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In a phase 3, double-blind, randomized, international study (the BOLERO-2), the addition of mTOR inhibitor everolimus to exemestane was evaluated in postmenopausal women with estrogen-receptor-positive (ER⁺) advanced/recurrent breast cancer that was refractory to any nonsteroidal aromatase inhibitor (NSAI). This report presents the safety and updated (18- month) efficacy results from the Japanese subset (n=106) of BOLERO-2. After a median follow-up of 18 months, the median progression-free survival time was 8.5 months with everolimus plus exemestane compared to 4.2 months with placebo plus exemestane. The most common adverse events (AEs) with everolimus plus exemestane were stomatitis, rash, dysgeusia, and non-infectious lung disease. The AEs reported with the combination therapy were mostly of grade 1 or 2 and manageable with appropriate intervention. In conclusion, this combination could be a useful addition to the armamentarium of treatments for Japanese postmenopausal women with ER⁺ advanced/recurrent breast cancer progressing on NSAIs.

Video-assisted breast surgery has been developed since the middle of 1990s mainly in Japan, and brought better cosmetic outcome to patients who underwent breast conserving surgery. It can shorten surgical wounds and move them to inconspicuous areas, such as the areola and axilla. However, postoperative breast deformity is a serious problem for patients with breast conserving surgery, which cannot be relieved only by shortening or moving the surgical wound. For such patients, combination of video-assisted surgery and immediate breast reconstruction will be the best way to achieve both curability and good cosmetic outcome. For successful surgery, it is important to judge the adequate resection area and chose appropriate reconstruction method based on tumor size, location, patient's backgrounds and their preference.

Recently, some new anticancer agents and hormonal agents can be used to treat breast cancer, and more patients are administering combinations of these drugs in clinical practice. Tegafur and Uracil (UFT) have been widely used for the postoperative chemotherapy of breast cancer, and often combined with hormonal agents. However, due consideration has not been given to safety and compliance of the combined use of UFT and aromatase inhibitor (AI). We therefore studied the safety and compliance with UFT alone and in combination with the hormonal agents tamoxifen or anastrozole as postoperative therapy in postmenopausal women with breast cancer. Our results confirmed that longterm postoperative therapy with UFT alone was feasible, provided that early adverse events are carefully monitored. Combined therapy was not associated with a significant increase in the incidence of adverse events or a decrease in compliance, even in older adult patients. Therefore, we consider UFT plus a hormonal agent (especially anastrozole) to be a treatment option for patients with HER2-negative highly or incompletely endocrine responsive disease who require relatively moderate chemotherapy or for older adult patients who require treatment with low toxicity.

Paclitaxel (PTX) is frequently used for a chemotherapy of breast cancer and gynecologic cancer. Besides a bone-marrow depression and hypersensitive reaction, the peripheral neuropathy is one of the serious adverse events of PTX. The mechanism of peripheral neuropathy has not been clarified, and few agents have been reported to be effective for the treatment and the prevention of that. Recently, it has been reported that Gosya-jinki-gan is useful for the PTX induced peripheral neuropathy, so we carried a retrospective study(n=82)to evaluate the effectiveness of Gosya-jinkigan with the medical records. It is suggested that peripheral neuropathy developed more rapidly in sequential administration of PTX every week than in administration in 4 weeks cycles consisting of 3 weeks on and 1 week off(5.4w vs. 9.4w). We have also found that Gosya-jinki-gan was possibly effective for the treatment and the prevention of peripheral neuropathy. Additionally Gosya-jinki-gan might be more effective for peripheral neuropathy when it is administered from the beginning of chemotherapy including PTX.

Docetaxel, a second-generation taxane, is one of the most powerful anticancer drugs for breast cancer. It has been widely used in the metastatic setting but also in the adjuvant or neoadjuvant setting for breast cancer patients. However, docetaxel is not effective for all breast cancers. The response rate is 40-60% even in first-line chemotherapy and it decreases to 20-30% in the second-or third-line chemotherapy. Therefore, it is very important to predict the sensitivity of docetaxel with high accuracy in order to avoid unnecessary treatment. Docetaxel binds to beta-tubulin and promotes polymerization, resulting in interference with mitosis. Unfortunately, the mechanism of sensitivity or resistance to docetaxel has not been fully understood. Recent studies in this area have demonstrated various mechanisms involved in the anti-tumor activity of docetaxel: (1) efflux (p-glycoprotein), (2) metabolism (CYP3A4), (3) beta-tubulin (isotype class I and III), (4) cell cycle (HER2, BRCA1), (5) apoptosis (p53, Bcl-2, thioredoxin), and (6) cell proliferation (MIB-1, nuclear grade). In addition, recently, gene expression profiling has been applied to the prediction of response to docetaxel in breast cancer. This work has reviewed recent studies, including ours, which have evaluated the association between these biological parameters and response to docetaxel in breast cancer.

We examined four problems of the ordering system type infusion center. In this system,regimen is made by chief physician and cared by the staff in the infusion center. 1) In securing of the staff, an upbringing of doctors and IV nurses are important. 2) An evidence-based regimen is necessary in order to minimize the differences of regimen made by each doctor. 3) A facility expansion might reduce an incident risk. 4) As the condition of patient suddenly changes,the chief physician of the patient should be contacted. We suggest that it is particularly important to make these problems clarified and solved by the team within the institution.

A phase-I clinical study of a combination therapy of vinorelbine and capecitabine was conducted in anthracycline- and taxane-pretreated patients with advanced/recurrent breast cancer. The objectives of this study in four medical institutions were to evaluate DLT (Dose Limiting Toxicity) and safety as primary endpoints, and tumor response and pharmacokinetics of vinorelbine as secondary endpoints. One 3-week course of treatment consisted of intravenous vinorelbine on Days 1 and 8 and oral capecitabine on Days 1 to 14, followed by a one-week rest. Vinorelbine was given at 20 mg/m(2) (Level 1) and 25 mg/m(2) (Level 2), and capecitabine was given at 1,650 mg/m(2)/day (in two divided doses, Levels 1 - 2). As the administration at each dose level in 3 patients did not cause DLT, 6 patients were additionally treated with vinorelbine at 25 mg/m(2) and capecitabine at 1,650 mg/m(2)/day (in two divided doses) to confirm safety. The major toxicities were bone marrow depression and gastrointestinal symptoms. In particular, the incidences of grade 3 or greater neutropenia (11 patients) and leukemia (10 patients) were high. They were reversible, however, and not severe enough to discontinue treatment. The response rate was 25.0% (3 PR/12). The combination with capecitabine did not affect the plasma pharmacokinetics of vinorelbine.

Patients with breast cancer accompanied by extensive intraductal components or multiple tumors are not considered to be candidates for breast-conserving surgery. To improve post-operative quality of life of such patients, skin-sparing mastectomy with immediate reconstruction has been performed recently. We described our experience of skin-sparing mastectomy and areola-nipple-sparing mastectomy followed by immediate reconstruction with the use of a latissimus dorsi myocutaneous flap, a transverse rectus abdominis myocutaneous flap, and a deep inferior epigastric artery perforator flap. These operations appear to be oncologically safe when patients are selected carefully, and have a great benefit for the patients both aesthetically and psychologically.

Recently, high-dose FEC (fluorouracil, epirubicin, and cyclophosphamide) has been increasingly used in adjuvant chemotherapy for breast cancer in Japan. However, the safety and tolerability of high-dose FEC are not well evaluated in Japanese breast cancer patients. We studied the feasibility of FEC (75) (fluorouracil: 500 mg/m(2), epirubicin: 75 mg/m(2), and cyclophosphamide:500 mg/m(2), q 3 w, 6 cycles) as adjuvant chemotherapy for 59 primary breast cancer patients. Out of these patients, 56 (94.9%) finished 6 cycles-FEC. The mean epirubicin dose received was 431.7 mg/m(2) (95.9% of the intended dose of 450 mg/m(2)). Forty-five (76.2%) of 59 patients experienced neutropenia of grade 3 or 4, while the rates of febrile neutropenia (grade 3) and infection (grade 2) were 3.4% and 10.2%, respectively. Anemia (88.2%), fatigue (42.4%), nausea (40.6%), liver dysfunction (40.7%), and vomiting (18.7%) occurred, however most of them were mild and categorized into grade 1 or 2. No patients developed any cardiac failure symptoms. This study shows FEC (75) is well tolerable as adjuvant chemotherapy for Japanese breast cancer patients.

The 12 th Oncology Forum discussed the progress and future strategy of cancer prevention in Japan. The National Cancer Center has established a research center for screening focusing on the most common six cancer, stomach, lung, liver, colon, breast and uterus cancer. The program so far had a cumulative detection rate of 3.3%, which is high,and may reflect the selection of subjects. Screening and chemoprevention is also being investigated in prostate cancer, but the issues centre on how to make this widely available. High risk subjects can also be identified for breast cancer. Obesity and family history are especially important. In colorectal cancer studies are evaluating different diets, but general application is not yet possible and the infrastructure to implement any general screening and prevention does not exist. Development of pharmaceutical treatments for prevention is difficult because of the need for very safe treatments, and also because of the length of time needed to carry out studies. Overall, cancer prevention is still in evolution. New approaches are needed, and new infrastructure will be needed at a government level to implement this.

We have a randomized trial to compare the operability and safety of ten 24-gauge intravenous catheters in the infusion room. In the present study, we used 3 intravenous catheters without safety covers (Jelco plus, Surflo flash, Intima) and 7 intravenous catheters with safety covers (Supercath, Introcan safety, Surshield surflo II, Insyte autoguard, Safetouch cath, Protective plus, Acuvance plus). All catheters were used 40 times. The detainment rate of the first time puncture and the incidence of needle accidents with Jelco plus and Insyte autoguard were 98% and 0%, respectively, against 100% and 0%, respectively, for all other catheters. There was no difference in the incidence of these two events in all groups (ANOVA; p > 0.05). On the other hand, all intravenous catheters with safety covers revealed that 1) an in situ needle has a resistance to the catheter (i.e., a resistance during catheter release), and/or 2) blood exposure can not be sufficiently avoided.

Based on reviews of the concept of diagnostics and in general and in specific tumour areas it was clear that development of diagnostic procedures involving genomics will allow for much better targeted and tailored treatments in the future. This will result in better efficacy and better tolerability of cancer treatments, but will also allow for progress in prediction, diagnosis and dose selection. Large collaborative projects studying the efficacy and safety of drugs on the genome level is promising to bring important benefits to both patients and the national economy by reducing useless drug therapy. In colorectal cancer there are several genetic defects identified that can act as the target for directed therapy in the future. Expressions of tumour specific antigens open the way for immunological targeted therapies. Developments in the understanding of the genomic basis for resistance to anti-tumour therapy is promising to help targeting patients likely to respond and not develop resistance. A Japanese model is being developed to determine the relative risk of breast cancer of Japanese women. Based on this prevention therapies can be instigated. The last four years have seen the introduction of four novel targeted therapies. If this model should become a standard in the future, much stronger collaboration between academic research and pharmaceutical industry need to develop.

Many investigators have reported micrometastases in sentinel lymph nodes, which have been detected by various methods. The most common method of detecting micrometastases is pathological examination using a combination of hematoxylin-eosin and immunohistochemical staining of multisectioned specimens. However, no standard method has been established concerning how to slice the specimen and how many slides should be examined. On the other hand, a more sensitive method utilizing the reverse-transcriptase polymerase chain reaction (RT-PCR) has also been applied for the detection of micrometastases. However, this method is so sensitive that it may detect isolated tumor cells (ITC), which are not defined as metastases according to the 6th edition of the American Joint Committee on Cancer and Union Internationale contre le Cancer cancer staging manuals for breast cancer. Therefore it is an urgent task to establish a standard method for detecting micrometastases in sentinel lymph nodes. For this purpose, further examination of many patients is needed to determine the most efficient and convenient way for detection of micrometastases in sentinel lymph nodes, whether the micrometastases influences the prognosis of patients, and whether regional lymph node clearance is needed in the case of micrometastases in sentinel lymph nodes.

Additional phase III multicenter clinical study was performed to investigate the efficacy, safety, and usefulness of somatostatin receptor scintigraphy using 111In-pentetreotide (MP-1727), which binds to somatostatin receptors. Forty patients were included in the study; Group A: 18 patients, gastrointestinal hormone producing tumors had been detected with conventional imaging modalities, Group B: 22 patients, no tumors had been detected with conventional imaging modalities in spite of high serum hormone levels. By comparing the results of the octreotide suppression test, 12/16 cases (75.0%) of Group A and 11/19 cases (57.9%) of Group B were assessed as "effective." By comparing the results of immunohistological examination, 5/9 cases (55.6%) of Group A and 2/4 cases (50.0%) of Group B were assessed as "effective." Severe adverse events were not observed in any of the evaluable 35 cases. MP-1727 was judged as clinically useful in 11/16 cases (68.8%) of Group A and 5/19 cases (26.3%) of group B. These results suggest that MP-1727 scintigraphy is very useful for the diagnosis and decision of the therapeutic strategy of gastrointestinal hormone producing tumors.

We report the case of a 58-year-old man with metastatic tumors 13 months after the initial surgery for paraganglioma at the left adrenal gland. A CT scan revealed a large tumor at the right scapula and abdominal paraaortic lymph nodes, and the patient received combination therapy of cyclophosphamide, vincristine and dacarbazine (CVD) every 3 to 4 weeks. After 11 courses, the serum catecholamine level was reduced to the normal range. The metastatic tumors showed optimal reduction in size, and the patient remains alive with no symptoms of the disease one year after the primary chemotherapy. The combination therapy of cyclophosphamide, vincristine and dacarbazine is considered a feasible and effective chemotherapy for metastatic malignant pheochromocytoma.

Endoscopic breast surgery has the advantage that it can be performed from a small, inconspicuous incision remote from the lesion. The cosmetic outcome is an important factor in the selection of the surgical technique as in addition to the oncologic effect on breast cancer. From this point of view, endoscopic partial mastectomy should be performed in patients with small tumors, especially those located in the upper quadrants. The approach should be selected for each case considering the size and location of the tumor. For patients with multiple tumors or with tumors accompanied by extended intraductal components, endoscopic total glandectomy or subcutaneous mastectomy with breast reconstruction is a good choice. Patients with a tumor located near the skin or invading the skin are not candidates for endoscopic surgery. Endoscopic axillary dissection is still controversial in its advantages compared with conventional surgery. To avoid surgical complications and an increase in the local failure rate of breast cancer, selection of patients and the surgical technique must be considered carefully.

Fifteen (13.3%) and 21 (18.6%) deleterious germline mutations were identified in BRCA1, and BRCA2 genes among 113 Japanese breast cancer families. We found a BRCA1 codon 63 (nucleotide 307) nonsense mutation and a 4-bp deletion at codon 1858 (nucleotide 5802) of BRCA2 in 4 and 7 independent families, respectively. Haplotype analysis has revealed that these two mutations were founder mutations. Lifetime risk of breast cancer in BRCA1 or BRCA2 mutation carriers was estimated at nearly 80%, and that of ovarian cancer in BRCA1 mutation carriers was about 40%. A questionnaire survey as to the genetic testing (BRCA1 and BRCA2) and prevention was carried out with 146 healthy women (hospital workers or medical students) and 84 breast cancer patients. About 80% of healthy women as well as breast cancer patients responded positively to the genetic testing, based on the assumption their's was a breast cancer family, and about 20% of each group answered that they would opt for prophylactic mastectomy and oophorectomy if they were found to be germline mutation carriers. These results indicate that genetic testing and prophylactic surgery would be acceptable among a considerable number of Japanese women, and seem to support the establishment an infrastructure for genetic testing in Japan.