original article
Annals of Oncology 22: 712–717, 2011
doi:10.1093/annonc/mdq412
Published online 1 September 2010
Cisplatin-based chemoradiation plus cetuximab in
locally advanced head and neck cancer: a phase II
clinical study
M. Merlano1*, E. Russi2, M. Benasso3, R. Corvò4, I. Colantonio1, R. Vigna-Taglianti2, V. Vigo3,
A. Bacigalupo4, G. Numico5, N. Crosetto1 , M. Gasco1à, C. Lo Nigro1à, R. Vitiello6, S. Violante7
& O. Garrone1
Departments of 1Medical Oncology; 2Radiation Therapy, S. Croce General Hospital, Cuneo; 3Department of Medical Oncology, La Spezia General Hospital, La Spezia;
4
Department of Radiation Therapy, National Institute for Cancer Research, Genoa; 5Department of Medical Oncology, Aosta General Hospital, Aosta; 6Department of
Otorhinolaryngology; 7Clinical Trials Office, Department of Medical Oncology, S. Croce General Hospital, Cuneo, Italy
Received 2 December 2009; revised 11 March 2010; revised 7 May 2010; accepted 21 June 2010
original
article
Background: Intensification of chemoradiation for advanced head and neck squamous cell carcinoma (HNSCC) is
unlikely due to toxicity. Cetuximab combined either with radiotherapy or with chemotherapy showed favourable toxic
profile with positive results in both combinations. Therefore, cetuximab could intensify chemoradiation without
worsening toxicity. We conducted a phase II study of chemoradiation and cetuximab.
Patients and methods: Eligible patients had stage III–IV M0 HNSCC. Treatment consisted of three cycles of
cisplatin (20 mg/m2/day · 5 days) and fluorouracil (200 mg/m2/day · 5 days) rapidly alternated to three split courses of
radiotherapy up to 70 Gy and concurrent weekly cetuximab. The primary end point of the study was complete
response (CR) rate. Secondary end points were toxicity, progression-free survival (PFS) and overall survival (OS).
Results: Fourty-five patients were enrolled: median age was 56 years, 38 had stage IV disease and 40 nodal
involvement. CR occurred in 32 patients (71%). PFS and OS was 21+ months and 32.6+, respectively. Acute grade
3–4 toxic effects were in the expected range, but grade 3 radiodermatitis occurred in 33 patients.
Conclusions: The combination of cetuximab, cisplatin, fluorouracil and radiotherapy leads to a very high proportion
of CR and it is feasible with toxic effects similar to those expected by radiochemotherapy. The only unexpected toxicity
was skin toxicity: grade 3 radiodermatitis occurred in 73% of the patients.
Key words: cetuximab, chemoradiation, head and neck cancer
introduction
Chemoradiation is widely accepted as the standard of care for
patients with unresectable, locally advanced head and neck
squamous cell carcinoma [1] (HNSCC). However, the 5-year
absolute survival rates remain poor [2, 3] and treatment is
hampered by major toxicity [4], thus making intensification
unlikely to be achieved. Therefore, novel therapies are needed
to produce survival gain without worsening toxicity.
Elevated levels of epidermal growth factor receptor (EGFR)
are common in HNSCC [5–7] and correlate with resistance to
radiation, higher risk of local relapse and poor overall survival
*Correspondence to: Dr M. Merlano, Department of Medical Oncology, S. Croce
General Hospital, Via M. Coppino 26, 12100 Cuneo, Italy. Tel: +39-0171-616739;
Fax: +39-0171-616737; E-mail: [email protected]
Present address: Institute of Biochemistry II, Goethe University Hospital, Frankfurt am
Main, Germany.
à
Present address: Department of Medical Oncology, Laboratory of Translational
Researches, Cuneo, Italy.
(OS) [7–12]. The anti-EGFR antibody cetuximab (Erbitux),
when associated with radiation therapy, significantly improves
locoregional control and survival in patients with HNSCC [13],
without increasing radiotherapy-related toxicity, compared
with radiotherapy alone. Similarly, combining cetuximab with
cisplatin and fluorouracil in recurrent or metastatic disease
significantly improves clinical outcome without major changes
in toxicity (EXTREME study) [14]. These positive results
suggest that cetuximab could allow for chemoradiation
intensification. Unfortunately, Pfister et al. [15] have shown
that cetuximab combined with chemoradiation increases severe
toxic effects and have therefore recommended that less toxic
chemoradiation schedules should be employed. Alternating
chemoradiation might be an acceptable alternative to strictly
concurrent chemoradiation [16]. Available clinical data show
that both acute and late toxic effects of radiotherapy are not
enhanced by alternating chemoradiation [17–19], indicating
that this schedule combined with cetuximab could avoid
excessive toxicity.
ª The Author 2010. 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
Annals of Oncology
We report a phase II study (Alternating Radiotherapy and
Chemotherapy combined with Cetuximab, AlteRCC) designed
to investigate the activity and safety profile of this combined
approach in patients suitable for chemoradiation but not for
surgery.
patients and methods
eligibility criteria
Enrolled patients were required to have hystologically confirmed HNSCC of
oral cavity, larynx, oropharynx or hypopharynx; age of 18 years or more;
adequate liver (total bilirubin <1.5 · upper normal limit, alkaline
phosphatase and aspartate aminotransferase <2.5 · upper normal
limit), kidney (creatinine <1.3 mg/dl) and bone marrow (white blood
cell ‡3000/ll, granulocytes ‡1500/ll, platelet count ‡100 000/ll and
haemoglobin ‡9 g/dl) function; Eastern Cooperative Oncology Group
performance status 0 or 1 and stage III or IVa to b with measurable lesions
(AJCC staging system, sixth edition [20]). All patients provided a written
informed consent for this study, which was approved by the institutional
Ethical Committee of S. Croce General Hospital. All patients accrued into
the present study were evaluated by a multidisciplinary team and were
considered unresectable due to disease extension or poor surgical curability.
Exclusion criteria were prior treatment of HNSCC, concurrent active
malignancies except in situ skin carcinoma, carcinoma of the nasopharynx
and pregnancy or breast-feeding.
treatment
Radiotherapy was administered as a single daily fraction (days 1–5 and
weeks 2–3, 5–6 and 8–10). A dose of 50 Gy/2 Gy per fraction to the clinical
target volume, including the tumour [gross tumor volume on primary
(GTVt)], the metastatic lymph nodes [gross tumor volume on node
(GTVn)] and the draining clinical negative lymphatic pathways [elective
clinical target volume (CTV)] [21, 22], was prescribed with a dose
homogeneity of 25% to + 7% as recommended by ICRU report no.
50 [23]. The five isocentric photon field techniques, described by Fogliata
et al. [24], was adapted to the single real clinical situation. A further booster
dose up to 66–70 Gy was prescribed to the clinical target volume including
only GTVt and GTVn using a not standardised three-dimensional
conformal technique. Organs at risk involved in this treatment and
normally considered were spinal cord, salivary glands and apexes of the
lungs. A maximum point dose of 45 Gy was set as an overall constraint to
the spinal cord. The schedule was alternating with chemotherapy as
described by Merlano et al. [17]. Chemotherapy was delivered on days 1–5
and weeks 1, 4 and 7. Cetuximab was delivered weekly on day 1, from weeks
1 to 10.
Chemotherapy consisted of cisplatin 20 mg/m2/day delivered i.v. in
15 min during a 2-h forced hydration with 2 l saline supplemented with
KCl 20 mEq and MgSO4 1 g. Fluorouracil 200 mg/m2/day was administered
as an i.v. bolus at the end of hydration.
Cetuximab was administered at an initial dose of 400 mg/m2 followed by
a weekly dose of 250 mg/m2. Pre-treatment with diphenhydramine 50 mg
and dexamethasone 8 mg was standard. No dose modification was allowed.
In case of grade 3 radiodermatitis, cetuximab was discontinued until
recovery to grade 2.
Patients with N2-3 disease at baseline were allocated to prophylactic neck
dissection irrespectively of their response. Patients with residual neck
disease were recommended for salvage surgery.
pre-study procedures and evaluation
Baseline evaluation included medical history, physical examination,
panendoscopy and basic nutritional evaluation. All patients were
offered dental prophylaxis and received a Hohn-type central venous
Volume 22 | No. 3 | March 2011
device. Computed tomography (CT) scan or magnetic resonance imaging
(MRI) of the primary site and neck were used for staging. Complete
haematological, coagulation and blood chemistry profiles together with
urine analysis, chest X-rays and electrocardiogram were requested to
confirm eligibility.
on-study patient evaluation and results assessment
During treatment, patients underwent weekly physical and nutritional
evaluation and blood cell count. Comprehensive blood chemistry profiles
were carried out at 21-day intervals or when clinically required.
Hospitalisation of patients developing grade ‡3 stomatitis or grade 4
haematological toxicity was mandatory. All patients showing a ‡5%
reduction of body weight in 2 months before treatment or during treatment
received nutritional support. In case of grades 3–4 stomatitis, nutritional
support was considered irrespective of body weight. Nutritional support
was administered orally until possible. Patients with severe dysphagia
received adequate enteral or parenteral nutrition. Antibiotic prophylaxis
with ciprofloxacin 500 mg twice a day was given to patients with <100
neutrophils/mm3. Standard therapy for febrile neutropenia consisted of
ceftriaxone and amikacyn.
In order to assess response, CT or MRI scans of the head and neck were
planned 1 and 3 months after the end of the treatment. Follow-up consisted
of physical examinations every second month and CT scan every fourth
month until 2 years past diagnosis. From years 3–5 after diagnosis, patients
underwent clinical control every fourth month and CT scan every sixth
month. Toxicity was graded according to National Cancer Institute–
Common Toxicity Criteria for Adverse Events version 3 system [25].
Tumour size was calculated by multiplying the maximal tumour
diameters measured on bidimensional imaging studies. Complete response
(CR) was a total disappearance of radiographic evidence of tumour. Partial
response (PR) was a ‡50% reduction in the product of the maximal
bidimensional tumour diameters. Stable disease was any change
between +25% and 250% in tumour size, and progressive disease included
any increase >25% from baseline or the appearance of any new lesion.
statistical methods
AlteRCC was a single-arm phase II study, conducted according to the
optimal two-stage design by Simon [26]. The primary end point was to
increase the CR rate. Assuming that the expected CR rate with alternating
chemoradiation is 50% [18] (p0) and the level of interest was established as
an increase up to 70% (p1). Therefore, accepting a and b errors of 0.10, at
least 26 CRs were to be observed out of 45 patients.
Secondary end points included toxicity, progression-free survival
(PFS) and OS. Acute toxicity and OS were evaluated in all treated
patients. PFS was evaluated in all patients except those lost during followup. In this case, patients were withdrawn at the time of the last follow-up
from PFS analysis, whereas information about life/death status were
obtained from the registry. PFS was computed as the time from the
beginning of treatment to disease progression or death for any cause (intent
to treat). Living patients without evidence of progression were censored at
the last follow-up. OS was considered as the time from the beginning of
treatment to death for any cause. Living patients were withdrawn at the last
follow-up. Both PFS and OS were estimated using the method of Kaplan
and Meier [27].
results
patient characteristics
Forty-five patients were accrued (October 2005 to December
2007). Table 1 summarises the relevant patients’ features.
Median age was 56 years (24–75). Males accounted for 82% of
the population and most patients had primary tumours of the
doi:10.1093/annonc/mdq412 | 713
original article
Annals of Oncology
Table 1. Main patient characteristics
Number of patients
Male/female
Median age (range)
Median Eastern Cooperative Oncology Group
performance status (range)
Primary site, n (%)
Oropharynx
Hypopharynx
Larynx
Oral cavity
Tx
Stage, n (%)
III
IV
Node, n (%)
N0
N1-2
N3
45
37/8
56 (24–75)
0 (0–1)
15
11
12
5
2
(34)
(24)
(27)
(11)
(4)
7 (16)
38 (84)
5 (11)
35 (78)
5 (11)
oropharynx, advanced neck involvement (>N2 = 78%) and
stage IV disease (84%).
Overall, 422 cetuximab administrations instead of 450 and
127 courses of chemotherapy instead of 135 were delivered.
Eighteen patients received 68–70 Gy, 23 received 66 Gy and 4 (3
on treatment deaths and 1 withdrawn consensus) received <66
Gy. Thirty-five patients (78%) required hospitalisation in order
to make full-dose delivery feasible.
activity
Overall, 32 CRs (71.1%) and 9 PRs (20%) were recorded
(Table 2). Three patients died during treatment (one acute
heart failure and two aspiration pneumonia). The protocol
advisory board considered all the deaths unrelated to the use of
cetuximab. One patient spontaneously withdrew from the
study. Since an intent-to-treat approach was pursued, these
patients were classified as treatment failure.
adverse events
Major adverse events are listed in Table 2. Stomatitis occurred
in all 45 patients (16 grade 4 and median duration 13.7 days).
Total parenteral nutrition was required in 22 patients (49%),
with median duration 30.5 days (5–90). Four patients (8%)
received enteral nutrition. Painful dysphagia (9% grade 2 and
7% grade 3) most likely was responsible for two fatal cases of
aspiration pneumonia.
Radiodermatitis occurred in all patients. One patient
underwent skin biopsy, revealing thin epidermis with highly
atrophic basal stratum and inflammatory infiltration of the
subepidermis. Rare areas showed limited necrosis of the
epidermis and of the superficial dermis. Clinically, the skin
became dry and inelastic, thus vulnerable to microinjuries, such
as contact with clothes, favouring the onset of pain, bleeding
and infections [28]. The first eight patients were treated with
usual supportive treatment (hygienic measures and emulsions
714 | Merlano et al.
containing trolamine), without adequate control of symptoms
of uncomfortable dermatitis. Further patients were treated
using hydrogel for the painful crusty exudate debridment and
covering the injured skin with ultrathin hydrocolloid dressing
until recovery as described by Russi et al. [28]. In all cases, the
irradiated skin completely recovered a few days after treatment.
Adequate prevention of excessive liquid loss from the skin
helped to avoid symptoms related to this toxicity, thus allowing
for correct treatment delivery [28]. A generalised acne-like rash
was observed in eight patients (18%). This type of rash has been
clearly correlated with the use of EGFR inhibitors, including
cetuximab [29–33]. Other acute adverse events were in line
with previous chemoradiation trials [34].
time to progression and OS
Data were analysed according to the intent-to-treat principle.
Six patients died without cancer and were considered as
relapsed at the time of death [causes of death: pneumonia (two
patients), myocardial infarction, bleeding, sepsis and unknown
in one case). Therefore, 26 of 45 patients have been considered
relapsed at the latest analysis (30 June 2009), yielding an
estimated median 21+ months PFS, with a projected 38% of
patients alive and progression free at 45 months (Figure 1). At
the same time point, 21 of 45 patients have died, giving an
estimated median 32.6+ months OS, with a projected 40% of
patients alive at 45 months (Figure 2).
toxicity and response in elder patients
Four patients were older than 70 (72–75) years. All had stage
IVa oropharyngeal cancer. All developed grade 3 leukopenia
and one died of acute ischaemic heart failure during treatment.
The remaining patients are currently alive and disease free at
15, 20 and 38 months. Among five patients between 65 and 70
years (four stage IVa and one stage IVb), two died of
progressive disease at 19 and 21 months, whereas three are alive
and disease free at 12, 28 and 32 months. Responses in nine
patients <65 years were six CRs, two PRs and one early death.
One partial responder underwent neck surgery, which rendered
him disease free, followed by a second neck surgery due to
nodal recurrence 6 months later. This patient is alive and
disease free at 28 months. Two patients that achieved CR
underwent prophylactic neck dissection because of gross neck
disease at diagnosis. Nonetheless, one of them relapsed in the
neck, lung and liver at 9 months and died of disease at 21
months.
role of prophylactic surgery
Eleven patients (seven were N2 and four N3 at diagnosis,
overall 24%) underwent prophylactic neck dissection, none
having residual microscopic disease. Three additional patients
underwent neck dissection due to positive CT scan at the end of
treatment (one was N3 and two N2 at diagnosis). Histology
confirmed residual disease and surgery rendered all of them
disease free. CR rate after salvage surgery was 77.7%. Among 14
patients that underwent neck dissection, 7 relapsed (5 previous
N2 and 2 previous N3). Two of them relapsed in the neck or in
neck and primary site, while the remaining developed distant
metastases (four patients) or T recurrence.
Volume 22 | No. 3 | March 2011
original article
Annals of Oncology
Table 2. Treatment responses and toxicities
Response
Objective response rate, %
CR, n (%)
PR, n (%)
Failures, n (%)
Grade
Relative frequencies of observed acute toxic effects
Haematological toxic effects, n (%)
Leukopenia
Neutropenia
Grade 3–4 with fever
Anaemia
Thrombocytopenia
Non-haematological toxic effects, n (%)
Stomatitis
Dysphagia
Radiodermatitis
C225-induced rash
Diarrhoea
Alopecia
Peripheral neuropathy
Fatigue
Worse non-haematological toxicity
Worse overall toxicity
45 evaluable patients
91.1%
32 (71.1)
9 (20)
4 (8.9)
0
1
2
3
17
15
8
4
6
12 (27)
12 (27)
1 (2)
1 (2)
14 (31)
14 (31)
13 (29)
26 (58)
12 (27)
5 (11)
16 (35)
7 (16)
2
38
0
37
34
30
44
6
3
0
1
3
4
10
1
18
11
4
11
2
3
4
0
20
(4)
(84)
(82)
(76)
(67)
(98)
(13)
(7)
(2)
(7)
(9)
(22)
(2)
(40)
(24)
(9)
(24)
(4)
(7)
(9)
(44)
4
(38)
(33)
(9)
(13)
13 (29)
3 (7)
33 (74)
3 (7)
4 (9)
1 (2)
0
1 (2)
Stomatitis
Stomatitis
Total
1 (2)
3 (7)
8
0
1 (2)
45
45
45
45
16 (36)
0
0
0
0
0
0
0
45
45
45
45
45
45
45
45
Figure 1. Progression-free survival distribution.
discussion
The AlteRCC trial was designed to evaluate the combination of
cetuximab and chemoradiation using a rapidly alternating
chemoradiation regimen, which is a minor variation of the
strictly concurrent chemoradiation approach [16]. Three
randomised trials have compared this rapidly alternating
chemoradiation regimen with standard radiotherapy[17],
partially accelerated radiotherapy [18], or induction
chemotherapy followed by radiation [19], showing similar or
even significantly lower acute toxic effects[19]. In contrast, all
Volume 22 | No. 3 | March 2011
the trials based on concurrent chemoradiation have reported
a significant increase in toxicity as compared with standard
radiotherapy [35]. Thus, rapidly alternating chemotherapy and
radiotherapy could represent a valuable solution for a less toxic
chemoradiation regimen, as suggested by Pfister et al. [15].
In line with our initial aim, AlteRCC succeeded to increase
the CR rate from 50% to 70%. We also notice that, despite
a case of heart attack, the nine patients >65 years showed
a generally good tolerance to treatment and six of them
achieved a CR.
doi:10.1093/annonc/mdq412 | 715
original article
Annals of Oncology
Figure 2. Overall survival distribution function.
Several trials have already improved the CR rate of cisplatin
based rapidly alternated chemoradiation either by adding
a third drug or by substituting fluorouracil with more active
drugs, yielding CR rates between 68% and 79% [36–39].
Nonetheless, all were hampered by a worrisome increase in lifethreatening toxic effects. In contrast, AlteRCC achieved a CR
rate >70% without significantly worsening life-threatening
toxic effects. Indeed, although three (7%) treatment-related
fatal events occurred during AlteRCC, this impressive data are
consistent with most regimens that use concurrent
chemoradiation [4]. For example, the regimen proposed by
Adelstein et al. [40], which is widely accepted as the standard
chemoradiation approach, is hampered by a 5% mortality rate.
The incidence of grade 3–4 toxic effects in AlteRCC was also
similar to that reported using concurrent or rapidly alternated
chemoradiation [4, 40], except for a higher rate of stomatitis
(65%) and for cutaneous toxicity in the irradiated area.
The high rate of stomatitis in AlteRCC might be due to the
addition of cetuximab to chemoradiation. Indeed, Lefebvre
et al. [19] reported only 23% grade 3–4 mucosal reaction using
the same chemoradiation regimen without cetuximab. Notably,
stomatitis was manageable with the use of total parenteral
nutrition or enteral nutrition. Incidentally, the high percentage
of patients receiving TPN in our study simply reflects the
expertise of our centre.
Cutaneous toxicity in the radiation field has been recently
described in patients treated with cetuximab and radiotherapy
without chemotherapy, but the incidence in our study appears
to be even higher [41–44]. Chemotherapy, and particularly
fluorouracil, may account for this. However, skin toxicity was
fully manageable [28], and rapid healing without scarring was
always achieved within a few days after the end of treatment.
Based on the biopsy carried out in one case, we have classified
this toxicity as grade 3 radiodermatitis [45]. Notably, all the
studies describing similar lesions have also reported complete
skin healing without disfiguring scars [42–44]. Overall, we
administered 422 of the 450 planned doses of cetuximab,
despite skin toxicity. This figure does not correspond with the
percentage of patients who developed grade 3 skin reactions
and who should have interrupted cetuximab according to the
protocol regulations. This was because, having acquired a good
716 | Merlano et al.
expertise with this toxicity and its management, we decided to
continue treatment without breaks and manage the skin
toxicity during therapy.
Single-arm phase II studies cannot produce reliable
information on PFS and OS. Nonetheless, patients treated with
AlteRCC show a favourable outcome, with a median 21+
months PFS and a median 32.6+ months OS.
In conclusion, the addition of cetuximab to rapidly
alternating chemoradiation allows for treatment intensification,
but it is hampered by an unexpected skin toxicity. The
incidence of mucositis also seems to be increased. Both these
toxic effects are manageable and do not preclude treatment.
However, in our opinion, skin toxicity could be reduced by
avoiding fluorouracil, which has its own additional skin
toxicity. Indeed, radiotherapy for head and neck cancer,
different from what observed, for example, in rectal cancer,
gives a significant radiation dose to the skin and, therefore, an
overlapping effect of radiotherapy, fluorouracil and cetuximab
may explain our observations. For this reason, we are now
evaluating a new similar phase II study excluding fluorouracil.
disclosure
Merlano and Benasso report serving on paid advisory boards
and receiving lecture fees from Merck. The authors declare no
conflict of interest.
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