2364 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 1 Division of Hematology/Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, Michigan. 2 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 patients). 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 48201. 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. H 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. PATIENTS AND METHODS 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- 2365 TABLE 1 Planned Dose Escalation Dose level Paclitaxel (3-hr) (mg/m2) Cisplatin (mg/m2) 5-FU (g/m2/day) 1 2 3 4 Day 1 135 135 175 200 Day 2 75 100 100 100 Days 2–6 1.0 1.0 1.0 1.0 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- 2366 CANCER December 1, 1999 / Volume 86 / Number 11 TABLE 2 Patients Characteristics (n 5 25) Characteristic Race African American White Gender Male Female Performance status 0, 1 2 Disease status Recurrent Metastatic Locally advanced Primary site Oropharynx Hypopharynx Oral cavity Larynx Unknown primary Stage of locally advanced n56 T3N2M0 T3N3M0 T4N2M0 T4N3M0 Prior therapy n 5 16 Surgery 1 radiation Radiation TABLE 3 Toxicities (n 5 25) No. of patients 10 15 21 4 6, 16 3 16 3 6 14 4 4 2 1 3 1 1 1 12 4 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 analysis. 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 progression. RESULTS Twenty-five patients were enrolled in the study from October 1994 to December 1997. Table 2 summarizes Toxicity Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Anemia Neutropenia Thrombocytopenia Nausea/vomiting Diarrhea Renal/creatinine Mucositis Neuropathy 5 0 8 5 4 1 0 0 3 3 1 5 2 1 3 1 3 7 0 0 0 0 4 0 1 6 0 0 0 0 3 0 0 1 0 0 0 0 1 0 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). Toxicity 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. 2367 TABLE 4 Response (n 5 25) Disease status No. of patients CR PR Overall response Recurrent/metastatic Locally advanced Total 19 6 25 4 1 5 7 3 10 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). Response 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. Survival 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. DISCUSSION 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 outcome. 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 2368 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 20%.15 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. 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