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Contents lists available at ScienceDirect

Lung Cancer
journal homepage: www.elsevier.com/locate/lungcan

RECIST progression patterns during EGFR tyrosine kinase inhibitor

treatment of advanced non-small cell lung cancer patients harboring
an EGFR mutation
Tatsuya Yoshida a,b,∗ , Kiyotaka Yoh a , Seiji Niho a , Shigeki Umemura a , Shingo Matsumoto a ,
Hironobu Ohmatsu a , Yuichiro Ohe a,c , Koichi Goto a
a
Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
b
Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
c
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Background: Progression patterns at the response evaluation criteria in solid tumors-progressive dis-
Received 11 June 2015 ease (RECIST-PD) during treatment with epidermal growth factor receptor tyrosine kinase inhibitors
Received in revised form 18 August 2015 (EGFR-TKIs) for advanced non-small cell lung cancer (NSCLC) in patients harboring an EGFR mutation are
Accepted 29 September 2015
clinically heterogeneous. We evaluated the association between progression patterns during EGFR-TKI
treatment and prognosis after treatment in such patients.
Keywords:
Methods: From 2008 to 2012, 160 consecutive patients with advanced NSCLC harboring an EGFR mutation
Non-small cell lung cancer
were treated with EGFR-TKIs (erlotinib or gefitinib). Among these, 104 who experienced RECIST-PD were
Epidermal growth factor receptor mutation
EGFR tyrosine kinase inhibitors
retrospectively evaluated for initial response to EGFR-TKIs, progression sites, focus of progression (soli-
tary lesion or multiple lesions), symptom status at RECIST-PD evaluation, and post-progression survival
(PPS).
Results: Of 104 patients, 96 (92%) had an EGFR major mutation, and 50 (48%) received EGFR-TKIs as
first-line treatment. Overall response rate and median time to RECIST-PD on EGFR-TKIs were 68% and 8.2
months, respectively. At the time of attaining RECIST-PD status, 44 (42%) patients were symptomatic, and
60 (58%) were asymptomatic. Progression sites at RECIST-PD were isolated brain in 17 (16%) patients and
systemic in 87 (84%): 24 (23%) had a solitary lesion, and 80 (77%) had multiple lesions. After RECIST-PD
assessment, 40 (38%) patients continued EGFR-TKIs, and 25 (24%) switched to cytotoxic agents; 10 (10%)
received local radiotherapy for an isolated progression site (brain 6; bone 3; lung 1). Median PPS was 10.8
months. Multivariate analysis revealed that asymptomatic or solitary lesion status was associated with
significantly longer PPS (asymptomatic: HR 0.36, 95% CI 0.21–0.62, P < 0.01; solitary progression lesion:
HR 0.45, 95% CI 0.18–99, P = 0.04).
Conclusions: Progression patterns at the RECIST-PD during EGFR-TKI treatment of advanced NSCLC in
patients harboring an EGFR mutation are widely diverse, and might be associated with clinical outcome
after treatment failure.
© 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction [1–3]. In randomized phase III trials, EGFR-TKIs were associated

Epidermal growth factor receptor (EGFR) mutations are predic-
tive of the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs)
in patients with advanced non-small cell lung cancer (NSCLC)
∗ Corresponding author at: Department of Thoracic Oncology, Aichi Cancer
Center Hospital, 1-1, Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan.
Fax: +81 52 764 2963.
E-mail address: t.yoshida@aichi-cc.jp (T. Yoshida).
with longer progression-free survival (PFS) and higher radiographic
response rates than treatment with standard first-line platinum-
based chemotherapy of NSCLC patients with an activating EGFR
mutation. Despite an initial dramatic response, almost all patients
treated with EGFR-TKIs eventually acquire resistance to these
drugs. Some mechanisms of acquired resistance have been iden-
tified, including the development of EGFR T790 M mutation, MET
amplification, transformation to small cell lung cancer, or PIK3CA
mutation [4–8].

http://dx.doi.org/10.1016/j.lungcan.2015.09.025
0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: T. Yoshida, et al., RECIST progression patterns during EGFR tyrosine kinase
inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation, Lung Cancer (2015),
http://dx.doi.org/10.1016/j.lungcan.2015.09.025
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Radiographic assessment of the response evaluation criteria in
solid tumors (RECIST) has become the most widely accepted stan-
dard for evaluation of treatment response of most solid tumors
during clinical trials and in practice, and has been typically regarded
as the major method for defining tumor progression and decid-
ing when to change a therapeutic regimen [9,10]. However, recent
reports have indicated that the strategy of continuing with signal
pathway blockade after initial progression of disease could con-
fer an advantage, especially for treatment of cancers harboring an
oncogenic dependence on the molecular target, such as a gastroin-
testinal stromal tumor treated with imatinib, a HER2-amplified
breast cancer treated with trastuzumab, or a colon cancer treated
with bevacizumab [11–13]. Among NSCLC patients with activating
EGFR mutations, although studies have been mostly retrospective
and based on small cohorts, continuing EGFR-TKI treatment after
attaining progressive disease (PD) status as assessed by RECIST
(RECIST-PD) seems to prolong survival time compared with switch-
ing to cytotoxic chemotherapy [14]. On the other hand, the IMPRESS
study showed that there was no statistically significant improve-
ment in PFS for continuation of gefitinib in addition to cisplatin and
pemetrexed beyond RECIST-PD assessment in patients with EGFR
mutation-positive NSCLC who were initially treated with EGFR TKIs
[15]. Optimal management for patients with acquired resistance to
EGFR-TKIs has yet to be defined. Additionally, symptomatic, rapid
tumor progression with radiographic confirmation after stopping
EGFR-TKIs on attaining the RECIST-PD status has been reported,
and continuing EGFR-TKI after the RECIST-PD assessment has
been regarded as a reasonable option for patients with activating
EGFR mutations [16]. The National Comprehensive Cancer Net-
work (NCCN) guidelines recommend the treatment strategy of
continuing EGFR-TKIs or switching to cytotoxic chemotherapy after
progression on EGFR-TKIs, depending on the progression pattern
(isolated brain vs. systemic progression) and the patient’s symp-
toms at the time of RECIST-PD assessment. However, results of
these treatment strategies and the precise classification of progres-
sion patterns at RECIST-PD remain unclear in the practice setting.
To our knowledge, associations between progression patterns at
RECIST-PD on EGFR-TKIs and prognosis have not yet been fully
elucidated.
The aim of this study was to evaluate progression patterns at the
time of RECIST-PD evaluation during treatment with EGFR-TKIs and
assess associations between these progression patterns and clinical
outcome in advanced NSCLC patients harboring an EGFR mutation.
2. Patients and methods
2.1. Patients
Between January 2008 and December 2012, 160 consecutive
patients with advanced NSCLC harboring a sensitizing EGFR muta-
tion were treated with EGFR-TKIs (erlotinib or gefitinib) at our
institution. On January 31, 2013, we retrospectively reviewed
104 patients with evidence of PD as assessed by RECIST version
1.1. RECIST-PD assessment required both a 5 mm increase and at
least a 20% increase of the sum of the longest diameters of the
target lesions, the appearance of new lesion(s) and/or an unequiv-
ocal increase of the non-target lesions during treatments with
EGFR-TKIs. The clinical characteristics evaluated in these patients
included an initial response to EGFR-TKIs; progression sites (iso-
lated brain or systemic); focus of progression (solitary lesion or
multiple lesions); status at RECIST-PD assessment (asymptomatic
or symptomatic); RECIST-PD patterns (the appearance of a new
lesion, or the progression of an existing lesion); presence of car-
cinomatous meningitis; subsequent treatment after RECIST-PD
assessment; and survival time after the initial RECIST-PD assess-
Please cite this article in press as: T. Yoshida, et al., RECIST progression patterns during EGFR tyrosine kinase
inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation, Lung Cancer (2015),
http://dx.doi.org/10.1016/j.lungcan.2015.09.025
ment. Isolated brain progression was defined as a case that only
exhibited brain metastasis at the first progression site. Systemic
progression was defined as a case that exhibited other progression
sites beyond the isolated brain involvement. With regard to the
focus of the progression, solitary lesion progression was defined as
a case having a single progression site at the time of the RECIST-
PD assessment. The date of the progression was defined based on
the routine surveillance imaging (computer tomography [CT] and
magnetic resonance imaging [MRI]). If clinically indicated, bone
scintigraphy, and positron emission tomography (PET)-CT were
also performed. Patients who were switched to another EGFR-TKI
after an initial EGFR-TKI failure were categorized as patients who
underwent EGFR-TKI after the initial RECIST-PD designation. There
was no formal institutional policy on the treatment strategy to be
used after patients were designated as RECIST-PD. All treatment
decisions were made in accordance to the individual judgment of
the treating providers.
2.2. Analysis of EGFR status and EGFR-TKI response
Tumor specimens were analyzed for the presence of somatic
mutations of EGFR using either the Scorpion Amplification Refrac-
tory Mutation System by SRL Inc. (Tokyo, Japan), or the PCR-Invader
Assay by BML Inc. (Tokyo, Japan). For the purpose of this study, the
following EGFR mutations were considered to be sensitizing: dele-
tions in exon 19; L858R point mutation; L861Q point mutation;
and G719 missense point mutations. The objective tumor response
was assessed according to the RECIST version 1.1 [10]. The objec-
tive response rate (ORR) was calculated as the total percentage of
patients with a complete response (CR) or a partial response (PR).
2.3. Statistical analysis
All the statistical analyses were performed using JMP for Win-
dows version 9 statistical software package (SAS Institute, Cary,
NC, USA). Differences in the baseline characteristics between the
groups were compared using Fisher’s exact tests for categori-
cal data. Time to RECIST-PD was measured from the start of the
EGFR-TKI treatment to the date of the RECIST-PD assessment. Post-
progression survival (PPS) was measured from the date of the
RECIST-PD designation to the date of death. Survival probabili-
ties were calculated by the Kaplan–Meier method and compared
among different groups using the log-rank test. Multivariate anal-
ysis of PPS was performed by using the Cox proportional hazards
model to evaluate the importance of seven clinically selected vari-
ables (EGFR mutation type, local therapy for isolated progression
site, progression site, focus of progression, patient status, treatment
beyond RECIST-PD, and carcinomatous meningitis). Covariates
with a P-value inferior or equal to 0.10 in the univariate analysis
were included in the multivariate model. This study was approved
by the Institutional Review Boards of the National Cancer Center.
3. Results
3.1. Patient characteristics and initial EGFR-TKI response
Enrolled-patient characteristics are listed in Table 1. The median
age was 64 years (range, 35–87 years), and 39 (45%) were male.
A total of 88 (84%) patients had an Eastern Cooperative Oncology
Group performance status of 0 or 1. Regarding the EGFR mutation
status, an exon 19 deletion and an L858R point mutation were
detected in 47 (45%) and 49 (47%) of the patients, respectively.
With regard to the brain metastasis status, 25 patients had brain
metastasis before treatment. Gefitinib 250 mg/day was adminis-
tered to 80 (77%) patients and 24 (23%) were treated with erlotinib
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Table 1 progression. With regard to the patient status at the point of the
Patient characteristics (N = 104).
RECIST-PD assessment, 44 (42%) patients were symptomatic and 60
Characteristics N % (58%) were asymptomatic. The most frequent symptom was dysp-
Age, median (Range) 64 (35–87) nea in 20 patients, followed by pain due to bone metastasis in 13,
Sex (male/female) 39/65 38/62 neurologic symptoms due to brain metastasis in 9, and fatigue in 2.
PS 0/1/2/3 26/62/15/1 25/59/15/1 With regard to the focus of the progression site, 24 (23%) patients
Smoking status had a solitary lesion while 80 (77%) had multiple lesions. The most
Current smoker 1 1 frequent site of the solitary progression failure included the lung
Former smoker 50 48 in 13 (54%), followed by the bone in 3 (13%), hilar lymph node in 2
Non-smoker 53 51
(8%), brain in 2 (8%), and liver in 2 (8%) patients.
EGFR mutation
Exon 19 deletion 47 45
L858R 49 47 3.3. Treatment after RECIST-PD evaluation and survival time
L861Q/G719X/L861Q+G719X 5/2/1 8 from RECIST-PD
Histology
Adenocarcinoma 100 96 The median follow-up time was 21.9 (4.0–55.3) months. Among
NSCLC 4 4 104 patients, 65 patients subsequently received anti-cancer ther-
EGFR-TKI
apy after RECIST-PD, including 40 (38%) who continued EGFR-TKIs
Gefitinib 80 77 and 25 (24%) who switched to cytotoxic chemotherapy; 39 (38%)
Erlotinib 24 23 had best supportive care alone. None of the patients received any
Treatment line combination of continued EGFR-TKI and cytotoxic chemotherapy.
1st line/≥2nd line 50/54 48/52 Overall, 10 (10%) patients received local radiotherapy for an iso-
lated progression site. These treatments consisted of whole brain
Brain metastasis
Yes/no 25/79 24/76 radiation in 3, stereotactic radiosurgery (SRS) for a solitary brain
lesion in 3, radiotherapy to bone in 3 and thoracic radiotherapy
NSCLC; non-small cell lung cancer, PS; performance status, EGFR-TKI; EGFR tyrosine
kinase inhibitor, BM; brain metastasis. in 1 patient. There were 8 patients who received local therapy in
conjunction with EGFR-TKI treatments that continued beyond the
point where RECIST-PD was first assessed. Table 2 presents the
details of the 10 patients who underwent local therapy for an iso-
lated progression lesion. The median PPS was 10.8 months (95%
CI, 6.6–13.6 months) in all patients (Fig. 3A). In the 10 patients
who received local radiotherapy for an isolated progression site,
the median PPS was 19.1 months (95% CI, 1 month-not reached
[NR]).

3.4. Predictive factors of PPS after RECIST-PD

The results of univariate and multivariate analyses determin-

Fig. 1. Kaplan–Meier curves for the median time to RECIST-PD status from the start
of EGFR-TKIs.
150 mg/day as the first EGFR-TKI therapy. EGFR-TKI was adminis-
tered as a first-line treatment for advanced or recurrent disease in
50 out of 104 patients, with 54 patients receiving EGFR-TKI as the
second or subsequent line treatment. Initial responses to EGFR-TKI
treatment included 71 patients with a PR, 21 patients with stable
disease (SD), and 12 patients with PD. The ORR was 68%, with a
median time of 8.2 months to RECIST-PD in all patients (Fig. 1).
3.2. Progression patterns at RECIST-PD evaluation
Fig. 2 summarizes the details of progression patterns on EGFR-
TKIs. At the time of RECIST-PD, isolated progression in the brain
occurred in 17 (16%) patients, including carcinomatous meningi-
tis (N = 9), and systemic progression occurred in 87 (84%) patients.
Among 9 patients with carcinomatous meningitis, 7 patients were
symptomatic and 2 patients asymptomatic. In the 17 patients
with isolated brain metastasis progression, the new progres-
sion was associated with the appearance of one or more new
lesions. In contrast, progression of the existing target or non-target
lesions occurred in 48 (55%) out of the 87 patients with systemic
ing predictive factors for PPS after RECIST-PD are shown in Table 3.
In univariate analysis, EGFR mutation type, focus of progression,
and patient status at the RECIST-PD evaluation were significant
factors for PPS. The median PPS was significantly longer among
patients with an EGFR major mutation than among those with
an EGFR minor mutation (median 13.0 months [95% CI, 7.4–16.4
months] vs. 1.1 months [95% CI, 0.2–10.2 months], P < 0.01);
among patients with a solitary progression site than among those
with multiple progression sites (median 22.5 months [95% CI,
8.5–32.7 months] vs. 9.7 months [95% CI, 6.2–13.0months], P < 0.01)
(Fig. 3B); and among asymptomatic compared with symptomatic
patients at the RECIST-PD evaluation (median 16.3 months [95%
CI, 12.6–21.6 months] vs. 4.8 months [95% CI, 2.4–10.2 months],
P < 0.01) (Fig. 3C). By multivariate analysis, we identified 3 factors
associated with duration of PPS: EGFR major mutation (HR 0.39, 95%
CI 0.19–0.91, P = 0.03), solitary progression lesion (HR 0.45, 95% CI
0.18–0.99, P = 0.04), and asymptomatic patient status (HR 0.36, 95%
CI 0.21–0.62, P < 0.01) at RECIST-PD were statistically significant
factors for predicting longer PPS (Table 3).
4. Discussion
Our study revealed that, among the enrolled patients, the pro-
gression patterns at RECIST-PD evaluation during treatment with
EGFR-TKIs were widely diverse, and that presence of a solitary
progression lesion and asymptomatic status were significantly
associated with clinical outcome after failure of EGFR-TKIs regard-
less of the subsequent treatment. To our knowledge, this is the first

Please cite this article in press as: T. Yoshida, et al., RECIST progression patterns during EGFR tyrosine kinase
inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation, Lung Cancer (2015),
http://dx.doi.org/10.1016/j.lungcan.2015.09.025
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Fig. 2. Details of progression patterns at RECIST-PD status on EGFR-TKIs in patients with (A) isolated brain progression site, and (B) systemic progression.
WBRT, whole brain radiotherapy; BSC, best supportive care; RT, radiotherapy; SRS, stereotactic radiosurgery.

Table 2
Outcomes for individual patients treated with local therapy (N = 10).

Age, sex Line Progression sites Symptom Local therapy Subsequent chemotherapy PPS (days)

1 68, F 1st Brain (solitary) Asymptomatic SRS EGFR-TKI beyond PD 321a

2 63, F 1st Brain (solitary) Asymptomatic SRS EGFR-TKI beyond PD (gefitinib → erlotinib) 167a
3 48, F 2nd Brain (multiple) Symptomatic WBRT BSC 31
4 65, F 2nd Brain (multiple) Symptomatic WBRT Pemetrexed 169a
5 63, M 1st Brain (multiple) Asymptomatic WBRT EGFR-TKI beyond PD 204a
6 56, M 1st Brain (multiple) Asymptomatic SRS EGFR-TKI beyond PD 180
7 46, M 2nd Bone (solitary) Symptomatic RT EGFR-TKI beyond PD 851a
8 37, F 1st Bone (solitary) Symptomatic RT EGFR-TKI beyond PD 574
9 67, M 1st Bone (solitary) Symptomatic RT EGFR-TKI beyond PD 320
10 59, F 1st Lung (solitary) Asymptomatic TRT EGFR-TKI beyond PD (gefitinib → erlotinib) 1016a

F; female, M; male, SRS; stereotactic radiosurgery, WBRT; whole brain radiotherapy, RT; radiotherapy, TRT; thoracic radiotherapy, EGFR-TKI; EGFR tyrosine kinase inhibitor,
BSC; best supportive care, PD; progressive disease.
a
Indicates patients who have not died or progressed during study follow-up.

report of evaluation of the details of progression patterns and prog-
nosis after the failure of treatment with EGFR-TKIs for advanced
NSCLC in patients harboring an EGFR mutation.
There have been some reports on isolated brain lesion progres-
sion after EGFR-TKI treatment failure. Lee et al. reported that 16
(13%) of 127 NSCLC patients treated with EGFR-TKIs had isolated
brain lesion progression after initial clinical benefit with EGFR-
TKIs, and patients with isolated brain lesions had better prognosis
than did those with other site failures [17]. Shukuya et al. showed
that 35 of 204 (17%) NSCLC patients, who had clinical benefit from
EGFR-TKIs, had PD in isolated brain metastases [18]: 17 of these
35 patients continued EGFR-TKIs following local therapy (such as

Please cite this article in press as: T. Yoshida, et al., RECIST progression patterns during EGFR tyrosine kinase
inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation, Lung Cancer (2015),
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Table 3
Factors predictive of PPS after RECIST-PD (N = 104).

Variables Univariate analysis Multivariate analysis

P-Value HR (95%CI) P-Value

EGFR mutation (major mutation) <0.01 0.39 (0.19–0.91) 0.03

Local therapy for isolated progression sites 0.06 0.56 (0.15–1.55) 0.28
Progression site (isolated brain) 0.37 – –
Focus of progression (solitary) <0.01 0.45 (0.18–0.99) 0.04
Patient status (asymptomatic) <0.01 0.36 (0.21–0.62) <0.01
Treatment after RECIST-PD (continue EGFR-TKI) 0.06 0.86 (0.50–1.45) 0.57
Carcinomatous meningitis (no) 0.07 0.88 (0.43–2.07) 0.76

to limited penetration of EGFR-TKIs through the blood-brain bar-

Fig. 3. Kaplan–Meier curves of post-progression survival (PPS) time from RECIST-PD
for (A) all patients, (B) asymptomatic vs. symptomatic patients, and (C) patients with
solitary progression vs. multiple progression sites. Vertical bars indicate censored
cases at the cut-off date.
radiotherapy) to the brain, leading to delay of extracranial progres-
sion and avoidance of a switch to cytotoxic agents, which usually
are more toxic. Isolated brain progression as the initial failure pat-
tern in patients treated with EGFR-TKIs is frequently observed due
rier, and the combination of continued EGFR-TKIs and local therapy
for the brain, such as SRS and whole brain radiotherapy (WBRT), in
patients with isolated brain failure is a reasonable treatment strat-
egy. Therefore, isolated brain progression is considered separately
from systemic progression sites outside of the brain.
In patients with systemic progression, a few reports have
recently shown that local therapy for oligometastatic disease fol-
lowed by continued treatment with EGFR-TKIs was associated
with longer overall survival, and can be a useful treatment option,
although local therapy is not commonly used in metastatic lung
cancer cases. Yu et al. reported a retrospective study on the efficacy
of the combination of local therapy and continued EGFR-TKIs in 18
patients who received local therapy for solitary or oligometastatic
disease without brain involvement and continuing EGFR-TKIs, the
median time to further progression and overall survival from local
therapy initiation were 10 months and 41 months, respectively
[23]. Conforti et al. also reported that for 15 (10%) of 147 NSCLC
patients treated with EGFR-TKIs who underwent the combination
of continuation of EGFR-TKIs and loco-regional treatment for a focal
progression lesion (such as radiotherapy), this was an efficacious
therapeutic strategy, and the median time from focal progres-
sion until further progression of disease was 10.9 months [19]. In
patients who have a focal progression site outside of brain dur-
ing EGFR-TKI treatment, the combination of local therapy (such
as radiotherapy and surgery) and continued EGFR-TKI treatment
might be a reasonable therapeutic strategy, similar to the situation
for isolated brain progression cases. Therefore, a single focal pro-
gression site in RECIST progression patterns is distinguishable from
multiple focal progressions. The NCCN guidelines recommend the
combination of continued EGFR-TKIs and local therapy for isolated
progression after treatment with EGFR-TKIs.
By multivariate analysis, our study indicated that patients with
asymptomatic or solitary progression lesions had significantly
better prognosis; whether administration of local therapy and con-
tinued EGFR-TKIs after progression occurred was not associated
with progression in these patients. These results may indicate that
tumor cells in a solitary progression site reflect more indolent
growth than do those in multiple progression sites. The combina-
tion of local therapy for a solitary progression site and continued
EGFR-TKIs to inhibit the growth of cells (except the resistant tumor
cells) after progression could prevent tumor growth in sites other
than the single progression site. On the other hand, patients who
developed multiple focal progression sites and were symptomatic
at RECIST-PD evaluation had poor prognosis compared with soli-
tary site/asymptomatic patients. Since tumor cells in symptomatic
patients with multiple focal sites could have more aggressively
growing cells, it is likely that simply continuing the administra-
tion of EGFR-TKIs after progression might not be enough to control
their condition. Therefore, stopping the administration of EGFR-
TKIs and switching to a cytotoxic chemotherapy might be a better
treatment of choice after the failure of EGFR-TKIs in symptomatic
patients with multiple focal sites.

Please cite this article in press as: T. Yoshida, et al., RECIST progression patterns during EGFR tyrosine kinase
inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation, Lung Cancer (2015),
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There were several limitations in our current study. First, this
was a retrospective study with only a small sample size. In addition,
this study did not use predefined treatment strategies according to
the different progression pattern types. The actual treatment strat-
egy utilized with regard to continuing the EGFR-TKI treatment or
switching to a cytotoxic chemotherapy after the RECIST-PD assess-
ment was dependent on the individual decision of the physician
responsible for the treatment. Furthermore, although we regu-
larly assessed the tumor response by chest X-ray, CT and MRI,
the intervals for the imaging studies were decided according to
the individual judgment of the treating providers. Thus, the imag-
ing was not performed as consistently as would be expected in a
prospective study.
Another limitation of our study was that our data did not include
any details on the possible mechanisms of acquired drug resistance
such as the presence of EGFR T790 M, MET amplification, or trans-
formation to small cell lung cancer. In addition, we did not include
information on patients who received the third generation EGFR-
TKIs, as third generation EGFR-TKIs were not available at the time
of our current analysis. Patients with T790 M after EGFR-TKI failure
have been reported to have better prognoses than those with-
out T790 M [20]. Moreover, since the third generation EGFR-TKIs,
AZD9291 and CO-1686, specifically target the T790 M mutation and
have been developed for overcoming this type of acquired resis-
tance, they have shown promising efficacy and encouraging safety
profiles [21,22]. Further investigations that evaluate the associa-
tion between these progression patterns and the mechanisms of
acquired drug resistance will need to be undertaken.
In conclusion, the multivariate analysis of the current study
showed that the asymptomatic status or presence of a solitary
progression site observed at the time of RECIST-PD assessment
were associated with a significantly longer survival after failure of
EGFR-TKIs, regardless of the subsequent treatment. Therefore, the
treatment strategy for a patient shown to be RECIST-PD needs to be
determined based on the progression patterns that are present at
that time of the initial RECIST-PD assessment. Further multicenter,
prospective studies will need to be performed in order to confirm
the association between the progression pattern at the time of the
RECIST-PD assessment and the clinical outcome.
Conflicts of interest
The authors declare that they have no conflict of interest.
Acknowledgement
This work was supported in part by a Grant-in-Aid for Cancer
Research from the Ministry for Health, Labour and Welfare, Japan.
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Please cite this article in press as: T. Yoshida, et al., RECIST progression patterns during EGFR tyrosine kinase
inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation, Lung Cancer (2015),
http://dx.doi.org/10.1016/j.lungcan.2015.09.025