Benefit of PET in patients with malignant lymphoma remains unclear

The value of positron emission tomography (PET) alone or in combination with computer tomography (CT) in the diagnosis of malignant lymphoma (lymph node cancer) is the subject of an investigation by the Institute for Quality and Efficiency in Health Care (IQWiG).

In its final report, published on 29 May 2009, the Institute comes to the conclusion that more accurate findings could possibly be produced using PET compared to conventional diagnostic procedures. However, it remains unclear whether these findings also lead to improved treatment outcomes. For example, it has not yet been sufficiently investigated whether a negative PET result following primary treatment dispenses with the need for subsequent radiation therapy.

Increase in metabolic activity made visible by PET

Conventional imaging procedures normally collect information on the anatomical structure and location of healthy and modified tissue. In contrast, PET identifies tumours by their increased metabolic activity, because malignant tumour cells absorb more sugar. Using a weakly radioactive substance, the PET image indicates where increased metabolic processes are taking place in the body. However, these are not tumour-specific; for example, the glucose metabolic rate is also increased by inflammation. In PET/CT integration, a CT scan is taken at the same time as the PET. A software program then carries out image fusion by superimposing the different images from both procedures. Tumour localization is expected to improve through using CT.

Only consequences that are perceptible by the patient are considered a benefit

The aim of the investigation was threefold, namely, to establish:

1) whether the tumour stage could be determined with more reliability using PET or PET/CT than by using conventional diagnostic procedures ("staging”),
2) whether the lymphoma responds to the treatment and can ultimately be successfully treated, and
3) whether, in the case of justified suspicion, the disease has actually recurred.

An additional examination is only of medical value if it also leads to better treatment, so the priority was to investigate whether the potentially greater diagnostic accuracy of PET or PET/CT can also have a positive influence on the outcome of the lymphoma therapy. However, only those changes that have perceptible consequences for the patient were classed as a benefit, for example, lower mortality or frequency of relapse, a more tailored choice of therapy or greater quality of life.

Prospective comparative intervention trials with and without random allocation of participants to the groups (randomization) were included by IQWiG in its benefit assessment. However, only one trial was found that, moreover, only indirectly investigated the benefit of PET; this trial had few participants and was susceptible to bias due to inadequacies in the methodology.

Data on diagnostic accuracy is inconsistent and contradictory

If trials only investigate the diagnostic accuracy, no conclusions can be drawn concerning the benefit for patients - because a higher diagnostic accuracy does not automatically mean that the therapy choice can be better tailored to suit the patient, that there is an increase in quality of life or that the mortality rate will fall. These potential consequences have to be investigated separately.

However, because there was a scarcity of trials focussing on benefit, the Institute also considered the diagnostic accuracy. To assess this, results from HTA reports, systematic reviews and meta-analyses were analysed in addition to primary trials. Although there are more trials in this area, their validity proved to be severely limited. Firstly, the number of participants per trial was low and secondly, due to methodological problems, the clinical comparisons were planned and/or carried out in such a way that not only could bias not be ruled out, but it was even probable.

Negative PET result following primary therapy does not offer adequate certainty

The only trial that performed a comparative investigation on the benefit of PET concludes that a negative result in the PET does not permit a definitive statement on whether a tumour has actually disappeared (remission) following first-line therapy.

Patients who had a suspicious (residual) result in the CT (residual tissue) after chemotherapy but whose PET was normal were assigned randomly to two groups in this trial. One group received the usual additional radiotherapy, the other group did not. The result showed that recurrences were more frequent in the group not receiving radiotherapy, which then called into question the diagnostic "accuracy” of PET despite its alleged higher specificity.

IQWiG is interpreting this result with caution: the trial gives no indication that a normal PET finding, after therapy for a particular type of lymphoma (Hodgkin's disease), offers adequate certainty that the cancer has completely disappeared. However, the chemotherapy schedule used in the trial is not common, at least not in Germany. A similar research question is currently being tested in a large multi-centre trial in Germany (HD-18 Trial). The results are expected to provide important findings on the patient-relevant benefit of PET.

As far as the diagnostic accuracy is concerned, the final report comes to the conclusion that the role of PET in the initial determination of tumour staging and in the detection of recurrences is currently still unclear. There is a complete lack of trials on recurrence diagnostics. In primary staging, the results of the existing trials are susceptible to bias, plus there is no reference standard.

IQWiG calls for valid trials

With regard to the tumour response to the therapy, IQWiG comes to a different conclusion: the diagnostic and prognostic accuracy of PET appears to be higher than that of gallium scintigraphy and CT. However, it is unclear whether there is actually any benefit for the patients. It is therefore necessary to wait for the results from the ongoing randomized and non-randomized prospective trials investigating the benefit of PET in therapy response.

In IQWiG's view, additional controlled trials, which should ideally be randomized, are needed to clarify the benefit of PET or PET/CT for all research questions in the report. This refers particularly to the benefit for children, because, firstly, this patient group has been the least investigated to date and, secondly, they would benefit particularly from a toxicity-reduced therapy. Additional valid trials were called for by several persons during the hearing procedure on the preliminary report.

Report preparation procedure

IQWiG published the preliminary results in the form of the preliminary report in October 2008 and interested parties were invited to submit comments. When the comments stage ended, the preliminary report was revised and sent as a final report to the contracting agency, the Federal Joint Committee, at the end of March 2009. Documentation of the written comments and the minutes of the oral debate are published in a separate document simultaneously with the final report.

Contact: tel. 0221-35685-0, info@iqwig.de