Abstract: Our literature search yielded 11,277 results. In total, we included 23 studies (99 references) with 7335 newly-diagnosed individuals with classic HL (all stages). Participants in 16 studies underwent (interim) PET combined with computed tomography (PET-CT), compared to PET only in the remaining seven studies. The standard chemotherapy regimen included ABVD (16) studies, compared to BEACOPP or other regimens (seven studies). Most studies (N = 21) conducted interim PET scans after two cycles (PET2) of chemotherapy, although PET1, PET3 and PET4 were also reported in some studies. In the meta-analyses, we used PET2 data if available as we wanted to ensure homogeneity between studies. In most studies interim PET scan results were evaluated according to the Deauville 5-point scale (N = 12). Eight studies were not included in meta-analyses due to missing information and/or data; results were reported narratively. For the remaining studies, we pooled the unadjusted hazard ratio (HR). The timing of the outcome measurement was after two or three years (the median follow-up time ranged from 22 to 65 months) in the pooled studies. Eight studies explored the independent prognostic ability of interim PET by adjusting for other established prognostic factors (e.g. disease stage, B symptoms). We did not pool the results because the multivariable analyses adjusted for a different set of factors in each study. Overall survival Twelve (out of 23) studies reported OS. Six of these were assessed as low risk of bias in all of the first four domains of QUIPS (study participation, study attrition, prognostic factor measurement and outcome measurement). The other six studies were assessed as unclear, moderate or high risk of bias in at least one of these four domains. Four studies were assessed as low risk, and eight studies as high risk of bias for the domain other prognostic factors (covariates). Nine studies were assessed as low risk, and three studies as high risk of bias for the domain 'statistical analysis and reporting'. We pooled nine studies with 1802 participants. Participants with HL who have a negative interim PET scan result probably have a large advantage in OS compared to those with a positive interim PET scan result (unadjusted HR 5.09, 95% confidence interval (CI) 2.64 to 9.81, I² = 44%, moderate-certainty evidence). In absolute values, this means that 900 out of 1000 participants with a negative interim PET scan result will probably survive longer than three years compared to 585 (95% CI 356 to 757) out of 1000 participants with a positive result. Adjusted results from two studies also indicate an independent prognostic value of interim PET scan results (moderate-certainty evidence). Progression-free survival Twenty-one studies reported PFS. Eleven out of 21 were assessed as low risk of bias in the first four domains. The remaining were assessed as unclear, moderate or high risk of bias in at least one of the four domains. Eleven studies were assessed as low risk, and ten studies as high risk of bias for the domain other prognostic factors (covariates). Eight studies were assessed as high risk, thirteen as low risk of bias for statistical analysis and reporting. We pooled 14 studies with 2079 participants. Participants who have a negative interim PET scan result may have an advantage in PFS compared to those with a positive interim PET scan result, but the evidence is very uncertain (unadjusted HR 4.90, 95% CI 3.47 to 6.90, I² = 45%, very low-certainty evidence). This means that 850 out of 1000 participants with a negative interim PET scan result may be progression-free longer than three years compared to 451 (95% CI 326 to 569) out of 1000 participants with a positive result. Adjusted results (not pooled) from eight studies also indicate that there may be an independent prognostic value of interim PET scan results (low-certainty evidence). PET-associated adverse events No study measured PET-associated AEs. This review provides moderate-certainty evidence that interim PET scan results predict OS, and very low-certainty evidence that interim PET scan results predict progression-free survival in treated individuals with HL. This evidence is primarily based on unadjusted data. More studies are needed to test the adjusted prognostic ability of interim PET against established prognostic factors.

Plain-language summary: We included 23 studies to explore the association between interim PET scan results after one to four cycles of chemotherapy and survival outcomes in adults with HL (all stages). We contacted 10 authors, and six provided us with relevant information and/or data. In 16 included studies, participants received either ABVD chemotherapy or BEACOPP chemotherapy (four studies) only, with or without radiotherapy. In 16 studies, participants underwent an interim PET scan in combination with a computed tomography (CT) (PET-CT), which have higher accuracy in detecting primary and secondary cancers than a PET scan alone. In the remaining seven studies, PET-only was conducted. Twenty-one studies conducted interim PET scans after two cycles (PET2) of chemotherapy. Eight studies did not report enough data on our outcomes or population of interest, so we reported the results from these studies narratively. We combined individual study results in meta-analyses to provide robust evidence for our outcomes of interest overall survival and progression-free survival. No study measured PET-associated adverse events (harms). For overall survival, combined results from nine studies (1802 participants) show that there is probably a large advantage in overall survival for people with a negative interim PET scan compared to people with a positive interim PET scan. For progression-free survival, combined results from 14 studies (2079 participants) show that interim PET-negative people may have an advantage for progression-free survival, compared to interim PET-positive people, but we are uncertain about this result. These are unadjusted results, where interim PET was tested as the only prognostic factor. Eight studies reported adjusted results, where the independent prognostic ability of interim PET was assessed against other established prognostic factors (e.g. disease stage, B symptoms). We could not combine individual study results because the studies did not include identical sets of covariates. Nevertheless, their results indicate a probable independent prognostic ability of interim PET to predict both outcomes. Regarding the unadjusted results, we rated our certainty of the evidence as 'moderate' for overall survival. This means that the true effect is likely to be close to the estimated effect, but there is a possibility that it is substantially different. For progression-free survival, we rated our certainty of the evidence as 'very low', meaning that we have little confidence in the effect estimate, and that the true effect is likely to be substantially different from the estimated effect. Regarding the adjusted results, we rated our certainty of the evidence as 'moderate' for overall survival, and 'low' for progression-free survival. We searched data bases up until 2 April 2019, and one trial registry on 25 January 2019.