title: Positron emission tomography-adapted therapy for first-line treatment in individuals with Hodgkin lymphoma.
abstract: BACKGROUND
  Hodgkin lymphoma (HL) is a B-cell lymphoma accounting for 10% to 15% of all lymphoma in industrialised countries. It has a bimodal age distribution with one peak around the age of 30 years and another after the age of 60 years. Although HL accounts for fewer than 1% of all neoplasms worldwide, it is considered to be one of the most common malignancies in young adults and, with cure rates of 90%, one of the most curable cancers worldwide. Current treatment options for HL comprise more- or less-intensified regimens of chemotherapy plus radiotherapy, depending on disease stage. [18F]-fluorodeoxy-D-glucose (FDG)-positron emission tomography (PET, also called PET scanning) is an imaging tool that can be used to illustrate a tumour's metabolic activity, stage and progression. Therefore, it could be used as a standard interim procedure during HL treatment, to help distinguish between individuals who are good or poor early responders to therapy. Subsequent therapy could then be de-escalated in PET-negative individuals (good responders) or escalated in those who are PET-positive (poor responders). It is currently unknown whether such response-adapted therapeutic strategies are of benefit to individuals in terms of overall and progression-free survival, and the incidence of long-term adverse events (AEs).
  
  
  OBJECTIVE
  To assess the effects of interim [18F]-FDG-PET imaging treatment modification in individuals with HL.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL; latest issue) and MEDLINE (from 1990 to September 2014) as well as conference proceedings (American Society of Hematology; American Society of Clinical Oncology; European Hematology Association; and International Symposium on Hodgkin Lymphoma) for studies. Two review authors independently screened search results.
  
  
  METHODS
  We included randomised controlled trials (RCTs) comparing FDG-PET-adapted therapy with non-adapted treatment in individuals with previously untreated HL of all stages and ages.
  
  
  METHODS
  Two review authors independently extracted data and assessed the quality of trials. As none of the included studies provided HRs for OS, we described risk ratios (RRs) for this outcome and did not pool the data. As an effect measure we used hazard ratios (HRs) for progression-free survival (PFS). We described RRs for the dichotomous data on AEs. We also calculated 95% confidence intervals (CIs).
  
  
  RESULTS
  Our search strategies led to 308 potentially relevant references. From these, we included three studies involving 1999 participants. We judged the overall potential risk of bias as moderate. The studies were reported as RCTs; blinding was not reported, but given the study design it is likely that there was no blinding. One study was published in abstract form only; hence, detailed assessment of the risk of bias was not possible.Two trials compared standard treatment (chemotherapy plus radiotherapy) with PET-adapted therapy (chemotherapy only) in individuals with early-stage HL and negative PET scans. The study design of the third trial was more complex. Participants with early-stage HL were divided into those with a favourable or unfavourable prognosis. They were then randomised to receive PET-adapted or standard treatment. Following a PET scan, participants were further divided into PET-positive and PET-negative groups. To date, data have been published for the PET-negative arms only, making it possible to perform a meta-analysis including all three trials.Of the 1999 participants included in the three trials only 1480 were analysed. The 519 excluded participants were either PET-positive, or were excluded because they did not match the inclusion criteria.One study reported no deaths. The other two studies reported two deaths in participants receiving PET-adapted therapy and two in participants receiving standard therapy (very-low-quality evidence). Progression-free survival was shorter in participants with PET-adapted therapy (without radiotherapy) than in those receiving standard treatment with radiotherapy (HR 2.38; 95% CI 1.62 to 3.50; P value < 0.0001). This difference was also apparent in comparisons of participants receiving no additional radiotherapy (PET-adapted therapy) versus radiotherapy (standard therapy) (HR 1.86; 95% CI 1.07 to 3.23; P value = 0.03) and in those receiving chemotherapy but no radiotherapy (PET-adapted therapy) versus standard radiotherapy (HR 3.00; 95% CI 1.75 to 5.14; P value < 0.0001) (moderate-quality evidence). Short-term AEs only were assessed in one trial, which showed no evidence of a difference between the treatment arms (RR 0.91; 95% CI 0.54 to 1.53; P value = 0.72) (very-low-quality evidence). No data on long-term AEs were reported in any of the trials.
  
  
  CONCLUSIONS
  To date, no robust data on OS, response rate, TRM, QoL, or short- and long-term AEs are available. However, this systematic review found moderate-quality evidence that PFS was shorter in individuals with early-stage HL and a negative PET scan receiving chemotherapy only (PET-adapted therapy) than in those receiving additional radiotherapy (standard therapy). More RCTs with longer follow ups may lead to more precise results for AEs, TRM and QoL, and could evaluate whether this PFS advantage will translate into an overall survival benefit.It is still uncertain whether PET-positive individuals benefit from PET-based treatment adaptation and the effect of such an approach in those with advanced HL.
authors.affiliation: Cochrane Haematological Malignancies Group, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Sickinger
authors.forename: Bastian
authors.initials: B
authors.lastname: von Tresckow
authors.forename: Carsten
authors.initials: C
authors.lastname: Kobe
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
authors.forename: Peter
authors.initials: P
authors.lastname: Borchmann
authors.forename: Nicole
authors.initials: N
authors.lastname: Skoetz
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D059248:Chemoradiotherapy / Q000379:methods; D018572:Disease-Free Survival; D005260:Female; D019788:Fluorodeoxyglucose F18; D006689:Hodgkin Disease / Q000000981:diagnostic imaging* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D016032:Randomized Controlled Trials as Topic; D015983:Selection Bias
chemical_list: D000970:Antineoplastic Agents; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18