Download Pretreatment FDG-PET standardized uptake value as a prognostic

ORIGINAL ARTICLE
PRETREATMENT FDG-PET STANDARDIZED UPTAKE VALUE
AS A PROGNOSTIC FACTOR FOR OUTCOME IN HEAD AND
NECK CANCER
Mitchell Machtay, MD,1 Mona Natwa, MD,2 Jocelyn Andrel, MS,3 Terry Hyslop, PhD,3
P. Rani Anne, MD,1 Jororsali Lavarino, BS,1 Charles M. Intenzo, MD,2 William Keane, MD4
1
Department of Radiation Oncology, Jefferson Medical College and the Kimmel Cancer Center,
Thomas Jefferson University, Philadelphia, Pennsylvania. E-mail: [email protected]
2
Department of Radiology–Nuclear Medicine, Jefferson Medical College and the Kimmel Cancer Center,
Thomas Jefferson University, Philadelphia, Pennsylvania
3
Department of Biostatistics, Jefferson Medical College and the Kimmel Cancer Center, Thomas Jefferson
University, Philadelphia, Pennsylvania
4
Department of Otorhinolaryngology–Head and Neck Surgery, Jefferson Medical College and the Kimmel
Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
Accepted 9 June 2008
Published online 23 December 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20942
Abstract: Background. We studied the potential prognostic
significance of pretreatment 18-fluorodeoxyglucose-positron
emission tomography (FDG-PET) standardized uptake value
(SUV) in squamous cell carcinoma of the head and neck
(SCCHN).
Methods. A retrospective review of the pretreatment FDGPET scans of 60 patients with SCCHN was performed. All
patients received radiotherapy and 37 also received concurrent
chemotherapy. SUV was calculated by 2 nuclear-medicine
physicians who were blinded to the clinical data. Disease-free
survival (DFS) was analyzed with respect to SUV (and other
potential prognostic factors).
Results. The median SUV was 7.2 (range, 1–24.7); 34
patients (57%) had SUV < 9.0 compared with 26 patients (43%)
with an SUV 9.0. The group with low SUV had significantly
Correspondence to: M. Machtay
This work was presented in part at the 2006 Annual Meeting of the American Society of Therapeutic Radiology and Oncology (ASTRO).
Contract grant sponsor: C.U.R.E. Commonwealth of Pennsylvania; contract grant number: 080-37340-A74701.
C
V
2008 Wiley Periodicals, Inc.
Pretreatment FDG-PET Standardized Uptake Value
better 2-year DFS compared with the high SUV group (72% vs
37%), p 5 .007. On multivariate analysis, stage and age were
also associated with DFS, but SUV remained an independent
predictor of DFS (hazard ratio: 1.08; p 5 .016).
Conclusion. SUV was significantly associated with outcome
C 2008 Wiley Periafter modern definitive therapy of SCCHN. V
odicals, Inc. Head Neck 31: 195–201, 2009
Keywords: PET scan; PET SUV; head and neck cancer; radiotherapy; prognostic factors
Cure rates have not improved for squamous cell
carcinoma of the head and neck (SCCHN) much
above 50% in the last 20 years despite improvements in surgery, radiotherapy, and chemotherapy.1 As with other types of cancer, there is great
interest in trying to identify factors other than
stage that predict for outcome. In particular, there
have been studies indicating that certain tumor
tissue biomarkers may be associated with
HEAD & NECK—DOI 10.1002/hed
February 2009
195
increased aggressiveness and/or treatment failure.2–4 A broad review of the hundreds of studies
done on this topic is beyond the scope of this article and the results have been inconsistent.
The development of functional imaging studies, particularly positron emission tomography
(PET) scanning offers the ability to noninvasively
study the physiology of cancers.5 Uptake of 18-fluorodeoxyglucose (18-FDG) represents high levels
of intracellular metabolic activity, which in turn
may be associated with active proliferation, invasion, and metastases. The advent of PET scanning
has significantly changed the workup and management of several types of cancer, most notably
lung cancer,6 and today’s radiologists and oncologists are now familiar with its use.
At our institution, we have obtained pretreatment PET scans as part of general workup of
selected new patients with locally advanced head
and neck cancer. We have utilized PET scanning
as a supplemental aide in assessing the extent of
local-regional disease and to rule out occult second
primary cancer and/or distant metastases. In this
article, we report retrospectively on the possible
relationship between the intensity of FDG uptake
in the primary tumor and long-term outcome.
gery prior to radiotherapy while oropharyngeal
and stages I–III larynx cancers were managed
with definitive radiotherapy. Many patients (37 of
60) also received concurrent chemotherapy during
irradiation. Absolute criteria for concurrent chemoradiotherapy at our institution during the time
period of the study were stage IV disease being
treated nonsurgically, or disease resected with a
positive margin(s) or nodal extracapsular extension. Relative indications for concurrent chemoradiotherapy were stage III disease being treated
nonsurgically, or disease resected with a T4 primary tumor and/or N2 nodal disease. Patient
characteristics are shown in Table 1. Radiotherapy quality assurance (QA) of radiotherapy treatment was reviewed by 1 of the authors (M.M.).
Conventional comprehensive irradiation was performed and included the primary tumor bed plus a
margin of normal tissue, as well as all regional
lymphatic spaces that were at risk for microscopic
cancer. Field sizes were not decreased in response
to an area(s) deemed negative by PET.
PET-FDG scans were performed using a Phillips Allegra PET scanner from 2003 through early
2005. Subsequently, FDG-PET scans were performed using a Siemens LSO high-resolution
Table 1. Patient characteristics.
PATIENTS AND METHODS
This is a retrospective review of 60 patients who
were newly diagnosed with SCCHN over a 2-year
period between June 2003 and June 2005, and
underwent FDG-PET scanning for workup prior
to any anticancer treatment.
All of the patients in this series were seen to
have a good performance status suitable for radical treatment of their head and neck cancer. All
patients had gross tumor that was evaluable by
physical examination and/or non-PET imaging
such as CT scanning. Most patients (52 of 60) had
stage III/IV disease; the remaining 8 patients had
stage I/II disease arising from a head and neck
subsite(s) considered to be at high risk for occult
regional lymph node metastases (eg, tongue,
supraglottic larynx). Patients with evidence of
distant metastases (whether by conventional
workup or by PET) were not included in this series
and will be the topic of a separate report.
All of the patients in this series received conventional head and neck cancer treatment including definitive or postoperative radiotherapy at
Thomas Jefferson University Medical Center. In
general, patients with oral cavity or T4 laryngeal/
hypopharyngeal cancers underwent ablative sur-
196
Pretreatment FDG-PET Standardized Uptake Value
Characteristic
Sex
Male
Female
Tumor site
Oral
Oropharynx
Larynx
Hypopharynx
Tumor stage
I/II
III
IVA
IVB
Surgery
None
Neck dissection only
Ablative surgery
Chemotherapy
Yes
No
Age
<60
60
FDG-PET SUV
<9
9
N
%
40
20
66.7
33.3
14
30
13
3
23.3
50.0
21.7
5.0
8
16
29
7
13.3
26.7
48.3
11.7
19
15
26
31.7
25.0
43.3
37
23
61.7
38.3
30
30
50.0
50.0
34
26
56.7
43.3
Abbreviation: FDG-PET SUV, 18-fluorodeoxyglucose-positron emission
tomography standardized uptake value.
HEAD & NECK—DOI 10.1002/hed
February 2009
PET/CT scan. The same protocol was used for
patient preparation prior to scanning and for
scanning itself. Specifically, patients fasted overnight prior to the PET scan, and glucose was
measured before each study. A dose of approximately 12 mCi of FDG was administered intravenously to each patient. After FDG injection,
patients quietly rested and began scanning
between 45 and 60 minutes after injection.
Scans were qualitatively reviewed and quantitative SUV measurements were calculated by 2
nuclear medicine specialists (M.N. and C.I.).
These readings were performed with these physicians ‘‘blinded’’ to the patients’ clinical data
including clinical T/N classification and follow-up
outcomes. SUV was calculated by defining a
region of interest (ROI) around the area of clinical
activity that corresponded to increased FDG
uptake due to tumor. In most cases, this referred
to the primary tumor; however, our study did
include 3 patients with unknown primary SCCHN
of the neck; in these cases, the SUV was determined based upon the neck node disease. The
maximal SUV within this ROI was used as the
SUV (SUVmax). The SUVmax was automatically
generated by the PET planning system and
referred to the single highest voxel within the
physician-defined ROI. SUVs were adjusted for
the amount of injected radioactivity and for
patient weight.
SUV ¼
Table 2. Univariate log-rank testing of potential risk factors
(including SUV).
Overall
survival
Subgroup
SUV
<9.0
9.0
T classification
T0–T2
T3–T4
N classification
N0–N1
N2–N3
AJCC stage
I–III
IV
Age
<60 y
60 y
Disease-free
survival
N
% failed
p value
% failed
p value
34
26
23.5
50.0
.016
35.3
65.4
.007
19
41
15.8
43.9
.019
26.3
58.5
.010
31
29
29.0
41.4
.265
41.9
55.2
.259
24
36
20.8
44.4
.057
33.3
58.3
.056
30
30
30.0
40.0
.494
46.7
50.0
.730
Abbreviations: SUV, standardized uptake value; AJCC, American Joint
Committee on Cancer.
the models. Multivariate models were also completed using American Joint Committee on Cancer (AJCC) stage in place of T and N classifications, with remaining covariates as indicated. All
analyses as described were also repeated for the
subset of patients in AJCC stage III/IV (details
not provided). Analyses were completed using
SAS v 9.1, with 2-sided tests, and p values < .05
were considered significant.
Regional activity ðBq=mlÞ
Injected activity ðBqÞ=body wt ðgÞ
RESULTS
Analysis. Based on previous data from
Schwartz et al,7 an SUV cutoff of 9.0 was used as a
potential predictor of outcome. The primary outcome measurement was disease-free survival
(DFS), where failure is defined as local-regional
recurrence, distant metastasis, or death from cancer even if failure patterns were unknown/uncertain. For this definition of DFS, patients were censored if/when they died from a cause clearly unrelated to the index cancer. If there was any doubt or
question about the cause of death, the cause was
considered to be the index cancer (and thus an
event for DFS). We also completed an analysis of
overall survival (OS). Univariate analysis of relationship between SUV and DFS or OS was performed using log-rank testing. Subsequently a
multivariate analysis was performed in which
SUV and clinical prognostic factors, T classification, N classification, and age, were included in
Data
Pretreatment FDG-PET Standardized Uptake Value
The median SUV in our series was 7.2 (range, 1.0–
24.7); the mean SUV was 8.5. There were
26 patients (57%) with an SUV 9.0. Patient
characteristics are shown in Table 1.
There were significant differences in outcomes
based upon SUV (<9.0 vs 9.0); as shown in Table
2, SUV and T classification were the most significant factors associated with OS and DFS. As
shown in Figure 1, there was a significant difference in DFS between the patient group with SUV
< 9.0 and the group with SUV 9.0 (p 5 .007).
The crude failure rate was 65% in the high SUV
group versus 35% in the low SUV group. Actually,
the 2-year DFS rates were 76% versus 37%.
Figure 2 displays OS data. OS was significantly worse in the group with high SUV (p 5
.016). Crude survival rate was 76% in the low
SUV group compared with 50% in the high SUV
group. Actually, the 2-year OS rates were 82%
versus 46%.
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197
FIGURE 1. Disease-free survival based upon standardized
uptake value.
As shown in Figure 3, there is an association
between stage and SUV; lower SUVs were associated with earlier stage. Therefore, multivariate
analysis was performed in which stage (I/III vs
IV) and age (<60 vs >60) were considered in addition to SUV. Multivariate analysis showed that
SUV remained a significant predictor of DFS (p 5
.03), with a hazard ratio (HR) of 2.41 (95% CI:
1.10, 5.32). There was no statistical significance
found for stage (p 5 .26) and age (p 5 .70). There
was a borderline significant association between
SUV and OS outcome (HR 5 2.47; p 5 .006); neither age (p 5 .54) nor stage was significantly associated with OS (p 5 .24). Details of the multivariate models are found in Table 3. Multivariate
models that incorporated T and N classifications
resulted in no significant associations for any of
the covariates considered. Further reduction of
these models led to a single T classification covariate which is identical to the univariate analysis
presented.
FIGURE 2. Overall survival based upon standardized uptake value.
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Pretreatment FDG-PET Standardized Uptake Value
FIGURE 3. Scatter plot demonstrating association between
stage and standardized uptake value (SUV).
Results of analysis using an SUV limit of 7.2
(based on our median) were similar and not
reported here in detail. In most cases, the association becomes slightly stronger than that reported.
However, we chose to report the results using 9 as
a limit in order to maintain consistency with several other reports in the literature.7,8 Finally,
results of analysis of just the patients with stages
II and IV cancer were similar in direction and
magnitude of HRs to those reported, with less statistical significance due to smaller sample size.
DISCUSSION
This study shows that FDG-PET SUV is an independent, noninvasive, prognostic tool for SCCHN.
Our study was performed in the modern era in
which concurrent chemoradiotherapy was used in
all patients in whom it was indicated. The aggressive use of concurrent chemoradiotherapy has significantly improved the outcomes for head and
neck cancer.9 FDG-PET SUV remains a significant predictor of outcome in the modern era of
multimodality therapy.
One of the earliest studies of SUV as a predictor of outcome was that by Minn et al.10 They
reviewed results in 37 patients with SCCHN, all
of whom were treated with radiotherapy 6 surgery (without chemotherapy). Results showed a
dramatic difference in survival with respect to an
SUV cutoff value of 9.0; specifically 3-year DFS
was 53% for patients with SUV < 9.0 compared
with a 3-year DFS of 24% for patients with SUV >
9.0.
Since that study, there have been several other
papers describing similar results (see Table 4).
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February 2009
Table 3. Multivariable Cox model results for overall survival and disease-free survival.
Overall survival
HR (95% CI)
SUV (9 vs <9)
T classification (T3–T4 vs T0–T2)
N classification (N2–N3 vs N0–N1)
Age (60 vs <60)
SUV (9 vs <9)
AJCC stage (IV vs I–III)
Age
1.65
3.00
1.42
1.32
2.47
1.89
1.31
(0.57,
(0.74,
(0.55,
(0.54,
(0.98,
(0.66,
(0.54,
Disease-free survival
p value
4.84)
12.18)
3.67)
3.22)
6.26)
5.44)
3.17)
.36
.55
.47
.55
.06
.24
.54
HR (95% CI)
1.58
2.53
1.15
1.12
2.41
1.64
1.16
(0.60,
(0.77,
(0.54,
(0.52,
(1.10,
(0.69,
(0.69,
p value
4.22)
8.35)
2.46)
2.40)
5.32)
3.91)
3.91)
.36
.13
.49
.71
.03
.26
.70
Abbreviations: HR, hazard ratio; CI, confidence interval; SUV, standardized uptake value; AJCC, American Joint Committee on Cancer.
Varying cutoff values of SUV were used, although
most of these studies used a cutoff between 8 and
10. An exception was the large study by Allal
et al,11 which found that a relatively low cutoff
level of 4.76 (the median SUV in that series) was
highly predictive for DFS. It is plausible that a
single cutoff value for SUV does not drive outcomes, but rather that there would be a continuous association between higher SUV and worsening outcome, analogous to serum prostate specific
antigen levels and outcomes for prostate cancer.
SUV indicates the amount of FDG uptake
within an ROI. It is well documented in the biological literature that high cellular glucose uptake
and metabolism is common in malignant cells.
High uptake of glucose may be mediated by the
GLUT glucose transport proteins, which have
been associated with adverse outcome in cancer.15
Glucose uptake and metabolism may in turn be
associated with the activation of 1 or more cellular
processes such as synthesis of DNA, RNA, and/or
proteins and thus proliferation and/or tumor invasiveness. For example, translational studies have
shown an association between high FDG-PETSUV and Ki-67, a tissue marker of proliferation.16
As is the case for all novel biomarkers, there
are potential limitations and concerns regarding
widespread applicability of SUV. For example, it
has been demonstrated that SUV varies with
respect to time after injection of FDG.17 The exact
plasma glucose value may also affect SUV even in
the absence of frank hyperglycemia/diabetes.18
The body habitus of the patient (independent of
his/her actual weight) may affect SUV, because
fatty tissue has a relatively low uptake of FDG.
Finally, there are a number of technical factors
that can affect SUV as reviewed in a provocative
editorial by Keyes.19 These include the recovery
coefficient (the ratio of the measured activity of a
ROI to its true activity) and partial volume aver-
Table 4. Summary of literature of FDG-PET-SUV and outcomes in SCCHN.
Series
No. of
patients
Machtay et al
(current series)
Schwartz et al7
Brun et al8
60
Minn et al10
37
Allal et al11
120
Roh et al12
79
Kitagawa et al13
20
Halfpenny et al14
58
54
47
Patient population
Results
Mixed SCCHN, mostly stage III/IV (SRT or
CRT)
Mixed SCCHN population. 22 had chemo.
47 patients (including 6 NPC); median SUV
9.0. 10 patients had neoadjuvant chemo.
37 patients (median SUV 9). 16 RT alone;
19 preop RT; 2 S 1 RT. No chemo.
Surgery 6 RT (47); RT 6 chemo (73) (most
patients did not have chemo).
Advanced laryngopharynx (SRT or CRT). All
had chemo.
20 patients all treated with intra-arterial chemo
1 RT protocol.
58 patients (median SUV 7.16).
SUV > 9 predicts worse DFS (p 5 .007).
SUV > 9.0 predicts worse DFS (p 5 .03).
SUV > 9.0 predicts worse DFS, OS, LRC
(LC 96% vs 55%, p 5 .002).
SUV > 9.0 predicts worse DFS – 73% vs 22%
3-y survival. MVA showed mitotic count was
most sig. factor.
High SUV (> median (4.76) had worse DFS
(p 5 .005).
SUV > 8 predicts worse DFS (p 5 .007),
especially with nonsurgical therapy.
SUV > 7 predicts less likely pCR (4/15)
versus 0/5 for SUV < 7.
SUV > 10.0 predicts worse survival
(p 5 .003), independent on MVA.
Abbreviations: FDG-PET SUV, 18-fluorodeoxyglucose-positron emission tomography standardized uptake value; SCCHN, squamous cell carcinoma of
the head and neck; SRT, surgery-radiotherapy; CRT, chemoradiotherapy; DFS, disease-free survival; NPC, nasopharnyx cancer; OS, overall survival;
LRC, local-regional control; LC, local control; RT, radiotherapy; S, surgery; MVA, multivariate analysis; pCR, pathologic complete response.
Pretreatment FDG-PET Standardized Uptake Value
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aging, which are affected by individual nuances of
the hardware and software of the PET scanner,
the size and geometry of the lesion, and respiratory motion.20,21 There may be interobserver variability in SUV calculation; for example, in a lung
cancer study, Marom et al22 showed that centrally
reviewed SUV measurements differed by 25% or
more from the clinically reported SUVs in 45% of
cases.
Another variable that can affect the results of
studies such as ours is whether analysis was performed on patients’ primary tumor vis-a-vis metastatic nodal disease. Our study evaluated primary
tumor SUV, with the exception of 3 patients with
unknown primary SCCHN of the neck (presumed
oropharyngeal cancer based on the patients’ demographics and nodal location). It is possible that
intrapatient/intratumor heterogeneity between
the primary tumor and metastatic neck nodes
exists and this can alter results. Our study was
unfortunately not designed or powered to address
this issue.
These issues have prompted us and several
other investigators to study and report on
SUV using a relatively simple and well-defined
method—specifically, an ROI surrounding the
entire 3-dimensional tumor is encircled and the
maximum SUV within this ROI is calculated. This
was shown by Marom et al to provide very reliable
inter- and intra-observer reproducibility.22 Our
institution follows very strict guidelines for QA of
our PET scanning hardware and software, including phantom measurements and accreditation by
the American College of Radiology Imaging Network. Additionally, we have a consistent protocol
for FDG dosing, injection technique, pretest fasting and glucose measurement, and image acquisition and analysis.
The association between SUV and outcomes in
our studies and other studies are strong, with a
large magnitude. Arguably, the differences in outcome between ‘‘low’’ and ‘‘high’’ SUV are as dramatic as the differences seen with respect to stage
and may be greater differences than are typically
observed with studies of tissue ‘‘biomarkers’’ such
as epidermal growth factor receptor overexpression or human papillomavirus status. An implication of this work is that patients with particularly
high PET SUV might be candidates for more
aggressive therapy, such as the addition of 1 or
more novel agents to conventional chemoradiotherapy. Conversely, patients with a low PET SUV
might be candidates for less-aggressive treatment
such as local therapy alone or less-toxic radiosen-
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Pretreatment FDG-PET Standardized Uptake Value
sitizers. Current PET SUV data like ours cannot
be used at this time to justify such a change in
clinical practice. However, it should be validated
in larger studies and potentially used as a stratification variable for developing clinical trials.
In conclusion, our results show that a high
SUV, in particular using a cutoff value of 9.0, is
strongly associated with poor outcome after modern, definitive therapy of SCCHN. These data are
extremely consistent with others’ studies and suggest that FDG-PET SUV is a valuable biomarker
that might be used to help guide the aggressiveness of therapy in future clinical trials and/or
practice.
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