Treatment Of Cancer In Japan Research Articles

The Benchmark Analysis of Gastric, Colorectal and Rectal Cancer Pathways: Toward Establishing Standardized Clinical Pathway in the Cancer Care

Most clinical pathways in treating cancers in Japan are based on individual physician's personal experiences rather than on an empirical analysis of clinical data such as benchmark comparison with other hospitals. Therefore, these pathways are far from being standardized. By comparing detailed clinical data from five cancer centers, we have observed various differences among hospitals. By conducting benchmark analyses, providing detailed feedback to the participating hospitals and by repeating the benchmark a year later, we strive to develop more standardized clinical pathways for the treatment of cancers. The Cancer Quality Initiative was launched in 2007 by five cancer centers. Using diagnosis procedure combination data, the member hospitals benchmarked their pre-operative and post-operative length of stays, the duration of antibiotics administrations and the post-operative fasting duration for gastric, colon and rectal cancers. The benchmark was conducted by disclosing hospital identities and performed using 2007 and 2008 data. In the 2007 benchmark, substantial differences were shown among five hospitals in the treatment of gastric, colon and rectal cancers. After providing the 2007 results to the participating hospitals and organizing several brainstorming discussions, significant improvements were observed in the 2008 data study. The benchmark analysis of clinical data is extremely useful in promoting more standardized care and, thus in improving the quality of cancer treatment in Japan. By repeating the benchmark analyses, we can offer truly clinical evidence-based higher quality standardized cancer treatment to our patients.

Evidence-based guidelines for treatment of uterine body neoplasm in Japan: Japan Society of Gynecologic Oncology (JSGO) 2009 edition

Endometrial carcinoma is one of the most common gynecologic malignancies in Japan and its incidence has increased recently. Although surgery is the cornerstone of the management of patients with endometrial cancer, there is significant variation in Japan with regard to the type of hysterectomy employed. Additionally, it remains controversial whether full nodal staging is required in all patients. Furthermore, adjuvant therapy differs between Japan and Western countries. To delineate clearly the standard of care for endometrial cancer treatment in Japan, the guidelines for the treatment of endometrial cancer were published in 2006 and revised in 2009. The 2009 edition included topics not addressed in the previous edition including the treatment of mesenchymal tumors, for example leiomyosarcoma, and sections covering the treatment of serous and clear-cell adenocarcinoma. These guidelines are composed of nine chapters and include nine algorithms. The guidelines also contain fifty-one clinical questions (CQs) and each CQ consists of recommendations, background, explanations, and references. The treatment recommendations herein are tailored to reflect current Japanese clinical practice and ensure equitable care for all Japanese women diagnosed with endometrial cancer.

Evidence-based guidelines for treatment of cervical cancer in Japan: Japan Society of Gynecologic Oncology (JSGO) 2007 edition

Clinical practice guidelines for gynecologic cancers have been published by the National Comprehensive Cancer Network and the National Cancer Institute. Whereas these guidelines form the basis for the standard of care for gynecologic malignancies in the United States, it has proven difficult to institute them in Japan due to differences in patient characteristics, health-care delivery systems, and insurance programs. Therefore, evidence-based guidelines for treating cervical cancer specifically in Japan have been under development. The Guidelines Formulation Committee and Evaluation Committee were independently established within the Committee for Treatment Guidelines for Cervical Cancer. Opinions from within and outside the Japan Society of Gynecologic Oncology (JSGO) were incorporated into the final draft, and the guidelines were published after approval by the JSGO. These guidelines are composed of ten chapters and comprise three algorithms. Each chapter consists of a clinical question, recommendations, background, objectives, explanations, and references. The objective of these guidelines is to clearly delineate the standard of care for cervical cancer treatment in Japan in order to ensure equitable care for all Japanese women diagnosed with cervical cancer.

Primary chemotherapy patterns for ovarian cancer treatment in Japan

Evidence-based clinical practices can improve patient outcomes, especially in the area of chemotherapy. In Japan, it is not known how well physicians adhere to evidence-based chemotherapy guidelines. This study aimed to assess physician compliance with national guidelines for ovarian cancer primary chemotherapy in Japan. Using an administrative database, we analyzed 209 cases of surgical laparotomy without neoadjuvant chemotherapy as the primary intervention for adnexal cancer. Cases were identified across seven teaching hospitals between 2003 and 2006. Of the 136 patients receiving inpatient chemotherapy, 101 cases (74%) were treated with platinum-taxane therapy. In five hospitals, platinum-taxane therapy was used in more than 75% of patients, compared to 56% and 32% in the other two hospitals, respectively. The proportion of patients receiving paclitaxel and carboplatin concomitant therapy (TC therapy) was 67%, although significant variation was noted between hospitals (range 32% to 94%, P < 0.001). Of the 91 patients receiving TC therapy, 59 (65%) were given full-dose monthly regimens, while 32 cases (35%) were treated with divided doses weekly. Weekly TC therapy was more frequently provided in hospitals with a low volume of patients receiving TC therapy. Patients under the age of 65 receiving inpatient chemotherapy were more likely to receive full-dose regimens than patients 65 or older (68% vs 43%, P = 0.005). Publication of national treatment guidelines did not appear to substantially impact chemotherapy practice patterns. Adherence to standardized chemotherapy was comparable to rates in European countries, although rates among hospitals differed significantly. Elderly patients were more likely to receive divided-dose regimens.

An Environmental and Biological Study of Occupational Exposure to Cyclophosphamide in the Pharmacy of a Japanese Community Hospital Designated for the Treatment of Cancer

Cancer treatment in Japan is considered to be very progressive in the use of antineoplastic agents. Pharmacists are required to compound more antineoplastic preparations recently and thus are at risk for exposure to antineoplastic agents. In Japan, healthcare professionals have recognized the need for protection, but there have been few reports of environmental contamination or occupational exposure to antineoplastic agents. In the present study, urine samples over 24 hr from compounding pharmacists and wipe samples from the compounding room were collected to analyze levels of cyclophosphamide (CP). CP was detected in urine samples from all 4 pharmacists (mean=165.3 ng/24 hr) and for all wipe samples of the compounding room. From the results of these tests, the standard operating procedure (SOP) of the pharmacy was revised as a protective measure. The tests were then repeated and CP was detected again in the urine of all 4 compounding pharmacists, though the mean CP level was reduced from 165.3 to 47.4 ng/24 hr after the revision of the SOP. Although there was no correlation between the amount of CP compounded and the CP levels in urine initially, the 2 values were significantly correlated after the revision of the SOP (R2=0.87).

Postoperative adjuvant treatments for biliary tract cancer

Surgery currently remains the only potentially curative treatment for biliary tract cancer, and most patients develop recurrence. Thus, effective adjuvant therapy is required to increase the curability of surgery and to prolong the survival in these patients. However, to date, no standard postoperative adjuvant therapy regimen has been established for patients with biliary tract cancer. Based on favorable results reported from phase II trials, gemcitabine and S-1 are currently available as promising agents for the treatment of unresectable biliary tract cancer in Japan. Both agents are also expected to be effective in the postoperative adjuvant therapy setting for biliary tract cancer, and well-designed randomized controlled trials (phase III trials) to determine the efficacy of these agents in the postoperative adjuvant setting should be pursued vigorously. In phase III trials, appropriate stratification of patients is important, and the primary disease (gallbladder cancer versus nongallbladder cancers), curability (R0 or R1), and presence/absence of lymph node metastasis should be taken into account.

Laparoscopically assisted total gastrectomy with lymph node dissection for upper and middle gastric cancer

In recent years, laparoscopic gastrectomy has been applied for the treatment of gastric cancer in Japan and Western countries. This report describes the short- and long-term results for patients with gastric cancer who underwent laparoscopically assisted total gastrectomy (LATG) with lymph node dissection. From September 1999 to December 2007, 20 patients underwent LATG, and 18 underwent conventional open total gastrectomy (OTG) for upper and middle gastric cancer. The indications for LATG included depth of tumor invasion limited to the mucosa or submucosa and absence of lymph node metastases in preoperative examinations. The LATG and OTG procedures for gastric cancer were compared in terms of pathologic findings, operative outcome, complications, and survival. No significant difference was found between LATG and OTG in terms of operation time (254 vs 248 min.), number of lymph nodes (26 vs 35), complication rate (25% vs 17%), or 5-year cumulative survival rate (95% vs 90.9%). Differences between LATG and OTG were found with regard to blood loss (299 vs 758 g) and postoperative hospitalization (19 vs 29 days). For properly selected patients, laparoscopically assisted total gastrectomy can be a curative and minimally invasive treatment for early gastric cancer.

Challenges in predicting the clinical outcome in S-1-based chemotherapy for gastric cancer patients

S-1 has been considered to be a key drug in the treatment of advanced gastric cancer in Japan as a standard option of chemotherapy. Interindividual variation in the enzymes of the S-1 metabolic pathway can affect the extent of S-1 metabolism and impact the efficacy of S-1-based chemotherapy. In this review, the role of the "candidate" genetic factors affecting the therapeutic efficacy of S-1 is discussed with a special emphasis on polymorphism and gene expressions involved in the S-1 metabolic pathway, including CYP2A6, thymidylate synthase, thymidine phosphorylase, and orotate phosphoribosyltransferase. The predictive values of these candidates might be overcome with drugs combined with S-1. Pharmacogenetic studies based on a "global" approach by DNA microarray are promising to identify gastric cancer patients with both survival benefit and clinical benefit more accurately than those based on the "candidate" approach, especially for S-1 combination therapy. Large and controlled studies are needed to justify changes in the chemotherapeutic strategies, from "one-size fits all" to "tailor-made."

Current trends in diagnostic and therapeutic principles for prostate cancer in Japan

This study aimed to clarify characteristics of the diagnosis and treatment of prostate cancer in Japan. In September 2005, questionnaire surveys were mailed to Japanese urologists (response rate, 43%; 474/1090) who were listed as voting members (VMs) of the Japanese Urological Association (JUA); the questionnaire surveys were also mailed to professors and chairmen (PCs) of urology departments at Japanese national, public, and private universities who were also VMs of the JUA (response rate, 76%; 68/90). The questionnaires asked about beliefs and practices regarding prostate cancer management. The answers of the VMs and PCs to the questionnaire were very similar. About 60% of these urologists answered that they did not set an age limit for prostate-specific antigen (PSA) testing, and about 40% answered that they did not set an age limit for prostate needle biopsy in individuals with an intermediately elevated PSA level. The age limit for radical prostatectomy (RP) was set at 75 years by 69% (322/470) of the VMs and 66% (45/68) of the PCs. The order of priority of factors considered for the selection of RP for early prostate cancer was radicality, including tumor grade (mean, 1.97); patient's wish for radical surgery (mean, 2.47); comorbidity (mean, 2.72); and age (mean, 2.81). There are trends in diagnostic and therapeutic principles for prostate cancer which are characteristic of Japan, and these trends are associated with the recent rapid extension of life expectancy in that country.

Possible Impact of the NHK Special Questioning Cancer Treatment in Japan on Clinicians' Prescriptions of Oxaliplatin

Medical information through media may influence physicians' prescriptions of medication. The Japan Broadcasting Corporation (NHK) aired on April and May 2005, a special program called 'Questioning Cancer Treatment in Japan', covering oxaliplatin. We investigated potential impact of this program on prescriptions, utilizing a post-marketing clinical trial monitoring of all patients receiving oxaliplatin. The post-marketing clinical trial reached the target sample size of 1200 by the 4th week of May, 44 weeks sooner than anticipated. The newly registered numbers of facilities and patients exhibited a bimodal peak in April and June. The viewer rating of NHK special was 8.3%, whereas three national newspapers and one weekly magazine took up the minor articles of oxaliplatin. In July 2007, 405 clinicians sent a written opinion to NHK, stating 'NHK special invites misperceptions and confusions to public.' NHK special might have had an impact on clinicians' prescriptions of oxaliplatin.

Gastric Carcinoma: Applying the Sentinel Node Paradigm to Improve the Understanding of Metastatic Patterns and the Possible Role of Selective Lymphadenectomy

Shortly after Morton et al. introduced the modern sentinel node concept and described its successful application to stage the regional lymphatics (cN0) of cutaneous melanoma, sentinel lymph node biopsy (SLNB) was adapted for other solid malignancies that spread via the lymphatics. We described the universal application of this technique in multiple solid tumors including gastric carcinoma in 1998. In this issue of Annals of Surgical Oncology, Gretschel et al. from Charite, University Medicine Berlin, Campus Bunch, Robert-Rossle-Cancer Hospital, HELIOS Klinikum Berlin, Germany, report the results from their prospective trial of SLNB in gastric cancer. In melanoma and breast cancer, SLNB can limit unnecessary lymphadenectomy in cN0 patients, thereby reducing morbidity. In early gastric carcinoma, SLNB may be used in a similar manner, allowing for limited lymphadenectomy in patients without nodal metastasis while accurately staging the regional lymphatics. The trial reported by Gretschel et al. is important because the extent of lymphatic dissection required in gastric carcinoma is controversial. Investigators from Japan prefer extensive lymphatic dissections (D2 and higher), while reports from the West have not identified an advantage in lymphadenectomy extending beyond D1. Several studies including a meta-analysis comparing D1 versus D2 lymphatic resections have concluded that D2 resections have no survival benefit and are associated with a higher morbidity. However, other investigators have shown that after slight modification of the D2 dissection, similar complication rates can be obtained when compared with D1 dissections. These findings suggest that limiting the extent of lymphatic dissection may have no advantage and could result in inadequate surgical treatment leading to understaging. The controversy regarding the extent of lymphatic dissection is further complicated as investigators from Japan who prefer extended lymphadenectomies have promoted the SLNB technique to limit the extent of lymphatic resection in selected patients. In Japan, the application of the SLNB technique in gastric cancer is well described by Kitagawa and others where 70% of patients present with T1 tumors. Prior to the SLNB technique, patients with early gastric cancer in Japan have been routinely treated with extensive lymphadenectomies (D2) for node-negative disease, resulting in some degree of unnecessary morbidity. Intra-operative SLN analysis is now used in selected cT1, N0 patients to predict the status of the remaining regional lymphatic basin; patients without metastases then undergo limited lymphatic dissections. There is a shifting paradigm in the treatment of early gastric cancer in Japan, as many patients undergo function-preserving endoscopic mucosal resection or laparoscopic wedge resections of the primary tumor in conjunction with SLNB with limited lymphatic dissections. The most critical component of implementing this technology is accurate identification of the SLN(s) within the complex regional lymphatics of the foregut. Published by Springer Science+Business Media, LLC 2007 The Society of Surgical Oncology, Inc. Received March 6, 2007; accepted March 7, 2007; published online: May 23, 2007. Address correspondence and reprint requests to: Anton Bilchik, MD, PhD; E-mail: bilchika@jwci.org Annals of Surgical Oncology 14(9):2432–2434 DOI: 10.1245/s10434-007-9411-y

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Hand-assisted laparoscopic total gastrectomy for early gastric cancer.

Laparoscopy-assisted distal gastrectomy has been applied to the treatment of early gastric cancer in Japan. However, there have been few reports on the laparoscopy-assisted total gastrectomy mainly because of the difficulty of the procedure. Here, we report a series of cases where hand-assisted laparoscopic total gastrectomies were performed successfully. The mobilization of the greater curvature was performed laparoscopically. About 7-cm mini-laparotomy was made at the epigastrium and duodenal transection was performed with linear stapler. After dissection of suprapyloric and anterosuperior lymph nodes was performed through the mini-laparotomy, dissection of lymph nodes along the celiac artery, and the left gastric artery was performed by hand-assisted laparoscopic surgery. Roux-en-Y reconstruction was performed through the mini-laparotomy. We successfully performed this procedure in 5 patients. The mean operating time and blood loss were 275 minutes and 177.5 mL, respectively. Hand-assisted laparoscopic total gastrectomy is suitable and feasible for early gastric cancer.

Development of RF and microwave heating equipment and clinical applications to cancer treatment in Japan

Development of RF and microwave (MW) heating equipment for hyperthermia and their clinical applications to various cancers undertaken in Japan have been reviewed in this paper. Originally developed heating devices include an RF capacitive and RF inductive heating device, an MW heating device with a lens applicator, an RF intraluminal heating device, an RF current interstitial heating device, and a ferromagnetic implant heating device. The concept and characteristics of those devices are described herein. Nonrandomized and randomized trials undertaken for superficial and deep-seated tumors demonstrated improved local response with the combined use of hyperthermia. Furthermore, the complications associated with treatment were not generally serious, except for chronic bowel damages suggested in a trial for colorectal cancers. These clinical results indicate the benefit of combined treatment of hyperthermia and radiotherapy. With the advancement of heating and thermometry technologies, hyperthermia will be more widely and safely used in the treatment of cancers.

Failure in antitumor activity by overdose of an immunomodulating beta-glucan preparation, sonifilan.

Schizophyllan (SPG, Sonifilan) is a soluble (1-->3)-beta-D-glucan, used as a biological response modifier (BRM) with radiation therapy for cancer treatment in Japan. The mechanism of SPG mediated antitumor activity is thought to be via immune stimulation, which includes cytokine production, hematopoietic response, and so on. In this paper, we found that the activity of SPG was quite long-lived and an overdose significantly failed to display the antitumor activity. To demonstrate the mechanism several parameters were examined using a high dose of SPG administration as follows: i) the effect on vascular permeability in vivo, ii) the priming effect on tumor necrosis factor (TNF-alpha) production in vivo, iii) the effect on macrophage adherence to plastic plate in vitro, and iv) anti-Sarcoma 180 antibody production in vivo. It was evident that vascular permeability and anti-Sarcoma 180 antibody production remained unchanged, but TNF-alpha production and adherence to a plastic plate was significantly reduced by a high dose of SPG. These facts strongly suggested that modulation of the cytokine syntheses and the leukocyte traffic would be the causative mechanisms of the failure of antitumor activity by an overdose of SPG.

The Confusion Associated with Breast Cancer Chemotherapy in Japan: The First Year's Experience at the Division of Oncology and Hematology, National Cancer Center Hospital East

The current status of breast cancer chemotherapy in Japan was examined and compared with internationally accepted standard therapy, by reviewing the previous treatment of patients with advanced or metastatic breast cancer who had been referred to the National Cancer Center Hospital East. Forty patients were referred mainly from middle-sized or large hospitals between July 1992 and June 1993. The most commonly used regimen for adjuvant therapy was a combination of long-term and oral low-dose fluoropyrimidine compounds (LDFU), which is rarely used in Western countries, and tamoxifen. Some patients had received perioperative intravenous mitomycin C. The adjuvant polychemotherapy most commonly used internationally has been given to only a few patients. The first-line treatment for advanced or metastatic disease in the previous hospitals varied, but myelosuppressive chemotherapy including anthracyclines was given to half of the patients. Oral LDFU was also used for some patients alone or in combination as the first-line chemotherapy. Local therapy for metastasis to soft tissue was performed in 9 patients. Oral LDFU therapy that is frequently used for cancer treatment in Japan should be evaluated in a well designed controlled trial.

Preventive effects of OK432 on murine acute myocarditis due to encephalomyocarditis virus

OK432, one of the immunomodulators used for cancer treatment in Japan was examined for its effects on murine myocarditis due to encephalomyocarditis (EMC) virus. The survival rate of mice administered with 1 KE of OK432 intraperitoneally every other day starting 2 days before viral inoculation was significantly higher than that of the control mice administered virus alone on days 10-21 (16/20 vs. 4/20, p less than 0.001), and the viral titer in the heart, the heart weight/body weight ratio, and the scores for myocardial inflammation and necrosis were significantly lower. The natural killer (NK) cell activity and interferon (IFN) titer on day 1 after infection were increased in comparison with the control group (NK cell activity: 51.1 vs. 37.9%, p less than 0.05. IFN: 1205 vs 512 U/ml), and the cytotoxicity of peritoneal macrophages was increased (50.6 vs. 29.1%). Thus, OK432 given before viral inoculation significantly improved survival and reduced both the viral titer in the heart and myocardial damage in this experimental model of acute EMC viral myocarditis. Accordingly, the stimulation of the host immunologic response by OK432 may be important for elimination of virus of the heart.

Current status of surgical therapy for primary liver cancer in Japan.

The current status of diagnosis and treatment of primary liver cancer in Japan and its problems are described. Most primary liver cancers in the Japanese prove to be hepatocellular carcinoma complicated with liver cirrhosis. Based on these characteristics, at least three factors are important for the diagnosis of early stage of liver cancer 1) follow-up of high risk individuals 2), alpha-fetoprotein screening, and 3), application of ultra sonography (US) or computerized tomography (CT) in suspected cases. With relation to surgery, the following two points should be considered; 1), complications of esophageal varices and 2), development of postoperative hepatic failure or multiple organ failure (MFO) after extensive resection.

Studies of analogs of fluorinated pyrimidine in Japan.

Ftorafur, 1-(2-tetrahydrofuryl)-5-fluorouracil, is a cancer drug very widely used in treatment of cancer in Japan; in particular, it is administered orally for treatment of tumors of the gastrointestinal tract. Recently a new preparation with an enteric coating became available for oral administration. Ftorafur itself is absorbed mainly from the jejunum and ileum, and slightly from the duodenum, but not from the stomach. This new preparation was designed to release ftorafur only in the intestine, and in experiments with beagle dogs it was shown to be absorbed more easily than the earlier preparation. With the same dose, approximately 20% greater total absorption into the blood was estimated with the new preparation. In clinical trials, side effects of the new preparation, especially to the upper digestive organs, were less evident than those of the previous one, which released nearly 100% ftorafur into the stomach within 10 min after the oral administration. The new preparation was tolerated by patients at daily doses of approximately 1 000 mg/m2 for continuous treatment.KeywordsAntitumor EffectLewis Lung CarcinomaAscitic Ehrlich CarcinomaRhythmic ContractionCumulative ExcretionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Recent Results of Cancer Treatment in Japan.

Recent Results of Cancer Treatment in Japan.