Abstract: 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. 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.

Plain-language summary: We searched important medical databases such as the Cochrane Central Register of Controlled Trials and MEDLINE. Two review authors independently screened, summarised and analysed the results. This lead to the inclusion of three randomised controlled trials (RCTs) with 1999 participants. Currently, only data for 1480 of these participants have been published and were included in this systematic review. Participants were randomised to receive either standard therapy (chemotherapy followed by radiotherapy) or PET-adapted therapy (chemotherapy only). The median age of participants was 32 years and 52% were male. The evidence provided is current to September 2014. We are unable to draw conclusions about the effect of PET-adapted therapy on OS as there was insufficient data available (4 deaths in 1480 participants). However, PFS was shorter following PET-adapted therapy than with standard treatment. Based on our data, we can assume that of 1000 individuals receiving PET-adapted treatment over 4 years, 222 individuals would experience disease progression or death compared with 100 of 1000 individuals receiving standard treatment. Only one trial reported on short-term adverse events and the findings were uncertain and do not provide reliable evidence. The studies did not provide any information on the outcomes of QoL, response to therapy or treatment-related mortality. We judged the quality of evidence for the outcomes of OS and adverse events as very low. We considered the quality of evidence for PFS to be moderate. To date, no robust data on OS are available. This systematic review shows that individuals with early-stage HL have a shorter PFS after PET-adapted therapy compared with those who receive standard therapy. More RCTs with longer follow ups may lead to more information on adverse events, treatment-related mortality and QoL, and could evaluate whether the PFS advantage seen with standard therapy will translate into a benefit in terms of OS.