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© 1999 American Society for Clinical Oncology Radiation Therapy With Concomitant Hydroxyurea and Fluorouracil in Stage II and III Head and Neck CancerFrom the Department of Radiation and Cellular Oncology, Section of Otolaryngology/Head and Neck Surgery, and Section of Hematology/Oncology, University of Chicago; Section of Medical Oncology, Department of Preventative Medicine, Section of Radiation Oncology, and Department of Otolaryngology/Head and Neck Surgery, Northwestern University; and Department of Otolaryngology/Head and Neck Surgery, University of Illinois, Chicago, IL. Address reprint requests to Daniel J. Haraf, MD, Department of Radiation Oncology, 5758 S. Maryland, MC 9006, Chicago, IL 60637; email dharaf{at}mcis.bsd.uchicago.edu
PURPOSE: In 1986, a multi-institutional phase II trial was begun to study the use of chemotherapy with concomitant radiation in patients with stage II and III head and neck cancer. End points were overall survival, progression-free survival, local/regional control, and toxicity in the setting of organ preservation with concomitant treatment. METHODS: Eligible patients with stage II or III disease received chemotherapy and radiation on a 2-week cycle. Chemotherapy consisted of continuous infusion fluorouracil (5-FU) at 800 mg/m2/d for 5 consecutive days (days 1 to 5) and hydroxyurea (HU) at 1 g orally every 12 hours for 13 doses starting the evening before the start of irradiation. Radiation therapy was given as single 1.8- to 2.0-Gy fractions for 5 consecutive days (days 1 to 5) with chemotherapy. Each 5 days of treatment was followed by a 9-day break (days 6 to 14), during which no additional treatment was given. Treatment cycles were repeated until the completion of the planned radiation dose (six to eight cycles). RESULTS: Between 1989 and 1996, 60 patients were enrolled. All patients were eligible for analysis, with a median follow-up of 52 months for surviving patients and 42 months for all patients. Grade 3 to 4 mucositis occurred in 57% of patients. The 5 year-actuarial overall survival, progression-free survival, and local/regional control were 65%, 82%, and 86%, respectively. Eight patients developed local and/or regional recurrence after treatment. Surgical salvage was possible in three of these patients. Thus, the ultimate 5-year local/regional control was 91%. CONCLUSION: Concomitant radiation and chemotherapy with 5-FU and HU is an effective regimen in patients with stage II and III head and neck cancer. Progression-free survival and local/regional control appear to be superior to expected rates in patients treated with surgery and radiation. Further testing of this regimen in a phase III setting is indicated.
SQUAMOUS CELL carcinoma of the head and neck constitutes about 5% of the neoplasms occurring in the United States. Although early-stage lesions (T1/T2, N0) can be treated successfully by surgery or radiation therapy (XRT) alone, the prognosis for advanced lesions (stage IV) remains poor, owing to a lack of local/regional control as well as distant metastases. There has been intense clinical investigation in patients with advanced disease and poor prognosis. Some studies have focused on the use of neoadjuvant chemotherapy before local therapy with surgery and/or XRT. Others have studied chemotherapy with radiation in the concomitant setting. The main focus of these investigations was to improve local control and thereby increase survival. A secondary end point has been to determine whether chemotherapy before or during radiation can allow for the use of less radical surgery and organ preservation in the overall treatment plan. Recent randomized studies in laryngeal and hypopharyngeal cancer found that a significant response to induction chemotherapy could allow for radiation therapy as the definitive local component of therapy.1,2 In these trials, induction chemotherapy and XRT were compared with surgery and postoperative XRT. Although there was no difference in survival, a functional larynx was preserved in most patients in the chemotherapy arm. Whereas many investigators have tested the use of chemotherapy with XRT in advanced disease, there have been few studies in intermediate-stage (stage II and III) head and neck cancer. This group of patients has a relatively favorable prognosis with standard treatment, consisting of surgery and/or XRT. However, this combination of treatment often results in significant morbidity with loss of organ function as a result of surgery, and approximately 30% to 40% of patients will fail therapy. The head and neck cancer program at the University of Chicago has completed several phase I/II studies of fluorouracil (5-FU), hydroxyurea (HU), and concomitant XRT in patients with advanced or recurrent head and neck cancer.3-5 This regimen demonstrated high response rates even in patients with recurrent disease and a prior history of radiation treatment. Durable local and regional control of disease was obtained in those patients without a history of prior treatment and locally advanced disease. In view of these results, we decided to investigate further the regimen of 5-FU, HU, and concomitant radiation therapy (FHX) in patients with intermediate-stage disease. The objective of the study was to test the effectiveness of the FHX regimen with limited or no surgery in patients with stage II and III head and neck cancer. The end points were survival, local/regional control, and organ preservation. We now report the long-term results of this trial.
Patients Between July 1989 and May 1996, 60 patients were enrolled onto a phase II study in three participating institutions. The purpose of the study was to determine the efficacy of concomitant chemotherapy and radiation in patients with intermediate-stage head and neck cancer. End points of the study were toxicity during treatment, overall survival, time to progression, and local/regional control. Eligible patients were required to have stage II or III squamous cell cancer of the head and neck. Patients considered to have very-high-risk presentations (stage III base of tongue cancer or stage III pyriform sinus cancer) were excluded from the study. All other head and neck sites with stage II or III disease were considered eligible. The staging work-up included an endoscopic evaluation by the attending surgeon. All patients were required to undergo computed tomographic scanning of the head and neck and the chest as well as a bone scan for staging. Histologic confirmation of squamous cell carcinoma was mandatory. Other requirements included an Eastern Cooperative Oncology Group performance status of 2 or lower, a WBC count of at least 3,500/µL, a platelet count of at least 100,000/µL, and a serum creatinine level of 1.5 mg/dL or lower. All patients underwent a dental examination before the start of treatment. Informed consent was obtained from all patients. Patients were evaluated for eligibility by a multidisciplinary team consisting of an otolaryngologist, medical oncologist, and radiation oncologist. Stage was determined clinically on the basis of the physical examination and diagnostic x-ray findings. Determination of stage, optimal local treatment, and its timing were determined at the time of the joint evaluation. Surgery before concomitant chemotherapy and radiation was permitted in the context of organ preservation. Organ preservation surgery such as laser debulking, modified neck dissection, or supraglottic laryngectomy was permitted at the discretion of the attending surgeon. Thus, total glossectomy, total laryngectomy, or mandibulectomy were not permitted except as salvage procedures for persistent disease.
Treatment The dose-intensity of chemotherapy was calculated according to the following formulas. The protocol required that patients receive 5-FU at 800 mg/m2/d for 5 consecutive days during each 2-week cycle. Thus, the total intended dose was 4,000 mg/m2 every 2 weeks or 2,000 mg/m2/wk, ie, (4,000 mg/m2/cycle)/(2 weeks/cycle). Similarly, the intended dose of HU was 5.5 g/wk, ie, (11 g/cycle)/(2 weeks/cycle). Radiation therapy was delivered with 4 to 6 MV from a linear accelerator. Each patient was simulated before treatment, and field sizes were individualized. Initial fields included all known areas of gross disease as well as areas at risk for subclinical disease. A shrinking-field technique was used to deliver the following doses. Areas at risk for microscopic disease received 45 to 50 Gy. Areas of gross disease received 66 to 70 Gy. The spinal cord dose was limited to 45 Gy. Electrons were used to boost the posterior neck nodes when necessary. Custom blocking was used on all cases to spare normal tissue. Patients were evaluated for response 4 weeks after the completion of treatment. Evaluation included a physical examination along with computed tomographic scans of the head, neck, and chest. A biopsy of the primary site was recommended. A complete response was defined as the complete disappearance of all detectable disease for at least 28 consecutive days. A partial response was a reduction by at least 50% of the products of the longest perpendicular diameters of the indicator lesion. Patients with an increase in the product of the perpendicular diameter of the indicator lesion by at least 10% were considered to have progressive disease. Patients who did not meet any of the above criteria were considered to have stable disease.
Statistical Analysis Local/regional control and progression-free survival were calculated from the first day of treatment until the date of local/regional progression or progression at any site, respectively. Ultimate local/regional control was calculated from the first day of treatment until the date of failure but allowed for surgical salvage. In all progression analyses, patients dying of toxicity were counted as treatment failures. Patients dying of intercurrent disease were censored at the time of death.
Between July 1989 and May 1996, 60 patients were entered onto the study. The median follow-up for surviving patients was 52 months (range, 17 to 103 months). Patient characteristics are listed in Table 1. The study population was heterogeneous with regard to the site of the primary lesion, with the most common site being carcinoma of the larynx (25 supraglottic and eight glottic). Most patients had moderately differentiated tumors. However, four patients were diagnosed by cytology, and the degree of differentiation of their tumors could not be determined. The clinical stage distribution is listed in Table 2.
Organ preservation surgery was permitted before treatment at the discretion of the attending surgeon. Thirty-nine patients had no surgery other than a biopsy for diagnosis, whereas 20 patients had some surgery before concomitant treatment. Five patients underwent laser debulking of the primary site only before chemoradiotherapy, nine patients had a resection of the primary tumor alone, and six patients underwent resection of the primary tumor along with a neck dissection before treatment. Twelve of these 20 patients had positive margins after surgery. One patient underwent a total laryngectomy midway through treatment for airway compromise. The surgical details are listed in Table 3.
The acute toxicity during treatment is summarized in Table 4. As expected, mucositis was common and the most severe toxicity encountered. Fifty-seven percent of patients developed grade 3 or 4 mucositis during treatment. Mucositis tended to peak during cycles 5 to 7 and resolve completely within 4 to 6 weeks after treatment. Hematologic toxicity was also frequent, with 45% of patients developing grade 3 or 4 neutropenia during treatment.
In spite of the toxicity, patients were able to tolerate therapy relatively well. Only five (8.3%) of 60 patients required a break in excess of the planned 1-week break. Two patients required 1 additional week of break during the course of treatment. Two patients required 2 additional weeks of break during the course of treatment, and one patient required 3 weeks of additional break. The intended dose of 5-FU was 2,000 mg/m2/wk, and the intended dose of HU was 5.5 g/wk. The median dose of 5-FU delivered was 1,900 mg/m2/wk (range, 1,194 to 2,000 mg/m2/wk; mean, 1,810 mg/m2/wk). The median dose of HU delivered was 5.4 g/wk (range, 2.8 to 5.5 g/wk; mean, 5.1 g/wk). Overall, 24 patients received the full intended dose of 5-FU, and 29 patients received the full intended dose of HU without any dose reductions during treatment.
Survival
The sites of failure are listed in Table 5, and time to progression is shown in Fig 2. The actuarial 2-, 3-, and 5-year progression-free survivals were 84%, 82%, and 82%, respectively. Local/regional control probability is shown in Fig 3. The probability of local/regional control at 2 years and beyond was 86%. There were 10 treatment failures. Two patients developed metastatic disease, and eight patients had a recurrence in local and/or regional sites. Surgical salvage was attempted in five of the patients with local/regional failure. Three patients are alive and well 16, 48, and 67 months after surgical salvage, and two patients died of persistent disease. Thus, the actuarial ultimate local/regional control (including surgical salvage) at 2 years and beyond is 91% (Fig 4).
Cox regression analysis was used in an attempt to determine whether any clinical features were useful in predicting time to progression or local failure. Univariate analysis of tumor stage, node stage, overall stage, radiation dose, 5-FU dose-intensity, HU dose-intensity, extent of surgical resection, age, sex, and performance status were examined. None of these were predictive of disease progression or local control. None of the patients who required a break in excess of the planned 1-week break had a local or regional recurrence.
The treatment of head and neck cancer continues to evolve. Most trials combining radiation and chemotherapy have been designed for advanced disease. Induction chemotherapy trials have demonstrated a reduced incidence of metastatic disease at first site of failure but no benefit in survival and have largely fallen out of favor, with the following exception.7-9 Induction chemotherapy appears to have a role in the setting of organ preservation, as demonstrated by two randomized trials.1,2 The main focus of the current trials in advanced disease involves the use of concomitant chemoradiotherapy, in which randomized trials have shown a survival benefit. Few studies have attempted to study specifically patients with intermediate disease (stage II and III). This group of patients has a relatively favorable prognosis after standard therapy, with cause-specific survivals ranging between 50% and 80%, depending on the site and stage of disease. Standard treatment for patients with stage II and III head and neck cancer continues to be surgery, irradiation, or both. Frequently, the surgery performed results in significant dysfunction for the patient. As a result of our previous studies with concomitant chemotherapy and radiation, in which we observed excellent local control in patients with advanced disease, we decided to investigate our regimen in patients with a more favorable prognosis.3,5 Our current trial has resulted in a 5-year survival of 65%. Furthermore, the primary cause of death in our series was not head and neck cancer. Most patients with head and neck cancer have other significant medical problems, and these comorbid conditions, along with second primary tumors, were the major cause of death in our series. The FHX regimen appears to be active, as only seven of 60 patients in this series died of head and neck cancer. These results suggest that chemotherapy with concomitant radiation may be useful in the treatment of intermediate-stage disease. Both time to progression and local/regional control were excellent in our series. The overall progression-free survival was 82% at 5 years. Stage was not a factor, as the progression-free survival at 5 years was 85% and 81% for stage II and stage III, respectively. The local/regional control was 86% and increased to 91% after surgical salvage. Again, stage was not a factor, as the 5-year local/regional control was 85% and 86% for stages II and III, respectively. However, the trial was not designed to test such differences, and the small sample limits this analysis. Our patient population was heterogeneous, and it is difficult to find an appropriate group for comparison. Thus, a randomized trial may be needed. Mendenhall et al10 recently reported the retrospective results of radiation therapy alone for patients with stage III squamous cell carcinoma of the glottic larynx. Mendenhall et al reported 5-year overall survival, cause-specific survival, local/regional control, and ultimate local/regional control of 54%, 78%, 61%, and 86%, respectively. In our series, 22 patients had T3 lesions of the larynx (17 supraglottic and five glottic cancers). Our 5-year results in these 22 patients are 77% overall survival, 86% cause-specific survival, 91% local/regional control, and 95% ultimate local/regional control, respectively. The overall survival for the five patients with glottic tumors was 75%, and none of the patients had a recurrence. Even the subgroup of patients treated with twice-daily radiation in the Mendenhall series did not fare as well as our patients. Local control with larynx preservation was 86% in our series, compared with 62% in that of Mendenhall et al. Our results also compare favorably with a recent large retrospective review of 16,936 patients with squamous cell carcinoma of the larynx.11 In that series, the 5-year disease-specific survival for 1,110 patients with stage III disease was 67%. Therefore, our approach compares favorably to the results of other series with similar groups of patients. However, the small sample size limits firm conclusions. Multiple analyses of radiation given as a single treatment modality have shown that the results of treatment are inferior when radiation is protracted. Therefore, many studies of concomitant treatment have attempted to integrate chemotherapy with a standard course of radiation by giving lower doses of drug on a more traditional chemotherapy schedule. Our regimen is unusual in that the radiation is administered on alternate weeks and that aggressive doses of chemotherapy are given concomitantly with irradiation 100% of the time. We have reported that traditional concepts of radiation time/dose may not apply when radiation is given with effective concomitant chemotherapy.12 Thus, newer models are necessary to account for the role of concomitant chemotherapy. These results indicate that concomitant chemotherapy and radiation in intermediate-stage head and neck cancer is feasible with very good tumor control (> 80% at 5 years). The toxicity of our regimen is acceptable and compares favorably with other series of combined modality therapy.13-15 Also, organ preservation was possible in the majority of patients. Disease was well controlled after the initial treatment in most patients. As seen in the Veterans Affairs larynx trial and the European Organization for Research and Treatment of Cancer trials, failures can be salvaged with traditional surgery.1,2 Unlike these trials, local or regional failures were uncommon in our study. These results may be partially attributable to the earlier tumor stage of patients in our study. Nevertheless, we believe that these results support the further investigation and use of concomitant chemoradiotherapy as an alternative to traditional surgery and/or radiation therapy in patients with intermediate-stage head and neck cancer. Plans are under way for a randomized trial.
Supported in part by University of Chicago Cancer Center grant no. 5-P30-CA14599-18 and Oral Cancer Research Center grant no. 1P50DE/CA11921-02. Additional support was received from the Geraldi Norton Memorial Corporation and the Robert H. Lurie Cancer Center.
1. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer: Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 324:1685-1690, 1991[Abstract]
2.
Lefebvre JL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial—EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88:890-899, 1996 3. Haraf DJ, Vokes EE, Panje WR, et al: Survival and analysis of failure following hydroxyurea, 5-fluorouracil and concomitant radiation therapy in poor prognosis head and neck cancer. Am J Clin Oncol 14:419-426, 1991[Medline]
4.
Haraf DJ, Weichselbaum RR, Vokes EE: Reirradiation with concomitant chemotherapy of recurrent unresectable head and neck cancer: A potentially curable disease. Ann Oncol 7:913-918, 1996 5. Haraf DJ, Vokes EE, Weichselbaum RR, et al: Concomitant chemoradiotherapy with cisplatin, 5-fluorouracil and hydroxyurea in poor prognosis head and neck cancer. Laryngoscope 102:630-636, 1992[Medline] 6. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 7. Schuller DE, Metch B, Mattox D, et al: Preoperative chemotherapy in advanced resectable head and neck cancer: Final report of the Southwest Oncology Group. Laryngoscope 98:1205-1211, 1988[Medline] 8. Adjuvant chemotherapy for advanced head and neck squamous carcinoma: Final report of the Head and Neck Contracts Program. Cancer 60:301-311, 1987[Medline] 9. Jacobs C, Mauch R: Efficacy of adjuvant chemotherapy for patients with resectable head and neck cancer: A subset analysis of the Head and Neck Contracts Program. J Clin Oncol 8:838-847, 1990[Abstract]
10.
Mendenhall WM, Parsons JT, Mancuso AA, et al: Definitive radiotherapy for T3 squamous carcinoma of the glottic larynx. J Clin Oncol 15:2394-2402, 1997 11. Shah JP, Karnell LH, Hoffman HT, et al: Patterns of care for cancer of the larynx in the United States. Arch Otolaryngol Head Neck Surg 123:475-483, 1997 12. Wong WW, Mick R, Haraf DJ, et al: Time-dose relationship for tumor control following alternate week concomitant radiation and chemotherapy of advanced head and neck cancer. Int J Radiat Oncol Biol Phys 29:153-162, 1994[Medline] 13. Merlano M, Vitale V, Russo R, et al: Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 327:1115-1121, 1992[Abstract]
14.
Merlano M, Benasso M, Corvo R, et al: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88:583-589, 1996
15.
Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798-1804, 1998 Submitted June 5, 1998; accepted October 23, 1998.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
