Phase II study of irinotecan plus leucovorin and bolus 5-fluorouracil as first- or second-line chemotherapy in patients with advanced gastric or esophageal-gastric junction adenocarcinoma

The aim of this study was to evaluate the activity and safety of 5-fluorouracil (5-FU)/leucovorin (LV) and irinotecan as first- or second-line treatment in patients with advanced gastric adenocarcinoma. Treatment consisted of irinotecan 80 mg/m(2) intravenously (i.v.), followed by LV 200 mg/m(2) (i.v.) and 5-FU 450 mg/m(2) as an i.v. bolus, administered weekly for 6 weeks, followed by a 2-week rest period. Thirty-one patients (23 chemo-na?ve, 8 chemo-exposed) were enrolled. The overall response rate was 22.6% and the disease control rate was 38.7%. Among the patients who received the regimen as first-line treatment, objective response rate was 30.4% and the disease control rate was 52.1%. However, progression of the disease was recorded in all the patients receiving the combination as second-line chemotherapy. The median time to disease progression (TTP) was 4 months and the median duration of survival was 7 months. The median TTP was 6 months for patients treated with first-line chemotherapy and 2.5 for those who received study treatment as second line. Furthermore, the median survival duration was 8 months and 6 months, respectively. The most frequent grade 3 toxicity was febrile neutropenia. Grade 3 non-hematological toxicities were rare. There were no treatment-related deaths. The combination of 5-FU/LV and irinotecan as first-line treatment was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation would be worthwhile, particularly in elderly or debilitated patients who cannot tolerate aggressive chemotherapy.     

A multicenter phase II study of irinotecan (CPT-11) alternated with 5-fluorouracil and leucovorin as first-line treatment of patients with metastatic colorectal cancer

Purpose In this multicenter phase II study the efficacy and safety of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) were assessed as first-line chemotherapy in patients with metastatic colorectal cancer (CRC).Patients and methods Enrolled in the study were 43 patients with advanced CRC. They received CPT-11 350 mg/m² i.v. on day 1, alternating with LV 20 mg/m² i.v. and 5-FU 425 mg/m² i.v. daily for five consecutive days, on days 22–26 (Mayo Clinic regimen). One cycle consisted of 6 weeks.Results A total of 179 cycles were administered with a median of four per patient (range one to nine). Efficacy was analyzed on an intention-to-treat basis. The overall objective response rate was 30% (95% CI 16–44), with four complete responses and nine partial responses, whereas 20 patients (4%) showed stable disease. The median time to disease progression was 9.0 months and median survival was 18.5 months. Grade 3/4 diarrhea was mainly related to CPT-11 rather than to 5-FU (9.3% vs 4.7% of patients), whereas grade 3/4 neutropenia was higher during 5-FU administration (16.3% vs 7.0% of patients).Conclusions The alternating schedule of CPT-11 with 5 days bolus of 5-FU and low-dose LV showed a clinical benefit in terms of tumor growth control as first-line treatment of patients with metastatic CRC. The overall safety data confirmed this alternating combination as a well-tolerated treatment.     

Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study

Background: Second-line irinotecan-based chemotherapy is commonly used in metastatic colorectal cancers after first-line oxaliplatin-based chemotherapy. No standard schedule of irinotecan has been established in this situation.Patients and methods: Metastatic colorectal cancer patients included in the OPTIMOX1 phase III study received first-line oxaliplatin-based chemotherapy (FOLFOX). No second line was defined in the protocol, but data concerning second line were prospectively registered. Inclusion criterion was patients receiving an irinotecan-based second-line chemotherapy. Second-line progression-free survival (PFS) and tumor response were evaluated according to type of irinotecan-based regimen administered.Results: A total of 342 patients received irinotecan-based chemotherapy as second-line chemotherapy: FOLFIRI-3 [n = 109, irinotecan 100 mg/m² days 1 and 3 combined with leucovorin (LV) 400 mg/m² day 1 and 46-h continuous 5-fluorouracil (5-FU) 2000 mg/m²], FOLFIRI-1 (n = 112, irinotecan 180 mg/m² day 1 combined with LV 400 mg/m² day 1, 5-FU bolus 400 mg/m² and 46-h continuous 5-FU 2400 mg/m²) and other various irinotecan-based regimens (n = 121). Median second-line PFS was 3.0 months (FOLFIRI-3: 3.7 months; FOLFIRI-1: 3.0 months; other regimens: 2.3 months). In multivariate analysis, FOLFIRI-3 regimen (relative risk 0.43, 95% confidence interval 0.28–0.68, P = 0.0003) and lactate deshydrogenase level at inclusion (P = 0.0006) in OPTIMOX1 were associated with a longer second-line PFS.Conclusion: In unselected patients pretreated with oxaliplatin, PFS in second line appeared to be improved by FOLFIRI-3 regimen.     

Grade 3/4 neutropenia is a limiting factor in second-line FOLFIRI following FOLFOX4 failure in elderly patients with metastatic colorectal cancer

Previous studies have reported improved outcomes for elderly patients with metastatic colorectal cancer (mCRC) treated with oxaliplatin or irinotecan as first-line chemotherapy. However, few studies regarding second-line chemotherapy with oxaliplatin or irinotecan are currenlty available. We analyzed retrospectively the efficacy and toxicity in elderly patients (median age, 74 years) treated with second-line FOLFIRI following first-line FOLFOX4 failure. From March 2005 to January 2008, 35 elderly patients with mCRC received first-line FOLFOX4 comprising leucovorin, 5-FU and oxaliplatin followed by second-line FOLFIRI comprising leucovorin, 5-FU and irinotecan. The median number of treatment courses with FOLFIRI was 5 (range 2-32). One patient responded to the treatment. The disease control rate was 38.2%. The median time to treatment failure was 3 months, and the median overall survival (OS) time from the beginning of first-line chemotherapy was 20.7 months. The incidence of grade 3/4 neutropenia was 71.4%, while febrile neutropenia was 11.4%. The incidence of non-hematological toxicity was low. The use of the three active drugs, 5-FU, oxaliplatin and irinotecan, in mCRC produced the longest OS in elderly as well as in younger patients. However, the elderly patients treated with second-line FOLFIRI had a high rate of hematological toxicity. Second-line FOLFIRI may therefore be used with caution in the elderly.     

New systemic frontline treatment for metastatic colorectal carcinoma

Options for first-line chemotherapy in patients with metastatic colorectal carcinoma have broadened considerably with the introduction of irinotecan and oxaliplatin. Furthermore, the oral fluoropyrimidine capecitabine has demonstrated efficacy in Phase III trials and recently was approved for first-line treatment in Europe and the United States. Capecitabine yielded similar median times to disease progression and median survival rates compared with bolus 5-fluorouracil (5-FU)/leucovorin (LV) (Mayo Clinic/North Central Cancer Treatment Group regimen), with superior and similar response rates, respectively. However, its role as a first-line, single-agent substitute for intermittent infusional 5-FU/LV remains to be defined. The addition of irinotecan or oxaliplatin to 5-FU/LV resulted in improved response rates and progression-free survival in large, randomized trials; moreover, irinotecan-containing regimens resulted in improved overall survival. Prevalent regimens of irinotecan/5-FU/LV and oxaliplatin/5-FU/LV have been compared in two randomized Phase III trials. One study demonstrated the statistical superiority of oxaliplatin/infusional 5-FU/LV over irinotecan/bolus 5-FU/LV in terms of response, time to disease progression, and median survival; however, those advantages may have been attributable to infusional administration or to major differences in second-line therapy. A randomized Phase III study comparing irinotecan and oxaliplatin in combination with the same infusional 5-FU/LV regimens and crossover in case of disease progression showed equivalent efficacy for both schedules in the first-line setting, but the irinotecan combination proved beneficial in terms of safety. New molecular targeted agents, such as angiogenesis-modulating compounds (e.g., bevacizumab) and epidermal growth factor receptor inhibitors (e.g., cetuximab), are under clinical investigation. This review updates current systemic frontline treatments and future perspectives for patients with advanced colorectal carcinoma.     

The role of 5-fluorouracil (5-FU) reintroduction with irinotecan or oxaliplatin in truly 5-FU-refractory advanced colorectal cancer patients

OBJECTIVES: Although several evidences have demonstrated a synergistic activity of 5-fluorouracil with irinotecan and oxaliplatin, thus explaining the use of this drug combination in the first-line treatment of advanced colorectal cancer, the need for the reintroduction of 5-FU in the second-line setting is more questionable. METHODS: We retrospectively evaluated the outcome of patients developing progressive disease while on an infusional 5-FU-based front-line chemotherapy and subsequently treated with one of the four following chemotherapy regimens: irinotecan, oxaliplatin and irinotecan or oxaliplatin both combined with the de Gramont schedule (LV5-FU2). RESULTS: 225 patients (137 males and 88 females), were eligible for analysis. Second-line chemotherapy consisted of irinotecan in 79 patients (35%, group A), oxaliplatin in 47 patients (21%, group B), irinotecan with LV5-FU2 in 53 patients (24%, group C) and oxaliplatin with LV5-FU2 in the remaining 46 cases (20%, group D). The response rate to second-line chemotherapy was obtained in 6/79 patients (8%) in group A, in 4/47 patients (9%) in group B, in 11/53 patients (21%) in group C and in 10/46 patients (22%) in group D (p = 0.04). CONCLUSIONS: These data suggest that reintroduction of 5-FU could increase irinotecan and oxaliplatin activity in patients progressing during a 5-FU-based first-line chemotherapy.     

Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05)

BackgroundIn Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC.Patients and methodsPatients who had disease progression during first-line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40–60 mg/m²) on days 1–14 and intravenous irinotecan (150 mg/m²) on day 1 of a 21-day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS).ResultsFrom February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78–1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group.ConclusionThe consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy.Clinical Trials.govNCT00639327.     

Long-term survival of patients with advanced colorectal cancer may not be due to the response to chemotherapy

Our primary objective was to determine the median and overall survival and secondarily the response rate to first- and second-line chemotherapy of patients with advanced colorectal metastatic disease. Three-hundred and seventy-nine patients (median age 60 years, range 30-87 years) were enrolled from April 1993 to March 2000. Median follow-up was 6 years (range 3-10 years), until July 2003. All patients were evaluable for survival and 342 were evaluable for response and toxicity. Thirty-seven patients did not undergo chemotherapy. All patients had confirmed histology as well as metastatic disease based on radiological tests. First-line treatment was administered to 342 patients: leucovorin (LV) 30 mg/m2 and 5-fluorouracil (5-FU) 425 mg/m2. Three different combinations were given as second-line treatment during different chronological periods: i) 5-FU, mitomycin-C and doxorubicin (FAM); ii) 5-FU and cisplatin (CDDP) and iii) 5-FU, LV and irinotecan (CPT-II). Responses were observed as follows: first-line treatment 16.37%, after FAM 25%, following 5-FU-CDDP 26.83% and after 5-FU-LV-CPT-II, 30.61%. Survival of all patients was as follows: median 25 months (range 16.1-33.9 months). The longest survival was of patients on 5-FU-LV-CPT-II. Median survival of patients with stable disease was 19 months and of untreated patients 12 months. Patients with advanced colorectal cancer have a long median (25 months) and overall survival, despite low responsiveness to chemotherapy.     

Advances in the treatment of metastatic colorectal cancer

The overall 5-year survival rate for patients with metastatic colorectal cancer (CRC) is less than 10%. Median survival with 5-fluorouracil (5-FU)/leucovorin (LV) therapy is approximately 12 months. Recent additions to the chemotherapy armamentarium for this disease have begun to prolong median survival times. In trials in which patients are exposed to all three approved chemotherapy agents, oxaliplatin, irinotecan, and 5-FU/LV, or capecitabine during the course of their disease, median survival has reached 20 months. The addition of oxaliplatin and irinotecan to 5-FU/LV regimens has also led to the maintenance of quality of life for longer intervals than were traditionally observed with 5-FU/LV alone. Current standard first-line regimens for metastatic CRC are FOLFOX (infusional 5-FU/LV with oxaliplatin) and FOLFIRI (infusional 5-FU/LV with irinotecan). The addition of bevacizumab to a two-drug regimen (irinotecan with 5-FU/LV) prolongs median survival to 20 months, with a modest amount of additional toxicity. Improvements in this median survival have not yet been realized with modifications to the current standard regimens; however, the oral agent capecitabine appears to be a reasonable substitute for infusional 5-FU/LV in combination regimens or as a single agent, with the advantage of reducing the inconvenience of the long infusion time. Ongoing investigations will identify a place for capecitabine, epidermal growth factor inhibitors, and new cytotoxics in the treatment of metastatic CRC.     

Biweekly oxaliplatin plus 1-day infusional fluorouracil/leucovorin followed by metronomic chemotherapy with tegafur/uracil in pretreated metastatic colorectal cancer

Purpose Metronomic chemotherapy, at a minimally toxic dose and with a frequent schedule, is a potentially novel approach to the control of advanced cancer disease via a different mechanism from maximum tolerable doses chemotherapy. Taking advantage of the potential effectiveness of metronomic therapy, tegafur/uracil (UFT) was incorporated into an oxaliplation/infusioanl fluouracil (5-FU)/leucovorin (LV) protocol in this study. The primary endpoints were response rate, time to progression (TTP) and safety profile in 5-FU-pretreated metastatic colorectal cancers (CRCs). Patients and methods Twenty-eight patients with metastatic CRCs resistant or refractory to 5-FU/LV were enrolled. Chemotherapy was administrated every 2 weeks sequentially with 2-h infusion of oxaliplatin (85 mg/m²) and LV (200 mg/m²), intravenous bolus 5-FU (400 mg/m²), 22-h infusion of 5-FU (600 mg/m²) on day 1 and then followed by 10-day daily oral UFT (200 mg/m²)/LV (30 mg/m²). Results Partial response was seen in ten (35.7%) patients. The median TTP was 5.2 (95% CI: 4.16–6.31) months and the median overall survival was 13.4 (95% CI: 6.39–20.5) months. No grade 3 toxicities above 5% according to National Cancer Institute-Common Toxicity Criteria (NCI-CTC) occurred except sensory neuropathy (10.7%). No grade 4 toxicity, treatment-related mortality or hand–foot syndrome was found. Conclusions This study protocol with favorable toxicity profile is thus promisingly effective against 5-FU-pretreated metastatic CRCs. Given the present experience, an evaluation of the regimen as front-line treatment of metastatic CRC is planned.     

Phase II study of biweekly cetuximab in combination with irinotecan as second-line treatment in patients with platinum-resistant gastro-oesophageal cancer

BackgroundThe purpose of this phase II trial was to evaluate the efficacy and safety of cetuximab and irinotecan as second-line treatment in patients with gastro-oesophageal adenocarcinoma.Patients and methodsPatients with failure to first-line platinum-based chemotherapy received cetuximab 500 mg/m² and irinotecan 180 mg/m² every second week until disease progression. Toxicity was evaluated according to The Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v. 3.0. Antitumour activity was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) v. 1.0.ResultsSixty-three patients were enrolled, median age was 60 years, median performance status was 1 (0–1), 35 patients had two or more organs involved. The median number of courses was 5 (range 1–25). Response rate was 11% (6 partial response (PR)) and 37% had stable disease. Median progression free survival was 2.8 months and overall survival (OS) was 6.1 months. Grade 3–4 toxicity included: diarrhoea (6%), fatigue (5%), vomiting (5%) and neutropenia (16%). Two patients developed febrile neutropenia. Forty-six patients (73%) had developed grade 1–2 skin rash. Patients developing skin rash had a prolonged survival with an OS at 7.1 months.ConclusionsThe combination of cetuximab and irinotecan is active as second-line therapy in patients with gastro-oesophageal cancer. Cetuximab induced skin rash was associated with prolonged survival.     

Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus ± LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m² per day and the l-LV dose being 5 mg/m² per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3–4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8–25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus ± LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin. Received: 22 September 1998 / Accepted: 5 January 1999     

A randomized phase II study of biweekly irinotecan monotherapy or a combination of irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line chemotherapy

Background

The aim of this study was to evaluate the efficacy of irinotecan (CPT-11) monotherapy and CPT-11 plus 5-fluorouracil (5-FU)/leucovorin (LV) combination (mFOLFIRI) as second-line treatment in patients with advanced gastric cancer (AGC).

Methods

A total of 59 patients were randomly assigned to either CPT-11 (150 mg/m² iv on day 1) or mFOLFIRI (CPT-11 150 mg/m² plus LV 20 mg/m² on day 1 followed by 5-FU 2,000 mg/m² over 48 h), every 2 weeks. The primary end point was objective response rate (ORR).

Results

Following random assignment, 29 patients received CPT-11 and 30 patients mFOLFIRI. The ORR was 17.2 % [95 % confidence interval (CI) 3.4–30.9] and 20.0 % (95 % CI 5.6–34.3) for the CPT-11 and mFOLFIRI arms, respectively (P = 0.525). There was no significant difference in median progression-free survival: 2.2 months (95 % CI 0.2–4.3) for CPT-11 versus 3.0 months (95 % CI 2.0–3.7) for mFOLFIRI (P = 0.481) or in median overall survival: 5.8 months (95 % CI 3.0–8.7), compared with 6.7 months (95 % CI 5.3–8.2) (P = 0.514). Grade 3/4 toxicity was observed in 21 and 28 events in the CPT-11 and mFOLFIRI arms, respectively.

Conclusions

Although this study had a small sample size and limited statistical power, CPT-11 monotherapy and mFOLFIRI appear to be equally active and tolerable as second-line chemotherapy for AGC. The addition of 5-FU/LV to CPT-11 did not significantly improve efficacy.     

晚期结直肠癌内科治疗进展

晚期转移性结直肠癌的5年生存率低于10％。5-FU／LV方案治疗的中位生存期大约12个月。最近化疗方案的更新延长了患者的中位生存期。研究发现奥沙利铂、伊立替康联合5-FU／LV或者卡培他滨等化疗方案使中位生存期延长到20个月。奥沙利铂，伊立替康联合5-FU／LV比传统的单药5-FU／LV使生活质量改善时间延长。目前转移性结直肠癌标准的一线治疗方案为FOLFOX和FOLFIRI。正在进行的研究关注新的分子靶向药物（molecular targeted therapy）联合化疗治疗转移性结直肠癌，且部分试验取得了较好的疗效。本文将对5-FU、新一代化疗药物以及分子靶向药物在转移性结肠癌治疗的演进及新进展作一综述。     

Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials

This study evaluates the efficacy of capecitabine using data from a large, well-characterised population of patients with metastatic colorectal cancer (mCRC) treated in two identically designed phase III studies. A total of 1207 patients with previously untreated mCRC were randomised to either oral capecitabine (1250 mg m(-2) twice daily, days 1-14 every 21 days; n=603) or intravenous (i.v.) bolus 5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates (P<0.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885-1.123, P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95, 95% CI 0.84-1.06, P=0.48; median 12.9 vs 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomised trials are evaluating capecitabine in combination with irinotecan, oxaliplatin and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the backbone of colorectal cancer therapy.     

伊立替康联合雷替曲塞或5-FU二线治疗晚期结直肠癌的疗效比较

目的 比较伊立替康联合雷替曲塞方案与伊立替康联合5-FU方案二线治疗晚期结直肠癌的临床疗效。方法 选取经一线化疗失败行二线治疗的60例晚期结直肠癌患者,根据不同二线治疗方案,将其分为观察组和对照组,每组30例。观察组采用伊立替康联合雷替曲塞方案治疗,对照组采用伊立替康联合5-FU方案（FOLFIRI方案）,治疗结束后比较两组患者的近期疗效及不良反应,并观察总生存期（OS）和疾病进展时间（TTP）。结果 观察组和对照组患者的总有效率比较差异无统计学意义（26.67% vs 13.33%,χ²=1.67,P=0.20）;观察组患者疾病控制率高于对照组,差异有统计学意义（63.33% vs 36.67%,χ²=4.27,P=0.04）;观察组中位OS和中位TTP较对照组长,两组比较差异均有统计学意义（9.9个月 vs 7.5个月,χ²=4.461,P=0.012;5.0个月 vs  3.7个月,χ²=6.735,P=0.022）;观察组骨髓抑制、胃肠道不良反应等发生率与对照组比较差异无统计学意义（P＞0.05）。结论 伊立替康联合雷替曲塞二线治疗晚期结直肠癌疗效肯定,较FOLFIRI方案可延长生存期,不良反应更轻,可作为一线化疗失败患者的可选治疗方案。     

FOLFIRI plus bevacizumab as a first-line treatment for Japanese patients with metastatic colorectal cancer: a JACCRO CC-03 multicenter phase II study

Purpose

The purpose of this multicenter phase II study was to evaluate the efficacy and safety of a combination of irinotecan, 5-fluorouracil (5-FU), and leucovorin (FOLFIRI) plus bevacizumab as first-line chemotherapy in Japanese patients with metastatic colorectal cancer.

Methods

Patients with metastatic colorectal cancer were eligible for enrollment. On day 1 of a 14-day cycle, patients received bevacizumab 5 mg/kg, irinotecan 150 mg/m², and l-leucovorin 200 mg/m² as an intravenous infusion, followed by 5-FU 400 mg/m² as an intravenous bolus and then 5-FU 2,400 mg/m² as an 46-h intravenous infusion. This treatment cycle was repeated. The primary endpoint was progression-free survival (PFS).

Results

We enrolled 40 patients, but one withdrew consent before starting treatment. The remaining 39 patients received a total of 509 cycles of FOLFIRI plus bevacizumab (median 11 per patient; range 1–30). The median PFS was 11.5 months, the median overall survival (OS) was 22.0 months, and the 1-year OS rate was 81.8 %. All 39 patients had adverse events. Grade 3 or 4 neutropenia and stomatitis occurred in 21 (53.9 %) and 4 (10.3 %) patients, respectively.

Conclusion

Our results suggest that FOLFIRI plus bevacizumab is a clinically effective regimen with a manageable toxicity profile as first-line chemotherapy in patients with metastatic colorectal cancer.     

Cost-effectiveness of second-line treatment with irinotecan or infusional 5-fluorouracil in metastatic colorectal cancer

Background:It has been shown that irinotecan is superior toinfusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancerafter 5-FU failure. In a recent trial, median survival was 10.8 months forpatients treated with irinotecan, compared to 8.5 months in patients receivinginfusional 5-FU. Considering the statistically significant but clinicallyrelatively small advantage of irinotecan over 5-FU, cost effectiveness shouldalso be part of treatment decision. Purpose:To relate the costs of each management approach tooverall survival in patients with metastatic colorectal cancer. Patients and methods:The healthcare costs and medical benefits(treatment-added survival) of second-line chemotherapy in patients (infusional5-FU: 129, irinotecan: 127) were compared. Data on overall survival were drawnfrom a multicenter randomised trial that compared infusional 5-FU (continuousinfusion, AIO, or LV5-FU2 regimens) to irinotecan alone. Costs were derivedfrom the accounting system in two university hospitals in Paris, France. Results:The range in total healthcare costs was 14,135 to 12,192US$ patient between management approaches, with irinotecan chemotherapycosting most and 5-FU-continuous infusion least. If survival was included asa treatment benefit, the cost-effectiveness ratio of irinotecan over 5-FUranged from 9,344 to 10,137 US$ per year of added survival. Conclusions:The least expensive management for metastaticcolorectal was 5-FU infusion but the additional cost of irinotecan wasbalanced by the added months of survival, with a cost-effectiveness ratioclose to that of other cancer treatments.     

Diagnosis and Treatment of Chronic Prostatitis Caused by Chlamydia trachomatis

Abstract

To investigate the therapeutic value and safety of the biweekly regimen of 5-fluorouracil (5-FU) and leucovorin (LV) plus irinotecan (CPT-11) in patients with previously untreated advanced gastric cancer (AGC). A total of 50 patients (M/F 35/15; median age = 65) with AGC, none of whom had received chemotherapy for advanced disease, were accrued in this trial. Fifteen patients (30%) were 70 years old or older. At the time of their accrual, cytotoxic chemotherapy, consisting of LV 100 mg/m² (2-hour i.v. infusion) followed by 5-FU 400 mg/m² (bolus) and 5-FU 600 mg/m² (22-hour continuous infusion) on therapeutic days 1 and 2 plus CPT-11 180 mg/m² (1-hour infusion) on day 1, was initiated. Treatment courses were repeated every 2 weeks until evidence of progressive disease, unacceptable toxicity or withdrawal of consent. All patients were assessable for toxicity and 48 of 50 for response evaluation, having completed at least four courses of chemotherapy. Complete response was achieved in 2 patients (4%, intent to treat) and partial response in 16 (32%) (overall response rate, 36%; 95% confidence interval [CI]: 22%-50%). Twenty-four patients (48%) had stable disease and 6 patients (16%) progressed. The median time to progression was 8 months (95% CI: 6-10 months) and median overall survival 14 months (95% CI: 6-22 months). Between the subgroups of patients <70 years old and 70 or older, there were no significant differences in efficacy. One toxic death occurred. Treatment tolerance was generally mild to moderate and easy to treat. The main grade 3/4 toxicities were neutropenia (32%), diarrhea (16%), and anemia (8%). Grade 3-4 neutropenia was the only treatment-related serious adverse event significantly more common in patients older than those aged ≤70 (53.3% vs 22.8%, respectively; P = 0.03). Our data suggest that the biweekly regimen of LV and 5-FU plus CPT-11 in untreated patients with AGC is active and has an acceptable safety profile. Further evaluation of this regimen seems to be warranted in a phase III trial.     

Medium-term results of neoadjuvant systemic chemotherapy using irinotecan, 5-fluorouracil,and leucovorin in patients with locally advanced rectal cancer

Aims

The aim of this study was to evaluate the usefulness of neoadjuvant systemic chemotherapy using irinotecan, 5-FU, and leucovorin (LV) for the treatment of locally advanced rectal cancer, which was a powerful ploychemotherapy in those days in Japan.

Methods

Between 2001 and 2004, 26 patients with T3 or T4 and N0-2 non-metastatic resectable rectal cancer were selectively enrolled in this study. Neoadjuvant chemotherapy consisted of two cycles of irinotecan (80 mg/m²), 5-FU (500 mg/m²), and LV (250 mg/m²) on days 1, 8, and 15 for 4 weeks. Surgical resection was performed in all the patients 2–4 weeks after the completion of chemotherapy.

Results

Overall down-staging was observed in 15 patients. T level and N level down-staging were observed in 12 and 13 patients, respectively. A pathological complete response was observed in one patients. The median follow-up period was 75 months (range, 8–97 months). Recurrences occurred in 5 patients including pelvic relapses in 3 and distant metastases in 2. The 5-year relapse-free and overall survival rates were 74% and 84%, respectively.

Conclusions

Neoadjuvant systemic chemotherapy comprised of a combination of multi-drugs as irinotecan, 5-FU, and LV may be beneficial to the prognoses of patients with locally advanced rectal cancer.