Successful treatment of disseminated breast cancer with combination therapy of 5'-deoxy-5'-fluorouridine (5'-DFUR), medroxyprogesterone acetate (MPA) and cyclophosphamide (CPA)]

A 54 year-old female patient with disseminated breast cancer refractory to various kinds of previous therapies was treated with a combination therapy of 5'-DFUR, MPA and CPA. Partial response (PR) was obtained both against pleural and liver metastases with complete disappearance (CR) of soft tissue lesions and was still being continued for the following 7 months. No serious side effects were observed except for a mild degree of diarrhea and moon face. The patient was enjoying a favorable quality of life. We confirmed that this combination regimen was effective as the second line treatment for disseminated breast cancer.     

Successful treatment of pleuritis carcinomatosa using combination therapy of 5'-DFUR, MPA and CPA as maintenance therapy

A 44-year-old female patient with inoperable, local advanced left breast cancer was treated with 3 cycles of high dose CAF therapy followed by combination therapy of 5'-DFUR, MPA and CPA. The patient was discharged after receiving 3 cycles of high-dose CAF therapy and continued to receive daily oral doses of 5'-DFUR (800 mg), MPA (800 mg), and CPA (100 mg) for 15 months. After 3 cycles of high-dose CAF therapy, tumor marker (CEA, CA 15-3) levels were reduced. Six months later, after 3 cycles of high-dose CAF therapy, the tumor marker levels were within the normal range. No serious side effects were observed during chemotherapy. The patient enjoyed a good quality of life. We thus confirmed that this combination regimen was effective as a maintenance therapy for local advanced breast cancer.     

A case of breast cancer with liver metastases responding remarkably to combination therapy of mitoxantrone (MIT), doxifluridine (5'-DFUR) and medroxyprogesterone acetate (MPA)]

A 60-year-old woman with her right breast cancer showing simultaneous and multiple liver metastases was initially treated with CEFT [cyclophosphamide (CPA), epirubicin (epi-ADM), 5-fluorouracil (5-FU), tamoxifen (TAM)]. After one treatment course the primary lesion did not decrease while tumor markers and liver lesion size increased. Therefore, the foul-smelling primary lesion was resected followed by treatment with mitoxantrone (MIT), 10 mg intravenously every 4 weeks as well as daily/oral administrations of doxifluridine (5'-DFUR) and medroxyprogester-one acetate (MPA). Following MIT administration, the tumor markers decreased markedly, so treatment was continued. After the third course, therapy was continued on an outpatient basis. During treatment WBC reduction to about 3,000/microliter was the only adverse reaction. After 10 courses, the tumor markers were normal, and after 15 courses there were no liver metastases on abdominal CT. Generally, patients with resistance to standard anthracycline chemotherapy are difficult to treat. Those with liver metastasis especially have a poor response which results in a poor prognosis. However, therapy with MIT, 5'-DFUR and MPA may be useful in previously treated, advanced and recurrent breast cancer. Furthermore, this therapy can be done on an outpatient basis, which presumably improves the quality of life (QOL).     

A case of breast cancer with multiple organ metastases responding remarkably to combination therapy of CAF (cyclophosphamide, adriamycin and 5-FU), 5'-DFUR and MPA (medroxyprogesterone acetate)

A 52-year-old woman complaining of breast tumor was diagnosed as having advanced breast cancer (T4bN1M1-Stage IV), with metastasis of multiple organs (lung, liver, mediastinal and unilateral axillary lymph nodes) after which she underwent tumorectomy. Postoperative adjuvant therapy was performed using combined chemoendocrine therapy (CAF + 5'-DFUR + MPA). Following the endocrine therapy, the metastatic lesions of the liver and lung had disappeared. The adverse effects were not remarkable. Complete remission was continued for 2 years and 3 months, and the patient enjoyed a favorable quality of life.     

A case of long surviving advanced recurrent breast cancer with multiple bone metastases responding to treatment with 5'-DFUR combined with MPA

The patient was a 69-year-old woman who had undergone right standard radical mastectomy on August 8, 1991, and was treated with chemo- and hormonal therapy of ADM, UFT and TMA. Three years later she showed multiple bone metastases with elevation of CEA, and 5'-DFUR 1,200 mg/day and MPA 800 mg/day were administered. Two years later her CEA levels were decreased, 5'-DFUR was discontinued and MPA 1,200 mg/day only was continued. Two months later a side effect of MPA, her body weight gain, was observed, and the dosage of MPA was reduced from 1,200 mg/day to 800 mg/day. Then the side effect was resolved. Bone scintigraphy and MRI showed that bone metastatic lesions were reduced 6 years after 5'-DFUR and MPA therapy. It is suggested that this combination therapy may be useful for advanced recurrent breast cancer patients with multiple bone metastases.     

A treatment for pulmonary metastases from colorectal cancer by pre-operative CPT-11/5'-DFUR combination therapy

There is no standardized consensus at each institution about a treatment for pulmonary metastases from colorectal cancer. A case of pulmonary radical resection can expect a good result. However, a result of a nonoperative case is extremely poor. A focal control until the time of operation to a metastatic lesion is very important. We want to have a safe and effective chemotherapy. We experienced a resectable case by CPT-11/5'-DFUR combination therapy.     

A case of recurrent breast cancer with multiple liver metastases responding to combination therapy of capecitabine and MPA

The patient was a 68-year-old woman who underwent left partial mastectomy on February 1999. The stage was T2N1. There were positive for estrogen and progesterone receptors in the tumor. After operation, adjuvant therapy consisting of oral administration of tamoxifen and radiation was performed. On February 2005, she felt dyspnea and right femoral pain. After examinations, she was diagnosed as recurrent breast cancer with pleuritis carcinomatosa and bone metastasis. The patient was treated with oral administration of anastrozole and pamidronate disodium 90 mg intravenously every 4 weeks, radiation of her right femur, and OK-432 injection into the intrapleural cavity. On November 2005, she felt general fatigue and anorexia. CT examination revealed multiple liver metastases. She was treated with oral combination chemoendocrine therapy with capecitabine (2,400 mg/day) and MPA (600 mg/day). After the four courses, multiple liver metastases were remarkably reduced in the CT findings. After twelve courses, the partial response continued. No adverse reactions occurred except for gain in weight of grade 1. It is suggested that this oral combination chemoendocrine therapy may be useful for recurrent breast cancer with consideration for treatment effectiveness and the quality of life of the patient.     

Combination therapy with Anastrozole and 5'-DFUR as a treatment for metastatic breast cancer

For metastatic breast cancer patients who have hormone receptor-positive tumors, hormonal therapy aiming at optimal palliation and prolongation of life is the initial treatment of choice. To enhance the effect of hormonal monotherapy, a combination therapy with Anastrozole 1 mg po and 5'-DFUR 800 mg po daily was given to 11 patients with metastatic breast cancer. At a median follow-up period of 15 months, the overall response rate was 45.5%. The median duration of response in responders was 25 months. The overall median survival for the entire series was 15 months after the start of treatment. No patients complained of adverse events of grade 2 and over. This combination therapy with good response and little side effects is useful for metastatic breast cancer patients.     

A case of breast cancer with multiple bone metastases that responded remarkably to doxifluridine (5'-DFUR), cyclophosphamide (CPA), medroxyprogesterone acetate (MPA) and pamidronate disodium therapy

A 49-year-old female underwent bilateral breast preserving surgery for heterochronic breast cancers. She later developed a sternal metastasis and was recommended for intravenous chemotherapy. However, she refused such an intensive therapy and opted for immunotherapy. Afterward, she came to our hospital because of spinal metastases with back pain. She was treated with oral administration of 5'-DFUR and MPA 1,200 mg/day for 3 weeks, respectively, CPA 100 mg/day for 2 weeks, and pamidronate disodium 30 mg intravenously every 4 weeks. This combined chemotherapy relieved her pain after one course. After 5 courses, tumor markers were reduced to the normal range. After 14 courses, bone X-P revealed that the osteolytic bone showed sclerotic changes and bone scintigraphy showed a complete remission (CR). The adverse effects were not remarkable. This regimen is possible on an outpatient basis, and it may play an important role from the standpoint of treatment effectiveness and the quality of life of the patient.     

Evaluation of weekly paclitaxel and doxifluridine (5'-DFUR) combination therapy in patients with advanced or recurrent breast cancer

To evaluate the feasibility and efficacy of weekly paclitaxel and 5'-DFUR combination therapy in advanced or recurrent breast cancer, 13 patients were enrolled in this pilot study. 5'-DFUR was administered orally at a dose of 800 mg/day for 14 consecutive days, and paclitaxel was administered by 1 hour infusion at a dose of 80 mg/m2 after short premedication on day 1 and 8. This was repeated every 3 weeks, until disease progression or severe side effects precluded further treatment. Antiemetic agents and G-CSF were also administered, as needed. Nine patients had not received prior therapy, and four patients had received prior anthracycline containing therapy, two of whom were concomitantly receiving docetaxel treatment. Median administration time was 14 weeks, and median time to progression was 16.6 weeks. The overall response rate was 46.2% with 7.7% complete response and 38.5% partial response, and the response rate was consistent regardless of metastatic sites. Two patients achieved stable disease for at least 6 months and the clinical benefit was 61.5%. Responses were observed in 25% of the patients with prior anthracycline therapy. Grade 3/4 side effects involved leukopenia in 15.4%, peripheral neuropathy in 7.7%, malaise in 23.1% and nausea in 7.7%. There were no complaints of severe diarrhea. Although one patient withdrew from this study because of a hypersensitive reaction, this regimen was generally well tolerated and QOL was high enough so that it was possible to continue the regimen. Weekly paclitaxel and 5'-DFUR combination therapy seems to be feasible and effective in patients with advanced or recurrent breast cancer.     

A comparative study with 5'-DFUR alone or in combination with tamoxifen (TAM) or medroxyprogesterone acetate (MPA) for advanced or recurrent breast cancer]

A comparative study of 5'-DFUR 600 mg/day alone (C-arm) or in combination with TAM 30 mg/day (A-arm) or MPA 600 mg/day (B-arm) was carried out. Thirty-four patients (aged 80 or less) with no prior treatment were evaluable, and the following results were obtained. 1) Patient characteristics were similar in each treatment group and the compliance in all groups was excellent. 2) The group B response rate (70.0%) was considerably higher than that of group A (23.1%) and C (27.3%). 3) In B, the response rates in soft tissues (80.0%) and bone (71.4%) were still good. 4) Mild side effects were encountered in about 15% of each group. We confirmed that combination chemotherapy with a low dose of 5'-DFUR and MPA was effective for first line treatment of metastatic breast cancer.     

Successful combination therapy with trastuzumab and paclitaxel for adriamycin- and docetaxel-resistant inflammatory breast cancer

We present a case of adriamycin-and docetaxel-resistant inflammatory breast cancer (IBC) in which partial response was achieved with combination therapy using trastuzumab and paclitaxel. A 48-year old woman noticed a lump in her right breast. She was diagnosed with IBC and the disease was staged as T4d N1 M0, stage III B. The patient was started on neoadjuvant chemotherapy with adriamycin (50 mg/m2) and docetaxel (60 mg/m2) administered every three weeks. Six courses were performed and the response was evaluated as no change. After one month, contralateral breast swelling indicated bilateral IBC. Bilatera1 mastectomy using the Halsted method was performed. The immunohistochemical results of the Hercep Test was strongly positive (3+). After the mastectomy, right pleural effusion appeared, and cytological examination revealed the cells to be classV(adenocarcinoma). To treat the clinically advanced breast cancer, combination therapy with trastuzumab (initially 4 mg/kg followed by two or more cycles of 2 mg/kg) and paclitaxel (80 mg/m2) were given intravenously every week for eight cycles and then every two weeks thereafter. A total of 32 courses of therapy were performed, the pleural effusion completely disappeared and partial response was maintained for a duration of 482 days. The adverse reactions were mild, and it was possible for her to be treated as an outpatient with high quality of life. This report suggests that weekly combination therapy of trastuzumab and paclitaxel was useful for treatment of adriamycin-and docetaxel-resistant metastatic breast cancer.     

The efficacy of combination chemotherapy of 5'-deoxy-5-fluorouridine (5'-DFUR), cyclophosphamide (CPA) and medroxyprogesterone acetate (MPA) for bone metastasis in breast cancer patients

5'-DFUR is a pro drug of 5-FU, which is known to be converted by thymidine phosphorylase (dThdPase). A recent pre-clinical study revealed that CPA upregulates dThdPase activity specifically in tumor cells. Furthermore, clinical trials have shown significant response rates in breast cancer patients, when using the chemotherapy combination of 5'-DFUR, CPA and MPA. The purpose of this study was to examine the efficacy of this regimen as a pain reduction therapy for breast cancer patients with bone metastasis. Ten patients who had bone metastasis with restricted ADL were included in the study. All of the patients had had previous exposure to such standard chemotherapy as CAF, CMF, taxol and oral 5-FU administration. The patients were administered daily oral doses of 5'-DFUR at 800-1,200 mg, CPA at 200 mg and MPA at 400-800 mg for two weeks as induction therapy, followed by two weeks rest (one to two cycles). Daily dose of 800 mg of 5'-DFUR, 100 mg of CPA, 400-800 mg of MPA was continuously administered thereafter. The main findings included a significant decrease in pain in eight patients, which continued for more than 6 months. In five patients, the effect lasted more than one year. As the pain decreased, the patients' QOL was improved. Hematological toxicity of more than grade 3 was observed in three patients but only during the induction therapy. One patient had pulmonary thrombosis and required hospitalization. In conclusion, oral administration of 5'-DFUR/CPA/MPA is well tolerated and useful in reducing pain.     

A patient with recurrent breast cancer whose liver metastasis regressed following combined use of weekly docetaxel and MPA.5'-DFUR]

A 28-year-old woman who was 10 months pregnant was diagnosed with left breast cancer. She received preoperative chemotherapy and underwent mastectomy after parturition. Endocrine therapy and adjuvant CMF and CAF was administered, but a bone metastasis appeared 2 years later and a liver metastasis 3 years later. Weekly docetaxel and MPA plus 5'-DFUR combination therapy were successively and simultaneously administered. The liver tumor regressed, and the survival time was prolonged by 1 year and 6 months. This case suggests that the combined use of both therapies was safe for the patient in serious bad condition and had a strong antitumor effect.     

A case of multiple lung metastases of colon cancer with long-term survival following 5'-DFUR and cimetidine therapy

A 77-year-old woman treated for diabetes mellitus was admitted to our hospital for further examination of abnormal findings on chest plain radiograph. Many nodular shadows in both lung fields were seen on chest X ray and chest CT scan. Colonoscopic examination revealed a type 2 tumor in the ascending colon. We diagnosed this case as ascending colon carcinoma with multiple lung metastases, and performed right hemicolectomy and D1 lymph node dissection. After surgery, the patient was administered 5'-DFUR 600 mg/body/day, cimetidine 800 mg/body/day orally. Though no remarkable reduction of tumors was recognized, the increase of tumor size was relatively slow. The patient remains alive 3 years after surgery.     

Clinical trial of 5'-DFUR in patients with recurrent breast cancer

5'-DFUR was administered orally to recurrent breast cancer patients at a daily dosage of 1,200 mg given 3 times a day for more than 8 weeks. Out of 16 evaluable cases, 1 CR, 5 PR, 5 NC and 5 PD were observed, and the overall response rate was 37.5%. There was no significant difference in the response rate between the patient with or without prior fluorinated pyrimidine therapy, or between sites of the lesion. Toxic effects consisted of gastrointestinal toxicity such as diarrhea (25%), anorexia (12.5%), abdominal pain (12.5%) and nausea and vomiting (6.3%). No other severe side effect was observed. These results suggest that 5'-DFUR can be useful for the treatment of breast cancer.     

A case of advanced breast cancer with multiple lung, bone and lymph node metastases successfully treated with 5'-DFUR alone

A 78-year-old female patient with locally advanced breast cancer, bleeding from a deep ulcer, and with multiple bone, lung and distant lymph node metastases was successfully treated with 5'-DFUR alone. She was at first treated with docetaxel + 5'-deoxy-5-fluorouridine (5'-DFUR) + tamoxifen, but they were discontinued because of deep venous thrombosis. She underwent simple mastectomy due to periodically recurring bleeding and infection. After administration of 5'-DFUR alone, a decrease of abnormal accumulation on a bone scintigram was obtained in 10 months, the lung metastases were diagnosed as being in complete remission (CR) at 11 months and the lymph node metastases were diagnosed as being in CR at 14 months. These states have continued to the present. The administration of 5'-DFUR alone is suitable for tumor dormancy in some cases.     

A long-term survivor with stage IV gastric cancer due to postoperative weekly paclitaxel and 5'-DFUR combination therapy

The patient was a 63-year-old woman who presented with upper abdominal discomfort. Type 3 gastric cancer in the midgastric region was diagnosed, and the patient underwent surgery. Because peritoneal metastasis and periaortic lymph node metastasis were confirmed, paraaortic lymph node metastasis, total gastrectomy and D 1 lymph node dissection were performed. Surgical and pathological findings were pType 3, pT 3(SE), sN 3, pP 1, sH 0, CY 1, Stage IV, and Cur C. After surgery, she was treated with five regimens of MTX/5-FU, TS-1 or DOC, but because progressive disease was confirmed, weekly paclitaxel and 5'-DFUR combination therapy was initiated as salvage therapy. Five months after the start of combination therapy, complete response was achieved, and combination therapy was continued for 19 more months. Since no recurrence was observed, therapy was terminated. No severe adverse reactions were observed. The patient has been recurrence-free for 25 months and remains alive as of 68 months after surgery. The present therapy may thus be effective in the treatment of previously treated Cur C advanced gastric cancer.     

Combination therapy with 5'DFUR and MPA as a second line treatment for advanced/recurrent breast cancer

As a second line therapy after failure to previous therapies, a combination therapy with MPA 1,200 mg po and 5'DFUR 1,200 mg po daily was given to 31 patients with recurrent breast cancer. At a median follow up period of 18 months, the overall response rate was 42%. The response rates for bone and visceral lesions were still good for the second line therapy. Patients previously exposed to tamoxifen (24 patients), 5-FU or its derivatives (21) and/or adriamycin (18) had response rates of 42%, 33%, 33%, respectively. The median duration of response in responders was 10 months. The overall median survival for the entire series was 9 months after start of the treatment. Thirteen (81%) of 16 patients with bone lesions were relieved from their bone pain. It is of special interest that the pain relief was also obtained in 7 out of 10 NC/PD patients with bone lesions, resulting in much improvement of their performance status. Side effects included obesity 52%, edema of the leg 35%, diarrhea 16% and so on. One patient developed venous thrombosis of her lower extremities and 4 were suspected to have the same condition. Fifty-five % of the patients underwent dose reduction of MPA at the 5th month of treatment in a median. This combination therapy is useful for recurrent disease even in late stages, so long as close observation is made for the occurrence of thrombosis.     

A phase I study of docetaxel (TXT) and doxifluridine (5'-DFUR) combination therapy in patients with advanced and recurrent breast cancer

We investigated efficacy and tolerance of chemotherapy with doxifluridine (5'-DFUR) and docetaxel (TXT) in advanced/recurrent breast cancer. Subjects were enrolled by central registration. The regimen included 5'-DFUR orally for 14 consecutive days, and TXT intravenously on day 8. It was repeated every 3 weeks, as long as possible, including dosage levels of 5 scheduled steps. Patient registration was started in August 1999 and 5 patients given level 1 regimen (5'-DFUR, 800 mg/day; TXT, 50 mg/m2) were evaluated. Although the results revealed neutropenia of grade 3 in 4/5 patients and leukocytopenia in 2/5 patients, no other side effects were observed. Taking into consideration the toxicity profiles of each drug in level 1, a level 2b regimen (5'-DFUR, 800 mg/day; TXT, 60 mg/m2) was accepted. Seven patients were registered for level 2b dosage and were examined for the safety of the regimen. Two patients discontinued the level 2b regimen due to percutaneous adverse reactions (DLT) and 6/7 patients developed neutropenia of grade 4. Clinical effects in level 1 group included: 1 CR, 2 PR, 1 long NC (NC longer than 24 weeks), and 1 NE, for a response rate of 60.0% (3/5 patients). Those in level 2b included: 2 CR, 2 PR, 1 NC, and 2 NE, for a response rate of 57.1% (4/7 patients). Based on the safety and efficacy of the combined therapy, the recommended dosage of this regimen is 5'-DFUR, 800 mg/day, combined with TXT, 60 mg/m2. A Phase II study is being conducted using this dosage.