Affiliations of authors: G. Calais, Centre Hospitalier
Universitaire Tours, France; M. Alfonsi, Clinique Sainte Catherine
Avignon, France; E. Bardet, Centre René Gauducheau, Nantes,
France; C. Sire, Centre Hospitalier, Lorient, France; T. Germain,
Centre Hospitalier Universitaire, Poitiers, France; P. Bergerot, Centre
Etienne Dolet, Saint Nazaire, France; B. Rhein, Centre Hospitalier
Universitaire, Limoges, France; J. Tortochaux, Centre Jean Perrin,
Clermont-Ferrand, France; P. Oudinot, Centre Guillaume Le
Conquérant, Le Havre, France; P. Bertrand, Département de
Biostatistiques, Université de Tours, France.
Correspondence to: Gilles Calais, M.D., Clinique d'Oncologie et
Radiothérapie, Hopital Bretonneau, 2 Boulevard Tonnellé, 37044 Tours, France
(e-mail: calais{at}med.univ-tours.fr).
Other authors included the following: P. Maillard (Centre Paul
Papin, Angers, France); A. Favre (Centre Hospitalier Régional,
Orléans, France); P. Desprez (Centre Saint Yves, Vannes, France);
J. M. Ardiet (Centre Hospitalier Universitaire, Lyon Sud, France); S.
Chaib-Rassou (Centre Hospitalier, Metz, France); C. Alavena (Centre C.
de Sienne, Nantes, France); A. Delpon (Centre J Bernard, Le Mans,
France); P. Gesta (Centre Hospitalier, Niort, France); J. J. Auregan
(Centre G de Varye, Saint Doulchard, France); P. E. Cailleux (Clinique
Fleming, Tours, France); Y. Raoul (Centre de Radiothérapie, Saint
Gregoire, France)
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ABSTRACT |
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INTRODUCTION |
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Other studies (7,8) have used a multidrug regimen with an alternating chemotherapy and radiotherapy regimen and reported better results compared with radiation therapy alone. Compared with sequential chemotherapy and radiotherapy, concomitant treatment appeared to be more efficacious (9).
Recently, three meta-analyses (10-12) have suggested that the impact of chemotherapy on survival in head and neck cancer is small but highly associated with the timing of chemotherapy. Concomitant administration of radiation therapy and chemotherapy led to an absolute benefit on 5-year survival of about 10%.
In 1994, within the French "Groupe d'Oncologie Radiothérapie Tête et Cou" (GORTEC), we initiated a prospective randomized, multicenter phase III clinical trial to test the hypothesis that conventional radiotherapy plus concomitant chemotherapy leads to a better disease-free survival than conventional radiotherapy alone. Carboplatin was used because of its reduced renal, digestive, and neurologic toxic effects compared with cisplatin and its high radiosensitizing effect, as suggested in at least one study (13).
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PATIENTS AND METHODS |
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The patients were evaluated by a multidisciplinary team consisting of an otolaryngologist and radiation and medical oncologists. All of the patients had medical histories taken and underwent physical examination, including endoscopic examination under anesthesia, esophagoscopy, chest x-ray film, and computed tomography of the head and neck. The tumors were classified according to the criteria of the International Union Against Cancer by use of the 4th edition of the TNM (tumor-node-metastasis) classification of malignant tumors (14).
Patients were included in the study if all of the following were true: they had invasive
squamous cell carcinoma of the oropharynx (stage III or IV, without evidence of distant
metastases), they were less than 75 years old, and they had a Karnofsky performance score of at
least 60. Patients were excluded if they had lost more than 20% of their body weight, if
they had previously undergone treatment for this disease or any other cancer (except basal cell
carcinoma of the skin), or if they had synchronous primary lesions. Other criteria for inclusion
included a neutrophil count greater than 1500 cells/mm3, a platelet count greater
than 120 000 cells/mm3, and a serum creatinine concentration of 1.4
mg/dL (120 µmol/L) or less. The protocol was approved by the regional ethics committee.
Written informed consent was obtained from all patients. The study design is shown Fig. 1.
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Radiotherapy. The radiotherapy regimen was the same in both treatment arms according to the recommendations of the International Commission on Radiation Units and Measurements (15). Radiation therapy was delivered by use of cobalt-60 gamma rays, 4- or 6-mV photons. The oropharynx tumor and the upper cervical lymph nodes were treated with two parallel, laterally opposed fields. The median, the lower part of the neck, and the supraclavicular lymph nodes were treated by use of a single anterior field with midline blocking. The inferior border of the lateral fields and the superior border of the anterior field coincided on the skin. All fields were treated at each session in both treatment arms. The total dose delivered to the primary tumor and the involved lymph nodes was 70 Gy (2 Gy per fraction, one fraction per day, and five fractions per week) without any planned interruption. Lateral field doses were prescribed at midplane. A supraclavicular field dose was prescribed at a 3-cm depth. If there were no palpable lymph nodes, 44 Gy was delivered in the lower part of the neck and in the spinal lymph nodes, and 56 Gy was delivered in the cervical areas adjacent to an involved lymph node area. Electron beams were used to give a boost to the posterior cervical lymph nodes. The dose to the spinal cord was kept below 44 Gy. Computed tomography scan dosimetry was performed to evaluate the maximal and minimal tumor doses.
Chemotherapy. In the experimental arm, patients received three cycles of chemotherapy given concurrently with radiation therapy during the 1st, 4th, and 7th weeks. Chemotherapy consisted of 5-FU and carboplatin. 5-FU was administered as a 24-hour continuous infusion at a dose of 600 mg/m2 of body surface area per day for 4 days. Carboplatin was given as a daily bolus dose of 70 mg/m2 per day for 4 days. Patients received antiemetics (metoclopramide and dexamethasone). The chemotherapy cycle was started on days 1, 22, and 43.
Follow-up: Quality Assurance
During treatment, the patients were examined at least weekly. Weight as well as mucosal and skin reactions were evaluated and scored according to the European Organization for Research and Treatment of Cancer scales for acute objective and functional mucosal reaction.
Follow-up evaluation was performed 6 weeks after the end of treatment and then every 4 months until death or the end of the study period. The first evaluation included a clinical examination and a computed tomography scan. Each 4-month evaluation included a clinical examination. Chest radiography and ultrasonography of the liver were performed each year. Locoregional or distant failures were considered as failures of treatment. Only the first failure in a patient was reported; subsequent sites of involvement were not recorded. After disease recurrence, the patients could be treated by any method considered to be useful. Late side effects were observed and scored in all patients and were analyzed in patients for whom locoregional control of the disease was obtained.
A quality-assurance program was established. It was realized by a team of independent reviewers, consisting of at least one radiation therapist and one radiation physicist. Quality control procedures included a review of the clinical chart (endoscopy and computed tomography scan) and all of the radiotherapy chart entries (simulation and control films and dosimetry). This review was performed for all of the patients included in the study.
Randomization and Statistical Analysis
Patients were randomly assigned to a treatment group by a central office after their eligibility was established. Randomization was balanced by institution and clinical stage. The two treatment groups were compared with respect to baseline characteristics by use of the Student's ttest for continuous variables and the chi-squared test for categoric variables. Gaussian distribution of the population was verified by use of the David-Hartley-Pearson test. When necessary, Fisher's exact test was used. To detect an improvement in 3-year overall survival from 25% in the radiotherapy-alone group to 40% in the combined-treatment group, with a one-sided type I error of .05 and a power of 80%, the intended number of randomly assigned patients was 220. Actuarial survival and disease-free survival were calculated according to the Kaplan-Meier method and compared with the stratified logrank test. All reported P values are two-sided and considered to be statistically significant for two-sided P<.05. Data on patients were analyzed according to the intention-to-treat principle. Survival was calculated from the date of random assignment to the most recent follow-up contact or to the date of disease recurrence or death and included all patients in the study. For survival, every death (regardless of cause) was considered as a failure. Since all of the patients were considered free of tumor at the end of therapy on the basis of clinical examination and CT scan, disease-free survival was used; every recurrence (whatever the type) and any death before recurrence was considered as a failure. All patients assigned to the treatment groups were included in all analyses of survival. No interim analysis was planned.
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RESULTS |
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From July 1994 through September 1997, a total of 226 patients were
enrolled. Four patients (two in each arm) were found to be ineligible.
The reasons for ineligibility were the presence of another primary
cancer in the esophagus (two patients) and distant metastasis (two
patients). Thus, a total of 222 patients (113 assigned to radiotherapy
alone and 109 assigned to combined treatment) remained in the analysis.
Two patients were randomly assigned to the combined-treatment arm but
treated with radiotherapy alone. Two patients died after random
assignments before any treatment (one in each arm). All of these four
patients were analyzed according to the intention-to-treat principle.
The two treatment groups were similar, except for a slightly higher
proportion of patients with N3 lymph nodes in the combined-treatment
group (Table 1).
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Among the 113 patients assigned to radiotherapy alone, one patient
died before any treatment; three patients received less than 8 Gy (two
because of early death and one because of refusal of treatment). Among
the 109 patients assigned to the combined-treatment group, two were
treated with radiotherapy alone (one because of refusal of chemotherapy
by the patient and one because of an error); one patient died before
any treatment was given. The mean total delivered dose of radiation was
69.2 and 69.6 Gy in the radiotherapy-alone arm and in the
combined-treatment arm, respectively. Compliance with radiation therapy
is shown in Table 2, A. No differences were observed
regarding the frequency of treatment breaks. However, when a treatment
break was decided because of toxicity, the mean duration of the
radiotherapy interruption was longer in the combined-treatment arm than
in the radiotherapy-alone arm: 6.2 days (95% confidence interval [CI]
=
3.0-9.0 days) versus 8.9 days (95% CI = 4.0-12.0 days) (P = .05).
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Acute Toxicity
One patient died of treatment toxicity (febrile neutropenia and
sepsis). Table 3, A, shows the acute toxicity of
treatment. Hematologic toxicity was more frequent in the
combined-treatment group, as expected with the use of chemotherapy
agents. The incidence of grades 3 and 4 mucositis was higher in the
combined-treatment arm than in the radiotherapy-only arm (71% versus
39%; 95% CI = 54%-85% and 29%-56%,
respectively). In
consequence, the nutritional status of the patients in the
combined-treatment group was poorer, with a higher proportion of
patients who lost more than 10% of body mass and who required
temporary nasogastric or gastrostomy feeding tubes.
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After a median follow-up of 35 months (range, 12-56 months), 116
patients had died (69 in the radiotherapy-only group and 47 in the
combined-treatment group). The median survival was 15.4 months in the
radiotherapy-only group and 29.2 months in the combined-treatment
group. Patients in the combined-treatment group had a better rate of
3-year overall survival: 51% (95% CI = 39%-68%) versus
31% (95%
CI = 18%-49%) for the radiotherapy-alone group (P = .02).
The 3-year disease-free survival rate was 42% (95% CI =
30%-57%)
for the combined-treatment group versus 20% (95% CI =
10%-33%) for
the radiotherapy-alone group (P = .04). Locoregional control
of the disease was 66% (95% CI = 51%-78%) for the
combined-treatment group versus 42% (95% CI = 31%-56%)
for the
radiotherapy-alone group (P = .03) (Fig. 2,
A and B).
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A tumor recurrence was observed in 65 patients who received radiotherapy alone. The site of the primary tumor was the most common location of recurrence (in 58 patients [89%]). Lymph nodes were involved in 35 patients (54%), and distant metastases were observed in 12 (18%). The percentage of recurrences totals more than 100 because some patients had recurrences at multiple sites.
The tumor recurred in 40 patients after combined therapy, with the most common location
being the site of the primary tumor (in 36 [90%] of 40 patients). Lymph node
relapse was present in 21 (52%) patients, and distant metastases were present in 12
(30%). The patients' status, patterns of treatment failure, and cause of death are
shown in Table 3, B.
Late Toxic Effects
With a median follow-up of 35 months, the overall incidence of
severe late toxicity (grades 3 and 4) was 9% in the radiotherapy-alone
arm and 14% in the combined-treatment group. A trend, the observation
of more severe cervical fibrosis in patients who received both
chemotherapy and radiation therapy, approached statistical significance. No bone necrosis and
radiation myelitis
were observed (Table 3, C).
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DISCUSSION |
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Radiotherapy and chemotherapy may be combined in several ways in treating head and neck cancer. The two treatments may be given simultaneously or in alternation. Radiotherapy may be delivered with a conventional fractionation or with an accelerated or hyperfractionated regimen. Conventionally fractionated radiotherapy with concurrent chemotherapy has been tested in several randomized trials. Early randomized trials used single-agent chemotherapy with bleomycin (16,17), methotrexate (18), 5-FU (6), mitomycin C (19), or low-dose cisplatin (5). Some of these trials showed statistically significant improvement in local control and/or survival. However, data from these studies remained controversial, and combined treatment with a single agent has not been used as standard therapy for nonresectable advanced disease. The cisplatin-5-FU regimen is one of the most active cytotoxic drug combinations against head and neck carcinoma. It was evaluated with concomitant radiotherapy in a randomized study from the Cleveland Clinic (20). Three-year disease-free survival was statistically significantly increased among the patients who received radiotherapy together with chemotherapy rather than radiotherapy alone (67% versus 52%, respectively). The reasons for using carboplatin in our study were as follows: fewer toxic effects on renal function; less nausea and vomiting; the ability to give the drug on an outpatient basis; and the existence of data, suggesting that the regimen has a radiosensitizing effect (13,21). The three-arm randomized study by Jeremic et al. (4) reported a higher 5-year survival rate when chemotherapy was added to radiation therapy as compared with radiation therapy alone. No differences were observed between cisplatin and carboplatin in that study.
The patient population in our study is homogeneous, with all of the patients diagnosed as having oropharyngeal carcinomas. Most of the earlier studies have enrolled patients with head and neck cancers, including some patients with nasopharynx or paranasal sinus tumors. The natural history, prognostic factors, and radiotherapy technique as used are very different from one tumor site to another. Data regarding treatment toxicity and efficacy will be more accurate in homogeneous groups of patients, and our further studies will each be focused on one selected primary tumor site.
Alternating radiotherapy and chemotherapy is supposed to produce a less acute mucosal reaction, but this regimen may prolong the overall treatment time, with a risk of tumor repopulation that may adversely affect the efficacy of radiotherapy. The trial from Italy's National Institute for Cancer Research (7,8) that compared radiotherapy alone with an alternating regimen of chemotherapy and radiotherapy in unresectable carcinoma of the head and neck reported improved 5-year survival rates in the combined-treatment group. However, the poor results in the control arm (5-year disease-free survival rate, 9%) could be explained by a high proportion of patients who experienced prolongation of their overall radiotherapy treatment time and who received a median total dose of only 62 Gy. Further studies are necessary to test the validity of this approach.
On the basis of the apparent advantages of hyperfractionated and/or accelerated radiotherapy when it is used as a single modality (22,23), randomized trials have been initiated to compare modified daily fractionation with or without concurrent chemotherapy (24-26). The largest study (24), performed in Germany, compared hyperfractionated radiotherapy alone or with concomitant chemotherapy with the use of cisplatin, 5-FU, and leucovorin. Three-year survival was 24% versus 48%, respectively, in favor of the combined-treatment group. Another study from the University of North Carolina (25) reported similar results by use of an accelerated split-course regimen of radiotherapy. In these two studies, treatment breaks were included in the combined modality arms to reduce the acute toxicity. The study reported by Brizel et al. (26) compared continuous-course, accelerated, hyperfractionated radiotherapy versus split-course, hyperfractionated radiotherapy plus concurrent chemotherapy with cisplatin and 5-FU. Survival was increased with the use of chemotherapy and radiation therapy (55% versus 34%, respectively).
Concurrent chemotherapy and radiotherapy appear to be more efficacious than conventional radiotherapy alone. However, some important questions remain unanswered concerning the optimal radiotherapy regimen to combine with chemotherapy. Acute mucosal toxicity is clearly the most important limiting factor, and the ability to reduce this toxic effect will play a significant role in determining the acceptance of this type of treatment.
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NOTES |
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We thank Marie-Hélène Calais for her data management assistance.
Presented in part at the 34th Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 1998.
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Manuscript received April 21, 1999; revised September 29, 1999; accepted October 12, 1999.
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