The efficacy of long-term oral chemotherapy with 5′-deoxy-5-fluorouridine and cyclophosphamide for recurrent breast cancer

Background 5-Deoxy-5-fluorouridine (5-DFUR) is a prodrug of 5-fluorouracil (5-FU), which is known to be converted by thymidine phosphorylase (dThdPase). A recent preclinical study revealed that cyclophosphamide (CPA) upregulated dThdPase activity, specifically in tumor cells. The purpose of the present study was to examine the efficacy of long-term administration of 5-DFUR/CPA for patients with recurrent breast cancer.Methods Fifteen breast cancer patients with recurrent tumors entered this study. Ten patients had bone metastasis, five had lung metastasis, and two had liver metastasis. Three patients had multiorgan metastases. All patients had had previous exposure to standard chemotherapy such as CAF (CPA, doxorubicin, and 5-FU) and CMF (CPA, methotrexate, and 5-FU). The patients were orally administered with daily doses of 5-DFUR at 800–1200mg and CPA at 200mg for 2 weeks as induction therapy, followed by 2 weeks rest (one to two cycles). Daily doses of 800mg of 5-DFUR and 100mg of CPA (as maintenance therapy) were continuously administered thereafter. Ten of the 15 patients received the maintenance therapy alone. The treatment was continued for at least 24 months (average, 35.2 months).Results The main findings included a significant decrease in pain in nine patients with bone metastasis, and this effect continued for more than 2 years. As the pain decreased, the patients quality of life (QOL) was improved. Liver metastasis was diminished in two out of two patients. Hematological toxicity of more than grade 3 was recognized in three patients, but only during the induction therapy.Conclusion Oral administration of 5-DFUR/CPA is well tolerated and useful for patients with recurrent breast cancer.     

Clinical usefulness of oral combination chemotherapy of 5′;-deoxy-5-fluorouridine (5′;-DFUR) and cyclophosphamide for metastatic Breast Cancer

BACKGROUND: It has been reported that 5'-deoxy-5-fluorouridine (5'-DFUR), the pro-drug of 5-FU, is effective treatment for breast cancer that express thymidine phosphorylase (dThdPase). Since oral cyclophosphamide (CPA) induces dThdPase, a synergistic effect can be expected by combining CPA with 5'-DFUR. We evaluated the usefulness of combination chemotherapy using CPA and 5'-DFUR in patients with relapsed breast cancer in this prospective phase II study. METHODS: Patients with relapsed, advanced breast cancer with evaluable lesions were given 5'-DFUR at 800 mg/day/body and CPA at 100 mg/day/body for 2 weeks, then underwent 2 weeks of drug withdrawal. This was considered one course of treatment. It was repeated until progressive disease (PD) was confirmed. The lesions were evaluated according to UICC criteria and compared with regard to the clinical status. RESULTS: Sixty-four patients with relapsed, advanced breast cancer were registered. Complete response (CR) was seen in 7 patients, partial response (PR) in 12 patients, no change (NC) in 25 patients, of whom 11 achieved long NC with the effect lasting for more than 6 months, and PD was seen in 20 patients. The response rate was 29.7%. The total number of CR, PR, and long NC cases was 30, which comprise-46.9% of the total 64 cases (the clinical benefit rate). As for adverse events, hematological toxicities were seen in 9 patients, with grade 3 toxicits was seen in 1 patient. All other adverse events were grade 1 or 2. CONCLUSION: For those patients who achieved an effect more than NC, it was possible to continue the therapy for an average of 53 weeks. This treatment method is worth considering for patients who have metastatic breast cancer, that is not life threatening.     

Pharmacokinetic and pharmacodynamic comparison of fluoropyrimidine derivatives, capecitabine and 5′-deoxy-5-fluorouridine (5′-DFUR)

Purpose Capecitabine is a three-step prodrug that was rationally designed to be a more effective and safer alternative to its intermediate metabolite, 5-deoxy-5-fluorouridine (5-DFUR). We compared the pharmacokinetics/pharmacodynamics of these drugs in metastatic breast cancer patients.Methods Six patients received oral capecitabine at 1657 mg/m² twice daily and 17 received 5-DFUR at 400 mg three times daily. Both drugs were administered for 21 days followed by a 7-day rest.Results Median daily 5-DFUR AUC was significantly higher for capecitabine than for 5-DFUR (81.1 vs 32.6 mmol h/l; P=0.01). Following treatment with 5-DFUR, the median AUC and C_max of 5-DFUR tended to be higher in patients with a partial response (3.83 g h/ml and 4.88 g/ml) and stable disease (6.46 g h/ml and 4.96 g/ml) than in those with disease progression (2.53 g h/ml and 1.36 g/ml). The AUC and C_max of 5-DFUR was significantly related to overall survival.Conclusions These results support the superiority of capecitabine over 5-DFUR.     

Effect of uridine coadministration on 5′-deoxy-5-fluorouridine disposition in rats

Summary Uridine (UR) inhibits the metabolic activation of 5-deoxy-5-fluorouridine (dFUR) to 5-fluorouracil (FU) by the intestinal pyrimidine nucleoside phosphorylases and could potentially reduce its intestinal toxicity. This study examined the effect of UR coadministration on the absorption and disposition of an oral dose of dFUR. Rats were given dFUR alone (500 mg kg^-1) and dFUR (300 mg kg^-1) plus UR (4.5 g kg^-1) in a random crossover experiment. Simultaneous injection of a tracer dose of [6-³H]dFUR was used to asses the total body clearance (Cl) of dFUR. The absorption of UR was rapid and variable. The UR dose produced a maximal blood concentration of 80 g/ml for UR and 100 g/ml for its metabolite uracil (U). The absorption of dFUR was slower than UR, as indicated by its later time of maximal concentration. UR did not alter the Cl of dFUR, but reduced the absorption rate of dFUR from the gastrointestinal tract and significantly reduced the absolute oral bioavailability of dFUR from 55.2% to 33.4%. The effects of UR coadministration on the dFUR metabolite FU were opposite to those on dFUR; the FU availability was increased sixfold, and the elimination of FU was reduced. Based on the known competition between pyrimidine bases for their saturable metabolic enzymes, the increase in FU availability by UR coadministration was likely due to a competitive inhibition of FU metabolism by U. This study established the complex pharmacokinetic interactions between dFUR and UR and between their metabolites, which may be important in the modulation of dFUR activity by UR.Supported in part by research grants CA-37110, CA-43365 and P30CA16058-12 from the National Cancer Institute, USPHS     

Potentiation of the chemotherapeutic action of 5′-deoxy-5-fluorouridine in combination with guanosine and related compounds

Summary The effect of inosine, guanosine, and guanosine 5-monophosphate (GMP) on the antitumor activity of 5-deoxy-5-fluorouridine (5-DFUR) was investigated using P388 leukemia and P815 mastocytoma.The antitumor activity of 5-DFUR was markedly enhanced by coadministration of inosine or guanosine. The increase in lifespan (ILS) of mice treated with 5-DFUR was augmented by the combination with guanosine or inosine in a dose-dependent fashion, and the maximum ILS was about 160% with the combination, while that in the case of 5-DFUR alone was only 48% in the P388 leukemia system. The therapeutic ratio (dose at ILS_max/dose at ILS₃₀) of the combination with guanosine or inosine was 333 and 136, respectively, whereas that of 5-DFUR alone was 3.6. GMP also markedly potentiated the antitumor activity of 5-DFUR in both P388 leukemia and P815 mastocytoma systems, just as it potentiated the activity of 5-fluorouracil in the latter system.The uric acid level in the serum was elevated after IP injection of guanosine or inosine but the value was much lower in the case of guanosine than in inosine.     

Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5′-deoxy-5-fluorouridine

The present study shows that various cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and interferon- (IFN) make tumor cells much more susceptible to the cytostatic 5-deoxy-5-fluorouridine (5-dFUrd) than to 5-fluorouracil (5-FUra) and other cytostaties. These three cytokines increased the susceptibility of human cancer cell lines (COLO201, MKN45 and WiDr) but did not affect that of normal fibroblast WI38 cells. The cytokine mixture induced a 50-fold increase in the susceptibility of COLO201 to 5-dFUrd, whereas a 12-fold increase and a less than 5-fold enhancement in the susceptibility to 5-FUra and other cytostatics, respectively, were observed. The increased susceptibility would be a result of the induction of thymidine phosphorylase (TdR Pase), which is the essential enzyme for the conversion of 5-dFUrd to 5-FUra. The cytokine mixture increased TdR Pase activity by up to 47 times and greatly induced its mRNA expression in the cancer cell lines. These results suggest that the therapeutic benefit of 5-dFUrd would be improved by its use in combination with the cytokines.     

New approach to metabolism of 5′-deoxy-5-fluorouridine in humans with fluorine-19 NMR

Summary The metabolism of 5-deoxy-5-fluorouridine (5dFUrd), an antitumor fluoropyrimidine, has been investigated in human biofluids (blood, plasma, urine) using a new method: fluorine-19 NMR spectrometry. This method allows direct study of the biological sample and simultaneous identification of all the fluorinated metabolites. In the blood of a patient treated with 5dFUrd during a 6-h continuous perfusion, we observed unmetabolized 5dFUrd, 5-fluorouracil, 5,6-dihydrofluorouracil, and another metabolite which has not previously been reported -fluoro--alanine. The two major metabolites in urine are unmetabolized 5dFUrd and -fluoro-alanine.     

Chemotherapy or Endocrine Therapy for Metastatic Breast Cancer?

Hispanic women differ from non-Hispanics in breast cancer incidence, stage at diagnosis, and survival. Ethnic differences in genetic makeup, reproductive patterns, diet, socioeconomic status, physical activity, and other unidentified cultural factors may be responsible for the disparity. This study investigated occurrences of p53 tumor suppressor gene mutations in South Florida white Hispanic and white non-Hispanic women with primary breast cancer. Tumor tissues were obtained from a consecutive series of women with breast cancer who underwent breast resection at the Jackson Memorial Hospital, Miami, Florida between 1984 and 1986. A total of 231 women with primary breast cancer, aged 31–85 years, were included in the study. Among them, 64 (27.7%) were white Hispanic and 167 (72.3%) were white non-Hispanic. The majority of the patients were white non-Hispanics (72.3%). Compared to white non-Hispanics, however, white Hispanics had significantly higher proportions of tumors larger than 2cm (53.1% v.s. 28.7%, p = 0.00) as well as larger tumor size at diagnosis (mean: 4.2 v.s. 3.0cm, p = 0.00). The p53 gene mutation rate was significantly lower in white Hispanics than in white non-Hispanics (51.6% v.s. 70.7%, p = 0.01). Furthermore, among node-negative breast cancer patients, after adjustment for tumor size at diagnosis, logistic regression results showed that white Hispanics were 71% less likely than white non-Hispanics to carry p53 mutations (OR = 0.29 and 95% CI = 0.09–0.91). We conclude that white Hispanic women with breast cancer might have lower p53 gene mutation prevalence than white non-Hispanic women.     

Comparative antitumor activity of ruthenium derivatives with 5′-deoxy-5-fluorouridine in chemically induced colorectal tumors in SD rats

Summary The activity of the newly synthesized ruthenium derivative imidazolium-bis(imidazole)tetrachlororuthenate (III) [ImH(RuIm₂Cl₄)] was compared with that of 5-deoxy-5-fluorouridine (5dFUR) in autochthonous acetoxymethyl-methylnitrosamine (AMMN)-induced colorectal cancer in SD rats. Following coloscopic diagnosis of colorectal tumors treatment was administered twice weekly for a 10-week period. ImH(RuIm₂Cl₄) exhibited considerable antitumoral efficacy compared with 5dFUR (20 T/C % and 60 T/C %, respectively) against the growth of AMMN-induced colorectal adenocarcinoma in SD rats. The mortality rates with ImH(RuIm₂Cl₄) were dose-related, but its efficacy did not vary in all doses administered.     

Long-Term Outcomes After Autologous or Tissue Expander/Implant–Based Breast Reconstruction and Postmastectomy Radiation for Breast Cancer

PurposeThe toxicity profile of breast reconstruction with postmastectomy radiation therapy (PMRT) varies by technique and timing, and long-term data are limited. We compared rates of complications requiring reoperation (CRR) and reconstruction failure (RF) between immediate autologous reconstruction (I-AR), immediate tissue expander/implant reconstruction (I-TE/I), delayed autologous reconstruction (D-AR), and delayed tissue expander/implant reconstruction (D-TE/I) in patients receiving PMRT.Methods and MaterialsPatients who received autologous reconstruction (AR) or tissue expander/implant reconstruction (TE/I) and PMRT between 2000 to 2008 were included. Reconstruction was immediate if performed on the same day as mastectomy followed by PMRT (I-AR or I-TE/I) or delayed if after PMRT (D-AR and D-TE/I). CRR was defined as an unplanned return to the operating room for infection, dehiscence, necrosis, hematoma, or hernia (with AR) and extrusion, leak, or contracture (with TE/I). RF was defined as unplanned conversion to another reconstruction technique or to flat chest wall. Cumulative incidence of CRR and RF was calculated using Kaplan–Meier and compared using the log-rank test. Logistic regression was used to identify variables associated with CRR and RF.ResultsTwo hundred four patients were included. Median follow-up was 8 years. There were 127 AR cases (63%) and 77 TE/I cases (38%). At 5 years, CRR was 18%, 38%, 34%, and 70% (P = .010) and RF was 4%, 22%, 7%, and 56% (P < .0001) for I-AR, I-TE/I, D-AR, and D-TE/I, respectively. On multivariate analysis, TE/I (hazard ratio [HR] 2.0; P = .011), body mass index ≥30 (HR 3.9; P = .002), and smoking (HR 2.7; P = .001) were significant predictors for CRR, and TE/I (HR 6.6; P < .0001), diabetes (HR 4.1; P = .044), and hypertension (HR 3.5; P = .005) were significant for RF. When excluding RF because of infection, the rate of RF was not significantly different among the 4 groups (P = .23).ConclusionsWith PMRT, TE/I reconstruction in the immediate and delayed setting is associated with higher CRR and RF compared with AR. Patient factors should guide selection of technique. Efforts to reduce rates of RF with TE/I should focus on minimizing risks for infection.     

A case of metastatic breast cancer achieving complete response by combination therapy with 5’-deoxy-5-fluorouridine and cyclophosphamide

Recently there have been several reports on the effectiveness of combination chemotherapy with 5'-deoxy-5-fluorouridine (5'-DFUR) and cyclophosphamide (CPA) for treating recurrent breast cancer. We report a case in which treatment of local recurrence and lung metastases responded was remarkably effective by this combination chemotherapy. A 45-year-old woman underwent modified radical mastectomy for left breast cancer (T2N0M0) three years previously. Involvement of a left supraclavicular lymph node (ScLN) and multiple lung metastases were revealed 2 years and 6 months after the operation. First, we opted for systemic endocrine therapy with local irradiation for the lung metastases and ScLN. However the lung metastases were found to have increased on chest x-ray 2 months after treatment, showing progressive disease (PD). A locally recurrent new lesion sized 2 x 2 cm had also developed. Thus, we changed the treatment to combination chemotherapy with 5'-DFUR 800 mg/body and oral CPA 100 mg/body once a day. The lung metastases had disappeared on chest x-ray and the local recurrence was not palpable after 7 weeks of the new treatment. Thymidine phosphorylase (dThdPase) immunostaining of the primary tumor was strongly positive in almost all cancer cells. We discuss the mechanism of the increased efficacy of combination chemotherapy with 5'-DFUR and CPA.     

A case of chest wall recurrence of breast cancer treated with paclitaxel weekly, 5’-deoxy-5’-fluorouridine,arterial embolization and chest wall resection

Chest wall resection and reconstruction has proved to be a safe surgical procedure for local recurrence of breast cancer. Recently, as second- or third-line chemotherapy for the patients with recurrent breast cancer or ovarian cancer, weekly paclitaxel has provided a significant response rate in those patients, and generated much clinical interest. We report here a case of chest wall recurrence of breast cancer successfully treated by a combination of weekly paclitaxel, 5'-deoxy-5-fluorouridine, arterial embolization, and chest wall resection. A 56-year-old woman presented with a large mass in the left anterior chest. A recurrent tumor developed and enlarged one-and-half years after undergoing modified radical mastectomy for advanced breast cancer (T4N2M0, stage III B) at another hospital. The mass had enlarged while the patient underwent chemotherapy with cyclophosphamide, doxorubicin, 5-fluorouracil, and anastozole, followed by low-dose cisplatin, 5-fluorouracil, and goserelin. To reduce the mass and inflammatory changes of the skin, weekly paclitaxel and 5'-deoxy-5-fluorouridine was given. Furthermore, to obtain hemostasis and promote the mass reduction, arterial embolization of the supply arteries was performed. Chest wall resection, reconstruction of the bony chest wall with polypropylene mesh folded 8 times, and soft tissue reconstruction with a contralateral myocutaneous flap were carried out successfully. The patient was discharged from the hospital ten weeks after the operation without any major morbidity, and remained well for ten months. A multimodal approach with chemotherapy and arterial embolization was effective in this case in treating chest wall recurrence of breast cancer. Reconstruction of the chest wall bone with polypropylene mesh folded 8 times and soft tissue reconstruction with a contralateral myocutaneous flap was a useful procedure after chest wall resection, even after chemotherapy and arterial embolization.     

Clinical results of thermoradiotherapy for locally advanced and/or recurrent breast cancer—comparison of results with radiotherapy alone

From August 1979 until 1988, 26 breast cancer patients with 30 tumours were treated by hyperthermia in combination with radiotherapy. Of the 30 tumours, 11 were locally advanced primary tumours (group 1), six were locally advanced recurrent tumours after operation (group 2) and 13 were locally recurrent tumours after radiotherapy (group 3). The thermal profiles showed that the capability of an RF capacitive heating device is comparatively high for large breast tumours with a volume of more than 100 cm³, and that of a 430 MHz microwave device with a single-lens applicator is excellent for localized tumours. The response rate of group 1 and 2 tumours was excellent, and superior to that of historically controlled tumours that were treated by radiotherapy alone from July 1962 until August 1979. In group 3 the tumour response to thermoradiotherapy was not different from that to radiotherapy, but the possibility of significantly reducing total irradiation dose was indicated. More than one good heating session led to a significantly high local response, and factors having a tendency to influence local response were average minimum tumour temperature, tumour volume, and number of effective heat treatments.     

Inducing or Preventing Subsequent Malignancies for Breast Cancer Survivors? Double-edged Sword of Estrogen Receptor and Progesterone Receptor

Introduction

Hormone receptor and human epidermal growth factor receptor 2 (HER2) status is important for breast cancer (BC) treatment. Previous studies have shown that the long-term treatment outcomes of BC are significantly impaired by the development of subsequent malignancies. Therefore, in the present study, we evaluated the effect of hormone receptor/HER2 status on subsequent malignancies in breast cancer survivors.

Is Partial Breast Irradiation a Safe and Effective Treatment Approach for Women with Early-Stage Breast Cancer?

Breast-conserving therapy (BCT) represents the standard care in the management of early-stage breast cancer, because long-term outcomes with breast conservation are comparable with those of mastectomy. Adjuvant radiation therapy remains an essential component of BCT with standard techniques requiring 5–6½?weeks. Accelerated partial breast irradiation (APBI) is a technique developed over the past two decades that enables completion of treatment in one week or less. Review of the expanding literature reveals increasing support for APBI using several techniques, including interstitial brachytherapy, balloon-based brachytherapy, and external beam therapy. Novel treatment strategies, including intraoperative radiation therapy, hypofractionated APBI, and proton therapy, require further results before definitive conclusions can be made. Although there is currently a lack of level I evidence, with the pending publication of multiple phase III trials comparing whole-breast irradiation and APBI, modern treatment incorporating APBI should soon be developed.