Featured Review: Imaging with PET during chemotherapy to predict outcome in adults with Hodgkin lymphoma

Hodgkin lymphoma (HL) is one of the most common haematological malignancies in young adults and, with cure rates of 90%, has become curable for the majority of individuals. Positron emission tomography (PET) is an imaging tool used to monitor a tumour’s metabolic activity, stage and progression. Interim PET during chemotherapy has been posited as a prognostic factor in individuals with HL to distinguish between those with a poor prognosis and those with a better prognosis. This distinction is important to inform decision-making on the clinical pathway of individuals with HL.

In this interview with the lead author of this Review we asked Research Associate, Angela Aldin from Cochrane Haematological Malignancies to tell us more about it.

What is (interim) PET and what does the PET scan result indicate?
A positron emission tomography (PET) is an imaging tool that is used for the diagnosis and/or monitoring of a disease. In individuals with Hodgkin lymphoma (HL), a PET scan at diagnosis helps to identify the stage of the disease and aids the treating physician in deciding upon the treatment pathway of the individual. An interim PET scan, however, is conducted during therapy, for instance after the second cycle of chemotherapy, to see whether the individual is responding to the allocated treatment. The Deauville five-point scale is the most commonly used scale for the interpretation of the scans and for assessing the extent of the disease. For example, individuals with a score of four or five are said to have a positive PET scan result, as the PET scan shows a higher uptake and metabolic activity of the cancer cells, and noticeable evidence of disease. Individuals with a score between one and three have a negative PET scan with a lower uptake of the cancer cells.

What was the objective of this review?
The objective of this review was to determine whether in previously untreated adults with HL (all stages) receiving first-line therapy, interim PET scan results (i.e. a positive or a negative result) can distinguish between those with a poor prognosis and those with a better prognosis, and thereby predict survival in each group.

How many studies were included? What was included and what was excluded?
We included twenty-three studies in total, in this review. In all studies, interim PET was conducted during first-line therapy and after two, three, and/or four cycles of chemotherapy in adults with HL (all stages). We included both retrospective and prospective studies that provided evidence on our prognostic factor of interest (interim PET-scan results) and outcomes of interest (overall survival, progression-free survival and PET-associated adverse events). It was important to include studies in which the treatment regimen of the participants was not adapted according to the interim PET scan results. In other words, irrespective of the interim PET scan result (interim PET-positive or interim PET-negative), participants should continue with the same treatment regimen as specified at the beginning of the study. The reason being that the occurrence of the predicted outcome in each group shall be attributable to the prognostic factor of interest (the interim PET scan result) rather than the modified treatments. Hence, we excluded studies that in their design allowed adaptation of the initially allocated treatment regimen of participants based on their interim PET scan result. In other words, modification of treatment based on the PET results would mask the true impact of the interim-PET as a prognostic factor. Once the significance of the interim-PET results is proven (as this was the aim of the review), then a different type of clinical study would be necessary before recommendations for treatment alterations based on PET results is offered to clinicians.

How certain is the evidence?
We pooled unadjusted effect estimates for overall survival (only nine studies offered relevant data) and progression-free survival (fourteen studies). Our concerns regarding the certainty of the evidence mainly lie with the methodology of the primary studies, particularly the reporting and presentation of the study results. Hence, we could not include all studies in meta-analysis and have very low to moderate certainty in the evidence.

For overall survival, we have moderate-certainty evidence that individuals with HL who have a negative interim PET scan result have better survival compared to those with a positive interim PET scan result.

For progression-free survival, we have very low certainty-evidence that individuals who have a negative interim PET scan result may have longer cancer free periods compared to those with a positive interim PET scan result. For this outcome, we also found some inconsistency as to how the outcome was defined as it is a composite outcome containing different endpoints.

We are not able to comment on PET-associated adverse events as no study measured nor reported these.

Are there different types of prognosis reviews?
This review is a systematic review of prognostic factor studies (type 2 below). However, there are four different types of studies on prognosis:

  1. Studies on overall prognosis (i.e. the likely outcome or course of a certain health condition)
  2. Prognostic factor studies (i.e. factors that are associated with a certain health outcome)
  3. Prognostic model studies (i.e. a combination/set of prognostic factors that together predict a certain health outcome)
  4. Stratified medicine research (i.e. using prognostic factors and models to guide the individual treatment path).

Reviews of studies on prognosis fit with the move towards new innovative review types, as the methodology behind the assessment of these studies as well as the pooling and summary of individual study results from studies on prognosis is still new and under development. An accurate and correct prognosis of health-related outcomes lies at the heart of each individual. Therefore, it is important to define and continuously refine the methodology of such reviews in order to be able to provide a good and thorough overview of the evidence on a specific research question related to prognosis.

Why was this topic considered to be high priority and therefore eligible for Cochrane’s Fast- Track initiative, and what was your experience of working with Cochrane Fast-Track?
This project was funded by the German Federal Ministry of Education and Research (01KG1709) as it answers a clinically relevant question that interim PET successfully distinguishes between individuals with a poor prognosis (interim PET-positive) and individuals with a good prognosis (interim PET-negative). This evidence can aid clinical decision-making on the treatment pathway of affected individuals with HL. The treatment pathway of an individual may be adapted based on their interim PET scan result in order to receive the treatment with the greatest efficacy and least toxicity possible. Furthermore, HL is a disease that is most common in young adults.

The evidence that this review provides may also be used in national and international clinical guidelines regarding the treatment pathways of individuals with HL. Further reasons as to why it was considered to be a high priority review and was therefore eligible for the Fast Track is because it is the first Cochrane prognostic factor review with meta-analysis in the Cochrane Library. It was developed through close collaboration with the Cochrane Prognosis Methods Group, as well as the GRADE Prognosis Working Group. The conduct of systematic reviews of prognosis studies is increasingly growing and with our review we try to contribute to the methodological developments and provide a guide for future authors of such reviews. Therefore, the author team applied to the Fast Track team due to the above mentioned reasons and the review met the eligibility criteria and was considered to be an important review for Cochrane. We had a very positive experience with the Cochrane Fast-Track team. We were guided and supported through each step of the editorial and publishing phase, and were continuously updated by the team regarding the status of our review. We received very thorough and detailed feedback from internal and external peer- reviewers who greatly helped in improving this review.

Photo credit: Uniklinik Köln

Wednesday, September 11, 2019