FOLFOX therapy is associated with a high incidence of neurotoxicity that is specific to oxaliplatin and liable to lead to marked deterioration in the patient's quality of life (QOL). Therefore, we conducted a survey on whether any prophylactic measures were taken to guard against the development of such neurotoxicity, and we investigated the incidence of the neurotoxicity and the efficacy of glutathione and Ca/Mg administration. The results of the survey indicated that 5 among 17 medical facilities engaged in prophylactic measures. The timing of the initial development of neurotoxicity was after 2.9 courses of FOLFOX therapy for those without prophylaxis, after 7.5 courses for those treated with glutathione, and 6.4 courses for those on Ca/Mg treatment. The glutathione or Ca/Mg treatment significantly delayed development of the neurotoxicity. The mean total number of cycles that had been given by the completion of FOLFOX therapy was 5, 9, 11.3 and 8.5, respectively, for no prophylactic treatment, treatment with glutathione and Ca/Mg, indicating that these prophylactic measures allow increases in the number of cycles of FOLFOX therapy given. It was concluded that glutathione or Ca/Mg administered with FOLFOX therapy can delay the development of neurotoxicity, thus contributing to an improvement in the patient's QOL.

A 63-year-old female with relapsed and refractory multiple myeloma, in whom the duration of disease and history of chemotherapy were 15 years and 9 years, respectively, was treated with bortezomib and dexamethasone. A very good partial response and about 500 days to progression were obtained at a total dose of 10.2 mg bortezomib, until the day 4 injection of the second course. Bone pain has completely disappeared. These findings suggested that the therapeutic efficacy of bortezomib may persist over a long period regardless of the duration of chemotherapy. When a favorable response is obtained, but continuous therapy with bortezomib is difficult for reasons such as adverse events (other than refractory to bortezomib), careful observation may be one of the important options.

A postoperative rectum cancer patient with lung metastasis undergoing hemodialysis was treated with mFOLFOX6 therapy. The primary dose of oxaliplatin (L-OHP) ranged from 60 mg/m(2) to 85 mg/m(2), and adverse reactions and serum platinum concentration were monitored. The free platinum concentration (f-Pt), was eliminated efficiently using dialysis. The patient was tolerant of L-OHP doses of 60 mg/m(2) and 70 mg/m(2), but grade 2 neutropenia and grade 3 hemoglobin decrease developed with an L-OHP dose of 85 mg/m(2). The f-Pt after hemodialysis was higher than that before hemodialysis with a dose of 85 mg/m(2). But even with an 85 mg/m(2) dose, mFOLFOX6 therapy could be continued by extending the dosing interval. The monitoring of serum platinum concentrations, as well as therapeutic monitoring based on pharmacokinetics, contributes to safety management of cancer chemotherapy.

A 69-year-old female who had undergone esophagectomy for esophageal cancer was given adjuvant chemotherapy (5-FU 750 mg/body x 5 day, cisplatinum (CDDP) 100 mg/body x 1 day). An electrolytic disorder was found on day 2, and her consciousness became unclear on 5 day (respective Na, K and Cl values of 113, 2.2 and 67 mEq/L in blood). It took 59 days for infusion therapy to control electrolyte for loss in urine. As the b2-microglobulin level was high in urine and the ADH level in blood was normal, cisplatinum nephrotoxicity was thought to make this accident. Electrolytes should be checked carefully for disorder during chemotherapy.

Gefitinib is an orally active, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is widely used in the treatment of advanced non-small-cell lung cancer (NSCLC). Erlotinib, which has the same mechanism of action as gefitinib, has been recently approved in Japan. We retrospectively investigated the adverse reactions in 16 patients who had received erlotinib after failure of gefitinib treatment. We examined the adverse reactions that occurred during gefitinib or erlotinib treatment using an electronic chart system. Anorexia was more frequent with erlotinib than with gefitinib treatment. Further, anorexia and diarrhea were significantly more severe with erlotinib than with gefitinib treatment. Most adverse reactions developed earlier during the course of erlotinib treatment than during the course of gefitinib treatment. In one patient who had received gefitinib treatment without pulmonary toxicity, erlotinib had to be discontinued due to the development of interstitial pneumonia. Our findings suggest that adverse reactions such as anorexia and diarrhea should be carefully monitored soon after starting erlotinib in advanced NSCLC patients in whom gefitinib treatment has been ineffective, because these reactions will occur sooner and would be more severe in erlotinib treatment.

In performing FOLFOX chemotherapy (infusional 5-FU/LV with oxaliplatin) for advanced colorectal cancer, the neurotoxicity of oxaliplatin (L-OHP) is the dose-limiting factor. A retrospective study of 25 consecutive patients, receiving modified FOLFOX6 (mFOLFOX6) for advanced colorectal cancer, was conducted. From March 2006 to February 2008, we investigated the process of development of sensory neuropathy by adverse effect grading and our original interview-based intake about the afflicted regions. Neurotoxicity developed in 21 cases (84%) after 6 courses and the cumulative L-OHP dose was 410 mg/m(2) in median. In 11 cases (52%), it developed from the fingers, while in 8 cases (38%), it occurred from the fingers and toes simultaneously. It developed from the toes or tongue only in one case each. In 6 cases (55%), in which it occurred from the fingers, the symptom aggravated to grade 2 (G2) according to the Neurotoxicity Criteria of DEBIOPHARM (DEBNTC). On the other hand, in cases of coexpression of the fingers and toes, 7 cases (88%) developed G2 neuropathy, among one of whom suffered from grade 3 (G3). The coexistence of diabetes mellitus without neuropathy had no influence on the development of the neurotoxicity in the grading of DEB-NTC. One month after the last mFOLFOX6 therapy, neurotoxicity newly developed in one case, and was aggravated in two cases two months after cessation of the chemotherapy. Therefore, careful observation of the course should be continued even after the end of mFOLFOX6 therapy. Our results suggest that L-OHP neurotoxicity develops on fingers or fingers and toes simultaneously in most cases. And when it occurred on fingers and toes simultaneously, it would aggravate to G2 or G3 during the chemotherapy. The interviewed-based intake about the afflicted region, such as ours, can be used to predict the deterioration of the neurotoxicity.

Amrubicin is a new anticancer drug that has been shown to exert efficacy against small cell lung cancer. The pharmacokinetic parameters of amrubicin have not yet been investigated in hemodialysis patients, although it had been expected that amrubicin might not be cleared by hemodialysis because of its high lipid solubility, high protein binding rate and low urinary excretion rate. We encountered a case of small cell lung cancer on hemodialysis who was treated with amrubicin. We assayed the plasma concentrations of amrubicin and amrubicinol (its active metabolite) and analyzed the pharmacokinetic parameters of the drug in this hemodialysis patient. The results revealed that the pharmacokinetic parameters of the drug in this patient undergoing hemodialysis were similar to those in patients not on hemodialysis. Our results suggest that amrubicin and amrubicinol are cleared by hemodialysis, and that dose adjustment of amrubicin might not be required in hemodialysis patients.

A 60-year-old man underwent retroperitoneal laparoscopic nephrectomy for left renal tumor (cT1bN0M0).The histopathological examination revealed Kidney cancer grade 3 pT1b. The following evaluations revealed multiple bone metastasis. The IFN-gamma with radiation therapy were performed. However the disease was progressive. So IL-2 70 million units per day 5 times a week started. The patient started to complain lower abdominal pain and watery diarrhea from administration day 28th. Blood test showed eosinophilia. At this point side effect of IL-2 therapy was suspected, then IL-2 was discontinued. But abdominal symptoms had continued. Consulting with a digestive physician, he diagnose as drug-induced colitis like ulcerative colitis by colon endoscopy. The symptoms were gradually improved by an antiallergic agent on our assumption that eosinophilia was concerned in this colitis. Many articles have reported that IL-2 was associated with the clinical mechanism of ulcerative colitis, but there seems no reports about such complications before. This case could suggest IL-2 relates to ulcerative colitis.

A balanced translocation involving 11q23 (MLL gene) could be observed in therapy related leukemia (TRL) patients generally treated with topoisomerase II inhibitors. Few reports have been published on TRL following docetaxel administration. Herein, we report a patient who developed acute myelomonocytic leukemia (AMMoL) with t (9; 11) (p22; q23) following chemotherapy mainly consisted of docetaxel for advanced prostatic carcinoma. A 69-year-old man was treated with a systemic chemotherapy containing docetaxel (total dose = 585 mg) for hormone-refractory metastatic poorly differentiated prostate carcinoma. Although, no disease progression of the prostatic carcinoma was observed, AMMoL with t (9; 11) (p22; q23) developed only ten months later from the administration of docetaxel. Docetaxel was considered to be the cause of TRL because of the presence of t (9; 11) (p22; q23) translocation and clinical course.

Because it is difficult to achieve local drug activity following administration by the conventional intravenous and oral routes, I sought to develop a new route of administration utilizing drug absorption from the liver surface in order to target that organ. Although direct application to the liver surface should yield local drug distribution, drug absorption from the liver surface has not been reported in the literature. Therefore, we analyzed, as a model, the efficiency of absorption of several organic anions and dextrans of various molecular weights following application to the rat liver surface in vivo using a cylindrical diffusion cell. Each compound appeared gradually in the plasma, followed by excretion into the bile and/or urine, indicating the possibility of drug absorption from the liver surface. The absorption process from the liver surface may not involve a specific transport system because dose and transport inhibitors had no detectable effect. In addition, molecular weight was found to be a determinant of absorption through the liver surface. The efficiency of targeting desired region in the liver was enhanced considerably by application to the liver surface, compared to intravenous administration. Moreover, I have obtained several promising results from the application of this new drug delivery system to anticancer drugs and gene therapy. On the other hand, I have also clarified the characteristics of drug absorption from the surfaces of the kidney, stomach, cecum and small intestine, and plan to apply the physiological findings to other fields.

Hormonal therapy against prostatic carcinoma brings to osteoporotic change and alendronate is effective to suppress the change. Urinary NTX and serum ICTP are shown to be useful markers to react with hormonal therapy. But most of bone metabolic markers are not within normal range at the time of starting hormonal therapy. The program, which evaluate the effect of hormonal therapy against non-metastatic prostatic carcinoma, is strongly expected. And it is still a serious problem to be solved when we start, how to use, how long we use biphosphonates.

The epidermal growth factor receptor (EGFR) plays an important role in tumorigenesis and tumor progression of colorectal cancer (CRC). As a result, the EGFR has evolved as a relevant target in the treatment of metastatic CRC. Cetuximab, a monoclonal antibody used to target the EGFR, were recently approved in Japan for use as single agents or in combination with other chemotherapy drugs in the treatment of metastatic CRC. Cetuximab has demonstrated the clinical activity and unique adverse event profiles. Predictive markers of efficacy, including development of skin rash and the absence of a K-ras mutation, have been evaluated in clinical studies to identify patients likely to respond to anti-EGFR monoclonal antibody therapy. This article reviews recent clinical studies of cetuximab in the management of metastatic CRC, predictive markers of their efficacy that lead towards treatment individualization, and common toxicities associated with their use.

A 50-year-old man undergoing operations for sigmoid colon cancer, small intestine invasion, and liver metastasis was given adjuvant chemotherapy postoperatively. During the course, lung, brain and bone metastasis were found, FOLFIRI therapy was started. Fifth FOLFIRI therapy was performed, but on the night of the next day, he was transported on an emergency basis to our hospital because of a coma. Laboratory examination revealed hyperammonemia, so aminoleban was started for its treatment. After 3 days in the hospital, consciousness and serum ammonia were improved. Cases of hyperammonemia caused by 5-FU have been reported in the literature, and this case was diagnosed with the same. Hyperammonemia should be taken into account as a differential diagnosis in the disturbance of consciousness in chemotherapy.

We report a rare case of reversible posterior leukoencephalopathy syndrome (RPLS) induced by 5-FU and oxaliplatin (FOLFOX regime). A 35-year-old woman with ileus was diagnosed with sigmoid cancer Stage IV (T4N4M0P2H0), and excision of the sigmoid colon, and left ureteroureteral anastomosis was performed. Postoperative chemotherapy with FOLFOX4 was performed. Complications of hypertension were seen on day 6, and convulsions on day 11 after chemotherapy. Headache and visual disturbance were also complications. MRI of the brain revealed bilateral high signal intensities of posterior lobes on T2 weighted and FLAIR images without enhancement. The patient was treated with antihypertensive therapy and anticonvulsive therapy. Her symptoms entirely disappeared, including the bilateral posterior lesions on MRI after two weeks. This report would suggest that medical oncologists should be aware that multidrug chemotherapies may increase the risk of fatal neurological complications like RPLS.

Oxaliplatin therapy is a standard treatment for advanced colorectal cancer, and oxaliplatin hypersensitivity is one of its side effects that should be particularly considered. In the present study, we observed a decrease in the incidence of oxaliplatin hypersensitivity since the introduction of preliminary medication involving the administration of escalated doses of steroids and the use of antihistamine agents. From the medical economics perspective, although the costs of the preliminary medication were generated, those for the treatment of oxaliplatin hypersensitivity, which were higher than the total cost of the preliminary medication, needed to be generated for all patients. Introduction of preliminary medication decreased the overall cost, since the medication decreased the incidence of hypersensitivity. Therefore, preliminary medication was recognized to be effective from the perspective of medical economics. The preliminary medication we introduced contributed to a safe, cost-effective, and high-quality treatment for advanced colorectal cancer by preventing oxaliplatin hypersensitivity.

The aim of this study is evaluation of the efficacy of the pharmacist in providing support at the ambulatory therapy center (ATC), especially in connection with chemotherapy side effects in patients. The unsigned questionnaire survey was conducted for patients receiving chemotherapy in ATC. 108 patients were enrolled, and 78 patients answered questions. Patients were asked which kind of specialists provide the most ideal support in the ATC, and what do patients suffer in the ATC. Interestingly, more patients chose pharmacists than nurses and doctors. Many of patients suffer hair loss, nausea and peripheral neuropathy, and many people feel time spent in the ATC is not so meaningful.

The mammalian target of rapamycin(mTOR)and its molecular pathways are supposed to be activated frequently in human renal cell carcinoma as well as other cancers. It has a kinase activity for 40S ribosomal protein kinase and eukaryotic translation initiation factor 4E-binding protein 1. These proteins, when phosphorylated, promote protein translation and RNA transcription in the nutrient-rich condition. mTOR inhibitors such as Temsirolimus (CCI779) and Everolimus (RAD001) are effective for suppressing cell growth with inhibiting mTOR kinase activity. Rapamycin and its related analogs such as Temsirolimus and Everolimus are less toxic for humans compared with other anti-VEGFR inhibitors and has been used as an immunosuppressive agent. These agents have an inhibitory activity against the mTORC1 complex. Since they do not have inhibitory activity against mTORC2 complex, the ability of mTOR inhibition by Temsirolimus is supposed to be 40 to 50% of full inhibition in mTOR kinase. Temsirolimus has modest anticancer activity against advanced clinical RCC patients with poor risk. The objective response rate was only 7%, 26% of patients experienced minor responses and another 17% of patients had stable disease that lasted 6 months. The median time to tumor progression and median survival for the study patients were 5.8 and 15.0 months, respectively. The overall survival of patients treated with Temsirolimus alone was statistically longer than in those treated with IFN alone in the 626 cases in phase II study. Combinations of mTOR with other anti- VEGFR agents were not effective. Vertical therapies of mTOR inhibitor in combination with AKT inhibitors, or newly development of stronger mTOR kinase which can suppress both mTORC1 and mTORC2 are planned at present.

Older patients are frequently excluded from randomized studies; further, it is unclear whether the morbidity associated with chemoradiotherapy with temozolomide (TMZ) outweighs the possible survival benefit in this population. TMZ administered at a dose of 150-200 mg/m2 for 5 days every 4 weeks is the standard of care in operated glioblastoma (GBM) after concurrent chemoradiotherapy. Alternative dosing regimens, such as 1-week on/1-week off, or 3-week on/1-week off, that deliver more prolonged exposure have been observed to result in higher cumulative doses than the standard 5-day regimen and may deplete tumor-derived O6-methylguanine-DNA methyltransferase (MGMT) in tumor cells, thus sensitizing tumor cells to the effects of TMZ. Currently, chemotherapy with TMZ is an interesting alternative to radiotherapy in patients with very large tumors or in the elderly who are exposed to a higher risk of delayed neurotoxicity. The DNA damage induced by nitrosoureas and TMZ is partially repaired by MGMT. Thus, administration of the combination of nitrosoureas and TMZ might overcome MGMT-mediated resistance via MGMT depletion, yielding superior treatment results compared to the administration of treatment alone. However, the results of 2 studies that administered BCNU and CCNU with TMZ reported contradictory results. The introduction of TMZ has enabled the extension of chemotherapy treatment by 1-3 years due to the improved toxicity profile and lack of cumulative toxicity. Treatment-induced myelodysplastic syndrome with or without acute myeloblastic leukemia is a well-recognized late treatment-related complication associated with TMZ administration.

Cells maintain their homeostasis by checkpoint mechanisms that exist at each phase of the cell cycle. Impairment of the checkpoint mechanisms induces DNA mutation and asymmetric segregation of chromosomes, which result in genomic instability, leading to malignant cell transformation. DNA-damaging agents, which are still the first-line chemotherapeutic drugs for various cancers, have recently been demonstrated to induce death in cancer cells alone just because these cells have abnormalities in their checkpoint mechanisms. The mitotic checkpoint, in particular, has been found to play a key role in the drug-induced cell death. An understanding of the molecular mechanisms of chemotherapy will enable us to use conventional drugs more appropriately for cancer treatment.