Clinical administration of oxaliplatin for patients previously treated for refractory advanced or recurrent colorectal cancer

Oxaliplatin (L-OHP) was administered to 10 patients previously treated for refractory advanced or recurrent colorectal cancer. The number of times each had received previous chemotherapy treatment ranged from 1 to 5 (median 3) for durations of 2.5 to 52.8 (median 11.7) months. At the time, L-OHP was not yet approved for sale in Japan, and could only be imported from overseas for personal use. As this made it very expensive,we used a low L-OHP dose of 100 mg/body. Combinations with 5-FU were administered differently from previous regimens; these included chronotherapy, weekly high-dose, FOLFOX 4, and FOLFOX 6. L-OHP was administered from 1 to 14 times (median 4.5), and the response to treatment was PR in 2 patients and NC in 5.The response rate was 22.2%.Although in NC there was a tendency toward tumor reduction in 2 of the 5 patients, the treatment had to be suspended because of their financial situations. Overall survival from commencement of the first treatment was 3.1 to 58.7 months (median 17.6+) and after starting L-OHP was 0.6 to 17.2 months (median 6.4+). Adverse events included bone marrow suppression in three patients, 3 cases of leukocytopenia (grade 3 in two patients and grade 4 in one), grade 4 thrombocytopenia in one patient,grade 3 sensory disturbance in one patient,and grade 3 anorexia in two patients. All reactions were able to be controlled except for one patient with Grade 4 thrombocytopenia. In summary,treatment with L-OHP as salvage chemotherapy can possibly contribute to prolongation of survival time in cases of refractory advanced colorectal cancer.It is useful to combine L-OHP with high-dose continuous administration of 5-FU,namely FOLFOX regimens.FOLFOX 6 is the most useful of the FOLFOX regimens because it is simple and can be administered on an outpatient basis.     

FOLFOX4方案和DP(O)F方案一线治疗晚期胃癌的疗效分析

背景与目的:晚期胃癌目前尚无标准方案,FOLFOX4方案(FOLFOX4组)和DP(O)F方案[TXT L-OHP/DDP 5-FU方案,DP(O)F组]是目前临床上常用且有效的治疗胃癌的方案。本研究对比这两个方案一线治疗晚期胃癌的疗效和不良反应。方法:收集70例接受FOLFOX4方案或DP(O)F方案一线治疗的晚期胃癌患者的临床资料,其中FOLFOX4组34例,醛氢叶酸(L-OHP)85mg/m2静滴,第1天;5-FU400mg/m2静推,第1、2天,5-FU600mg/m2持续静注22h第1、2天,14d为一周期。DP(O)F组36例,多西紫杉醇(TXT)剂量强度为20mg.(m2.w)-1;DDP40mg/m2静滴,第2、3天;L-OHP100mg/m2静滴第2天;5-FU500mg/m2静滴,第1～5天,21d为一周期。结果:FOLFOX4组和DP(O)F组的客观缓解率分别为45.5%和52.8%(P=0.628);中位疾病进展时间为5.27个月和4.70个月(P=0.848);中位生存时间分别为8.97个月和12.17个月(P=0.095)。两组方案主要不良反应为血液学毒性及恶心呕吐,FOLFOX4组和DP(O)F组Ⅲ～Ⅳ度白细胞下降发生率为11.8%和36.1%(P=0.025),Ⅲ～Ⅳ度中性粒细胞下降发生率为17.6%和41.7%(P=0.038),FOLFOX4组中有1例患者死于化疗相关的肝功能衰竭。结论:FOLFOX4方案和TXT L-OHP/DDP 5FU方案一线治疗晚期胃癌疗效相近,后者血液学毒性较重。     

双周多西紫杉联合FOLFOX4方案和DCF方案治疗晚期胃癌对照研究

目的:比较双周多西紫杉联合FOLFOX4方案和DCF方案治疗晚期胃癌的疗效及不良反应。方法:将53例经病理确诊的晚期胃癌患者随机分为两组。A组27例,采用双周多西紫杉联合FOLFOX4方案化疗:多西紫杉50mg/m2,静脉滴注,d1;草酸铂85mg/m2,静脉滴注2h,d1;亚叶酸钙200mg/m2,静脉滴注2h,d1、d2;氟尿嘧啶400mg/m2,静脉推注,d1、d2,氟尿嘧啶600mg/m2,持续静脉泵输注22h,d1、d2。每2周为1周期。B组26例,采用DCF方案化疗:多西紫杉75mg/m2,静脉推注,d1;氟尿嘧啶750mg/m2,静脉滴注,d1-5;顺铂20mg/m2,静脉滴注,d1-3。每3周为1周期。对两组的近期疗效、疾病进展时间、总生存期、生活质量改善情况、不良反应进行分析比较。结果:A组和B组的有效率分别为55.6%(15/27)和53.8%(14/26),无显著性差异(P=0.9005)。A组和B组的中位疾病进展时间为6.0月(1.9-12月)和5.1月(1-12月)(P=0.0414);中位生存时间10.5月(1-18月)和10.1月(1-17月)(P=0.7805)。A组和B组的生活质量改善为74.1%(20/27)和50.0%(13/26),无显著性差异(P=0.0707);两组主要不良反应在Ⅳ度白细胞减少、血小板减少以及恶心呕吐方面具有一定差异(P<0.05),腹泻、口腔炎、神经毒性、脱发、心脏毒性等指标无显西著性差异。结论:双周多紫杉联合FOLFOX4方案和DCF方案一线治疗晚期胃癌近期疗效较好,双周多西紫杉联合FOLFOX4方案在一定程度上延长了无进展生存时间,在生活质量改善上似乎也有一定的优势。在重度白细胞减少以及相关的感染发生率上优于DCF方案。提示晚期胃癌患者对双周多西紫杉联合FOL-FOX4方案具有更好的耐受性。     

ＦＯＬＦＯＸ６方案治疗晚期原发性肝癌的临床观察

目的　探讨奥沙利铂联合亚叶酸钙、氟尿嘧啶（ＦＯＬＦＯＸ６）方案治疗３１例晚期原发性肝癌患者的疗效及毒性反应。方法　入组３１例晚期原发性肝癌患者,接受奥沙利铂１００ｍｇ／ｍ^２静脉滴注１８０ｍｉｎ,第１天,亚叶酸钙２００ｍｇ／ｍ^２静脉滴注１２０ｍｉｎ,第１天,氟尿嘧啶４００ｍｇ／ｍ^２静脉推注＋２４００ｍｇ／ｍ^２４６ｈ静脉泵注,每２周重复,４周为１周期。治疗至疾病进展或出现不能耐受的毒性,持续至多６周期,每２周期评价疗效,随访２４个月。客观疗效按照ＲＥＣＩＳＴ标准评价,毒性反应按照美国ＮＣＩＣＴＣ标准评价。结果　３１例患者均可评价疗效及毒性,其中ＣＲ１例,ＰＲ４例,有效率１６.１３％,ＳＤ８例,有１６例患者（５１.６１％）的主要临床症状得以明显改善或消失,Ｋａｒｎｏｆｓｋｙ评分稳定或增高,生存质量明显提高。中位肿瘤进展时间（ＴＴＰ）为５.５个月,中位总生存时间（ＯＳ）为９.７个月。毒副反应主要为粒细胞减少３８.７１％（１２／３１）,血红蛋白减少２９.０３％（９／３１）,血小板减少３２.２６％（１０／３１）和较轻的神经毒性３８.７１％（１２／３１）。结论　ＦＯＬＦＯＸ６方案治疗晚期原发性肝癌有效,毒性反应可以接受,值得进一步研究。     

参芪扶正注射液联合FOLFOX4方案治疗晚期胃癌的疗效观察

目的观察参芪扶正注射液联合FOLFOX4方案治疗晚期胃癌的临床疗效及不良反应。方法将48例经病理检查确诊为晚期胃癌的患者随机分为两组。治疗组24例,每日给予参芪扶正注射液250ml,静脉滴注,共10天,联合采用FOLFOX4化疗方案：奥沙利铂85mg/m2,静脉滴注2h,第1天;亚叶酸钙200mg/m^2,静脉滴注2h,第1、2天;氟尿嘧啶400mg/m^2,静脉推注,第1、2天,氟尿嘧啶600mg/m^2,持续静脉泵输注22h,第1、2天。每2周为1个周期。对照组24例,单用FOLFOX4方案（用药与治疗组相同）。治疗4周期后评价疗效及毒副反应。对两组的缓解率、生活质量改善率、不良反应进行分析比较。结果治疗组与对照组的缓解率分别为62.5%（15/24）和50.0%（12/24）,有显著性差异（P〈0.05）;生活质量改善率分别为83.3%（20/24）和50.0%（12/24）,有显著性差异（P〈0.05）;两组主要不良反应白细胞减少、腹泻、口腔炎、神经毒性和脱发等指标的差异具有显著性（P〈0.05）。结论参芪扶正注射液联合FOL-FOX4方案治疗晚期胃癌,在疗效、生存质量方面优于单用FOLFOX4方案,且不良反应轻。     

Phase I clinical and pharmacokinetic study of protein kinase C-alpha antisense oligonucleotide ISIS 3521 administered in combination with 5-fluorouracil and leucovorin in patients with advanced cancer.

The present study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PKs), and antitumor activity of the protein kinase C-alpha antisense oligonucleotide ISIS 3521 (ISIS Pharmaceuticals, Inc., Carlsbad, CA) when administered in combination with 5-fluorouracil (5-FU) and leucovorin (LV). Patients with refractory solid tumors received ISIS 3521 as a 21-day continuous infusion administered simultaneously with 5-FU and LV given daily for 5 days repeated every 4-5 weeks (one cycle). 5-FU and ISIS 3521 PK analysis were performed on samples taken during the first cycle in all patients. Fifteen patients received ISIS 3521 at one of three dose levels: (a) 1.0 (n = 3 patients); (b) 1.5 (n = 3 patients); and (c) 2.0 (n = 9 patients) mg/kg/day. All patients simultaneously received 5-FU (425 mg/m(2)/day) and LV (20 mg/m(2)/day) for 5 consecutive days. Grade 1-2 toxicities included alopecia, fatigue, mucositis, diarrhea, anorexia, nausea/vomiting, and tumor pain. One patient had grade 3 chest pain considered to be related to 5-FU therapy, another patient had dose-limiting grade 3 mucositis resolving in <7 days, and one patient with a history of gastritis had an acute upper gastrointestinal bleed thought to be 5-FU-induced toxicity. Five patients developed cycle 1 grade 4 neutropenia, which resolved without colony-stimulating factors before the next treatment cycle. There were no effects on prothrombin time and activated partial thromboplastin time. A clinically defined MTD was not reached. The character and severity of these toxicities do not seem to be dose related, and, as such, there was no classical dose-limiting toxicity defining the MTD. ISIS 3521 PKs in the presence of 5-FU was consistent with those reported previously. 5-FU PK parameters were also similar in the presence or absence of ISIS 3521. Six of 14 patients ( approximately 43%) across all dose cohorts had an improvement in measurable tumor response ranging from minor reduction in tumor size (4 patients) to objective partial response (>50% reduction in tumor size, 2 patients). ISIS 3521 is tolerable at its recommended single-agent dose when given with 5-FU and LV. There is no apparent PK interaction between ISIS 3521 and 5-FU and LV. Antitumor activity was observed with the combination; however, it is uncertain whether clinical activity is a result of enhanced drug interaction. Our study warrants further exploration of efficacy in a Phase II and/or Phase III clinical trial setting.     

The value of oxaliplatin in combination with continuous infusion +/- bolus 5-fluorouracil and levo-folinic acid in metastatic colorectal cancer progressing after 5FU-based chemotherapy: a GISCAD (Italian Group for the Study of Digestive Tract) cancer phase II trial

AIMS AND BACKGROUND: The phase II trial was designed to evaluate the activity of combined oxaliplatin (L-OHP), continuous infusion (CI) +/- bolus 5-fluorouracil (5FU) and levo-folinic acid (I-FA) in patients with metastatic colorectal cancer progressing after one or more lines of 5FU-based chemotherapy. PATIENTS AND METHODS: We designed two contemporary studies: in the former we enrolled patients previously treated with 1 line of chemotherapy, and in the latter, patients previously treated with 2, 3 and 4 lines. Seventy-six consecutive patients were enrolled: 45 received L-OHP (85 mg/m2 i.v. 2 h on day 1) + I-FA (100 mg/m2 i.v. 2 h on days 1 and 2) + 5FU i.v. bolus (400 mg/m2 days 1 and 2) + 5FU (600 mg/m2 CI 22 h days 1 and 2 (FOLFOX 4); 31 received L-OHP (100 mg/m2 i.v. 2 h on day 1) + I-FA (250 mg/m2 i.v. 2 h on days 1 and 2), followed by 5FU (1500 mg/m2 Cl 24 h days 1 and 2 (FOLFOX 2). The treatment was recycled every 2 weeks and continued until progression and/or unacceptable toxicity or patient preference. The primary end point was activity (tumor growth control [TGC]: partial response [PR] + stable disease [SD]); the secondary end points were time to progression (TTP), overall survival (OS) and toxicity. RESULTS: Forty-five patients in 2nd line (22 FOLFOX 4, 23 FOLFOX 2), 23 (17 FOLFOX 4, 6 FOLFOX 2) in 3rd, 4 in 4th and 1 in 5th line were assessable; 3 were lost to follow-up. In 15 patients (11 FOLFOX 4, 4 FOLFOX 2), disease involved the liver only. A total of 533 courses were administered with a range of 1-14 in FOLFOX4 and 1-12 in FOLFOX2; dose intensity was 92.85%, and the total dose of the administered L-OHP was 98.29%. As a 2nd line treatment, FOLFOX 4 achieved TGC in 72.8% of the patients (PR, 18.2%; SD, 54.6%), with a median TTP of 6 months and a median OS of 7 months, whereas in the FOLFOX 2 group these figures were 78.3% (PR 21.8%, SD 56.5%), and 5 and 9 months. As a 3rd line treatment, FOLFOX 4 produced TGC in 41.1% of patients (PR 23.5%, SD 17.6%), with a median TTP of 5 months and median OS of 7+ months, whereas FOLFOX 2 obtained respective values of 50% (PR 16.7%, SD 33.3%), 7 and 9 months. As a 4th line of treatment, TGC was achieved in 2 patients (1 PR, 1 SD); the patient in 5th line therapy obtained a SD. With "de Gramont" as the first-line regimen, patients assessable were 24 in FOLFOX 4 and 18 in FOLFOX 2. In the former population, TGC was 70.8% (PR 37.5%, SD 33.3%), with a TTP of 6 months and OS of 10 months, whereas with FOLFOX2 these values were 61.1% (PR 5.6%, SD 55.5), 5 and 7 months. In patients with liver involvement only, FOLFOX 4 obtained TGC in 63.6% of cases (with a TTP of 7 months and OS of 6+ months), FOLFOX 2 in 100% (with a TTP of 9.5 months and OS of 13.5+ months). Both schedules exhibited an acceptable toxicity: neurologic, hematologic and hepatic grade 3 side effects occurred in a limited number of patients, with a higher frequency in the FOLFOX 2 group. CONCLUSIONS: Treatment with L-OHP, CI +/- bolus 5FU and I-FA was well tolerated. The activity in terms of TGC was interesting and comparable with results reported in the literature for the standard treatment for 2nd line, i.e. irinotecan alone. Treatment was effective in 2nd line and in patients previously treated with more than two chemotherapy lines; in particular, treatment was active in patients with hepatic disease only. Although the two schedules seemed to achieve the same benefit with the same tolerance, we could not define from the study the better regime.     

A phase II study of irinotecan alternated with a weekly schedule of oxaliplatin, high-dose leucovorin and 48-hour infusion 5-fluorouracil in patients with advanced colorectal cancer

OBJECTIVES: To evaluate the safety and efficacy of irinotecan (CPT-11) alternated with a weekly treatment for 4 weeks of oxaliplatin (L-OHP), high-dose leucovorin (LV) and a 48-hour 5-fluorouracil infusion (5-FU 48 h) as first-line chemotherapy for patients with advanced colorectal cancer (ACC). Patients and METHODS: Previously untreated patients with ACC received chemotherapy consisting of a weekly treatment for 4 weeks of L-OHP (65 mg/m2), high-dose LV (150 mg/m2) followed by a 5-FU 48 h infusion (2,300 or 1,800 mg/m2) alternated with CPT-11 (350 mg/m2). A cycle was to be performed every 8 weeks. Treatment was continued up to tolerance, disease progression or patient refusal. Forty consecutive patients with measurable ACC, aged 26-70, performance status < or =2, entered our study. RESULTS: Six complete and 17 partial responses were observed (overall response rate, 57.5%; 95% confidence interval, CI: 38.8-71.1%); an additional 35% of the patients had stable disease. The median duration of response was 10.9 months (range, 6.5-30+ months). The median time to progression and the median overall survival time were 11.4 (95% CI: 10.4-12.3) and 20.3 (95% CI: 16.4-23.7) months, respectively. At the median follow-up period of 24 months, 17 patients (42.5%) are still alive. After a median number of 4 cycles, one toxic death occurred. The incidence of grade 3-4 toxicity per patient in any cycle was: stomatitis 7.5%, nausea/vomiting 2.5% and diarrhea 45% for the infusional part, neutropenia 37.5%, anemia 2.5%, thrombocytopenia 5%, alopecia 5% and diarrhea 10% for the CPT-11 part of the regimen. Gastrointestinal toxicity was different according to the dose of 5-FU. Serious adverse events occurred most frequently when 5-FU was given at a dose of 2,300 mg/m2 with a high incidence of grade 3-4 diarrhea (72.2%) and stomatitis (16.6%), and led to dose reduction of 5-FU in 13 of 18 patients (72.2%). For 22 patients who started 5-FU at a dose of 1,800 mg/m2, a dose reduction of 5-FU was necessary only 5 times (22.7%). No patient discontinued treatment because of severe neurotoxicity. CONCLUSIONS: The activity of our alternating regimen of L-OHP/LV/5-FU 48 h and CPT-11 for not previously treated ACC patients is counterbalanced by a high toxicity and a inconvenient schedule.     

Combined 5-FU and CDDP in a gastric cancer patient undergoing hemodialysis--pharmacokinetics of 5-FU and CDDP

The pharmacokinetics of 5-FU and CDDP was examined in a gastric cancer patient receiving regular hemodialysis (HD) for renal failure. The patient received combination chemotherapy of 5-FU and CDDP, then on the day of HD we measured the plasma concentration of 5-FU, total platinum, and non-protein-bound platinum of the patient. In the present case, the 5-FU concentration was kept at an almost even level during HD. Non-protein-bound platinum disappeared after being maintained in blood for a certain time when HD was started 30 minutes after the end of CDDP administration. From these findings, we conclude that combined 5-FU and low-dose CDDP therapy should be done by decreasing the dose of 5-FU, administrating CDDP only on the day the patient undergoes HD, and starting HD 30 minutes after the end of CDDP administration.     

FOLFOX4方案治疗晚期胃癌的近期疗效分析

目的：评价FOLFOX4方案治疗晚期胃癌的近期疗效及安全性。方法：32例晚期胃癌患者均有可评价的病灶，行FOLFOX4方案化疗：奥沙利铂（OXA）85mg／m^2静脉滴注2h，第1天；醛氢叶酸（LV）200mg／m^2静脉滴注2h，第1、2天；氟脲嘧啶（5-FU）400mg／m^2静脉推注后，以600mg／m^2持续静脉滴注22h，第1、2天；2周重复1次，每2次为1个周期，所有患者至少接受4个周期的治疗。结果：完全缓解1例，部分缓解14例，总有效率46．9％（15／32），中位至疾病进展时间5．6个月。主要不良反应为轻度的外周神经系统感觉障碍、恶心呕吐及白细胞计数降低，无治疗相关死亡。结论：FOLFOX4方案对晚期胃癌疗效确切，毒副反应轻，可以作为晚期胃癌患者化疗方案选择。     

Whole-body hyperthermia (41.8 degrees C) combined with bimonthly oxaliplatin, high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer: a phase II study.

BACKGROUND: Second- and third-line treatments remain a challenge in advanced colorectal cancer. Studies of bimonthly regimens of high-dose leucovorin (LV) and 5-fluorouracil (5-FU) by continuous infusion combined with oxaliplatin (L-OHP) have shown encouraging response rates in patients not responding to a bimonthly LV/5-FU regimen. Hyperthermic enhancement of L-OHP efficiency by increased DNA adduct formation has been demonstrated in vitro. This study was designed to address feasibility, toxicity and efficacy issues of whole-body hyperthermia (WBH) as an adjunct to L-OHP/LV/5-FU in pretreated patients after progression to first- and second-line treatments with LV/5-FU by continuous infusion and irinotecan. PATIENTS AND METHODS: Forty-four patients with advanced colorectal cancer, who had progressed during or within 3 months after completion of chemotherapy with LV/5-FU 24-h infusion (LV/5-FU(24h)) (eight patients) or irinotecan combined with or after LV/5-FU(24h )(36 patients), were treated with L-OHP 85 mg/m(2), 2-h intravenous (i.v.) infusion, followed by LV 200 mg/m(2), 1-h i.v. infusion, and 5-FU 3 g/m(2), 48-h continuous infusion. Every second cycle of the biweekly regimen was combined with WBH, thus allowing a comparison of toxicity with and without WBH in the same patient. Whole-body hyperthermia was administered by a humidified radiant heat device. The target temperature of 41.8 degrees C was maintained for 60 min. L-OHP (2-h infusion) was started at a core body temperature of 39 degrees C. RESULTS: All patients could be evaluated for toxicity, and 41 patients were evaluable for response. A total of 273 L-OHP-containing regimens were administered, 130 with and 143 without WBH. Hyperthermic treatment combined with L-OHP/LV/5-FU showed no unexpected toxicities. WHO grade 3 toxicities were rare and evenly balanced between cycles given with or without WBH. One early death occurred due to sepsis and tumor lysis. The overall response rate was 20%, with two complete and six partial responses. Twenty-three patients (56%) had stable disease and nine patients (22%) progressive disease. With a median observation time of 70 weeks, the median time to progression was 21 weeks [95% confidence interval (CI) 17-25 weeks] and the median survival was 50 weeks (95% CI 39-61 weeks) from the start of therapy. CONCLUSIONS: This trial suggests some advantage of combining L-OHP/LV/5-FU with WBH. Results compare favorably with the activity of similar regimens without WBH in less extensively pretreated patients. These data support further evaluation and warrant phase III studies.     

FOLFOX4方案和TP方案一线治疗晚期胃癌的疗效分析R735．2

目的：观察FOLFOX4和TP方案一线治疗晚期胃癌的疗效和不良反应。方法：收集41例接受FOL—FOX4方案或TP方案一线治疗的晚期胃癌患者的临床资料,其中FOLFOX4组21例,奥沙Nell（L—OHP）85mg／m2,静滴,第1天;CF200mg／m2,静滴,第1、2天;5-FU400mg／m2,静推,第1、2天;5-FU600mg／m0持续静注22h,第1、2天,14d为一周期,共12周期。TP组20例,紫杉醇（TAX）剂量为135mg／m2,静滴,第1天;DDP80mg／m0静滴,第1天,21d为一周期,共6周期。结果：FOLFOX4组和TP组的客观缓解率分别47．6％和45％（P=0．958）;中位疾病进展时间为6．70个月和6．20个月（P=0．943）;中位生存时间分别为9．50个月和7．80个月（P=0．587）。两组方案主要不良反应为血液学毒性及恶心呕吐,FOLFOX4组和TP组Ⅲ度～Ⅳ度白细胞下降发生率为14．3％和30．0％（P=0．321）,Ⅲ度-Ⅳ度中性粒细下降发生率为19．0％和30．0％（P=0．731）。结论：FOLFOX4方案和TP方案-线治疗晚期胃癌疗效相近,毒性均可耐受。     

Safety and efficacy of S-1, a novel oral fluorouracil antitumor drug, for a chronic renal failure patient maintained on hemodialysis

OBJECTIVE: S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase, and potassium oxonate (Oxo), a reducer of gastrointestinal toxicity. S-1 has safe and potent antitumor effects in patients with gastric cancer via these respective functions. However, the plasma 5-FU concentration is suspected to accumulate in patients with renal dysfunction, because 50% of the CDHP is excreted into the urine. There are no useful data on safety and efficacy of S-1 in chronic renal failure patients maintained on hemodialysis (HD). We examined the influence of HD on the pharmacokinetics (PK) of S-1 and its therapeutic efficacy in liver metastases from gastric cancer. METHODS: For the HD patient, the dose of S-1 in a single-administration study was set at 50 mg/body/day (41.7% of the recommended dose of 80 mg/m2/day). S-1 was given to the patient 24 h after HD. Blood samples were obtained before administration and 2, 4, 6, 8, and 24 h thereafter and 1, 2, 4, and 72 h after the following HD session. The PK parameters (5-FU, CDHP, Oxo, and FT) were measured, and Cmax, Tmax, AUC0-24, and T1/2 were calculated. The dose of consecutive or maintained administrations was determined. RESULTS: Both an increase in Cmax and an elongation of T1/2 for 5-FU, CDHP, and Oxo, but not for FT, occurred in this case as compared with controls. The AUC0-24 of 5-FU in this case was similar to that of controls at the standard dose. After HD, 87.8, 54.5, 77.4, and 66.2% of 5-FU, CDHP, Oxo, and FT, respectively, were eliminated. A slight accumulation of CDHP did not alter the 5-FU PK. Consecutive or maintained S-1 oral administration at the same dose showed similar effects on all PK parameters of a single-administration test. Liver metastases almost totally regressed with no adverse events 4 weeks after S-1 treatment (50 mg/body/day three times a week). CONCLUSION: Adjusted doses of S-1 according to the results of PK studies may provide therapeutic safety and high efficacy in liver metastases from gastric cancer, even in chronic renal failure patients maintained on HD.     

A phase I study of modified FOLFOX 6 therapy for advanced colorectal cancer

Oxaliplatin (L-OHP) has been established as a key drug for advanced colorectal cancer, and combination therapy with 5-FU/Leucovorin (LV)(FOLFOX regimen) is commonly used in Europe and the US. A phase I study of modified (m) FOLFOX 6 therapy was conducted to determine the recommended dose (RD) of 5-FU infused for 46 hours. Inclusion criteria were unresectable advanced colorectal cancer,measurable lesions, performance status (PS; ECOG) 0-2, age 20-75 years, and adequate organ functions. L-OHP and l-LV was administered over 2 hours and followed by bolus injection and continuous infusion of 5-FU for 46 hours every 2 weeks. Two cycles of mFOLFOX 6 therapy were performed. Doses of L-OHP, l-LV, and bolus injection of 5-FU were fixed at 85 mg/m(2), 200 mg/m(2), and 400 mg/m(2), respectively. The dose of continuous infused 5-FU was escalated from 1,600 mg/m(2), (level 1), 2,000 mg/m(2), (level 2), 2,400 mg/m(2), (level 3), and 2,800 mg/m(2), (level 4). RD was determined in a dose escalation manner, and safety was evaluated according to NCI-CTC Ver 2.0. A total of 13 patients were enrolled. Male/female=7/6, PS 0/1/2=2/4/7, mean age 64 years (range 55-75). Thrombocytopenia was not observed, and grade 2 of neutropenia and peripheral neuropathy was observed in 4 and 6 out of 13 patients. No dose-limiting toxicity (DLT) was observed at level 1 (n=3), 2 (n=4), and 3 (n=4), but at level 4 (n=2), 2 patients experienced DLT; grade 3 easy fatigue and anorexia required treatment delay over 7 days. Level 3 was therefore determined as RD. A phase II study is ongoing to evaluate the efficacy of mFOLFOX 6 therapy.     

Modified FOLFOX6 with oxaliplatin stop-and-go strategy and oral S-1 maintenance therapy in advanced colorectal cancer: CCOG-0704 study

Background

A combination of fluorouracil and leucovorin (5-FU/LV) with oxaliplatin (FOLFOX) is an established first-line therapy for metastatic colorectal cancer (mCRC). However, the cumulative neurotoxicity of oxaliplatin often requires therapy to be discontinued while the patient is still responding. A strategy to stop FOLFOX, deliver 5-FU/LV as a maintenance therapy and reintroduce FOLFOX was found to be equivalent in terms of efficacy while neurotoxicity was substantially reduced. The aim of this study was to evaluate feasibility of a stop-and-go strategy with S-1, an oral fluoropyrimidine derivative, as a maintenance therapy administered between modified FOLFOX6 (mFOLFOX6) as a first-line treatment of mCRC.

Methods

Thirty patients with untreated mCRC were treated with six cycles of mFOLFOX6 followed by maintenance therapy with oral S-1. Reintroduction of mFOLFOX6 was scheduled after four cycles of S-1 or upon tumor progression. The primary endpoint was duration of disease control (DDC).

Results

Twenty-one of the 30 patients who achieved responses or stabilizations received S-1 maintenance therapy. mFOLFOX6 was reintroduced in 15 patients. Median DDC and progression-free survival were 9.3 and 7.9?months, respectively. The response rates and disease control rates were 40.0 and 86.6% for the initial mFOLFOX6, 23.8 and 57.1% for S-1 maintenance therapy and 20.0 and 73.3% for mFOLFOX6 reintroduction, respectively. Twenty-eight patients (93.3%) had peripheral neuropathy, but grade 3 neurotoxicity was observed in only 1 patient (3.3%).

Conclusion

The planned oxaliplatin stop-and-go strategy with oral S-1 maintenance therapy was feasible as a first-line treatment for Japanese mCRC patients. Further prospective randomized control study is warranted.     

Oxaliplatin in combination with infusional 5-fluorouracil and leucovorin every 2 weeks as first-line treatment in patients with advanced colorectal cancer: a phase II study

PURPOSE: To evaluate the efficacy and safety of oxaliplatin (L-OHP) in combination with leucovorin (LV)-modulated bolus plus infusional 5-fluorouracil (5-FU; de Gramont schedule) every 2 weeks in chemotherapy-naive patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: Thirty-two patients (median age: 69 years) with histologically confirmed and two-dimensionally measurable metastatic CRC were enrolled. The patients' performance status (WHO) was 0 in 14 (44%), 1 in 15 (47%), and 2 in 3 (9%) patients. Twenty (62.5%) patients had at least two metastatic sites. LV was administered at a dose of 200 mg/m2/day as a 2-hour intravenous infusion, followed by 5-FU as an intravenous bolus at the dose of 400 mg/m2 and then, as a 22-hour continuous infusion at the dose of 600 mg/m2/day for 2 consecutive days. L-OHP was administered on day 1 at the dose of 85 mg/m2 as a 2-hour infusion in parallel with LV but using different infusion lines. Treatment was administered every 2 weeks. RESULTS: In an intention-to-treat analysis, 2 (6.2%) complete and 9 (28%) partial responses (28%; odds ratio 34.2%; 95% confidence interval 17.92-50.83%) were achieved while 8 (25%) patients had stable disease and 13 (41%) progressive disease. The median duration of response was 5 months, but the median time to progression has not yet been reached. After a median follow-up period of 11 months, the median survival has not yet been attained, but the projected probability for 1-year survival was 72%. Grade 3/4 neutropenia occurred in 16 (50%) patients while 1 (3%) of them developed febrile neutropenia. There was no treatment-related death. Peripheral neuropathy grade 2 and > or =3 occurred in 5 (16%) and 7 (21%) patients, respectively. CONCLUSIONS: The bimonthly administration of L-OHP in association with LV-modulated bolus plus infusional 5-FU ('de Gramont' regimen) is a well-tolerated and effective front-line treatment for metastatic CRC.     

Preliminary observations indicate variable patterns of plasma 5-fluorouracil (5-FU) levels during dose optimization of infusional 5-FU in colorectal cancer patients

Efforts to improve efficacy and minimize toxicity have led to pharmacokinetic monitoring of plasma 5-Fluorouracil (5-FU) levels in colorectal cancer patients undergoing chemotherapy. We observed variation in basal 5-FU levels in 21 patients and significant variation during subsequent dose optimization. Tumor KRAS, BRAF mutations and TS mRNA levels were determined. Regimens included FOLFOX6 + Avastin (N = 8), FOLFOX6 (N = 11), FOLFIRI (N = 1) and FOLFOX4 (N = 1). Mutations identified in tumors included G12V KRAS (N = 2), G12A KRAS (N = 1), and V600E BRAF (N = 3). Six-of-eleven patients with normalized tumor TS mRNA levels < 4.0 had a 5-FU AUC of 20 mg.h/L or greater, and 80% of patients (4 of 5) with TS levels > 4.0 had a plasma 5-FU AUC of less than or equal to 20 mg.h/L. Approximately 2/3 of patients achieved therapeutic 5-FU AUC levels with 0-2 dose adjustments while a sub-group of ~1/3 of patients slowly achieved therapeutic levels (> 3-4 dose increases leading to supra-therapeutic 5-FU and subsequent reductions to lesser than original doses). Liver metastases and tumor TS levels did not fully account for variable 5-FU AUC optimization patterns. The 5-FU level during continuous infusion was half-therapeutic in one patient who received FOLFOX4. The observed heterogeneous patterns at baseline and during dose optimization of 5-FU levels suggest variations in 5-FU metabolism among treated patients. Physiological and/or genetic differences underlying heterogeneity in 5-FU levels during dose optimization require further study of patient demographics, single nucleotide polymorphisms in Dihydropyrimidine Dehydrogenase (DPD), TS, or other genes that impact 5-FU metabolism and gene expression changes in liver after 5-FU therapy.     

FOLFOX4方案和ECF方案治疗老年晚期胃癌的疗效比较

目的:比较FOLFOX4方案和ECF方案治疗老年晚期胃癌的疗效及不良反应.方法:将56例经病理确诊的老年晚期胃癌患者随机分为两组.A组29例,采用FOLFOX4方案化疗:草酸铂75mg/m2 ,静脉滴注2h,d1;亚叶酸钙200mg/m2 ,静脉滴注2h,d1-2;氟尿嘧啶400mg/m2 ,静脉推注,d1、d2 ,氟尿嘧啶600mg/m2 ,持续静脉泵输注22h,d1-2.每2周为1周期.B组27例,采用ECF方案化疗:表柔比星45mg/m2 ,静脉推注,d1;氟尿嘧啶675mg/m2 ,持续静脉泵输注120h;顺铂20mg/m2 ,静脉滴注,d1-3 .每3周为1周期.对两组的近期疗效、疾病进展时间、总生存期、生活质量改善情况、不良反应进行比较.结果:A组和B组的有效率分别为41.4% (12/29)和44.4% (12/27),无显著性差异(P=0.8168).A组和B组的中位疾病进展时间4.6月(1-15月 ),4.8个月(1-14月)(P= 0.8899);中位生存时间7月(2-16月),6.9月(2-16月)(P=0.2905).A组和B 组的生活质量改善为65.5% (19/29)和37.0% (10/27)有显著性差异(P=0.0331);两组主要不良反应白细胞减少、腹泻、口腔炎、神经毒性、脱发、心脏毒性等指标的差异具有显著性(P＜0.05).结论:FOLFOX4方案和ECF方案治疗老年晚期胃癌近期疗效较好,在生活质量改善以及不良反应方面,FOLFOX4方案优于ECF方案,具有更好的耐受性.     

Hypersensitivity reaction caused by folinic acid administration: a case report and literature review

5-Fluorouracil (5-FU) is combined with folinic acid (FA) for enhancing its cytotoxic effects in the colon cancer chemotherapy treatment. Folinic acid has rarely been involved in hypersensitivity reactions. Here, we report a case of FA hypersensitivity in an adult patient initially attributed to oxaliplatin administered concurrently. A 56-year-old male patient diagnosed with colon cancer received twelve cycles of FOLFOX4, one cycle of FOLFIRI plus cetuximab and nine cycles of FOLFOX6 uneventful. At the tenth cycle of FOLFOX6 chemotherapy, after 15?minutes of starting the infusion of oxaliplatin and FA, the patient reported flushing, pruritus and abdominal pain and erythema and oedema developed over the face and thorax. After progression, FOLFIRI plus aflibercept was scheduled and another reaction occurred. At this time, FA was discontinued and the patient received another cycle consisted on irinotecan plus 5-FU without incidences. This episode of hypersensitivity reaction following FA infusion with no oxaliplatin empirically confirmed that the hypersensitivity reaction was secondary to FA. Clinicians should be aware of hypersensitivity reaction with FA, especially when FA is administered concomitantly with oxaliplatin, despite its lower risk to cause hypersensitivity reactions. Furthermore, the similar signs and symptoms associated to the hypersensitivity reactions of each agent, highlight the importance of having a specialised allergist team for to make a prompt diagnose of the causative agent in order to prevent patient harm and proceed properly without unnecessary delays in the scheduled chemotherapy treatments.     

A case of neurotoxicity reduced with goshajinkigan in modified FOLFOX6 chemotherapy for advanced colon cancer

In performing FOLFOX (infusional 5-FU/LV with oxaliplatin) for advanced colorectal cancer, neurotoxicity of oxaliplatin (L-OHP) is the serious dose limiting factor. On the other hand, goshajinkigan is recently considered as an effective agent for the neurotoxicity of taxanes in Japan.We have applied goshajinkigan (TJ 107) for a case of advanced colon cancer with mFOLFOX 6, and experienced a reduction in numbness, the adverse effect of LOHP. A 57-year-old woman with descending colon cancer (H 1, P 3, Stage IV) underwent hemicolectomy D 2, rt.colectomy, bilateral oophorectomy, cholecystectomy and transverse colonostomy. After operation, mFOLFOX 6 was applied. In order to reduce the neurotoxicity of L-OHP, TJ 107 was used together from the third course. The severities of neurotoxicity before and after administration of TJ 107 were grade 2 and 1,respectively. TJ 107 could reduce or prevent the neurotoxicity of L-OHP.