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635
Outpatient Weekly Chemotherapy in Patients with
Nasopharyngeal Carcinoma and Distant Metastasis
Jin-Ching Lin, M.D.1,2,3
Jian-Sheng Jan, M.D.1,2
Chen-Yi Hsu, M.D.4
1
Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung, Taiwan.
2
School of Medicine, China Medical College,
Taichung, Taiwan.
3
Institute of Clinical Medicine, National Yang-Ming
University, Taipei, Taiwan.
4
Department of Otorhinolaryngology, Taichung
Veterans General Hospital, Taichung, Taiwan.
Presented at the 46th Annual Meeting of The
Radiological Society of the Republic of China, Taipei, Taiwan, March 27–28, 1997.
Supported by grants from Taichung Veterans General Hospital, Taiwan, Republic of China (TVGH857102).
Address for reprints: Jin-Ching Lin, M.D., Department of Radiation Oncology, Taichung Veterans
General Hospital, 160, Sec. 3, Taichung-Kang
Road, Taichung, Taiwan.
Received July 7, 1997; revisions received November 21, 1997, and February 9, 1998; accepted
February 9, 1998.
© 1998 American Cancer Society
BACKGROUND. Distant metastasis is a more common pattern of failure than
locoregional recurrence after adequate radiotherapy in patients with nasopharyngeal carcinoma (NPC). The objective of this Phase II study was to assess the efficacy
and toxicity of weekly chemotherapy in NPC patients with distant metastasis.
METHODS. Patients with a histologic diagnosis of NPC and documented distant
metastasis were eligible, including those who 1) had metastatic disease at presentation; 2) had developed metastatic disease during or at any time after local radiotherapy; or 3) had developed progressive disease or recurrence of metastasis after prior
chemotherapy. The weekly chemotherapy regimen was comprised of 5-fluorouracil
(5-FU), 1250 mg/m2, plus cisplatin, 25 mg/m2, as a 24-hour continuous intravenous
infusion via a subcutaneous implanted port, using an ambulatory pump in an outpatient setting for the first 19 patients. Because of the low incidence and reduced severity
of toxicity, the dosage of chemotherapy was escalated to 5-FU, 1667 mg/m2, plus
cisplatin, 33.3 mg/m2, for the subsequent 25 patients.
RESULTS. Between October 1992 and June 1996, a total of 44 patients with
metastatic NPC were studied. They were 36 males and 8 females with a median age
of 48 years (range, 30 –72 years). Poorly differentiated epidermoid carcinoma or
undifferentiated carcinoma were the major pathologic types. Twenty-six patients
had single organ metastasis, whereas 18 patients had multiple organ involvement.
Locoregional disease existed simultaneously in 16 patients. The majority of patients had received previous radiotherapy (33 patients) and chemotherapy (23
patients: 16 as concurrent therapy for localized disease, 6 as salvage therapy for
metastatic disease, and 1 for a postradiation adjuvant purpose). Among 38 patients
with measurable disease, 8 obtained a complete response (CR) (21.1%), 12 obtained a partial response (PR) (31.6%), 17 had stable disease (SD) (44.7%), and 1
had progressive disease (2.6%). The median duration of CR, PR, and SD were 6.5
months, (range, 2–12 months), 5.5 months (range, 2–9 months), and 2.5 months
(range, 1– 6 months), respectively. Toxicity was found to be very mild. Only one
patient developed a World Health Organization (WHO) Grade 1 mucositis. No
visible alopecia and no treatment-related deaths occurred. WHO Grade 3– 4 hematologic toxicities occurred in 1.0% of patients for leukopenia, 4.1% for anemia,
and 2.9% for thrombocytopenia.
CONCLUSIONS. Data from the current study indicate that 24-hour weekly infusion
of 5-FU plus cisplatin has moderate activity but very low toxicity for NPC patients
with distant metastasis. Further study is necessary to find more effective therapy.
Cancer 1998;83:635– 40. © 1998 American Cancer Society.
KEYWORDS: nasopharyngeal carcinoma, distant metastasis, weekly, chemotherapy.
N
asopharyngeal carcinoma (NPC) is unique to the head and neck
region. It has several different characteristics among head and
neck malignancies. It is a geographically endemic, Epstein-Barr virus-
636
CANCER August 15, 1998 / Volume 83 / Number 4
associated carcinoma of epidermoid origin and poorly
differentiated or undifferentiated pathology with a
higher incidence of neck lymph node metastasis,
greater radiosensitivity, and greater chemosensitivity.
Treatment primarily is by radiation with more distant
failure and a lower rate of second malignant tumor
occurrence. Radiotherapy is the mainstay of treatment
of NPC, primarily because of anatomic constraints
and a high degree of radiosensitivity. Although early
stage NPC is highly radiocurable, the treatment result
of locoregionally advanced NPC is disappointing. Unfortunately, the majority of NPC patients present with
late stage disease. Lee et al. reported that only 9% of
the 5037 cases collected from the Queen Elizabeth
Hospital in Hong Kong had their tumor confined to
the nasopharynx without clinically involved lymph
nodes.1 The major pattern of failure after adequate
radiotherapy is distant metastasis.1–5 Distant metastasis has been shown to be the most important determinant of survival.5– 8 Although a small percentage of
patients with locoregionally recurrent NPC can be salvaged, nearly all those with distant metastasis die of
the disease in a rapidly progressive course. How to
develop effective therapy for patients with distant metastasis is a great challenge for oncologists. Weekly
chemotherapy is a new schedule of drug delivery that
has become more popular in the treatment of various
cancers in recent years. To date, there is little information regarding the role of systemic chemotherapy
in the management of patients with metastatic NPC.
In October 1992, a prospective Phase II study was
initiated to evaluate the compliance, response, and
toxicities of outpatient, weekly, 24-hour continuous
infusion chemotherapy for NPC patients with distant
metastasis.
PATIENTS AND METHODS
Patients with metastatic NPC were eligible, including
those who 1) had metastatic disease at presentation; 2)
had developed metastatic disease during or at any
time after local radiotherapy; or 3) had developed
progressive disease or recurrence of metastasis after
prior chemotherapy. Other eligibility criteria were 1)
histologic diagnosis of NPC; 2) Karnofsky performance
status . 50%; 3) pretreatment leukocyte count .
3000/mm3 and a platelet count . 100,000/mm3 (except for patients with bone marrow metastases); 4) a
serum creatinine level , 2.0 mg/dL; 5) normal liver
function with total bilirubin , 2.5 mg/dL (unless attributable to hepatic metastasis); 6) minimal 3-week
interval from prior chemotherapy, radiotherapy, or
surgery; and (7) obtaining informed consent.
Treatment Schedule
The weekly chemotherapy was comprised of cisplatin,
25 mg/m2, plus 5-fluorouracil (5-FU), 1250 mg/m2,
mixed in 100 –150 mL of normal saline given by continuous intravenous (i.v.) infusion for 24 hours via a
subcutaneous implanted port, using an ambulatory
pump in an outpatient setting for the first 19 patients.
Because of the low incidence and reduced severity of
toxicity, the dosage was escalated to cisplatin, 33.3
mg/m2, plus 5-FU, 1667 mg/m2, for the remaining 25
cases. A total of 24 doses was planned. Chemotherapy
was administered until documentation of disease progression, patient refusal, or delivery of 24 cycles. The
weekly chemotherapy was delayed if World Health
Organization Grade 3– 4 toxicity developed, and resumed after recovery. Two patients received a 20%
dose reduction because of one patient developing
bone marrow metastasis with pancytopenia and the
other having a past history of chemotherapy-induced
Grade 4 bone marrow toxicity. This dose reduction
was not defined prospectively.
Evaluation of Treatment
Objective responses and toxicity were assessed according to WHO criteria.9 Response evaluation was
planned after every 6 – 8 weeks. The duration of complete response (CR), partial response (PR), and stable
disease (SD) was calculated from the day when these
responses were documented.
RESULTS
Patient Characteristics and Previous Treatment
From October 1992 through June 1996, a total of 44
NPC patients with distant metastasis (14 initial M1
and 30 initial M0 after a disease free interval ranging
from 3– 80 months; median, 12 months) were entered.
Patient characteristics are shown in Table 1. All patients except four were symptomatic. Approximately
half the patients (47.7%) had metastasis documented
pathologically by either resection, biopsy, or fine-needle needle aspiration of the metastatic lesion. Before
weekly chemotherapy, a detailed survey of possible
disease sites was performed. Single organ metastasis
was noted in 26 patients, and 18 patients had multiple
organ metastasis. At the time of initiation of weekly
chemotherapy, locoregional disease existed simultaneously with distant metatasis in 16 patients, either
recurrent or as the initial presentation.
Thirty-three patients had received previous radiotherapy, and 23 patients had been exposed to various
forms of chemotherapy before being entered into this
trial. The preceding radiation therapy was comprised
Weekly Chemotherapy for Metastatic NPC/Lin et al.
TABLE 1
Patient Characteristics
Characteristic
Gender
Male/female
Age (yrs)
Range
Median
Prechemotherapy Karnofsky performance status
90%
80%
70%
60%
50%
Pathology
WHO type 1
WHO type 2
WHO type 3
Previous radiotherapy
Yes
No
Previous chemotherapy
Yes
No
Metastasis proven by biopsy
Yes
No
Associated with locoregional disease
Yes
No
637
Patient Compliance and Actual Dose Delivery
No.
%
36/8
30–72
48
4
9
14
9
8
9.1
20.5
31.8
20.5
18.2
1
32
11
2.3
72.7
25.0
33
11
75.0
25.0
23
21
52.3
47.7
21
23
47.7
52.3
16
28
36.4
63.6
WHO: World Health Organization.
of curative irradiation (18 patients), curative concurrent chemoradiotherapy (13 patients), and palliative
locoregional irradiation (2 patients). Reirradiation was
given to four patients who developed primary and/or
neck recurrence. Palliative radiotherapy for painful
bony metastasis was performed on six patients. Previous chemotherapy was comprised of concurrent chemotherapy during curative locoregional radiotherapy
for 13 patients, and during the second irradiation for 3
recurrent patients with a regimen of cisplatin, 75– 80
mg/m2, on Day 1 plus 5-FU, 400 mg/m2/day, on Days
1– 4, continuous i.v. infusion, monthly for 2 cycles; a
different schedule of systemic chemotherapy for metastatic disease for 6 patients was comprised of a regimen of cisplatin, 100 mg/m2, on Day 1 plus 5-FU,
1000 mg/m2/day, on Days 1–5, continuous i.v. infusion, every 3– 4 weeks (1 patient also received neoadjuvant chemotherapy comprised of bleomycin, epirubicin, and cisplatin before his curative radiotherapy);
in 1 patient postradiation adjuvant chemotherapy was
a regimen of cisplatin, 50 mg/m2, on Day 1 plus 5-FU,
500 mg/m2/day, on Days 1–5, continuous i.v. infusion,
monthly for 2 cycles.
Eighteen of 44 patients completed the planned 24
cycles of weekly chemotherapy. The causes of premature interruption were disease progression (14 patients) and patient refusal (12 patients). The reasons
for patient refusal were the psychologic stress of a
more frequent drug delivery schedule (eight patients),
SD (three patients), and because one patient was a
single elderly veteran without any family support. Although the original design was only 24 cycles of chemotherapy, we continued to treat patients if they so
requested, or when the tumor recurred after treatment
withdrawal. As of March 1997, there were two patients
still receiving treatment. By that time a total of 920
cycles had been delivered to 44 patients, with a median of 19 doses (range, 2– 48 doses).
Tumor Response and Patient Survival
Of 44 patients entered, 38 had measurable lesions for
response evaluation. We observed 8 CR (21.1%) and 12
PR (31.6%) for an overall response rate of 52.7%. Seventeen patients had SD (44.7%), and 1 patient had
progressive disease. The median durations of CR, PR,
and SD were 6.5 months (range, 2–12 months), 5.5
months (range, 2–9 months), and 2.5 months (range,
1– 6 months), respectively. No patients were lost to
follow-up. By May 1997, all patients had disease progression, and only four patients were still alive with
active disease. The median survival for the whole cohort was 9 months (range, 2–25 months); the 1-year
survival rate was 40%.
Toxicity
Acute toxicity was very mild and well tolerated. Some
patients experienced mild anorexia and weakness during the chemotherapy. Nausea and emesis occurred in
only 6 of the 44 patients during treatment, but usually
was mild (less than Grade 2). No patients developed
mucositis except for one who was graded as only
Grade 1. Alopecia was very mild and usually invisible.
Loss of body weight seldom was noted and no diarrhea occurred. Hematologic toxicity was infrequent
and mild. WHO Grade 3– 4 toxicities occurred in 1.0%
of patients for leukopenia, 2.9% of patients for thrombocytopenia, and 4.1% of patients for anemia. They
recovered soon after transient discontinuation of the
chemotherapy infusion.
DISCUSSION
NPC is a common cancer in Taiwan. Although early
stage NPC is highly radiocurable, the cure rate of
radiotherapy alone for advanced NPC is low. The pat-
638
CANCER August 15, 1998 / Volume 83 / Number 4
TABLE 2
Chemotherapy for Metastatic/Recurrent Nasopharyngeal Carcinoma
% outcome for MET/REC
Ref.
Total cases
No. of MET/REC/LA
Regimen
CR
PR
RR
14
19
20
21
22
23
111
24
49
44
21
70
38/6/67
24/0/0
41/8/0
9/14/21
19/2/0
31/39/0
24
25
26
27
28
108
24
35
42
39
44
22/86/0
21/3/0
15/6/14
17/5/20
15/24/0
44/0/0
BEC
Paclitaxel
PBF
FEBP
Low dose protracted F
Various single agent
Combined
Mitoxantrone
PF
PFL
Weekly PFL
PBM, PF, PFL
Weekly PF
20
0
19
35
10
7.5
23.3
5
14
13.3
23.5
20.5
21.1
25
26
60
45
15
17.5
46.7
20
42
67.6
47.1
43.5
31.6
45
26
79
80
25
25
70
25
66
80a
70.6a
64
52.7b
MET: metastatic; Rec: recurrent; LA: locally advanced but nonmetastatic; CR: complete response; PR: partial response; RR: overall response rate; P: cisplatin; B: bleomycin; F: 5-fluorouracil; E: epirubicin; C: cisplatin;
L: leucovorin; M: methotrexate.
a
The response rate was calculated for distant metastasis only.
b
Current study.
terns of failure in the past have been high rates of both
local recurrence and distant metastasis. Because of
recent advances in radiation oncology such as megavoltage radiation, improved immobilization and simulation systems, and precise localization of the tumor
extension by computed tomography scan, the failure
pattern predominantly has changed to distant metastasis.1–5 Distant metastasis has been shown to be the
most important determinant of patient survival.5– 8
How to overcome the problem of distant metastasis
remains an urgent issue.
For symptomatic patients with distant metastasis,
systemic chemotherapy usually is recommended. Although NPC usually is regarded as a chemosensitive
tumor, the cure rate for metastatic NPC is nearly zero,
with a 2-year survival rate , 10%.10 –13 The median
survival is 3– 6 months for untreated patients and 8 –12
months for those treated by chemotherapy. The reports focusing on NPC patients with distant metastasis
are very rare in the literature. The majority of chemotherapy protocols in this setting may originate from
the vast experiences of neoadjuvant chemotherapy for
previously untreated patients with advanced but nonmetastatic NPC.
Cisplatin-based combination chemotherapy, such
as BEC (bleomycin, epirubicin, and cisplatin) or PF
(cisplatin and 5-FU) are the most active regimens for
NPC in the literature. When the BEC regimen was used
as neoadjuvant chemotherapy for patients with non-
metastatic NPC, very high overall response rates
(range, 91–98%) and CR rates (range, 44 – 62%) were
reported.14 –16 Comparably high overall response rates
(range, 81–93.2%) but lower CR rates (range,
19 –20.5%) were observed when PF was given.17,18 Although highly chemoresponsive for previously untreated NPC, the toxicity of cisplatin-based regimens
is moderate and their contribution to survival benefit
remains controversial.
Because of the infrequent occurrence of NPC in
the U.S. and other developed countries, the response and survival outcome of NPC patients with
distant metastasis who receive systemic chemotherapy usually have been reported as part of the collective database of studies of patients with locoregional recurrence or previously untreated, advanced
stage disease. To the best of the our knowledge, so
far there have been no articles published that discuss metastatic NPC alone, with the exception of a
Phase II study from Singapore in the form of a
meeting abstract.19 We reviewed all studies in the
literature containing at least 15 patients with distant
metastasis. The findings are summarized in Table
2.14,19 –28 The response rate ranged from 25– 80%
with a CR rate of between 0 –35%.
Based on a thorough review of the literature, we
believe there is no existing highly effective protocol
for the treatment of metastatic NPC. The CR usually
is , 20%, the duration of response is brief, the
Weekly Chemotherapy for Metastatic NPC/Lin et al.
median survival is approximately 1 year, and the
toxicity usually is higher if a more aggressive combination chemotherapy delivery is attempted. In our
previous experience dealing with metastatic NPC
patients receiving monthly PF chemotherapy, we
noticed high rates of toxicity and poor patient
compliance. Some patients refused further chemotherapy and dropped out of the study after one
to two cycles. We accordingly have changed our
management, and tried to develop a less toxic therapy. We divided the original PF regimen into three
to four weekly doses. The dose intensity was the
same as in a monthly schedule. From our data of
weekly 24-hour infusional PF chemotherapy, we
found a comparable response rate but a marked
reduction in acute toxicity. The outpatient nature of
this treatment and no noted occurrence of alopecia
allowed normal social activity. Regrettably, this regimen produced no long term survivors. The further
escalation of weekly PF dose intensity because of its
very low toxicity or the addition of leucovorin because of its well demonstrated enhancing effect in
combined use may be attempted. Given the brief
response duration of chemotherapy and lack of
overall survival advantage in patients with metastatic NPC, a further option to be considered is
withholding treatment from patients who remain
asymptomatic.
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