Adjuvant Chemotherapy for Adenocarcinoma of the Lung — Is the Standard of Care Ready for Change?
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《新英格兰医药杂志》
The treatment for stage I non–small-cell lung cancer, regardless of cell type, is wide surgical resection (lobectomy or pneumonectomy) of the involved area.1 Although the propensity of non–small-cell lung cancer to metastasize early is well recognized, there is no convincing evidence that postoperative radiotherapy or adjuvant chemotherapy improves survival in stage I disease. As a result, guidelines in the United States do not recommend any adjuvant treatment outside of the clinical-trial setting.1 Many of the relatively small studies that have suggested that chemotherapy can improve survival in non–small-cell lung cancer2,3 used the same agents that have proved useful in advanced disease, such as cisplatin, an agent generally recognized as one of the most active in non–small-cell lung cancer. Nevertheless, most studies of adjuvant chemotherapy with cisplatin have failed to show convincingly that this agent provides any meaningful improvement in survival.
Therefore, many U.S. oncologists were somewhat surprised when initial studies in Japan showed that a combination of the naturally occurring pyrimidine uracil and tegafur (ftorafur) (often referred to as UFT) in a 4:1 ratio had activity in advanced non–small-cell lung cancer4 and as adjuvant chemotherapy after complete resection,5 particularly when combined with cisplatin. This result was especially striking because the parent drug itself, fluorouracil, had no clinical activity or effect on survival. Despite the skepticism of the U.S. oncology community, additional Japanese studies — including a meta-analysis — have disclosed a potential survival benefit of adjuvant chemotherapy with uracil–tegafur.6
It is against this background that the study reported by Kato and colleagues7 in this issue of the Journal is of interest. The study was designed to address several concerns about earlier studies of adjuvant treatment of non–small-cell lung cancer with uracil–tegafur. Of note is the decision by Kato et al. to include only patients with non–small-cell lung cancer of the adenocarcinoma cell type, because it was observed that the drug had a more pronounced effect on this cell type. Also, the surgical procedure performed at the many participating clinical sites was more standardized in the study by Kato et al. than were the surgical procedures used in earlier studies. Furthermore, in contrast to previous studies, the number of patients enrolled in this investigation gave it the statistical power to permit conclusions about the therapeutic effectiveness of uracil–tegafur in patients with stage I adenocarcinoma and either T1 or T2 disease.
As a result, the study by Kato et al. provides compelling evidence that after complete resection, oral administration of uracil–tegafur, given twice daily at a dose of 250 mg of tegafur per square meter of body-surface area per day for two years, can improve survival in patients with pathological stage I adenocarcinoma of the lung. The data point to improvement particularly in patients with T2 disease. Not only was a statistically significant survival benefit shown, but also toxicity was tolerable; grade 3 or higher toxic effects developed in only 2 percent of the patients.
Uracil–tegafur is a chemotherapy drug that most U.S. oncologists will not recognize, since it has not been approved in the United States and has been used in relatively few clinical trials in this country, despite widespread approval elsewhere. Uracil–tegafur, a prodrug of fluorouracil, is one of several oral fluoropyrimidine drugs that have been synthesized by the pharmaceutical industry in the past few years.8 Most of these drugs have been designed as a means of improving the delivery of fluorouracil over time. The rationale is that the administration of fluorouracil by prolonged continuous infusion increases the efficacy of the drug and reduces its toxicity,8 a benefit that has been demonstrated impressively in recent trials involving patients with colon cancer.9
The beneficial effect of uracil–tegafur is believed to derive from its relatively slow conversion to fluorouracil by metabolism through the cytochrome P-450 pathway, thus somewhat mimicking a fluorouracil infusion. Once released from the prodrug tegafur, fluorouracil competes with uracil for catabolism by the rate-limiting enzyme dihydropyrimidine dehydrogenase (Figure 1). Although uracil and fluorouracil have a similar affinity for dihydropyrimidine dehydrogenase, the presence of excess uracil is thought to decrease the degradation of fluorouracil, and thus more fluorouracil is available for the inhibition of thymidylate synthase and incorporation into RNA, with subsequent dysfunction of RNA. Since uracil–tegafur is typically administered orally in split daily doses over a period of up to two years, there is prolonged exposure to fluorouracil, which, although not pharmacokinetically identical to an infusion of fluorouracil, approximates the effects of an infusion. The option of using an orally administered drug with decreased adverse effects is attractive. Patients have been shown to prefer oral therapy as long as efficacy is not sacrificed.10
Figure 1. Modulation of Fluorouracil by Dihydropyrimidine Dehydrogenase.
Uracil–tegafur consists of uracil and tegafur in a 4:1 molar ratio. Tegafur is converted to fluorouracil by the cytochrome P-450 system. Excess uracil competes with fluorouracil for dihydropyrimidine dehydrogenase; as a result, the catabolism of fluorouracil is inhibited.
The incorporation of uracil–tegafur into chemotherapy in the United States has had a difficult path. An earlier large phase 3 study of advanced colorectal cancer compared uracil–tegafur plus leucovorin with fluorouracil plus leucovorin. Although the results suggested that the two regimens were equivalent,11 uracil–tegafur has thus far not been approved by the the Food and Drug Administration (FDA), and clinical studies of uracil–tegafur in the United States were terminated in 2001. In a large phase 3 study of adjuvant chemotherapy for colorectal cancer, the National Surgical Adjuvant Breast and Bowel Project compared uracil–tegafur plus leucovorin with an intravenous bolus of fluorouracil plus leucovorin. An interim analysis of the results showed less toxicity in the uracil–tegafur group, with excellent acceptance by patients.12 The survival data are expected to be available this year.
Another oral fluoropyrimidine, capecitabine (Xeloda), has received FDA approval for use in patients with breast cancer and colorectal cancer. This prodrug differs from uracil–tegafur8 in that capecitabine is metabolized to fluorouracil in three enzymatic steps, but inhibition of dihydropyrimidine dehydrogenase does not occur. Certain side effects of capecitabine (e.g., palmar–plantar erythroplasia, or the hand–foot syndrome) are not seen as frequently with fluoropyrimidines that are inhibited by dihydropyrimidine dehydrogenase. Whether capecitabine is beneficial for the treatment of non–small-cell lung cancer is unknown.7 The recent demonstration of the overexpression of dihydropyrimidine dehydrogenase in non–small-cell lung cancer13 may explain why many fluoropyrimidine drugs that do not have a mechanism that inhibits dihydropyrimidine dehydrogenase, such as fluorouracil and capecitabine, may not be as effective in non–small-cell lung cancer as they are in other tumors.14 Although the uracil in uracil–tegafur interferes with the degradation of fluorouracil formed from tegafur, and thereby permits the released fluorouracil to be available at relatively high concentrations over time, the process is actually somewhat inefficient, because the excess uracil merely competes for dihydropyrimidine dehydrogenase with low concentrations of fluorouracil.
A few potent inhibitors of dihydropyrimidine dehydrogenase (e.g., eniluracil) have been examined in combination with fluorouracil in clinical trials for the treatment of tumor types other than non–small-cell lung cancer,8 but the effects of the newer fluoropyrimidines that inhibit dihydropyrimidine dehydrogenase, such as S-1, a recently developed combination of tegafur, 5-chloro-2,4-dihydroxypyridine (a dihydropyrimidine dehydrogenase inhibitor), and oxonic acid (which is thought to decrease the incidence of diarrhea, a common toxic effect of fluoropyrimidines), have yet to be studied.15 If adjuvant chemotherapy with uracil–tegafur improves survival among patients with adenocarcinoma of the lung, as several studies now suggest, the effect of S-1 on survival may be even greater.
Dr. Diasio reports having received consulting and lecture fees from Bristol-Myers Squibb, Roche, and Taiho Pharmaceutical.
Source Information
From the Departments of Medicine and Pharmacology and Toxicology and the Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham.
References
Smythe WR. Treatment of stage I non-small cell lung carcinoma. Chest 2003;123:Suppl:181S-187S.
George S, Schell MJ, Detterbeck FC, Socinski MA. Adjuvant chemotherapy for resected non-small cell lung carcinoma of the lung: why we still don't know. Oncologist 1998;3:35-44.
Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004;350:379-392.
Shimizu E, Kimura K, Sone S, et al. A phase II study of UFT in non-small cell lung cancer. Gan To Kagaku Ryoho 1986;13:2970-2973.
Wada H, Hitomi S, Teramatsu T. Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. J Clin Oncol 1996;14:1048-1054.
Hamada C, Ohta M, Wada H, et al. Efficacy of oral UFT for adjuvant chemotherapy after complete resection of non-small cell lung cancer: meta-analysis of six randomized trials in 2003 patients. Proc Eur Cancer Conf 2003;39:S231. abstract.
Kato H, Ichinose Y, Ohta M, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 2004;350:1713-1721.
Diasio RB. Current status of oral chemotherapy for colorectal cancer. Oncology (Huntingt) 2001;15:Suppl 5:16-20.
Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23-30.
Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997;15:110-115.
Douillard JY, Hoff PM, Skillings JR, et al. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2002;20:3605-3616.
Smith R, Wickerham DL, Wieand HS, Colangelo L, Mamounas EP. UFT plus calcium folinate vs 5-FU plus calcium folinate in colon. Oncology (Huntingt) 1999;13:Suppl 3:44-47.
Fukushima M, Morita M, Ikeda K, Nagayama S. Population study of expression of thymidylate synthase and dihydropyrimidine dehydrogenase in patients with solid tumors. Int J Mol Med 2003;12:839-844.
Diasio RB, Johnson MR. The role of pharmacogenetics and pharmacogenomics in cancer chemotherapy with 5-fluorouracil. Pharmacology 2000;61:199-203.
Sakai H, Ichinose Y, Yoshimori K, et al. Phase II trial of S-1 plus cisplatin (CDDP) in patients with non-small-cell lung cancer (NSCLC). Prog Proc Am Soc Clin Oncol 2003;22:653. abstract.(Robert B. Diasio, M.D.)
Therefore, many U.S. oncologists were somewhat surprised when initial studies in Japan showed that a combination of the naturally occurring pyrimidine uracil and tegafur (ftorafur) (often referred to as UFT) in a 4:1 ratio had activity in advanced non–small-cell lung cancer4 and as adjuvant chemotherapy after complete resection,5 particularly when combined with cisplatin. This result was especially striking because the parent drug itself, fluorouracil, had no clinical activity or effect on survival. Despite the skepticism of the U.S. oncology community, additional Japanese studies — including a meta-analysis — have disclosed a potential survival benefit of adjuvant chemotherapy with uracil–tegafur.6
It is against this background that the study reported by Kato and colleagues7 in this issue of the Journal is of interest. The study was designed to address several concerns about earlier studies of adjuvant treatment of non–small-cell lung cancer with uracil–tegafur. Of note is the decision by Kato et al. to include only patients with non–small-cell lung cancer of the adenocarcinoma cell type, because it was observed that the drug had a more pronounced effect on this cell type. Also, the surgical procedure performed at the many participating clinical sites was more standardized in the study by Kato et al. than were the surgical procedures used in earlier studies. Furthermore, in contrast to previous studies, the number of patients enrolled in this investigation gave it the statistical power to permit conclusions about the therapeutic effectiveness of uracil–tegafur in patients with stage I adenocarcinoma and either T1 or T2 disease.
As a result, the study by Kato et al. provides compelling evidence that after complete resection, oral administration of uracil–tegafur, given twice daily at a dose of 250 mg of tegafur per square meter of body-surface area per day for two years, can improve survival in patients with pathological stage I adenocarcinoma of the lung. The data point to improvement particularly in patients with T2 disease. Not only was a statistically significant survival benefit shown, but also toxicity was tolerable; grade 3 or higher toxic effects developed in only 2 percent of the patients.
Uracil–tegafur is a chemotherapy drug that most U.S. oncologists will not recognize, since it has not been approved in the United States and has been used in relatively few clinical trials in this country, despite widespread approval elsewhere. Uracil–tegafur, a prodrug of fluorouracil, is one of several oral fluoropyrimidine drugs that have been synthesized by the pharmaceutical industry in the past few years.8 Most of these drugs have been designed as a means of improving the delivery of fluorouracil over time. The rationale is that the administration of fluorouracil by prolonged continuous infusion increases the efficacy of the drug and reduces its toxicity,8 a benefit that has been demonstrated impressively in recent trials involving patients with colon cancer.9
The beneficial effect of uracil–tegafur is believed to derive from its relatively slow conversion to fluorouracil by metabolism through the cytochrome P-450 pathway, thus somewhat mimicking a fluorouracil infusion. Once released from the prodrug tegafur, fluorouracil competes with uracil for catabolism by the rate-limiting enzyme dihydropyrimidine dehydrogenase (Figure 1). Although uracil and fluorouracil have a similar affinity for dihydropyrimidine dehydrogenase, the presence of excess uracil is thought to decrease the degradation of fluorouracil, and thus more fluorouracil is available for the inhibition of thymidylate synthase and incorporation into RNA, with subsequent dysfunction of RNA. Since uracil–tegafur is typically administered orally in split daily doses over a period of up to two years, there is prolonged exposure to fluorouracil, which, although not pharmacokinetically identical to an infusion of fluorouracil, approximates the effects of an infusion. The option of using an orally administered drug with decreased adverse effects is attractive. Patients have been shown to prefer oral therapy as long as efficacy is not sacrificed.10
Figure 1. Modulation of Fluorouracil by Dihydropyrimidine Dehydrogenase.
Uracil–tegafur consists of uracil and tegafur in a 4:1 molar ratio. Tegafur is converted to fluorouracil by the cytochrome P-450 system. Excess uracil competes with fluorouracil for dihydropyrimidine dehydrogenase; as a result, the catabolism of fluorouracil is inhibited.
The incorporation of uracil–tegafur into chemotherapy in the United States has had a difficult path. An earlier large phase 3 study of advanced colorectal cancer compared uracil–tegafur plus leucovorin with fluorouracil plus leucovorin. Although the results suggested that the two regimens were equivalent,11 uracil–tegafur has thus far not been approved by the the Food and Drug Administration (FDA), and clinical studies of uracil–tegafur in the United States were terminated in 2001. In a large phase 3 study of adjuvant chemotherapy for colorectal cancer, the National Surgical Adjuvant Breast and Bowel Project compared uracil–tegafur plus leucovorin with an intravenous bolus of fluorouracil plus leucovorin. An interim analysis of the results showed less toxicity in the uracil–tegafur group, with excellent acceptance by patients.12 The survival data are expected to be available this year.
Another oral fluoropyrimidine, capecitabine (Xeloda), has received FDA approval for use in patients with breast cancer and colorectal cancer. This prodrug differs from uracil–tegafur8 in that capecitabine is metabolized to fluorouracil in three enzymatic steps, but inhibition of dihydropyrimidine dehydrogenase does not occur. Certain side effects of capecitabine (e.g., palmar–plantar erythroplasia, or the hand–foot syndrome) are not seen as frequently with fluoropyrimidines that are inhibited by dihydropyrimidine dehydrogenase. Whether capecitabine is beneficial for the treatment of non–small-cell lung cancer is unknown.7 The recent demonstration of the overexpression of dihydropyrimidine dehydrogenase in non–small-cell lung cancer13 may explain why many fluoropyrimidine drugs that do not have a mechanism that inhibits dihydropyrimidine dehydrogenase, such as fluorouracil and capecitabine, may not be as effective in non–small-cell lung cancer as they are in other tumors.14 Although the uracil in uracil–tegafur interferes with the degradation of fluorouracil formed from tegafur, and thereby permits the released fluorouracil to be available at relatively high concentrations over time, the process is actually somewhat inefficient, because the excess uracil merely competes for dihydropyrimidine dehydrogenase with low concentrations of fluorouracil.
A few potent inhibitors of dihydropyrimidine dehydrogenase (e.g., eniluracil) have been examined in combination with fluorouracil in clinical trials for the treatment of tumor types other than non–small-cell lung cancer,8 but the effects of the newer fluoropyrimidines that inhibit dihydropyrimidine dehydrogenase, such as S-1, a recently developed combination of tegafur, 5-chloro-2,4-dihydroxypyridine (a dihydropyrimidine dehydrogenase inhibitor), and oxonic acid (which is thought to decrease the incidence of diarrhea, a common toxic effect of fluoropyrimidines), have yet to be studied.15 If adjuvant chemotherapy with uracil–tegafur improves survival among patients with adenocarcinoma of the lung, as several studies now suggest, the effect of S-1 on survival may be even greater.
Dr. Diasio reports having received consulting and lecture fees from Bristol-Myers Squibb, Roche, and Taiho Pharmaceutical.
Source Information
From the Departments of Medicine and Pharmacology and Toxicology and the Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham.
References
Smythe WR. Treatment of stage I non-small cell lung carcinoma. Chest 2003;123:Suppl:181S-187S.
George S, Schell MJ, Detterbeck FC, Socinski MA. Adjuvant chemotherapy for resected non-small cell lung carcinoma of the lung: why we still don't know. Oncologist 1998;3:35-44.
Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004;350:379-392.
Shimizu E, Kimura K, Sone S, et al. A phase II study of UFT in non-small cell lung cancer. Gan To Kagaku Ryoho 1986;13:2970-2973.
Wada H, Hitomi S, Teramatsu T. Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. J Clin Oncol 1996;14:1048-1054.
Hamada C, Ohta M, Wada H, et al. Efficacy of oral UFT for adjuvant chemotherapy after complete resection of non-small cell lung cancer: meta-analysis of six randomized trials in 2003 patients. Proc Eur Cancer Conf 2003;39:S231. abstract.
Kato H, Ichinose Y, Ohta M, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 2004;350:1713-1721.
Diasio RB. Current status of oral chemotherapy for colorectal cancer. Oncology (Huntingt) 2001;15:Suppl 5:16-20.
Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23-30.
Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997;15:110-115.
Douillard JY, Hoff PM, Skillings JR, et al. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2002;20:3605-3616.
Smith R, Wickerham DL, Wieand HS, Colangelo L, Mamounas EP. UFT plus calcium folinate vs 5-FU plus calcium folinate in colon. Oncology (Huntingt) 1999;13:Suppl 3:44-47.
Fukushima M, Morita M, Ikeda K, Nagayama S. Population study of expression of thymidylate synthase and dihydropyrimidine dehydrogenase in patients with solid tumors. Int J Mol Med 2003;12:839-844.
Diasio RB, Johnson MR. The role of pharmacogenetics and pharmacogenomics in cancer chemotherapy with 5-fluorouracil. Pharmacology 2000;61:199-203.
Sakai H, Ichinose Y, Yoshimori K, et al. Phase II trial of S-1 plus cisplatin (CDDP) in patients with non-small-cell lung cancer (NSCLC). Prog Proc Am Soc Clin Oncol 2003;22:653. abstract.(Robert B. Diasio, M.D.)