The combination of tegafur(Drug information on tegafur) and uracil (UFT) is active in the treatment of advanced breast cancer, with a response rate of 20%. For this reason, and because it can be given orally with a low level of toxicity, the Grupo Oncologico de Sevilla decided to evaluate the use of adjuvant UFT in two different groups of patients with breast cancer, organized according to menopausal status. The two trials are considered independently.
The goal of the first study was to determine whether oral administration, considered more comfortable and less costly than parenteral administration, would be feasible and active in a premenopausal population. To assess this issue, we combined UFT with prednimustine, a molecule that combines an alkylating agent (chlorambucil [Leukeran]) with an ester of prednisolone(Drug information on prednisolone) (Prelone, Prednisone) and has been shown to be active against advanced breast cancer when taken orally. The comparative treatment used in this study was cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar)/ methotrexate(Drug information on methotrexate)/fluorouracil (5-FU) (CMF), a combination traditionally used in the adjuvant treatment of breast cancer.
Materials and Methods
A total of 200 consecutive patients with proven breast cancer, who had undergone either radical or conservative surgery, were randomly allocated to receive 6 cycles of one of the following treatments: arm A (CMF) consisted of cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil(Drug information on fluorouracil) 600 mg/m2 on day 1, repeated every 28 days; arm B consisted of oral prednimustine 60 mg/m2 for 7 consecutive days, repeated every 28 days, and oral UFT 400 mg/day given in two divided doses continuously for 24 weeks.
All patients were premenopausal or within 3 years following cessation of menses. Their surgery could have been radical or simple mastectomy with axillary dissection or lumpectomy with axillary dissection. In the case of lumpectomy, radiotherapy was mandatory. Axillary node involvement was required for this study. (On preparing the material for these studies for the first time, node-negative high-risk cancers were included in error. This error went unnoticed in oral presentation material and in the abstracts P34 and P35 of the Seventh International Congress on Anticancer Treatment [Paris, February 1997], as they were prepared simultaneously. The author profoundly regrets these errors.) Hormonal receptor status was not considered. The performance status had to be 50% or more by the Karnofsky scale, with no major pathology.
Initial staging evaluation consisted of physical examination, complete blood counts, study of renal and hepatic function, x-ray film of the chest, and bone scan. The patients were reevaluated every 3 months during the first year, every 4 months for the next 2 years, every 6 months until the fifth year, and once yearly thereafter. An event was defined as the appearance of distant metastases or a local relapse. Disease-free survival was measured from the time of surgery to an event. Overall survival was considered the time between surgery and the death of the patient, whatever the cause.
The disease-free survival and the overall survival rates were studied by the Kaplan-Meier method and the comparison between curves by the log rank test. The chi-square test was used to study the balance of prognostic factors between arms, and toxicity was evaluated according to the World Health Organization scale.
Of 200 patients enrolled in this study (105 in arm A and 95 in arm B), 13 were considered ineligible (nine in arm A and four in arm B). The reasons for ineligibility were error of randomization (N = 4), failure to meet inclusion criteria (N = 3), and lack of follow-up (N = 6). Ultimately, 187 patients (96 in arm A and 91 in arm B) were considered eligible. Patient characteristics are shown in Table 1. There were more young patients in arm A, but this was not taken into consideration, as no difference in outcome was seen between age groups in the series as a whole.
With a mean follow-up of 5.09 years (range, 2.9 to 7.1) 98 patients have relapsed (55 in arm A and 43 in arm B), and 43 patients have died (20 in arm A and 23 in arm B).
Regarding disease-free survival, no difference was seen between the two arms (Figure 1), with a 5-year cumulative disease-free survival rate of 0.40 in arm A and 0.50 in arm B (P = .47). The same findings are seen with overall survival (Figure 2), with a 5-year cumulative survival of 0.67 in arm A and 0.66 in arm B (P = .51)
No difference was seen between arms in the groups of patients with three or fewer positive axillary nodes, as was the case between groups with four or more involved nodes.
As expected, patients with three positive nodes or fewer had an advantage over patients with a greater number of involved nodes, both for arm A and arm B, and in terms of both disease-free survival (5-year cumulative disease-free survival, 0.66 in the group with three or fewer nodes and 0.31 in the group with greater than three nodes [P = .002]), and overall survival (5-year cumulative overall survival of 0.80 and 0.50, respectively [P = .014]).
The main toxicities observed are shown in Table 2, either as maximal individual toxicity or as percent of cycles in which each grade of toxicity appeared. As can be seen, the side effect encountered most commonly was nausea/vomiting, which was severe in 30% of patients in arm B and 26% of those in arm A. This small difference is eliminated when toxicity is evaluated by cycles of treatment rather than patients; nausea/vomiting was severe in only 10% of cycles but was responsible for the only treatment withdrawal (arm B). Surprisingly, diarrhea was not a prominent side effect in either arm of this study. Bone marrow toxicity was mild, mainly grade 1 and 2, and occurred more frequently in arm B.
We are not familiar with other studies evaluating breast cancer treatment with orally administered agents in the adjuvant setting. In patients with advanced disease, the same drug combinations have been used, and recently two studies have reported encouraging results with a new anthracycline, idarubicin(Drug information on idarubicin) (Idamycin) in the treatment of advanced breast cancer.[7,8]
Our major concern in the present study is the poor outcome of the patients in the control arm, principally with regard to disease-free survival. When we planned the study, we thought that low doses would be better tolerated by patients who were otherwise healthy, without compromising the drugs effect on tumor cells. This idea does not seem to be true, although some trials have not shown any difference regardless of doses used. A recent study has demonstrated that high and intermediate doses of doxorubicin(Drug information on doxorubicin) and cyclophosphamide are more effective than low doses.
Low-dose CMF has been used in three different trials, and all of them have shown an effect on overall survival.[12-14] However, the effect on disease-free survival has been minimal or null. Our results are consistent with those of these three different trials, although we used chemotherapy for fewer cycles because the studies from Milan had shown that 6 cycles of CMF were as effective as 12.
Our second concern is toxicity. The bone marrow is scarcely affected by either treatment and does not pose a concern when considering oral therapy. Gastrointestinal toxicity is, however, more prevalent and, as expected, is the limiting toxicity of the oral arm, because nausea and vomiting are the most commonly reported side effects of UFT and prednimustine. These toxicities were not so important as to jeopardize the treatment, even though some patients complained about prolonged, low-level symptoms.
We conclude that UFT-prednimustine is as active a combination as CMF as used in this trial and is a treatment that could be considered in patients who, for physical or sociologic reasons, are ineligible for intravenous therapy or who simply prefer oral administration of therapy.