Continuous-infusion 5-fluorouracil (5-FU) is not a new therapeutic concept. The clinical use of long-term infusional fluorinated pyrimidines was first described in the 1960s, but interest has been renewed in recent years as the limitations of conventional chemotherapy in common solid tumors have become increasingly clear. 5-FU has been the major drug studied.
Treatment of advanced breast cancer with continuous-infusion 5-FU has been evaluated in several small phase II studies, usually involving heavily pretreated patients. In a review of these studies, Cameron et al cite an overall objective response rate of 29% among the 199 patients treated with 5-FU doses of 200 to 300 mg/m²; some of these patients previously had received conventional 5-FU therapy. There was considerable variation between studies in response rates, including one report of a 54% response.
More recently, a Swiss group reported their findings from a larger, retrospective analysis of 106 consecutive patients treated on an outpatient basis with 5-FU infused at 250 mg/m² every 24 hours for 3 weeks, followed by a 1-week pause. In this group, 21% of 80 evaluable patients achieved an objective response, including a 20% response rate among patients previously treated with conventional administration of 5-FU. Interestingly, the authors also reported subjective symptom improvement in 44% of 104 patients evaluable for this endpoint, and in general treatment was well tolerated. These results highlight the potential value of continuous 5-FU infusion as palliative therapy and hint at activity as first-line treatment, although no phase II trial data have been reported.
Based on this evidence of high activity in metastatic breast cancer associated with continuous infusion of 5-FU, at the Royal Marsden Hospital we have attempted to expand on these results by combining continuous-infusion 5-FU with other chemotherapeutic agents with known activity against this disease. Our experiences are reported here.
At the Royal Marsden Hospital, we have some experience with 5-FU delivered by ambulatory pump and Hickman line. When administered to patients with metastatic or locally advanced breast cancer at a dosage of 200 mg/m²/day for up to 6 months, in combination with bolus epirubicin(Drug information on epirubicin) 60 mg/m² intravenously and cisplatin(Drug information on cisplatin) 60 mg/m² intravenously given every 3 weeks (ECisF), we observed an overall response rate of 84%, including a complete clinical remission rate of 36% in locally advanced disease.
In a subsequent phase II trial, we used the same regimen as that for preoperative/neoadjuvant chemotherapy for patients with early operable breast cancer (tumor size ³ 3 cm). An overall response rate of 98% and a complete clinical remission rate of 66% were observed among the 50 patients included in the study. We have since incorporated this treatment into a randomized trial (see below) involving 123 patients. Combined results from these two reports indicate an objective response rate of 96%, complete clinical remission among 57%, and an actuarial 5-year survival rate of 75%. These findings warranted further investigation.
There are two national, multicenter, randomized trials of infusional chemotherapy ongoing at the Royal Marsden Hospital. In the firstTrial of Primary Infusional Chemotherapy (TOPIC)patients with tumors ³ 3 cm in maximum diameter are randomized to preoperative chemotherapy with infusion ECisF vs conventional AC (Adriamycin [doxorubicin] 60 mg/m², cyclophosphamide(Drug information on cyclophosphamide) 600 mg/m² intravenously every 3 weeks for six courses). To date, 402 patients have been entered.
In the Trial of Adjuvant 5-FU Infusional Chemotherapy (TRAFIC), the efficacy of adjuvant therapy with infusional ECisF is being compared with that of standard conventional FEC (5-FU 600 mg/m², epirubicin 60 mg/m², cyclophosphamide 600 mg/m² every 3 weeks for six courses). This trial opened recently, and so far 202 patients have been entered. Participating centers for these trials are listed in Table 1.
Is Cyclophosphamide Better?
One of the disadvantages of the ECisF regimen is the extended duration of drug administration. The use of cisplatin in ECisF necessitates prolonged outpatient or overnight inpatient administration because of the need for intravenous hydration. In addition, cisplatin is associated with a greater risk of emesis, renal impairment, neurotoxicity, and high-tone hearing loss than other standard cytotoxic agents used in the treatment of breast cancer.
Cyclophosphamide has a long track record in the treatment of breast cancer, both as a single agent and in combination with 5-FU and Adriamycin (doxorubicin) (FAC), or 5-FU and epirubicin (FEC). Cyclophosphamide has a number of practical advantages over cisplatin: it may be given readily on an outpatient basis, nonhematologic toxicities are minor, and it does not require careful monitoring of renal function during treatment. These features may provide the combination regimen of infusional 5-FU, epirubicin, and cyclophosphamide (ECycloF) with some advantages over the same current standard regimen with cisplatin. Therefore, we recently performed a randomized phase II study to evaluate the safety and efficacy of continuous infusion of ECycloF vs ECisF in a 2:1 randomization.
Ninety-six women (median age, 49 years; range, 28 to 73) with breast cancer (59 metastatic, 37 locally advanced) received 200 mg/m²/day of 5-FU by continuous infusion (Hickman line) and six cycles of epirubicin (60 mg/m² every 21 days) plus either cyclophosphamide 600 mg/m² every 21 days (38 metastatic, 24 locally advanced) or cisplatin 60 mg/m² every 21 days (21 metastatic, 13 locally advanced). There were no significant differences in patient characteristics between these two groups.
ECycloF was better tolerated than ECisF in terms of lethargy (P = .005), stomatitis (P = .008), plantar-palmar erythema (P = .02), constipation (P < .001), thrombosis (P = .0014), and nausea and vomiting (P = .005). Although there was a trend toward more anemia and leukopenia with ECisF (P = .01), there was no significant difference in the rates of infection. Comparable efficacy was evident in overall response rates (69% vs 68%), complete response rates (13% vs 15%), and median progression-free survival (9 vs 8 months) for ECycloF vs ECisF, respectively.
In conclusion, this study indicated that ECycloF was a simple outpatient regimen with a lower incidence of severe nonhematologic toxicity than inpatient ECisF. In addition, it had comparable efficacy and was considerably more economical. Although the results of this phase II trial should not be interpreted in the same manner as those of a phase III study, we addressed the major sources of variability in phase II trials.
We selected a randomized trial design to reduce the risk of selection bias in interpreting efficacy and to allow a valid comparison of toxicity and side effects for ECycloF vs the infusional ECisF control, using standard World Health Organization criteria. On this basis we feel comfortable suggesting that cyclophosphamide be substituted for cisplatin in future trials of infusional 5-FU combination chemotherapy in the treatment of breast cancer.
Replacing 5-FU With UFT/Calcium Folinate
The major disadvantage of infusional 5-FU is that it involves the use of ambulatory pumps with Hickman lines, which is resource intensive and inconvenient for patients. Complications of ambulatory infusions include central venous thrombosis, chemical phlebitis, pneumothorax, and infections, at rates as high as 13%. An oral 5-FU preparation with pharmacokinetics and efficacy similar to those of continuous-infusion 5-FU would offer an important advantage in terms of resource utilization and ease of administration.
UFT (uracil plus tegafur in a 4:1 molar ratio) plus oral calcium folinate is combined in a compound called Orzel. It has a selective antineoplastic effect due to biochemical modulation by uracil, which enhances 5-FU concentration more specifically within tumor tissues than within normal tissues. UFT plus oral calcium folinate(Drug information on calcium folinate) also has fewer side effects than other agents of the fluorinated pyrimidine series.
Data from in vivo studies conducted in Japan suggest that UFT plus oral calcium folinate and tegafur(Drug information on tegafur) distribute 5-FU comparably in blood and other normal tissues, but UFT plus oral calcium folinate results in five to 10 times greater distribution of 5-FU in tumors. In 3- to 9-month chronic toxicity studies, UFT plus oral calcium folinate produced no greater toxicity than did 5-FU.
Clinical phase I and II studies described elsewhere in this supplement have shown that UFT plus oral calcium folinate is relatively well tolerated (dose-limiting toxicities in phase I studies were leukopenia, thrombocytopenia, nausea, vomiting, diarrhea, stomatitis, mucositis, fever, and fatigue), and has activity in gastrointestinal and breast carcinomas. Furthermore, its clinical and pharmacokinetic activity is comparable to that of intravenously administered 5-FU when each is combined with calcium folinate.
The recommended phase II dose on a 28-day schedule with a 2-week rest period is 200 mg/m²/day of UFT with 90 mg of calcium folinate. UFT plus oral calcium folinate is therefore an orally available agent with a favorable side-effect profile and efficacy that should compare well with that of conventional regimens.
We are therefore carrying out a nonrandomized, single-center, open-label, dose-escalation study of epirubicin, cyclophosphamide, and UFT plus oral calcium folinate (ECO) in the treatment of patients with locally advanced/metastatic breast cancer. The primary objective of this study is to determine the maximum tolerated dose and the testing for phase II of this regimen. Secondary objectives include determining side effects, dose-limiting toxicities, response rate, and time to progression. We also plan to measure tumor-related symptom relief. The schedule is outlined in Table 2.
The dose escalation will be carried out in cohorts with at least six patients in each cohort, as outlined in Table 3.
The maximum tolerated dose for UFT plus oral calcium folinate in combination with epirubicin and cyclophosphamide will be defined as the dose level at which a dose-limiting toxicity occurs in three or more of the first six patients, or six or more of 12 patients in a given cohort. Once the maximum tolerated dose is defined, additional patients will be treated at the dose level below the maximum tolerated dose. The number treated will be expanded to 20 patients to better characterize the phase II dose and to allow assessment of tumor response at the recommended dose.
The main inclusion criteria are locally advanced or metastatic breast cancer in patients who have received either no prior chemotherapy or adjuvant chemotherapy completed at least 12 months prior to study entry; prior anthracycline treatment if the total dose was £ 360 mg/m² or prior mitoxantrone(Drug information on mitoxantrone) treatment with a total cumulative dose £ 66 mg/m² is acceptable if this treatment was completed at least 12 months before study entry.
We have designed an open-label dose-escalation study to determine the maximum tolerated dose and recommended phase II dose of the combination of UFT plus oral calcium folinate, epirubicin, and cyclophosphamide. The trial has received scientific and ethical approval at the Royal Marsden Hospital. We will soon begin to enroll patients.