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
    Institute for Medical Biometry, University Hospitals Charite, 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
    Department of Radiation Oncology, University Hospitals of Erlangen, Erlangen, Germany

    ABSTRACT

    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.

    INTRODUCTION

    PATIENTS AND METHODS

    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

    MMC, as one component of the chemoradiotherapy, was introduced for its selective cell-kill properties to hypoxic cells. FU was used as a radiosensitizer and also to trigger a maximum regenerative response of the oral mucosa as early as the first week of radiation therapy. FU was administered as a continuous infusion for 120 hours at 600 mg/m2/d days 1 to 5. On days 5 and 36, MMC was administered as a single intravenous bolus injection of 10 mg/m2. Initially, a second course of FU was planned during the sixth week of irradiation, but it had to be cancelled during phase I because of excessive mucosal reactions.

    Randomization and Statistical Analyses

    Estimating a 15% difference between HART and C-HART with respect to LRC, a first kind error of 5%, a power of 85%, an accrual of 4 years, a follow-up of 2 years, and a loss to follow-up of 10% for a time base of survival of 3 years, a total sample size of 350 patients was calculated to test a two-sided alternative hypothesis of differences between HART and C-HART using the log-rank test. Randomization was carried out in blocks of four patients to obtain fully balanced treatment groups.16 The randomization scheme allowed for stratification with regard to well-known prognostic factors such as stage, site, and participating center.

    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 {alpha}1 = .005 at the interim ({alpha}2 = .048 at end of study).17 Treatment effects were evaluated according to intent-to-treat (ITT) analysis, available for therapy and per protocol principle. The survival curves in both treatment groups were estimated according to the Kaplan-Meier method and compared both univariately with log-rank statistics (stratified for centers and sites) as well as multivariately with Cox proportional hazards regression.18 Additionally, OS, FFM, and PFS rates were analyzed to evaluate the well-known problem of competing risks in clinical studies.19 Survival rates with 95% CIs and median survivals were determined as usual. For detection of potential prognostic factors, hazard ratios with 95% CIs were calculated using Cox regression analysis. Follow-up maturity was checked by exclusively analyzing follow-up curves for the living patients.18 Acute and late reactions were scored weekly during treatment and quarterly and biannually during follow-up. Potential differences between both treatments were tested during treatment and the successive surveillance period by the {chi}2 test and corresponding exact tests in contingency tables.20,21 P < .05 (two-tailed) was considered to be significant.

    Surveillance Program

    All patients underwent a strict surveillance program with regular physical examinations, chest x-rays, abdominal ultrasounds, CT and magnetic resonance imaging scans of the head and neck region, and mucosal endoscopies including rebiopsies on suspicion of recurrence. The follow-up intervals were scheduled quarterly during the first and second year and biannually thereafter up to the fifth year. Acute reactions were scored using an arbitrary scale modified according to European Organisation for Research and Treatment of Cancer acute morbidity scales, and late reactions were scored according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer late morbidity scales. Locoregional or distant relapses were classified as treatment failures. Their treatment was left to the discretion of the attending physician.

    RESULTS

    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, {chi}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).

    DISCUSSION

    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.

    Appendix

    Contributing centers, principal investigators, and numbers of patients are as follows: Berlin (Charite, 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, Charite University Hospitals, Robert-Rssle-Klinik im Helios Klinikum, Campus Buch, Berlin, Germany.

    Authors' Disclosures of Potential Conflicts of Interest

    NOTES

    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.

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