Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002)

Abstract

BackgroundNEJ002 study, comparing gefitinib with carboplatin (CBDCA) and paclitaxel (PTX; Taxol) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival (PFS). Subsequent analysis was carried out mainly regarding overall survival (OS).Materials and methodsFor all 228 patients in NEJ002, survival data were updated in December, 2010. Detailed information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the impact of some key drugs on OS was evaluated.ResultsThe median survival time (MST) was 27.7 months for the gefitinib group, and was 26.6 months for the CBDCA/PTX group (HR, 0.887; P = 0.483). The OS of patients who received platinum throughout their treatment (n = 186) was not statistically different from that of patients who never received platinum (n = 40). The MST of patients treated with gefitinib, platinum, and pemetrexed (PEM) or docetaxel (DOC, Taxotere; n = 76) was around 3 years.Conclusions
No significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study, probably due to a high crossover use of gefitinib in the CBDCA/PTX group. Considering the many benefits and the risk of missing an opportunity to use the most effective agent for EGFR-mutated NSCLC, the first-line gefitinib is strongly recommended.

Full text

Updated overall survival results from a randomized
phase III trial comparing gefitinib with
carboplatin–paclitaxel for chemo-naïve non-small
cell lung cancer with sensitive EGFR gene mutations
(NEJ002)
A. Inoue1*, K. Kobayashi2, M. Maemondo3, S. Sugawara4, S. Oizumi5, H. Isobe6, A. Gemma7,
M. Harada8, H. Yoshizawa9, I. Kinoshita10, Y. Fujita11, S. Okinaga12, H. Hirano13, K. Yoshimori14,
T. Harada15, Y. Saijo16, K. Hagiwara17, S. Morita18 & T. Nukiwa1for the North-East Japan Study
Group
1
Department of Respiratory Medicine, Tohoku University Hospital, Sendai;
2
Department of Respiratory Medicine, Saitama Medical University International Medical Center,
Saitama;
3
Department of Respiratory Medicine, Miyagi Cancer Center, Miyagi;
4
Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai;
5
First Department
of Medicine, Hokkaido University School of Medicine, Sapporo;
6
Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo;
7
Department of Internal
Medicine, Division of Pulmonary Medicine, Infections Disease and Oncology, Nipppon Medical School, Tokyo;
8
Department of Respiratory Medicine, National Hospital
Organization Hokkaido Cancer Center, Sapporo;
9
Bioscience Medical Research Center, Niigata University Medical & Dental Hospital, Niigata;
10
Department of Medical
Oncology, Hokkaido University Graduate School of Medicine, Sapporo;
11
Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center,
Asahikawa;
12
Department of Respiratory Medicine, Kesennuma City Hospital, Miyagi;
13
Department of Respiratory Medicine, Iwate Prefectural Central Hospital, Morioka;
14
Division of Pulmonary Medicine, Anti-Tuberculosis Association Fukujuji Hospital, Tokyo;
15
Center for Respiratory Diseases, Hokkaido Social Insurance Hospital,
Sapporo;
16
Department of Medical Oncology, Graduate School of Medicine, Hirosaki University, Hirosaki;
17
Department of Respiratory Medicine, Saitama Medical
University, Saitama;
18
Department of Biostatistics and Epidemiology, Yokohama City University Medical Center, Yokohama, Japan
Received 7 March 2012; revised 26 May 2012; accepted 30 May 2012
Background: NEJ002 study, comparing gefitinib with carboplatin (CBDCA) and paclitaxel (PTX; Taxol) as the first-line
treatment for advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR)
mutation, previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival (PFS). Subsequent
analysis was carried out mainly regarding overall survival (OS).
Materials and methods: For all 228 patients in NEJ002, survival data were updated in December, 2010. Detailed
information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the
impact of some key drugs on OS was evaluated.
Results: The median survival time (MST) was 27.7 months for the gefitinib group, and was 26.6 months for the
CBDCA/PTX group (HR, 0.887; P= 0.483). The OS of patients who received platinum throughout their treatment
(n= 186) was not statistically different from that of patients who never received platinum (n= 40). The MST of patients
treated with gefitinib, platinum, and pemetrexed (PEM) or docetaxel (DOC, Taxotere; n= 76) was around 3 years.
Conclusions: No significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study,
probably due to a high crossover use of gefitinib in the CBDCA/PTX group. Considering the many benefits and the risk
of missing an opportunity to use the most effective agent for EGFR-mutated NSCLC, the first-line gefitinib is strongly
recommended.
Key words: EGFR mutation, gefitinib, individualized treatment, lung cancer
introduction
Two pivotal studies have revealed that somatic mutations in
the kinase domain of the epidermal growth factor receptor
(EGFR) strongly correlate with responsiveness to gefitinib, the
first EGFR tyrosine kinase inhibitor (EGFR-TKI) used to treat
non-small cell lung cancer (NSCLC) [1,2]; subsequently,
several phase II studies have demonstrated the promising
efficacy of individualized treatment for advanced NSCLC
patients with EGFR-TKI on the basis of EGFR gene mutation
status [3–10]. Subsequently, we have conducted a phase III
*Correspondence to: Dr A. Inoue, Department of Respiratory Medicine, Tohoku
University Hospital, 1-1, Seiryomachi, Aobaku, Sendai, 980-8574, Japan. Tel: +81-22-
717-8539; Fax: +81-22-717-8549; E-mail: akinoue@idac.tohoku.ac.jp
original
articles
original articles Annals of Oncology 24: 54–59, 2013
doi:10.1093/annonc/mds214
Published online 11 September 2012
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study comparing gefitinib with the standard platinum doublet
regimen, carboplatin (CBDCA, Nippon Kayaku, Tokyo) and
paclitaxel (PTX, Bristol-Myers Squibb, Tokyo), as the first-line
treatment for advanced NSCLC harboring EGFR gene mutations
(NEJ002) [11]. The study revealed that gefitinib provided
significantly longer progression-free survival (PFS), the primary
endpoint of the study, than CBDCA/PTX. Other phase III
studies also have demonstrated the superiority of EGFR-TKI over
the platinum doublet regimen [12,13]; thus EGFR-TKIs are now
globally recognized as the standard first-line treatment for
advanced NSCLC with sensitive EGFR mutations [14].
Regarding overall survival (OS), one of the secondary
endpoints of NEJ002, the rate of events was <40% in the
previous report, for which the data cutoff point was December
2009. Although our study was not powered for OS, we
proceeded with this OS analysis to evaluate the long-term
survival result for each treatment group. We updated the data
for PFS, OS, and safety examined in a longer follow-up period
and also assessed the impact of subsequent chemotherapy on
OS in patients with EGFR-mutated NSCLC.
materials and methods
study design and treatment
Full details of the NEJ002 study have been published previously. Eligible
patients had chemo-naïve advanced NSCLC with a sensitive EGFR
mutation detected by the highly sensitive peptide nucleic acid-locked
nucleic acid PCR clamp method [15]. Patients were randomly assigned
(1:1) to gefitinib (250 mg/day) or CBDCA (AUC 6.0)/paclitaxel (Taxol,
200 mg/m
2
) on day 1 every 3 weeks (up to six cycles). The primary
endpoint of NEJ002 was to evaluate the superiority of gefitinib over
CBDCA/PTX in PFS. The secondary endpoints included response rate, OS,
quality of life (QOL), and safety profiles (see Supplementary data, available
at Annals of Oncology online). Patients provided a written informed
consent. The study was conducted in accordance with the Helsinki
Declaration of the World Medical Association. The protocol was approved
by the institutional review board of each participating institution.
updated evaluation
PFS, OS, and safety data evaluated by the Common Terminology Criteria
for Adverse Events version 3.0 were re-evaluated at the data cutoff point in
December 2010 for the entire intent-to-treat population (n= 228), which
was initially unplanned. Detailed information on subsequent chemotherapy
carried out after the protocol treatment was also assessed for all patients
retrospectively.
statistical analysis
The Kaplan–Meier survival curves were drawn for PFS and OS and
compared using a two-sided non-stratified log-rank test with a significance
level of 0.05. The hazard ratio (HR, gefitinib:CBDCA/PTX) and its two-
sided 95% confidence interval (CI) were calculated by Cox regression
analysis including only the treatment arm as a covariate. Subgroup analyses
for OS, which were shown in a forest plot, were carried out to examine the
interaction effect of treatment arm with age, gender, performance status,
smoking status, type of histology, and type of EGFR mutation using a Cox
regression model including treatment arm, each of the clinical factors, and
their interaction effects as covariates. We did not account for adjustment
for multiplicity due to the repetition of subgroup analyses, because we
carried out them as exploratory analyses. Other comparative analyses were
evaluated on the basis of a two-sided 5% significance level and 95% CI. All
analyses were carried out using SAS for Windows release 9.1 (SAS Institute
Inc., Cary, NC, USA).
Results
updated PFS
Among the 224 patients assessable, the updated median PFS of
the gefitinib group and that of the CBDCA/PTX group were
10.8 months and 5.4 months, respectively (HR, 0.322; 95% CI
0.236–0.438; P< 0.001), which was quite similar to the
previous results (Table 1). The number of events for PFS at the
last data cutoff (December 2010) was 98 in the gefitinib group
and 101 in the CBDCA/PTX group. The rate of events for PFS
slightly increased from the previous report (from 83% to 88%).
updated OS
At the last data cutoff point, the median follow-up time was
704 days (range 30–1659) and 69 death events were observed
in each arm. The rate of events for OS increased from 36% in
the previous report to 61% in the current study (Table 1). The
MST and the 2-year survival rate were 27.7 months and 58%,
Table 1. Previous and updated results of survival
Previous results (in 2009) Updated results (in 2010)
First-line treatment group Gefitinib CBDCA/PTX Gefitinib CBDCA/PTX
PFS
Median PFS, months 10.8 5.4 10.8 5.4
Hazard ratio (95% CI) 0.296 (0.215–0.408) 0.322 (0.236–0.438)
One-year PFS rate 42.1% 3.2% 43.8% 4.2%
Number of events (%) 87 (76%) 100 (91%) 98 (86%) 101 (92%)
Overall survival
Median survival time, months 30.5 23.6 27.7 26.6
Hazard ratio (95% CI) 0.798 (0.517–1.232) 0.887 (0.634–1.241)
1-year survival rate 84.7% 86.4% 85.0% 86.8%
2-year survival rate 61.4% 46.7% 57.9% 53.7%
Number of events (%) 39 (34%) 43 (38%) 69 (61%) 69 (61%)
CBDCA/PTX, carboplatin plus paclitaxel; CI, confidence interval; PFS, progression-free survival.
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respectively, for the gefitinib group, and 26.6 months and 54%
for the CBDCA/PTX group (HR, 0.887; 95% CI 0.634–1.241;
P= 0.483) (Figure 1). No factor, including the type of EGFR
mutation, had a substantial impact on OS between the groups
(Figure 2).
safety
No additional serious adverse event (NCI-CTC grade ≥3) was
reported in either group after the previous report. Briefly, the
most common adverse events reported were rash and diarrhea
with gefitinib, and appetite loss, sensory neuropathy, and
myelotoxicities with CBDCA/PTX. The combined incidence of
serious adverse events combined was significantly higher in the
CBDCA/PTX group than in the gefitinib group (71.7% versus
41.2%; P< 0.001).
post-protocol chemotherapy
The chemotherapy regimens employed in NEJ002 are
summarized in Table 2. Regarding the number of subsequent
regimens, >50% of patients had received third-line
chemotherapy or more, which was quite compatible with
general practice in Japan (Figure 3A).
In the gefitinib group, 82 patients (72%) received at least one
subsequent regimen. Among these, 74 patients (65%) were
treated with the platinum doublet regimen including a
crossover use of CBDCA/TXL in 59 patients (52%). Some
patients received pemetrexed (PEM) combined with a platinum
agent because it became available for the treatment of NSCLC
in Japan in May 2009. Twelve patients went back on gefitinib
and 32 received erlotinib in one of their later-line treatments.
Among the 32 patients who received no subsequent regimen,
12 (11%) had been still treated with their first-line gefitinib at
the data cutoff point (8 patients had still maintained their
response to gefitinib, while 4 had continued gefitinib after the
documentation of disease progression, in accordance with the
patient’s wishes). There were various reasons why the other 20
patients (18%) did not receive any subsequent regimens:
deterioration of PS due to the progression of NSCLC (n= 11),
interstitial lung disease due to gefitinib treatment (n= 3),
exacerbation of co-morbidities (n= 2), or in accordance with
the patient’s wishes (n= 4). On the other hand, 113 patients
(99%) in the CBDCA/PTX group had received at least one
subsequent regimen, of whom 112 (98%) had moved to
gefitinib.
The standard second-line chemotherapeutic agents PEM or
docetaxel (DOC, Sanofi-Aventis K.K., Tokyo), which are used
for advanced NSCLC, were used in 29% and 25% of patients in
the gefitinib group, respectively, and in 16% and 19% of those
in the CBDCA/PTX group, respectively. More than >20% of
patients in both the arms received other agents such as
irinotecan, S-1, gemcitabine, vinorelbine, or amrubicin as
third- or later-line chemotherapy.
evaluation of the impact of key drugs on OS
To examine the impact of the platinum agent on OS of
patients with EGFR-mutated NSCLC, we compared the OS of
patients who received both gefitinib and a platinum agent in
their treatment (n= 186) with that of patients who had never
received a platinum agent (n= 40) in NEJ002. We found no
significant difference between the OS of each group
(Figure 3B). The number of patients who received a platinum
agent but had not received gefitinib was only two in NEJ002.
We then assessed the impact of standard second-line agents
(PEM and DOC) on OS. We divided patients who had
received third-line or more in NEJ002 (n= 131) into two
groups: the first group received EGFR-TKI, platinum agent,
and PEM or DOC (P/D group, n= 76), and the second group
received EGFR-TKI, platinum agent, but neither PEM nor
DOC (no P/D group, n= 55). The MST of the P/D group was
significantly longer than that of the no P/D group (34.8
months versus 22.6 months, P= 0.003) (Figure 3C).
Figure 1. Kaplan–Meier curves for updated overall survival (OS) in the
intent-to-treat population of NEJ002.
Figure 2. Forest plot of updated overall survival (OS) by clinical factors
and the type of epidermal growth factor receptor (EGFR) mutation. Hazard
ratio (HR) <1 implies a lower risk of death for patients treated with first-
line gefitinb.
original articles Annals of Oncology
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discussion
Although the NEJ002 study met its primary endpoint, in that
gefitinib was superior to CBDCA/PTX in PFS, OS data were
also important in evaluating the efficacy of the entire treatment
including the regimens investigated. The current updated
analysis demonstrated that the treatment course initiated with
gefitinib achieved OS at least equivalent to a traditional
treatment course initiated with a platinum doublet regimen for
patients with advanced NSCLC harboring a sensitive EGFR
mutation. Since the median follow-up time increased from 17
months in the previous report to 23 months in the current
analysis, the OS results should become more accurate. We have
already reported that the QOL was significantly better in the
gefitinib group than in the CBDCA/PTX group in NEJ002
[16]. Moreover, gefitinib attained a high response rate, rapid
improvement of symptoms, and exhibited low toxicity. Taking
these factors together, we recommend the use of gefitinib as
the first-line treatment.
There is a conservative opinion which states that the
platinum doublet regimen should still be used as the first-line
treatment for advanced NSCLC. This is because there has been
no prospective study showing superiority of first-line EGFR-
TKI over platinum doublet regimens for OS. Furthermore,
some retrospective analyses have suggested that EGFR-TKI
might be similarly effective in EGFR-mutated NSCLC
regardless of the line at which it is used [17]. However, it is
very important to recognize from our study that, though
almost 100% of patients in the CBDCA/PTX group crossed
over to gefitinib, the OS curve of the first-line gefitinib group
was not inferior to that of the CBDCA/PTX group. While the
risk associated with missing the administration of platinum
agents after first-line gefitinib may be of concern, our post-hoc
analysis suggested that the impact of the platinum agent on OS
would not be larger than that of EGFR-TKI for patients with
EGFR-mutated NSCLC. Figure 3B shows the MST of patients
treated without platinum to be >2 years, which is a quite
favorable result compared with previous historical data
obtained when EGFR-TKI was not available. Thus, we feel that
it is a concern if the chance to use gefitinib is missed when
chemotherapy is carried out as the first-line treatment. The
extremely high crossover rate in NEJ002 is hard to attain in
general practice. In fact, only 51.5% of patients in the first-line
CBDCA/PTX group received subsequent EGFR-TKI in the
IPASS study [12]. Thus, we strongly recommend that the best
drug should be used in the first instance.
Patients in the first-line gefitinib group tend to be treated
with PEM or DOC monotherapy more intensively; this was
because we supposed that some of these did not receive
platinum doublet treatment for various reasons. However, we
consider that the ideal treatment strategy for appropriate
patients is to make use of available standard drugs. The most
important finding in the post-hoc analysis shown in Figure 3C
was that patients treated with EGFR-TKIs, platinum, and
Table 2. Summary of regimens for entire treatment in NEJ002
Second-line n(%) Third- or later-line n(%) Total n(%)
First-line gefitinib group (n= 114)
EGFR-TKI 8 (7.0) 34 (29.8) 114 (100)
Gefitinib 2 (1.8) 10 (8.8) 114 (100)
Erlotinib 6 (5.3) 26 (22.8) 32 (28.1)
Chemotherapy 74 (64.9) 52 (45.6) 76 (66.7)
Platinum based 71 (62.3) 11 (9.6) 74 (64.9)
CBDCA/PTX
a
56 (49.2) 3 (2.6) 59 (51.8)
Platinum/PEM
b
11 (9.6) 4 (3.5) 15 (13.2)
PEM (monotherapy) 2 (1.8) 16 (14.0) 18 (15.8)
DOC 0 28 (24.6) 28 (24.6)
Others
c
1 (0.9) 26 (22.8) 27 (23.7)
First-line CBDCA/PTX group (n= 114)
EGFR-TKI 109 (95.6) 42 (36.8) 112 (98.2)
Gefitinib 109 (95.6) 8 (7.0) 112 (98.2)
Erlotinib 0 33 (28.9) 33 (28.9)
BIBW2992 0 2 (1.8) 2 (1.8)
Chemotherapy 3 (2.7) 52 (45.6) 114 (100)
Platinum based 2 (1.8) 9 (7.9) 114 (100)
CBDCA/PTX 1 (0.9) 1 (0.9) 114 (100)
Platinum/PEM 0 4 (3.5) 4 (3.5)
PEM (monotherapy) 0 14 (12.3) 14 (12.3)
DOC 1 (0.9) 21 (18.4) 22 (19.3)
Others
c
0 26 (22.8) 26 (22.8)
CBDCA/PTX, carboplatin plus paclitaxel; PEM, pemetrexed; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; DOC, docetaxel.
a
Includes two CBDCA/PTX plus bevacizumab.
b
Includes one CBDCA/PEM plus bevacizumab.
c
Includes irinotecan, S-1, gemcitabine, vinorelbine, and amrubicine.
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PEM/DOC achieved MST of around 3 years even though they
had systemically advanced disease; however, the analysis may
not conclusively show the difference between the two groups
because they were not randomly assigned. This suggests that
patients with EGFR-mutated NSCLC and with good PS
enough to complete many lines of treatment may further
benefit from a proper use of the above mentioned ‘key drugs’.
Although PEM and DOC were equally recognized as standard
second-line agents at the time of the NEJ002 study [18], we
now consider PEM to be more appropriate for EGFR-mutated
NSCLC where adenocarcinoma is much common [14]. Since at
least 14 patients (12%) failed to move to subsequent
chemotherapy and ∼20% of patients had never received
platinum agents or PEM after their disease progressed in the
gefitinib group, we think there may be a room for
improvement of OS in these populations. Thus, we are now
investigating a new treatment strategy, in which the first-line
gefitinib is combined with CBDCA and PEM, for patients with
EGFR-mutated NSCLC (UMIN000002789).
There are some limitations in the current analysis. First, the
sample size of NEJ002 had inadequate power for evaluation of
the difference in OS between the two groups. Since death
events in one-third of patients have not yet occurred, the true
OS curve may change slightly from that shown in this report.
A meta-analysis combining several phase III studies and
comparing EGFR-TKI with platinum doublet in an EGFR-
mutated NSCLC population would be warranted. Second, the
post-hoc analysis on subsequent chemotherapies may have
been biased, because post-protocol treatments were not
restricted under the NEJ002 protocol; however, they were very
similar to those used in general practice in Japan. In addition,
the unplanned comparative analysis between the subgroups
shown in Figure 3B and C cannot draw definitive conclusions.
It may be difficult to find whether the additive effect of
platinum agents or PEM/DOC or good PS itself, that enabled
patients to receive those agents irrespective of chemotherapy
effects, influenced survival prolongation in the superior group
more directly. However, we believe that they give us some
interesting suggestions for future investigations such as that
underway in our new study.
The reason there was no significant difference in OS between
the first-line gefitinib group and the first-line CBDCA/PTX
group in NEJ002 was very likely a high rate of crossover use of
gefitinib in the CBDCA/PTX group. Considering the many
benefits from EGFR-TKI use and the risk of missing an
opportunity to use the most effective agent for treatment of
EGFR-mutated NSCLC, the first-line gefitinib is strongly
recommended in general practice for this population.
funding
This work is supported by grant-in-aids from Japan Society for
Promotion of Science and Japanese Foundation for the
Multidisciplinary Treatment of Cancer. This study is also
supported by the Tokyo Cooperative Oncology Group.
disclosure
KK, AG, YS, and TN had received research grants from
AstraZeneca. AI, KK, MM, HI, KH, and TN had received
lecture fees from AstraZeneca. All remaining authors have
declared no conflicts of interest.
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doi:10.1093/annonc/mds242
Published online 10 August 2012
Pemetrexed-based chemotherapy in patients with
advanced, ALK-positive non-small cell lung cancer
A. T. Shaw1*, A. M. Varghese2, B. J. Solomon3, D. B. Costa4, S. Novello5, M. Mino-Kenudson6,
M. M. Awad1, J. A. Engelman1, G. J. Riely2, V. Monica5,B.Y.Yeap
1& G. V. Scagliotti5
1
Department of Medicine Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston;
2
Department of Thoracic Oncology, Memorial Sloan-Kettering
Cancer Center, New York, USA;
3
Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Australia;
4
Division of Hematology/Oncology, Beth
Israel Deaconess Medical Center, Boston, USA;
5
Department of Clinical and Biological Sciences, University of Torino, Torino, Italy;
6
Department of Pathology,
Massachusetts General Hospital, Boston, USA
Received 16 May 2012; revised 11 June 2012; accepted 13 June 2012
Background: Anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) is highly responsive to
crizotinib. To determine whether ALK-positive NSCLC is also sensitive to pemetrexed, we retrospectively evaluated
progression-free survival (PFS) of ALK-positive versus ALK-negative patients who had been treated with pemetrexed-
based chemotherapy for advanced NSCLC.
Patients and methods: We identified 121 patients with advanced, ALK-positive NSCLC in the USA, Australia, and
Italy. For comparison, we evaluated 266 patients with advanced, ALK-negative, epidermal growth factor receptor
(EGFR)-wild-type NSCLC, including 79 with KRAS mutations and 187 with wild-type KRAS (WT/WT/WT). We
determined PFS on different pemetrexed regimens.
*Correspondence to: Dr A. T. Shaw, Thoracic Oncology, Massachusetts General
Hospital Cancer Center, Yawkey 7B-7508, 32 Fruit Street, Boston, MA 02114, USA.
Tel: +1-617-724-4000; Fax: +1-617-726-0453; E-mail: ashaw1@partners.org
Annals of Oncology original articles
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