodeoxy-D-glucose (FDG)-positron emission tomography (PET, also called PETscan). It has become a standard procedure for numerous oncological situations. The principle of FDG-PET is based on FDG being a labelled glucose analogue and therefore being a good representative of the glucose metabolism of the tissue. More precisely 18F-FDG consists of two parts: a vector part (2-deoxy-D-glucose) and the 18F part which is a positron emitting nuclide. When FDG is taken up by cells, preferably by those with a high basis metabolic rate, it is not metabolised but is 'trapped' within the cell and can then be detected by scintigraphy. This process is used to give evidence about FDG-avid tumours like HL, their state and progression (Boellaard 2010).
FDG-PET is not only used for tumour staging, but also for response evaluation in lymphoma patients, and has been widely accepted (Kobe 2010b; Markova 2009; Specht 2007). Recent data demonstrate that early interim FDG-PET is a good predictor of prognosis and therefore could help to distinguish between good and poor responders at an early time point of therapy (Gallamini 2007; Kobe 2010a; Markova 2012). The differentiation of responding and non-responding patients could lead to response adapted therapeutic strategies such as de-escalation in responding patients or escalation in non-responding patients. A potential therapy adaptation is a fairly new method which was introduced with the exploration of FDG-PET (Engert 2012; Kobe 2008). However, the question to be answered is whether patients could benefit from such an aligned therapy in terms of response and overall survival.
How the intervention might work
PET-based treatment modifications are broadly used in numerous trials. As FDG-PET imaging gives us a good insight into the tumour's metabolic activity, treatment modification will include escalation in PET-positive as well as de-escalation in PET-negative patients. More precisely this means chemotherapy intensification (e.g. number of cycles or number of chemotherapeutic agents or additional immunotherapy) on the one hand, and chemotherapy reduction (e.g. number of cycles or number of chemotherapeutic agents, or no further treatment/no radiotherapy) on the other. The idea behind this method is to achieve maximum efficacy in terms of overall and progression-free survival, and to reduce long-term adverse events.
Why it is important to do this review
To our knowledge, no systematic review on the effectiveness of interim PET-based treatment modification in Hodgkin lymphoma patients has been performed to date. As the question of PET-guided therapy adaptation is very important, and pivotal for decision-making, it has been evaluated in several randomised controlled trials. At least two published randomised controlled trials and nine ongoing trials are assessing the potential advantages and disadvantages of interim PET-based treatment adaptation. The available data from these randomised studies will be summarised in our review, and we will be provided with more precise and reliable evaluation of intervention effects by meta-analysing single trials. Thereby we will overcome the limitations of individual studies due to small sample sizes and lack of statistical power. Summing up all results will help to identify the best available therapeutic strategy, as well as drawing conclusions on the treatment modification in question.