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© 2002 American Society for Clinical Oncology Phase II Trial of Docetaxel and Cisplatin Combination Chemotherapy in Patients With Squamous Cell Carcinoma of the Head and NeckByFrom the University of Texas M.D. Anderson Cancer Center, Houston, TX; Vanderbilt University, Nashville, TN; Carolina Health Care, Blumenthal Cancer Center, Charlotte, NC; and Johns Hopkins University, Baltimore, MD. Address reprint requests to Bonnie S. Glisson, MD, Box 432, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4008; email: bglisson{at}mdanderson.org
PURPOSE: To assess the antitumor activity and toxicity of docetaxel plus cisplatin chemotherapy in patients with recurrent or incurable squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with recurrent or incurable SCCHN were eligible if they were chemotherapy naive or if they had received one prior regimen as neoadjuvant or concurrent treatment with radiation. Patients who had received chemotherapy for recurrence or prior taxanes were ineligible. Patients received docetaxel 75 mg/m2 and cisplatin 75 mg/m2 on day 1; cycles were repeated every 21 days. RESULTS: Toxic effects and length of survival were assessable in 36 patients and tumor response was assessable in 32, for whom the overall response rate was 40% (13 of 32) (6% complete response and 34% partial response). Median time to response was 5 weeks, and median duration was 4.9 months. In the intent to treat population (n = 36), median time to disease progression was 4 months. Median survival (n = 36) was 9.6 months, and the 12-month survival rate was 27%. Grade 4 neutropenia was observed in 71% of patients. Two patients (6%) experienced serious fever during grade 4 neutropenia (without documented infection) that required intravenous antibiotics, and an additional four patients had grade 3 infection. Other severe (grades 3 and 4) toxic effects were asthenia (25%), nausea (11%), fever (8%), vomiting (8%), severe hypersensitivity reactions (8%), and diarrhea (8%). Severe stomatitis (grade 3) occurred in only one patient. CONCLUSION: Docetaxel plus cisplatin is an effective regimen with an acceptable safety profile for palliation of recurrent SCCHN. Relative to the standard regimen of cisplatin/fluorouracil, this regimen may offer higher tumor response and survival rates with short outpatient administration and a lower incidence of severe mucosal toxicity.
SQUAMOUS CELL carcinomas account for most malignancies that arise in the head and neck region.1 Although prognosis of early-stage squamous cell carcinoma of the head and neck (SCCHN) is favorable, with 5-year survival rates of 70% to 90% after standard therapy (surgery, radiotherapy, or both), some two thirds of patients present with advanced locoregional (stage III and IV) disease.2 Despite aggressive initial management of the primary tumor, locoregional recurrence occurs in up to 60% and distant metastatic spread in up to 25% of these cases,3,4 and the 3-year survival rate remains below 30%.2,5 In addition, approximately 10% of patients have distant metastases at the time of initial presentation or locoregional disease that is deemed incurable. For patients with incurable cancer at presentation or recurrent disease, either locoregionally or at distant sites, prognosis is particularly poor, with a median length of survival of only 6 months with conventional palliative chemotherapy.2 Cisplatin-based combination therapy with fluorouracil (5-FU) is presently the standard treatment for patients with recurrent SCCHN after maximal surgery or radiotherapy and for those with disease deemed incurable with local treatment. For those with marginal performance status who are unable to tolerate cisplatin-based regimens, standard-dose methotrexate is commonly used.1 Randomized trials have demonstrated superior objective response rates with cisplatin plus 5-FU (approximately 30%) compared with single-agent cisplatin, 5-FU, or methotrexate (10% to 20%) in advanced SCCHN. However, this advantage is not reflected in improved overall survival rates for combination therapy compared with monotherapy.6-10 Furthermore, the cisplatin/5-FU combination is associated with significant mucosal toxicity and prolonged administration time, factors that are problematic in this patient population and that detract from the palliative intent of the therapy. These data clearly point to the need for new approaches in this setting. Of the newer agents that have demonstrated activity against SCCHN, the most promising seem to be the taxanes.11,12 The semisynthetic taxane docetaxel demonstrates in vitro and in vivo activity against a variety of mammalian solid tumors.13,14 Moreover, docetaxel lacks cross-resistance with cisplatin in several tumor cell lines, including human ovarian carcinoma.15,16 Importantly, human SCCHN cell lines and murine SCCHN xenografts are highly sensitive to the antiproliferative effects of docetaxel.17,18 In phase III studies, single-agent docetaxel 100 or 75 mg/m2 administered as a 1-hour infusion has shown efficacy in metastatic breast cancer19 and in platinum-refractory non–small-cell lung cancer.20 In locoregionally recurrent or metastatic SCCHN,21,22 single-agent docetaxel at a dose of 100 mg/m2 every 3 weeks has been associated with tumor response rates (21% to 42%) comparable with those achieved with conventional cisplatin plus 5-FU combination chemotherapy.8,9 Fluid retention and hypersensitivity reactions, which were common side effects in earlier phase I studies of docetaxel,23,24 have proved manageable with oral corticosteroid premedication. Based on the demonstrated activity of both cisplatin and docetaxel in SCCHN and their nonoverlapping toxicity profiles, the combination was deemed promising. This multicenter, open-label, nonrandomized phase II study evaluated tumor response, survival rates, and toxic effects when the combination of docetaxel plus cisplatin was given to patients with recurrent disease or those deemed incurable at initial presentation.
Patient Population Patients were enrolled at four centers in the United States. For inclusion in the study, patients were required to be 18 years of age or older with cytologically or histologically confirmed SCCHN that was recurrent or deemed incurable and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, life expectancy of 12 weeks or longer, and adequate bone marrow, hepatic, and renal function (reflected by an absolute neutrophil count > 2.0 x 109/L, platelet count > 100 x 109/L, normal bilirubin level, AST or ALT levels of < 1.5 x the upper limit of normal, alkaline phosphatase level < 5 x the upper limit of normal, serum creatinine level < 1.2 mg/dL or creatinine clearance > 50 mL/min, and a normal serum calcium level). Patients who had undergone prior chemotherapy for recurrent disease, previous taxane therapy, systemic anticancer therapy in the previous 6 months, or radiation to major bone marrow areas or target lesions within the previous month were excluded from the study, as were patients with grade 2 or higher peripheral neuropathy or other serious comorbid conditions. Patients could have received up to one prior regimen of chemotherapy as neoadjuvant, adjuvant, or concurrent therapy (with radiation) if the therapy did not include taxanes and was completed more than 6 months before disease recurred. Patients with measurable disease in a previously radiated area were required to have a 12-week progression-free interval from the completion of radiation. Patients with prior malignancies were eligible if they had been treated with curative intent and had been disease free for longer than 2 years. Patients were required to give written informed consent before inclusion in the study. The study protocol was approved by the institutional review boards at each study center, and the study was conducted in accordance with the principles of the Declaration of Helsinki. Within 2 weeks before initiation of treatment, all patients had a complete physical examination and medical history, blood count, serum biochemistry tests (hepatic and renal function tests and electrolytes), urinalysis, and echocardiogram; a chest radiograph and computed tomography (CT) or magnetic resonance imaging (MRI) scans of all disease sites were obtained during the 3 weeks before study entry.
Treatment Plan Complete and differential blood counts were performed at weekly intervals throughout the study. Follow-up history and physical examination, serum biochemistry, urinalysis, and tumor measurement (for lesions accessible to physical examination) were performed before each cycle of chemotherapy, and a chest x-ray and CT or MRI scans of disease sites were repeated after every third cycle. Tumors that could be assessed bidimensionally were considered measurable; those that could be assessed in only one dimension were considered assessable. Toxic effects were recorded on a continuous basis, assessed for relationship to the study medication, and, where possible, monitored until they were resolved satisfactorily.
Outcomes Secondary efficacy parameters included duration of response, time to treatment, failure time to disease progression, and overall survival time. Duration of response was calculated in patients with disease response as the interval from first administration of treatment to the first sign of disease progression. Time to treatment failure was defined as disease progression, additional anticancer therapy, treatment discontinuation attributable to toxicity, withdrawal of patient consent, or death. Survival time was defined as duration from initiation of chemotherapy until death or date of last contact if there was no documentation of death. Adverse events were categorized and graded according to the National Cancer Institute (NCI) common toxicity criteria and according to Coding Symbols for Thesaurus of Adverse Reaction Terms classification when grading was not available in NCI.
Statistical Analysis
Patients A total of 36 patients entered the study. Toxic effects and length of survival could be assessed in all 36 patients, and disease response could be assessed in 32 patients. Three patients were ineligible: one because of prior chemotherapy for recurrent disease, one because of pre-existing grade 2 neuropathy, and one with baseline hypercalcemia. One patient died on the second day of the first cycle of treatment, before response could be assessed. Demographic and clinical characteristics of the study population are summarized in Table 1. On study entry, patients presented with locoregionally advanced SCCHN that was incurable with standard therapy (six patients), locoregionally recurrent SCCHN (14 patients), or metastatic SCCHN (16 patients). Of those with incurable locoregionally advanced disease, two had second primary head and neck cancers. A total of 11 patients had previously received chemotherapy; of these, nine (82%) had been treated with cisplatin and six (54%) with 5-FU. The interval since previous chemotherapy ranged from 6 to 78 months (median, 25 months).
A total of 135 cycles of docetaxel plus cisplatin chemotherapy were administered (median, four cycles; range, one to eight per patient). Most chemotherapy cycles (79%) were given at the planned dose level of 75 mg/m2 for each drug, and only 3% of courses were delayed beyond 1 week. Hematologic and nonhematologic toxic effects necessitated docetaxel dose attenuation in four (11%) and three patients (8%), respectively, and cisplatin dose attenuation in three (8%) and five patients (14%), respectively. In addition, side effects led to treatment discontinuation in 11 patients (31%), with neurotoxicity (five patients) and asthenia and infection (three patients each) being the most common. One patient died on day 2 of cycle one from unknown causes; the investigator considered this death to be possibly related to drug therapy. There were no other deaths during the study that were felt to be either possibly or probably related to treatment. Two patients died of progressive disease within 30 days of their last infusion.
Response
With respect to the extent of disease at presentation, 35% (six of 17) of cases of locoregionally recurrent disease responded compared with a response rate of 47% (seven of 15) in cases of metastatic disease (Table 3). The response rate did not change significantly when the four patients with nasopharyngeal primary tumors were excluded from the response analysis (overall response in 39% or 11 of 28 patients). Similarly, the response rate was also unchanged if the six patients with locoregionally advanced disease deemed incurable were excluded from the analysis (overall response in 42% or 11 of 26 cases).
Survival Time In the intent to treat population, the median time to treatment failure was 3 months (95% CI, 2.1 to 3.9 months), whereas the median time to disease progression was 4 months (95% CI, 3.0 to 4.6 months) (Fig 1). Exclusion of the four patients with nasopharyngeal carcinoma from the analysis did not alter either time to treatment failure or time to disease progression.
Median survival time was 9.6 months (95% CI, 6.4 to 10.9 months), whereas the 1-year and 2-year survival rates were 28% (95% CI, 13% to 42%) and 19% (95% CI, 7% to 32%), respectively. Median survival time was estimated at 9.2 months for the 32 patients with nonnasopharyngeal SCCHN. With a median follow-up time of 40 months, five patients remain alive at the time of this report.
Toxic Effects
Overall, 47% (17 of 36) of patients reported grade 3 or 4 nonhematologic side effects (Table 5). The most common and severe included asthenia in 25%, infection in 17%, and nausea in 11% of patients. Grade 1 or 2 stomatitis was observed in 44% of patients; however, grade 3 stomatitis occurred in only one patient, and grade 4 toxicity was not observed. Similarly, grade 3 diarrhea occurred in only two patients. Neurotoxicity of any type or grade was reported in 50% of patients, with neurosensory deficits being most common (42%). Grade 3 neurotoxicity was seen in a total of three patients (8%), with one case each of neurosensory, neuromotor, and neurocerebellar toxicity. No grade 4 neurotoxic events were observed. Fluid retention developed in seven patients (19%) through the course of treatment; one of these patients had facial edema only. There were no cases of severe generalized edema, and no patients discontinued therapy because of edema.
Of the 25 patients who had serial documentation of performance status during therapy, three had no change and 21 had deterioration (increase by at least one ECOG category) during at least one evaluation. The median time to deterioration in performance was 3 months. Weight loss of at least 10% from the baseline value was observed in four patients (11%) during treatment. As regards tumor-related symptoms, worsening was defined as an increase of at least one grade by NCI criteria. Twenty-four patients (67%) were either asymptomatic or had no worsening during the study. Six patients each experienced increased cough and pain. Number of patients who were using at least one opioid was similar at baseline (15 patients [42%]) and at the end of the study (14 patients [39%]).
In this study of patients with incurable or recurrent SCCHN, the docetaxel/cisplatin combination was associated with a 40% overall response rate and median survival of 9.6 months. These rates are somewhat higher than those consistently reported for the standard regimen of cisplatin/5-FU (approximately 30% response rate and 5- to 7-month median survival time).6-9 However, the sample size in this phase II trial is small, confidence limits are wide, and the hazards of comparing phase II to phase III data are well-known. Although the incidence of severe neutropenia was high, only 17% (six of 35) of patients experienced severe infection associated with grade 4 neutropenia or required intravenous antibiotics for neutropenic fever without documented infection. Admittedly, the incidence of severe neutropenia and the rate of infection we observed with docetaxel/cisplatin is greater than what has generally been reported with the cisplatin/5-FU regimen. The incidence of grade 3 to 4 neutropenia and severe infection in the cisplatin/5-FU arm of the study by Jacobs et al8 was 10% and 4%, respectively. The most problematic on-myelosuppressive toxic effects we observed were asthenia and neurosensory toxicity. These resulted in early treatment discontinuation in 30% of patients. Nevertheless, most patients completed four cycles of therapy. The regimen was nearly devoid of severe stomatitis, which is particularly problematic in this patient population and is severe (grade 3 or 4) in 15% to 300% of those receiving cisplatin with infusional 5-FU for recurrent disease. The single-day outpatient administration of docetaxel/cisplatin is also advantageous from a logistical and perhaps the patient’s perspective in that the need for ambulatory pumps, central venous access, or prolonged hospitalization for infusional 5-FU is avoided. Two other trials of docetaxel and cisplatin-based combination therapy for recurrent SCCHN have been reported (Table 6). Specht et al28 evaluated the same doses of docetaxel and cisplatin as those used in the present trial and observed a response rate of 32% and a median survival time of 11 months in 25 patients with locoregionally recurrent or metastatic SCCHN. In a small study of 19 patients, Janinis et al29 added 5-FU to docetaxel/cisplatin and observed a 44% response rate and 11-month median survival.
Clinical trials in which docetaxel has been studied as monotherapy for patients with recurrent SCCHN and therapy-naive patients deemed incurable are reviewed in Table 7.21,22,30,31 It is notable that the cumulative response rate to docetaxel in these four trials is 35% (37 of 106), a rate that is similar to or slightly higher than that reported for combination therapy with cisplatin and 5-FU.6-9 The complete response rate was low at 5%, and only one trial reported median survival time (7 months).30 Notably, the cumulative response rate for docetaxel and cisplatin-based combinations is 36%, similar to the rate for docetaxel monotherapy.
Historically, before the taxane era, combination chemotherapy was associated with an increased response rate but not an improved median survival time relative to monotherapy in the treatment of recurrent SCCHN. Both paclitaxel and docetaxel produce single-agent response rates that equal or exceed those with cisplatin/5-FU. With a few notable exceptions, however, combinations containing taxanes and taxane monotherapy yield similar response rates.28,32 It remains to be seen whether taxane-based combination therapy improves median or long-term survival times compared with taxane monotherapy in this setting. In summary, we observed a 40% overall response rate and 9.6-month median survival with docetaxel plus cisplatin, establishing it as an effective regimen with an acceptable safety profile for the treatment of incurable or recurrent SCCHN. The convenience of the single-day infusion every 21 days in the outpatient setting makes cisplatin plus docetaxel a suitable alternative to cisplatin plus infusional 5-FU. The results from an ongoing phase III trial in which these two combinations are directly compared will be the final arbiter of whether docetaxel/cisplatin is truly superior at halting disease progression or prolonging life for patients with recurrent SCCHN.
Supported by Aventis Pharmaceuticals, Bridgewater, NJ. We thank Vanessa B. Valiare and Catherine DiMare-D’Souza for their editorial assistance.
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Clavel M, Vermorken J, Cognetti F, et al: Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck: A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 5: 521-526, 1994 8. Jacobs C, Lyman G, Velez-Garcia E, et al: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10: 257-263, 1992[Abstract]
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Forastiere AA, Metch B, Schuller DE, et al: Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous cell carcinoma of the head and neck: A Southwest Oncology Group study. J Clin Oncol 10: 1245-1251, 1992 10. Liverpool Head and Neck Oncology Group: A phase III randomized trial of cisplatinum, methotrexate, cisplatinum + methotrexate and cisplatinum + 5-FU in end-stage squamous carcinoma of the head and neck. Br J Oncol 61: 311-315, 1990 11. Gelmon K: The taxoids: Paclitaxel and docetaxel. Lancet 344: 1267-1272, 1994[CrossRef][Medline] 12. Crown J, O’Leary M: The taxanes: An update. Lancet 355: 1176-1178, 2000[CrossRef][Medline]
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Shin DM, Glisson BS, Khuri BS, et al: Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma. J Clin Oncol 16: 1325-1330, 1998 Submitted July 3, 2001; accepted November 16, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1.5 x 109/L; platelet count 
