aguchi T

Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group.

PURPOSE A phase II study was conducted to evaluate the antitumor effect and toxicity of CPT-11 in patients with metastatic colorectal cancer. PATIENTS AND METHODS From December 1989 to March 1991, 67 patients with metastatic colorectal cancer were enrolled in this study. Sixty-three patients were assessable for toxicity and response. Their median age was 57 years (range, 24 to 72). Forty-six patients (73%) had a good performance status of 0 or 1. Fifty-one patients (81%) had received prior chemotherapy. The major sites of metastasis were liver (63%) and lung (44%). CPT-11 was administered as a 100 mg/m2 weekly intravenous infusion, or as 150 mg/m2 every 2 weeks. The dose was reduced based on the grade of leukopenia and diarrhea, if necessary. RESULTS A partial response was obtained in 17 of 63 assessable patients (27%; 95% confidence interval, 16% to 38%). The response rate in patients with prior radiotherapy or chemotherapy was 25% (13 of 52). Liver metastases showed a 15% (six of 40) response and lung metastases showed a 39% (11 of 28) response. The median duration of partial response was 127 days (range, 49 to 353) and the median overall duration of response was 208 days (range, 99 to 381). The major toxicities (> or = grade 3) were leukopenia (16%), diarrhea (13%), nausea and vomiting (13%), and alopecia (11%). Adverse effects were generally well tolerated and reversible. Treatment could be continued on an outpatient basis for patients without severe toxicity. Hemorrhagic cystitis was not encountered in this study. CONCLUSION CPT-11 showed promising antitumor activity against metastatic colorectal cancer that was resistant to prior therapy. Further clinical trials of combination chemotherapy using CPT-11 are justified.

An early phase II study of oral S-1,a newly developed 5-fluorouracil derivative for advanced and recurrent gastrointestinal cancers

5-Fluorouracil (5-FU) or a 5-FU derivative 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) has been widely prescribed for patients with gastrointestinal cancer. However, the phosphorylation of 5-FU in the digestive tract causes gastrointestinal toxicities. 5-FU is also rapidly degraded to α-fluoro-β-alanine after contact with dihydropyrimidine dehydrogenase (DPDase) which is mainly present in the liver. Therefore, to overcome these metabolic events, S-1, an antitumor agent was developed, based on the biochemical modulation of FT by 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo), in a molar ratio of 1:0.4:1. The antineoplastic effect of S-1, was examined in Japanese patients with advanced gastric (G) or colorectal (C) cancer in a multicenter early phase II study involving 24 centers throughout Japan. The patients were prescribed a minimum of 2 courses of S-1 orally, with each course consisting of 75 or 50 mg (in terms of FT) twice a day for 28 days followed by withdrawal for 2 weeks. Thirty-one patients with G and 31 C were entered into this study. The clinical response and extent of toxicity were evaluated in G 28 and C 30 cases, respectively. Nine (32.1%) G patients and 14 (46.7%) C patients had been treated previously with other anticancer drugs. In G patients, there was a 53.6% (15/28) and in C patients a 16.7% (5/30) response rate (90% confidence interval G 38.4–68.1% and C 8.4–30.5%) with 15 (53.6%) (G) and 5 (16.7%) (C) partial responses (PR), and these responses persisted for 79 days (G) and 120 days (C) (median value). In particular, the response rate for the primary lesion was 27.8% (5/18) (G) and 33.3% (1/3) (C). No change (NC) in the disease was observed in 4 (14.3%) (G) and 13 (43.3%) (C) patients, and in 6 (21.4%) (G) and 7 (23.3%) (C) the disease progressed (PD). At the time of analysis, the median survival was 298 days (G) and 358 days (C). Major adverse effects consisted of gastrointestinal symptoms and myelosuppression while toxicities of grade 3 or more occurred in 35.7% (10/28) (G) and 33.3% (10/30) (C). Based on these data, S-1 is considered to have positive effects in patients with advanced gastrointestinal cancer.

Phase I Study of YM155, a Novel Survivin Suppressant, in Patients with Advanced Solid Tumors

Purpose: YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors. Experimental Design: Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles. Results: Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m2/d. The MTD was determined to be 8.0 mg/m2/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m2/d. The most common adverse reactions judged to be related to YM155 were urine microalbumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients. Conclusions: YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m2/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.

Phase I study of recombinant human tumor necrosis factor

SummaryA phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1x105 units/m2. The dose was escalated up to 16x105 units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16x105 units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12x105 units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5x105 units/m2.

An Early Phase Ii Study of a 3-hour Infusion of Paclitaxel for Advanced Gastric Cancer

The purpose of this study was to evaluate the feasibility and efficacy of 3-hour infusional paclitaxel for the treatment of advanced gastric cancer with measurable metastatic diseases. Eligibility criteria included no more than one regimen of prior chemotherapy. Paclitaxel was administered as an intravenous infusion over 3 hours at a dose of 210 mg/m2 every 3 weeks. Premedication of dexamethazone, ranitidine, and diphenhydramine were given to all patients. Sixteen patients were registered in the study. One patient did not receive paclitaxel because of gastrointestinal bleeding before the initiation of drugs administration. Thirteen of the 15 patients had a prior history of chemotherapy. Although 10 patients (67%) developed grade 4 neutropenia, no serious infections occurred during the study. Nonhematologic toxicities were generally mild. Three (20%) patients who showed evidences of resistance to the previous intensive regimen achieved a partial response. In conclusion, a 3-hour infusion of paclitaxel is a safe and promising treatment for advanced gastric cancer. Paclitaxel appears to be non-cross resistant to other agents that are commonly used for gastric cancer. A large-scale phase II study is now underway.

A Pilot Phase II Study of Capecitabine in Advanced or Recurrent Gastric Cancer

Objectives: To evaluate the efficacy and safety of capecitabine in patients with advanced or recurrent gastric cancer, we conducted a pilot phase II study in Japan. Methods: Patients with advanced or recurrent gastric cancer were given oral capecitabine 828 mg/m2 twice daily for 3 weeks, followed by 1 week of no treatment. Two or more cycles were administered. From July 1996 to December 1997, 32 patients were enrolled in the study. The response to capecitabine was evaluated in 31 patients, excluding 1 found to be ineligible. Results: The overall response rate was 19.4% (6/31, 95% confidence interval: 7.5–37.5%). The median duration of response was 124.5 days, the median time to disease progression 85.0 days, and the median survival time 247.5 days. Drug-related adverse events of grade 3 or higher were infrequent: in 2 patients (6.3%) total bilirubin concentration increased, and 1 patient (3.1%) each had elevation of GOT, anemia, lymphopenia, increased creatinine, and hand-foot syndrome. No patient had gastrointestinal toxicity of grade 3 or higher. Conclusion: Capecitabine was suggested to be safe and effective in the treatment of advanced or recurrent gastric cancer. Further phase II studies of capecitabine on a large scale are warranted.

Phase II study of paclitaxel with 3-h infusion in patients with advanced gastric cancer

Abstract.Abstract.Background: To increase the options for agents for gastric cancer chemotherapy, we performed a phase II clinical trial on the use of a 3-h infusion of paclitaxel to confirm its efficacy and the feasibility of its use in patients with advanced gastric cancer.Methods: Thirty-two (32) patients with measurable metastatic gastric cancer were enrolled in this study. Seventeen patients (53%) had received prior chemotherapy for metastatic disease, 4 patients (13%) had adjuvant chemotherapy alone, and 11 patients (34%) were chemotherapy-naive.Paclitaxel was intravenously infused for 3 h, at a dose of 210 mg/m2, once every 3 weeks. To prevent hypersensitivity reactions, standard premedication was administered to all patients.Results: Nine (28%; 9/32 ) objective partial responses (PRs) were observed (95% confidence interval [CI], 14%–47%), and the remaining 23 patients showed stable (12 patients; 37.5%) and progressive disease (11 patients; 34.4%). The median time to response was 20 days (range, 14–38 days). The median response duration was 87 days (range, 50–103 days). The median survival of all patients was 234 days (range, 13–646+ days). The major adverse reactions were myelosuppression (grade 3/4 leukopenia and neutropenia were observed in 59% and 88% of the patients, respectively), alopecia, and peripheral neuropathy. Peripheral neuropathy was observed in 19 patients, however, most of the patients recovered after the completion of treatment.Conclusion: A 3-h infusion of paclitaxel is an effective therapy for advanced gastric cancer and is clinically well tolerated by the patients.

A Phase II Study of S-1 in Patients with Metastatic Breast Cancer : A Japanese Trial by the S-1 Cooperative Study Group, Breast Cancer Working Group

BackgroundS-l is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoro-pyrimidine drug consisting of 1 M tegafur (FT), 0.4 M 5-chloro-2, 4-dihydroxypyrimidine (gimeracil), and 1 M potassium oxonate (oteracil), with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric, head and neck cancers. We investigated its clinical efficacy against metastatic breast cancer.MethodsA non-blind phase II study was carried out to evaluate the efficacy and toxicity in metastatic breast cancer patients. Patients with measurable metastasis foci (n = 111) were enrolled, and 108 patients were regarded as eligible. S-l was administered orally at a standard dose of 80 mg/m2/day b.i.d. One course consisted of 28 consecutive days of administration followed by a 14-day rest, and courses were repeated up to six times.ResultsAmong the eligible patients, 10 had a complete response and 35 had a partial response, with an overall response rate (CRplus PR) of 41.7% (95% confidence interval: CI, 32.3–51.5%). The incidences of toxicity (≧ grade 3) were neutropenia 9.1%, anemia 0.9%, anorexia 3.6%, stomatitis 1.8%, nausea/vomiting 1.8%, diarrhea 0.9%, and fatigue 2.7%, however no treatment-related deaths were observed. The median survival time was 872 days (95% CI, 572-1,110 days). There was no difference in response rate or toxicity between the under 65-year-old group and the older group.ConclusionS-l was demonstrated to have high efficacy with low gastrointestinal toxicity even in older patients and will be a promising new chemotherapy drug for metastatic breast cancer.

Postoperative adjuvant chemotherapy for gastric carcinoma analysis of data on 1805 patients followed for 5 years

The effectiveness of combination chemotherapy with mitomycin‐C (MMC) plus Futraful (N1‐(2′‐tetrahydrofuryl)‐5‐fluorouracil) for gastric cancer was investigated in a prospective randomized and controlled study. Two thousand sixty‐four Japanese patients in 297 hospitals were entered, and 1805 could be followed. All patients had undergone gastrectomy from May 1975 to July 1976. These patients were grouped into two protocols: protocol I (intermittent intravenous injection of a moderate dose of MMC), and protocol II (bolus intravenous injection of MMC), each of which was allocated to group A (without Futraful) and group B (MMC plus oral administration of Futraful for 3 months). Statistically, this randomized study showed that the 5‐year survival rate of patients with advanced cancer was not enhanced. However, with protocol II the Futraful administration seemed to improve the 5‐year survival rate for those with Stage III cancer and for those with positive lymph node metastasis plus obvious serosal invasion.

Clinical Application of Biochemical Modulation in Cancer Chemotherapy: Biochemical Modulation for 5–FU

The addition of Uracil to Tegafur, a prodrug of 5-fluorouracil (5-FU), has been shown to enhance the antineoplastic effect of 5-FU while reducing the side effects attributed to 5-FU catabolism. Studies of 5-FU levels have shown that the 5-FU concentration in the tumor tissues of patients with head and neck cancer was 16.9 times greater than that in serum and approximately 2-6 times greater than in normal tissue. Similar observations have been made in tumor tissues of patients with breast cancer. The clinical efficacy of UFT, the combination of Uracil and Tegafur in a molar ratio of 4:1, has been studied in a variety of tumor types. An overall response rate of about 23% was obtained, with responses exceeding 30% in patients with head and neck, breast, and bladder cancer. Side effects are predominantly that of gastrointestinal toxicity. Hematologic toxicity is minimal and hepatotoxicity is rare. The UFT combination produces a good clinical effect in a variety of tumor types and is well tolerated.