Journal of Cancer Therapy, 2012, 3, 372-378 Published Online September 2012 (
18FDG-PET/CT Is a Useful Tool in Staging Procedure
before Chemo-Radiotherapy in Patients with Limited
Disease Small-Cell Lung Cancer. Pattern of Failure and
Survival Is Analyzed
Anne Winther Larsen, Azza A. Khalil, Peter Meldgaard, Marianne M. Knap
Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
Received July 29th, 2012; revised August 30th, 2012; accepted September 12th, 2012
Background: Th e purpose of this study was to evaluate the use of 18FDG-PET/CT in staging procedure, the pattern of
failure and survival in patients with small-cell lung cancer limited disease (LD-SCLC) undergoing chemo-radiotherapy.
Methods: A total of 79 LD-SCLC patients were treated with a combination of chemotherapy and chest radiotherapy.
Radiotherapy of the tumour and the pathological lymph nodes was performed either as 45 Gy twice-daily or 46 - 50 Gy
once-daily. 18Fluro-2-deoxy-D-glucose (18FDG)-PET/CT was performed in 35 patients as part of the staging procedure.
Results: With a median follow-up time of 17 months 6% developed isolated loco-regional failures while 57% deve-
loped distant metastases. No isolated regional failures were seen. Median overall survival was 22 months. Patients
staged with a 18FDG-PET/CT had a significantly lower incidence of distant failures and a significantly improved overall
survival compared with patients only staged with a CT scan (p = 0.03) (median ov erall surv ival of 34 versu s 17 months,
respectively). Conclusion: The pattern of failure showed a high risk of distant metastases but a low incidence of iso-
lated loco-regional failures. Patients staged with an 18FDG-PET/CT had a significantly lower incidence of distant fail-
ures and better overall survival, indicating that 18FDG-PET could be beneficial in patients with LD-SCLC before decid-
ing on treatment regimen.
Keywords: Small-Cell Lung Cancer; Limited Disease; Thoracic Radiotherapy; Positron Emission Tomography;
Pattern of Failure
1. Introduction
Small-cell lung cancer (SCLC) accounts for about 12% -
15% of all lung cancers. It is an aggressive disease with a
rapid doubling time and a considerable potential for early
development of metastases. Only 20% - 30% of SCLC
patients have limited disease (LD) at diagnosis and hence
considered potentially curable. SCLC has a high sensiti-
vity to chemotherapy (CT) and radiotherapy (RT), and an
improvement in overall survival was achieved when CT
and RT were combined [1,2]. Optimal dose, timing and
fractionation of RT have been investigated previously but
results are conflicting [3-5]. Despite the high sensitivity
to treatment, most patients experience a relapse of dis-
ease, particularly with distant metastases, but also in the
form of local and regional failures, and overall survival
rate is always low. Optimal treatment strategies should
partly be based on an understanding of patterns of failure
in standard therapies. Moreover, accurate staging is of
utmost importance in the management of SCLC. During
the last decade, 18FDG-PET scans have been incorpo-
rated in the staging procedure in some institutes, but the
documentation for its usefulness is not as robust as in
non-small-cell lung carcinoma (NSCLC) [6].
The aim of this study was to present the treatment re-
sults of consecutively enrolled LD-SCLC patients un-
dergoing radical CT and RT over a four-year period par-
ticularly focusing on pattern of failu re and effect of PET/
2. Materials and Methods
2.1. Patient Population
All consecutive LD-SCLC patients treated with chest RT
at the Department of Oncology at Aarhus University
Hospital, Denmark between 2007 and 2010 were in-
cluded. The inclusion criteria were: a pathologically pro-
ven diagnosis of SCLC, a staging confirming LD and
Copyright © 2012 SciRes. JCT
18FDG-PET/CT Is a Useful Tool in Staging Procedure before Chemo-Radiotherapy in Patients with
Limited Disease Small-Cell Lung Cancer. Pattern of Failure and Survival Is Analyzed 373
initiation of treatment with RT in curative doses regard-
less of whether the patient actually completed the treat-
The diagnostic work-up was performed at three dif-
ferent institutes in Denmark and includ ed complete blood
count, bronchoscopy with biopsy and CT imaging of the
chest and abdomen. CT/MR scans of the br ain and bones
were only performed if clinically indicated in accordance
with clinical guidelines at our department at the time of
study. 18FDG-PET/CT scans were gradually incorpo-
rated as part of the diagnostic process during the study
Data on patient characteristics, treatment and relapses
were obtained from patient records. The date of diagnosis
was defined as the date of the first positive biopsy. The
clinical staging by the TNM system was retrospectively
determined by reviewing the CT- and PET-scans and
done by the authors. The date of death was documented
in our electronic patient file system. If follow-up was in
another department the patient record and scans were
retrieved. Two patients had another malignant disease at
the time of diagnosis and were thus excluded from the
2.2. Chemotherapy
The patients were treated with a standard combinatio n of
a platinum derivative and etoposide given every third or
fourth week. Dosage of carboplatin was AUC5 and cis-
platin dose was 75 mg/m2; both given on day one of
every cycle. Etoposide dose was 120 mg/m2 i.v. or 240
mg/ m 2 orally on day 1, 2 and 3 of every cycle.
2.3. Radiation Therapy
The RT was given twice-daily with 45 Gy in 30 F, 10 F
per week and either concomitan t with or sequen tial to CT
(Table 1). A few patients with large tumours, comorbi-
dity and advanced age were treated once-daily regime
(46 - 50 Gy in 23 - 25 F, 5 F per week) to lo wer the risk
of acute toxicity.
The treated volume was planned from a pre-treatment
CT scan and a PET/CT scan if available. Elective irradia-
tion of uninvolved lymph nodes (ENI) was not per-
formed. The gross target volume (GTV) for the primary
tumour (GTVt) and pathological lymph nodes (GTVn)
was delineated on the planning 3D-CT scans by two
clinical oncologists assisted by a radiologist using both
lung window and mediastinal window and guided by the
visual interpretation of the PET/CT scan. Nodal involve-
ment was defined as nodes > 1 cm in the short axis. A
margin of 0.5 cm was added to the GTVt and GTVn to
create respective Clinical Target Volumes (CTV) modi-
fied for overlap with bones and major blood vessels in
Table 1. Treatment and patient characteristics.
Patient characteristics No. patients
Median age in year s (range) 64 (44 - 78)
Gender: male/female 34/45
PS: 0/1/2 37/40/2
Stage (TMN): IB/IIA/IIB/IIIA/IIIB 2/2/2 27/46
RT total dose in Gy: 45/46/50 66/3/10
Timing of RT: concurrent/sequential 70/9
Series of chemotherapy: 2/3/4/5/6/7 2/2/37/3/34/1
PCI: yes/no 69/10
PS: ECOG Performance Status; RT: radiotherapy; PCI: prophylactic cere-
bral irradiation.
the mediastinum. The CTV volumes were expanded to
the Internal Target Volume (ITV) by adding another 0.5
cm in all directions. The Plann ing Target Volume (PTV)
was then achieved by adding 0.5 mm laterally and 0.8
mm cranio-caudally to th e ITV.
The spinal cord, lungs, heart and oesophagus were
contoured as organs of risk. The tissue constraints were a
maximum dose of 45 Gy to the spinal-cord at any point
and a maxi mum of 50 Gy t o maxi mum 2 0% of t he hear t.
The percentage of the total lung vo lume receiving 20 Gy
(V20) was maximum 40%. Mean lung dose (MLD) was
maximum 19 Gy.
Patients with a good performance (PS = 0 - 1) at the
end of the CT-RT and with no signs of disease progres-
sion were offered prophylactic cranial irradiation (PCI).
The PCI dose given was 2 5 Gy in 1 0 F, 5 F pe r week .
2.4. Follow-Up
After completion of treatment, patients were followed
with CT imaging of chest and abdomen and clinical
evaluation every third to fourth months in the first year
and every sixth months in the following years. Imaging
of brain and bones was only performed if clinically
indicated. If there was sign of relapse, the CT scan was
evaluated by a multidiscip linary tumour board to confirm
the evidence of radiological tumour progression. If re-
lapse was considered likely, a biopsy was performed. If a
biopsy was not possible, a PET scan would be used to
confirm the diagnosis of relapse, except in patients with
metastases in the brain. A few patients, however, pro-
gressed clinically in such a way that a biopsy became
unnecessary. Date of relapse was defined as the date of a
positive CT scan, even if a biopsy or a PET-scan was
subsequently carried out to confirm the recurrence. All
patients received all follow-up scans and no were lost to
Local relapse was defined as recurrence in the ra-
diation field, and regional relapse as recurrence in the
Copyright © 2012 SciRes. JCT
18FDG-PET/CT Is a Useful Tool in Staging Procedure before Chemo-Radiotherapy in Patients with
Limited Disease Small-Cell Lung Cancer. Pattern of Failure and Survival Is Analyzed
regional lymph nodes of the mediastinum or supracla-
vicular region outside of the original PTV. Distant me-
tastases were defined as metastases anywhere else than
mentioned above. All RT treatment plans were evaluated
by the authors to define the loco-regional relapses.
2.5. Statistical Analysis
The statistical analyses were performed using SPSS 18.0
for windows. The survival functions were calculated
from the time of diagnosis for the endpoints and overall
survival by the methods of Kaplan and Meier. The in-
cidence of local, regional and distant relapse was cal-
culated from the time of diagnosis. Patients were cen-
sored from the date of last follow-up. The log rank test
was used for comparison of groups.
3. Results
3.1. Patient Characteristics
The median follow-up time was 17 months (range, 3 - 48
months) for all patients and 28.5 months (range, 14 - 48
months) for patients still alive at the time of analysis.
Treatment and patient characteristics are summarized in
Table 1. Ten patients (13%) were diagnosed in 2007, 23
patients (29%) in 2008, 30 patients (38%) in 2009 and 16
patients (20%) in 2010. During the diagnostic process, all
patients had a CT scan of the chest and abdomen, but
only 8 patients (10%) had a CT/MR scan of the brain.
Thirty-five patients (44%) underwent a FDG-PET scan
as part of the diagnostic process, and this was mainly
patients diagnosed in 2009 and 2010. The frequency of
PET scans in patients diagnosed in 2007 was 20%, 17%
in 2008, 50% in 2009 and 88% in 2010 .
The median follow-up time for patients still alive at
the time of analysis was in the PET-staged group 25
months (range, 14 - 48 months) and 33.5 months (range,
17 - 48 months) in the CT-staged group. Sixty-two pa-
tients (78%) received carboplatin and 17 patients (22%)
cisplatin. All patients received the planned dose of RT.
For patients receiving RT concomitant with CT the me-
dian time from CT to start of RT was 29 days. The size
of the chest radiation fields varied considerably. One
patient had a pathological lymph node in the supraclavi-
cular region as the only disease manifestation and RT
was only performed in the affected supraclavicular re-
gion resulting in a very small radiation field.
The GTV of the primary lung tumour and the patho-
logical lymph nodes had a median value of 93 cm3 (range,
3 - 494 cm3); PTV 581 cm3 (range, 86 - 2055 cm3). The
median V20 was 29% (range, 10% - 52%) and the MLD
was 14 Gy (range, 6 - 24 Gy). Four patients had a V20
exciding the tissue constraints of maximum 40% (41%,
42%, 44% and 52%, respectively) because of special cir-
cumstances specified in the patients records.
Prophylactic cerebral irradiation (PCI) was given me-
dian 19 days (range, 0 - 138 days) after the patient had
finished chemotherapy. The most common reason not to
receive (PCI) was deterioration of the patient’s general
3.2. Pattern of Tumour Recurrence
At the end of analysis 50 of the 79 patients (63%) had a
recurrence of disease.
Figure 1 illustrates pattern of first failure. Seventeen
patients (22%) had a local relapse and five patients (6%)
a regional relapse. No patients had isolated regional
failure. Forty-five patients (57%) developed distant meta-
stases and 15 of these patients (33%) had synchronously
loco-regional relapse.
The most common sites to develop the first distant
metastases were the liver (n = 18), bones (n = 11) oppo-
site lung (n = 10) and the brain (n = 8). Figure 2 shows
the incidence of distant relapse is significantly different
between the PET/CT-staged patients and the CT-staged
patients (p = 0.03). Fifteen of the 35 PET/CT-staged
patients (43%) developed distant failure compared with
30 of the 44 CT-staged patients (68%). No significant
difference was seen in loco-regional relapses; 23% ver-
sus 27%, respectively (p = 0.2) .
The incidence of local relapse was 15% (95% Con-
fidence Interval (CI): 10% - 20%) after 12 months and
30% (95% CI: 23% - 37%) after 24 months, for regional
relapse 6% (95% CI: 3% - 9%) after 12 months and 8%
(95% CI: 4% - 12%) after 24 months, while the incidence
for distant metastases was 43% (95% CI: 37% - 49%)
after 12 months and 58% (95% CI: 52% - 74%) after 24
months (Figure 3).
3.3. Survival
The median overall survival for all patients was 22
months (95% C I: 16 - 28 m ont hs) with a one-year overall
4 1
First failure
Local (n=17)
Regional (n=5)
Distant (n=45)
Figure 1. Pattern of first failure showed as local, regional
and/or distant relapse.
Copyright © 2012 SciRes. JCT
18FDG-PET/CT Is a Useful Tool in Staging Procedure before Chemo-Radiotherapy in Patients with
Limited Disease Small-Cell Lung Cancer. Pattern of Failure and Survival Is Analyzed 375
Months from dia
nosis to rela
Incidence of distant metastases
Figure 2. The incidence of distant metastases in all 79 pa-
tients related to the pre-treatment staging procedure with
Months from diagnosis to relapse
Incidence of relapse
Distant metastases
Local relapse
Regional relapse
Figure 3. The incidence of local relapses, regional relapses
and distant metastases. Each site is analyzed for all 79 pa-
survival of 72% (Standard deviation (SD): 67% - 77 %), a
two-year survival of 45% (SD: 39% - 51%) and a
three-year survival of 28% (SD: 22% - 34%) (Figure 4).
Figure 5 shows a significantly better overall survival
Months from diagnosis
Overall survival
Figure 4. Overall survival of all 79 patients with LD-SCLC
treated with chemo-radiotherapy.
Months from diagnosis
Overall survival
Figure 5. Overall survival of all 79 patients related to the
pre-treatment staging procedure with PET/CT or CT.
in the PET/CT-staged patients with a median overall sur-
vival of 34 versus 17 months in the CT-staged patients (p
= 0.03).
When stratifying the median survival for Eastern Co-
Copyright © 2012 SciRes. JCT
18FDG-PET/CT Is a Useful Tool in Staging Procedure before Chemo-Radiotherapy in Patients with
Limited Disease Small-Cell Lung Cancer. Pattern of Failure and Survival Is Analyzed
operative Oncology Group status (0 versus 1), stage, gen-
der, RT schedule (twice-daily RT versus once-daily),
concomitant CT-RT versus sequential, cisplatin versus
carboplatin and the number of cycles of CT; none showed
any significant difference in overall survival.
3.4. Treatment Time
The median overall treatment time (from start of any
treatment to the end of radiotherapy) was 57 days (range;
25 - 246 days). We stratified the patients in three groups
of equal size according to their overall treatment time
and compared the surv ival between the gro ups, but found
no significant difference in the overall survival (p = 0.9).
3.5. Deaths
At the time of analysis, 49 patients (62%) had died.
Seven patients died without a diagnosed relapse; one pa-
tient died of febrile neutropenia during chemotherapy
and the death was related to the treatment. One patient
died 2.5 months after end of treatment with symptoms of
radiation pneumonitis. The V20 for this patient was 34%
and the MLD 18 Gy. The last five patients died of causes
not related to the treatment or to lung cancer.
4. Discussion
These data describe the outcome of a consecutive patient
population over a period of four years. The survival data
are comparable with other retrospective consecutive stu-
dies of non-selected patients [7,8].
We stratified for differences in patient characteristics
and treatment and found no significant difference in
overall survival, which was expected due to the low
number of patients. However, did we observe a sig-
nificantly improved overall survival for the 44% of the
patients staged with 18FDG-PET/CT scans. Additionally,
these patients had a lower incidence of distant failure;
43% versus 68%. This difference most likely indicates a
more exact staging in the PET/CT group with some
patients with extended disease (ED) erroneously staged
with limited disease in the CT-staged group. However, as
patients staged with a PET/CT scan were primarily
diagnosed in 2009 and 2010, the median follow-up time
for these patients was shorter than for the CT-staged
group (25 months versus 33.5 months, respectively for
surviving patients) and this could influence the result.
A PET scan was found to be superior to a CT scan in
the detection of lymph nodes and distant metastases in
NSCLC and is now established in th e staging of NSCLC
patients [9]. However, the documentation for the use of
PET in SCLC is not as robust as in NSCLC [6], and its
usefulness is still debated. Studies have been made to
evaluate the stage migration phenomenon in SCLC pa-
tients staged using a PET/CT scan, and these seem to up-
stage 0% - 33% of the patients from LD seen on con-
ventional imaging to ED after PET scan [6,10,11]. These
results, however, have to be interpreted with caution
since the studies were small and half of them retro-
spective. However, the use of 18FDG-PET in the staging
of SCLC has increased in recent years. Azad A. et al. [11]
have evaluated the difference in overall survival in a re-
trospective group of 46 consecutive patients undergoing
staging by PET scans and found a significantly longer
overall survival in patients with LD on PET staging
compared with patients upstaged to ED on the PET scan
(median 18.6 months versus 5.9 months). However, this
result could easily be confounded by different subsequent
One important question remains: Is the right staging in
patients with a low burden of metastatic disease clini-
cally important? These patients might benefit from a
combined treatment with CT and RT. In a randomized
study by Jeremic et al. [12], the effects of RT in patients
with SCLC-ED were evaluated. A total of 206 patients
with a complete response at distant sites and a complete
or partial response in the thorax after three cycles of CT
were randomized to either CT alone or accelerated hy-
perfractionated RT (54 Gy; 1.5 Gy/F). The median over-
all survival was found to be significantly higher in the
RT-group (17 months versus 11 months). Two other
trials are now ongoing to confirm this result (REST
(NTR 1527) and RTOG-0937) [13,14]. Until this matter
is properly clarified, it is of a great importance that pa-
tients are protected from potentially toxic thoracic RT as
a standard procedure.
During follow-up, only few isolated loco-regional re-
lapses (no = 5; 6%) and no isolated regional relapses
were observed. The RT was planned so only the primary
tumour and the pathological lymph nodes were encom-
passed with omission of ENI resulting in a smaller ra-
diation field. This strategy is, however, debated due to
the potential risk of increasing the isolated nodal failure
outside the radiation field. In 2006 two phase II [15,16]
studies was preformed to evaluate concurrent CT and
involved-field RT (45 Gy, 1.5 Gy/F) in 27 and 37 pa-
tients, respectively. Baas et al. [15] observed an isolated
regional relapse rate of 6% and De Ruysscher et al. [16]
a higher rate of 11%. In both studies the RT was based
solely on the pre-treatment CT imaging, and it was stated
that a more precise staging with an 18FDG-PET scan
might improve the rate of isolated regional nodal failures.
A prospective study [17], by the same Dutch research
group including De Ruysscher, in 2009 used 18FDG-PET
scans to make omission of ENI in 60 LD-SCLC patients
receiving concurrent CT (carboplatin and etoposide) to-
gether with twice-daily RT (45 Gy, 1.5 Gy/F) and
Copyright © 2012 SciRes. JCT
18FDG-PET/CT Is a Useful Tool in Staging Procedure before Chemo-Radiotherapy in Patients with
Limited Disease Small-Cell Lung Cancer. Pattern of Failure and Survival Is Analyzed 377
observed a low rate of isolated nodal failures (3%). How-
ever, it should be noticed that a difference in definition of
isolated nodal failure was used in this study compared to
the phase II trial by De Ruysscher et al. [16] making
comparison difficult. In 2010 18FDG-PET guided omi-
ssion of ENI was evaluated in a retrospective study by
Shirvani et al. [18], where data on 60 patients treated with
concurrent CT and RT resulting in a low rate of isolated
elective nodal failure (1.7%). In contrast to the pr eviou sly
mentioned study, intensity-modulated radiation therapy
(IMRT) was used and the authors concluded that omis-
sion of ENI was safe using a combination of 18FDG-PET
and IMRT. Recently, two studies [19,20] again evaluated
the omission of ENI guided by only a CT scan and found
low rates of loco-regional relapses in 108 and 38 patients
respectively, treated with RT concomitant with CT. In
our study, omission of ENI was guided by 18FDG-PET in
44% of the patients and by CT scan in the remaining, and
we observed no difference in locoregional relapse rate
between the two groups. Further studies are needed to
clarify the safety of omission of ENI. Results from two
ongoing studies [13] evaluating RT regimes are expected.
In the UK-led phase III CONVERT trial comparing the
twice-daily RT regime (45 Gy in 30F) with a once-daily
RT regime (66 Gy in 33 F), the use of ENI is not allowed.
This differs from the U S-led CALG B 30610 /RTOG 05 38
trial, evaluating three different RT regimes where medi-
astinal lymph nodes are irradiated electively.
Another question is timing of the RT. Several authors
support an early start of RT concomitant with CT [3,4,
21]. In a meta-analysis comparing phase III trials in
LD-SCLC, De Ruysscher [22] showed that the most
important predictor of five-year survival is the time from
the start of any treatment until the end of RT (SER). The
significantly higher five-year survival rate (>20%) was
found in patients with a short SER of less than 30 days.
In our study we had a median SER of 57 days with only
one patient having a SER shorter than 30 days.
We acknowledge that the limi tation of this stud y is the
small number of patients included and the retrospective
design. There were variations in the diagnostic work-up
and the treatment, resulting in the possibility of selection
bias for both the use of PET scans, imaging of the brain
and for the choice of treatment. PET/CT was incorpo-
rated in the diagnostic process during this time period
and there might be a selection bias due to the availability
of PET scanners. Patients were staged at three different
institutes and only one of the institutes had a specific
PET center. This could have influenced the patient
Carboplatin was the primary choice of platinum deri-
vative. This is in contrast to most other studies where
cisplatin is the treatment of choice and considered su-
perior to carboplatin. Whether this could have affected
the frequency of relapse and the overall survival is un-
Despite the retrospective design of this study, the
population is consecutive and no patients were lost to
follow-up. Our data on relapse is therefore validated.
Time and course of death are validated as well due to a
complete registration of all patients in Denmark.
5. Conclusions
The pattern of failure in patients with LD-SCLC under-
going CT-RT showed that the challenge is still a very
high risk of distant metastases. The incidence of isolated
loco-regional failure was low, and this supports the
safety of a treatment strategy of selective irradiation of
pathological lymph nodes.
Patients staged with an 18FDG-PET/CT scan had a sig-
nificantly lower incidence of distant failure and a sig-
nificantly better overall survival compared to patients
staged with a CT scan only. This probably indicates the
value of including an 18PET-CT scan in the staging of
patients with SCLC before deciding on a treatment regi-
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