Docetaxel, cisplatin and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer: a phase I–II feasibility study

D. Schrijvers1, C. Van Herpen2, J. Kerger3, E. Joosens4, C. Van Laer1, A. Awada3, D. Van den Weyngaert4, H. Nguyen3, C. Le Bouder5, J. A. Castelijns6, J. Kaanders2, P. De Mulder2 and J. B. Vermorken1,*

1 University Hospital Antwerp, Edegem, Belgium; 2 University Medical Center, Nijmegen, The Netherlands; 3 Institut Jules Bordet, Brussels Belgium; 4 Algemeen Ziekenhuis Middelheim, Antwerp, Belgium; 5 Aventis, Pharma, France, Paris; 6 Free University Medical Center, Amsterdam, The Netherlands

Received 17 June 2003; revised 27 December 2003; accepted 31 December 2003


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Purpose:

To determine the safety profile and activity of the combination of docetaxel, cisplatin and 5-fluorouracil (5-FU) in chemotherapy-naive patients with squamous cell carcinoma of the head and neck (SCCHN).

Patients and methods:

Patients with locally advanced unresectable SCCHN were treated with docetaxel and cisplatin both as a 1-h infusion on day 1 followed by a continuous infusion of 5-FU for 5 days. Cycles were planned every 3 weeks up to four cycles, whereafter the patients were treated with locoregional radiotherapy. Two dose levels were studied. Doses in level I were 75 mg/m2 of docetaxel, 75 mg/m2 of cisplatin and 750 mg/m2/day of 5-FU; in level II the cisplatin dose was escalated to 100 mg/m2. Following chemotherapy, all patients were to receive curative radiotherapy according to the standards in the different institutions.

Results:

Twenty-five patients were treated at dose level I with 86 cycles (median four; range one to four), and 23 at dose level II with 84 cycles (median four; range two to four). The median relative dose intensity was 0.99 (range 0.86–1.04) at level I and 0.94 (range 0.79–1.02) at level II. The response rate in the intention-to-treat population was 64% [95% confidence interval (CI) 42.5% to 82%] in level I and 78.3% (95% CI 56.3% to 92.5%) in level II; all were partial responses. The maximum tolerated dose was reached at level II with renal toxicity, nausea, stomatitis and thrombocytopenia as principal dose-limiting toxicities. The median survival of the 48 patients was 18.5 months. The survival at 12, 18, 24 and 30 months was 69, 54, 41 and 31%, respectively.

Conclusions:

The combination of docetaxel, cisplatin and 5-FU associated with prophylactic ciprofloxacin is feasible and active in patients with SCCHN. Dose level I is recommended for phase III testing.

Key words: cisplatin, combination chemotherapy, docetaxel, 5-FU, head and neck cancer, phase I-II


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The prognosis of patients with locally advanced head and neck cancer remains dismal, and new approaches are necessary to improve the outcome of these patients. The development of newer agents and the integration of these agents in the primary treatment with locally advanced disease is an important area of research.

In the locally advanced disease setting induction chemotherapy leads to high response rates, can quickly reduce symptoms, may predict subsequent radioresponsiveness and can lead to a reduced rate of distant metastases as first site of relapse, but does not seem to have much impact on locoregional control or survival [1]. Even though induction chemotherapy may not improve cure rates, its ability to achieve high response rates serves another purpose, that of organ preservation [2, 3]. The combination that has most often been used in patients with resectable and unresectable locally advanced disease is cisplatin and infusional fluorouracil (PF) [4]. In large randomized trials, response rates have varied between 75% and 85%, with 25% to 35% of patients showing a complete response (CR) [2, 3, 5, 6]. Only a subset analysis in one of the several well conducted randomized trials evaluating this PF regimen suggested a survival advantage for patients with unresectable disease [5]. It is also the only trial in which four cycles instead of the usual three cycles of induction chemotherapy was given.

Several new agents with activity against squamous cell carcinoma of the head and neck (SCCHN) have been introduced into the clinic in the 1990s, including paclitaxel, docetaxel, ifosfamide, vinorelbine, topotecan and gemcitabine [7]. Among these agents the taxoid docetaxel showed significant antitumor effects in vitro against different human tumor cell lines, and on a concentration basis was more cytotoxic in the majority of human primary tumor specimens than paclitaxel [8]. Docetaxel is active against squamous cell carcinoma of the head and neck xenografts, and in that setting also showed activity in cell lines less sensitive to cisplatin, indicating that no cross-resistance exists [9, 10]. What is even more important with reference to the PF regimen is the fact that preclinical models showed a potential synergy between docetaxel and cisplatin and 5-fluorouracil (5-FU), respectively [11]. Several phase II studies have studied single-agent activity of docetaxel in patients with recurrent and metastatic SCCHN [1215]. In these studies, most of them using a dose of 100 mg/m2 intravenously, once every 3 weeks, response rates varied from 21% to 42%. Main toxicity was neutropenia, which was rarely complicated by fever. Other toxicities observed were alopecia, fatigue, anorexia, stomatitis, diarrhea, peripheral neuropathy and fluid retention. However, these latter toxicities occurred in only a minority of patients, and the drug was generally considered to be well tolerated.

European and American investigators have studied the combination of docetaxel and cisplatin in six phase II studies [1621], mostly in the recurrent or metastatic setting. In five studies, docetaxel was given at a dose of 75–80 mg/m2 and combined with cisplatin at doses of either 70–75 mg/m2 (four studies) or 100 mg/m2 (one study). Response rates ranged from 33% to 86%, depending on patient and tumor characteristics, and amount of prior treatment. The treatment was generally considered as feasible, although several patients had to stop treatment early because of toxicity. Toxic deaths were mentioned in several of these studies, and the most frequently occurring toxicity was grade 3–4 neutropenia. In the sixth study, 46 patients with mainly unresectable locally advanced SCCHN were treated with three courses of docetaxel 75 mg/m2 and cisplatin 100 mg/m2. The overall response rate was 46% [95% confidence interval (CI) 31% to 60%] and the CR rate was 11%. After radiotherapy, nine of 21 evaluable patients were rendered disease-free. Median survival was 11 months. Toxicity was substantial. Six early deaths were considered to be possibly treatment-related, and diarrhea and vomiting were the most troublesome non-hematological toxicities [21]

European investigators also studied the combination of docetaxel and 5-FU [2224] and performed a phase I study on the combination of docetaxel with cisplatin and 5-FU (TPF).

In the study reported by Fillipi et al. [22], 44 patients with recurrent or metastatic head and neck cancer received a dose of 75 mg/m2 of docetaxel on day 1 (given over 1 h) and then 5-FU at a dose of 1000 mg/m2/day for five consecutive days by continuous intravenous infusion. This was repeated every 4 weeks. Because of neutropenic fever and mucositis, the dose of 5-FU had to be reduced to 750 mg/m2/day, but the overall response rate was an acceptable 34% [22]. The feasibility of this 5-day continuous infusion schedule of 5-FU was confirmed by Biakhov et al. [23] and Van Den Neste et al. [24].

Finally, the above-mentioned phase I study was performed in patients with variable solid tumors, indicating that a dose of 75 mg/m2 of docetaxel could be combined with 75 or 100 mg/m2 of cisplatin and 750 mg/m2/day of 5-FU for five consecutive days in a tolerable regimen (J. Kerger, personal communication).

Studies performed at the Dana Farber Institute showed tremendous activity when the three drugs were combined with leucovorin and given to patients with untreated locally advanced SCCHN. The first study, with the so-called TPFL-5 regimen, which included different doses of docetaxel (25, 45 and 60 mg/m2), with 5 days of continuous infusion of cisplatin (25 mg/m2/day) and leucovorin (500 mg/m2/day) and 4 days of 5-FU (700 mg/m2/day), induced 100% responses (61% CRs) in 23 patients [25]. However, toxicity was dramatic, with febrile neutropenia, mucositis, diarrhea and sodium-wasting nephropathy being dose-limiting and frequently leading to hospitalization. A 4-day regimen of the same drugs (TPFL-4), studied by the same investigators, showed similar activity (overall response rate 93%, CR rate 63%) but with fewer complications, at least in patients with a good performance status [26]. Both TPLF-5 and TPFL-4 were given at 4-week intervals.

Based on the above-mentioned observations and the suggestion that, with an adequate number of induction chemotherapy cycles, survival benefit could be obtained in patients with inoperable disease, as shown by Paccagnella et al. [5], we initiated a phase I–II study with the three drugs in such patients. The main objectives of this study were to determine the tolerability of the combination of docetaxel with cisplatin and 5-FU in patients with locally advanced unresectable SCCHN when given for four cycles before definitive radiotherapy, to test its efficacy and to study its safety profile.

This phase I–II study was also performed to recommend a safe dose of this regimen to be used for further phase III studies in a multicenter setting.


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
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This multinational, multicenter, non-blinded, non-randomized, phase I–II study was carried out in three centers in Belgium (Institut Jules Bordet, University Hospital Antwerp, Algemeen Ziekenhuis Middelheim) and one in The Netherlands (University Medical Center Nijmegen). The local ethics committees of each of the participating centers approved the study protocol.

Patient selection
In order to be considered eligible for the study, patients had to have measurable, histologically or cytologically confirmed, unresectable stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx without distant metastases, and had to be willing to sign the informed consent. A team consisting of a head and neck surgeon, a radiotherapist and a medical oncologist made a judgement beforehand of the unresectability of the disease. Disease was considered to be unresectable if the possibility of a complete resection with pathological free resection margins (R0) was low. In addition, patients with high volume disease who were potential candidates for larynx preservation trials were excluded from the study. Patients also could not have had previous treatment with chemotherapy, radiotherapy or surgery.

Patients were to have a good performance status (WHO 0 or 1), be ≥18 and ≤70 years of age, and have an anticipated life expectancy of at least 12 weeks. The bone marrow, liver and renal function had to be within predefined limits [absolute neutrophil count ≥2 x 109/l; platelet count ≥100 x 109/l; total bilirubin within normal limits; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5x the upper normal limit (UNL) when associated with alkaline phosphatase (AP) >2.5x the UNL, otherwise the cut-off levels were ≤2.5x UNL for AST and ALT and ≤5x UNL for AP separately; serum creatinine ≤120 µmol/l and creatinine clearance ≥60 ml/min, as calculated by the Cockroft–Gault formula].

Pregnant and lactating women were excluded, as well as fertile women, unless they used adequate contraceptives or barrier methods. Other reasons for exclusion were the presence of prior malignancies other than adequately treated non-melanoma skin cancer or excised cervical carcinoma in situ within 5 years, known intracerebral or leptomeningeal metastases, peripheral neuropathy grade ≥2 by the National Cancer Institute Common Toxicity Criteria (NCI CTC), disturbed mental conditions, congestive heart disease or angina, uncontrolled hypertension, arrhythmias, myocardial infarction within 6 months, active infection, active peptic ulcer disease, uncontrolled diabetes mellitus or other contraindications for the use of corticosteroids. Patients with clinical hearing loss, treatment with another investigational drug within 30 days prior to study entry and patients treated with corticosteroids during the last 6 months or at a high dose (≥20 mg of prednisone or equivalent) were also excluded.

Evaluation and registration
The patients were screened for eligibility. A physical examination, blood analysis (blood cell count, hepatic and renal parameters), urinalysis, radiology [chest X-ray, computed tomography (CT) scans of disease localization] and electrocardiography were carried out. After signing the written informed consent form, patients were registered at a central office.

Treatment schedule
The patients were treated at two dose levels. At dose level I, they received docetaxel 75 mg/m2 followed by cisplatin 75 mg/m2, both as a 1-h infusion, on day 1, followed by 5-FU 750 mg/m2/day as a 5-day continuous intravenous infusion. Chemotherapy was planned to be given every 3 weeks for a maximum of four cycles, but was expected to be less in case of disease progression, unacceptable toxicity or patient refusal. Thereafter, locoregional treatment (radiotherapy ± surgery) was given.

The patients at dose level II received the same treatment, except the dose of cisplatin was increased to 100 mg/m2. No dose escalation was allowed within the same patient.

All patients were pretreated with oral dexamethasone 8 mg every 12 h for a total of six doses, starting the evening before the administration of chemotherapy. Antiemetics were used at the discretion of the physician, but the use of a 5-hydroxytryptamine-3 antagonist followed by a dopamine antagonist was recommended. Each center had a standard regimen.

No prophylactic support of hematological growth factors was allowed. However, after the first 24 patients had been entered, all subsequent patients received oral prophylactic antibiotic therapy (ciprofloxacin 500 mg twice a day for 10 days, starting at day 5).

Dose modifications were planned in case of acute hypersensitivity reactions, hematologic toxicity, cutaneous reactions, liver toxicity, edema, renal dysfunction, neurotoxicity, hearing loss, mucositis or diarrhea. No dose modifications were planned in the event of nausea and vomiting.

Dose modification of docetaxel
If on day 21 the neutrophil count was <1.5 x 109/l, treatment had to be postponed for 1 week. If the treatment had to be delayed for >2 weeks, the patient went off study. In case of a neutrophil nadir <0.5 x 109/l, which persisted for >7 days or was accompanied by fever lasting for >3 days, the dose of docetaxel had to be decreased from 75 to 60 mg/m2.

If a grade 3 cutaneous reaction according to the NCI CTC occurred, treatment was to be delayed until grade ≤1 and the patient was retreated at 60 mg/m2 of docetaxel. Without a recovery of toxicity to grade <1 within 2 weeks, or in case of grade 4 toxicity, docetaxel was stopped.

If a grade 2 impairment of liver function occurred, the dose of docetaxel was decreased to 60 mg/m2; in case of a grade 3 impairment of >2 weeks, the patient was taken off protocol.

In case of localized or generalized edema, no dose reduction was planned. In case of symptomatic effusions, a paracentesis was allowed.

Dose modification of cisplatin
If the creatinine clearance, calculated according to the Cockcroft–Gault formula, was between 40 and 59 ml/min, the dose of cisplatin had to be reduced by 50% in the subsequent cycle; if the creatinine clearance was <40 ml/min, cisplatin was withheld for that cycle.

In case of grade 2 peripheral neuropathy, the dose of cisplatin had to be decreased by 20%; in case of grade 3 toxicity, the patient had to go off protocol. If hearing loss grade >2 occurred, the patient also had to go off protocol.

Dose modification of 5-FU
In case of grade 3 stomatitis, the dose of 5-FU had to be reduced by 20%; in case of grade 4 mucositis patients went off protocol.

In case of persistent diarrhea grade ≥3, the dose of 5-FU had to be reduced by 20%.

When other grade 3 or 4 side effects occurred, treatment was delayed until recovery to grade 1 and reinstituted at the discretion of the investigator.

Calculation of dose intensity
The relative dose intensity was calculated as the ratio of the actual dose intensity (mg/m2/week) to the planned dose intensity (mg/m2/week). The combined relative dose intensity was the average of the ‘by compound’ relative dose intensity.

Evaluation of toxicity and tumor response
Toxicity evaluation was carried out according to the NCI CTC scale. The Costart classification was used for reporting adverse events not described in the NCI CTC scale.

Dose-limiting toxicity was defined as grade 4 neutropenia for >7 days or grade 3 or 4 neutropenia with concomitant fever lasting >3 days; grade 4 thrombocytopenia; grade 3 or 4 infections; grade 4 vomiting despite prophylactic antiemetic treatment, and all other grade ≥3 non-hematological toxicity (excluding nausea).

The maximum tolerated dose was defined as the dose level at which three out of six patients developed the same dose-limiting toxicity.

It was planned to enter at least six patients at dose level I, and if the maximum tolerated dose had not been reached, the study proceeded to dose level II. Thereafter patients were entered at random in both dose levels.

Response to chemotherapy was evaluated according to modified WHO criteria.

All patients who received a minimum of two cycles were evaluable for response if all baseline lesions were assessed at least once after the second cycle using the same method as used at baseline. Patients with progression earlier than cycle 2 were classified as ‘early progression’. Since radiotherapy was started as soon as possible after the end of chemotherapy, some responses were not confirmed 4 weeks after final response assessment.

An independent review panel of radiologists evaluated the radiological images of the primary tumor and/or cervical lymph node metastases in all patients with measurable disease.

Time to progression, duration of response and survival time were calculated from the first day of treatment.

Statistical analysis
Statistical analysis was carried out on UNIX with SAS software, version 6.12. Descriptive statistics were tabulated by initial planned dose level and overall. The 95% CIs for proportions were calculated with the exact method. The Kaplan–Meier method was used to analyze variables associating duration and an event with possible censoring.

Groups were compared by {chi}2-test analysis and means by Student’s t-test.


    Results
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 Introduction
 Patients and methods
 Results
 Discussion
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Patients
Forty-eight patients were recruited between 3 September 1997 and 29 December 1998: 25 in level I and 23 in level II. All patients were treated and evaluable for safety. Patient and disease characteristics at baseline are given in Table 1.


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Table 1. Patient and disease characteristics at baseline
 
Four patients in level I and one in level II had minor deviations of all eligibility criteria, but were included in the analysis: two had a previously cured cancer (bladder cancer, tongue cancer), one had a slightly decreased renal function (creatinine clearance of 51 ml/min), one (level II) had no measurable lesion on CT scan, as judged retrospectively by the radiologists, and one had a slightly increased bilirubin level.

There were no differences in patient and disease characteristics between the two dose levels at baseline.

Treatment
At dose level I, 17 patients completed treatment; three patients stopped treatment due to progressive disease (one after two and two after three cycles); two patients went off treatment due to an adverse event [one due to asthenia after two cycles and one due to a cytomegalovirus (CMV) colitis after one cycle]; one patient withdrew his consent (after three cycles), one patient died due to an infectious complication after two cycles, and one patient stopped after two cycles with stable disease by the decision of the investigator and was treated with radiotherapy.

At dose level I, 79 out of 86 cycles were given without dose modification. The dose of docetaxel was reduced to 60 mg/m2 in one patient due to elevation of transaminases in cycle 2, but was re-escalated in the subsequent two cycles. Cisplatin was reduced in one patient due to nephrotoxicity and neurotoxicity, and 5-FU was reduced in three patients for stomatitis. There was no treatment delay in 84 cycles, while two cycles were delayed due to renal dysfunction and asthenia. The median number of cycles was four (range one to four). The median combined relative dose intensity was 0.99 (range 0.86–1.04).

At dose level II, 17 patients completed treatment, two had progressive disease after two cycles, one patient stopped due to an adverse event (hearing loss) after three cycles and one patient died due to an infectious complication after four cycles. Two patients withdraw their consent (one after three and one after two cycles).

At level II, 64 out of 84 cycles were given as planned. The dose of docetaxel was reduced in four patients. Reasons for reduction of docetaxel were allergic reactions, stomatitis, renal insufficiency and fever. Cisplatin was reduced in three patients as a result of renal toxicity. 5-FU was reduced due to stomatitis in four patients.

There were no treatment delays in 73 cycles, while 11 cycles were postponed for the following reasons: renal toxicity, nausea, stomatitis or thrombosis. The median number of cycles was four (range two to four). The median combined relative dose intensity was 0.94 (range 0.79–1.02).

After chemotherapy, 23 of 25 (92%) patients in level I and 21 of 23 (91%) patients in level II were treated with radiotherapy. In level I, 16 patients received radiotherapy with conventional fractionation, six with accelerated fractionation and one with both fractionation schemes. In level II, 10 patients were irradiated with conventional fractionation and 11 received accelerated radiotherapy.

Irradiation had to be temporarily interrupted in one of 23 patients at dose level I due to an infection (pneumonia and CMV colitis), and in four of 21 patients at dose level II due to toxicity in two patients (skin and not specified), refusal in one and worsening of the general condition in another.

Radiation had to be definitively stopped early in two of 23 patients in level I as the result of skin toxicity, with the development of a fistula in the first and a CMV colitis in the second. Two of 21 patients in level II stopped radiotherapy, both due to patient refusal.

Efficacy results
Table 2 summarizes the response data based on the independent radiological review data. The response in dose level II was somewhat higher than in dose level I. However, this difference is not statistically different, as suggested by the overlapping CIs.


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Table 2. Response rate in the intention-to-treat population
 
After a median follow-up of 36 months, median survival for all patients was 18.7 months (95% CI 13.3–25.6). The overall survival at 12, 18, 24 and 36 months was 68.8, 53.8, 40.9 and 31.1%, respectively (see Figure 1).



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Figure 1. Overall survival in all patients.

 
Toxicity
All patients were evaluable for toxicity. It is of note that after the first eight patients were treated at dose level I and the maximum tolerated dose had not been reached, the study proceeded to dose level II. Thereafter, patients were entered at random in both dose levels.

The worst grade hematological and non-hematological toxicities per patient according to the NCI CTC are summarized in Table 3.


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Table 3. Number of patients with worst NCI CTC grade/Costart classified adverse events possibly or probably related to the study treatment
 
Anemia occurred in most patients (93.8%), but did not seem to be different at the two dose levels. Leukopenia was observed more often and was more severe at dose level II than dose level I. Grade 4 neutropenia was observed in 78% of patients at dose level II versus 64% at dose level I. Grade 3 or 4 thrombocytopenia was mainly observed in patients at dose level II: 23% had grade 3 thrombocytopenia in level II, while only one patient had a grade 4 toxicity in level I (25% of 79 evaluable cycles in dose level II versus 13% of 85 evaluable cycles in dose level I).

The incidence of diarrhea (70% versus 48%), stomatitis (65% versus 48%), nausea (83% versus 64%) and vomiting (70% versus 36%) was higher in dose level II than in dose level I, respectively. Grade 3–4 non-hematological toxicities did not occur frequently at either dose level, except for stomatitis: this was observed in >20% of patients treated at dose level II, and only in 12% of those treated at dose level I.

Ciprofloxacin was given routinely after inclusion of the first 24 patients. At the time this protocol amendment became operational, most patients of dose level I had been entered, explaining why ciprofloxacin was given only in 43% of 86 treatment cycles in level I and 70% in level II. Before the introduction of ciprofloxacin, febrile neutropenia occurred in 4% and 12% of cycles in dose levels I and II, respectively. After the introduction of ciprofloxacin, these figures were 0% and 5%, respectively, clearly illustrating its positive effect.

A total of seven patients experienced nephrotoxicity: one at dose level I and six at dose level II. Two patients at dose level II developed moderate acute renal failure. Abnormalities in kidney function was reported in one patient at level I (mild) and four patients at level II (one mild, three moderate).

Two patients died within 30 days after the last infusion. One patient from dose level I developed, on day 2 of cycle 2, an acute, life-threatening stridor that led to tracheotomy and to early termination of the cycle. The patient developed pneumonia and died 2 weeks later due to sepsis and pneumonitis, possibly related to the study treatment. The second patient, treated at dose level II, was found dead at home on day 14. Autopsy revealed a bronchopneumonia and suggested that the patient had suffered of septicemia. The infections were considered probably related to the study treatment.


    Discussion
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The present study was an extension of a phase I study in patients with locally advanced inoperable SCCHN to further optimize the schedule for further use in a phase III study. Two different dose levels were studied, differing only in the cisplatin dose.

The administration of this combination was indeed feasible, and 68% of patients in level I and 74% in level II received all four cycles. The combined relative dose intensity was 0.99 in level I and 0.94 in level II. This higher combined relative dose intensity in level I indicates that more dose reductions or delay were necessary at dose level II than at dose level I.

During the first phase of the study, infections and infections without an infectious focus occurred in 9% and 12% of cycles, respectively. In addition, febrile neutropenia was reported in 4% and 8% of cycles at dose levels I and II, respectively.

This high rate of infectious complications led to the use of prophylactic treatment with ciprofloxacin. After treatment with ciprofloxacin, all infectious complications decreased: infection to 4%, and infection without a focus to 3%, of cycles, and febrile neutropenia decreased to 0% and 5% at dose levels I and II, respectively. Therefore, this prophylactic treatment is indicated in further studies with this regimen.

The incidence of adverse reactions was higher in patients treated at dose level II compared with those treated at dose level I. The incidence of grade 3 and 4 toxicity was higher in level II for nausea (13% versus 8%), stomatitis (22% versus 12%) and thrombocytopenia (22% versus 4%). The incidence of these dose-limiting toxicities did not allow us to formally conclude that the maximum tolerated dose was reached; however, the combination of several serious toxicities and six cases of renal dysfunction at dose level II that led to the decision to recommend dose level I for further studies.

The response rate in our study population was 71% (0% CRs), which is lower than that reported by other authors using a similar combination of drugs with or without the addition of leucovorin.

Colevas et al. [25, 26] reported response rates of 100% (61% CRs) with the TPFL-5 regimen and of 93% (63% CRs) with the TPFL-4 regimen. Recently, the same group also reported on an outpatient TPFL regimen, in which the 5-FU and leucovorin were again given over 4 days [27]. The overall response rate with the latter regimen was 94%, with 44% CRs.

Posner et al. [28] treated 43 patients with SCCHN with docetaxel 75 mg/m2 on day 1, 5-FU 1000 mg/m2/day for 4 days, and cisplatin in doses of either 75 or 100 mg/m2/day on day 1, every 3 weeks for three cycles. They were able to administer the higher cisplatin dose without serious complications, although the higher dose level induced more neutropenia and renal problems. The response rate in that study was 93% (40% CRs).

There are several differences between the studies performed at the Dana Farber Institute and our study. First, and most importantly, the patient population was different. Both the US studies and our study were performed in patients with locally advanced SCCHN. However, all our study patients had unresectable disease, while the US studies also included patients with resectable disease. In the US studies, exophitic T3N0 and T1N1 (both stage III) were excluded, while nasopharyngeal cancer (excluded from our study) accounted for 17% of subsites. Moreover, in the US studies, 17% of cases were oral cavity cancers and 17% laryngeal cancers, whereas in the present study these figures were 10% (five of 48) and 27% (13 of 48) for both disease sites, respectively. Also, in the US studies, a low number of patients had hypopharyngeal cancer, while this constituted 35% of our study population.

Secondly, most of the US studies used a higher dose of cisplatin, whether given by continuous infusion or by bolus injection, every 3 or 4 weeks. This higher dose of cisplatin, although reasonably well tolerated in their patient population, led to unacceptable toxicity in our patients, and in addition led to a lower relative dose intensity. Unfortunately, no data on the relative dose intensity of cisplatin were reported by the US group.

Thirdly, in the US studies the responses were evaluated clinically. When we evaluated our patients clinically, four patients seemed to have a CR (8%) (data not shown). However, when an independent review panel of radiologists evaluated the radiological responses in our population, no CRs could be diagnosed. Moreover, contrary to the US studies, no biopsies were taken in our study to confirm any responses. Irregularities left after chemotherapy do not necessarily contain malignant cells. This underlines the difficulties of response evaluation in patients with head and neck cancer, and in future, clinical but also radiological evaluation should be included in studies in head and neck cancer.

Any real benefit of the docetaxel–cisplatin–5-FU (TPF) combination should be judged against the neo-adjuvant chemotherapy now mostly used, i.e. PF regimen. In fact, at present two phase III studies are underway to compare the TPF regimen with the PF regimen in patients with inoperable locally advanced SCCHN, one in Europe and one in the USA. The regimen used in Europe consists of docetaxel 75 mg/m2 and cisplatin 75 mg/m2, both given both intravenously on day 1, and 5-FU 750 mg/m2/day, given by continuous infusion from day 1 to 5 every 3 weeks, and is based on the presently described feasibility study. The control arm of that randomized study consists of cisplatin 100 mg/m2 on day 1 in combination with 5 days continuous infusion of 5-FU (1000 mg/m2/day).


    FOOTNOTES
 
* Correspondence to: Dr J. B. Vermorken, Department Medical Oncology, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium. Tel: +32-3-821-3375; Fax: +32-3-825-1592; E-mail: Jan.B.Vermorken{at}uza.be Back


    REFERENCES
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
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