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© 2001 American Society for Clinical Oncology Concomitant Infusional Paclitaxel and Fluorouracil, Oral Hydroxyurea, and Hyperfractionated Radiation for Locally Advanced Squamous Head and Neck CancerFrom the Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; Departments of Medicine and Radiation Oncology, University of Illinois Cancer Center; Departments of Radiology and Otolaryngology-Head and Neck Surgery and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School; and the Section of Hematology/Oncology, Department of Radiation and Cellular Oncology and the Comprehensive Cancer Center, the University of Chicago, Chicago, IL. Address reprint requests to Everett E. Vokes, MD, University of Chicago Medical Center, 5841 S Maryland Ave, MC2115, Chicago, IL 60637-1470.
PURPOSE: To improve local disease control and survival with organ preservation, we conducted a phase II multi-institutional trial with a concomitant taxane-based chemotherapy and hyperfractionated radiation regimen. PATIENTS AND METHODS: Sixty-four patients with locally advanced squamous cancers (stage IV, 98%; N2/3, 81%) were treated on an intensive regimen consisting of 5-day (120-hour) infusions of paclitaxel (20 mg/m2/d) and fluorouracil (600 mg/m2/d), oral hydroxyurea 500 mg every 12 hours for 11 doses, and radiation 1.5 Gy bid (T-FH2X). Chemoradiation was administered concomitantly on days 1 to 5 of each 14-day cycle. A full treatment course consisted of five cycles during a 10-week period to a total radiation dose of 72 to 75 Gy. RESULTS: The median follow-up for the group is 34 months. At 3 years, progression-free survival is 63%, locoregional control is 86%, and systemic control is 79%; overall survival is 60%. Seventeen patients died of recurrent cancer, two died of second primary cancers, and four died of other causes. Side effects observed include anemia (22% required transfusion), leucopenia (34%, grade 3 to 4), and mucositis (84%, grade 3 to 4). Organ preservation principles were maintained. At 1 year posttreatment, 61% of patients had severe xerostomia and 47% had compromised swallowing. There was little disturbance of speech quality in 97% of patients at the same follow-up point. CONCLUSION: T-FH2X is a highly active and tolerable concomitant chemotherapy and hyperfractionated radiation regimen that induces sustained local tumor control and holds promise for improved survival with organ preservation in high-risk patients. Identification of less toxic therapy and improved distant disease control are needed. T-FH2X should be tested in a randomized trial and compared with a less intensive concomitant regimen that uses once-daily radiation fractionation.
COMBINED TREATMENT approaches have become standard for patients with locally advanced squamous cancers of the head and neck.1 In advanced oropharyngeal primary disease, strong evidence demonstrates the superiority of chemotherapy and concomitant radiation versus radiation alone for locoregional control and survival.2 Multiple randomized trials3-6 and data from meta-analysis7 support this approach for other head and neck sites, including the oral cavity and hypopharynx that are usually unresectable for disease. Earlier clinical investigations8,9 demonstrated that a sequential approach, with induction chemotherapy followed by radiation, allows larynx preservation with a reduced incidence of distant metastasis as a site of first treatment failure. At Northwestern University, the University of Chicago, and the University of Illinois, we have had a sustained interest in the development of chemotherapy and radiation treatment programs with improved survival and organ preservation as study end points.10-12 We reported previously on the notable activity of sequential treatment with induction cisplatin, fluorouracil (5-FU), leucovorin, and interferon alfa followed by 5-FU, hydroxyurea, and concomitant radiation, which demonstrated overall survival that exceeded 60% at 5 years.13 Locoregional tumor recurrence was observed in 25% of patients and distant metastases in 10% of patients. To improve local disease control and shorten overall treatment duration, in a subsequent trial we deleted the induction phase of therapy and added cisplatin to the 5-FU, hydroxyurea, and concomitant radiation regimen (C-FH2X) as we intensified the radiotherapy fractionation schedule to twice-daily administration of 1.5 Gy.14 Overall progression-free survival was 72%, and locoregional control improved to 92% at 3 years. The regimen was toxic, however, and patients frequently experienced severe dermatitis, mucositis, and myelosuppression. In a phase I experience,15 we observed that the addition of infusional paclitaxel to hydroxyurea, 5-FU, and hyperfractionated radiation was feasible and active. Seventy percent of assessable poor-prognosis patients achieved complete disease remission. Therefore, we then substituted cisplatin with paclitaxel to be used with 5-FU, hydroxyurea, and hyperfractionated radiation (T-FH2X) in our next phase II trial, which is the subject of this report. Our aim was to maintain the high degree of locoregional control, improve systemic activity, and lower acute and long-term toxicity. We report a mature analysis of treatment outcomes on this study with the T-FH2X regimen as primary treatment for previously untreated patients.
Sixty-four patients were eligible for and were entered onto this phase II trial, which opened in November 1995 and closed to patient accrual in July 1997. Patients were entered onto the study from one of three participating institutions: the University of Illinois, Northwestern University, and the University of Chicago or affiliates. Eligible patients had locoregionally advanced, stage IV squamous head and neck cancer arising from the oral cavity, pharynx, larynx, or paranasal sinuses. Patients with stage III disease were eligible only if the primary site was the base of the tongue or the hypopharynx. All patients were untreated previously and no patients had distant metastases. Therapy was given with curative intent. The study objectives were to determine tumor response rate and response duration, improve survival, preserve organ function, and maintain quality of life (QOL). Before entry onto the study, all patients were evaluated and assigned a tumor stage by a multidisciplinary team that included the attending surgeon, a radiation oncologist, a speech pathologist, and a medical oncologist. All patients had biopsy-proven squamous cell carcinoma. Also required were performance status 0 to 2 according to Cancer and Leukemia Group B criteria, normal visceral organ function, and a staging evaluation that included triple endoscopy and computed tomographic or magnetic resonance imaging. Staging was determined according to the criteria of the 1992 American Joint Committee for Cancer Staging Manual. All patients were counseled, and all provided written informed consent in accordance with institutional guidelines.
Surgery
Chemotherapy and Radiation
The protocol plan was to continue treatment cycles despite mucositis, dermatitis, or diarrhea. For grade IV toxicity, 5-FU was decreased to 500 mg/m2/d and paclitaxel to 15 mg/m2/d. For myelosuppression, treatment cycles were postponed for 1 week or interrupted if the patient experienced persistent fever or if a serious infection was detected. If a WBC count of 1,000 to 1999/µL or a platelet count of 50,000 to 74,000/µL was measured during the treatment cycle, the paclitaxel dose was decreased to 15 mg/m2, and the hydroxyurea dosage was reduced by 50%. If a WBC count of less than 1,000/µL or a platelet count of less than 50,000/µL occurred during the treatment cycle, paclitaxel and hydroxyurea were withheld, but 5-FU and radiotherapy continued.
Radiotherapy Guidelines
QOL Measures
Statistical Analysis Data were summarized using frequencies, percentages, means, SDs, and ranges. Survival time, progression-free survival time, time to locoregional progression, and time to distant progression were analyzed using Kaplan-Meier product limit curves. "Locoregional" is used to describe disease in the primary tumor region, the neck, or both. In the progression-free survival analysis, progression was defined as the occurrence of at least one of the following events: locoregional progression, distant progression, toxic death, or death from disease. QOL data were summarized using means, SDs, and percentage of patients scoring above or below a specified value to indicate moderate to severe dysfunction.19,21,22 Change over time was examined using paired t tests or McNemar tests.
Sixty-four eligible patients who were untreated previously and had locally advanced disease were entered onto the study. Five ineligible patients also were registered; one patient had undergone a total laryngectomy, one had an adenosquamous carcinoma of the nose, one died of aspiration pneumonia before cancer treatment, and two patients exhibited distant metastases on pretreatment scans. Follow-up data are available through May 2000. Three centers participated; pretreatment patient characteristics for 64 patients are listed in Table 1. All patients had squamous cell cancer, and 88% had performance status of 0 or 1. Ninety-five percent of patients were smokers, and 63% had a history of moderate to heavy alcohol use. Thirty-one percent of patients had experienced weight loss estimated at 5% or greater at the start of treatment. The most commonly involved primary sites were oropharynx (33%) and oral cavity (27%). Staging information is listed in Table 2. Fifty-eight percent of patients had T4 disease, and 81% had N2/3 involvement.
Response Twelve patients were not assessable for response; 10 had no measurable disease after initial surgery, and two patients were not available for clinical response assessment. Thirty-six (69%) of 52 patients had clinical CR. All of these patients demonstrated substantive response on repeat computed tomographic or magnetic resonance imaging scans. Only 24 of these 36 patients, however, had a complete radiographic response. Fifteen patients achieved clinical partial remission status. One patient had documented progressive disease during the chemoradiation schedule. Of the 51 patients who achieved disease remission after chemoradiation, 38 underwent biopsy or surgery with histologic assessment of response status. Fifteen of 17 patients with clinical and radiographic CR had histologically documented CR. Of 11 patients with clinical CR but radiographic PR, eight were histologically negative after biopsy or surgery, and three were found to have residual tumor. Of 10 patients with clinical and radiographic PR, six had no demonstrable tumor revealed by pathologic examination of the resected specimen. Of the 29 patients in histologic CR, five (17%) eventually developed disease recurrence versus 27% of the entire study group.
Toxicity
Treatment dose intensity was maintained ( Table 4). The intended doses were paclitaxel 50 mg/m2/wk, 5-FU 1,500 mg/m2/wk, and hydroxyurea 2,750 mg/wk, and these were the median doses administered. A median radiation dose of 73.5 Gy was delivered. Treatment delays were infrequent. Forty-six patients (74%) had no delays in their scheduled treatment weeks, and only 6% of the entire group were delayed 2 weeks or more from the intended treatment plan. Sixty-one patients (95%) received all planned weeks of treatment.
Surgery Patients were evaluated for organ-sparing surgical resection ( Table 5). Eighteen patients underwent surgery after diagnosis and before commencement of chemoradiation. Six had primary site operations, including two composite resections, one partial laryngectomy, one partial glossectomy, a tonsillectomy, and a wide floor of mouth excision. Organ preservation guidelines were adhered to in all patients. Twenty-two neck dissections were performed in these 18 patients. Eighteen patients also underwent surgery after the completion of chemoradiation. Salvage primary procedures consisted of two laryngectomies and one base of tongue resection. Two of these three patients later died because of widely metastatic cancer. Twenty-two nodal dissections were performed in the 18 patients. Thus, definitive surgery at the primary site was performed in only four (6%) advanced-stage patients in primary management.
Outcome The median follow-up time for all 64 patients is 34 months. The minimum follow-up for the 37 living patients is 26 months (range, 26 to 53 months). The minimum follow-up for all patients is 4 months. Progression-free survival, time to locoregional or distant recurrence, and overall survival are shown in Figs 2 through 4. Progression-free survival denotes survival free of recurrence or death caused by disease or toxicity. Seventeen patients (27%) have experienced disease recurrence: five locoregional, nine distant, and three both locoregional and distant recurrences. All observed events occurred within 3 years after diagnosis. Ten of the 12 patients with distant disease recurrence were staged at N2/3 (10 of 52 v 2 of 12 at N0/1). There have been 27 deaths, including four caused by toxicity. Two deaths were considered acute postoperative events, and two were related to more chronic laryngeal effects. One patient died at 6 months with inspissated secretions, mucous plugging, and aspiration, and the other died at 10 months with laryngeal necrosis. Seventeen patients died of disease. Four patients died of intercurrent illnesses and two patients of second primary cancers.
QOL Of the 64 patients enrolled onto the protocol, 47 had data captured in the QOL database. Missed data collection in this area related to the timing of patient identification and data management resources at participating institutions. Thirty-nine of the 47 patients were alive at 12 months posttreatment, and QOL data were available for 30 patients. Data presentation ( Table 6) is limited to these 30 patients for whom long-term data (ie, 12 months) are available. Additional analyses indicated that at baseline, these 30 patients were not significantly different from the remaining 17 (those who had died or for whom 12-month data were not available). In addition, this group was similar to the entire protocol sample of 64 patients in disease site, tumor stage, sex, and race.
As listed in Table 6, acute toxicities during treatment were associated with decline in performance status and increased symptomatology. All patients had severely restricted diets that were limited to soft foods and/or tube feeding. Up to two thirds of patients reported moderate to severe problems with dry mouth, swallowing dysfunction, hoarseness, and loss of taste. Eighty-six percent reported problems with "sticky" saliva. Conversely, there was less disturbance in speech. By 12 months after completion of treatment, many symptoms had improved and returned to pretreatment levels. Exceptions included dry mouth and sticky saliva, which remained significantly problematic for 61% and 44% of patients, respectively. Six patients (20%) were completely dependent on a feeding tube at that point. Five of these six patients had oro- or hypopharyngeal primary sites. Of the 37 surviving patients, 34 were contacted at the time of this report; five (15%) had a gastric tube in place, and two of these five patients also were able to eat by mouth. Despite performance deficits and the severity of side effects during treatment, patients experienced little long-term change in emotional or social well-being ( Table 7). Physical and functional well-being and global QOL declined during treatment (P = .0001, P = 05, and P = .02, respectively) but had fully recovered by 12 months after treatment; there were no significant differences between pretreatment and 12-month scores. Emotional well-being improved over time, with 12-month scores significantly higher (P = .01) than before treatment.
The objectives of this phase II study were achievement of a high level of local and distant disease control with preservation of organ function. Much attention was given to supportive speech and swallowing care, and reduction of long-term toxicity was a study end point. Sixty-four patients were entered onto the study, and all but one had stage IV disease. We shifted successfully from earlier cisplatin-based regimens to T-FH2X; overall tumor control was favorable, with 73% of patients free of tumor recurrence. Locoregional control was maintained in 86% of patients; this was an especially favorable result, because 58% of patients had T4 primaries and 81% had N2/3 lymph node involvement. With C-FH2X, also a hyperfractionated concomitant schedule,14 we observed local control in greater than 90% of patients, but at the cost of potential grade 3 or 4 toxicity in a majority. The T-FH2X regimen derives from our phase I trial15 and maintains the 5-day alternate-week treatment plan. The data demonstrate that a high level of locoregional disease control was achieved with less toxicity. Although acute mucositis occurred routinely, we observed a marked reduction in severe leucopenia and thrombocytopenia, from 81% and 78% to 34%, and 2%, respectively. Overall survival data also provide encouragement: 60% of patients are alive at 3 years. This figure is compromised in part by deaths related to treatment, other medical conditions, and second cancers. The results of this phase II trial can be considered relative to recent larger randomized trials. The Radiation Therapy Oncology Group23 reported improved locoregional control in unresectable patients after hyperfractionated radiotherapy compared with standard daily fractionation; patients received either 1.2 Gy bid for 5 days per week or accelerated fractionation with 1.8 Gy daily for five days per week and 1.5 Gy to a "boost" field in a second daily treatment for the final 12 days, to a total dose 72 Gy. Brizel et al5 reported control of locoregional disease in 70% of patients randomized to concomitant cisplatin and 5-FU with hyperfractionated radiation. Forty-five percent of patients had T4 primaries, and 45% had N2/3 disease. In patients with oropharyngeal cancer, Calais et al2 observed locoregional control in 66% of patients randomized to the combined treatment arm, with concomitant radiation given in a conventional daily fractionation schedule and chemotherapy with carboplatin and 5-FU. Thirty-nine percent of patients had T4 primaries, and 50% had N2/3 nodal disease. Pending final analysis of a second T-FH2X trial by our group in which the paclitaxel was given in a more convenient schedule on day 1 of each treatment week,24 we have repeatedly observed superior locoregional control in patients with more advanced staging at diagnosis. A randomized trial with T-FH2X as the experimental arm should be performed. Although there is no widely accepted "standard" concomitant chemotherapy and radiation regimen, the data of Adelstein et al6 support a once-daily radiation schedule with concomitant cisplatin given on days 1, 22, and 43 as the comparator. This schedule has demonstrated efficacy and safety in a national multi-institutional trial. Analysis of tumor recurrence patterns demonstrates a total of eight local or regional recurrences and 12 (21%) recurrences in sites below the clavicles. This is a reversal of the predominately local relapse risk reported previously25,26 in squamous head and neck cancers, and it is a finding consistent with our recent trial.14 Because earlier randomized trials8,9 demonstrated a reduction in the incidence of distant metastases after induction chemotherapy, we have resumed an induction schedule and maintained T-FH2X as definitive local treatment in an ongoing phase II study.27 We were not accurate in our prediction of histologic response status by routine clinical examination and radiographic imaging. A high percentage of patients with clinical and radiographic CR had histologic confirmation after biopsy or surgery. But in 14 of 21 patients with clinical or radiographic evidence of PR status, no residual disease was found in a wide-field biopsy or surgical resection. Therefore, we must recognize that response assessment is imprecise, and often it underestimates the profound effects of chemoradiation. Conversely, 5 of 29 patients with histologic confirmation of CR status eventually experienced disease recurrence. None of our current measures of response to treatment establishes that disease has been eradicated, and systematic follow-up remains a necessary component of overall management. Important end points of this study were organ preservation, reduction of acute toxicity, and maintenance of QOL. In a large majority of patients, surgery at the primary site was limited in primary management to biopsy or wide excision. Two patients with oral cavity primary tumors had composite resections, and one patient each underwent supraglottic laryngectomy, partial glossectomy, and tonsillectomy. Salvage laryngectomies were performed in two patients, one of whom survives. Acute toxicity was acceptable, although much supportive treatment was needed. Severe anemia, in-field dermatitis, and mucositis were frequent. These side effects necessitated attention to oral and skin care, RBC transfusion for hemoglobin levels less than 10, gastric feeding tubes in most patients, and G-CSF administration during off-week intervals. As a result, only 6% of patients experienced treatment delays of more than 2 weeks. Two patients died of postoperative complications, and two additional deaths were attributed to laryngeal toxicity after completion of treatment. Thus, there were no deaths related to bone marrow suppression, but we must be vigilant for possible insidious effects after intensive chemoradiation that could compromise surgical healing or result in excessive tissue fibrosis or necrosis. It is clear that concomitant chemoradiotherapy leads to increased acute and potentially long-term toxicity. In addition, the potential exists for unwarranted dose reduction or schedule interruptions, which may compromise prospects for a curative outcome. Therefore, administration of intensive regimens such as T-FH2X may be done best in dedicated referral centers with experienced, multidisciplinary care terms. Organ preservation does not necessarily equate to maintenance of function. However, our QOL evaluation suggests that despite the persistence of significant side effects, patients function at an acceptable level 12 months after treatment. Of interest, emotional well-being scores were higher at 1 year than at baseline. However, patients experienced substantial difficulty with dry mouth and thick saliva, and 47% of our patients had restricted diets limited to soft foods. Fifteen percent of survivors use feeding tubes. Furthermore, as long-term survival is achieved in a majority of patients with advanced disease at diagnosis, functional outcome data will be needed increasingly to better assess the value of new treatment approaches. In summary, we successfully integrated paclitaxel with infusional 5-FU, oral hydroxyurea, and concomitant hyperfractionated radiation. Cisplatin is not a necessary component for effective combined treatment. Despite the high percentage of patients with T4 and N2/3 disease, locoregional disease control was achieved after limited or no surgery and with organ preservation. Overall survival is promising. With early follow-up data, functional status also is encouraging. It is important to note that we now routinely incorporate longitudinal assessment of QOL measures and functional parameters in our outcomes analyses. Current trials in our group reintroduce induction chemotherapy for better systemic control, integrate more sophisticated radiation treatment strategies to limit exposure to normal tissues, and increasingly emphasize rehabilitative therapy to improve long-term outcomes. In the future, a randomized trial of induction chemotherapy followed by concomitant chemotherapy and hyperfractionated radiation versus a more conventional chemoradiation schedule is anticipated.
Supported in part by National Institutes of Health grant nos. P30-CA14599 and P50 DE/CA11921. We thank Jessie Stewart for assistance in the preparation of this article; Maggie Miller, Mary Jessie, and Mary Ellen Witt, nurses; and Jed Craig and Tammy Marrero for data management.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
