Schedule dependency for fluorinated
pyrimidine-based therapy has been an issue since Ansfields
early investigations. Until very recently, the pharmacologic
armamentarium against colorectal cancer was extremely limited.
Because single-agent 5-fluorouracil (5-FU) has been the mainstay in
treatment of this disease, much of the clinical study of this drug
has occurred in the setting of colorectal cancer. Consequently,
clinical trials of 5-FUbased regimens for disseminated
colorectal cancer have focused on biochemical modulation and schedule
dependency as a means of enhancing therapeutic efficacy.
Mechanism of Action
A major mechanism of 5-FU action is inhibition of thymidylate
synthase activity by competitive binding of F-dUMP (5-fluorodeoxyuridine
monophosphate) with the dUMP binding site on the enzyme molecule,
thus inhibiting the rate-limiting step for thymidine and, therefore,
DNA synthesis. This process is cell-cycle (S-phase) specific, making
drug activity irregular against the sensitive portion of the tumor
cell population. Potential for cytotoxic activity is further impaired
by the rapid catabolic rate for the drug, reflected in the short
plasma half-life of 10 to 20 minutes, when given as a bolus injection.[2,3]
5-FU has also been shown experimentally and in clinical trials to
function as a radiation sensitizer. In this setting, short half-life,
overlapping toxicities, and enhanced toxicity with the addition of
modulators have additional therapeutic implications. Furthermore, in
the disseminated disease setting, where palliation is a goalin
addition to enhancement of response rates, time-to-progression, and
survivalthe issue of type and degree of toxicity is an
To increase tumor cellkill and response rates in the
disseminated disease setting and to project the best regimen for
eradication of micrometastases in the adjuvant setting, dose
intensity may be important in determining the schedule for optimal
drug delivery. Dose intensity is defined as the amount of drug
delivered per unit of time, typically reported as milligrams per
square meter per week or per 28 days, regardless of the schedule
used. A dose-intense regimen may or may not be associated with
high peak drug levels. Continuous administration of chemotherapeutic
regimens may be quite dose-intensive but may also be associated with
lower peak concentrations. Acceptability of dose-intense regimens
is dependent on the degree of toxicity encountered, which, in turn,
may depend on whether the goal of therapy is palliative or curative.
Drug metabolism and catabolism also need to be taken into account in
the design of dose-intense chemotherapy regimens.
For the standard Mayo daily times 5, once-a-month regimen of 5-FU
plus low-dose calcium folinate being used in both adjuvant and
disseminated settings, a 5-FU dose of 375 to 425 mg /m² yields a
28-day dose of 1,900 to 2,100 mg/m². For the Roswell Park weekly
regimen of 500 mg/m² of 5-FU with high-dose calcium folinate
administered for 6 of 8 weeks in the same settings, a 28-day dose of
1,500 mg/m² is received. For continuous infusions of 5-FU, 200
to 300 mg/m²/day, with or without calcium folinate, the
comparable 28-day dose is 5,600 to 8,400 mg/m², and for the
intermittent, weekly, high-dose 24-hour infusion of 2,600 mg/m²,
the 28-day dose is 10,400 mg/m². These doses are contingent on
no dose reduction, so the additional question is raised of what
relative percentage of patients receiving each regimen will
experience a degree of toxicity requiring dose reduction.
In the face of an obvious dose-intensity advantage conferred by the
infusional regimens, it is noteworthy that we fail to see comparable
differences in activity. Is the explanation that there is a maximum
dose intensity of 5-FU beyond which no further clinical activity is
achieved? Dose intensity is based on area under the
concentration-time curve for plasma pharmacokinetics. As such, is the
constant level of drug for diffusion into the cell, which
characterizes the infusional regimens, balanced by ternary complex
formation and degree of intracellular polyglutamylation of bolus
regimens administered with calcium folinate? Or, do other factors,
such as intratumor levels of thymidylate synthase or mutations of
oncogenes and tumor suppressor genes, ultimately override both dose
intensity and biochemical modulation in determination of response?
The value of altering the schedule of or biochemically modulating
5-FU was tested in phase I and II trials designed to identify
intravenous and oral doses of calcium folinate for addition to
continuous infusion 5-FU.[7,8] Toxicities
encounteredpredominantly plantar-palmar erythrodysesthesia
(hand-foot syndrome) and stomatitiswere of higher grade and
earlier onset than those that occurred with single-agent 5-FU,
resulting in a net reduction in dose intensity of 5-FU. The question
remained, however, about the relative roles of biochemical modulation
vs schedule dependency. To answer this question, the Southwest
Oncology Group (SWOG)  conducted a phase II trial in which more
than 600 patients were randomized over a 3-year period to paired
regimens of bolus (daily times 5, once a month; weekly) and
infusional (protracted low-dose; weekly high-dose) 5-FU, with and
without biochemical modulators (calcium folinate, PALA [N-phosphoroacetyl-L-aspartic
acid]). None of the regimens tested demonstrated a statistical
superiority for either response or survival. Response rates ranged
from 15% to 29%; median survival ranged from 11 to 15 months.
In a subsequent phase III trial conducted by the Eastern Cooperative
Oncology Group (ECOG), investigators randomly assigned more than
1,100 patients to five treatment arms of 5-FU given by weekly bolus
or weekly infusion, with or without modulation (intravenous or oral
calcium folinate, PALA, or a-interferon). Again, no regimen
demonstrated statistically superior activity over the others. Median
survival was nearly identical to that in the Southwest Oncology Group
trial, ranging from 13 to 15 months.
In both of these trials, the infusion arms demonstrated a lower
percentage of grades 3 and 4 toxicity. Furthermore, the pattern of
dominant toxicitiesie, stomatitis and hand-foot
syndromeallows for earlier intervention with careful patient
observation, thus avoiding higher toxicity grades with consequent
extensive dose reduction. Given the inherent increased dose and the
less frequent dose reduction encountered, the dose-intensity
advantage persists for these arms. Though not reaching statistical
significance, in the SWOG trial a trend toward response and survival
benefit was seen for the single-agent 5-FU infusion arms (Figure
1, Figure 2, and Figure
The Meta-Analysis Group in Cancer examined data from seven
international randomized trials that included com-
parable bolus and infusion regimens, with or without calcium folinate
modulation. Pooled data demonstrated a statistically significant
response advantage for continuous-infusion 5-FU compared with bolus
5-FU (Table 1). A small
survival advantage was also detected for the infusion treatment (Table
2). Differences were less obvious when both methods of 5-FU
administration were modulated by calcium folinate. As expected,
toxicity patterns differed between bolus and infusion regimens.
In addition to response, survival, and toxicity analyses, the issue
of comparative costs has become important in todays
increasingly controlled medical market. A major component of cost
differential between these two modes of drug administration is the
up-front cost of catheter placement. When amortized over the course
of treatment, this cost, along with pump rental charges, tends to
lessen the cost differences over time, particularly for those
patients who respond to therapy. The expense of calcium folinate used
with the bolus regimens may also serve to offset differences when
compared with single-agent infusion regimens.[12,13]
Treatment of toxicity related to the different therapeutic regimens
also needs to be included in this analysis: hospitalization for
dehydration and neutropenic sepsis is more commonly required for
calcium folinatemodulated bolus 5-FU schedules, whereas the
expense of treating catheter infections and thromboses needs to be
figured into the analyses for infusional regimens. These analyses are
difficult to accurately perform, as regional differences in the cost
of medical services also enter the equation. The Meta-Analysis Group
in Cancer is currently undertaking this task for the patients
included in the report cited above.
1. Ansfield F, Klotz J, Nealon T, et al: A phase III study comparing
the clinical utility of four regimens of 5-fluorouracil: A
preliminary report. Cancer 39:34-40, 1977.
2. Danenberg PV, Lockshin A: Fluorinated pyrimidines as tight-binding
inhibitors of thymidylate synthase. Pharmacol Ther 13:69-90, 1981.
3. Calabro-Jones PM, Byfield JE, Ward JF: Time-dose relationships for
5-fluorouracil cytotoxicity against human epithelial cancer cells in
vitro. Cancer Res 42:4413-4420, 1982.
4. Byfield JE: The clinical use of 5-fluorouracil and other
halopyrimidines as radiosensitizers in man, in: Lokich JJ (ed):
Cancer Chemotherapy by Infusion. Chicago, Precept Press, 1987.
5. Hryniuk WM, Bush H: The importance of dose intensity in
chemotherapy of breast cancer. J Clin Oncol 2:1281-1288, 1984.
6. Savarese DMF, Hsieh C, Stewart FM: Clinical impact of chemotherapy
dose escalation in patients with hematologic malignancies and solid
tumors. J Clin Oncol 15:2981-2995, 1997.
7. Leichman CG, Leichman L, Spears CP, et al: Biological modification
of protracted infusion 5-fluorouracil with disseminated
gastrointestinal cancers. Cancer Chemother Pharmacol 26:57-61, 1990.
8. Tempero M, Berg A, Block M, et al: A phase II trial of protracted
therapy with 5-fluorouracil and leucovorin in metastatic colorectal
cancer (abstract). Proc Am Soc Clin Oncol 12:594, 1993.
9. Leichman CG, Fleming TR, Muggia FM, et al: Phase II study of
fluorouracil and its modulation in advanced colorectal cancer: A
Southwest Oncology Group study. J Clin Oncol 13:1303-1311, 1995.
10. ODwyer PJ, Ryan LM, Valone FH, et al: Phase III trial of
biochemical modulation of 5-fluorouracil by IV or oral leucovorin or
by interferon in advanced colorectal cancer: An ECOG/CALGB phase III
trial (abstract). Proc Am Soc Clin Oncol 15:469, 1996.
11. Meta-Analysis Group in Cancer: Efficacy of intravenous continuous
infusion of fluorouracil compared with bolus administration in
advanced colorectal cancer. J Clin Oncol 16:301-308, 1998.
12. Lokich JJ, Moore CL, Anderson NR: Comparison of costs for
infusion versus bolus chemotherapy administration: Analysis of five
standard chemotherapy regimens in three common tumorsPart one.
Model projections for cost based on charges. Cancer 15:294-299, 1996.
13. Buroker TR, OConnell MJ, Wieand HS, et al: Randomized
comparison of two schedules of fluorouracil and leucovorin in the
treatment of advanced colorectal cancer. J Clin Oncol 12:14-20, 1994.
14. Poplin EA, Jacobson J, Herskovic A, et al: Evaluation of
multimodality treatment of locoregional esophageal carcinoma by
Southwest Oncology Group 9060. Cancer 78:1851-1856, 1996.
15. Urba S, Orringer M, Turrisi A, et al: A randomized trial
comparing surgery (S) to preoperative concomitant chemoradiation plus
surgery in patients (pts) with resectable esophageal cancer (CA):
Updated analysis (abstract). Proc Am Soc Clin Oncol 16:983, 1997.
16. Wibault P, Bensmaine MA, de Forni M, et al: Intensive concomitant
chemoradiotherapy in locally advanced unresectable squamous cell
carcinoma of the head and neck: A phase II study of radiotherapy with
cisplatin and 7-week continuous infusional fluorouracil. J Clin Oncol
17. Olver IN, Hughes PG, Smith JG, et al: Concurrent radiotherapy and
continuous ambulatory infusion 5-fluorouracil in advanced head and
neck cancer. Eur J Cancer 32:249-254, 1996.
18. Formenti SC, Dunnington G, Lenz H, et al: Original p53 status
predicts for pathological response to 5-fluorouracil and radiation in
locally advanced breast cancer (abstract). Proc Am Soc Clin Oncol
19. OConnell MJ, Martenson JA, Wieand HS, et al: Improving
adjuvant therapy for rectal cancer by combining protracted-infusion
fluorouracil with radiation therapy after curative surgery. N Engl J
Med 331:502-507, 1994.
20. DiCostanzo F, Gasperoni S, Malacarne P, et al: High-dose folinic
acid and 5-fluorouracil alone or combined with hydroxyurea in
advanced colorectal cancer: A randomized trial of the Italian
Oncology Group for Cancer Research. Am J Clin Oncol 21:369-375, 1998.
21. Hartmann JT, Kohne CH, Schmoll HJ, et al: Is continuous 24-hour
infusion of 5-fluorouracil plus high-dose folinic acid effective in
patients with progressive or recurrent colorectal cancer? A phase II
study. Oncology 55:320-325, 1998.
22. Nobile MT, Barzacch MC, Sanguinetti O, et al: Activity of high
dose 24 hour 5-fluorouracil infusion plus L-leucovorin in advanced
colorectal cancer. Anticancer Res 18:517-521, 1998.
23. 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 16:418-426, 1998.
24. Klaassen U, Wilke H, Weyhofen R, et al: Phase II study with
cisplatin and paclitaxel in combination with weekly high-dose 24 h
infusional 5-fluorouracil/leucovorin for first-line treatment of
metastatic breast cancer. Anticancer Drugs 9:203-207, 1998.
25. Cheng AL, Yeh KH, Lin JT, et al: Cisplatin, etoposide and weekly
high-dose 5-fluorouracil and leucovorin infusion (PE-HDFL)A
very effective regimen with good patients compliance for
advanced gastric cancer. Anticancer Res 18:1267-1272, 1998.
26. Klaassen U, Wilke H, Harstrick A, et al: Fluorouracil-based
combinations in the treatment of metastatic breast cancer. Oncology 12:31-35,1998.
27. Bleiberg H, de Gramont A: Oxaliplatin plus 5-fluorouracil:
Clinical experience in patients with advanced colorectal cancer.
Semin Oncol 25:32-39, 1998.