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Phase II Study of Uracil-Tegafur With Leucovorin in Elderly ( 75 years old) Patients With Colorectal Cancer: ECOG 1299

Howard S. Hochster, Weixiu Luo, Elizabeta C. Popa, Bruce T. Lyman, Mary Mulcahy, Peter A. Beatty, Al Bowen Benson

From the New York University Cancer Institute, New York; Capitol District Hematology/Oncology, Latham, NY; Dana-Farber Cancer Institute, Boston, MA; Northwestern University, Chicago, IL; and Meriter Hospital, Madison, WI

Address reprint requests to Howard S. Hochster, MD, New York University Cancer Institute, 160 E 34th St, New York, NY 10016; e-mail: howard.hochster{at}med.nyu.edu

	ABSTRACT

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Purpose To evaluate the tolerability and effectiveness of uracil-tegafur (UFT) with leucovorin (LV) in the treatment of elderly patients with advanced colorectal cancer.

Patients and Methods Patients 75 years of age with previously untreated colorectal cancer were eligible for this phase II, single-arm, open-label, multicenter cooperative group clinical trial. UFT 100 mg/m² plus LV 30 mg orally every 8 hours for 28 days every 35 days was administered until progression.

Results Fifty-eight patients were enrolled between June 2000 and July 2001, and 55 were treated. The median age of treated patients was 81 years (range, 75 to 90 years), 26 patients were (47%) women, and 80% had good performance status (0 to 1). The observed overall response rate was 22% (95% CI, 11.8% to 35.0%). The estimated median overall survival time was 13.0 months (95% CI, 9.6 to 17.4 months), and median progression-free survival time was 4.6 months (95% CI, 2.6 to 6.7 months). Among the 56 treated patients (including one ineligible patient), 31 (55%) experienced grade 3 to 4 toxicities, most commonly diarrhea (25%) and GI toxicity (36%), with patients older than 85 years of age at highest risk.

Conclusion The results of this trial support the efficacy of oral UFT/LV in elderly patients with colorectal cancer. The regimen is tolerated moderately well overall, particularly as compared with other fluoropyrimidine regimens, although there is increased GI toxicity in the most elderly. These results suggest that studies using newer oral fluoropyrimidine analogs should be investigated in this patient population.

	INTRODUCTION

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One goal of current drug development is more effective, less toxic, and more convenient treatment. A number of oral fluorouracil (FU) prodrug compounds have been developed and are in current use around the world in the setting of colorectal cancer. We report the results of an Eastern Cooperative Oncology Group (ECOG) study using a modulated oral fluoropyrimidine, uracil-tegafur (UFT) with leucovorin (LV; Orzel, Bristol Myers-Squibb Co, New York, NY) in a truly elderly patient population. Although the design of new treatments for malignancies in general should take into account that the majority of cancers (60% to 70%) arise in patients older than age 65 years, this population is generally underrepresented. In the United States, this age group will double in size to 70 million persons in the next 25 years.^1,2

FU-based therapies are the mainstay of colorectal cancer treatment both in the adjuvant and metastatic settings. In the metastatic setting, the response rates for bolus FU/LV range from 10% to 15%, with median survival times of approximately 12 months. A large randomized trial from the late 1990s suggested that a protracted infusion results in improved response rates, but no gain in survival could be demonstrated. However, a meta-analysis of six prospectively randomized trials showed a 1-month benefit in survival for infusional FU compared with bolus and far less neutropenia.³ The addition of newer cytotoxics has increased response rates to 45% to 50% and has improved overall survival to 15 to 17 months, at the cost of additional toxicity.⁴

Most trials that have demonstrated the effectiveness of these treatments have tended to exclude the elderly, mostly through eligibility and selection issues. The median age of patients entered onto advanced colorectal cancer trials is generally 59 to 60 years, approximately 10 years younger than the median age for all patients. Some data are available on tolerability and effectiveness in the aged. Sargent et al⁵ performed a pooled analysis of seven phase III trials of adjuvant FU (FU with LV or levamisole) based on individual patient data that revealed comparable survival benefits across age groups, with similar toxicity in those older than 70 years old, although these patients had more leukopenia. Folprecht et al⁶ conducted a retrospective analysis of more than 20 clinical trials that cumulatively contained a total of 629 elderly patients (age > 70 years) and compared them to the larger majority of patients younger than 70 years of age in the same trials (n = 3,195). The analysis found that the benefits of infusional FU over bolus FU were present in both age groups. Progression-free survival was actually found to be significantly increased in the older age group, but this did not translate into a difference in median overall survival. Similar results were shown for infusional FU, LV, and oxaliplatin (FOLFOX) therapy in a pooled analysis of cooperative group studies.⁷

UFT is a 1:4 molar combination of tegafur (almost 100% orally bioavailable FU prodrug) and uracil (an inhibitor of dihydropyrimidine dehydrogenase [DPD], which is responsible for its variable oral absorption and the major enzyme in FU catabolism). Tegafur is converted via the hepatic cytochrome P450 system to FU. The dosing of UFT has ranged from 300 to 800 mg/m²/d on a continuous schedule in phase I and II studies.⁸ Ho et al⁹ compared the pharmacokinetics of FU 250 mg/m²/d continuous infusion with UFT 370 mg/m²/d, in three divided doses, and described a similar average steady-state concentration for the two regimens. Borner et al¹⁰ compared bolus FU 425 mg/m²/d and LV 20 mg/m²/d for 5 days with UFT 300 mg/m²/d and LV 90 mg/d and confirmed a lower toxicity profile for UFT, with diarrhea as the dose-limiting toxicity and no severe myelosuppression. One hypothesis for the lack of dermatologic toxicity is that uracil may act in limiting peripheral tissue formation of toxic catabolites of FU through its inhibition of DPD. In addition, the pharmacokinetics for this class of drugs requires caution in the elderly because DPD inhibition converts metabolism renal clearance, rather than hepatic.⁹

At the time this study was initiated in 2000, two large phase III randomized trials of UFT compared with the Mayo regimen had already been completed. They ultimately demonstrated the equivalency of UFT/LV to bolus intravenous FU in metastatic colorectal cancer. Both Douillard et al¹¹ (UFT 300 mg/m²/d with LV 150 mg/m²/d) and Carmichael et al¹² (UFT 300 mg/m²/d with LV 90 mg/m²/d) showed response rates ranging from 9% to 14.5% and median survival times of 10.3 to 13.4 months. Both regimens were administered for 28 of 35 days. Toxicity was reportedly as significantly lower with the oral regimen in the two trials. Nogue et al¹³ reported similar results.

UFT and LV, like other oral fluoropyrimidines, have the potential to provide the benefits of prolonged FU infusion without the inconvenience of using an infusion pump. This study aimed to determine whether the previously reported results with UFT/LV are applicable to the truly elderly population, with an age of at least 75 years, and to elucidate the toxicity pattern for this specific cohort of patients.

	PATIENTS AND METHODS

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Patient Population
From June 2000 to July 2001, 58 patients were enrolled from 18 centers in the United States. Eligibility included histologically confirmed metastatic colorectal adenocarcinoma, age 75 years, and measurable disease. No prior therapy of any type for metastatic disease was allowed, with the exception of radiotherapy to treat locally symptomatic disease, and adjuvant treatment had to have been completed at least 6 months before study enrollment. Other inclusion criteria were as follows: ECOG performance status of 0 to 2; absolute granulocyte (neutrophil) count more than 1,500/µL; platelets more than 100,000/µL; total bilirubin less than 1.5 mg/dL; serum creatinine less than 1.5x the institutional upper normal limit; and AST or ALT less than 2.5x the institutional upper normal limit. All patients provided written informed consent as approved by their local institutional review boards.

Treatment Plan
UFT capsules (300 mg/m²/d in three divided doses, every 8 hours) and LV tablets (30 mg administered with each dose of UFT) were administered for 28 days followed by 7 days of rest; this cycle was repeated every 35 days until progression. The UFT dose was rounded up or down to the nearest 100 mg. If the total number of capsules a patient received in 1 day could not be divided equally, the highest dose was administered in the morning. For patients with a body-surface area of more than 2.0 m², the UFT dose was calculated using a body-surface area of 2.0 m². LV was to be taken with 4 to 8 oz of water. Patients were not to consume any food for 1 hour before and 1 hour after the ingestion of trial medication.

Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. If the absolute neutrophil count was less than 1,000/µL or platelets were less than 50,000/µL (grade 3 hematologic toxicity), then trial medication was withheld until the absolute neutrophil count was more than 1,500/µL and/or platelets were more than 100,000/µL. After recovery, UFT therapy was resumed at the same dose. Any grade 2 or higher nonhematologic toxicity (including diarrhea, mucositis, and nausea) required interruption of therapy until recovery to baseline was documented. Treatment delay of up to 2 weeks was allowed for recovery. For grade 3 to 4 toxicity, dose reduction by 50 mg/m²/d was implemented for subsequent cycles.

Evaluation of Toxicity and Response
All baseline imaging was performed 6 weeks before the start of treatment, and laboratory studies were performed less than 4 weeks before the start of treatment. Complete physical examination was performed at the start of treatment, before each treatment cycle, and at treatment termination. Subsequent monitoring with computed tomography scans during treatment was performed at 10-week intervals to document response. After patients stopped treatment, follow-up examination and imaging were requested every 3 and 6 months, respectively.

ECOG solid tumor response criteria¹⁴ were used for both measurable and nonmeasurable but assessable disease based on bidimensional measurements and confirmatory scans. Toxicities were graded on a scale of 1 to 5 according to the National Cancer Institute Common Toxicity Criteria version 2.0.

Statistical Methods
This was a phase II, single-arm, open-label, multicenter clinical trial of UFT with LV (Orzel) in elderly patients with measurable metastatic colorectal cancer. The primary end point was overall objective response (complete plus partial response) rate. The historical true response rate was assumed to be 10% in this patient population, and UFT with LV would be considered a promising regimen for further study if this was exceeded. A two-stage design was used; 20 patients were entered, assuming that 18 would be eligible, and if one response was observed among the first 18 eligible patients, 35 additional patients would be entered. The total accrual goal was 55 patients, assuming 50 would be eligible. The study medication would be considered promising if at least nine responses were observed in 50 eligible patients. The study had 91% power to detect a 15% absolute improvement in the true response rate from 10% to 25% at significance level of 0.06. The overall objective response rate was estimated with a 95% CI taking the early stopping rule into account,¹⁵ which would be no wider than 29%.

Overall survival was defined as the time from registration to date of death (from any cause). Progression-free survival was the time from registration to progression or to death without documentation of progression. Overall survival and progression-free survival were estimated using the Kaplan-Meier method.¹⁶ To examine the effect of baseline patient characteristics on the risk of grade 3 to 4 GI toxicities, multivariate logistic regression was performed using the LogXact program of Cytel Studio version 6.3.0 (Cytel Inc, Cambridge, MA). Two-sided exact P < .05 was considered statistically significant.

	RESULTS

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Patient Characteristics
A total of 58 patients were accrued onto the study from 18 ECOG centers between June 2000 and July 2001. The study was not suspended for interim evaluation because five responses had been observed by the end of the first stage of accrual. Two patients did not receive any protocol medication, and one additional patient was deemed ineligible after enrollment. Table 1 provides the baseline characteristics of the 55 eligible and treated patients who were evaluated for efficacy. At the time of registration, patients ranged in age from 75 to 90 years, with a median age of 81 years; age distribution by half decade was as follows: 20 patients were aged 75 to 79 years, 25 were aged 80 to 84 years, and 11 were aged 85 to 90 years. The majority of patients were male, were white, had a performance status of 1, and had surgery only as prior treatment. Among the patients whose tumor involvement status was known, 41 patients (79%) had tumor(s) in liver, and 22 patients (45%) had tumor(s) in lung or pleura.

Toxicity
Fifty-six treated patients (including one ineligible patient) were evaluated for toxicities. Twenty-seven patients (48%) experienced toxicities with a worst grade of 3, four (7%) experienced toxicities with a worst grade of 4, and one patient (2%) experienced toxicity with a worst grade of 5. A total of 31 patients (55%) experienced grade 3 to 4 toxicities at their most severe grade. There was one (2%) possibly treatment-related lethal toxic event. The patient died from cerebrovascular ischemia during cycle 1. The most common grade 3 toxicity event was diarrhea, followed by fatigue and nausea (Table 2). There was no grade 3 or higher hand-foot reaction reported. Thirty-one (55.4%) of 56 treated patients required dose modifications, which included 22 dose reductions and nine dose delays. Twenty (64.5%) of the 31 patients required dose modifications as a result of toxicities (17 patients for GI toxicities, two for neutropenia, and one for weight loss).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier curves of (A) overall survival and (B) progression-free survival. (–– ––) 95% CI.

	DISCUSSION

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Some limitations of our study are notable, including lack of standard geriatric measures of functional status (which were not widely used in oncology at the time of this study in 1999) such as the Activity of Daily Living scale and Mini-Mental State Examination. It is likely that the patients enrolled functioned at a high level. In addition, we cannot estimate the percentage of all patients older than 75 years of age those entered here represent or how many may have been considered for the study but not entered.

The overall response rate of 22% (of all entered) in this study is well within the reported range, particularly for multicenter studies. Previous phase II studies had response rates ranging from 16% to 42%. Magne et al¹⁷ performed a four-way comparison of 86 patients aged 70 years. Final analysis revealed equivalency of the regimens with nonsignificant differences between bolus and continuous infusion schedules. Additional stratification into two groups with ages 70 to 74 and 75 years also failed to show any differences. A study similar to ours using capecitabine, conducted by the Oncopaz group,¹⁸ produced a similar overall survival but showed 25% hand-foot syndrome and 55% grade 3 to 4 toxicity.

A 36% incidence of grade 3 to 4 GI toxicity was observed, mainly consisting of diarrhea. In practice, when using oral fluoropyrimidines, this might be reduced with more aggressive use of loperamide at the first sign of diarrhea and every 2 hours. The incidence of neutropenia was minimal, which resulted in mainly uncomplicated episodes of grade 3 to 4 diarrhea. Additionally, we did not observe any severe hand-foot syndrome in this study, with the potential of contributing to falls in the elderly.

In the National Surgical Adjuvant Breast and Bowel Project C-06 adjuvant colorectal cancer trial, the same UFT/LV regimen was compared with the Mayo Regimen (daily x 5 bolus FU and LV).¹⁹ In that study, 774 patients, with a median age of 63 years, were treated with UFT/LV. Grade 3 to 4 diarrhea rate was 29%, with an overall grade 3 to 4 nonhematologic toxicity rate of 38%. This toxicity profile is similar to our results in a much older patient population. Jensen et al²⁰ performed another study aiming to test the feasibility of chemotherapy compared across age groups using either capecitabine or capecitabine and oxaliplatin. These investigators also found nonsignificant trends toward increased toxicity (largely neuropathy and low-grade infection not associated with neutropenia) in the population older than age 70 years (n = 57). They also noted a surprising benefit in the oldest age group ( 75 years; response rate of 72% v 31% for younger patients; P = .0006), albeit patient numbers were small (n = 18). Bennouna et al²¹ reported a phase II study of UFT/LV with oxaliplatin obtaining a response rate of 34% and median survival time of 18 months. Capecitabine and oxaliplatin in the elderly showed a 36% response rate and a median survival time of 13.2 months, which was comparable to our results with single-agent fluoropyrimidine.²²

In conclusion, our study of elderly patients is consistent with previous findings that oral UFT/LV is a tolerable and effective regimen in the general colorectal cancer patient. It can be used in elderly patients 75 years old, preserving the activity of fluoropyrimidine therapy with less toxicity than seen with daily x 5 bolus FU and LV (Mayo Regimen) or capecitabine, which is associated with a notable incidence of hand-foot syndrome. Newer fluoropyrimidines such as S-1 are currently in development within the United States and Europe and may be useful in this group of patients as a platform for use of biologic and targeted agents. Our future plans include such studies in the same age group, with greater focus on functional status evaluation and quality of life.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Al Bowen Benson, Bristol-Myers Squibb Co Stock: N/A Honoraria: N/A Research Funds: Howard S. Hochster, Bristol-Meyers Squibb Co; Al Bowen Benson, Bristol-Myers Squibb Co Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Howard S. Hochster, Al Bowen Benson

Administrative support: Weixiu Luo, Al Bowen Benson

Provision of study materials or patients: Howard S. Hochster, Bruce T. Lyman, Mary Mulcahy, Peter A. Beatty

Collection and assembly of data: Howard S. Hochster, Elizabeta C. Popa

Data analysis and interpretation: Howard S. Hochster, Weixiu Luo, Elizabeta C. Popa

Manuscript writing: Howard S. Hochster, Elizabeta C. Popa

Final approval of manuscript: Howard S. Hochster, Bruce T. Lyman, Mary Mulcahy, Peter A. Beatty, Al Bowen Benson

	NOTES

 
Supported by Grants No. CA23318, 66636, 21115, 11083, 17145, 21076, and 16087 from the National Institutes of Health.

Presented in part at 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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12. Carmichael J, Popiela T, Radstone D, et al: Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3617-3627, 2002[Abstract/Free Full Text]

13. Nogue M, Salud A, Batiste-Alentorn E, et al: Randomized study of tegafur and oral leucovorin versus intravenous 5-fluorouracil and leucovorin in patients with advanced colorectal cancer. Eur J Cancer 41:2241-2249, 2005[CrossRef][Medline]

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19. Lembersky BC, Wieland S, Petrelli N, et al: Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: Results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol 24:2059-2064, 2006[Abstract/Free Full Text]

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Submitted December 23, 2006; accepted August 8, 2007.

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