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We conducted a phase II study to determine the availability and safety of combination chemotherapy with weekly paclitaxel and doxifluridine (a capecitabine metabolite) in the treatment of advanced or recurrent breast cancer. Patients were treated with a combination chemotherapy regimen: doxifluridine was orally administered at 800 mg/day for 14 days, followed by a 7-day washout period. Paclitaxel was given intravenously on days 1 and 8 at 80 mg/m2 for 1 h, followed by a 1-week washout period. This 3-week cycle of therapy was repeated as long as possible (at least eight cycles) until the progression of the tumor and drug-related adverse effects were no longer observed. From May 2003 to December 2005, 26 patients were enrolled in the study. The overall response rate was 53.8% (95% confidence interval, 33.4-73.4%). The clinical benefit rate, including long-term no change, was 65.4% (95% confidence interval, 44.3-82.8%). Time to progression and survival time were 297 and 1182 days, respectively, for the 26 enrolled patients. No severe toxicities were observed. Grade 3/4 leucopenia in three patients, neutropenia in five patients, increased serum creatinine in three patients, hypercalemia in one patient, hypocalcemia in one patient, nausea/vomiting in two patients, and diarrhea in one patient. The good response rate and long time to progression and overall survival time of this doxifluridine combined with weekly paclitaxel therapy indicate its potential as a first-line or second-line treatment for advanced or recurrent breast cancer patients.

Sonodynamically induced antitumor effect of a gallium porphyrin complex, ATX-70 was evaluated on a chemically induced mammary tumor in Sprague-Dawley rats. The timing of 24 h after the administration of ATX-70 was chosen for ultrasonic exposure, based on pharmacokinetic analysis of ATX-70 concentrations in the tumor, plasma, skin, and muscle. At an ATX-70 dose not less than 2.5 mg/kg and at a free-field ultrasonic intensity not less than 3 W/cm(2), the synergistic effect between ATX-70 administration and ultrasonic exposure on the tumor growth inhibition was significant. These results suggest that ATX-70 is a potential sonosensitizer for sonodynamic treatment of spontaneous mammary tumors.

The sonodynamically induced antitumor effect of porfimer sodium (PF) was evaluated on a chemically induced mammary tumor in Sprague-Dawley rats. The timing of 24 h after the administration of PF was chosen for the ultrasonic exposure, based on pharmacokinetic analysis of the PF concentrations in the tumor, plasma, skin and muscle. At a PF dose not less than 2.5 mg/kg and at a free-field ultrasonic intensity not less than 3 W/cm2, the synergistic effect between PF administration and ultrasonic exposure on the tumor growth inhibition was significant. The ultrasonic intensity showed a relatively sharp threshold for the synergistic antitumor effect, which is typical of an ultrasonic effect mediated by acoustic cavitation. These results suggest that PF is a potentially useful as a sonosensitizer for sonodynamic treatment of chemically induced tumors.

Fundamental studies have confirmed that combination chemotherapy with docetaxel and doxifluridine (a capecitabine metabolite) is very useful in the treatment of breast cancer. This study investigated the usefulness and tolerability of a combination chemotherapy consisting of docetaxel administration on day 8 of doxifluridine therapy in 40 advanced/recurrent breast cancer patients. The overall response rate was 41.0% in 39 eligible patients. The median time to progression (TTP) for all patients was 295 days. Many responders had lung metastasis, soft tissue metastasis or a good performance status, whereas the clinical response showed no correlations with the estrogen receptor status or prior treatment with an anthracycline. The most common hematological toxicities were leukopenia and neutropenia, but dose reduction or delay of administration of either drug was unnecessary.The good response rate and long TTP of this doxifluridine plus docetaxel regimen indicate its potential as a first- or second-line treatment for advanced/recurrent breast cancer patients.

The formation of microvessels in tumors by angiogenesis is considered to be an important prognostic factor, and closely correlates with lymph node metastasis. We used color Doppler ultrasound to examine the relationship between the amount of blood vessels in tumors and pulsatility index (PI), and tumor size in breast cancers, with and without regional lymph node metastasis. Doppler ultrasound was performed on 80 patients with breast cancer prior to surgery. The concentration of vascular endothelial growth factor (VEGF) within the tumors was measured following surgery in 42 cases chosen at random. In the negative metastatic nodes group, the number of vessels in the tumor correlated positively with tumor diameter. In the positive metastatic nodes group, however, the number of blood vessels in the tumor did not correlate with tumor diameter. Differences in tumor vascularity between node positive and negative groups were useful in determining the status of node metastasis in subsequent analysis. Fifteen of 17 cases of tumors that measured20 mm, and in which there were no blood vessels, were node-negative. There were no node-negative tumors measuring20 mm in diameter (p=0.003). Conversely, in nodes with positive metastasis, blood vessels were observed in 5 of 7 tumors that measured15 mm in diameter (p=0.019). These findings may be useful in estimating the likelihood of metastasis to regional lymph nodes. PI was directly proportional to tumor size in the negative nodes group (r=0.47). There was no such correlation in the positive nodes group. There was no correlation between VEGF concentration in the tumor and the number of blood vessels in that tumor. In conclusion color Doppler analysis of blood vessels appears to be useful in predicting lymph node metastasis, especially for small tumors.

In case of sternal resection, it is necessary to preserve bone material indispensable for the stability of the anterior chest wall and air tightness of the thoracic cavity, and the support of the chest wall integrity must be restored by some means. Various techniques have been applied to the reconstruction of the chest wall following resection. During the last 10 years, we have performed reconstructive operation for 6 cases of the chest wall following resection of the sternum in recurrent cases of breast cancer or invaded case of primary breast cancer. In these patients, the chest wall was reconstructed using a rib-latissimus dorsi osteomyocutaneolus flap or a latissimus dorsi myocutaneous flap. The sternum was totally resected in 3 cases, and in all 3 cases, reconstructed using a rib-latissimus dorsi osteomyocutaneous flap. Although postoperative pulmonary function decreased, all cases could be relieved from endotracheal intubation within 17 hours after operation, and had no problems in activities of daily living or occurrence of chest flailing or paradoxical movement of the chest. An artificial material (expanded polytetrafluoroethlene patch) was used in only one patient for the reconstruction of the osseous thorax, but this case developed infection during postoperative chemotherapy. After this experience, we used only biological materials for the reconstruction of the chest wall and postoperatively performed radiotherapy and/or chemotherapy on all cases. We have observed no flap infection or detachment since then. One characteristic of using the latissimus dorsi myocutaneous flap is that it is easily elevated and rarely causes serious postoperative esthetic or functional problems. The flap is also easily utilized to reinforce the osseous thorax because ribs immediately below the latissimus dorsi muscle are readily mobilized as a pedicle graft. Reconstruction of the chest wall following resection of the sternum, described in this report, allowed us to perform radiotherapy and/or chemotherapy without serious postoperative complications on the cases relapsing after treatment of breast cancer. The 2-year survival rate is 50% and one of these cases survived up to 10 years after resection of the sternum. Thus we prefer to perform resection of the sternum for sternal recurrence of breast cancer if there are no metastatic lesions in other organs.