Immunotherapy response evaluation with F-FDG-PET in patients with advanced stage renal cell carcinoma

Article (PDF Available)inWorld Journal of Urology 31(4) · July 2011with97 Reads
DOI: 10.1007/s00345-011-0723-y · Source: PubMed
Abstract
Background CT imaging is widely used for response evaluation of immunotherapy in patients with advanced stage renal cell carcinoma (RCC). However, this kind of treatment may not immediately be cytoreductive, although the treatment is successful. This poses new demands on imaging modalities. Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) proved to be useful in monitoring the effect of several antitumour treatments. We investigated the potential of FDG-PET for the evaluation of response to immunotherapy. Methods In seven patients with metastasized RCC, who were treated with either interferon-alpha (IFN-α) monotherapy or a combination of IFN-α, interleukin-2 and 5-fluorouracil, FDG-PET was performed prior and after 5 and 9 weeks of treatment. Quantitative changes of glucose metabolic rate (MRGlu) were compared with changes in tumour size on CT imaging using Response Evaluation Criteria in Solid Tumors (RECIST) and to survival and progression-free survival. Results No consistent changes in MRGlu were observed within different response groups. And no correlation with CT imaging, neither with survival or progression-free survival, was found. Conclusion In contrast to the positive results reported on (chemo) therapy response evaluation with FDG-PET in different malignancies, this imaging modality appears not useful in response monitoring of immunotherapeutic modalities in RCC.

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World J Urol (2013) 31:841–846
DOI 10.1007/s00345-011-0723-y
123
ORIGINAL ARTICLE
Immunotherapy response evaluation with
18
F-FDG-PET
in patients with advanced stage renal cell carcinoma
Rozemarie Gilles · Lioe-Fee de Geus-Oei ·
Peter F. A. Mulders · Wim J. G. Oyen
Received: 3 June 2010 / Accepted: 22 June 2011 / Published online: 8 July 2011
© The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract
Background CT imaging is widely used for response
evaluation of immunotherapy in patients with advanced
stage renal cell carcinoma (RCC). However, this kind of
treatment may not immediately be cytoreductive, although
the treatment is successful. This poses new demands on
imaging modalities. Positron emission tomography (PET)
using
18
F-Xuorodeoxyglucose (FDG) proved to be useful in
monitoring the eVect of several antitumour treatments. We
investigated the potential of FDG-PET for the evaluation of
response to immunotherapy.
Methods In seven patients with metastasized RCC, who
were treated with either interferon-alpha (IFN-) mono-
therapy or a combination of IFN-, interleukin-2 and
5-Xuorouracil, FDG-PET was performed prior and after 5 and
9 weeks of treatment. Quantitative changes of glucose met-
abolic rate (MR
Glu
) were compared with changes in tumour
size on CT imaging using Response Evaluation Criteria in
Solid Tumors (RECIST) and to survival and progression-
free survival.
Results No consistent changes in MR
Glu
were observed
within diVerent response groups. And no correlation with
CT imaging, neither with survival or progression-free
survival, was found.
Conclusion In contrast to the positive results reported on
(chemo) therapy response evaluation with FDG-PET in
diVerent malignancies, this imaging modality appears not
useful in response monitoring of immunotherapeutic
modalities in RCC.
Keywords Renal cell carcinoma · Immunotherapy ·
FDG · PET
Introduction
Renal cell carcinoma (RCC) is a relative rare tumour type.
It accounts for 2.1% of all malignancies and is responsible
for 1.5% of all cancer deaths worldwide [1]. Almost 25%
of patients have metastatic disease at presentation, and
30–40% of patients that initially present with localized
disease, develop metastases during the course of their
disease [2]. At that stage, patients cannot longer be cured,
and 5-year survival rates do not reach 5% [3]. Since chemo-
therapeutic and hormonal agents appeared to be of limited
beneWt, diVerent treatment strategies have been developed
[4]. One frequently used strategy is immunotherapy with
interferon-alpha (IFN-) or combination therapy with IFN-
and interleukin-2 (IL-2) together with the biological agent
5-Xuorouracil (5-FU).
Response assessment for these therapies has traditionally
been made by anatomical imaging modalities, such as CT,
using the Response Evaluation Criteria in Solid Tumors
(RECIST) [5]. These treatments, however, are rather cyto-
static than cytoreductive, in which case successful
treatment may not lead to a decrease in tumour size. An
unchanged residual mass does not necessarily imply poor
therapeutic response. This makes anatomical imaging less
suitable for monitoring the eVect of treatment strategies.
R. Gilles (&) · L.-F. de Geus-Oei · W. J. G. Oyen
Department of Nuclear Medicine, Radboud University
Nijmegen Medical Centre, PO Box 9101,
6500 HB Nijmegen, The Netherlands
e-mail: rozemariegilles@gmail.com
P. F. A. Mulders
Department of Urology, Radboud University Nijmegen
Medical Centre, Nijmegen, The Netherlands
842 World J Urol (2013) 31:841–846
123
Furthermore, diVerentiation between vital tumour and
Wbrosis or necrosis is diYcult using morphological
imaging. Therefore, functional imaging techniques to mon-
itor response to therapy may be an attractive alternative to
morphological imaging. Positron emission tomography
(PET) with
18
Xuorodeoxyglucose (FDG) is an imaging
modality, which has already an established role for many
indications in clinical oncology [6, 7]. With PET, using the
Xuoride-18-labelled glucose analogue FDG, tissue with a
high-glucose metabolic rate is visualized, which is useful
for initial diagnosis or staging. Furthermore, quantiWcation
and measurement of therapy-induced changes in glucose
metabolism is possible with PET as well.
Earlier studies on FDG-PET for evaluation of malignant
lymphoma after chemotherapy show that FDG-PET was
superior to CT in predicting progression-free survival
[8, 9]. Similar results were found in recent studies in
patients with non-small cell lung cancer and colorectal can-
cer in which chemotherapeutic response was evaluated with
FDG-PET [10, 11].
Furthermore, FDG-PET has also shown to be useful in
monitoring the response to targeted therapy in various
malignancies as for instance malignant gastrointestinal
stromal tumours [12]. Concerning immunotherapy, promis-
ing results have been obtained from recent studies on
response evaluation with FDG-PET in patients with non-
Hodgkin lymphoma with suggestion of superiority to CT as
well [13, 14].
In this study, we investigated whether FDG-PET is a
useful modality for monitoring therapeutic response and for
predicting outcome in terms of survival and progression-
free survival in patients who were treated by either IFN-
monotherapy or triple therapy with IFN-, IL-2 and 5-FU.
Quantitative FDG-PET analysis using glucose metabolic
rate (MR
Glu
) was compared with conventional CT imaging
using RECIST. Survival and progression-free survival
served as the standard of reference.
Materials and methods
Patients
The present study was carried out as part of a large
multicenter protocol that studied the therapeutic eVect of
IFN-, IL-2, 5-FU triple therapy compared with IFN--
monotherapy on advanced stages of RCC. All patients
considered eligible for this multicenter trial (Table 1) were
asked to participate in this side study. An exclusion
criterion for the side study was diabetes mellitus. Patients
participating in the multicenter trial were randomized for
treatment with IFN- monotherapy or triple therapy includ-
ing IFN-, IL-2 and 5-FU.
FDG-PET
FDG-PET was performed prior to treatment and respec-
tively after 5 and 9 weeks for response evaluation
(Table 2). Patients were fasted for at least six hours prior to
injection of 200 MBq
18
F-FDG. FDG-PET was performed
on an ECAT-EXACT47 PET scanner (Siemens/CTI, Knox-
ville, TN, USA). Patients were positioned supine. The
dynamic data acquisition was started simultaneously with
the injection of FDG.
Tumour time-activity curves
Tumour time-activity curves were obtained by placing vol-
umes of interest (VOIs) semi-automatically over the
tumour and metastases using a threshold of 50% of the
maximum pixel value within the lesion. The locations of
the lesions were evaluated visually on the transaxial, coro-
nal and sagittal images. For this purpose, the late frames
(frame 14–16) were summed, yielding a static image of
30 min and a scan mid-time of 35 min post-injection. The
tumour VOIs were then copied to all dynamic time frames
Table 1 Inclusion criteria multicenter trial
Disease characteristics
Histological conWrmed renal cell carcinoma
Advanced metastatic disease that requires treatment
No brain metastases
Prior/concurrent therapy
No prior biological therapy
No prior chemotherapy
No prior endocrine therapy
At least 4 weeks since prior radiotherapy
Prior resection of the primary tumour recommended
but not required
No prior major organ allografts
Patient characteristics
Age 18–81 years
Performance status WHO 0–1
Life expectancy of more than 12 weeks
WBC greater than 3,000/mm
3
Platelet count greater than 100,00/mm
3
Haemoglobin greater than 10 g/dL
No myocardial infarction within the past 6 months
No unstable angina pectoris
Not pregnant or nursing
Female patients must use eVective contraception during
and for at least 6 months after study participation
No other current disease or prior malignancy that would
preclude study treatments or comparisons
No current active infection requiring antibiotics
World J Urol (2013) 31:841–846 843
123
to obtain time–activity curves. A volume-weighted mean
value of all lesions in each PET scan was derived to provide
one MR
Glu
for each study.
Image-derived input function
The image-based input functions were determined by mea-
suring FDG counts in VOIs over the ascending aorta or
abdominal aorta, depending on the body location of the
study. An early time frame (frame 3, i.e., 60–90 s post-
injection) was used, in which the bolus of activity was best
visualized, and time-activity curves were created using
VOIs that consisted of several regions of interest drawn
over the blood pool area in as many planes as possible. For
VOI deWnition, a semi-automatic threshold-based region-
growing programme was used. All VOIs were conWrmed
visually [15].
Patlak graphical analyses
For quantitative measurement of glucose metabolism,
Patlak graphical analysis was used to calculate the MR
Glu
(expressed in mol ml
¡1
min
¡1
) in tumour tissue [16]. The
Patlak approach takes into account diVerences in the whole-
body distribution of FDG at the time of scanning, which
may aVect the accumulation of FDG in the tumour tissue.
Therefore, the MR
Glu
is in principle a more reliable mea-
sure of tumour glucose use than the standardized uptake
value (SUV). Patlak graphical analysis is based on the
assumption that the ratio of the tracer concentration in tis-
sue to that in plasma increases linearly when plotted as a
function of normalized time. This linear relationship fol-
lows directly from the FDG model when the free tissue
FDG concentration is constant and unidirectional transport,
i.e., trapping of FDG can be assumed. This assumption in
practice occurs about 5 min post-injection. The Patlak anal-
ysis was performed over the period from 5 to 50 min after
injection. Furthermore, the MR
Glu
(expressed in mol ml
¡1
min
¡1
) in tumour was calculated by multiplication of the
slope of the Patlak-plot (K
1
k
3
.(k
2
+k
3
)
¡1
) and the basic
blood glucose level (expressed in mol ml
¡1
), measured
before FDG injection (hexokinase method, Aeroset, Abbott
diagnostics, Illinois, USA). In this study the lumped con-
stant used was set to 1 and was assumed to be constant over
time, because no studies on the actual value of the lumped
constant in tumours outside the central nervous system
have been reported yet.
Patient evaluation and follow-up
The Wrst response evaluation PET was performed after Wve
weeks when immunotherapy with IL-2 in the triple-
therapy-group was completed and therapy with 5-FU was
not yet started. Furthermore, patients treated with IFN-
monotherapy were maximally boosted at that time. The second
evaluation at nine weeks was chosen because of the concur-
rent CT evaluation at that time-point, in order to obtain
more comparable results. Data derived from the Patlak
analysis were compared with those from CT-response eval-
uation based on RECIST guidelines [5].
Clinical follow-up took place at 9, 19 and 26 weeks, at 8,
10 and 12 months, subsequently every 4 months for 1 year
and every 6 months thereafter. In this follow-up period, CT
was used to determine response. The median follow-up
period was 37.5 months (range 22–47 months).
Progression-free survival was deWned as the duration of
response/stable disease as determined by CT, starting from
the day on which the baseline PET was performed. Overall
survival was deWned as the time from baseline PET until
death.
Statistical considerations
When designing the study, a power analysis was performed
to estimate the required size of the patient population. Data
from the literature suggest that 15% of patients show
response on immunotherapy and 30% of patients show
Table 2 Treatment and evaluation: patients were treated either
with triple combination therapy consisting of IFN-, IL-2 and 5-FU or
IFN--monotherapy
FDG-PET was performed at baseline, in week 5 and week 9
Week Day IFN-
(MU/m
2
)
IL-2
(MU/m
2
)
5-FU
(mg/m
2
)
IFN-
(MU)
Baseline FDG-PET-scan
116 5
310 5
410
510 10
2–3 1 6 5 10
36 5 10
56 5 10
416 10
310 10
410
510 10
First evaluation FDG-PET-scan
19 750 10
39 10
59 10
6–8 1 9 750 10
39 10
5 9 10
Second evaluation FDG-PET-scan
844 World J Urol (2013) 31:841–846
123
stable disease according to RECIST [17]. Conventional
imaging, however, often underestimates immunotherapy
treatment response. Thus, to detect 20% more treatment
responses using FDG-PET, a sample size of 15 patients is
required (alpha 0.05, power 0.80, McNemar test, two-
sided), assuming that PET does not underestimate therapy
response.
An agreement was made to perform an interim analysis
halfway the study and to discontinue if the interim analysis
would not show an association between metabolic and mor-
phologic response assessment or (progression-free) sur-
vival.
Results
FDG-PET was performed in 7 patients with metastatic
RCC. All patients were nephrectomized (6 men, 1 woman;
mean age 59 years; range, 49–66 years) and had histologi-
cally conWrmed RCC, all of the clear cell type. Four
patients already had metastatic disease at initial diagnosis.
Metastases were located in the lung, lymph nodes and adre-
nal gland. The median follow-up period was 37.5 months
(range, 22–47 months).
Two patients received triple therapy, and Wve were
treated with IFN- monotherapy. According to CT, per-
formed 9 weeks after starting therapy, one patient had
partial response, four had stable disease, and two had
progressive disease. Complete remission was not
observed. The median progression-free survival after
starting immunotherapy was 9 months (range, 3–37
months). Four patients died, all within 40 months after
initial diagnosis.
The average glucose metabolic rate measured at baseline
was 0.0665 mol/ml/min (range, 0.0365–0.1028). There
was a large variation of glucose metabolic rate within the
group of patients. No association between metabolic and
morphologic response, progression-free survival and over-
all survival was found at interim analysis (Fig. 1), which
resulted in a discontinuation of the study.
Fig. 1 Metabolic rate of glu-
cose of each response group,
measured at baseline (MR
Glu
1)
and after 5 and 9 weeks of treat-
ment (MR
Glu
2 and MR
Glu
3
respectively). Therapy consisted
of either IFN- (straight line) or
triple therapy (dashed line).
Response groups were deWned
as partial response (a), stable
disease (b) and progressive
disease (c) according to RECIST
on CT Wndings. No association
between glucose metabolic rate
and response to therapy, as
established by CT, and progres-
sion-free survival (PFS) and
overall survival (OS) was found
World J Urol (2013) 31:841–846 845
123
Discussion
At present, response monitoring of antitumour treatments
with FDG-PET is still in its infancy. Not for all kinds of
antitumour treatment it is elucidated whether FDG-PET is
capable of predicting response and whether FDG-PET
shows added value in response evaluation of a certain treat-
ment. The present study, however, could not conWrm the
utility of FDG-PET-based response evaluation of immuno-
therapy in patients with metastatic RCC.
In the present study, the variable metabolic response pat-
tern on immunotherapy without correlation to morphologi-
cal response and overall survival or progression-free
survival may be explained by some biological features of
RCC tumour cells and by the eVect of immunotherapy on
these biological features. One could speculate, on the possi-
ble eVects on glucose metabolism of the hypoxia inducible
factor 1 (HIF-1), activated T cells and the expression of
c-myc in RCC.
The latter one is a proto-oncogene that regulates cell pro-
liferation, cell growth and apoptosis. Evidence for over-
expression in c-myc in most cases of RCC has been found
and is correlated with T status, nuclear grade and venous
invasion. However, the expression of c-myc, which variates
within patients with RCC, is not correlated with clinical
parameters such as nodal or distant metastasis, tumour type
and neither is an independent predictor of survival [18];
consequently, IFN- is not equally eVective in each patient.
It is known that c-myc enhances glucose metabolism
[19]. In case of such a straightforward relation, one would
expect some correlation between (progression-free) sur-
vival, morphological response and the degree of MR
Glu
prior to therapy. However, this was not seen in the present
study. This suggests more unknown mechanisms that inter-
fere with glucose metabolism as for instance HIF-1 over-
expression which is associated with loss of functional Von
Hippel-Lindau (VHL) gene which occurs in approximately
70% of clear cell RCCs [20]. HIF-1 over-expression in
RCC is also associated with high GLUT-1 expression [21].
Furthermore, in the two patients who were treated with
triple therapy, activation of T cells by IL-2 could also
have contributed to an enhancement of glucose metabo-
lism after therapy as well. In this case, an increment in
MR
Glu
due to inXammatory reaction could mask a true
therapeutic eVect.
On staging of RCC and in the preoperative diagnostic
work-up, far more studies concerning the role of FDG-PET
have been published. For instance, Kang and colleges
investigated a group of 66 patients with renal cell carci-
noma. Although the speciWcity of FDG-PET was 100%,
which was superior to CT, sensitivity was low for both pri-
mary and metastatic lesions (60 and 77%, respectively) due
to variation in FDG avidity of these tumours [22].
It remains unclear why FDG uptake (glucose metabo-
lism) varies among patients with RCC. In some malignan-
cies, FDG uptake is correlated with glucose transporter
protein 1 (GLUT-1) expression [23, 24]. No evidence for
such a correlation in RCC, however, has been found [25].
In our group of patients with metastasis who had resection
of the primary tumour, glucose metabolic rate prior to
immunotherapy varied widely as well.
Finally, there are more radiopharmaceuticals for PET
beyond FDG. The goal of more targeted, individualized
therapies probably needs more speciWc, biologically
directed imaging, a role for which PET is ideally suited.
Future applications of PET for therapy response assessment
will likely involve other tracers in addition to FDG, to
better characterize tumour biology and more eVectively
measure response to antitumour therapy, such as immuno-
therapy. New PET tracers for imaging RCC, like
18
F-Xuor-
omisonidazole (
18
F-FMISO),
11
C-acetate and
89
Zr-labelled
cG250 monoclonal antibody already have been investigated
with promising results [2628]. However, these studies all
focussed on staging and on imaging the primary RCC prior
to therapy.
Conclusion
In contrast to the positive results reported on (chemo) ther-
apy response evaluation in a wide variety of malignancies,
FDG-PET seems not to be useful for response monitoring
of immunotherapeutic modalities in RCC.
ConXict of interest The authors declare that they have no conXict of
interest.
Open Access This article is distributed under the terms of the Cre-
ative Commons Attribution Noncommercial License which permits
any noncommercial use, distribution, and reproduction in any medium,
provided the original author(s) and source are credited.
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Biother Radiopharm 19(2):155–163. doi:10.1089/108497804
323071922
  • [Show abstract] [Hide abstract] ABSTRACT: Background Most patients treated for lung cancer experience disease recurrence or progression, resulting in high mortality rates. Computed tomography (CT) is central in evaluating treatment response; however, positron emission tomography (PET) may provide a more rapid and prognostically relevant assessment of changes in disease activity during and after treatment. Methods We present a case which illustrates the potential role of PET in assessing treatment response in non-small cell lung cancer (NSCLC) and review the relevant literature. Results A 49-year-old woman presented with an inoperable pancoast tumour of the lung and was treated with radiochemotherapy (RTCT). PET-CT showed that, while her tumour had not changed in size, the metabolic activity of the tumour had decreased significantly following RTCT. The decision was made to resect the tumour, which was found to contain only a small cluster of viable tumour cells. This case illustrates the clinical relevance of assessing metabolic tumour response in addition to morphologic tumour response. Clinical studies have shown PET to be a valuable addition to treatment response assessments performed using CT in a wide range of clinical situations. Following surgical treatment PET is more effective than CT alone in identifying recurrence, and may be useful in differentiating postoperative scar tissue from active tumour. During systemic treatment, whether with chemotherapy or EGFR-TKIs, the early metabolic response seen in PET can be predictive of the degree of clinical benefit. Conclusions In addition to the structural information provided by CT, the metabolic information from PET during or following treatment for NSCLC is increasingly valuable in clinical decision making.
    Article · Jun 2015
  • [Show abstract] [Hide abstract] ABSTRACT: Rationale: We demonstrated before that autologous tumor lysate-pulsed dendritic cell-based immunotherapy in patients with malignant pleural mesothelioma is feasible, well-tolerated, and capable of inducing immunological responses against tumors. In our murine model we found that reduction of regulatory T cells with metronomic cyclophosphamide increased the efficacy of immunotherapy. Objectives: To assess the decrease in number of peripheral blood regulatory T cells during combination therapy of low-dose cyclophosphamide and dendritic cell immunotherapy and to determine the induction of immunological responses with this treatment in mesothelioma patients. Methods: Ten malignant pleural mesothelioma patients received metronomic cyclophosphamide and dendritic cell-based immunotherapy. During the treatment, peripheral blood mononuclear cells were analyzed for regulatory T cells and immunological responses. Measurements and main results: Administration of dendritic cells pulsed with autologous tumor lysate combined with cyclophosphamide in mesothelioma patients was safe, the only side effect being moderate fever. Dendritic cell vaccination combined with cyclophosphamide resulted in radiographic disease control in eight of the ten patients. Overall survival was promising, with seven out of ten patients having a survival of ≥24 months and two patients still alive after 50 and 66 months. Low-dose cyclophosphamide reduced the percentage of regulatory T cells of total CD4 cells in peripheral blood from 9.43 (range 4.34-26.10) to 4.51 (range 0.27-10.30) after 7 days of cyclophosphamide treatment (P=0.02). Conclusions: Consolidation therapy with autologous tumor lysate-pulsed dendritic cell-based therapy and simultaneously reducing the tumor-induced immune suppression is well-tolerated, and shows signs of clinical activity in mesothelioma patients. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01241682.
    Article · Dec 2015
  • [Show abstract] [Hide abstract] ABSTRACT: Immunotherapy has emerged as a promising alternative in the arsenal against cancer by harnessing the power of the immune system to specifically target malignant tissues. As the field of immunotherapy continues to expand, researchers will require newer methods for studying the interactions between the immune system, tumor cells, and immunotherapy agents. Recently, several noninvasive imaging strategies have been employed to map the biodistribution of immune checkpoint molecules, monitor the efficacy and potential toxicities of the treatments, and identify patients who are likely to benefit from immunotherapies. In this concise review article, we outline the current applications of noninvasive techniques for the preclinical imaging of immunotherapy targets, and suggest future pathways for molecular imaging to contribute to this developing field.
    Full-text · Article · Jul 2016