Hyperfractionated Irradiation with or without Concurrent Chemotherapy for Locally Advanced Head and Neck Cancer
David M. Brizel, M.D., Mary E. Albers, M.D., Samuel R. Fisher, M.D., Richard L. Scher, M.D., William J. Richtsmeier, M.D., Ph.D., Vera Hars, M.S., Stephen L. George, Ph.D., Andrew T. Huang, M.D., and Leonard R. Prosnitz, M.D.
Background Radiotherapy is often the primary treatment for advancedhead and neck cancer, but the rates of locoregional recurrenceare high and survival is poor. We investigated whether hyperfractionatedirradiation plus concurrent chemotherapy (combined treatment)is superior to hyperfractionated irradiation alone.
Methods Patients with advanced head and neck cancer who weretreated only with hyperfractionated irradiation received 125cGy twice daily, for a total of 7500 cGy. Patients in the combined-treatmentgroup received 125 cGy twice daily, for a total of 7000 cGy,and five days of treatment with 12 mg of cisplatin per squaremeter of body-surface area per day and 600 mg of fluorouracilper square meter per day during weeks 1 and 6 of irradiation.Two cycles of cisplatin and fluorouracil were given to mostpatients after the completion of radiotherapy.
Results Of 122 patients who underwent randomization, 116 wereincluded in the analysis. Most patients in both treatment groupshad unresectable disease. The median follow-up was 41 months(range, 19 to 86). At three years the rate of overall survivalwas 55 percent in the combined-therapy group and 34 percentin the hyperfractionation group (P=0.07). The relapse-free survivalrate was higher in the combined-treatment group (61 percentvs. 41 percent, P=0.08). The rate of locoregional control ofdisease at three years was 70 percent in the combined-treatmentgroup and 44 percent in the hyperfractionation group (P=0.01).Confluent mucositis developed in 77 percent and 75 percent ofthe two groups, respectively. Severe complications occurredin three patients in the hyperfractionation group and five patientsin the combined-treatment group.
Conclusions Combined treatment for advanced head and neck canceris more efficacious and not more toxic than hyperfractionatedirradiation alone.
Cure of locally advanced squamous-cell carcinoma of the headand neck is uncommon whether a single treatment, including high-doseexternal-beam irradiation, or a combination of treatments isused. The rate of relapse-free survival is approximately 25percent, and most patients die from complications of progressivelocal disease. Repopulation of tumor cells during treatment,tumor hypoxia, and resistance to radiotherapy have all beenimplicated as causes of treatment failure after primary radiotherapy.1,2,3
Accelerated fractionation irradiation, which shortens the totaltime of treatment, has been employed to increase the probabilityof locoregional control by reducing the risk of tumor repopulation.With hyperfractionated irradiation, multiple small fractionsof radiation are given each day to increase the total dose butnot the risk of long-term toxicity.4 Retrospective studies ofpatients treated with accelerated fractionation and hyperfractionationhave demonstrated an improvement in disease control of about20 percentage points, as compared with historical controls treatedwith conventional daily radiation, without an increase in long-termtoxicity.5,6,7 A prospective, randomized trial by the EuropeanOrganization for the Research and Treatment of Cancer (EORTC)showed an increase of 20 percentage points in the rate of locoregionalcontrol of oropharyngeal carcinoma at five years and an improvementof 14 percentage points in survival after treatment with 8050cGy of radiation in hyperfractionated doses as compared withthe rates achieved with once-daily radiotherapy (total dose,7000 cGy), without any increase in acute or chronic toxic effects.8
Combination radiotherapy and chemotherapy is another promisingapproach to locally advanced head and neck cancer. Most studieshave used sequential chemotherapy followed by radiotherapy.However, as compared with the use of radiotherapy alone, thisstrategy has generally failed to improve overall survival ordisease-free survival.9,10
We initiated a phase 3 trial in 1990 to test the hypothesisthat accelerated hyperfractionation irradiation plus concurrentchemotherapy followed by adjuvant chemotherapy (combined therapy)leads to better locoregional control, relapse-free survival,and overall survival than accelerated hyperfractionation alone.We have demonstrated the feasibility of this program in a phase1–2 study.11 Accelerated hyperfractionation alone wasselected as the control treatment because it represented themost intensive approach to primary radiotherapy, even thoughit had not been proved at the time to be superior to once-dailytreatment.
Methods
Patient Population and Eligibility Criteria
In this multicenter study, all patients were initially evaluatedby a multidisciplinary team consisting of otolaryngologists,radiation oncologists, and medical oncologists. The tumors wereclassified according to the criteria of the American Joint Committeeon Cancer Staging.12 The stage of the tumor was determined onthe basis of each patient's history and physical examination(including examination with the patient under anesthesia), chestX-ray films, and computed tomographic or magnetic resonanceimaging studies (or both) of the head and neck. Computed tomographyor magnetic resonance imaging was usually repeated four to sixweeks after treatment was completed to help assess the responseto treatment.
To be eligible for the study, patients had to have previouslyuntreated, histologically proven squamous-cell carcinoma; atumor that was more than 4 cm in diameter (stage T3), or a tumorthat was more than 4 cm in diameter and invaded deep tissuesor bone or extended into an adjacent anatomical area (stageT4), with or without massive cervical lymphadenopathy (metastasisto a lymph node measuring more than 6 cm; stage N3); and noevidence of distant metastases. Patients with tumors of thebase of the tongue that were between 2 and 4 cm in diameterwithout palpable cervical lymph nodes (stage T2N0) were alsoeligible. Primary tumors were classified as resectable or unresectable.Unresectable lesions were defined as those in which a resectionplane could not be created without a high probability of grossresidual disease.13 Resectable primary tumors were defined asthose with a low probability of residual disease after surgery.Most patients with resectable primary tumors were enrolled inthe protocol for the purpose of preserving the function of theaffected organ. Patients had to be at least 18 years of ageand no older than 75 years with a Karnofsky performance scoreof at least 60, a serum creatinine concentration of 2.0 mg perdeciliter (177 µmol per liter) or less, a white-cell countof at least 3000 per cubic millimeter, and a platelet countof at least 100,000 per cubic millimeter.
Patients who had had invasive cancer within the preceding fiveyears, synchronous primary lesions, or squamous-cell carcinomaof the skin of the head and neck were excluded from the study,as were those who were pregnant. The protocol was approved bythe protocol-review committee of the Duke Cancer Center andthe institutional review board of Duke University Medical Center.Written informed consent was obtained from all patients.
Accelerated Hyperfractionated Irradiation
The primary tumor and draining lymphatic system were treatedisocentrically with 4-MV or 6-MV photons and parallel opposedlateral portals with a source-to-isocenter distance of 80 to100 cm. Supraclavicular nodes and nodes in the lower part ofthe neck were treated with the use of a single anterior field,with midline blocking to prevent spinal cord overlap. The spinalcord was blocked in the inferior aspect of both lateral fieldsfor laryngeal primary tumors. The inferior border of the lateralfields and the superior border of the supraclavicular fieldscoincided on the skin.
Lateral-field doses were prescribed at midplane, whereas a depthof 3 cm was used for the supraclavicular field. Initial fieldsreceived a total of 4000 cGy, given in dosages of 125 cGy twicea day with a six-hour interval between doses. The use of thesupraclavicular field was discontinued after 4000 cGy had beenadministered if there were no palpable lymph nodes in the lowerpart of the neck. In order to shield the spinal cord, the sizeof the lateral fields was reduced after 4000 cGy had been administered.Electron-beam irradiation was used to boost the dose to theposterior cervical lymph-node chains. The size of the fieldwas again reduced after 5500 to 6000 cGy had been administered.The total dose delivered to the primary tumor was 7500 cGy ina six-week period. Treatment was delivered continuously withoutany planned interruptions.
Accelerated Hyperfractionated Irradiation and Concurrent Chemotherapy
The dosage and techniques of irradiation were the same as inthe group that received accelerated hyperfractionated irradiationalone. A seven-day interruption of radiotherapy was plannedafter 4000 cGy had been administered, since our phase 1–2trial had shown that this was necessary to manage treatment-inducedmucositis. The total dose intended for the primary tumor was7000 cGy in a seven-week period.
Chemotherapy
Chemotherapy was administered during weeks 1 and 6 of the courseof treatment. Patients received prophylactic hydration and antiemetics.Chemotherapy consisted of fluorouracil and cisplatin (Platinol,Bristol-Myers Squibb, Princeton, N.J.). Fluorouracil was administeredas a continuous infusion at a dose of 600 mg per square meterof body-surface area per day for five days. Cisplatin was givenas a daily bolus of 12 mg per square meter per day for fivedays, for a total dose of 60 mg per square meter. Two additionalcycles of cisplatin and fluorouracil were planned after thecompletion of all local therapy, with the cisplatin again dividedinto five daily boluses, and the dose increased to 80 mg persquare meter in cycle 3 and to 100 mg per square meter in cycle4. There were no provisions for reductions in the doses of chemotherapy.
Management of the Neck
Patients with no regional lymph-node metastases of the neck(stage N0) or metastasis to a single ipsilateral lymph nodemeasuring 3 cm or less in diameter (stage N1) were treated onlywith radiotherapy, or radiotherapy and chemotherapy. Patientswho presented with neck disease of stage N2 (metastasis to asingle ipsilateral lymph node that was more than 3 cm in diameterbut not more than 6 cm) or higher were reevaluated four to sixweeks after irradiation. Elective neck dissection was plannedin patients who had a complete response at the primary siteeven if they also had a complete response in the neck.14
Experimental Design
The primary outcome measures were the rate of complete responseat the primary site and the rate of locoregional control. Weestimated that 126 patients (63 in each group) were needed inorder to achieve an approximate power of 0.80 to detect a differencein complete-response rates of 0.20 (0.60 in the hyperfractionationgroup and 0.80 in the combined-treatment group at an alpha levelof 0.05 with a one-sided test). The achievement of the responserates stipulated by the experimental design would in turn leadto a power of 0.80 to detect a difference in the rate of locoregionalcontrol of 0.25.
Randomization Procedures
The randomization strategy was designed by the biostatisticsunit of the Duke Cancer Center and executed independently bythe cancer-center protocol office. The principal investigatortelephoned the protocol office to receive a patient's treatmentassignment, with subsequent written confirmation provided bythe protocol registrar.
The randomization scheme was a permuted block design with anequal probability of assignment to either treatment and stratificationaccording to the resectability of the tumor (resectable or unresectable)and the hemoglobin concentration at randomization (<12 gper deciliter vs. 12 g per deciliter). The hemoglobin concentrationwas selected because of the adverse prognostic effect of anemiain patients undergoing radiotherapy.15,16 The block size wassix.
Statistical Analysis
Exact tests for contingency tables, Kaplan–Meier estimatesof survival,17 and stratified log-rank tests were used to testfor differences in response rates, estimated times to events,and differences in the distributions of these events. All Pvalues are two-sided. Competing risk factors are a fundamentalproblem in the design of studies that use local control as anend point, since relapses at distant sites or deaths may occurbefore the end point is reached.18,19 This problem ordinarilyrequires one to assume that the risk factors are independent,an untestable and potentially implausible assumption. Therefore,in addition to analyzing locoregional control, we analyzed bothrelapse-free survival — that is, survival free of relapseat a local or a distant site — and overall survival, whichincluded death from any cause.
Results
Characteristics of the Patients
From June 1990 to December 1995, 142 eligible patients wereidentified. Twenty patients declined to enroll in the study.Of the 122 who underwent randomization, 6 were excluded fromthe analysis for the following reasons: synchronous primarytumors (2 patients), distant metastases at diagnosis (2), lossto follow-up before the start of treatment (1), and refusalof all treatment (1). Thus, only 116 patients were includedin the analysis.
Table 1 outlines the characteristics of the patients. Fifty-fivepercent of the 60 patients in the hyperfractionation group and52 percent of the 56 patients in the combined-treatment grouphad unresectable disease. Eighty-seven percent of the patientsin the hyperfractionation group and 90 percent of those in thecombined-treatment group had stage T3 or T4 primary tumors.The mean diameter of the primary tumor exceeded 5 cm in bothgroups. Nodal metastases were present in 73 percent of the patientsin the hyperfractionation group and 70 percent of those in thecombined-treatment group. Sixty-three percent of the patientsin the hyperfractionation group had advanced nodal disease (stageN2 or N3), as compared with 44 percent of those in the combined-treatmentgroup (P=0.31). Most patients (89 percent) were enrolled atDuke University Medical Center or the Durham Veterans AffairsHospital.
Table 1. Characteristics of the Patients at Randomization.
Treatment
Radiotherapy in the hyperfractionation regimen was designedto be more intensive than in the combined-treatment regimen,in terms of both total dose and the time of delivery. The mean(±SD) dose delivered to the primary tumor was 7400±273cGy in the hyperfractionation regimen and 7050±160 cGyin the combined-treatment regimen (P<0.001 by the two-tailedt-test). The average numbers of days of administration were42±6 and 47±5, respectively (P<0.001 by thetwo-tailed t-test). There were no unplanned treatment breaks.
Fifty-five of the patients in the combined-treatment group (98percent) received two cycles of chemotherapy concurrently withirradiation; a cardiac arrhythmia developed in one patient asa result of fluorouracil therapy, and he received only one cycleof chemotherapy. Thirty-two patients in this group (57 percent)received the third and fourth cycles of post-radiation chemotherapy.Seventeen patients refused to undergo post-radiation chemotherapy,and it was not offered to the seven patients who did not havea complete response at the primary site after combined therapy.
Toxicity of Treatment
Table 2 outlines the adverse effects of treatment. Sepsis, includingone case that was fatal, was more frequent in the combined-treatmentgroup, as is expected with the use of myelosuppressive agents.The incidence of confluent mucositis was virtually the samein the two treatment groups, although the mean length of timebefore mucositis resolved was longer in the combined-treatmentgroup (six vs. four weeks). There were no significant differencesregarding weight loss, although a higher proportion of patientsin the combined-treatment group required temporary nasogastricor gastronomy feeding tubes. Severe long-term effects requiringsurgery or hyperbaric oxygen — namely, osteonecrosis andsoft-tissue necrosis — were rare in both groups.
Table 2. Short-Term and Long-Term Adverse Effects of Treatment.
Outcome
A complete response was defined as the disappearance of allclinical and radiographic evidence of disease at the primarysite six weeks after radiotherapy. Of the 60 patients in thehyperfractionation group, 44 (73 percent) had a complete response,whereas 49 of the 56 patients in the combined-treatment group(88 percent) had a complete response (P=0.52). The responsewas pathologically confirmed in patients who subsequently underwentelective neck dissection, since the presence of persistent diseasewould have necessitated more comprehensive surgery than a neckdissection.
Of the 37 patients in the hyperfractionation group who had stageN2 or N3 cervical lymphadenopathy, 25 had a complete response.Neck dissection was performed in 16 of these patients, and residualcancer was identified in specimens from 6. Among the 25 patientsin the combined-treatment group with adenopathy of stage N2or N3, 19 had a complete response. Neck dissection was performedin 14 patients, and residual cancer was present in 3.
The median follow-up of surviving patients was 41 months (range,19 to 86); 82 percent of such patients were followed for atleast 2 years. All relapses occurred within 18 months afterenrollment. Patients in the combined-treatment group had betterrates of locoregional control of disease at three years (70percent vs. 44 percent, P=0.01) (Figure 1), relapse-free survival(61 percent vs. 41 percent, P=0.08) (Figure 2), and overallsurvival (55 percent vs. 34 percent, P=0.07) (Figure 3) thanthe patients in the hyperfractionation group. The respectiveP values for these three end points were 0.01, 0.11, and 0.12after adjustment for differences in nodal stage at base linebetween the two treatment groups.
Figure 1. Kaplan–Meier Estimates of the Duration of Locoregional Control of Disease.
Combined treatment was better than hyperfractionation alone (P=0.01). The I bars indicate the 95 percent confidence intervals for the hyperfractionation group (0.32 to 0.58) and the combined-treatment group (0.56 to 0.82). Data on patients with distant metastases as a first event were not censored, and such patients were still considered to be at risk for local failure.
Figure 2. Kaplan–Meier Estimates of Relapse-free Survival.
Combined treatment was better than hyperfractionation alone (P=0.08). The I bars indicate the 95 percent confidence intervals for the hyperfractionation group (0.27 to 0.53) and the combined-treatment group (0.48 to 0.74). Data on patients who died of other causes were censored at the time of death.
Figure 3. Kaplan–Meier Estimates of Overall Survival.
Combined treatment was better than hyperfractionation alone (P=0.07). The I bars indicate the 95 percent confidence intervals for the hyperfractionation group (0.22 to 0.48) and the combined-treatment group (0.42 to 0.68). Death from any cause was included in the analysis.
Patterns of Relapse
The tumor recurred in 33 patients who received only hyperfractionation.The primary site was the most common location of a first recurrence(in 21 of 33 patients, or 64 percent). Lymph nodes were involvedin 15 patients (45 percent), and distant metastases were a componentin 6 patients (18 percent). The percentage of recurrences totalsmore than 100 because some patients had recurrences at multiplesites.
The tumor recurred in 22 patients after combined therapy, withthe most common location being the primary site (in 16 of 22patients, or 73 percent). In the remaining 6 patients (27 percent)the recurrences consisted of distant metastases; 5 of thesepatients were among the 17 who refused to undergo post-radiationchemotherapy. There were no recurrences in the neck in the patientswho underwent elective neck dissection in either treatment group.
Discussion
In most patients with advanced head and neck cancer, conventionalradiotherapy does not result in long-term locoregional controlof the tumor, and it is this failure that ultimately provesfatal. Investigators have sought to improve this situation throughthe use of several strategies.
Accelerated fractionation and hyperfractionation both use multipledaily dosages of irradiation. The purpose of accelerated fractionationis to reduce tumor proliferation during therapy by shorteningthe overall treatment time. With hyperfractionated irradiation,the treatment time is kept constant relative to once-daily treatment.Hyperfractionation is an attempt to improve the therapeuticratio by increasing the total dose of radiation, but not therisk of long-term toxicity. The size of each fraction is lessthan that delivered with standard once-daily treatment. Phase2 trials have reported that these approaches have considerablebenefits. Phase 3 trials of the EORTC have confirmed these findings.8,20,21,22
Two randomized trials of sequentially administered chemotherapyand radiation, with or without surgery depending on the resectabilityof the tumor, for advanced laryngeal and hypopharyngeal cancerhave demonstrated that this approach can result in a high degreeof organ preservation; it can obviate the need for laryngectomyand result in survival rates equivalent to those reported aftersurgery and postoperative radiation.23,24 Despite its widespreaduse, however, this strategy has not been proved superior toradiation alone.25
Regimens of concurrently administered radiation and chemotherapyhave typically employed once-daily irradiation with doses rangingfrom 65 to 70 Gy. This approach has an apparent advantage ascompared with radiation alone.26 Moreover, a randomized studydemonstrated the superiority of concurrent combined therapyover sequential combined therapy.27 Recent meta-analyses havealso concluded that concurrent administration is superior tosequential treatment.9,10
We combined accelerated hyperfractionated irradiation with concurrentchemotherapy. When our study began in 1990, phase 2 data attestedto the superiority of hyperfractionation over conventional radiotherapy.5,6,7Other results suggested the superiority of concurrent chemotherapyand radiotherapy for esophageal, anal, and rectal cancer. Wetherefore decided to compare maximally intensive radiotherapyalone (total dose, 7500 cGy) with a slightly less intense radiotherapyprogram (total dose, 7000 cGy) plus concurrent chemotherapy.
We found that overall survival, relapse-free survival, and locoregionalcontrol were all improved by the addition of concurrent chemotherapyto the hyperfractionation program. Moreover, these results wereachieved without a corresponding increase in severe toxicity;long-term complications were the same in both groups, with aslight increase in acute adverse effects in the combined-treatmentgroup.
The outcome of this trial must be interpreted with caution.Despite randomization, there were some imbalances in the twotreatment groups. There were more patients with advanced nodaldisease (N2 or N3) in the hyperfractionation group than in thecombined-treatment group (63 percent vs. 45 percent, P=0.31),perhaps making the prognosis worse in the former group. Therewere other, smaller imbalances regarding the primary site, withmore patients with the hypopharynx as a primary site (whichis associated with a less favorable result) in the combined-treatmentgroup and more patients with the oropharynx (tonsil and baseof tongue) as a primary site (which is associated with a morefavorable result) in the hyperfractionation group. The trialwas, however, well balanced with respect to resectability, themost important prognostic variable, as well as the stage ofthe tumor, hemoglobin concentration, and Karnofsky performancestatus.
Our protocol specified that patients with stage N2 or N3 tumorscould undergo elective neck dissection, but the procedure wasnot always performed. The absence of any relapses in the neckamong patients who underwent dissection implies that the overallfailure rate in the neck would have been lower had this aspectof the protocol been rigorously followed. A greater proportionof the patients in the combined-treatment group underwent neckdissection than in the hyperfractionation group, another possiblecontribution to the improved outcome for this group.
This trial was not designed to test the value of adjuvant chemotherapy.Nonetheless, the fact that five of the six recurrences at distantsites occurred among the 17 patients in the combined-treatmentgroup who did not receive post-irradiation chemotherapy suggeststhat relapse-free survival in this group might have been higherhad patients received all planned chemotherapy. The IntergroupStudy 0034 demonstrated a reduction in distant metastases withadjuvant chemotherapy with cisplatin and fluorouracil in patientswith resectable head and neck cancer, albeit with no improvementin overall survival.28
Despite the improvements in overall survival, relapse-free survival,and locoregional control of disease with the use of hyperfractionatedirradiation and concurrent chemotherapy, approximately halfthe patients who received this treatment ultimately died oftheir disease, mostly from sequelae of uncontrolled locoregionaldisease. Clearly, there is a need for improvement in the treatmentof locoregional disease in advanced head and neck cancer.
Supported by a grant (CA14236) from the National Cancer Institute.
Source Information
From the Departments of Radiation Oncology (D.M.B., L.R.P.), Medicine (M.E.A., A.T.H.), and Surgery (S.R.F., R.L.S., W.J.R.) and the Department of Community and Family Medicine, Division of Biometry (V.H., S.L.G.), Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, N.C.
Address reprint requests to Dr. Brizel at the Department of Radiation Oncology, Box 3085, Duke University Medical Center, Durham, NC 27710.
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Specenier, P. M., Van den Weyngaert, D., Van Laer, C., Weyler, J., Van den Brande, J., Huizing, M. T., Dyck, J., Schrijvers, D., Vermorken, J. B.
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Langer, C. J., Harris, J., Horwitz, E. M., Nicolaou, N., Kies, M., Curran, W., Wong, S., Ang, K.
(2007). Phase II Study of Low-Dose Paclitaxel and Cisplatin in Combination With Split-Course Concomitant Twice-Daily Reirradiation in Recurrent Squamous Cell Carcinoma of the Head and Neck: Results of Radiation Therapy Oncology Group Protocol 9911. JCO
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Salama, J. K., Seiwert, T. Y., Vokes, E. E.
(2007). Chemoradiotherapy for Locally Advanced Head and Neck Cancer. JCO
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Kawashima, M., Fujii, H., Hayashi, R., Tahara, M., Nasu, K., Arahira, S., Ogino, T.
(2007). Influence of Delayed Tumor Clearance on Reliability of Complete Response Rate in Chemoradiotherapy for Head and Neck Cancer. Jpn J Clin Oncol
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Chen, A. Y., Schrag, N. M., Halpern, M., Stewart, A., Ward, E. M.
(2007). Health Insurance and Stage at Diagnosis of Laryngeal Cancer: Does Insurance Type Predict Stage at Diagnosis?. Arch Otolaryngol Head Neck Surg
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van den Broek, G. B., Wreesmann, V. B., van den Brekel, M. W.M., Rasch, C. R.N., Balm, A. J.M., Rao, P. H.
(2007). Genetic Abnormalities Associated with Chemoradiation Resistance of Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res.
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Kawashima, M., Hayashi, R., Tahara, M., Yamazaki, M., Miyazaki, M., Arahira, S., Ogino, T.
(2007). Accelerated Radiotherapy and Larynx Preservation in Favorable-risk Patients with T2 or Worse Hypopharyngeal Cancer. Jpn J Clin Oncol
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Curran, D., Giralt, J., Harari, P. M., Ang, K. K., Cohen, R. B., Kies, M. S., Jassem, J., Baselga, J., Rowinsky, E. K., Amellal, N., Comte, S., Bonner, J. A.
(2007). Quality of Life in Head and Neck Cancer Patients After Treatment With High-Dose Radiotherapy Alone or in Combination With Cetuximab. JCO
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Fuwa, N., Kodaira, T., Tachibana, H., Nakamura, T., Daimon, T.
(2007). Dose Escalation Study of Nedaplatin with 5-Fluorouracil in Combination with Alternating Radiotherapy in Patients with Head and Neck Cancer. Jpn J Clin Oncol
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(2007). Targeting receptor tyrosine kinases and their signal transduction routes in head and neck cancer. Ann Oncol
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(2007). Can Pretreatment CT Perfusion Predict Response of Advanced Squamous Cell Carcinoma of the Upper Aerodigestive Tract Treated with Induction Chemotherapy?. Am. J. Neuroradiol.
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Quintela-Fandino, M., Hitt, R., Medina, P. P., Gamarra, S., Manso, L., Cortes-Funes, H., Sanchez-Cespedes, M.
(2006). DNA-Repair Gene Polymorphisms Predict Favorable Clinical Outcome Among Patients With Advanced Squamous Cell Carcinoma of the Head and Neck Treated With Cisplatin-Based Induction Chemotherapy. JCO
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Tsao, A. S., Garden, A. S., Kies, M. S., Morrison, W., Feng, L., Lee, J. J., Khuri, F., Zinner, R., Myers, J., Papadimitrakopoulou, V., Lewin, J., Clayman, G. L., Ang, K. K., Glisson, B. S.
(2006). Phase I/II Study of Docetaxel, Cisplatin, and Concomitant Boost Radiation for Locally Advanced Squamous Cell Cancer of the Head and Neck. JCO
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Mendenhall, W. M., Hinerman, R. W., Amdur, R. J., Malyapa, R. S., Lansford, C. D., Werning, J. W., Villaret, D. B.
(2006). Postoperative radiotherapy for squamous cell carcinoma of the head and neck.. Clin Med Res
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Buckner, J. C., Ballman, K. V., Michalak, J. C., Burton, G. V., Cascino, T. L., Schomberg, P. J., Hawkins, R. B., Scheithauer, B. W., Sandler, H. M., Marks, R. S., O'Fallon, J. R.
(2006). Phase III Trial of Carmustine and Cisplatin Compared With Carmustine Alone and Standard Radiation Therapy or Accelerated Radiation Therapy in Patients With Glioblastoma Multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest Oncology Group 9503 Trials. JCO
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Pfister, D. G., Laurie, S. A., Weinstein, G. S., Mendenhall, W. M., Adelstein, D. J., Ang, K. K., Clayman, G. L., Fisher, S. G., Forastiere, A. A., Harrison, L. B., Lefebvre, J.-L., Leupold, N., List, M. A., O'Malley, B. O., Patel, S., Posner, M. R., Schwartz, M. A., Wolf, G. T.
(2006). American Society of Clinical Oncology Clinical Practice Guideline for the Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer. JCO
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Bourhis, J., Lapeyre, M., Tortochaux, J., Rives, M., Aghili, M., Bourdin, S., Lesaunier, F., Benassi, T., Lemanski, C., Geoffrois, L., Lusinchi, A., Verrelle, P., Bardet, E., Julieron, M., Wibault, P., Luboinski, M., Benhamou, E.
(2006). Phase III Randomized Trial of Very Accelerated Radiation Therapy Compared With Conventional Radiation Therapy in Squamous Cell Head and Neck Cancer: A GORTEC Trial. JCO
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Brizel, D. M., Esclamado, R.
(2006). Concurrent Chemoradiotherapy for Locally Advanced, Nonmetastatic, Squamous Carcinoma of the Head and Neck: Consensus, Controversy, and Conundrum. JCO
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(2006). Does Induction Chemotherapy Have a Role in the Management of Locoregionally Advanced Squamous Cell Head and Neck Cancer?. JCO
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(2006). 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. JCO
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(2006). Multiagent Concurrent Chemoradiotherapy for Locoregionally Advanced Squamous Cell Head and Neck Cancer: Mature Results From a Single Institution. JCO
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(2006). Concurrent Cetuximab, Cisplatin, and Concomitant Boost Radiotherapy for Locoregionally Advanced, Squamous Cell Head and Neck Cancer: A Pilot Phase II Study of a New Combined-Modality Paradigm. JCO
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Bonner, J. A., Harari, P. M., Giralt, J., Azarnia, N., Shin, D. M., Cohen, R. B., Jones, C. U., Sur, R., Raben, D., Jassem, J., Ove, R., Kies, M. S., Baselga, J., Youssoufian, H., Amellal, N., Rowinsky, E. K., Ang, K. K.
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(2006). Single-Cycle Induction Chemotherapy Selects Patients With Advanced Laryngeal Cancer for Combined Chemoradiation: A New Treatment Paradigm. JCO
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Pfister, D. G., Ridge, J. A.
(2006). Induction Chemotherapy for Larynx Preservation: Patient Selection or Therapeutic Effect?. JCO
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(2006). Alternating chemotherapy and radiotherapy in locally advanced head and neck cancer: an alternative?. The Oncologist
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(2005). Acute Toxicity and Preliminary Clinical Outcomes of Concurrent Radiation Therapy and Weekly Docetaxel and Daily Cisplatin for Head and Neck Cancer. Jpn J Clin Oncol
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Robbins, K. T., Kumar, P., Harris, J., McCulloch, T., Cmelak, A., Sofferman, R., Levine, P., Weisman, R., Wilson, W., Weymuller, E., Fu, K.
(2005). Supradose Intra-Arterial Cisplatin and Concurrent Radiation Therapy for the Treatment of Stage IV Head and Neck Squamous Cell Carcinoma Is Feasible and Efficacious in a Multi-Institutional Setting: Results of Radiation Therapy Oncology Group Trial 9615. JCO
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Bernier, J., Cooper, J. S.
(2005). Chemoradiation after Surgery for High-Risk Head and Neck Cancer Patients: How Strong Is the Evidence?. The Oncologist
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Budach, V., Stuschke, M., Budach, W., Baumann, M., Geismar, D., Grabenbauer, G., Lammert, I., Jahnke, K., Stueben, G., Herrmann, T., Bamberg, M., Wust, P., Hinkelbein, W., Wernecke, K.-D.
(2005). Hyperfractionated Accelerated Chemoradiation With Concurrent Fluorouracil-Mitomycin Is More Effective Than Dose-Escalated Hyperfractionated Accelerated Radiation Therapy Alone in Locally Advanced Head and Neck Cancer: Final Results of the Radiotherapy Cooperative Clinical Trials Group of the German Cancer Society 95-06 Prospective Randomized Trial. JCO
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Rischin, D., Peters, L., Fisher, R., Macann, A., Denham, J., Poulsen, M., Jackson, M., Kenny, L., Penniment, M., Corry, J., Lamb, D., McClure, B.
(2005). Tirapazamine, Cisplatin, and Radiation Versus Fluorouracil, Cisplatin, and Radiation in Patients With Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). JCO
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Urba, S. G., Moon, J., Giri, P.G. S., Adelstein, D. J., Hanna, E., Yoo, G. H., LeBlanc, M., Ensley, J. F., Schuller, D. E.
(2005). Organ Preservation for Advanced Resectable Cancer of the Base of Tongue and Hypopharynx: A Southwest Oncology Group Trial. JCO
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Huguenin, P., Beer, K. T., Allal, A., Rufibach, K., Friedli, C., Davis, J. B., Pestalozzi, B., Schmid, S., Thoni, A., Ozsahin, M., Bernier, J., Topfer, M., Kann, R., Meier, U. R., Thum, P., Bieri, S., Notter, M., Lombriser, N., Glanzmann, C.
(2004). Concomitant Cisplatin Significantly Improves Locoregional Control in Advanced Head and Neck Cancers Treated With Hyperfractionated Radiotherapy. JCO
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Ang, K. K.
(2004). Concurrent Radiation Chemotherapy for Locally Advanced Head and Neck Carcinoma: Are We Addressing Burning Subjects?. JCO
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Zorat, P. L., Paccagnella, A., Cavaniglia, G., Loreggian, L., Gava, A., Mione, C. A., Boldrin, F., Marchiori, C., Lunghi, F., Fede, A., Bordin, A., Da Mosto, M. C., Sileni, V. C., Orlando, A., Jirillo, A., Tomio, L., Pappagallo, G. L., Ghi, M. G.
(2004). Randomized Phase III Trial of Neoadjuvant Chemotherapy in Head and Neck Cancer: 10-Year Follow-Up. JNCI J Natl Cancer Inst
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Jeremic, B., Milicic, B., Dagovic, A., Vaskovic, Z., Tadic, L.
(2004). Radiation Therapy With or Without Concurrent Low-Dose Daily Chemotherapy in Locally Advanced, Nonmetastatic Squamous Cell Carcinoma of the Head and Neck. JCO
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Milano, M. T., Haraf, D. J., Stenson, K. M., Witt, M. E., Eng, C., Mittal, B. B., Argiris, A., Pelzer, H., Kozloff, M. F., Vokes, E. E.
(2004). Phase I Study of Concomitant Chemoradiotherapy with Paclitaxel, Fluorouracil, Gemcitabine, and Twice-Daily Radiation in Patients with Poor-Prognosis Cancer of the Head and Neck. Clin. Cancer Res.
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Cooper, J. S., Pajak, T. F., Forastiere, A. A., Jacobs, J., Campbell, B. H., Saxman, S. B., Kish, J. A., Kim, H. E., Cmelak, A. J., Rotman, M., Machtay, M., Ensley, J. F., Chao, K.S. C., Schultz, C. J., Lee, N., Fu, K. K., the Radiation Therapy Oncology Group 9501/Intergro,
(2004). Postoperative Concurrent Radiotherapy and Chemotherapy for High-Risk Squamous-Cell Carcinoma of the Head and Neck. NEJM
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Bernier, J., Domenge, C., Ozsahin, M., Matuszewska, K., Lefebvre, J.-L., Greiner, R. H., Giralt, J., Maingon, P., Rolland, F., Bolla, M., Cognetti, F., Bourhis, J., Kirkpatrick, A., van Glabbeke, M., the European Organization for Research and Treatme,
(2004). Postoperative Irradiation with or without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer. NEJM
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Crombet, T., Osorio, M., Cruz, T., Roca, C., del Castillo, R., Mon, R., Iznaga-Escobar, N., Figueredo, R., Koropatnick, J., Renginfo, E., Fernandez, E., Alvarez, D., Torres, O., Ramos, M., Leonard, I., Perez, R., Lage, A.
(2004). Use of the Humanized Anti-Epidermal Growth Factor Receptor Monoclonal Antibody h-R3 in Combination With Radiotherapy in the Treatment of Locally Advanced Head and Neck Cancer Patients. JCO
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Cohen, E. E.W., Lingen, M. W., Vokes, E. E.
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Eisbruch, A.
(2004). Dysphagia and aspiration following chemo-irradiation of head and neck cancer: major obstacles to intensification of therapy. Ann Oncol
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Nguyen, N. P., Moltz, C. C., Frank, C., Vos, P., Smith, H. J., Karlsson, U., Dutta, S., Midyett, F. A., Barloon, J., Sallah, S.
(2004). Dysphagia following chemoradiation for locally advanced head and neck cancer. Ann Oncol
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Aguilar-Ponce, J., Granados-Garcia, M., Villavicencio, V., Poitevin-Chacon, A., Green, D., Duenas-Gonzalez, A., Herrera-Gomez, A., Luna-Ortiz, K., Alvarado, A., Martinez-Said, H., Castillo-Henkel, C., Segura-Pacheco, B., De la Garza, J.
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Airoldi, M., Cortesina, G., Giordano, C., Pedani, F., Gabriele, A. M., Marchionatti, S., Bumma, C.
(2004). Postoperative Adjuvant Chemoradiotherapy in Older Patients With Head and Neck Cancer. Arch Otolaryngol Head Neck Surg
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Denis, F., Garaud, P., Bardet, E., Alfonsi, M., Sire, C., Germain, T., Bergerot, P., Rhein, B., Tortochaux, J., Calais, G.
(2004). Final Results of the 94-01 French Head and Neck Oncology and Radiotherapy Group Randomized Trial Comparing Radiotherapy Alone With Concomitant Radiochemotherapy in Advanced-Stage Oropharynx Carcinoma. JCO
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Trotti, A., Bentzen, S. M.
(2004). The Need for Adverse Effects Reporting Standards in Oncology Clinical Trials. JCO
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Haraf, D. J., Rosen, F. R., Stenson, K., Argiris, A., Mittal, B. B., Witt, M. E., Brockstein, B. E., List, M. A., Portugal, L., Pelzer, H., Weichselbaum, R. R., Vokes, E. E.
(2003). Induction Chemotherapy followed by Concomitant TFHX Chemoradiotherapy with Reduced Dose Radiation in Advanced Head and Neck Cancer. Clin. Cancer Res.
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Lamont, E. B., Hayreh, D., Pickett, K. E., Dignam, J. J., List, M. A., Stenson, K. M., Haraf, D. J., Brockstein, B. E., Sellergren, S. A., Vokes, E. E.
(2003). Is Patient Travel Distance Associated With Survival on Phase II Clinical Trials in Oncology?. JNCI J Natl Cancer Inst
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(2003). Intensive Concurrent Chemoradiotherapy for Head and Neck Cancer with 5-Fluorouracil- and Hydroxyurea-Based Regimens: Reversing a Pattern of Failure. The Oncologist
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Rosen, F. R., Haraf, D. J., Kies, M. S., Stenson, K., Portugal, L., List, M. A., Brockstein, B. E., Mittal, B. B., Rademaker, A. W., Witt, M. E., Pelzer, H., Weichselbaum, R. R., Vokes, E. E.
(2003). Multicenter Randomized Phase II Study of Paclitaxel (1-Hour Infusion), Fluorouracil, Hydroxyurea, and Concomitant Twice Daily Radiation with or without Erythropoietin for Advanced Head and Neck Cancer. Clin. Cancer Res.
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Haddad, R., Tishler, R. B., Norris, C. M., Mahadevan, A., Busse, P., Wirth, L., Goguen, L. A., Sullivan, C. A., Costello, R., Case, M. A., Posner, M. R.
(2003). Docetaxel, Cisplatin, 5-Fluorouracil (TPF)-Based Induction Chemotherapy for Head and Neck Cancer and the Case for Sequential, Combined-Modality Treatment. The Oncologist
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Vokes, E. E., Stenson, K., Rosen, F. R., Kies, M. S., Rademaker, A. W., Witt, M. E., Brockstein, B. E., List, M. A., Fung, B. B., Portugal, L., Mittal, B. B., Pelzer, H., Weichselbaum, R. R., Haraf, D. J.
(2003). Weekly Carboplatin and Paclitaxel Followed by Concomitant Paclitaxel, Fluorouracil, and Hydroxyurea Chemoradiotherapy: Curative and Organ-Preserving Therapy for Advanced Head and Neck Cancer. JCO
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Adelstein, D. J., Li, Y., Adams, G. L., Wagner, H. Jr, Kish, J. A., Ensley, J. F., Schuller, D. E., Forastiere, A. A.
(2003). 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. JCO
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Weber, R. S., Berkey, B. A., Forastiere, A., Cooper, J., Maor, M., Goepfert, H., Morrison, W., Glisson, B., Trotti, A., Ridge, J. A., Chao, K. S. C., Peters, G., Lee, D. J., Leaf, A., Ensley, J.
(2003). Outcome of Salvage Total Laryngectomy Following Organ Preservation Therapy: The Radiation Therapy Oncology Group Trial 91-11. Arch Otolaryngol Head Neck Surg
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Monnerat, C., Faivre, S., Temam, S., Bourhis, J., Raymond, E.
(2002). End points for new agents in induction chemotherapy for locally advanced head and neck cancers. Ann Oncol
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(2002). Randomized Controlled Trials for Evaluating Surgical Questions. Arch Otolaryngol Head Neck Surg
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Mendenhall, W. M., Morris, C. G., Stringer, S. P., Amdur, R. J., Hinerman, R. W., Villaret, D. B., Robbins, K. T.
(2002). Voice Rehabilitation After Total Laryngectomy and Postoperative Radiation Therapy. JCO
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Rischin, D., J. Peters, L.
(2002). The Local-Regionally Advanced Nasopharyngeal Carcinoma Jigsaw Puzzle: Where Does the Chemotherapy Piece Fit?. JCO
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(2002). Concomitant Chemoradiotherapy in Pyriform Sinus Carcinoma. Arch Otolaryngol Head Neck Surg
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Gupta, A. K., McKenna, W. G., Weber, C. N., Feldman, M. D., Goldsmith, J. D., Mick, R., Machtay, M., Rosenthal, D. I., Bakanauskas, V. J., Cerniglia, G. J., Bernhard, E. J., Weber, R. S., Muschel, R. J.
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Poole, M. E., Sailer, S. L., Rosenman, J. G., Tepper, J. E., Weissler, M. C., Shockley, W. W., Yarbrough, W. G., Pillsbury III, H. C., Schell, M. J., Bernard, S. A.
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Robert, F., Ezekiel, M. P., Spencer, S. A., Meredith, R. F., Bonner, J. A., Khazaeli, M. B., Saleh, M. N., Carey, D., LoBuglio, A. F., Wheeler, R. H., Cooper, M. R., Waksal, H. W.
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Kies, M. S., Haraf, D. J., Rosen, F., Stenson, K., List, M., Brockstein, B., Chung, T., Mittal, B. B., Pelzer, H., Portugal, L., Rademaker, A., Weichselbaum, R., Vokes, E. E.
(2001). Concomitant Infusional Paclitaxel and Fluorouracil, Oral Hydroxyurea, and Hyperfractionated Radiation for Locally Advanced Squamous Head and Neck Cancer. JCO
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Posner, M. R., Glisson, B., Frenette, G., Al-Sarraf, M., Colevas, A. D., Norris, C. M., Seroskie, J. D., Shin, D. M., Olivares, R., Garay, C. A.
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[Abstract][Full Text]
Eisbruch, A., Shewach, D. S., Bradford, C. R., Littles, J. F., Teknos, T. N., Chepeha, D. B., Marentette, L. J., Terrell, J. E., Hogikyan, N. D., Dawson, L. A., Urba, S., Wolf, G. T., Lawrence, T. S.
(2001). Radiation Concurrent With Gemcitabine for Locally Advanced Head and Neck Cancer: A Phase I Trial and Intracellular Drug Incorporation Study. JCO
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Clayman, G. L., Johnson II, C. J., Morrison, W., Ginsberg, L., Lippman, S. M.
(2001). The Role of Neck Dissection After Chemoradiotherapy for Oropharyngeal Cancer With Advanced Nodal Disease. Arch Otolaryngol Head Neck Surg
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Rischin, D., Peters, L., Hicks, R., Hughes, P., Fisher, R., Hart, R., Sexton, M., D'Costa, I., von Roemeling, R.
(2001). Phase I Trial of Concurrent Tirapazamine, Cisplatin, and Radiotherapy in Patients With Advanced Head and Neck Cancer. JCO
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Baselga, J.
(2000). New Therapeutic Agents Targeting the Epidermal Growth Factor Receptor. JCO
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Brizel, D. M., Wasserman, T. H., Henke, M., Strnad, V., Rudat, V., Monnier, A., Eschwege, F., Zhang, J., Russell, L., Oster, W., Sauer, R.
(2000). Phase III Randomized Trial of Amifostine as a Radioprotector in Head and Neck Cancer. JCO
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Brockstein, B. E., Jeremic, B.
(2000). Reduction of Distant Metastases in Head and Neck Cancer With Concomitant Chemotherapy. JCO
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Mendenhall, W. M., Amdur, R. J., Stringer, S. P., Villaret, D. B., Cassisi, N. J.
(2000). Radiation Therapy for Squamous Cell Carcinoma of the Tonsillar Region: A Preferred Alternative to Surgery?. JCO
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Jeremic, B., Shibamoto, Y., Milicic, B., Nikolic, N., Dagovic, A., Aleksandrovic, J., Vaskovic, Z., Tadic, L.
(2000). 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. JCO
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[Abstract][Full Text]
12 g per deciliter). The hemoglobin concentration was selected because of the adverse prognostic effect of anemia in patients undergoing radiotherapy.15,16 The block size was six. 
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