In Japan, JSCN/JSMO/JASPO Joint Guidelines for Safe Handling of Cancer Chemotherapy Drugs was published in July, 2015. Occupational exposure of hazardous drugs (HD) should be prevented and safely managed by comprehensive team approaches throughout all processes of cancer chemotherapy; preparation, delivery, administration to abandonment of HD. All medical stuffs who deal with HD occupationally should acquire knowledge and skills for safe handling of HD. Understanding of hierarchy control and practical use of BSC, CSTD, PPE are keys for prevention of HD exposure.

Although anti-EGFR monoclonal antibodies, including cetuximab and panitumumab, are highly effective in KRAS wild-type advanced colorectal cancer, these drugs frequently cause several adverse events. These events include hypomagnesemia and acneiform rash, which may lead to the dose reduction or discontinuation of therapy. In the present study, we retrospectively investigated the incidence of hypomagnesemia and acneiform rash in patients with metastatic colorectal cancer (mCRC). We examined the relationship between the incidence of such adverse events and the therapeutic effect.

Nanoparticle albumin-bound paclitaxel(nab-PTX)was approved for the treatment of gastric cancer without a large-scale clinical trial in Japan. Its safety and efficacy should be validated in clinical practice. We retrospectively investigated prognostic factors related to time to treatment failure(TTF)in 11 patients with unresectable or recurrent gastric cancer treated with nab- PTX in our hospital. In univariate analysis, Onodera's prognostic nutritional index(PNI)and the time from the start of first-line chemotherapy to the start of nab-PTX were related to TTF. In multivariate analysis, Onodera's PNI was identified as an independent predictive factor for TTF (hazard ratio 0.056, p=0.022). PNI could contribute to adequate patient selection and the improvement of nab-PTX therapy efficacy ingastric cancer.

Stomatitis is a characteristic adverse event of everolimus and other mTOR inhibitors, and occurs at a high incidence and impairs QOL owing to pain. Most cases of stomatitis are mild to moderate. However, when stomatitis becomes serious, it can interfere with the continuation of medication. Therefore, it is important to place more emphasis on the prevention as well as early detection and treatment. In addition, patient education is also important. The possible occurrence of stomatitis, its signs and symptoms, as well as the importance of oral care need to be thoroughly explained prior to starting treatment. In order to smoothly carry out these measures, it will also be essential that cancer-treating physicians coordinate and collaborate with dentists, nurses, and pharmacists. It is desirable to establish appropriate prevention and management methods on the basis of the results of the Phase III prospective study, Oral Care-BC, currently ongoing in Japan.

Chemoradiotherapy using fluorouracil was initially investigated as a postoperative adjuvant therapy for pancreatic cancer. However, a large randomized controlled trial (RCT) of surgery, chemoradiotherapy, and chemotherapy demonstrated that chemoradiotherapy was inferior to no chemoradiotherapy, while the efficacy of radiotherapy as adjuvant therapy was controversial. Since gemcitabine was established as a standard therapy for unresectable pancreatic cancer, several RCTs have revealed that gemcitabine is also an effective adjuvant therapy. In Japan, S-1, an oral fluoropyrimidine, was approved for the treatment of pancreatic cancer, and a phase III study compared S-1 with gemcitabine as adjuvant therapy. This study examined whether S-1 was non-inferior to gemcitabine and found it superior. As a result, S-1 is recognized as the first-choice adjuvant therapy for pancreatic cancer in Japan. FOLFIRINOX or gemcitabine plus nab-paclitaxel was recently demonstrated to prolong survival in patients with metastatic pancreatic cancer. To improve the survival rate of patients who undergo surgery, these chemotherapeutic regimens with higher response rate are also currently under investigation compared with gemcitabine as adjuvant therapies in RCTs. Furthermore, neoadjuvant therapy using gemcitabine plus S-1, FOLFIRINOX, or gemcitabine plus nab-paclitaxel is expected to improve outcomes of surgical treatments, and various clinical trials of neoadjuvant therapies using those regimens are currently under investigation.

Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease characterized by intense liver steatosis accompanied by hepatocyte destruction, inflammation and fibrous, despite little or no history of alcoholic consumption. There are also cases of drug-induced secondary steatohepatitis. Drug-induced steatohepatitis is a relatively rare type of drug-induced liver disease, but close attention to the possible onset of steatohepatitis is needed when drugs with the potential to induce fatty liver are prescribed for long term use. Estrogen is a factor indispensable to smooth fatty acid β-oxidation in hepatocytes. However, treatment with Tamoxifen markedly suppresses fatty acid β-oxidation in the liver. As free fatty acids are toxic, their accumulation results in the activation of alternative fatty acid oxidation pathways mediated by CYP2E1 in cytosol and lipid peroxidases in peroxisomes in hepatocytes. CYP2E1 enhances lipid peroxidation and dicarboxylic acid synthesis via the activation of fatty acid ω-oxidation that injures mitochondria and results in the emergence of ballooned hepatocytes. In such cases, the attenuation of alternative fatty acid oxidation pathways could have some beneficial effects on mitochondrial injury, since fibrates (PPAR-α ligands) are potent enough to stimulate neutral fat consumption through the activation of peroxisomal fatty acid β-oxidation. Fortunately, fibrates attenuate serum estrogen levels by affecting estrogen receptor expression, so the co-administration of fibrates with Tamoxifen is expected to exert higher efficacy in breast cancer patients with Tamoxifen-induced hepatic steatosis.

An 81-year-old man was referred to our hospital because of a right renal tumor with vena cava thrombus and multiple lung metastases that were detected by computed tomography (CT) scan during evaluation of respiratory discomfort. We started medical treatment with sunitinib at a dose of 50 mg daily in a 2-week-on, 1-week-off schedule after confirming clear cell renal cell carcinoma by tumor biopsy. After 2-week sunitinib treatment, thrombocytopenia continued and platelet count decreased to 1.8×10(9)/l at day 11 after stopping sunitinib. We needed to administer a total of 60 units platelet transfusion because of persistent thrombocytopenia. Bone marrow aspiration did not reveal myelosuppression or carcinoma invasion to bone marrow. Under the clinical diagnosis of drug-induced thrombocytopenia secondary to sunitinib, we started immunoglobulin therapy at day 23 after stopping sunitinib. Platelet count returned to normal 10 days after starting immunoglobulin. The patient developed exacerbating lung metastasis and carcinomatous lymphangiosis during subsequent course and died of renal cell carcinoma 79 days after starting sunitinib. Thrombocytopenia after sunitinib therapy is often encountered but prolonged thrombocytopenia is rare after stopping sunitinib. This case suggests that immunoglobulin therapy is effective for drug-induced prolonged thrombocytopenia through immunological mechanism.

The Japanese Ministry of Health, Labor, and Welfare lists hand-foot syndrome as a serious adverse drug event. Therefore, we evaluated its association with anticancer drug therapy using case reports in the Japanese Adverse Drug Event Report (JADER) and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). In addition, we calculated the reporting odds ratio (ROR) of anticancer drugs potentially associated with hand-foot syndrome, and applied the Weibull shape parameter to time-to-event data from JADER. We found that JADER contained 338224 reports from April 2004 to November 2014, while FAERS contained 5821354 reports from January 2004 to June 2014. In JADER, the RORs [95% confidence interval (CI)] of hand-foot syndrome for capecitabine, tegafur-gimeracil-oteracil, fluorouracil, sorafenib, and regorafenib were 63.60 (95%CI, 56.19-71.99), 1.30 (95%CI, 0.89-1.89), 0.48 (95%CI, 0.30-0.77), 26.10 (95%CI, 22.86-29.80), and 133.27 (95%CI, 112.85-157.39), respectively. Adverse event symptoms of hand-foot syndrome were observed with most anticancer drugs, which carry warnings of the propensity to cause these effects in their drug information literature. The time-to-event analysis using the Weibull shape parameter revealed differences in the time-dependency of the adverse events of each drug. Therefore, anticancer drugs should be used carefully in clinical practice, and patients may require careful monitoring for symptoms of hand-foot syndrome.

Peripheral neuropathy is a common adverse effect of paclitaxel and oxaliplatin treatment. The major dose-limiting side effect of these drugs is peripheral sensory neuropathy. The symptoms of paclitaxel-induced neuropathy are mostly sensory and peripheral in nature, consisting of mechanical allodynia/hyperalgesia, tingling, and numbness. Oxaliplatin-induced neurotoxicity manifests as rapid-onset neuropathic symptoms that are exacerbated by cold exposure and as chronic neuropathy that develops after several treatment cycles. Although many basic and clinical researchers have studied anticancer drug-induced peripheral neuropathy, the mechanism is not well understood. In this review, we focus on (1) analysis of transient receptor potential vanilloid 1 (TRPV1) channel expression in the rat dorsal root ganglion (DRG) after paclitaxel treatment and (2) analysis of transient receptor potential ankyrin 1 (TRPA1) channel in the DRG after oxaliplatin treatment. This review describes that (1) paclitaxel-induced neuropathic pain may be the result of up-regulation of TRPV1 in small- and medium-diameter DRG neurons. In addition, paclitaxel treatment increases the release of substance P, but not calcitonin gene-related peptide, in the superficial layers of the spinal dorsal horn. (2) TRPA1 expression via activation of p38 mitogen-activated protein kinase in small-diameter DRG neurons, at least in part, contributes to the development of oxaliplatin-induced acute cold hyperalgesia. We suggest that TRPV1 or TRPA1 antagonists may be potential therapeutic lead compounds for treating anticancer drug-induced peripheral neuropathy.

S-1 (tegafur/gimeracil/oteracil potassium) is an effective oral anticancer drug for treatment of a wide spectrum of cancers. However, it may incur serious adverse effects through factors such as interactions with other drugs, renal dysfunction, or an insufficient washout period. In view of this, pharmacists should play an increasingly significant role in managing the medication history of patients treated with S-1. As there seems to be no standardized management tool for patients receiving S-1, we conducted a retrospective study to evaluate medication history management methods, which are commonly available in community pharmacies as well as hospitals. We identified 128 outpatients who were prescribed S-1 for the first time at the National Cancer Center Hospital from July to December of 2011. These patients were divided into in-hospital (n=48) and out-of-hospital (n=80) groups. The percentage of patients, who dropped out during the first course of S-1 treatment, was 16.7% for the in-hospital group, and 10% for the out-of-hospital group. Examining renal dysfunction, non-elderly patients with low creatinine clearance (Ccr) were found. These results suggest that there is the possibility of side effect occurrence in both the in-hospital and out-of-hospital prescription groups. Community pharmacists should check prescriptions with particular attention to the Ccr. It is necessary to develop mechanisms for cooperation between hospital and community pharmacists, with clear role sharing between them, allowing the community pharmacists to exercise medication history management for patients prescribed S-1 to the same degree as hospital pharmacists based on available information including laboratory test values.

Advancements in cancer chemotherapy and the introduction of Japanese traditional medicine"Kampo"have been successful in improving the prognosis of malignant tumors. Many Kampo drugs have been used in the treatment of adverse effects. We investigated the safety and efficacy of Hangeshashinto in the prevention and treatment of chemotherapy-induced oral mucositis in patients with gastric and colorectal cancer. Hangeshashinto was shown to reduce the risk of development of mucositis. We also investigated the efficacy of Goshajinkigan in the prevention of chemotherapy-induced neurotoxicity. Goshajinkigan appears to have a promising effect in delaying the onset of neurotoxicity of gradeB2 without reducing the efficacy of treatment. Kampo drugs such as Rikkunshito, Jyuzentaihoto, and Hochuekkito have also been used successfully in the prevention and treatment of chemotherapy-induced adverse effects. It is very important to know the efficacy and safety of Kampo drugs for alleviating the adverse effects of anticancer drugs in patients undergoing cancer treatment with chemotherapy.

Patients with cancer exhibit various symptoms induced by cancer itself and its therapy leadingto fatigue; however, their vital energy can be restored by administration of Kampo, which is a traditional Japanese herbal medicine. Restoration and maintenance of mental and physical energy are important for successful cancer treatment. For this purpose, appropriate use of Kampo formulas, such as"Ho-zai", formulas to vitalize fatigued patients (eg, Hochu-ekki-to, Juzen-taiho-to, Ninjin-yoeito), "Hojin-zai", formulas to restore energy (eg, Gosha-jinki-gan), and"Kuoketsu-zai ", formulas to resolve stagnant blood flow (eg, Keishi-bukuryo-gan, Tokaku-joki-to, Toki-shakuyaku-san) are administered in combination. Consequently, basic autonomic functions, such as appetite, sleep, defecation, and urination normalize and the nutritional and mental conditions are restored. These favorable changes in the patients' condition allow completion of the standard cancer therapy course, resultingin an improved outcome of cancer therapy and successful treatment. Kampo therapy can be administered as the final treatment option for patients with last-stage cancer who do not have any other effective therapy options. If patients with cancer are administered Kampo formulas, their vital energy is restored, and they develop a will to fight the cancer. As a result, communication becomes easier.

A 67-year-old woman underwent total mastectomy, postoperative radiation therapy, and adjuvant hormonal therapy more than 9 years 4 months previously. There were no symptoms of recurrence for 3.5 years after completing adjuvant hormonal therapy. A hard mass appeared on the front chest wall and was diagnosed as recurrence of breast cancer histopathologically. A computed tomography (CT) scan revealed multiple metastases in the left side of the chest wall, in the left Level Ⅱ axillary lymph nodes, and in the left lung. The patient was prescribed high-dose tremifene (HD-TOR 120 mg/day). After less than 4 months, she presented with general fatigue and yellow skin, and was admitted with grade 4 hyperbilirubinemia and grade 3 hepatic dysfunction (AST and ALT). CT and magnetic resonance imaging (MRI) showed no abnormal findings in the liver or biliary tract. Drug-induced liver injury (DILI) caused by HD-TOR was suspected and this therapy was discontinued. The liver dysfunction showed a tendency to improve with conservative treatment and the patient was discharged on the 10th day of illness. She had almost recovered after 5.5 months. A liver biopsy, a drug-lymphocyte stimulation test, and other detailed examinations were not performed, but we judged this case to be one of liver failure caused by HD-TOR-induced DILI.

By remarkable progress of chemotherapy for pancreatic cancer, we sometimes achieve resection of initially unresectable pancreatic cancer after chemotherapy. Otherwise, the safety and feasibility of radical pancreatic resection after chemotherapy is not still clear. In this report, we evaluated the safety and feasibility of conversion surgery for initially unresectable pancreatic cancer in our center.

Neovascular glaucoma is a serious complication associated with retinal ischemic changes, which increase the production of vascular endothelial growth factor. Vascular endothelial growth factor has been implicated as a key molecule in the development of newly formed vessels and neovascular glaucoma. Intravitreal injection of bevacizumab, a full-length humanized anti-vascular endothelial growth factor monoclonal antibody, leads to a dramatic regression of the new iris and iridocorneal angle vessels on slitlamp examination. However, anterior segment angiography reveals that bevacizumab does not cause a regression of the neovascular vessels themselves but reduces vascular permeability while newly formed vessels are still present in the iris and iridocorneal angle. This review focuses on the pathology and diagnosis of neovascula glaucoma and the effect of intravitreal bevacizumab on the iris and iridocorneal angle neovascularization.