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Paclitaxel, Cisplatin, and 5-Fluorouracil for Patients
with Advanced or Recurrent Squamous Cell
Carcinoma of the Head and Neck
Maha Hussain, M.D.1
Shirish Gadgeel, M.D.1
Omer Kucuk, M.D.1
Wei Du, Ph.D.1
Walter Salwen, M.D.2
John Ensley, M.D.1
Division of Hematology/Oncology, Barbara Ann
Karmanos Cancer Institute and Wayne State University, Detroit, Michigan.
Surgical Service, John D. Dingle Veterans Administration Medical Center, Detroit, Michigan.
BACKGROUND. The combination of cisplatin and 5-flurouracil (5-FU) is considered
standard therapy for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Paclitaxel has exhibited single-agent activity
in patients with this disease. The authors conducted this study to evaluate the
feasibility and efficacy of combining paclitaxel with cisplatin and 5-FU for patients
with advanced or recurrent SCCHN.
METHODS. Patients with recurrent, metastatic, or locally advanced SCCHN who
had measurable or evaluable disease and no prior chemotherapy were eligible. The
starting dose level consisted of paclitaxel 135 mg/m2 on Day 1, cisplatin 75 mg/m2
on Day 2, and 5-FU 1gm/m2/day on Days 2– 6. Due to Grade 4 mucositis, dose level
1 of 5-FU was reduced to 800 mg/m2/day on Days 2– 6 (for 7 patients), and
subsequently the 5-FU dose was adjusted to 1 gm/m2/day on Days 2–5 (for 17
RESULTS. Twenty-five patients were enrolled, with a median age of 60 years and a
Presented in part at the 34th annual meeting of the
American Society of Clinical Oncology, Los Angeles, California, May 16 –19, 1998.
Supported in part by a grant from Bristol-Myers
Squibb, Princeton, New Jersey.
Address for reprints: Maha Hussain, M.D., Harper
Hospital, 5 Hudson, 3990, John R, Detroit, MI
Received March 22, 1999; revision received July
27, 1999; accepted July 27, 1999.
© 1999 American Cancer Society
median Southwest Oncology Group performance status of 1. Of the 25 patients, 16
had recurrent disease, 3 had metastatic disease at diagnosis, and 6 had untreated
locally advanced SCCHN. Ninety-nine courses of therapy were administered, with
a median of 5 courses. Major toxicities were neutropenia and mucositis. Significant
neurotoxicity or nephrotoxicity were not observed. There were two treatmentrelated deaths (one each due to mucositis and neutropenic pneumonia), and these
precluded further dose escalation. Fifteen of the 25 patients (60%) achieved a
major response. Of significance is the response rate of 58% (11 of 19 patients) in
those with recurrent or metastatic disease who had a duration of response ranging
from 3 to 191 months. Two of these 19 patients continue to be in remission of 191
and 151 months’ duration, respectively. The median survival for patients with
recurrent or metastatic disease was 6 months (range, 1–26 months), with a 1-year
survival rate of 37%.
CONCLUSIONS. The dose and schedule for the combination of paclitaxel, 5-FU, and
cisplatin as determined in this study are feasible, with encouraging outcomes and
activity in patients with recurrent or metastatic SCCHN. The results of this trial
warrant larger-scale evaluation to determine the role of this combination in the
management of patients with this disease. Cancer 1999;86:2364 –9.
© 1999 American Cancer Society.
KEYWORDS: paclitaxel, cisplatin, 5-fluorouracil, squamous cell carcinoma of the
head and neck.
ead and neck cancer has been an important model for multimodality therapy in which chemotherapy is used as one tool to
promote organ preservation, enhance local control, and reduce systemic relapse. The past few years have witnessed increased investi-
Paclitaxel, Cisplatin, and 5-FU in Advanced SCCHN/Hussain et al.
gation of systemic chemotherapy for patients with
locally advanced disease and its successful application
in the management of laryngeal and nasopharyngeal
cancers, with organ preservation in laryngeal cancer
patients and improved survival of nasopharyngeal
cancer patients documented in randomized trials.1,2
In contrast, little progress has been made in the treatment of patients with recurrent or metastatic disease.
Despite higher response rates reported with combination chemotherapy, the median survival of patients
with recurrent or metastatic squamous cell carcinoma
of the head and neck (SCCHN) is still 6 months.3,4 The
combination of cisplatin and 5-fluorouracil (5-FU) is
considered the standard, with reported response rates
varying from 11% to 80% but without a demonstrable
impact on survival.5– 8
Paclitaxel 250 mg/m2 given as a 24-hour infusion
has demonstrated clinical activity in patients with advanced SCCHN, with a single-agent response rate of
40% (4 complete and 8 partial responses in 30 patients).9 Experimentally, it has been shown that paclitaxel can induce p53-independent apoptosis in tumor
cells;10 this is a noteworthy feature because the majority of head and neck cancers develop p53 mutations.11 In vitro studies indicate sequence-dependent
(synergy) cytotoxicity, with paclitaxel followed by cisplatin resulting in greater antitumor activity,12 making
the combination attractive in the treatment of patients
with a variety of solid tumors, including head and
neck cancer. Paclitaxel dose and schedule continue to
evolve. The cumbersome longer infusion schedules of
paclitaxel have been replaced by shorter infusions.
Plasma concentrations achieved with the different
dosing schedules are capable of inducing relevant biologic cytotoxic effects in vitro.13
The activity of single-agent paclitaxel and its synergy with cisplatin provided the rationale for combining paclitaxel with the combination of 5-FU and cisplatin. We conducted this pilot study in an attempt to
determine the feasibility and efficacy of such a combination in the treatment of patients with advanced or
recurrent SCCHN.
The objectives of this study were to determine the
maximum tolerated dose (MTD) and the quantitative
and qualitative toxicities of the combination of paclitaxel, cisplatin, and 5-FU for patients with advanced
or recurrent SCCHN and to determine the response
and survival rates. Eligible patients were required to
have histologically or cytologically confirmed SCCHN
with one of the following criteria: recurrent or metastatic SCCHN, or nonmetastatic Stage IV disease
deemed incurable by surgery and/or radiation. Pa-
Planned Dose Escalation
Dose level
Paclitaxel (3-hr)
Day 1
Day 2
Days 2–6
5-FU: 5-fluorouracil.
tients with undifferentiated carcinoma of the head
and neck were eligible if they were also deemed incurable with surgery and/or radiation. All patients
were required to have measurable or evaluable disease, a Southwest Oncology Group (SWOG) performance status of 0 –2, a granulocyte count of .1500
and a platelet count of .100,000, bilirubin of ,2
mg/dL %, a creatinine clearance of .60 mL/minute,
and an anticipated life expectancy of at least 12 weeks.
Prior surgery and/or radiotherapy was permitted. Patients were excluded if they had received prior chemotherapy or had clinical evidence of peripheral neuropathy. All patients had to sign an informed consent
form in accordance with Wayne State University institutional review board guidelines.
Study Design and Treatment Plan
The study was designed as a Phase I/II trial, with the
planned dose levels illustrated in Table 1. Patients
were premedicated with oral dexamethasone 20 mg 12
and 6 hours prior to paclitaxel and with 50 mg of
diphenhydramine and 50 mg of ranitidine 30 minutes
prior to paclitaxel. Courses were administered every
21 days. A minimum of 3 patients were required on
each dose level before proceeding to the subsequent
dose level. If 1 instance of Grade 3 or greater nonhematologic toxicity was observed, an additional 3 patients were placed on the same dose level. Dose escalation was terminated if 2 instances of Grade 3 or
greater nonhematologic toxicity were observed at 1
dose level, and the prior dose level was deemed the
MTD. Dose escalation was also to be terminated in the
event of the following: hematologic toxicities, neutropenic fever, or a hemorrhagic episode with a platelet
count of ,50,000 or platelet count below 20,000 with
or without associated hemorrhage. Toxicities were
graded according to National Cancer Institute toxicity
criteria, and standard solid tumor response definitions
were used.
Patients with locoregional disease were to be evaluated after three courses of chemotherapy, and fur-
CANCER December 1, 1999 / Volume 86 / Number 11
Patients Characteristics (n 5 25)
African American
Performance status
0, 1
Disease status
Locally advanced
Primary site
Oral cavity
Unknown primary
Stage of locally advanced
Prior therapy
n 5 16
Surgery 1 radiation
Toxicities (n 5 25)
No. of patients
6, 16
ther management was left to the discretion of the
managing physician. In the absence of progression or
unacceptable toxicity, therapy for patients with recurrent or metastatic SCCHN was continued until complete response was achieved or disease progression
occurred. Patients were considered evaluable for toxicity and response after receiving one course of therapy. All patients registered were included in survival
Statistical Analysis
Treatment response rates were calculated with a 95%
confidence interval. Actuarial survival curves and median survival duration were calculated using the
Kaplan–Meier product-limit method. Overall survival
duration was measured from the date of study entry to
death, and response duration was measured from the
time that the best response was observed to disease
Twenty-five patients were enrolled in the study from
October 1994 to December 1997. Table 2 summarizes
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
the patients’ characteristics. The median age was 60
years (range, 38 –74 years) and the median performance status was 1. Twelve of the 16 patients with
recurrent SCCHN had prior surgery and radiation.
Among the recurrent patients, 14 had only local recurrences, whereas 2 patients had local and systemic
disease on enrollment.
The first patient in the study, who had metastatic
disease at presentation, developed Grade 5 mucositis
during the first course. As a result, 5-FU dose level 1
was reduced by 20% to 800 mg/m2/day on Days 2– 6
(total, 4.0 g/m2). Seven additional patients were
treated at this modified dose, and then the 5-FU dose
was adjusted to 1.0 g/m2/day on Days 2–5 (total, 4.0
gm/m2) for patient convenience. Due to an episode of
neutropenic sepsis leading to the death of Patient 8,
further dose escalation was terminated and the study
was continued at the adjusted dose level to accumulate response and toxicity data. In summary, of the 25
patients, 24 were treated with the following dose and
schedule: paclitaxel at 135 mg/m2 (Day 1), cisplatin 75
mg /m2 (Day 2), and 5-FU at 4 gm/m2 over 5 days (7
patients) and 4 days (17 patients).
A total of 99 cycles were administered, with a median
of 5 (range, 1–10 cycles per patient). Table 3 shows the
highest reported toxicities for all patients. Two patients had treatment-related deaths, one associated
with mucositis (Patient 1) and the other due to neutropenic pneumonia (Patient 8). Both patients who
died had recurrent or metastatic disease. Neutropenia
and mucositis were the major toxicities encountered.
Seven patients (28%) developed Grade 4 neutropenia.
However, except for the patient who died of neutropenic sepsis, no other patients developed infections
associated with neutropenia. None of the patients received growth factors, though this was not specifically
precluded by the study. Grade $3 mucositis was observed in 8 patients (32%) and resolved prior to the
subsequent course except in Patient 1. Significant
Paclitaxel, Cisplatin, and 5-FU in Advanced SCCHN/Hussain et al.
Response (n 5 25)
Disease status
No. of patients
Overall response
Locally advanced
11/19 (58%)
4/6 (66%)
15/25 (60%)
CR: complete response; PR: partial response.
neuropathy or renal toxicities were not observed. One
patient developed mild symptoms of peripheral neuropathy, which resolved after completion of therapy.
No obvious differences in toxicity were noted among
the 7 patients who were treated with 5-FU infusion
over 5 days versus the 17 patients who received the
same dose over 4 days. Overall, patients tolerated the
modified dose fairly well. Thus, we determined the
MTD for this combination to be at the following dosages: paclitaxel 135mg/m2 over 3 hours on Day 1,
cisplatin 75mg/m2 on Day 2, and 5-FU 1gm/m2/ day
as continuous infusion for 4 days (on Days 2–5).
Of the 25 patients, 6 died after 1 course of therapy; 4 of
these 6 had recurrent or metastatic disease and died of
disease progression after the first course. Though response assessment was planned after two courses of
therapy, all patients were included in response analysis. Overall, 10 patients with recurrent disease, one
patient with metastatic disease, and four with locally
advanced disease had a documented major response.
The overall response rate was 60% (Table 4). Among
patients with recurrent or metastatic disease the response rate was 58%, with 4 patients achieving a complete response (21%). Duration of response among
these patients varied from 3 months to 191 months,
with a median response duration of 4.5 months. Five
of the 11 responders were in remission for 7 or more
months, with 2 patients in continued remission at 191
and 151 months at last follow-up. Duration of response for patients with locally advanced disease, all
of whom received further radiation therapy, varied
from 6 months to 15 months, with a median duration
of 9 months.
The median survival for the entire study group was
11months (range, 1–26 months), whereas the median
survival for patients with recurrent or metastatic disease was 6 months (range, 1–26 months). Three patients, all with recurrent or metastatic disease at presentation, are alive at last follow-up, with 2 patients in
FIGURE 1. A Kaplan-Meier survival curve is shown for 19 patients with
recurrent or metastatic squamous cell carcinoma of the head and neck who
received cisplatin, 5-fluorouracil, and paclitaxel.
continuous remission. None of the patients with recurrent or metastatic disease were lost to follow-up.
The 1-year survival rate in this group of patients was
37% (Fig. 1). Among patients with locally advanced
disease, 3 patients have died and 3 patients were lost
to follow-up at varying periods after enrollment.
Locally advanced SCCHNC and recurrent or metastatic diseases are associated with significant morbidity and mortality. Sixty percent of patients with locally
advanced disease have local and/or systemic recurrences.14
Patients with recurrent or metastatic SCCHNC
have a dismal outcome, with a median survival of 6
months and a 1-year survival of 20%.15 Combination
cisplatin and 5-FU first reported from our institute5
has remained the standard for patients with recurrent
and metastatic disease but has failed to exhibit a significant impact on the survival of these patients. Taxanes have exhibited encouraging single-agent activity,9 which has generated interest in combining these
agents with other drugs in an attempt to improve
The primary objective of this study was to determine the MTD and toxicity of the combination of
paclitaxel, cisplatin, and 5-FU. The first dose level
selected was based on Phase I data for the combination of paclitaxel and cisplatin16 and dosages previously used for the combination of cisplatin and 5-FU
in the treatment of patients with SCCHN.5 Phase I data
had suggested that primary toxicities observed with
the combination of cisplatin and paclitaxel were neutropenia and neuropathy. Because infusional 5-FU is
CANCER December 1, 1999 / Volume 86 / Number 11
less likely to cause neutropenia and is not known to
cause neuropathy, we maintained the original 5-FU
dose and used dosages suggested by the Phase I studies for paclitaxel and cisplatin with planned dose escalation. We were unable to escalate the dose as
planned and had to reduce the original 5-FU dose by
20% because severe mucositis was observed in the first
patient. The MTD of this combination was determined
at this modified dose level 1 dose, administered to 24
of the 25 patients on the study. Patients tolerated this
reduced dose well, as suggested by the median number of five courses delivered. Major toxicities encountered were mucositis and neutropenia, with only one
of the patients requiring hospitalization for treatmentrelated toxicities at this reduced dose. Neuropathy was
not observed, in contrast to other reports of the combination of paclitaxel and cisplatin.17,18 This was most
likely related to the relatively lower dose of paclitaxel
used in this study. There were six early deaths, two of
which were associated with treatment-related toxicities. The early deaths of four patients from disease
progression reflects the overall poor prognosis of patients with recurrent SCCHN, added to an overall poor
physiologic condition secondary to concomitant medical problems.
The overall response rate of 60%, with a response
rate of 58%, among patients with recurrent or metastatic disease is encouraging. Higher response rates
have been reported using the combination of cisplatin
and 5-FU, but reported response rates with this combination have varied significantly.5,7 Clinical assessment of response with both physical examination and
radiologic evaluation is known to be difficult in these
patients, which may partly account for the variability
in response rates. Because median survival has not
been significantly impacted despite the high reported
response rates with different combinations, other outcomes, such as the proportion of patients surviving at
1 and 2 years and the response duration, may provide
intermediate surrogates for treatment efficacy in this
difficult clinical setting. We are encouraged by the 1
year survival of 37% among patients with recurrent or
metastatic disease, despite the small number of patients in this study, because historical data suggests
that 1-year survival among these patients is about
Our results are comparable to those in a recent
report from the M. D. Anderson Cancer Center by Shin
et al.19 Paclitaxel was combined with ifosfamide and
cisplatin in 53 patients with recurrent or metastatic
SCCHNC. The response rate was 58% with a duration
of response of 4.9 months, which were very similar to
the results of our study. The median survival of 8.8
months was superior to the median survival associ-
ated with the current combination, but the 1-year
survival rate of 41% was similar. Neutropenia was the
major toxicity observed. The Eastern Cooperative Oncology Group has reported in abstract form a randomized study of 197 patients with eligibility criteria similar to the those of the current study, in which high
dose paclitaxel 200mg/m2 over 24 hours was compared with low dose paclitaxel 135mg/m2 over 24
hours (both in combination with cisplatin).20 The authors reported a dropout rate of 32% due to toxicity.
There were no differences in either response rates or
survival outcomes between the 2 dosages of paclitaxel,
with a 1-year survival of about 30%. The authors concluded that low dose paclitaxel was as active as the
higher dose and that toxicity limited therapy. This
data correlates with our inability to dose escalate this
three-drug combination as originally planned. Bennaso et al. reported results of a Phase I study using the
same combination to treat patients with relapsed or
metastatic SCCHN and found the MTD to be paclitaxel
160mg/m2, cisplatin 75mg/m2 (25mg/m2/day), and
5-FU 750mg/m2 (250mg/m2/day).21
Combination chemotherapy regimens containing
paclitaxel have been studied as induction therapy for
patients with locally advanced SCCHN. Hitt et al.22
reported the preliminary results of a Phase II trial of
the same three-drug combination as an induction regimen for patients with untreated locally advanced
SCCHN. The paclitaxel dose was 175 mg/m2 on Day 1,
cisplatin was 100 mg/m2 on Day 2, and 5-FU was given
at 500 mg/m2/day on Days 2– 6. Major high grade
(Grade 3 and 4) toxicities were neutropenia in 22% in
addition to 2 early deaths, whereas 16% of patients
had Grade 2 neuropathy. Complete and partial response rates at the primary site of 74% and 15%,
respectively, and at the lymph node sites of 76% and
34%, respectively, were reported. Like our observation,
this study indicates that the combination is very active
and feasible. The high complete response rate is a
reflection of the recognized difference in chemosensitivity between untreated versus recurrent or metastatic SCCHN.
In conclusion, the combination of paclitaxel with
cisplatin and 5-FU at the evaluated dosages is feasible.
This combination appears to be active; however, further evaluation in larger studies is needed to confirm
its activity in patients with advanced SCCHN.
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