|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1125-1135 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.07.010 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 TrialFrom the Department of Radiation Oncology, Campus Benjamin Franklin; Department of Radiation Oncology, Campus Mitte; Department of Radiation Oncology, Campus Wedding; Department of Head and Neck Surgery; and Institute for Medical Biometry, University Hospitals Charité, Berlin; Departments of Radiation Oncology and Head and Neck Surgery, University Hospitals of Essen, Essen; Department of Radiation Oncology, University Hospitals of Tuebingen, Tuebingen; Department of Radiation Oncology, University Hospitals of Dresden, Dresden; and Department of Radiation Oncology, University Hospitals of Erlangen, Erlangen, Germany Address reprint requests to Volker Budach, MD, Strahlenklinik, Universitaetsklinikum Charité, Campus Mitte, 10098 Berlin, Germany; e-mail: volker.budach{at}charite.de
PURPOSE: To report the results and corresponding acute and late reactions of a prospective, randomized, clinical study in locally advanced head and neck cancer comparing concurrent fluorouracil (FU) and mitomycin (MMC) chemotherapy and hyperfractionated accelerated radiation therapy (C-HART; 70.6 Gy) to hyperfractionated accelerated radiation therapy alone (HART; 77.6 Gy). PATIENTS AND METHODS: Three hundred eighty-four stage III (6%) and IV (94%) oropharyngeal (59.4%), hypopharyngeal (32.3%), and oral cavity (8.3%) cancer patients were randomly assigned to receive either 30 Gy (2 Gy every day) followed by 1.4 Gy bid to a total of 70.6 Gy concurrently with FU (600 mg/m2, 120 hours continuous infusion) days 1 through 5 and MMC (10 mg/m2) on days 5 and 36 (C-HART) or 14 Gy (2 Gy every day) followed by 1.4 Gy bid to a total dose of 77.6 Gy (HART). The data were analyzed on an intent-to-treat basis. RESULTS: At 5 years, the locoregional control and overall survival rates were 49.9% and 28.6% for C-HART versus 37.4% and 23.7% for HART, respectively (P = .001 and P = .023, respectively). Progression-free and freedom from metastases rates were 29.3% and 51.9% for C-HART versus 26.6% and 54.7% for HART, respectively (P = .009 and P = .575, respectively). For C-HART, maximum acute reactions of mucositis, moist desquamation, and erythema were lower than with HART, whereas no differences in late reactions and overall rates of secondary neoplasms were observed. CONCLUSION: C-HART (70.6 Gy) is superior to dose-escalated HART (77.6 Gy) with comparable or less acute reactions and equivalent late reactions, indicating an improvement of the therapeutic ratio.
The prognosis of locally advanced and inoperable head and neck cancer is still dismal. Radiation therapy is the mainstay for this group of patients because chemotherapy alone has only palliative means. Apart from intrinsic radioresistance and sublethal damage repair of tumor cell clonogens, hypoxia and repopulation are also known to be major causes of radioresistance.1-3 The results of standard fractionation from control arms of randomized trials are poor, with median 3-year overall survival (OS) and locoregional control (LRC) rates of approximately 30% and 40%, respectively.4,5 A number of strategies have been explored during the last two decades to improve the outcome in locally advanced head and neck cancer. Altered fractionation schedules alone have not shown a survival benefit.5-7 Since the 1970s, treatment has usually consisted of cisplatin, carboplatin, fluorouracil (FU), and mitomycin (MMC)-based, single- or multiple-agent chemotherapies that have been combined with radiotherapy in various time sequences.8-13 A large meta-analysis showed a small but distinct survival benefit of 8% at 5 years, corresponding to a 19% reduction in mortality (P < .0001), with concurrent chemoradiotherapy but not with sequential chemoradiotherapy.14 However, concurrent chemoradiotherapy was generally associated with increased rates of acute and, in some instances, late reactions.15 This study was carried out between 1995 and 1999 to test whether chemotherapy and hyperfractionated accelerated radiation therapy (C-HART; 70.6 Gy) is superior to hyperfractionated accelerated radiation therapy alone (HART; 77.6 Gy) in terms of LRC and OS (Fig 1). The total radiation dose was reduced with C-HART to counterbalance potential MMC- and FU-induced acute and late reactions. To avoid different rates of accelerated tumor clonogen repopulation, the overall treatment time was kept constant at 6 weeks (40 days) for both treatment regimens.
This study was approved by the Ethical Committee of the University Hospitals Charité (Berlin, Germany). The patient eligibility was checked by an interdisciplinary board of otolaryngologists and radiation and medical oncologists. Inclusion criteria were as follows: previously untreated and, according to surgeon assessment, inoperable stage III and IV (International Union Against Cancer 1987 criteria) head and neck carcinomas of the oropharynx and hypopharynx and oral cavity with no evidence of distant metastases; age between 18 and 70 years; Karnofsky performance score more than 70; and squamous cell or undifferentiated histologies. Patients were randomly assigned after they gave written informed consent. Patients who had a history of earlier or synchronic cancer other than skin, lymphoepithelial carcinoma of the nasopharynx, surgery exceeding biopsy, previous chemotherapy or radiation therapy, severe vascular risk factors, insulin-dependent diabetes, symptomatic liver cirrhosis, HIV, pregnancy, or a serum creatinine of more than 1.5 mg/dL or clearance of less than 80 mL were excluded. The tumor stage was classified after a thorough diagnostic work-up, including the patient's history, physical examination, panendoscopy, computed tomography (CT) or magnetic resonance imaging of the head and neck region, chest x-rays, and CT of the abdomen. The patients' baseline characteristics are listed in Table 1. Our experience is that most of the patients suffer from a weight loss of more than 10% during the course of an intensive chemoradiotherapy. Therefore, we recommended gastric feeding tubes for routine use in these patients to prevent major weight loss and subsequent infections. In our study, 82% of the patients received gastric feeding tubes.
Radiotherapy The external-beam radiation dose was prescribed and delivered based on International Commission on Radiation Units and Measurements Report No. 50. Tumors of the oral cavity or oropharynx with lymphadenopathy were treated by opposing lateral fields and an anterior neck field matched below. Central lead shielding was used to protect the larynx, spinal cord, and lung apices, if appropriate. To avoid overlap of beams at the junction with the lateral fields, asymmetric jaws were used. For cancer of the hypopharynx involving pyriform sinus, postcricoid region, and pharyngeal wall, two lateral 15-degree double-wedged fields angled inferiorly by an 11-degree couch rotation were used. Radiotherapy was performed with 6 MV photons up to 36 to 40 Gy when the posterior neck was blocked to shield the spinal cord. Instead, bilateral electron fields of adequate energy were used for the posterior neck nodes. The maximum doses to the spinal cord did not exceed 45 Gy. The first order target volume included the macroscopic tumor and pathologic lymph nodes, which received 77.6 Gy (HART) or 70.6 Gy (C-HART). The second and third order target volumes comprised the regions of high and low risk for lymphatic spread and received a total dose of 60 and 50 Gy by conventional fractionation, respectively. At 50 Gy and again at 60 Gy, a stepwise cone down of the target was used. The fractionation was carried out as described earlier. The overall treatment time was kept constant at 6 weeks for both treatment regimens (Fig 1).
Chemotherapy
Randomization and Statistical Analyses
The primary study end point was an improved LRC. Secondary end points were OS, progression-free survival (PFS), and freedom from distant metastases (FFM) rates. PFS was defined as freedom from locoregional and distant disease. Acute and late reactions were evaluated in both treatment arms. It was assumed that the levels of acute and late reactions as induced after C-HART with 70.6 Gy could not be worse than after HART with 77.6 Gy. An interim analysis after 4 years of randomization was carried out to evaluate the data quality. In addition, a test for LRC differences between HART and C-HART was performed, with a nominal significance level of
Surveillance Program
Treatment Compliance Between March 1995 and June 1999, 384 patients from 10 different institutions were randomly assigned to either C-HART (n = 190) or HART (n = 194) and processed for the ITT analysis. Because of the detection of metastases or secondary primaries, ineligibility for chemotherapy, or death, seven patients in the C-HART arm and four patients in the HART arm had to be withdrawn to generate the population that was available for therapy. Another 32 patients (C-HART) and 15 patients (HART) had to be excluded because of incorrect radiotherapy or chemotherapy, noncompliance, or death during therapy to generate the per protocol population (Fig 2).
Actuarial Results The end points analyzed in this study were the LRC, OS, PFS, and FFM rates. Figure 3 shows the corresponding Kaplan-Meier curves. Using the ITT method and log-rank statistics, the 5-year outcome turned out to be significantly better after chemoradiotherapy than radiotherapy alone. The LRC, OS, and PFS rates for C-HART versus HART were 49.9% versus 37.4% (P = .001), 28.6% versus 23.7% (P = .023), and 29.3% versus 26.6% (P = .009, Table 2), respectively. However, the FFM rates were not statistically significant different for C-HART versus HART (51.9% v 54.7%, respectively; P = .575). The median LRC, OS, and PFS survival times for C-HART versus HART were 48 v 15 months, 23 v 16 months, and 16 v 11 months, respectively. The median time to distant metastases was not yet reached for both treatments. Corresponding hazard ratios derived from Cox regression analyses were 0.71 for OS (95% CI, 0.52 to 0.96), 0.48 for LRC (95% CI, 0.33 to 0.71), and 0.60 for PFS (95% CI, 0.44 to 0.84; Table 3). The multivariate proportional hazards Cox regression analyses revealed the treatment as independent prognostic factor for LRC, PFS, and OS. Nodal status and grading were significant parameters for OS, and nodal status was a significant parameter for PFS; whereas for LRC and FFM, only N0 versus N3 status was significant.
Acute Reactions Considering maximum scores alone, grade 3 and 4 mucositis, moist desquamation, and erythema were observed in 65.7% v 75.7% (P = .045), 29.6% v 46.3% (P = .002), and 31.4% v 45.8% (P = .008,  2 test) of all patients in the C-HART versus HART arms, respectively. Significant differences were not observed in any other item (Table 4). Hematotoxicity, which was only monitored for C-HART, was minimal; the maximum degrees of leucopenia, thrombocytopenia, and anemia were observed at the end of the treatment (day 42) with 8.5% (nine of 106 patients), 1.9% (two of 106 patients), and 2.8% (three of 106 patients) of patients with grade 3 scores, respectively. No grade 4 acute toxicities were observed. Six patients died during treatment (1.6%); five received HART, and one received C-HART. The causes of death were tumor progression (local, n = 2; distant, n = 1), myocardial infarction (n = 1), previously unknown ventricular tachycardia (n = 1), and pulmonary embolism (n = 1).
Late Morbidity Twelve items were documented for late reactions quarterly during the first 2 years of surveillance and biannually thereafter. Taking into account maximal scores, no significant differences between the two therapies were observed (Table 5). Additionally, plots of cumulative incidences for xerostomia and skin fibroses during FU also showed no differences (Fig 4). During the whole surveillance period of 5 years, 6.0% v 5.1% of all patients developed osteoradionecrosis, 3.0% v 3.8% developed transient plexopathy, and 3.6% v 3.8% developed L'Hermitte's syndrome after C-HART versus HART therapy, respectively. A 5.2% (n = 20) overall rate of secondary neoplasms was observed at 5 years, which was not significantly different for both treatment arms by using cumulative incidences (log-rank test, P = .114).
Several phase III randomized trials have shown a high efficacy of concurrent chemoradiotherapy with one or two cycles of MMC at doses of 10 to 20 mg/m2 in squamous cell carcinomas of the head and neck, anus, and esophagus.10,22-24 Viable hypoxic tumor cells of lower radiation sensitivity are suggested to be one of the major causes of local failures in head and neck cancer.25 Experimental and clinical evidence indicates that hypoxia also has some impact on local tumor control.26 In vitro and animal studies have shown that MMC as a bioreductive alkylating agent is selectively cytotoxic in hypoxic tumor cells.27 Because radiation therapy is highly effective for well-oxygenated tumor cells, a combination with MMC should enhance the tumor-cell kill. In this study, we prescribed two cycles of 10 mg/m2 MMC at days 5 and 36 of radiotherapy. The negative impact of tumor-cell repopulation during prolonged treatment periods on the outcome has been addressed in this study by moderately shortening the overall treatment time, which usually ranges between 49 days (2.0 Gy per fraction) and 54 days (1.8 Gy per fraction) for a standard fractionation schedule to 40 days with HART and C-HART. Recent experimental data suggest that MMC may also significantly reduce the rate of tumor-cell repopulation.28 The Radiation Therapy Oncology Group trial 90-03, which tested different fractionation regimens, supports the hypothesis that a moderately accelerated treatment regimen, such as the concomitant boost, is superior in terms of LRC compared with standard fractionation.6 The addition of FU in a wide dose range of 250 to 1,200 mg/m2 concurrent with radiotherapy is also well established in head and neck cancer.8,29 In this study, we used a continuous infusion regimen of FU 600 mg/m2 days 1 through 5 of the first week. According to the phase I results, a second cycle in the sixth week was not feasible because of excessive mucosal reactions resulting in noncompliance of the patients.30 Therefore, a clinical phase I to II study was launched in 1990 testing C-HART in 97 patients followed by dose-escalated HART alone in 12 patients. The LRC and OS rates of 74% and 68%, respectively, for C-HART after 2 years in the phase II study were so promising that the German Cancer Aid supported this multicentric phase III trial (ARO 95-06).31 The 5 years’ results of this study indicate that C-HART with 70.6 Gy is more effective for locally advanced head and neck cancer compared with HART with 77.6 Gy in terms of OS, LRC, and PFS at 2, 3, and 5 years (Fig 3, Table 6). This therapeutic benefit was not associated with an overall increased acute toxicity or late radiation morbidity. Brizel et al,32 who used a similar radiotherapeutic regimen combined with two cycles of cisplatin-FU, also showed superior results for chemoradiotherapy of 70 Gy in terms of LRC and a trend for PFS and OS versus the dose-escalated radiation therapy of 75 Gy alone, with comparable acute and late reactions in both treatment arms. The underlying mechanism of this observation for both studies may be a supra-additive or synergistic effect of the MMC-FU or cisplatin-FU combination. However, quantitatively, the results of Brizel et al's study were superior to this study, which can be attributed to the following reasons: nearly half of all patients (47%) in the Brizel et al study were considered operable, and in the combined group, 57% received two additional cycles of adjuvant cisplatin-FU. The percentage of patients with N2 and N3 disease (86%) in our study was approximately 30% higher compared with the percentage of patients with N2 and N3 disease (54%) reported by Brizel et al.32 Eight different sites, in particular some laryngeal and nasopharyngeal cancer cases, were included, which themselves generally imply a better prognosis. Moreover, some imbalances in patient accrual were observed favoring chemoradiotherapy, with 61% of patients with N2 or N3 disease in the radiotherapy arm versus 44% of patients in the chemoradiotherapy arm. For OS at 3 years, a positive trend for chemoradiotherapy was observed. The major observation of the study by Brizel et al and this study was a definitive improvement in LRC (P = .01 v P = .005, respectively). In addition, this study showed a significant improvement in PFS (P = .02) and OS (P = .05) at 3 years for the concurrent chemoradiotherapy. For C-HART, lower or comparable acute reactions and equivalent late effects were observed. This indicates a benefit in the therapeutic ratio.
The 3-year results of our study compare well with data published by Dobrowsky et al,22 who conducted a three-arm trial with one standard fractionated regimen of 70 Gy and two extremely accelerated 17-day treatment regimens (V-CHART) with 55.3 Gy with or without 20 mg/m2 MMC total dose. However, only 77.1% v 94.0% of all patients in our study had stage IV disease, and more favorable laryngeal cancers were also included. Actuarial distant metastases rates of 7% for V-CHART compared with 36.8% for C-HART at 2 years also indicate a more favorable patient population. However, an OS rate for C-HART of 48.0% v 51% for V-CHART plus MMC at 2 years and a LRC of 57% for both therapies at 2 years are comparable. With V-HART, nearly all patients experienced a severe confluent mucositis 12 to 14 days after the start of treatment, which was more pronounced than with C-HART (66%). Haffty et al10 also showed a benefit of adding MMC to radiotherapy alone in two consecutive randomized trials comprising 195 eligible patients. It is of note that, in Haffty et al's study, only 37.4% of patients had stage IV disease, 32.8% had prognostically more favorable cancer of the larynx and nasopharynx, and the majority of patients (68%) received postoperative chemoradiotherapy. The total dose ranged between 60 and 66 Gy, depending on the treatment group. Grade 3 and 4 hematologic toxicities occurred in only approximately 10% of the patients, and grade 3 mucositis occurred in 22%, indicating a much less aggressive treatment than C-HART.10 The OS and LRC rates of 48% and 76%, respectively, at 5 years mirror the favorable prognostic factors involved and cannot be compared with our study population. The largest MMC-based randomized trial was conducted by the International Atomic Energy Agency and accrued 478 eligible patients.33 Approximately half of the patient population suffered from oral cavity cancer and stage IV tumors, which are both known prognostic unfavorable subgroups. Standard radiotherapy of 66 Gy in 33 fractions over 6.5 weeks and one concurrent cycle of MMC 15 mg/m2 day 5 were administered. Hematologic side effects of MMC were only modest, with less than 5% of grade 3 and 4 toxicities. Despite the lower radiation dose of 66 Gy, the rate of confluent mucositis (57%) showed only a modest difference of 9% compared with C-HART, and in both studies, MMC did not obviously enhance the extent of mucositis. There was no overall benefit of MMC observed for LRC or OS except for 161 N0 patients, in whom LRC at 3 years was significantly improved with MMC (29% v 16%, P = .01). Therefore, Grau et al33 stated that MMC is not effective in patients with higher tumor burden, which is in contrast to our results. OS and LRC rates were 31% and 21% in the study by Grau et al versus 37.5% and 51.8% for C-HART at 3 years. Even with the exclusion of laryngeal and oral cavity cancers, a 27% LRC rate for oropharyngeal and hypopharyngeal cancers may be attributed to the low dose-intensity of MMC with only one course of 15 mg/m2 and to the total dose of only 66 Gy in this study.33 Another randomized study with 209 eligible patients suffering from locally advanced hypopharyngeal and laryngeal cancer compared 50 Gy in 4 weeks with two cycles of 25 Gy in 2 weeks split by 1 month with two concomitant cycles of MMC and FU.34 The combined therapy was not superior because of the prolonged overall treatment time. Most of the chemoradiotherapy studies published up to now are based on the same total dose of irradiation modified in the experimental arm by the addition of various drugs. A detailed analysis of adverse effects in these studies showed that this procedure often led to increased acute toxicities and, in some instances, late reactions to chemoradiotherapy.6,9,29,35,36 However, in our study as well as in the reports of Staar et al11 and Brizel et al,32 acute grade 3 and 4 mucositis was not enhanced in the respective chemoradiotherapy arms. The long-term LRC rate after C-HART in this study is promising. However, OS rates are compromised by the high incidence of distant metastases, prompting the quest for an optimized chemotherapy. So far, only two of numerous phase III studies with cisplatin-based chemoradiotherapy indicate such a reduction of distant metastases.37,38 Therefore, a successive study has been launched by the German Clinical Trials Cooperative Group (ARO/AHMO 04-01, funded by the German Cancer Aid) comparing a weekly cisplatin-based concurrent C-HART regimen with the MMC-based C-HART regimen reported here. A 5.2% absolute rate of secondary neoplasms at 5 years is in the lower range of the published incidence rates.36,39 Using cumulative incidences, no significant differences were observed between C-HART and HART (log-rank test, P = .114). The study by Brizel et al32 and our study showed, in contrast to many other studies, an improvement of the therapeutic ratio and LRC rate. In addition, in this study with C-HART, a significant benefit in PFS and OS was noted compared with dose-escalated HART, with comparable levels of acute and late normal tissue reactions.
Contributors to the trial included the following: V. Budach developed the protocol and coordinated the study; K.-D. Wernecke did the statistical analysis; and M. Fritsche was responsible for data collection. All investigators enrolled patients and were involved in the writing of this report. Contributing centers, principal investigators, and numbers of patients are as follows: Berlin (Charité, Campus Benjamin-Franklin, W. Hinkelbein, 22 patients; Campus Buch, S. Koswig, four patients; Campus-Mitte, V. Budach, 95 patients; and Campus Virchow, P. Wust, 24 patients); Essen (University Hospitals of Essen, M. Stuschke, 76 patients); Dresden (University Hospitals of Dresden, M. Baumann, 56 patients); Tübingen (University Hospitals of Tübingen, W. Budach, 41 patients); Erlangen (University Hospitals of Erlangen, G. Grabenbauer, 32 patients); Fribourg (University Hospitals of Fribourg, H. Frommhold, 14 patients); Halle (University Hospitals of Halle, J. Dunst, 12 patients); and Karlsruhe (University Hospitals of Karlsruhe, M.-L. Sautter-Bihl, eight patients). The following clinical investigators provided and cared for study patients: Herrmann Frommhold, MD, Department of Radiation Oncology, University Hospitals of Fribourg, Fribourg; Juergen Dunst, MD, Department of Radiation Oncology, University Hospitals of Halle, Halle; Marie-Luise Sautter-Bihl, MD, Department of Radiation Oncology, University Hospitals of Karlsruhe, Karlsruhe; and S. Koswig, MD, Department of Radiation Oncology, Charité University Hospitals, Robert-Rössle-Klinik im Helios Klinikum, Campus Buch, Berlin, Germany.
The authors indicated no potential conflicts of interest.
Supported by grant No. 70-1693 of the Deutsche Krebshilfe e.V. Presented in part at the 19th Annual Meeting of the European Society for Therapeutic Radiology and Oncology ESTRO, Istanbul, Turkey, September 19-23, 2000; 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001; 43rd Annual Meeting of the American Society of Therapeutic Radiology and Oncology, San Francisco, CA, November 4-8, 2001; and 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Baumann M, DuBois W, Suit HD: Response of human squamous cell carcinoma xenografts of different sizes to irradiation: Relationship of clonogenic cells, cellular radiation sensitivity in vivo, and tumor rescuing units. Radiat Res 123:325-330, 1990[Medline] 2. Hoeckel M, Schlenger K, Mitze M, et al: Hypoxia and radiation response in human tumors. Semin Radiat Oncol 6:3-9, 1996[CrossRef][Medline] 3. Withers HR, Taylor JM, Maciejewski B: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 27:131-146, 1988[Medline] 4. Rudat V, Wannenmacher M: Role of multimodal treatment in oropharynx, larynx, and hypopharynx cancer. Semin Surg Oncol 20:66-74, 2001[CrossRef][Medline] 5. Budach W, Belka C, Budach V: Konventionell und unkonventionell fraktionierte alleinige strahlentherapie bei plattenepithelkarzinomen des pharynx und larynx. Onkologe 7:550-555, 2001[CrossRef] 6. 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] 7. Stuschke M, Thames HD: Hyperfractionated radiotherapy of human tumors: Overview of the randomized clinical trials. Int J Radiat Oncol Biol Phys 37:259-267, 1997[CrossRef][Medline] 8. Lo TC, Wiley AL, Ansfield FJ, et al: Combined radiation therapy and 5-fluoro-uracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: A randomized study. Am J Roentgenol Radium Ther Nucl Med 126:229-235, 1976 9. Adelstein DJ, Sharan VM, Earle AS, et al: Simultaneous versus sequential combined technique therapy for squamous cell head and neck cancer. Cancer 65:1685-1691, 1990[CrossRef][Medline]
10. Haffty BG, Son YH, Papac R, et al: Chemotherapy as an adjunct to radiation 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 11. Staar S, Rudat V, Stuetzer H, et al: Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy: Results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 50:1161-1171, 2001[CrossRef][Medline]
12. Denis F, Garaud P, Bardet E, et al: 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. J Clin Oncol 22:69-76, 2004 13. Budach V, Budach W: Sequentielle und simultane radiochemotherapie bei lokal fortgeschrittenen kopf-hals-tumoren. Onkologie 7:533-549, 2001 14. 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]
15. El Sayed S, Nelson N: Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region: A meta-analysis of prospective and randomized trials. J Clin Oncol 14:838-847, 1996 16. Pocock SJ: Clinical Trials: A Practical Approach. New York, NY, Wiley & Sons Co, 1983 17. O'Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 35:549-556, 1979[CrossRef][Medline] 18. Parmar MKB, Machin D: Survival Analysis. New York, NY, Wiley & Sons Co, 1995 19. Caplan RJ, Pajak TF, Cox JD: Analysis of the probability and risk of cause-specific failure. Int J Radiat Oncol Biol Phys 29:1183-1186, 1994[Medline] 20. Armitage P, Berry G: Statistical Methods in Medical Research. Oxford, United Kingdom, Blackwell Science, 1994 21. Mehta CR, Patel NR: Exact inference for categorical data, in Armitage P, Colton T (eds): Encyclopedia of Biostatistics. New York, NY, Wiley Co, 1998, pp 1411-1422 22. Dobrowsky W, Naude J, Widder J, et al: Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancer. Int J Radiat Oncol Biol Phys 42:803-806, 1998[CrossRef][Medline] 23. Flam M, John M, Pajak TF, et al: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: Results of a phase III randomized intergroup study. J Clin Oncol 14:2527-2539, 1996[Abstract] 24. Smith TJ, Ryan LM, Douglass HO Jr, et al: Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: A study of the Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys 42:269-276, 1998[CrossRef][Medline] 25. Rockwell S, Moulder JE: Hypoxic fractions of human tumors xenografted into mice: A review. Int J Radiat Oncol Biol Phys 19:197-202, 1990[Medline] 26. Rudat V, Stadler P, Becker A, et al: Predictive value of the tumor oxygenation by means of pO2 histography in patients with advanced head and neck cancer. Strahlenther Onkol 177:462-468, 2001[CrossRef][Medline] 27. Sartorelli AC, Hodnick WF, Belcourt MF, et al: Mitomycin C: A prototype bioreductive agent. Oncol Res 6:501-508, 1994[Medline] 28. Budach W, Paulsen F, Welz S, et al: Mitomycin C in combination with radiotherapy as a potent inhibitor of tumour cell repopulation in a human squamous cell carcinoma. Br J Cancer 86:470-476, 2002[CrossRef][Medline] 29. Sanchiz F, Milla A, Torner J, et al: Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys 19:1347-1350, 1990[Medline] 30. Stuschke M, Budach V, Dinges S, et al: Accelerated hyperfractionated radiotherapy combined with simultaneous chemotherapy in locally advanced pharyngeal and oral carcinomas. Strahlenther Onkol 170:689-699, 1994[Medline] 31. Dinges S, Budach V, Stuschke M, et al: Chemo-radiotherapy for locally advanced head and neck cancer: Long-term results of a phase II trial. Eur J Cancer 33:1152-1155, 1997
32. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798-1804, 1998 33. Grau C, Prakash AJ, Jabeen K, et al: Radiotherapy with or without mitomycin c in the treatment of locally advanced head and neck cancer: Results of the IAEA multicentre randomised trial. Radiother Oncol 67:17-26, 2003[CrossRef][Medline] 34. Keane TJ, Cummings BJ, O'Sullivan B, et al: A randomized trial of radiation therapy compared to split course radiation therapy combined with mitomycin C and 5 fluorouracil as initial treatment for advanced laryngeal and hypopharyngeal squamous carcinoma. Int J Radiat Oncol Biol Phys 25:613-618, 1993[Medline]
35. 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 36. Adelstein DJ, Lavertu P, Saxton JP, et al: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88:876-883, 2000[CrossRef][Medline] 37. 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]
38. 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 39. Pigott KH, Dische S, Saunders MI: The long-term outcome after radical radiotherapy for advanced head and neck cancer. Clin Oncol (R Coll Radiol) 5:343-349, 1993 Submitted July 1, 2004; accepted September 1, 2004.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
1 = .005 at the interim (
