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© 2001 American Society for Clinical Oncology Phase I Trial of Concurrent Tirapazamine, Cisplatin, and Radiotherapy in Patients With Advanced Head and Neck CancerFrom the Divisions of Hematology and Medical Oncology, and Radiation Oncology, and Statistical Centre, Peter MacCallum Cancer Institute, Melbourne, Australia, and Sanofi-Synthelabo, Great Valley, PA. Address reprint requests to Danny Rischin, MD, Division of Hematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag No 1, A’Beckett St, Melbourne 8006, Australia; email drischin@ petermac.unimelb.edu.au.
PURPOSE: To determine the maximum-tolerated dose of tirapazamine when combined with cisplatin and radiation in patients with T3/4 and/or N2/3 squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: The starting schedule was conventionally fractionated radiotherapy (70 Gy in 7 weeks) with concomitant cisplatin 75 mg/m2 and tirapazamine 290 mg/m2 (before cisplatin) in weeks 1, 4, and 7 and tirapazamine alone 160 mg/m2 three times a week in weeks 2, 3, 5, and 6. Positron emission tomography scans for tumor hypoxia (18F misonidazole) were performed before and during radiotherapy. RESULTS: We treated 16 patients with predominantly oropharyngeal primary tumors, including 10 patients with T4 or N3 disease. Febrile neutropenia occurred toward the end of radiotherapy in three out of six patients treated on the initial dose level. Two of these patients also developed grade 4 acute radiation reactions. Another 10 patients were treated with the same doses, but the week 5 and week 6 tirapazamine doses were omitted. This resulted in less neutropenia and only one dose-limiting toxicity (DLT) (febrile neutropenia), and eight out of 10 patients completed treatment without any dose omissions. In these 10 patients, the acute radiation toxicities were not obviously enhanced compared with chemoradiotherapy regimens using concurrent platinum and fluorouracil. 18F misonidazole scans detected hypoxia in 14 of 15 patients at baseline, with only one patient having detectable hypoxia at the end of treatment. With a median follow-up of 2.7 years, the 3-year failure-free survival rate was 69% (SE, 12%), the 3-year local progression-free rate was 88% (SE, 8%), and the 3-year overall survival rate was 69% (SE, 12%). CONCLUSION: DLT was due unexpectedly to febrile neutropenia, which could be overcome by omitting tirapazamine in weeks 5 and 6. The combination of tirapazamine, cisplatin, and radiotherapy resulted in remarkably good and durable clinical responses in patients with very advanced head and neck cancers. It warrants further investigation.
THE OUTCOMES IN locally advanced head and neck cancer treated with conventional radiation alone are dependent on the primary tumor site and stage but are generally poor.1 In order to improve the outcome in locally advanced head and neck cancer, several approaches have been investigated, including altered radiation fractionation regimens, the addition of chemotherapy to radiotherapy, and treatments designed to overcome hypoxia. Altered fractionation regimens have been investigated extensively, with evidence of a significant improvement in locoregional control and disease-free survival in several trials but no major impact on overall survival.2 Most recently, the Radiation Therapy Oncology Group demonstrated an improved 2-year locoregional control rate of 54%, from 45%, by use of accelerated fractionation with concomitant boost or hyperfractionation compared with conventionally fractionated radiotherapy.3 Despite high response rates, induction (or neoadjuvant) chemotherapy was shown in a recent definitive meta-analysis to have no significant benefit in terms of overall survival.4 However, neoadjuvant regimens using cisplatin and fluorouracil (5FU) gave better results than other regimens. The feasibility of larynx-preservation protocols that use neoadjuvant cisplatin and 5FU, with definitive radiotherapy given only to responders, has been demonstrated in randomized trials in locally advanced laryngeal and pyriform sinus carcinomas.5,6 However, this approach was associated with a nonsignificant trend toward worse overall survival compared with initial surgery in the meta-analysis.4 Trials of concurrent chemoradiation have yielded more promising results. In particular, recently reported randomized trials that have addressed the role of concurrent platinum and 5FU have demonstrated improved locoregional control and overall survival.7-9 In the trial reported by Calais et al,9 three cycles of carboplatin and 5FU were added to conventionally fractionated radiotherapy, resulting in an improvement in locoregional control from 42% to 66% and in 3-year overall survival from 31% to 51%. In the accompanying editorial, Forastiere and Trotti10 state that "radiochemotherapy should be considered an accepted standard of care in cancers of the oropharynx." Hypoxic cells have long been known to be resistant to radiation.11 Furthermore, the presence of significant hypoxia in head and neck cancers treated with radiation is an adverse prognostic factor.12-14 One approach is to target hypoxic cells by combining a hypoxic cytotoxin with radiation. Tirapazamine is a benzotriazine bioreductive compound that demonstrates differential toxicity for hypoxic cells.15 Preclinical studies have demonstrated at least additive effects when tirapazamine is combined with radiation.16 Tirapazamine also results in a marked potentiation of cisplatin cytotoxicity.17 These preclinical findings are supported by the results of a randomized trial in non–small-cell lung cancer that demonstrated a higher response rate and improved survival for the cisplatin and tirapazamine combination when compared with cisplatin alone.18 In this phase I trial, we set out to develop a concurrent chemoradiation regimen that included tirapazamine. We sought to exploit both the hypoxic cytotoxicity of tirapazamine and its potentiation of cisplatin cytotoxicity in a patient group with a high likelihood of tumor hypoxia. To provide objective evidence of tumor hypoxia in these patients, positron emission tomography (PET) with fluorine-18 fluoromisonidazole (FMISO) was performed. FMISO is differentially retained by hypoxic tissue.19
Eligibility Patients were required to have histologically proven squamous cell carcinoma of the head and neck. Patients had to have T3/4 and/or N2/3 disease, at least one bidimensionally measurable lesion, and no systemic metastatic disease (M0) on conventional staging. Other eligibility criteria were age more than 18 years, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, absolute neutrophil count  1.5 x 109/L, platelet count 100 x 109/L, serum creatinine level  the upper limit of normal, and serum bilirubin level less than two times the upper limit of normal. Written informed consent was obtained from all patients, and the institutional ethics committee approved the protocol. Patients were excluded from the trial for any of the following reasons: prior radiotherapy or chemotherapy for head and neck cancer, concurrent active cancer, class III or IV cardiac failure according to the New York Heart Association classification, any uncontrolled intercurrent illness, and pregnancy or lactation.
Pretreatment and Follow-Up Evaluations FDG PET scans were performed after a fast of at least 6 hours, with imaging at least 60 minutes after radiotracer administration. FMISO PET scans were obtained 2 hours after radiotracer administration. All PET imaging was performed on a dedicated PET scanner (PENN-PET 300H; UGM Medical System Inc, Philadelphia, PA) with the data processed using measured attenuation correction and iterative reconstruction. Paired FDG and FMISO PET scans were coregistered. While on study, patients were clinically assessed for toxicity and complete blood counts, including differentials measured weekly during treatment and for the first 3 weeks after completion of treatment. Electrolytes, serum creatinine, and liver function were also assessed weekly during treatment. FMISO PET scans were repeated in weeks 4 or 5 of treatment and in the week after completion of treatment. Assessment of tumor response by clinical examination and CT scanning took place at 12 weeks and 26 weeks after completion of treatment. Systemic toxicity from treatment was graded according to the National Cancer Institute common toxicity criteria. Skin and mucus membrane radiation toxicity was graded according to the European Organization for Research and Treatment of Cancer–Radiation Therapy Oncology Group toxicity criteria. Antitumor activity was assessed according to World Health Organization response criteria. Response duration was calculated from the date of treatment commencement.
Treatment Plan
Radiation Therapy
Dose Levels
At least three patients were entered at each dose level. If dose-limiting toxicity (DLT) occurred in one patient, up to six patients were treated at that dose level. DLT outside the irradiated volume was defined as febrile neutropenia (fever > 38°C with grade 4 neutropenia), grade 4 neutropenia lasting 5 days or longer, grade 4 thrombocytopenia, or grade 3 or 4 nonhematologic toxicity, excluding alopecia and emesis. If three or more patients experienced DLT, enrollment at this dose level was ceased and the preceding dose level was deemed to be the maximum-tolerated dose (MTD) and the dose recommended for phase II trials. Ten patients were to be treated at the recommended dose level. For toxicity within the irradiated volume, grade 4 mucosal or skin toxicities were DLTs. If two or more out of six patients experienced a radiation-related DLT, enrollment at this dose level was ceased and the preceding dose level was deemed to be the MTD and the dose recommended for phase II trials.
Dose Modification for Toxicity
Statistics
Patient Characteristics From January 1997 to March 1998, 17 patients were enrolled onto this study. One patient withdrew consent on day 5 of treatment and was replaced. The details of the other 16 patients treated on this study are given in Table 1. Patients had predominantly oropharyngeal primary tumors and had very advanced disease, with 10 patients having T4 or N3 disease (Table 2).
Toxicity At the first dose level, DLT occurred in three out of six patients (Table 3). All three patients experienced febrile neutropenia occurring in weeks 5, 6, and 8, with one patient also having pneumonia. In addition, one of these three patients experienced grade 4 mucositis with hemorrhagic confluent mucositis and another had grade 4 acute radiation skin toxicity with hemorrhagic confluent moist desquamation. No significant myelosuppression was seen before the end of the fifth week of treatment, but five out of the six patients had grade 3 or 4 neutropenia in weeks 5 through 8. The DLT of febrile neutropenia was unexpected based on previous tirapazamine trials. Only one of these six patients completed the treatment without any DLT or dose omissions. Four patients had the following chemotherapy dose omissions: week 7 dose omitted due to febrile neutropenia, week 7 dose omitted due to grade 3 neutropenia, weeks 6 and 7 doses omitted due to febrile neutropenia, and two doses omitted in week 3 due to rash. We decided to proceed by treating another cohort with the same doses but omitting the six tirapazamine doses in weeks 5 and 6 (dose level 1b). This resulted in less neutropenia, with only three out of 10 patients treated having grade 3 or 4 neutropenia (Table 4). Furthermore, only one patient experienced a DLT (febrile neutropenia), and eight patients completed treatment without any DLTs or dose omissions. Two patients had the week 7 chemotherapy dose omitted, due to febrile neutropenia in one patient and grade 2 hearing loss in the other patient. All patients on both dose levels completed their radiation therapy. Hence, this dose level with the modified schedule is the recommended dose and schedule for future trials.
Thrombocytopenia was uncommon, with one patient on the first dose level experiencing uncomplicated grade 3 thrombocytopenia in week 7. At the recommended dose level, one patient had grade 1 thrombocytopenia (Table 4). The chemotherapy-related nonhematologic toxicity was similar to that reported in previous trials of tirapazamine and cisplatin (Table 5). Muscle cramps were troublesome in some patients during the first 2 weeks of treatment. However, the cramps had generally subsided and, in fact, had largely resolved in most patients by the third week of treatment, without any alteration to chemotherapy doses and irrespective of the treatment given for the cramps. Transient skin rashes due to tirapazamine were observed in four patients. Although three patients had grade 3 cramps and two had grade 3 skin rashes, these toxicities were transient and not deemed to be DLTs.
The observed peak acute mucosal and skin radiation toxicities observed at dose level 1b, the recommended dose level, were comparable to those observed with 70-Gy radiation given with more standard platinum and 5FU concurrent chemotherapy (Table 6). The time course for healing of acute mucositis was not unduly prolonged (median, 8 weeks; range, 1.4 to 15 weeks). Ten patients required enteral feeding via a percutaneous endoscopic gastrostomy or nasogastric tube. Mean weight loss as a percentage of baseline was 14.6% (SD, 6.5%).
No grade 3 or 4 late toxicity was observed, except in three patients who had posttreatment neck dissection. These consisted of postsurgical neck and shoulder pain in two patients, and one patient developed a neuropathic swallowing disorder. Two other patients developed grade 2 hearing loss consistent with cisplatin toxicity. These patients had no clinically apparent hearing impairment before treatment, although baseline audiometry was not performed on this trial. No acute hearing loss, as has been reported in prior tirapazamine trials,18 was observed in this trial.
PET Scans
Efficacy Fourteen (88%) out of 16 patients (95% confidence interval, 62% to 98%) achieved a complete response at the primary tumor site on clinical and CT examination. Five of these 14 patients had persistent neck masses 12 weeks after treatment and proceeded to neck dissection. Three of the five patients with persistent neck masses had N3 disease. In four of these cases, a pathologic complete response was found, and in one patient, a 6-mm focus of residual cancer in a necrotic node was removed. Curiously, this was the only site of disease in all 16 patients who did not have any FDG uptake on the baseline FDG scan, and it was also the only site of residual FMISO uptake after treatment. This patient remains disease-free 2.7 years after neck dissection. Hence, 13 (81%) out of 16 patients (95% confidence interval, 54% to 96%) achieved a complete locoregional response after chemoradiation, and an additional patient was rendered disease-free after neck dissection. Two patients achieved an initial partial response but had progressed by weeks 12 and 16 after treatment. One of these patients had a very extensive T4 primary tumor involving the oral tongue and base of tongue that progressed at the primary tumor site only. The other patient had a tonsillar primary tumor staged as T3N3. His primary tumor recurred at the edge of the radiation portal, although he had a complete response in the neck. He was also the only patient with no detectable hypoxia on a baseline FMISO scan. Two patients subsequently relapsed with distant metastases without locoregional recurrence. One of these patients had evidence of a pleural metastasis on baseline FDG PET, but since this could not be confirmed by correlative structural imaging, he remained eligible for the trial. One patient was diagnosed with a second primary tumor 1.8 years after completing treatment. He was found to have a T1N0 non–small-cell lung cancer that has since been resected, and he remains alive and disease-free from both his cancers. The median potential follow-up time from commencing treatment to the close-out date was 2.7 years (range, 2.0 to 3.1 years). No patients were lost to follow-up. Eleven patients remain alive and disease-free. One patient died of unrelated causes while in complete remission. Failure-free survival, overall survival, and time to local progression curves are shown in Fig 3. The 3-year failure-free survival rate was 69% (SE, 12%), the 3-year local progression-free rate was 88% (SE, 8%), and the 3-year overall survival rate was 69% (SE, 12%).
In this phase I trial, we have established the MTD and recommended doses and schedule of tirapazamine, cisplatin, and radiation in locally advanced head and neck cancer. The DLT of febrile neutropenia was unexpected. Significant neutropenia had been infrequent in previous tirapazamine trials. The initial doses and schedule of cisplatin and tirapazamine were derived from preceding clinical trials of tirapazamine and radiation and trials of tirapazamine and cisplatin.20-22 In a preclinical study of tirapazamine given daily for 6 weeks, myelosuppression was in fact dose-limiting.23 Although we could not be sure of the etiology of the neutropenia, we hypothesized that the large number of doses or cumulative dose of tirapazamine may have been a major contributory factor. In view of the observation of dramatic early responses to treatment in several patients and the resolution of hypoxia on FMISO scans by weeks 4 and 5 in all but one patient, we were reluctant to alter the cisplatin or tirapazamine doses or schedule in the first 4 weeks of treatment. We elected to modify the schedule by omitting the six tirapazamine doses in weeks 5 and 6. The modified schedule resulted in acceptable toxicity with considerably less myelosuppression. Acute and late radiation toxicities with the modified tirapazamine schedule were comparable to those reported with concomitant cisplatin/5FU and radiotherapy regimens. Similar to many chemoradiation regimens, intensive support is required during and after treatment. Although 10 out of 16 patients eventually received enteral feeding, many patients had already lost a considerable amount of weight before commencing enteral feeding. Earlier and more aggressive use of enteral feeding may limit the degree of weight loss with this regimen. The chemotherapy-related nonhematologic toxicities were similar to those in previous trials of tirapazamine and cisplatin and were quite manageable.19,22 The presence of hypoxia has long been recognized as a major obstacle to the successful treatment of locally advanced head and neck cancers with radiation.24 Previous attempts to overcome hypoxia have focused mainly on the use of hyperbaric oxygen, hypoxic cell sensitizers, or high linear energy transfer radiation. These trials have not demonstrated consistent benefit, although a recent meta-analysis showed a statistically significant (albeit small) advantage for the addition of modifiers of hypoxia to radiation in head and neck cancer.25 Combining radiation with hyperbaric oxygen is logistically difficult, precluding the use of standard fractionation schedules.26 Tirapazamine is a hypoxic cell cytotoxin, rather than a hypoxic cell sensitizer, that maintains its differential toxicity relative to aerobic cells over a wide range of low oxygen concentrations.27 Under hypoxic conditions, tirapazamine is reduced to its active free radical moiety, which produces DNA strand breaks.15 Recent evidence suggests that the activating enzyme that results in DNA damage is located in the cell nucleus,28 and that under hypoxic conditions, tirapazamine may act as a topoisomerase II inhibitor.29 It has been proposed that, based on preclinical models, it would be preferable to give the tirapazamine as often as possible with fractionated radiation.30 Therefore, in our initial schedule, tirapazamine was administered throughout radiation. The rationale for "front-end loading" the administration of tirapazamine in the modified schedule with omission of weeks 5 and 6 tirapazamine was that tumor hypoxia was likely to be quantitatively greater at this time and the fact that serial FMISO scans showed rapid reduction of imageable hypoxia during the first half of treatment. However, it must be acknowledged that other schedules and doses of cisplatin (or carboplatin) and tirapazamine combined with radiation may also warrant investigation. Furthermore, as all six patients treated on dose level 1a are alive and disease-free, it would be of interest to determine whether the weeks 5 and 6 tirapazamine doses could be retained, without reducing cisplatin or tirapazamine doses, by commencing granulocyte colony-stimulating factor after the week 4 dose of cisplatin and tirapazamine. However, this may not be feasible as, in addition to febrile neutropenia, grade 4 mucositis and grade 4 acute radiation skin toxicity were observed at the first dose level. There has been a previous report of a trial of tirapazamine and radiation without cisplatin in head and neck cancer.20 In this phase II trial, tirapazamine 159 mg/m2 was given three times a week during the first 4 weeks of radiation. The authors only reported a control rate for the primary tumor site, which was estimated to be 59% at 2 years with a median follow-up of only 13 months (range, 3 to 31 months). The acute radiation toxicity did not seem to be enhanced compared with radiation alone. Uncomplicated grade 3 or 4 neutropenia occurred in 10% of patients. Most studies investigating the prognostic importance of tumor hypoxia have been based on oxygen electrode measurements, 12,13 an invasive and somewhat cumbersome procedure that is difficult to repeat during treatment and may be susceptible to sampling error owing to variation in the extent of hypoxia within any given tumor. Imaging of hypoxia with FMISO PET scans is less invasive, can be repeated during treatment, and may potentially detect all hypoxic areas below a certain threshold, believed to be around 10 mmHg based on previous work.31 Disadvantages of this technique include problems with quantitation, nonspecific binding, and the limited availability of PET. As would be expected in patients selected on the basis of locally advanced disease, the majority of patients in this trial had detectable hypoxia on baseline FMISO imaging. Furthermore, the pattern of FMISO uptake was consistent with the expected pattern of hypoxia in tumor tissue being either adjacent to areas of tumor necrosis or in the center of nonnecrotic lesions. The rapid normalization of FMISO PET suggests successful treatment of the hypoxic component. Although this response is encouraging, the specific contribution of tirapazamine is difficult to evaluate, as there are no reported studies with serial FMISO scans in head and neck cancers treated by radiation with or without chemotherapy in the absence of tirapazamine. However, in non–small-cell lung cancer treated with radiation with or without chemotherapy, serial FMISO scans demonstrated substantial residual FMISO accumulation at the end of radiation in six out of seven patients.19 On the basis of these preliminary data, we believe further evaluation of FMISO PET as a technique for selecting patients for tirapazamine-containing regimens and for monitoring such therapy is warranted. Although our study was a phase I trial not designed to evaluate treatment efficacy, the remarkably good and durable responses seen in patients with very advanced head and neck cancers are noteworthy. The proportion of patients with T4 or N3 disease was high, as eligible patients with less advanced disease were generally entered onto an altered-fractionation randomized trial that was open at our institution. The fact that none of the 14 patients who achieved a locoregional complete response with this chemoradiation regimen with or without neck dissection has relapsed locoregionally is particularly impressive. We are currently conducting a randomized phase II trial under the auspices of the Trans-Tasman Radiation Oncology Group, which is evaluating this regimen along with a regimen based on concurrent platinum/5FU during the last 2 weeks of radiation.32 The main aim of this trial is to determine the feasibility of these regimens in the multi-institutional setting, before proceeding to phase III trials. Further trials to determine the potential benefit of adding tirapazamine to chemoradiation in locally advanced head and neck cancer are warranted.
Supported by Sanofi-Synthelabo Pharmaceuticals, Sydney, Australia. We thank Andrew Sizeland, Bernie Lyons, Steven Kleid, Neil Vallance, Andrew Hays, and Jack Kennedy for referring patients for this study, David Binns for assistance with the PET scans, and Henri Tochon-Danguy for supply of the 18F misonidazole.
1. Cooper JS, Farnan FC, Asbell SO, et al: Recursive partitioning analysis of 2105 patients treated in Radiation Therapy Oncology Group studies of head and neck cancer. Cancer 77: 1905-1911, 1996[Medline] 2. Ang KK: Altered fractionation trials in head and neck cancer. Semin Radiat Oncol 8: 230-236, 1998[Medline] 3. 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: Preliminary results of RTOG 0/9003. Int J Radiat Oncol Biol Phys 45: 145, 1999 (suppl, abstr)[Medline] 4. 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. Lancet 355: 949-955, 2000[Medline] 5. The Department of Veterans Affairs Laryngeal Cancer Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 324:1685-1690, 1991
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Forastiere A, Trotti A: Radiotherapy and concurrent chemotherapy: A strategy that improves locoregional control and survival in oropharyngeal cancer. J Natl Cancer Inst 91: 2065-2066, 1999 11. Gray LH, Conger AD, Ebert M, et al: Concentration of oxygen dissolved in tissues at the time or irradiation as a factor in radiotherapy. Br J Radiol 26: 638-648, 1953 12. Gatenby RA, Kessler HB, Rosenblum JS, et al: Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 14: 831-838, 1988[Medline] 13. Nordsmark M, Overgaard M, Overgaard J, et al: Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 41: 31-39, 1996[Medline] 14. Brizel DM, Sibley GS, Prosnitz LR, et al: Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 38: 285-289, 1997[Medline] 15. Brown JM: SR 4233(tirapazamine): A new anticancer drug exploiting hypoxia in solid tumours. Br J Cancer 67: 1163-1170, 1993[Medline]
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von Pawel J, von Roemeling R, Gatzemeier U, et al: Tirapazamine plus cisplatin versus cisplatin in advanced non–small-cell lung cancer: A report of the International CATAPULT I Study Group. J Clin Oncol 18: 1351-1359, 2000 19. Koh WJ, Bergman KS, Rasey JS, et al: Evaluation of oxygenation status during fractionated radiotherapy in human nonsmall cell lung cancer using (F-18) fluoromisonidazole positron emission tomography. Int J Radiat Oncol 33: 391-398, 1995[Medline] 20. Lee DJ, Trotti A, Spencer S, et al: Concurrent tirapazamine and radiotherapy for advanced head and neck carcinomas: A phase II study. Int J Radiat Oncol Biol Phys 42: 811-815, 1998[Medline] 21. Hancock SL, Mariscal M, Spencer S, et al: Clinical evaluation of the hypoxic cytotoxin tirapazamine (SR 4233) with fractionated irradiation: Phase I experience at Stanford University and the University of Alabama. Ninth International Conference on Chemical Modifiers of Cancer Treatment, August 22-26, 1995, Oxford, United Kingdom (abstr) 22. Treat J, Rodriguez G, Miller V, et al: An integrated phase I/II analysis of tirazone (tirapazamine) + cisplatin: Safety and efficacy in advanced non-small cell lung cancer (NSCLC) patients. Proc Am Soc Clin Oncol 17: 472a, 1998 (abstr 1815) 23. Spiegel JF, Spear MA, Brown JM: Toxicology of daily administration to mice of the radiation potentiator SR 4233 (WIN 59075). Radiother Oncol 26: 79-81, 1993[Medline] 24. Henk JM, Kunkler PB, Smith CW: Radiotherapy and hyperbaric oxygen in head and neck cancer: Final report of first controlled trial. Lancet 2: 101-103, 1977[Medline] 25. Overgaard J, Horsman MR: Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitisers. Semin Radiat Oncol 6: 10-21, 1996[Medline] 26. Haffty B, Hurley R, Peters LJ: Radiation therapy with hyperbaric oxygen at 4 atmospheres pressure in the management of squamous cell carcinoma of the head and neck: Results of a randomised clinical trial. Cancer J 5: 341-347, 1999
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Garden A, Glisson B, Ang K, 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 Submitted April 14, 2000; accepted September 7, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
