Nasopharyngeal carcinoma (NPC) has several characteristics that distinguish it from
other head and neck malignancies. It is a geographically endemic, Epstein–Barr virus-associated
carcinoma of epidermoid origin. The NPC cells are poorly differentiated or undifferentiated
with a high incidence of lymphatic and haematologic dissemination, and have greater
radiosensitivity. Radiotherapy is the most effective treatment for NPC because anatomic
constraints make surgery difficult. Although early-stage NPC is highly radiocurable,
the treatment results of locoregionally advanced NPC have been disappointing.
Combined chemoradiotherapy has been accepted by most oncologists as the standard treatment
of advanced NPC. There is still great controversy, however, regarding the optimal
drugs, timing, dosage, and duration of chemotherapy. In general, there are three different
ways to incorporate chemotherapy into a curative course of radiotherapy: before (neoadjuvant),
during (concurrent), and after (adjuvant) radiation therapy. Each mode of combined
therapy has advantages and disadvantages, and has been extensively investigated during
past years. The major flaws of neoadjuvant chemotherapy (NeoCT) are triggering of
accelerated repopulation and crossresistance during subsequent radiotherapy. The dose
intensity of concurrent chemotherapy that can be delivered safely during 7–8 weeks
radiotherapy is usually lower than chemotherapy alone. This may compromise its efficacy
in eradication of micrometastasis. Poor compliance and compromised blood supply are
the two major problems of adjuvant chemotherapy. In this prospective study, we designed
a novel schedule of outpatient weekly NeoCT plus radiotherapy for very advanced NPC.
Patients and methods
In our hospital, all patients with biopsy-proven NPC are subjected to careful staging
and evaluation before treatment. This included clinical examination of the head and
neck region, fibre nasopharyngoscopy, computed tomography (CT) scan or magnetic resonance
imaging (MRI) from the skull base to the whole neck, chest radiography, whole-body
bone scan, abdominal sonography, complete blood count with differential count, platelet
count, biochemical profile, and EBV serology. Chest CT scan and bone marrow biopsy
were not routine, but selectively performed when suspicion of lung metastasis in chest
radiography and abnormal blood routine were noted. Cancer stage was defined according
to the American Joint Committee on Cancer (AJCC) 1997 staging system.
Patient selection for NeoCT
According to our past experience, patients with one of the following criteria were
found to have a high incidence of distant failure: (1) neck nodal size >6 cm; (2)
supraclavicular node metastasis; (3) skull base destruction/intracranial invasion
plus multiple nodes metastasis; (4) multiple neck nodes metastasis with one of nodal
size >4 cm, and (5) elevated serum LDH level. From November 1998 to August 2001, 90
NPC patients meeting our selection criteria received NeoCT plus radiotherapy after
obtaining informed consent. Other eligibility criteria were: (1) Karnofsky performance
status ⩾60%; (2) white blood cell (WBC) count >3000 μl−1 and platelet count >100 000 μl−1;
(3) serum creatinine level <2.0 mg dl−1; (4) normal liver function with total bilirubin
<2.5 mg dl−1; and (5) no detectable distant metastasis.
Treatment schedule
All patients received a subcutaneous implanted port. Weekly P–FL NeoCT consisted of
cisplatin 60 mg m−2 2-h infusion after hydration and antiemetics, alternating with
5-fluorouracil (5-FU) 2500 mg m−2 plus leucovorin 250 mg m−2, mixed in 240 ml of normal
saline by continuous intravenous infusion for 24 h using an ambulatory pump in an
outpatient setting. The NeoCT will be delayed if Grade 4 toxicity developed, and resumed
after recovery. No dose modification was made and 10 weekly doses were planned. There
were no problems with the subcutaneous port for chemotherapy administration except
for the occurrence of catheter obstruction in one patient who needed surgical revision.
Radiotherapy was started within 1 week after completion of NeoCT using a linear accelerator
of 6 MV photons by the same technique and fractionation as described previously (Lin
and Jan, 1999), except for the incorporation of a 3-D conformal beam for the last
10–14 Gy. The total dose to the primary tumour is 70 Gy for T1-3 and 74 Gy for T4
disease. During the initial period of this trial (before June 1999), two courses of
concurrent chemotherapy comprising 96-h continuous infusion of cisplatin 15 mg m−2 day−1
+5-FU 300 mg m−2 day−1 were planned at the first and fifth weeks of radiotherapy.
Another 10-weekly postradiation adjuvant chemotherapy (cisplatin 25 mg m−2+5-FU 1250 mg m−2+bleomycin
10 mg m−2+leucovorin 120 mg m−2) was also recommended 2 months after radiotherapy.
We discontinued the concurrent and adjuvant chemotherapy since June 1999 because of
poor patient compliance.
Patient assessments
Chemotherapy toxicity and tumour response were assessed according to the World Health
Organization (WHO) criteria (Miller et al, 1981). Complete response (CR) was defined
as the complete disappearance of all clinical and radiographic evidence of disease
at the time of objective reevaluation. Partial response (PR) was defined as a ⩾50%
decrease in the sum of the products of the greatest dimensions of all measurable lesions.
Included in the definition of PR were no new lesions and no progression of any existing
lesions. Stable disease (SD) was defined as a reduction in tumour size less than PR
and an increase in tumour size less than that defined as progressive disease (PD)
or no response. PD was defined as ⩾25% increase in total tumour size of ⩾1 lesion,
or the appearance of a new lesion.
All patients were routinely assessed by indirect mirror examination for nasopharynx,
palpation of neck nodes, measurement of body weight, complete blood count and platelet
count once a week, or when patients experienced suffering and requested check-up during
the course of chemoradiotherapy. CT scan of nasopharynx and neck was usually repeated
at the ninth to tenth week for evaluation of tumour response and radiotherapy planning.
Rebiopsy of nasopharynx under fibroscopy was performed before radiotherapy. Liver
and renal function tests were rechecked before and after radiotherapy. After completion
of the whole treatment, patients were followed every 2 months during the first year,
every 3 months for the second and third years, and every 6 months thereafter. CT scan,
chest radiograph, abdominal sonography, whole-body bone scan, blood count, and biochemistry
tests were routinely performed annually or at the time of clinical suggestion of tumour
relapse.
Results
Patient characteristics
Table 1
Table 1
Patient characteristics
Characteristics
No. of cases
%
Age (years)
Range
24–71
Median
43
Mean
45
Sex
Male
66
73.3
Female
24
26.7
Karnofsky scale
⩾80%
82
91.1
<80%
8
8.9
Pathology (WHO classification)
Type I
4
4.4
Type II
70
77.8
Type III
16
17.8
T-stage (1997 AJCC)
T1
6
6.7
T2a
2
2.2
T2b
19
21.1
T3
12
13.3
T4
51
56.7
N-stage (1997 AJCC)
N2
56
62.2
N3
34
37.8
Concurrent chemotherapy
Yes
11
12.2
No
79
87.8
Adjuvant chemotherapy
Yes
11
12.2
No
79
87.8
lists the pretreatment patient and tumour characteristics for the 90 patients. Although
one of our eligibility criteria was Karnofsky performance status of 60 or greater,
most of our patients (91.1%) belong to a performance status of 80–100. The TNM stage
distribution of our patients (1997 AJCC T1/T2a/T2b/T3/T4=6/2/19/12/51 and N2/N3=56/34)
demonstrates very advanced stage disease.
Patient compliance to P–FL NeoCT
Of 90 patients, 84 finished the planned 10-week P–FL NeoCT without interruption. Two
patients stopped NeoCT prematurely after seven doses because of their refusal, with
complete regression of their tumour clinically and pathologically. One patient received
two more doses (12 doses) than planned because of a 4-week interruption by earthquake
and personal affair. Another patient escaped after 8-week NeoCT with clinical complete
remission. The tumour relapsed 11 months later and he received 10-week NeoCT followed
by radiotherapy as schedule. Except for four treatment interruptions during NeoCT
mentioned above, two additional patients completed the planned NeoCT with a 1-week
delay because of gastrointestinal bleeding and operation for suspected intra-abdominal
metastasis, but proven as benign tumour arising from the lesser omentum.
Toxicity of P–FL NeoCT
Acute toxicity was mild and well tolerated (Table 2
Table 2
Acute toxicities of neoadjuvant P–FL chemotherapy
Grade
Toxicity
0
1
2
3
4
Leucopaenia
21 (23.3%)
30 (33.3%)
32 (35.6%)
7 (7.8%)
0
Anaemia
15 (16.7%)
34 (38.9%)
24 (26.7%)
14 (15.6%)
3 (3.3%)
Thrombocytopaenia
82 (91.1%)
2 (2.2%)
4 (4.4%)
2 (2.2%)
1 (1.1%)
Mucositis
87 (96.7%)
1 (1.1%)
2 (2.2%)
0
0
Nausea/vomiting
40 (44.4%)
33 (36.7%)
13 (14.4%)
4 (4.4%)
0
Weight loss
42 (46.7%)
33 (36.7%)
14 (15.6%)
1 (1.1%)
0
Alopecia
86 (95.6%)
4 (4.4%)
0
0
0
). Some patients experienced a mild degree of anorexia and weakness during the NeoCT.
Nausea and emesis occurred in 50 of the 90 patients during their treatment, but was
usually mild (only four patients experienced Grade 3 vomiting). Mucositis was observed
in only three patients of Grade 1–2. In all, 96% of the patients had no observable
hair loss and only 4% patients experienced Grade 1 alopecia. No patients complained
of diarrhoea. Body weight loss was defined as the difference between prechemotherapy
body weight and the nadir body weight during chemotherapy. About half of the patients
experienced body weight loss of mild degree (only 1.1% belong to Grade 3). There was
no liver or renal function impairment. Haematological toxicity was also mild. Grades
3–4 toxicities occurred in 7.8% of patients for leucopaenia, 3.3% of patients for
thrombocytopaenia, and 18.9% of patients for anaemia.
Tumour response to P–FL NeoCT
At the end of NeoCT, we observed 52 patients with CR (57.8%), 36 with PR (40.0%),
and 2 with SD (2.2%), for an overall response rate of 97.8% (Table 3
Table 3
Tumour response
Site
Response
Nasopharynx
Neck
Overall
Clinical
CR
66 (73.3%)
64 (71.1%)
52 (57.8%)
PR
23 (25.6%)
24 (26.7%)
36 (40.0%)
SD
1 (1.1%)
2 (2.2%)
2 (2.2%)
Pathologicala
CR
55 (62.5%)
Residual tumour
33 (37.5%)
a
A total of 88 out of 90 patients received rebiopsy of nasopharynx after neoadjuvant
chemotherapy before radiotherapy.
CR=complete response, PR=partial response, SD=stable disease.
). Clinically, CR rates of primary tumour and neck nodes were 73.3% (66 out of 90)
and 71.1% (64 out of 90), respectively. Figure 1
Figure 1
Pretreatment CT scan (A, B) showed a big nasopharyngeal tumour with intracranial invasion
in a patient presenting as multiple cranial nerve palsy. The tumour regressed completely
with bony regeneration of the destructed skull base after 10-week neoadjuvant chemotherapy
(C, D).
shows the complete disappearance of original huge NPC with intracranial invasion after
10-week P–FL NeoCT. A total of 88 out of 90 patients received rebiopsy before radiotherapy
and pathologically CR was observed in 55 patients (62.5%).
Toxicity and compliance to subsequent radiotherapy
All except one patient finished radiotherapy ⩾70 Gy. One patient presented with T4N3
tumour that responded poorly to NeoCT. He refused radiotherapy after 34 Gy with stable
disease. Most patients received 70 (31 patients) and 74 Gy (54 cases). The average
treatment duration of radiotherapy was 52 days (range 44–84 days). Only five patients
completed local radiotherapy more than 9 weeks. Acute toxicity was moderate and manageable
(Table 4
Table 4
Acute toxicities of subsequent radiotherapy
Grade
Toxicity
0
1
2
3
4
Leucopaenia
9 (10.0%)
26 (28.9%)
41 (45.6%)
14 (15.6%)
0
Anaemia
11 (12.2%)
32 (35.6%)
31 (34.4%)
9 (10.0%)
7 (7.8%)
Thrombocytopaenia
85 (94.4%)
0
3 (3.3%)
1 (1.1%)
1 (1.1%)
Mucositis
0
19 (21.1%)
24 (26.7%)
47 (52.2%)
0
Skin reaction
0
22 (24.4%)
44 (48.9%)
24 (26.7%)
0
Weight loss
22 (24.4%)
34 (37.8%)
33 (36.7%)
1 (1.1%)
0
Nausea/vomiting
84 (93.3%)
6 (6.7%)
0
0
0
). Since we have no gap between NeoCT and subsequent radiotherapy, chemotherapy-induced
bone marrow suppression persisted during the period of the first to third weeks of
radiotherapy. In all, 61% (55 out of 90) of patients encountered the nadir WBC count
<3000 μl−1, usually occurring in the first 3 weeks of radiotherapy. A total of 52%
(47 out of 90) of patients experienced nadir haemoglobin <8 g%. The major toxicity
induced by radiotherapy was mucositis with 52.2% Grade 3 and 26.7% Grade 2. Grades
3 and 2 skin reactions were noted in 26.7 and 48.9% of the patients, respectively.
Compliance to additional concurrent/adjuvant chemotherapy
Before June 1999, additional concurrent/adjuvant chemotherapy was also planned after
NeoCT. For the 17 patients intended to be treated during this period, the compliance
to concurrent and/or adjuvant chemotherapy is poor. At the end of NeoCT, we did not
recommend concurrent chemotherapy because of persistent leucopaenia <2500 μl−1 in
six out of 17 patients. CCRT was delivered for 11 out of 17 patients, but five patients
needed more delay (>1 week) to start CCRT and four patients refused the second cycle
of concurrent chemotherapy. Adjuvant chemotherapy was given for 11 out of 17 patients,
2 months after the completion of radiotherapy. Four of 11 patients had 1–4 weeks interruption
during the adjuvant chemotherapy period and two patients refused further treatment
after 6-week adjuvant chemotherapy. Thus, we modified our original three-phase chemotherapy
to NeoCT+radiotherapy alone for the last 73 patients.
Patterns of failure and survival
The patient who received incomplete radiotherapy at 34 Gy was counted as locoregional
failure. The current status of the remaining 89 patients, after a median follow-up
of 24 (range 9–42) months, showed that two patients failed at primary, one patient
failed regionally, one patient failed in neck and distant site, and 14 patients developed
distant metastases alone. The 2-year nasopharynx disease-free, neck disease-free,
and distant disease-free survival rates for all patients are 98.9, 95.9, and 80.0%,
respectively. The 2-year overall and progression-free survival rates are 92.1 and
77.5%, respectively (Figure 2
Figure 2
Overall and progression-free survival curves for all 90 patients.
).
We also analysed the impact of additional concurrent/adjuvant chemotherapy on treatment
outcome and found no statistically significant difference in terms of progression-free
and overall survivals. When we evaluated the influence of tumour response after NeoCT,
overall survival (Figure 3A
Figure 3
Comparison of overall survival (A) and progression-free survival (B) according to
tumour response after neoadjuvant chemotherapy using the Kaplan–Meier estimate and
the log-rank test. CR=complete response.
) and progression-free survival (Figure 3B) were significantly higher in the group
who had a complete response than in the group who had less than a complete response.
Late complications
The late complications that occurred up to the time of this writing were usually mild.
All patients suffered from xerostomia of varying degrees. A total of 18 patients complained
of hearing impairment. Six patients experienced neck fibrosis of different degrees.
Six patients had trismus and four patients suffered from transient Lhermitte's sign.
The severe late morbidities (⩾Grade 3–4) consist of temporal lobe oedema in one case,
trismus 0.2 cm in one case, severe neck fibrosis in four patients, and marked hearing
loss in six patients. Four of these six patients also received additional cisplatin-based
chemotherapy as a salvage for distant metastases that might contribute to their hearing
loss.
Discussion
Treatment failures for advanced NPC in the past have been both high rates of local
recurrence and distant metastasis. As a result of recent advances in radiation oncology
and the combined use of chemotherapy, the patterns of failure have been predominantly
because of distant metastasis (Huang et al, 1985; Lee et al, 1992; Chan et al, 1995;
Cvitkovic and INCSG, 1996; Lin et al, 1996; Al-Sarraf et al, 1998; Chua et al, 1998;
Cheng et al, 2000; Ma et al, 2001; Wolden et al, 2001). Adding more chemotherapy into
original radiotherapy schedule for patients with high risk of distant failure is a
reasonable and critical approach to enhance cure rate.
NeoCT for NPC had been tried more than 10 years ago, but seemed to be abandoned during
recent years. Instead, concurrent chemoradiotherapy (CCRT) with adjuvant chemotherapy
has become popular especially after the Intergroup report (Al-Sarraf et al, 1998).
We agree that concurrent chemotherapy has a good timing and has some benefits, such
as different cell-killing effect, avoidance of crossresistance, independent toxicity
(if careful selection of the drug), and potentially additive or synergistic action
between radiation and chemotherapy. However, it does not exclude the potential effect
of a different chemotherapy schedule.
To the best of our knowledge, there have been nine phase III randomised trials to
investigate the role of combined chemoradiotherapy in NPC so far (Rossi et al, 1988;
Chan et al, 1995, 2002; Cvitkovic and INCSG, 1996; Al-Sarraf et al, 1998; Chua et
al, 1998; Ma et al, 2001; Chi et al, 2002; Hareyama et al, 2002).
Table 5
Table 5
Literature review of phase III studies in NPC
Authors (published year)
Entry criteria
Treatment
No. of cases
Reported survival (%)
Estimateda 2-year OS (%)
Rossi et al (1988)
1978 UICC
RT
116
67 (4-year OS)
83
Stage II–IV
RT+AdjCT
113
59
70
Chi et al (2002)
1988 AJCC/UICC
RT
77
60.5 (5-year OS)
80
Stage IV
RT+AdjCT
77
54.5
78
Al-Sarraf et al (1998)
1988 AJCC/UICC
RT
69
37 (5-year OS*)
58
Stage III–IV
CCRT+AdjCT
78
67
82
Chan et al (2002)
Ho's N2-3 or
RT
176
69 (2-year RFS)
node⩾4 cm
CCRT
174
76
Chan et al (1995)
Ho's N3 or
RT
40
81 (2-year OS)
81
node ⩾4 cm
NeoCT+RT+AdjCT
37
80
80
Cvitkovic and INCSG (1996)
1987 UICC
RT
168
54 (3-year OS)
60
N2-3
NeoCT+RT
171
60
65
Chua et al (1998)
Ho's T3, N2-3
RT
167
71 (3-year OS)
81
or node ⩾3 cm
NeoCT+RT
167
78
81
Ma et al (2001)
1992 Chinese
RT
228
56 (5-year OS)
82
Stage III–IV
NeoCT+RT
228
63
87
Hareyama et al (2002)
1988 AJCC/UICC
RT
40
48 (5-year OS)
85
Stage I–IV
NeoCT+RT
40
60
88
Current series
1997 AJCC
NeoCT+RT
90
92.1 (2-year OS)
92.1
Stage III–IV
*
P<0.05.
a
For comparison purposes, we estimated a 2-year overall survival rate from the reported
survival curve.
RT=radiotherapy, AdjCT=adjuvant chemotherapy, CCRT=concomitant chemoradiotherapy,
NeoCT=neoadjuvant chemotherapy, OS=overall survival, RFS=relapse-free survival.
summarises the results. Unfortunately, most studies showed no survival benefit. Because
of different staging systems, different prognostic factors, different drugs, and schedules,
it is difficult to compare which one is better. Using concurrent chemotherapy of cisplatin
100 mg m−2 every 3 weeks during radiotherapy followed by three monthly cycles of PF
(cisplatin+5-FU) postradiation adjuvant chemotherapy, the Intergoup study of the United
States reported that chemoradiotherapy is superior to radiotherapy alone (Al-Sarraf
et al, 1998). Of 193 patients with 1987 AJCC/UICC stage III–IV registered, 147 were
eligible for analysis. The 3-year progression-free survival (69 vs 24%, P<0.001) and
overall survival (78 vs 47%, P=0.005) favoured the chemoradiotherapy group. Although
this is the only randomised trial of positive results in survival analysis, its wide
application to non-American NPC patients should be considered with caution. First,
about 30% patients of the Intergroup study have WHO type I histology (keratinising
squamous cell carcinoma), but European (Cvitkovic et al, 1996), Japanese (Hareyama
et al, 2002), or Chinese (Chan et al, 1995, 2002; Chua et al, 1998; Ma et al, 2001;
Chi et al, 2002) series usually contain less than 5% WHO type I patients. Second,
the survival data of radiotherapy alone are unexplainedly low–24% 3-year progression-free
survival rate and 47% 3-year overall survival rate. The Asian-Oceanian Clinical Oncology
Association (AOCOA) trial (Chua et al, 1998) presented 42% 3-year relapse-free survival
rate and 71% 3-year overall survival for the radiotherapy alone arm. The Hong Kong
trial (Chan et al, 1995) reported 72% 2-year disease-free survival rate and 80.5%
2-year overall survival rate for patients receiving radiotherapy alone. The Italian
trial (Rossi et al, 1988) obtained 55.8% 4-year relapse-free survival rate and 67.3%
4-year overall survival rate. A recent nonrandomised study from the Memorial Sloan-Kettering
Cancer Center, New York, showed 54% of 3-year progression-free survival and 71% of
3-year overall survival for radiotherapy alone (Wolden et al, 2001). A retrospective
review from the MD Anderson Cancer Center (Sanguineti et al, 1997) covering NPC patients
who received radiotherapy alone between 1954 and 1992 also showed a better survival
profile than the radiotherapy alone arm of the Intergroup randomised trial.
NeoCT is usually regarded as no benefit at first glance. However, we reconsider it
based on a 10-year experience of combined chemoradiotherapy in our hospital and a
careful literature review. Our previous study shows that CCRT is better than radiotherapy
alone in local control rate and overall survival for patients with 1992 AJCC stage
III–IV diseases. Subgroup analysis for very advanced disease (such as selection criteria
in this study) revealed no significant difference between CCRT and radiotherapy alone.
A phase II study from the Koo Foundation Sun Yat-Sen Cancer Center, Taipei, reported
excellent results using CCRT plus adjuvant chemotherapy similar to those of the Intergroup.
They reported 96.6% 3-year disease-free survival for 1997 AJCC stage II patients,
87.7% for stage III, but only 51.9% for stage IV (Cheng et al, 2000). The editorial
comment (Cooper, 2000) recommended that stage IV patients need more effective systemic
chemotherapy, such as moving adjuvant therapy to a neoadjuvant position, or adding
NeoCT to Cheng's regimen, or inserting another drug with activity in head and neck
cancer (e.g. a taxane, mitomycin). A recent study from the National Taiwan University
hospital, Taipei, reported 70% 5-year overall survival for stage IV patients using
NeoCT of MEPFL (mitomycin, epirubicin, cisplatin, 5-FU, and leucovorin) followed by
radiotherapy (Hong et al, 2001). The 5-year distant metastasis-free rate of N3a and
N3b diseases of AJCC 1997 staging system were 79 and 74%, respectively.
A recent randomised trial from the People's Republic of China allocated 456 patients
of the Chinese 1992 staging III/IV disease into 2–3 cycles of PBF (cisplatin, bleomycin,
and 5-FU) NeoCT followed by radiotherapy vs radiotherapy alone (Ma et al, 2001). Although
they failed to demonstrate significant benefit in freedom from distant metastasis,
there is a trend to favour the chemoradiotherapy group in terms of 5-year relapse-free
survival (59 vs 49%, P=0.05) and overall survival (63 vs 56%, P=0.11).
There were several nonrandomised studies showing better results of NeoCT. In a matched
cohort study from the MD Anderson Cancer Center, significant better 5-year disease-free
survival (64±6 vs 42±7%, P=0.015) and overall survival (69±6 vs 48±7%, P=0.012) were
obtained for the NeoCT group compared with radiotherapy alone (Geara et al, 1997).
The 5-year cumulative incidence of distant metastasis was 19±5% for the chemoradiotherapy
group and 34±6% for the radiotherapy alone group (P=0.019). A retrospective study
from Korea reported significant better 5-year overall survival (71 vs 59%, P=0.04)
and freedom from distant metastasis rate (84 vs 66%, P=0.01), favouring NeoCT compared
with radiotherapy alone (Hong et al, 1999). A larger series containing 618 node-positive
NPC patients from the Prince of Wales Hospital, Hong Kong, compared NeoCT plus radiotherapy+adjuvant
chemotherapy (n=209) with radiotherapy alone (n=409). After a median follow-up of
5.5 years, the NeoCT group had significantly less local failures than radiotherapy
alone, especially for stage IV patients (Teo et al, 1999).
Before changing policy from CCRT with adjuvant chemotherapy to NeoCT for very advanced
NPC, we also re-evaluate why some phase III randomised trials could not demonstrate
a significant effect of NeoCT. The possible reasons included a relatively lower dose
of 5-FU (1000 mg m−2 day−1 for 3 days infusion instead of 4 or 5 days in other studies)
in the Hong Kong trial (Chan et al, 1995), a relatively lower dose of cisplatin (120–180 mg m−2 person−1)
in the AOCOA trial (Chua et al, 1998), an excess of chemotherapy-related death and
of radiotherapy refusal in the International Nasopharynx Cancer Study Group (INCSG)
trial (Cvitkovic and INCSG, 1996), or a less advanced stage (Chua et al, 1998). In
subgroup analysis for patients with bulky neck lymph nodes >6 cm in the AOCOA trial
(Chua et al, 1998), NeoCT improved 3-year relapse-free survival (63 vs 28%, P=0.026)
and overall survival (73 vs 37%, P=0.057). The NeoCT arm had a significant better
disease-free survival but not overall survival in the INCSG trial (Cvitkovic and INCSG,
1996). If medical care can be improved to avoid excess treatment-related death and
good communication can be achieved to reduce radiotherapy refusal, we think that adequate
NeoCT followed by radiotherapy may have the potential to improve survival.
Except for the considerations mentioned above, we also think that (1) the timing of
NeoCT is better than that of concurrent or adjuvant setting, for example, the best
blood supply in the tumour and the best tolerance in the host; and (2) the dose intensity
of concurrent chemotherapy during 7–8 weeks of radiotherapy is too low to reduce distant
failure. At the beginning of this trial, we initially designed three-phase chemotherapy
(neoadjuvant+concurrent+adjuvant) combined with radiotherapy. After the first 17 patients
intended to be treated, the compliance to concurrent and/or adjuvant chemotherapy
is poor. Thus, we modified our original three-phase chemotherapy to NeoCT plus radiotherapy
alone.
Under our unique outpatient weekly F–PL NeoCT, we obtained high CR rate and low toxicity.
Clinically and pathologically, CR rates of the primary tumour were 73.3% (66 out of
90) and 62.5% (55 out of 88), respectively. Although the median follow-up (24 months)
time is short, a high CR rate has reflected low local recurrence–only 3 of 90 patients
with locally advanced tumour (56.7% 1997 AJCC T4, 13.3% T3, and 21.1% T2b disease)
suffered from recurrent (2) or persistent (1) primary disease. Other exciting findings
of our P–FL NeoCT are rare incidence of mucositis and nearly no hair loss that made
patients more comfortable than any other chemotherapy regimen. In all, 47% (42 out
of 90) patients had no body weight loss during NeoCT. The outpatient nature of this
treatment and lack of alopecia allowed normal social activity and saved more cost.
The only weak point we are concerned with is that 10-week NeoCT may be inadequate
for eradication of micrometastasis. So far, 16.7% (15 out of 90) distant failure rate
is rather good for very advanced NPC. Of 64 (31.3%) NPC patients with the same disease
extent who received radiotherapy alone before September 1998 in our department, 20
developed distant metastasis within 2 years of follow-up (unpublished data). Of course,
we need a longer time to follow up and evaluate the final outcomes. Now, we consider
adding less toxic adjuvant chemotherapy regimen, such as low-dose 5-FU+leucovorin
in colorectal cancer. Based on our encouraging results, a phase III randomised trial
to compare NeoCT+radiotherapy+adjuvant chemotherapy of low-dose 5-FU+leucovorin with
CCRT+adjuvant chemotherapy for very advanced NPC will be initiated in the near future.