Biomodulation Of 5fu

Biomodulation is a strategy that involves the alteration of tumor cell susceptibility to anticancer drugs through the modification of biochemical pathways to produce an accentuated or selective action on the cancer cells. This approach differs from that of combination chemotherapy because the biomodulator is not a cytotoxic agent. The most widespread use of biomodulation involves the use of leucovorin (LV) to increase intracellular folate cofac-tors and, thus, enhance the binding of fluorodeoxyuridylate to thymidylate synthase (TS), the enzyme involved in the biosynthesis of nucleic acids (8-10). This enhanced binding leads to increased cytotoxicity of 5-FU, and clinical trials have demonstrated that the response to 5-FU in colorectal cancer can be increased by concomitant administration of LV.

The first LV/5-FU protocol to be clinically evaluated involved the administration of highdose LV (500 mg/m2) plus weekly 5-FU (600 mg/m2), administered for 6 wk with a 2-wk rest, to 343 patients with previously untreated metastatic colorectal cancer (11). The combination was associated with significantly improved tumor response rates compared with 5-FU alone (30.3% vs 12.1%), although there was no significant difference in overall survival. A second LV/5-FU regimen has been developed by researchers at the Mayo Clinic in conjunction with the North Central Cancer Treatment Group (NCCTG) (12). This is a monthly regimen involving 5-d courses of 5-FU bolus therapy (425 mg/m2) plus low-dose LV (20 mg/m2). In a large study of 429 patients, the clinical efficacy of several 5-FU-based regimens were compared with that of 5-FU alone. The NCCTG-Mayo Clinic regimen was associated with significantly higher tumor response rates compared with 5-FU alone (43% vs 10%, respectively) and this was reflected in a significant increase in median survival among patients treated with LV/5-FU (12.0 mo vs 7.7 mo, respectively, p = 0.05).

A meta-analysis of nine randomized clinical trials, involving 1381 patients, also demonstrated significantly improved response rates following combination therapy with LV/5-FU, compared with 5-FU alone (23% vs 11%, respectively), although there was no significant impact on survival (11.5 mo vs 11.0 mo, respectively) (13).

3. THE BIMONTHLY LV/5FU REGIMENS

The bimonthly LV/5-FU regimens combine 5-FU continuous infusion and biomodulation by LV. In addition, based on the different mechanisms of action of 5-FU depending on the dose and schedule of administration, the bimonthly regimens also combine 5-FU bolus and continuous infusion. This combination is supported by the in vitro demonstration of a syner-gism between 5-FU administered by bolus and continuous infusion (14). Lastly, the

Fig. 1. Outline of the three main LV/5-FU bimonthly regimens that have been investigated in patients with advanced colorectal cancer. Treatment cycles were repeated every 2 wk.

*The dose was administered at the lower level for two cycles, then at the higher level for subsequent cycles, if toxicity < WHO grade 2.

Fig. 1. Outline of the three main LV/5-FU bimonthly regimens that have been investigated in patients with advanced colorectal cancer. Treatment cycles were repeated every 2 wk.

*The dose was administered at the lower level for two cycles, then at the higher level for subsequent cycles, if toxicity < WHO grade 2.

bimonthly schedule, which is also in accordance with the in vitro optimal TS inhibition duration, was selected as the optimal method to keep the toxicity at a low level.

After a preliminary study which showed that a bimonthly 48-h schedule was well tolerated, the first bimonthly regimen to be investigated was administered to 37 chemotherapy-naive patients with advanced colorectal cancer (15). This approach permitted a doubling of the total administered dose of 5-FU compared with the monthly NCCTG-Mayo Clinic regimen (4.0 g/m2 vs 2.1 g/m2 per month, respectively). Furthermore, the bimonthly regimen produced encouraging clinical results, with tumor responses occurring in 54% of patients, and a median survival of 18 mo.

Further evaluation of the bimonthly schedule, performed by the French Intergroup, has confirmed the favorable toxicity profile of this treatment regimen compared with monthly 5-FU/LV. In a randomized trial of 433 previously untreated patients, a bimonthly regimen of high-dose LV plus 5-FU bolus and infusion of low-dose 5-FU (2-h infusion of LV, 200 mg/m2, followed by iv bolus of 5-FU, 400 mg/m2/d, then 22-h infusion of 5-FU, 600 mg/m2/d, the LV/5-FU2 regimen, Fig. 1) was compared with the monthly NCCTG-Mayo Clinic regimen (16). Tumor response rates were significantly higher among patients who received LV/5-FU2 compared with the NCCTG-Mayo Clinic regimen (32.6% vs 14.4%, respectively, p = 0.0004). In addition, the median progression-free survival was significantly improved by the bimonthly regimen (27.6 wk vs 22 wk, p=0.001). Median survival was not significantly increased compared with the monthly regimen (62.0 wk vs 56.8 wk respectively, p=0.067). However, crossovers between treatment groups and the use of second line therapies were permitted during the study, and this may have reduced any differences that could be detected between the original treatment groups. Importantly, the bimonthly regimen was associated with lower toxicity than the monthly regimen, with World Health Orga nization (WHO) grade 3-4 toxicities occurring in 11.1% of patients who received LV/5-FU2, compared with 23.9% for the NCCTG-Mayo Clinic regimen (p=0.0004).

In view of these promising findings, a modified bimonthly regimen was subsequently investigated in 101 patients with advanced colorectal cancer (The FOLFUHD study; FOLinic acid, 5-FU High Dose) (17). The regimen consisted of high-dose LV (500 mg/m2) plus a 2-h infusion of high-dose 5-FU (1500-2000 mg/m2/d for 2 d), repeated every 2 wk until there was evidence of disease progression (Fig. 1). An overall response rate of 33.7% was reported, with five complete responses (5%) and 29 partial responses (28.7%). Survival rates were also encouraging, with median progression-free and overall survival rates of 8 and 18 mo, respectively. The efficacy of this bimonthly regimen was not affected by treatment status and was equivalent among previously treated and chemotherapy-naive patients. In addition, the low toxicity of bimonthly LV/5-FU2 was confirmed; 15.2% of patients experienced no toxic effects with the bimonthly regimen, and a further 28.3% had only grade 1 toxicity.

On the basis of the assumption that high-dose 5-FU infusion has equivalent activity to 5FU bolus plus low-dose 5-FU infusion, the LV/5-FU2 regimen has recently been simplified so that, instead of requiring patients to be admitted to the hospital for two consecutive days every 2 wk, the procedure requires only 2 h at the hospital. A single, 2-h LV infusion (400 mg/m2) is given immediately before the bolus of 5-FU (400 mg/m2), followed by a 46-h infusion of 5-FU (2400-3000 mg/m2), administered via a disposable pump, which is fitted before the patient is discharged (Fig. 1) (18). In a study involving 93 patients, the new simplified regimen demonstrated antitumor efficacy combined with low toxicity and, interestingly, this regimen appears to be even more active than the first two bi-monthly regimens to be investigated, with an overall response rate of 41%, a median progression-free survival of 9.4 mo (personal communication).

4. BIMONTHLY LV/5-FU IN COMBINATION WITH NOVEL CYTOTOXIC AGENTS

The efficacy and low toxicity of the LV/5-FU2 regimen provides the opportunity to add other antitumor agents to the regimen with the aim of improving patient survival, and combination regimens with LV/5-FU2 have been extensively investigated.

4.1. Oxaliplatin

Oxaliplatin is the first platinum compound to demonstrate significant activity in colorectal cancer (19). In clinical studies, single-agent oxaliplatin produces objective responses in 20-24% of patients with previously untreated advanced colorectal cancer (20,21) and 10% of those with tumors that are resistant to 5-FU, (21,22). Strong synergistic cytotoxic activity has been demonstrated with oxaliplatin and 5-FU, both in vitro and in vivo, and this syner-gism is maintained even in 5-FU-resistant cell lines (23).

The value of adding oxaliplatin to LV/5-FU2 (Fig. 1) has been evaluated recently in a large study of the first-line treatment of colorectal cancer. The full-dose regimen was administered when toxicity remained at a tolerable level, and treatment was continued until the development of unacceptable toxicity or in the event of disease progression. In 420 patients with previously untreated advanced colorectal cancer, the addition of oxaliplatin, 85 mg/m2, to LV/5-FU2 was associated with substantially enhanced activity compared with the bimonthly regimen alone (24). Patients allocated to oxaliplatin plus LV/5-FU2 showed significantly longer progression-free survival (median, 9.0 mo vs 6.2 mo, p=0.0003) and improved response rates (50.7% vs 22.3%, p = 0.001) compared with those who received LV/5-FU2 alone. In this study, where crossovers between treatment groups were permitted, there was also a trend toward increased overall survival in the oxaliplatin group, although this did not reach statistical significance (median 16.2 mo vs 14.7 mo, p = 0.12). The incidence of toxicities was higher with the combination regimen than LV/5-FU2 alone; grade 3-4 neutropenia, diarrhea, and grade 3 neurosensory toxicity were all observed more frequently among patients treated with oxaliplatin than those who were not (p < 0.05). However, as this did not result in impairment of quality of life, the small survival benefit observed with the combination regimen may be considered to be of value. Importantly, multivariate analysis revealed that oxaliplatin was a strong independent predictor of overall survival. Furthermore, metastectomy was possible in twice as many patients who received oxaliplatin than among those who received LV/5-FU2 alone (6.7% vs 3.3%), raising the possibility of potentially curative surgery for metastatic disease.

The efficacy of various doses of oxaliplatin in combination with 48-h bimonthly regimens of LV/5-FU has also been evaluated in the second-line setting, among patients with tumors that had demonstrated resistance to treatment with LV/5-FU alone (the FOLFOX studies; FOLinic acid,5-FU,OXaliplatin). The doses and schedules of administration were modified with the aim of minimizing the incidence of toxicity while enhancing the efficacy of oxaliplatin. With the exception of FOLFOX 7, all of the regimens were administered until disease progression or the development of unacceptable toxicity.

A feasibility study (FOLFOX 1) evaluated the bimonthly FOLFUHD regimen with oxaliplatin (130 mg/m2) added at every other treatment cycle (Fig. 2) (25). An encouraging response rate of 31% was observed in 13 patients who received the FOLFOX 1 regimen, with median and progression-free survival times of 6 and 11 mo, respectively (Table 1). The low level of toxicity associated with the FOLFOX 1 regimen led to the design of FOLFOX 2, in which the total dose of oxaliplatin was increased to 100 mg/m2, administered at every treatment cycle to 46 patients (Fig. 2) (26). The dose of 5-FU was 1500 mg/m2/d for the first two treatment cycles and this was increased to 2000 mg/m2/d in subsequent cycles if maximal tox-icity remained below WHO grade 2. The major dose-limiting toxicities were neutropenia and peripheral neuropathy. The FOLFOX 2 regimen produced a high response rate of 46%, with median and progression-free survival times of 7 and 17 mo, respectively. The high response rate was attributed to an effective synergy between the FOLFUHD regimen and oxaliplatin, given that patients had tumors that were already refractory to LV/5-FU regimens.

These findings prompted further trials in which the dose of the 5-FU infusion was reduced to 1500 mg/m2/d, and that of oxaliplatin to 85 mg/m2 (FOLFOX 3) (27,28). The FOLFOX 4 regimen used the LV/5-FU2 regimen in combination with oxaliplatin (85 mg/m2). Both regimens were administered to patients whose disease had progressed while receiving the LV/5-FU regimen alone and the studies provided further clinical confirmation of the synergistic effects of oxaliplatin and LV/5-FU. However, the response rates and survival times were lower than those observed with the FOLFOX 2 regimen (Table 1). Subsequent trials have used the new simplified LV/5-FU2 regimen, which retains the low toxicity of the standard LV/5-FU2 regimen and demonstrates at least equivalent efficacy (18). In FOLFOX 6, oxaliplatin 100 mg/m2 was added to the simplified regimen (29). A higher dose intensity of oxaliplatin (130 mg/m2) was added in FOLFOX 7 and treatment was suspended after eight cycles, in an attempt to limit toxicity (30). Patients were then evaluated every 2 mo and the FOL-FOX 7 regimen as resumed in the event of disease progression. Among the 34 patients treated, a high response rate of 44% was observed and the regimen was well tolerated.

Folfox Regimen Colorectal Cancer

Fig. 2. Regimens used in FOLFIRI and the FOLFOX 1-7 studies. Treatment cycles were repeated every two weeks. Oxaliplatin was administered at every other cycle in FOLFOX 1, and at every cycle in FOLFOX 2-6.

*The dose was administered at the lower level for two cycles, then at the higher level for subsequent cycles, if toxicity < WHO grade 2. Hy: hydroxyurea

Fig. 2. Regimens used in FOLFIRI and the FOLFOX 1-7 studies. Treatment cycles were repeated every two weeks. Oxaliplatin was administered at every other cycle in FOLFOX 1, and at every cycle in FOLFOX 2-6.

*The dose was administered at the lower level for two cycles, then at the higher level for subsequent cycles, if toxicity < WHO grade 2. Hy: hydroxyurea

Furthermore, median and progression-free survival (12.6 mo and 6.2 mo, respectively) were not adversely affected by the break in therapy.

Taken together, the FOLFOX trials indicate that the dose intensity of oxaliplatin may be important in determining the efficacy of the triple agent regimen (31). No other factors, such as age, number of metastatic sites, carcinoembryonic antigen level, or response to first-line therapy, have been shown to influence the response to second-line therapy. The FOLFOX 7

Folfox6 Regimen

Fig. 2. Continued.

Fig. 2. Continued.

Table 1

Summary of the Findings of the FOLFOX Studies, in which LV/5-FU Are Administered with Oxaliplatin in the Second-Line Therapy of Advanced Colorectal Cancer^

Regimen

Response rate (%)

Median PFSb (mo)

Median survival (mo)

FOLFOX 1 13 31 6 11

FOLFOX 2 46 46 7 17

FOLFOX 3 30 20 6 10

a There were two FOLFOX 3 studies and FOLFOX 5 was not conducted. b PFS = progression-free survival.

regimen is currently being evaluated in the first-line setting; the OPTIMOX study (aimed at identifying the optimal FOLFOX regimen) is comparing the efficacy of FOLFOX 7 with FOLFOX 4 in previously untreated patients with advanced colorectal cancer. In addition, the combination of oxaliplatin with LV/5-FU2 is to be evaluated in the adjuvant treatment of patients with this disease (the Multicenter International Study of Oxaliplatin in the Adjuvant treatment of Colon Cancer study).

4.2. Irinotecan

Irinotecan (or CPT-11) is a topoisomerase inhibitor that is active against colorectal cancer cells (32). The drug does not demonstrate crossresistance with 5-FU and is active via a novel molecular mechanism (33). In phase II clinical trials, irinotecan has shown antitumor activity in patients with colorectal cancer, including those whose disease had progressed on 5-FU-based therapy (34-36). The first large phase III trial of irinotecan demonstrated a significant survival advantage among patients who received the drug in addition to supportive care, compared with those who received supportive care alone (overall 1-yr survival 36.2% vs 13.5%, respectively, p = 0.001) (37). In another phase III trial, irinotecan was associated with significantly improved survival, compared with continuous infusion of 5-FU (overall 1-yr survival 45% vs 32%, respectively, p = 0.035), among patients with metastatic colorectal cancer who had failed to respond to first-line 5-FU-based regimens (38). Importantly, the irinotecan regimens were well tolerated and the survival advantages reported in these two trials were not gained at the expense of quality of life.

Preclinical data have indicated a potential synergy between irinotecan and LV/5-FU (39). This synergy appears to be sequence-dependent. In view of the potential clinical benefit of this combination, the addition of irinotecan to the simplified bimonthly LV/5-FU2 regimen has been investigated. A recent phase II study has demonstrated that this combination is active even in heavily pretreated patients (28). The FOLFIRI-1 trial (FOLinic acid, 5FU, IRInotecan) evaluated LV/5-FU in combination with irinotecan as third-line therapy in 33 patients with advanced colorectal cancer. Patients received a twice weekly schedule of irinotecan, 180 mg/m2, as a 90-min infusion on day 1, at the same time as a 2-h infusion of LV, 400 mg/m2. This was immediately followed by a bolus of 5-FU, 400 mg/m2, and a 46-h continuous infusion of 5-FU, 2400-3000 mg/m2. Treatment was continued until disease progression, unless significant toxicity occurred. Diarrhea and neutropenia were the main limiting toxicities. Overall, 30% of patients experienced grade 3-4 toxicities which resolved with treatment or dose reduction, and the tolerability of the regimen was regarded as acceptable. Although the overall response rate was low (6%), with median and progression-free survival times of only 9.9 mo and 4.1 mo respectively, the FOLFIRI-1 trial nonetheless indicates that third-line therapy can be of benefit for some patients with metastatic colorectal cancer.

Following this study, a further attempt was made to improve the regimen in the FOLFIRI-2 study (40). Hydroxyurea was added to enhance the 5-FU RNA pathway, based on the assumption that the inhibition of TS is not of primary importance in patients with tumors that are refractory to 5-FU, and that 5-FU-RNA and hydroxyurea can impair cellular repair mechanisms after irinotecan exposure. The FOLFIRI-2 regimen consisted of hydroxyurea, 1500 mg, administered on d 1-3, plus LV, 400 mg/m2, as a 2-h infusion on day 1, immediately followed by a 46-h continuous infusion of 5-FU, 2000 mg/m2, and irinotecan, 180 mg/m2 as a 90-min infusion on d 3. The regimen was repeated every 2 wk. Twenty-nine patients with metastatic colorectal cancer, who had received at least two previous chemotherapy regimens including LV/5-FU and oxaliplatin, received the FOLFIRI-2 regimen. Partial responses were obtained in five patients (17%), while 15 patients (51%)

achieved disease stabilization, three patients (10%) showed disease progression, and six (21%) were withdrawn from the study due to toxicity or absence of clinical benefit. Median progression-free survival was 4.1 mo and median survival was 9.7 mo. Grade 3-4 neutropenia was observed in 52% of patients (febrile neutropenia in 7%), while other grade 3-4 toxicities were diarrhea (21%), nausea and mucositis (10%). In spite of the dose-limiting hematological toxicity, the FOLFIRI-2 regimen produced higher rates of response and disease stabilziation than the FOLFIRI-1 regimen.

A phase III trial has recently shown promising results in 387 patients with advanced disease (41). In this multicenter study of the first-line treatment of metastatic colorectal cancer, patients received LV/5-FU, either with or without irinotecan, in a once or twice weekly regimen (according to local clinical practice or preference). The once weekly regimen involved 5-FU, 2300-2600 mg/m2 by 24-h infusion and LV, 500 mg/m2, with or without irinotecan, 80 mg/m2. In the bimonthly regimen 5-FU, 400 mg/m2, was administered on d 1 as an iv bolus followed by a 22-h infusion of 5-FU, 600 mg/m2, and LV, 200 mg/m2, on d 1 and 2, with or without irinotecan. Treatment was continued until disease progression or the occurrence of unacceptable toxicity. The addition of irinotecan to LV/5-FU was associated with improved tumor response rates (35% vs 22%, p < 0.005, in the intention-to-treat population), progression-free survival (6.7 mo vs 4.4 mo, p < 0.001) and overall survival (17.4 mo vs 14.1 mo, p = 0.031), compared with LV/5-FU alone. Furthermore, the combination had acceptable tolerability and although the incidence of grade 3-4 neutropenia, leukopenia, diarrhea, and asthenia was higher in the irinotecan group (p < 0.05), these effects were reported to be predictable, reversible, manageable, and noncumulative.

The combination FOLFOX-6 and FOLFIRI-1 regimens are currently being evaluated in another randomized study which aims to determine whether FOLFIRI followed by FOLFOX (arm A), or vice versa (arm B), is the most desirable sequence in the treatment of advanced colorectal cancer. Preliminary results are promising, with response rates of 55% observed for both arms (42).

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