Second-line treatment with oxaliplatin + raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin-based chemotherapy

Background:To evaluate the efficacy and tolerance of combined raltitrexed and oxaliplatin in patients with advanced colorectal cancer pretreated with fluoropyrimidine–leucovorin-based chemotherapy. Patients and methods:Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within six months after withholding palliative chemotherapy with fluoropyrimidines–leucovorin ± irinotecan, participated in this study. Treatment consisted of oxaliplatin 130 mg/m² and raltitrexed 3.0 mg/m² both given on day 1 every three weeks for a total of eight courses unless prior evidence of progressive disease. Results:The overall objective response rate was 33.3% for all 36 evaluable patients (95% confidence interval (CI): 18.6%–51%). Seventeen additional patients (47.2%) had stable disease, and only seven (19.5%) progressed. The median progression-free survival was 6.5 months (range 1.2–14.0). After a median follow-up time of 12 months, 23 patients (63.8%) are still alive. The tolerance of treatment was acceptable with only 8 of 36 patients (22%) experiencing grade 3 or 4 neutropenia. Grade 3 non-haematological adverse reactions included peripheral sensory neuropathy in three, asthenia in one, diarrhea in two, and clinically insignificant increase in serum transaminases in two patients, respectively. Conclusions:Our data suggest that the combination of oxaliplatin and raltitrexed has substantial antitumour activity in patients with progressive fluoropyrimidine–leucovorin ± irinotecan pretreated colorectal cancer. Because of its favorable toxicity profile and convenient three-weekly outpatient administration schedule, further evaluation of this regimen seems warranted.     

Bimonthly high-dose leucovorin, 5-fluorouracil infusion and oxaliplatin (FOLFOX3) for metastatic colorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen

Background: FOLFOX2, a bimonthly regimen of high-dose leucovorin (LV), 48-hour continuous infusion of 5-fluorouracil (5-FU) (LV–5-FU) and oxaliplatin (100 mg/m2) produced a high response rate (46%; 95% confidence interval (95% CI): 31%–60%) in 5-FU pre-treated patients with metastatic colorectal cancer. In this phase II study, pre-treated patients were given a lower dose of oxaliplatin to reduce the toxic effects of the regimen.Patients and methods: Thirty patients with advanced colorectal adenocarcinoma and progression while receiving bimonthly LV–5-FU (LV: 500 mg/m2, 5-FU: 1.5–2 g /m2/ 22 hours, days 1–2, every two weeks), were given the same LV–5-FU schedule with the addition of oxaliplatin (85 mg/m2) every two weeks (FOLFOX3).Results: The main toxic effects were peripheral neuropathy (90%) with four severe sensitive neuropathies (WHO grade 2: 13%). The response rate was 20% (95% CI: 8%–39%). Median progression-free survival was 26 weeks, median survival was 57 weeks from the start of FOLFOX3 and median duration of the response was 37 weeks.Conclusions: Results obtained with FOLFOX3 confirmed the synergy between oxaliplatin and 5-FU in 5-FU-resistant metastatic colorectal cancer. However, the response rate seems to be lower than that obtained with FOLFOX2. Further studies to determine the best oxaliplatin dose intensity are in progress.     

Biweekly oxaliplatin combined with oral capecitabine (OXXEL regimen) as first-line treatment of metastatic colorectal cancer patients: a Southern Italy Cooperative Oncology Group phase II study

Oxaliplatin 100 mg/m² iv on day 1, and capecitabine 1,000 mg/m² orally bid from day 1 (evening) to day 11 (morning) were administered every 2 weeks (OXXEL regimen) to 38 patients as first-line treatment for metastatic colorectal carcinoma. A total of 318 cycles were administered, with a median of 8 (range, 4–12) cycles per patient. Response rate (RR) was 45% (95% confidence interval (CI), 29%–62%), with 7 complete responses and 10 partial responses; furthermore, 12 patients showed a stable disease, so that a disease control was achieved in 29 (76%) patients. RR was greater among patients with performance status 0 (52%), without weight loss (52%), younger than 65 years (50%), and previously unexposed to adjuvant chemotherapy (48%), while no correlation was found with the actually delivered oxaliplatin dose intensity. Overall, haematological side effects were negligible, with no case of grade 4 toxicity, and only one patient suffering from an episode of grade 3 neutropenic fever. Severe anaemia occurred in 4 (11%) patients, and grade 3 neuropathy affected 9 (24%) patients. Median progression-free survival was 7.9 (95% CI, 6.2–9.6) months, and median overall survival has not been reached yet. In conclusion, the OXXEL regimen resulted safe and active, and it deserves further evaluation in metastatic colorectal cancer patients.     

Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer.

PURPOSE: This Nordic multicenter phase II study evaluated the efficacy and safety of oxaliplatin combined with the Nordic bolus schedule of fluorouracil (FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer. PATIENTS AND METHODS: Eighty-five patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1, followed by a 3-minute bolus injection with FU 500 mg/m(2) and, 30 minutes later, by a bolus injection with FA 60 mg/m(2) every second week. The same doses of FU and FA were also given on day 2. RESULTS: Fifty-one of 82 assessable patients achieved a complete (n = 4) or partial (n = 47) response, leading to a response rate of 62% (95% CI, 52% to 72%). Nineteen patients showed stable disease, and 12 patients had progressive disease. Thirty-eight of the 51 responses were radiologically confirmed 8 weeks later (confirmed response rate, 46%; 95% CI, 36% to 58%). The estimated median time to progression was 7.0 months (95% CI, 6.3 to 7.7 months), and the median overall survival was 16.1 months (95% CI, 12.7 to 19.6 months) in the intent-to-treat population. Neutropenia was the main adverse event, with grade 3 to 4 toxicity in 58% of patients. Febrile neutropenia developed in seven patients. Nonhematologic toxicity consisted mainly of neuropathy (grade 3 in 11 patients and grade 2 in another 27 patients). CONCLUSION: Oxaliplatin combined with the bolus Nordic schedule of FU+FA (Nordic FLOX) is a well-tolerated, effective, and feasible bolus schedule as first-line treatment of metastatic colorectal cancer that yields comparable results compared with more complex schedules.     

Second-Line Treatment of Advanced Colorectal Cancer with a Biweekly Oxaliplatin plus Irinotecan Combination Regimen

BACKGROUND: Both oxaliplatin and irinotecan have demonstrated antitumor activity in pretreated colorectal cancer; experimental and early clinical data suggest that these two drugs may act synergistically. The aim of this study was to document the therapeutic index of a biweekly combination regimen in patients with metastatic colorectal cancer failing prior palliative first-line chemotherapy with raltitrexed. PATIENTS AND METHODS: In this study 27 patients with metastatic colorectal cancer were analyzed, who progressed while on or within 6 months after discontinuation of palliative first-line chemotherapy with raltitrexed. They received oxaliplatin 85 mg/m(2) and irinotecan 150 mg/m(2) both given on days 1 and 15 every 4 weeks. RESULTS: The confirmed overall response rate was 37% (95% confidence interval, 19.4-57.7%), including 2 complete and 8 partial remissions. 12 additional patients (44.4%) had stable disease, and in only 5 cases (18.5%) disease progression was not influenced by chemotherapy. The median progression-free survival for all 27 patients was 8 months (range, 1-16+ months), and 16 patients (59%) are still alive after a median follow-up time of 12.5 months. Hematologic adverse reactions, specifically leukocytopenia and neutropenia, were common though generally mild to moderate with grade 4 toxicity occurring in only 2 cases. The most frequent non-hematologic adverse events included gastrointestinal symptoms; severe nausea/emesis and diarrhea, however, were noted in only 2 and 3 patients, respectively. CONCLUSIONS: Our data suggest that the described biweekly combination regimen of oxaliplatin and irinotecan has substantial antitumor activity in patients with progressive, raltitrexed-pretreated metastatic colorectal cancer. Because of its favorable toxicity profile, further evaluation of this combination seems warranted.     

Phase II study with oxaliplatin and S-1 for patients with metastatic colorectal cancer

BackgroundTo evaluate the efficacy and safety of the combination of oxaliplatin and S-1 (OS) in treating metastatic colorectal cancer.Patients and methodsEligible patients were those with measurable lesions, no previous history of chemotherapy (except adjuvant chemotherapy), an age of 18–70 years, and an Eastern Cooperative Oncology Group performance status of zero to two. Oxaliplatin 130 mg/m² was administered i.v. on day 1, and S-1 40 mg/m² b.i.d. was administered orally on days 1–14, every 3 weeks.ResultsForty-eight patients (median age, 56 years) were enrolled: 23 had colon cancer, seven rectosigmoid colon cancer; and 18 rectal cancer. Of the 48 patients, 31 were diagnosed with metastatic cancer and 17 had relapsed cancer after surgery, with adjuvant chemotherapy or chemoradiotherapy. In total, 413 cycles were administered (median 6 per patient; range 2–24). Toxicity was evaluated in 48 patient and response in 46. Major toxic effects were grade 3/4 thrombocytopenia (13%) and neutropenia (10%). The overall response rate was 54% [95% confidence interval (CI) 40% to 68%]. The median time to progression and median survival time were 8.5 (95% CI 6.2–10.9) months and 27.2 (95% CI 20.3–34.0) months, respectively.ConclusionsThese data indicate that the OS regimen is effective and well tolerated in patients with advanced colorectal cancer.     

Single-agent oxaliplatin in pretreated advanced breast cancer patients: A?phase II study

Purpose:Oxaliplatin (L-OHP), a new platinum analogue, is anactive drug in colorectal and ovarian cancer. In this phase II study weexplored tolerability and activity of oxaliplatin as a single agent inmetastatic breast carcinoma patients. Patients and methods:Fourteen anthracycline pretreated advancedbreast cancer patients were enrolled. Oxaliplatin was given at 130mg/m² on day 1 and repeated every three weeks. Analysis oftoxicity, response rate and survival was performed. Results:The median number of courses per patient was four (range2–6). The median administered dose-intensity was 43.3mg/m²/week (range 32.5–43.3) which represents 100% ofprojected dose-intensity. No severe toxicity was encountered. Three patientsdeveloped acute transient laryngeal symptoms. Three patients displayed apartial response (21%), (95% confidence interval (CI):0%–43%), two stable disease (14%) and nineprogressed (64%). Response lasted five, four and five monthsrespectively. Median survival was 12 months. Conclusions:In this limited experience, oxaliplatin appeared tobe well tolerated and moderately active in advanced anthracycline-pretreatedbreast cancer patients. Combination chemotherapy with other active drugs suchas 5-fluorouracil (5-FU), anthracyclines and taxanes should represent the nextstep of development of this new drug.     

晚期大肠癌患者外周血ERCC1基因多态性与奥沙利铂化疗疗效相关性的研究

目的：研究ERCC1 Asn118Asn（C→T，rs11615）多态性与中国汉族晚期大肠癌患者对奥沙利铂（Oxaliplatin）一线化疗效果的关系。方法：99例晚期大肠癌患者化疗前取静脉血并提取DNA，以实时荧光定量PCR法对ERCC1 Asn118Asn进行SNP分型。患者接受奥沙利铂化疗，观察至疾病进展时间（1TrP）及疾病控制率（DCR），比较不同基因型与化疗效果的关系。结果：ERCC1 Asn118Asn基因位点在本研究人群中的突变频率C／C为50．51％，C／T为41．41％，T／T为8．08％。其中62例Ⅳ期大肠癌患者疾病控制率为54．84％，C／C与C／T＋T／T基因型在疾病控制组（CR＋PR＋SD）和未控组（PD）之间分布差异有统计学意义（OR：3．764，95％CI：1．310～10．813）。37例Ⅲ期大肠癌患者中位DFS为7个月（95％CI：5．483～9．653），C／C型患者中位DFS为10个月（95％CI：8．215～11．642），而C／T＋T／T型患者为5个月（95％CI：4．663～7．267），两者差异显著（Log—rank X^2=12．864，OR=2．237，P〈0．01）。结论：ERCC1 Asn118Asn基因多态性与中国汉族晚期大肠癌患者接受奥沙利铂一线化疗后的临床效果有关。     

Protracted infusional 5-fluorouracil (5-FU) with bolus mitomycin in 5-FU-resistant colorectal cancer

Background:MF (protracted infusion 5-fluorouracil (5-FU), 300mg/m²/24 hours plus bolus mitomycin, 7 mg/m² every 6weeks, maximum 4 doses), was recently shown in a randomised trial to besuperior to protracted 5-FU alone, as first-line chemotherapy for metastaticcolorectal cancer (Ross et al. Ann Oncol 1997; 8: 995–1001 [5]). We haveexamined the same regimen in patients with 5-FU-resistant disease. Patients and methods:MF was given to 24 patients with metastaticcolorectal cancer, median age 63 years. Two had progressed within four monthsof adjuvant 5-FU; the rest had already received palliative 5-FU, withprogression during (11 patients), within four months (5 patients) or afterfour months of completion (6 patients). The prior 5-FU regimens were bolus5-FU/FA (8 patients); 48 hour bolus + infusion 5-FU/FA (18 patients) orprotracted 5-FU alone (3 patients). Five patients had received more than oneprior 5-FU regimen. Results:Three patients, 12.5%, achieved WHO partialresponse; seven others had minor response or stable disease (SD or better =42%, 95% confidence interval (95% CI):22%–64%). Median failure-free survival (FFS) was 15 weeks;median overall survival was 9.0 months. No grade 3 or 4 drug toxicityoccurred, but dose reduction and/or interruption for persistent grade 2toxicity was required in eight patients (33%). Three patients(12.5%) had venous line problems (2 thrombosis; 1 dislodged). Therewere no toxic deaths. 12 patients (50%) went on to receive third-linetherapy after MF, including irinotecan or oxaliplatin. Conclusions:MF is a low-cost, well-tolerated regimen insecond-line treatment of metastatic colorectal cancer. The response rate andFFS obtained in this small group are similar to those reported for singleagent irinotecan. Half our patients obtained a useful period of control withMF before moving on to further treatment with new agents such as irinotecanand oxaliplatin.     

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。     

The combination of capecitabine and irinotecan in treating 5-Fluorouracil- and Oxaliplatin-pretreated metastatic colorectal cancer

Purpose Since the combination of capecitabine and irinotecan has successfully been used as a first-line treatment in metastatic colorectal cancer (MCRC), we expected promising results when given as a second-line treatment to metastatic colorectal patients who had been pretreated with 5-Fluorouracil and Oxaliplatin. Methods Thirty-three MCRC patients participated in this study and received an oral dose of 1,000 mg/m² capecitabine twice daily on days 1–14 and a dose of 100 mg/m² irinotecan infused over 90 min on days 1 and 8, every 3 weeks. Results The overall response rate in intent-to-treat was 33.3% (95% CI, 21.5–58.3%), including one complete response (3.0%) and ten partial responses (30.3%); 12 patients (36.4%) had disease stabilization and only 9 (27.3%) progressed. The median time to progression was 6.7 months (95% CI, 4.8–8.6 months). After a median follow-up time of 12 months, nine patients (27.3%) were still alive with metastatic disease. The median response duration for all patients was 6.7 months (95% CI, 3.9–9.5 months) and the median overall survival was 13.4 months (95% CI, 11.0–15.8 months) with a 1-year survival rate of 55.4%. Myelosuppression was commonly observed; NCI-CTC (v 2.0) grade 3/4 neutropenia, however, occurred in eight (24%) patients and grade 3 anemia was seen in one patient (3%). The most common (grade 3/4) non-hematological toxicity was diarrhea (15%) and the other severe grade 3/4 toxicities included nausea/vomiting in one patient (3%), stomatitis in one patient (3%), hand-foot syndrome in one patient (3%). Conclusions The combination of capecitabine and irinotecan is an effective and well-tolerated regimen for second-line treatment of metastatic colorectal cancer. However, further phase III trials are required to clarify its use in the treatment of metastastic colorectal cancer patients who have been pretreated with 5-fluorouracil and oxaliplatin.     

Raltitrexed plus oxaliplatin (TOMOX) as first-line chemotherapy for metastatic colorectal cancer. A phase II study of the Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD).

BACKGROUND: To evaluate the safety and efficacy of the novel raltitrexed/oxaliplatin combination (TOMOX) as first-line chemotherapy for patients with advanced colorectal cancer. MATERIALS AND METHODS: Previously untreated patients with metastatic colorectal cancer received raltitrexed 3 mg/m2 plus oxaliplatin 100 mg/m2, both intravenously, on day 1 every 3 weeks. Patients were re-evaluated after every third cycle and chemotherapy was continued up to tolerance or disease progression. RESULTS: Fifty-eight patients from 13 Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD) centers were accrued from September 1999 to November 2000. According to the intention-to-treat analysis from 58 patients, the overall response rate was 50% [95% confidence interval (CI) 38% to 62%], with three complete responses and 26 partial responses. The median overall survival (44 patients currently alive) was >9 months and the median time to disease progression was 6.5 months (range 1-15 months). The main hematological toxicity was grade III/IV neutropenia, which occurred in 17% of patients, while anemia and thrombocytopenia were uncommon. Grade III/IV non-hematological toxicities were transient transaminitis (17% of patients); asthenia (16% of patients); neurotoxicity (10% of patients) and diarrhea (7% of patients). No toxic death was observed, one patient with grade IV asthenia after the first cycle refused chemotherapy. CONCLUSIONS: The results of this study suggest that the TOMOX combination is an effective and well tolerated regimen for the treatment of advanced colorectal cancer. Its ease of administration and patient tolerance warrant further investigation as an alternative to fluoropyrimidine-based regimens with repeated and prolonged fluorouracil infusions.     

XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer.

PURPOSE: Capecitabine has demonstrated high efficacy as first-line treatment for metastatic colorectal cancer (MCRC). Oxaliplatin shows synergy with fluorouracil (FU), with little toxicity overlap. The XELOX regimen (capecitabine plus oxaliplatin), established in a previous dose-finding study, should improve on infused oxaliplatin with FU and leucovorin (FOLFOX) regimens. The present studies further characterize efficacy and safety of the XELOX regimen. PATIENTS AND METHODS: The antitumor activity of XELOX was investigated in a colon cancer xenograft model. Patients with MCRC received first-line XELOX in 3-week treatment cycles: intravenous oxaliplatin 130 mg/m(2) (day 1) followed by oral capecitabine 1,000 mg/m(2) twice daily (day 1, evening, to day 15, morning). RESULTS: A preclinical study confirmed that capecitabine has supra-additive activity with oxaliplatin. In the clinical study, 53 of 96 patients (55%) achieved an objective response, and 30 (31%) experienced disease stabilization for >/= 3 months following treatment. After 24 months' minimum follow-up, median time to disease progression (TTP) and median overall survival were 7.7 and 19.5 months, respectively. XELOX safety was predictable and similar to the FOLFOX4 regimen, except that myelosuppression was uncommon with XELOX (grade 3 or 4 neutropenia, 7%). Most adverse events were mild to moderate, the most common being acute sensory neuropathy (85%). Sixty-day, all-cause mortality was 2%. CONCLUSION: XELOX is a highly effective first-line treatment for MCRC. Response rates, TTP, and overall survival are similar to those observed with FU/leucovorin/oxaliplatin combinations. XELOX provides a more convenient regimen, likely to be preferred by both patients and healthcare providers. Capecitabine has the potential to replace FU/LV in combination with oxaliplatin for MCRC.     

Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery

Context: Long-term survival of patients with metastatic colorectal cancer has been achieved only in patients who underwent complete resection of metastases. Such surgery could be performed in a greater proportion of patients if effective chemotherapy could downstage previously unresectable metastases. This approach has been limited by the low tumor response rate achieved with conventional chemotherapy.Objective: We studied the outcome of patients with initially unresectable liver metastases from colorectal cancer treated with a three-drug chemotherapy regimen followed by liver metastases surgery whenever possible.Patients and methods: From March 1988 to June 1994, 151 patients with colorectal liver metastases were considered initially unresectable because of large tumor size (>5 cm), multinodular (>4) or ill-located metastases. All patients received fully ambulatory chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronotherapy in 83% of them). They were periodically reassessed for surgery by a joint medico-surgical team.Results: In 151 patients, the size of liver metastases decreased by >50% in 89 patients (59%) and median overall survival was 24 months (95% confidence interval (95% CI): 19–28 months), with 28% surviving at five years (20%–35%). Surgery with curative intent was attempted in 77 patients (51%), complete resection of liver metastases was achieved in 58 patients (38%). The median survival of the 77 operated patients was 48 months (25–71), with a five-year survival rate of 50% (38–61).Conclusion: This new strategy of combining effective chemotherapy with surgery apparently altered the natural history of unresectable colorectal cancer metastases.     

Docetaxel plus vinorelbine as salvage chemotherapy in advanced breast cancer: a phase II study

Précis Administration of a combined regimen of docetaxel plus vinorelbine every 4 weeks is feasible and shows activity in heavily pretreated patients with advanced breast cancer. Purpose. To determine the activity and tolerance of docetaxel plus vinorelbine in heavily pretreated patients with advanced breast cancer. Methods. Thirty-five metastatic breast cancer patients with ECOG performance status of 0–2 received docetaxel (80 mg/m² given intravenously) on day 1 and vinorelbine (30 mg/m² given intravenously) on days 1 and 14, every 4 weeks. The median number of prior chemotherapy regimens was 2 (range: 1–4). Twenty-five patients (71.4%) had been treated previously using intensive therapy approaches with peripheral blood-derived stem cell (PBSC) support, including high-dose chemotherapy (11 patients), multicyclic dose-intensive chemotherapy supported with repeated PBSC infusions (seven patients), or both (seven patients). Twenty-eight patients (80%) received previous chemotherapy for metastatic disease. Adjuvant therapy in the remaining seven patients consisted of high-dose chemotherapy and PBSC support or an anthracycline-containing regimen. Results. The total number of courses was 229, and the median number of courses per patient was 6 (range: 1–16). There was one toxic death (2.8%). Grade 3–4 toxicities included mucositis (17.1%), neutropenia (37.1%), anemia (5.7%), vomiting (2.9%), and asthenia (14.3%). Eighteen patients (58%; 95% CI: 40.6–75.4%) achieved an objective response, including four complete responses (12.9%) and 14 partial responses (45.1%). Overall response rate was 51.4% (95% CI: 34.8–67.9%). After a median follow-up of 20 months (range: 2–42), overall survival was 20 months (95% CI: 16–24), and median time to progression was 13 months (95% CI: 7–19). Conclusion. This combination shows activity and an acceptable toxicity profile in patients with advanced breast cancer.     

Second-line chemotherapy with weekly oxaliplatin and high-dose 5-fluorouracil with folinic acid in metastatic colorectal carcinoma: A Hellenic Cooperative Oncology Group (HeCOG) phase II feasibility study

Backround:Oxaliplatin is a novel platinum derivative, which,combined with 5-fluorouracil (5-FU), and folinic acid (FA), demonstratessynergistic activity in metastatic colorectal cancer (MCC). The HeCOGperformed a multicenter phase II study of a weekly oxaliplatin administrationschedule in patients with previously treated MCC to evaluate the antitumorefficacy and toxicity of this combination. Patients and methods:Eligible patients included those whorelapsed after or during chemotherapy with 5-FU and FA and/or irinotecan.Prior radiotherapy was accepted provided that measurable disease was outsidethe radiation fields. Other eligibility criteria included written informedconsent, a WHO performance status 2 and adequate bone marrow, liver andrenal function. Treatment consisted of Oxaliplatin 50 mg/m² bytwo-hour intravenous (i.v.) infusion followed by FA 500 mg/m²(two-hour i.v. infusion) and 5-FU 2500 mg/m² (24-hour continuousi.v. infusion) on days 1, 8, 15, 22, 29, 36. The regimen was repeated every50 days. Results:Thirty-two patients (Median age 61 years, range25–76) entered the trial. The majority (75%) had progressed afterreceiving first-line chemotherapy.Diarrhea was the main non-hematologic toxicity. More than half of thepatients (53%) developed grades 3 or 4 diarrhea. Due to this sideeffect only 29% of cycles were given with at least 90% of theplanned dose of 5-FU. Hematologic toxicity included grade 3 neutropenia andthrombocytopenia (10% for each), and grade 4 thrombocytopenia(3%). Two patients (6%) died of sepsis, one related toneutropenia and one due to urinary tract sepsis. Sixteen patients (50%)developed grades 1 and 2 neurotoxicity in the form of sensory neuropathy,which was mild and transient. The objective response rate was 13%(95% CI: 3%–29%). All four responses were partial.Twelve patients (38%) had stable disease and 8 (25%) progressivedisease. The median time to progression was three months and the mediansurvival was nine months from the start of therapy. The Kaplan–Meierestimated probability of one-year survival for the group as a whole was32%. Conclusions:The weekly administration of oxaliplatin with 5-FUand FA was associated with considerably less neurotoxicity than otherschedules. However, the high percentage of diarrhea suggests that a dosereduction of 5-FU in this regimen may result in better therapeutic synergy.     

Oxaliplatin as first-line treatment in inoperable biliary tract carcinoma: a multicenter phase II study

BACKGROUND: A multicenter phase II study was conducted in order to evaluate the efficacy and safety of oxaliplatin as first-line treatment of patients with locally advanced or metastatic carcinoma of the biliary tract. PATIENTS AND METHODS: Twenty-nine chemo-na?ve patients with locally advanced or metastatic biliary tract carcinoma received oxaliplatin 130 mg/m(2) i.v. every 21 days. Patients were treated until tumor progression or unacceptable toxicity. RESULTS: An objective response (3 complete responses, 3 partial responses) was achieved in 6 patients (20.6%, 95% CI 5.95-35.4). Disease control (complete response, partial response and stable disease) was observed in 14 patients (48.2%). The median time to tumor progression was 3 months (range 0.7-39) and the median overall survival was 7 months (range 1-39). The 1-year survival rate was 32%. Toxicity was mild. CONCLUSION: Oxaliplatin is an active agent against biliary tract carcinoma and therefore should be further investigated in combination with other cytotoxic drugs.     

ERCC1 Asn118Asn polymorphism as predictor for cancer response to oxaliplatin-based chemotherapy in patients with advanced colorectal cancer

Objective: To assess whether the polymorphism of ERCC1 Asn118Asn (C→T) had effects on cancer response to chemotherapy and outcome in Chinese patients treated with oxaliplatin as first-line chemotherapy regimen for advanced colorectal cancer.Methods: ERCC1 Asn118Asn polymorphism was analyzed in 99 patients with stages Ⅲ and Ⅳ advanced colorectal cancer treated with oxaliplatin-based chemotherapy.For all of the patients, ERCC1 Asn118Asn genotype was analyzed for associations with treatment response and time to disease progress (TTP).Results: The allele frequencies of the ERCC1 gene codon 118 were C/C 50.51% (50/99), C/T 41.41% (41/99), T/T 8.08% (8/99), respectively.Patients with C/C genotype showed higher response rate than those with C/T T/T (OR = 3.764, 95% CI: 1.310-10.813).The median TTP of all patients was 7 months (95% CI: 5.569-8.431).Patients with C/C genotype showed a median TTP of 10 months (95% CI:8.924-11.076), which was longer than 5 months (95% CI: 4.424-5.576) in patients with C/T T/T genotypes.Conclusion:Our results showed a link between ERCC1 Asn118Asn genetic polymorphism and cancer response to oxaliplatin-based chemotherapy and time to disease progress in Chinese patients with advanced colorectal cancer.ERCC1 Asn118Asn genotyping may be of predictive benefit in selecting treatment regimen for advanced colorectal cancer.     

奥沙利铂辅助化疗失败后一线再引入治疗晚期结直肠癌的研究

  目的  奥沙利铂辅助化疗后疾病进展的晚期结直肠癌患者优先推荐含伊立替康的方案, 然而部分患者因费用或禁忌症不能接受伊立替康的治疗。本回顾性研究探讨奥沙利铂辅助化疗失败后一线再引入治疗的疗效和安全性。  方法  奥沙利铂辅助化疗结束6个月后疾病进展一线治疗再引入的27例晚期结直肠癌患者纳入研究, 化疗方案包括mFOLFOX6和CapeOX。  结果  27例均可评价疗效, 完全缓解1例, 部分缓解7例, 稳定7例, 总有效率29.6%, 疾病控制率55.5%, 中位疾病进展时间和中位总生存分别为7.26个月(95%CI, 6.34~13.43个月)和19.1个月(95%CI, 19.3~33.1个月)。Ⅲ~Ⅳ度不良反应包括Ⅲ度粒细胞下降2例、Ⅲ度贫血1例、Ⅲ度和Ⅴ度血小板下降各1例、Ⅲ度呕吐1例、Ⅲ度口腔粘膜炎1例、Ⅲ度神经毒性2例。  结论  对于奥沙利铂辅助化疗失败后不能接受伊立替康治疗的晚期结直肠癌患者, 奥沙利铂再引入可以给患者带来生存获益, 安全可行。      

奥沙利铂一线治疗后再引入与雷替曲塞联合二线治疗晚期结直肠癌的临床观察*

目的:评估奥沙利铂一线用于治疗晚期结直肠癌后与雷替曲塞联合再引入二线治疗的疗效及安全性。方法:收集2010年5 月至2014年12月广西中医药大学附属瑞康医院收治的48例晚期结直肠癌患者,根据一线应用奥沙利铂的情况分为两组:A 组（一线使用不含奥沙利铂方案）20例;B 组（一线使用含奥沙利铂方案）28例。二线治疗方案:雷替曲塞3 mg/m2,静脉滴注,d1;奥沙利铂100～130 mg/m2,静脉滴注,d1;每21天1 次。结果:48例均可评价疗效,两组有效率分别为30.0%（6/ 20）、32.1%（9/ 28）;疾病控制率分别为80.0%（16/ 20）、75.0%（21/ 28）;中位无进展生存期分别为6.5 个月、7.0 个月;中位总生存期分别为10个月、13个月;两组有效率、疾病控制率、中位无进展生存期及中位总生存期比较差异均无统计学意义（P = 0.264,0.514,0.713,0.788）。 主要不良反应为骨髓抑制、转氨酶异常和胃肠道反应,以Ⅰ～Ⅱ级为主;两组感觉神经异常Ⅰ～Ⅱ级发生率相近。结论:奥沙利铂再引入联合雷替曲塞二线化疗对曾使用过奥沙利铂一线化疗的患者仍然有效,无耐药性,安全可行,对不能接受伊立替康二线治疗的晚期结直肠癌患者是较好选择。