UFT in Combination as Adjuvant Therapy for Breast Cancer

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Article
OncologyONCOLOGY Vol 11 No 9
Volume 11
Issue 9

Between 1989 and 1993, 409 evaluable patients with breast cancer have been treated with tegafur and uracil (UFT) in an adjuvant setting in two different trials. Data from both trials were reviewed in December 1995 after a

ABSTRACT: Between 1989 and 1993, 409 evaluable patients with breast cancer have been treated with tegafur and uracil (UFT) in an adjuvant setting in two different trials. Data from both trials were reviewed in December 1995 after a mean follow-up of 5.09 ± 1.1 years (range, 2.9 to 7.1 years). The aim of the first trial was to demonstrate the activity of UFT 400 mg/day for 6 months plus prednimustine 60 mg/m2 for 7 consecutive days, every 28 days in 6 cycles given orally (arm B). This scheme was compared with 6 cycles of cyclophosphamide 600 mg/m2, plus methotrexate 40 mg/m2, plus fluorouracil 600 mg/m2, every 4 weeks (arm A). In this study, 187 premenopausal women were evaluable, 96 in arm A and 91 in arm B, all of whom had positive axillary nodes. Although there were more younger patients in arm A than in arm B, prognostic factors were similar in both groups. Disease-free survival and overall survival were similar in both arms. However, some concern is raised by the low disease-free survival rate. The toxicity was mild (mainly nausea and vomiting and alopecia) and slightly worse in arm A. We believe that oral administration could be a useful alternative to the parenteral route. In the second trial, 222 evaluable patients received 20 mg/day of tamoxifen (Nolvadex) for 1 year (arm A), or the same dose of tamoxifen plus UFT 400 mg/day for 6 months. All patients were postmenopausal, and the characteristics of the tumors were the same as those in patients in the first trial. In arm A there were 109 patients and in arm B, 113. The groups were well balanced. The overall survival and the disease-free survival rates were equal in both arms, but were longer in arm B in the subset of patients with five or more axillary-involved nodes. The toxicity was negligible in both arms. We conclude that UFT/tamoxifen might be useful in postmenopausal patients with five or more involved nodes who are unable to follow a more aggressive schedule because of their age or low performance status.[ONCOLOGY 11(Suppl 10):74-81, 1997]

Introduction

The combination of tegafur and uracil (UFT) is active in the treatment of advanced breast cancer,[1] with a response rate of 20%. For this reason, and because it can be given orally with a low level of toxicity,[2] 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.

UFT In Premenopausal Women

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 (Prelone, Prednisone) and has been shown to be active against advanced breast cancer when taken orally.[3] The comparative treatment used in this study was cyclophosphamide (Cytoxan, Neosar)/ methotrexate/fluorouracil (5-FU) (CMF), a combination traditionally used in the adjuvant treatment of breast cancer.[4]

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 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[5] and the comparison between curves by the log rank test.[6] 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.

Results

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.

Discussion

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 (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,[9] although some trials have not shown any difference regardless of doses used.[10] A recent study has demonstrated that high and intermediate doses of doxorubicin and cyclophosphamide are more effective than low doses.[11]

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.[15]

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[2] and prednimustine.[3] 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.

UFT In Postmenopausal Women

The aim of the second trial was to evaluate the feasibility of adding UFT to tamoxifen (TMX) (Nolvadex) and to determine whether this combination produced a better outcome than tamoxifen alone in the treatment of postmenopausal women with breast cancer.

Materials and Methods

In this study, 255 postmenopausal women were randomly allocated to one of two treatment groups: Patients in arm A were treated with tamoxifen 10 mg/12 hours for one year. Those in arm B were given tamoxifen, as in arm A, plus UFT 400 mg in two divided doses daily for 6 months.

All the procedures of staging, surgery, follow-up, and statistical analysis were the same as for the first trial. Inclusion criteria also were identical, except for menopausal status and patient’s age, which for this study had to be less than 75 years. Postmenopausal status was defined as 3 years or more past cessation of menses.

Results

Of 225 patients initially enrolled in this trial (127 in arm A and 128 in arm B), 33 were considered ineligible (18 in arm A and 15 in arm B). Although the major reason for ineligibility was failure to meet eligibility criteria (22 patients), 11 patients gave up treatment after the first visit. The remaining 222 patients (109 in arm A and 113 in arm B) were eligible for evaluation of disease-free survival, overall survival, and toxicity. Characteristics of these patients are shown in Table 3.

With the same follow-up period as the previous trial, there have been 42 relapses and 21 deaths in arm A and 50 relapses and 20 deaths in arm B. There were no statistical differences between outcomes for the two groups. The 5-year cumulative disease-free survival rate was 0.58 for patients on arm A and 0.54 for those on arm B (P = .662) (Figure 3). The 5-year overall survival for the treatment groups was 0.75 and 0.73, respectively (P = .507) (Figure 4).

In the group treated with tamoxifen alone, there was no difference in outcome related to the number of involved nodes, as has been described elsewhere.[16] In the group treated with tamoxifen/UFT, however, the disease-free survival was better for patients with three or fewer involved nodes than for those with four or more (5-year cumulative disease-free survival of 0.72 and 0.43, respectively [P = .027]). This difference was reflected in overall survival (5-year cumulative survival, 0.81 and 0.69, respectively [P = .256]).

When we compare the results between arms, we find no difference when we consider the traditional groups of patients with three or fewer involved nodes vs more than three involved nodes: 5-year cumulative disease-free survival was 0.64 in arm A and 0.72 in arm B for those with three or fewer nodes (P = .52) and 0.52 in arm A and 0.43 in arm B for those with more than three involved nodes; corresponding figures for 5-year overall survival were 0.84 vs 0.81 for those with three or fewer positive nodes (P = .75) and 0.69 in both arms for patients with more than three involved nodes (P = .85).

However, if we look at patients with greater than four involved nodes (Figure 5 and Figure 6), we find a trend toward a better outcome for patients in arm B: 5-year disease-free survival was 0.38 in arm A and 0.45 in arm B (P = .09), and 5-year overall survival was 0.39 in arm A and 0.71 in arm B (P = .134). This difference was even more evident in the group with more than five involved nodes (Figure 7 and Figure 8): 5-year disease-free survival was 0.30 in arm A and 0.44 in arm B (P = .032); 5-year overall survival was 0.24 in arm A and 0.74 in arm B (P = .024).

In this study, toxicity was scarce in both arms, with few documented grade 3-4 toxicities (Table 4). The most frequently observed side effects in both treatment groups were nausea and vomiting, but intensity was mild, reaching only grade 1 in most cases. Seven patients in each arm developed grade 3 diarrhea.

Discussion

The issue addressed in this trial is the utility of combining hormone therapy and chemotherapy. In vitro studies have indicated that the combination would be less effective than using each therapy separately,[17] even more disparate if the drugs combined were tamoxifen and fluorouracil. Some recent works seemed to prove this assumption,[18] but other trials, including the Ludwig III[19] and the National Surgical Adjuvant Breast Project B-16[20] studies showed different results, with an advantage seen with combination therapies. When this trial was being planned, the common belief was that the combination of chemotherapy plus tamoxifen was a better approach to treatment for postmenopausal women with more than three involved nodes, as Glick suggested.[21]

Results of trials using tamoxifen and UFT have not been available, although we are aware that such trials are being conducted in Japan. However, there are a number of studies of combination tamoxifen plus tegafur, the active principle of UFT; the majority of these studies compare tamoxifen/tegafur with tegafur alone, and most show some advantage for the combination overall in postmenopausal and/or estrogen receptor-positive patients.[22-24]

Our results should be considered with caution. However, they do agree with the proposal by Glick[21] in that they show an improvement in outcome for patients with the worst prognostic factors when they are treated with combination tamoxifen/UFT. No effect has been seen for the group as a whole or for low-risk patients.

The low toxicity profile of the combination regimen may be attributable to the low dose of UFT, selected specifically to avoid excessive toxicity.

Conclusions

We conclude that tamoxifen/UFT is a feasible adjuvant treatment option, with a low toxicity profile, for postmenopausal women. It could have some activity in patients with poor prognostic factors and, consequently, could be useful to treat patients for whom more aggressive therapy in unsuitable.

We emphasize the risk of drawing conclusions from a study of patient subsets, but we believe our results hint at something worthy of further study.

References:

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2. Martin M, Estape J, Guillem V, et al: Toxicidad del UFT (ftorafur-uracilo) oral. Neoplasia 4:63-66, 1987.

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4. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294:405-410, 1976.

5. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958.

6. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163-170, 1966.

7. Barnadas A, Mendiola C, Casado A, et al: Oral idarubicin and prednimustine combination in advanced breast cancer (abstract). Ann Oncol 3(suppl 5):89, 1992.

8. Alberto P: Phase II study of an oral combination of doxifluridine, prednimustine and idarubicin (Fuprida) for first-line treatment of advanced breast cancer. Ann Oncol 4:423-525, 1993.

9. Goldhirsch A, Wood SC, Senn HJ, et al: International consensus panel on the treatment of primary breast cancer. Eur J Cancer 31A:1754-1759, 1995.

10. Ludwig Breast Cancer Study Group: A randomized trial of adjuvant combination chemotherapy with and without prednisone in premenopausal breast cancer patients with metastases in one to three auxiliary lymph nodes. Cancer Res 45:4454-4459, 1985.

11. Wood WC, Budman DR, Korzun AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330:1253-1259, 1994.

12. Clahsen PC, van de Velde CJH, Welvaart K, et al: Ten year’s results of a randomized trial evaluating prolonged low dose adjuvant chemotherapy in node-positive breast cancer: A joint European Organization for Research and Treatment of Cancer—Dutch Breast Cancer Working Party study. J Clin Oncol 13:33-41, 1995.

13. Dombernowsky P, Hansen PS, Mouridsen HT, et al: Randomized trial of adjuvant CMF + radiotherapy vs CMF alone vs CMF + tamoxifen (TAM) in pre- and menopausal stage II breast cancer (abstract) . Ann Oncol 5(suppl 8):2, 1994.

14. Scottish Cancer Trial Office and ICRF Breast Unit, Guy’s Hospital, London: Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: The Scottish trial. Lancet 341:1293-1298, 1993.

15. Tancini G, Bonadonna G, Valagussa P, et al: Adjuvant CMF in breast cancer. Comparative 5-year results of 12 versus 6 cycles. J Clin Oncol 1:2-10, 1983.

16. Baun M, Brinkley DM, Dosset JA, et al: Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Analysis at eight years by Nolvadex Adjuvant Trial Organization. Br J Cancer 57:608-611, 1988.

17. Kitten L, Osborne K: Antiestrogens antagonize melphalan but not cyclophosphamide cytotoxicity in human breast cancer cells by estrogen receptor-independent mechanisms (abstract). Proc Am Soc Clin Oncol 7:9, 1988.

18. Rivkin SE, Green S, Merch B, et al: Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal node-positive and estrogen receptor positive breast cancer patients. A Southwest Oncology Group study. J Clin Oncol 12:2078-2085, 1994.

19. Goldhirsch A, Gelber RD: Adjuvant chemo-endocrine therapy or endocrine therapy alone for postmenopausal patients. Ludwig studies III and IV. Recent Results. Cancer Res 115:153-162, 1989.

20. Fisher B, Redmon C, Legault-Poisson S, et al: Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 8:1005-1018, 1990.

21. Glick JH: Meeting highlights: adjuvant therapy for breast cancer. J Natl Cancer Inst 80:471-475, 1988.

22. Toi M, Hattori T, Akagi M, et al: Randomized adjuvant trial to evaluate the addition of tamoxifen and PSK to chemotherapy in patients with primary breast cancer. Five-year results from the Nishi-Nippon Group ofthe Adjuvant Chemoendocrine Therapy for Breast Cancer Organization. Cancer 70:2475-2483, 1991.

23. Abe R, Tsuchiya A, Koie H, et al: A randomized controlled study of adjuvant chemoendocrine therapy for breast cancer in Japan. Am J Clin Oncol 17:103-108, 1994.

24. Sakai K, Kosaki G, Seno T, et al: A randomized trial comparing Ftorafur alone with Ftorafur plus tamoxifen on postoperative adjuvant therapy for breast cancer. Kinki Area Research Group for postoperative adjuvant therapy for breast cancer. Cancer Chemother Pharmacol 37:587-592, 1996.

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