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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.)
In patients in remission after treatment with curative intent for non-Hodgkin's lymphoma (NHL), the purpose of follow-up during the first 2-3 years is early detection of relapse for timely re-treatment to improve survival prospects. Follow-up visits usually include a review of symptoms, physical examination, full blood count and biochemical profile including serum LDH. Surveillance scans are performed routinely in some centres, in others this is done only as clinically directed (i.e. if relapse is suspected). With longer follow-up, the risk of relapse diminishes and the focus shifts to monitoring for late effects of treatment, and educating patients about individualised risks and, where appropriate, risk reduction strategies; some centres monitor late effects themselves, others discharge patients back to their general practitioners for follow-up.
The variation in follow-up practice in the UK reflects controversial views on the role and optimal frequency and duration of follow-up including the value of follow-up investigations per se, and the role of the specialised centre.
People with DLBCL in complete metabolic remission after treatment have an excellent prognosis with a low relapse rate and a 5-year overall survival rate of approximately 80%. Follow-up is routinely offered to this patient group. The optimal follow-up strategy has not been well defined. However, since most relapses occur in the first 2 years after treatment, most people are seen frequently during this period, typically 2-3 monthly, followed by 6-12 monthly visits for up to 5 years. Centres with an interest in late effects of treatment may offer longer follow-up. The nature of follow-up is variable and may include a history, physical examination, blood tests and routine surveillance scanning in the form of CT or PET-CT.
This topic addresses DLBCL as it is the most common subtype of curable high grade non-Hodgkin lymphoma.
Clinical question: In patients in remission after treatment with curative intent for non-Hodgkin's lymphoma, what are the optimal method(s), frequency and duration of follow-up?
Evidence came from a retrospective case series and a retrospective cohort study.
Very low quality evidence from one study with 106 patients (Hong et al, 2014) suggests that more relapses were detected during unplanned patient-initiated visits (11/33 visits) than during routine visits (4/823 visits) and the 3-year event-free and overall survival were 86.4% and 93.6%, respectively.
Very low quality evidence from one study of 162 patients (Hiniker et al, 2015) reported 5-year freedom from progression and overall survival rates = 80.8% and 81.2%, respectively. 18 patients ultimately experienced relapse. No relapses were detected by surveillance LDH. Similar time from treatment initiation to relapse for patients with relapses suspected by imaging and clinically. Similar survival from the date of relapse or of initial therapy between patients whose relapse was suspected by imaging or clinically.
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 | For people in complete remission after first-line treatment with curative intent for diffuse large B-cell lymphoma:
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| Relative value placed on the outcomes considered | The GC considered detection of recurrence to be the critical outcome when drafting the recommendations because early detection is likely to be associated with a better outcome as a result of the treatment options available for fitter patients. Other important outcomes included overall survival, disease progression, disease-specific survival, test related complications, health-related quality of life, patient experience, patient preference, number of scans. Disease-specific survival, test related complications, health-related quality of life, patient experience and patient preference were not reported in the evidence. |
| Quality of the evidence | The quality of the evidence, assessed using GRADE methodology was very low for all reported outcomes. This was because of the observational, non-comparative design of the studies and imprecision. This meant that the GC treated the evidence with caution and used their clinical expertise alongside the evidence to make the recommendations. |
| Trade off between clinical benefits and harms | The GC noted that most relapses of diffuse large B-cell lymphoma (DLBCL) will occur within the first 2-3 years following the end of first-line treatment and so recommended routine follow up during this time. The GC recognised that patients may experience symptoms suspicious of recurrence between routine appointments. The evidence indicated that over 70% of relapses were detected during unplanned (patient intiated) visits rather than routine appointments. In addition, not all relapses will occur during the first 2-3 years and patients may experience a recurrence of lymphoma symptoms or new symptoms suspicious for disease relapse outside of this time period. For this reason the GC recommended urgent appointments for people who experience a recurrence of lymphoma symptoms or new symptoms suspicious for disease relapse. The GC recommended that LDH surveillance for disease relapse should not be undertaken because the evidence suggests low sensitivity and specificity and is unreliable when performed in isolation (no relapses were detected by surveillance LDH in the one study that examined it). The GC recommended that routine surveillance imaging in asymptomatic patients for disease relapse should not be undertaken because chest X-ray, CT and PET-CT detect very few relapses in asymptomatic patients and carry a risk of false positive results leading to unnecessary investigations. In the single relevant study PET-CT and CT identified asymptomatic relapse in 1% and 0.5% of follow-up imaging tests respectively. False positives occurred at a rate of 14% and 2% respectively in follow-up PET-CT and CT tests. It was GC consensus, in the absence of evidence, that chest X-ray, CT and PET-CT pose additional risks including radiation exposure and increased patient anxiety The GC noted that a potential harm of the recommendations is that asymptomatic patients whose relapse would be detected by routine imaging will experience a delay in the detection of their relapse and initiation of therapy, although this will not affect prognosis for the vast majority of patients. The GC also noted that by the time a relapse can be reliably detected in asymptomatic patients, it will only be a matter of a few weeks before the relapse will be detected clinically, and this short delay is unlikely to have an impact on treatment options and efficacy. The GC also considered that this delay, which would only affect a low number of patients, is far outweighed by the benefits of not being exposed to radiation by routine imaging in a much larger number 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. The GC estimated that the recommendations will result in a decrease in costs due to removing LDH testing, fewer routine scans being performed and fewer follow up appointments being undertaken. These reductions in the intensity of follow-up were not anticipated to have any negatve consequences on effectiveness. As stated above, any delay in detection is likely to be short and would be unlikely to have any impact on treatment options or efficacy. Therefore, the recommendations are likely to reduce costs without changing effectiveness and are therefore likely to be cost-effective. |
| Other considerations | In some centres that routinely do surveillance scanning and LDH testing, there will be a cost saving change in practice. |
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