Phase I dose-escalating study of 24-h continuous infusion of 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer

Purpose

To determine the maximum-tolerated dose (MTD) of a 24-h continuous infusion of 5-fluorouracil (5-FU) when administered in combination with a fixed weekly dose of docetaxel and cisplatin in patients with advanced gastric cancer.

Methods

Patients with advanced gastric adenocarcinoma (n = 21) received a weekly regimen of docetaxel, cisplatin and 5-FU (DCF) for 3 consecutive weeks every 4 weeks. The doses of docetaxel and cisplatin were fixed at 33.3 and 30 mg/m², respectively. The dose of 5-FU was increased from a starting dose of 1,000 mg/m² to the MTD.

Results

A total of 53 cycles of chemotherapy were administered (median = 3 cycles/patient). The MTD of 5-FU was 1,750 mg/m². All 21 patients were assessed for toxicity and 19 patients (90%) were evaluated for response. Both grade 3–4 hematologic and non-hematologic toxicities occurred in less than 10% of patients and there were no treatment-related deaths. Among the 19 patients, we observed 1 complete and 4 partial responses for an overall response rate of 26% (95% CI: 6–46%). This rate increased to 39% (95% CI: 12–66%) in 13 chemotherapy-naïve patients.

Conclusions

A consecutive weekly DCF regimen at 4-week intervals appears feasible for advanced gastric cancer with a favorable toxicity profile. The recommended doses are 33.3 mg/m² of docetaxel, 30 mg/m² of cisplatin and 1,500 mg/m² of a 24-h continuous intravenous infusion of 5-FU. The response of this weekly regimen in our study was favorable and deserved further investigation in a phase II trial.     

Phase I-II study of biweekly paclitaxel administration with fixed-dose-rate cisplatin in advanced gastric cancer

Background Both paclitaxel (TXL) and cisplatin (CDDP) show efficacy against gastric cancer. The aim of this phase I-II study was to determine the maximum tolerated dose (MTD) and to evaluate the toxicity and efficacy of combination chemotherapy with these two agents. Methods Nineteen patients entered the phase I part of the study, and 21 patients entered the phase II part. TXL infusions were administered on days 1 and 15, with a fixed 3mg/m² dose of CDDP. Results In the phase I part of the study, we determined dose level 5, which represented a TXL dose of 18mg/m², with CDDP 3mg/m², to be the MTD. The recommended dose (RD) was level 4, with a TXL dose of 16mg/m² with CDDP, 3mg/m². In the phase II part of the study, the response rate was 25.0%; five patients had a partial response, seven had stable disease, 6 had progressive disease, and 2 were not evaluable. Grade 3 or 4 neutropenia was the most common adverse event and occurred in 65% of the patients. During treatment, 25% of the patients received granulocyte colony-stimulating factor, but febrile neutropenia was not shown in any of the patients. Major nonhematological toxicities were nausea/vomiting, anorexia, fatigue, alopecia, and sensory neuropathy. Adverse reactions of grade 3 or 4 were shown by two patients, one with anorexia (5%) and the other with sensory neuropathy (5%). Conclusion The RD was determined to be TXL 14mg/m², with CDDP 3mg/m².     

Multicenter phase II study of weekly paclitaxel plus cisplatin combination chemotherapy in patients with advanced gastric cancer

Purpose Since a weekly administration of paclitaxel has demonstrated a sustained efficacy and more favorable toxicity profile than a 3-weekly administration for various solid tumors, the present study was conducted to evaluate the efficacy and safety of a combination regimen of weekly paclitaxel plus cisplatin in patients with advanced gastric cancer. Patients and methods Patients with previously untreated metastatic or recurrent, measurable gastric cancer received intravenous paclitaxel 100 mg/m² plus cisplatin 35 mg/m² on days 1 and 8 based on a 3-week cycle. Results Fifty-two patients were enrolled in the current study. Two complete responses and 17 partial responses were confirmed, giving an overall response rate of 36.5%. At a median follow-up of 8.5 months, the median time to progression and median overall survival was 6.0 and 10.8 months, respectively. Grade 3 neutropenia occurred in ten patients, while no grade 4 neutropenia or febrile neutropenia was observed. The most common non-hematologic toxicity was nausea (grade 1/2, 56.9%). There were no treatment-related deaths. Conclusion A weekly paclitaxel and cisplatin combination was found to be well-tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as an important first-line treatment option for advanced gastric cancer.     

A phase II trial of weekly fractionated irinotecan and cisplatin for advanced gastric cancer

Purpose This study was to evaluate the activity and the safety of a combination chemotherapy regimen of weekly fractionated irinotecan and cisplatin in advanced gastric cancer patients. Methods Patients with advanced gastric adenocarcinoma with either chemotherapy-naive or only one prior chemotherapy regimen received irinotecan 50 mg/m² followed by cisplatin 30 mg/m². Both drugs were administered weekly for 3 consecutive weeks, followed by 1-week rest. Treatment was repeated until disease progression occurred. Response evaluation was performed according to the RECIST criteria. Results Forty-seven patients (13 chemo-naive, 34 prior chemotherapy) were enrolled. Of 46 evaluable patients, overall response rate was 25.5% (95% CI, 12.9–39.3%) and disease control rate was 63.8% (95% CI, 50.9–79.5%) by intent-to-treat analysis. The time to progression and overall survival duration were 21 and 44 weeks, respectively. One-year survival rate was 41.6%. The most frequent grade 4 toxicity was neutropenia, which was the major cause of treatment delay. Non-hematological toxicities of grade 3–4 were rare with occurrence rate of 14.9% for anorexia and emesis. Conclusions Fractionated irinotecan combined with cisplatin with 3-week-on and 1-week-off schedule produced favorable clinical results for advanced gastric cancer. Because of the feasible efficacy and low non-hematologic toxicity, this treatment could be a promising salvage regimen in patients who have failed to taxanes. Authors’ Disclosure of Potential Conflicts of Interest: the authors indicated no potential conflicts of interest.     

In-vitro effect of a combination of 5-fluorouracil (5-FU) and cisplatin (CDDP) on human gastric cancer cell lines: timing of cisplatin treatment

Abstract. Background: To date, we have few effective chemotherapeutic agents against advanced and recurrent gastric cancer. 5-Fluorouracil (5-FU) and cisplatin (CDDP) are the most widely used drugs, and their combination has demonstrated favorable outcomes. However, the method (especially the timing) of CDDP administration is not well established. Methods: We examined the in-vitro effect of a combination of 5-FU and CDDP on four human gastric cancer cell lines: MKN-1, MKN-28, MKN-45, and MKN-74. The cell lines were exposed to 50% of the inhibitory concentrations of 5-FU and CDDP for 72 h and 8 h, respectively. CDDP was applied before, simultaneously with, and after the start of treatment with 5-FU. Results: When CDDP was applied after 5-FU, the cytotoxic activity against MKN-28, MKN-45, and MKN-74 was significantly potentiated. Against MKN-1, the earlier the initiation of CDDP treatment, the stronger was the cytotoxic effect. Conclusion: Our results suggest that the cytotoxicity of a combination of 5-FU and CDDP against human gastric cancer cells is both cell-line- and schedule-dependent and is especially affected by the timing of the CDDP treatment. Received: August 22, 2001 / Accepted: December 7, 2001     

A phase I study of palliative chemoradiation therapy with paclitaxel and cisplatin for local symptoms due to an unresectable primary advanced or locally recurrent gastric adenocarcinoma

Purpose  To establish the maximum tolerated dose and dose-limiting toxicity of chemoradiation with paclitaxel (PTX) and cisplatin (CDDP) for patients with local symptoms due to unresectable primary advanced or locally recurrent gastric adenocarcinoma located at left-upper abdomen. Methods  Chemotherapy consisted of PTX at escalating doses of 40–80 mg/m² per day and CDDP at escalating doses of 20–25 mg/m² per day on days 1, 15, and 29. Concurrent radiation was administered up to a dose of 45 Gy for 5 weeks. Results  A total of nine patients were enrolled, of which six were into level 1 (PTX 60 mg/m² and CDDP 20 mg/m²) and three into level −1 (PTX 50 mg/m² and CDDP 20 mg/m²). At level 1, one patient developed grade 3 fatigue, and the other experienced grade 5 DIC, grade 5 pneumonia, grade 4 thrombocytopenia, grade 3 hyponatremia, and grade 3 esophagitis as dose-limiting toxicities. A palliative effect was observed in eight of nine patients; six of six patients at level 1 and two of three at level −1. Conclusion  PTX 50 mg/m² and CDDP 20 mg/m² given biweekly with concurrent radiation therapy of 45 Gy were well tolerated.     

A phase I study of irinotecan and infusional cisplatin for advanced non-small-cell lung cancer

 A phase I study was performed to establish the optimum dose for combination therapy with infusional cisplatin and irinotecan (CPT-11) in non-small-cell lung cancer (NSCLC). The subjects were 20 patients with a performance score of 0–2 with untreated advanced NSCLC. Cisplatin was administered by 5-day continuous intravenous infusion at 20–25 mg/m² per day. CPT-11 was administered by bolus infusion at a starting dose of 20 mg/m² on days 1 and 8 or 60 mg/m² per day on day 1 alone, followed by serial increments of 20 mg/m². Since grade 4 granulocytopenia was observed in two of the five patients receiving 20 mg/m² per day cisplatin (days 1–5) and 100 mg/m² CPT-11 (day 1), and since one of them developed severe pneumonia and sepsis associated with the granulocytopenia, the regimen was considered to be intolerable. In the same patient, grade 4 thrombocytopenia and grade 3 diarrhea were observed. Therefore, the optimum dose appeared to be 20 mg/m² per day (days 1–5) for cisplatin and 80 mg/m² (day 1) for CPT-11. The side effects were grade 2 diarrhea in one of three patients, and grade 2 vomiting in three patients, but grade ≥2 hemotoxicity was not observed. This combined regimen resulted in a partial response in 9 out of 19 assessable patients. The dose-limiting factor in this combination therapy was granulocytopenia, and a high efficacy rate was obtained. Received: 14 August 1995 / Accepted: 3 June 1996     

紫杉醇联合氟尿嘧啶和顺铂方案治疗晚期胃癌

目的：观察紫杉醇联合氟尿嘧啶及顺铂（PFC）方案治疗国人晚期胃癌的临床疗效和毒副反应.方法：晚期胃癌患者25例,给予紫杉醇（PTX）50mg/m^2,静滴3小时,第1、8、15天给药;氟尿嘧啶（5-FU）750mg/m^2,持续静脉输注24小时,第1～5天;顺铂（CDDP）20mg/m^2,静脉滴注,第1～5天,28天为1周期.分别化疗2～6周期后按WHO标准评价疗效和毒副反应.结果：全组25例均可评价疗效,获得CR 2例,PR 11例,SD 7例,PD 5例,近期客观有效率52.0%,中位TTP为6.5月.主要毒副反应为骨髓抑制、恶心呕吐和脱发.结论：PFC方案治疗国人晚期胃癌疗效较高,毒副反应轻,多数患者耐受良好,值得推广应用.     

Weekly docetaxel for patients with platinum/paclitaxel/irinotecan-resistant relapsed ovarian cancer: a phase I study

Background This study was designed to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended dose (RD) of weekly docetaxel treatment in patients with relapsed ovarian cancer after the administration of platinum/paclitaxel/irinotecan.Methods Patients were enrolled on the basis of inclusion and exclusion criteria. Docetaxel was administered intravenously over a 60-min period on days 1, 8, and 15. Four dosage levels, 30, 35, 40, and 45mg/m², were employed, and the dosage was escalated from level 1 to level 4. DLT criteria were established, and the DLT was used as the criterion for deciding the MTD and RD.Results Twelve patients were enrolled. No grade 3/4 hematological toxicities were manifested at any dosage level. Grade 3/4 nonhematologic toxicities were manifested at level 4, consisting of fatigue/asthenia in 2 patients and neuropathy/sensory toxicity in 1 patient. Level 4 (45mg/m²) was thus judged to be the MTD, and the RD was concluded to be one level lower, i.e., level 3 (40mg/m²).Conclusions It was concluded that the RD for weekly docetaxel therapy is 40mg/m² per week in patients with relapsed ovarian cancer after the administration of platinum/paclitaxel/irinotecan.     

Capecitabine and paclitaxel combination chemotherapy for inoperable or recurrent breast cancer: a phase I dose-finding study by the Kinki Breast Cancer Study Group

Background The combination of capecitabine and paclitaxel (XP) has demonstrated synergistic antitumor activity in preclinical models. Three-weekly XP regimens have demonstrated excellent efficacy in phase II and III trials in metastatic breast cancer. We conducted a dose-finding study to identify the recommended 4-weekly XP regimen in patients with inoperable or recurrent breast cancer for phase II evaluation. Methods Eligible patients had inoperable or recurrent breast cancer previously treated with chemotherapy (but not capecitabine or paclitaxel) in the (neo)adjuvant or metastatic setting. Each 4-week treatment cycle consisted of escalating doses of capecitabine (628 or 829 mg/m² twice daily [b.i.d.] on days 1–21) and paclitaxel (80 or 90 mg/m² on days 1, 8, and 15). Dose-limiting toxicities (DLT) were evaluated during the first two cycles. Results Nine patients were treated. At dose level 1 (capecitabine 628 mg/m² b.i.d. plus paclitaxel 80 mg/m²), one patient experienced a DLT (grade 3 non-hematologic toxicity). There were no further DLTs at dose level 1 or 2. Although the MTD was not reached, dose level 2 (capecitabine 829 mg/m² b.i.d., days 1–21, plus paclitaxel 80 mg/m², days 1, 8, and 15, every 28 days) is recommended for phase II evaluation, taking into consideration the single-agent doses used in Japan and the doses identified in Western studies of 3-weekly XP. The overall response rate was 44%; all patients treated at dose level 2 achieved a partial response. Conclusions This 4-weekly XP regimen was well tolerated, active in patients with pretreated advanced breast cancer, and could be given as outpatient treatment. These results are consistent with findings of phase II and III trials evaluating 3-weekly regimens, and indicate that further investigation of a 4-weekly XP regimen is warranted.     

A phase II study of doxorubicin, cisplatin, and 5-fluorouracil in patients with advanced adenocarcinoma of the stomach or esophagus

Background: The combination of epirubicin, cisplatin, and infusional 5-fluorouracil (ECF) currently represents a standard and effective regimen for the treatment of advanced gastroesophageal cancer. The use of doxorubicin as an alternative to epirubicin in the ECF regimen has not been evaluated. Methods: Thirty-two patients with metastatic adenocarcinoma of the stomach, gastroesophageal junction, or esophagus were treated with cisplatin 60 mg/m² and doxorubicin 30 mg/m² repeated every 21 days, in combination with infusional 5-fluorouracil 200 mg/m²/day (ACF). Results: Major objective responses were observed in 28 percent of patients (46 percent previously untreated; 13 percent previously treated), with one complete response. The median progression-free survival was 4.0 months, and the median overall survival was 5.8 months (9.3 months previously untreated; 4.5 months previously treated). The major (Grade 3-4) toxicities were neutropenia (34 percent), anorexia (31 percent), nausea (28 percent), diarrhea (19 percent), and stomatitis (16 percent). Conclusion: In comparison with historical data taken from published trials of ECF, the ACF regimen appears similar in efficacy when differences in prior treatment status are taken into account. However, ACF appears to be associated with a higher incidence of major toxicities. Our findings therefore support the continued use of epirubicin rather than doxorubicin in combination chemotherapy regimens for advanced gastroesophageal cancer.     

紫杉醇联合氟尿嘧啶和顺铂治疗晚期胃癌疗效观察

目的观察紫杉醇联合氟尿嘧啶、顺铂治疗晚期胃癌的临床疗效及毒副反应。方法 51例晚期胃癌患者随机以紫杉醇联合氟尿嘧啶、顺铂的方案或表柔比星联合氟尿嘧啶、顺铂的方案化疗,均化疗2个周期以上。每个周期28 d。结果紫杉醇联合氟尿嘧啶、顺铂方案的有效率（CR＋PR）为51.9%,毒副反应有神经毒性、脱发、关节肌肉疼痛及血液学毒性,胃肠道反应发生率为51.8%。表柔比星联合氟尿嘧啶、顺铂方案的有效率（CR＋PR）为50.0%,有脱发、心肌毒性、血液学毒性,胃肠道反应发生率为87.5%。结论紫杉醇联合氟尿嘧啶、顺铂治疗晚期胃癌与表柔比星联合氟尿嘧啶、顺铂治疗晚期胃癌相比,副反应均可耐受,但胃肠道反应相对较轻,疗效相当。     

A phase I combination chemotherapy study of biweekly paclitaxel and S-1 administration in patients with advanced gastric cancer

The aim of the current study was to determine the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of a combination of paclitaxel and S-1 in patients with advanced gastric cancer. Fifteen patients were enrolled. The dose for S-1 was set at 80 mg/m²/day (days 1–14), while the dose for paclitaxel increased by 10 mg/m² for every three patients, with a starting dose of 100 mg/m² and was given biweekly on day 1 and 15. There was no severe toxicity (grade 4) recorded in patients receiving up to 120 mg/m² of paclitaxel. Leukopenia/neutrophilia with grade 1 to 3 occurred in six patients up to level 3. At 130 mg/m² of paclitaxel, grade 4 leukocytopenia and neutropenia events and grade 3 diarrhea developed in one out of three patients. One patient in another group of three patients that were enrolled at level 3, developed grade 4 granulocytopenia with fever (a body temperature higher than 38°C) and grade 3 leukocytopenia. Eight patients, out of a total of 15, showed a partial response, resulting in an objective response rate of 53%. Five patients received gastrectomy. Median survival time was 428 days and the 1 year survival rate was 53%. Biweekly paclitaxel/S-1 combination chemotherapy could be safely used for the treatment of advanced gastric cancer. The recommended doses for a phase II study with paclitaxel and S-1 are 120 mg/m² and 80 mg/m², respectively.     

氟尿嘧啶/亚叶酸钙+紫杉醇联合化疗双周方案治疗晚期胃癌

背景与目的：近来有临床研究显示紫杉醇(paclitaxel,PTX)可用于治疗胃癌,与5．氟尿嘧啶(5-fluorouracil,5-FU)联合治疗晚期胃癌疗效显著,不良反应轻。本研究观察5-Fu／亚叶酸钙(1eueovorin,CF) PTX联合化疗双周方案治疗晚期胃癌的临床疗效和不良反应。方法：采用高剂量5-FU／CF PTX深静脉输注方案(CF 200mg／m^2,静滴2小时,第1天;5-FU 500mg／m^2,静脉推注,第1天;5-FU 1500mg／m^2,静滴46小时;PTX90mg／m^2,静脉输注3小时,第1天),化疗方案以每两周为1周期,重复4周期后评定疗效。结果：全组20例均可评价疗效,总有效率为65．0％(13／20),其中完全缓解(CR)率为10.0％(2／20),部分缓解率为55．0％(11／20)。无治疗相关死亡,主要不良反应为口腔炎、手足综合征和脱发。结论：5-FU／CF PTX联合化疗双周方案治疗晚期胃癌缓解率较高、不良反应可耐受,是治疗晚期胃癌安全有效的化疗方案。     

周剂量紫杉醇、顺铂联合醛氢叶酸/5-氟脲嘧啶二线治疗晚期胃癌

目的：评价周剂量紫杉醇、顺铂联合持续输注醛氢叶酸／5-氟脲嘧啶(TPLF)二线治疗晚期胃癌的疗效和毒性。方法：对36例晚期胃癌予国产紫杉醇60mg/m^2第1、8、15，顺铂25mg/m^2第1、8、15，醛氢叶酸60mg/m^2第1、8、15，5-氟脲嘧啶500mg/m^2第1、8、15方案治疗2～3周期，观察评价疗效、毒副反应。结果：全组可评价病例36例，其中CR2例，PR13例，总有效率41．6％。主要毒副反应为骨髓抑制和脱发，绝大部分病人均能耐受。结论：TPLF方案是目前治疗晚期胃癌较理想的二线方案。     

A triplet chemotherapy with cisplatin, docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer: a phase I/II study

Purpose We conducted a phase I/II study of triplet chemotherapy consisting of cisplatin (CDDP), docetaxel (DCT) and gemcitabine (GEM) in patients with advanced non-small-cell lung cancer (NSCLC). Methods Fifty-three untreated patients with stage IIIB or IV NSCLC were enrolled. All drugs were given on days 1 and 8. The doses of CDDP and DCT were fixed at 40 mg/m² and 30 mg/m², respectively. In the phase I portion, a dose escalation study of GEM with starting dose of 400 mg/m² was conducted and primary objective in the phase II portion was response rate. Results The maximally tolerated dose (MTD) and recommended dose (RD) of GEM were determined as 800 mg/m² because grade 3 non-hematological toxicity (liver damage, diarrhea, and fatigue) developed in three of nine patients evaluated at that dose level. In pharmacokinetic analysis, C _max and AUC of dFdC and dFdU were increased along with the dose escalation of GEM. However, no relationship between pharmacokinetic parameters and toxicity or response was observed. Objective response rate was 34% and median survival time was 11.7 months. Though major toxicity was myelosuppression, there were no life-threatening toxicities. Conclusion These results indicate that this triplet chemotherapy is feasible and effective in patients with advanced NSCLC.     

A phase I study of recombinant human interferon alpha-2b combined with 5-fluorouracil and cisplatin in patients with advanced cancer

To determine the maximum tolerated dose (MTD) of escalating doses of interferon--2b (IFN, Intron A) with 5-fluorouracil (5-FU) and cisplatin (DDP) in patients with advanced cancer, 15 patients were accrued between May 1990 and July 1991. Primary sites were unknown (3), colorectal (3), head and neck (2), lung (2), gynecologic (1), gallbladder (1), sarcoma (1), anal canal (1) and pancreas (1). IFN was given s.c. on days 1–5 and then three times weekly with DDP (75 mg/m², day 1) and 5-FU [750 mg/m², days 1–5, continuous infusion (CI) on a 28-day cycle. The first two patients treated at level I (3×10⁶ U/m² s.c.) experienced possible neurotoxic deaths [massive cerebrovascular accident (CVA) and metabolic encephalopathy], and patient 3 had a grade 4 toxicity of performance status decline. Analysis of these events led us to exclude the enrollment of patients on i.v. morphine and of those with prior exposure to DDP. This resulted in grade 3 toxicity in terms of nausea, vomiting, fatigue and leukopenia but in no further CNS event. All patients were evaluable for toxicity but only ten were evaluable for response. Only two partial responses were seen, one in a patient with an unknown primary tumour and one in a patient with head and neck cancer. The combination of IFN is possible with 5-FU and DDP. The recommended dose of IFN is 2×10⁶ U/m² s.c. in patients with no prior exposure to DDP or i.v. morphine, given together with 5-FU (750 mg/m², days 1–5, CI) and DDP (75 mg/m², day 1) on a 28-day cycle.Supported in part by a grant from Schering Canada Inc.     

Phase II trial of biweekly paclitaxel plus infusional 5-fluorouracil and leucovorin in patients with advanced or recurrent inoperable gastric cancer

Purpose  To investigate the efficacy and safety of combination chemotherapy with biweekly paclitaxel plus infusional 5-fluorouracil and leucovorin in the treatment of patients with advanced or metastatic gastric cancer. Patients and methods  Chemonaive patients with histologically confirmed advanced or recurrent inoperable gastric cancer were enrolled in the present study. Treatment consisted of paclitaxel (75 mg/m²) and leucovorin (40 mg/m²) as a 2-h intravenous infusion, followed by 5-fluorouracil (2,400 mg/m²) as a 46-h continuous infusion. Cycles were repeated every 2 weeks. Results  Thirty patients were enrolled in this study. There were 12 partial responses, giving an overall response rate of 40.0%. At a median follow-up of 10.6 months, the median time to progression and median overall survival were 3.9 and 8.8 months, respectively. The most common hematological toxicity was grade 1–2 anemia, which was seen in 83.3% of patients. No grade 4 leukopenia, thrombocytopenia, or anemia was noted. The most common non-hematological toxicity was anorexia, which was seen in 70% of patients, although grade 3 anorexia was noted in only 10% of cases. There was no severe treatment-related morbidity or death. Conclusion  Combination chemotherapy consisting of biweekly paclitaxel plus infusional 5-fluorouracil and leucovorin was effective and well tolerated in patients with advanced gastric cancers.     

Phase I study of the combination of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer

Purpose This trial was conducted to determine the maximum tolerated dose (MTD), principal toxicity, and recommended dose for phase II study of the combination of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). Methods Patients with previously untreated NSCLC, either stage IIIB with pleural effusion or stage IV, were eligible if they had a performance status of 0–2, were 75 years or younger, and had adequate organ function. The respective doses of nedaplatin (day 1) and weekly paclitaxel (days 1, 8, and 15) studied were 80/60, 80/70, 80/80, 80/90, and 100/90 (mg m⁻²), repeated every 4 weeks. Results From May 2004 through June 2005, 21 patients (18 men and 3 women; median age, 63 years; age range, 53–75 years) were enrolled. The MTD was determined to be 100 mg m⁻² of nedaplatin and 90 mg m⁻² of weekly paclitaxel. Dose-limiting toxicities at the MTD were neutropenic fever and hepatic dysfunction. We recommend doses of 80 mg m⁻² of nedaplatin and 90 mg m⁻² of weekly paclitaxel for phase II study. Grade 3–4 hematologic toxicities included neutropenia in 29% of patients, thrombocytopenia in 0%, and anemia in 5%. Although the most frequent non-hematologic toxicity was hepatic dysfunction, all cases were only mildly to moderately severe. Although two patients had grade 3 or 4 pulmonary toxicity due to Pneumocystis carinii pneumonia, these patients recovered after receiving trimetoprim-sulfamethoxazole, steroid therapy, and supplemental oxygen. There were no treatment-related deaths. The overall response rate was 19.0% (95% confidence interval, 5.4–41.9%), and all responses were in patients receiving the recommended doses. The median dose-intensities for nedaplatin and paclitaxel were 91.6 and 87.1%, respectively, of the planned doses. Conclusion This combination chemotherapy is active and well tolerated and warrants phase II study.     

Combined radiotherapy, 5-fluorouracil continuous infusion and weekly oxaliplatin in advanced rectal cancer: a phase I study

The aim of this study was to determine the maximum-tolerated dose (MTD) of weekly oxaliplatin combined with 5-fluorouracil (5FU) continuous infusion administered concomitantly with fractionated radiotherapy in patients presenting advanced rectal cancer. Forty-three patients with rectal cancer (stage T3/T4 (n = 24), metastatic (n = 17) and 2 with local recurrence), were included. The radiotherapy dose delivered was 45 Gy over 5 weeks (1.8 Gy/fraction/day, 5 days per week). The initial weekly oxaliplatin dosage was 30 mg/m² and the 5FU dosage 150 mg/m²/d. The oxaliplatin and 5FU doses were escalated. Eight dose levels were tested. At dose level 8 (oxaliplatin 80 mg/m², 5FU 225 mg/m²/d), 2 patients out of 4 presented dose-limiting toxicity (severe diarrhoea with dehydration and fatal shock, rectovesical fistula). At dose level 7, 2 further patients presented with grade 3 diarrhoea. The main toxicity of the combination was diarrhoea. The hematological and neurological toxicities were not severe and were not dose-limiting. Out of the 30 patients undergoing surgery, 4 (13.3%) presented with pathological complete response and 4 (13.3%) only presented with microscopic residual disease. The results from this study enabled determination of the recommended weekly oxaliplatin dose (60 mg/m²) combined with 5FU continuous infusion (225 mg/m²) and fractionated radiotherapy (45 Gy) in the pre-operative treatment of advanced rectal cancer. The good safety profile of the regimen, associated with promising results in terms of histological response, suggest that the regimen could be developed in future phase II/III studies.