Download Randomized Trial of Induction Chemotherapy

ARTICLE
Randomized Trial of Induction Chemotherapy With
Cisplatin and 5-Fluorouracil With or Without
Docetaxel for Larynx Preservation
Yoann Pointreau, Pascal Garaud, Sophie Chapet, Christian Sire, Claude Tuchais, Jacques Tortochaux,
Sandrine Faivre, Stephane Guerrif, Marc Alfonsi, Gilles Calais
Background
Chemotherapy with cisplatin (P) and 5-fluorouracil (F) followed by radiotherapy in patients who respond
to chemotherapy is an alternative to total laryngectomy for patients with locally advanced larynx and
hypopharynx cancer. Data suggest that docetaxel (T) may add to the efficacy of PF. The objective of this
trial was to determine whether adding T to PF could increase the larynx preservation rate.
Methods
Patients who had larynx and hypopharynx cancer that required total laryngectomy were randomly assigned
to receive three cycles of TPF or PF. Patients who responded to chemotherapy received radiotherapy with
or without additional chemotherapy. Patients who did not respond to chemotherapy underwent total
laryngectomy followed by radiotherapy with or without additional chemotherapy. The primary endpoint
was 3-year larynx preservation rate. Secondary endpoints included acute toxicities and overall response.
All statistical tests were two-sided.
Results
Baseline patient and tumor characteristics were well balanced between the TPF (n = 110) and PF (n = 103)
groups. With a median follow-up of 36 months, the 3-year actuarial larynx preservation rate was 70.3%
with TPF vs 57.5% with PF (difference = 12.8%; P = .03). Patients in the TPF group had more grade 2 alopecia, grade 4 neutropenia, and febrile neutropenia, whereas patients in the PF group had more grade 3 and
4 stomatitis, thrombocytopenia, and grade 4 creatinine elevation. The overall response was 80.0% in the
TPF group vs 59.2% in the PF group (difference = 20.8%; P = .002).
Conclusions
In patients with advanced larynx and hypopharynx carcinomas, TPF induction chemotherapy was superior
to the PF regimen in terms of overall response rate. These results suggest that larynx preservation could
be achieved for a higher proportion of patients.
J Natl Cancer Inst 2009;101:498–506
Until the early 1990s, the standard treatment for locally advanced
larynx and hypopharynx squamous cell carcinoma was total laryngectomy followed by conventional radiotherapy. Different treatments have since been tested, including partial surgery,
radiotherapy, and chemotherapy, without optimal schedule. The
main courses of failure are locoregional recurrences and distant
metastases (40%–60%) (1,2). Total laryngectomy is one of the
surgical procedures that is most feared by patients. This procedure
has a negative impact on patients, with tracheotomy, loss of natural
voice, social isolation, loss of employment, and depression. To
preserve larynx function, chemotherapy before surgery, or induction chemotherapy, has been developed. Induction chemotherapy
with cisplatin (P) and 5-fluorouracil (F) followed by radiotherapy
in patients who respond to chemotherapy was considered as an
alternative to total laryngectomy. Two large experimental randomized trials comparing this treatment with total laryngectomy
have shown good larynx preservation rates (40%–64% of patients)
without compromise to disease control and survival rates (2,3).
Concurrent radiotherapy and chemotherapy were developed
for many types of cancer and appeared to be the best regimen,
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particularly for head and neck cancer (4). This treatment was
tested in patients with larynx cancer in a Radiation Therapy
Oncology Group trial (RTOG 91-11) that compared three treatments: induction chemotherapy with PF followed by radiotherapy,
concurrent chemoradiation with cisplatin, and radiotherapy alone.
This trial suggested the superiority of the concomitant regimen in
terms of laryngeal preservation and locoregional control (5).
Affiliations of authors: Centre Hospitalier Régional et Universitaire, Henry
Kaplan Center, Clinique d’Oncologie et de Radiothérapie, Tours, France (YP,
PG, SC, GC); Centre Hospitalier de Lorient, Lorient, France (CS); Centre Paul
Papin, Angers, France (CT); Centre Jean Perrin, Clermond-Ferrand, France
(JT); Institut Gustave Roussy, Villejuif, France (SF); Centre Hospitalier
Universitaire Poitiers, Poitiers, France (SG); Clinique Sainte Catherine,
Avignon, France (MA).
Correspondence to: Gilles Calais, Henry Kaplan Center, Clinique d’Oncologie
et de Radiothérapie, Centre Hospitalier Régional et Universitaire de Tours,
2 Blvd Tonnellé, 37044 Tours, France (e-mail: [email protected]).
See “Funding” and “Notes” following “References.”
DOI: 10.1093/jnci/djp007
© The Author 2009. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: [email protected].
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Recent data from phase I, phase II, and phase III trials with
curative intent suggest that docetaxel (T) may add to the efficacy
of PF, with an increased response rate (6–14) and an increased
overall survival rate (13,14). In 2000, we (French Head and Neck
Oncology Radiotherapy Group) initiated a randomized phase III
multicenter prospective trial to test the hypothesis that induction
chemotherapy using TPF leads to better larynx preservation rate
than the PF regimen. This trial was especially designed to evaluate
larynx preservation.
Patients and Methods
Patients
Random assignment started in December 15, 2000, and was closed
in May 16, 2005. Only operable patients were included if they had
larynx or hypopharynx cancer requiring total laryngectomy.
Patients were included in the study if all of the following were
true: they had histologically proven larynx or hypopharynx invasive
squamous cell carcinoma that was previously untreated stage III or
IV according to the American Joint Committee on Cancer classification (15) without distant metastases, Karnofsky performance
status was greater than or equal to 70, and were between 18 and 75
years of age. Other criteria for inclusion included a neutrophil
count greater than 2000 cells per cubic millimeter, a platelet count
greater than 100 000 cells per cubic millimeter, a hemoglobin level
greater than 100 g/L, a serum creatinine level less than 120 µmol/L
(or a creatinine clearance level greater than 60 mL/min), transaminase levels less than 2.5 times the upper limit of normal, alkaline
phosphatase level less than 5 times the upper limit of normal, and
total bilirubin levels within normal limits. Patients with previous
head and neck cancer, other cancers, inadequate organ function,
and peripheral neuropathy grade 2 were excluded.
Patients were treated at the Henry Kaplan Center at the
Regional and University Hospital Center in Tours, Saint Catherine
Clinic in Avignon, Lorient Center Hospital in Lorient, Paul Papin
Center in Angers, Jean Perrin Center in Clermont Ferrand,
Gustave Roussy Institute in Villejuif, Poitiers Regional and
University Hospital Center in Poitiers, Eugène Marquis Center in
Rennes, Limoges Hospital Center in Limoges, Tenon Hospital
Center in Paris, Dubos Center in Pontoise, Brive Hospital Center
in Brive, Saint Yves Center in Vannes, and Versaille Hospital
Center in Versaille. The regional ethics committees approved the
protocol, and all patients provided written informed consent
before enrollment. The trial was registered as ClinicalTrials.gov
number NCT00169182.
Study Design
This was a randomized phase III trial to compare larynx preservation in patients with larynx or hypopharynx invasive squamous cell
carcinoma after three cycles of induction chemotherapy with
either TPF or PF, followed by radiotherapy with or without additional chemotherapy in patients with tumors that responded to
induction chemotherapy. The CONSORT flow diagram for the
trial is shown in Figure 1.
Three to five weeks after the last chemotherapy cycle, patients
were evaluated for tumor response by using direct laryngoscopy
and computed tomography (or magnetic resonance imaging) of the
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CONT E XT AND CAVE AT S
Prior knowledge
Treatment with chemotherapy using cisplatin and 5-fluorouracil
followed by radiation therapy for those who respond to chemotherapy is an alternative to total laryngectomy for patients with
advanced cancer of the larynx and hypopharynx. Adding docetaxel
may increase the efficacy of the chemotherapy regimen and the
ability to preserve the larynx.
Study design
Randomized phase III trial of cisplatin plus 5-fluorouracil with or
without docetaxel for patients with advanced cancer of the larynx
and hypopharynx that required total laryngectomy. Outcomes
were 3-year larynx preservation rate, acute toxicities, and overall
response.
Contributions
The 3-year larynx preservation rate was 70.3% with the cisplatin,
5-fluorouracil, docetaxel combination and 57.5% without docetaxel. Patients who were treated with the regimen containing
docetaxel had more severe infections but had better overall
response than those who did not receive docetaxel (80% vs
59.2%).
Implications
The addition of docetaxel to cisplatin and 5-fluorouracil improved
overall response and increased larynx preservation in patients with
advanced cancers of the larynx and hypopharynx.
Limitations
The study was designed for advanced cancers of the larynx and
hypopharynx; thus, the findings should not be generalized to all
sites of advanced cancers of the head and neck.
From the Editors
head and neck. Laryngeal mobility, which was defined as normal
mobility of the vocal cord, was measured during direct
laryngoscopy.
Patients whose cancer responded well to chemotherapy (complete response at the primary site or partial response and recovered
normal larynx mobility) were treated with radiotherapy with or
without additional chemotherapy. Neck dissection was not planned
but performed only in patients with residual tumor in the lymph
nodes. Patients who did not respond to induction chemotherapy
underwent total laryngectomy with neck dissection, followed by
radiotherapy with or without additional chemotherapy. Additional
chemotherapy with radiotherapy was allowed and applied for all
patients enrolled in the same institute, according to its practice.
The primary endpoint was 3-year larynx preservation rate.
Treatment was considered to have failed on the date of laryngectomy. Secondary endpoints included overall survival, overall
response rate to induction chemotherapy, disease-free interval,
and acute and late toxicity rates. All events were measured from the
date of random assignment to the date of their occurrence or the
date of the last follow-up visit, whichever occurred first.
Induction Chemotherapy
In the experimental group, chemotherapy consisted of docetaxel
at 75 mg/m2 on day 1, cisplatin at 75 mg/m2 on day 1, and
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Figure 1. CONSORT flow diagram of this study
design. Patients with operable advanced larynx
or hypopharynx carcinomas were randomly
assigned to three cycles of induction chemotherapy with either docetaxel, cisplatin, plus
5-fluorouracil (TPF) or cisplatin plus 5-fluorouracil
(PF). Seven patients were not eligible due to having Karnofsky performance status less than 70 or
distant metastases.
5-fluorouracil at a dose of 750 mg/m2 by 24-hour continuous
infusion for 5 days; three cycles with a 21-day interval were
planned. Adequate intravenous hydration (1 L of normal saline
before and after cisplatin infusion with or without mannitol,
potassium chloride, or magnesium sulfate as per local institute
practice), 8 mg of oral dexamethasone daily (day –1, day 1, and day 2),
and 1000 mg of oral ciprofloxacin from day 5 to day 15 were
given. Primary prophylaxis with recombinant granulocyte colonystimulating factor (G-CSF) was not used. The chemotherapy regimen in the reference group consisted of cisplatin 100 mg/m2 on
day 1 (with the same hydration) and 5-fluorouracil given at a dose
of 1000 mg/m2 by 24-hour continuous infusion for 5 days for
three cycles with a 21-day interval.
If patients had an absolute neutrophil count of less than
0.5 g/L for more than 7 days or febrile neutropenia, the use of
G-CSF 150 µg/m2/d for10 days was allowed for the next cycles.
Dose reduction was applied in case of recurrent neutropenia
despite G-CSF use or in case of grade 4 thrombocytopenia. The
docetaxel dose was reduced to 60 mg/m2. In the PF group,
5-fluorouracil and cisplatin doses were reduced to 800 mg/m2/d
and to 80 mg/m2, respectively. If patients experienced a
National Cancer Institute Common Toxicity Criteria (NCICTC) grade 3 gastrointestinal adverse effect, the dose of
5-fluorouracil was reduced to 600 mg/m2/d in the TPF group
and to 800 mg/m2/d in the PF group. In case of NCI-CTC
grade 3 neurological adverse effects, the cisplatin dose was
reduced to 50 mg/m2/d in the TPF group and to 70 mg/m2/d in
the PF group.
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Radiotherapy for Responders
Radiation therapy was initiated between 3 and 7 weeks after the
last chemotherapy cycle. It was delivered using 4- to 6-MV photon
beams. Two target volumes were defined: 1) the therapeutic planning target volume that encompassed the primary tumor volume
and involved lymph nodes as they were before induction therapy
and 2) the prophylactic planning target volume that encompassed
the area presumed to be at risk for microscopic disease. The therapeutic and prophylactic planning target volumes received 70 and
50–54 Gy, respectively. Five daily fractions of 2 Gy/wk were used.
The dose to the spinal cord was less than 44 Gy.
Chemotherapy (cisplatin, carboplatin, and 5-fluorouracil or a
combination of two drugs) during radiotherapy was allowed for all
patients who were treated at the same institute, according to its
practice.
Surgery and Postoperative Radiotherapy
Patients whose tumors did not respond to induction chemotherapy
underwent total laryngectomy with neck dissection. Surgery was
performed 3–7 weeks after the last chemotherapy cycle. Radiation
therapy was given postoperatively to a total dose of 50–66 Gy according to pathologic risk features (50 Gy in patients with complete resection without nodal involvement, 54 Gy in patients with complete
resection with nodal involvement but without extracapsular extension,
and 66 Gy in patients with positive surgical margins or extracapsular
extension of nodal disease). Neck dissection was not systematically
planned but was performed in patients who had residual disease in the
lymph nodes at 3 months after the end of radiotherapy.
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Chemotherapy (cisplatin, carboplatin, and 5-fluorouracil or a
combination of two drugs) during radiotherapy was allowed for all
patients who were treated at the same institute according to the
institute’s practice.
Assessment of Outcomes
Tumor response was assessed at each center by clinical evaluation
and computed tomography or magnetic resonance imaging and
characterized by modified World Health Organization criteria (16)
3 weeks after the last chemotherapy cycle, 9 weeks after radiotherapy, and 4 months after the end of the complete treatment.
Overall survival was calculated from the date of random assignment
to the date of death (regardless of cause), and the progression-free
interval was from the date of random assignment until recurrence
(local, lymph node, or metastasis recurrence) or death before recurrence. Patients were followed up every 3 months during the first
year, every 6 months during the next 3 years, and every year thereafter until death or censoring. Toxic effects were graded according
to the NCI-CTC v2.0 (17) during induction chemotherapy and
according to the RTOG toxicity scoring system (18) for acute and
late radiotherapy toxic effects. Late toxicity was reported if it
appeared more than 3 months after the end of the treatment.
Statistical Analysis
The study was designed to test two induction chemotherapy schedules and to detect an absolute improvement in 3-year laryngeal
preservation rate of 15%, with estimated rates of 55% in the PF
reference group and 70% in the TPF experimental group. The type
I error was .05 (two-sided), and the power was 70%. Patients were
randomly assigned to a treatment group by a central office after
eligibility was established. No stratification was used. Screening for
eligibility and exclusions was performed after registration in the
study and before random assignment. If patients were registered but
did not meet all inclusion criteria, they were excluded and not
treated in the trial. Baseline characteristics of patients in the two
treatment groups were compared using the Student t test or Mann–
Whitney U test for continuous variables and the chi-square test or
Fisher exact test for categorical variables. Patient data were analyzed
according to the intention-to-treat principle. All events were calculated from the date of random assignment to the most recent
follow-up contact or from data of specific disease recurrence or death,
and all eligible patients in the study were included. Overall survival,
disease-free interval, and 3-year larynx preservation rates were calculated according to the Kaplan–Meier method and compared with the
log-rank test (19). All reported P values were two-sided and were
considered to be statistically significant if less than .05. The sample
size was further increased by 10% to account for patients who were
deemed ineligible or were lost to follow-up before 2 years had
elapsed. The target sample size was calculated with an improved
approximate formula (binomial model) and was 220 patients.
Results
Patients
A total of 220 patients were enrolled between December 4, 2000,
and May 3, 2005. Seven patients were found to be ineligible and
were excluded from the intention-to-treat population (three in the
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TPF group and four in the PF group). The reasons for ineligibility
were a Karnofsky performance status less than 70 (four patients)
and distant metastases (three patients). A total of 213 patients were
randomly assigned (110 to TPF and 103 to PF) and remained in
the analysis. The two treatment groups were equally balanced with
regard to age, sex, stage, Karnofsky performance status, hemoglobin level, and histology (Table 1).
Acute Chemotherapy Toxicity
A total of 600 cycles of chemotherapy were administered. Five
patients died due to acute toxicity during induction chemotherapy—
three were in the TPF group (two with diarrhea with dehydration
and one with digestive bleeding) and two were in the PF group
(one with acute renal insufficiency and one with aplasia with acute
infection). Compared with patients who were treated in the PF
group, patients who were treated in the TPF group experienced
more grade 2 alopecia (19.4% vs 2.0%), more grade 4 neutropenia
(31.5% vs 17.6%), and more grade 3 infections (febrile neutropenia: 10.9% vs 5.8%). Patients treated in the PF group experienced
more grade 3 and 4 stomatitis (7.8% vs 4.6%), more grade 3 and 4
thrombocytopenia (7.8% vs 1.8%), and grade 4 creatinine elevation (2.0% vs 0%). Other toxicities are shown in Table 2.
Table 1. Baseline characteristics of patients with larynx and hypopharynx cancer treated by induction chemotherapy with cisplatin
and 5-fluorouracil with or without docetaxel followed by radiotherapy or chemoradiotherapy in patients with objective response
for larynx preservation*
Characteristic
Age, y
Mean
Range
Sex, No. (%)
Male
Female
Karnofsky performance
status, No. (%)
100
90
80
Site of primary tumor,
No. (%)
Hypopharynx
Larynx
Stage of primary tumor,
No. (%)
T2
T3
T4
Node stage, No. (%)
N0
N1
N2a
N2b
N2c
N3
TPF (N = 110)
PF (N = 103)
P
.82
57
33–72
56
37–75
.59
101 (91.8)
9 (8.2)
97 (94.2)
6 (5.8)
.21
51 (46.4)
41 (37.2)
18 (16.4)
51 (49.5)
28 (27.2)
24 (23.3)
.68
61 (55.5)
49 (44.5)
54 (52.4)
49 (47.6)
.14
15 (13.6)
80 (72.8)
15 (13.6)
24 (23.3)
63 (61.2)
16 (15.5)
36
28
12
13
14
7
48
22
9
15
7
2
.16
(32.7)
(25.5)
(10.9)
(11.8)
(12.7)
(6.4)
(46.6)
(21.4)
(8.7)
(14.6)
(6.8)
(1.9)
* TPF = docetaxel, cisplatin, plus 5-fluorouracil; PF = cisplatin plus 5-fluorouracil;
T = tumor; N = node. P values were calculated using two-sided Student t test
or Mann–Whitney U test for continuous variables and the chi-square test or
Fisher exact test for categorical variables.
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Table 2. Acute toxicity of chemotherapy in patients with larynx
and hypopharynx cancer treated by two different induction chemotherapy regimens and followed by radiotherapy or chemoradiotherapy for larynx preservation in patients with objective
response to the induction regimen*
TPF, %
PF, %
Grade
Toxicity
Nausea–vomiting
Hemoglobin level
above normal
Bilirubin level
above normal
Transaminase level
above normal
Alkaline
phosphatase level
above normal
GGT level above
normal
Grade
0
1–2
3
0
1–2
3
55.6
64.8
40.7
31.5
3.7
3.7
55.9
53.5
40.2
44.5
3.9
2.0
97.9
2.1
0
98.9
1.1
0
89.9
10.1
0
95.5
4.5
0
99.0
1.0
0
98.9
1.1
0
82.5
16.5
1.0
78.4
19.3
2.3
* TPF = docetaxel, cisplatin, plus 5-fluorouracil; PF = cisplatin plus 5-fluorouracil;
GGT = gamma-glutamyl transferase.
Chemotherapy Response
The specific treatment according to the protocol was delivered to
90.0% of patients in the TPF group vs 80.0% in the PF group.
Among the 110 patients who were assigned to the TPF group, 69
(62.7%) received complete treatment without delay or dose reduction. In the PF group, only 33 (32.0%) patients received treatment
without delay or dose reduction (P < .001).
The overall response rate after induction chemotherapy was
80.0% (41.8% complete response and 38.2% partial response) in
the TPF group and 59.2% (30.1% complete response and 29.1%
partial response) in the PF group (difference = 20.8%; P = .002).
Stable and progressive disease rates after induction chemotherapy
were 11.8% and 3.2% in the TPF group vs 35.0% and 5.8% in the
PF group.
More patients in the TPF group than the PF group recovered
to normal larynx mobility (42.7% vs 29.1%, respectively; P = .034).
Larynx mobility was evaluated during direct laryngoscopy. Biopsies
were performed during laryngoscopy in 50% of patients because
biopsies were not planned in the trial design and were performed
according to surgeon practice. No residual tumor was found in
64.4% of patients in the TPF group and in 35.8% of patients
in the PF group. Squamous cell carcinoma or dysplasia was found
in the other patients. Larynx preservation using radiotherapy was
proposed for 78.3% of patients in the TPF group vs 55.3% of
patients in the PF group (P < .001).
Radiotherapy
The radiation therapy for larynx preservation was performed in
76.4% of patients in the TPF group (all were responders to
induction chemotherapy) and in 61.2% of patients in the PF
group (57 patients responded to induction chemotherapy and 6
had refused surgery). The median time between the end of
induction chemotherapy and the first day of radiotherapy was
50 days. This delay was due to the time to evaluate response
(3–5 weeks) and the time to plan the radiotherapy (3–4 weeks).
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One patient in the TPF group who achieved an objective
response did not receive radiotherapy because of early death.
Patients received a median dose of 70 Gy, which was given in 35
fractions of 2 Gy each during a 7-week period (range = 49–76
Gy). In the TPF group, 17 of 85 (20.0%) patients received concomitant chemotherapy using cisplatin, carboplatin, 5-fluorouracil or a combination of two drugs according to institute
practice. In the PF group, 9 of 57 (15.8%) patients received
concomitant chemoradiation (P = .67). The 6 patients who
refused surgery were treated by chemoradiation (4) or radiation
alone (2). All patients completed the planned radiotherapy
treatment (Figure 2).
Surgery
Following induction chemotherapy, 17 patients underwent total
laryngectomy, 2 patients did not receive surgery (1 was lost to
follow-up and 1 died before surgery), 2 patients underwent other
treatments (1 partial surgery and 1 died before radiotherapy), and
2 patients underwent neck dissection only in the TPF group. The
above treatments were applied to 35, none, and 2 (partial surgery)
patients, respectively, in the PF group. No residual tumor was
found in 5 patients—3 in the TPF group and 2 in the PF group.
Microscopic residual tumors were found in 7 patients in the PF
group and in none in the TPF group. Large tumors were found in
15 and 28 patients in the TPF and PF groups, respectively. The 3
other patients who underwent neck dissection only before radiotherapy all had positive lymph nodes. A total of 46 patients received
postoperative radiotherapy (17 in the TPF group and 29 in the PF
group), of whom 19 received concurrent chemotherapy (6 in the
TPF group and 13 in the PF group). A total dose from 50 to 65 Gy
was delivered, depending on surgical margin and lymph node status
on pathologic review. The median delay between surgery and
radiotherapy was 42 days.
Larynx Preservation and Survival
With a median follow-up of 36 months, the 3-year actuarial larynx
preservation rate was 70.3% following TPF induction chemotherapy
and 57.5% after the PF regimen (difference = 12.8%; P = .03) (Figure
3). The 3-year overall survival (60% in each arm) and disease-free
interval (58% in the TPF arm vs 44% in the PF arm; difference
= 14%) rates were not statistically significantly different between
TPF and PF groups (P = .57 and P = .11, respectively) (Figures 4 and
5). Causes of death were as follows in the TPF and the PF groups:
acute toxicity of induction chemotherapy (three vs two), larynx cancer (26 vs 25), second primary cancer (two vs one), noncancer-related
causes (four vs seven), and unknown causes (four vs five).
Patterns of Failure
At the time of evaluation, in July 2008, the rates of local and
regional failures were 18.6% vs 23.7% and 14.7% vs 20.2% in the
TPF and PF groups, respectively. Four patients developed a second cancer in the TPF group vs 10 in the PF group (P = .12).
Twelve patients developed distant metastasis in the TPF group vs
16 in the PF group (P = .38). Relapses were treated by surgery,
radiotherapy, chemotherapy, or combined treatment. After induction chemotherapy and radiotherapy for larynx preservation, 25
patients required a salvage total laryngectomy (13 and 12 patients
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Figure 2. Outcomes among patients who were randomly assigned to docetaxel, cisplatin, plus 5-fluorouracil (TPF) or to cisplatin plus 5-fluorouracil
(PF). Of the 213 patients randomly assigned (R), 85 of 106 who received TPF responded sufficiently for larynx preservation via further radiotherapy
or chemoradiation, whereas only 57 of 100 who received PF responded sufficiently for larynx preservation via further radiotherapy or chemoradiation. Nonresponding patients received a laryngectomy.
in the TPF and PF groups, respectively), 7 of whom (5 and 2 in
the TPF and PF groups, respectively) were considered to be in
complete response after induction chemotherapy (P = .51).
Late Toxicity
Grade 4 larynx toxicity occurred in 6.2% of patients in the TPF
group (of whom two were treated by concurrent chemoradiotherapy after induction) and in 13.6% of patients in the PF group (of
whom three were treated by concurrent chemoradiotherapy after
induction) (P = .1). Other late toxic effects were comparable
between each group (Table 3). Long-term follow-up is necessary
to further evaluate late toxicities.
Discussion
For operable locally advanced larynx and hypopharynx cancer,
patients who received an induction TPF regimen achieved a statistically significantly superior 3-year larynx preservation rate compared with those who received the PF regimen (70.3% vs 57.5%,
difference = 12.8%; P = .03). The TPF regimen was better than the
Table 3. Late toxicities in patients with larynx and hypopharynx
cancer treated by two different induction chemotherapy regimens
and followed by radiotherapy or chemoradiotherapy for larynx
preservation in patients with an objective response*
Tissue
Figure 3. Rates of laryngeal preservation among patients who were
randomly assigned to docetaxel, cisplatin, plus 5-fluorouracil (TPF) vs
cisplatin plus 5-fluorouracil (PF). At 3 years, the rates of laryngeal preservation were as follows: 70.3% among the patients who received
induction chemotherapy in the TPF group and 57.5% among those who
received induction chemotherapy in the PF group (P = .03, two-sided
log-rank test).
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Mucous membrane
Salivary glands
Bone
Subcutaneous tissue
TPF, %
PF, %
Grade
Grade
0
1–2
3–4
0
1–2
3–4
54.5
18.2
99.0
37.4
44.5
75.7
2.0
58.6
1
6.1
0
4.0
60.0
32.2
98.9
35.6
40.0
65.6
1.1
57.8
0
2.2
0
6.6
* TPF = docetaxel, cisplatin, plus 5-fluorouracil; PF = cisplatin plus 5-fluorouracil.
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Figure 4. Overall survival among patients who were randomly assigned
to docetaxel, cisplatin, plus 5-fluorouracil (TPF) vs cisplatin plus 5fluorouracil (PF). At 3 years, overall survival rates were not statistically
different (P = .57, two-sided log-rank test).
Figure 5. Disease-free interval among patients who were randomly
assigned to docetaxel, cisplatin, plus 5-fluorouracil (TPF) vs cisplatin
plus 5-fluorouracil (PF). At 3 years, disease-free intervals were not statistically different (P = .11, two-sided log-rank test).
PF regimen for tumor control rate, and both regimens were comparable in terms of late toxicity rates.
Various larynx preservation protocols have been tested during
the last 20 years using either concurrent chemoradiotherapy or
induction chemotherapy followed by locoregional treatment. This
trial was especially designed to evaluate the ability to preserve the
organ.
Concurrent chemoradiotherapy had the highest impact on survival in the meta-analysis of chemotherapy on head and neck cancer (4), an individual patient data analysis of published and
unpublished trials. Chemotherapy delivered as a neoadjuvant, concurrent, or adjuvant treatment was found to confer an absolute
overall survival benefit of 4% at 5 years. The highest benefit was
observed in the concurrent chemoradiotherapy group (8% at 5
years).
The phase III US Intergroup trial RTOG 91-11 that was
designed to evaluate larynx preservation confirmed the superiority
of the concurrent regimen (5,20). At 2 years, the proportion of
patients who had an intact larynx after radiotherapy with concurrent
cisplatin therapy (88%) differed statistically significantly from the
proportions in the groups given induction chemotherapy (using
cisplatin and 5-fluorouracil standard combination) followed by
radiotherapy (75%, P = .005) or radiotherapy alone (70%, P < .001).
However, severe toxicity was more frequent with the concurrent
schedule, and no differences in overall survival were observed.
This standard regimen was evaluated in the Veterans Group
study (3) and in the European Organisation for Research and
Treatment of Cancer 24891 trial (2) in comparison with total laryngectomy and was considered as an alternative without compromising disease control and survival. In the Veterans Group trial, the
estimated 2-year survival was 68% in each group (surgery vs organ
preservation). More local recurrences and fewer distant metastases
were reported in the chemotherapy group than in the surgery
group. In the EORTC trial, treatment failures at local and regional
sites occurred at the same frequencies in the immediate surgery
group (12% and 19%, respectively) and in the induction chemotherapy group (17% and 23%, respectively). The 3- and 5-year
estimates of functional larynx in patients who were treated in the
induction chemotherapy group were 42% and 35%, respectively.
Another recent innovation was the development of the monoclonal antibody cetuximab, which targets the epidermal growth factor
receptor. Cetuximab was tested in combination with radiotherapy
compared with radiotherapy alone (21), and it improved locoregional
control and overall survival rates without increasing acute mucosal
reaction. The reported median duration of locoregional control
was 24.4 months among patients who were treated with cetuximab
plus radiotherapy and 14.9 months among those treated with
radiotherapy alone. Cetuximab plus radiotherapy statistically prolonged the progression-free interval. Incidence of grade 3 or
greater toxic effects, including mucositis, did not statistically differ
between the two groups.
The introduction of docetaxel in combination with PF improved
the overall tumor response rate and has led to renewed interest in
induction chemotherapy. The TPF regimen with a dose adaptation of PF was reported in phase I and II trials with an increased
complete response rate (6–14,22,23) and a 2-year survival benefit
(11). Two randomized phase III trials using the TPF regimen followed by radiotherapy alone (TAX 323) or with carboplatin (TAX
324) confirmed for nonsurgical patients the superiority of TPF
(13,14) compared with the PF regimen for response, overall survival, and progression-free interval. In the TAX 323 trial (13),
patients were randomly assigned to the TPF group or the PF
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group. The median progression-free interval was 11.0 months in
the TPF group and 8.2 months in the PF group (P = .007). The
median overall survival was 18.8 months in the TPF group as compared with 14.5 months in the PF group. In the TAX 324 trial (14),
the median overall survival was 71 months (95% confidence interval [CI] = 49 to not reached) in the TPF group and 30 months
(95% CI = 21 to 52) in the PF group, with a statistically significant
increase for the TPF group (P = .006). The locoregional control
rate was higher in the TPF group than in the PF group. These
trials (13,14,24) reported a better compliance and quality of life
with the TPF regimen than the PF regimen.
In this study, the TPF regimen was compared with the standard
PF induction chemotherapy regimen followed by radiotherapy or
chemoradiotherapy in responding patients. The results we obtained
in the PF group were comparable to previous results reported in
the literature (2,3,5) for larynx preservation, overall survival, and
disease-free interval rates. TPF improved larynx preservation with
a better tolerance but without gain in survival.
Compared with a concurrent chemoradiotherapy schedule,
induction chemotherapy for head and neck cancer was less toxic
for patients, particularly those with larynx cancer who more frequently develop severe late toxicities following concurrent chemoradiation (25). Moreover, in the RTOG 91-11 trial (5), the 5-year
probability of survival with a functional larynx was 45% in the
concurrent chemoradiotherapy group and 43% in the induction
chemotherapy group, but laryngeal preservation rate and locoregional control rate were statistically significantly superior in the
chemoradiotherapy group (5,20).
Induction chemotherapy is an attractive alternative treatment
for larynx cancer patients. It is based on the hypothesis that a
chemosensitive patient will also be radiosensitive, and it enables
operable patients to preserve their larynx if they respond to induction chemotherapy treatment. An added benefit, in the case of
locoregional failure, is that the salvage surgical procedure is easier
before than after chemoradiation.
Concurrent chemoradiotherapy was the standard treatment for
locally advanced head and neck cancer (5), but several trials (13,14)
concluded that induction chemotherapy was a good alternative if
the chemotherapy regimen included taxanes, particularly the TPF
regimen. Induction chemotherapy could be followed by less toxic
locoregional approaches (standard or hyperfractionated radiotherapy alone or combined with platinum-based chemotherapy or
with molecular targeted therapy) to preserve larynx function.
In this study, we obtained excellent results, but there are potential limitations. Because we proposed treatment to a select population of patients with only larynx and hypopharynx cancer and this
trial was especially designed for organ preservation, we cannot generalize the findings to all locally advanced head and neck cancers.
Future trials should be designed to compare the concomitant
schedule with the induction approach using TPF. Emphasis should
be put on the functional results of these approaches.
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Funding
GORTEC—French Head and Neck Oncology Radiotherapy Group.
Notes
Dr J Tortochaux died on January 22, 2008.
The sponsors had no role in the study design, data collection and analysis,
the interpretation of the results, the preparation of the manuscript, or the decision to submit the manuscript for publication.
Manuscript received August 7, 2008; revised December 12, 2008; accepted
January 7, 2009.
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