Routine blood investigations have limited utility in surveillance of ...

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Methods
We conducted a multi-centre retrospective analysis of all patients
diagnosed with aggressive lymphoma treated with curative-intent chemotherapy who
achieved CR for at least 3 months between 2000 and 2015. An abnormal blood test
was defined as any new and unexplained abnormality for full blood examination,
lactate dehydrogenase or erythrocyte sedimentation rate.
Results
Three hundred and forty-six patients attended a total of 3084
outpatient visits; blood tests were performed at 90% of these appointments.
Fifty-six (16%) patients relapsed. Routine laboratory testing detected relapse in
only three patients (5% of relapses); in the remaining patients, relapse was
suspected clinically (80%) or detected by imaging (15%). The sensitivity of all
blood tests was 42% and the positive predictive value was 9%. No significant
difference in survival was shown in patients who underwent a routine blood test
within 3 months prior to relapse versus those who did not (p = 0.88).
Conclusions
Routine blood tests demonstrate unacceptably poor performance
characteristics, have no impact on survival and thus have limited value in the
detection of relapse in routine surveillance.
Subject terms: Hodgkin lymphoma, Non-hodgkin lymphoma, Lymphoma
Introduction
While the majority of patients with aggressive lymphomas achieve
complete remission (CR) with anthracycline-based combination chemotherapy, up to 50%
of patients will relapse.1–3 As a significant proportion of patients who relapse
are considered for salvage chemotherapy and curative-intent autologous stem cell
transplant, surveillance after first-line therapy is
recommended.4
In patients achieving CR, the optimal frequency, duration and type of
surveillance are not established. As follow-up imaging is associated with increased
radiation-related risk and minimal benefit in asymptomatic patients, such
surveillance is no longer routine.5–7 Regular laboratory testing (Labs)
still features in internationally recognised surveillance guidelines, despite
limited evidence for their use in detecting relapse.7–10 Studies conducted prior to
modern treatment response assessments and routine rituximab administration suggested
that lactate dehydrogenase (LDH) and erythrocyte sedimentation rate (ESR) may be
useful as surveillance tools, and that, more recently, the absolute lymphocyte count
(ALC) and lymphocyte–monocyte ratio (LMR) have shown promise in small
series.11–13
However, large-scale data are lacking, particularly in the era of positron emission
tomography (PET)-defined complete metabolic response (CMR).
Clinically significant scan-related anxiety has been established in
both lymphoma and solid malignancies14,15;
this is reported in up to 80% of patients and does not abate over time. It is likely
that blood tests have similar consequences. In addition, routine laboratory
investigations have cost implications and are potentially falsely reassuring if
normal. Abnormal results are also associated with the potential for expensive,
unnecessary additional investigations.
To evaluate the role of routine blood testing in follow-up of patients
with aggressive lymphoma, we analysed the use of blood tests in patients with
high-grade lymphomas undergoing surveillance after achieving CMR from
curative-intent combination chemotherapy at three large Australian cancer centres.
In particular, we examined the utility of routine tests for the detection of relapse
in the absence of clinical symptoms or signs, and whether performing such tests was
associated with significant differences in post-relapse survival.
Methods
Patients
Patients were identified from an electronic database at three
institutions. Eligible patients were aged 16 years or older, with a documented
histological diagnosis of diffuse large B cell lymphoma (DLBCL), Hodgkin's
lymphoma (HL), T cell lymphoma (TCL) or Burkitt lymphoma (BL) who received
curative-intent first-line treatment and in documented CR on PET/CT for at least 3
months after completion of therapy. Those with primary progressive lymphoma, in
partial remission (PR) at the end of first-line treatment, primary central nervous
system lymphoma, HIV-associated lymphoma and transformation from indolent subtypes
were excluded from the analysis.
All information was obtained from electronic patient records. Data
were collected on gender, age, disease stage, comorbidities, presence of B
symptoms, Eastern Cooperative Oncology Group performance status, extranodal sites
of disease, prognostic score and first-line chemotherapy treatment. Details of
each outpatient appointment were recorded, including pathology results, presence
of relevant symptoms and/or clinical signs (the absence of both was deemed
‘asymptomatic’), whether the visit was scheduled or unplanned, and outcomes
including routine subsequent visit, earlier planned review and results of
additional investigations ordered. Relapse date, site and method of diagnosis, any
further treatment and date of death or last follow-up were also documented.
Patient follow-up at all three institutions was according to
institutional guidelines as follows: 3-monthly for the first 2 years after
completion of therapy, and then every 6 to 12 months for the following 3 years for
at least 5 years in total. Blood tests were recommended but performed at the
treating physician’s discretion. Imaging was also performed according to
the treating physician’s discretion but removed from the institutional guidelines
in 2014.
Statistical analysis
The primary endpoints of the study were to assess whether full
blood examination (FBE: haemoglobin, white cell count and platelet count), LDH,
ESR, ALC, absolute monocyte count (AMC) and LMR during follow-up are reliable
markers to predict relapse. Secondary endpoints include methods of relapse
detection, event-free survival (EFS) and overall survival (OS). EFS was defined as
the period from the date of diagnosis until relapse, disease progression or death
from any cause. OS was measured from the date of diagnosis until death from any
cause.
Laboratory results were considered abnormal if all of the following
were fulfilled: (a) any component of FBE, LDH or ESR fell outside local laboratory
normal limits, (b) the derangement was not present previously and (c) could not be
explained by a concurrent medical condition. Abnormal laboratory results were
investigated at clinician discretion. Laboratory results were evaluated based on
their independent ability to detect relapse within 3 months of confirmation.
Sensitivity, specificity, negative predictive value (NPV) and positive predictive
value (PPV) were derived from 2 × 2 contingency tables and 95% confidence
intervals (CIs) were determined exactly.
In addition, receiver operating characteristics (ROC) and area
under the curve (AUC) analysis were undertaken to determine the utility of ALC,
AMC and LMR as a marker for relapse. AMC and ALC were evaluated as continuous
variables, and LMR was calculated by dividing the ALC by the AMC. Survival
analysis was performed using the Kaplan–Meier method and compared by the log-rank
test between different groups. All values were two-sided and statistical
significance was accepted at p < 0.05. The
study was approved by the local institutional review boards (LR117/2015).
Results
Between January 2000 and January 2015, 346 eligible patients
underwent 3048 outpatient visits. The median follow-up from CR1 was 30 months (range
3–184). Baseline demographics are detailed in Table 1. Laboratory investigations were performed at 2746 visits (90%),
with FBE being the most common test ordered (Table 2). LDH was predominantly performed in non-Hodgkin's lymphoma (NHL)
and ESR in HL.
Relapse of lymphoma occurred in 56/346 (16%) patients (33 DLBCL, 19
HL, 4 other). The median age at relapse was 64.3 years (range 18–91), and 51% were
over 60 years of age. Forty-three out of 56 (77%) had advanced stage disease and
18/56 (32%) were at high risk (as defined in Table 1). Only one patient (high-risk HL) received an abbreviated
chemotherapy course; the remaining 45 patients received a full course of standard
treatment. The median duration from treatment completion until relapse was 14 months
(range 3–84 months), with 48% of relapses occurring in the first year, 31% in the
second year and the remainder (21%) occurring up to 7 years after the end of
treatment.
Relapse was diagnosed by routine laboratory investigations in 3/56
(5%) and routine imaging in 10/56 (18%) patients. Clinical symptoms/signs lead to
diagnosis of relapse in 43/56 (80%; 40 with symptoms, 3 with signs only); 19 of
which were detected at unscheduled visits. Unscheduled appointments due to
patient-reported symptoms (3% of all visits) showed a significantly stronger
association with relapse than scheduled visits (odds ratio 50.4, p < 0.001).
Abnormal laboratory results were recorded at 404/3048 follow-up
visits: 304 in asymptomatic and 100 in symptomatic patients.
Asymptomatic patients
An unexplained abnormal result prompted a change in management at
46/304 (15%) visits in asymptomatic patients: 19/46 (41%) had repeat interval
laboratory investigations only, 13/46 (28%) underwent additional imaging, 10/46
(22%) were booked for an earlier future review with repeat labs and 4/46 (9%) had
biopsies in addition to imaging. The specific laboratory abnormalities and
associated changes in management in asymptomatic patients at scheduled
appointments are described in Table 3.
Almost all elevations in LDH and ESR were <2 times the upper limit of normal
(ULN), and leukopaenia was the most common FBE abnormality (12/29; 41%) resulting
in change in management.
aIncluding cases where relapse was
diagnosed only after symptoms developed
Relapse was diagnosed by 3/304 (1%) abnormal results in
asymptomatic patients; one TCL with neutropaenia and thrombocytopaenia, and two HL
patients; one with elevated LDH and one with elevated ESR. No relapses in NHL were
diagnosed on the basis of an abnormal LDH alone.
In five additional patients, relapse was detected within 3 months
of an abnormal result; however, in these cases, suspicion of relapse arose only
after the patient developed symptoms. The abnormalities were: lymphopaenia,
elevated LDH and both elevated LDH and abnormal FBE in three patients.
Symptomatic patients
In contrast, 67/100 (67%) of symptomatic patients with an abnormal
result underwent a change in their management. The most common changes were
further imaging (n = 35; 52%) and imaging with
biopsy (n = 17; 25%), followed by earlier
future review and labs (n = 7; 10%) and repeat
interval laboratory investigations only (n = 8;12%).
The sensitivity, specificity, PPV and NPV of all routine lab tests
(FBE, LDH and ESR combined) in detecting relapse was 42%, 87%, 9% and 98%,
respectively. Performance characteristics of individual lab tests are detailed in
Table 4. The PPV of LDH remained the
same even in the subset of 115 NHL patients with elevated baseline LDH (8%,
confidence interval (CI), 5–12). In the 43 HL patients with an elevated baseline
ESR, the PPV of ESR was even lower (6.5%, CI, 2–17).
ROC and AUC analysis showed that ALC, AMC and LMR at each
appointment (n = 2660) were all very poor
markers for relapse (AUC = 0.517, 0.529 and 0.577 respectively); thus, their
performance characteristics were not calculated.
Two-year OS and EFS were 76% (95% CI, 71–80) and 70% (95% CI,
65–80), respectively, in the whole cohort. There was no significant difference in
post-relapse survival between patients who had laboratory investigations performed
≤3 months prior to documented relapse versus patients who did not (p = 0.88, Fig. 1).
Survival curve in relapsed patients. This shows the post-relapse
survival based on whether a blood test was performed in preclinical period
(3 months) for relapse
Discussion
This analysis, from one of the largest and most comprehensive series
in the modern era to our knowledge, demonstrates little benefit of including routine
laboratory testing to detect relapse in follow-up of asymptomatic patients with
aggressive lymphoma achieving metabolic CR after first-line chemotherapy. In line
with published reports, our results confirm that clinical symptoms and signs are the
single most important predictor of relapse,16,17 with 80% of relapsed patients having symptoms at
presentation and only 1% of isolated abnormal blood test results leading to a
diagnosis of relapse. There was no difference in survival between patients who had
blood tests and those who did not.
Previous studies have reported that routine blood tests do not
reliably predict relapse.17–19 However, all have assessed either only one
parameter or ‘blood tests’ as a whole without describing which tests were performed
or omitted. Our study is the only one to assess the performance of individual tests,
their role in the detection of relapse and their impact on management and overall
outcomes in a population with PET-confirmed CR at 3 months.
ESR had been proposed as a useful marker of relapse in HL in
199120,
but subsequent studies dispute this, with the vast majority of relapses detected by
clinical findings rather than by ESR alone.21,22 Nevertheless, ESR is still frequently performed
during follow-up. In our cohort, ESR had a sensitivity of only 39% for detection of
relapse in HL, and only one relapse was diagnosed by an isolated elevated
ESR.
LDH has also been proposed as a useful screening test for relapse in
DLBCL in the pre-rituximab era23, but recent studies are consistent with ours in
showing its lack of predictive value in the absence of symptoms or signs suggesting
relapse.13,18,24,25 The PPV of an elevated LDH in our aggressive NHL
cohort was 8%, even after accounting for known causes of LDH elevation such as liver
disease and infection. No relapses in NHL were detected on the basis of LDH alone.
Our findings confirm results from a previous smaller series of 100 DLBCL
patients,19 which analysed LDH at every appointment and
reported a low PPV of 9% and sensitivity of 47% for relapse. Interestingly, LDH was
ordered at 69% of HL follow-up appointments, despite a lack of evidence or
recommendations by guidelines for its use in monitoring this subtype, and lead to
the detection of one HL relapse.
FBE was the most commonly performed test in our study, with an
abnormal result in 10% of samples, yet was associated with a change in management in
<15% of the time. There was one relapse diagnosed on the basis of FBE alone.
These findings are also consistent with the literature, with several studies
reporting no relapses detected by FBE abnormalities.21–23
Baseline lymphocyte and monocyte counts and the LMR have prognostic
value for both DLBCL26 and HL27 and three retrospective studies concluded that a
low ALC and LMR during follow-up is a useful indicator of relapse in DLBCL. PPV and
NPV in these studies ranged between 68–74% and 49–96%, respectively, with
sensitivity 68–89% and specificity 88%.11–13 However, these studies analysed
parameters at a single time point just prior to relapse without accounting for
symptomatology or confirming initial CR on PET. In contrast, our analysis
demonstrated that ALC, AMC and LMR had almost no ability to discriminate between
relapsed and non-relapsed patients, with far lower AUC values than previously
reported (0.52 versus 0.91 for ALC).13
It may be argued that the NPV of laboratory tests was high in our
study (98%) and provides reassurance to patients with normal results. Conversely,
15% of blood tests had an unexplained abnormality; not only are they of poor PPV in
asymptomatic patients, they almost always result in unnecessary patient anxiety and
often lead to further investigations, which are seldom abnormal. Routine blood tests
have been postulated as a method of monitoring for therapy-related myelodysplastic
syndromes (MDS). The incidence of therapy-related MDS in patients receiving
induction chemotherapy for aggressive lymphomas is only marginally higher than the
general population (0.4–1.2% post treatment versus 0.3% in the general
population28–30). More importantly, there is limited evidence
for early detection of MDS in asymptomatic patients and current guidelines do not
recommend treatment for the majority of this cohort. Additionally, screening for MDS
would, at most, warrant a FBE alone, but not other currently recommended blood tests
in lymphoma surveillance guidelines.
Recognising this study is retrospective, and the design remains
robust. The patients were treated uniformly, as demonstrated by the high percentage
of patients undergoing the individual blood tests, consistent use of end of
treatment PET to confirm metabolic remission and limited variation in treatment
regimens. Unlike the majority of prior analyses,17–19 this study reviewed all labs
performed for the duration of follow-up in patients with PET-confirmed CR for at
least 3 months following treatment. Our study included all major histological
subtypes of aggressive lymphoma and is likely relevant to a wider population.
Although of note, the exclusion of primary refractory disease in our cohort to
accurately analyse the role of blood tests in detection of relapse led to a lower
proportion of high-risk patients than many published series.
This study confirms that common blood tests do not reliably detect
relapse of aggressive lymphoma in asymptomatic patients treated in the modern era
and should not be recommended by current international guidelines. They are no
longer performed in this context in our institutions. More novel methods of relapse
detection such as circulating tumour DNA have demonstrated greater specificity and
sensitivity than standard blood parameters; however, this technology is yet to be
widely available and affordable.
Author contributions
E.A.H. and A.G. designed the study, Z.L. and O.E. performed the research
and F.J.H. and M.G. contributed additional data. Z.L. analysed the data, Z.L. and
E.A.H. wrote the paper and A.G. and G.C. critically revised the paper. All authors
approved the final version.
Ethics approval and consent to participate
This study was approved by the local institutional review boards.
Austin Health Human Research Ethics Committee, reference number LNR/15/AUSTIN/432.
Eastern Health Human Research Ethics Committee, reference number LR117/2015
Availability of data and material
Materials, data and associated protocols are available from the
corresponding author on reasonable request.