An intravenous, modulated, bolus 5-fluorouracil (5-FU)-based regimen is the standard treatment for colorectal cancer. According to a meta-analysis, overall response rates are 19% to 23%, and median survival is 10.7 to 11.5 months.[1,2] According to our experience, overall response rates are 19.2% to 25.7%, and median survival is 10.6 to 14.3 months.[3,4] Several studies suggest that the alternative therapy of continuous-infusion 5-FU increases response rate, possibly due to a higher dose intensity and longer exposure of tumor cells to this drug, which has a short half-life (£ 11 minutes) when administered as a bolus infusion. Continuous-infusion 5-FU also has a better toxicity profile than bolus infusion, and a recently published meta-analysis has shown a small but significant improvement in survival with this regimen. Nevertheless, continuous infusion necessitates a subcutaneous port, a portable infusion pump, frequent hospital visits, weekly complete blood cell counts, and toxicity and treatment costs that are not negligible.
These limitations are especially important in the elderly. Elderly patients do not tolerate chemotherapy as well as younger patients, and concomitant medical conditions may preclude certain treatments. Furthermore, patients 70 years of age or older are often insufficiently staged and treated. By the year 2000, it is estimated that 70% of cancer cases will occur in patients over 65 years old, making it desirable to identify a more tolerable and nontoxic chemotherapy that exhibits at least comparable activity to continuous-infusion 5-FU.
Several studies carried out in Japan have proved the activity of the oral fluoropyrimidine agent, uracil and tegafur (in a molar ratio of 4:1 [UFT]), in colorectal cancer.[8-10] In Europe, Malik et al demonstrated a response rate of 16.6% using UFT alone. Recently, in the United States and Europe, calcium folinate modulation of UFT yielded improved results, producing response rates of 42% and 39%.[12-14] The continuous oral administration of UFT pharmacokinetically simulates delivery of protracted 5-FU by continuous intravenous infusion, making this oral therapy a possible substitute for intravenous chemotherapy. Based on these data, the Gastrointestinal Tumor Therapy (TTD) Spanish Cooperative Group initiated a study (study 1) of UFT plus calcium folinate modulation. Because the results suggested that modulation is not necessary when 5-FU is administered as a continuous infusion at the maximum tolerated dose,[15-18] a second study (study 2) with UFT alone was organized.
From September 1994 to September 1998, the Gastrointestinal Tumor Therapy Spanish Cooperative Group performed two consecutive studies involving elderly patients with advanced colorectal cancer. The final results of study 1 (N = 106) and preliminary results from study 2 (N = 95) are hereby presented. Eligibility criteria were similar in the two trials: age ³ 72 years, confirmed colorectal adenocarcinoma, no resectable or metastatic tumor, measurable disease (at least one lesion with dimensions of 2 × 2 cm at the longest diameter), a Karnofsky performance status of ³ 60%, and no other malignancies except skin basocellular carcinoma or in situ carcinoma of the cervix. Patients could not have received prior systemic chemotherapy for metastatic disease. Patients who had received adjuvant therapy were eligible providing the therapy was completed at least 6 months before enrollment in this study. Laboratory criteria included an absolute granulocyte count of ³ 1,500 µL, a platelet count of ³ 100,000/µL, serum bilirubin levels of £ 1.5 mg/dL, and a serum creatinine level of £ 1.5 mg/dL. Informed consent was required.
Study 1—A fixed dose of UFT 400 mg/day was administered in two daily doses every 12 hours continuously, plus calcium folinate 45 mg/day in three divided doses administered every 8 hours indefinitely.
Study 2—UFT 400 mg/m²/day was administered in two daily doses every 12 hours indefinitely.
In both studies, treatment was continued until toxicity or disease progression. If grade 3 or grade 4 toxicity appeared, treatment was stopped until recovery, wherein patients resumed treatment at the same doses.
Patient characteristics are listed in Table 1. Of the 106 patients entered in study 1, 80 (75%) had only one site of metastasis, and 26 (25%) had two or more sites. The predominant sites of metastasis were the liver (56%), local and peritoneum (27%), and lymph node (21%). In study 2, 63 (66%) of the 95 patients had only one metastatic site, and 32 (34%) had two or more sites. In this study, 68% of patients had liver metastasis.
Response and toxicity were evaluated using standard criteria. Toxicity was evaluated monthly, and response to treatment was evaluated every 2 months by computed tomography scan (chest radiography for lung metastasis was permitted). Only responses lasting 2 months were considered objective responses. The Kaplan-Meier method was used to calculate the actuarial median survival.
The median treatment time for these 106 patients was 4 months (range, 1 to 23 months) and minimum follow-up was 5 months to a maximum of 24 months. Toxicity, calculated as the maximum grade for the patient, was evaluable in 98 patients (Table 2). Six patients were lost to follow-up, and two patients had protocol violations. One patient (1%) had grade 3 or grade 4 thrombocytopenia, six patients (6%) experienced grade 3 nausea/vomiting, 11 patients (11%) had grade 3 or grade 4 diarrhea, and one patient (1%) had grade 3 mucositis. Other toxicities included one case of grade 1 lacrimation and five cases of grade 1 alopecia. Toxicity resulted in delayed chemotherapy in 20 patients (20%) for a median 10-day delay per patient over the treatment period (range, 1 to 48 days).
The median UFT dose intensity was 400 mg/day. Response to treatment was evaluable in 96 patients. Two additional patients refused treatment before they completed 2 months of therapy. Responses included five complete responses (CR) and 12 partial responses (PR), for an overall response rate of 17.7% (95% confidence interval [CI], 10% to 27%). Stable disease (SD) was noted in 24 patients (25%). The total number of patients with nonprogressive disease (objective response plus SD) was 41 (43%); 55 patients (57%) had progressive disease (Table 3).
Median survival for the entire group was 13.7 months (Figure 1), with no differences observed among responders and stable patients. The difference between patients with nonprogressive disease (CR + PR + SD) and patients with progressive disease was significant (P < .01) (Figure 2).
This preliminary data analysis includes 95 patients (of the 117 patients who entered the study [to date, 81% of patients have been analyzed]), including 80 patients evaluable for toxicity and 62 patients evaluable for response. The median treatment time was 14 months, with a minimum follow-up of 0.3 months and a maximum follow-up of 20.3 months. No patient experienced grades 3-4 hematologic toxicity; 7% of patients had grades 3-4 diarrhea; and 2% of patients had grades 3-4 nausea/vomiting. Grades 1-2 toxicity included nausea/vomiting, occurring in 24% of patients (Table 2). Chemotherapy delay due to toxicity occurred in 11% of patients.
Treatment response was evaluated in 62 patients. There were five complete responses (8%) and eight partial responses (13%), for an overall response rate of 21% (95% CI, 13% to 30%). Twenty-five patients had stable disease (40%), and 24 patients had progressive disease (39%). The total number of patients with nonprogressive disease (objective response plus SD) was 38 (61%) (Table 3). At this time, the data are not mature enough for an overall survival analysis.
1. Piedbois P, Buyse M, Rusum Y, et al: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 10:896-903, 1992.
2. Piedbois P, Buyse M, Blijham G, et al: Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. J Clin Oncol 12:960-969, 1994.
3. Abad A, Garcia P, Gravaios C, et al: Sequential methotrexate, 5-fluorouracil (5-FU) and high-dose leucovorin versus 5-FU and high-dose leucovorin versus 5-FU alone for advanced colorectal cancer. Cancer 75:1238-1244, 1995.
4. Aranda E, Díáz-Rubio E, Cervantes A, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with high-dose 48-hour continuous infusion fluorouracil for advanced colorectal cancer: A Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol 9:727-731, 1998.
5. The Meta-analysis Group in Cancer: Efficacy of intravenous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16:301-308, 1998.
6. Fentiman S: Are the elderly receiving appropriate treatment for cancer? Ann Oncol 7:657-658, 1996.
7. Monfardini S, Chabner B: Joint NCI-EORTC Consensus meeting on neoplasia in the elderly. Eur J Cancer 27:653-654, 1991.
8. Watanabe H, Yamamoto S, Naito T: Clinical results of oral UFT therapy under cooperative study. Gan To Kagaku Ryoho 7:1588-1596, 1980.
9. Murakami M, Ota K: Clinical results of UFT therapy for malignant tumors under cooperative study. Gan To Kagaku Ryoho 7:1579-1586, 1980.
10. Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer Chemother Pharmacol 22:333-338, 1998.
11. Malik STA, Talbot D, Clarke PI, et al: Phase II trial of UFT in advanced colorectal and gastric cancer. Br J Cancer 62:1023-1025, 1990.
12. Pazdur R, Lassere Y, Rhodes V, et al: Phase II trial of uracil and tegafur plus oral leucovorin: An effective oral regimen in the treatment of metastatic colorectal carcinoma. J Clin Oncol 12:2296-2300, 1994.
13. Pazdur R: Phase II study of UFT plus leucovorin in colorectal cancer. Oncology 54(suppl 1):19-23, 1997.
14. Gonzalez Baron M, Feliu J, de la Gandara I, et al: Efficacy of oral tegafur modulation by uracil and leucovorin in advanced colorectal cancer: A phase II study. Eur J Cancer 31:2215-2219, 1995.
15. Díáz-Rubio E, Aranda E, Camps C, et al: A phase II study of weekly 48 hours infusion with high-dose fluorouracil in advanced colorectal cancer: An alternative to biochemical modulation. J Infus Chemother 4:58-61, 1994.
16. Aranda E, Cervantes A, Dorta J, et al: A phase II trial of weekly high-dose continuous infusion 5-fluorouracil plus oral leucovorin in patients with advanced colorectal cancer. Cancer 76:559-563, 1995.
17. Aranda E, Cervantes A, Carrato A, et al: Outpatient weekly high-dose continuous infusion 5-fluorouracil plus oral leucovorin in advanced colorectal cancer: A phase II trial. Ann Oncol 7:581-585, 1996.
18. Díáz-Rubio E, Aranda E, Martin M, et al: Weekly high-dose infusion 5-fluorouracil in advanced colorectal cancer. Eur J Cancer 26:727-729, 1990.
19. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 40:207-214, 1981.
20. Feliu J, Gonzalez Baron M, Espinosa E, et al: Uracil and tegafur modulated with leucovorin: An effective regimen with low toxicity for the treatment of colorectal carcinoma in the elderly. Cancer 10:1884-1889, 1997.