Key findings
• The effect of treatment adaptation depends on the interim PET result and the stage of an individual with Hodgkin lymphoma (HL).
• While the effect of treatment de-escalation based on a negative interim PET scan is uncertain in early-stage HL, it may have little effect on overall and progression-free survival in intermediate-stage HL.
• In advanced-stage HL, reduction of chemotherapy or radiotherapy after a negative interim PET scan is probably beneficial for overall survival.
• Treatment escalation with rituximab after a positive interim PET scan probably increases adverse events without improving survival.
What is Hodgkin lymphoma?
Hodgkin lymphoma (HL) is a rare cancer of the lymphatic system (part of the immune system which keeps body fluid levels in balance and defends the body against infections). Its symptoms are painless swelling of lymphatic tissue, and some people experience fever, night sweats, and unintended weight loss. HL is one of the most curable cancers worldwide and is usually treated with chemotherapy, sometimes in combination with radiotherapy, depending on the stage.
What is positron emission tomography?
Positron emission tomography (PET) is an imaging technique that can visualise the activity of cells within body tissues using a radioactive liquid injection, i.e. based on sugar. As cancer cells usually grow quickly, they need a lot of energy. They thus take up more of the radio-labelled sugar injection and are brighter on the scan. PET is commonly used in the determination of the extent (stage) of cancers or as a response assessment tool to therapy. Recently, it has also been used to look at whether it can be used during treatment to adapt according to the cell's activity level. Treatment could be reduced in individuals who show a good response to chemotherapy, thus those with less activity, which is called PET-negative, to decrease the risk of long-term unwanted effects (adverse events). Treatment may be increased in those showing a poor response, thus more activity, which is called PET-positive.
What did we want to find out?
We wanted to know whether treatment adaptation after a PET scan during treatment improves overall survival, time without disease progression (progression-free survival), treatment-related mortality, unwanted effects, and quality of life. This included less treatment after a negative PET scan, or more treatment after a positive PET scan.
What did we do?
We systematically searched for studies in relevant medical databases and found 10 randomised controlled studies published before 17 November 2023, which we evaluated and meta-analysed according to PET status (negative or positive) and stage (early-to-intermediate or advanced).
What did we find?
From the 10 studies we found, one included 667 individuals with early-stage HL, one included 651 individuals with intermediate-stage HL, and three included 1639 individuals with early-to-intermediate stage HL (with one separating those two groups). Five studies included 3629 individuals with advanced-stage HL. All studies explored whether leaving out radiotherapy after a negative PET has beneficial outcomes, but only three studies looked at outcomes after more intensive treatment in those with a positive PET scan.
The standard therapy in early-stage and intermediate-stage HL usually includes chemotherapy and radiotherapy. In early-stage HL, it is uncertain whether leaving out radiotherapy after a negative PET scan is beneficial or not regarding survival and progression-free survival. It may have little to no effect on serious unwanted effects or the development of another cancer.
In intermediate-stage HL, leaving out radiotherapy after a negative interim PET may not affect overall survival and progression-free survival negatively.
The standard therapy for advanced-stage HL nowadays is more intensive chemotherapy. Reducing the intensity of the chemotherapy based on a negative PET scan probably increases overall survival and has little effect on progression-free survival. It may also reduce the development of another cancer. Some countries use, similar to early stages, chemotherapy and radiotherapy. Leaving out radiotherapy based on having negative PET scans both during and after chemotherapy may increase overall survival and progression-free survival, and may reduce the development of another cancer.
Evidence from one study suggests that more intensive chemotherapy after a positive PET scan in early-to-intermediate stage HL may increase overall survival and progression-free survival, but could not determine whether people develop more or fewer other cancers.
Two studies tested whether rituximab, a monoclonal antibody, in addition to standard chemotherapy could improve outcomes. It does probably not increase overall or progression-free survival, but probably increases serious unwanted effects and treatment-related mortality.
What are the limitations of the evidence?
Many studies did not report unwanted effects in the format we need to use the data, although they were assessed. None of the studies has published their data on quality of life.
The certainty in the evidence varies between comparisons. It is mostly moderate for leaving out radiotherapy in early-to intermediate-stage PET-negative individuals, less intensive chemotherapy in PET-negative advanced-stage HL, and rituximab in PET-positive advanced-stage participants, but low-to-very-low for omitting radiotherapy after negative PET in advanced stage and intensifying chemotherapy after positive PET in early-to-intermediate stage HL.
In early-stage HL, the effect of interim-PET-based treatment adaptation by omission of radiotherapy is uncertain. No effect was seen on long-term adverse events, although the follow-up of around five years may be too short to see an effect. In intermediate-stage HL, omission of radiotherapy may have little effect on both overall and progression-free survival, serious adverse events and secondary malignancies.
In advanced-stage HL, reducing chemotherapy upon negative interim-PET has the potential to increase overall survival while not negatively affecting progression-free survival and long-term adverse events. If combined modality treatment is opted for, omitting radiotherapy may increase both overall and progression-free survival, while reducing the negative effect of radiotherapy on secondary malignancies.
Interim-PET-positive treatment intensification by providing more chemotherapy in early-to-intermediate stage HL may be beneficial, while adding rituximab to standard chemotherapy in advanced-stage HL does not result in the expected improvement, but increases adverse events.
Hodgkin lymphoma (HL) is one of the most curable cancers worldwide. Treatment options comprise more- or less-intensified regimens of chemotherapy plus radiotherapy depending on the disease stage. An interim-[18F]-fluorodeoxy-D-glucose (FDG)-positron emission tomography (PET), a procedure to illustrate a tumour's metabolic activity, stage and progression, could be used during treatment to distinguish between individuals who are good or poor early responders to therapy. Subsequent therapy could be de-escalated in PET-negative individuals (good responders) or escalated in those who are PET-positive (poor responders).
To assess the effects of interim [18F]-FDG-PET-imaging treatment modification in previously untreated individuals with HL.
For this review update, we searched MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, clinicaltrials.gov and the WHO ICTRP up to 17 November 2023.
We included randomised controlled trials (RCTs) comparing interim-FDG-PET-adapted therapy with non-adapted standard treatment in adults with untreated HL of all stages.
Two review authors independently screened results for inclusion, extracted data into a standardised data extraction sheet and assessed the risk of bias according to the Cochrane risk of bias tool. We collected (modified) intention-to-treat effect estimates for the predefined outcomes: overall survival (OS), progression-free survival (PFS), treatment-related mortality (TRM), adverse events (AE) including secondary malignancies and quality of life (QoL), where available, and used random-effects models for meta-analysis. We analysed early, intermediate and advanced stage HL and PET-negative versus PET-positive participants separately. We used the GRADE approach to rate our certainty in the evidence.
We included 10 studies covering early (1 RCT, 667 participants), intermediate (1 RCT, 651 participants), early-to-intermediate (3 RCTs, 1639 participants) and advanced-stage HL (5 RCTs; 3629 participants). We did not identify eligible ongoing studies.
Generally, the risk of bias was low or, sometimes, unclear except for detection bias, which was rated as high for all studies for subjective outcomes such as PFS, TRM and AE due to the lack of blinding.
PET-based adaptation in early-stage PET-negative participants
The effect of treatment adaptation (omission of radiotherapy with or without additional chemotherapy) on OS and PFS is uncertain (HR 0.84, 95% CI 0.13 to 5.32; and HR 4.52, 95% CI 0.72 to 28.41, 1034 participants). Adaptation may have little to no effect on the incidence of secondary malignancies (RR 0.83, 95% CI 0.46 to 1.50; 984 participants; low-certainty). No studies reported on TRM, serious adverse events (SAE) or QoL.
PET-based adaptation in intermediate-stage PET-negative participants
Treatment adaptation by omission of radiotherapy (with or without additional chemotherapy) may have little effect on OS (HR 0.91, 95% CI 0.42 to 1.96; 1073 participants; low-certainty) and PFS (HR 1.59, 95% CI 0.95 to 2.67; 1073 participants; low-certainty) compared to standard therapy. The effect on TRM is very uncertain. De-escalation may have little effect on the incidence of SAE (RR 1.01, 95% CI 0.84 to 1.21; 1096 participants, low-certainty) and secondary malignancies (RR 1.01, 95% CI 0.57 to 1.82; 1515 participants; low-certainty). No studies reported on QoL.
PET-based de-escalation in advanced-stage PET-negative participants
Three RCTs examined interim-PET-based de-intensification of chemotherapy compared with standard in advanced-stage PET-negative participants; this probably increases OS (HR 0.65, 95% CI 0.40 to 1.07; 2633 participants, moderate-certainty), although the confidence interval included the possibility of no effect, while it has probably little effect on PFS (HR 0.98, 95% CI 0.78 to 1.25; 2633 participants, moderate-certainty). Treatment de-escalation may reduce TRM (RR 0.21, 95% CI 0.06 to 0.73; 2761 participants, low-certainty) and the incidence of secondary malignancy (RR 0.87, 95% CI 0.60 to 1.26; 2757 participants; low-certainty), although for this latter finding, the CI included the possibility of no effect. No studies reported SAE and QoL.
Two RCTs considered combined modality treatment as standard for advanced stages and de-escalated by omitting radiotherapy. De-escalation may increase OS (HR 0.63, 95% CI 0.11 to 3.69; 296 participants; low-certainty), PFS (HR 0.78, 95% CI 0.43 to 1.43; 412 participants; low-certainty), and may reduce the incidence of secondary malignancy (RR 0.41, 95% CI 0.08 to 2.09; 349 participants; low-certainty), although for all these findings, the CI included the possibility of no effect. No studies reported TRM, SAE and QoL.
PET-based escalation in mixed early-and-intermediate-stage, PET-positive participants
One study compared intensified chemotherapy (BEACOPPescalated) and radiotherapy with standard chemotherapy (ABVD) and radiotherapy based on positive interim-PET after two cycles in early-to-intermediate-stage HL. Treatment escalation may increase OS (HR 0.92, 95% CI 0.43 to 1.97; 260 participants; low-certainty) and PFS (0.67, 95% CI 0.37 to 1.20; 260 participants; low-certainty), although the CI included the possibility of no effect. The effect on secondary malignancies is very uncertain (RR 1.23, 95% CI 0.43 to 3.55; 234 participants, very low-certainty). No studies reported TRM, SAE and QoL.
PET-based escalation in advanced-stage, PET-positive participants
Two studies examined interim-PET-based escalation of PET-positive participants with rituximab in addition to chemotherapy in advanced-stage HL, which likely does not increase OS (HR 1.39, 95% CI 0.74 to 2.63; 795 participants; moderate-certainty) or PFS (HR 1.03, 95% CI 0.68 to 1.54; 582 participants; moderate-certainty). It may increase TRM (RR 4.00, 95% CI 0.45 to 35.5; 434 participants; very low-certainty), although the CI included the possibility of no effect. Escalation probably increases the number of participants with SAE (RR 1.61, 95% CI 1.00 to 2.60; 148 participants, moderate-certainty), and may reduce the number of participants with secondary malignancy (RR 0.67, 95% CI 0.28 to 1.60; 582 participants; low-certainty), although for this latter finding, the CI included the possibility of no effect. No study reported QoL.