Background
Hodgkin lymphoma (HL) is a malignant disease of the lymphatic system of the body. It accounts for 10% to 15% of all lymphoma in industrialised countries and tends to show two peaks in incidence at around 30 and 60 years of age. While it is considered a relatively rare disease, it is one of the most common malignancies in young adults. With cure rates of up to 90% over 5 years, it is one of the most curable cancers worldwide.
The imaging of tumour tissue using a technique termed positron emission tomography (PET) has been shown to provide a good way of estimating the activity of a tumour. The question therefore arises of whether this technique could be used as an tool during therapy to identify individuals who are, or are not, responding to chemotherapy. This would enable further treatment to be modified, resulting in individualised therapy. Treatment could be reduced or stopped in individuals who show a good response to chemotherapy, thus reducing the risk of long-term adverse events, or increased in those showing a poor response to chemotherapy.
Review question
In this systematic review we address the issue of whether PET-adapted therapy in individuals with HL results in beneficial outcomes such as longer overall survival (OS) and survival without disease progression (termed progression-free survival or PFS), higher responses to therapy and participant quality of life (QoL), or reductions in adverse events (such as second malignancies) or treatment-related mortality.
Study characteristics
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.
Key results
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.
Quality of evidence
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.
Conclusion
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.
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.
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).
To assess the effects of interim [18F]-FDG-PET imaging treatment modification in individuals with HL.
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.
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.
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).
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.