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A Phase II Study of Adjuvant Chemotherapy of Tegafur–Uracil For ANTICANCER RESEARCH 36 : 6505-6510 (2016) doi:10.21873/anticanres.11250 A Phase II Study of Adjuvant Chemotherapy of Tegafur –Uracil for Patients with Breast Cancer with HER2-negative Pathologic Residual Invasive Disease After Neoadjuvant Chemotherapy SATORU TANAKA 1, MITSUHIKO IWAMOTO 2, KOSEI KIMURA 2, YUKO TAKAHASHI 3, HIYOYA FUJIOKA 2, NAYUKO SATO 4, RISA TERASAWA 2, KANAKO KAWAGUCHI 2, AYANA IKARI 2, TOMO TOMINAGA 2, SAKI MAEZAWA 2, NODOKA UMEZAKI 2, JUNNA MATSUDA 2 and KAZUHISA UCHIYAMA 2 1Breast Surgery, National Hospital Organization Osaka-Minami Medical Center, Kawachinagano, Japan; 2Breast and Endocrine Surgery, Osaka Medical College Hospital, Takatsuki, Japan; 3Breast and Endocrine Surgery, Hirakata City Hospital, Hirakata, Japan; 4Breast Surgery, Saiseikai Suita Hospital, Suita, Japan Abstract. Background: There is no consensus on the need an opportunity for down-staging to avoid mastectomy for for adjuvant chemotherapy for patients with pathological inoperable tumors or breast-conserving surgery in cases residual invasive breast cancer (non-pCR) after neoadjuvant originally requiring mastectomy (1, 2). Anthracyclines and chemotherapy (NAC). We evaluated the tolerability and taxanes have been used as the standard chemotherapeutic safety of tegafur-uracil (UFT) as adjuvant chemotherapy for regimens for breast cancer, however, tumoral estrogen patients with human epidermal growth factor receptor 2- receptor (ER) and human epidermal growth factor receptor negative breast cancer that resulted in non-pCR after NAC. 2 (HER2) statuses are important predictors of response to Patients and Methods: We treated patients with 270 mg/m 2 chemotherapy (3-5). Sensitivity to NAC is lower in ER- UFT per day for 2 years after definitive surgery and positive and HER2-negative cancer than in other subtypes. radiotherapy, if necessary. In cases with hormone-sensitive An earlier study of NAC with anthracyclines and taxanes cancer, patients received concurrent endocrine therapy. The reported an approximately 25% pathological complete primary end-point was the rate of completion of scheduled response (pCR) rate in cases of operable breast cancer UFT therapy. Secondary end-points included safety and without taking in mind the ER and HER2 status (6). disease-free survival. Results: Twenty-one out of 29 patients Furthermore, patients achieving pCR have a more favorable (72%) completed the scheduled therapy. Eight patients prognosis than patients with pathological residual invasive discontinued the study treatment because of disease disease (non-pCR) (6-8). Adjuvant endocrine therapy for ER- recurrence, toxicities, and patients’ wish. Excluding liver positive breast cancer and anti-HER2 therapy ( e.g. dysfunction, adverse events were quite mild. Conclusion: Trastuzumab) for HER2-positive breast cancer after NAC Adjuvant UFT therapy after NAC was feasible and safe. currently represent the gold-standard of care. There is a lack of consensus regarding the requirement for an adjuvant Neoadjuvant chemotherapy (NAC) is widely used for both chemotherapy in cases with non-pCR after NAC; however, locally advanced and early-stage breast cancer. The further chemotherapy may improve patient outcomes. advantages of NAC include determining tumor responses to Adjuvant chemotherapy is typically appropriate in patients specific treatment regimens in clinical practice and providing with non-pCR because patients with operable breast cancer frequently experience tumor recurrence approximately 2 years after initial surgery (9). Long-term, daily oral treatment with tegafur-uracil (UFT) Τhis article is freely accessible online. is widely used as an adjuvant chemotherapy for breast, gastric, and colorectal cancer in Japan. (10). A pooled analysis of six Correspondence to: Satoru Tanaka, Breast Surgery, National randomized, controlled trials demonstrated the survival Hospital Organization Osaka-Minami Medical Center, 2-1 benefits of adjuvant UFT plus tamoxifen compared to Kidohigashicho, Kawachinagano, Osaka 586-8521, Japan. Tel: +81 tamoxifen alone for ER-positive early breast cancer (11). 721535761, Fax: +81 721538904, e-mail: [email protected] Moreover, two randomized, controlled trials demonstrated that Key Words: Tegafur-uracil, breast cancer, neoadjuvant chemotherapy, UFT therapy for 2 years had similar efficacy to six cycles of pathologic complete response. cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) 0250-7005/2016 $2.00+.40 6505 ANTICANCER RESEARCH 36 : 6505-6510 (2016) (12, 13). A combined analysis of these trials demonstrated that Table I. Dose and administration of tegafur-uracil. UFT was non-inferior to CMF in terms of inhibiting the Body surface area (m 2) Daily dose (mg) Morning–evening (mg) recurrence of ER-positive, early breast cancer (14). UFT therapy is associated with a lower rate of adverse events ( e.g. <1.3 300 200-100 gastrointestinal symptoms, bone marrow suppression, and hair 1.3-1.67 400 200-200 loss) and better quality of life compared with CMF therapy ≥1.67 500 300-200 (10, 12). However, the safety of UFT therapy in patients previously treated with NAC remains unknown. Therefore, we evaluated the tolerability and safety of adjuvant UFT chemotherapy for 2 years in patients with Table II. Dose reduction of tegafur-uracil per day. HER2-negative breast cancer with non-pCR after standard anthracycline- and taxane-based NAC to assess the Body surface Starting dose 1st step 2nd step preliminary efficacy of UFT therapy. area (m 2) (mg) (mg) (mg) <1.3 300 Discontinued - Patients and Methods 1.3-1.67 400 300 Discontinued ≥1.67 500 400 300 This present study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Osaka Medical College (approval number: 10-798). All the patients provided written informed consent. This study was registered with the University Hospital Medical Information Network-Clinical Trials Registry (UMIN000003835). Adverse Events (version 4.0) (15) and blood examinations throughout the treatment. Treatment was withheld for hematological Patients. This study was a single-center, prospective, open-label, toxicities, including leukocyte count of <3,000/ml, thrombocyte single-arm, phase II clinical trial. Eligible patients were females aged count of <7.5×10 4/ml, hemoglobin level of <9.0 g/dl, AST/ALT ≥20 years with HER2-negative operable breast cancer or locally level of ≥100 IU/l, bilirubin level of ≥2.0 mg/dl, or grade 2 or advanced breast cancer that was suitable for definitive surgery after higher non-hematological toxicities (anorexia, nausea, vomiting, NAC with anthracycline and taxane. Moreover, all the patients were diarrhea, and stomatitis), until improvement of these toxicities was required to have non-pCR that was defined as no histological evidence confirmed. Once adverse events (AEs) had improved following of residual invasive tumor cells in the breast or axillary lymph nodes treatment interruption, the UFT dose was reduced from the initial (ypT0/Tis and ypN0), according to histological assessments of surgical dose at the discretion of the treating physician. The UFT dose specimens. Immunohistochemical analyses for ER, progesterone reductions are shown in Table II. Study treatment was discontinued receptor (PgR), and HER2 were performed for all tumors. Tumors in cases of disease progression or unacceptable toxicity. Supportive with ≥1% positively stained tumor cells were classified as positive for care was provided according to standard practices. All the patients ER and PgR. HER2 negativity was defined as 0 or 1+ staining with ER-positive tumors concurrently underwent UFT therapy with intensity using immunohistochemistry (IHC) or in case with 2+ by adjuvant tamoxifen or aromatase inhibitor endocrine therapy IHC with negative for HER2 gene amplification by fluorescence in (postmenopausal women only). Additional treatment with a situ hybridization (FISH). A FISH ratio of <1.8 was considered luteinizing hormone-releasing hormone analog could be provided to negative. Patients were required to have an Eastern Cooperative premenopausal patients. UFT administration was initiated after Oncology Group performance status of <2, adequate organ function radiotherapy in patients requiring postoperative radiotherapy. [aspartate transaminase (AST), alanine transaminase (ALT), and bilirubin levels at ≤1.5-times the upper limit of normal; leukocyte Study endpoints. The primary study endpoint was the rate of count of ≥3,000/ml; neutrophil count of ≥2,000/ml; thrombocyte count completion of scheduled adjuvant UFT therapy after 2 years. of ≥10×10 4/ml; serum creatinine level of ≤1.5 mg/dl; and normal Secondary endpoints included safety and disease-free survival (DFS) cardiac function on electrocardiography], and no carry-over grade 2 rate. DFS was defined as the time from the initiation of UFT therapy or higher adverse events (except for alopecia) from NAC. Patients to either the first recurrence or relapse, second cancer, or death. with a confirmed infection, serious concomitant illness ( e.g. severe cardiovascular disease, uncontrolled diabetes, malignant hypertension, Statistical analyses. As this trial was an exploratory study to or hemorrhagic disease), active concomitant malignancy, brain evaluate the utility of continuous adjuvant UFT therapy in patients metastasis, history of severe drug allergy, or previous treatment with previously treated with NAC and there are currently no data from oral CMF-based chemotherapy were excluded from this study. previous studies
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