Phase I trial of postoperative 5-FU, radiation therapy, and high dose leucovorin for resectable rectal cancer.

Following surgery for Stages T3-4N0-2M0 primary and recurrent resectable rectal cancer limited to the pelvis, 25 patients have been entered on a Phase I trial of pelvic radiation therapy (RT) [5040 cGy] and 12 cycles of postoperative 5-FU and high dose Leucovorin (LV) chemotherapy. 5-FU was escalated 50 mg/m2 while the LV remained constant at 200 mg/m2. The initial doses of 5-FU were: combined-RT/chemotherapy = 200 mg/m2 and post-RT chemotherapy = 325 mg/m2. The median F/U was 25 months (range: 13-36). Two maximum tolerated doses (MTD's) have been determined, one for combined-RT/chemotherapy and one for post-RT chemotherapy. The MTD for combined-RT/chemotherapy was 250 mg/m2; therefore, the recommended dose of 5-FU is 200 mg/m2. The MTD for post-RT chemotherapy was 375 mg/m2; therefore, the recommended dose of 5-FU is 325 mg/m2. The dose limiting toxicities were diarrhea, tenesmus, frequent bowel movements, dysuria, and myelosuppression. For the nine patients who received 5-FU at the recommended dose level the median low counts were WBC 3.5 (2.2-4.0), HGB 10.3 (9.0-12.3), and PLT (x 1000) 167 (133-280), and the incidence of any grade greater than or equal to 3 toxicity was 22% diarrhea, 17% tenesmus, and 22% frequent bowel movements. The recommended dose of combined-RT/chemotherapy as used in this protocol was relatively well tolerated. However, optimal doses of 5-FU cannot be delivered until the fourth postoperative month. Therefore, despite the encouraging results reported with high dose LV in patients with advanced disease, we do not recommend that high dose LV be used with combined RT and 5-FU in the treatment regimen as presently designed.     

Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy.

PURPOSE: To determine if fluorouracil (5-FU) plus high-dose leucovorin (LV) enhances local response in patients receiving preoperative radiation therapy (RT) for adenocarcinoma of the rectum, we compared the degree of downstaging in patients receiving preoperative RT with or without chemotherapy. PATIENTS AND METHODS: For this comparison, three groups of patients who were treated with identical doses and techniques of preoperative pelvic RT (total dose of 5,040 cGy) were examined. Group 1 included 20 patients with unresectable disease who received combined RT and LV/5-FU. Group 2 included 11 patients with unresectable disease who received preoperative RT. Group 3 included 21 patients with invasive, resectable, primary disease who received preoperative RT. RESULTS: Patients with unresectable disease who received LV/5-FU had a higher rate of pathologic complete response (20% v 0%) and a lower incidence of positive nodes (30% v 64%) compared with those who did not receive chemotherapy. Even when the most favorable group of patients was included (group 3), patients who received LV/5-FU still had a higher complete response rate (20% v 6%) and a lower incidence of positive nodes (30% v 53%) compared with those who received RT without LV/5-FU. Of those patients with initially unresectable disease, the resectability rate was higher in those who received LV/5-FU compared with those who did not receive LV/5-FU (90% v 64%). Patients who received LV/5-FU experienced slightly more grade 1 to 2 fatigue, stomatitis, nausea, and grade 3 diarrhea, tenesmus, and dysuria. CONCLUSIONS: Despite the fact that patients who received chemotherapy (group 1) had more advanced disease compared with those with resectable disease (group 3), the addition of LV/5-FU increased the resectability and downstaging rates. The ultimate impact of a complete response as well as a decrease in the incidence of pelvic nodes on local control and survival remains to be determined. However, given the enhancement of down-staging in patients with unresectable rectal cancer, we are encouraged by the combined modality approach.     

Phase I and pharmacokinetic study of weekly 5-fluorouracil administered with granulocyte-macrophage colony-stimulating factor and high-dose leucovorin: a potential role for growth factor as mucosal protectant

Diarrhea is dose-limiting with weekly 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been associated with a decrease in chemotherapy-associated mucosal toxicity. This study was conducted to determine the maximum tolerated dose (MTD) of weekly 5-FU when administered with GM-CSF and high-dose LV. Patients were treated with intravenous LV 500 mg/m2 plus 5-FU weekly for six doses followed by a 2-week rest. GM-CSF 250 mg/m2 was administered subcutaneously 5 days each week. Cohorts were treated with 5-FU at 600, 700, and 800 mg/m2 weekly. Twenty-nine patients were treated. The MTD of 5-FU in this schedule was 700 mg/m2/week, with diarrhea dose-limiting. 5-FU delivered dose intensity at the MTD was 424 +/- 23.7 mg/m2/week, including rest periods. 5-FU and LV pharmacokinetics were not altered by concurrent treatment with GM-CSF. In a weekly schedule with high-dose LV and GM-CSF, the MTD of 5-FU and 5-FU delivered dose intensity were higher than previously reported with 5-FU and LV administered without GM-CSF.     

Combined modality therapy of rectal cancer: decreased acute toxicity with the preoperative approach.

PURPOSE: We compared the combined radiation therapy (RT) plus chemotherapy segments of two separate parallel phase I trials to determine if combined pelvic RT, fluorouracil (5-FU), and high-dose leucovorin (LV) had less acute toxicity when delivered preoperatively versus postoperatively in patients with rectal cancer. PATIENTS AND METHODS: Patients with unresectable disease received preoperative RT plus LV and 5-FU followed by surgery and postoperative LV and 5-FU. Patients with resectable disease received identical doses, techniques, and schedules of RT and LV and 5-FU except all therapy was delivered postoperatively. On day 1, patients received LV and 5-FU times one cycle. RT began on day 8. A second cycle of LV and 5-FU was given concurrently with the fourth week of RT. RESULTS: Although more patients (75% v 32%; P = .02) received the higher dose level of 5-FU (250 mg/m2), significantly fewer experienced acute grade 3 to 4 toxicity with preoperative versus postoperative therapy (13% v 48%; P = .045). There was no grade 3 to 4 myelosuppression in either group. The two grade 3 toxicities in the preoperative group were gastrointestinal. The grade 3 toxicities in the postoperative group included seven gastrointestinal and two genitourinary; four patients had a grade 4 toxicity. CONCLUSION: Given the high incidence of grade 3 to 4 toxicity also reported in the postoperative combined modality adjuvant randomized trials, future adjuvant trials should explore the preoperative approach.     

An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/ 5-fluorouracil every 2 weeks in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to determine the maximum-tolerated dose (MTD) and the recommended dose of irinotecan and oxaliplatin with a fixed 5-fluorouracil (5-FU)/leucovorin (LV) regimen in patients with metastatic solid tumors. PATIENTS AND METHODS: The trial was designed to evaluate escalating doses of oxaliplatin and irinotecan, starting at 60 mg/m2 and 90 mg/m2, respectively, given at day 1 with the full-dose LV5FU2 regimen, given on days 1 and 2 as follows: folinic acid 200 mg/m2 followed by 5-FU 400 mg/m2 bolus and 600 mg/m2 22 h continuous infusion, every 2 weeks. The second cohort of patients was treated at the recommended dose for oxaliplatin and irinotecan with the simplified LV5FU regimen: on day 1, a 2-h infusion of folinic acid (400 mg/m2), followed by a 10-min intravenous bolus of 5-FU (400 mg/m2), followed by a continuous infusion of 5-FU (2400 mg/m2) over 46 h. RESULTS: Thirty-four patients were treated at the following dose levels (oxaliplatin/irinotecan mg/m2): 60/90, 60/120, 85/120, 85/150, 85/180, 85/200 and 85/220 and seven patients were treated at the recommended dose with the simplified LV5FU scheme. The MTD was reached at dose level 85/220 mg/m2 but the recommended dose chosen for the second step was 85/180 mg/m2 to keep a better compliance with the biweekly schedule. Main grade 3/4 toxicities per patient included the following: neutropenia in 78% (febrile episodes in 12%), diarrhea in 27%, nausea/vomiting in 24% and peripheral neuropathy in 37% (Lévi's scale). Antitumor activity was observed at almost all dose levels. Most objective responses were observed in digestive malignancies, since 10 out of 11 were obtained in five colorectal cancers, two pancreatic cancers, two cholangiocarcinoma and one gastric cancer. CONCLUSION: The recommended dose for the triple association is 85/180 mg/m2 of oxaliplatin and irinotecan, respectively, with LV5FU2 or simplified LV5FU. The antitumor activity in gastrointestinal malignancies should be evaluated in phase II studies in different tumor types.     

Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.     

Phase I study of CPT-11 and continuous 5-FU / l-leucovorin combination therapy(modified AIO regimen)in patients with metastatic colorectal cancer

A combination of CPT-11, continuous 5-fluorouracil(5-FU)and leucovorin(LV), the Arbeitsgemeinschaft für Internistische Onkologie(AIO)regimen, is widely used for the treatment of metastatic CRC. The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC. Our objective was to evaluate the safety of the AIO regimen plus CPT-11 in Japanese colorectal carcinoma(CRC)patients. We investigated the maximum tolerated dose(MTD), dose-limiting toxicity(DLT), and recommended dose(RD)for CPT-11 and continuous 5-FU. CPT-11, 5-FU, and l-LV were administered on days 1, 8, and 15 of a 28-day cycle. The dose of CPT- 11 was escalated from 40 mg/m2 (level 1)to 80 mg/m2 (level 3). The 5-FU dose was then escalated from 1,000 mg/m2 (level 4)to 2,000 mg/m2 (level 5). If neither level met the criteria for the MTD, the recommended dose was defined as level 5, and the dose escalation was discontinued, because the maximum approved weekly dose of CPT-11 alone in Japan is 80 mg/m2 and the dose of 5-FU in the original AIO regimen was 2,000 mg/m2. A total of 18 patients were enrolled in this study. Hematological and non-hematological toxicity were infrequent and mild. There were no toxicities greater than grade 2 at each dose level. Level 5 did not meet the MTD criteria. Our results confirm that the modified AIO plus CPT-11 regimen is safe for Japanese patients. The recommended doses in the present study were CPT-11 80 mg/m2, 5-FU 2,000 mg/m2, and l-LV 250 mg/m2.     

Intensified bimonthly cisplatin with bolus 5-fluorouracil, continuous 5-fluorouracil and high-dose leucovorin (LV5FU2) in Patients with advanced gastrointestinal carcinomas: a phase I dose-finding and pharmacokinetic study

5-fluorouracil (5FU) and cisplatin are commonly used in the treatment of gastric cancer. Continuous 5FU appears to be more effective and less toxic than bolus administration, while increasing the dose intensity of cisplatin may be advantageous. We conducted a phase I study to establish the maximum tolerated dose (MTD) of cisplatin, which could be combined with a hybrid bolus/continuous 5-FU regimen (LV5FU2), given every 2 weeks. Thirty-six patients with advanced upper gastrointestinal carcinomas entered the study. Starting cisplatin dose was 40 mg/m2 and it was increased by 10 mg/m2 in cohorts of 3-6 patients. The pharmacokinetics of 5-fluorouracil in 14 patients were compared with those of 6 patients receiving LV5FU2 alone. All patients received prophylactic granulocyte colony-stimulating factor at cisplatin doses > or =50 mg/m2. MTD was reached at 100 mg/m2 of cisplatin and, therefore, the 90 mg/m2 dose is recommended for phase II studies. Bone marrow toxicity was the most frequent dose-limiting toxicity with 1 patient dying of neutropenic sepsis. Grade III/IV neutropenia was observed in 10 patients (27.7%). Nonhematological toxicity was infrequent and mild. Pharmacokinetic analysis showed that the addition of 90 mg/m2 or 100 mg/m2 of cisplatin to LV5FU2 significantly reduced the 5FU area under the curve. Objective response rate in 23 evaluable patients was 39.2%. The combination of LV5FU2 with bimonthly 90 mg/m2 cisplatin is feasible and active and should be further evaluated in patients with advanced gastric cancer.     

A dose escalation study of leucovorin (LV) and 48-hour continuous infusion of 5-fluorouracil in combination with cyclophosphamide and vinorelbine in pretreated patients with metastatic breast cancer

PURPOSE: To determine the maximum tolerated doses (MTD) and dose-limiting toxicities (DLTs) of vinorelbine (VNR) with fixed doses of cyclophosphamide (CPM) and 5-fluorouracil/leucovorin (5-FU/LV) in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. PATIENTS AND METHODS: Eighteen patients with MBC pretreated with anthracyclines and taxanes were enrolled. VNR was administered as a 10-min intravenous infusion (i.v.) on day 1 at escalated doses with CPM 300 mg/m2 i.v. bolus and LV 500 mg/m2 as a 2-hour i.v. infusion, followed by 5-FU 1500 mg/m2 as a 22-hour continuous infusion (c.i.) for two consecutive days. Treatment was repeated every two weeks. RESULTS: At the dose of VNR 22.5 mg/m2 without rhG-CSF and 25 mg/m2 with rhG-CSF support, the DLT had been reached. Grade 3 or 4 neutropenia occurred in six (33%) patients and in fourteen (27%) cycles with no episode of febrile neutropenia. One (5.5%) patient developed grade 4 thrombocytopenia. Grade 3 neurotoxicity occurred in two patients and grade 2 and 3 asthenia in five (28%). CONCLUSION: The recommended doses for phase II studies are 20 mg/m2 for VNR (22.5 mg/m2 with rhG-CSF support) and 300 mg/m2 for CPM on day 1, with 500 mg/m2 for LV and 1500 mg/m2 for 5-FU on days 1 and 2.     

Increased tolerability of bimonthly 12-hour timed flat infusion 5-fluorouracil/irinotecan regimen in advanced colorectal cancer: A dose-finding study

A dose-finding study was designed to determine the maximum tolerated dose (MTD) of a bimonthly 12-h (10:00 p.m to 10:00 a.m), timed flat infusion (TFI) of 5-fluorouracil (5-FU) plus irinotecan (CPT-11), without leucovorin (LV), for metastatic colorectal carcinoma (CRC). A total of 33 patients were treated. Seven dose levels included a fixed CPT-11 dose of 180 mg/m2 on days 1 and 15 (d(1,15)) and escalating doses of 5-FU 600-1200 mg/m2 on days 1-4 and 15-18 (d(1-4,15-18)). Dose-limiting toxicities (DLTs) were: grade 3-4 non-hematologic, grade 4 hematologic and any toxicity causing a more than a 2-week delay in treatment. The MTD was reached at the seventh dose level. DLTs were observed in 5/8 patients (63%): G3 diarrhea, 2 patients, associated with G3 mucositis in one instance; G4 neutropenia, 2 patients, associated with severe asthenia in 1 patient; G3 hand-foot syndrome, 1 patient. The recommended doses (RDs) were established at the sixth dose level: 5-FU, 1100 mg/m2/d(1-4,15-18); CPT-11 180 mg/m2/d(1,15) [5-FU and CPT-11 dose intensity (DI), 2200 and 90 mg/m2 per week (w), respectively]. At the recommended dose, the DLTs in 38 cycles were: mucositis, 2 cycles (5%); afebrile G4 neutropenia and hand-foot syndrome, 1 cycle (3%). In 24 assessable patients, the overall response rate was 37.5%. The present CPT-11/5-FU schedule is highly tolerable in an outpatient setting using the highest recommended 5-FU dose effective in advanced CRC.     

Irinotecan combined with bolus fluorouracil, continuous infusion fluorouracil, and high-dose leucovorin every two weeks (LV5FU2 regimen): a clinical dose-finding and pharmacokinetic study in patients with pretreated metastatic colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and recommended dose of irinotecan (CPT-11) in combination with fluorouracil (5-FU) and leucovorin (LV), using a biweekly LV5FU2 regimen and increasing doses of CPT-11, and to assess the efficacy of this combination in pretreated patients with colorectal cancer (CRC). PATIENTS AND METHODS: All patients had metastatic CRC and a World Health Organization performance status of 0 or 1. CPT-11 was administered over a 90-minute infusion every 2 weeks at a range of dose levels (100, 120, 150, 180, 200, 220, and 260 mg/m(2)). LV5FU2 was started 1 hour after the end of the biweekly CPT-11 infusion and was also administered on day 2. RESULTS: Fifty-five patients were entered onto this trial; 549 cycles were administered. The MTD was not reached at 260 mg/m(2), and a dose level of 300 mg/m(2) was added. The MTD as defined in the protocol was not reached at this dose level either, but all patients had cycles delayed and/or required a dose reduction. This dose was deemed to be the MTD. To take into account both the toxicity of and compliance with the biweekly schedule, the recommended CPT-11 dose was established at 180 to 200 mg/m(2). Antitumor activity was observed at almost all dose levels, with an objective response rate of 22%. Median time to progression was 6.3 months and overall survival was 15 months. CONCLUSION: The biweekly CPT-11/LV5FU2 combination is feasible and safe, without overlapping toxicity. CPT-11 at 180 to 200 mg/m(2) in combination with LV5FU2 has been selected as the recommended dose for further studies.     

Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors.

BACKGROUND: CCI-779 is a novel ester of the immunosuppressive agent sirolimus that exerts cytostatic effects by the inhibition of the translation of cell-cycle regulatory proteins. We investigated the maximum tolerated dose (MTD) and pharmacokinetics (PK) of CCI-779 in combination with leucovorin (LV) and 5-fluorouracil (5-FU) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were treated with LV at 200 mg/m(2) as a 1-h i.v. infusion directly followed by continuous 24-h i.v. infusion of 5-FU, in the first patient at 2000 mg/m(2) and in subsequent patients at 2600 mg/m(2). CCI-779 was administered directly prior to LV as a 30-min i.v. infusion at a starting dose of 15 mg/m(2) beginning at day 8 and escalated in subsequent cohorts of patients. One cycle consisted of six weekly administrations followed by 1 week of rest. Blood samples were drawn to assess PK of CCI-779 as well as its effect on steady-state 5-FU exposures. RESULTS: Twenty-eight patients entered the study, the majority having tumor types for which 5-FU is used as a treatment. CCI-779 doses of 15, 25, 45 and 75 mg/m(2) were investigated. Skin toxicity (rash) was prominent at all dose levels examined. Stomatitis was the dose-limiting toxicity (DLT) for 75 mg/m(2) doses of CCI-779. Subsequently the cohort at 45 mg/m(2) was expanded to a total of 15 patients, and at this dose level two treatment-related deaths occurred due to mucositis with bowel perforation. Based on the toxicities observed, it was decided to discontinue the study. Partial responses were observed in three patients with gastrointestinal tumors. No pharmacokinetic interaction between CCI-779 and 5-FU was observed. CONCLUSIONS: The safety profiles of CCI-779 and 5-FU/LV suggest an overlap of drug-related toxicities, and the administration of these drugs at these doses and schedule resulted in unacceptable toxicity and therefore cannot be recommended. If CCI-779 is to be used in combination with 5-FU/LV, other doses or schedules of administration will need to be explored.     

Sequence effect of irinotecan and fluorouracil treatment on pharmacokinetics and toxicity in chemotherapy-naive metastatic colorectal cancer patients.

PURPOSE: To investigate the sequence effect of irinotecan and a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) on the plasma pharmacokinetics of irinotecan and its metabolites, the toxicity profile of this combination, and irinotecan's maximum-tolerated dose (MTD). PATIENTS AND METHODS: Thirty-three metastatic colorectal cancer patients were randomized to receive a 60-minute infusion of irinotecan before or after a 48-hour infusion of 5-FU modulated by LV. The reverse sequence was used after 21 days for the second cycle. 5-FU 3,500 mg/m2 was preceded by l-LV 250 mg/m2. Irinotecan 150 mg/m2 (starting dose) was administered to the first three patients. The dose was escalated by 50 mg/m2 in subsequent groups of three to six patients to determine the MTD for both sequences. Pharmacokinetic analysis of irinotecan and its metabolites was performed after each cycle. RESULTS: Toxicities were affected by the sequence of administration of irinotecan and 5-FU, with an improved tolerability for irinotecan followed by 5-FU. The irinotecan MTD was reached at 300 mg/m2 when irinotecan followed 5-FU and at 450 mg/m2 when it preceded 5-FU. In seven of 23 patients who received both sequences at identical irinotecan doses, the dose-limiting toxicity was observed only when irinotecan followed 5-FU. Pharmacokinetic analysis revealed that the administration sequence significantly affected the SN-38 area under the concentration-versus-time curve (AUC), which was 40.1% lower (P <.05) when irinotecan preceded 5-FU. CONCLUSION: The sequence of treatment with irinotecan and infusional 5-FU affects the tolerability of this combination. This can be explained in part by a reduced SN-38 AUC when irinotecan preceded infusional 5-FU. Well-defined 5-FU/irinotecan regimens are needed because the administration sequence or the interval between the agents might affect treatment tolerance and perhaps also activity.     

Phase I study of preoperative oral uracil and tegafur plus leucovorin and radiation therapy in rectal cancer.

PURPOSE: Preoperative combined-modality therapy for rectal cancer may allow for sphincter preservation, while decreasing recurrence rates and improving the overall prognosis. Oral chemotherapy with uracil and tegafur (UFT) plus leucovorin (LV) may reduce costs and complications associated with protracted infusions of fluorouracil. Our goal was to evaluate the safety of UFT plus LV combined with preoperative radiation and determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of UFT plus LV in this setting. PATIENTS AND METHODS: Patients with tumor-node-metastasis stage II or III rectal cancer received escalating doses of UFT (starting at 250mg/m(2)/d, with 50-mg/m(2)/d increments between consecutive cohorts) and fixed doses of LV (90 mg/d). The UFT and LV combination was given 5 days per week concurrently with a 5-week course of preoperative radiation totaling 45 Gy (1.8 Gy/fraction). Surgery was performed 4 to 6 weeks after radiation and was followed by four 35-day cycles of fixed doses of UFT and LV (28 days of therapy each cycle). RESULTS: Fifteen patients were treated, and 13 received the full preoperative chemotherapy. All planned radiation was delivered successfully. The MTD of UFT with radiation was 350 mg/m(2)/d with 90 mg/d of LV. Diarrhea was the DLT. Sphincter-preserving surgery was performed in 12 of 14 patients. One patient had progressive disease before surgery. Pathologic evaluation of 14 resected specimens showed a complete response in three cases. CONCLUSION: Preoperative chemoradiation with oral UFT plus LV is feasible and well tolerated and should be further investigated.     

Phase I trial of UFT/leucovorin and irinotecan in patients with advanced cancer

UFT (BMS-200604, Uftoral) is an oral fluoropyrimidine that combines uracil and the 5-fluorouracil (5-FU) prodrug, ftorafur, in a 4:1 molar ratio with single-agent activity in breast and gastrointestinal cancers. In vitro studies have shown that irinotecan downregulates thymidylate synthase (TS) expression in tumour cells, leading to synergy between irinotecan and 5-FU that is maximal when irinotecan is given 24 h prior to 5-FU. Given this observed synergy and the confirmatory clinical activity of combination therapy with 5-FU, leucovorin (LV) and irinotecan, we performed a phase I trial to determine the maximum tolerated doses (MTD) of UFT, LV, and irinotecan. Treatment consisted of irinotecan administered as a 90-min intravenous (i.v.) infusion on day 1 followed by twice daily oral UFT/LV on days 2-15, repeated every 21 days. Initial doses were irinotecan 200 mg/m(2) and UFT 200 mg/m(2)/day, with LV dose fixed at 60 mg/day. 31 patients received a total of 130 cycles of UFT/LV and irinotecan. 3 of 9 patients experienced grade 3/4 diarrhoea at the highest dose level of irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day. Other toxicities included neutropenia, anaemia, alopecia, nausea/vomiting and fatigue. Further dose escalation was not pursued since this level of toxicity was appropriate for future phase II study. One patient with colorectal cancer experienced a partial response and 9 patients with non-small cell lung, colorectal and gastro-oesophageal junction carcinomas had disease stabilisation lasting 4-26 (median 6) cycles. Methylenetetrahydrofolate reductase (MTHFR) C677T genotype was analysed in peripheral mononuclear cells (PMNs) obtained from 24 patients. 2 patients had the homozygous TT polymorphism and 1 of them had grade 3 diarrhoea at the first dose level. Irinotecan on day 1 followed by a 14-day course of oral UFT/LV beginning on day 2 is well tolerated, and suitable for testing in several tumour types. Doses recommended for further study on this schedule are irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day, with LV 60 mg/day.     

Phase I study of UFT plus leucovorin with radiotherapy in patients with inextirpable non-rectal gastrointestinal cancer.

BACKGROUND AND PURPOSE: Chemoradiotherapy is increasingly used in the primary management of patients with loco-regionally advanced gastrointestinal (GI) cancer. Oral chemotherapy with uracil and tegafur (UFT) plus leucovorin (LV) may represent a convenient way of delivering protracted infusion of fluorouracil. Our goal was to evaluate the safety of UFT plus LV combined with radiation and determine the maximum-tolerated dose (MTD) and a recommended dose for further testing. PATIENTS AND METHODS: Patients with inextirpable GI cancer received escalating doses of UFT (starting at 300 mg/m(2)/d with 50 mg/m(2)/d increments between consecutive cohorts) and fixed doses of LV (90 mg/d). UFT and LV were given 5 days per week concurrently with radiation to 50 Gy (2 Gy/fraction). RESULTS: Twenty-five patients were treated, and 22 received the planned treatment. Three patients were withdrawn from treatment, two due to disease-progression and one due to toxicity. The MTD of UFT with radiation was 400 mg/m(2)/d with 90 mg/d of LV. Diarrhoea was the main dose limiting toxicity (DLT). Since some toxicity (3/12 DLTs) was seen in the expanded cohort at the level below, but none (0/9 DLT) at the starting level, the recommended dose chosen for further testing is 300-350 mg/m(2)/d depending upon the size of the target volume. CONCLUSION: Concomitant chemoradiation with oral UFT plus LV is feasible and well tolerated and should be further investigated since tumour responses were frequently seen.     

CPT-11联合CF/5-FU方案治疗胃肠道癌的Ⅰ期临床研究

目的探索CPT-11(开普拓)联合CF/5-FU治疗胃肠道癌的最大耐受剂量(MTD)和剂量限制性毒性(DLT).方法 CPT-11初始剂量为120mg/m2,然后150mg/m2,180mg/m2和200mg/m2 iv d1,递增剂量直至出现DLT.CF 200mg/m2iv 2h,然后5-FU 400mg/m2快速静滴,接着5-FU 600mg/m2持续静滴22h,第1天、第2天给药,2周重复.结果 20例胃肠道癌患者共完成化疗111周期,中位数6周期.MTD为200mg/m2,DLT为腹泻和WBC减少.结论我们推荐CPT-11180mg/m2联合CF/5-FR每2周重复的方法,作为国内PS为0～1胃肠癌患者的一线二线化疗方案.     

Irinotecan plus oxaliplatin: a promising combination for advanced colorectal cancer

The standard treatment for advanced colorectal cancer (CRC) has been 5-fluorouracil (5-FU)-based chemotherapy. However, addition of irinotecan, a topoisomerase I inhibitor, to the combination of 5-FU and leucovorin (LV) has proven to be superior to treatment with 5-FU/LV alone in both chemonaive as well as previously treated patients. Oxaliplatin, a 1,2 diaminocyclohexane platinum compound, in combination with 5-FU and LV, has demonstrated superiority as first-line therapy over 5-FU and LV in terms of response rate and time to progression. The irinotecan/oxaliplatin combination showed synergistic activity in vitro, and the optimal dose safety profile has been explored in several phase I studies. Neutropenia and diarrhea were the dose-limiting toxicities. The recommended dose of irinotecan/oxaliplatin in every-2-week and every-3-week schedules ranged from 150-200 mg/m2 and 85 mg/m2, respectively. In the weekly schedule, the recommended doses of irinotecan/oxaliplatin were 65 mg/m2 and 60 mg/m2. Promising clinical efficacy in CRC was observed in all studies. A recent randomized phase II study revealed that the irinotecan/oxaliplatin combination has equivalent clinical activity to other 5-FU-based combinations and a manageable toxicity profile. The evaluation of irinotecan/oxaliplatin in phase III trials as well as in combination with 5-FU is ongoing.     

A phase I study of sequential irinotecan and 5-fluorouracil/leucovorin.

BACKGROUND: Irinotecan (CPT-11) and 5-fluorouracil (5-FU)/leucovorin are active agents in colorectal cancer. A sequence-dependent synergism of SN-38 followed by 5-FU/leucovorin in vitro led us to conduct a phase I trial of CPT-11 followed by 5-FU/leucovorin to determine the maximum tolerated dose (MTD) and toxicities of this regimen and to obtain preliminary indications of its activity in patients with advanced solid tumors. PATIENTS AND METHODS: Fifty-six patients were enrolled in sequential cohorts to receive escalating doses of CPT-11 (90 min infusion) on day 1, followed by leucovorin 20 mg/m(2) (intravenous push) and 5-FU (90 min infusion) on days 2-5 of each 21-day cycle. RESULTS: A total of 347 treatment cycles (median 4, range 1-25) were administered. Dose-limiting toxicities were diarrhea, neutropenia and fatigue. Nine patients with colorectal cancer and one with gastric cancer had partial or minor responses. Eight of the 10 had prior chemotherapy. CONCLUSIONS: CPT-11 and 5-FU/leucovorin, as constituents of this novel mechanism-based schedule, have promising activity in patients who have received prior chemotherapy. The recommended phase II/III starting doses are CPT-11 275 mg/m(2) over 90 min on day 1, and 5-FU 400 mg/m(2) plus leucovorin 20 mg/m(2) on days 2-5 every 21 days. This combination can be administered safely to this schedule if there is strict adherence to the 90 min infusion time for both CPT-11 and 5-FU.     

Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors.

PURPOSE: To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. PATIENTS AND METHODS: Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter. RESULTS: Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m(2). The MTD was initially found at 45 mg/m(2), with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m(2), which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 micromol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU. CONCLUSION: The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m(2) bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2) bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.