An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
National Guideline Alliance (UK). Non-Hodgkin's Lymphoma: Diagnosis and Management. London: National Institute for Health and Care Excellence (NICE); 2016 Jul. (NICE Guideline, No. 52.)
The observation that many lymphomas are fluorodeoxyglucose (FDG)-avid has led to significant interest in the technique of FDG-PET scanning being applied to stage patients with lymphoma. Functional imaging with this technique has the potential to identify disease sites even when there is minimal or no anatomical distortion of tissues. Stage is an important factor in many prognostic indices and may affect treatment decisions, so an accurate assessment of stage is an important aspect of patient care.
Pre-treatment staging defines disease extent enabling appropriate therapy. The Ann Arbor staging system was originally developed to define patients who may be candidates for radiation therapy from those who would benefit from systemic treatment. Originally relying on physical examination and bone marrow assessment, the system has evolved over the last 40 years to include anatomical computed tomography (CT), which is currently routinely used for baseline staging in lymphoma. CT relies on lesion size however, and numerous studies demonstrate that metabolic imaging with positron emission tomography (PET-CT) is more accurate than CT for detecting sites of disease involvement in a number of lymphoma histological subtypes. Discordance between PET-CT and CT occurs in a proportion of patients at staging, predominantly in favour of PET-CT (with more lesions being detected); however, in most patients stage is not usually changed and treatment is altered in an even smaller proportion. There is currently no evidence for a change in patient outcome as a result of staging PET-CT data. It should be noted that PET only scanners are no longer manufactured and all radiology departments in the UK now use PET-CT.
Most lymphomas are 18F-Fluorodeoxyglucose (FDG) avid, including high grade aggressive disease such as diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma and aggressive T-cell lymphomas, as well as some low grade lymphomas such as follicular lymphoma (FL). Mantle cell lymphoma (MCL) and mucosal associated lymphoid tissue (MALT) lymphoma demonstrate more variable levels of FDG uptake with false negative PET findings in various anatomical sites (e.g. diffuse gastrointestinal tract infiltration). PET-FDG is not reliable for differentiating FL from high grade lymphoma, because FL also demonstrates high PET FDG activity levels.
Clinical question: What is the staging value of pre-treatment functional imaging with PET-CT compared with other initial assessments for people with different subtypes of non-Hodgkin's lymphoma?
The evidence included 27 cross-sectional studies (21 using retrospectively collected data) of FDG-PET-CT for staging and 16 cohort studies (seven prospective) reporting the use of both pre and post treatment FDG-PET-CT.
Moderate quality evidence from 14 studies including 1737 patients suggests FDG-PET-CT has a sensitivity of 79.5% (95% CI 69.8% to 86.6%) and a specificity of 96% (95%CI 93.1% to 97.7%) for the detection of bone marrow involvement in patients with newly diagnosed DLBCL. If prevalence of BMI is assumed to be 15% then FDG-PET-CT has a positive predictive value of 80% and a negative predictive value of 96% for bone marrow involvement.
Moderate quality evidence from 12 studies including 1603 patients suggests bone marrow biopsy of the iliac crest has a sensitivity of 55.8% (95%CI 43.2% to 67.7%) and a specificity of 100% for the detection of bone marrow involvement in patients with newly diagnosed DLBCL. If prevalence of BMI is assumed to be 15% then bone marrow biopsy has a positive predictive value of 100% and a negative predictive value of 92% for bone marrow involvement.
Three studies including 289 patients (Morimoto et al 2008; Pinilla et al 2010; Papajik et al 2010) provided low quality evidence on the sensitivity and specificity of FDG-PET-CT for the detection of lymph node involvement in NHL. One study (Morimoto et al, 2008; n=66), limited to retroperitoneal and pelvic lymph nodes, reported FDG-PET-CT sensitivity ranging from 75% to 100% (PPV 60% to 98%) and specificity from 81% to 92% (NPV 71% to 100%), depending on the location of the lymph node. Pinilla et al (2010) and Papajik et al (2010) reported FDG-PET-CT diagnostic accuracy for any lymph nodal involvement, sensitivity ranged from 97% to 100% with specificity 94% to 96%.
Two studies including 223 patients (Papajik et al 2011; Pinilla et al 2010) provided low quality evidence on the sensitivity and specificity of FDG-PET-CT for the detection of extranodal organ involvement in NHL. The sensitivity ranged from 94% to 96% and specificity from 81% to 92%, but insufficient detail was provided to calculate predictive values.
FDG-PET-CT changed the allocated stage of patients with localised follicular lymphoma to stage III/IV in most cases. 5/10 (50%) of patients with stage I-II follicular lymphoma in Le Dortz et al (2010) were upstaged to stage III or IV and 15/24 (63%) in Luminari et al (2013). Although the impact of this change on treatment was not reported it could have implications for the use of limited-field radiotherapy in this population.
Staging with FDG-PET-CT increased the number of patients with stage IV DLBCL by as much as 25% when compared to staging using bone marrow biopsy (Khan et al 2013; Pelosi et al 2010) but it was not reported whether treatment was also changed.
Raanani et al (2005) reported that compared to CT-scan stage, disease was upstaged by FDG-PET-CT in 31% and down staged in 1% in a cohort of 68 patients with NHL. The suggested treatment strategy (based on CT scan) was changed following FDG-PET-CT in 17/68 patients (25%). Papajik et al (2011) reported that treatment strategy (based on CT-scan stage) was changed following FDG-PET-CT in 3/122 patients (2%).
Use of pretreatment FDG-PET-CT to evaluate end of treatment response Sixteen studies observational did baseline FDG-PET-CT as well as interim or end of treatment FDG-PET-CT. Although some used baseline FDG-PET-CT to evaluate the quality of interim treatment response, none reported the use of baseline FDG-PET-CT in evaluating end of treatment response
A literature review of published cost-effectiveness analyses did not identify any relevant papers for this topic. Whilst there were potential cost implications of making recommendations in this area, other questions in the guideline were agreed as higher priorities for economic evaluation. Consequently no further economic modelling was undertaken for this question.
| Recommendations | Offer FDG-PET-CT imaging to confirm staging for people diagnosed with:
|
|---|---|
| Relative value placed on the outcomes considered | Treatment change was the outcome of most importance for this topic due to its potential impact on patient outcome. Other important outcomes included diagnostic accuracy, test-related morbidity, health-related quality of life, bone marrow involvement and upstaging/down-staging. No evidence was identified about test related morbidity or health related quality of life. |
| Quality of the evidence | The quality of evidence was low as assessed using QUADAS-2. The main source of bias was that the reference standards used in the individual studies usually included the index tests. For example focal bone marrow involvement seen on FDG-PET-CT would often be classified as true positive in the absence of other confirmatory tests. The GC decision to recommend the use of FDG-PET-CT to confirm staging in patients with stage I diffuse large B-cell lymphoma by clinical and CT criteria, stage I/II follicular lymphoma or early stage Burkitt lymphoma, was based on the evidence. However due to the low quality of the evidence, the GC were not confident in the evidence suggesting superior sensitivity of FDG-PET-CT and chose not to offer routine staging in all patients in NHL but to consider this where the results would change management. |
| Trade off between clinical benefits and harms | The GC thought the recommendations would result in fewer patients with false positive results on staging which could lead to unnecessary treatment or further tests. The GC made different recommendations for subtypes and stages of NHL based on their consensus about the impact of FDG-PET-CT staging on the management of patients in these subgroups. The GC thought that while FDG-PET-CT could improve the accuracy of staging in general, it would be particularly useful for staging I/II follicular lymphoma and early stage Burkitt lymphoma due to the impact it would have on therapy. As a result of the recommendations such patients will receive more appropriate treatment (for example localised radiotherapy). The evidence indicated that patients with apparently localised follicular lymphoma were often upstaged to stage III or IV following FDG-PET-CT. There was little published evidence that a baseline FDG-PET-CT contributed to the interpretation of the end of treatment FDG-PET-CT for people with NHL or influences management decisions. For this reason the GC made a research recommendation. The GC also acknowleded the body of clinical opinion and international guidelines that baseline FDG-PET-CT has a role for end of treatment FDG-PET-CT response assessment and in dectecting extradnodal sites during staging. The GC therefore made a recommendation to consider FDG-PET-CT to confirm staging if the results would alter managemement. The potential harms considered by the GC were the side-effects of addtional scans, and this was therefore reflected in the recommendation to consider FDG-PET-CT only where it could change the management decision. The GC thought that the ability to make more appropriate management decisions outweighed the harms which would be experienced by a small proportion of patients |
| Trade off between net health benefits and resource use | No health economic evidence was identified and no health economic model was built for this topic. Overall, the GC estimated that there should be no change in the number of FDG- PET-CT scans performed as the recommendations reinforce clinical practice. In cost-effectiveness terms, the GC thought that the high cost of FDG PET-CT scans (relative to other investigations) was justified by the more appropriate management decisions that could be made based on improved staging accuracy. The GC expected that there would be QALY gains and cost offsets associated with making better management decisions. For example, upstaging a patient to a more intensive treatment following a FDG PET-CT scan should lead to improved clinical outcomes (PFS, OS) and could reduce the number of treatment lines that a patient requires. The GC thought that such QALY gains and cost offsets should be substantial enough to make the use of FDG PET-CT cost-effective in cost per QALY terms. |
| Other considerations | The GC did not make recommendations on CT as it is a routine and established test used in UK haematology and lymphoma units for staging and for assessment of interim and end of treatment response. The GC noted, however, that the use of FDG-PET-CT in this context is variable across the UK and made the recommendations due to the need for guidance on the use of FDG-PET-CT for staging, interim response assessment and end of treatment response. |
| Research Recommendation | In people with diffuse large B-cell lymphoma stage II or above, does a baseline FDG-PET-CT scan have any advantages over a baseline CT scan in the correct interpretation of the end-of-treatment FDG-PET-CT scan? |
| Why is this important | A number of consensus-based guidelines and a body of clinical opinion advocate baseline FDG-PET-CT imaging as being important for interpreting end-of-treatment response using FDG-PET-CT, although there is little published evidence for this. Baseline FDG-PET-CT is also considered to have an important contribution ‘over and above’ that of contrast-enhanced diagnostic CT in assigning the International Prognostic Index (IPI), in terms of identifying disease stage and number of extranodal sites involved (influencing the decision to offer central nervous system prophylaxis). A prospective trial is needed to determine whether baseline FDG-PET-CT is needed to interpret end-of-treatment FDG-PET-CT and its role in assigning IPI. People with newly histologically diagnosed diffuse large B-cell lymphoma would have baseline contrast-enhanced CT, baseline FDG-PET-CT and end-of-treatment FDG-PET-CT imaging. Readers would need to be trained in both imaging techniques and be experienced members of lymphoma multidisciplinary teams. The reference standard would be histological confirmation of any positive or equivocal end-of-treatment FDG-PET-CT findings, or follow-up if there is a negative end-of-treatment scan. |
Only a proportion of patients with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) are cured with a rituximab-CHOP-like regimen. A prolonged progression free survival (PFS) is achieved only in a proportion of treatment resistant or relapsed patients following salvage therapy (high-dose therapy followed by autologous stem cell transplantation). A tool able to reliably predict an unfavourable outcome early in the management of these patients may lead to risk-adapted change in therapy.
Anatomical Computed Tomography (CT) is conventionally used for interim response evaluation, assessing changes in lesion size. Tumour volume reduction may require time, with metabolic changes on Positron Emission Tomography (PET-CT) preceding anatomical volume changes. In DLBCL rapid reduction in FDG (Fluorodeoxyglucose) uptake during chemotherapy with a negative interim PET-CT scan seems to predict a favourable outcome. In the rituximab era, the positive predictive value (the ability of a positive PET scan to predict persistent disease or future relapse) is limited due to false positive uptake.
The current evidence base in this area is largely limited to DLBCL, as there was very limited evidence or current clinical application in other NHL subtypes.
Clinical question: What is the prognostic value of an interim assessment using functional imaging with PET-CT during the treatment of diffuse large B-cell non-Hodgkin's lymphoma?
Moderate quality evidence came from seventeen cohort studies including 2326 patients compared survival outcomes according to FDG-PET-CT scan during RCHOP or RCHOP-like chemotherapy for DLBCL. The interim FDG-PET-CT was typically done following cycle 2 and across studies the mean proportion with a positive interim FDG-PET-CT scan was 35% (range 20% to 60%). Survival outcomes were consistently poorer in those with positive interim FDG-PET-CT. Progression free survival at three years was between 18% and 78% (median 32%) lower in patients with positive interim FDG-PET-CT. Overall survival at three years was between 0% and 48% (median 26%) lower and event free survival between 22% and 59% (median 41%) lower in those with positive interim FDG-PET-CT.
In multivariate analysis (taking other prognostic variables such as IPI and its components and post treatment FDG-PET-CT into account) interim FDG-PET-CT (negative versus positive) was not always an independent prognostic factor for outcome. In four studies reporting multivariate analyses of overall survival in patients with DLBCL (Cox et al 2012, Lanic et al 2011, Mamot et al 2015 and Mylam 2014), interim FDG-PET-CT (negative versus positive) was a significant independent prognostic factor for survival in all studies except for Mamot et al (2015).
There was uncertainty about the usefulness of interim FDG-PET-CT as an independent predictor of progression free survival (Cox et al, 2012; Lanic et al, 2011; Mylam et al, 2014, Pregno et al 2012) and event free survival (Carr et al, 2012; Mamot et al 2015 and Gonzalez-Barca et al 2013) when other prognostic variables such as interim CT and post-treatment FDG-PET-CT are taken into account.
A literature review of published cost-effectiveness analyses did not identify any relevant papers for this topic. Whilst there were potential cost implications of making recommendations in this area, other questions in the guideline were agreed as higher priorities for economic evaluation. Consequently no further economic modelling was undertaken for this question.
| Recommendation | Do not routinely offer FDG-PET-CT imaging for interim assessment during treatment for diffuse large B-cell lymphoma. |
|---|---|
| Relative value placed on the outcomes considered | The GC considered progression free survival (PFS) and treatment change the critical outcomes in drafting this recommendation. |
| Quality of the evidence | The quality of the evidence was moderate as assessed using NICE checklists for prognostic studies. This was because some studies had not controlled for the effect of potential confounders when looking at the prognostic utility of interim FDG-PET-CT. |
| Trade off between clinical benefits and harms | The evidence concerned the prognostic utility of interim FDG-PET-CT rather than its direct impact on patient outcomes. Although the evidence showed that interim FDG-PET-CT results did predict survival, a number of studies showed that the end-of-treatment scan was a better predictor (see following section) and that some patients with positive iterim scans would have negative end-of treatment scans. It was the consensus of the GC that the recommendation would stop inappropriate therapy changes and reduce radiation exposure and discomfort from FDG-PET-CT. No harms associated with the recommendation were identified. The GC thought that patients who would benefit from more intensive treatment would be identified on their post-treatment FDG-PET-CT scan. |
| Trade off between net health benefits and resource use | No health economic evidence was identified for this topic and no health economic model was built. The GC estimated that, as a result of this recommendation, there should be fewer FDG-PET-CT scans. Fewer patients would require intensification in therapy, because some patients with positive interim FDG-PET-CT scans have negative post-treatment scans. |
| Other considerations | The GC thought the recommendations would generate a moderate change in practice because although some centres will need to stop interim FDG-PET-CT scanning, most centres have already stopped. The GC acknowledged that interim FDG-PET-CT may be useful in a small number of patients to investigate clinical concerns. For this reason the recommendation was worded in such a way as to allow interim scans such patients. |
Achieving complete remission after first-line systemic therapy is important in high-grade non-Hodgkin lymphoma (NHL) patients, as this usually leads to a longer progression-free survival (PFS), whereas incomplete response is usually associated with poorer patient outcomes. Computed Tomography (CT) is usually used for response assessment in patients at treatment completion. However, in the common situation of a mass remaining at the end of treatment, anatomical CT imaging cannot accurately discriminate residual active lymphoma from either necrosis or fibrosis. Defining the true nature of the residual mass is important, enabling consolidation treatment in patients with remaining active disease, and avoiding unnecessary further therapy or treatment related morbidity in patients in complete remission. The positive predictive value (PPV) of CT (the ability of a positive CT scan to predict persistent disease or future relapse) is low.
In contrast, functional imaging using Positron Emission Tomography (FDG-PET-CT) provides metabolic information and is more accurate than anatomical CT alone in this setting, due to its superiority to CT at distinguishing viable remaining lymphoma from fibrosis in residual mass (es). In general, the negative predictive value (NPV) of PET (the ability of a negative PET scan to exclude persistent disease or future relapse) across studies including high-grade NHL such as diffuse large B-cell NHL is high. The false-negative rate with FDG-PET is mostly related to its inability to detect microscopic disease which results in future relapse. The PPV of FDG-PET-CT in high-grade NHL is lower and more variable, however superior to CT. The lower PPV is due to the non-specific nature of the PET tracer 18F-Fluorodeoxyglucose (FDG), taken up in tissues affected by inflammation, which can occur due to immunochemotherapy.
Clinical question: What is the prognostic value of functional imaging with PET-CT performed after the various types of treatment for non-Hodgkin's lymphoma are completed?
Moderate quality evidence about the post treatment FDG-PET-CT scan results and outcomes came from ten retrospective cohort studies including 915 patients. Five concerned DLBCL (Abo-Sheisha et al 2014; Mylam et al 2014; Gonzalez-Barca et al 2013; Pregno et al 2012; Cashen et al, 2011) , three follicular lymphoma (Trotman et al, 2014; Tychyj-Pinel, 2014; Le Dortz et al, 2010) and one each mantle cell (Mato, 2012) and primary mediastinal B-cell lymphoma (Martelli et al, 2014).
The usefulness of post treatment FDG-PET-CT as a predictor of outcome was examined in multivariate analyses of survival (Cox et al, 2012; Mylam et al, 2014 and Mato et al 2012), progression free survival (Cox et al, 2012; Mylam et al, 2014, Pregno et al 2012 and Mato et al 2012) and event free survival (Carr et al, 2012 and Gonzalez-Barca et al 2013). In all of the DLBCL studies (Carr et al, 2012; Cox et al, 2012; Gonzalez-Barca et al 2013; Pregno et al 2012 and Mylam et al, 2014) post-treatment FDG-PET-CT was an independent prognostic factor for each outcome survival examined. In Mato et al (2012) post-treatment FDG-PET-CT was an independent prognostic factor for progression-free survival but not for overall survival in patients with Mantle cell lymphoma.
Evidence from two retrospective studies including 167 patients (The PRIMA study [Trotman et al, 2010 and Tychyj-Pinel et al, 2014] and Le Dortz et al, 2010) suggests that FDG-PET-CT post-induction therapy predicts progression free survival and overall survival in patients with follicular lymphoma. Patients with positive FDG-PET-CT (interpreted by local physicians) following induction therapy had progression free survival of 33% at 3.5 years compared with 71% for those with negative FDG-PET-CT (Trotman et al 2010). Overall survival at 3.5 years was 79% versus 97% for patients with positive versus negative post-induction FDG-PET-CT respectively (Trotman et al 2010). Subsequent analysis of the PRIMA FDG-PET-CT data by Tychyj-Pinel et al (2014) suggests that the difference is less clear when FDG-PET-CT scans are reviewed centrally using standardised criteria – 3 year progression free survival was 41% versus 59% for FDG-PET-CT positive and negative patients in this analysis (HR 1.9 [95% C.I. 0.8 to 4.6]).
A literature review of published cost-effectiveness analyses did not identify any relevant papers for this topic. Whilst there were potential cost implications of making recommendations in this area, other questions in the guideline were agreed as higher priorities for economic evaluation. Consequently no further economic modelling was undertaken for this question.
| Recommendations | Offer FDG-PET-CT imaging to assess response at completion of planned treatment for people with:
Consider FDG-PET-CT imaging to assess response to treatment before autologous stem cell transplantation for people with high-grade non-Hodgkin's lymphoma. |
|---|---|
| Relative value placed on the outcomes considered | The GC considered progression free survival (PFS) and treatment management change to be the critical outcomes for this topic. Health related quality of life (HRQL) was also considered though no evidence was identified |
| Quality of the evidence | The quality of the evidence was moderate as assessed using NICE checklists for prognostic studies. This was because some studies had not controlled for the effect of potential confounders when looking at the prognostic utility of end-of-treatment FDG-PET-CT. |
| Trade off between clinical benefits and harms | The GC considered the benefit of the recommendations to be the accurate identification of patients who may require closer follow-up or more intensive treatment leading to improved survival outcomes. Similarly those not requiring more intensive treatment would avoid the harms of over-treatment. The GC made recommendations according to subtype of NHL based on their consensus about the impact of FDG-PET-CT staging on the management of these patients. Their consensus view was that FDG-PET-CT at the completion of planned treatment would usually inform further treatment decisions for patients with DLBCL or Burkitt lymphoma but was not routinely useful for those with follicular lymphoma, mantle cell lymphoma or MALT lymphoma. The GC noted that residual masses are sometimes observed on completion of treatment CT scans in some patients with DLBCL or Burkitt lymphoma. It is not possible on CT alone to assess whether these masses are inactive treated tissue (fibrotic residua) or whether active lymphoma is still present. The ability of FDG-PET-CT to visualise metabolic activity in patients with active DLBCL or Burkitt lymphoma means it is useful in differentiating fibrotic residua from remaining active disease. It was the GC consensus that offering patients with remaining active disease further radiotherapy or systemic treatment should improve their outcome, whereas those who are FDG-PET-CT negative can be spared such potentially toxic treatment. Although evidence suggested that post-induction FDG-PET-CT is predictive of outcome in patients with follicular lymphoma the GC decided to recommend that FDG-PET-CT should not be rountinely offered to this group of patients unless the results will alter management. The GC considered the initial results of the PRIMA study (which this evidence was based on), were biased due to its retrospective nature and the reliance on the local physician's interpretation of the nuclear medicine report. The GC noted there is uncertainty about whether additional treatment should be given according to results of post-induction FDG-PET-CT with ongoing trials in this area. The GC thought that much of this patient group would have bone marrow infiltration by follicular lymphoma (stage IV disease) and questioned the specificity of FDG-PET-CT for the detection of bone marrow disease. Currently standard staging and response assessment in this patient group comprises CT, bone marrow aspirate and trephine biopsy and the GC agreed there was insufficient evidence to suggest that FDG-PET-CT would be of additional benefit to this standard workup. The GC acknowledged that there could be increased radiation exposure for patients. There is also the potential for false positive results which may lead to over-treatment in some patients as well as anxiety. Further diagnostic tests may also be needed to investigate a positive FDG-PET-CT. The GC considered that although there was a risk of over-treatment in patients who have a false positive result, this would affect a minority of patients and this risk was outweighed by the fact that FDG-PET-CT assessment would lead to an overall increase in the number of patients treated appropriately. |
| Trade off between net health benefits and resource use | No health economic evidence was identified and no health economic model was built for this topic. The GC considered that, overall there would be an increase in the number of FDG-PET-CT scans as a result of these recommendations. However, while this would increase upfront costs, there are potential cost savings downstream associated with a reduction in over- and under-treatment. Overall it was thought that the recommendations would most likely lead to a net cost increase. However, it was expected that the additional costs would be justified by the effectiveness improvements expected with more appropriate treatment decisions. Thus, the recommendations were considered likely to be cost-effective in cost per QALY terms. |
| Other considerations | The GC considered the recommendations would lead to a moderate change in practice as current practice is variable so many centres will need to start doing end of treatment FDG-PET-CT scans. |
All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Your browsing activity is empty.
Activity recording is turned off.
See more...
