A combination of uracil and tegafur(Drug information on tegafur) in a 4:1 molar ratio concentration is an oral anticancer agent known as UFT. Tegafur (1-[2-tetrahydrofuryl]-5-fluorouracil) is a prodrug of 5-fluorouracil (5-FU); uracil competes with 5-FU as a substrate for dihydropyrimidine dehydrogenasean enzyme responsible for 5-FU catabolism.
The authors have previously reported that combination chemotherapy with UFT and cisplatin(Drug information on cisplatin) (Platinol) to treat inoperable nonsmall-cell lung cancer (NSCLC) provided activity comparable to that of other cisplatin-based combinations, and that it was associated with an extremely low incidence of adverse events. These observations were recently confirmed by a multi-institutional phase II trial in which the overall response rate was 29.1% and grade 3 leukopenia occurred in only 0.9% of the 108 eligible patients.
In patients with locally advanced nonsmall-cell lung cancer, the combined-modality treatment of radiotherapy and chemotherapy produced both a higher response rate and longer survival rate than radiotherapy alone.[4-6] However, the optimal sequence of chemotherapy and radiotherapy has not yet been determined.
Both 5-FU and cisplatin have been reported to have a radiosensitizing effect,[7,8] and the combination of UFT and cisplatin is associated with an extremely low incidence of hematologic toxicity.[2,3] Based on these findings, we conducted a phase II trial of UFT plus cisplatin with concurrent radiotherapy in patients with locally advanced nonsmall-cell lung cancer.
Eligibility required cytologically or histologically confirmed, unresectable stage III nonsmall-cell lung cancer for which radical dose radiotherapy was prescribed. All patients were required to meet the following criteria: measurable disease; an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; a projected life expectancy of more than 3 months; a leukocyte count of ³ 4,000/µL; a platelet count of ³ 100,000/µL; a blood gas oxygen level of ³ 70 Torr; a serum bilirubin level below 1.5 mg/dL; serum glutamic oxaloacetic transaminase/glutamic pyruvic transaminase levels of no more than twice the upper limit of normal; a normal creatinine level; and a creatinine clearance level of ³ 60 mL/min. Other eligibility criteria included no prior treatment, age £ 75 years, and signed informed consent. All eligible patients underwent computed tomography scans of the thorax and abdomen and radioisotope bone scan.
Figure 1 depicts a schema of the treatment protocol. UFT (400 mg/m²) in the form of a 100-mg capsule (100-mg tegafur and 224-mg uracil) was administered orally from days 1 to 52. The dose was rounded up or down to the nearest 100 mg. If the number of capsules could not be equally divided, the higher dose was administered in the morning, and the lower dose, in the evening. In practice, most patients received 600 mg UFT per day. Cisplatin (80 mg/m²) was administered by a 90-minute infusion on days 8, 29, and 50. Patients were also hydrated with ³ 2,500 mL saline infusion on the days they received cisplatin.
Radiotherapy was administered in five fractions per week from a megavolt linear accelerator at a daily dose of 1.6 Gy from days 1 to 52, up to a total dose of 60.8 Gy (38 fractions). The target volume included the primary disease site with a 2-cm margin around the mass and the ipsilateral hilum. The entire width of the mediastinum was included, with a 2-cm margin around the radiographically visible area of involvement (as determined by a pretreatment computed tomography scan). The inferior margin extended 4 cm below the carina or 2 cm below the radiographically visible tumor mass. When no tumor in the area was detected by a physical or radiographic examination, the supraclavicular fossa was not irradiated.
Complete blood cell counts and biochemistry were performed weekly. If leukocytes decreased to < 3,000µL, platelets decreased to < 75,000/µL, or abnormal results of hepatic or renal function tests (levels higher than eligibility criteria) were observed, the administration of cisplatin was suspended. Radiotherapy and UFT administration were discontinued if grade 4 hematologic toxicity occurred.
Patients were evaluated for response based on the standard World Health Organization criteria. Toxicity was graded according to the Japan Clinical Oncology Group criteria. Survival analysis was performed using the Kaplan-Meier method.
The primary end point of this study was to determine the tumor response rate produced with this treatment protocol. Based on the assumption that a response rate higher than 80% would warrant further investigation of this combined-modality treatment, and that a rate below 50% would make such an investigation unnecessary, a sample size of 15 patients was required with an alpha error of 0.1 and a beta error of 0.2.
Seventeen patients were entered into this study between January 1995 and March 1998. Patient characteristics are shown in Table 1. All patients were eligible. The median follow-up period was 24 months (range 4 to 42 months). Five patients were diagnosed with clinical stage IIIA, bulky N2 disease; three patients had T2, N2 disease; and two patients had T3, N2 disease. Three of the 12 stage IIIB patients were diagnosed with T1 to T2, N3 disease, and the other nine had T4, N2-3 disease.
Sixteen (94%) of the 17 patients achieved a partial response (95% confidence interval, 83% to 100%), and one patient showed no change. Of the 16 responding patients, 12 eventually developed progressive disease, with a median time to progression of 30 weeks (range 8 to 87 weeks). Local regrowth of tumor occurred in four patients. The 1-year survival rate was 80% (Figure 2).
Both radiotherapy and oral UFT were administered according to the treatment schedule. However, 10 patients were unable to receive the third cycle of cisplatin, primarily due to prolonged leukopenia following the second cycle. The toxicities observed throughout the entire course of treatment are shown in Table 2. Grade 3 leukopenia (1,000/mL to 1,900/µL) was observed in 10 (59%) patients, and grade 3 anemia (< 8 g/dL) was reported in three (18%) patients. Grade 3 thrombocytopenia (25,000/µL to 49,000/µL) was noted in only one (6%) patient. All patients were able to ingest food throughout the entire course of treatment. Severe pulmonary toxicity was not seen. No other toxicitiesincluding cardiac, neurologic, or renal toxicities (not listed in Table 2)were observed. No treatment-related deaths occurred.
Recent meta-analyses of randomized trials of combined-modality radiotherapy and chemotherapy vs radiotherapy alone for patients with locally advanced nonsmall-cell lung cancer have indicated that the addition of chemotherapy to radiotherapy improves survival.[13,14] Despite the modest improvement in survival (a 4% survival advantage at 2 years or a 1.7-month increase in median survival time), combined-modality treatment is now generally used and recommended by the American Society of Clinical Oncology. However, the optimal sequence of chemotherapy and radiotherapy has yet to be determined.
Theoretically, concurrent chemotherapy and radiotherapy is the ideal combined-modality approach, provided each can be administered without delay at doses adequate to control the tumor. In addition, both cisplatin and 5-FU have been demonstrated to be radiosensitizers in preclinical studies.[7,8] Randomized studies using single-agent cisplatin or 5-FU in conjunction with radiotherapy have indicated that each agent, in terms of local control and patient survival, improved the effect of radiotherapy alone.[4,16] While no data could be found comparing the radiosensitizing effect of 5-FU with that of UFT, oral UFT has been reported to generate a higher plasma level of 5-FU than protracted intravenous infusion of 5-FU administered in an equimolar dose to tegafur in UFT. Thus, it would seem likely that UFT expresses high radiosensitizing activity. In the present study, combined-modality treatment with UFT plus cisplatin and concurrent radiotherapy yielded a tumor response rate of 94% in locally advanced nonsmall-cell lung cancer. Although it remains unclear whether UFT and cisplatin possess synergistic radiosensitizing activity, UFT plus cisplatin is considered a radiosensitizing combination.
The principal disadvantage of concurrent chemoradiotherapy is the enhancement of normal tissue toxicity, especially hematologic, esophageal, and pulmonary toxicities. These toxicities may result in increased morbidity and mortality and may also attenuate radiotherapy and/or chemotherapy delivery. Hematologic toxicity, especially grade 4 leukopenia, was observed in more than 50% of patients when combination chemotherapy was used concurrently with radiotherapy.[18,19] However, no grade 4 hematologic toxicity was observed in the present study, possibly because of the limited hematologic toxicity of combination UFT and cisplatin.[2,3]
According to a recent multi-institutional phase II study of UFT plus cisplatin in 108 patients with nonsmall-cell lung cancer, grade 3 leukopenia was observed in only 0.9% of the patients; no grade 4 leukopenia was observed. Both the pulmonary and esophageal toxicities of the combined-modality treatment were found to be modest, whereas severe esophagitis was reported to occur in at least one third of patients receiving other combined-modality treatments.[18,20]
According to a preliminary report by the Japan Clinical Oncology Group, compared with chemotherapy followed by radiotherapy, concurrent chemotherapy and radiotherapy seems to significantly prolong survival in patients with locally advanced nonsmall-cell lung cancer. The present study demonstrated that the combination of UFT plus cisplatin with concurrent radiotherapy has a favorable effect (response rate of 94% and 1-year survival rate of 80%) and a low incidence of toxicity. Although some modifications of this treatment protocol are necessary due to the fact that a majority of the patients could not receive the third cycle of cisplatin and because the daily dose of radiation was slightly lower than the standard dose (1.8 to 2.0 Gy), we consider this combined-modality treatment worthy of further investigation in a multi-institutional trial in order to more fully elucidate the antitumor and survival effects of the combination.