Head and neck cancer: treatment of nasopharyngeal cancer

A. T. C. Chan
Chinese University of Hong Kong, Department of Clinical Oncology at the Sir Y.K. Pao Centre for Cancer, HKSAR, China
Introduction
Nasopharyngeal carcinoma (NPC) is a rare disease in most
parts of the world, with an age-standardised annual incidence
of less than 1 per 100 000. However, in Southern China, parts
of Southeast Asia and the Mediterranean basin, NPC is an
endemic disease with an incidence of 1030 per 100 000 [1].
The three major well-dened aetiological factors for NPC
include genetically determined susceptibility, early-age
exposure to chemical carcinogens particularly of Southern
Chinese salted sh, and association with a latent Epstein
Barr virus (EBV) infection [2]. Three histopathological types
are recognised in the WHO classication [3]. Type I is squa-
mous cell carcinoma with varying degrees of differentiation,
type II is non-keratinising carcinoma and type III is undiffer-
entiated carcinoma. WHO types II and III can be considered
together as undifferentiated carcinoma of the nasopharyngeal
type (UCNT), which accounts for >95% of cases in endemic
areas and 50% of cases in non-endemic areas. The histo-
logical subtype may be of prognostic signicance, with
UCNT having a higher local control rate after treatment with
radiotherapy and a higher propensity for development of
distant metastases [4].
EBV DNA monitoring
Tumour-derived cell-free EBV DNA was rst detected by Lo
et al. [5] in NPC patients, with a sensitivity of 96% and speci-
city of 93% using a real-time quantitative PCR technique.
Subsequent studies have found that pretreatment EBV DNA
levels correlated with disease stage [6] and that it was a highly
signicant prognosticator for treatment outcome and survival
[7]. EBV DNA is a useful tool for monitoring patients during
radiotherapy and chemotherapy [8], as well as for early detec-
tion of tumour recurrence [9]. In a prospective study of 170
NPC patients, a EBV DNA level of >500 copies/ml at 68
weeks after radiotherapy completion was signicantly associ-
ated with poorer overall survival (hazard ratio 8.6) compared
with patients with low or undetectable EBV DNA levels [10].
Further studies are required to investigate the use of this
marker in risk-stratication of patients for treatment.
Treatment
Radiotherapy has been the standard treatment for NPC and
achieves high 5-year overall and disease-free survival rates in
early-stage disease. However, >60% of NPC patients present
with advanced-stage disease, for which there are signicant
rates of local failure and distant metastases subsequent to
radiotherapy. The disease is highly chemosensitive and hence
efforts have been made to improve treatment results by integ-
rating chemotherapy with radiotherapy in the primary treat-
ment [1122]. At the same time, improvements in radiation
treatment, including altered fractionation and more precise
delivery of a high dose to the tumour target by intensity-
modulated radiotherapy (IMRT), have been reported to
improve local control rates [23, 24]. The clinical trial results
on the various chemotherapyradiotherapy sequencing
approaches are summarised in the following sections.
Adjuvant chemotherapy
Neither of the two randomised studies of adjuvant chemo-
therapy given after radiotherapy demonstrated any overall
survival advantage compared with radiotherapy alone [11, 12].
Both of these studies have major limitations. The failure of
the study by Rossi et al. [11] to demonstrate any advantage
for adjuvant chemotherapy could be due to the relatively low
efcacy of the combination (vincristine, cyclophosphamide
and adriamycin) in comparison with a cisplatin combination,
the high percentage of patients failing to receive the assigned
treatment and the long time interval after completion of loco-
regional radiotherapy before randomisation was undertaken
and adjuvant chemotherapy initiated. The failure of the
Taiwan study [12] to show a reduction in distant metastasis,
or a survival benet, could be due to the high patient drop-out
rate from the chemotherapy arm and the high non-tumour-
related mortality rate after chemotherapy. Both studies
reported a signicant rate of patient-refusal to complete
planned adjuvant chemotherapy, and this is consistent with
our own experience [13]. In our randomised study comparing
radiotherapy with neo-adjuvant and adjuvant chemotherapy
against radiotherapy alone, only 55% of patients completed
the planned adjuvant chemotherapy owing to poor tolerance.
Similarly, in the Intergroup 0099 study, only 55% of patients
completed the planned adjuvant chemotherapy [17]. The main
limiting toxicity was oral and oropharyngeal mucositis with
exacerbations during chemotherapy, causing difculty in
feeding and swallowing. It therefore appears that after radical
radiotherapy for NPC, which delivers a signicant dose to the
oral and oropharyngeal mucosa, patients tolerance to chemo-
therapy is poor.
Annals of Oncology 16 (Supplement 2): ii265ii268, 2005
doi:10.1093/annonc/mdi732
q 2005 European Society for Medical Oncology

b
y

g
u
e
s
t

o
n

J
u
n
e

7
,

2
0
1
4
h
t
t
p
:
/
/
a
n
n
o
n
c
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
m

Neo-adjuvant chemotherapy
Two of the four randomised studies on the use of neo-adjuvant
chemotherapy showed positive results (Table 1) [1214, 17].
The VUMCA I study [14] showed signicant reduction of
both local and distant failures after chemotherapy. Ma et al.
[16] also showed signicant improvement in local control
after neo-adjuvant chemotherapy. The negative study by Chan
et al. [13] is limited by its low power, since it included only
77 evaluable patients. In the overall negative AOCOA study
[15], an unplanned subgroup analysis showed signicant
improvement in local control among 53 patients with very
large nodes. Nevertheless, none of the studies demonstrated
a signicant overall survival benet. Hence neo-adjuvant
chemotherapy at this time is only routinely recommended for
patients with very bulky intracranial NPC extending to such
close proximity to the optic chiasma and/or the brainstem that
even with IMRT adequate dose-sparing to within radiation
tolerance of these important neural organs is not possible. In
such cases, neo-adjuvant chemotherapy may help to shrink the
tumour away from the critical structures and provide a wider
safety margin around the gross tumour volume.
Concurrent chemo-radiation
In non-NPC head and neck cancers, meta-analysis of random-
ised studies (MACH-NC) [25] concluded that the addition of
chemotherapy to locoregional treatment yielded a pooled
hazard ratio of death of 0.9, with signicant benet from con-
current chemo-radiation but no signicant benet from adju-
vant or neo-adjuvant chemotherapy. Concurrent chemotherapy
and radiotherapy appears to be the most optimal way of
sequencing the two modalities that consistently improves
survival in head and neck cancers.
The rst evidence that concurrent chemo-radiation with
adjuvant chemotherapy produces survival advantage over
radiotherapy alone in NPC was provided by the Intergroup
study 0099 [17, 18] (Table 2). Cisplatin 100 mg/m
2
3 weekly
3 given concurrently with radiotherapy, followed by
Table 1. Randomised studies on neo-adjuvant chemotherapy in nasopharyngeal carcinoma
Study Neo-adjuvant chemotherapy 5-year OS 5-year PFS
CT RT CT RT
Chan et al. [13] (n = 77),
median follow-up
28.5months
2 cycles neo-adjuvant (every 3 weeks) and 4 cycles
adjuvant (every 3 weeks): cisplatin 100 mg/m
2
day 1;
5-FU 1000 mg/m
2
continuous iv infusion days 24
80% (2 year
gures, NS)
80.5% 68% (2 year
gures, NS)
72%
VUMCA I [14] (n =339),
median follow-up
49 months
3 cycles (every 3 weeks): cisplatin 100 mg/m
2
day 1;
bleomycin 15 mg day 1 then 12 mg/m
2
/day days 15;
epirubicin 70 mg/m
2
day 1
60% (3 year
gures, NS)
52% 58% (3 year
gures, P<0.01)
35%
AOCOA [15] (n =334),
median follow-up
30 months
23 cycles (every 3 weeks): cisplatin 60 mg/m
2
day 1;
epirubicin 110 mg/m
2
day 1
78% (3 year
gures, NS)
71% 48% (3 year
gures, NS)
42%
Ma et al. [16] (n =456),
median follow-up
62 months
23 cycles (every 3 weeks): cisplatin 100 mg/m
2
day 1;
bleomycin 10 mg/m
2
days 1 and 5; 5-FU 800 mg/m
2
continuous iv infusion days 15
63% (NS) 56% 59% (P=0.05) 49%
OS, overall survival; PFS, progression-free survival; CT, chemotherapy treated group; RT, radiotherapy alone group; 5-FU, 5-uorouracil; iv, intravenous;
NS, not signicant.
Table 2. Randomised studies on concurrent chemo-radiation in nasopharyngeal carcinoma
Study Concurrent schema 5-year OS 5-year PFS
CT RT CT RT
Intergroup 0099 [17, 18]
(n =193), median
follow-up >5 years
Cisplatin 100 mg/m
2
day 1 every 3 weeks for 3 cycles+adjuvant
cisplatin 80 mg/m
2
day 1, 5-FU 1 g/m
2
days 14 every
3 weeks for 3 cycles
67% (P<0.001) 37% 58% (P<0.001) 29%
Chan et al. [19, 20]
(n =350), median
follow-up 5.5 years
Cisplatin 40 mg/m
2
weekly 70.3% ( P= 0.049) 58.6% 60.2% (P=0.06) 52.1%
Lin et al. [21] (n =284),
median follow-up
65 months
Cisplatin 20 mg/m
2
/day and 5-FU 400 mg/m
2
/day, 96-h infusion
2 cycles weeks 1 and 5
72.3% (P= 0.0022) 54.3% 71.6% (P=0.0012) 53.0%
Kwong et al. [22] (n =219),
median follow-up
37 months
UFT 200 mg 3 times per day adjuvant 6 cycles alternating
PF/VBM (cisplatin 100 mg/m
2
day 1, 5-FU 1 g/m
2
days 13;
vincristine 2 mg day 1, bleomycin 30 mg day 1,
methotrexate 250 mg/m
2
day 1)
86.5% (3 year
gures, P=0.06)
76.8% 69.3% (3 year
gures, P=0.14)
57.8%
OS, overall survival; PFS, progression-free survival; CT, chemotherapy treated group; RT, radiotherapy alone group; 5-FU, 5-uorouracil; UFT, uracil
and tegafur; NS, not signicant.
ii266

b
y

g
u
e
s
t

o
n

J
u
n
e

7
,

2
0
1
4
h
t
t
p
:
/
/
a
n
n
o
n
c
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
m

adjuvant cisplatin 80 mg/m
2
day 1 and 5-uorouracil (5-FU)
1 g/m
2
days 14 3 has been considered standard treatment
for advanced-stage NPC in the USA.
Although the radiotherapy control arm of the Intergroup
study [17, 18] has been criticised for its poor results in a
heterogenous histological mix of WHO type I, II and III
NPC patients, raising questions of the applicability of the
results for WHO type II and III NPC patients in endemic
areas, a conrmatory study from Taiwan by Lin et al.
[21] demonstrated progression-free and overall survival
advantage using two cycles of concurrent chemotherapy
with cisplatin 20 mg/m
2
/day plus 5-FU 400 mg/m
2
/day by
96-h continuous infusion during weeks 1 and 5 of
radiotherapy.
Two further studies in Hong Kong have been undertaken at
the Prince of Wales Hospital in collaboration with Queen
Elizabeth Hospital [19, 20], and at the Queen Mary Hospital
[22], in patients with nodally advanced NPC (Table 2). The
overall survival analysis of the rst study demonstrated signi-
cant benet in favour of chemo-radiation using cisplatin
40 mg/m
2
weekly during radiotherapy [20]. In the second
factorial study with patients sequentially randomised to
receive uracil and tegafur (UFT) or not concurrently with
radiotherapy, and then further randomised to receive adjuvant
chemotherapy or not using PF/VBM (cisplatin, 5-FU, vincris-
tine, bleomycin and methotrexate); a borderline overall survi-
val benet was shown for UFT concurrent with radiotherapy
arms and no survival advantage was shown for the arms with
adjuvant chemotherapy [22].
It thus appears that one can condently apply concurrent
cisplatinradiation with/without adjuvant chemotherapy using
cisplatin and 5-FU as standard treatment for the locoregionally
advanced NPC. The optimal cisplatin schedule has not been
dened.
Neo-adjuvant chemotherapy followed by
concurrent chemo-radiation
Since the use of both neo-adjuvant chemotherapy and concur-
rent chemo-radiation has been shown consistently to improve
progression free and/or overall survival in advanced NPC, the
development of sequential neo-adjuvant chemotherapy and
concurrent chemo-radiation would seem a logical strategy in
an attempt to summate the benet from both approaches. In
addition, when concurrent chemo-radiation, rather than
radiotherapy alone, is used as the mainstay treatment, patients
tolerate neo-adjuvant chemotherapy better than adjuvant
chemotherapy for reasons discussed earlier. This strategy has
been tested in two phase II studies at Peter Macallum Institute
in Australia [26] and Prince of Wales Hospital in Hong Kong
[8]. Both studies demonstrated that neo-adjuvant chemother-
apy followed by concurrent chemo-radiotherapy was well
tolerated, with encouraging survival rates. The strategy of
neo-adjuvant chemotherapy followed by concurrent chemo-
radiation should be further studied in a prospective random-
ised fashion against concurrent chemo-radiation.
Metastatic disease
Combination chemotherapy using cisplatin (100 mg/m
2
) admi-
nistered together with a 3- to 5-day infusion of 5-FU (1 g/m
2
)
consistently yields a response rate of 6678% with a median
survival of 11 months [27, 28], and is regarded as the standard
therapy for metastatic NPC. Newer agents including paclitaxel
and gemcitabine have demonstrated high response rates and
favorable toxicity prole given in combination with cisplatin
or carboplatin [2933]. However, patient survival remains
poor after initial response to chemotherapy and hence novel
therapy is very much needed. Ongoing research is focusing
on biological agents that target epidermal growth factor recep-
tor, with a phase II study demonstrating that the addition of
cetuximab to carboplatin in patients with platinum-refractory
metastatic NPC has clinical benet [34].
References
1. Parkin DM, Whelan SL, Ferlay J, et al. Cancer Incidence in Five
Continents, Vol. 8. IARC Scientic Publications No. 155. Lyon:
IARC 2002.
2. Simons MJ, Shanmugaratnam K (eds): The biology of nasopharyngeal
carcinoma. UICC Technical Report Series. Geneva, Switzerland:
International Union Against Cancer 1982.
3. Shanmugaratnam K, Sobin LH. The World Health Organization histo-
logical classication of tumours of the upper respiratory tract and ear.
A commentary on the second edition. Cancer 1993; 71: 26892697.
4. Reddy SP, Raslan WF, Gooneratne S et al. Prognostic signicancer of
keratinization in nasopharyngeal carcinoma. Am J Otolaryngol 1995;
16: 1038.
5. Lo YM, Chan LY, Lo KW et al. Quantitative analysis of cell free
Epstein-Barr virus DNA in plasma of patients with nasopharyngeal
carcinoma. Cancer Res 1999; 59: 11881191.
6. Lo YM, Leung SF, Chan LYS et al. Plasma cell-free Epstein-
Barr virus DNA quantitation in patients with nasopharyngeal
carcinoma: correlation with clinical staging. Ann NY Acad Sci 2000;
906: 99101.
7. Lo YM, Chan AT, Chan LY et al. Molecular prognostication of naso-
pharyngeal carcinoma by quantitative analysis of circulating Epstein
Barr virus DNA. Cancer Res 2000; 60: 68786881.
8. Chan ATC, Ma BBY, Lo YMD et al. Phase II study of neoadjuvant
carboplatin and paclitaxel followed by radiotherapy and concurrent
cisplatin in patients with locoregionally advanced nasopharyngeal
carcinoma: Therapeutic monitoring with plasma EpsteinBarr virus
DNA. J Clin Oncol 2004; 22: 30533060.
9. Lo YMD, Chan LYS, Chan ATC et al. Quantitative and temporal
correlation between circulating cell-free EpsteinBarr virus DNA and
tumor recurrence in nasopharyngeal carcinoma. Cancer Res 1999; 59:
54525455.
10. Chan AT, Lo YM, Zee B et al. Plasma EpsteinBarr virus DNA and
residual disease after radiotherapy for undifferentiated nasopharyngeal
carcinoma. J Natl Cancer Inst 2002; 94: 16141619.
11. Rossi A, Molinari R, Boracchi P et al. Adjuvant chemotherapy with
vincristine, cyclophosphamide, and doxorubicin after radiotherapy in
local-regional nasopharyngeal cancer: results of a 4-year multicenter
randomized study. J Clin Oncol 1988; 6: 14011410.
12. Chi KH, Chang Y, Guo W et al. A phase III study of radiotherapy
with or without adjuvant chemotherapy in advanced stage nasophar-
yngeal carcinoma patientsTaiwan Cooperative Oncology Group
(TCOG) Trial. Proc Am Soc Clin Oncol 2001; 20: 889 (Abstr).
ii267

b
y

g
u
e
s
t

o
n

J
u
n
e

7
,

2
0
1
4
h
t
t
p
:
/
/
a
n
n
o
n
c
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
m

13. Chan ATC, Teo PML, Leung WT et al. A prospective randomized
study of chemotherapy adjunctive to denitive radiotherapy in
advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys
1995; 33: 569577.
14. International Nasopharynx Cancer Study Group. Preliminary results
of a randomized trial comparing neoadjuvant chemotherapy (cisplatin,
epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in
stage IV (>_N2, M0) undifferentiated nasopharyngeal carcinoma: A
positive effect on progression-free survival. Int J Radiat Oncol Biol
Phys 1996; 35: 463469.
15. Chua DTT, Sham JST, Choy D et al. Preliminary report of the Asian-
Oceanian Clinical Oncology Association randomized trial comparing
cisplatin and epirubicin followed by radiotherapy versus radiotherapy
alone in the treatment of patients with locoregionally advanced naso-
pharyngeal carcinoma. Cancer 1998; 83: 22702283.
16. Ma J, Mai HQ, Hong MH et al. Results of a prospective randomized
trial comparing neoadjuvant chemotherapy plus radiotherapy with
radiotherapy alone in patients with locoregionally advanced nasophar-
yngeal carcinoma. J Clin Oncol 2001; 19: 13501357.
17. Al-Sarraf M, LeBlanc M, Giri P et al. Chemoradiotherapy versus radio-
therapy in patients with advanced nasopharyngeal cancer: phase III ran-
domized intergroup study 0099. J Clin Oncol 1998; 16: 13101317.
18. Al-Sarraf M, LeBlanc M, Giri P et al. Superiority of ve year survival
with chemo-radiotherapy vs radiotherapy in patients with locally
advanced nasopharyngeal cancer NPC Intergroup 0099. Proc Am Soc
Clin Oncol 2001; 20: 905 (Abstr).
19. Chan ATC, Teo PML, Ngan RK et al. Concurrent chemotherapy-radio-
therapy compared with radiotherapy alone in locoregionally advanced
nasopharyngeal cacinoma: progression free survival analysis of a phase
III randomized trial. J Clin Oncol 2002; 20: 20382044.
20. Chan ATC, Leung SF, Ngan RKC et al. Overall survival after concur-
rent cisplatin-radiotherapy compared with radiotherapy alone in loco-
regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst
2005; 97: 536539.
21. Lin JC, Jan JS, Hsu CY et al. Phase III study of concurrent chemora-
diotherapy versus radiotherapy alone for advanced nasopharyngeal
carcinoma: Positive effect on overall and progression-free survival.
J Clin Oncol 2003; 21: 631637.
22. Kwong DLW, Sham JST, Au GKH et al. Concurrent and adjuvant
chemotherapy for nasopharyngeal carcinoma: a factorial study. J Clin
Oncol 2004; 22: 26432653.
23. Lee N, Xia P, Quivey JM et al. Intensity-modulated radiotherapy in
the treatment of nasopharyngeal carcinoma: an updated of the UCSF
experience. Int J Radiat Oncol Biol Phys 2002; 53: 1222.
24. Kam MKM, Teo PML, Chau RMC et al. Treatment of nasopharyn-
geal carcinoma with intensity-modulated radiotherapy: the Hong
Kong experience. Int J Radiat Oncol Biol Phys 2004; 60:
14401450.
25. Pignon JP, Bourhis J, Domenge C et al. Chemotherapy added to
locoregional treatment for head and neck squamous-cell carcinoma:
three meta-analyses of updated individual data. MACH-NC Colla-
borative Group. Meta-analysis of chemotherapy on head and neck
cancer. Lancet 2000; 355: 949955.
26. Rischin D, Corry J, Smith J et al. Excellent disease control and survi-
val in patients with advanced nasopharyngeal cancer treated with che-
moradiation. J Clin Oncol 2002; 20: 18451852.
27. Wang TL, Tan YO. Cisplatin and 5-uorouracil continuous infusion
for metastatic nasopharyngeal carcinoma. Ann Acad Med Singapore
1991; 20: 601603.
28. Au E, Ang PT. A phase II trial of 5-uorouracil and cisplatinum in
recurrent or metastatic nasopharyngeal carcinoma. Ann Oncol 1994;
5: 8789.
29. Au E, Tan EH, Ang PT. Activity of paclitaxel by three-hour infusion
in Asian patients with metastatic undifferentiated nasopharyngeal
cancer. Ann Oncol 1998; 9: 327329.
30. Yeo W, Leung TW, Chan AT et al. A phase II study of combination
paclitaxel and carboplatin in advanced nasopharyngeal carcinoma.
Eur J Cancer 1998; 34: 20272031.
31. Tan EH, Khoo KS, Wee J et al. Phase.II trial of a paclitaxel and
carboplatin combination in Asian patients with metastatic nasopharyn-
geal carcinoma. Ann Oncol 1999; 10: 235237.
32. Ma BB, Tannock IF, Pond GR et al. Chemotherapy with gemcitabine-
containing regimens for locally recurrent or metastatic nasopharyngeal
carcinoma. Cancer 2002; 95: 25162523.
33. Ngan RK, Yiu HH, Lau WH et al. Combination gemcitabine and
cisplatin chemotherapy for metastatic or recurrent nasopharyngeal
carcinoma: report of a phase II study. Ann Oncol 2002; 13:
12521258.
34. Chan ATC, Hsu M, Goh B et al. A phase II study of cetuximab in
combination with carboplatin in patients with recurrent or metastatic
nasopharyngeal carcinoma who failed to a platinum-based chem-
otherapy. Proc Am Soc Clin Oncol 2003; 23: 2000 (Abstr).
ii268

b
y

g
u
e
s
t

o
n

J
u
n
e

7
,

2
0
1
4
h
t
t
p
:
/
/
a
n
n
o
n
c
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
m