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Preliminary Results of Radiation Therapy Oncology Group 97-03: A Randomized Phase II Trial of Concurrent Radiation and Chemotherapy for Advanced Squamous Cell Carcinomas of the Head and Neck

From The University of Texas M.D. Anderson Cancer Center, Houston, TX; Radiation Therapy Oncology Group Headquarters; Fox Chase Cancer Center Philadelphia, PA; University of Chicago School of Medicine, Chicago, IL; the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Radiotherapy Associates of Sacramento, Sacramento, CA; University of Alabama, Birmingham, AL; New York University, New York, NY; Akron Hospital, Akron, OH; Medical College of Wisconsin, Milwaukee, WI

Address reprint requests to Adam S. Garden, MD, Department of Radiation Oncology, Unit 97, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: agarden{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To define further the role of concurrent chemoradiotherapy for patients with advanced squamous carcinoma of the head and neck.

PATIENTS AND METHODS: The Radiation Therapy Oncology Group developed this three-arm randomized phase II trial. Patients with stage III or IV squamous carcinoma of the oral cavity, oropharynx, or hypopharynx were eligible. Each of three arms proposed a radiation schedule of 70 Gy in 35 fractions. Patients on arm 1 were to receive cisplatin 10 mg/m² daily and fluorouracil (FU) 400 mg/m² continuous infusion (CI) daily for the final 10 days of treatment. Treatment on arm 2 consisted of hydroxyurea 1 g every 12 hours and FU 800 mg/m²/d CI delivered with each fraction of radiation. Arm 3 patients were to receive weekly paclitaxel 30 mg/m² and cisplatin 20 mg/m². Patients randomly assigned to arms 1 and 3 were to receive their treatments every week; patients on arm 2 were to receive their therapy every other week.

RESULTS: Between 1997 and 1999, 241 patients were entered onto study; 231 were analyzable. Ninety-two percent, 79%, and 83% of patients on arms 1, 2, and 3, respectively, were able to complete their radiation as planned or with an acceptable variation. Fewer than 10% of patients had unacceptable deviations or incomplete chemotherapy in the three arms. Estimated 2-year disease-free and overall survival rates were 38.2% and 57.4% for arm 1, 48.6% and 69.4% for arm 2, and 51.3% and 66.6% for arm 3.

CONCLUSION: We have demonstrated that three different approaches of concurrent multiagent chemotherapy and radiation were feasible and could be delivered to patients in a multi-institutional setting with high compliance rates.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Historically, the standard therapy for patients presenting with advanced squamous cell carcinomas of the head and neck has been surgery followed by postoperative radiation. Patients with unresectable disease were treated with radiation alone; chemotherapy alone was reserved for palliation. Five-year survival rates with these approaches have been poor, often due to frequent local and regional recurrences. To increase survival, improvement in locoregional control is required. One approach to this goal, investigated over the last two decades, is to deliver chemotherapy concurrently with radiotherapy.¹

Researchers have generally tested agents that have activity in the treatment of advanced squamous carcinoma of the head and neck. Early trials used concurrent methotrexate and/or bleomycin,² and more recently fluorouracil (FU) and cisplatin,^3-5 because these two agents appeared to produce the highest response rates as second-line therapy in head and neck squamous cell carcinoma before the use of taxanes for this disease. Other investigators have studied drugs believed to provide specific synergism with radiation, such as hydroxyurea (HU)⁶ or mitomycin.⁷

Investigating combination radiation and chemotherapy, researchers have not only studied different drugs, but also different approaches to the timing of drug delivery. One common method has been to deliver the drugs using the same schedule as delivered in the adjuvant setting—that is, every 3 weeks.^4,8 Others have studied weekly⁹ or daily administration.¹⁰ Some drug and radiation regimens have been considered more intense, and to keep the toxicity profile within acceptable limits, planned breaks in treatment (in addition to the usual weekend interruptions in radiation therapy) were designed into these differing regimens.^3,11

An additional question is the number of drugs that can and should be added to radiation. The Radiation Therapy Oncology Group (RTOG) has conducted several investigations of concurrent chemoradiotherapy for patients with advanced head and neck cancers. Most of these studies used single-agent cisplatin. A large randomized trial of weekly cisplatin (20 mg/m²) added to radiation compared with radiation alone did not demonstrate a survival benefit,⁹ and the most widely used approach has been single-agent cisplatin 100 mg/m² delivered every 3 weeks.¹² The most impressive results with this approach were demonstrated in the phase III Intergroup study 0099,⁸ which showed significant improvements in disease control and survival in patients with nasopharyngeal cancer treated with high-dose cisplatin and radiation as compared with radiation alone. However, other randomized trials of patients with advanced head and neck cancer have used two or even three drugs in combination with radiation.^4,5,13,14 It is not clear whether multiple drugs add a therapeutic benefit or just increase toxicity.

To define further the role of concurrent chemoradiotherapy, and to address questions of timing and the specific drugs to use in the setting of chemoradiotherapy, the RTOG developed a three-arm randomized phase II trial.¹⁵ Each arm evaluated a different two-drug combination. In addition, the timing of the drug delivery during the course of radiation was varied in the three approaches. The three regimens studied were all based on single institutional phase I and II experiences.^11,16-18 This study tested these regimens in a multi-institutional phase II setting to determine feasibility as well as toxicity. Survival outcomes for each regimen were compared with two previously completed RTOG studies.

	PATIENTS AND METHODS

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Patient Selection
Patients 18 years or older with a Karnofsky performance score (KPS) 70 and who had histologically proven stage III or IV, but M0, squamous cell carcinoma of the oral cavity, oropharynx, or hypopharynx and were previously untreated were eligible for this trial. The disease was staged according to the 1992 classification of the American Joint Committee on Cancer. Patients with a prior (within 5 years) or synchronous malignancy other than nonmelanoma skin cancer were excluded. Patients were required to have adequate bone marrow, hepatic, and renal function and normal prothrombin time and partial thromboplastin time. Patients with clinically significant heart disease were ineligible.

The National Cancer Institute and the participating institutions approved the protocol. Study-specific informed consent was obtained from each patient by the treating institution.

Pretreatment Evaluation
A medical history, physical examination, and complete blood work were required. Additional tests and studies required included chest x-ray, computed tomography or magnetic resonance imaging of the head and neck, a diagram and measurements of the primary tumor and neck nodes, electrocardiogram, and a dental evaluation.

Randomization Procedures and Treatment Arms
Patients were enrolled by telephone call to the RTOG headquarters. Following confirmation of eligibility, patients were stratified by KPS (90 to 100 v 70 to 80). The randomization scheme described by Zelen¹⁹ was used to achieve balance in the treatment assignments among the institutions.

The trial evaluated three treatment arms. The total radiation dose in all three arms was 70 Gy, delivered in 35 fractions. One fraction was delivered daily Monday through Friday. Patients randomly assigned to arm 1 were to receive cisplatin, 10 mg/m² daily and FU 400 mg/m² continuous infusion daily for the final 10 days of radiation treatment. Treatment on arm 2 consisted of HU 1 gram every 12 hours (given orally, 11 doses per cycle) and FU 800 mg/m²/d continuous infusion delivered concurrently with each daily fraction of radiation. Patients randomized to arm 3 were to receive paclitaxel 30 mg/m² every Monday and cisplatin 20 mg/m² every Tuesday; chemotherapy was to be given before radiation. Patients randomly assigned to arms 1 and 3 were to receive their treatments every week for 7 consecutive weeks; patients on arm 2 were to receive their therapy (concurrent radiation and chemotherapy) every other week for a total treatment duration of 13 weeks.

Follow-Up
Disease and vital status and grades of acute reactions (using the RTOG criteria for radiation effects and the Cooperative Group common toxicity grading system for systemic effects)^20,21 were recorded. During treatment, patients were examined at least weekly. Once treatment ended, patients were evaluated every 4 weeks until their acute reactions resolved, then no less often than every 3 months for 2 years, every 4 months through year 3, and every 6 months starting with year 4. Late (occurring > 90 days from start of treatment for arms 1 and 3, and > 132 days for arm 2) normal tissue effects were graded using the RTOG/European Organization for Research and Treatment of Cancer scale.

Quality Control
Radiotherapy records of each patient, including simulation and verification port films, total dose, number of fractions, and elapsed treatment days relative to the protocol prescription were reviewed by the radiation oncology study cochair (A.S.G.) with the RTOG staff. Chemotherapy administration records were reviewed by the medical oncology cochairs (A.A.F. and E.E.V.) and all reports of severe adverse reactions were reviewed and scored by all cochairs. Each institution had its records audited at least once every 3 years, as mandated by the National Cancer Institute.

Statistical Analysis
The trial was designed to determine the feasibility and tolerance of each of the three concurrent chemoradiotherapy regimens. Tolerance was determined by the ability to complete treatment either per protocol or with minor deviation for total dose to the primary and overall elapsed days. For total dose to the primary tumor, a regimen was considered per protocol if the dose was within 5% of the protocol specification; acceptable variation was up to 10%. For elapsed days, a regimen was considered per protocol if completed within 46 to 54 days for arms 1 and 3 and 88 to 95 days for arm 2; acceptable variation was 55 to 60 days for arms 1 and 3, and 96 to 102 days for arm 2. Treatment extending beyond 60 days for arms 1 and 3 and 102 days for arm 2 was considered an unacceptable major deviation. A regimen was considered tolerable if 75% of the eligible patients successfully completed the regimen. Tolerance was also assessed by the severe ( grade 4) acute toxicity rate, though only grade 5 toxicity was considered for an early stopping point.

Additional end points were the complete response rate, locoregional control, time to distant metastases, and disease-free and overall survival. All failure-time end points were calculated from the date of randomization. Survival and disease-free survival rates were calculated using the Kaplan-Meier method,^22,23 and the rates of locoregional failure and distant metastases were calculated using the method of cumulative incidence,²⁴ because this accounts for competing risks—in this case, death without locoregional or distant failure.

The complete response rate was determined by the absence of visible (clinical or radiographic) and palpable disease both in the primary site and neck. Complete response to the primary could only be achieved through the chemoradiotherapy regimen. A complete response in the neck could be achieved with a postchemoradiotherapy neck dissection that achieved negative margin status. Planned neck dissections were not mandatory in this study.

Overall survival for each RTOG 97-03 regimen was compared with a historical database of three regimens from previous RTOG trials using Cox proportional hazards models²⁵ stratified by the RTOG Recursive Partitioning Analysis (RPA) prognostic class.²⁶ This analysis was done to provide additional information to be used in determining whether a regimen should be further tested in a phase III trial. The three regimens were (1) radiation and concurrent cisplatin from RTOG 81-17,¹² (2) conventionally fractionated radiation from RTOG 90-03, and (3) accelerated concomitant boost fractionation from RTOG 90-03.²⁷ Only patients that would potentially have been eligible for RTOG 97-03 (KPS 70 to 100; stage III-IV; primary site oral cavity, oropharynx, or hypopharynx) were included in these comparisons. However, it should be noted that only patients with unresectable stage III or IV disease were eligible for RTOG 81-17, whereas resectability status was not specified for either RTOG 90-03 or this current trial. Resectability is not included in the RTOG RPA prognostic classification for head and neck cancer.

	RESULTS

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Patient and Tumor Characteristics
Between July 1997 and June 1999, 241 patients were entered onto study. Nine patients were retrospectively found ineligible (six with laryngeal primary tumors, two with stage II disease, and one with concurrent primary tumors) and one patient had inadequate data, leaving 231 patients suitable for analysis. Patient characteristics, primary site distribution, and primary and nodal staging for the three arms are shown in Table 1. Sixty-four percent of patients had KPS 90. More than two thirds of the patients presented with tumors in the oropharynx. Seventy-five percent of patients had T3 or T4 disease, and 70% had N2 or N3 disease. At the time of analysis, 130 of 231 analyzable patients (56%) were alive; the median follow-up for surviving patients ranged from 2.6 to 2.9 years for the three arms (range, 0.34 to 4 years).

Study chair evaluation of the overall radiation delivery (including days of therapy, dose, and field borders) as prescribed in the protocol is presented in Table 2. Only two patients' treatments were scored as a major deviation from the protocol—one for tight field borders, one for inadequate field borders, and the same field used through the entire course; both patients were treated on arm 3. Three patients on arm 1 (4%) and four patients on arm 2 (5%) had incomplete radiation due to death, disease progression, or patient refusal, compared with nine patients (12%) on arm 2.

Twenty-six percent, 28%, and 27% of patients on arms 1, 2, and 3 had feeding tubes (including gastrostomy feeding tubes) placed before initiation of their therapy. An additional 56%, 45%, and 55% of patients on the three respective arms required feeding tubes during their therapy. At last follow-up of patients alive and without evidence of disease, six patients (22%) on arm 1, five patients (14%) on arm 2, and two patients (6%) on arm 3 remained with a feeding tube.

Patient Outcomes
The complete response rates were 76%, 75%, and 82% for the three treatment arms. The estimated 2-year rates of locoregional failure were 41.1% (95% CI, 30.1 to 52.1), 40.8% (95% CI, 29.6 to 51.9) and 27.5% (95% CI, 17.4 to 37.6) for arms 1, 2, and 3, respectively (Fig 1). The estimated 2-year rates of distant metastases were 23.2% (range, 13.7% to 32.7%), 21.2% (range, 11.9% to 30.5%), and 22.7% (range, 13.1% to 32.3%) for arms 1, 2, and 3, respectively. Patterns of first failure are summarized in Table 6. Only 8% of patients in arm 2 had distant failure as the first site of failure. The lung was the most common site of distant metastases in all three arms.

View larger version (15K): [in this window] [in a new window]   Fig 1. Time to locoregional failure. RT, radiation therapy; FU, fluorouracil.

View larger version (16K): [in this window] [in a new window]   Fig 2. Disease-free survival. NED, no evidence of disease; RT, radiation therapy; FU, fluorouracil.

View larger version (16K): [in this window] [in a new window]   Fig 3. Overall survival. RT, radiation therapy; FU, fluorouracil.

	DISCUSSION

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The toxicity profile was high but acceptable according to the protocol definitions. The incidence of grade 3 acute toxicity ranged from 69% to 87%, and the incidence of grade 4 acute toxicity was similar in all three arms developing in about one fourth of all patients, with a slightly higher rate on arm 2. However, arm 1 had three deaths attributed to protocol therapy. The incidence of severe toxicity is markedly higher than that seen in RTOG 90-03 (radiation alone), in which the incidence of acute grade 4 toxicity was less than 1%, but it seems comparable with other experiences of concurrent chemoradiotherapy treating patients with advanced head and neck cancer.^5,13,27

The outcomes with respect to survival, when compared with the regimens from previous RTOG trials, appear to be greater. The 2-year survival rates in the three experimental arms rival the 1-year survival rates seen in the historic controls of patients treated with radiation alone or radiation with single-agent cisplatin from RTOG 90-03 and 81-17. When the treatment comparisons are adjusted for RPA prognostic classes, all 97-03 regimens showed an estimated reduction in the death rate ranging from 24.8% to 57.1%. These results can be considered as evidence for a possible positive treatment effect that must, in turn, be established by a definitive phase III trial.

An initial concern in the trial development was that arm 2 had treatment breaks, and the overall time was 13 weeks, compared with 7 weeks in arms 1 and 3. However, proponents suggest that when intensive chemotherapy is delivered concurrently with radiation, the issue of overall time is less critical than when radiation is the sole modality.²⁸ Arm 2 did have a higher rate of incomplete radiation either due to death, disease progression or patient refusal. There was also a slightly higher rate of grade 4 acute toxicity primarily due to higher rates of grade 4 mucositis. Despite this, the incidence of feeding tube placement during therapy was lower for patients on arm 2, and preliminary grade 4 late toxicity rates for this arm were low. In addition, survival rates and disease outcomes of patients treated on arm 2 were extremely favorable despite the protracted regimen. Further intensification and modification of this approach has demonstrated very high disease control rates in patients with advanced head and neck cancer.^29,30

Subsequent to the trial design and activation, several randomized trials comparing radiation alone to concurrent chemoradiotherapy have been published, most with results favoring chemoradiotherapy. In particular, these trials have tested cisplatin combined with FU, administered every 3 weeks (or longer). RTOG 91-11, the larynx preservation trial,³¹ and the Eastern Cooperative Oncology Group/Southwest Oncology Group Head and Neck Intergroup trial for advanced unresectable head and neck cancer³² both demonstrated improvements in locoregional control with single-agent cisplatin, adding to the positive results seen in the Intergroup 0099 nasopharynx study⁸ of concurrent cisplatin and radiation. Questions regarding the number of systemic agents as well as the best agents to add to radiation remain unanswered. Our phase II trial indicates that the three different approaches tested all resulted in similarly high rates of toxicity with improved survival. Thus the heterogeneity of regimens seen in numerous trials testing concurrent chemotherapy and radiation may not be as important as was suggested in a recent meta-analysis.³³ The overall concept appears to be valid.

RTOG 90-03 demonstrated that treatment intensification by altered fractionation resulted in an improvement in locoregional control.²⁷ The current phase II trial kept the radiation fractionation relatively conventional at a rate of 10 Gy per week, once daily. The role of altered fractionation with concurrent chemotherapy is unclear. Results of several phase II trials suggest that both hyperfractionated radiation³⁴ and accelerated radiation³⁵ improve results when compared with each institution's experience with historical controls treated with daily fractionation. Several phase III trials testing concurrent chemoradiotherapy have used altered fractionation, but the fractionation scheme was similar in both the radiation alone control and the experimental arms, thus not specifically addressing the radiation question.^5,10,14 Following the present study, the RTOG conducted a phase II trial, RTOG 99-14, testing concomitant boost fractionation combined with concurrent single agent cisplatin (100 mg/m² on days 1 and 22).³⁶ Preliminary results of this regimen also appear encouraging. The RTOG is now comparing concomitant boost radiation combined with cisplatin to conventional radiation and cisplatin in a phase III trial (RTOG 01-29).

In conclusion, we have demonstrated that three different approaches of concurrent multiagent chemotherapy and radiation were feasible and could be delivered to patients in a multi-institutional setting, with high compliance rates. Future directions include comparing multiagent concurrent chemoradiotherapy with single-agent chemoradiotherapy. The phase II design did not allow for statistical comparisons between the three arms. However, the excellent locoregional control rates, simplicity of concept and current interest in taxane-based therapy for treatment of advanced head and neck cancer led us to recommend arm 3 as an experimental arm in future phase III trials testing concurrent chemoradiotherapy for advanced head and neck cancer. Toxicity modifiers to reduce the high rates of toxicity and agents that may be more target specific and have lower toxicity profiles also warrant further investigation.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We acknowledge the work of the clinical investigators, statisticians, research associates, administrative staff, and dosimetrists who contributed to this trial. We are grateful for the valuable contributions of Thomas F. Pajak in statistics, Linda Messett and Rebecca Allegretto in data management, and Bernadine Dunning and Julie McIlvaine in quality assurance.

	NOTES

 
Supported by National Cancer Institute grants CA21661, CCOP U10, CA37422, Stat U10, and CA32115.

Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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

	REFERENCES

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1. Vokes EE, Weichselbaum RR, Lippman SM, et al: Medical progress: Head and neck cancer. N Engl J Med 328:184–194, 1993[Free Full Text]

2. Fu KK, Phillips TL, Silverberg IJ: Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: Update of a Northern California Oncology Group randomized trial. J Clin Oncol 5:1410–1418, 1987[Abstract/Free Full Text]

3. Taylor SG, Murthy AK, Vannetzel JM, et al: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 12:385–395, 1994[Abstract]

4. Adelstein DJ, Saxton JP, Lavertu P, et al: A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: Preliminary results. Head Neck 19:567–575, 1997[CrossRef][Medline]

5. Brizel DM, Leopold KA, Fisher SR, et al: A phase I/II trial of twice daily irradiation and concurrent chemotherapy for locally advanced squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 28:213–220, 1994[Medline]

6. Stefani S, Eells RW, Abbate J: Hydroxyurea and radiotherapy in head and neck cancer. Radiology 101:391–396, 1971[Medline]

7. Haffty BG, Son YH, Papac R, et al: Chemotherapy as an adjunct to radiation therapy in the treatment of squamous cell carcinoma of the head and neck: Results of the Yale Mitomycin Randomized Trials. J Clin Oncol 15:268–276, 1997[Abstract/Free Full Text]

8. Al-Sarraf M, LeBlanc M, Giri P, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310–1317, 1998[Abstract/Free Full Text]

9. Haselow RE, Warshaw MG, Oken MM, et al: Radiation alone versus radiation with weekly low dose cisplatinum in unresectabel cancer of the head and neck, in Fee W, Goepfert H, Johns M, et al (eds): Head and Neck Cancer. Toronto, Canada, Decker, 1990, pp 279–281

10. Jeremic B, Shibamoto Y, Milicic B, et al: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: A prospective randomized trial. J Clin Oncol 18:1458–1464, 2000[Abstract/Free Full Text]

11. Vokes EE, Panje WR, Schilsky RL, et al: Hydroxyurea, 5-fluorouracil and concomitant radiotherapy in poor prognosis head and neck cancer: A phase I-II study. J Clin Oncol 7:761–768, 1989[Abstract]

12. Marcial VA, Pajak TF, Mohiuddin M, et al: Concommitant cisplatin chemotherapy and radiotherapy in advanced mucosal squamous cell carcinoma of the head and neck. Cancer 66:1861–1868, 1990[CrossRef][Medline]

13. Calais G, Alfonsi M, Bardet E, et al: Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 91:2081–2086, 1999[Abstract/Free Full Text]

14. Wendt TG, Grabenbauer GG, Rodel CM, et al: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: A randomized multicenter study. J Clin Oncol 16:1318–1324, 1998[Abstract/Free Full Text]

15. Simon R, Wittes R, Ellenberg S: Randomized phase II clinical trials. Cancer Treat Rep 69:1375–1381, 1985[Medline]

16. Garden AS, Glisson BS, Ang KK, et al: Phase I/II trial of radiation with chemotherapy "boost" for advanced squamous cell carcinomas of the head and neck: Toxicities and responses. J Clin Oncol 17:2390–2395, 1999[Abstract/Free Full Text]

17. Haraf DJ, Kies M, Rademaker AW, et al: Radiation therapy with concomitant hydroxyurea and fluorouracil in stage II and III head and neck cancer. J Clin Oncol 17:638–644, 1999[Abstract/Free Full Text]

18. Flood W, Lee DJ, Trotti A, et al: Multimodality therapy of patients with locally advanced squamous cell cancer of the head and neck: Preliminary results of two pilot trials using paclitaxel and cisplatin. Semin Radiat Oncol 9:64–69, 1999[Medline]

19. Zelen M: The randomization and stratification of patients to clinical trials. J Chron Dis 27:365–375, 1974[CrossRef][Medline]

20. Trotti A, Byhardt R, Stetz J, et al: Common toxicity criteria: Version 2.0. an improved reference for grading the acute effects of cancer treatment: Impact on radiotherapy. Int J Radiat Oncol Biol Phys 47:13–47, 2000[CrossRef][Medline]

21. Cox J, Stetz J, Pajak T: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 32:567–576, 1995[CrossRef][Medline]

22. Kaplan EL, Meier P: Nonparameteric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef]

23. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170, 1966[Medline]

24. Kalbfleish J, Prentice R: The statistical analysis of failure time data. New York, NY, John Wiley and Sons, 1980

25. Cox DR: Regression models and life tables. J Royal Stat Soc Series B 34:187–229, 1972

26. Cooper JS, Berkey B, Marcial V, et al: Validation of the RTOG Recursive Partitioning Classification for head and neck tumors. Head Neck 23:669–677, 2001[CrossRef][Medline]

27. Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. Int J Radiat Oncol Biol Phys 48:7–16, 2000[CrossRef][Medline]

28. Wong WW, Mick R, Haraf DJ, et al: Time-dose relationship for local 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]

29. Kies M, Haraf D, Rosen F, et al: Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer. J Clin Oncol 19:1961–1969, 2001[Abstract/Free Full Text]

30. Vokes E, Stenson K, Rosen F, et al: Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: Curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol 21:320–326, 2003[Abstract/Free Full Text]

31. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091–2098, 2003[Abstract/Free Full Text]

32. Adelstein DJ, Li Y, Adams GL, et al: An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21:92–98, 2003[Abstract/Free Full Text]

33. Pignon JP, Bourhis J, Domenge C, et al: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data—MACH-NC Collaborative Group: Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 355:949–955, 2000[Medline]

34. Adelstein DJ, Saxton JP, Lavertu P, et al: Maximizing local control and organ preservation in stage IV squamous cell head and neck cancer with hyperfractionated radiation and concurrent chemotherapy. J Clin Oncol 20:1405–1410, 2002[Abstract/Free Full Text]

35. Poole ME, Sailer SL, Rosenman JG, et al: Chemoradiation for locally advanced squamous cell carcinoma of the head and neck for organ preservation and palliation. Arch Otolaryngol Head Neck Surg 127:1446–1450, 2001[Abstract/Free Full Text]

36. Ang KK, Harris J, Garden AS, et al: Concomitant boost radiation and concurrent cisplatin for advanced head and neck carcinomas: Preliminary results of a phase II trial of the RTOG (99-14). Int J Radiat Oncol Biol Phys 54:71, 2002

Submitted December 2, 2003; accepted April 30, 2004.

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				D. Rischin, R. J. Hicks, R. Fisher, D. Binns, J. Corry, S. Porceddu, and L. J. Peters Prognostic Significance of [18F]-Misonidazole Positron Emission Tomography-Detected Tumor Hypoxia in Patients With Advanced Head and Neck Cancer Randomly Assigned to Chemoradiation With or Without Tirapazamine: A Substudy of Trans-Tasman Radiation Oncology Group Study 98.02 J. Clin. Oncol., May 1, 2006; 24(13): 2098 - 2104. [Abstract] [Full Text] [PDF]

				M. R. Posner and L. J. Wirth Cetuximab and Radiotherapy for Head and Neck Cancer N. Engl. J. Med., February 9, 2006; 354(6): 634 - 636. [Full Text] [PDF]

				K. K. Ang, J. Harris, A. S. Garden, A. Trotti, C. U. Jones, L. Carrascosa, J. D. Cheng, S. S. Spencer, A. Forastiere, and R. S. Weber Concomitant Boost Radiation Plus Concurrent Cisplatin for Advanced Head and Neck Carcinomas: Radiation Therapy Oncology Group Phase II Trial 99-14 J. Clin. Oncol., May 1, 2005; 23(13): 3008 - 3015. [Abstract] [Full Text] [PDF]

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