Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer.

To determine a standard combination chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC), we conducted a phase III trial of irinotecan (CPT-11) to test the hypotheses that CPT-11+cisplatin is superior to cisplatin+vindesine and that CPT-11 monotherapy is not inferior to cisplatin+vindesine. A total of 398 patients with previously untreated NSCLC were randomised to receive cisplatin+CPT-11 (CPT-P), cisplatin+vindesine (VDS-P) or CPT-11 alone (CPT). In the CPT-P arm, CPT-11 60 mg m(-2) was administered on days 1, 8 and 15, and cisplatin 80 mg m(-2) was administered on day 1. In the VDS-P arm, cisplatin 80 mg m(-2) was administered on day 1, and vindesine 3 mg m(-2) was administered on days 1, 8 and 15. In the CPT arm, CPT-11 100 mg m(-2) was administered on days 1, 8 and 15. The median survival time was 50.0 weeks for patients on CPT-P, 45.6 weeks for those on VDS-P and 46.0 weeks for those on CPT (P=0.115, CPT-P vs VDS-P; P=0.089, CPT vs VDS-P), and the hazard ratio was 0.85 (95% confidence interval (CI): 0.65-1.11) for CPT-P vs VDS-P and 0.83 (0.64-1.09) for CPT vs VDS-P. The response rate was 43.7% for patients on CPT-P, 31.7% for those on VDS-P and 20.5% for those on CPT. Major adverse reactions were grade 4 neutropenia observed in 37, 54 and 8% of the patients on CPT-P, VDS-P and CPT, respectively; and grades 3 and 4 diarrhoea observed in 12, 3 and 15% of the patients, respectively. CPT-P therapy produces comparable survival to VDS-P in patients with advanced NSCLC. CPT-11 monotherapy is not inferior to VDS-P in terms of survival. The CPT-11-containing regimen is one of the most efficacious and well tolerated in the treatment of advanced NSCLC.

The quality of life questionnaire for cancer patients treated with anticancer drugs (QOL-ACD): validity and reliability in japanese patients with advanced non-small-cell lung cancer.

The quality of life questionnaire for cancer patients treated with anticancer drugs (QOL-ACD), which consists of four domains (functional, physical, mental, and psychosocial) and a global face scale, was developed as a generic questionnaire for Japanese cancer patients undergoing chemotherapy. We examined the validity and reliability of this questionnaire in Japanese patients with advanced non-small-cell lung cancer (NSCLC), who participated in two randomized phase III trials. After excluding two items, one showing low test-retest reliability and the other showing poor convergent validity for the target population, Cronbach's alpha coefficients ranged from 0.795 to 0.897 and the intra-class correlation coefficients ranged from 0.612 to 0.866. These results confirmed the high reliability of the questionnaire. The results of factor analysis provided strong support for the domain structure used in the questionnaire. Each of the four domains had a moderate to strong association with important clinical variables, such as performance status or weight loss, and correlation analysis showed that the face scale provided an appropriate measure of the global quality of life. These results indicated that the QOL-ACD is potentially useful for clinical research on Japanese patients with advanced NSCLC.

Early phase II study of S-1, a new oral fluoropyrimidine, for advanced non-small-cell lung cancer.

BACKGROUND: The efficacy and safety of S-1, a new oral fluoropyrimidine, were evaluated in patients with non-small-cell lung cancer (NSCLC). The objective of this study was to determine whether the drug should be investigated in a late phase II study. METHODS: Each treatment course consisted of an oral dose of S-1, 50 mg/body or 75 mg/body, twice a day for 28 days followed by a 2-week washout period. RESULTS: Fifty-six eligible patients were enrolled. Five of the 40 previously untreated patients (12.5%; 90% confidence interval, 6.2%-23.5%) showed a partial response (PR), and no tumor response was observed in the 16 previously treated patients. The median survival duration in all eligible patients was 8.4 months, with a 1-year survival rate of 27.3%. The incidences of grade 3 or more severe adverse effects were: anemia, 5.4%; leukopenia, 5.4%; neutropenia, 5.4%; thrombocytopenia, 1.8%; anorexia, 3.6%; diarrhea, 3.6%; and general fatigue, 5.4%. These effects disappeared after cessation of the drug or appropriate treatment. One patient died as a result of aggravated interstitial pneumonitis, but the relationship of this event to S-1 was not clear. CONCLUSION: S-1 showed modest activity with mild toxicity in the treatment of non-small-cell lung cancer. Based on this result, we will progress to the next stage of a late phase II study for advanced NSCLC, and a phase II study of S-1 and cisplatin for advanced gastric cancer. Final results will be reported as they are obtained.

Phase II study of S-1, a novel oral fluorouracil, in advanced non-small-cell lung cancer.

The purpose of this study was to evaluate the efficacy and safety of a novel oral anticancer fluoropyrimidine derivative, S-1, in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC). Between June 1996 and July 1998, 62 patients with NSCLC who had not received previous chemotherapy for advanced disease were enrolled in this study. 59 patients (22 stage IIIB and 37 stage IV) were eligible for the evaluation of efficacy and safety. S-1 was administered orally, twice daily, after meals. 3 dosages of S-1 were prescribed according to body surface area (BSA) so that they would be approximately equivalent to 80 mg m(-2)day(-1): BSA < 1.25 m(2), 40 mg b.i.d.; BSA> or =1.25 but <1.5 m(2); 50 mg b.i.d., and BSA> or =1.5 m(2): 60 mg b.i.d. One cycle consisted of consecutive administration of S-1 for 28 days followed by a 2-week rest period, and cycles were repeated up to 4 times. The partial response (PR) rate of the eligible patients was 22.0% (13/59); (95% confidence interval: 12.3-34.7%). A PR was observed in 22.7% (5/22) of the stage IIIB patients and 21.6% (8/37) of the stage IV patients. The median response duration was 3.4 months (1.1-13.7 months or longer). Grade 4 neutropenia was observed in one of the 59 patients (1.7%). The grade 3 or 4 toxicities consisted of decreased haemoglobin level in 1.7% of patients (1/59), neutropenia in 6.8% (4/59), thrombocytopenia in 1.7% (1/59), anorexia in 10.2% (6/59), diarrhoea in 8.5% (5/59), stomatitis in 1.7% (1/59), and malaise in 6.8% (4/59), and their incidences were relatively low. There were no irreversible, severe or unexpected toxicities. The median survival time (MST) of all patients was 10.2 months (95% confidence interval: 7.7-14.5 months), and the one-year survival rate was 41.1%. The MST of the stage IIIB patients was 7.9 months, and that of the stage IV patients was 11.1 months. The one-year survival rates of the stage IIIB and IV patients were 30.7% and 47.4%, respectively. S-1 was considered to be an active single agent against NSCLC. Further study of S-1 with other active agents is warranted.

A study of the combination of gemcitabine hydrochloride (LY188011) and cisplatin in non-small-cell lung cancer: 3-week schedule.

BACKGROUND: It has been reported that the combination of gemcitabine (LY188011; GEM) and cisplatin (CDDP) in a 4-week schedule showed a high response rate for patients with non-small-cell lung cancer (NSCLC), but GEM could not be administered on day 15 because of increased myelosuppression in many patients. The present study was performed to evaluate the efficacy and safety of GEM and CDDP in a 3-week schedule. METHODS: Patients with unresectable NSCLC without prior chemotherapy were enrolled. We administered 1000 mg/m2 of GEM on days 1 and 8, and 80 mg/m2 of CDDP on day 1. The feasibility of the combination therapy was confirmed in 8 patients, and then 20 more patients were enrolled, to evaluate the efficacy and safety of this combination therapy for all 28 patients. RESULTS: The response rate was 42.9% (12/28) and the median survival time was 12.6 months. Neutropenia, leukopenia, anemia, thrombocytopenia or lymphocytopenia of grade 3 or higher were observed as hematological toxicity, and anorexia, nausea, fatigue, or vomiting of grade 3 were the nonhematological toxicities, but most of these toxicities were of grade 2 or less. For GEM and CDDP, 89% and 91% of the scheduled doses, respectively, were administered. CONCLUSION: This is the first study of the combination of GEM and CDDP with a 3-week schedule in Japan, and the results showed a low level of myelosuppression, high dose intensity, and high response rate, similar to the results reported in other countries. Accordingly, the combination of GEM and CDDP with a 3-week schedule may be a promising regimen for the treatment of NSCLC in Japan.

Phase I and pharmacologic study of docetaxel and irinotecan in advanced non-small-cell lung cancer.

PURPOSE: We conducted a phase I trial of docetaxel, a new antimicrotubule agent, combined with irinotecan (CPT-11), a topoisomerase I inhibitor. The aim was to determine the maximum-tolerated dose (MTD) of docetaxel combined with CPT-11, as well as the dose-limiting toxicities (DLTs) of this combination in advanced non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Thirty-two patients with stage IIIB or IV NSCLC were treated at 4-week intervals with docetaxel (60 minutes, day 2) plus CPT-11 (90 minutes, days 1, 8, and 15). The starting doses of docetaxel/CPT-11 were 30/40 mg/m(2), and doses were escalated in 10-mg/m(2) increments until the MTD was reached. RESULTS: The MTD of docetaxel/CPT-11 was 50/60 mg/m(2) (level 5A), or 60/50 mg/m(2) (level 5B). Neutropenia and diarrhea were the DLTs. CPT-11 did not affect the pharmacokinetics of docetaxel. There were 11 (37%) partial responses among 30 patients. The median survival time was 48 weeks, and the 1-year survival rate was 44.9%. CONCLUSION: The combination of docetaxel and CPT-11 seems to be active against NSCLC, with acceptable toxicity. The recommended dose for phase II studies is 50 mg/m(2) of CPT-11 (days 1, 8, and 15) and 50 mg/m(2) of docetaxel (day 2) administered every 28 days.

[A phase II study of irinotecan combined with cisplatin in non-small cell lung cancer. CPT-11 Lung Cancer Study Group].

Based upon the results of phase I study of irinotecan (CPT-11) combined with cisplatin (CDDP) on non-small cell lung cancer (NSCLC), a combination phase II study on NSCLC was carried out from Feb., 1992 to Sep., 1992. CPT-11 (60 mg/m2) and CDDP (80 mg/m2) were administered by i.v. drip infusion, with administration schedules of Days 1, 8, 15 and only Day 1, respectively. This therapy course was repeated every 4 weeks. Subjects were NSCLC patients of stage III B or IV disease. Those without prior chemotherapy (Group A) and those with prior therapy (Group B) were enrolled separately. Seventy patients were entered into Group A and 32 patients into Group B. One of the patients of Group A was ineligible. The characteristics of the eligible cases of Group A were: male/female, 51/18; median age, 61 years old; PS 0/1/2, 18/39/12; stage IIIB/IV, 26/43; and adeno/squamous/large, 51/15/3. Those of group B were: male/female, 20/12; median age, 62 years old; PS 0/1/2, 5/18/9; stage I/IIIB/IV, 1/7/24, adeno/squamous/large/ad-sq, 28/2/1/1. Thirty-three patients (47.8%) responded in Group A and B patients (25.0%) responded in Group B. Major adverse reactions (grade 3 or higher) of Group A/Group B were neutropenia (80.3%/73.3%), anemia (35.3%/34.4%), diarrhea (18.8%/28.1%) and nausea/vomiting (34.8%/34.4%). Median survival times for Group A and Group B were 308 and 295 days, respectively. CPT-11 in combination with CDDP is effective against NSCLC, suggesting that further studies are needed to determine the usefulness of this therapy.

UFT plus cisplatin combination chemotherapy in the treatment of patients with advanced nonsmall cell lung carcinoma: a multiinstitutional phase II trial. For the Japan UFT Lung Cancer Study Group.

BACKGROUND: Combination chemotherapy comprised of oral UFT (a combination of tegafur and uracil) and cisplatin was shown to be an effective regimen for the treatment of advanced nonsmall cell lung carcinoma and to be associated with a low incidence rate of toxicity in a previous, single institution, Phase II trial on a small patient sample. Therefore, the current multiinstitutional Phase II trial was conducted to confirm the earlier results. METHODS: Eligible patients had histologically or cytologically confirmed Stage IIIB or IV nonsmall cell lung carcinoma and good performance status. Patients who had received prior treatment were excluded. All had measurable disease. UFT (400 mg/m(2)) was administered orally on Days 1-14, and cisplatin (80 mg/m(2)) was injected intravenously on Day 8. Treatment was repeated every 3-4 weeks. RESULTS: Approximately 70% of the 108 eligible patients had systemic metastatic disease. All 108 patients were assessable for toxicity and survival, and 103 were assessable for response. Among these 103 patients there was 1 complete response and 29 partial responses, for an overall response rate of 29.1% (95% confidence limits [CL], 20.4-37.9%). The median survival time was 40 weeks and the 1-year survival rate was 39% (95% CL, 30-49%). The median progression free survival time was 28 weeks. Eastern Cooperative Oncology Group Grade 3 leukopenia and thrombocytopenia were observed in only 1 patient (0.9%) and 3 patients (2.8%), respectively. Grade 3/4 nonhematologic toxicities included elevated bilirubin (6.5%) and emesis (7.4%). One patient who had a past history of duodenal ulcer died of ulcer perforation 15 days after completing the first treatment cycle. CONCLUSIONS: Oral UFT plus cisplatin is a moderately active regimen with an extremely low rate of incidence of myelosuppression as an adverse event, and warrants comparison with other cisplatin-based regimens in a prospective randomized trial.

Effects of anti-emetic drug (tropisetron) on quality of life during chemotherapy: use of a diary-type questionnaire and application of summary measures for assessment in a randomized, multicentre study. Joint Research Group for Tropisetron Double-Blind Comparative Study.

The role of tropisetron as an anti-emetic drug in the prevention of delayed nausea and vomiting remains unclear. Therefore, effectiveness of tropisetron in patients receiving cancer chemotherapy was evaluated by application of summary measures using a quality of life (QOL) questionnaire. The diary-type QOL self-rating questionnaire was constituted by seven scales. A double-blind randomized, multicentre study was performed in 33 hospitals. Quality of life was measured in 98 patients. Patients receiving cisplatin were randomized to group T (administration of tropisetron before and 4 days after cisplatin treatment) and group P (administration of tropisetron before cisplatin treatment and followed by placebo for 4 days). The rate of complete protection from delayed emesis in the groups T and P was 46.3 and 36.5%. All scales, except social wellbeing changed immediately in both groups and reached a nadir on days 2-3, after that returning to the control levels during 2 weeks after cisplatin treatment. Group T was significantly better than group P in physical wellbeing, mental wellbeing, functional wellbeing and global QOL scores summarized by area under the curve and Difmax (maximum differences of QOL scales' score from the best score throughout the entire period). These results indicate that continuous administration of tropisetron could contribute to preventing patient QOL influenced by cisplatin treatment, and the combined use of summary measures may be useful for the evaluation of QOL in cancer clinical trial.

[Navelbine (vinorelbine): a review of its antitumor activity and toxicity in clinical studies].

Navelbine is a derivative of vinca alkaloid that interferes with tubulin assembly and exhibits antitumor activity. Clinical trials with single-agent Navelbine proved it to be effective against non-small cell lung cancer (NSCLC), breast cancer, and other tumors. At present, clinical trials by combination with various drugs are ongoing NSCLC and breast cancer. Navelbine+cisplatin is considered to be a standard therapy for NSCLC in Europe and SWOG. In breast cancer, the combination chemotherapy of Navelbine with anthracyclines, 5-FU, and other agents has been reported to be effective. The main adverse reactions caused by Navelbine are leukopenia and neutropenia. It causes less nerve neuropathy than vindesine. As Navelbine is a central therapeutic drug in combination therapy for NSCLC, more effective combination therapy with it are expected to be developed.

[Phase I study of gemcitabine hydrochloride (LY 188011) combination therapy with cisplatin in the patients with non-small cell lung cancer].

The combination Phase I study of gemcitabine hydrochloride with cisplatin was conducted in the patients with non-small cell lung cancer (NSCLC) at 5 investigation sites. Gemcitabine was administrated on day 1, 8 and 15 and cisplatin on day 1 of each 28-day cycle. The dosage of cisplatin was fixed to 80 mg/m2 and the dosage of Gemcitabine was gradually escalated in 3 dosing level from 600, 800 to 1,000 mg/m2. The maximum tolerated dose (MTD) and the recommended dose was determined with Continual Reassessment Method. For each dose level, 6 cases, 3 cases and 6 cases were registered respectively and all 15 cases were evaluable. In the dose level 3 with 1,000 mg/m2 of gemcitabine and 80 mg/m2 of cisplatin, grade 4 neutropenia was observed as DLT in 3 out of 6 cases, thus dose level 3 was considered as MTD and the recommended dose. Major adverse events were leukopenia, neutropenia, nausea/vomiting and anorexia. The incidence of such adverse events seemed to be dose-dependent and especially the grade of neutropenia seemed to be more serious as the dose increased. Also, the grade of liver function tests abnormal seemed to be more serious as the dose increased but the incidence as well as the grade did not have tendency of dose-dependent in another events including renal function tests abnormal. On the other hand, as to the efficacy PR was observed in 4 out of 15 cases. Based upon the results, it is necessary to discuss further the efficacy in the recommended dose in the combination therapy of gemcitabine and cisplatin.

[Short history of the clinical developments in lung cancer treatment].

Through the 1980's and the early part of the 1990's several new anti-cancer drugs to fight lung cancer were clinically introduced, bringing cytotoxic chemotherapy to play an important role as a mainstay in the combined modality therapy for both small cell and non-small cell lung cancer. This is different from the state prior to the introduction of these drugs. There is no need to say that these advances were supported by the unceasing efforts of oncologists and their patience in performing the many randomized controlled trials. This review attempts to summarize the history of the clinical developments in lung cancer treatment since the beginning of the 20th century.

[Early phase II trial of oral etoposide administered for 21 consecutive days in patients with cervical or ovarian cancer. ETP 21 Study Group--Cervical-Ovarian Cancer Group].

We conducted multi-site early phase II trial or oral etoposide administered for 21 consecutive days in patients with cervical or ovarian cancer in cooperation with 19 institutes. Fifty mg/body of oral etoposide was administered daily for 21 consecutive days. Cycles were repeated every 28 days. In cervical cancer, 24 patients were enrolled and 17 of them were evaluated. The overall response rate including CR and PR was 23.5% (4/17). In ovarian cancer, 18 patients out of 21 enrolled were evaluated. The overall response rate was 16.7% (3/18). The primary toxicity observed was myelosuppression such as leukopenia, neutropenia, hemoglobin decrease and thrombocytopenia. Other adverse effects were anorexia, nausea, vomitting, fatigue, alopecia and stomatitis. From these results we concluded that oral etoposide administered for 21 consecutive days was effective against cervical cancer.

[Phase I study of raltitrexed (ZD-1694)].

A multicenter cooperative phase I study of ZD-1694 (raltitrexed), a novel, folate-based thymidylate synthase (TS) inhibitor, was conducted with single and repeated doses in 30 patients with various malignant tumors. ZD-1694 was intravenously infused over 15 minutes. In the single-dose study, the initial dose was fixed at 1.0 mg/m2 (1n), and the dose was escalated stepwise up to 3.5 mg/m2 (3.5 n). Based on the results of the single-dose study, in the repeated-dose study, doses of 2.5 n and 3 n were infused every three weeks (3 weeks/one course). In principle, patients received 2 courses or more. Of the 29 eligible patients, 16 were in the single-dose study and 13 in the repeated-dose study. Adverse reactions were evaluated in all eligible patients. In the single-dose study, neutropenia, nausea/vomiting, diarrhea, and transaminase (GOT, GPT) increases, of grade 3 or higher, occurred at high doses of 3 n and 3.5 n. These were regarded as dose-limiting toxicities (DLT). DLT of grade 3 or higher were observed in 1 of 4 patients given 3 n and 2 of 4 patients given 3.5 n. These results suggested that the maximum tolerated dose (MTD) of ZD-1694 was 3.5 n (3.5 mg/m2). In the repeated-dose study, DLT of grade 3 or higher was observed in no more than one third of each dose group, 2 of the 6 patients given 2.5 n and 2 of the 7 patients given 3 n. These results suggested that 3 n (3.0 mg/m2), a dose nearer to MTD, was the recommended dose for the phase II study. Although transaminase increases were observed in all patients, in 12 of them the increase was grade 2 or lower and reversible. A pharmacokinetic investigation showed the mean elimination half life of ZD-1694 plasma concentration was 91.5 hours in the single-dose group and 119.1 hours in the repeated dose group. It was suggested that ZD-1694 is metabolized to polyglutamates after uptake and retained in the cells for a long duration. However, no accumulation was seen in plasma concentration of ZD-1694 following repeated doses at 3-weekly intervals. One PR was observed in a patient with colorectal cancer receiving 2.5 n in the repeated-dose study. Based on these results, the recommended dosage and administration for the phase II study of ZD-1694 was 3 n (3.0 mg/m2) intravenously infused over 15 minutes every 3 weeks.

[Phase I clinical study of oxaliplatin].

Oxaliplatin is a new platinum derivative. A multicentric phase I study was conducted with a monotherapy of Oxaliplatin. A total of 20 patients were enrolled who had histologically proven 6 ovarian cancers, 5 uterine cervix cancers, 3 lung cancers, 3 breast cancers, 1 endometrial cancer, 1 gastric cancer, and 1 colorectal cancer. Oxaliplatin was administered as a 2-hour infusion at doses of 20, 40, 80, 130, and 180 mg/m2 every 3 weeks, for a total of 30 cycles. A dose-related and reversible peripheral sensory neuropathy was the dose-limiting toxicity with minimal hematotoxicity and no nephrotoxicity. No hydration was needed. The plasma platinum concentration was biphasically decreased. Cmax and AUC were dose-dependent. T1/2 beta was 31.3 hours. The recommended dose for further studies was 130 mg/m2. A partial response was observed in endometrial cancer.

A phase II trial of combination of CPT-11 and cisplatin for advanced non-small-cell lung cancer. CPT-11 Lung Cancer Study Group.

A phase I trial of the combination of irinotecan (CPT-11) with cisplatin in advanced non-small cell lung cancer (NSCLC) showed a very promising response rate of 54% in previously untreated NSCLC patients. This study was conducted to confirm the activity and toxicities of CPT-11 and cisplatin combination for previously untreated NSCLC in a multi-institutional phase II study. Seventy patients with stage IIIB or IV NSCLC received CPT-11 60 mg m(-2) intravenously (i.v.) on days 1, 8 and 15, and cisplatin 80 mg m(-2) (i.v.) on day 1 every 4 weeks. Assessments were made of response, survival and toxicities. Sixty-nine were eligible, and evaluable for toxicities and survival, and 64 patients evaluable for response. Thirty-three patients (52%; 95% confidence interval 39-64%) achieved an objective response, with one complete response (2%) and 32 partial responses (50%). The median duration of response was 19 weeks and the overall median survival time was 44 weeks. The 1-year survival rate was 33%. The major toxic effects were leucopenia and diarrhoea. Grade 3 or 4 leucopenia, neutropenia, and diarrhoea occurred in 32 patients (46%), 53 patients (80%), and 13 patients (19%) respectively. A combination of CPT-11 and cisplatin is very effective against non-small-cell lung cancer with acceptable toxicities.

Phase I study of E7010.

E7010 is a novel sulfonamide which was discovered using slow-growing colon 38 carcinoma cells as a screening model. E7010 exhibits a broad spectrum of antitumor activity against human tumor xenografts. The mechanism of action is by arresting the progression of cells in M phase of the cell cycle by inhibiting tubulin polymerization. The objective of this phase I study was to determine the maximum allowable dose (MAD), toxicity, and pharmacokinetics of single or 5-day repeated doses of E7010. In the single-dose study, E7010 was administered orally to 16 patients at doses ranging from 80 to 480 mg/m2. The dose-limiting toxicity was peripheral neuropathy at a dose of 480 mg/m2. Hematological and gastrointestinal toxicities were mild. In the 5-day repeated-dose study, 41 patients were given E7010 at doses ranging from 30 to 240 mg/m2 per day. The dose-limiting toxicities were peripheral neuropathy and intestinal paralysis. Gastrointestinal toxicity was dose-dependent but not severe. Hematological toxicity was not dose-dependent. Pharmacokinetic analysis in the single-dose study showed a rapid increase in the plasma levels of the drug after administration, followed by disappearance with a t1/2 of 4.4-16.6 h. The variation in area under the plasma concentration-time curve (AUC) between the patients was small and increased in a dose-dependent manner. Total drug recovery in urine 72 h after administration was 77.8+/-11.4%, indicating that E7010 has favorable absorption and elimination profiles. The changes in the plasma levels of E7010 on day 5 in the 5-day repeated-dose study were almost the same as those on day 1, indicating that the drug did not accumulate. In the single-dose study, spinal cord metastasis exhibited a 74% reduction in a patient with uterine sarcoma and a minor response (MR) was observed in a pulmonary adenocarcinoma patient. In the 5-day repeated-dose study decreases in the tumor markers carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC) were observed in a patient with stomach cancer and in a patient with recurrent uterine cervical carcinoma, respectively. The recommended phase II doses are 320 mg/m2 for a single-dose study and 200 mg/m2 per day for a 5-day repeated-dose study. Since the activity of E7010 is time-dependent, i.e. a certain concentration of E7010 is required for more than 12 h to suppress the growth of P388 leukemia cells, it is recommended that subsequent phase I/II studies be conducted using a divided dose schedule in order to maintain the blood level of E7010.

[Phase I study of orally administered UFT plus l-leucovorin].

A Phase I study of UFT plus l-LV was conducted in 29 patients (pts) with G.I. cancer on a multicenter cooperative study. UFT and l-LV were given orally in two divided doses for 28 consecutive days, followed by a 14 day-rest period. UFT was fixed in three doses, 250, 313 and 375 mg/m2/day, and l-LV was increased in dose from 25 to 50 and to 100 mg/body/days. Dose-limiting toxicities were anorexia, diarrhea, and nausea/vomiting. The maximum tolerated dose of UFT was 375 mg/m2/day, and l-LV 25 mg/body/day. Severe myelotoxicity was not observed. There were three responders (PR) out of 21 pts with measurable disease at UFT doses of 313 mg/m2/day and l-LV 50 and 100 mg/body/day. Responses observed were abdominal mass (rectal ca), liver metastasis (pancreas ca) and metastasis of liver and lymph-node (gastric ca). As a result of pharmacokinetics, plasma concentrations of 5-methyl-THF were maintained > 1.0 microM for over 5 hours that was considered to have a modulating effect on the plasma concentration. In doses of 50 mg and 100 mg/body/day of l-LV. No accumulations in plasma were observed in patient treated in 28 days by l-LV/UFT therapy. It was suggested UFT and l-LV did not interfere with each other's absorption. A Phase II study is recommended, with doses of 313 mg/m2/day of UFT and 50 or 100 mg/body/day of l-LV.

[A clinical phase III trial of ulinastatin (MR-20) for nephrotoxicity of cisplatin].

UNLABELLED: MR-20 was administered to 140 lung cancer patients who presented with nephrotoxicity due to cisplatin (CDDP) treatment at 59 institutions throughout Japan during the period from September 1992 through March 1994 to study its suppressive effect on the nephrotoxicity as well as its safety. The results are reported in this paper. METHODS: The efficacy and usefulness of MR-20 were studied in a placebo-controlled, double-blind manner. An efficacy rate of 58.7% was achieved in the MR-20 group, and 36.8% in the placebo group: MR-20 was significantly more effective for nephrotoxicity than placebo (U-test). Serum Cr, Ccr and FENa were prevented from significant variations in the MR-20 group, compared with the control group. It was considered that MR-20 is a safe drug, and that it is useful in suppressing the nephrotoxicity of CDDP treatment.

Activity of gemcitabine in non-small-cell lung cancer: results of the Japan gemcitabine group (A) phase II study.

PURPOSE: This phase II study was conducted to determine the response and toxicity of gemcitabine (2',2'-difluorodeoxycytidine) in chemotherapy-naive patients with non-small-cell lung cancer (NSCLC). METHODS: A group of 73 patients were entered into the study. The patients had received no previous chemotherapy and all had measurable disease. The initial starting dose of gemcitabine was 1000 mg/m2 per week x 3 followed by a week of rest, and was escalated for the next cycle to 1250 mg/m2, provided there were no signs of hematologic toxicity (WBC < 3000/microl and/or platelets < 70,000/microl) in the previous cycle. RESULTS: Among 73 eligible patients, there were 19 partial responses (PRs), with an overall response rate of 26.0% (95% confidence interval 16.5-37.6%). The response rate for stage IIIa and IIIb disease was significantly higher than that for stage IV disease [41.4% (12/29) vs 15.9% (7/44); P = 0.028]. The median duration of response in patients showing a PR was 4.6 months (1.7 10.4 months). The median number of cycles given was two per patient (range one to seven). Grade 3 anemia, leukopenia and neutropenia occurred in 15 patients (20.5%), 7 patients (9.6%) and 20 patients (27.4%), respectively. Grade 3 thrombocytopenia occurred in one patient (1.4%) which was not associated with any bleeding. There was no evidence of cumulative toxicity in the later courses of gemcitabine treatment with regard to leukopenia and thrombocytopenia. Other toxicities, including hepatic toxicity, fatigue, nausea/vomiting and fever were mild (grade 2 or less) and transient. One patient was withdrawn from the trial because of a rash. Pulmonary toxicity was experienced in two patients and one patient died of respiratory insufficiency which was thought to be drug-related. CONCLUSIONS: Gemcitabine as a single agent has proven to be an active drug for NSCLC with a favorable, generally mild side-effect profile. Further trials in combination with other agents for this disease are currently underway.