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Phase I Trial of Gefitinib in Combination With Radiation or Chemoradiation for Patients With Locally Advanced Squamous Cell Head and Neck Cancer

Changhu Chen, Madeleine Kane, John Song, John Campana, Adam Raben, Kenneth Hu, Louis Harrison, Harry Quon, Janet Dancey, Anna Baron, Sherif Said, S. Gail Eckhardt, David Raben

From the Departments of Radiation Oncology, Medical Oncology, Otolaryngology, Preventive Medicine and Biometrics, and Pathology, University of Colorado, Aurora, CO; Department of Radiation Oncology, Christiana Hospital Medical Center, Wilmington, DE; Department of Radiation Oncology, Beth Israel Medical Center, New York, NY; Department of Radiation Oncology, University of Pennsylvania Medical Center, Philadelphia, PA; and National Cancer Institute, Bethesda, MD

Address reprint requests to David Raben, MD, Department of Radiation Oncology, University of Colorado Health Sciences Center, 1665 N Ursula St, Mail Stop F706, Aurora, CO 80045; e-mail: David.Raben{at}uchsc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix 1: Gefitinib Dose... Appendix 2: Radiation Therapy REFERENCES

 
Purpose: To establish the safety and toxicity profile of daily gefitinib with radiation alone or with concurrent chemoradiotherapy in previously untreated patients with locally advanced squamous cell head and neck cancer (LAHNC).

Patients and Methods: Patients with intermediate-stage LAHNC were treated with concomitant boost radiation (RT) alone with escalating doses of daily gefitinib (250 or 500 mg; cohort I). Once a safety profile was determined with RT alone, patients with high-risk disease were then treated with daily gefitinib (250 or 500 mg), weekly cisplatin (CDDP; 30 mg/m²), and once-daily RT (cohort II). Patients also received post-RT gefitinib at 250 mg daily for a period of up to 2 years.

Results: Twenty-three patients were enrolled and assessable for toxicity. No dose-limiting toxicities (DLTs) were observed in patients treated in cohort I at either 250 or 500 mg of gefitinib daily with concomitant boost RT to 72 Gy. In patients receiving chemoradiotherapy and gefitinib (cohort II), DLTs included one grade 4 diarrhea and one grade 4 neutropenic fever. Fifteen patients started maintenance gefitinib, and eight (53%) experienced grade 1 to 2 acne-like skin rash and diarrhea, but no grade 3 or 4 toxicity occurred.

Conclusion: Gefitinib (250 or 500 mg daily) was well tolerated with concomitant boost RT or concurrent chemoradiotherapy with weekly CDDP. Protracted administration of gefitinib for up to 2 years at 250 mg daily was also tolerated well.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix 1: Gefitinib Dose... Appendix 2: Radiation Therapy REFERENCES

 
The introduction of targeted agents against the epidermal growth factor receptor (EGFR) pathway has improved survival in locally advanced squamous cell head and neck cancer (LAHNC). Bonner et al¹ demonstrated in a phase III randomized trial that concomitant radiation (RT) therapy plus cetuximab, an EGFR-specific antibody, improved locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) in LAHNC patients.

Gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE) works as a potent and specific EGFR tyrosine kinase inhibitor (EGFR-TKI) by competing with adenosine triphosphate for the binding site on the intracellular domain of the receptor and by noncompetitively inhibiting epidermal growth factor peptide ligand. EGFR agents radiosensitize tumor cells by a variety of mechanisms, including reduction in the proportion of cells in the radioresistant S phase by inducing G₀/G₁ cell cycle arrest, inhibition of RT-induced damage repair, and induction of apoptosis.² Gefitinib has been shown to inhibit repair of RT-induced DNA double-strand breaks.³ EGFR expression levels in head and neck cancer (HNC) cell lines correlated with increased RT resistance,⁴ and gefitinib enhanced radiosensitivity in HNC cells.⁵ In xenograft tumor models, gefitinib in combination with RT resulted in synergistic growth inhibition.⁶ Al-Hazzaa et al⁷ observed a significant decrease in the percentage of surviving cells on treatment with gefitinib and cisplatin (CDDP) compared with CDDP or gefitinib alone in a human HNC cell line. Gefitinib applied before RT and before and/or during CDDP/fluorouracil improved the cytotoxic effect in HNC cell lines.⁸ Thus, combining gefitinib with RT or chemoradiotherapy showed cooperative effects in preclinical studies and warranted clinical investigation in patients with LAHNC.^9,10

Phase I studies indicated that gefitinib monotherapy was well tolerated, generally with mild, manageable, and reversible adverse effects at doses up to 600 mg/d. The most frequent drug-related adverse events were acne-like skin rash in 46% to 64% of patients and diarrhea in 47% to 55% of patients.^11,12

Gefitinib was tested as a single therapeutic agent in phase II trials in patients with recurrent or metastatic squamous cell HNC. A daily dose of 500 mg was well tolerated, with grade 1 to 2 skin rash in 48% of patients, grade 1 to 2 diarrhea in 42% of patients, and grade 3 diarrhea in 6% of the patients. The observed response rate was 10.6%, and the disease control rate was 53%, with a suggestion that 500 mg seemed more active than 250 mg.^13-15

The toxicity and safety of combining gefitinib with RT or chemoradiotherapy as definitive therapy for LAHNC has not been reported. We conducted a National Cancer Institute (NCI) Clinical Trials Evaluation Program (CTEP) –sponsored, multi-institutional, phase I, dose-escalation study of gefitinib in combination with RT or chemoradiotherapy in patients with LAHNC to establish the safety and toxicity profile regarding this therapeutic strategy. Because EGFR overexpression seems to be important in HNC carcinogenesis and HNC patients have increased risk in developing a secondary primary tumor and distant metastasis, we also studied the safety, feasibility, and toxicity profile of protracted administration of gefitinib as maintenance therapy for a period of up to 2 years.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix 1: Gefitinib Dose... Appendix 2: Radiation Therapy REFERENCES

 
Eligibility Criteria
This study and its subsequent amendments were approved by CTEP and by the University of Colorado institutional review board as well as by institutional review boards at all participating institutions. All patients provided written informed consent before trial entry. Patients with pathologically confirmed, American Joint Committee on Cancer stage III or IV LAHNC involving the oral cavity, oropharynx, hypopharynx, or supraglottic or glottic larynx were eligible. Patients were 18 years old and had an Eastern Cooperative Oncology Group performance status 2 (Karnofsky performance status > 60%) and a life expectancy of more than 6 months. Patients had to be medically suitable for definitive RT or chemoradiotherapy with normal organ and bone marrow function. Exclusion criteria included evidence of distant metastasis, previous RT within the intended treatment volume, previous chemotherapy, definitive surgery for the tumor under study other than biopsy, and prior anti-EGFR therapy.

Study Design
The trial was designed to initially treat patients with intermediate-stage LAHNC with RT and gefitinib. Once the safety of this approach was established, the trial then proceeded to concurrent chemoradiotherapy and gefitinib. Cohort I consisted of patients with intermediate-stage LAHNC (T1-2, N1-2a and T3, N0-1) deemed appropriate for management with 72 Gy of concomitant boost RT. Cohort II accrued patients with high-risk LAHNC (T3-4, N2b-3) treated with 70 Gy of once-daily RT with weekly CDDP at 30 mg/m². In both cohorts, the gefitinib dose was escalated from the initial 250 mg daily to 500 mg daily (Table 1). The rules for gefitinib dose escalation and the actual number of patients accrued to each dose level are described in Appendix 1 (online only).

Planned follow-up consisted of visits every month for the first year, once every 4 months for the second year, and once every 6 months in years 3 to 5. Evaluations at each follow-up visit consisted of a physical examination, hematology and chemistry profiles, tumor assessments, and an objective assessment of adverse events.

RT
Patients in cohort I received concomitant boost RT to a total dose of 72 Gy. For patients in cohort II receiving concurrent chemoradiotherapy, two RT techniques were used. In the early stage of the trial, patients were treated with conventional three-dimensional RT. This trial was later amended to allow for intensity-modulated RT with salivary sparing. For both RT techniques, 70 Gy was administered. More detailed description of the RT techniques can be found in Appendix 2 (online only).

Chemotherapy
Concurrent CDDP chemotherapy was administered at 30 mg/m² intravenously (IV) once a week during RT for patients in cohort II. All patients were premedicated with antiemetics and were prehydrated with IV fluids. CDDP was administered in 250 mL of normal saline with mannitol 12.5 g IV over 30 to 60 minutes. Chemotherapy was administered on Monday or Tuesday of each full week of RT.

Gefitinib Therapy
Patients started taking gefitinib by mouth 7 days before RT and continued during RT or chemoradiotherapy at 250 or 500 mg daily per the protocol. Patients stopped gefitinib at the completion of RT or chemoradiotherapy for 4 to 8 weeks to recover from acute adverse effects. Patients then resumed gefitinib at 250 mg daily for up to 2 years or until disease recurrence or progression or dose-limiting toxicity (DLT).

Definition of DLT and Maximum-Tolerated Dose
Toxicities were scored with NCI Common Toxicity Criteria version 2. DLT was defined as any grade 4 nonhematologic or hematologic toxicity that lasted 7 days, any delay in RT greater than 1 week, and any toxicity that required a treatment break from gefitinib for more than 2 weeks during RT. Toxicities associated with maintenance gefitinib were reviewed separately. The maximum-tolerated dose was defined as one dose level below that at which two of six patients experienced a DLT.

Definition of Response
Response and progression were evaluated using the Response Evaluation Criteria in Solid Tumors.¹⁶

Statistical Considerations
The primary end points are DLT and maximum-tolerated dose. The secondary end points are response rate, DFS, and OS.

Data Analysis
All patients who started the treatment were evaluated for safety analysis. Toxicity was classified by type, grade, and probable relationship to study treatment. Response to treatment was presented using the descriptive method. LRC, DFS, and OS were described using the Kaplan-Meier method. LRC was defined as disease control within the RT field. DFS was defined as the time from treatment start to locoregional or distant failure, and OS was defined as the time from treatment start until death from any cause.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix 1: Gefitinib Dose... Appendix 2: Radiation Therapy REFERENCES

 
Patient and Disease Characteristics
Between August 2002 and June 2006, 23 patients were enrolled. The patient characteristics are listed in Table 2, and tumor and nodal staging are listed in Table A1 (online only). Eight patients had intermediate-stage disease that was treated with concomitant boost RT and gefitinib. Fifteen patients had more advanced disease and received concurrent chemoradiotherapy and gefitinib. At the time of analysis, 17 of the 23 patients were alive. The median follow-up time was 33 months (range, 7.4 to 54.4 months) for surviving patients and 26.3 months (range, 5.0 to 54.4 months) for all patients.

Toxicity
Acute toxicities during concurrent gefitinib and RT or chemoradiotherapy therapy are listed in Table 3. The most common acute toxicity was mucositis, which occurred in all 23 patients, reaching grade 3 in 12 patients (52%) and grade 4 in one patient (4%). Gefitinib-related acne-like skin rash occurred in 18 patients (78.3%), and all rashes were grade 1 or 2. Two patients experienced DLT. One patient on cohort II with concurrent chemoradiotherapy and gefitinib at 250 mg developed grade 4 diarrhea. This patient also had concurrent Clostridium difficile infection. The patient was on break from concurrent chemoradiotherapy for 17 days and was taken off gefitinib. Another patient who was treated on cohort II with gefitinib at 500 mg developed grade 4 neutropenic fever, requiring hospital admission and a break from chemoradiotherapy for 12 days. This patient subsequently developed diffuse bony metastasis and grade 3 hypercalcemia. Table 4 lists the grade 3 to 4 toxicities stratified by patient cohort. The incidence of grade 3 to 4 radiation dermatitis (12.5% in cohort I and 13.3% in cohort II) and mucositis (62.5% in cohort I and 60% in cohort II) was similar in both cohorts. Grade 3 to 4 neutropenia and dehydration as well as electrolyte disturbances all occurred in cohort II patients receiving concurrent CDDP chemotherapy.

Treatment Outcomes
Two patients had stable disease, and the rest (91%) had a clinical complete response in the primary tumor. Of the 17 patients with N1 disease in the neck, 14 (82%) had a clinical complete response, two (12%) had a partial response, and one had persistent disease. The latter three patients underwent neck dissection, and all had residual tumor. Three additional patients also underwent neck dissection (one with initial N2b disease and two with N3 disease), and pathology revealed no residual tumor. With a median follow-up time of 26.3 months (range, 5 to 54.4 months), one patient developed local recurrence only, one patient developed local recurrence and distant metastasis in the lung, and one patient experienced recurrence in the neck lymph node. Four patients developed distant metastasis only (two in the lungs, one in the liver, and one with diffuse bony metastasis; Table 5). Six patients died; two died from disease progression of distant metastasis, one died from disease progression in the primary tumor and distant metastasis, one died from non–small-cell lung cancer, one died from chronic obstructive pulmonary disease, and one died from pneumonia. The estimated rates of 1-year LRC, DFS, and OS were 91%, 82%, and 87%, respectively; at 3 years, these rates were 85%, 61%, and 74%, respectively (Fig 1).

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier curves of locoregional control (LRC), disease-free survival (DFS), and overall survival (OS). All enrolled patients are included in the analysis.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix 1: Gefitinib Dose... Appendix 2: Radiation Therapy REFERENCES

In cohort II, two patients experienced DLT. One patient developed grade 4 diarrhea. The relationship of this patient's grade 4 diarrhea to gefitinib was compromised by concurrent C difficile infection. The second patient experienced grade 4 neutropenia, which was attributed to bone marrow suppression from concurrent CDDP chemotherapy. Seven (30%) of 23 patients developed grade 3 to 4 neutropenia (five had grade 3 and two had grade 4); all of these patients received concurrent CDDP. No patient in cohort I treated with gefitinib and RT developed neutropenia.

The profile of acute toxicity during concurrent gefitinib and chemoradiotherapy was consistent with the toxicity profile reported in the larger chemoradiotherapy trials, with grade 3 mucositis in the range of 43% to 77%.^17,18 Gefitinib does not seem to increase chemoradiotherapy-related mucositis and skin reaction.

The effect of erlotinib, an alternative EGFR-TKI, at 150 mg/d combined with CDDP-RT in LAHNC was reported in phase II preliminary data with acceptable toxicity but a high incidence (45%) of grade 3 to 4 in-field dermatitis.²⁰ Further phase II and III trials are needed to determine the efficacy of combining EGFR-TKIs (gefitinib or erlotinib) with chemoradiotherapy in LAHNC. We recently completed a randomized, multicenter, phase II trial to evaluate CDDP-RT with either placebo or gefitinib at 250 or 500 mg daily. Patients were also randomly assigned to maintenance gefitinib or placebo. It is unclear at this point where EGFR-TKIs will fit into the targeted therapy armamentarium with chemoradiotherapy. The potential advantages of EGFR-TKIs include ease of administration and no issues with infusion reactions. Monotherapy trials seem to show similar response rates and survival rates between EGFR antibodies and EGFR-TKIs in metastatic, chemotherapy-refractory HNC. It is unlikely that a clinical trial will directly compare the two approaches with RT. The success of combining cetuximab with RT led to the ongoing Radiation Therapy Oncology Group 0522 phase III trial comparing chemoradiotherapy with chemoradiotherapy and cetuximab.

An intriguing area for investigation is the strategy of blocking two aspects of the same pathway. The combination of cetuximab plus gefitinib or erlotinib enhanced growth inhibition compared with either agent alone in a mouse xenograft model, suggesting that combined treatment with distinct EGFR inhibitory agents can augment the potency of EGFR signaling inhibition.²¹ This approach suggests potential new strategies to maximize target inhibition, which may improve the therapeutic ratio for anti-EGFR–targeted therapies.

Protracted administration of gefitinib as maintenance therapy was well tolerated in the study patients. Six patients completed maintenance gefitinib for 2 years, and the median time for patients on gefitinib was 19 months. Although patients discontinued the study drug for a variety of reasons, no patient stopped as a result of grade 3 or 4 toxicity. No other toxicity was encountered during maintenance gefitinib.

Recent data have emerged in patients with stage III non–small-cell lung cancer, in whom gefitinib 250 mg daily after chemoradiotherapy and consolidative chemotherapy did not improve survival.²² At the time our trial was designed, there was no information regarding the efficacy of maintenance EGFR inhibition. Our goal was to evaluate whether maintenance gefitinib was indeed feasible and safe. The true efficacy of gefitinib maintenance therapy in LAHNC can only be determined in phase II and III trials. Recent preclinical data have demonstrated that, after combination treatment with cetuximab and RT, further maintenance cetuximab in an animal model bearing human head and neck squamous cell carcinoma xenografts resulted in an improved RT dose modification factor of 2.7 when administered both during and after RT versus 1.8 when administered during RT only. Cetuximab effectiveness was greater when administered as both concurrent and maintenance therapy.²³

In conclusion, to our knowledge, this is the first report that, in the definitive treatment of LAHNC patients, gefitinib at daily dose of either 250 or 500 mg was well tolerated with concomitant boost RT or concurrent chemoradiotherapy with weekly CDDP. Oral administration of gefitinib for up to 2 years at 250 mg daily was also tolerated well. Adverse effects did not seem to accumulate over protracted administration.

The clinically appropriate dose of gefitinib (250 or 500 mg) in combination with chemoradiotherapy and the efficacy of gefitinib as concurrent and maintenance therapy in LAHNC can only be determined in efficacy trials. The preliminary results of a phase II study from the University of Chicago demonstrate that adding gefitinib 250 mg daily to concurrent chemoradiotherapy after induction therapy and as adjuvant therapy for 2 years is tolerable and feasible. Favorable survival (73% at 3 years) and complete response data (91%) suggest that this is a promising regimen for patients with LAHNC.^24,25 A phase II, randomized, double-blind, placebo-controlled, seven-arm, multicenter study sponsored by AstraZeneca Pharmaceuticals has completed patient accrual and is currently under analysis. The primary objective of the study was to assess the additive effect of gefitinib 250 or 500 mg (administered either concomitantly or as maintenance) with CDDP plus RT in terms of local disease control and disease-free survival rate at 2 years.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix 1: Gefitinib Dose... Appendix 2: Radiation Therapy REFERENCES

 
Employment or Leadership Position: None Consultant or Advisory Role: S. Gail Eckhardt, AstraZeneca Pharmaceutical Inc (C); David Raben, AstraZeneca Pharmaceutical Inc (C) Stock Ownership: None Honoraria: None Research Funding: Changhu Chen, AstraZeneca Pharmaceuticals Inc; Madeleine Kane, AsreaZeneca Pharmaceutical Inc; S. Gail Eckhardt, AstraZeneca Pharmaceutical Inc; David Raben, AstraZeneca Pharmaceutical Inc Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix 1: Gefitinib Dose... Appendix 2: Radiation Therapy REFERENCES

 
Conception and design: S. Gail Eckhardt, Anna Baron, David Raben

Administrative support: Janet Dancey, David Raben

Provision of study materials or patients: Changhu Chen, Madeleine Kane, John Song, John Campana, Adam Raben, Kenneth Hu, Louis Harrison, Harry Quon, Sherif Said, S. Gail Eckhardt, David Raben

Collection and assembly of data: Changhu Chen, David Raben

Data analysis and interpretation: Changhu Chen, Madeleine Kane, Anna Baron, David Raben

Manuscript writing: Changhu Chen, Madeleine Kane, David Raben

Final approval of manuscript: Changhu Chen, Madeleine Kane, John Song, John Campana, Adam Raben, Kenneth Hu, Louis Harrison, Harry Quon, Janet Dancey, Anna Baron, Sherif Said, S. Gail Eckhardt, David Raben

	Appendix 1: Gefitinib Dose Escalation

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix 1: Gefitinib Dose... Appendix 2: Radiation Therapy REFERENCES

 
The initial plan was to accrue six patients to each dose level (250 and 500 mg daily) in each cohort. If one or none of six patients had dose-limiting toxicity (DLT), then escalation proceeded. If DLT occurred in two or more patients at a dose level, then escalation was stopped. The dose level below that at which two of six patients experienced a DLT was defined as the maximum-tolerated dose. Escalation to the next dose level was not allowed until at least six patients in a given dose level had completed radiotherapy. A minimum of 4 weeks of observation was required after completion of radiation within each gefitinib dose level before accrual to the next level.

However, in cohort I, after the first five patients experienced no adverse events with concomitant boost radiation and gefitinib 250 mg daily, a decision was made to return to a more traditional 3 + 3 design for gefitinib 500 mg with concomitant boost radiation. Therefore, five patients were treated with gefitinib 250 mg daily and three patients were treated with gefitinib 500 mg daily with concomitant boost external-beam radiation. When the study proceeded to the second cohort of gefitinib with chemoradiotherapy, six patients were treated at the 250-mg gefitinib dose level. One patient experienced grade 4 diarrhea with Clostridium difficile infection. Gefitinib probably contributed to the diarrhea. Another patient experienced grade 3 dehydration and grade 3 hypokalemia, hyponatremia, and hypocalcemia. A third patient developed pulmonary embolism. Although the latter two patients' toxicity was deemed not related to gefitinib, an amendment was made to add three more patients to the 250-mg gefitinib dose level in cohort II to ensure that the treatment was tolerated. In the end, nine patients were treated on cohort II with gefitinib 250 mg daily with concurrent chemoradiotherapy. Finally, six patients were accrued to the last dose level of gefitinib 500 mg with chemoradiotherapy. A total of 23 patients were treated on the study. All of the changes were discussed with the study biostatistician and approved by National Cancer Institute Cancer Therapy Evaluation Program and local institutional review board.

	Appendix 2: Radiation Therapy

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix 1: Gefitinib Dose... Appendix 2: Radiation Therapy REFERENCES

 
Computed tomography (CT) simulation was required for treatment planning. The patients were simulated in the supine position. An aquaplast mask was used for immobilization. CT images were obtained for target delineation with 3-mm slice thickness.

Dosimetric volume definitions. The gross tumor volume (GTV) represented primary tumor and positive lymph nodes as documented by clinical examination, CT, or magnetic resonance imaging studies. The clinical target volume (CTV) represented the GTV plus areas that were at high risk for microscopic involvement. Generally, the minimal margin that was included around GTV was 5 mm. The planning target volume (PTV) represented the CTV plus appropriate margin. The minimum margin around the CTV was 5 mm.

Because all of the patients enrolled onto this trial had stage III and IV disease, treatment of the regional lymphatics was required depending on the site of the primary tumor. In general, the lymphatics covered included lateral retropharyngeal lymph nodes (primarily for oropharyngeal lesions); upper, middle, and lower internal jugular vein lymph nodes; and supraclavicular nodes. Other lymph node regions were included if they were clinically involved.

Radiation portals, dose, and fractionation. Initially, patients entered onto this trial were treated using conventional radiation techniques followed by three-dimensional conformal boost (Bonner JA, Harari PM, Giralt J, et al: N Engl J Med 354:567-578, 2006; Fu KK, Pajak, TF, Trotti A, et al: Int J Radiat Oncol Biol Phys 48:7-16, 2000). This trial was later amended to allow for the use of intensity-modulated radiation therapy (IMRT) with salivary sparing. Regarding the former, patients were initially treated using two opposed lateral upper neck fields covering the primary tumor and regional lymphatics. A single lower anterior neck field was matched to the upper field. Tissue equivalent compensators were used to ensure homogeneity of dose distribution so that radiation dose variation within the target volume did not exceed 10% of the target dose.

When chemoradiotherapy was delivered, radiation was administered once daily at 2 Gy per fraction. The upper opposed lateral ports received an initial photon dose of 54 Gy, and the spinal cord and posterior neck were blocked after a dose of 42 Gy. Electrons (9 to 12 MeV) were used to bring the posterior neck radiation dose up to 50 to 54 Gy. A dose of 50 Gy (2 Gy/fraction) was delivered to the lower neck and supraclavicular area. Three-dimensional conformal techniques were used to deliver an additional 16 Gy final boost to the PTV for a total dose of 70 Gy.

For the concomitant boost regimen, radiation field sizes and arrangements were similar to our once-daily conventional radiation regimen. No IMRT was used with concomitant boost. A dose of 54 Gy in 1.8-Gy fractions was administered through the initial upper neck lateral fields with electrons again used to supplement the dose to the posterior neck as described earlier. A similar dose of 50 Gy was delivered to the lower neck and supraclavicular fossae through a matching lower anterior neck field. Three-dimensional conformal techniques were used to deliver an additional 18 Gy at 1.5 Gy/fraction to the PTV in the PM during the last 12 days of treatment with a 6-hour interfraction interval. The total tumor dose was 72 Gy over 6 weeks.

When IMRT was used, GTV, regional lymphatic drainage, and normal critical structures, such as the spinal cord and parotids, were outlined. Dose constraints to each outlined structure were specified for IMRT planning. Step-and-shoot IMRT was used to deliver a total dose of 70 Gy in 2-Gy fractions to the PTV and 57.75 Gy in 1.65-Gy fractions to the regional lymphatics. The maximum dose to the spinal cord was limited to 50 Gy, and the mean dose to at least one parotid gland was limited to less than 26 Gy when feasible without compromising tumor coverage.

	NOTES

 
Supported by the National Cancer Institute Clinical Trials Evaluation Program.

Presented in part at the 47th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 16-20, 2005, Denver, CO.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix 1: Gefitinib Dose... Appendix 2: Radiation Therapy REFERENCES

 
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Submitted June 14, 2007; accepted August 10, 2007.

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