Introduction
Since the early 1980s, induction or neoadjuvant chemotherapy has been promoted as a new therapeutic approach to the treatment of cancer.[1] Several neoadjuvant chemotherapy trials have been conducted to reduce initial tumor burden, destroy possible pre-existing micrometastases before surgery, and, in some cases, improve overall survival and/or disease-free survival. Most of these studies have involved patients with head and neck squamous cell carcinoma, transitional cell bladder carcinoma, bone and soft-tissue sarcomas, and lately, stage IIIA non-small cell lung cancer (NSCLC).[2-4]
For patients with head and neck cancer, this approach to therapy has the additional potential to allow preservation of organ anatomy and function, as the use of radiotherapy following neoadjuvant chemotherapy could substitute for radical surgery. This treatment would thus afford responding patients a superior quality of life and the possibility of maintaining their normal work and social activities.
The combination of cisplatin(Drug information on cisplatin) (Platinol) followed by fluorouracil(Drug information on fluorouracil) (5-FU) as a 120-hour continuous infusion has been considered standard neoadjuvant chemotherapy for head and neck cancer ever since this therapeutic regimen was published by Al-Sarraf.[5] Other investigators have tried to improve on this therapeutic approach using changes in drug combinations or administration methods, with the aim of reducing hospitalization time. The impact on survival of these modifications is not yet clear, however, and their ultimate value in neoadjuvant chemotherapy is still controversial.[6]
The combination of tegafur(Drug information on tegafur) and uracil (UFT) is an oral formulation that is rapidly absorbed, and has antitumor activity similar to that of 5-FU. Continuous administration of oral UFT has proved to be therapeutically equivalent to 5-FU given by continuous infusion, but it does not require hospitalization.[7] Based on these factors, we have undertaken a prospective study to compare the standard Al-Sarraf regimen with neoadjuvant treatment using cisplatin plus UFT in patients with locally advanced head and neck cancer. Efficacy, toxicity, survival, and time to progression have been analyzed for the two therapeutic approaches.
Patients and Methods
The primary study objective was to compare partial and complete response rates after chemotherapy and after treatment completion and to investigate differences in time to progression and overall survival between the two therapeutic approaches. A secondary goal of the study was to evaluate the toxicity of the two chemotherapy regimens.
Patient Selection
A total of 67 patients diagnosed with locally advanced head and neck carcinoma (squamous cell or undifferentiated) between 1988 and 1992 were included in a randomized prospective study of neoadjuvant chemotherapy. Patients were selected according to the following criteria: confirmed tumor histology, locoregional spread, stage III or IV (M0), Karnofsky index greater than 70%, no previous treatment of any kind, evaluable or measurable tumor lesions, adequate renal and liver functions, no previous neoplasia, and patients’ written consent.
Patients included 59 men and 8 women with a median age of 56.5 years (range, 20 to 75 years) and a median Karnofsky index ranging from 90% to 100%. A weight-loss greater than 5 kg was observed at diagnosis in 26 of 67 patients. Histologic examination confirmed squamous carcinoma in 51 patients and undifferentiated carcinoma in 16. Tumor differentiation was grade 1 or 2 in 31 cases, grade 3 in 17, and unknown in 19. The primary tumor site was the oropharynx in 26 cases, the cavum in 16, the hypopharynx in eight, the larynx in six, and the oral cavity in eight; three patients had cervical lymph node metastases at diagnosis, with unknown primary site. Head and neck carcinoma was stage IV (M0) in 58 patients and stage III in the other nine.
Patients were randomly assigned to treatment according to the classic Al-Sarraf regimen (34 patients) or the cisplatin/UFT regimen (33 patients). Characteristics of the two groups of patients detailed in Table 1, indicated a good balance between them.
Study Design and Therapeutic Schemes
Once selection criteria were confirmed and the patients randomized, the two treatment groups began therapy: 34 patients received cisplatin (100 mg/m2) on day 1, followed by a continuous infusion of 5-FU 1000 mg/m2/day on days 2 through 6; 33 patients received cisplatin 100 mg/m2 on day 1, followed by oral administration of UFT at a dose of 300 mg/m2/day in three doses on days 2 through 20. Both treatment regimens were started every 21 days and repeated four times. Responding patients received locoregional standard radiotherapy (50 to 70 Gy) after chemotherapy.
Evaluation of Response
Response to treatment was evaluated after chemotherapy and, in responding patients, again after radiotherapy. Patients underwent a physical examination, blood test, renal and liver function evaluation, chest x-ray, head and neck computed tomography, and endoscopic evaluation of the otorhinolaryngeal area. Complete response (CR) was defined as no evidence of disease for at least 4 weeks, and partial response (PR) as a greater than 50% reduction in measurable tumor mass for the same time period. Stable disease was assumed if tumor reduction was less than 50% or an increase was less than 25%. Progression was inferred in patients with a greater than 25% increase in measurable tumor mass and/or new lesions.
Statistical Analysis
Overall survival was calculated from the beginning of chemotherapy until death, and disease-free survival from the beginning of treatment until the date of relapse or disease-free death. Duration of CR was measured from the date of response until the date of relapse. Partial response was measured from the beginning of treatment until relapse. The Kaplan-Meier method was used to construct overall and disease-free survival curves, and the Mantel-Haenszel test was used to compare response rates, overall survival, and disease-free survival. A value of P < .05 was considered statistically significant.[8]
Results
Responses after four cycles of chemotherapy are summarized in Table 2. In the cisplatin/5-FU arm, the overall response rate was 73.5% (25 of 34 patients), with a CR rate of 20.6%, a PR rate of 52.9%, two patients with stable disease (5.9%) and seven patients with progressive disease (20.5%). In the UFT/cisplatin arm, the response rate was 78.8% (26 of 33 patients), with a CR rate of 18.2%, a PR rate of 60.6%, one patient with stable disease, and six with progressive disease. In both groups, the median number of cycles required for maximum response was three. There were two toxic deaths in each arm, categorized as progressive disease. No statistically significant difference in response was observed between the two arms.
Response to chemotherapy of the primary tumor and involved regional lymph nodes was analyzed separately and the results are presented in Table 3. In the cisplatin/5-FU arm, the primary tumor response rate was 71% (22 of 31 patients), with 29% complete response and 41.9% partial response. Two patients had stable disease (6.5%) and seven had progressive disease (22.6%). In the cisplatin/UFT arm, the tumor response was 84.4% (21.9% complete response and 62.5% partial response), one stable disease (3.1%), and four progressive disease (12.5%). When the data for the two groups were compared, no statistically significant differences were found (P > .05).
When nodal response was analyzed in the cisplatin/5-FU group, the overall response was 76.7% (23/30 cases), with 30% CR and 46.7% PR, two patients with stable disease (6.7%) and five with progressive disease (16.7%). The cisplatin/UFT group had a 76% overall response (19/25 cases), with 28% CR and 48% PR, two with stable disease (8%), and four with progressive disease (16%). Again, no statistically significant differences were found between the two arms (P > .05) (Table 3).
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