Original Article
Treatment of Advanced Squamous-Cell Carcinoma of the Head and Neck with Alternating Chemotherapy and Radiotherapy
N Engl J Med 1992; 327:1115-1121October 15, 1992
- Abstract
- Abstract
Background.
For patients with advanced, unresectable squamous-cell carcinoma of the head and neck, radiotherapy is the standard treatment but has poor results. We therefore designed a randomized trial to determine whether alternating chemotherapy with radiotherapy would improve the survival of such patients.
Methods.
Patients in the trial had biopsy-confirmed unresectable, previously untreated Stage III or IV, squamous-cell carcinoma of the oral cavity, pharynx, or larynx. They were randomly assigned to chemotherapy consisting of four cycles of intravenous cisplatin (20 mg per square meter of body-surface area per day for five consecutive days) and fluorouracil (200 mg per square meter per day for five consecutive days) alternating with radiotherapy in three two-week courses (20 Gy per course; 2 Gy per day, five days per week), or to radiotherapy alone (up to 70 Gy; 2 Gy per day, five days per week).
Results.
The 80 patients given chemotherapy alternating with radiotherapy and the 77 given radiotherapy alone were comparable in terms of age, sex, performance status, disease stage, and site of the primary tumor. Complete responses were obtained in 42 percent of the patients in the combined-therapy group and 22 percent of those in the radiotherapy group (P = 0.037). The median survival was 16.5 months in the combined-therapy group and 11.7 months in the radiotherapy group (P<0.05); the 3-year survival was 41 percent and 23 percent, respectively. Severe mucositis occurred in 19 percent of the patients in the combined-therapy group and 18 percent of those in the radiotherapy group.
Conclusions.
In patients with advanced unresectable squamous-cell carcinoma of the head and neck, chemotherapy alternating with radiotherapy increases the median survival and doubles the probability of survival for three years as compared with radiotherapy alone. However, since local disease cannot be controlled in over half the patients who receive the combined treatment and since almost two thirds die within three years, further improvements in management are necessary. (N Engl J Med 1992;327:1115–21.)
Media in This Article
Figure 1
Progression-free Survival in the Treatment Groups.Figure 2
Overall Survival in the Treatment Groups.Article Activity
- Article
IN patients who receive radiotherapy alone for advanced, inoperable squamous-cell carcinoma of the head and neck, the expected five-year survival is lower than 25 percent,1 and in patients with local invasive and massive nodal involvement, it may be as low as 1 to 2 percent.2 Chemotherapy has been combined with radiotherapy in an attempt to improve the outcome in such patients. However, adjuvant chemotherapy has had no advantage over standard local therapy alone, even though responsiveness to chemotherapy has proved to be the best predictor of responsiveness to radiotherapy and subsequent survival.3 Comparisons of simultaneous chemotherapy and radiotherapy with radiotherapy alone have produced contradictory results, with some trials showing an advantage from the combined treatment,4 5 6 and others not.7 8 9 These studies involved a single chemotherapeutic agent, but more recent trials have shown improved response rates and better long-term survival with the use of simultaneous polychemotherapy and radiotherapy.10 , 11
A third way of combining chemotherapy and radiotherapy — alternating polychemotherapy with divided courses of radiotherapy12 , 13 — avoids the toxic effects of concomitant administration of drugs and radiation. It allows time for critical normal tissue to recover after each type of therapy, and therefore permits the delivery of full doses of both chemotherapeutic agents and radiation. This approach also avoids long intervals between treatments, limiting the repopulation of tumor cells and allowing treatment at very high intensity.
In 1979 the National Institute for Cancer Research in Genoa, Italy, began to study alternating chemotherapy and radiotherapy for squamous-cell carcinoma of the head and neck. Results collected over a decade have suggested that such treatment led to higher rates of complete response and longer overall survival and survival without disease progression than did neoadjuvant (preoperative) chemotherapy followed by definitive radiotherapy. This impression was recently confirmed in a randomized trial in which chemotherapy with bleomycin, vinblastine, and methotrexate in alternation with radiation was compared with radiation alone.14 However, the standard approach to the treatment of inoperable head and neck cancer is still to administer radiation therapy alone, and others have questioned whether neoadjuvant therapy might actually decrease survival, as compared with radiation alone.15 Consequently, we designed the current trial to compare standard radiation alone with alternating chemotherapy and radiation.
The chemotherapy used in our study was a combination of five daily injections of cisplatin and fluorouracil, both of which have established activity against squamous-cell cancer of the head and neck.16 When these drugs are given daily, they are less toxic to the gastrointestinal system and mucous membranes than continuous infusion,17 allowing them to be administered on an outpatient basis and to be better tolerated when combined with radiation therapy.18 We have reported our preliminary results previously.18 , 19 The combination of a bolus injection of cisplatin and fluorouracil20 had a response rate in patients with recurrent disease that was similar to the rate achieved by Kish et al. with fluorouracil given as a continuous infusion.21
Methods
Selection of Patients
Patients were eligible for the study if they had the following features as determined by a multidisciplinary team including a medical oncologist, a radiation oncologist, and a head-and-neck surgeon: histologically confirmed squamous-cell carcinoma of the pharynx, larynx, or oral cavity; unresectable Stage III or IV disease without distant metastases; age less than 76 years; a performance status of 3 or lower, according to the scale of the Eastern Cooperative Oncology Group22; no major impairment of liver, kidney, bone marrow, lung, or heart function; a life expectancy of six months or more; no other neoplasms; and residence reasonably near the study center.
A tumor was defined as unresectable as suggested by Fu et al.6 — i.e., it was technically unresectable because surgical evaluation had shown that it was fixed to a bone structure in the region, involved the nasopharynx, was fixed to lymph nodes, or had other invasive features making surgical removal improbable. Patients with severe medical problems precluding surgery were also included in the study.
Staging was dependent on the site of the primary tumor. Computerized tomography was performed in patients with nasopharyngeal or hypopharyngeal cancer, endoscopy in patients with pharyngeal lesions, and ultrasonographic examination of the neck in patients with oropharyngeal or oral-cavity lesions. Chest films, complete blood counts, and blood chemistry profiles were obtained for all patients, and liver sonograms and bone scans when indicated. Physical examination, including a complete staging of oral and pharyngeal features, was performed separately by surgical and radiation-oncology specialists in all patients. The extent of the disease was defined with the TNM system (assessment of the tumor extension [T], nodal involvement [N], and metastatic spread [M]).
Each patient gave informed consent before entering the study, in accordance with the guidelines of the ethics committee of the National Institute for Cancer Research.
Treatment
Patients given the combined therapy received four courses of chemotherapy during weeks 1, 4, 7, and 10, which alternated with three courses of radiotherapy (20 Gy per course) during weeks 2 and 3, 5 and 6, and 8 and 9; these patients were also given weekend rest intervals between chemotherapy and radiotherapy. Patients given definitive radiotherapy alone were treated with external-beam megavoltage irradiation (2 Gy per fraction, one fraction per day, five days per week).
Chemotherapy consisted of cisplatin (20 mg per square meter of body-surface area) and fluorouracil (200 mg per square meter), both given intravenously from day 1 through day 5 of each 21-day course. A total of four courses was delivered. Cisplatin was given during a two-hour period of forced hydration with 2 liters of saline containing 6 meq (mmol) of potassium chloride per liter and 2 g of magnesium sulfate; fluorouracil was administered as an intravenous bolus dose at the end of hydration. Metoclopramide (1 mg per kilogram of body weight) was used as an antiemetic.
The patients underwent clinical examination for identification of response and toxic reactions, a platelet count, a hematology profile (including a complete blood count), and measurement of serum electrolytes (sodium, potassium, chloride, magnesium, phosphorus, and calcium), creatinine, lactate dehydrogenase, aminotransferases, and creatine kinase before each course of chemotherapy. No modification of the dosage because of treatment-related toxicity was planned. Treatment was to be delayed until recovery if grade III mucositis22 occurred, the white-cell count was less than 3000 per cubic millimeter (3×109 per liter), or the platelet count was less than 90,000 per cubic millimeter (90×109 per liter). Radiation was delivered with megavoltage equipment, according to the site and extent of disease; two lateral coaxial fields were used to cover the primary tumor and the upper nodes. The dose to unilateral tumors was specified in relation to the midplane or the isocenter along the central axis. A single anterior beam or two opposed anteroposterior beams with a midline shield were used to treat the neck below the lateral fields. The shield was not employed for irradiation of laryngeal or hypopharyngeal tumors. The prescribed total dose to the primary tumor and clinically positive lymph nodes was 60 Gy for the combined-therapy group and 70 Gy for the radiotherapy group. The dose to the spinal cord was no more than 46 Gy. Shrinking of fields was performed after 50 Gy was delivered. Electron beams were employed so that the dose to posterior cervical nodes involved by pharyngeal tumors could be increased by 60 Gy or more and the residual disease could be treated with a booster dose. The schedule of fractionated doses for both treatment groups was conventional — a daily dose of 1.8 to 2 Gy per day five days a week. The combined-therapy group received three courses, each consisting of 20 Gy given in 10 fractions over a 12-day period. The radiotherapy group received a standard continuous course of five daily treatments each week.
At the end of treatment, each patient was reevaluated. Patients with complete responses received no further treatment unless their disease progressed. Patients with partial responses underwent surgical evaluation; patients in whom resection of the tumor was technically feasible and potentially definitive received this treatment regardless of their therapy group; among patients whose tumors were unresectable, those in the combined-therapy group received a booster dose to residual tumors (10 Gy in five fractions over five days, up to a total dose of 70 Gy) and those in the radiotherapy group received no further treatment unless their disease progressed. Patients with stable disease (those with no response) were treated with palliative chemotherapy if their disease progressed. Patients with disease progression during treatment were withdrawn from the study and treated with palliative chemotherapy.
Post-treatment follow-up differed according to the response to treatment and the site of the primary tumor. Patients with complete responses underwent a physical examination every month during the two years after the end of treatment, and every three months after the second year. Patients with partial responses were examined monthly. The same methods used to stage disease and assess response were also employed during the post-treatment follow-up.
Second-line treatment was chosen according to the site and extent of relapse, the response to previous therapy, and the time to disease progression. Local or regional treatment (radiation, surgery, or both) was used whenever possible as salvage therapy. When chemotherapy was indicated, patients assigned to the radiotherapy group received cisplatin and fluorouracil, and patients assigned to the combined-therapy group who had had complete responses lasting at least 12 months also received cisplatin and fluorouracil when relapse occurred. To prevent neurotoxicity, the total cumulative dose of cisplatin was limited to 700 mg per square meter. Patients for whom treatment with cisplatin was not suitable received fluorouracil and high doses of folate.23
Statistical Analysis
The trial was a prospective, randomized study. Patients were stratified according to study center and then randomly assigned to receive either chemotherapy alternating with radiotherapy or radiotherapy alone. Randomization was accomplished by telephoning the trial office (the National Institute for Cancer Research in Genoa). Specific lists of randomization numbers were available for each participating center. Treatment assignment was balanced in blocks of six and eight. A sample of 180 patients was required on the basis of a projected increase of 20 percent in the probability of survival at two years in the combined-therapy group, with an alpha error of 5 percent and a beta error of 20 percent.
The primary objective of the study was to compare overall survival in the two treatment groups. Its secondary goals included assessing the objective response rate, toxicity, and survival without disease progression (progression-free survival) in the two groups. Actuarial survival and progression-free survival were calculated according to the Kaplan–Meier method24 and compared by the log-rank test.25 The response rates of the groups were compared with the chi-square test. All patients assigned to the treatment groups were included in all analyses of progression-free survival and survival. The statistical office reviewed the records of all patients at the completion of the study. This review corroborated the submitted data with the complete records.
Evaluation of Response
Responses to treatment were defined as complete if all clinically detectable malignant disease completely disappeared for at least four weeks and no new lesions appeared, and as partial if the total tumor size remained decreased for at least four weeks (by 50 percent in the case of lesions measurable in two dimensions or by 30 percent in the case of unidimensional lesions) with no new lesions.
Treatment failure was indicated by stable disease, defined as a lack of marked change in the size of a measurable lesion (a decrease of less than 50 percent or an increase of less than 25 percent), with no new lesions; disease progression, defined as an increase of more than 25 percent in the size of one or all the lesions present at the start of the therapy or the appearance of a new lesion; early death, defined as any death occurring before the end of treatment; or early discontinuation of treatment because of severe toxicity.
The method for staging was repeated to assess response.
Progression-free Survival
Progression-free survival was computed from the time of randomization to that of disease progression. Disease progression was defined as the appearance of a new lesion or an increase of more than 25 percent in the size of one or all the residual lesions. Patients who died without disease progression were considered to have progression at the time of death.
Patients lost to follow-up were included in the analysis up to the last available observation.
Overall Survival
Overall survival was computed from the time of randomization to that of the last follow-up observation or death. The status of patients lost to follow-up was obtained from the population registry of the Census Bureau.
Evaluation of Toxicity
Acute and subacute toxic reactions were graded according to the scale established by the World Health Organization.22 Patients with life-threatening toxic or allergic reactions, cardiac side effects, or neurotoxic reactions were withdrawn from treatment, and their treatment was considered to have failed. Patients with reactions that were not life-threatening were temporarily withdrawn from treatment until they recovered.
Results
Enrollment of patients began on February 1, 1987, and stopped on December 31, 1990. Twenty patients were enrolled in 1987, 30 in 1988, 55 in 1989, and 52 in 1990, for a total of 157 patients; 80 patients were assigned to chemotherapy alternating with radiotherapy, and 77 to radiotherapy alone. The total enrolled was lower than the planned total of 180 patients because participating centers eventually refused to treat further patients with radiotherapy alone, in the light of a twofold increase in the rate of complete responses that was associated with the combined therapy. Since the protocol had not provided formal rules for interim analysis and early termination of the study, no correction for the number of interim analyses was possible. We decided to publish our results with the explicit reservation that the nominal P values of the tests for significance may be misleading. All patients enrolled were included in the analyses of toxicity, response, survival, and progression-free survival.
The characteristics of the patients and their tumors are summarized in Table 1Table 1
Characteristics of the Patients and Tumors, According to Treatment Group., and the results of staging (TNM system) in Table 2Table 2
Tumor and Node Stages of the Treatment Groups (TNM System).. The patients had predominantly Stage IV disease (74 percent of the combined-therapy group and 77 percent of the radiotherapy group), including many with T4N2 or T4N3 disease (23 percent of the combined-therapy group and 19 percent of the radiotherapy group).On review, two patients were found to have been ineligible for enrollment. In the first patient, the disease was classified as Stage III at the time of randomization, but subsequently it was classified as Stage II. In the second patient, the tumor was initially diagnosed as a squamous-cell carcinoma of the nasopharynx, but on review it was considered to be an undifferentiated tumor. Both patients were included in the analysis of the results. In all the remaining 155 patients, the results of the initial staging and histologic examination were confirmed on review.
The doses of chemotherapy and radiotherapy actually delivered were determined for 73 patients in the combined-therapy group and 71 in the radiotherapy group, since 13 patients never started the assigned treatment. The median dose of radiation was 60 Gy (range, 20 to 60) in the combined-therapy group and 62 Gy (range, 26 to 70) in the radiotherapy group. The chemotherapeutic dose actually delivered was more than 90 percent of the planned dose in 85 percent of the patients in the combined-therapy group. Treatment was delayed for one week in 21 percent of the combined-therapy group and 32 percent of the radiotherapy group, for two weeks in 11 percent of each group, and for more than two weeks in 4 percent of the combined-therapy group and 14 percent of the radiotherapy group.
Toxicity
Major radiotherapy-related toxic reactions included xerostomia, edema, and mucositis. Grade III or IV mucositis occurred in 18 percent of all patients in the study (19 percent in the combined-therapy group and 18 percent in the radiotherapy group). No late toxic reactions have been observed.
Major chemotherapy-related toxic reactions in the combined-therapy group included leukopenia (grade III in 20 percent and grade IV in 1 percent), thrombocytopenia (grade III in 4 percent and grade IV in 1 percent), and nausea and vomiting (grade III in 4 percent and grade IV in 1 percent). Grade III or IV mucosal toxicity occurred in 19 percent of the group.
Supportive care included enteral nutrition administered through a nasogastric feeding tube in three patients (two in the combined-therapy group and one in the radiotherapy group). Six patients required red-cell transfusions, and one needed a platelet transfusion (all were in the combined-therapy group). Eight patients received antibiotics (six in the combined-therapy group and two in the radiotherapy group); these drugs were given prophylactically to one of the eight patients, who had severe granulocytopenia.
The incidence of recorded toxic reactions is shown in Table 3Table 3
Toxic Reactions in the Treatment Groups, According to Grade.*.Response to Treatment
All patients were included in the analysis of response. The two treatment groups did not differ significantly in their rates of overall response, but they did differ significantly in their rates of complete and partial responses (Table 4Table 4
Response to Treatment.); the difference was especially great for the rate of complete response (P = 0.037).At the end of the treatment, 12 of the patients with partial responses (9 in the combined-therapy group and 3 in the radiotherapy group) were considered to be suitable candidates for surgery, and 11 (8 in the combined-therapy group and 3 in the radiotherapy group) had no disease after surgery. Therefore, when the responses to surgery are included among the complete responses, the rate of complete responses was 53 percent in the combined-therapy group and 26 percent in the radiotherapy group.
Progression-free Survival
The median duration of follow-up at the time of analysis (April 1992) was 35 months.
The median progression-free survival was 10 months in the combined-therapy group and 6 months in the radiotherapy group. At three years the progression-free survival was 25 percent in the combined-therapy group and 7 percent in the radiotherapy group (Fig. 1Figure 1
Progression-free Survival in the Treatment Groups.). The survival curves showed significantly better survival in the combined-therapy group (P<0.009).Disease Recurrence
Among the patients with complete responses, local or regional relapse occurred in 12 of the 34 patients (35 percent) in the combined-therapy group (in 9 patients at the T level and in 3 at both the T and N levels) and in 10 of the 17 patients (59 percent) in the radiotherapy group (in 9 patients at the T level and in 1 at the N level).
Distant metastases were noted in six patients in the combined-therapy group and five in the radiotherapy group (7.5 percent and 6.5 percent, respectively). Metastatic deposits were observed in the lungs (six patients), bone (three patients), and liver (two patients).
Second primary tumors were observed in five patients (6.2 percent; three patients in the combined-therapy group and two in the radiotherapy group). Two of these tumors were carcinomas of the upper aerodigestive tract, two were lymphomas, and one was an adenocarcinoma of the lung.
Overall Survival
One hundred two patients have died — 48 patients in the combined-therapy group (60 percent) and 54 in the radiotherapy group (70 percent). The median survival was 16.5 months in the combined-therapy group and 11.7 months in the radiotherapy group and the three-year survival was 41 percent and 23 percent, respectively. The survival curves (Fig. 2Figure 2
Overall Survival in the Treatment Groups.) showed a significant difference in favor of the combined-therapy group (P<0.05).Discussion
The most important finding of the present trial is the increase in survival observed among the patients treated with chemotherapy alternating with radiotherapy. The addition of chemotherapy to radiotherapy increased the number of cases in which local or regional disease was controlled from 22 percent to 42 percent, and moreover, the analysis of cases of relapse suggests that the probability of local or regional relapse in patients with complete responses is higher if they are treated with radiotherapy alone. Consequently, the interaction between chemotherapy and radiotherapy delivered according to the alternating regimen appeared to improve both the rate and duration of complete responses. These results are consistent with the improved regional control achieved with combined chemotherapy and radiotherapy in patients with esophageal cancer26 and patients with pancreatic cancer.27
The number of patients with partial responses who underwent surgery differed in the two treatment groups. The decision to perform surgery was based on the resectability of the tumors that had been sufficiently reduced. Nine patients with partial responses in the combined-therapy group had surgery, but only three in the radiotherapy group. This difference was consistent with the higher proportion of patients with complete responses in the combined-therapy group and could be explained by the possibility that chemotherapy with radiotherapy was more effective in rendering the tumors of patients with partial responses operable. It is not possible, however, to exclude retrospectively a bias toward surgery in the combined-therapy group.
A further important finding relates to toxicity. As expected, the combined therapy resulted in the toxic reactions associated with both chemotherapy and radiotherapy. The absence of any increase in toxic reactions common to both types of therapy, especially grade III or IV mucositis, was noteworthy, however. This clinical observation supports the hypothesis of Looney et al. that alternating treatment can reduce the toxicity of chemotherapy combined with radiation.28
Our previous experiences with alternating chemotherapy and radiotherapy showed that the incidence of mucositis increased greatly when we used a regimen based on methotrexate.14 The simultaneous delivery of radiation and fluorouracil by continuous infusion required frequent planned interruptions to avoid similar severe reactions.29 We have suggested elsewhere that aggravation of toxic reactions common to chemotherapy and radiotherapy may be avoided by carefully choosing drugs that have no cross-toxicity with radiotherapy.30 The results of the present trial seem to confirm this opinion.
During the past two decades, other trials have compared radiotherapy alone with single-agent chemotherapy combined with radiotherapy. These trials have rarely shown an advantage for the combination therapy, and severe reactions in the local normal tissues have frequently led to interruptions of treatment. For example, the Northern California Oncology Group study6 was designed to study the efficacy of combined radiotherapy and bleomycin for Stage III or IV inoperable squamous-cell carcinomas of the head and neck. The rates of complete response and progression-free survival were significantly improved by the addition of chemotherapy, but there was no clear improvement in overall survival. It should be noted that most of these trials used suboptimal chemotherapy, probably because their main goal was to exploit the radiosensitizing effect of the chosen drugs.
The thrust of more recent trials, including those by our group, is completely different: the target is the development of an additive or synergistic effect resulting from the biologic interaction of two active antineoplastic treatments. Taylor et al.10 studied the effects of treatment with simultaneous continuous infusion of cisplatin and fluorouracil over a five-day period and radiotherapy given every other week. Although the rate of complete responses was similar to that reported in the literature, progression-free and overall survival appeared to be substantially improved. However, this combined treatment must still be compared with standard therapy in a randomized trial.
Another issue is the role of second-line treatment. Patients in the present trial were treated uniformly when relapse occurred, whenever possible. We doubt that subsequent treatment would have had any major effect on the outcome of our trial. In theory, however, second-line treatment may affect survival. To our knowledge, no randomized trial comparing different regimens for relapses has been able to show a difference in overall survival, notwithstanding any difference in the response rate. This suggests that the chemotherapy regimens available to date are unable to influence the survival of patients with relapses. Furthermore, if there were a regimen that would influence the survival of patients with relapses, one would expect that it would more often be effective in patients not previously treated with chemotherapy. As a consequence, any differences between effective second-line treatments would reduce any differences in survival between the treatment groups.
Finally, it must be emphasized that better results have been achieved with the combined therapy despite the lower total radiation dose and also the "split-course" fractionation scheduling of radiation. The main weakness of our study is probably the early termination of the enrollment of patients. This was related to treatment outcome and therefore may have biased the interpretation of results. However, in the light of the observed results, it appears highly unlikely that the results of this study could have been modified by the addition of 23 more patients (10 to the combined-therapy group and 13 to the radiotherapy group). Nevertheless, the P values produced by our comparisons should be regarded with caution, and replication of our findings is warranted.
We are indebted to Samuel G. Taylor, IV, M.D., for his help and suggestions.
Source Information
From the Department of Medical Oncology (M.M., R.R., M.B., M.C.), the Department of Radiation Oncology (V.V., R.C., G. Sanguineti, A.B.), and the Department of Surgical Oncology (F. Badellino, G.M.), National Institute for Cancer Research, Genoa; the Department of Medical Oncology (F. Brema, G.P.) and the Department of Radiation Oncology (C.M.), S. Paolo Hospital, Savona; the Department of Radiation Oncology, Galliera Hospital, Genoa (A.G.); the Department of Head and Neck Surgery, Celesia Hospital, Genoa (F.S., G. Sperati); the Department of Head and Neck Surgery, S. Martino Hospital, Genoa (E.P., G.G., E.A.); the Department of Head and Neck Surgery, University of Genoa, Genoa (G. Cordone); the Department of Medical Oncology, Pascale Institute, Naples (G. Comella, A.D.); and the Department of Clinical Epidemiology and Trials (A.R., P.B.) and the Office of the Director (L.S.), National Institute for Cancer Research, Genoa — all in Italy. Address reprint requests to Dr. Merlano at the Department of Medical Oncology, National Institute for Cancer Research, V.le Benedetto XVn. 10, 16132 Genoa, Italy.
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