Is breast cancer the same disease in Asian and Western countries?

UNLABELLED: A mini-symposium was held in Montreal, Canada, at the International Surgical Week for the Breast Surgical International in 2007 addressing the question whether breast cancer is the same disease in Asian and Western countries. Numerous investigators from Asian and Western countries presented the epidemiologic and clinical outcome data of women with breast cancer. Although there are significant similarities, the striking difference is that the peak age for breast cancer is between 40 and 50 years in the Asian countries, whereas the peak age in the Western countries is between 60 and 70 years. Also, the incidence of breast cancer in Asia is rising and is associated with increased mortality. In the West, although the incidence is increasing, the mortality rate is definitely decreasing. Future prospective data collection from Asian and Western countries may provide further interesting epidemiologic and outcome data regarding the outcome of women with breast cancer from Asian and Western countries. BACKGROUND: Whether breast cancer is the same disease in Asian and Western countries was the topic of a 2007 Breast Surgery International symposium at International Surgical Week. METHODS: Participating investigators from China, Taiwan, India, Japan, South Korea, Sweden, Canada, and the United States were asked beforehand to provide data on the epidemiology and treatment outcome of women in their countries. RESULTS: Comparisons of the epidemiologic and clinical outcome data of women with breast cancer showed significant similarities, but the striking difference is that the peak age is between 40 and 50 years in Asian countries, but is between 60 and 70 years in Western countries. The incidence of breast cancer in Asia is rising and is associated with increased mortality. In the West, although the incidence is also increasing, the mortality rate is definitely decreasing. DISCUSSION: Future prospective data collection from Asian and Western countries may provide further interesting epidemiologic and outcome data regarding the outcome of women with breast cancer from Asian and Western countries.

Phase II study of weekly paclitaxel for advanced or metastatic breast cancer in Japan.

BACKGROUND: The efficacy and safety of weekly paclitaxel was evaluated in Japanese women with advanced or metastatic breast cancer. PATIENTS AND METHODS: Paclitaxel was given by single weekly intravenous infusion at 100 mg/m2 on days 1, 8, 15, 22, 29 and 36 of a 49-day cycle to women with advanced or metastatic breast cancer not responding to other chemotherapy. RESULTS: A total of 69 enrolled patients received a median of 3 (range 1-13) cycles of treatment. The overall response rate was 44.9%, comprising 3 complete responses (CRs) and 28 partial responses (PRs). Median durations of CR and PR were 64.0 (range 57-499) and 113.0 (range 29-590) days, respectively. Grade 3 or greater adverse reactions included neutropenia in 37.7%, leukopenia in 31.9% and neuropathy in 5.8%. CONCLUSION: A weekly regimen of paclitaxel was well tolerated and achieved a relatively high response rate in Japanese breast cancer patients with advanced or metastatic disease.

Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208.

A randomized controlled trial was conducted to evaluate the efficacy of high-dose chemotherapy (HDC) as consolidation of the treatment of high-risk postoperative breast cancer. Patients under 56 years of age with stage I to IIIB breast cancer involving 10 or more axillary lymph nodes were eligible. The primary endpoint was relapse-free survival (RFS). Between May 1993 and March 1999, 97 patients were enrolled, and two patients became ineligible. The median age of the 97 patients was 46 years (range 27-55 years), and 72 (74%) were premenopausal. The median number of involved axillary nodes was 16 (range 10-49). All patients had undergone a radical mastectomy. Major characteristics were well balanced between the treatment arms. Forty-eight patients in the standard-dose (STD) arm received six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen. Forty-nine patients were assigned to undergo HDC with cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen; however, 15 of these patients (31%) did not undergo HDC. HDC was well tolerated without any treatment-related mortality. At a median follow-up of 63 months, the 5-year RFS of 47 eligible patients in the STD arm and 48 eligible patients in the HDC arm was 37% and 52% on an intent-to-treat basis, respectively (P = 0.17). Five-year overall survival of all randomized patients was 62% for the STD arm and 63% for the HDC arm (P = 0.78). Although the prespecified values of the two arms were not so accurate as to allow detection of the observed difference, no advantage of HDC was observed in terms of RFS or overall survival.

[Improving the surgeon's image: introduction].

The number of medical students who aspire to become surgeons has been decreasing in recent years. With a vicious spiral in the decreasing number and the growing deterioration of surgeons' working conditions, there is fear of deterioration of surgical care and subsequent disintegration of overall health care in Japan. The purpose of this issue is to devise a strategy for improving surgeons' image and their working conditions to attract future medical students. However, we cannot expect a quick cure for the problem of the decreasing number of applicants for surgery since this issue is deeply related to many fundamental problems in the health care system in Japan. The challenge for surgical educators in coming years will be to solve the problem of chronic sleep deprivation and overwork of surgery residents and to develop an efficient program to meet the critical educational needs of surgical residents. To solve this problem it is necessary to ensure well-motivated surgical residents and to develop an integrated research program. No discussion of these issues would be complete without attention to the allocation of scarce medical resources, especially in relation to financial incentives for young surgeons. The authors, who are conscientious representatives of this society, would like to highlight these critical problems and issues that are particularly relevant to our modern surgical practice, and it is our sincere hope that all members of this society fully recognize these critical issues in the Japanese health care system to take leadership in improving the system. With the demonstration of withholding unnecessary medical conducts we may be able to initiate a renewal of the system and eventually to fulfill our dreams of Japan becoming a nation that can attract many patients from all over the world. Furthermore, verification of discipline with quality control and effective surgical treatment is needed to avoid criticism by other disciplines for being a self-centered field. The Japanese Surgical Society appears to be the only medical society that is capable of leading a revolution in the health care system of this country with its autonomy and self-discipline. It is timely for the Japanese Surgical Society to consider a modification of its stated mission by adding "to improve the care of the surgical patient" as dictated by the American College of Surgeons.

Immunohistochemical evaluation of hormone receptors in breast cancer: which scoring system is suitable for highly sensitive procedures?

To evaluate hormone receptors immunohistochemically, standardized staining procedures and scoring systems are required. The authors previously reported that highly sensitive procedures affected basic factors for technical validation. The aim of the present study was to show the characteristics of scoring systems for highly sensitive procedures. To examine how highly sensitive procedures enhance the staining intensity and increase the positive cell population, two different staining methods were compared. To evaluate scoring systems, three systems--cell counting score, modified immunoreactive score, and H score--were compared using the same samples stained by an autostaining system. It was found that the highly sensitive procedure increased the positive cell population, especially in breast cancers with a low enzyme immunoassay (EIA) level of less than 100 fmol/mg, and strengthened the staining intensity. This enhancement led to a correlation in a logarithmic curve rather than a linear correlation by all three scoring systems. The results showed that scoring systems including a factor of staining intensity did not have an absolute advantage because boosted staining intensity by highly sensitive procedure did not reflect EIA value or protein contents accurately. To the authors' knowledge, there is no report discussing the nonlinear correlation between biochemical and immunohistochemical assay by highly sensitive procedures; however, it is important to select a scoring system and threshold based on nonlinear correlation.

Prophylactic hepatic arterial infusion chemotherapy for the prevention of liver metastasis in patients with colon carcinoma: a randomized control trial.

BACKGROUND: The liver is the most frequent site of recurrence after curative resection in patients with colon carcinoma. For liver metastasis, a high response rate can be achieved with hepatic arterial infusion (HAI) chemotherapy. In the current study, the authors administered 5-fluorouracil (5-FU) as adjuvant chemotherapy by HAI to patients with colon carcinoma without liver metastases and studied its effects on recurrence in the liver and survival. METHODS: A total of 316 patients with preoperative Stage II or Stage III colon carcinoma (according to the 1997 revision of the International Union Against Cancer TNM staging system) were randomly assigned to receive surgery plus 3-week continuous HAI of 5-FU or surgery alone. There were 305 eligible patients, of whom the 119 patients assigned to the HAI arm actually received 5-FU. The primary endpoint was disease-free survival, whereas the secondary endpoints were overall survival and liver metastasis-free survival. Analysis was by intent to treat. RESULTS: There were no significant differences noted in morbidity between the two treatment arms. During the follow-up period (median, 59.0 months), the incidence of liver metastasis was significantly decreased in the HAI arm whereas there were no significant differences reported between the 2 arms with regard to the frequency of metastasis at other sites. In the HAI arm, the risk ratio for recurrence was 0.40 (95% confidence interval [95% CI], 0.24-0.64; P=0.0002), the risk ratio for death was 0.37 (95% CI, 0.21-0.67; P=0.0009), and the risk ratio for liver metastasis was 0.38 (95% CI, 0.22-0.66; P=0.0005). These differences were found to be significant only for patients with Stage III disease. Toxicities were mild. CONCLUSIONS: A schedule of 3-week HAI of 5-FU given as adjuvant chemotherapy to patients with Stage III colon carcinoma appeared to contribute to a significant decrease in the frequency of liver metastases and was associated with an improved survival rate.

Combination of trastuzumab and vinorelbine in metastatic breast cancer.

BACKGROUND: Since the clinical introduction of trastuzumab (Herceptin) for metastatic breast cancers that overexpress human epidermal growth factor receptor 2 (HER2), this anticancer agent has played an important role in breast cancer treatment. We examined the effects of trastuzumab and vinorelbine (Navelbine) as a second- or third-line therapy in 24 patients whose HER2-positive tumors did not respond to or relapsed after administration of trastuzumab alone or in combination with taxane. METHODS: Trastuzumab was administered at 2 mg/kg (loading dose 4 mg/kg) once weekly and vinorelbine at 25 mg/m(2) once weekly. The median treatment duration was 118.5 days (range, 22-351 days). RESULTS: The response rate was 42% (95% confidence interval (CI): 22%-63%). The adverse events of NCI-CTC grade 3 or above consisted of neutropenia in three patients; other adverse events, including vasculitis, generalized fatigue, anemia and thrombocytopenia, were grade 1 or 2. All adverse events were reversible after treatment withdrawal and were easily manageable. CONCLUSION: A combination of trastuzumab and vinorelbine can be safely administered on an outpatient basis, and is useful in the treatment of patients with HER2-overexpressing metastatic breast cancer.

Proliferative, infiltrative, and metastatic activities in colorectal tumors assessed by MIB-1 antibody.

MIB-1 antibody staining discriminates the cells in phases other than G0 of the cell cycle. The current study examined the proliferative activity assessed by MIB-1 antibody in colorectal adenoma, primary lesions of colorectal carcinoma (CRC) to investigate the relation between the histologic atypia, the proliferative, infiltrative, and metastatic activities. The MIB-1 antibody positive rate was immunohistologically determined in primary lesions in 311 patients, 22 having adenoma or carcinoma in situ, 207 invasive CRC without distant metastasis, and 82 invasive CRC with distant metastasis. The MIB-1 antibody positive rate was significantly higher in cases of adenoma with severe atypia and carcinoma in situ, showing a close relation between histologic atypia and proliferative activity. Among invasive CRC, the positive rate in poorly differentiated adenocarcinoma and mucinous carcinoma is significantly lower than in well differentiated and moderately differentiated adenocarcinomas. The positive rate was significantly lower in carcinomas with subserosa or deeper invasion than in carcinomas with submucosa or muscularis propria invasion, showing no distinct relation between the proliferative activity and the infiltrative activity. The positive rate of primary lesion was significantly lower in cases with metachronous liver or lung metastasis than in synchronous cases, indicating that metachronous hematogenous metastasis occurs even in cancers with low proliferative activity. The MIB-1 antibody positive rate showed a close relation between histologic atypia and proliferative activity in mucosal colorectal tumors although its relation with infiltrative activity was unclear in invasive CRC. It was apparent that metachronous hematogenous cancer metastasis might take place even in cases with low proliferative activity.

Recurrence patterns after curative resection of colorectal cancer in patients followed for a minimum of ten years.

BACKGROUND/AIMS: To investigate the recurrence patterns and interval from initial surgery in patients with curatively resected colorectal cancer followed for a minimum of 10 years. METHODOLOGY: We retrospectively reviewed 418 patients who had undergone curative resection for colon cancer (n = 246) or rectal cancer (n = 169). Follow-up periods ranged from 10 to 23 years. Main outcome measures were interval until recurrence, site of first recurrence, and influence of adjuvant chemotherapy. RESULTS: 26 (6%) had been lost to follow-up by 10 years and 143 (34%) had died. The most common site of recurrence was liver in colon cancer and locoregional in rectal cancer. The cumulative recurrence rate in colon cancer was 100% at 4 years. In rectal cancer, it was 89% at 5 years, 98% at 7 years and 100% at 10 years. The interval until recurrence was longer in rectal cancer (26.0 +/- 24.2 months) than in colon cancer (17.1 +/- 11.0 months) (p = 0.03). It was also longer in patients receiving than in those not receiving adjuvant chemotherapy (p < 0.01). The interval until lung metastasis was longer than that until liver metastasis in colon cancer (p = 0.04), and longer than that until locoregional recurrence in rectal cancer (p = 0.03). The interval until recurrence in the colon cancer was shorter for stage III than for stage II (p = 0.02). CONCLUSIONS: Surveillance for recurrences, particularly for relapses in the liver and lung, should be performed for at least 4 years in colon cancer patients. Patients with rectal cancer should be followed for a longer period than those with colon cancer, focusing on locoregional, liver and lung recurrence. It is particularly noteworthy that adjuvant chemotherapy may prolong the interval until recurrence and the interval until lung metastasis is relatively longer.

[A case of advanced gastric cancer with multiple liver metastases responding to TS-1 and CDDP].

A 44-year-old male presented to our hospital with abdominal pain. The upper endoscopy revealed advanced gastric cancer. On the abdominal CT, there was evidence of multiple, massive liver metastases. After total gastrectomy, the patient was treated with daily oral administration of 120 mg TS-1 for 4 weeks followed by 2 weeks' rest and 6 weekly infusions of 10 mg CDDP in an intra-hepatic artery as 1 cycle. On the follow-up CT, the liver metastases had decreased significantly both in size and number after 2 cycles. The current case suggests that TS-1 and CDDP may have a potent therapeutic efficacy in cases of advanced gastric cancer with multiple liver metastases.

Gastrointestinal cytomegalovirus infection in collagen diseases.

Cytomegalovirus infection of the gastrointestinal tract is a rare serious complication in patients with collagen diseases receiving immunosuppressive agents. We report 3 such cases diagnosed by endoscopy followed by proper treatment. The patients include 38 and 53 years old females with systemic lupus erythematosus. They presented epigastric pain after pulse steroid therapy and combination therapy with steroids and cyclophosphamide, respectively. Their endoscopical findings were multiple small gastric erosions. The other patient was a 60-year-old female with polymyositis who developed rectal bleeding after steroid and imuran therapy. Her endoscopical finding was a discrete, irregular rectal ulcer. The diagnosis of all the patients was confirmed by biopsies of those lesions showing giant cell inclusion bodies and positive staining with anti- cytomegalovirus -antibodies. All patients were treated properly with ganciclovir. We should always keep in mind of a cytomegalovirus infection of the gastrointestinal tract in a patient with collagen disease receiving immunosuppressive agents.

The stability of dihydropyrimidine dehydrogenase activity in colorectal cancer tissue after resection.

Dihydropyrimidine dehydrogenase (DPD) is the first and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). DPD activity in tumor tissue may consequently serve as a predictive factor for sensitivity to 5-FU. The purpose of this study was to elucidate the stability of DPD activity over time in resected colorectal cancer tissue. DPD activity was measured in samples frozen immediately after the tumor was resected and in samples that had been allowed to stand at room temperature for 15, 30, 60, 120, and 180 min before being frozen. Surgical specimens obtained from 15 cases with advanced colorectal cancer were analyzed. The effects of differences among individuals and differences in time between collection and freezing were assessed by two-way analysis of variance (ANOVA). Significant differences in DPD activity were found among tumors (p=0.001), but there were no significant differences in the same tumor depending on the time between collection and freezing (p=0.496). Based on these results, it appears possible to make comparative assessments of DPD activity in colorectal cancer tissue without strictly stipulating the time between resection and freezing.

Gastric tube cancer after esophagectomy for esophageal squamous cell cancer and its relevance to Helicobacter pylori.

BACKGROUND/AIMS: Improvement of surgical skills and postoperative management has allowed longer postoperative survival for patients with esophageal cancer, among those some develop gastric tube cancer. We analyzed the characteristics of such patients we encountered as well as of reported cases of Japan. Furthermore, we investigated if Helicobacter pylori plays a role in carcinogenesis of the gastric tube in our cases. METHODOLOGY: We analyzed the clinicopathological features of our 8 patients with gastric tube cancer from 1991 to 2000 as well as the status of H. pylori on the gastric tube biopsy. Moreover the features of gastric tube cancer from domestic reported cases up to the year 2000 were also summarized. RESULTS: According to the review of our cases, the frequent tumor location was the distal portion of the gastric tube. Seventy-eight percent were detected in early stage during postoperative follow-up, 71% of those were treated endoscopically. No cases showed H. pylori positivity. From the previous domestic reports, early cancer is increasing as the screening becomes popular. Type 0-IIa and 0-IIc were the most popular images for early cancer, while type 2 and 3 were for advanced cancer. CONCLUSIONS: The carcinogenesis of the gastric tube seemed not to be related to H. pylori. Subdermal route of reconstruction at esophagectomy seemed superior regarding early recognition of gastric tube cancer and easiness of its treatment.

[Prospects for standardization of surgical treatment for breast cancer].

Surgical treatment of breast cancer in general guided cancer surgery in the direction of extensive radical operations until two decades ago. More recently, the trend has been toward conservative, less-extensive surgery. Moreover, breast cancer has become a model case for establishing standardization of surgical care of cancer. The Japanese Breast Cancer Society issued "Guidelines for Breast-Conserving Therapy" in 1999, and the Clinical Research Group for Establishing Guidelines for Standardized Diagnosis and Treatment for Breast Cancer became active in 2002 under the auspices of the Ministry of Health, Welfare and Labor. There are several areas of controversy in terms of surgical care in breast cancer. Examples are yet-immature breast-conserving surgery which is performed with wide variations (15-90%) depending upon the institution, and sentinel lymph node biopsy which must await long-term results before being recognized as standard care. The installation of expensive diagnostic devices indispensable for standardized surgical care might not be necessary at each institution, and it must be noted that postoperative follow-up policies practiced in Japan differ greatly from those recommended by the American Society of Clinical Oncology. Despite the anticipated difficulties, a consensus on what constitutes standardized surgical treatment for breast cancer might be easily reached among breast cancer surgeons. However, it may be somewhat difficult to popularize the standardized surgical treatment among ordinary general surgeons in Japan, since there is a wide disparity in the level of clinical care offered by individual physicians and healthcare institutions. Standardization of medical care guided by the government is mainly designed to reduce healthcare costs, which is instrumental in eliminating unnecessary medical interventions and may in turn shed light on valuable medical care advances. This may be the moment for the Japanese Surgical Society and its members who practice life-saving surgery to lead a genuine national medical reformation.

Heterogeneous gene alterations in primary breast cancer contribute to discordance between primary and asynchronous metastatic/recurrent sites: HER2 gene amplification and p53 mutation.

The aim of the present study was to clarify differences in genetic events between primary breast cancers and asynchronous metastatic/recurrent lesions, by examining HER2 gene amplification and p53 mutation. The subjects were 44 breast cancer patients with asynchronous metastasis or recurrence. Synchronous metastases were excluded. HER2 overexpression and gene amplification were examined using immunohistochemistry and fluorescent in situ hybridization (FISH). P53 point mutation was examined by immunohistochemistry, laser-captured microdissection, PCR-single-strand conformation polymorphism, and a direct sequencing method. Immunohistochemistry showed that, for HER2, p53, ER and PgR, discordance rates between primary and recurrent tumor were 2 (4.5%), 1 (2.3%), 7 (15.9%) and 10 (22.7%), respectively. Two primary tumors with discordant HER2 overexpression were composed of at least two populations of carcinoma cells, with and without HER2 gene amplification. Distribution of HER2 gene amplification was consistent with protein overexpression. Corresponding recurrent tumors consisted of carcinoma cells without HER2 gene amplification. Of 6 recurrent tumors in which the primary carcinoma had a p53 point mutation, 3 tumors had identical mutations, 1 tumor had a different point mutation, and 2 tumors had no mutation. It was suspected that the latter 3 recurrent tumors comprised a minor component of the primary tumor. In the present study, we examined a large series of asynchronous recurrent tumors. A limited number of these tumors showed discordance between primary and recurrent tumors. Detailed observations revealed that cell populations present in recurrent tumors were also present in the primary tumors, although they comprised a minor component of the primary tumor. Heterogeneity of the primary tumor apparently contributed to discordance.

Immunohistochemical evaluation of hormone receptor for routine practice of breast cancer: highly sensitive procedures significantly contribute to the correlation with biochemical assays.

Immunohistochemical evaluation of hormone receptors for breast cancer has been performed parallel to biochemical assays. Recently, immunohistochemistry has tended to substitute the biochemical method in Japan. To clarify the factors concerned and problems to be resolved, we reviewed our evaluation system for hormone receptors by immunohistochemistry from 1990. A total of 861 breast cancer samples were examined by immunohistochemistry and biochemistry. In 3 main periods, phase 1 (1990-1993), phase 2 (1995-1998), and phase 3 (1999-2001), increasing sensitivity of the immunohistochemical method was provided by commercially available staining systems and shown to range from 83.6% (phase 1) to 92.0% (phase 3). The highly sensitive procedures of the antigen retrieval and peroxidase-conjugated polymer method are main contributing factors. The authors examined how these procedures influenced the distribution of positive cell population; concordance rate, including sensitivity and specificity; cutoff points; and evaluation categories. The correlation between biochemistry and immunohistochemistry was extensively studied in the 1980s and 1990s. In reference to the progress achieved in the United States and United Kingdom to control the current situation in Japan, it should be recognized that recently developed, highly sensitive procedures boost the immunoreactivity, which will affect the basic factors for technical validation.

Sentinel lymph node detection with Tc-99m tin colloids in patients with esophagogastric cancer.

BACKGROUND: The aim of this study was to determine by radioisotope use whether the sentinel lymph node concept is applicable to esophagogastric cancers. In addition, we examined radioactivities of hot nodes and compared them with the sensitivity of a gamma probe. METHODS: The subjects were 44 patients, 23 with esophageal cancer and 21 with gastric cancer. The day before surgery, patients underwent endoscopic submucosal injection of 184 MBq of Tc-99m tin colloids into sites surrounding the tumor. Radioisotope activities of lymph nodes dissected at surgery were measured with a well-typed gamma detector and each lymph node was categorized as a hot or cold node. Histopathology of the lymph nodes was examined by hematoxylin and eosin staining. Radioisotope activities and histopathological results were compared to determine whether radioisotope flow reflects lymphatic flow to regional lymph nodes. The sensitivity of a gamma probe was measured in a laboratory study and the relation between the radioisotope activities of hot nodes and the detection sensitivity of the gamma probe was examined. RESULTS: Histopathological examination revealed lymph node metastasis in 18 of the 44 patients. In 15 of these 18 patients, metastatic foci were recognized in at least one hot node. Subsequent analysis was performed on the 36 patients in whom tumor invasion was confined to the muscle layer and in whom endoscopic clippings had not been applied. Lymph node metastases were observed in 12 of these 36 patients. In these 12 patients, at least one hot node was positive for metastasis. The laboratory study revealed that the gamma probe was able to detect radioisotope activities of >/=0.02 micro Ci. Thirty-two of 63 (51%) esophageal cancer hot nodes and 16 of 86 (19%) gastric cancer hot nodes showed radioisotope activities below the detection sensitivity of the gamma probe. CONCLUSION: The sentinel lymph node concept is applicable to patients with esophageal and gastric cancers; however, further studies are necessary to identify hot nodes accurately using gamma probes.