Description of the condition

Hodgkin lymphoma (HL) is a cancer of the lymph nodes and lymphatic system with possible involvement of other organs such as the liver, lung, bone or bone marrow (Lister 1989). With an annual incidence of approximately two to three per 100,000 inhabitants in Western countries, HL is a comparatively rare disease, but it is one of the most common malignancies in young adults (Howlader 2015). In industrialised countries, the age distribution of HL shows a first peak in the third decade and a second peak after the age of 50 (Thomas 2002).

The World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues distinguishes between two types of HL: classic HL, representing about 95% of all HL, and lymphocyte‐predominant HL, representing about 5% of all HL (Swerdlow 2008). Both types differ in morphology, phenotype and molecular features, and therefore in clinical behaviour and presentation (Re 2005).

The Ann Arbor Classification is used for staging and distinguishes between four different tumour stages. Stages one to three indicate the degree of lymph node and localised extranodal organ involvement or both, stage four includes disseminated organ involvement, which can be found in 20% of cases. Factors associated with a poor prognosis include a large mediastinal mass, three or more involved lymph node areas, a high erythrocyte sedimentation rate, extranodal lesions, B symptoms (weight loss > 10%, fever, drenching night sweats) and advanced age, but the factors considered significant vary slightly between different study groups ((German Study Hodgkin Lymphoma Study Group (GSHG), European Organization for Research and Treatment of Cancer (EORTC), and the National Cancer Institute of Canada (NCIC)). The Cotswold modification of the Ann Arbor Classification also takes into consideration the occurrence of bulky disease (largest tumour diameter greater than 10 cm) (Lister 1989). 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. The early unfavourable‐stage group includes individuals with Ann Arbor stages I or II and one or more risk factors. Most individuals with stages IIB, III or IV disease are included in the advanced‐stage risk group (Engert 2003).

With cure rates of up to 90%, HL is one of the most curable cancers worldwide (Engert 2010; Engert 2012; Rancea 2013a; von Tresckow 2012). A combination of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) is widely accepted as the standard chemotherapy regimen in early‐stage HL (Canellos 1992; Engert 2010). Individuals in this stage usually receive a combination of chemotherapy and involved‐field radiation therapy (IF‐RT) (Engert 2010; von Tresckow 2012), whereas those with advanced‐stage disease receive an intensified regimen, such as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) (Bauer 2011; Borchmann 2011; Engert 2012; Skoetz 2013), or ABVD. A large randomised study showed that two cycles of ABVD followed by 20 Gy of IF‐RT is sufficient for the treatment of early‐favourable HL (Engert 2010), which is implemented into current standard treatment, whereas four cycles of chemotherapy followed by 30 Gy IF‐RT is more suitable for individuals with early‐unfavourable HL. Approximately 10% of people with HL will be refractory to initial treatment or will relapse; this is more common in those people with advanced stage or bulky disease. These individuals can be treated with high‐dose chemotherapy and autologous stem cell transplantation (Rancea 2013).

The current treatment approach for HL is to maximise progression‐free and overall survival and to minimise acute and long‐term toxicities like cardiac and pulmonary damage, infertility and secondary cancers. Development of a secondary cancer is one of the major causes of morbidity and mortality once the risk of progression and relapse of HL is over, i.e. from about five years after first‐line treatment onwards. In a large systematic review based on individual patient data in people with HL, Franklin and colleagues demonstrated that treatment de‐intensification by avoiding additional radiotherapy reduces the risk of a secondary cancer (Franklin 2005).

Description of prognostic factor

This protocol for a systematic review of prognostic factors is an exemplar protocol of a new review type within the Cochrane Library. Methods have not been standardised by Cochrane, thus this protocol can serve as an exemplar protocol to be adapted for other research questions.

A prognostic factor is a characteristic of a patient or the disease that is likely to affect patient outcomes or health events, often related to overall survival and disease‐free survival. Summaries of prognosis are particularly useful when associated with a treatment strategy, including helping to stratify patients for treatment. However, to arrive to an unbiased and meaningful assessment of prognosis, prognostic factors should be first evaluated in a cohort of patients treated in the same way (i.e. there should be no variation in their treatment based on a ‘potential’ prognostic factor), and at the same time point of their treatment. It is this differentiation that makes studies of prognosis a challenge to assess and include in a systematic review.

[18F]‐fluorodeoxy‐D‐glucose (FDG)‐positron emission tomography (PET, also called PET scanning) is an imaging tool that shows the tumour's metabolic activity, its stage and progression. The principle of FDG‐PET is based on a radio‐labelled glucose analogue being a good indicator of the glucose metabolism of a tissue. It comprises two parts: a vector (2‐deoxy‐D‐glucose) being taken up by cells with a high metabolic rate, and 18F, a positron‐emitting nuclide which is detected by scintigraphy. FDG‐PET scanning provides the opportunity to identify the state and degree of progression of FDG‐avid tumours and has therefore become a standard imaging tool for various cancers (Boellaard 2010). Hodgkin lymphoma is a FDG‐avid tumour; in a study of 233 people with HL, 100% were FDG‐avid (Weigler‐Sagie 2010).

Over the last few decades FDG‐PET has been used more and more for staging, potential prognosis, treatment planning and response evaluation in people with HL, and is a widely accepted procedure (Kobe 2010a; Markova 2009; Specht 2007). Interim FDG‐PET scan identifies the state of disease after a few cycles of chemotherapy and it has been suggested to be a good predictor of prognosis, aiding the distinction between patients with poor prognosis from those with a better prognosis, while undergoing early treatment for HL (Gallamini 2007; Kobe 2010; Markova 2012). If we are able to establish the prognostic value of the interim PET, individuals at high risk of progression or relapse will potentially be identified by PET‐positivity in interim PET‐imaging and might benefit from an intensified therapy. At the same time, the majority of the individuals with a lower risk for relapse may be identified by interim PET‐negativity status. This approach of therapy adaptation is a fairly new one, introduced after detailed exploration of the FDG‐PET procedure (Engert 2012; Kobe 2008). The idea behind this approach is to achieve maximum efficacy in terms of overall survival and progression‐free survival, by reducing the rate of long‐term adverse events.

A recent Cochrane review on the role of PET‐adapted treatment modification for people with HL found some evidence that progression‐free survival was decreased in people with early‐stage HL and a negative PET scan receiving chemotherapy only (PET‐adapted therapy) compared to those receiving additional radiotherapy (standard therapy). However, it is still unclear whether individuals who are PET‐positive could benefit from PET‐adapted treatment and the effect of such an approach in those with advanced HL, as no randomised controlled trials (RCTs) on these research questions have been published (Sickinger 2015).

Why it is important to do this review

Guidelines by UK‐based medical experts and patient representatives stated that interim PET is highly predictive of outcome in patients treated with ABVD (Follows 2014), while the German evidence‐based guidelines do not give recommendations regarding interim PET due to limited evidence, but state that the treating physician may, however, have special reasons for requesting interim PET as an aid to therapeutic decision‐making (Rancea 2013). Thus, the decision‐making process for or against interim PET is usually confusing for patients and physicians, as there are no clear recommendations for a consistent approach in international guidelines. Cancer burden, economic and societal impact are introduced in discussions on the best strategy as patients are usually young and will likely survive, however, they will carry a risk of developing a relapse or secondary malignancies.

To our knowledge, there is one systematic review on the potential prognostic value of interim PET in individuals with HL (Adams 2015). However, this review looked at 'treatment failure' as an outcome of the interim PET scan, which is different to the outcomes the current review will explore. Moreover, and despite the fact that it is entitled as a prognostic review, the methodology used is akin to diagnostic test evaluation (with calculations of diagnostic odds ratio, specificity and sensitivity) rather than using established prognostic methodology and crucially, the confidence in the calculated estimates was not rated. Last but not least, the review included studies published before December 2014, and hence important research published since that time is not included; we are aware of at least four studies (Miltenyi 2015; Rigacci 2015; Simon 2015; Simontacchi 2015), and there may be more. Moreover, the authors of the systematic review did not rate the confidence in the calculated estimates.

As the question of the prognostic role of interim PET is very important and will strongly influence decision‐making, we will summarise all data available from identified studies and include a meta‐analysis if the primary studies are sufficiently homogeneous. Our aim is to produce robust evidence based on the improved power that a meta‐analysis provides over the limitations of individual primary studies, and grade the evidence. A reliable answer to the question of the potential prognostic role of interim PET scan in adults with HL will strongly influence decision‐making at a crucial point of patients’ treatment pathway. Moreover, the rating of the evidence about the prognostic role of an interim PET scan will provide readers with an estimate of how much they can rely on the calculated results.

The aim of this prognostic factor systematic review is to provide a comprehensive overview on the benefits and harms of interim PET for patients with HL. The meta‐analysis and grading of the evidence will allow a conclusion, of whether interim PET is a prognostic factor which results translate into a clinical important difference. This comprehensive overview is necessary for clinical decision‐making; it will have a great impact on international guidelines and clinical pathways, and will contribute to a high‐grade decision support for effective, supportive strategies for the individual patient.