Annals of Oncology 10: 475-478, 1999.
© 1999 Kluwer Academic Publishers Printed in the Netherlands.
Short report
Paclitaxel and gemcitabine in advanced non-nasopharyngeal
head and neck cancer: A phase II study conducted by the
Hellenic Cooperative Oncology Group
G. Fountzilas,1 G. Stathopoulos,2 C. Nicolaides,3 A. Kalogera-Fountzila,1 H. Kalofonos,4
A. Nikolaou,1 C. Bacoyiannis,5 E. Samantas,6 C. Papadimitriou,7 P. Kosmidis,5
J. Daniilidis1 & N. Pavlidis3
1
'AHEPA'Hospital, Aristotle University oj Thessaloniki, Thessaloniki, 2'Ippokration'Hospital, Athens; 3University of loannina, Ioannina,
RIO'Hospital, University of Patras, Patras; 5'Metaxa'Cancer Hospital, Piraeus; 6Agii Anargyri' Cancer Hospital, Athens;
7
Alexandra'Hospital, Athens, Greece
4
Results: Twenty-four (55%) patients completed all six cycles
of treatment. A total of 205 cycles were administered, 165
Background: Paclitaxel as monotherapy or in combination (81%) of them at full dose. The median relative dose intensity
with other drugs has demonstrated significant activity in pa- (DI) of gemcitabine was 0.93 and of paclitaxel 0.95. Except
tients with squamous cell carcinoma of the head and neck for alopecia, which was universal, grade 3-4 toxicities inregion (SCCHN). Preclinical studies have shown gemcitabine cluded neutropenia (21%), thrombocytopenia (5%), anemia
(5%), infection (5%), flu-like syndrome (5%) and peripheral
to be highly active in SCCHN cell lines.
Purpose of the study; To evaluate the activity and toxicity of neuropathy (2%). Five (11%) patients achieved complete and
the combination of paclitaxel by three-hour infusion and 13 (30%) partial responses, for an overall response rate of
gemcitabine as first-line chemotherapy in patients with recur- 41%. After a median follow-up of 13 months, the median time
to progression was four months and median survival nine
rent and/or metastatic head and neck cancer (HNC).
Patients and methods: From September 1996 until May months.
1998, 44 patients with non-nasopharyngeal recurrent and/or
Conclusions: The combination of paclitaxel and gemcitabine
metastatic HNC entered the study. There were 37 men and is active and well tolerated in patients with recurrent and/or
seven women with a median age of 61 years (range 35-79) and metastatic HNC - randomized studies comparing this combia median performance status of 1 (range 0-2). The location of nation with other regimens are warranted.
the primary tumor in the majority of them was either the
larynx or the oral cavity. Treatment consisted of six cycles of
gemcitabine 1100 mg/m2 over 30 min on days 1 and 8 immediately followed on day 1 by paclitaxel 200 mg/m2 by three-hour Key words: chemotherapy, gemcitabine, head and neck tumors,
infusion. The treatment was repeated every three weeks.
paclitaxel
Summary
Introduction
The prognosis of patients with recurrent or metastatic
head and neck cancer (HNC) is poor. Cisplatin-containing regimens are the most widely used and produce an
overall response rate (ORR) in the range of 30%-35%
[1, 2]. Combination chemotherapy produces higher response rates than single agents but median survival does
not exceed six months in either case [1].
Taxanes in the treatment of HNC have been recently
introduced. Paclitaxel and docetaxel have shown significant activity in patients with SCCHN [3,4]. In a phase II
study [3] conducted by the Eastern Cooperative Oncology Group (ECOG), paclitaxel at a dose of 250 mg/m2
over 24 hours produced an ORR of 40%.
Gemcitabine is a new deoxycytidine analog with
unique activity against a wide range of solid tumors.
Experience with the use of gemcitabine in advanced
HNC is limited. In a phase II trial [5] the drug was given
initially at a dose of 800 mg/m2 on days 1, 8 and 15 every
three weeks in patients who had previously undergone
chemotherapy. In that study the dose was increased to
1250 mg/m2 in chemotherapy-naive patients. The ORR
was 13%.
Results concerning the cytocidal effect of the combination of gemcitabine and paclitaxel in vitro have been
contradictory: less than additive in selected human tumor
cell lines [6] and synergistic in others [7].
Motivated by in vitro data and the need for the identification of effective regimens in patients with HNC, the
Hellenic Cooperative Oncology Group (HeCOG) conducted a phase II study to evaluate the activity and toxicity profile of the combination of paclitaxel and gemcitabine in patients with recurrent or metastatic HNC.
476
Table 1. Patients and tumor characteristics.
Number of patients
Age (in years)
Median
Range
44
61
35-79
Sex
Male
Female
Performance status
0
1
2
Primary site
Oropharynx
Hypopharynx
Larynx
Oral Cavity
Paranasal sinuses
Salivary glands
SCC histologic type
Tumor grade
I
II
III
IV
Unknown
Primary treatment
Induction chemotherapy
RT
Surgery
Site of disease
Locoregional
Primary
Nodes
Skin
Primary and nodes
Distant
Lung
Mediastinal nodes
Locoregional and distant
37
7
12
25
7
4
2
18
15
3
2
44
9
13
14
1
7
The chemotherapy regimen consisted of gemcitabine at a dose 1100
mg/m2 in 500 ml N/S over 30 min on days 1 and 8 immediately
followed on day 1 by paclitaxel at a dose of 200 mg/m2 by three-hour
infusion, with standard premedication. Treatment was repeated every
three weeks. Methyprednisolone 16 mg orally twice daily was prescribed for two days after gemcitabine infusion. Ondansentron was
administered as antiemetic treatment in all cases. Clinical examination, CBC and biochemical analysis were performed on the first day of
each cycle. CBC were repeated on day 8. Examination with imaging
techniques was repeated every two cycles. All imaging material pertinent to tumor response to chemotherapy was scanned (by a scanner
model Mirage II, maximum resolution 9800 x 9800 dpi, UMAX Data
Systems Inc., Hsinchu, Taiwan) and evaluated after completion of the
study by one of the authors (A. Kalogera-Fountzila) and one independent radiologist.
The ANC had to be 5= 1500/ul and the platelet count > 100,000/ul
prior to the beginning of the next treatment cycle. Dose modifications
of paclitaxel have been described in detail previously [8]. G-CSF
(Filgrastim, 5 ug/kg/d) was administered in instances of ANC
<500/ul or of febrile neutropenia. If ANC on day 8 was between 1.01.5 x 109/l then gemcitabine could be administered also with G-CSF to
maintain DI. In such cases G-CSF was given prophylactically in all
subsequent cycles If ANC was less than 1.0 x 1O9/1 then treatment was
postponed for one week. In instances of grades 2 or 3 toxicity the dose
of gemcitabine was reduced by 25% or 50%, respectively, in all subsequent cycles. In case of any grade 4 toxicity the patient was taken off
the study. Toxicity criteria were those adopted from the World Health
Organization. Standard ECOG criteria were used for evaluation of
tumor response. Duration of response, time to progression (TTP) and
survival were calculated as previously described [8].
10
35
15
40
26
29
6
16
8
8
1
7
Results
Compliance with treatment, and toxicity
Twenty-four (55%) patients completed all six cycles of
treatment. Reasons for treatment discontinuation were
progression of the disease in 12 patients, early death in
three (due to the disease, myocardial infarction and nonspecified in one patient, respectively), voluntary withdrawal in two, physician decision in two non-responding
patients and grade 4 neutropenia in one patient.
Patients and methods
A total of 205 cycles were administered, 165 (81%) of
Patients with histologically proven recurrent or metastatic non-naso- them at full dose (Table 2). Except for alopecia, the most
pharyngeal SCC of the head and neck region, aged 3s 18 years with a common grades 3-4 toxicities were neutropenia (21%),
performance status (PS) <2 of the ECOG scale and a life expectancy
thrombocytopenia (5%), anemia (5%), infection (5%),
of > 3 months were eligible for the study. Measurable or evaluable flu-like syndrome (5%) and peripheral neuropathy (2%).
disease outside of preirradiated areas was required for inclusion,
G-CSF was administered in 11 patients at some time on
unless a subsequent progression of the lesion had been documented.
Previous chemotherapy prior to or concomitantly with radiation was trial because of neutropenia, red blood cell transfusions
allowed, if administered ;& I year before entry in the study. All patients in eight, platelet transfusion in one and antibiotics in
should have had leukocyte and platelet counts greater than 4000/ul
seven patients for febrile neutropenia (two patients),
and 100,000/ul, respectively, serum creatinine concentration less than
infection (two) and local inflammation (three).
0.3 mg/dl above the institutional upper limit of normal and normal
total and direct bilirubin levels.
A detailed informed consent was obtained from all patients before
their entry into the study. The protocol was approved by the Protocol
Review Committee (PRC) of HeCOG and by the Ethics Committees
of all participating institutions.
Pretreatment evaluation included a complete medical history,
clinical examination, EKG, complete blood count (CBC), complete
biochemistry survey, chest X-ray, bone scan and computed tomography (CT) scan, as indicated.
From September 1996 until May 1998, 44 patients entered the
study. Selected patient and tumor characteristics are listed in Table 1.
Best response and survival
In four patients response could not be assessed because
three of them died prior to first evaluation of tumor
response and one decided to stop treatment after the
second cycle.
Five patients (11%, 95% CI: 4%-25%), all of them
with locoregional relapse (primary in three patients,
nodes in four and skin in one patients), achieved CR
477
Table 2. Selected treatment characteristics.
Number of cycles per patient
Total number of cycles
Number of cycles at full dose
Number of cycles with a delay
Delay on day 1
Delay on day 8
Interruption on day 8
DI of paclitaxel
Planned
Delivered
Median
Range
Relative DI of paclitaxel
Median
Range
DI of gemcitabine
Planned
Delivered
Median
Range
Relative DI of gemcitabine
Median
Range
Number of
cycles
Number of
patients
1
2
3
4
5
>6
3
5
5
5
2
24
205
165
61
35
32
7
66.6
63
39-73
0.95
0.6-1.1
733
683
314-788
0.93
0.4-1.1
Dl-dose intensity (mg/m 2 /week).
In the present study we used slightly higher doses
than in the previous study in order to maximize activity
without compromising the DI of the two drugs. The
response rate of 41% reported here is interesting. In our
previous study in such patients, using the combination
of paclitaxel and carboplatin, we reported an ORR of
only 23% [10], which could be partially attributable to
patient selection.
Except for alopecia the grade 3-4 side effect most
frequently seen was neutropenia, observed in one-fifth
of our patients. Phase I studies [reviewed in Ref. 11], with
the combination of paclitaxel and gemcitabine have
repeatedly shown the principal dose-limiting toxicity to
be grade 4 neutropenia. Even though episodes of sepsis
are infrequently seen with this combination, probably
because of the transient nature of the neutropenia, the
prophylactic use of G-CSF may be necessary in order to
maintain DI. Androulakis et al. [12], administering, as
second-line treatment in patients with NSCLC, the
combination of gemcitabine 900 mg/m2 on days 1 and 8
and paclitaxel 175 mg/m2 over three hours on day 8,
with the prophylactic use of G-CSF, every three weeks,
reported that grades 3-4 neutropenia occurred in only
2 of 26 (8%) patients. The incidence of grades 2-3
peripheral neuropathy reported in this study - higher
than in ours (32% vs. 16%) - is probably due to the fact
that in the latter study twice as many patients had
previously received cisplatin-based chemotherapy.
In conclusion, the combination of paclitaxel and
gemcitabine is active and well tolerated in patients with
recurrent and/or metastatic HNC and deserves further
exploration in randomized studies.
and 13 (30%, 95% CI: 17%-45%) PR, for an overall
response rate (ORR) of 41% (95% CI: 26%-57%). The
five CRs lasted for 20.5, 24, 38, 43+ and 55 weeks.
Furthermore, 14 patients (32%, 95% CI: 19%-48%)
References
demonstrated stabilization of the disease. Median duration of response was eight months. As of 15 October
1. Vokes EE, Athanasiadis I. Chemotherapy for squamous cell
1998, after a median follow-up of 13 months (range 0.7carcinoma of head and neck. The future is now. Ann Oncol 1996;
7: 15-29.
21+) 36 patients (82%) had demonstrated disease pro2. Jacobs C, Lyman G, Velez-Garcia E, Sridhar K.S et al. A phase 111
gression and 23 (52%) had died. Median TTP was four
randomized study comparing cisplatin and fluorouracil as single
months (range 0.8-19+) and median survival nine months
agents and in combination for advanced squamous cell carci(range 0.7-21+). Ten patients were treated with addinoma or the head and neck. J Clin Oncol 1992; 10: 257-63.
tional chemotherapy after they had progressed. Among
3. Forastiere AA, Shank D, Neuberg D et al. Final report of a phase
II evaluation of paclitaxel in patients with advanced squamous
10 patients who received induction chemotherapy there
cell carcinoma of the head and neck: An Eastern Cooperative
were two CRs and one PR. Six of eight partial responders
Oncology Group Trial (PA 390). Cancer 1998; 82: 2270-4.
demonstrated PR of the primary tumor within a pre4. Catimel G, Verweij J, Mattijssen Vet al. Docetaxel (Taxotere): An
irradiated area. Responses were seen in all metastatic
active drug of the treatment of patients with advanced squamous
sites except bone.
cell carcinoma of the head and neck. Ann Oncol 1994; 5: 533-7.
Discussion
The optimal dose of paclitaxel in combination with
gemcitabine has not yet been defined. In a phase I study
[9] in patients with ovarian cancer, in which gemcitabine
and paclitaxel was delivered every three weeks in a
manner similar to that used in our study, the maximum
tolerable dose of gemcitabine was 1 g/m2 on days 1 and 8
and of paclitaxel 175 mg/m2 on day 8.
5. Catimel G, Vermorken JB, Clavel M et al. A phase II study of
gemcitabine (LY 188011) in patients with advanced squamous cell
carcinoma of the head and neck. Ann Oncol 1994; 5: 543-7.
6. Theodossiou C, Cook JA, Fisher J et al. Interaction of gemcitabine with paclitaxel and cisplatin in human tumor cell lines. Int J
Oncol 1998; 12: 825-32.
7. Jensen PB, Holm B, Sorensen M. In vitro cross resistance and
collateral sensitivity in seven resistant small-cell lung cancer cell
lines. Preclinical identification of suitable drug partners to Taxotere, topotecan and gemcitabine Br J Cancer 1997; 75: 869-77.
8. Fountzilas G, Papadimitriou V, Bafaloukos D et al. Paclitaxel and
carboplatin as first-line chemotherapy for advanced breast cancer. Oncology 1998; 12 (Suppl 1): 45-8.
478
9. Poole CJ, Perren T, Hogberg Tet al. Phase I study to investigate
alternate sequencing of the combination of gemcitabine and
paclitaxel in ovarian carcinoma. Eur J Cancer 1997: 33 (Suppl 8):
SI 21 (Abstr).
10. Fountzilas G, Skarlos D, Athanassiadis A et al. Paclitaxel by
three-hour infusion and carboplatin in advanced carcinoma of
nasopharynx and other sites of the head and neck. A phase II
study. Ann Oncol 1997; 8: 451-5.
11. Dombernowsky P, Giaccone G, Sandier A et al. Gemcitabine and
paclitaxel combinations in non-small-cell lung cancer. Semin
Oncol 1998; 25: 44-50.
12. Androulakis N, Kouroussis C, Kakolyris S et al. Salvage
treatment with paclitaxel and gemcitabine for patients with non-
small-cell lung cancer after cisplatin-or docetaxel-based chemotherapy A multicenter phase II study. 1998; 9: 1127-30.
Received 23 November 1998; accepted 2 February 1999.
Correspondence to:
George Fountzilas, MD
1st Department of Internal Medicine
Oncology Section
AHEPA Hospital
Aristotle University of Thessaloniki
Thessaloniki, Macedonia
Greece