VOLUME 27 NUMBER
JOURNAL OF CLINICAL ONCOLOGY
From the Department of Clinical Oncol-
ogy; Department of Diagnostic Radiol-
ogy and Organ Imaging, Prince of
Wales Hospital; State Key Laboratory in
Oncology in South China, Sir Y.K. Pao
Centre for Cancer, Hong Kong Cancer
Institute; Center for Clinical Trials,
School of Public Health, The Chinese
University of Hong Kong; and Sanofi-
aventis Hong Kong, Hong Kong
SAR, China.
Submitted May 16, 2008; accepted
August 18, 2008; published online
ahead of print at www.jco.org on
December 8, 2008.
Supported in part by a research grant
from Sanofi-aventis Hong Kong Limited.
Presented in part at the 41st Annual
Meeting of the American Society of
Clinical Oncology, May 13-17, 2005,
Orlando, FL; the 13th European Cancer
Conference, October 30-November 3,
2006, Paris, France; and the 43rd
Annual Meeting of the American Soci-
ety of Clinical Oncology, June 2-5,
2007, Chicago, IL.
Authors disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of
this article.
Corresponding author: Anthony T.
Chan, MD, FRCP, Department of Clini-
cal Oncology, The Chinese University of
Hong Kong, Prince of Wales Hospital,
Shatin, New Territories, Hong Kong SAR,
China; e-mail: anthonytcchan@cuhk.edu.hk.
The Appendix is included in the
full-text version of this article,
available online at www.jco.org.
It is not included in the PDF version
(via Adobe Reader).
2008 by American Society of Clinical
Oncology
0732-183X/09/2702-242/$20.00
DOI: 10.1200/JCO.2008.18.1545
242 2008 by American Society of Clinical Oncology
2 JANUARY 10 2009
O R I G I N A L R E P O R T
Randomized Phase II Trial of Concurrent Cisplatin-
Radiotherapy With or Without Neoadjuvant Docetaxel
and Cisplatin in Advanced Nasopharyngeal Carcinoma
Edwin P. Hui, Brigette B. Ma, Sing F. Leung, Ann D. King, Frankie Mo, Michael K. Kam, Brian K. Yu,
Samuel K. Chiu, Wing H. Kwan, Rosalie Ho, Iris Chan, Anil T. Ahuja, Benny C. Zee, and Anthony T. Chan
A B S T R A C T
Purpose
To compare the toxicities, tumor control, survival, and quality of life of nasopharyngeal cancer
(NPC) patients treated with sequential neoadjuvant chemotherapy followed by concurrent
cisplatin-radiotherapy (CRT) or CRT alone.
Patients and Methods
Previously untreated stage III to IVB NPC were randomly assigned to (1) neoadjuvant docetaxel 75
mg/m2 and cisplatin 75 mg/m2 every 3 weeks for two cycles, followed by cisplatin 40 mg/m2/wk
concurrent with radiotherapy, or (2) CRT alone. Planned accrual was 30 patients per arm to detect
20% difference of toxicities based on 95% CIs.
Results
From November 2002 to November 2004, 65 eligible patients were randomly assigned to
neoadjuvant chemotherapy followed by CRT (n 34) or CRT alone (n 31). There was a high rate
of grade 3/4 neutropenia (97%) but not neutropenic fever (12%) during neoadjuvant chemother-
apy. No significant differences in rates of acute toxicities were observed between the two arms
during CRT. Dose intensities of concurrent cisplatin, late RT toxicities and quality of life scores
were comparable in both arms. The 3-year progression-free survival for neoadjuvant versus control
arm was 88.2% and 59.5% (hazard ratio 0.49; 95% CI, 0.20 to 1.19; P .12). The 3-year overall
survival for neoadjuvant versus control arm was 94.1% and 67.7% (hazard ratio 0.24; 95% CI,
0.078 to 0.73; P .012).
Conclusion
Neoadjuvant docetaxel-cisplatin followed by CRT was well tolerated with a manageable toxicity
profile that allowed subsequent delivery of full-dose CRT. Preliminary results suggested a positive
impact on survival. A phase III study to definitively test this neoadjuvant-concurrent strategy
is warranted.
J Clin Oncol 27:242-249. 2008 by American Society of Clinical Oncology
by chemoradiotherapy would seem a logical strategy
INTRODUCTION
to maximize the benefit from both approaches. In
The current standard treatment for advanced fact, this neoadjuvant-concurrent strategy has been
nasopharyngeal cancer (NPC) is concurrent che- pursued by several groups in uncontrolled phase
moradiotherapy with or without adjuvant chemo- II studies, with favorable outcome reported.9-11
therapy.1,2 Randomized trials of neoadjuvant The taxanes have demonstrated considerable
chemotherapy followed by RT alone have resulted in single-agent activity in head and neck cancers and
encouraging response rates and improvement in NPC.12-16 The combination of paclitaxel and carbo-
disease-free survival, but not overall survival.3-8 Be- platin has yielded high response rates in the range of
cause the use of chemotherapy in the neoadjuvant 59% to 75% in metastatic NPC,17,18 and has demon-
setting, or as concurrent therapy to RT, has been strated encouraging activity and safety profile in the
consistently shown to improve progression-free neoadjuvant setting of NPC.11 Docetaxel is associ-
survival (PFS) and/or overall survival (OS) in ad- ated with less neurotoxicity than paclitaxel and can
vanced NPC, the development of a sequential therefore be more tolerably combined with cispla-
schedule of neoadjuvant chemotherapy followed tin. Docetaxel and cisplatin in combination is highly
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 Neoadjuvant Chemotherapy Followed by Concurrent Cisplatin-RT in NPC

active in head and neck cancer.19-21 Therefore, this combination was
investigated in NPC and was expected to be highly active in the
neoadjuvant setting.
With the experience of a weekly cisplatin schedule from a com-
pleted phase III study of chemoradiotherapy in NPC22,23 and the
evidence from other cancers that this may be the best tolerated schedule of
chemoradiotherapy,24 the schedule of weekly cisplatin 40 mg/m2 for
up to 8 weeks concurrently with RT was used in the present protocol.
The primary objective of this study was to compare the toxicities
of patients with advanced NPC treated with chemoradiotherapy with
or without neoadjuvant docetaxel and cisplatin. Secondary objectives
were to compare the tumor response, PFS, OS, and the quality of life of
patients between the two treatment arms.
PATIENTS AND METHODS
Patient Eligibility and Random Assignment
Patients were eligible if they had biopsy-proven, previously untreated,
locoregionally advanced NPC of International Union Against Cancer 1997
stages III to IVB. Other eligibility criteria included assessable disease, Eastern
Cooperative Oncology Group performance status grade 0 or 1, age of at least
18 years, adequate bone marrow reserve (WBC count and platelet count of at
least the lower limit of normal) and renal function (serum creatinine 1.5
the upper limit of normal or creatinine clearance 50 mL/min), and absence
of hypercalcemia or second malignancy.
Patients were required to provide written informed consent before
study entry. The study protocol was approved by the institutional review
board and was conducted in accordance with the principles of the Decla-
ration of Helsinki.
The registration and randomization procedure were carried out by tele-
phone from the central office of the Comprehensive Cancer Trials Unit of The
Chinese University of Hong Kong (Hong Kong SAR, China) A computer
program was used to generate the allocation list. Patients were stratified for
stage (stage III v IV) and randomized with equal probability to one of the two
treatment arms (Appendix Fig A1, online only): (1) neoadjuvant chemother-
apy followed by CRT or (2) CRT alone.
Chemotherapy
In the investigational arm, the neoadjuvant chemotherapy schedule was
docetaxel 75 mg/m2 as intravenous (IV) infusion over 1 hour on day 1 and
cisplatin 75 mg/m2 IV over 1 hour with hydration on day 1. Docetaxel was
preceded by premedication with oral dexamethasone 8 mg twice daily for 3
days starting 1 day before the infusion. Cycles were repeated every 3 weeks for
two cycles. This was followed by RT delivered concurrently with cisplatin 40
mg/m2 IV over 2 hours weeks 7 through14 (Appendix Fig A2, online only). In
the control arm, RT concurrent with cisplatin 40 mg/m2 was administered
from week 1 to week 8 without the neoadjuvant chemotherapy.22,23
Chemotherapy was delayed by 1 week if the absolute neutrophil count
(ANC) was less than 1.5 109/L or platelet count was less than 75 109/L.
Both cisplatin and docetaxel were reduced to 65 mg/m2 if the nadir ANC was
less than 0.5 109/L or platelet count was less than 50 109/L. No growth
factor support was used. During CRT, cisplatin was delayed by 1 week if ANC
was less than 1.5 109/L or platelet count was less than 75 109/L until the
counts recovered. Cisplatin was stopped if there were any grade 4 toxicities. RT
delays were strongly discouraged. Enteral tube feeding was used as required at
the investigators discretion.
RT
RT was planned and delivered by the Hos technique.11,22 The same RT
technique was used for both arms. From March 1, 2004, the protocol was
amended to adopt intensity-modulated radiation therapy (IMRT) technique
to treat all T3/T4 disease in both arms25 (a detailed description of the RT
treatment appears in the Appendix, online only).
Assessment and Follow-Up
All patients completed pretreatment screening procedures within 28
days before the day of random assignment. Staging investigations included

Table 1. Baseline Characteristics

Neoadjuvant Control Arm
Patients assessed Arm (n 34) (n 31)
(n = 68)
Characteristics No. % No. %

Excluded (n = 3) Age, years

Did not meet (n = 2) Median 50 45
inclusion criteria Range 31-70 32-70
Refused to participate (n = 1) Sex
Male 21 61.8 24 77.4
Female 13 38.2 7 22.6
Random assignment
ECOG performance status
(n = 65)
0 29 85.3 26 83.9
1 5 14.7 5 16.1
UICC T-classification
Neoadjuvant chemotherapy arm Control arm
T1 2 5.9 2 6.4
Allocated to intervention (n = 34) Allocated to intervention (n = 31)
T2 12 35.3 7 22.6
Received allocated (n = 34) Received allocated (n = 26)
intervention intervention T3 13 38.2 15 48.4
Did not receive (n = 0) Did not receive (n = 5) T4 7 20.6 7 22.6
allocated intervention allocated intervention UICC N-classification
Reasons: N0 8 23.5 4 12.9
Withdrew consent (n = 2) N1 4 11.8 8 25.8
Diagnosed (n = 1)
dermatomyositis N2 13 38.2 12 38.7
Mandated IMRT (n = 1) N3 9 26.5 7 22.6
Suspected lung lesion (n = 1) UICC stage
III 19 55.9 19 61.3
Lost to follow-up (n = 0) Lost to follow-up (n = 0) IV 15 44.1 12 38.7
Analyzed (n = 34) Analyzed (n = 31)
Abbreviations: ECOG, Eastern Cooperative Oncology Group; UICC, Interna-
tional Union Against Cancer.
Fig 1. Flow of trial participants. IMRT, intensity modulated radiation therapy.

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 Hui et al

100
Neoadjuvant arm
90 Control arm
Relative Dose Intensity (%)

80

70

60
Fig 2. Mean relative dose intensities of
cisplatin and docetaxel during two cycles
50
of neoadjuvant chemotherapy and eight
weeks of cisplatin-radiotherapy (C cispla-
40
tin 75 mg/m2, D docetaxel 75 mg/m2,
P cisplatin 40 mg/m2).
30

20

10

0
Cycle 1 Cycle 1 Cycle 2 Cycle 2 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8
C D C D P P P P P P P P

computed tomography (CT) scan and magnetic resonance imaging (MRI) of
nasopharynx and neck, chest x-ray, ultrasound scan of abdomen, and radio-
nuclide bone scan.
CBC, serum biochemistry, and adverse events were evaluated on days 1
and 10 of neoadjuvant chemotherapy and weekly during CRT, and were
graded according to the National Cancer Institute Common Toxicity Criteria
(NCI-CTC) version 2.0. Tumor response to neoadjuvant therapy was eval-
uated before commencement of CRT by nasopharyngoscopy, physical
examination, and CT scan. Tumor response after CRT was evaluated by
nasopharyngoscopy and biopsy, physical examination, and CT scan at 6
weeks after completion of CRT. Tumor response was classified according to
WHO response criteria.26
Patients were followed up every 3 months in the first 2 years, then every
6 months in the third and fourth year, and yearly thereafter. The following
assessments were performed at each follow-up visit: (1) history and physical
examination, (2) nasopharyngoscopy, and (3) late RT toxicity of the skin,
subcutaneous tissue, and salivary gland using the Radiation Therapy Oncology
Group and European Organisation for Research and Treatment of Cancer
(EORTC) late radiation morbidity scoring schema.27
Quality-of-Life Assessment
The EORTC QLQ-C30 core questionnaire28 together with the head and
neck cancer (H&N35) module29 were administered at baseline, on day 1 of

Table 2. Summary of Grade 3 and 4 Adverse Events During Treatment

Neoadjuvant Arm (n 34) Control Arm (n 26)

Grade 3 Grade 4 Grade 3 Grade 4

Events No. % No. % No. % No. % P

During neoadjuvant chemotherapy
Hematologic
Neutropenia 6 17.6 27 79.4
Neutropenic fever 4 11.8 0 0
Nonhematologic
Fatigue 2 5.9 0 0
Nausea/vomiting 3 8.8 0 0
During cisplatin-radiotherapy
Hematologic
Anaemia 3 8.8 0 0 5 19.2 0 0 .23
Thrombocytopenia 1 2.9 2 5.9 0 1 3.8 .44
Neutropenia 8 23.5 1 2.9 3 11.5 1 3.8 .30
Neutropenic fever 1 2.9 0 0 1 3.8 0 0 .16
Nonhematologic
Anorexia/nausea/vomiting 3 8.8 0 0 2 7.7 0 0 .87
Dehydration/renal 8 23.5 0 0 6 23.1 0 0 .96
Fatigue 5 14.7 0 0 2 7.7 0 0 .40
Electrolytes 10 29.4 0 0 9 34.9 0 0 .66
Mucositis/odynophagia 8 23.5 0 0 2 7.7 0 0 .11
Transfusion 5 14.7 0 0 4 15.4 0 0 .94

NOTE. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0.

P values, calculated with the use of Fishers exact test, are for the difference in the incidence of grade 3 and 4 adverse events between the two treatment arms.

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 Neoadjuvant Chemotherapy Followed by Concurrent Cisplatin-RT in NPC

each cycle of neoadjuvant chemotherapy, weekly during CRT, and at each
follow-up visits.
Statistical Analysis
The incidence of toxicity was the primary end point. We calculated in this
study the 95% CIs for the incidence of toxicities with an adjustment of the type
I error for multiple comparisons of approximately 10 commonly encountered
hematologic and nonhematologic toxicities. Using 30 patients in each arm, we
would be able to exclude at least 20% difference using the lower bound of the
95% CI in a reasonable range of toxicities commonly found in most NPC trials
(ie, approximately 0% to 25%). Therefore, approximately 30 patients in each
of the two arms would allow us to exclude a difference of 20% on one side of
95% CI with 80% power. Secondary end points include tumor response, PFS,
OS, and quality of life. The accrual goal was 60 patients.
OS was defined as the duration from the date of random assignment to
the date of death resulting from any cause or censored at the date of last
follow-up. PFS was defined as the duration from the date of random assign-
ment to the date of disease progression or censored at the date of last follow-up.
The survival analysis was based on intention-to-treat (ITT) principle and
included all randomly assigned patients (ITT cohort, n 65). Analysis of
toxicities and responses was based on per-protocol treatment cohort (n 60).
The 2 test was used to compare the adverse events and other categoric
variables between the two treatment arms. The PFS and OS curves were
computed by Kaplan-Meier method and compared by log-rank test. The
hazard ratios and the corresponding 95% CIs were calculated by Cox propor-
tional hazards model. For quality-of-life scores, a difference or change of 10
units or more on a 0 to 100 scale was regarded as clinically important. Test of
differences between the two arms were performed by Wilcoxon test.
RESULTS
Patients
From November 2002 to November 2004, 68 patients were
assessed and 65 were randomly assigned to one of the two study
arms. Thirty-four patients were randomly assigned to the neoad-
juvant chemotherapy arm and 31 patients to the control arm
(Fig 1). The two treatment arms were well balanced in the baseline
characteristics (Table 1). All patients in the neoadjuvant arm re-
ceived the allocated treatment, but five patients in the control arm
did not receive the allocated treatment. Of these five patients, two
withdrew consent before treatment commencement, one was di-
agnosed to have dermatomyositis, one mandated IMRT mode of
RT, and one required further investigation for lung lesion (which
was later confirmed to be related to old tuberculosis on CT scan of

Table 3. Response to Neoadjuvant Chemotherapy and Cisplatin-Radiotherapy

Response Rate

Neoadjuvant Arm (n 34) Control Arm (n 26)

NP (n 34) LN (n 26) NP (n 26) LN (n 24)

Response No. % No. % No. % No. % P

After neoadjuvant chemotherapy
CR 8 23.5 14 53.8
PR 20 58.8 8 30.8
SD 6 17.6 4 15.4
PD 0 0 0 0
Combined response (NP LN, n 34)
CR
No. 6
% 17.6
ORR (CR PR)
No. 26
% 76.5
After cisplatin-radiotherapy
CR 32 94.1 21 8.8 22 84.6 16 66.7 .22
.26
PR 2 5.9 4 15.4 4 15.4 8 33.3
SD 0 0 1 3.8 0 0 0 0
PD 0 0 0 0 0 0 0 0
Combined response
CR .07
No. 28 16
% 82.4 61.5
ORR (CR PR) .38
No. 33 26
% 97.1 100

Abbreviations: NP, nasopharynx; LN, regional neck lymph nodes; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR,
overall response rate.

Patients with N0 at baseline were excluded for the calculation of LN response.
P values, calculated with the use of 2 test, are for the difference in the response rate between the two treatment arms.
Difference in the CR rate of NP between the two treatment arms.
Difference in the CR rate of LN between the two treatment arms.
NP LN (n 34).
NP LN (n 26).

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 Hui et al

thorax). Of the two patients who withdrew study consent after

random assignment, one sought herbal medicine for 1 month and A
1.0
then received CRT. The other patient sought herbal medicine for 1

Progression-Free Survival (probability)

year before development of distant metastases and subsequently
received palliative chemotherapy. All other three patients received 0.8
CRT. All together, four of the five patients who withdrew from
study received CRT as per standard institutional protocol, which
0.6
was the same as the control arm to which they were originally
allocated. All five patients were followed and included in the
ITT analysis. 0.4

Treatment Administration Neoadjuvant chemotherapy

0.2
All patients in the neoadjuvant arm completed the scheduled two Control
cycles of neoadjuvant chemotherapy. The median duration from day
1 of cycle 1 to day 1 of cycle 2 neoadjuvant chemotherapy was 21 days
(range, 21 to 27 days), and from day 1 of cycle 2 chemotherapy to day 0 1 2 3 4 5 6
1 of RT was 24 days (range, 20 to 28 days). The mean relative dose Time (years)
intensities of cisplatin and docetaxel during neoadjuvant chemother- B
apy and that of weekly cisplatin during CRT are shown in Figure 2. In 1.0
the neoadjuvant arm, 100%, 97%, 94%, 88%, 74%, 35%, 7%, and 3%
of patients completed 1, 2, 3, 4, 5, 6, 7, and 8 weeks of cisplatin during

Overall Survival (probability)

0.8
CRT, respectively. The corresponding numbers for the control arm
were 100%, 96%, 92%, 84%, 76%, 48%, 20%, and 0%. The propor-
tion of patients who completed cisplatin at different time points dur- 0.6
ing CRT were comparable in the two arms (P .94).
All patients in both arms completed RT to the prescribed dose.
0.4
Twenty-nine percent in the neoadjuvant arm and 23% in the control
arm were treated with IMRT plan. The mean RT total dose was 78.4
Gy ( 8.6 Gy) in the neoadjuvant arm and 76.5 Gy ( 7.4 Gy) in the 0.2 Neoadjuvant chemotherapy
Control
control arm. The mean RT overall treatment time was 58.8 days ( 7.6
days) in the neoadjuvant arm and 56.6 days ( 6.6 days) in the
control arm. 0 1 2 3 4 5 6

Acute Toxicity
No grade 5 toxicity (death) occurred during treatment. The main
grade 3 to 4 (G3/G4) adverse events during neoadjuvant chemother-
apy were hematological (Table 2). Although G3/G4 neutropenia oc-
curred in 97% of patients during neoadjuvant docetaxel-cisplatin
chemotherapy, the rate of febrile neutropenia was only 12%, which
were all uncomplicated. During the CRT phase, no significant differ-
ences were observed in the rates of G3/G4 neutropenia, other hema-
tologic or nonhematologic toxicities between the two study arms. The
mean time to first onset of G3/G4 neutropenia during CRT was also
similar in both arms (33 2.8 days in the neoadjuvant arm and 33
14.7 days in the control arm).
Efficacy
The responses after neoadjuvant chemotherapy and CRT are
summarized in Table 3. After a median follow-up of 4.3 years, we
observed a total of 20 disease progressions and 17 deaths in the ITT
population. The pattern of failure according to treatment arm was
summarized in Appendix Table A1 (online only). The 3-year PFS for
the neoadjuvant versus control arm was 88.2% and 59.5% (hazard
ratio 0.49; 95% CI, 0.20 to 1.19; P .12; Fig 3A). The 3-year OS for
the neoadjuvant versus control arm was 94.1% and 67.7% (hazard
ratio 0.24; 95% CI, 0.078 to 0.73; P .012; Fig 3B).
We have repeated the survival analysis based on per-protocol
treatment cohort by excluding the five patients who did not receive the
Time (years)
Fig 3. Kaplan-Meier estimates of survival curves for the two treatment arms. (A)
Progression-free survival. There was a trend for improvement of progression free
survival in favor of neoadjuvant chemotherapy arm (log-rank P .11). (B) Overall
survival. There was a significant improvement of overall survival in favor of
neoadjuvant arm (log-rank P .0066).
allocated treatment. The result of this per-protocol analysis was simi-
lar to that for the ITT cohort. The 3-year PFS for the neoadjuvant
chemotherapy versus control arm was 88.2% and 63.5% (hazard
ratio 0.55; 95% CI, 0.21 to 1.44; P .23). The 3-year OS for the
neoadjuvant chemotherapy versus control arm was 94.1% and 69.2%
(hazard ratio 0.26; 95% CI, 0.081 to 0.83; P .022).
Late Toxicity
There were no significant differences in the cumulative incidence
of grade 3 or above late radiation morbidity or adverse events during
follow-up between the two study arms (Table 4).
Quality of Life
No significant difference was observed in the global quality-of-
life scores in the two treatment arms. More information is provided in
the Appendix.

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 Neoadjuvant Chemotherapy Followed by Concurrent Cisplatin-RT in NPC

Table 4. Late Radiation Morbidity and Adverse Events

Neoadjuvant Arm (n 34) Control Arm (n 26)

Grade 3 Grade 4 Grade 3 Grade 4

Morbidity and Events No. % No. % No. % No. % P

Late radiation morbidity
Esophagus 1 2.9 0 0 0 0 0 0 .38
Eye 0 0 0 0 0 0 1 3.8 .24
Mucous membrane 3 8.8 0 0 0 0 0 0 .12
Salivary glands 11 32.4 0 0 8 30.8 0 0 .89
Skin 4 11.8 0 0 5 19.2 0 0 .49
Subcutaneous tissue 7 20.6 0 0 3 11.5 0 0 .35
Total (any) 26 76.5 0 0 16 61.5 1 3.8 .17
Late adverse events
CNS hemorrhage 0 0 0 0 0 0 1 3.8 .24
Conjunctivitis/keratitis 0 0 0 0 0 0 1 3.8 .24
Dysphagia 0 0 0 0 0 0 1 3.8 .24
Ear 3 8.8 0 0 1 3.8 0 0 .44
Epistaxis 0 0 1 2.9 0 0 0 0 .38
Fatigue 1 2.9 0 0 0 0 0 0 .38
Hepatic 0 0 0 0 1 3.8 0 0 .24
Hearing 1 2.9 2 5.9 3 11.5 0 0 .73
Hypoxia 0 0 1 3.8 0 0 0 0 .38
Irregular menses 0 0 0 0 1 3.8 0 0 .24
Lymphoedema (submental) 0 0 0 0 1 3.8 0 0 .24
Musculoskeletal 1 2.9 0 0 2 7.7 0 0 .72
Pain 1 2.9 0 0 0 0 0 0 .38
Pulmonary 1 2.9 0 0 4 15.4 0 0 .07
Second cancer (primary site) 0 0 2 5.9 0 0 1 3.8 .72
Transfusion 3 8.8 0 0 0 0 0 0 .12
Total (any) 11 32.4 6 17.6 13 50.0 4 15.4 .23

NOTE. Late radiation morbidity was graded according to Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer
scoring schema. Late adverse events were graded according to National Cancer Institute Common Toxicity Criteria version 2.0.

P values, calculated with the use of Fishers exact test, are for the difference in the incidence of grade 3 and 4 events between the two treatment arms.
Breast, tongue.
Colon.

feasibility of this approach, it is difficult to draw further conclusion

DISCUSSION
Recently, there has been a renewed interest in the re-exploration of
neoadjuvant chemotherapy in advanced NPC. This has resulted from
two observations. First, there is the recognition that more effective
neoadjuvant chemotherapy regimens may well exist. The second has
been the observation that with the use of high-precision RT delivery
such as with IMRT, coupled with the wide adoption of concurrent
CRT, the local control rate in NPC has improved, and distant metas-
tases has emerged as the predominant mode of treatment failures.25,30
Although no significant improvement in OS was seen in all the
published neoadjuvant chemotherapy trials, the body of available
clinical data strongly supports neoadjuvant chemotherapy in terms of
improvement in PFS.3-8 Benefit has been seen in reduction of both
local and distant failures.7 However, the selection and dosage of drugs
may be crucial because an overly toxic schedule has been shown to
impair the delivery of subsequent RT, and any possible benefit on
survival may be offset by increased treatment-related mortality.4
A number of uncontrolled phase II studies,9,10,31,32 including our
own report,11 have explored this sequential schedule of neoadjuvant
chemotherapy followed by CRT approach in NPC. The results have
been encouraging, and toxicity has been acceptable. Except for the
from these uncontrolled phase II data. There is also concern about the
additional toxicity, cost, prolonged treatment duration, compliance,
and impact on late physical function and quality of life that could
result from this approach.
The results of the present randomized phase II study suggest that
neoadjuvant docetaxel and cisplatin chemotherapy followed by CRT
is a highly feasible sequential strategy for advanced NPC. The in-
creased acute toxicity during the neoadjuvant chemotherapy was
mainly hematologic (neutropenia and neutropenia fever) which was
uncomplicated and manageable. Most importantly, this did not com-
promise the delivery of subsequent CRT. The hematologic toxicity
could be further ameliorated with the use of growth factor support and
prophylactic antibiotics. The comparable late toxicities and quality-
of-life scores in both arms are encouraging. The preliminary results on
pattern of failures suggest that the potential benefit of neoadjuvant
chemotherapy is in the reduction of distant metastases (11.8% in the
neoadjuvant arm v 23.1% to 29.0% in the control arm; Appendix
Table A1). There is a suggestion of a positive impact on PFS and OS,
although this needs to be confirmed in a definitive phase III trial.
Recently, [18F]fluorodeoxyglucose positron emission tomogra-
phy (PET) was compared with conventional staging procedures (ie,

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 Hui et al

chest x-ray, abdominal ultrasound and bone scan) in the staging of
advanced NPC, and it was suggested that PET may be more sensitive in
detecting distant metastases.33,34 Sixty-three of the 65 patients enrolled
in this trial also participated in a parallel study of PET-CT scan and
tumor marker study.35 No distant metastases were detected on
PET-CT after conventional staging procedures at study entry. There-
fore, it would be unlikely that there was significant imbalance of occult
distant metastases between the two treatment arms.
Unlike the traditional cisplatin and fluorouracil combination,
docetaxel and cisplatin combination can be conveniently adminis-
tered as outpatient without the need for a central venous catheter
device. A recent phase II study from The University of Texas M. D.
Anderson Cancer Center (Houston, TX) has tested docetaxel and
carboplatin combination as neoadjuvant therapy in NPC. Their result
also confirmed that this regimen could be more conveniently admin-
istered in the outpatient setting and was devoid of serious nonhema-
tologic toxicity.36
The triple combination of docetaxel, cisplatin, and fluorouracil
(TPF) was compared with cisplatin and fluorouracil (PF) as induction
chemotherapy in advanced head and neck cancer in the EORTC/
TAX323 and TAX324 studies, and demonstrated superior PFS and
OS.37,38 It was worth noting that in the TAX323 study, TPF induced
more neutropenia (76.9%) than PF (52.5%), but did not lead to more
frequent infectious complications when patients received prophylac-
tic antibiotics. In the TAX324 study, patients in the TPF group had
more G3/G4 neutropenia (83% in TPF v 56% in PF) and more febrile
neutropenia (12% in TPF v 7% in PF), but there were fewer treatment
delays in the TPF group. Similarly, no significant differences in the rate
of adverse events during RT were observed in both studies. It should
also be noted that in the aforementioned two neoadjuvant trials,
neoadjuvant chemotherapy was administered in both arms, followed
by RT alone in the EORTC/TAX323 study by Vermorken,37 or by
concurrent carboplatin-RT in the TAX324 study by Posner.38 Our
study adopted a pure concurrent CRT as control arm. We used weekly
cisplatin during the CRT. However, any conclusion on tolerability of
this schedule may not necessarily be extrapolated to the high-dose
cisplatin regimen (100 mg/m2 every 3 weeks), another commonly
used schedule in previous trials. It remains to be proven in head and
neck cancer and in NPC whether the addition of any neoadjuvant
chemotherapy regimen to concurrent CRT improves OS compared
with concurrent CRT alone in a phase III setting.39,40 To answer the
latter question, several phase III studies comparing a sequential ap-
proach of neoadjuvant chemotherapy followed by CRT versus CRT
alone are ongoing in head and neck cancer.41,42 In NPC, a Radiother-
apy Oncology Group for Head and Neck (GORTEC) multicenter
phase III trial of neoadjuvant chemotherapy (TPF) followed by con-
current weekly cisplatin-RT versus weekly cisplatin-RT alone has
been started.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a financial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a U are those for which no compensation was received; those
relationships marked with a C were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCOs conflict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Employment or Leadership Position: Iris Chan, Sanofi-aventis (C)
Consultant or Advisory Role: None Stock Ownership: None
Honoraria: None Research Funding: None Expert Testimony: None
Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Edwin P. Hui, Benny C. Zee, Anthony T. Chan
Financial support: Iris Chan, Anthony T. Chan
Administrative support: Frankie Mo, Rosalie Ho, Iris Chan, Benny C.
Zee, Anthony T. Chan
Provision of study materials or patients: Edwin P. Hui, Brigette B. Ma,
Sing F. Leung, Ann D. King, Michael K. Kam, Brian K. Yu, Samuel K.
Chiu, Wing H. Kwan, Rosalie Ho, Anil T. Ahuja, Anthony T. Chan
Collection and assembly of data: Edwin P. Hui, Brigette B. Ma,
Sing F. Leung, Ann D. King, Frankie Mo, Michael K. Kam, Brian K.
Yu, Samuel K.Chiu, Wing H. Kwan, Rosalie Ho, Anil T. Ahuja
Data analysis and interpretation: Edwin P. Hui, Brigette B. Ma, Sing F.
Leung, Frankie Mo, Benny C. Zee, Anthony T. Chan
Manuscript writing: Edwin P. Hui, Brigette B. Ma, Sing F. Leung,
Benny C. Zee, Anthony T. Chan
Final approval of manuscript: Edwin P. Hui, Brigette B. Ma, Sing F.
Leung, Ann D. King, Frankie Mo, Michael K. Kam, Brian K. Yu, Samuel
K. Chiu, Wing H. Kwan, Rosalie Ho, Iris Chan, Anil T. Ahuja, Benny C.
Zee, Anthony T. Chan

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