Phase I/II study of 3-week combination of S-1 and cisplatin chemotherapy for metastatic or recurrent gastric cancer

Purpose To define the maximum-tolerated dose (MTD) of S-1, given daily for 2 weeks followed by a 1-week rest, with a fixed dose of cisplatin on the initial day, and to determine the activity and safety of this regimen at the recommended dose (RD) when used as first line treatment of advanced gastric cancer (AGC). Patients and methods Cisplatin was fixed at a dose of 60 mg/m² on day 1 (D1) and the starting dose of S-1 was 60 mg/m²/day (30 mg/m² bid) (level I) on D1 to D14, every 3 weeks. The dose of S-1 was increased by 5 mg/m² bid up to 100 mg/m²/day (level V) unless the MTD was achieved. Results Sixty-two eligible patients were enrolled. MTD was set at level V with two of three patients developing grade 3 diarrhea or febrile neutropenia. The RD was determined at level IV (90 mg/m²/day). After the first 20 patients were enrolled in phase II, the protocol was amended; the S-1 dose was reduced to 80 mg/m²/day (N = 23) because of poor bone marrow recovery. The objective response was observed in 20 of 42 evaluable patients (48%). SD was achieved in 15 (36%). The median PFS was 5.3 months (95% CI, 4.6–6.0 months) with a median OS of 10.0 months (95% CI, 5.1–14.8 months). Grade 3–4 toxicities included neutropenia (33%), anemia (31%), and anorexia (24%). Conclusions The 3-week combination of cisplatin plus S-1 is active against AGC with favorable toxicitiy profiles. The phase II schedule or doses may need further refinements.     

Oral fluoropyrimidines (capecitabine or S-1) and cisplatin as first line treatment in elderly patients with advanced gastric cancer: a retrospective study

Background: This study aimed to evaluate the safety and efficacy of oralfluoropyrimidines and cisplatin therapy in elderly patientswith untreated advanced gastric cancer (AGC) retrospectively.In addition, we evaluated the relative activity and toxicityof these agents in this patient population. Methods: Clinical data from 72 patients with previously untreated AGC,who were treated with capecitabine/cisplatin and S-1/cisplatin,were reviewed. Oral fluoropyrimidines were administered orallytwice a day on Days 1–14. The dose of capecitabine was1250 mg/m² and that of S-1 was 50 mg [body surface area (BSA)< 1.5 m³] or 60 mg (BSA > 1.5 m³) twice a day. Cisplatinwas administered intravenously on Day 1 (before the first doseof capecitabine or S-1) at a dose of 70 mg/m² over a 2 h period.The chemotherapy cycle was of 3 weeks (with oral capecitabineor S-1). Results: Thirty-two and 40 patients received the S-1 and capecitabineregimens, respectively, and were included in the analysis. TheS-1 protocol had a response rate of 40.6%, a median time-to-progression(TTP) of 5.4 months and a median survival of 9.6 months. Thecapecitabine had a response rate of 55%, a median TTP of 5.9months and a median survival of 10.2 months. Each protocol hada similar incidence of Grade 3 or 4 adverse events. However,there was a higher rate of the hand–foot syndrome (6 versus37%) and diarrhea (25 versus 32%) in the capecitabine group. Conclusion: Oral fluoropyrimidines and cisplatin in elderly patients withuntreated AGC showed encouraging results. The treatment waswell tolerated with a manageable toxicity profile. The comparisonof S-1 with capecitabine showed that capecitabine had a slightlyhigher response rate (statistically not significant) in additionto a higher rate of adverse events such as the hand–footsyndrome and diarrhea. These data should be warranted with furtherprospective studies.     

Phase I/II trial of combination therapy with S-1 and weekly paclitaxel in patients with unresectable or recurrent gastric cancer

Purpose  We aimed to examine the safety and antitumor effects of a combination of S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer in a phase I/II setting. Patients and methods  The study was designed as a phase I/II clinical trial. In phase I portion, the dose of paclitaxel was escalated to estimate the maximum-tolerated dose (MTD) and recommended dose (RD) of paclitaxel with fixed dose of S-1. S-1 (daily dose, 80 mg/m²) was given orally on days 1–21 every 35-day cycle (rest on days 22–35). Paclitaxel was administered intravenously on days 1, 8 and 15, at an initial dose of 40 mg/m², stepping up to 70 mg/m² in 10-mg/m² increment. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity, grade 3 or higher nonhematological toxicity, and treatment discontinuation due to adverse reactions during the first course of treatment. In phase II portion, the efficacy and toxicity at the RD of paclitaxel with S-1 were assessed. Results  The MTD of paclitaxel was estimated to be 60 mg/m², because >33.3% of patients (2/3) developed DLTs. DLT included postponement of treatment due to grade 2 neutropenia, and grade 3 stomatitis, anorexia, and nausea. Therefore, the RD of paclitaxel was estimated to be 50 mg/m². In the phase II portion, 22 patients were evaluated with 50 mg/m² paclitaxel and 80 mg/m² S-1 in a 35-day cycle. The response rate was 54.5% (95% CI, 32.2–75.6%). The median survival time was 283 days (95% CI, 218–508 days). The median number of treatment courses was 4 (range 1–10), indicating that this regimen could be given repeatedly. Conclusions  This phase I/II trial of combination therapy with S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer showed that this regimen has substantial antitumor activity and can be given safely.     

Combination phase I trial of a novel oral fluorouracil derivative S-1 with low-dose cisplatin for unresectable and recurrent gastric cancer (JFMC27-9902).

PURPOSE: The Japanese Foundation for Multidisciplinary Treatment of Cancer conducted a Phase I study of a novel oral fluorouracil derivative, S-1, combined with a low dose of cisplatin in unresectable and recurrent gastric cancer. EXPERIMENTAL DESIGN: S-1 was administered orally at 80-120 mg/body/day, depending on body surface area. One course consisted of consecutive administration for 28 days followed by a rest of 14 days. Low-dose cisplatin was given i.v. on days 1-5, 8-12, 15-19, and 22-26 of each course. The dose escalation of cisplatin began with an initial dose of 1 mg/m(2)/day as level 1 and was stepped up to 2, 3, 4, and 6 mg/m(2)/day as level 2, 3, 4, and 5, respectively. The regimen was repeated for at least two courses. RESULTS: A total of 24 patients was entered in the study. There was no treatment-related death. At level 5, consisting of 5 evaluable patients, dose-limiting toxicity was experienced as grade 3 appetite loss in 2 patients and grade 4 neutropenia in 1 patient. The maximum-tolerated dose of cisplatin was estimated to be 6 mg/m(2)/day. We decided on a recommended dose of cisplatin of 4 mg/m(2)/day because the dosage was one level under the maximum-tolerated dose. All 3 patients at level 4 showed partial response, suggesting promising clinical efficacy with this dosage. The serum concentration of cisplatin at level 4 was 918 +/- 92 ng/ml on day 26 of the first course. CONCLUSIONS: S-1 with low-dose cisplatin may become an effective regimen with acceptable toxicity for gastric cancer.     

A phase I study of bi-weekly paclitaxel/cisplatin as initial therapy for advanced ovarian cancer: A study of the National Cancer Institute of Canada Clinical Trials Group

PURPOSE:: Given the potential for improved outcomes, a phase I trial wasinitiated to develop a paclitaxel/cisplatin regimen that couldbe delivered every two weeks to women with newly diagnosed advancedovarian cancer. PATIENTS AND METHODS:: From 1992 to 1994, 29 (28 eligible) patients were enrolled ina dose-seeking trial. All received 60 mg/m² of cisplatin precededby paclitaxel infused over three hours. The paclitaxel dosewas excalated from an initial level of 90 mg/m² by 10 mg/m²increments in successive cohorts of patients. RESULTS:: At 1^{20 mg/m}2 of paclitaxel, the dose-limiting toxicity was granulocytopeniawhich prevented retreatment on time. The recommended dose levelwas therefore paclitaxel 110 mg/m² infused over three hourswith cisplatin 60 mg/m², repeated bi-weekly for eight cycles. CONCLUSION:: This bi-weekly schedule of paclitaxel/cisplatin provides noadvantage in terms of dose-intensity nor total dose of paclitaxelin comparison to more common regimens given tri-weekly. cisplatin, ovarian cancer, paclitaxel, phase I study     

A phase I trial of S-1 with concurrent radiotherapy in patients with locally recurrent rectal cancer

Background

The purpose of this phase I trial of S-1 chemotherapy in combination with pelvic radiotherapy for locally recurrent rectal cancer was to determine the maximum tolerated dose (MTD), recommended dose (RD), and dose-limiting toxicity (DLT) of S-1.

Methods

We enrolled 9 patients between April 2005 and March 2009. Radiotherapy (total dose, 60 Gy in 30 fractions) was given to the gross local recurrent tumor and pelvic nodal metastases using three-dimensional radiotherapy planning. We administered oral S-1 twice a day on days 1–14 and 22–35 during radiotherapy. The dose of S-1 was initially 60 mg/m²/day and was increased to determine the MTD and RD for this regimen.

Results

DLT appeared at dose level 2 (70 mg/m²/day) in 2 patients, who experienced grade 3 enterocolitis and consequently required suspension of S-1 administration for longer than 2 weeks. Hematological toxicity was mild and reversible. At the initial evaluation, complete regression and partial regression were seen in 1 patient (11%) and 2 patients (22%), respectively.

Conclusion

This phase I trial of S-1 chemotherapy with pelvic radiotherapy for locally recurrent rectal cancer revealed that the MTD for S-1 was 70 mg/m²/day and the RD was 60 mg/m²/day.     

Phase II study of a closely spaced ifosfamide--cisplatin schedule with the addition of G-CSF in advanced non-small-cell lung cancer and malignant melanoma

BACKGROUND:: Ifosfamide and cisplatin are frequently combined cytotoxic agents.Both have a dose-response relationship. In view of this it appearsattractive to study regimens with a higher dose intensity thanusual. One way to increase the dose intensity is to shortenintervals between chemotherapy cycles. As bone marrow toxicityis dose limiting in ifosfamide-cisplatin combinations we starteda phase II study with both drugs administered every 2 weeksin combination with G-CSF. PATIENTS AND METHODS:: Patients with advanced non-small-cell lung cancer or malignantmelanoma were eligible for the study. The treatment consistedof ifosfamide 2 gram/m²/day days 1–3 combined with mesna,and cisplatin 33 mg/m²/day days 1–3, administered in hypertonicsaline (3% NaCl). G-CSF was started on day 4 at a dose of 5µg/kg/day and was continued until day 12. The cycles wereto be repeated every 2 weeks for a maximum of 6 cycles. RESULTS:: Thirty-two patients were entered in the study; 30 patients wereevaluable for response and toxicity. Neutropenia (grade 4 in16 patients) and thrombocytopenia (grade 4 in 15 patients) werethe most common toxicities. Thrombocytopenia incidence and -durationincreased per cycle and was the main cause of treatment delaysespecially after the third cycle. Only 4 patients were ableto complete the planned treatment without any delay or dosereduction and reached the intended dose intensity of 3 gram/m²/weekof ifosfamide and 50 mg/m²/week of cisplatin. Non haematologictoxicities were generally mild. Out of 22 evaluable patientswith non-small cell lung cancer 6 responded (27%; 95% CI: 10%–48%)while only one out of 8 patients with melanoma responded. Themedian response duration was 26 weeks (range 16–36 weeks). CONCLUSION:: The planned high-dose intensity of ifosfamide and cisplatincould be reached only for the first 2–3 cycles. Haematologictoxicity, especially cumulative thrombocytopenia, necessitatedtreatment delays jeopardizing the dose intensity. The responserate in non-small-cell lung cancer and melanoma was not superiorto what can be expected from more conventional regimens. cisplatin, G-CSF, ifosfamide, phase II study     

Prospective multicenter study to investigate the introduction rate of second-line S-1 in gemcitabine-refractory unresectable pancreatic cancer

Purpose

S-1 is one of the second-line candidate agents for gemcitabine-refractory unresectable pancreatic cancer. Two phase II studies have been reported for second-line chemotherapy with S-1, but these studies did not investigate introduction rate and suitable dose of second-line S-1. Therefore, we conducted a prospective multicenter study in which chemo-na?ve patients were enrolled and had two levels of S-1 dose.

Methods

Chemo-na?ve patients with unresectable pancreatic cancer were enrolled. This study started with 80?mg/m²/day dose of S-1 as second-line chemotherapy and tolerability was checked. When tolerability was not confirmed in initial patients, the dose of S-1 was shifted to 60?mg/m²/day. When tolerability was confirmed at 80 or 60?mg/m²/day, the study continued, and up to 20 patients were accumulated with the dose. In addition, the introduction rate of second-line S-1 was examined.

Results

Six of the initial 7 patients with 80?mg/m²/day dose of S-1 completed one course of second-line chemotherapy. Twenty patients were accumulated with an 80?mg/m²/day dose of S-1. With the exception of one patient continued gemcitabine chemotherapy, two of the remaining 19 patients withdrew from this study because of toxicity during the period of gemcitabine chemotherapy. Fifteen of the remaining 17 gemcitabine-refractory patients could complete one course of S-1 as second-line chemotherapy with acceptable toxicity.

Conclusions

This prospective multicenter study showed that 15 (78.9%) out of 19 chemo-na?ve unresectable pancreatic cancer patients could complete one course of 80?mg/m²/day dose of S-1 as second-line chemotherapy after first-line gemcitabine chemotherapy failure with tolerable toxicity.     

Phase I study of weekly high-dose cisplatin combined with long-term oral etoposide in advanced solid tumors

BACKGROUND: In a previous phase I study we showed that single-agent cisplatincan be given weekly for six weeks at a dose of 80 mg/m²/wk.It has been suggested that etoposide has synergistic activitywith cisplatin and the drug can be given orally continuously.We therefore performed a phase I study with weekly cisplatincombined with oral etoposide. PATIENTS AND METHODS: Nineteen patients with metastases of a solid tumor were enteredin the study. Cisplatin was administered in hypertonic saline(NaCl 3%). Etoposide was administered as 50-mg capsules. RESULTS: The starting dose was cisplatin weekly at a dose of 70 mg/m²for six weeks combined with daily oral etoposide at a dose of50 mg. At the maximum tolerable dose of cisplatin 75 mg/m²/wkand etoposide 50 mg/m² daily, leukocytopenia and thrombocytopeniawere dose-limiting toxic effects which resulted in frequenttreatment delays. Other toxicities were mild. Finally, a doseof cisplatin 70 mg/m²/wk weeks 1–2–3 and weeks 5–6–7in combination with etoposide 50 mg orally days 1–15 anddays 29–43 combined a high median cisplatin dose intensityof 52.5 mg/m²/wk with a good patient tolerance. CONCLUSION: It is feasible to administer frequently dosed cisplatin in combinationwith oral etoposide. Leuko-cytopenia and thrombocytopenia aredose-limiting toxicities. The schedule will be explored furtherin phase n studies. phase I, cisplatin, etoposide, dose intensity     

A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601)

Purpose

We conducted a phase II study to evaluate the efficacy and safety of a triplet regimen of docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer.

Methods

Docetaxel (40?mg/m²) and cisplatin (70 or 60?mg/m²) were given on day 1 of a 28-day cycle. S-1 (40?mg/m²) was given twice daily on days 1?C14. Treatment with this regimen was continued for a maximum of 6 cycles. Subsequently, patients with no disease progression received a combination of docetaxel and S-1.

Results

Fifty-nine patients were enrolled. The median number of administered cycles was 8 (range, 1?C25). Because some patients had serious myelosuppression and renal dysfunction with 70?mg/m² of cisplatin, dose of cisplatin was reduced to 60?mg/m² after 19 patients had been treated. Common severe toxic effects of grade 3 or 4 were leukocytopenia (44%), neutropenia (72%), anemia (15%), and febrile neutropenia (14%). The overall response rate of this group was 81% (95% confidence interval (CI), 71?C91%). The median overall survival and progression-free survival were 18.5 (95% CI, 15.6?C21.5) and 8.7 (95% CI, 6.7?C10.7) months, respectively.

Conclusions

Triplet of docetaxel, cisplatin, and S-1 is a well-tolerated and highly active regimen for advanced or recurrent gastric cancer. A 60?mg/m² of cisplatin is as effective as 70?mg/m² of cisplatin.     

S-1 plus cisplatin: another option in the treatment of advanced head and neck cancer?

Evaluation of: Fujii M, Tomita K, Nishijima W et al. Phase I/II study of S-1 plus cisplatin combination chemotherapy in patients with advanced/recurrent head and neck cancer. Jpn. J. Clin. Oncol. 40(3), 214–221 (2010).

A combination of 5-fluorouracil (5-FU) and cisplatin is the most commonly used chemotherapy regimen in patients with advanced head and neck cancer (HNC). Japanese investigators replaced 5-FU with the oral fluoropyrimidine S-1 (40 mg/m² twice daily on days 1–14 every 4 weeks) to treat patients with locally advanced, recurrent, or metastatic HNC; and determined that the dose of cisplatin on day 8 should be 70 mg/m². The authors also studied the efficacy and safety of this regimen in a continuing Phase II trial. Treatment with S-1 plus cisplatin resulted in a confirmed response rate of 44.1% and a median overall survival duration of 16.7 months. The most common grade 3 or 4 adverse events included anorexia (26.5%), nausea (14.7%), and neutropenia/thrombocytopenia (11.8%). Despite inclusion of patients heterogeneous in disease status and incomplete response evaluation, this study demonstrated that S-1 in combination with cisplatin is feasible for treatment of advanced/recurrent HNC.     

Phase II study of sequential high-dose methotrexate (MTX) and 5-fluorouracil (F) alternated with epirubicin (E) and cisplatin (P) [FEMTX-P] in advanced gastric cancer

BACKGROUND:: FAMTX (5-fluorouracil, adriamycin, methotrexate) is one of themost effective drug combinations in gastric cancer. Therefore,modifications of FAMTX appear of interest and the FEMTX-P regimentwas conceived. PATIENTS AND METHODS:: Fifty patients with unresectable locally advanced and/or metastaticgastric carcinoma were treated with methotrexate 1500 mg/m²i.v. and 5-fluorouracil 1500 mg/m² i.v. on day 1; leucovorinrescue 15 mg/m² orally every 6 hours for 8 doses on days 2 and3; epirubicin 60 mg/ m² i.v. and cisplatin 50 mg/m² i.v. onday 15, q 4 weeks. RESULTS:: Of forty-seven patients evaluable for response, five (11%) achievedcomplete responses and seventeen (36%) partial responses (totalresponse rate 47%). The median duration of response was 8+ months(range: 5–25+ months). Four of 14 patients with locallyadvanced disease were successfully downstaged and subsequentlyresected. The median duration of survival of all patients was10 months (range: 1–25+ months). Leukopenia grade 4 occurredin 18% of patients and thrombocytopenia grade 4 and mucositisgrade 4 in 4% and 2%, respectively. Treatment postponement forhematologic toxicity was necessary in 54% of patients. CONCLUSIONS:: The FEMTX-P regimen is an active regimen in advanced gastriccarcinoma, with acceptable toxicity. chemotherapy, FEMTX-P, gastric cancer     

Longterm survival of a Western patient with metastatic gastric cancer treated with S-1 plus cisplatin

The prognosis for patients with metastatic gastric cancer is poor. Fewer than 10% of patients with metastatic gastric cancer live beyond 2 years. Chemotherapy is offered with a palliative intent. We report the case of a Western patient with metastatic gastric cancer successfully treated with S-1 plus cisplatin. S-1 was administered orally every 12 h at a dose of 30 mg/m² (60 mg/m² daily) for 21 consecutive days, followed by 7 days of recovery. Cisplatin was administered intravenously on day 1, at a dose of 60 mg/m². The cycles were repeated every 28 days. The patient first received seven cycles of S-1 plus cisplatin; however, cisplatin was discontinued secondary to nephrotoxicity, and S-1 was administered alone for an additional five cycles. The patient achieved a clinical complete response to S-1 plus cisplatin. The complete response has now been maintained for 12 months without any chemotherapy. A total of 28 months have elapsed since the date of registration on the study and the patient currently has no symptoms. This patient exemplifies the strategy of maintenance therapy with S-1 alone and shows a prolonged and excellent response to S-1 and cisplatin.     

A phase I study of S-1 in combination with <Emphasis Type="Italic">nab</Emphasis>-paclitaxel in patients with unresectable or recurrent gastric cancer

Background

In Japan, S-1, an oral fluoropyrimidine, plus cisplatin is a standard regimen for advanced gastric cancer, whereas nab-paclitaxel is a treatment option. We aimed to evaluate the tolerance, pharmacokinetics, safety, and clinical efficacy of S-1 combined with nab-paclitaxel in patients with advanced gastric cancer in a phase 1 study.

Methods

The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 plus nab-paclitaxel. The study was designed in accordance with a standard 3 + 3 method. Patients received 3-week cycles of treatment. S-1 was administered orally at 80 mg/m² twice daily for 14 days, and nab-paclitaxel was administered as an intravenous infusion at 180, 220, or 260 mg/m² on day 1 or 8.

Results

Among the 16 patients enrolled, dose-limiting toxicity was observed in one patient at level 2a (S-1 80 mg/m² twice daily plus nab-paclitaxel 220 mg/m² on day 1). The MTD was not obtained, but the RD was established as level 3a (S-1 80 mg/m² twice daily plus nab-paclitaxel 260 mg/m² on day 1). The most common grade 3–4 toxicity was neutropenia (62.5 %). The overall response rate was 54.5 %. The pharmacokinetic profiles of coadministered S-1 and paclitaxel were comparable to those of nab-paclitaxel or S-1 alone.

Conclusions

Based on the present results, the RD was determined as level 3a (S-1 80 mg/m² twice daily plus nab-paclitaxel 260 mg/m² on day 1). This combination therapy was well tolerated and showed antitumor efficacy in patients with advanced gastric cancer.

     

A phase I study of combination therapy with S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer

Background

To investigate the combination of S-1 and irinotecan (CPT-11) as an alternative to infusional 5-fluorouracil/leucovorin plus CPT-11, we performed a phase I trial to determine the maximum tolerated dose, recommended dose (RD), and dose-limiting toxicities (DLTs) in patients with metastatic or recurrent colorectal cancer.

Patients and methods

S-1 and CPT-11 doses were escalated using a standard 3?+?3 design. S-1 was administered orally at 70?mg/m² (levels 1?C3) or 80?mg/m² (levels 4 and 5) for 14 consecutive days followed by 1-week rest. CPT-11 was administered intravenously on day 1, at 175?mg/m² (level 1), 200?mg/m² (level 2), 225?mg/m² (levels 3 and 4), or 250?mg/m² (level 5). Treatment was repeated every 3?weeks, unless disease progression or severe toxicities were observed.

Results

Twenty-three patients were treated. One patient at each of levels 2 and 4 developed a DLT, grade 3 ileus, and grade 3 diarrhea, respectively. At both levels, an additional three patients did not experience DLTs. At level 5, two of five patients experienced DLTs, including grade 3 enteritis and grade 4 neutropenia for more than 5?days. The RD was determined at level 4 (80?mg/m² S-1 and 225?mg/m² CPT-11). An objective response was observed in 7 of 17 patients with measurable disease: 2 of 5 at level 2; 3 of 4 at level 4; and 2 of 4 at level 5.

Conclusions

The RDs of CPT-11 and S-1 were determined as 225 and 80?mg/m², respectively, and further phase II trials are warranted.     

Phase I/II trial of biweekly docetaxel and cisplatin with concurrent thoracic radiation for stage III non-small-cell lung cancer

Objectives: We conducted phase I and II studies of biweekly docetaxel and cisplatin with concurrent radiotherapy, followed by consolidation chemotherapy with the same drugs in patients with locally advanced, unresectable non-small-cell lung cancer (NSCLC). Our objectives were to define the maximum-tolerated dose and dose-limiting toxicity (DLT) in the phase I study, and to determine the response rate, toxicity, and survival rate at the recommended dose (RD) in the phase II study. Methods: Patients with unresectable stage IIIA and IIIB NSCLC were studied. Six to eight cycles of docetaxel and cisplatin were administered at 2-week intervals. In the phase I study, patients received four dose levels: level 1, docetaxel/cisplatin=30/40 mg/m²; level 2, 35/40; level 3, 40/40; and level 4, 45/40. Radiotherapy was delivered at a rate of 2 Gy per fraction/day up to a total dose of 60 Gy over the course of 6 weeks, during the first three cycles of chemotherapy. Results: DLT comprised neutropenia at level 4 in the phase I study (n=15), and level 3 was considered the RD. In the phase II study (n=46), two patients had a complete response (4.3%) and 34 had a partial response (73.9%), for an overall response rate of 78.2% [95% CI (66.3–90.2%)]. The survival rate was 69.1% at 1 year and 39.6% at 2 years, with a median survival time of 19.1 months. Leukopenia, neutropenia, anemia, and radiation esophagitis were the most common toxic reactions, with Grade ≥3 reactions occurring at rates of 77, 70, 17, and 8%, respectively. Conclusion: Biweekly docetaxel and cisplatin with concurrent RT was active and well tolerated in patients with unresectable stage III NSCLC.     

Application of prolonged microdialysis sampling in carboplatin-treated cancer patients

Purpose  To determine the dose-limiting toxicity (DLT) and activity of combination with docetaxel and S-1 on unresectable gastric cancer. Patients and methods  Docetaxel was administered intravenously on day 1 and S-1 was administered orally on days 1–14, every 3 weeks. Doses of each drug in phase I study were docetaxel 60–75 mg/m² and S-1 60–80 mg/m². A phase II study was conducted with the recommended dose (RD) based on phase I. Results  Sixty-five patients (median age 54 years) were enrolled. The DLTs were neutropenia with fever or stomatitis. The RD was docetaxel 75 mg/m² and S-1 60 mg/m². Two patients (aged 66 and 64 years) developed septic shock during the initial part of phase II study. A phase I study at lower dose (docetaxel 60 mg/m² and S-1 80 mg/m²) was conducted for patients older than 60 years, and this dose was determined as the RD for these patients. In the phase II study, frequent grade 3/4 toxicities were neutropenia (47%) and febrile neutropenia (26%). The overall response rate was 50% (95% CI, 35–66%) and median survival was 15.3 months (95% CI, 10.0–20.6 months). Conclusions  Combination with docetaxel and S-1 was active against advanced gastric cancer and gave manageable toxicities. Supported in part by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (0412_CR01_0704_0001).     

Phase II Study of Co-Administration of Uracil and Tegafur (UFT) in Hepatocellular Carcinoma

A Phase II study of co-administration of uracil and tegafur(UFT) was performed in 32 patients with unresectable hepatocellularcarcinoma. A dose of 400 mg/m²/day of UFT was administered orally,three times a day, for more than 4 weeks. Of 26 patients evaluablefor response, one (3.8%) showed a partial response of 9 months'duration. There were no complete responders. A dose-limitingtoxicity was gastrointestinal tract disturbance. Six patients(18.8%) had to discontinue UFT treatment because of gastrointestinaltoxicity. The clinical advantage of tegafur in the treatmentof hepatocellular carcinoma was not enhanced by co-administrationof uracil.     

Phase I study of 3-weekly combination chemotherapy using epirubicin, oxaliplatin, and S-1 (EOS) in patients with previously untreated advanced gastric cancer

Purpose

This study was performed to determine the recommended dose (RD) and dose-limiting toxicity (DLT) associated with epirubicin, oxaliplatin, and S-1 (EOS) combination therapy in patients with previously untreated advanced gastric cancer (AGC).

Materials and methods

Previously untreated patients with histologically proven metastatic AGC, with an ECOG performance status of 0?C2, were enrolled in this study. A fixed dose of epirubicin (50?mg/m²) and oxaliplatin (130?mg/m²) was intravenously administered on day 1 of treatment, followed by oral S-1 administration twice daily on days 1?C14. The S-1 dose was escalated according to the following schedule: level I, 35?mg/m²; level II, 40?mg/m²; level III, 45?mg/m²; Level IV, 50?mg/m². Each cycle was repeated every 21?days. DLTs were evaluated during the first two cycles of treatment.

Results

Nineteen patients with a median age of 53?years (range, 40?C71?years) were enrolled in this study. One case of DLT (grade 4 neutropenia lasting more than 5?days) developed from among the six dose level II patients, while 2 DLTs (grade 3 diarrhea and nausea) were observed among the 4 dose level III patients. Based on these results, dose level II was determined as the RD. Of the 13 patients with measurable lesions, eight achieved partial response, three showed stable disease, and the objective response rate was 61.5?% (95?% confidence interval (CI), 13.3?C66.6?%). The median progression-free survival and overall survival of all patients was 6.8?months (95?% CI, 1.4?C9.5?months) and 13.3?months (95?% CI, 1.9?C24.6?months), respectively.

Conclusion

The RD of the EOS regimen in patients with previously untreated AGC was 50?mg/m² of epirubicin and 130?mg/m² of oxaliplatin on day 1, with administration of 40?mg/m² of S-1 twice a day on days 1?C14 for each 21-day cycle. The EOS regimen described produced promising results.     

Performance of outpatient regimen of S-1 in combination with fractional cisplatin for advanced or recurrent gastric cancers: a phase I study

Background We designed an outpatient regimen consisting of fractional cisplatin in combination with S-1, a novel oral fluoropyrimidine derivative for the treatment of recurrent or advanced gastric cancer and conducted a phase I study to determine the dose limiting toxicities (DLTs) and recommended dose (RD).Methods Escalating dosages of cisplatin (15, 20, and 25 mg/m², as levels 1, 2, and 3, respectively) were administered over 2 h on days 1, 8, and 15, with a fixed dose of S-1 for 3 consecutive weeks (days 1–21), repeated every 5 weeks. National Cancer Institute common toxicity criteria(NCI-CTC) grade 2 toxicities required treatment delay.Primary first cycle DLTs were defined as NCI-CTC grade 3 or 4 toxicities (except for hemoglobin levels, nausea, andvomiting).Results Nine patients were initially enrolled, and DLTs did not appear; however, one level-3 patient experienced grade 3 anemia. An additional three patients were enrolled in level 3 to confirm the toxicity profiles, and none experienced DLTs. Toxicity evaluations throughout a total of 62 cycles revealed that grade 1 or 2 hematological toxicities were common, although mostly transient, with recovery without specific treatment. One patient each in levels 1 and 3 required hospitalization due to grade 3 toxicities in the later cycles. Mean dose intensities for S-1 and cisplatin were both more than 91%. There were no treatment-related deaths. The preliminary response rate was 44%.Conclusions It was concluded that the RD of cisplatin in this regimen was 25 mg/m² (level 3). S-1 in combination with fractional cisplatin is a promising regimen that allows repeated drug administration, in an outpatient setting, for advanced or recurrent gastric cancers. A phase II study of the RD is now under way.