Challenges in breast and cervical cancer control in Japan.

Since the mid-1990s, there has been an increasing incidence of, and mortality from, cervical and breast cancers in Japan. Such an increase has raised concerns over the efficiency of Japan's screening programmes for these cancers. Although citizens benefit from universal health coverage, the Japanese health insurance system mostly focuses on tertiary prevention and disease treatment, while secondary prevention (screening) is low priority. Citizens have multiple opportunities to be screened for cancer-either through programmes organised by municipalities, or individual or collective, opportunistic and comprehensive health check-ups on a voluntary basis. Despite this, however, participation is as low as 35% of the target population for both cancers. In this Policy Review, we discuss the challenges in the prevention of breast and cervical cancers in Japan, particularly focusing on the structure of the National Health Insurance system and the National Cancer Control Plan, reasons for low participation as a result of social and political attitudes, as well as providing recommendations to overcome these challenges. Japanese women would benefit from new measures to increase participation, a national data surveillance programme to monitor screening activities, and the implementation of a quality assurance system among all providers.

Promotion of quality-controlled mammography alone as a screening modality in Japan.

BACKGROUND: The rate of breast cancer screening in Japan has not increased, and it is thought that one of the reasons is the principle that mammography (MMG) and clinical breast examination (CBE) be carried out in combination. Nationwide, there is a shortage of physicians qualified to perform CBE, and in some regions mass-screening is performed by MMG alone out of a mobile MMG bus. In Shikoku, MMG is performed alone as a screening examination in Kochi and Ehime Prefectures. METHODS: A comparative analysis of the data generated by MMG alone in breast cancer screening in the four prefectures of Shikoku during the 2005-2009 period was performed. RESULTS: The overall attendance rates, recall, cancer detection, early-stage cancer detection, and the positive predictive value (PPV) were 16.8-24.5, 6.0-12.8, 0.26-0.37, 63.1-79.7, and 2.8-4.3 %, respectively. Almost no differences were seen between the results for MMG alone and combined MMG/CBE screening. In addition, the cancer detection rates based on the Japan Cancer Society's nationwide data were 0.25 % with combined MMG/CBE screening and 0.21 % with MMG alone, showing almost no difference. CONCLUSIONS: No differences were seen between the results (i.e., recall rate, cancer detection rate, early-stage cancer detection rate, PPV) for MMG alone and MMG/CBE screening in the four prefectures of Shikoku compared with the Japan Cancer Society's nationwide data. In order to improve the mammographic screening rate in Japan, quality-controlled mammography as a stand-alone examination should be promoted, and performed biennially for women aged 50-74 years.

A randomized, double-blind, controlled study of exemestane versus anastrozole for the first-line treatment of postmenopausal Japanese women with hormone-receptor-positive advanced breast cancer.

The aromatase inhibitors exemestane and anastrozole are approved in Japan for first-line treatment of postmenopausal patients with advanced, hormone-receptor-positive breast cancer. This phase 3, randomized, double-blind study directly compared time to progression (TTP) for exemestane and anastrozole therapy in this patient population. Eligible patients were randomized to receive exemestane 25 mg or anastrozole 1 mg, each once daily. The primary endpoint was TTP based on assessment by an expert radiologic images review committee (ERIRC). Secondary endpoints included investigator-assessed TTP, time to treatment failure, overall survival, objective response rate, clinical benefit rate, and safety. A total 298 patients were randomized to receive exemestane (n = 149; mean age 63.4 years) or anastrozole (n = 149; mean age 64.0 years). Median ERIRC-assessed TTP was 13.8 and 11.1 months (hazard ratio = 1.007; 95 % confidence interval [CI]: 0.771, 1.317) and median investigator-assessed TTP was 13.8 and 13.7 months (hazard ratio = 1.059; 95 % CI: 0.816, 1.374) in the exemestane and anastrozole arms, respectively. Median overall survival was 60.1 months in the anastrozole arm and was not reached in the exemestane arm at data cutoff. The objective response rate was 43.9 % (95 % CI: 35.3, 52.8) and 39.1 % (95 % CI: 30.6, 48.1) in the exemestane and anastrozole arms, respectively. Treatment-related adverse events grade ≥3 occurred in 9.4 and 6.0 % of patients, and treatment-related serious adverse events occurred in 4.0 and 3.4 % of patients in the exemestane and anastrozole arms, respectively. In this study, the efficacy and safety profiles of exemestane were similar to those of anastrozole in Japanese patients with advanced, hormone-receptor-positive breast cancer; however, TTP non-inferiority of exemestane versus anastrozole was not confirmed.

Basic study of a diagnostic modality employing a new electrical impedance tomography (EIT) method for noninvasive measurement in localized tissues.

The objective of this study is to develop a device for noninvasive local tissue electrical impedance tomography (EIT) using divided electrodes with guard electrodes and to validate its effectiveness using bioequivalent phantoms. For this purpose, we prepared a measurement device and bioequivalent phantoms, measured the electrical characteristics of the phantoms, and validated the method using the phantoms. Monolayer phantoms mimicking the brain and muscle and bilayer phantoms consisting of muscle and brain layers were prepared. The relative differences between the measured electrical conductivities of the monolayer brain and muscle phantoms and the true values determined by the 4-electrode method were both less than 10%. The relative differences between the measured and true values in the bilayer phantoms were less than 20% in both layers. The biological impedance measurement device that we developed was confirmed to be effective for impedance measurement in bilayer phantoms with different electrical impedances. To develop a device for the early diagnosis of breast diseases, the development of a multi-layer phantom and demonstration of the effectiveness of the device for its examination are necessary. If the device that we developed makes impedance measurement in breast tumors possible, it may be used as a new diagnostic modality for breast diseases.

Current status of breast cancer screening in the world.

The mortality associated with breast cancer is decreasing in Europe and the United States. There are various reasons for these trends, including an increase in detection of early-stage breast cancers due to increased use of mammographic screening and the establishment of standardized systemic treatments based on evidence-based medicine. However, in Japanese women, both the morbidity and the mortality of breast cancer are increasing. In this manuscript, we describe the current status of mammographic screening in Europe and the United States, and the status of breast cancer screening in Japan. Quality control systems are also introduced, and the need for practical measures, such as implementation of quality control systems aimed at improving the cancer screening rate (with a target of 50%) and population-based screening (organized screening), based on the Cancer Control Act, is described. Current countermeasures for dense breasts in women in their 40s, both overseas and in Japan, are also described, together with discussions of the diagnostic capability of digital mammography, the usefulness of screening combined with computer-aided diagnosis, and the current status of screening using MRI in Europe and the United States.

International exchange activities with East Asian countries through mammography.

The Japanese NPO Central Committee on Quality Control of Mammographic Screening has initiated international exchange activities regarding quality control of mammographic screening with the concerned organizations in East Asian countries with the objective of contributing to reducing breast cancer mortality in the region. This paper describes the status of the international exchanges that are being carried out in various East Asian countries in relation to mammography and also discusses future aspects.

Bilateral male breast cancer with male potential hypogonadism.

BACKGROUND: Male breast cancer is a comparatively rare disease, and simultaneous bilateral male breast cancer is considered to be an extremely rare event. Risk factors are said to be genetic factors and hormonal abnormalities due to obesity or testicular diseases. CASE PRESENTATION: The patient was a 47-year-old Japanese male. His family had no history of female breast cancer. This patient also had hypospadias and hormonal examination indicated the presence of primary testicular potential hypogonadism, and these hormonal abnormalities seemed to be present since childhood or the fetal period. The bilateral breast cancer developed in this man at a comparatively young age, and histopathological studies of multiple sections showed that there was almost no normal epithelial cell in the ducts, while the ducts were almost completely filled with breast cancer cells. CONCLUSION: It is thought that male breast cancer is caused by an imbalance between estrogen and testosterone. We cannot rule out the possibility that the breast cancer developed due to the effect of the slight elevation of estrogen over a long period of time, but the actual causative factors in this patient were unable to be definitively identified. In the future, we hope to further elucidate the causes of male breast cancer.

Chromosomal aneusomy (chr 1, 11, 17) detected by fluorescence in situ hybridization may be a prognostic factor in breast cancer.

The relationship between clinicopathological findings and the long-term prognosis was investigated in 42 breast cancer patients in whom aneusomy was detected for chromosomes 1, 11 and 17. The frequencies of aneusomy of those chromosomes were 78.6%, 47.5% and 52.5%, respectively, and more than 90% of anomalies consisted of polysomy. The relationship between aneusomy and the clinicopathological findings showed a statistical correlation with a high histological grade in the case of polysomy of chromosome 17 compared with disomy, indicating a tendency for a high incidence of lymph node metastasis. Analysis of the survival data revealed that the prognosis was poor when there was polysomy of chromosomes 1 or 11. These results indicate the possibility that aneusomy of chromosomes 1, 11 and 17 can serve as prognostic factors of poor outcome in breast cancer patients.

Current status of sentinel lymph node navigation surgery in breast and gastrointestinal tract.

Sentinel lymph node biopsy (SLNB) has been developed as a new diagnostic and therapeutic modality in melanoma and breast cancer surgery. The purpose of the SLNB include preventing the operative morbidity and improving the pathologic stage by focusing on fewer lymph nodes using immunocytochemic and molecular technology has almost achieved in breast cancer surgery. The prognostic meaning of immunocytochemically detected micrometastases is also evaluating in the SLN and bone marrow aspirates of women with early-stage breast cancer. SLNB using available techniques have suggested that the lymphatic drainage of the gastrointestinal tract is much more complicated than other sites, skip metastasis being rather frequent because of an aberrant lymphatic drainage outside of the basin exist. At the moment, the available data does not justify reduced extent of lymphadenectomy, but provides strong evidence for an improvement in tumor staging on the basis of SLNB. Two large scale prospective multi-center trials concerning feasibility of gamma-probe and dye detection for gastric cancer are ongoing in Japan. Recent studies have shown favorable results for identification of SLN in esophageal cancer. CT lymphography with endoscopic mucosal injection of iopamidol was applicable for SLN navigation of superficial esophageal cancer. The aim of surgical treatment is complete resection of the tumor-infiltrated organ including the regional lymph nodes. Accurate detection of SLN can achieve a selection of a more sophisticated tailor made approach. The patient can make a individualized choice from a broader spectrum of therapeutic options including endoscopic, laparoscopic or laparoscopy-assisted surgery, modified radical surgery, and typical radical surgery with lymph node dissection. Ultrastaging by detecting micrometastasis at the molecular level and the choice of an adequate treatment improve the postoperative quality of life and survival. However these issues require further investigation.

[Evaluation of safety and efficacy for bi-weekly Docetaxel and 5'-DFUR combination therapy in patients with advanced or recurrent breast cancer--Phase I study].

BACKGROUND: A clinical trial of Docetaxel was performed by tri-weekly administration in patients with advanced or recurrent breast cancer. However, careful observation is necessary for outpatients because serious neutropenia often occurs during the therapy. A bi-weekly schedule is recommended since weekly administration requires more visits to the hospital. Docetaxel is proved to express synergistic efficacy in combination with 5'-DFUR by induced dThdPase in vivo. But there are no clinical trials to evaluate efficacy of bi-weekly Docetaxel and 5'-DFUR combination therapy. PURPOSE: To evaluate safety, the recommended dose of Docetaxel and the efficacy of biweekly Docetaxel and 5'-DFUR combination therapy. PATIENTS AND METHODS: Patients with advanced or recurrent breast cancer within 1 regimen of prior chemotherapy and without prior use of both Docetaxel and 5'-DFUR were enrolled. 5'-DFUR was orally administered by 600 mg/day. Docetaxel was intravenously given for at least 2 cycles (8 weeks) by 30 mg/m(2) for level 1, 40 mg/m(2) for level 2 and 50 mg/m(2) for level 3. At each level with 3 cases enrolled,the maximum tolerated dose (MTD) level was defined as that in which 2 or 3 cases showed dose limiting toxicity (DLT). The recommended dose was defined as the dose before MTD level. Therapeutic safety was evaluated by analyses of adverse events with the recommended dose. RESULTS: MTD was in level 3 and the recommended dose of Docetaxel was 40 mg/m(2) of level 2. No DLT was observed in level 2, and this combination therapy seemed safe and feasible for outpatients. In addition, all 6 cases for whom therapeutic efficacy was evaluated expressed a clinical response.

False-positives in fine-needle aspiration cytology of breast disease can be reduced with p63 immunostaining--a preliminary report.

Myoepithelial cells of the mammary gland are considered to be a key to distinguishing benign from malignant disease in fine-needle aspiration (FNA) cytology. However, identification of these cells with Papanicolaou staining is not easy. The identification of myoepithelial cells was investigated using p63 antibodies to carry out immunostaining of FNA specimens that had been used at the time of Papanicolaou staining for 37 patients who yielded false-positives in FNA. Positively-stained cells were observed in overlying cell clusters or the background in 67.6% of the patients. There is a possibility that over-diagnosis could have been avoided by performing p63 staining for these patients. The controls consisted of stamp samples of fresh specimens obtained from 23 patients at the time of surgery for invasive carcinoma and the results of p63 immunostaining did not reveal any positive staining of tumor cells. Accordingly, these results indicate that there is a strong likelihood that there is no invasive carcinoma when many p63-positive cells are observed in the tumor cell population or the background and that p63 immunostaining has the potential to aid in reducing false-positives at the time of FNA diagnosis of breast disease.

[Late phase II clinical study of KW-2307 in advanced/recurrent breast cancer patients (II)].

A late phase II clinical study (II) of a novel vinca alkaloid derivative KW-2307 (vinorelbine ditartrate) in advanced/recurrent breast cancer patients was performed at 22 institutions throughout Japan. An intravenous dose of KW-2307, 20 mg/m2, was administered once a week. Of the 60 patients enrolled in the study, 58 were eligible and 56 were evaluable. The response rate was 33.9% (19/56; 95% confidence interval: 21.8 to 47.8%) with one CR and 18 PRs. The response rate was as high as 37.0% (17/46; 95% confidence interval: 23.2 to 52.5%) when KW-2307 was used as a first-line chemotherapy for advanced/recurrent disease. The most common adverse event was myelosuppression including leukopenia in 96.4% (54/56) and neutropenia in 94.3% (50/53). Other events observed were increased GOT in 51.8% (29/56), increased GPT in 55.4% (31/56), LDH increased in 50.0% (27/54), serum total protein decrease in 39.3% (22/56), anorexia in 41.1% (23/56), nausea and vomiting in 66.1% (37/56), constipation in 30.4% (17/56), alopecia in 33.9% (19/56) and general fatigue in 46.4% (26/56). None of them were serious. This study demonstrated that KW-2307 was an effective and safe treatment for advanced/recurrent breast cancer patients.

A fundamental study on parameter estimation of layerd local tissue impedance for EIT.

Electrical Impedance Tomography (hereinafter referred to as EIT) is 2-D or 3-D image of electrical impedance distribution in a living tissue. Unlike usual imaging methods, i.e., Xray-CT, MRI and US Imagings, EIT is used for imaging the information of tissue structure and functions. This paper provides a new estimation method as a fundamental study to realize a EIT for local biological tissue. Up until now we has proposed a new configuration of the electrodes, called divided electrode, for a high-speed measurement of bio-impedance in a cross section of a local tissue. The cross section of the tissue was represented by space distributed equivalent circuits of tissue structure known, and their parameters were estimated by inverse algorithm. In this paper, we try to estimate the parameter value of a layered structural model, the thickness of the layer, and the boundary without using US-imaging by using the divided electrode. Its capability is examined by computer simulations, where a distributed equivalent circuit is used as a model of the tissue. Estimation of impedance parameter is carried out by use of the Gauss-Newton method. Usefulness of the proposed method is confirmed by computer simulations using a typical layered tissue model.

Basic study of new diagnostic modality according to non-invasive measurement of the electrical conductivity of tissues.

The purposes of this study were to estimate the electrical conductivity of tissues by non-invasively measuring the electrical bio-impedance, to develop a new method for tissue diagnosis, i.e., electrical impedance tomography (EIT). Tissue models were first designed taking into consideration the distribution of the fat tissue, muscle and bone in the human forearm, and then the intra-tissue distributions of electrical potential and field, and the electrical impedance in the models was theoretically analyzed by the three-dimensional finite element method. The electrical impedance of both forearms was measured in healthy human subjects, and estimated the electrical conductivity of individual local tissues. The results of the analysis showed that the distributions of electrical potential and field were affected by the presence of fat tissue but not by the presence or absence of bone. In addition, as a result of calculation of the electrical resistance of the extracellular fluid (Re) in each model, it was found that the value of bio-impedance was influenced by the presence of fat tissue, and the value of bio-impedance was increased by the intervention of a fat layer. The electrical conductivity estimated by fitting the observed values to the values obtained by finite element analysis was 0.40 S/m and 0.15 S/m for male muscle and fat tissue, and 0.35 S/m and 0.11 S/m for female muscle and fat tissue, respectively. The sex difference in the slope of linear approximation in the estimation of electrical conductivity of the males and females was thought to be due to sex differences in the properties and structure of fat tissue. These results suggest that local tissues can be diagnosed differentially and electrically by percutaneous measurement of local bio-impedance and subsequent estimation of the electrical conductivity of each tissue.

3-dimensional computed tomography lymphography-guided identification of sentinel lymph nodes in breast cancer patients using subcutaneous injection of nonionic contrast medium: a clinical trial.

OBJECTIVE: Simple and reliable identification methods for sentinel lymph nodes (SLNs) which do not use radioisotope are essential for early breast cancer patients in community hospitals in Japan. The purpose of this paper is to demonstrate the feasibility and efficacy of computed tomography (CT) lymphography for SLN detection. METHODS: The study included 15 cases with T1 or T2 breast cancer. After subcutaneous injection of 1 mL of iopamidol in 1 subareolar area of the affected breast, CT scanning was carried out and 3-dimensional (3D) CT images were created. SLNs predicted from images and CT values were assessed as to whether they were identical to those identified by the dye method. RESULTS: An enhanced lymph vessel draining into SLN was demonstrated in 11 cases (73%) and an enhanced SLN in 10 cases (67%). 3D images clearly revealed the anatomic relationship between lymph vessels, SLN, and the surrounding structures. In addition, SLN could be predicted by the change of CT value in the time-course in another case. In total, SLN in 13 cases (87%) could be predicted. All SLNs suggested from CT lymphography were identified by the dye method. No significant adverse effect was noted in any case. CONCLUSIONS: The present clinical trial indicated that subcutaneous injection of nonionic contrast medium with CT scanning seems to be a promising method for the demonstration of a draining lymph vessel and SLN. The CT value time-course may also provide some important information. Further trials will be needed for the successful establishment of this CT lymphography-guided method for SLN identification.

Current status and goals of mammographic screening for breast cancer in Japan.

In Europe and the United States, the proportion of women receiving mammographic screening for breast cancer has increased to 60-80%, resulting in an increase in the detection of early-stage cancer and a reduction in the mortality rate. The objectives of breast cancer screening have thus already been achieved there. In Japan, both the incidence and mortality of breast cancer have increased recently. Breast cancer screening has long been performed by clinical breast examination (CBE) alone. A reduction in the mortality of breast cancer cannot be expected from CBE. Mammographic screening for breast cancer was recommended in a notification issued by Ministry of Health, Labour and Welfare in 1999. An important aspect of mammographic screening is quality control. The Central Committee on Quality Control of Mammographic Screening(Central Committee)was organized by six screening-related societies, and attempts have since been made to establish a quality control system. Both the social recognition of the Central Committee and its cooperation with the "Quality Control Committee " of each community will become important. The cover rate of nationwide breast cancer screening by CBE alone is 12-13%, while the implementation rate of mammographic screening is presently very low and its cover rate is considered to be about 2%. With such a low cover rate, it is absolutely impossible to reduce the mortality of breast cancer. To achieve this, the administration and clinicians will be required to cooperate with each other to increase the spread and cover rate of high-quality mammographic screening.

Evaluation of a new rehabilitation program for postoperative patients with breast cancer.

The purpose of the present study was to evaluate the efficacy of a newly designed rehabilitation program for postoperative patients with breast cancer. This was achieved through examinations to clarify the range of motion (ROM) of the shoulder joint, postoperative pain and recovery of activities of daily living (ADL). The ROM of the shoulder joint was evaluated with respect to five items and determinations were carried out five times. Patients were orally questioned four times regarding their pain after surgery, movement-associated chest pain, pain at night and operative wound pain. Evaluation of the ADL after discharge was conducted using a three-level rating method at postoperative week 4 and week 12. A total of 72 patients were studied, comprising 39 who underwent pectoral muscle-conserving mastectomy and 33 who underwent breast-conserving surgery. The arm movement of forward raising showed the greatest decline, followed by lateral raising of the arm. Postoperative time-course changes in internal/external arm rotation, as well as backward arm raising were slight. Comparison of the operative procedures revealed differences only for lateral arm raising at postoperative week 4, while there were no differences in any of the shoulder joint movements. Lowering of the ROM of the shoulder joint was more marked at an earlier time (week 1 to week 2) after surgery, but it was not statistically significant. Pain at night and operative wound pain were prolonged over the period, and reported in postoperative week 1 to week 12 by 3-15% of patients. All ADL items became almost normal in approximately 90% of patients at postoperative week 4. The efficacy of the present rehabilitation program early after surgery was demonstrated in terms of recovery of ADL as well as the ROM of the arm on the affected side.

Axillary 3D CT imaging with lymphoscintigraphy is useful for sentinel node biopsy in breast cancer.

BACKGROUND: This study examined whether 3D CT imaging with lymphoscintigraphy (LSG) is useful when performing sentinel node biopsy (SNB) in a community hospital where radioisotope with gamma-probe (RI method) is unavailable. MATERIALS AND METHODS: From June to November 2002, 35 T1/T2 clinically node-negative breast cancer patients underwent LSG in a university nuclear medicine department. Skin areas above LSG hot spots were marked, helical CT scanning was performed and axillary 3D images were created in our hospital. The SLN predicted from the 3D images were examined for agreement with the dye method. RESULTS: SLNs were detected with dye in 32 out of 35 patients (91.4%). In 31 of those 32 (96.9%), the SLN predicted from 3D CT images was the same. Even in the 3 dye-negative patients, CT imaging predicted the SLN. SNB including sampling was successful in 34 patients (97.1%). CONCLUSION: 3D CT imaging with LSG enables SNB even if the RI method is impossible.

Randomized controlled trial comparing oral doxifluridine plus oral cyclophosphamide with doxifluridine alone in women with node-positive breast cancer after primary surgery.

PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.