Temsirolimus is an inhibitor of mammalian target of rapamycin, with proven efficacy against advanced renal cell carcinoma (RCC), particularly poor risk and/or non-clear cell RCC, in a randomized first-line phase III trial. In this trial, adverse events (AEs)≥grade 3 occurred in 47.6% of patients treated with temsirolimus alone (n＝208), and the common AEs included asthenia, anemia and hyperglycemia. During the observation period of this trial, drug-related pneumonitis was detected ; 4 patients developed temsirolimus-related pneumonitis, including 2 with ≥grade 3. To date, there have not been any reports analyzing data from a large number of Japanese RCC patients treated with temsirolimus. However, judging from our experience, the severity as well as the frequency of AEs associated with temsirolimus in Japanese patients seem to be similar to those in the Western population. In this study, we summarize our clinical experience with the use of temsirolimus focusing on its AEs and try to clarify the characteristics of temsirolimus-related AEs in Japanese patients, and then present our data relevant to this point from our clinical studies in order to discuss the significance of the management of AEs encountered during treatment with temsirolimus.

From July, 2007 to June, 2008, we prospectively investigated the influence of Hange-shashin-to on the therapeutic and adverse effects of chemotherapy and the changes in quality of life(QOL)scores of the patients with metastatic gastric and colorectal cancer. Twenty patients receiving S-1/Irinotecan (CPT-11) therapy were randomly allocated into group A (with Hange-shashin-to) and B (without Hange-shashin-to). While the anti-tumor effects did not differ significantly between these two groups, severe side effects of more than grade 3 occurred less frequently in group A. Our results suggested that the decrease in QOL scores on day 15 might be alleviated in group A, compared to group B. Therefore, Hange-shashin-to can be one of the useful supportive medicines in the combination therapy of S-1/CPT- 11.

Subjects were 239 patients with colorectal cancer who underwent curative resection surgery from December 1994 to March 1997(Stage I-III b). The patients were given 5'-DFUR for postoperative 10 months as scheduled. They had been allocated into either a 1-year group or a 3-year group by dynamic randomization. 5'-DFUR was administered by an intermittent regimen such as 1,200 mg/body/day for five days followed by two days rest. All patients were followed for five years at least.

Intravesical chemotherapy is performed after transurethral resection of bladder tumor (TURBT) for superficial bladder cancer. We conducted a prospective randomized controlled study on the prophylactic effects of intravesical instillation of epirubicin (EPI) against recurrence to determine the effective administration schedule. Between April 1999 and March 2003, 54 patients with superficial bladder tumor (pTa or pT1, and G1 or G2 cancer) were assigned to two groups (25 in Group A, 29 in Group B) after TURBT. The schedule of instillation (intravesically 40 mg of EPI dissolved in 40 ml saline) was subsequently once every two weeks for 3 months (7 times) starting one week after TURBT (Group A, short period), and subsequently added every two weeks for 3 months starting 6 months after TURBT (Group B, long period). The patients were followed up by cystoscopy and urinary cytology. There was no significant difference in non-recurrence rates after either one year (A; 62.5%, B; 82.8%) or three years (A; 53.6%, B; 67.3%). A univariate analysis demonstrated that tumor grade and staging were significant predictors of high risk for recurrence. A multivariate analysis performed by using the Cox's proportional hazard model showed that the schedule of instillation was an independent prognostic factor for reccurence. In the present study, only 2 patients showed progression and one patient died of UC. There was no adverse event that forced discontinuation of the therapy. In conclusion, epirubicin instillation influenced the prevention of recurrence, but the benefit of long-term period was not confirmed.

There were few studies which reported the longitudinal quality of life (QOL) for Japanese men who received endocrine therapy for advanced or metastatic prostate cancer. A pilot randomized trial was conducted to assess QOL and the incidence of hot flash following endocrine therapy using luteinizing hormone-releasing hormone (LH-RH) agonist goserelin acetate 1-month or 3-month depot alone in patients with advanced or metastatic prostate cancer.

We performed a controlled study to compare the response to cyclophosphamide (CPA), adriamycin (ADM), and fluorouracil (5-FU) (CAF therapy) with that to uracil-tegafur (UFT) plus tamoxifen (TAM) (UFT+TAM therapy), when given as postoperative adjuvant therapy to women with breast cancer. The patients were registered from September 1991 through February 1995 at 51 institutions in the Kinki district of Japan. All patients had stage I, II, or IIIa breast cancer with four or more lymph-node metastases and underwent mastectomy. CAF therapy and UFT+TAM therapy were started within 4 weeks after surgery. CAF therapy consisted of CPA (100 mg/day) on days 1 to 14, followed by 2 weeks of rest, plus ADM (20 mg/m(2)/day) on days 1 and 8 and 5-FU (300 mg/m(2)/day) on days 1 and 8. A total of 6 courses were delivered. UFT+TAM therapy consisted of 3 years of UFT (400 mg/day) plus TAM (20 mg/day), given daily. CAF therapy and UFT+TAM therapy were each assigned to 82 patients. The 5-year survival rate was significantly higher in the UFT+TAM group (82.1%) than in the CAF group (66.2%; p=0.04, logrank test). The 5-year relapse-free survival rate was higher in the UFT+TAM group (61.8%) than in the CAF group (46.3%; p=0.07, logrank test). As for adverse events, the rates of leukopenia, anorexia, nausea and vomiting, general malaise, and hair loss were lower in the UFT+TAM group than in the CAF group. These results suggest that long-term treatment with UFT+TAM may be a useful alternative adjuvant therapy for the management of breast cancer, especially in elderly patients.

Goserelin (GOS) therapy in an adjuvant setting for estrogen receptor(ER)-positive premenopausal patients with breast cancer was assessed in a randomised comparative study.

A prospective randomized study was conducted to evaluate the efficacy of prophylactic intravesical instillation of pirarubicin (THP) prior to transurethral resection (TUR) of superficial bladder cancer. A total of 63 patients were randomized into two groups, the THP group and the control group. In the THP group, 30 mg of THP dissolved in 50 ml saline was administered 4 times intravesically for 4 consecutive days before TUR. In the control group, no instillation was performed before TUR. The patients were followed by cystoscopy and urinary cytology every 3 months. The non-recurrence rates in the THP group and control group were 54.1% versus 37.6% at 1 year and 40.4% versus 26.8% at 2 years, respectively (P = 0.086). Time to recurrence for tumors larger than 1 cm was significantly longer in the THP group (P = 0.0137). Time to recurrence for single and grade 1+2 tumors tended to be longer in the THP group (P = 0.09, P = 0.079). No significant adverse effects were observed in any patient. Our findings suggest that intravesical THP instillation prior to TUR would be effective for patients with single, low grade lesions larger than 1 cm of superficial bladder cancer.

A randomized controlled trial of intermittent hepatic arterial infusion of weekly high-dose 5-FU (WHF) after resection of hepatic metastases from colorectal cancer was conducted to study the survival benefit of two regimens. Patients were randomly assigned to receive one of two arms after resection of hepatic metastases: the WHF arm (study group), 1000 mg/m2 of 5-FU administered over the course of 5 hr once a week by hepatic arterial infusion; or the CVI arm (control group), 300 mg/m2 of 5-FU administered as a continuous intravenous infusion daily for 5 days followed 2 days' rest. This study is the first randomized trial of hepatic arterial infusion chemotherapy with percutaneous hepatic catheter placement and assessment of liver drug distribution by CT angiography after resection of hepatic metastases from colorectal cancer in the world. Fifty-two centers participated, and 91 patients were enrolled. Although the target number of patients was not enrolled, problems of this study and future prospects for trials of hepatic arterial infusion after resection of hepatic metastases were assessed by questionnaire surveys of the participating centers.

The multinational, multi-institutional clinical Phase II trial of gefitinib monotherapy, IDEAL (IRESSA Dose Evaluation in Advanced Lung Cancer) 1, included Japanese and non-Japanese patients with advanced non-small-cell lung cancer (NSCLC) pretreated with one or more chemotherapy regimens, at least one including platinum. To investigate whether survival is affected by gender or histological type of cancer, a retrospective, exploratory subset analysis was conducted including only Japanese patients from IDEAL 1 (n = 102 in total, 51 each in 250 and 500 mg/day groups). The median survival time of the 102 patients was 12.0 months and the one year survival rate was 50%. The median survival time was 13.8 months for the 250 mg/day group and 11.2 months for the 500 mg/day group and the one-year survival rate was 57% and 45% respectively. Survival was longer in patients with adenocarcinoma than those with other histological types of cancer, and was longer in those with symptom improvement than without. The median survival time in females was longer than that in males. The results suggest that gefitinib could be superior to classical anticancer agents with regard to not only the response rate but also survival time in patients with NSCLC, particularly adenocarcinoma, previously treated with chemotherapy. Further studies are needed to identify factors affecting survival.

We conducted a joint study of different duration of drug administration for oral adjuvant chemotherapy using camphor (HCFU) with patients having advanced colorectal cancer who underwent curative resection. The patients were randomly divided into 2 groups, according to length of HCFU administration (6-month group and 2-year group), and followed up for 5 years postoperatively. In total, 239 patients were originally enrolled, out of which 155 were chosen as subjects for this study. There was significant difference in the overall cumulative 5-year survival rate between the short-term group and the long-term group (78.1% vs 89.6%). Between the respective subgroup that was defined by tumor location (colon or rectum), no differences were observed, but there was significant difference in the subgroup that was defined by the presence/absence of lymph node metastasis (59.4% vs 83.9%). It appears that oral adjuvant chemotherapy with HCFU is more effective when administered for 2 years than for 6 months.

A randomized, multicenter, double-blind, parallel-group study was conducted in order to evaluate the hormonal kinetics, pharmacokinetics, efficacy and safety of TAP-144-SR (3M) a three-month sustained-release injectable preparation of leuprorelin acetate, a highly active luteinizing hormone-releasing hormone (LH-RH) derivative by comparing the treatment with two subcutaneous doses of the test medication TAP-144-SR (3M) and the treatment with six subcutaneous doses of the reference medication TAP-144-SR (1M), a 1-month sustained-release injectable preparation. Study participants were 103 patients with prostate cancer in whom a stable anti-tumor effect had been obtained with Leuplin Injection 3.75. The hormonal kinetics revealed that the proportion of the patients "maintaining the castration level of serum testosterone (maximum serum testosterone level during treatment below the castration level [100 ng/dl])" was 100% in both treatment groups. With regard to the efficacy, the proportions of the patients in whom the anti-tumor effects (> or = Stable) of the baseline treatment prior to the initiation of the treatment with the study medication were maintained during the study treatment period (6 months) were comparable; 84.0% with TAP-144-SR (1M) and 80.4% with TAP-144-SR (3M). On evaluation of the pharmacokinetics, the mean value of AUC1-12w of the serum TAP-144 concentration (including the metabolite M-I) for the treatment with TAP-144-SR (3M) was 77.0% that of the treatment with TAP-144-SR (1M). Adverse events were similar in the subjects on TAP-144-SR (3M) and in those on TAP-144-SR (1M). There existed no big differences in kind, incidence or time of occurrence of adverse events between two groups. TAP-144-SR (3M) showed no clinically relevant findings in particular. These results indicate that one dose of TAP-144-SR (3M) is comparable to three doses of the already approved Leuplin injection 3.75 in serum testosterone level-inhibitory effect, efficacy and safety. Hence, it is considered that TAP-144-SR (3M) is a drug suitable for treatment of prostate cancer over a prolonged period of time.

Exemestane was administered orally to postmenopausal women with advanced/recurrent breast cancer at a dose of 10 mg/day or 25 mg/day once daily for more than 8 weeks in order to evaluate the drug's anti-tumor effects and safety in a dose-finding study. The response rate (CR + PR) in the 10 mg and 25 mg group was 25.0% (8/32) and 31.4% (11/35), respectively, demonstrating no significant differences between the two groups, yet a higher efficacy rate was observed in 25 mg group. The efficacy rate in hormone-treatment-resistant patients within the 10 mg and 25 mg groups was 14.3% (3/21) and 26.1% (6/23), respectively, demonstrating more than a 20% response rate in 25 mg group. Incidences of the adverse events of which relevance to the drug could not be excluded were 30.6% (11/36) in the 10 mg group. 13.9% (5/36) in the 25 mg group and 22.2% (16/72) in the total group. The major adverse events were, hot flashes, numbness of the limbs, nausea, headache etc. Abnormal findings in clinical laboratory tests were as follows: ALP increase; GOT increase; GPT increase; gamma-GTP increase; total cholesterol increase; urinary sediment present. Abnormal findings in endocrine function were as follows: aldosterone decrease; testosterone.cortisol.DHEA-S decrease. But discontinuation due to abnormal laboratory findings was not found. No abnormal findings in physical tests were observed. A significant decrease in plasma estrogen concentration at week 4 was observed in both the 10 mg and 25 mg groups compared with baseline. These low levels were maintained throughout the study period. On the basis of these results, the efficacy of exemestane 25 mg/day was verified to be slightly higher than 10 mg/day. In addition the safety profile had no major adverse events to notice. In these patients with advanced/recurrent breast cancer, 25 mg/day was recommended as the most appropriate dose to be used clinically.

A multiple-dose administration study of exemestane (0.5-50 mg/day after breakfast for 7 days) was conducted in 32 normal healthy postmenopausal Japanese women using a single-blind, 3-step dose-titration method in order to investigate the safety, effect on serum concentration, amount of urinary estrogen excretion, and pharmacokinetics of the drug. Subjective/objective symptoms, in which a causal relationship with exemestane administration could not be excluded, were as follows: headache (8 cases: 1 each in the 0.5 and 25 mg groups, 2 in the 10 mg group and 4 in the 50 mg group), dizziness (2 cases: 1 each in the 0.5 and 25 mg groups), and fever (1 in the 25 mg group), all of which were mild and disappeared without treatment. The only abnormal laboratory findings were a mild increase in levels of GOT and GPT in 1 case and in the number of basophils in another case. There were no notable abnormal findings in vital signs, body weight or EKG. A dose-dependent decrease in serum estrogen level was observed between doses of 0.5 mg and 25 mg. The decrease was maximal at 25 mg, at which serum estrogen concentrations decreased to 14-27% of those observed at day 0. This decrease was maintained for one week, returning to baseline levels 2 weeks after the completion of drug administration. A similar result was also observed in the suppression of 24-hour urinary estrogen excretion. Exemestane was absorbed immediately after initial administration, reaching Cmax 0.9-2.6 hours post-administration. This was followed by a rapid decrease over the next 4-8 hours followed by a gradual decrease Cmax reached normal steady state values on day 5. Cmax and AUC0-24 values taken between administration of the first and final doses increased proportionally in a dose-dependent manner, suggesting that exemestane has a linear pharmacokinetic profile. Furthermore, results of the comparison of the trough concentrations of the initial dose with those of the final dose suggested no accumulative effects of the study drug.

To determine the recommended clinical dose of CGS20267 (Letrozole), we conducted a randomized comparative study as a late phase II study (first part) in postmenopausal women with advanced or recurrent breast cancer. Forty-one patients were randomly assigned to receive 0.5 mg or 1.0 mg once daily. There were no statistically significant differences in background between the two groups. Although there was no significant difference in the objective response rates between the two groups, the rate was higher at 1.0 mg (44.4%) than at 0.5 mg (38.1%). We also combined these data with the results of an early phase II study. The objective response rates (CR + PR) were 31.4% at 0.5 mg and 42.2% at 1.0 mg, and response rates consisting of CR, PR, and NC for longer than 6 months were significantly higher at a dose of 1.0 mg (68.9%) than 0.5 mg (41.2%). Side effects included drug-related adverse events in 36.8% at 0.5 mg and in 31.6% at 1.0 mg. All of the events were grade 2 or lower, indicating a favorable tolerability of CGS20267. These results demonstrated that CGS20267 1.0 mg once daily is more effective than 0.5 mg, and has comparable safety, in the treatment of postmenopausal women with advanced or recurrent breast cancer. We conclude the recommended clinical dose of CGS20267 should be 1.0 mg once daily.

A multicenter, open labeled, randomized early Phase II study for CGS 20267 was conducted at the doses 0.5 mg once daily and 1.0 mg once daily in postmenopausal women with advanced breast cancer. Sixty-four patients were randomly assigned to the doses of either 0.5 mg once daily (n = 33) or 1.0 mg once daily (n = 31). Thirty-one patients were eligible for 0.5 mg group, and 29 for 1.0 mg group. A total of 57 patients (30 in the 0.5 mg group and 27 in the 1.0 mg group) were eligible for the evaluation of efficacy. There were 3 CR, 5 PR, 5 stable disease (SD: NC lasting over 24 weeks), 7 NC and 10 PD in the 0.5 mg group. The objective response rate (ORR) was 26.7%. There were 4 CR, 7 PR, 8 SD, 3 NC and 5 PD in the 1.0 mg group. The ORR was 40.7%. A total of 57 patients (29 in the 0.5 mg group and 28 in the 1.0 mg group) were eligible for safety evaluation. Adverse clinical events related to CGS 20267 in the 0.5 mg group were headache, nausea, cold sweat, sleepiness and muscle ache in the lower extremities (2 patients, incidence rate 6.9%) whereas those in the 1.0 mg group were generalized itching and generalized hot feeling (2 patients, incidence rate 7.1%). All of the adverse events were grade 1 except the generalized itching which was grade 2. CGS 20267-related abnormalities in the laboratory tests for the 0.5 mg group were a decrease in WBC, and increases in GOT, GPT, LDH and gamma-GTP (5 patients, 14.3%) whereas those in the 1.0 mg group were increases in GPT, gamma-GTP, alkaline phosphatase, and total bilirubin (1 patient, 3.6%). The increases in GOT and GPT were grade 2, but others were grade 1. The data show both CGS 20267 0.5 mg once daily and 1.0 mg once daily to be effective and tolerable in the treatment of postmenopausal women with advanced breast cancer.

The anti-emetic effect and safety in patients receiving ondansetron hydrochloride (OND group) and concurrent use of ondansetron and dexamethasone (DEX group) in cases of acute and delayed onset emesis induced by a single high dose of cisplatin, given as a chemotherapy to lung cancer patients, were comparatively studied. The study subjects were 78 lung cancer patients. The OND group received 4 mg of ondansetron via slow intravenous injection on Day 1, 30 minutes prior to cisplatin, and for Days 2 to 5, the subjects orally received 4 mg ondansetron tablet each day. The DEX group received the same dose regimen of ondansetron as the OND group for Days 1-5, but in addition the subjects received dexamethasone injection in doses of 8 mg twice daily on Day 1 and 4 mg (1 mg QID) daily for Days 2-5. An anti-emetic effect against acute nausea and vomiting was achieved in 83.8% of the OND group and in a higher rate of 94.6% of the DEX group. Significantly better efficacy was seen in the DEX group as to the complete suppression rate of nausea and vomiting and the improvement of food intake. The group also achieved better efficacy in delayed onset of emesis. Two cases of adverse reactions (hiccups and elevation of ALT and BUN) were observed in the DEX group; however, since the symptoms were all mild, we did not consider there was any problem in safety. We conclude from the above findings that concurrent administration of ondansetron hydrochloride and dexamethasone is a clinically useful treatment for acute and delayed onset emesis induced by a single high dose of cisplatin given to lung cancer patients.

In order to determine the modality of prophylactic intravesical instillation of pirarubicin (THP = tetrahydropyranyladriamycin) following transurethral resection (TUR) of superficial bladder cancer, a prospective randomized study was performed. A total of 79 patients were randomized into "2-hour instillation" (A), "5-min instillation" (B) and "control" (C) groups. Prophylactic efficacy and side effects were analyzed in each group. In groups A and B, 20 mg of THP was first dissolved in 10 ml of distilled water, adjusted to 40 ml with saline and was administered intravesically once a week for 10 weeks, starting from 1 week after TUR. The recurrence-free rate was calculated in 65 evaluable patients. The one-year recurrence-free rate was 70.2% in group A, 62.8% in group B and 52.1% in group C. The one-year recurrence-free rate was significantly higher in group A than in group C. Adverse effects were observed in 21.4% of the patients in group A and 40.7% in group B. There was no significant difference in the occurrence rate of side effects between these two groups. Taking the prophylactic efficacy and side effects into consideration, "2-hour instillation" seemed to be better than "5-min instillation".

The authors analyzed the histological effect of preoperative chemotherapy for 62 advanced colorectal cancer patients using resected specimens. Thirty-one patients in the 5'-DFUR + LV group received 800 mg/day of 5'-DFUR and 30 mg/day of leucovorin for 10-14 days just before the operations. Thirty-one patients in the 5'-DFUR group received 5'-DFUR 800 mg/day during the same period. None of the patients in either group developed any side effects. The results of the histological examination showed the number of Grade 1a and 1b cases in the 5'-DFUR + LV group was 22 (66.7%) and 5 (15.2%), respectively, and in the 5'-DFUR group 21 (65.6%) and 5 (15.6%). In the 5'-DFUR + LV group, 3 lesions showed Grade 2 histological degeneration, while there were no such lesions in the 5'-DFUR group. However, our results did not demonstrate any statistical difference between the two groups (p = 0.25, U test).

An early phase II study (dose-finding study) of amrubicin hydrochloride for superficial bladder cancer was conducted. Amrubicin was dissolved in 30 ml of physiological saline and injected intravesically for 6 consecutive days. The drug solution was retained for 2 hours. Patients were randomly assigned to four groups, which were administered amrubicin at doses of 30, 60, 90, and 120 mg/day, respectively. Of 65 patients registered in this study, 63 were eligible and assessable for toxicities, and 55 assessable for efficacy. The response rate at each dose level was 50.0% (7PRs/14 patients) at 30 mg/day, 53.3% (8 PRs/15) at 60 mg/day, 61.5% (2 CRs + 6 PRs/13) at 90 mg/day, and 69.2% (2 CRs + 7 PRs/13) at 120 mg/day, respectively. These data suggests that the efficacy was related to the doses of amrubicin. The major toxicities were cystic irritabilities, such as micturition pain, pollakisuria and hematuria. These toxicities were related to the doses of amrubicin. Their incidence and the severity were not high compared with those reported about other anthracyclines such as doxorubicin and epirubicin. The optimal dose of amrubicin was estimated to be 90 to 120 mg/day in the intravesical treatment for superficial bladder cancer once a day for 6 consecutive days.