Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction

G. F. Fleming1,2,+, R. L. Schilsky1,2, L. P. Schumm2, A. Meyerson3, A. M. Hong3, N. J. Vogelzang1,2 and M. J. Ratain1,2,4

1 Department of Medicine, University of Chicago Medical Center; 2 University of Chicago Cancer Research Center; 3 University of Chicago Pritzker School of Medicine; 4 University of Chicago Committee on Clinical Pharmacology, Chicago, IL, USA

Received 24 September 2002; revised 28 February 2003; accepted 26 March 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Patients with hepatic or renal dysfunction are often treated with 5-fluorouracil (5-FU), but there are few data to confirm the safety of this practice.

Patients and methods:

Patients with solid tumors were eligible if they were able to fit into one of three organ dysfunction cohorts: I, creatinine >1.5 but <=3.0 mg/dl and normal bilirubin; II, bilirubin >1.5 but <5.0 mg/dl with normal creatinine; or III, bilirubin >=5.0 mg/dl with normal creatinine. 5-FU doses were escalated separately within each of the three cohorts. Leucovorin (LV) dosage was fixed at 500 mg/m2. 5-FU was given as a 24-h infusion at 1000, 1800 or 2600 mg/m2, and plasma concentrations were measured every 3 h during the first two infusions for each patient.

Results:

Sixty-four patients were treated. Toxicities did not appear to be related to organ dysfunction cohort. A weekly dose of of 5-FU 2600 mg/m2 produced dose-limiting toxicity (DLT) in six of 20 evaluable patients.These DLTs included grade 3 fatigue (n = 3), grade 2 neutropenia precluding weekly dosing (n = 1), grade 3 thrombocytopenia (n = 1) and grade 3 mental status changes (n = 1). There was no relationship between serum bilirubin or serum creatinine and 5-FU clearance.

Conclusions:

Patients with elevated bilirubin may be safely started on a weekly regimen of 5-FU 2600 mg/m2 with leucovorin 500 mg/m2 as a 24-h continuous infusion.

Key words: 5-fluorouracil, hepatic dysfunction, leucovorin, pharmacokinetics, 24-h infusion


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
5-Fluorouracil (5-FU) is a fluorinated pyrimidine analog used for the treatment of common solid tumors, including breast, colorectal, and head and neck carcinomas. Leucovorin (LV) is a reduced folate that potentiates the activity of 5-FU by increasing the amount of intracellular 5–10 methylene tetrahydrofolate (CH2FH4) and thereby stabilizing the ternary complex formed by thymidylate synthase and fluorodeoxyuridine monophosphate (5-FdUMP) [1]. 5-FU and LV can be administered on many schedules. A weekly 24-h i.v. infusion of 5-FU 2600 mg/m2 given concurrently with LV 500 mg/m2 has been shown to be an effective and tolerable treatment for patients with metastatic colorectal carcinoma who have normal renal and hepatic function. The toxicities occurring in the phase II trial using this regimen were predominately diarrhea, stomatitis and hand–foot syndrome [2].

The toxicities of 5-FU have been reported to increase with increased 5-FU plasma levels and area under the concentration versus time curve (AUC) [35]. Approximately 90% of a dose of 5-FU is eliminated by metabolism, and only a small percentage undergoes renal excretion. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in 5-FU catabolism [6]. DPD is found in the liver, gastrointestinal tract and tissues throughout the body. It could therefore be hypothesized that no reduction in 5-FU dose needs to be made for patients with hepatic or renal dysfunction. However, a significant portion of 5-FU degradation does take place in the liver [7]. Moreover, it has been reported that patients with clinically evident hepatic metastases have significantly higher plasma levels of 5-FU than patients without liver metastases [8] and that patients with liver metastases associated with jaundice encounter severe toxicity when treated with full doses of 5-FU [9].

We therefore undertook a phase I and pharmacokinetic trial of a 24-h continuous i.v. infusion of 5-FU with leucovorin in patients with elevated bilirubin or mild renal dysfunction to determine the tolerability of this treatment, and to determine whether elevated bilirubin or creatinine affect 5-FU pharmacokinetics in the dose ranges studied. Since it has been reported that drug levels of 5-FU given by continuous i.v. infusion vary significantly over time [1012], we measured 5-FU plasma levels every 3 h.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient eligibility
Adult patients (>=18 years) with a histologically confirmed solid tumor that had not responded to standard treatment, for which no standard treatment existed, or for which treatment had been withheld due to elevated bilirubin or creatinine levels, were eligible for this study. Other eligibility criteria included WHO performance status 0–2, life expectancy >=2 months and measurable or evaluable disease. At least 4 weeks were to have elapsed since prior antineoplastic chemotherapy, hormonal therapy, or radiation therapy, and at least 8 weeks since administration of mitomycin or nitrosoureas. Other eligibility criteria were absolute neutrophil count >=500/µl, platelet count >=100 000/µl and hemoglobin >=8 g/dl. Patients had to fit into one of three organ dysfunction groups: cohort I, creatinine >1.5 mg/dl (133 µmol/l) but <=3.0 mg/dl (265 µmol/l), and normal bilirubin (high creatinine group); cohort II, bilirubin >1.5 mg/dl (26 µmol/l) but <5.0 mg/dl (86 µmol/l), with normal creatinine (intermediate bilirubin group); or cohort III, bilirubin >=5.0 mg/dl (86 µmol/l) with normal creatinine (high bilirubin group). Exclusion criteria included concomitant use of steroids or dipyridamole, significant cerebellar dysfunction or uncontrolled angina, and brain metastases, unless the patient was asymptomatic and off all therapy. An implanted or tunneled central venous catheter was required. The University of Chicago Institutional Review Board approved the protocol. Written informed consent was obtained from all patients enrolled in the study.

Treatment
For inpatients 5-FU was mixed together with LV 500 mg/m2 in 5% dextrose 1000 ml in water and administered i.v. over 24 h. Portable infusion pumps were used for outpatients, and 5-FU and LV were run through separate lines to avoid solubility problems when the drugs were administered in small volumes. Antiemetic therapy was not specified; this trial was initiated prior to the commercial availability of 5HT3 antagonists. Treatments were repeated weekly. Four weekly treatments constituted one cycle.

Doses or dose levels were not changed based on subsequent changes in bilirubin or creatinine. Patients with external biliary drainage catheters were eligible, and continued on study at the same dose even if their bilirubin levels normalized subsequently. Otherwise, each weekly treatment required the same laboratory parameters as the initial treatment, and all treatment-related toxicities except alopecia and anemia must have resolved or be grade <=1 or the subsequent treatment was delayed and the 5-FU dose permanently reduced by 400 mg/m2 (200 mg/m2 if at dose level 1). Patients with grade 4 myelosuppression or mucositis, or grade 3 non-hematological toxicity were also treated with a 5-FU 400 mg/m2 dose reduction. Patients with grade 4 toxicities other than myelosuppression or mucositis were removed from the study. Patients who required more than one dose reduction were removed from the study. Changes in bilirubin or creatinine were not treated as toxicity unless regarded by the treating physician as being probably or definitely caused by therapy.

The first two infusions were administered in the Clinical Research Center at the University of Chicago. To eliminate potential confounding by any circadian variation in 5-FU toxicity or plasma levels, the starting time for the first infusion was randomly assigned to be either 6 a.m. or 6 p.m. The starting time for the second infusion was the alternate time point. Blood was obtained every 3 h for measurement of 5-FU plasma concentrations. Subsequent doses could be administered in either the inpatient or outpatient setting at the discretion of the treating physician. A complete blood count with differential count was required weekly while the patient was on study. Electrolytes, creatinine, bilirubin and liver function tests were repeated weekly just prior to each treatment during the first 4 weeks of therapy and monthly thereafter. In this analysis, assignment to a treatment cohort is based on the creatinine and bilirubin values obtained just prior to (same day of) the first 5-FU dose.

Response was not a primary end point of the study, and measurable disease was not an eligibility requirement. However, disease status was reassessed after every eight 5-FU infusions (two cycles). Complete response was defined as disappearance of all clinical and laboratory signs and symptoms of disease for a minimum of 1 month. Partial response was defined as a >=50% reduction in the sum of the products of the longest perpendicular diameters of all measured lesions lasting for a minimum of 1 month. Minor response was defined as a 25–49% decrease in the sum of the products of the longest perpendicular diameters of all measured lesions lasting for at least 1 month, or objective but incomplete response in patients with nonmeasurable disease and with no lesion growth or new lesions. Progressive disease was a >25% increase in sum of the products of the longest perpendicular diameters of all measured indicator lesions compared with the smallest previous measurement or appearance of new lesions. Stable disease was disease not meeting criteria for response or progression.

Dose escalation
Initial 5-FU doses were the same for all organ dysfunction groups. Dose escalation proceeded as follows: level 1, 1000 mg/m2; level 2, 1800 mg/m2 and level 3, 2600 mg/m2. Doses did not exceed 2600 mg/m2, as this is the recommended 5-FU dose for this regimen in patients with normal hepatic and renal function [2]. For the most part, each organ dysfunction group was to be separately dose escalated. However, if patients in the high bilirubin group were safely escalated to a higher dose level than those in the intermediate bilirubin group, subsequent intermediate bilirubin patients were to be treated at the dose level to which the high bilirubin group was accruing. Doses could be escalated in a given patient if the next higher dose level had been shown to be tolerable in at least three patients of the same cohort, but no patients were actually dose escalated.

At least three patients were treated at each 5-FU dose level. All three were to have completed at least four treatments plus 1 week of observation before patients could be entered at the next higher dose level. The Cancer and Leukemia Group B common toxicity criteria were used, and dose-limiting toxicity (DLT) was defined as any grade 3 or 4 toxicity (excluding anemia) in cycle one or inability to receive one of the first four doses on schedule. If one of the first three patients at a dose level had a DLT, then three more patients were treated at that dose level; at least six patients were to be treated at the recommended phase II dose in each organ dysfunction cohort. The recommended phase II dose was the highest dose level tested at which <=1 patients had grade 4 toxicity and <=2 patients had grade 3 or higher toxicity.

5-FU plasma concentrations
Seven to ten ml of blood were drawn into a heparinized tube at baseline and then every 3 h during the first two 24-h infusions. Samples were centrifuged promptly, and the plasma was removed and stored at –80°C until high-performance liquid chromotography assay. A modification of a standard assay was used [13]. In brief, proteins (plasma 1 ml) were precipitated with trichloroacetic acid 100 µl and the supernatant was extracted with ethyl acetate 8 ml. The sample was then dried with nitrogen and reconstituted with 0.1 N sodium hydroxide 220 µl. Samples (30 µl) were injected on two Beckman Ultrasphere ODS columns (inside diameter 4.6 ml and length 25 cm) that were connected in series. The mobile phase was sodium perchlorate 3 mM, pH 3, at 1.2 ml/min. The internal standard was 0.1 M bromouracil 100 µl with a detection wavelength of 254 nm. The lower limit of quantitation was 55.4 ng/ml.

Statistical and pharmacokinetic analysis
Patient characteristics, number of doses received and the incidence of DLT were summarized separately by organ dysfunction cohort, as defined by serum bilirubin and creatinine measured on the first day of 5-FU infusion. For the first two doses, the area under the 5-FU concentration–time curve (AUC) was computed using the linear trapezoidal rule. Since some of the 24-h samples were taken following the end of the infusion (and are therefore lower than they would have been during the infusion), all 24-h values were replaced with the average of the prior values for that dose, and the AUC following 24 h was ignored. 5-FU clearance was computed as (total dose)/AUC, and is reported in ml/min. Clearance was then regressed on serum bilirubin and creatinine, 5-FU dose, body surface area (BSA), gender, age, serum albumin and performance status [14]. Creatinine clearance (as estimated using the Cockcroft–Gault formula) [15] was also tried in place of serum creatinine. These models were initially fit to the data from the first dose only, but were then fit to the data from both doses using bilirubin and creatinine measured prior to the second infusion for the corresponding observations. The latter models were specified as marginal regression models, and were fit using the generalized estimating equations approach with the ‘robust’ (i.e. sandwich) variance estimator due to the correlation between clearances from the same patient [16].

All computations were performed using the Stata statistical software package, release 7.0 [17]. All reported P values are two-sided.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Between August 1991 and March 1998, 64 patients were enrolled onto this study. During the days between registration and treatment initiation, two patients initially assigned to cohort I experienced a decline in creatinine to below 1.5 mg/dl, and three patients initially assigned to cohort II experienced a decline in bilirubin to below 1.5 mg/dl. In addition, three patients initially assigned to cohort II became eligible for cohort III (had a rise in bilirubin), and one cohort III patient had a fall in bilirubin and was re-assigned to cohort II. The five patients who no longer fit into one of the organ dysfunction cohorts have been grouped into a fourth cohort for purposes of presentation; all other patients are included in the cohort they qualified for immediately prior to the start of their first infusion.

Table 1 shows patient characteristics summarized by cohort, and Table 2 shows the diagnoses of all patients enrolled in the study. Patients in cohort III (bilirubin >=5.0 mg/dl) tended to have a poorer performance status and less prior therapy than patients in the other two cohorts. Forty-three of the 59 patients who fit into cohort I, II or III were considered evaluable for toxicity, meaning that they either completed at least four consecutive doses of treatment or experienced a DLT (Table 3). The remaining 16 patients were removed from study therapy for reasons unrelated to toxicity prior to having completed four weekly treatments. Most had progressive disease or died of disease. No deaths among any of the 64 patients were attributed to therapy.


View this table:
[in this window]
[in a new window]
 
Table 1. Patient characteristics
 

View this table:
[in this window]
[in a new window]
 
Table 2. Patient diagnoses
 

View this table:
[in this window]
[in a new window]
 
Table 3. Treatment cohorts
 
The distribution of patients and DLTs within each cohort by dose level is shown in Table 3. There was no apparent difference in the likelihood of DLT observed across the three organ dysfunction cohorts. There was also no increase in the likelihood of DLT with poor performance status. A logistic regression of DLT on performance status controlling for dose yielded a P-value of 0.197. The primary toxicities for the 10 patients with DLT are shown in Table 4. Although several of these toxicities were low grade, they did not resolve in time to permit weekly dosing for the first four doses. Only two of the 10 patients with DLT stayed on study, one receiving a dose reduction. The patient in cohort III at the 2600 mg/m2 dose level with grade 3 fatigue did not have his dose reduced, as the treating physician did not attribute the fatigue to study therapy. Attribution of toxicities in this group of patients was sometimes difficult. In particular, the two patients suffering thrombocytopenia in cohort III died within 2 weeks of being removed from study and had other indications of progressive hepatic failure, including increased prothrombin time and increasing somnolence. Their deaths were attributed to liver replacement by tumor. Table 5 shows worst toxicity in any cycle for all patients treated.


View this table:
[in this window]
[in a new window]
 
Table 4. Dose-limiting toxicities
 

View this table:
[in this window]
[in a new window]
 
Table 5. Toxicities among all 64 patients treated
 
Two patients achieved minor responses, one with bladder cancer and one with pancreatic cancer. Both were treated at 1800 mg/m2.

Pharmacokinetics
Maximum 5-FU concentration, AUC and clearance for the first two doses are summarized in Table 6, and are comparable to published data for a 24-h 5-FU infusion at these doses [6]. In a multivariate regression model including dose level, gender, age, BSA, performance status and serum albumin, only BSA was correlated with clearance at the 0.05 level; an increase in BSA of 0.1 m2 was associated with an increase in clearance of 201 ml/min (P = 0.028).


View this table:
[in this window]
[in a new window]
 
Table 6. Summary of 5-fluorouracil pharmacokinetics; mean (SD)
 
Controlling for BSA only, there was no statistical evidence of a relationship between clearance and either serum bilirubin (P = 0.517) or creatinine (P = 0.396). Replacing serum creatinine with estimated creatinine clearance (ml/min) also failed to yield a statistically significant effect (P = 0.287). The apparent increase in clearance in the two higher dose levels in Table 6 is substantially reduced and not statistically significant when controlling for BSA (P = 0.581).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Fatigue and thrombocytopenia were the most common serious toxicities in our trial, which contrasts with the mucositis and hand–foot syndrome reported in the phase II trial of this regimen. It is possible that patients with hepatic dysfunction are more susceptible to this type of toxicity, although one case of dose-limiting fatigue and two cases of dose-limiting thrombocytopenia were observed in the renal dysfunction cohort (with normal hepatic function). Other investigators using slight variations on 24-h infusion 5-FU plus LV regimens have also reported fatigue and sporadic leukopenia [18, 19].

We have shown that patients with mildly elevated creatinine or elevated bilirubin tolerate usual doses (2600 mg/m2) of 5-FU administered concurrently with LV 500 mg/m2 as a 24-h continuous infusion. We found no evidence of a correlation between either bilirubin level or creatinine level and 5-FU clearance. While we did not study patients with both normal liver and normal renal function, the fact that bilirubin level over a very wide range of values had no discernible effect on 5-FU concentrations suggests that levels in patients with elevated bilirubin will be similar to those seen in patients with normal organ function. Although it is possible for a group of patients to suffer more toxicity for reasons other than increased plasma drug concentrations, we saw no evidence that patients with a higher bilirubin or creatinine level were more likely to suffer toxicity.

The increase in 5-FU clearance with increasing BSA is consistent with that observed by other investigators. Gusella et al. [20] and Port et al. [21] both examined the relationship between body surface area and 5-FU pharmacokinetics using a bolus dosing schedule, and found significant correlations between BSA and clearance [20, 21]. This is compatible with the hypothesis that 5-FU undergoes extensive extra-hepatic drug metabolism that may be increased in larger individuals, and is consistent with our findings that liver dysfunction does not appear to impact significantly on 5-FU pharmacokinetics. For this drug, unlike agents for which there is no association between body weight or BSA and clearance, an increase in dose for patients of increasing size (as is usual clinical practice) remains appropriate.

Creatinine clearance was not used for determining eligibility and the degree of renal dysfunction in the ‘high creatinine’ group could vary. For example, using the Cockroft–Gault formula, a hypothetical 70-year-old woman, 60 kg (weight), 160 cm (height) with a creatinine of 3 mg/dl (the upper limits of eligibility), would have an estimated creatinine clearance of 16.5 ml/min (or 10 ml/min/m2). The actual range of creatinine values for patients entered on the renal dysfunction cohort of this trial was 1.6–2.6 mg/dl, with a median of 2.1 mg/dl. Renal clearance is not of major importance in the metabolism of 5-FU, but our data do not allow us to comment on the safety of this regimen in patients with severe renal dysfunction.

Our trial also did not examine tolerance of patients to standard 5-FU doses on a bolus schedule. It is well known that the pharmacokinetics of bolus 5-FU are dose-dependent, with lower clearance at higher doses and with shorter infusion times. Much higher peak plasma levels are achieved with a bolus dose of 5-FU, and the effects of organ dysfunction might be more detectable.

It is already fairly common to treat patients who have an elevated bilirubin level with standard doses of continuous-infusion 5-FU. Our large sample confirms the appropriateness of and provides pharmacokinetic rationale for this practice.


    Acknowledgements
 
This work was supported in part by grants GCRC MO1 RR00055, 3MO1 RR00055–33S1 and CA 14599.


    Footnotes
 
+ Correspondence to: Dr G. F. Fleming, University of Chicago Medical Center, Section of Hematology/Oncology, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637-1470, USA. Tel: +1-773-702-6712; Fax: +1-773-702-0963; E-mail: gfleming{at}medicine.bsd.uchicago.edu Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Keyomarsi K, Moran RG. Folinic acid augmentation of the effects of fluoropyrimidines on murine and human leukemic cells. Cancer Res 1986; 46: 5229–5235.[Abstract]

2. Ardalan B, Chua L, Tian EM et al. A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma. J Clin Oncol 1991; 9: 625–630.[Abstract]

3. Remick SC, Grem JL, Fischer PH et al. Phase I trial of 5-fluorouracil and dipyridamole administered by seventy-two-hour concurrent continuous infusion. Cancer Res 1990; 50: 2667–2672.[Abstract]

4. Thyss A, Milano G, Renee N et al. Clinical pharmacokinetic study of 5-FU in continuous 5-day infusions for head and neck cancer. Cancer Chemother Pharmacol 1986; 16: 64–66.[ISI][Medline]

5. van Groeningen CJ, Pinedo HM, Heddes J et al. Pharmacokinetics of 5-fluorouracil assessed with a sensitive mass spectrometric method in patients on a dose escalation schedule. Cancer Res 1988; 48: 6956–6961.[Abstract]

6. Grem JL. 5-Fluoropyrimidines. In Chabner BA, Longo DL (eds): Cancer Chemotherapy and Biotherapy, 2nd edition. Philadelphia, PA: Lippincott-Raven 1996; 146–211.

7. Tateishi T, Watanabe M, Nakura H et al. Dihydropyrimidine dehydrogenase activity and fluorouracil pharmacokinetics with liver damage induced by bile duct ligation in rats. Drug Metab Dispos 1999; 27: 651–654.[Abstract/Free Full Text]

8. Floyd RA, Hornbeck CL, Byfield JE et al. Clearance of continuously infused 5-fluorouracil in adults having lung or gastrointestinal carcinoma with or without hepatic metastases. Drug Intell Clin Pharm 1982; 16: 665–667.[ISI][Medline]

9. Ansfield FJ, Schroeder JM, Curreri AR. Five years clinical experience with fluorouracil. JAMA 1962; 181: 295–299.[ISI]

10. Petit E, Milano G, Levi F et al. Circadian rhythm-varying plasma concentration of 5-fluorouracil during a five-day continuous venous infusion at a constant rate in cancer patients. Cancer Res 1988; 48: 1676–1679.[Abstract]

11. Harris BE, Song R, Soong SJ, Diasio RB. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res 1990; 50: 197–201.[Abstract]

12. Metzger G, Massari C, Etienne MC et al. Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin: relationship with mucosal toxicity in patients with cancer. Clin Pharmacol Ther 1994; 56: 190–201.[ISI][Medline]

13. Vokes EE, Schilsky RL, Choi KE et al. A randomized study of inpatient versus outpatient continuous infusion chemotherapy for patients with locally advanced head and neck cancer. Cancer 1989; 63: 30–36.[ISI][Medline]

14. Weisberg S. Applied Linear Regression, 2nd edition. New York: John Wiley & Sons 1985; 33–63.

15. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41.[ISI][Medline]

16. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986; 73: 13–22.[ISI]

17. StataCorp. Stata Statistical Software. Release 7.7. College Station, TX: Stata Corporation 2001.

18. Kohne CH, Schoffski P, Wilke H et al. Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: results of a randomized trial in patients with advanced colorectal cancer. J Clin Oncol 1998; 16: 418–426.[Abstract]

19. Yang TS, Hsu KC, Chiang JM et al. A simplified regimen of weekly high dose 5-fluorouracil and leucovorin as a 24-hour infusion in patients with advanced colorectal carcinoma. Cancer 1999; 85: 1925–1930.[CrossRef][ISI][Medline]

20. Gusella M, Toso S, Ferrazzi E et al. Relationships between body composition parameters and fluorouracil pharmacokinetics. Br J Clin Pharmacol 2002; 54: 131–139.[CrossRef][ISI][Medline]

21. Port RE, Daniel B, Ding RW, Herrmann R. Relative importance of dose, body surface area, sex, and age for 5-fluorouracil clearance. Oncology 1991; 48: 277–281.[ISI][Medline]





This Article
Abstract
Full Text (PDF)
E-letters: Submit a response
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (2)
Disclaimer
Request Permissions
Google Scholar
Articles by Fleming, G. F.
Articles by Ratain, M. J.
PubMed
PubMed Citation
Articles by Fleming, G. F.
Articles by Ratain, M. J.