Improving the Toxicity of Irinotecan/5-FU/ Leucovorin: A 21-Day Schedule
Improving the Toxicity of Irinotecan/5-FU/ Leucovorin: A 21-Day Schedule
Irinotecan (CPT-11, Camptosar) is
a semisynthetic derivative of
camptothecin sodium, which itself
is the active extract from the bark of
the Chinese/Tibetan deciduous tree
Camptotheca acuminata (Nyssaceae
family). Although early development
of this camptothecin was stymied by
the toxicity of the compound, in particular
myelosuppression and hemorrhagic
cystitis, irinotecan has been
much better tolerated, with the primary
toxicities being myelosuppression
and diarrhea. Subsequent studies
in humans have demonstrated that
irinotecan has activity in a number of
malignancies, including colorectal,[
2,3] gastroesophageal,[4-6] pancreatic,[
7] lung,[8,9] breast, and
gynecologic cancers.[11,12] In the
Unite States, irinotecan is currently
indicated for use in patients with advanced
In 1998, two studies proved the
benefit of irinotecan in patients with
advanced colorectal cancer that had
progressed despite prior therapy with
the then-standard therapy, fluorouracil
(5-FU). Cunningham et al reported
that salvage irinotecan (n = 189) at
300 to 350 mg/m2 intravenously (IV)
every 3 weeks significantly increased
1-year survival in comparison to supportive
care alone (n = 90): 36.2%
compared to 13.8%. In the same patient
population, Rougier et al randomized
267 patients to 300 mg/m2
of irinotecan every 3 weeks or infusional
5-FU. Again, the 1-year and
median survivals were increased in
patients treated with irinotecan
(n = 133), at 45% and 10.8 months vs
32% and 8.5 months, respectively.
Other studies confirmed that irinotecan
has antitumor activity in patients
without previous chemotherapy for metastatic
colorectal cancer.[2,3,15,16] As
a result, irinotecan has become widely
accepted for use in patients with
metastatic colorectal cancer.
Irinotecan and 5-FU
Based on the differing mechanisms
of activity of the two most active antineoplastic
agents in colorectal and other
gastrointestinal cancers, these
drugs-irinotecan and 5-FU-have
been administered together. A number
of methods of combining irinotecan
and 5-FU with leucovorin (IFL)
have been evaluated, but the optimal
combination and schedule remain uncertain
(Table 1). Given the multitude
of 5-FU treatment schedules used
around the world, this is not surprising.
However, the most widely used
combinations of irinotecan and 5-FU
are based upon a bolus administration
In a phase I study, Saltz et al
combined irinotecan, 5-FU, and leucovorin in a weekly for 4 weeks schedule,
with cycles repeated every 6
weeks (therapy administered on days
1, 8, 15, and 22 every 42 days). Sequential
escalations of 5-FU, then
irinotecan, were performed, and the
doses recommended for further evaluation
were 125 mg/m2 of irinotecan
infused IV over 90 minutes, 500 mg/
m2 of 5-FU by bolus, and 20 mg/m2 of
leucovorin by IV bolus. The primary
dose-limiting toxicity was neutropenia,
although diarrhea was common.[
Furthering the evaluation of this
promising combination, Saltz et al
reported a study of 683 patients who
were randomized to either weekly IFL
with this schedule (n = 231), 5-FU
and leucovorin on the Mayo clinic
schedule (n = 226), or irinotecan at
125 mg/m2 IV for 4 consecutive weeks
(n = 226), again followed by a 2-week
break. This study demonstrated a significant
superiority of IFL in median
progression-free survival, objective
response rate, and median survival. In
particular, therapy with IFL resulted
in a 36% decrease in risk of progression, and a 22% decrease in risk of
death in comparison to the previous
standard therapy, 5-FU and leucovorin.[
The so-called de Gramont regimen
has been an accepted standard combination
of 5-FU and leucovorin for advanced
colorectal cancer in
France. A simplified version of
this regimen, with the 5-FU administered
as a 400 mg/m2 IV bolus, followed
by a 46-hour continuous
infusion at 2,400 to 3,000 mg/m2, every
2 weeks, has been combined with
180 mg/m2 irinotecan on the first day
of therapy (FOLFIRI), in a study reported
by Andre et al. As salvage
therapy, limited antitumor activity was
noted. In 33 treated patients, two (6%)
patients had partial responses and 20
experienced stabilization of disease.
Therapy was well tolerated, with 15%
of patients experiencing severe vomiting
and myelosuppression, and severe
diarrhea seen in 12%.
The popular German Arbeitsgemeinschaft
(AIO) schedule of high-dose 5-FU
administered as a 24-hour infusion weekly has also been combined with
irinotecan. Vanhoefer et al delivered
the full dose of 5-FU (2,600 mg/
m2 weekly) and leucovorin (500 mg/
m2) with 80 mg/m2 of irinotecan. The
dose-limiting toxicity was severe diarrhea;
was not a significant problem.
Other researchers have evaluated
further combinations of the agents.
Falcone et al combined a 48-hour
continuous infusion of 5-FU (3,500
mg/m2) with irinotecan in 33 patients,
evaluating irinotecan both preceding
and following 5-FU. Cycles prior to
5-FU and leucovorin permitted a higher
dose of irinotecan administration
(recommending a dose of 350 mg/m2)
in this combination, with less toxicity
overall than the reverse schedule. Severe
neutropenia was noted in 22% of
patients, and grade 3/4 diarrhea in
4%. In a phase I study in 42 patients
with metastatic colon cancer,
Kakolyris et al combined a 4-day
continuous infusion of 5-FU with
irinotecan immediately afterwards.
The doses recommended for subsequent
evaluation were 600 mg/m2/d
and 350 mg/m2, respectively. At these
doses, 20% of 25 cycles reported grade
3/4 neutropenia, and dose-limiting
toxicities were noted in two of six
patients: severe neutropenia with severe
diarrhea, and neutropenic fever.[
Capecitabine (Xeloda), an oral fluoropyrimidine,
was found to have superior
activity and less toxicity in
comparison to bolus 5-FU and leucovorin
administered on the Mayo clinic
schedule.[24,25] Because of its ease
of administration and good toxicity
profile, capecitabine has been combined
with irinotecan, with promising
results. Several schedules have been
evaluated. Cassata et al combined
1,000 mg/m2 of capecitabine twice
daily for 14 days with irinotecan, with
the latter administered either as 300
mg/m2 on day 1 or 150 mg/m2 on days
1 and 8 of each 21-day treatment cycle.
Both schedules were fairly well
tolerated, and active in the first-line
treatment setting (71% overall response
Others have evaluated similar
schedules and slightly lower irinotecan
doses yielding similar findings
with regard to efficacy, as well as a
suggestion of somewhat better toxicity
profiles.[27,28]. On the former
schedule, Delord et al used 250
mg/m2 of irinotecan on day 1 of treatment,
and reported grade 3 neutropenia
in two of seven patients, and grade
3 diarrhea in one patient. As part of a
randomized phase II study, Jordan et
al treated advanced colorectal cancer
patients with irinotecan at 100 mg/
m2 on days 1 and 8 of each 21-day
treatment cycle. Severe diarrhea was
reported in three and severe neutropenia
in two of the 28 patients. However,
two patients died from neutropenic
sepsis with diarrhea and pulmonary
Despite evaluations of these various
schedules, the preferred combination
of irinotecan and 5-FU remains
uncertain. The schedules that have
been the most intensely evaluated to
date are the weekly IFL schedule, and
irinotecan in combination with some
variation of the bimonthly de Gramont
IFL as First-Line Therapy
in Colorectal Cancer
The superior antitumor activity of IFL in comparison to 5-FU and leucovorin administered by the Mayo or de Gramont schedules, as well as irinotecan alone in patients with metastatic colorectal cancer with no prior chemotherapy for metastatic disease, was established by two reports published in 2000. The first by Saltz et al, in the New England Journal of Medicine as described above, demonstrated superior response, time to progression, and survival with the addition of irinotecan to 5-FU and leucovorin in comparison to irinotecan alone, or 5-FU and leucovorin administered according to the Mayo clinic schedule. Similarly, Douillard et al randomized 387 patients to one of two 5- FU/leucovorin treatment regimens (de Gramont schedule with this schedule [288 patients] or AIO schedule [97 patients] at the investigator's discretion) with or without irinotecan. Irinotecan was administered at either 180 mg/m2 IV on day 1 of therapy every 2 weeks with the de Gramont schedule, or 80 mg/m2 IV weekly. Again, irinotecan significantly increased the response rate (P < .005), time to progression (P < .001), and median survival (P < .031) in comparison to patients treated with 5-FU and leucovorin alone, regardless of the schedule employed. With these studies demonstrating the efficacy of IFL, this combination subsequently became the standard initial therapy for patients with metastatic colorectal cancer. Although the preferred combination was uncertain, in the United States the weekly schedule was most widely used, in part because of the ease of administration. However, subsequent reports have raised concerns about the tolerability of this schedule. Toxicity
Not surprisingly, the toxicity profile of IFL depends in great part on the schedule of 5-FU administered with irinotecan (Table 2). The weekly IFL toxicities reported by Saltz et al in the phase III study were primarily myelosuppression, with 53.8% of patients experiencing grade 3/4 neutropenia, and neutropenic fevers in 7.1%. Severe or life-threatening diarrhea was also a prominent toxicity, occurring in 22.7% of patients, and grade 3/4 nausea/vomiting in 9.7%. Overall though, therapy was considered to be well tolerated, with only 2 (0.9%) of 225 patients dying as a consequence of therapy. With the combination of the de Gramont schedule of 5-FU and leucovorin with irinotecan administered every other week, grade 3/4 neutropenia remained the most common toxicity, occurring in 46.2% of patients, with neutropenic fever in 5.5% of patients. Severe diarrhea occurred in 13.1% of patients, and grade 3/4 nausea/ vomiting in about 3% of patients. When combined with 5-FU and leu- covorin administered on the AIO schedule, IFL resulted in somewhat more toxicity, including severe diarrhea in 44.4% and vomiting in 11.1% of the 54 patients treated. Grade 3/4 neutropenia was reported in 28.8%, and febrile neutropenia in 9.3%. This difference in toxicities among these regimens was most likely a consequence of the 5-FU/leucovorin schedule employed, and the resultant difference in irinotecan schedule. Again, the regimens appeared to have a similar efficacy, despite the difference in toxicity. With the combination of irinotecan, 5-FU, and leucovorin becoming the standard therapy for patients with metastatic colorectal cancer, its use in the late 1990s and early 21st century escalated dramatically. In the United States, the weekly regimen of IFL, the so-called Saltz regimen, had become the predominant schedule employed because of the relative ease of administration, which did not require the placement of prolonged venous access. However, dramatic reports from two Intergroup studies-Cancer and Leukemia Group B (CALGB) 89803 and North Central Cancer Treatment Group (NCCTG) 9741- evaluating the efficacy of this schedule of IFL in the respective adjuvant and metastatic settings have led to renewed concerns about the tolerability of this regimen (Table 3). In April 2001, the External Data Monitoring Committee for NCCTG 9741 reported deaths within the first 60 days of study entry in 13 (4.5%) of 289 patients. A subsequent review of the CALGB study found that 16 (2.5%) of 635 patients treated with IFL also died within 60 days of initiating treatment. Of interest, the initial report of IFL in a phase III study noted that 0.9% of 225 patients died from drug-related causes, compared to 1.4% of 219 patients treated with bolus 5-FU/leucovorin on the Mayo Clinic schedule. The deaths that occurred on this study were later reviewed, and the 60-day mortality, the same yardstick applied to the Intergroup studies, revealed rates of 6.7% with IFL and 7.3% with 5-FU/leucovorin.[ 32] An independent review of these deaths attributed them to "gastrointestinal syndrome," including diarrhea, nausea, vomiting, abdominal cramping leading to dehydration and electrolyte abnormalities, and often in the setting of neutropenia, fever, or infection; or "vascular syndrome," including myocardial infarction, pulmonary embolism, or cerebrovascular accidents. The gastrointestinal syndrome was felt to cause, exacerbate, or contribute to the deaths of 12 patients in the CALGB study and 6 in the NCCTG study. The vascular syndrome was believed to cause or contribute to the deaths of five patients in the CALGB study and three in the NCCTG study. The panel found that the median age of the patients treated with IFL who died was 69.5 years in CALGB 89803 and 65 years in NCCTG 9741, older than the median ages of patients typically enrolled in studies of colorectal cancer. A number of recommendations were made by this expert panel, including close monitoring of patients treated with IFL, especially older patients, and an aggressive approach to the treatment of diarrhea and abdominal cramping, including aggressive use of antibiotics in patients with diarrhea and neutropenia.[ 33] In addition to the concerns about the toxicities of weekly IFL, another difficulty of the regimen is that severe toxicities occurred despite a relatively low dose intensity of chemotherapy. In particular, great difficulty was encountered in administering weeks 3 and 4 of chemotherapy because of myelosuppression and diarrhea. As a result, the median relative dose intensities (calculated by dividing the actual dose of the agent delivered by the intended dose of the agent) of irinotecan and 5-FU were 72% and 71%, respectively. 21-Day Schedule
Considering the difficulties of dose delivery and toxicity in weekly IFL according to the Saltz schedule, which appeared to be cumulative within a cycle, one manner of improving the therapeutic index of weekly IFL would seem to be to create a break after the second week of therapy, prior to resuming IFL. To evaluate this hypothesis, 23 patients have been treated with weekly IFL at the Lombardi Cancer Center at Georgetown University Medical Center. However, therapy was administered on days 1 and 8 every 21 days. For patients who were 75 years or older, the initial dose of irinotecan was 100 mg/m2. The planned dose intensity of this schedule would be identical to the Saltz schedule of IFL. The patient population was similar to other studies of patients with ad- vanced colorectal cancer (Table 4). However, none of the patients had received prior chemotherapy. All patients had a good performance status (Eastern Cooperative Oncology Group 0 or 1). The median age of the population was 57 years, encompassing a range of ages from 38 to 77; two patients were 75 years or older. Fourteen of the patients were males. Fifteen of the patients were given chemotherapy as adjuvant treatment. Only eight of these patients received therapy as treatment for measurable metastatic disease. One patient has received 6 weeks of therapy and is not yet evaluable for response. Three of the other seven had stable disease, and four had progression of disease on their follow- up evaluation. This schedule was well tolerated, with grade 3/4 neutropenia occurring in eight (35%) patients, and severe diarrhea in only two (9%). Two patients experienced one episode each of febrile neutropenia with the first cycle of therapy, but tolerated further treatment with IFL on the 21-day schedule after a 25% dose reduction. No other grade 3/4 toxicities were noted (Table 5). Supporting these data that demonstrate the tolerability of this schedule of IFL was the ability to deliver the therapy. In the first 18 patients treated with this schedule, the median relative dose intensities, calculated by the same method as Saltz et al, of irinotecan and 5-FU were 94% and 92% (Table 6). Half of these patients received therapy without requiring any dose modifications. Full doses were administered in 104 of 141 cycles, with a 10% dose reduction occurring in 26 cycles (18.4%), and 25% and 50% dose reductions in 9 and 2 cycles, respectively. These results, especially with regard to the ability to deliver a high dose intensity of the regimen with a simple modification of the schedule of administration, support the hypothesis that altering the schedule of therapy will improve the therapeutic index of IFL. However, because of the potentially confounding differences between study populations, the comparison of median relative dose intensity between these two study groups requires confirmation in a prospective randomized study. Furthermore, the change in the schedule may not be the only, or primary, reason for the ability to deliver such a high proportion of the intended dose. In particular, the patient population must be considered to be favorable. First, the median age of the treated patients was 57 years, with only two patients being over 75, and thus may be considered inadequately representative of the population of patients with advanced colorectal cancer. Moreover, as many of the patients who were treated in this program had only a high risk for disease recurrence, and essentially received adjuvant therapy, they may have been a "healthier" population overall. The antitumor activity and tolerability of the 21-day schedule of IFL, then, can only be assessed in the context of a prospective randomized trial. Future Directions At the 2002 meeting of the American Society of Clinical Oncology, Goldberg et al reported the preliminary results of NCCTG 9741. A total of 795 patients with advanced colorectal cancer were randomized to weekly IFL using the Saltz schedule as the control arm, or oxaliplatin (Eloxatin), 5-FU, and leucovorin on the de Gramont schedule (FOLFOX 4), or a combination of irinotecan and oxaliplatin every 3 weeks. The median progression-free survival and median overall survival were significantly longer for patients treated with FOLFOX 4 than IFL on the Saltz schedule, at 8.8 vs 6.9 months, and 18.6 compared to 14.1 months, respectively. As a result of these findings, the US Food and Drug Administration approved oxaliplatin in August 2002 for use in combination with infusional 5-FU and leucovorin for the treatment of patients with advanced colorectal cancer. An additional question is whether oxaliplatin-based chemotherapy will become the new standard first-line therapy for patients with metastatic colorectal cancer. Irinotecan, oxaliplatin, and 5-FU possess activity in advanced colorectal cancer, and should be made available to all. However, the appropriate combination and best sequence of these agents will need to be elucidated, including the optimal method of administering 5-FU (ie, bolus, infusional, or oral) (Figure 1). Finally, the potential role of the targeted therapies, such as the epidermal growth factor receptor (EGFR) antagonists including erbitux (C-225), gefitinib (ZD1839, Iressa), and OSI- 774 (Tarceva), and vascular endothelial growth factor antagonists including bevacizumab, are being evaluated. About 70% of patients with colorectal cancer have tumors that overexpress EGFR, making this a promising target for intervention. Preliminary studies have suggested that the combination of irinotecan and erbitux has activity in patients with metastatic colorectal cancer. The precise contribution of erbitux in this combination, as well as the optimal method of combining chemotherapy and these targeted therapies, also remain unknown . With a plethora of other potential targets and agents against these targets being identified and developed, a variety of options may be available for patients in the future, offering an opportunity to tailor therapy to the patient, maximize activity, and minimize toxicity. A modification of the weekly bolus IFL, altering the schedule to administer therapy on days 1 and 8 every 21 days, may improve the therapeutic index of IFL and allow physicians to continue offering patients a relatively easily delivered and effective chemotherapy regimen, and encourage investigators to explore the regimen as a backbone to further study of new agents and combinations in the treatment of advanced colorectal cancer.
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34. Goldberg RM, Morton RF, Sargent DJ, et al: N9741: Oxaliplatin (oxal) or CPT-11 + 5- fluorouracil (5-FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC). Initial toxicity and response data from a GI Intergroup study (abstract 511). Proc Am Soc Clin Oncol 21:128a, 2002.
35. Saltz LB, Rubin M, Hochster H, et al: Cetuximab (IMC-C225) plus irinotecan (CPT- 11) is active in CPT-11 refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR) (abstract 7). Proc Am Soc Clin Oncol 20:3a, 2001.
36. Bergsland E, Hurwitz H, Fehrenbacher L, et al: A randomized phase III trial comparing rhuMAb VEGF (recombinant humanized monoclonal antibody to vascular endothelial cell growth factor) plus 5-fluorouracil/leucovorin (FU/LV) to FU/LV alone in patients with metastatic colorectal cancer (abstract 939). Proc Am Soc Clin Oncol 19:242a, 2000.