The predictive value of 18 F-FDG PET-CT for assessing the clinical outcomes in locally advanced NSCLC patients after a new induction treatment: low-dose fractionated radiotherapy with concurrent chemotherapy
Mattoli et al. Radiation Oncology
18 The predictive value of F-FDG PET-CT for assessing the clinical outcomes in locally advanced NSCLC patients after a new induction treatment: low-dose fractionated radiotherapy with concurrent chemotherapy
Maria Vittoria Mattoli 2
Mariangela Massaccesi 0 1
Alessandra Castelluccia 0 1
Valentina Scolozzi 2
Giovanna Mantini 0 1
Maria Lucia Calcagni 2
0 Department of Radiation Oncology, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Largo A. Gemelli , 8, 00168 Rome , Italy
1 Department of Radiation Oncology, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Largo A. Gemelli , 8, 00168 Rome , Italy
2 Institute of Nuclear Medicine, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Largo A. Gemelli , 8, 00168 Rome , Italy
Background: Patients with locally advanced non-small-cell lung cancer (LA-NSCLC) have poor prognosis despite several multimodal approaches. Recently, low-dose fractionated radiotherapy concurrent to the induction chemotherapy (IC-LDRT) has been proposed to further improve the effects of chemotherapy and prognosis. Until now, the predictive value of metabolic response after IC-LDRT has not yet been investigated. Aim: to evaluate whether the early metabolic response, assessed by 18F-fluoro-deoxyglucose positron emission-computed tomography (18F-FDG PET-CT), could predict the prognosis in LA-NSCLC patients treated with a multimodal approach, including IC-LDRT. Methods: Forty-four consecutive patients (35males, mean age: 66 ± 7.8 years) with stage IIIA/IIIB NSCLC were retrospectively evaluated. Forty-four patients underwent IC-LDRT (2 cycles of chemotherapy, 40 cGy twice daily), 26/44 neo-adjuvant chemo-radiotherapy (CCRT: 50.4Gy), and 20/44 surgery. 18F-FDG PET-CT was performed before (baseline), after IC-LDRT (early) and after CCRT (final), applying PET response criteria in solid tumours (PERCIST). Patients with complete/partial metabolic response were classified as responders; patients with stable/progressive disease as non-responders. Progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meyer analysis; the relationship between clinical factors and survivals were assessed using uni-multivariate regression analysis. Results: Forty-four out of 44, 42/44 and 23/42 patients underwent baseline, early and final PET-CT, respectively. SULpeak of primary tumour and lymph-node significantly (p = 0.004, p = 0.0002, respectively) decreased after IC-LDRT with a further reduction after CCRT (p = 0.0006, p = 0.02, respectively). At early PET-CT, 20/42 (47.6%) patients were classified as responders, 22/42 (52.3%) as non-responders. At final PET-CT, 19/23 patients were classified as responders (12 responders and 7 non-responders at early PET-CT), and 4/23 as non-responders (all non-responders at early PET-CT). Early responders had better PFS and OS than early non-responders (p ≤ 0.01). Early metabolic response was predictive factor for loco-regional, distant and global PFS (p = 0.02, p = 0.01, p = 0.005, respectively); surgery for loco-regional and global PFS (p = 0.03, p = 0.009, respectively). (Continued on next page) © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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Conclusions: In LA-NSCLC patients, 18F-FDG metabolic response assessed after only two cycles of IC-LDRT predicts the
prognosis. The early evaluation of metabolic changes could allow to personalize therapy. This multimodality approach,
including both low-dose radiotherapy that increases the effects of induction chemotherapy, and surgery that removes
the disease, improved clinical outcomes. Further prospective investigation of this new induction approach is warranted.
Lung cancer is the leading cause of death from cancer
worldwide due to both its high incidence (estimated
incidence of 1.8 million new cases in 2012) and fatality
(overall ratio of mortality incidence of 0.87)
. Non-small-cell lung cancer (NSCLC) is the most
frequent among lung cancers and, unfortunately,
approximately 30% of patients are diagnosed with locally
advanced NSCLC (LA-NSCLC), including unresectable
stage II to III disease. Patients with LA-NSCLC, still
represent a challenge for clinicians because the optimal
treatment has not been clearly established and the
prognosis is poor. To date, the Tumor-Node-Metastasis
(TNM) staging system  - mainly based on
morphologic and dimensional criteria and on anatomic
localization - is considered the most important tool to
define the disease stage, to guide treatment, and to
estimate the prognosis. There is a general agreement among
national and international guidelines that in patients
with stage III NSCLC, the standard care is definitive
concurrent chemo-radiotherapy (http://www.nccn.org/
professionals/physician_gls/pdf/nscl.pdf ) [3–7]. Despite
the risk of severe toxicity of this therapeutic approach,
and occasionally death from pneumonitis, less than 20%
of the patients is free from disease progression after
5 years . The prognosis, in addition to being poor, is
variable because it differs among patients despite
belonging to the same TNM stage (homogenous group); it
is multifactorial because it may be influenced by
environmental, patient and tumour factors, including
molecular profile [9, 10]; it is dynamic because it may be
different at staging, after treatment or at recurrence
. Therefore, aiming to improve the prognosis, the
attention is focused on: 1) finding new therapeutic
approaches, such as induction chemotherapy with or
without concurrent low-dose radiotherapy before the
standard treatment; 2) personalizing the therapy taking
into account several factors, such as patient-related
characteristics, tumour histology, co-morbidities; 3)
assessing, as early as possible, the response to treatment.
18Ffluoro-deoxyglucose positron emission tomography
(PET) is a well-established and useful tool to assess the
metabolic response (early or late) [12, 13] and to select
non-responder from responder patients allowing to
tailor the treatment [14, 15], as well as to predict the
outcome on the basis of early or late changes in tumour
metabolism [16–18]. PET response criteria in solid
tumours (PERCIST)  has been proposed in 2009 to
evaluate the metabolic changes after treatment using the
standardized uptake value normalized to lean body mass
Until now, the predictive value of metabolic response
after low-dose radiotherapy concurrent to the induction
chemotherapy (IC-LDRT) in NSCLC patients has not
yet been investigated. The aim of our study was to
retrospectively evaluate whether the early metabolic
response - assessed by 18F-fluoro-deoxyglucose
positron emission-computed tomography (18F-FDG
PETCT) - could predict the disease progression free
survival and the overall survival in patients with NSCLC
stage III treated with a multimodal approach
including IC-LDRT, neoadjuvant chemo-radiotherapy, and
We retrospectively reviewed the clinical charts and
electronic database of consecutive patients with
histologically diagnosed NSCLC stage III, according to the 7th
edition of the TNM classification for lung cancer ,
between January 2009 and October 2014. All patients,
although judged medically fit for neo-adjuvant
concurrent chemo-radiotherapy and for surgery, were either
unresectable (due to N3 contralateral nodal involvement,
mediastinal invasion, or bulky N2 disease) or resectable
requiring a pneumonectomy.
Pulmonary physician evaluated the preoperative risk of
mortality and long-term disability for major anatomic
resection, according to Brunelli A et al.  performing
cardiovascular evaluation and spirometry to measure the
predicted post-operative Forced Expiratory Volume in
1 s (FEV1) and the diffusing capacity for carbon
monoxide (DLCO). When considered appropriate, the following
additional tests were performed: a low technology
exercise test (stair climbing altitude -SCA- or shuttle walk
distance -SWD), and a cardiopulmonary exercise test
(peak oxygen consumption -VO2peak). In addition,
quality-of-life was assessed using the Eastern
Cooperative Oncology Group Performance Status (ECOG PS).
Each patient of our cohort had ECOG PS less or equal
to 1, and were classified as at low risk for anatomic
surgical resection (FEV1 and DLCO >60%; FEV1 and DLCO
within 30–60% plus SCA > 22 m or SWD > 400 m; FEV1
and DLCO within 30–60% plus SCA < 22 m or SWD <
400 m plus VO2peak >75%).
The staging evaluation included: total body diagnostic
computed tomographic (CT), bone scintigraphy, brain
CT or magnetic resonance (MR), and 18F-FDG PET-CT
(baseline PET-CT). The pathologic proof of N2 and/or
N3 involvement was required whenever lymph-nodes
showed or the short axis higher than 1 cm on diagnostic
CT or increased metabolic activity on 18F-FDG PET-CT.
This retrospective study has been approved by the Ethics
Committee of Fondazione Policlinico Universitario A.
Treatment and follow-up
The induction treatment protocol - consisted of two
cycles of platinum-based chemotherapy - administered
concurrently with “ultra-fractionated low dose”
radiotherapy (LDRT, 40 cGy twice daily, days 1–2 and 8–9,
every cycle) delivered with a conformal technique to the
primary tumour, involved regional lymph-nodes and
those adjacent, as showed in Fig. 1. After concurrent
low-dose radiotherapy to induction chemotherapy
(ICLDRT), patients were re-evaluated and underwent: 1)
surgery when medically fit patients showed a complete
metabolic response on mediastinal lymph-nodes and/or
resectable residual primary tumour extension; 2)
neoadjuvant concurrent chemo-radiotherapy (CCRT, total
dose 50.4Gy, fractionation 1.8Gy/day) delivered with
Linac using a conformal or intensity modulated
technique to the sites of residual disease and, in case of
mediastinal nodal clearance, originally involved nodal
stations were also included in medically fit non-surgical
patients without distant progression; 3) best supportive
care, second-line chemotherapy, and/or palliative
radiotherapy, according to the referring physician’s
preference, in medically fit patients with distant progression
and patients with poor medical conditions. After CCRT,
patients were re-evaluated and underwent surgery or
best supportive care, as reported above. Patients were
followed every 3 months for 2 years with diagnostic
total-body CT and brain MR or CT; then every 6 months
18F-FDG PET-CT acquisition protocol and response
Three 18F-FDG PET-CT were performed using the same
acquisition and reconstruction protocols: before starting
IC-LDRT (baseline PET-CT), at the end of IC-LDRT
(early PET-CT), and at the end of CCRT (final PET-CT).
The details of the study were explained and all patients
provided written informed consent. All patients fasted
for at least 6 h and presented a blood glucose level
<150 mg/dl. PET-CT was performed 60 ± 10 min after
administration of 240Mq of 18F-FDG (range: 185–
333 MBq), according to the body mass index. No oral
or intravenous contrast agents were administered nor
bowel preparation were applied for patients. All the
studies were performed using an integrated PET-CT
device (3D Gemini GXL, Philips Healthcare,
Cleveland, OH) with the same injected dose activity
(±20%). An X-ray scout was carried to precisely define
the spatial range of CT acquisition and a low-dose CT
scan was performed from the base of the skull to the
thighs (120 kV, 75 mA). CT images were used for the
anatomical localization, for attenuation correction and
fusion with PET images. Matched CT and PET
images were reconstructed with a field-of-view of
50 cm. PET data were also shown in a rotating
maximum intensity projection. PET and CT datasets were
transferred to an independent computer workstation
by DICOM (Digital Imaging and Communications in
A semi-quantitative analysis was performed on
PETCT images using the Syntegra Philips fusion program by
two nuclear medicine physicians (M.V.M. and V.S.) with
Fig. 1 Treatment scheme of low-dose fractionated radiotherapy concurrent with induction chemotherapy. Legend: Solid bars represent 40 cGy
PET-CT experience. PET Response Criteria in Solid
Tumours (PERCIST) version 1.0 criteria  were used to
evaluate the metabolic response on early and final
PETCT. According to the PERCIST criteria, the Standardized
Uptake Value (SUV) corrected for lean body mass (SUL)
was calculated ; the SULpeak was determined using
spheric regions of interest (with a diameter of about
1.2 cm) manually drawn over the primary tumour and
over the lymph-node showing the highest 18F-FDG
uptake. The percentage changes in SULpeak (ΔSULpeak)
were also calculated between PET-CT scans. Patients
with complete or partial metabolic response were
classified as responder, and patients with stable or progressive
disease as non-responders.
The data were analysed by using the MedCalc Statistical
Software version 12.7.2 with statistical significance set at
p < 0.05. Results were reported with 95% Confidence
Intervals (CI). Student’s paired t test was used to compare
the SULpeak at different time points. Disease progression
free survivals (loco-regional, distant and global) and
overall survival were calculated according to the Kaplan
Meyer method and differences between groups were
tested with the log-rank. Predictive factors for survivals
were identified using univariate and multivariate
regression analysis. Each factor whose p value was less than
0.1 in the univariate analysis was included in the
Population and treatment
Forty-four patients (mean age: 66 ± 7.8 years, range: 47–
81; 35 males) with NSCLC stage III were included in this
analysis. The patients’ clinical characteristics are
illustrated in Table 1. The majority of patients reported
mediastinal lymph-node involvement of whom 26 with N2
(59.1%), and 10 with N3 (22.7%). Twenty-six out of 44
(59.1%) patients had stage IIIA, 18/44 (40.9%) patients
stage IIIB. Figure 2 shows the treatment flow-chart. In
particular: 44, 42 and 23 patients underwent baseline,
early and final PET-CT, respectively.
All 44 patients completed the IC-LDRT and,
subsequently, 4 (9.0%) underwent surgery, 26 (59.1%)
underwent neo-adjuvant CCRT, 14 (31.8%) received palliative
or best supportive care (in 3 patients the medical
conditions worsened after IC-LDRT, 4 developed distant
metastasis, and in 7 the CCRT was considered unsafe).
Twenty-six out of 44 patients (59.1%) underwent
CCRT and, subsequently, 16/26 patients (61.5%)
underwent surgery and 10/26 (38.5%) received palliative or
best supportive care for the worsening of medical
conditions or for the development of distant metastasis.
Table 1 Patients’ characteristics
Squamous cell carcinoma
Not otherwise specified
All 44 patients underwent baseline PET-CT (mean time
from diagnosis: 6.6 ± 3.4 weeks): the mean value of
SULpeak of the primary tumour and lymph-node was 14.9
(±6.7) and 9.3 (±6.6), respectively.
Fig. 2 Treatment flow-chart. Legend: IC-LDRT: low-dose radiotherapy
performed during induction chemotherapy; BSC: best supportive
care; CCRT: concurrent chemo-radiotherapy; PET-CT: positron emission
Forty-two out of 44 patients (95.5%), who completed
IC-LDRT, underwent early PET-CT (after a mean time
of 4.5 ± 2.8 weeks): the mean value of SULpeak of the
primary tumour and lymph-node was 11.8 (±7.8) and 5.3
(±6.3), respectively. A significant reduction in SULpeak of
the primary tumour and lymph-node (p = 0.004, p =
0.0002), respectively was observed between baseline
PET-CT and early PET-CT, as shown in Fig. 3. The
mean value of ΔSULpeak of the primary tumour and
lymph-node between early PET-CT and baseline
PETCT was −14.9% (±63.5%) and −43.3% (±53.9%),
respectively. No significant difference in tumour SULpeak or
lymph-node SULpeak was found between stage IIIA and
stage IIIB, either at baseline PET-CT or at early
Applying the PERCIST criteria at early PET-CT, 20/42
(47.6%) patients were classified as early responders of
whom one with complete and 19 with partial metabolic
response; 22/42 (52.3%) patients were classified as
nonresponders of whom 20 with stable disease and 2 with
progressive disease. We describe, in detail, the treatment
scheme performed after IC-LDRT and the follow-up of
the 22 NR patients at early PET-CT. Twelve out of 22
NR patients underwent CCRT of whom: 7/12 showed
local disease progression, 8/12 developed distant
metastases, and 10/12 showed global disease progression.
Eight out of 22 NR patients underwent palliative
treatments, such as chemotherapy and/or palliative
radiotherapy, of whom: 4 developed distant metastasis and 4
showed local disease progression. One out of 22 NR
patient underwent surgery and developed distant
metastasis. One out of 22 NR patient underwent best supportive
care due to worsening of medical conditions.
At baseline PET-CT, responder patients did not show
any significant difference in SULpeak of the primary
tumour and lymph-node when compared with
Twenty-three out of 26 patients (88.5%) who
completed CCRT underwent final PET-CT (after mean time
5.5 ± 1.7 weeks): the mean value of SULpeak of the
primary tumour and lymph-node was 5.6 (±2.8) and 1.8
(±2.2), respectively. A significant reduction (p = 0.0001,
p = 0.0002, respectively) was observed in SULpeak of the
primary tumour and lymph-node between baseline
PETCT and final PET-CT, as well as between early PET-CT
and final PET-CT (p = 0.0006, p = 0.02, respectively), as
shown in Fig. 3.
Applying the PERCIST criteria at final PET-CT, 19/23
(82.6%) patients were classified as responders of whom
two with complete and 17 with partial metabolic
response; 4/23 (17.4%) patients were classified as
nonresponders all with stable disease. All patients classified
as responders at early PET-CT remained responders at
final PET-CT (12/12); 7/11 patients classified as
nonresponders at early PET-CT became responders at final
PET-CT: 100% vs 63.6%, p = ns.
Metabolic response and clinical outcomes
In all patients (n = 44), the two-year loco-regional,
distant and global disease progression free survival rates
were 51.7, 48.3, and 34%, respectively; the two-year
overall survival rate was 59%. The median loco-regional,
distant, and global disease progression free survival times
were 33, 24, and 17 months, respectively; the median
overall survival time was 51 months. After IC-LDRT,
responder patients at early PET-CT (20/42) had significant
better loco-regional, distant, and global disease
progression free survival and overall survival than
nonresponder patients (22/42): p = 0.0007, p = 0.0007, p =
0.0002, p = 0.01 (Fig. 4, Table 2).
In patients who underwent CCRT (n = 26), the
twoyear loco-regional, distant, and global progression
disease free survival rates were 67.3, 54.6, 44.7%,
respectively; the two-year overall survival rate was 65.4%.
Regarding patients who underwent baseline, early and
final PET-CT (n = 23), patients classified as responders
at early PET-CT (n = 12/23) had significant better
locoregional, distant, and global progression disease free
survival than patients classified as non-responder at early
PET-CT (11/23): p = 0.007, p = 0.03, p = 0.02, respectively
Fig. 3 SULpeak of primary tumour (a) and lymph node (b) in each patient at baseline PET-CT (n = 44), early PET-CT (n = 42), and final PET-CT
(n = 23). Legend: Dashed lines represent mean values
Fig. 4 Loco-regional (a), distant (b) and global (c) progression free survival and overall survival (d) according to early metabolic response
In patients who underwent surgery (n = 20), the
twoyear loco-regional, distant and global disease progression
free survival rates were 77.3, 67.5, and 59.8%,
respectively; the two-year overall survival rate was 78.6%. Also
in this sub-group, patients classified as responders at
early PET-CT (n = 13) had significant better
locoregional, distant and global disease progression free
survival than non-responder patients (n = 7): p = 0.04, p =
0.01, p = 0.04, respectively (Table 2).
At univariate analysis, surgery, SULpeak of N at staging,
and metabolic response evaluated at early PET-CT were
significant predictive factors for loco-regional disease
progression free survival (p = 0.0001, p = 0.02, p = 0.001,
respectively); SULpeak of T at staging and metabolic
response evaluated at early PET-CT were significant
predictive factors for distant disease progression free
survival (p = 0.02, p = 0.01, respectively); surgery and
metabolic response evaluated at early PET-CT were
significant predictive factors for global disease progression
free survival (p = 0.0006, p = 0.0002, respectively);
surgery and metabolic response evaluated at early PET-CT
were significant predictive factors for overall survival (p
= 0.02, p = 0.02, respectively). The multivariate analysis
showed, surgery and metabolic response at early
PETCT were significant predictive factors for loco-regional
disease progression free survival (p = 0.03, p = 0.02,
respectively); SULpeak of T at staging and metabolic
response at early PET-CT were significant predictive
factors for distant disease progression free survival (p =
0.04, p = 0.01, respectively); age, surgery and metabolic
response at early PET-CT were significant predictive
factors for global disease progression free survival (p = 0.04,
p = 0.009, p = 0.005, respectively). No parameter was a
significant predictive factor for overall survival (Table 3).
Table 2 Two-year survival endpoints according to metabolic response at early PET-CT in different patients’ groups
Patients who underwent final PET-CT 23 R
100% p = 0.007
67.9% p = 0.03
67.9% p = 0.02
77.8% p = 0.06
Patients who underwent surgery
100% p = 0.04
83.3% p = 0.01
83.3% p = 0.04
87.5% p = 0.16
R responder, NR non-responder, PFS progression free survival, PET-CT positron emission tomography-computed tomography
Table 3 Multivariate analysis for potential prognostic factors
Baseline SULpeak of T
Baseline SULpeak of N
Early metabolic response
SULpeak standardized uptake value corrected for lean body mass, PFS progression free survival, OR Odds ratio, CI confidence interval, T primary tumour,
To the best of our knowledge, this is the first study that
has evaluated the role of 18F-FDG PET-CT performed
early after low-dose fractionated radiotherapy
concurrent to the induction chemotherapy for predicting the
clinical outcomes in patients with non-small-cell lung
cancer stage III. In these patients, several efforts have
been made to find the best therapeutic approach to
improve the prognosis. The National Comprehensive Cancer
Network guidelines (NCCN)
concurrent definitive chemo-radiotherapy as the standard
treatment in patients with locally advanced disease.
However, in patients with ipsilateral mediastinal or sub-carinal
lymph-node disease (N2), the induction chemotherapy
with or without concurrent radiotherapy, is an additional
option to reinforce the effects of neo-adjuvant
chemoradiotherapy aiming to downstage the disease. In
N2patients, the choice between concurrent definitive
chemoradiotherapy and induction therapy is based on factors
regarding either the patient or the neoplastic disease: clinical
conditions, primary tumour resectability, and extension
and bulkiness of mediastinal lymphadenopathy .
Despite these different approaches, the patients have a slight
chance of survival or being free from disease long-term
progression. In particular, in patients treated with
concurrent chemo-radiotherapy the predominant failure is the
loco-regional recurrence ranging from 63 to 84% at three
years . From these data, it is possible to state that the
current radiation dose seems insufficient to reliably
establish the local control. A randomized study (the Intergroup
0139)  in patients with NSCLC stage IIIA (N2) has
demonstrated that, by completely removing the tumour
and the lymph-node metastasis, surgery improves the
local control when compared with radiotherapy, however,
not improving the overall survival. Therefore, it is still
debated whether surgery with comorbidity risk is a justifiable
option in patients with such an aggressive and
unfavourable disease. In this scenario, it is of paramount
importance to have a reliable tool to evaluate the response to
treatment as early as possible, in order to prompt select
patients who either continue, or change or intensify the
treatment, personalizing it. 18F-FDG PET-CT is largely
used in oncology particularly to monitor the early changes
in glucose metabolism after treatment and for prognostic
information [12–18]. The PERCIST criteria were proposed
as a functional method to evaluate the treatment response
in several cancers .
From our results, we observed that at baseline
PETCT, the glucose avidity of primary tumours and
lymphnodes, as expressed by SULpeak, was high and variable
among patients and similar to that reported by Ding et
al. . The enhanced trapping and the large variability
of 18F-FDG in the tumour cells is still being studied
because several biological mechanisms, such as the
upregulation of glucose transporters and hexokinase
enzymes, tumour aggressiveness, hypoxia, etc. [26–29] are
responsible for the different levels of 18F-FDG uptake, as
well as the histotype and the histological grading. In our
population, the predominant histotype was
adenocarcinoma, as expected being the most frequent histotype ,
that has a relatively low 18F-FDG avidity [31, 32]; on the
other hand, also the squamous histotype was
wellrepresented that has a high 18F-FDG avidity [33, 34]. In
addition, in both histotypes the histological grading was
G2 or G3 (moderately or poorly differentiated) that are
typically more 18F-FDG avid than G1
(well-differentiated) [33–36]. Moreover, we did not find any significant
difference in metabolic activity between stage IIIA and
stage IIIB. This result can be explained because this
classification is based on two morphological criteria (size of
primary tumour and anatomic localization of
lymphnode) and it does not take into account any metabolic
characteristic (18F-FDG uptake/SUV) that, conversely,
reflects biological features of tumour cells.
In the last years, low-dose fractionated radiotherapy
(<1 Gy) concurrent to the induction chemotherapy has
been proposed to further improve the effects of
induction chemotherapy in several solid tumours, such as
locally advanced breast cancer [37, 38], pancreatic cancer
, head neck carcinoma , glioblastoma  and
NSCLC . In-vitro studies have demonstrated that
LDRT chemo-potentiates the effects of cisplatin ,
and that concomitant four low-dose radiotherapy
fractions provide the optimal cell killing, either with
apoptosis or clonogenic inhibition [43, 44], without further
increasing toxicity. Moreover, in-vivo studies on several
types of epithelial cancer have demonstrated that LDRT
is feasible and well tolerated , having an overall
response rate of 45% [42, 45]. In our study, after two
cycles of IC-LDRT, we observed a significant reduction of
the metabolic activity, as expressed by the SULpeak
reduction, indicating that also this approach acts on all
tumour cells both in primary tumours and lymph-nodes.
In particular, the metabolic reduction was more evident
in lymph-nodes: this finding could be probably due to
their higher radio-sensitivity that could be linked either
to a higher cell replication rate or to their less amount
of hypoxia and/or necrosis in lesions with small size
. In addition, after IC-LDRT, approximately 50% of
patients showed good results, such as complete and/or
partial metabolic response and, therefore, defined as
responders. This finding allows to state that also this
induction approach, considered preparatory for the
stronger subsequent therapies, acts on tumour cells
killing or stunning them [42, 43] as demonstrated by the
reduction of metabolic activity. These favourable results
allowed modifying, although in few patients, the planned
therapeutic scheme leading them directly to surgery.
Regarding non-responder patients, 18F-FDG PET-CT
allowed to identify not only patients with stable disease
but also those who developed earlier distant metastasis.
In our study, the rate of patients with progressive
metabolic disease after IC-LDRT was remarkably lower than
that recently reported in literature  in a similar
population treated with induction chemotherapy and
assessed with PERCIST criteria. The addition of
lowdose radiotherapy to the induction chemotherapy,
probably induces an early improvement of anti-tumour
immune-response also against micrometastases outside
of the radiation field .
We did not find any significant difference in SULpeak
either in primary tumour or in lymph-node by
analysing the baseline PET-CT in responder and in
nonresponder patients. Since the metabolic activity of the
primary tumour and/or neoplastic lymph-nodes at
baseline PET-CT did not distinguish responders from
non-responders, and considering that tumours are
inhomogeneous, it is hoped that SULpeak limitation could
be overcome by using either more sophisticated
parameters (Ki, k1, k2, ecc) obtained by absolute
quantification, or evaluating additional metabolic pathways
(hypossia, aminoacids, ecc.) with other radiotracers.
These new approaches could highlight differences
between responders and non-responders at baseline
PETCT, still hidden at SULpeak..
Lastly, in patients that completed the treatment
(ICLDRT plus CCRT), we found a further reduction of
18FFDG uptake at final PET-CT, as expected, in primary
tumours and lymph-nodes when compared either with
baseline PET-CT or early PET-CT, suggesting a further
effect of the CCRT on tumour cells. The completed
treatment provided very good results: while all
responder patients at early PET-CT persisted as responder
at final PET-CT, the CCRT allowed to rescue several
patients defined as non-responders after IC-LDRT
increasing the rate of responder patients at final PET-CT.
In our population, we found good overall survival: this
result is in line with that reported by some Authors [49,
50] in patients treated with standard chemo-radiotherapy
and surgery but remarkably higher than that reported by
other Authors [47, 51] in patients treated with induction
chemotherapy. These data further suggest that the
improvement of the overall survival seems to be influenced
by: 1) surgery, that removing the disease, can play an
important role in patients with locally advanced NSCLC; 2)
induction therapy, particularly when concurrent low-dose
radiotherapy is added, that boosts the subsequent
treatment; 3) the personalization of the treatment that allows
to tailor the therapy to the individual patient. Finally, in
our population we observed that the rate of loco-regional
recurrence was less than 30% with a tendency to decrease
when loco-regional treatments, in particular surgery, were
performed allowing to achieve a more effective
Regarding the relationship between clinical outcomes
and metabolic response, we observed that patients
classified as non-responders at early PET-CT had a shorter
loco-regional, distant, and global disease progression free
survival, and overall survival than those classified as
responders. This result was also observed in patients that
completed all treatment (IC-LDRT, CCRT) and in those
who underwent surgery. Therefore, we can assert that
the early metabolic response performed after two cycles
of IC-LDRT using “functional” PERCIST criteria, allows
to identify patients with poor prognosis: indeed, the
majority of patients classified as non-responders showed
early disease progression during follow-up. From a
clinical point of view, non-responder patients after
ICLDRT despite becoming responders after CCRT and/or
surgery, have poor prognosis: therefore, the choice of a
more appropriate therapy after IC-LDRT still represents
a difficult challenge. Probably for these patients even
more intensified local treatment are needed.
Similarly to our study, Fledelius J et al.  applied
PERCIST criteria to retrospectively evaluate the
prognostic value of PET-CT after induction chemotherapy.
Although the metabolic response rate appears similar
(almost 50%) between the two studies, the clinical
outcomes were different: both our responder and
nonresponder patients had remarkable longer disease
progression free survival and overall survival. This finding
could be due to differences in baseline features of the
included patients or to a potential effect of low-dose
radiation therapy as a chemo-enhancer  to the
subsequent concurrent radio-chemotherapy or to the
“tailored” treatment scheme for the individual patients.
From our data, even if only at a univariate analysis, we
found that the distant and the loco-regional progression
free survival were affected by SULpeak of the primary
tumour and SULpeak of the lymph-nodes at staging,
respectively: higher SULpeak, higher aggressiveness, higher
chances to develop distant micrometastasis, as well as
loco-regional recurrences. The multivariate analysis
showed that surgery was a predictive factor for assessing
the loco-regional and global disease progression free
survival, suggesting that medically fit patients could benefit
from surgery improving the disease control. Moreover,
the early metabolic response was the only predictive
factor for assessing all disease endpoints: it is well known
that the tumour metabolism, as expressed by SULpeak,
reflects the metabolic behaviour in terms of cell
aggressiveness, proliferation, and de-differentiation [52, 53].
Therefore, the early SULpeak reduction suggests that the
tumour cells are either more sensitive to treatment or,
probably, not so aggressive, despite their high metabolic
activity at staging. From a clinical point of view, the
early metabolic response, being predictive of prognosis,
allows to personalize the subsequent therapeutic
strategy, taking into account the functional changes in
addition to the clinical conditions and the morphological
aspects. Lastly, any parameter was able to predict the
overall survival: NSCLC stage III still remains a shadow
area for clinicians and further efforts should be made.
The main limitations of our study are: the relatively
small size of the population and its retrospective
characteristics, however a series of consecutive patients with
LA-NSCLC were included and clinical data were
prospectively collected on an electronic data-base.
18F-FDG PET-CT is a reliable tool to: assess the
metabolic response also in LA-NSCLC patients after
lowdose radiotherapy concurrent to the induction
chemotherapy; early select non-responder from responder
patients allowing to tailor the subsequent therapeutic
approach; predict the clinical outcomes on the basis of
early metabolic changes. Indeed, patients with
LANSCLC are a heterogeneous group in terms of tumour
volume/extension, lymph-nodal spread and prognosis;
therefore, the important functional information provided
earlier by 18F-FDG PET-CT could allow to select
different subgroups of patients that may deserve different
therapeutic strategies, beyond TNM staging based on
morpho-dimensional criteria and anatomic localization.
Moreover, this multimodal approach, including both the
low-dose radiotherapy that increases the effect of
induction chemotherapy, and surgery that removes the
disease, has proven to be a promising treatment option,
improving the clinical outcomes in patients with such an
aggressive and unfavourable disease. Further randomized
and controlled prospective investigations of this new
induction strategy are warranted.
18F-FDG PET-CT: 18F-fluoro-deoxyglucose positron emission-computed
tomography; CCRT: Concurrent chemo-radiotherapy; IC-LDRT: Concurrent
lowdose radiotherapy to induction chemotherapy; LA-NSCLC: Locally advanced
non-small-cell lung cancer; PERCIST: PET response criteria in solid tumours;
SUL: SUV corrected for lean body mass; SUV: Standardized uptake value;
TNM: Tumor-Node-Metastasis staging system
MLC and GM were responsible for the primary concept and design of the
study; MVM, MM, VS and AC performed the data capture and analysis. MVM,
MLC, MM and AC drafted the manuscript. VS and MM performed the
statistical analysis. MLC supervised the study. All authors read and approved
the final manuscript.
Ethics approval and consent to participate
This retrospective study has been approved by the Ethics Committee of
Fondazione Policlinico Universitario A. Gemelli, Rome.
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