Japanese Journal of Clinical Oncology 30:510-514 (2000)
© 2000 Foundation for Promotion of Cancer Research
Phase II Study of Oral Tegafur-Uracil and Folinic Acid as First-line Therapy for Metastatic Colorectal Cancer: Taiwan Experience
1Division of Colorectal Surgery, Department of Surgery, 2Division of Medical Oncology, Department of Medicine, Veterans General Hospital–Taipei and National Yang-Ming University School of Medicine, 3Division of Hematology/Oncology, Department of Medicine and 4Department of Colorectal Surgery, Mackay Memorial Hospital–Taipei, Taipei, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Background: Tegafur-uracil has become an important regimen in the treatment of metastatic colorectal cancer. Tegafur is a prodrug that is converted to 5-fluorouracil (5-FU) and has been reported to be less toxic and to have a higher therapeutic index. The additional advantage of tegafur is oral administration, an important consideration to improve the quality of life in these patients. Tegafur in combination with uracil is thought to have greater anti-tumor activity due to the inhibitory effect of uracil on the degradation of 5-FU by hepatic dihydropyrimidine dehydrogenase. Tegafur with folinic acid has been reported with modest efficacy and acceptable toxicity. The purpose of this study was to evaluate the effectiveness and toxicity profile of oral tegafur-uracil plus folinic acid in Chinese patients with metastatic colorectal cancer.
Methods: Between May 1998 and August 1999, 40 patients with metastatic colorectal carcinoma were enrolled in this study. All the patients had to have measurable lesions. The initial dose of tegafur-uracil was 300 mg/m2/day for 28 days, followed by a 7-day rest period. Folinic acid was administered orally at a dose of 60 mg/day concurrently with tegafur-uracil. For patients with neutrophil count <1500/µl or a platelet count <100 000/µl after treatment, the treatment was postponed for a maximum of 2 weeks. After that time, if the neutrophil count was 1000–1500/µl and the platelet count was 70 000–100 000 µl, the dose of tegafur-uracil was reduced by 50%, and if lower values resulted, the treatment was discontinued.
Results: Forty patients received a total of 318 courses of treatment and a response rate of 32.5% (95% CI, 18–47%), including five complete remissions and eight partial remissions, was achieved. Toxicity was mild and generally tolerable. Gastrointestinal toxicities, including diarrhea, nausea and vomiting, were the major side effects. Seven incidences (17.5%) of grade 3–4 gastrointestinal toxicity were observed. Hematological toxicities were minimal with no evidence of severe (grade 3 or 4) leukopenia and thrombocytopenia. No episode of hepatic, renal, cardiac or neurological toxicity occurred. Two patients (5%) developed transient painful fissuring erythroderma over their palms and soles (the hand–foot syndrome).
Conclusions: The data from our study indicate that oral tegafur-uracil plus folinic acid is an active and tolerable first-line treatment for Chinese patients with metastatic colorectal cancer, with the additional advantage of being easily administered at home.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Colorectal cancer is among the leading causes of cancer-related morbidity and mortality in Taiwan. Resection of the primary tumor is the mainstay of treatment for patients in early stages with localized disease and may offer a chance of cure. However, for metastatic diseases, cure is rarely achieved (1). Treatment of metastatic diseases consists mainly of chemotherapy. 5-Fluororuacil (5-FU) and folinic acid (FA) have remained the standard recommended chemotherapy (2). Over the past decades, there have been numerous attempts to increase the efficacy of 5-FU by changing the dose, the schedule or the route of administration (3). The reported response rate of 5-FU in metastatic colorectal cancer varies among many institutions, but generally, the activity of all these regimens is limited to a response rate of about 20%, with no significant impact on survival (2). Because of the poor prognosis of these patients, the development of more effective and less toxic chemotherapeutic agents is clearly essential to improve the outcome.
Recently, tegafur-uracil has become an important regimen in the treatment of metastatic colorectal cancer. Tegafur [1-(2-tetrahydrofuryl)-5-fluorouracil] is a prodrug that is converted to 5-FU in tissue and has been reported to be less toxic and to have a higher therapeutic index (4). Tegafur is given orally for prolonged periods in divided doses to simulate a protracted continuous infusion of 5-FU. The activity of orally administered tegafur is similar to that of intravenous 5-FU in advanced colorectal cancer, with superior response and survival results as shown in several comparative trials (5,6). The additional advantage of tegafur is oral administration, an important consideration to improve the quality of life of patients with metastatic colorectal cancer.
Tegafur in combination with uracil is thought to have greater anti-tumor activity owing to the inhibitory effect of uracil on the degradation of 5-FU by hepatic dihydropyrimidine dehydrogenase, which is the rate-limiting enzyme in 5-FU catabolism (7). Previous studies have demonstrated that 5-FU can be modulated by FA with a higher response rate in colorectal cancer (2) and a few studies of tegafur with FA have been reported with modest efficacy and acceptable toxicity (8,9). Whether oral tegafur-uracil plus FA is active and tolerable in Chinese patients is of interest to us.
The purpose of this study was to evaluate the effectiveness and toxicity profile of oral tegafur-uracil plus folinic acid in first-line treatment of Chinese patients with metastatic colorectal cancer.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Patients
Between May 1998 and August 1999, 40 patients with metastatic colorectal carcinoma were enrolled in this study. All the patients were diagnosed as having metastatic adenocarcinoma of the colon or rectum. None of them had received prior systemic chemotherapy for metastatic diseases. Prior adjuvant chemotherapy was allowable if it had been completed at least 6 months before this study. For the patient to be eligible for inclusion, the disease had to be measurable in two dimensions by computed tomographic (CT) scan, ultrasound (lesions in liver) or chest X-ray (lesions in lung) or caliber measurement of palpable lesions elsewhere. All patients were required to have an ECOG performance status of
2 and to have adequate hematopoietic function as evidenced by leukocyte counts >4000/µl and platelet counts >100 000/µl. Patients with any active infection or previous history of any other malignancy were excluded from this study. All patients had to have serum transaminase less than three times the upper normal limit. Patients had to have recovered from the effects of recent surgery or radiotherapy at least 3 weeks apart. All patients enrolled in this study were requested to sign an informed consent after full explanation. The patients’ characteristics are shown in Table 1.
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Treatment
The initial dose of tegafur-uracil (UFUR; Taiwan Tung Yang Chemical Industries) was 300 mg/m2/day administered orally for 28 days, followed by a 7-day rest period. The total daily dose was divided into three doses every 8 h (at approximately 7 a.m., 3 p.m. and 11 p.m.). If the capsule dose could not be divided equally, the highest dose was administered in the morning and the lowest in the evening. FA was supplied as 15 mg tablets and administered orally at a dose of 60 mg/day concurrently with tegafur-uracil. The first FA dose (at 7 a.m.) was 30 mg and the 3 and 11 p.m. doses were each 15 mg. For patients with neutrophil count <1500/µl or platelet count <100 000/µl after treatment, the treatment was postponed for a maximum of 2 weeks. After that time, if the neutrophil count was 1000–1500/µl and the platelet count was 70 000–100 000/µl, the dose of tegafur-uracil was reduced by 50% and if lower values resulted, the treatment was discontinued. If patients had grade 3 or 4 non-hematological toxicity, they had to have recovered completely within a maximum of 6 weeks and the dosage of tegafur-uracil was reduced by 50 mg/m2/day in subsequent courses. If treatment could not be started on day 43, the patient was removed from the study.
Response Criteria
Response was evaluated using Eastern Cooperative Oncology Group (ECOG) criteria. Complete response (CR) was defined as complete disappearance of all known lesions documented by two separate observations at least 4 weeks apart and without the appearance of any new lesions. Partial response (PR) required at least a 50% reduction in the cross-sectional area of the indicator lesion (or sum of areas if there was more than one indication lesion), again documented by two separate observations at least 4 weeks apart, with no individual lesion growing and no new lesion appearing. Stable disease (SD) was defined as <50% reduction or <25% increase in the sum of cross-sectional areas of all measurable lesions, with no appearance of new lesions for at least 4 weeks. Patients were considered to have progressive disease (PD) when any lesion grew >25% in cross-sectional area or when any new lesion appeared.
Evaluation and Follow-up
Before treatment, all patients underwent evaluation including a detailed history and physical examination, tumor measurement, chest X-ray, liver imaging (CT and sonogram), complete blood count (CBC), blood chemistry and CEA. All patients visited the outpatient clinic regularly for physical examination and check-up of CBC, liver and renal functions and serum CEA level during treatment. Chest X-ray and sonogram of the liver or CT scan of the abdomen were examined every 2 months. Colonoscopy was scheduled on an annual basis. Adverse effects were evaluated according to the ECOG criteria. Patients with CR, PR or SD remained in the protocol until progressive disease or unacceptable toxicity was documented.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Response to Therapy
The response data, including the response to each target organ, are summarized in Table 2. The 40 patients received a total of 318 courses of treatment and a response rate of 32.5%, including five CR and eight PR, was achieved. The 95% confidence interval was 18.0–47.0%. The median number of treatment courses was 7.95 (range, 4–16). The median cumulative dose of tegafur-uracil was 66 780 mg/m2 (range, 33 600–134 400 mg/m2). The median cumulative dose of FA was 13 356 mg (range, 6720–26 880 mg). The responses of all involved lesions were confirmed by sonogram, CT scan or chest X-ray.
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Toxicity
Toxicities were evaluated and graded according to the ECOG criteria (Table 3). These toxicities were generally tolerable. Gastrointestinal toxicities, including nausea, vomiting and diarrhea, were the major adverse effects, but they were generally tolerable and could easily be controlled by symptomatic treatment. Hematological toxicities were minimal with no evidence of severe (grade 3 or 4) leukopenia and thrombocytopenia. Two patients developed a transient painful fissuring erythroderma over their palms and soles (the hand–foot syndrome), including grade 2 in one and grade 3 in the other. Throughout the whole course of the treatment, no episode of hepatic, renal, cardiac or neurological toxicity occurred. In our study, owing to the toxicity being generally tolerable, no patient required to postpone or reduce the dose of treatment. No treatment-related death was observed.
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Survival
The median time to progression was 6.8 months. With a maximum follow-up of 20 months at the time of this report, the median survival was not reached.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Since its discovery by Heidelberger et al. about 40 years ago (10), 5-FU remains the most extensively studied drug and is considered the standard treatment in metastatic colorectal cancer. However, optimal dose scheduling of 5-FU is still controversial. The most popular method of administration of 5-FU is monthly intravenous bolus injection, but it is generally accepted that bolus injection of 5-FU will produce an objective response rate of only 15–20% in metastatic colorectal cancer. When 5-FU was modulated with FA, the combination could produce a response rate of 20–25% with a median survival of 9–12 months. Because of the poor prognosis of these patients, the development of a more effective and less toxic regimen is clearly important to improve the outcome.
Oral fluoropyrimidines have been proved to have high, consistent bioavailability profiles and have been in clinical use for about 30 years. Tegafur was initially synthesized in 1967 as a prodrug of 5-FU and proved active in the management of metastatic colorectal cancer. Tegafur is metabolized to 5-FU in vivo, predominantly in the liver, and has been reported to be less toxic and to have a higher therapeutic index (4). Because the bioavailability of tegafur by the oral route was nearly complete, interest in the drug as an oral chemotherapeutic agent persisted.
Uracil is a naturally occurring pyrimidine which is capable of incorporating into nucleic acids. Tegafur-uracil was devised in Japan in 1978 by Fujii et al. by the addition of uracil to tegafur to form a new drug, ‘UFT’ (11). A higher anti-tumor activity was identified when tegafur was combined with uracil. The reason is thought to be the inhibitory effect of uracil on the degradation of 5-FU by hepatic dihydropyrimidine dehydrogenase, which is the rate-limiting enzyme in 5-FU catabolism (7). Preclinical studies established that the optimum molar ratio of uracil to tegafur is 4:1. This ratio resulted in the highest 5-FU tumor–blood and tumor–normal tissue partition coefficients and a greater anti-tumor activity (12). In animal experiments, tegafur-uracil gave a comparable distribution of 5-FU in blood and in other normal tissue, but it resulted in a 5–10 times greater distribution of 5-FU in tumor tissues (13). A comparative study of tegafur-uracil and tegafur, which was administered in the same institutions for equal evaluation, revealed that tegafur-uracil had a significantly better effect than tegafur without more pronounced side effects (14). In another study, tegafur plus uracil was shown to be less toxic than the drug alone and uracil was found to decrease the toxicity of tegafur (15).
Early clinical trials of UFT by Japanese investigators were performed in the late 1970s and early 1980s. In these studies, a total daily dose of UFT in the range 400–600 mg divided into two or three doses was considered feasible for long-term administration. In a study reported by Ota et al. (16), 14 out of 56 assessable patients (25%; 95% CI, 14–38) achieved a partial response. The median survival was 227 days for all assessable patients and 339 days for patients responded to treatment. Toxicity was low and without significant hematological side effects. In another study conducted by Malik et al. in the UK which enrolled 40 chemotherapy-naive patients, UFT was administered at 600 mg daily in three divided doses. In 36 assessable patients, a response rate of 17% (95% CI, 6–33) was achieved without excessive toxicity (17).
FA was reported to be capable of enhancing the anti-tumor efficacy of 5-FU in the treatment of metastatic colorectal cancer (2,3). The daily dose of FA in combination with UFT varied from 15 to 150 mg in different institutes (18). In our study, the daily dose of 60 mg of FA was based on a study conducted by Nogue and Saigi (19). In their study, FA was administered at a starting dose of 30 mg daily and could be safely increased to 45 and then 60 mg daily. In 1995, Saltz et al. reported their experience with UFT plus ‘low-dose’ FA. UFT 350 mg/m2/day was administered concomitantly with oral FA 5 mg three times daily (total 15 mg/day) to 21 patients (20). Five out of 20 patients (25%) achieved objective responses (95% CI, 6–44), including one CR. With a median follow-up of 12 months at the time of report, the median survival was not reached. In phase II studies, a relatively higher response rate was observed when UFT was combined with ‘high-dose’ FA. In 1994, Pazdur et al. reported their experience of UFT plus ‘high-dose’ FA (21). A total of 45 patients were enrolled. The initial seven patients received a daily dose of UFT at 350 mg/m2 plus FA 150 mg daily for 28 days every 5 weeks. The dose of UFT was then decreased in the next 38 patients to 300 mg/m2/day owing to unacceptable toxicity (diarrhea). The response rates were similar at both dose levels: 43% at 350 mg/m2/day and 42% at 300 mg/m2/day. Whether UFT in combination with ‘high-dose’ FA is indeed better than ‘low-dose’ deserves further randomized studies.
Our study achieved a response rate of 32.5% (95% CI, 18–47), including five CR and eight PR (Table 2), which was comparable to previous studies. The median time to progression was 6.8 months. With a maximum follow-up of 20 months at the time of this report, the median survival was not reached. In our study, the CR rate (12.5%) was observed to be relatively higher than in previous reports. Generally, the majority of patients tolerated the treatment well. The most frequently observed adverse effects in our study were nausea and diarrhea. Twenty-two patients (55%) developed grade 1–3 nausea and 18 patients (45%) developed grade 1–4 diarrhea. However, grade 3–4 diarrhea (n = 4, 10%) and nausea (n = 2, 5%) were rarely found. Myelosuppression was mild, with no episode of grade 3–4 leukopenia or thrombocytopenia. Throughout the whole course of the study, no hepatic, renal, cardiac or neurological toxicity occurred. Two patients developed a transient painful erythroderma over their palms and soles (the hand–foot syndrome), grade 3 in one and grade 2 in the other. However, their symptoms subsided quickly after supportive treatment, which required no interruption of therapy or dose reduction. The treatment-related toxicity is shown in Table 3.
In conclusion, the data from our study indicate that oral tegafur-uracil at 300 mg/m2/day plus FA 60 mg/day is an effective and well-tolerated first-line treatment for Chinese patients with metastatic colorectal cancer, with the additional advantage of convenience for outpatient use. Whether oral tegafur-uracil plus FA is superior to conventional intravenous ‘monthly 5-day’ or ‘weekly bolus’ 5-FU plus FA in the treatment of metastatic colorectal cancer deserves further phase III studies.
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Acknowledgment |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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This work was supported by a grant from the Yen Tjing-Ling Medical Foundation.
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FOOTNOTES |
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+ For reprints and all correspondence: Wei-Shu Wang, Division of Medical Oncology, Department of Medicine, Veterans General Hospital–Taipei 11217, Taiwan
Abbreviations: 5-FU, 5-fluorouracil; FA, folinic acid; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Received August 14, 2000; accepted August 25, 2000.
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