Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas: Results of the GORTEC 2007-02 Phase III Randomized Trial

Abstract

Purpose:
Both concurrent chemoradiotherapy (CT-RT) and cetuximab radiotherapy (cetux-RT) have been established as the standard of care for the treatment of locally advanced squamous cell carcinoma of the head and neck. It was not known whether the addition of induction chemotherapy before cetux-RT could improve outcomes compared with standard of care CT-RT.

Patients and methods:
The current trial was restricted to patients with nonmetastatic N2b, N2c, or N3 squamous cell carcinoma of the head and neck and fit for taxotere, cisplatin, fluorouracil (TPF). Patients were randomly assigned to receive three cycles of TPF followed by cetux-RT versus concurrent carboplatin fluorouracil and RT as recommended in National Comprehensive Cancer Network guidelines. The trial was powered to detect a hazard ratio (HR) of 0.66 in favor of TPF plus cetux-RT for progression-free survival at 2 years. The inclusion of 180 patients per arm was needed to achieve 80% power at a two-sided significance level of .05.

Results:
Between 2009 and 2013, 370 patients were included. All patients and tumors characteristics were well balanced between arms. There were more cases of grade 3 and 4 neutropenia in the induction arm, and the induction TPF was associated with 6.6% treatment-related deaths. With a median follow-up of 2.8 years, 2-year progression-free survival was not different between both arms (CT-RT, 0.38 v TPF + cetux-RT, 0.36; HR, 0.93 [95% CI, 0.73 to 1.20]; P = .58). HR was 0.98 (95% CI, 0.74 to 1.3; P = .90) for locoregional control and 1.12 (95% CI, 0.86 to 1.46; P = .39) for overall survival. These effects were observed regardless of p16 status. The rate of distant metastases was lower in the TPF arm (HR, 0.54 [95% CI, 0.30 to 0.99]; P = .05).

Conclusion:
Induction TPF followed by cetux-RT did not improve outcomes compared with CT-RT in a population of patients with advanced cervical lymphadenopathy.

Full text

JOURNAL OF CLINICAL ONCOLOGY RAPID COMMUNICATION
Induction Chemotherapy Followed by Cetuximab
Radiotherapy Is Not Superior to Concurrent
Chemoradiotherapy for Head and Neck Carcinomas: Results
of the GORTEC 2007-02 Phase III Randomized Trial
Lionnel Geoffrois, Laurent Martin, Dominique De Raucourt, Xu Shan Sun, Yungan Tao, Philippe Maingon, Jo¨elle
Buffet, Yoann Pointreau, Christian Sire, Claude Tuchais, Emmanuel Babin, Alexandre Coutte, Fr´
ed´eric Rolland,
Marie-Christine Kaminsky, Marc Alfonsi, Michel Lapeyre, Marie Saliou, C´edric Lafond, Eric Jadaud, Bernard
Gery, Ayman Zawadi, Jean-Marc Tourani, C´edric Khoury, Anne Rose Henry, Ali Hasbini, François Guichard,
Christian Borel, Nicolas Meert, Pierre Guillet, Marie-H´el`ene Calais, Pascal Garaud, and Jean Bourhis
ABSTRACT
Purpose
Both concurrent chemoradiotherapy (CT-RT) and cetuximab radiotherapy (cetux-RT) have been
established as the standard of care for the treatment of locally advanced squamous cell carcinoma of
the head and neck. It was not known whether the addition of induction chemotherapy before cetux-
RT could improve outcomes compared with standard of care CT-RT.
Patients and Methods
The current trial was restricted to patients with nonmetastatic N2b, N2c, or N3 squamous cell
carcinoma of the head and neck and fit for taxotere, cisplatin, fluorouracil (TPF). Patients were
randomly assigned to receive three cycles of TPF followed by cetux-RT versus concurrent car-
boplatin fluorouracil and RT as recommended in National Comprehensive Cancer Network
guidelines. The trial was powered to detect a hazard ratio (HR) of 0.66 in favor of TPF plus cetux-RT
for progression-free survival at 2 years. The inclusion of 180 patients per arm was needed to achieve
80% power at a two-sided significance level of .05.
Results
Between 2009 and 2013, 370 patients were included. All patients and tumors characteristics were
well balanced between arms. There were more cases of grade 3 and 4 neutropenia in the induction
arm, and the induction TPF was associated with 6.6% treatment-related deaths. With a median
follow-up of 2.8 years, 2-year progression-free survival was not different between both arms (CT-RT,
0.38 vTPF + cetux-RT, 0.36; HR, 0.93 [95% CI, 0.73 to 1.20]; P= .58). HR was 0.98 (95% CI, 0.74 to
1.3; P= .90) for locoregional control and 1.12 (95% CI, 0.86 to 1.46; P= .39) for overall survival. These
effects were observed regardless of p16 status. The rate of distant metastases was lower in the TPF
arm (HR, 0.54 [95% CI, 0.30 to 0.99]; P= .05).
Conclusion
Induction TPF followed by cetux-RT did not improve outcomes compared with CT-RT in a population
of patients with advanced cervical lymphadenopathy.
J Clin Oncol 36:3077-3083. © 2018 by American Society of Clinical Oncology
INTRODUCTION
Head and neck cancers are common cancers—
predominately squamous cell carcinomas (SCCHNs)
of the oral cavity, larynx, oropharynx, and/or
hypopharynx—and related to the use of alcohol
and tobacco
1,2
A growing proportion of SCCs
from the oropharynx are associated with human
papillomavirus (HPV) in parallel with decreased
tobacco consumption. HPV-positive cancers
are generally associated with better outcomes
compared with HPV-negative tumors, but there
are important geographical variations in HPV-
related oropharyngeal cancers.
3
The majority
of patients with SCCHN present with locally
and/or regionally advanced disease, with locore-
gional or distant failure rates between 30% and
Author affiliations and support information
(if applicable) appear at the end of this
article.
Published at jco.org on July 17, 2018.
Processed as a Rapid Communication
manuscript.
L.G. and L.M. contributed equally to this
work.
Clinical trial information: NCT01233843.
Corresponding author: Jean Bourhis, MD,
Centre Hospitalier Universitaire de
Lausanne, Bugnon 46, Lausanne 1007,
Switzerland; e-mail: jean.bourhis@
chuv.ch.
© 2018 by American Society of Clinical
Oncology
0732-183X/18/3631w-3077w/$20.00
ASSOCIATED CONTENT
Appendix
DOI: https://doi.org/10.1200/JCO.
2017.76.2591
Data Supplement
DOI: https://doi.org/10.1200/JCO.
2017.76.2591
DOI: https://doi.org/10.1200/JCO.2017.
76.2591
© 2018 by American Society of Clinical Oncology 3077
VOLUME 36 •NUMBER 31 •NOVEMBER 1, 2018
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65%.
4
On the basis of phase III randomized trials, concurrent
chemoradiotherapy (CT-RT) is a well-established standard of care
(SOC) for patients with nonoperated locally advanced SCCHN
(LA-SCCHN).
5-7
The 5-year survival benefit of adding CT to
radiotherapy (RT) compared with RTalone in the Meta-Analysis of
Chemotherapy in Head and Neck Cancer (MACH-NC) group was
6.5% and 13% for locoregional control.
7
The most common
standard CT-RT regimen is a combination of conventional frac-
tionated RT (70 Gy for 7 weeks) plus concomitant high-dose
cisplatin (100 mg/m
2
every 3 weeks), as recommended in Na-
tional Comprehensive Cancer Network (NCCN) guidelines.
6
An
alternative CT-RT regimen also recommended as category 1 is the
combination of conventional RT with carboplatin and fluorouracil
(FU), which was used as the reference treatment in our study.
5,6
Finally, the combination of cetuximab, a monoclonal antibody
that targets epidermal growth factor receptor, with RT has been
established as an alternative SOC as recommended in NCCN
guidelines.
6,8
Several attempts to challenge concurrent CT-RT
either by adding induction chemotherapy, intensifying RT, and/
or using alternative concurrent treatments failed to demonstrate
a benefit compared with CT-RT alone
9-12
; however, induction TPF
(docetaxel, FU, and cisplatin) could be of interest for decreasing the
rate of distant metastases in patients with advanced nodal spread.
Indeed, this was suggested by the DeCIDE trial,
11
which was re-
stricted to patients with N2/N3 disease and showed a significant
benefit of induction TPF in decreasing distant metastases.
11
This
benefit in distant metastases, specifically for patients with N2/N3
disease, was also reported later in the update of the MACH-NC
database when comparing induction TPF with FU and cisplatin.
13
This update of the MACH-NC database was based on six ran-
domized trials and demonstrated the superiority of induction TPF
compared with FU and cisplatin for overall survival (OS),
progression-free survival (PFS), distant metastases, and locore-
gional control, thereby establishing the TPF regimen as a reference
induction chemotherapy regimen in LA-SCCHN. The TPF regi-
men has also been established as a reference treatment in a larynx
preservation strategy,
14
and in this context found to be feasible
when followed by cetux-RT. In a recent randomized trial, TPF
followed by cetux-RT demonstrated equivalent survival and
a better toxicity profile compared with TPF followed by CT-RT.
15
On the basis of this rationale, whether TPF followed by cetux-RT
could improve outcomes in patients with LA-SCCHN compared
with CT-RT, which is the most well-established SOC, was an open
question, and we tested this hypothesis in our study. Given the
potential benefit of induction TPF on distant metastases, this study
was restricted to a population of patients with bulky N2b-N3
disease that was known to be associated with a higher rate of distant
metastases related to their massive nodal spread.
PATIENTS AND METHODS
Study Design and Patients
This study was a multicenter, randomized phase III trial. All patients
gave written informed consent, and the study was performed in accordance
with good clinical practice guidelines, the Declaration of Helsinki, and was
approved by our local ethical committee (Nancy, Comit´
e de Protection des
Personnes de France-Est France). The current trial (GORTEC 2007-02)
was restricted to patients with bulky nodal spread—N2b or N2c to
N3—and was run in parallel with another complementary randomized
trial (GORTEC 2007-01) that investigated the addition of concurrent
chemotherapy to cetux-RT in patients with limited nodal spread, mainly
N0 to N2a/N2b non–clinically palpable disease.
Not eligible
(n = 5)
Not eligible
(n = 5)
Analyzed
(n = 179)*
Eligible
(n = 179)*
Eligible
(n = 181)*
Had metastasis (n = 2)
Had other concomitant
tumor (n = 2)
Withdrew consent (n = 1)
Had PS > 1 (n = 3)
Had other concomitant
tumor (n = 1)
No initial
evaluation (n = 1)
Between May 2009
and August 2013
Randomly assigned
(N = 370)
Carboplatin + FU + RT
(n = 184)
TPF + cetuximab + RT
(n = 186)
Treated with
cetuximab + RT
(n = 151)
Completed TPF
(n = 161)
Had PD
(n = 10)
Fig 1. CONSORT diagram. Three hun-
dred seventy patients were randomly
assigned, 360 patients were eligible and
analyzed, and five patients were ineligible
in each arm. (*) Analysis performed on
eligible patients: total n = 360. FU, fluoro-
uracil; PD, progressive disease; PS, per-
formance status; RT, radiotherapy; TPF,
taxotere, cisplatin, fluorouracil.
3078 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Geoffrois et al
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Between May 2009 and August 2013, 360 of 370 randomly assigned
patients were eligible for treatment, with 181 in the TPF plus cetux-RTarm
and 179 in the CT-RTarm. Ten patients were ineligible, five in each arm as
shown in Figure 1. Inclusion criteria were as follows: age between 18 and 80
years, Eastern Cooperative Oncology Group performance status of 0 to 1,
nonmetastatic, nonoperated stage III to IV histologically proven SCC of
the oral cavity, oro/hypopharynx, and larynx, with N2b, N2c, or N3 nodal
spread. HPV status was determined centrally for oropharyngeal cancer
(OPC) using p16 immunostaining as a surrogate. p16 was considered
positive when diffuse, strong, and homogeneous nuclear and cytoplasmic
staining was $70% of tumor cells.
Patients must have had adequate liver, renal (creatinine clearance
$60 ml/min), cardiac, and coronary function, and adequate hematologic
blood counts to allow the delivery of TPF or carboplatin and FU.
Treatments
In the experimental arm, the TPF regimen was delivered as previously
reported,
16,17
with docetaxel 75 mg/m
2
day 1 (T) plus cisplatin 75 mg/m
2
day 1 (P) plus FU 750 mg/m
2
days 1 to 5 (F), associated with the rec-
ommended use of prophylactic granulocyte colony-stimulating factor and
the systematic use of ciprofloxacin from days 6 to 15 after chemotherapy.
An evaluation was planned after three cycles, head and neck computed
tomography or magnetic resonance imaging, and head and neck clinical
evaluation. For all patients who achieved complete response (CR), partial
response (PR), or stable disease, TPF was followed by cetux-RT admin-
istered as a loading dose of 400 mg/m
2
8 days before RT starting and
a weekly dose of 250 mg/m
2
during RT for seven doses. Patients who
experienced tumor and/or nodal progression after TPF were treated at the
discretion of the investigators with either curative RT, palliative RT, or best
supportive care. In the reference arm, RT was administered concurrently
with chemotherapy, which consisted of carboplatin 70 mg/m
2
per day, days 1
to 4, and FU 600 mg/m
2
per day, days 1 to 4 continuous infusion, both ad-
ministered every 3 weeks for three cycles (during weeks 1, 4, and 7 of ra-
diotherapy), as previously reported.
9
In both arms, RT total dose was 70 Gy
with 2 Gy per day, 5 days per week. Intensity-modulated RT was recommended,
but three-dimensional conformal RT was also accepted. A dose of 50 Gy
(2 Gy per day, 5 days per week) was prescribed to the prophylactic volume.
Random Assignment and Statistical Analysis
Random assignment between TPF plus cetux-RT and CT-RT was
stratified by centers. To avoid deterministic minimization and assure al-
location concealment, the treatment that minimized the imbalance was
assigned with a probability of 0.80 (ie, ,1.0). Random assignment was
performed centrally at the GORTEC data center.
The primary end point was PFS, which was defined as the time from
random assignment to first progression—locoregional or distant—or
death from any cause. To detect a hazard ratio (HR) of 0.66 (increase in
2-year PFS from 45% to 59%), the inclusion of 180 eligible patients per
arm was required to achieve 80% power at a two-sided significance level of
.05. PFS analysis was performed according to the intent-to-treat principle
on eligible patients and using a Cox proportional hazards regression model
adjusted for the minimization factors. Secondary end points were OS,
locoregional failure, distant failure, and acute or late toxicities according to
NCI-CTCAE version 3 criteria. Median follow-up was estimated using the
reverse Kaplan-Meier method.
RESULTS
Patient and Tumor Characteristics
All patients had biopsy-proven SCC of the oral cavity, oro/
hypopharynx, or larynx. The distribution of patients according to
age, performance status, tumor site, p16 immunostaining, and
nodal and tumor stage were well balanced between the two arms
and is given in Table 1. In both arms, the majority of patients had
T3 to T4 and/or N2c to N3 disease. The inclusion of patients with
N2b disease was allowed only if the cervical masses were clinically
considered to be bulky (palpable). All patients with oral cavity
carcinoma had unresectable disease in the neck and/or at the
primary site. More than 60% of patients in both arms had an
oropharyngeal cancer, with a majority being p16 negative (Tables 1
and 2). Figure 1 shows that five patients in both arms were not
eligible—two distant metastasis, two patients with other con-
comitant tumor, and one patient withdrew consent in the CT-RT
arm; and three patients with performance status of 2, one patient
with other concomitant tumor, and one patient with no initial
evaluation in the TPF plus cetux-RT arm—and random assign-
ment was continued after including 360 patients, with 10 addi-
tional patients enrolled for a total of 370 patients, to maintain the
initial plan of analyzing 360 patients.
Compliance With Treatment
In the experimental TPF plus cetux-RTarm (n = 181 patients),
1.5%, 10.5%, 5%, and 83% of the patients received zero or one, two,
and three cycles of induction TPF, respectively. The proportion of
the theoretical TPF dose administered was 99.1%, 97.3%, and 96.8%
for cycles 1, 2, and 3 respectively. A total of 151 patients completed
cetux-RT and 71% received at least seven injections of cetuximab.
In the reference CT-RT arm (n = 179 patients), 8.4%, 21.7%,
and 69.5% of patients received zero or one, two, and three cycles,
respectively, of concurrent carboplatin and FU during the course of
RT. The proportion of the theoretical CT-RT dose administered
was 97.9%, 99.1%, and 98.6% for cycles 1, 2, and 3, respectively.
Compliance with RT was not different between the two arms,
with a mean overall treatment time of 52.3 days and 52.6 days in
the TPF plus cetux-RT and CT-RT arms, respectively. Mean ra-
diation dose was 68.2 Gy (standard deviation, 7.7) in 175 patients
in the CT-RT arm and 69.2 Gy (standard deviation, 5.9) in 151
patients in the TPF plus cetux-RT arm who received RT. The
Table 1. Patient and Tumor Characteristics
Characteristic CT-RT (n = 179) TPF + Cetux-RT (n = 181)
Male sex 153 (85) 157 (87)
Median age, years 56.5 56
Performance status
0 63 (35) 71 (39)
1 116 (65) 110 (61)
Stage
T2 29 (16) 30 (17)
T3 64 (36) 59 (33)
T4 86 (48) 91 (50)
Nodal status
N2b 57 (32) 46 (26)
N2c 81 (45) 98 (54)
N3 41 (23) 37 (21)
Anatomic site
Oral cavity 24 (14) 18 (10)
Oropharynx 108 (60) 123 (68)
Larynx 8 (5) 12 (7)
Hypopharynx 39 (22) 28 (15)
NOTE. Data are given as No. (%).
Abbreviations: cetux-RT, cetuximab radiotherapy; CT-RT, chemoradiotherapy;
TPF, taxotere, cisplatin, fluorouracil.
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proportion of temporary RT interruption ($7 days) was 18% and
13%, and discontinuation of RT was 3% and 8% in the TPF plus
cetux-RT and CT-RT arms, respectively.
To evaluate a potential imbalance of RT quality between the
two arms, a review of the quality assurance of RTwas performed by
GORTEC quality assurance experts. RT records of the first two
patients of each center were analyzed, and one third of the other
enrolled patients per center were also reviewed. Items reviewed
included total dose, planned target volume of 70 Gy coverage, dose
to spinal cord and brainstem, dose per fraction, overall treatment
time, and adequate verification imaging. No difference in any of
these items was observed between both arms.
Tolerance and Response to TPF in the Experimental Arm
Despite the recommended prophylactic use of lenograstim
and the systematic use of ciprofloxacin, 30 patients had febrile
neutropenia (17%) and 12 patients died during or in the 30 days
after TPF (6.6%), and all causes of death, with the exception of one,
were considered to be related to TPF. Among these 12 patients,
three died at home of unknown cause and were registered as toxic
deaths, one patient died of hemorrhage (registered as toxic death),
six patients died from infectious disease with neutropenia (five
grade IV and one grade III), and two patients died as a result of
diarrhea and renal failure (one patient was reclassified as septic
shock). Overall, the most common pattern of death was infectious
disease, mainly associated with neutropenia. Of 181 patients
who received TPF, seven patients (4%), 73 (40.5%), 71 (39%),
and 10 (5.5%) exhibited CR, PR, disease stabilization, or dis-
ease progression, respectively, after induction TPF. After TPF,
20 patients did not complete the evaluation and did not receive RT
as initially planned, and 10 additional patients who experienced
progression with TPF did not receive RT. Overall, only 151 (83%)
of 181 patients were treated with cetux-RT as planned.
Adverse Events
The rate of grade 3 and 4 adverse events is listed in Table 3.We
observed significantly more grade 3 and 4 fever (9% v0.6%; P,
.001), grade 3 and 4 neutropenia (26% v6%; P,.001), and
significantly more febrile neutropenia (17% v0%; P,.001) in the
TPF plus cetux-RTarm. Grade 3 and 4 mucositis was not different
between the two arms—50% in the CT-RT arm versus 48% in the
cetux-RTarm (P= .7). Grade 3 and 4 skin reactions inside RT fields
were significantly increased in the cetux-RT arm compared with
the CT-RT arm (53% v29%, respectively; P,.001). In contrast to
6.6% TPF-related deaths, only one patient died during CT-RT
(0.6%; P= .0016). There was also a difference between the two
arms for grade 3 and 4 skin reactions outside RT fields, with 11% in
the cetux-RT arm and 7% grade 3 and 4 hypersensitivity to
cetuximab. Other relevant toxicities were not different between the
two arms.
Oncologic Results
Median follow-up was 2.8 years for the TPF plus cetux-RT arm
(interquartile range, 1.9 to 4.0) and 2.6 years for the CT-RT arm
(interquartile range, 2.2 to 3.8). There was no difference in PFS
between the two arms with an HR of 0.93 (95% CI, 0.73 to 1.20; P=
.58), no difference for locoregional control with an HR of 0.98 (95%
CI, 074 to 1.30; P=.90;Figs 2A and 2B), and finally no difference in
OS with an HR of 1.12 (95% CI, 0.86 to 1.46; P=.39;Fig 2C). A
significant difference was obser ved in favor of the TPF plus cetux-RT
arm regarding the rate of distant metastases when considered as
afirst event with an HR of 0.54 (95% CI, 0.30 to 0.99; P=.05;Fig
2D) and also when considered as the first or later event with an HR
of 0.62 (95% CI, 0.40 to 0.95; P= .03; Appendix Fig A1, online only).
Oncologic Results by p16 Status
p16 expression was assessed by immunostaining in 172 pa-
tients with OPC (74%) with 84 in the CT-RTarm and 88 in the TPF
Table 3. Occurrence of Grade 3 and 4 Adverse Events
RT-CT (%) TPF (%) Cetux-RT (%)
PGrade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4
Fever 0.6 —9.0 —2.0 —.001
Mucositis (RTOG) 48.0 2.0 3.0 —46.0 2.0
Neutropenia 3.0 3.0 8.0 18.0 ——.001
Renal toxicity 0.6 —3.5 —2.5 —
Liver enzyme 4.0 ——— 1.0 —
Skin reactions NA NA .001
Outside RT fields —— 10.0 1.0
Inside RT fields 28.0 1.0 48.0 5.0
Hypersensitivity to cetuximab (n = 151) NA NA NA NA 5.0 2.0
NOTE. There was significantly more grade 3 and 4 fever (9% with TPF v0.6%; P= .001), grade 3 and 4 neutropenia (26% v6%; P,.001), and significantly more febrile
neutropenia (17% v0%; P,.001) in the TPF+ cetux-RT arm. Grade 3 and 4 mucositis was not different between the two arms: 50% in the CT-RT arm v48% in the cetux-
RT arm (P= .7). Grade 3 and 4 skin reactions inside radiotherapy fields were significantly increased during cetux-RT compared with CT-RT (53% v29%, respectively; P,
.001).
Abbreviations: cetux-RT, cetuximab radiotherapy; CT-RT, chemoradiotherapy; NA, not applicable; RT, radiotherapy; RTOG, Radiation Therapy Oncology Group; TPF,
taxotere, cisplatin, fluorouracil.
Table 2. p16 Status in Patients With Oropharyngeal Tumors (172 analyzed and
59 unknown)
p16 Status CT-RT (n = 84), No. (%) TPF + Cetux-RT (n = 88), No. (%)
Negative 58 (69) 69 (78)
Positive 26 (31) 19 (21)
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plus cetux-RT arm. Twenty-six patients were found to be p16
positive in the CT-RT arm (31%) and 19 in the TPF plus cetux-RT
arm (21.5%). Only eight (18%) of 45 p16-positive patients were
nonsmokers, which indicates that the majority of patients with
OPC were p16 negative (74%) and smokers (90%). Overall,
a significant improvement in PFS was found in p16-positive OPC
compared with p16-negative OPC (P,.001); however, the ab-
sence of benefit for PFS associated with TPF plus cetux-RT
compared with CT-RT was observed both in p16-positive OPC
with an HR of 0.78 (95% CI, 0.28 to 2.20; P= .64) and in p16-
negative OPC with an HR of 1.28 (95% CI, 0.84 to 1.93; P= .25),
and the interaction between p16 and treatment modality was
not significant (P= .35). Finally, the benefit in favor of TPF plus
cetux-RT with regard to distant metastasis was not different be-
tween p16-positive and p16-negative OPC
DISCUSSION
Two phase III randomized trials were run in parallel within the
GORTEC network. The current study was restricted to patients
with stage IV bulky nodal, N2b clinically palpable, or N2c or N3
disease, whereas the second trial (GORTEC 2007-01) was restricted
to patients with limited nodal disease and assessed the addition of
concurrent chemotherapy to the cetux-RT SOC.
In the current study, in addition to the N2b to N3 status,
a majority of patients were smokers (90%) with T4 and p16
negative disease, which indicated that nearly all fell into the high-
risk category as described by Ang et al.
18
The effect of induction
TPF followed by cetux-RT compared with well-established SOC
CT-RT in this particular selection of patients was unknown. Our
HR, 0.93 (95% CI, 0.73 to 1.20)
Two-sided log-rank P = .58
CT-RT
TPF + Cetux-RT
179
181
89
87
59
57
32
33
16
16
6
2
No. at risk
CT-RT
TPF-cetux-RT
Time Since Random Assignment (years)
20
40
60
80
100
123456
Progression-Free Survival (%)
0
A
HR, 0.98 (95% CI, 0.74 to 1.30)
Two-sided log-rank P = .90
179
181
89
87
59
57
32
33
16
16
6
2
No. at risk
CT-RT
TPF-cetux-RT
Time Since Random Assignment (years)
20
40
60
80
100
123456
Locoregional Control (%)
0
CT-RT
TPF + Cetux-RT
B
HR, 1.12 (95% CI, 0.86 to 1.46)
Two-sided log-rank P = .39
CT-RT
TPF + Cetux-RT
179
181
122
122
79
76
43
39
22
17
6
2
No. at risk
CT-RT
TPF-cetux-RT
Time Since Random Assignment (years)
20
40
60
80
100
123456
Overall Survival (%)
0
C
HR, 0.54 (95% CI, 0.30 to 0.99)
Two-sided log-rank P = .05
CT-RT
TPF + Cetux-RT
179
181
111
115
75
73
40
36
22
16
6
1
No. at risk
CT-RT
TPF-cetux-RT
Time Since Random Assignment (years)
20
40
60
80
100
123456
Distant Metastasis–Free Survival (%)
0
D
Fig 2. (A) Progression-free survival. (B) Locoregional control. (C) Overall survival. (D) Distant metastasis–free survival (first event), showing a significant difference in favor
of the taxotere, cisplatin, fluorouracil (TPF) plus cetuximab radiotherapy (cetux-RT) arm. CT-RT, chemoradiotherapy; HR, hazard ratio.
jco.org © 2018 by American Society of Clinical Oncology 3081
Induction Chemotherapy, Radiotherapy
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study failed to find a benefit for PFS in favor of the TPF approach,
and the primary end point was not met. Overall, relatively similar
results were observed in PFS, locoregional control, and OS between
the two arms. There was one interesting finding regarding the
decrease in distant metastases—either as the first or nonfirst
event—that was observed in the TPF arm, which confirmed the
hypothesis that TPF can be active in micrometastases and could be
of interest in patients with the most advanced nodal spread who
carry the highest risk of distant metastases. This observation is in
agreement with the DeCIDE
11
randomized trial, which was also
restricted to patients with N2/N3 disease and demonstrated
a comparable benefit of TPF on distant metastases. This obser-
vation is also in agreement with the update of the MACH-NC
database when comparing induction TPF with induction FU and
cisplatin.
13
Overall, use of induction TPF markedly modified the clinical
presentation of the disease as only 151 (83%) of 181 patients who
were randomly assigned to TPF could be offered RT as planned
(cetux-RT) after induction TPF, either because they died or be-
cause of disease progression or as a result of other interferences.
This implies that 17% of patients in this arm did not have the
opportunity to receive curative RT, which may have a substantial
influence on final outcomes in patients compared with SOC CT-
RT, in which the majority of patients received full-dose RT (92%).
This observation is in good agreement with other randomized
studies in locally advanced head and neck cancer, such as the
Tremplin
15
study, in which a large proportion of patients (37
[24%] of 153) who received induction TPF could not receive
additional RT as planned.
We report an 83% disease control rate after induction TPF, but
the objective response rate was only 45.5% (CR + PR), which is
lower than the response rates of 60% or more that have been
reported in other phase III studies by Vermorken et al
16
and Cohen
et al.
11
This may be as result, in part, of our selection of patients,
essentially with more advanced and bulky disease (N2c to N3;
75%). Another aspect related to TPF in our patients with classical
tobacco- and alcohol-related SCCHN and mostly p16-negative
disease was the high rate of TPF-related deaths (6.6%), which
might not be acceptable. This rate was significantly higher than that
observed in the CT-RT arm and in agreement with other ran-
domized studies that investigated induction TPF. Indeed, in these
studies, TPF-related death has been reported to be 0% (in a ran-
domized study on nasopharynx),
19
and 2.9% in the DeCIDE
11
randomized trial and 5% in the seminal randomized trial reported
by Vermorken et al.
16
These considerations do suggest that, if TPF
is a reference induction chemotherapy regimen, which was found
to be superior to cisplatin and FU, it should be carefully handled,
especially in this type of patient with advanced local disease and
tobacco- and alcohol-related comorbidities, as was the case with
our study.
In conclusion, compared with the well-established CT-RT
SOC, induction TPF followed by cetux-RT failed to provide
a benefit in PFS, locoregional control, and OS in a selection of
patients with N2b to N3 LA-SCCHN. A benefit from TPF on
distant metastases confirmed previous observations, but this
should be carefully considered, given the potential TPF-related
toxicity.
AUTHORS’DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Lionnel Geoffrois, Pascal Garaud, Jean Bourhis
Administrative support: Lionnel Geoffrois, Pascal Garaud, Jean Bourhis
Provision of study materials or patients: Lionnel Geoffrois, Laurent
Martin, Dominique De Raucourt, Xu Shan Sun, Yungan Tao, Philippe
Maingon, Jo¨
elle Buffet, Yoann Pointreau, Christian Sire, Claude Tuchais,
Emmanuel Babin, Alexandre Coutte, Fr´
ed´
eric Rolland, Marie-Christine
Kaminsky, Marc Alfonsi, Michel Lapeyre, Marie Saliou, C´
edric Lafond,
Eric Jadaud, Bernard Gery, Ayman Zawadi, C´
edric Khoury, Anne Rose
Henry, Ali Hasbini, François Guichard, Christian Borel, Nicolas Meert,
Pierre Guillet, Jean Bourhis
Collection and assembly of data: All authors
Data analysis and interpretation: Lionnel Geoffrois, Pascal Garaud, Jean
Bourhis
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
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Affiliations
Lionnel Geoffrois, Marie-Christine Kaminsky, Institut de Canc´
erologie de Lorraine, Vandoeuvre L`
es Nancy; Laurent Martin,
Centre Guillaume le Conqu´
erant; Dominique De Raucourt, Bernard Gery, Centre François Baclesse; Emmanuel Babin, Hopital
Universitaire, Caen; Xu Shan Sun, Jo¨
elle Buffet, Centre Hospitalier Universitaire de Besançon, Besançon; Hˆ
opital de Mulhouse,
Mulhouse; Yungan Tao, Gustave-Roussy Institute, Villejuif; Philippe Maingon, Centre François Leclercq, Leclercq; Yoann Pointreau,
C´
edric Lafond, Marie-H´
el`
ene Calais, Pascal Garaud, Centre Jean Bernard, Le Mans; Centre Hospitalier Universitaire de Tours, Tours;
Christian Sire, Centre Hospitalier de Lorient, Lorient; Claude Tuchais,Eric Jadaud, Centre Paul Papin, Angers; Alexandre Coutte,
Centre Hospitalier Universitaire Amiens, Amiens; Fr´
ed´
eric Rolland, Centre Ren´
e Gauducheau, Saint Herblain; Marc Alfonsi, Clinique
Sainte Catherine, Avignon; Michel Lapeyre, Centre Jean Perrin, Clermont; Marie Saliou, Clinique Mutualiste, Saint Nazaire; Ayman
Zawadi, Centre Hospitalier de La Roche-sur-Yon, La Roche-sur-Yon; Jean-Marc Tourani, Centre Hospitalier Universitaire, Poitiers,
Poitiers; C´
edric Khoury, Centre Saint Louis; Pierre Guillet,H
ˆ
opital Font-Pr´
e, Toulon, Toulon; Ali Hasbini, Hopital de Saint Brieuc, Saint
Brieuc; François Guichard, Polyclinique de Bordeaux-Nord, Bordeaux; Christian Borel, Centre Paul Strauss, Strasbourg, France; Anne
Rose Henry,Hˆ
opital Montigny le Tilleul, Montigny-le-Tilleul; Nicolas Meert, Centre Hospitalier de Charlebois, Charlebois, Belgium; and
Jean Bourhis, Centre Hospitalier Universitaire Vaudois Lausanne, Lausanne, Switzerland.
nnn
jco.org © 2018 by American Society of Clinical Oncology 3083
Induction Chemotherapy, Radiotherapy
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Copyright © 2021 American Society of Clinical Oncology. All rights reserved.

AUTHORS’DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas:
Results of the GORTEC 2007-02 Phase III Randomized Trial
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Lionnel Geoffrois
Consulting or Advisory Role: MSD Oncology, Bristol-Myers Squibb,
AstraZeneca, Novartis
Travel, Accommodations, Expenses: Ipsen, Bristol-Myers Squibb,
Novartis
Laurent Martin
No relationship to disclose
Dominique De Raucourt
No relationship to disclose
Xu Shan Sun
No relationship to disclose
Yungan Tao
No relationship to disclose
Philippe Maingon
No relationship to disclose
Jo¨
elle Buffet
No relationship to disclose
Yoann Pointreau
Honoraria: Merck, MSD Oncology, Bristol-Myers Squibb
Consulting or Advisory Role: Merck, MSD Oncology, Bristol-Myers
Squibb
Christian Sire
No relationship to disclose
Claude Tuchais
No relationship to disclose
Emmanuel Babin
No relationship to disclose
Alexandre Coutte
No relationship to disclose
Fr´
ed´
eric Rolland
Consulting or Advisory Role: Novartis, Pfizer, Bristol-Myers Squibb,
Bayer
Travel, Accommodations, Expenses: Novartis, Pfizer
Marie-Christine Kaminsky
No relationship to disclose
Marc Alfonsi
No relationship to disclose
Michel Lapeyre
No relationship to disclose
Marie Saliou
No relationship to disclose
C´
edric Lafond
No relationship to disclose
Eric Jadaud
No relationship to disclose
Bernard Gery
No relationship to disclose
Ayman Zawadi
No relationship to disclose
Jean-Marc Tourani
No relationship to disclose
C´
edric Khoury
Honoraria: Janssen-Cilag
Anne Rose Henry
No relationship to disclose
Ali Hasbini
No relationship to disclose
François Guichard
No relationship to disclose
Christian Borel
Honoraria: Merck, Bristol-Myers Squibb
Consulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb
Travel, Accommodations, Expenses: Merck
Nicolas Meert
No relationship to disclose
Pierre Guillet
No relationship to disclose
Marie-H´
el`
ene Calais
No relationship to disclose
Pascal Garaud
No relationship to disclose
Jean Bourhis
Consulting or Advisory Role: Merck Serono, MSD Oncology,
AstraZeneca, Bristol-Myers Squibb
© 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Geoffrois et al
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Copyright © 2021 American Society of Clinical Oncology. All rights reserved.

Appendix
The following people contributed to this work:
Montbelliard/Besançon, France: X.S. Sun, J. Buffet
Lorient, France: C. Sire
Villejuif, France: Y.G. Tao, S. Temam, F. Janot, P. Blanchard, J. Guigay, C. Even, N. Ollivier, A. Auperin
Le Havre, France: L. Martin
Toulon, France: C. Khoury, P. Guillet, X. Tchiknavorian
Dijon, France: P. Maingon
Nantes, France: F. Rolland, E. Bardet, D. Vansteene, O. Mallard
Nancy, France: M.C. Kaminski, L. Geofffrois, P. Graff
Clermont, France: M. Lapeyre, A.F. Dillies
Saint Nazaire, France: T. Chatelier, M. Saliou, F. Drouet
Avignon, France: M. Alfonsi, W. Hilgers, S. Kirscher
La Mans, France: Y. Pointreau, C. Lafond
Tours, France: G. Calais, A, Ruffier-Loubiere
Angers, France: E. Jadaud, O. Capitain, P. Maillard, C. Tuchais
Caen, France: B. Gery, C. Florescu, E. Babin, A. Lasne Cardon, D. DeRaucourt
La Roche/Yon, France: A. Zawadi
Poitiers, France: X. Dufour, J.M. Tourani
Amiens, France: A. Coutte, A. Biet, B. Chauffert
St Brieuc, France: P. Burban, A. Hasbini, D. Besson
Charlebois, Belgium: N. Meert
Montigny-le-Tilleul, Belgium: A.R. Henry
Strasbourg, France: C. Borel, O. Gallocher
Bordeaux, France: F. Guichard
GORTEC: M.H. Girard-Calais, P. Garaud, N. Vintonenko
Lausanne, Switzerland: J. Bourhis
HR, 0.62 (95% CI, 0.40 to 0.95)
Two-sided log-rank P = .03
CT-RT
TPF + Cetux-RT
179
181
109
111
73
72
37
36
22
16
6
1
No. at risk
CT-RT
TPF-cetux-RT
Time Since Random Assignment (years)
20
40
60
80
100
123456
Distant Metastasis–Free Survival
(first and later event) (%)
0
Fig A1. Distant metastasis–free survival (first and later event), with a significant
difference in favor of the taxotere, cisplatin, fluorouracil (TPF) plus cetuximab
radiotherapy (cetux-RT) arm. CT-RT, chemoradiotherapy; HR, hazard ratio.
jco.org © 2018 by American Society of Clinical Oncology
Induction Chemotherapy, Radiotherapy
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Copyright © 2021 American Society of Clinical Oncology. All rights reserved.