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© 1999 American Society for Clinical Oncology Phase I/II Trial of Radiation With Chemotherapy "Boost" for Advanced Squamous Cell Carcinomas of the Head and Neck: Toxicities and ResponsesFrom the Departments of Radiation Oncology, Thoracic Head and Neck Medical Oncology, and Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Adam S. Garden, MD, Department of Radiation Oncology, Box 97, U. T. M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email agarden{at}notes.mdacc.tmc.edu
PURPOSE: Extrapolating from our experience delivering a "boost" field of radiation concurrently with fields treating both gross and subclinical disease at the end of a course of radiation therapy, we developed a regimen to deliver concurrent chemotherapy during the last 2 weeks of a conventionally fractionated course of radiation. PATIENTS AND METHODS: Patients had stage III or IV biopsy-proven squamous cell carcinoma originating from a head and neck mucosal site. The regimen was 70 Gy delivered over 7 weeks with concurrent fluorouracil (5-FU) and cisplatin given daily with each radiation dose during the last 2 weeks. A phase I study was performed to determine the maximum-tolerated dose (MTD) before a phase II study was conducted. RESULTS: The MTD was 400 mg/m2 per day for 5-FU and 10 mg/m2 per day for cisplatin. Mucositis persisting more than 6 weeks after therapy was the dose-limiting toxicity. A total of 60 patients were treated on the two phases of the study. Eighteen patients (35%) treated at the MTD developed prolonged mucositis. There were two cases of neutropenic sepsis, including one fatality. The actuarial 2-year rates for overall survival, freedom from relapse, and local control were 62%, 59%, and 80%, respectively. CONCLUSION: Preliminary locoregional control rates seem to be higher than those reported for treatment with radiation alone. Toxicity was also greater than that seen with radiation alone, but the regimen was designed to deliver an intense treatment schedule, which could be completed without significant interruptions, and to obtain high control rates above the clavicles. These end points were achieved.
MORE THAN 40,000 Americans present annually with malignancies arising from mucosal head and neck sites.1 It is estimated that one half to two thirds of these patients will present with locally and/or regionally advanced disease.2 Surgery is the treatment often chosen for patients with advanced head and neck cancers, usually in combination with radiation. In our experience using combined surgery and postoperative radiation for this group of patients at The University of Texas M.D. Anderson Cancer Center, locoregional control rates range from 70% to 80%, and 5-year survival rates range from 30% to 40%.3 These results are consistent with those of other large studies using combined surgery and radiation for this cohort.4-6 Several approaches have been tested, primarily in the past decade, to improve nonsurgical results of treatment of advanced head and neck cancers. Numerous centers have participated in both randomized and nonrandomized trials evaluating more aggressively fractionated radiation schedules in an attempt to improve both disease control rates and survival for patients with advanced squamous cell carcinomas. Encouraging results have been seen in some of these trials, particularly for patients with intermediate staged (T2 to T3) disease.7-13 Other studies have either not shown a disease control advantage or have demonstrated limits to the amount of treatment acceleration that can be tolerated.14-17 At the M.D. Anderson Cancer Center, we have used a radiation schedule colloquially referred to as "concomitant boost."18,19 This is a schedule of accelerated fractionation in which a smaller, or boost, dose is given as a second daily fraction to a volume encompassing gross disease only. This boost is given in the latter half of a 6-week radiation schedule. The timing of the boost was evaluated in a randomized trial,7 and the advantage of giving the boost dose at the end of the schedule seemed consistent with the radiobiologic principle of accelerated repopulation.20 When this schedule was used, control rates of T2 and selected T3 oropharyngeal lesions were greater than 90% and 75%, respectively. A second avenue pursued to improve results of nonsurgical treatment of advanced head and neck cancers is to combine systemic therapies with radiation. Neoadjuvant chemotherapy and radiation have been tested in large randomized trials,21,22 which have demonstrated that organ preservation without a compromise in survival is possible. However, these trials have not demonstrated that local control is improved with sequential chemotherapy and radiation compared with radiation alone. To improve local and regional control, many investigators have studied concurrent administration of chemotherapy and radiation.23-27 Similar to experiences with accelerated radiation, the ability to improve disease control with these more intensive regimens has to be balanced with an acceptable toxicity of treatment.28,29 Our goal was to design a combination therapy program that would improve control rates, have acceptable toxicity, and be deliverable without significant interruptions. Because the modes and timing of chemotherapy and radiation are quite different, investigators have taken widely varying approaches in delivering their combination programs.30-32 We believed it was important to design a program in which, ideally, the toxicities of one modality would not hinder the ability to deliver the other. By delivering the systemic therapies at the end of the radiation, we believed patients would be able to tolerate the therapy best because the toxic effects would not occur until the latter portion of therapy. Local toxicity would be lessened because the drugs would be delivered when the radiation volume was smallest. Furthermore, moderate-dose radiotherapy is sufficient to sterilize subclinical disease in the neck, making combined-modality treatment during this phase of the therapy unnecessary. Finally, from a biologic standpoint and based on our experience with the radiation-alone concomitant boost schedule, we inferred that late intensification of treatment, particularly with a phase-specific agent such as fluorouracil (5-FU), would be the best strategy to counter accelerated repopulation of surviving tumor clonogens. At the time of designing the trial, we chose 5-FU and cisplatin as the most efficacious drug combination for treating head and neck cancer. Two randomized trials had just demonstrated greater efficacy with this combination compared with either agent alone or with single-agent methotrexate.33,34 The study design was to use conventionally fractionated, once-daily 2-Gy fractions of radiation with chemotherapy added during the last 2 weeks of therapy, when we traditionally reduce the volume of radiation. Because these drugs are more typically given over a 4- or 5-day schedule and the study was designed to deliver the drugs over 2 weeks, we began with a phase I design to determine the maximum-tolerated dose (MTD) with this schedule. Once the MTD was determined, we proceeded with a phase II study.
Patients were required to have histologic evidence of squamous cell carcinoma from a mucosal head and neck site. Nasopharyngeal primary tumors were excluded. Only patients with stage III or IV disease were eligible, and patients with distant metastases were excluded. Patients were required to have a Zubrod performance status score of less than or equal to 2, and those with a prior history of cancer, excluding early skin cancer (defined as stage I or II basal or squamous cell carcinomas of the skin), were ineligible. Minimum laboratory criteria required included an absolute granulocyte count of more than or equal to 1,500 cell/mL, a platelet count of more than or equal to 100,000 cells/mL, a bilirubin count of less than or equal to 1.5 mg/dL, an AST level no more than four times the upper limit of normal, and a serum creatinine level of less than or equal to 1.5 mg/dL. Planned treatment consisted of a total dose of radiation of 70 Gy delivered in 35 fractions in 7 weeks. A shrinking field technique was used. The initial 50 Gy was delivered both to the gross clinically evident disease and to subclinical sites of disease extension. These sites included the draining lymphatics of the neck to the supraclavicular fossa. The radiation fields were reduced to limit the spinal cord to a maximum dose of 45 Gy. The uninvolved posterior cervical nodes excluded from this field reduction were supplemented with separate electron fields to 50 Gy. The final 20 Gy, the boost component, was delivered to the original clinically evident disease only. These boost fields had a 1- to 1.5-cm margin around this disease. The chemotherapy was to be delivered concurrently with the radiation therapy boost. Concurrent with the radiation, cisplatin (10 mg/m2) was infused over 30 minutes to 1 hour daily, 5 days per week for 2 weeks. 5-FU was to be delivered as a 24-hour infusion during each of the last 10 days of radiation therapy. The study was divided into phase I and phase II. The radiation component was fixed, and the goal of phase I was to determine the MTD of the two drugs. The initial dose of 5-FU was 260 mg/m2. This was escalated in the study cohorts to 320, 400, and 500 mg/m2. The dose of cisplatin was maintained at 10 mg/m2. Planned de-escalation of the dose of cisplatin was designed into the study only if the initial cohort did not tolerate the regimen. Planned cisplatin dose escalation was never reached because it was to be delivered with even higher doses of 5-FU that were deemed too toxic. The dose-limiting toxicity (DLT) was based on the toxic effects that developed in cohorts of three to six patients at each dose level. Both systemic and in-field (mucosal and skin) toxic effects were evaluated. The development of grade 3 or 4 systemic toxicities (Cooperative Group Common Toxicity Criteria, 1989) in two of six patients was considered DLT, and the previous dose level would then be evaluated. Confluent mucositis was an expected sequela. If grade 4 mucositis, defined as confluent mucositis of greater than one half the treated mucosal volume, developed in all three patients in a cohort, then that dose was considered the MTD and an additional three patients would be accrued in that cohort. However, the development of mucositis lasting longer than 6 weeks after completion of all therapies was considered to be a grade 4 systemic toxicity, and the same criteria for determining DLT were applied. After determination of the MTD, patients were enrolled onto the phase II component. Patient enrollment onto the study began in November 1993 and was completed in June 1997. Before enrollment of patients, our institutional review board and clinical research committee approved the trial. Written informed consent was obtained from each patient before his or her participation in the study. Data analysis was performed during July 1998. Actuarial survival curves were generated using the Kaplan-Meier method.35
Seventeen patients were enrolled onto the phase I portion of the study. One patient's performance status deteriorated rapidly after registration. He was treated with palliative radiation and supportive care and removed from the study. DLT for 5-FU was reached at 500 mg/m2 because all three patients at this dose level had in-field mucositis persisting longer than 6 weeks. Seven patients were treated at the MTD of 400 mg/m2 of 5-FU with acceptable toxicity before beginning the phase II portion of the study. There were no cases of neutropenic sepsis in the phase I cohort and only one case of grade 4 neutropenia and one case of grade 3 thrombocytopenia, both occurring in one of the seven patients treated at the MTD. Forty-seven patients were enrolled onto the phase II component of the study. Three patients refused chemotherapy during their treatment but completed their planned courses of radiation. Thus, 60 (94%) of the 64 patients registered onto the study received the planned combined therapy. Patient and tumor characteristics of these 60 patients are detailed in Table 1. Patients' ages ranged from 19 to 73 years (median, 58 years). Forty-eight (80%) of these patients had stage IV disease, and the remaining 12 patients had stage III disease. Table 2 is a matrix of tumor stage versus node stage. The 60 patients completed the therapy over a range of 45 to 53 days (median, 48 days).
Fifty-one patients were treated at the MTD. Hematologic and in-field toxic effects are detailed in Table 3. Forty-seven patients (92%) developed confluent mucositis, and 18 patients (35%) had mucositis persisting longer than 6 weeks. There was one case of skin necrosis, but this developed in a patient with moist desquamation of the skin at 40 Gy. The median granulocyte and platelet nadirs were 1,300 and 112,000 cells/mL, respectively. There were two cases of neutropenic sepsis. Forty-three patients (84%) had nutritional support during their therapy. Forty patients had percutaneous fluoroscopically guided gastrostomy tubes placed. Seven patients had their tubes placed at the start of treatment. Two patients had nasogastric tubes placed, and one patient received total parenteral nutrition.
Three patients died before their first planned evaluation at 6 weeks after treatment, including one patient with neutropenic sepsis. The second patient had sudden death at 6 weeks, and the third death was attributed to a pulmonary embolism 3 weeks after treatment. Fifty-four patients (90%) had complete responses at their primary tumor sites. Forty-eight patients had assessable nodal disease at the start of treatment. One patient with N1 disease had a diagnostic excisional biopsy performed before his treatment and therefore could not be evaluated for nodal response. Twenty-seven (57%) of the 47 patients with assessable nodal disease had clinical complete responses in their necks. Two patients with positive nodes died before their first evaluation (described above), and two patients had distant disease at their first posttherapy evaluation so the residual neck disease was not addressed. Seventeen patients had neck dissections for residual masses, and 10 (59%) of these patients had negative pathologic specimens. The median duration of follow-up was 20 months (range, 2 to 55 months), and all surviving patients had a minimum of 1-year follow-up. The actuarial 2-year survival rate was 62%. The actuarial 2-year primary control rate was 80% (Fig 1). Only one patient who achieved a complete response in the neck had disease recur in the neck, and this was associated with primary and distant recurrence. None of the patients with negative nodes and none of the patients who had neck surgery developed regional disease. The actuarial 2-year freedom from relapse rate was 59% (Fig 1) because 13 patients developed distant metastases but remained free of disease above the clavicles. Six (46%) of these 13 patients originally presented with stage N3 disease.
We believe the goals of this trial were met successfully. All patients (except three patients who refused the systemic component after enrollment and one who deteriorated rapidly after registration and was removed from the study) completed their combined therapies. Treatment breaks were uncommon and were limited to 4 days at most, primarily because of holidays and adverse weather conditions rather than treatment toxicity requiring discontinuation of therapy. Toxic effects, for most patients, were acceptable. The rates of confluent mucositis were comparable to those seen in our concomitant boost radiation–only experience.7 There was a higher proportion of patients with prolonged mucositis in this study, but all patients had their mucosal ulcerations heal. Late toxicities have yet to be evaluated. More than 80% of the patients had feeding tubes, which highlights the importance of supporting these patients aggressively. We achieved a high, primary site, complete response rate of 90%. The majority of these responses seem to be durable, with a 2-year local control rate of 80%, although longer follow-up will be required to establish this result. This control rate is comparable to control rates of our patients treated in concomitant boost radiation–alone trials, but the patients in this current trial generally had more advanced-stage disease. The locoregional control rate in this trial of concurrent chemoradiation therapy is also comparable to locoregional control rates for patients treated with combined surgery and postoperative irradiation. In this study, however, surgery to the primary sites was avoided, which resulted in a better functional outcome for many of the treated patients. Two issues raised by this trial, one involving mortality and the other involving metastatic disease, require further thought. Three patients died in the interval immediately after treatment. One death was related to therapy. The other two events were cardiopulmonary, and although the deaths were not clearly related to therapy, the temporal relationship of these events to treatment is disturbing. Second, as locoregional results seem to improve, the problem of patients succumbing to distant metastases becomes more prominent, particularly for patients with advanced nodal disease. Therefore, intensification of local therapies alone is not the entire solution for all patients with advanced head and neck cancers. Numerous trials have demonstrated that either neoadjuvant or adjuvant chemotherapy can decrease the incidence of hematogenous metastases.6,21 Thus, integrating active systemic therapy, either before or after concurrent chemoradiation therapy may be the next approach,36 particularly as newer drug combinations show higher response rates in the treatment of patients with squamous cell carcinomas of the head and neck.37 Subsequent to the completion of our trial, reports of two randomized single-institution trials of 5-FU plus cisplatin and concurrent radiation for treating head and neck cancer have been published.25,38 Both trials used two 4- or 5-day cycles of the drugs during continuous radiation without planned breaks. Adelstein et al25 used cumulative doses per cycle of 4,000 mg/m2 of 5-FU and 80 mg/m2 of cisplatin delivered during weeks 1 and 4 of radiation. They demonstrated that progression-free survival was improved in patients treated with concurrent therapy compared with a control group of patients treated with radiation alone, but the latter group was treated over a median time of 56 days. Brizel et al38 used cumulative doses per cycle of 3,000 mg/m2 of 5-FU and 60 mg/m2 of cisplatin. The drugs were given during weeks 1 and 5 of a course of hyperfractionated radiation. Locoregional control was improved in the patients receiving chemotherapy, compared with a control group receiving hyperfractionated radiation only. Although the improvement in control rates is attributed to the concurrent therapy, the study also planned two additional courses of postradiotherapy chemotherapy, which were administered to 65% of patients who had complete responses to combination chemotherapy and radiation. The patients who did not receive the planned adjuvant chemotherapy component of the trial had a crude isolated distant metastases rate of nearly 30%. Although the previously mentioned studies and our study evaluated patients with stage III and IV squamous cell carcinomas of the head and neck, direct comparisons among them are difficult. Our study had a greater proportion of patients with pharyngeal primaries, as well as a higher percentage of patients with N2 and N3 nodal disease. Our locoregional control rates, however, seem similar to those reported in the experimental arms of the other two randomized concurrent chemotherapy and radiation trials. It is noteworthy that the improvements in locoregional control seen in the trial by Brizel et al38 seem attributable to improved regional control, inasmuch as there were no regional failures in the experimental study group. Similarly, we did not see any isolated regional recurrences, despite 81% of our patients presenting with nodal disease. In conclusion, this trial demonstrated the feasibility and activity of a novel approach for combining chemotherapy and radiation. Although clearly not every patient with advanced head and neck cancer can tolerate such an intensive regimen, the approach of chemotherapy delivered concurrently with the latter, or boost, portion of radiation may achieve a high rate of local and regional control for patients whose disease does not seem suitable for treatment with radiation alone. This regimen currently is being assessed in a three-arm Radiation Therapy Oncology Group randomized trial, along with two other novel concurrent chemotherapy-radiation regimens, one evaluating concurrent 5-FU and hydroxyurea and the other evaluating weekly paclitaxel and cisplatin.
Supported by National Institutes of Health research grant no. CA06294
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Brizel D, Albers M, Fisher S, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med338:1798-1804, 1998 Submitted October 15, 1998; accepted March 30, 1999. This article has been cited by other articles:
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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
