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original article
Annals of Oncology 20: 1369–1374, 2009
doi:10.1093/annonc/mdp005
Published online 20 May 2009
Feasibility of radiotherapy with concomitant
gemcitabine and oxaliplatin in locally advanced
pancreatic cancer and distal cholangiocarcinoma:
a prospective dose finding phase I–II study
Received 22 July 2008; revised 22 December 2008; accepted 23 December 2008
Background: The prognosis of pancreaticobiliary tumors is poor. The aim was to assess the feasibility of
radiotherapy (RT) and concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal
cholangiocarcinoma.
Patients and methods: Twenty-two patients with locally advanced pancreatic (n = 17) or biliary tract cancer (n = 5)
were included. They received two cycles of gemcitabine/oxaliplatin followed by 5 weeks of RT in combination with
a weekly fixed dose gemcitabine and an escalating dose of oxaliplatin from 40 up to 70 mg/m2. National Cancer
Institute—Common Toxicity Criteria 3.0 was used to score weekly the treatment-related toxicity.
Results: The patients treated at a dose of 40 mg/m2 of oxaliplatin had no dose-limiting toxicity. At 50 mg/m2, two
patients developed grade 4 thrombocytopenia. Nine patients received 60 mg/m2, one developed grade 4
thrombocytopenia. Grade 4 thrombocytopenia in two patients and grade 3 diarrhea in one patient were observed with
70 mg/m2. Median time to progression was 8 months and median overall survival was 17 months.
Conclusions: RT in combination with gemcitabine and oxaliplatin is feasible in patients with locally advanced
pancreaticobiliary cancer. The reported time to progression underlines the potential activity of this regimen. The dose
of 60 mg/m2 of oxaliplatin can be considered as the recommended dose.
Key words: chemotherapy, cholangiocarcinoma, gemcitabine, oxaliplatin, pancreatic cancer, radiotherapy
introduction
Pancreatic cancer accounts for 3% of all cancers and is the fifth
leading cause of cancer deaths in Western countries [1]. The
incidence of cholangiocarcinoma is even lower, 1.5 per
100 000.
The prognosis is very poor with a 5-year survival of <5% for
pancreatic cancer [2]. The only potentially curative therapy for
early stages is radical surgical resection, resulting in 5-year
survival rate between 18% and 24% [3, 4]. The median survival
time after pancreatic resection varies between 13 and 20
months [5, 6]. Unfortunately, only a limited number of patients
(<15%) are resectable at the time of diagnosis. More than 30%
*Correspondence to: Dr M. Peeters, Digestive Oncology Unit, Department of
Gastroenterology, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium.
Tel: +32-9-3322371; Fax: +32-9-3324984; E-mail: [email protected]
Senior Clinical Investigator of the fund for Scientific Research-Flanders (FWO).
of all patients present with locally advanced non-resectable
disease, usually due to invasion of the celiac vessels or the
mesenteric artery, with a median survival time ranging from 5
to 11 months [7]. Moreover, a majority of patients have
metastatic disease at the time of the diagnosis. The prognosis of
cholangiocarcinoma is even worse with <6 months overall
survival (OS). Most patients present initially with inoperable
disease. For advanced pancreaticobiliary cancer, it has been
shown that chemotherapy improves OS without impairing the
patient’s quality of life [8, 9]. Gemcitabine is the standard
treatment of advanced or metastatic pancreatic cancer.
However, objective tumor response is observed in only 6%–
11%, and OS remains around 4–6 months [10]. Toxicity is
variable and an initial phase I trial recommended a dose of 1200
mg/m2 [11] in a 3 out of 4 weeks’ schedule. The pivotal trial in
pancreatic cancer randomized 126 patients between
gemcitabine and 5-fluorouracil (5-FU). Overall 23.8% of the
patients treated with gemcitabine 1000 mg/m2 per week
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
original
article
1
Department of Gastroenterology; 2Department of Radiotherapy, Ghent University Hospital, Ghent; 3Department of Gastroenterology, Erasme University Hospital,
Brussels; 4Department of Gastroenterology, Université catholique de Louvain, Cliniques universitaires Saint-Luc, Brussels; 5Department of Gastroenterology, CHU
Sart-Tilman, Liège; 6Department of Gastroenterology, Institut Jules Bordet; 7Department of Surgery, Ghent University Hospital, Ghent; 8Department of Radiotherapy,
Institut Jules Bordet, Brussels and 9Department of Radiotherapy, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Downloaded from http://annonc.oxfordjournals.org/ at Universite catholique de Louvain on March 21, 2014
S. Laurent1, E. Monsaert1, T. Boterberg2, A. Demols3, I. Borbath4, M. Polus5, A. Hendlisz6,
B. de Hemptinne7, C. Mahin8, P. Scalliet9, J.-L. Van Laethem3 & M. Peeters1* original article
patients and methods
Exclusion criteria were as follow: previous chemotherapy or RT; previous
or coexistent malignant disease except non-melanoma skin cancer or
adequately treated cervix carcinoma in situ; presence of distant metastases;
active infection; inadequate liver function (bilirubin > 3 mg/dl, aspartate
aminotranferase > 10 times normal) after derivative surgery or endoscopic
biliary drainage; inadequate renal function (creatinine > 1.5 mg/dl);
pregnancy or breast feeding; use of any other investigational agent
within the month before enrollment into the study; patient with grade 2 or
more neuropathy.
pretreatment evaluation
Pretreatment examinations were carried out within 4 weeks before the start
of treatment and included complete history, physical examination,
evaluation of weight loss in kilogram and percent of usual body weight,
evaluation of jaundice, liver function, bone marrow reserve, renal function
and CA 19.9 dosage, endoultrasonography, upper abdominal CT or
magnetic resonance imaging (MRI), chest CT, or standard chest X-ray for
staging. Special attention was paid to the relationship between tumor and
vessels. The inclusion of every patient in the trial was based on
a multidisciplinary decision. All patients with jaundice underwent a careful
and complete drainage of the bile ducts.
surgery
Patients eligible for curative surgery were not entered into this study unless
they refused or were unfit for surgery. On the other hand, patients who
underwent a derivative procedure (surgical or other) could be included
in the study. Patients undergoing a surgical attempt resulting in R2
resection could also be entered. If the tumor became operable, surgery was
proposed 6 weeks after the completion of therapy.
study objectives and definition of dose-limiting toxicity
The aim of this study was to determine the maximal tolerated dose of
oxaliplatin combined with 300 mg/m2 of gemcitabine weekly and RT 45 Gy
and to evaluate the feasibility of this combination in patients with locally
advanced and unresectable, but non-metastatic pancreaticobiliary cancer.
Dose-limiting toxicity (DLT) was defined as grade 3 acute gastrointestinal
(GI) toxicity or any acute grade 4 toxicity following National Cancer
Institute—Common Terminology Criteria of Adverse Events (NCI-CTC)
version 3.0.
Originally, five patients were planned at each dose level. A consensus
process has been determined as follows: when DLT was reached for
a patient, the chemotherapy was delayed until recuperation. Afterwards,
the dose of chemotherapy was reduced to 50% of the starting dose for the
next administration. The steering committee could decide to go to a higher
dose level if the patient did not experience a new DLT in a given level.
treatment regimens
The first two cycles of combined gemcitabine and oxaliplatin were given
without RT (Figure 1). The regimen consisted of gemcitabine (Gemzar,
purchased from Eli Lilly, Belgian Affiliate), 1000 mg/m2, administered as
eligibility criteria
Eligible patients had a histologically proven and unresectable
adenocarcinoma of the pancreas or cholangiocarcinoma with no evidence
of metastatic disease as shown by thoracic and abdominal computed
tomography (CT) scan. Patients unfit for surgery could also be included in
the study, provided that they met all other criteria. Eligibility criteria
included age ‡18 years; World Health Organisation performance status
between zero and one; complete recovery from surgery in case of enteric
and/or biliary tract by-pass operation, with a maximum delay after surgery
of 8 weeks; life expectancy >6 months, and adequate hematologic, renal,
and hepatic function. Written informed consent was obtained from all
patients before initiation of therapy.
1370 | Laurent et al.
4 weeks
Staging
Week 1 and 3
oxaliplatin +
gemcitabine
5 weeks
4 weeks 2 weeks
Radiochemotherapy
Staging Surgery
Figure 1. Treatment plan summary: treatment planning with
chemotherapy alone in week 1 and week 3 and chemoradiation from week
5 to week 9.
Volume 20 | No. 8 | August 2009
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experienced a clinical benefit compared with 4.8% for the 5FU-treated patients [10]. The median survival was also
significantly prolonged with gemcitabine. Subsequent phase III
trials comparing gemcitabine to other agents confirmed these
results [12, 13].
Oxaliplatin has also been investigated as a potential
treatment for advanced pancreatic cancer. The combination
with 5-FU is feasible with a response rate (RR) of 10% and
a higher OS in the combination arm [14]. Moreover,
oxaliplatin appears to enhance the activity of gemcitabine in
vitro and thus may improve response to this agent [15, 16].
A phase II study testing the combination of gemcitabine and
oxaliplatin was very promising in terms of clinical benefit, RR,
progression-free survival (PFS) and OS [17]. However, more
recently the result of the randomized phase III trial in
comparison with gemcitabine alone was disappointing in terms
of OS. The study failed to demonstrate a statistically significant
advantage, probably due to its lack of power. However, this
combination can be safely administered with clinical benefit
and high RRs [18]. Therefore, it deserves further investigation.
A survival benefit has been demonstrated for chemoradiation
over radiotherapy (RT) alone [19] in patients with locally
advanced pancreatic cancer. This was confirmed by a recent
review [20]. For patients with localized but unresectable
malignancy, radiation therapy combined with fluorouracil,
gemcitabine, or paclitaxel has shown modest improvement
in survival and palliation of symptoms [21] over
chemotherapy alone.
RT combined with gemcitabine has been increasingly
investigated in locally advanced and adjuvant setting of
pancreatic cancer and was shown to be feasible, well tolerated,
and active [22–24]. However, up to now, insufficient evidence
is available to recommend chemoradiation in patients with
locally advanced pancreaticobiliary cancer as a superior
alternative to chemotherapy alone [20]. Intensification of this
combination with platins could be attractive.
With limited benefit from available treatments, there is an
urgent need for active modalities that improve response,
subsequent respectability, and survival in this poor prognostic
population. The integration of oxaliplatin into a full-dose
gemcitabine and RT regimen could enhance local and systemic
effects. This led us to investigate the combination of oxaliplatin,
gemcitabine, and RT in locally advanced unresectable
pancreaticobiliary tumors.
Annals of Oncology
original article
Annals of Oncology
gemcitabine and oxaliplatin dose adjustments before
and during combination therapy
The dose modifications were followed on the base of weekly absolute
neutrophil count and platelets count, within 48 h before infusion of
gemcitabine/oxaliplatin and clinical assessment of non-hematologic
toxicity.
For cumulative, characteristic peripheral sensitive neuropathy more than
grade 2, only oxaliplatin was discontinued.
The decision to hold both RT and chemotherapy instead of only
chemotherapy was left to the investigator’s discretion.
If toxicity required a treatment break of RT, both RT and chemotherapy
were held until toxicity has declined to grade 2 or less.
In case of grade 3 acute GI toxicity or any acute grade 4 toxicity (DLT),
chemotherapy was delayed until recuperation and restarted at 50% of the
starting dose for the next administration. If the combination therapy
should be delayed for >2 weeks, the treatment administration was
definitely discontinued.
If chemotherapy alone or in combination with RT was omitted due to
toxicitiy for a total of ‡2 weeks in three out of five consecutive patients,
the dose of gemcitabine was de-escalated to 200 mg/m2 and oxaliplatin to
30 mg/m2.
follow-up assessment of response to chemoradiation
and subsequent surgery
Tumor evaluation by chest and abdominal CT and measurement of CA 19.9
in serum were carried out at baseline, before any treatment, and 1 month
after stopping the chemoradiation. At that moment, operability was
discussed at the multidisciplinary meeting. Follow-up was carried out every
3 months for a total period of 2 years. Determination of disease progression
was based on imaging and not on an increase in CA 19.9 alone. Therapyrelated complications were recorded. Evidence of progressive disease,
Volume 20 | No. 8 | August 2009
Day
1
8
15
22
29
Radiotherapy
(1.8 Gy/day)
Gemcitabine
(300 mg/m²)
Oxaliplatin
(40-70 mg/m²)
Figure 2. Concomitant chemoradiation regimen: gemcitabine and
oxaliplatin were given once every week during radiotherapy.
patient’s request, unacceptable toxicity, or if the responsible physician
thought that a change of therapy would be in the best interest of the patient
were potential reasons for protocol discontinuation.
The study was approved by the ethical committee and monitored by
a steering committee composed of delegates from the participating centers.
results
patient characteristics
Twenty-four patients were enrolled over a period of 24 months
in four Belgian centers. Two patients prematurely discontinued
the treatment. One had a lymphoma as final diagnosis and
the other one stopped the treatment for personal convenience
without major toxicity. Patient characteristics are summarized
in Table 1. Median age was 60.5 years (range 43–72).
Baseline performance status was zero in 16 patients and one
in six patients. Male : female ratio was 12 : 10. Seventeen
patients had locally advanced pancreatic tumors and five
patients had inoperable bile duct tumors.
dose escalation and DLTs
The number of patients assigned to each dose level is listed in
Table 1.
Five patients were treated at the first dose level (40 mg/m2).
No DLT was recorded in these patients and so the dose of
oxaliplatin was escalated to 50 mg/m2 in four patients. Two of
them developed DLT (grade 4 thrombocytopenia). The fifth
patient had a lymphoma and was excluded from the study and
never received therapy. The steering committee decided to
proceed to the next dose level based on the fact that
thrombocytopenia is frequently seen with gemcitabine and
more importantly, there was no clinical impact (i.e. bleeding)
of this side-effect.
A cohort of nine patients was treated at a dose of 60 mg/m2
and only one developed DLT. Four patients were treated at
a dose of 70 mg/ m2, two developed a DLT.
acute adverse events and dose intensity
The number of patients developing adverse events is
summarized in Table 2. The safety results are presented for 22
patients. Grade 1/2 and grade 3/4 adverse events according to
doi:10.1093/annonc/mdp005 | 1371
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a 100-min i.v. infusion, followed by oxaliplatin (Eloxatin, provided by
Sanofi-Aventis), 100 mg/m2, administered i.v. as a 2-h infusion. The doses
were based on the initially calculated body surface area.
This was followed by combination therapy consisting of RT to a total
dose of 45 Gy (25 factions of 1.8 Gy in 5 weeks). During the irradiation,
gemcitabine, given a dose of 300 mg/m2, and oxaliplatin at escalating doses
(40–70 mg/m2) were administered weekly, respectively, at days 1 and 2
(Figure 2). Gemcitabine was infused over 30 min, 1–4 h before irradiation.
Oxaliplatin was infused over 2 h.
RT was delivered on a linear accelerator, using megavoltage photon
beams of 6 MV or more. Usually 15 MV or higher were necessary. SAD
technique was recommended, with an isocenter distance of 100 cm. Most
patients were treated with three or four fields and three-dimensional
(3D) conformal planning was highly recommended.
A CT in treatment position was obtained with joined slices, allowing 3D
reconstruction on a treatment planning system. The gross target volume
(GTV) included all macroscopic tumor, including enlarged lymph nodes.
The GTV was expanded with 1 cm and the lymph node regions to obtain
a clinical target volume. Planning target volume (PTV) expansion was done
according to the institute’s standard guidelines.
The reference dose per fraction was 1.8 Gy at the isocenter, according to
International Commission on Radiation Units (and measurements) ICRU
report 50 (1.8 Gy per fraction, 5 days per week). The total prescribed dose
was 45 Gy at the isocenter. The PTV was included at least in the 95%
isodose of the reference isodose. The maximum dose did not exceed 107%
of the reference dose. Less than 50% of the total renal parenchyma
received a dose of 20 Gy or more. The mean dose to the liver did not
exceed 30 Gy.
original article
Annals of Oncology
Table 1. Patients’ characteristics (n = 22)
Oxaliplatin
40 mg/m2
(n = 5)
50 mg/m2
(n = 4)
60 mg/m2
(n = 9)
70 mg/m2
(n = 4)
Overall
population
Median age, years (range)
Gender
Male
Female
ECOG performance status
0
1
Tumor type
Pancreas
Bile duct
56 (53–68)
62 (43–71)
60 (50–67)
62 (59–72)
60.5 (43–72)
2
3
3
1
5
4
2
2
12 (55%)
10 (45%)
5
0
2
2
7
2
2
2
16 (73%)
6 (27%)
4
1
3
1
7
2
3
1
17 (77%)
5 (23%)
Table 2. Number of patients developing adverse events according to NCI-CTC
NCI-CTC grade
adverse event
Gastrointestinal
Nausea
Diarrhea
Vomiting
Stomatitis
Neuropathy
Hematologic
Anemia
Thrombocytopenia
Neutropenia
Febrile neutropenia
Other
Infection
Rash
Fatigue
Abdominal pain
Edema
Oxaliplatin 50 mg/m2
Oxaliplatin 60 mg/m2
Oxaliplatin 70 mg/m2
Overall population
Oxaliplatin 40 mg/m2
(n = 5)
(n = 4)
(n = 9)
(n = 4)
(n = 22)
Grades 1–2 Grades 3–4 Grades 1–2 Grades 3–4 Grades 1–2 Grades 3–4 Grades 1–2 Grades 3–4 Grades 1–2 Grades 3–4
3
0
1
1
2
0
0
0
0
1
2
2
2
0
2
0
0
0
0
0
7
3
3
0
3
0
0
0
0
0
1
2
2
0
3
1
1
1
0
0
13
7
8
1
10
(59%)
(32%)
(36%)
(5%)
(45%)
2
2
1
0
0
0
2
0
3
3
2
0
0
2
2
0
2
6
4
0
0
3
5
0
2
3
1
0
0
3
1
0
9 (41%)
14 (64%)
8 (36%)
0
0
1
2
0
0
1
0
0
0
0
1
0
3
1
0
0
0
0
0
0
1
0
4
2
0
1
0
1
0
0
0
0
2
1
1
0
0
0
0
1
2
1
11
4
1
(9%)
(5%)
(50%)
(18%)
(5%)
1 (5%)
1 (5%)
1 (5%)
0
1 (5%)
0
8 (36%)
10 (45%)
0
2 (9%)
0
1 (5%)
0
1 (5%)
NCI-CTC, National Cancer Institute—Common Toxicity Criteria.
the NCI-CTC (version 3.0) are shown in Table 2. The most
frequent grade 1/2 toxic effects were thrombocytopenia
(64%), nausea (59%), and fatigue (50%). These side-effects
did not result in any treatment interruption or dose
modification. The most frequent grade 3 adverse event was
neutropenia (50%). One patient had grade 3 neuropathy
(4%) at dose level 1. Five patients (23%) experienced a grade
3 thrombocytopenia, one at each dose levels 2, 3, and 4.
Grade 3 diarrhea was observed in one patient (5%) at dose
level 4. Grade 4 thrombocytopenia occurred in five patients
(23%), two at dose level 2, one at dose level 3, and two at dose
level 4. The treatment was adapted in function of the
adjustments previously described. One patient (5%)
experienced grade 4 nausea and vomiting at dose level 4. No
other major toxicity was observed.
1372 | Laurent et al.
Other serious adverse events occurring during the treatment
period and not considered to be DLTs were seen in four
patients. One patient developed cholangitis, the second one
a mycotic oesophagitis, the third one a sepsis and infectious
ascites, and the fourth one a pneumonia.
All patients received the prescribed radiation dose without
interruption. The patients received at least 70% of the planned
dose of chemotherapy. Three patients (14%) received the full
dose, one at dose levels 2, 3, and 4.
response assessment and patient’s outcome
Efficacy was assessed by CT/MRI. Partial response was
obtained in three patients and complete response in one
patient. One of the partial responses was obtained in an
inoperable biliary tract adenocarcinoma. The median time to
Volume 20 | No. 8 | August 2009
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ECOG, Eastern Cooperative Oncology Group.
original article
Annals of Oncology
progression was 8 months with a median OS of 17 months.
Follow-up was carried out until January 2008. To date, six
patients are still alive.
surgery
After the combined treatment, surgery became possible in four
patients. A R0 resection was obtained in three patients with
pancreatic cancer.
discussion
Volume 20 | No. 8 | August 2009
funding
Eli Lilly and Sanofi-Aventis.
acknowledgements
The authors are grateful to the study nurses Tine Derre, Peggy
De Clercq, Anja Carlier, and Nancy Van Damme and to the
patients. Disclosure of potential conflicts of interest: Marc
Peeters has served as an advisory board member for Eli Lilly.
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Improved treatments for locally advanced unresectable
pancreaticobiliary tumors are urgently needed as demonstrated
by their limited prognosis and the frequency of their
presentation. The challenge of clinical research is well reflected
by the controversies resulting from available studies and the
difficulties in designing and performing clinical trials in
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locally advanced disease [25]. Both chemotherapy and
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[18, 31, 32]. It seems logical that the combination of radiation
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improve the treatment of locally advanced tumors. The strategy
of using chemotherapy followed by chemoradiation seems
effective in locally advanced pancreatic carcinoma [33] but
until now, this strategy failed to prove its superiority in
comparison to chemotherapy alone.
The combination of RT and gemcitabine and oxaliplatin has
recently been investigated in a phase I study in (un)resectable
or metastatic pancreatic carcinoma. This study showed an
acceptable tolerance [34]. A concomitant administration of
weekly oxaliplatin, fluorouracil continuous infusion, and RT
after 2 months of gemcitabine and oxaliplatin induction in
patients with locally advanced pancreatic cancer was also
carried out by the GERCOR with encouraging results [35].
Our study was initially designed to determine the optimal
dose of oxaliplatin that could be safely added to a 300 mg/m2
weekly dose of gemcitabine, as previously reported, and
radiation therapy in patients with unresectable pancreatic or
biliary tract cancer without evidence of metastatic disease. We
designed this trial with escalating doses of oxaliplatin, given
once a week during the RT period. Two cycles of gemcitabine
and oxaliplatin were given upfront. A moderate radiation dose
was used to allow full systemic doses of oxaliplatin and
gemcitabine.
All patients completed their RT. Dose intensity for
chemotherapy was calculated and the patients received at
least 70% of planned chemotherapy doses. The safety profile of
the combined modality was found favorable and treatmentrelated toxicity manageable in most patients. The most frequent
grade 4 toxicity was thrombocytopenia, which is consistent
with the data recently published in another phase I study [34].
Other grade 4 toxic effects were very uncommon. Based on the
fact that only one out of nine patients in the 60 mg/m2 dose
level showed a DLT and two out of four in the 70 mg/m2, the
dose of 60 mg/m2 was selected for further trials. Since the
RT-specific toxicity was low with no need for treatment
modifications, increasing the radiation dose with the same
chemotherapy regimen also seems a feasible option for
future trials.
Although this study was designed to determine the
appropriate dose of oxaliplatin and evaluate safety, favorable
response was seen in 18% of the patients. Three of those
patients had a R0 resection. A partial response was observed in
three patients and a complete response in one patient reflecting
an overall RR of 18%.
In conclusion, the combination of oxaliplatin, gemcitabine,
and radiation therapy in locally advanced pancreaticobiliary
tumors is feasible. The recommended dose of oxaliplatin for
further trials is 60 mg/m2. Further investigations are needed to
better define the efficacy and the place of this new
chemoradiation regimen in the therapeutic arsenal of locally
advanced pancreaticobiliary cancer.
In addition to the results found in the published study from
Desai et al [34], this combined regimen could be one of the
most active in the neoadjuvant approach of biliary tumors and
deserves further investigations.
original article
1374 | Laurent et al.
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Annals of Oncology