Bevacizumab: new drug. Metastatic colorectal cancer: good in theory, not in practice

(1) The prognosis for metastatic colorectal cancer is grim. The best treatment results are obtained by adding irinotecan to first-line fluorouracil + folinic acid therapy and then oxaliplatin to second-line fluorouracil + folinic acid therapy (or the reverse sequence), but median survival time still fails to exceed 2 years. (2) Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), a mediator involved in angiogenesis. Bevacizumab is marketed in Europe for first-line treatment of metastatic colorectal cancer, in combination with fluorouracil + folinic acid (with or without irinotecan). (3) The clinical evaluation includes 3 comparative trials. A double-blind trial involving 813 patients compared the American IFL protocol (irinotecan + fluorouracil + folinic acid) + placebo with the IFL protocol + bevacizumab. Median survival time was shorter with IFL + placebo (15.6 versus 20.3 months), but the results are difficult to extrapolate to the situation in Europe, where the FOLFIRI protocol is used (irinotecan + fluorouracil + folinic acid). This protocol is more effective than the IFL protocol. (4) Another double-blind trial, involving 204 patients, compared another American protocol, fluorouracil + folinic acid + placebo, with fluorouracil + folinic acid + bevacizumab. Median survival time did not differ significantly between the groups (12.9 and 16.6 months). (5) A combined analysis of 3 comparative trials showed an increase in median survival time of 3.3 months (17.9 versus 14.6 months) when bevacizumab was added to a fluorouracil + folinic acid combination. An indirect comparison suggests that this is no better than adding irinotecan. (6) In second-line treatment, preliminary data from a trial of bevacizumab + FOLFOX 4 (oxaliplatin + fluorouracil + folinic acid) fail to show a tangible benefit for bevacizumab. (7) Bevacizumab adjunction to current chemotherapy protocols increased the frequency of some potentially serious reactions, such as cardiovascular disorders (hypertension, arterial thrombosis); tumour haemorrhage; intestinal perforation; wound healing; and haematological disorders (severe leukopenia, etc.). (8) In practice, there is no evidence that bevacizumab is any better than current European chemotherapy protocols for first-line treatment of metastatic colorectal cancer.     

奥沙利铂的安全性评价

奥沙利铂作为第三代铂类抗癌药物，具有特异的细胞毒性。其与5-氟尿嘧啶和亚叶酸联合应用作为一线治疗转移性结肠癌。其抗癌作用明确，具有较顺铂和卡铂疗效好、毒性低等特点，在抗肿瘤治疗上应用比较广泛。奥沙利铂主要不良反应力感觉神经毒性和胃肠道反应等。本文就奥沙利铂临床使用的安全性问题与顺铂、卡铂、伊立替康进行对比评价。     

Adjuvant chemotherapy for localised colon cancer. Fluorouracil + folinic acid for node-positive, non-metastatic disease

The standard treatment for colon cancer is surgical excision. Adjuvant chemotherapy is intended to reduce the risk of relapse, which is responsible for the death of nearly half of all patients treated surgically for localised disease. After surgery for stage III disease (node involvement without metastases), the 5-year survival rate is about 63% with adjuvant chemotherapy combining fluorouracil and folinic acid, versus 51% with placebo, a statistically significant difference. After surgery for stage II disease (tumour spread beyond the intestinal wall but no node involvement), a meta-analysis updated in 2008 showed no impact of adjuvant chemotherapy on the overall survival rate. Fluorouracil + folinic acid administration according to the de Gramont protocol is the standard adjuvant treatment. The addition of regional fluorouracil chemotherapy did not further improve outcome in a trial in 1501 patients with stage II or stage III disease. The fluorouracil precursors, capecitabine and tegafur, provide no advantages in terms of efficacy or tolerability. These oral drugs have not been compared with the de Gramont protocol. A trial comparing raltitrexed versus fluorouracil + folinic acid was stopped because of an excess of deaths in the raltitrexed arm. In two large trials, each including more than 2000 patients, the addition of oxaliplatin to the fluorouracil + folinic acid combination (Folfox 4 protocol) in patients with stage III disease appeared to slightly improve overall survival in patients under 65 years of age, but severe neuropathy, diarrhoea, nausea and vomiting were more frequent. In three trials in a total of more than 3000 patients with stage III disease, the addition of irinotecan did not improve the efficacy of the fluorouracil + folinic acid combination, while serious adverse effects were more frequent. No new drugs intended for the treatment of colon cancer have been introduced since 2006, but better evaluation of existing drugs means that patients with stage III colorectal cancer can now be offered a choice between standard intravenous fluorouracil and oral capecitabine or tegafur. Oxaliplatin adjunction is another option for patients under 65. The adverse effect profile is an important factor in the choice of treatment.     

Successful desensitization protocol for hypersensitivity reactions caused by oxaliplatin

OBJECTIVE: To report the successful desensitization of a patient with a hypersensitivity reaction to oxaliplatin. CASE SUMMARY: A 57-year-old woman with metastatic colon cancer was receiving oxaliplatin, fluorouracil and leucovorin every 2 weeks and showed a partial response to therapy. During the fourth cycle, an anaphylactic reaction with palpitations and rash occurred. The patient was hypotensive with mild pulmonary wheezing. Since oxaliplatin was the probable cause of the hypersensitivity reaction, therapy with this drug was discontinued. Therapy in the patient was continued using cetuximab and irinotecan but this resulted in progression of the cancer. In view of the initial satisfactory response to the oxaliplatin-based regimen, it was decided to attempt desensitization to oxaliplatin using a protocol adapted from carboplatin regimens. The desensitization procedure was successful and the patient subsequently tolerated an additional three cycles using this regimen without further symptoms of hypersensitivity. DISCUSSION: In cases with moderate-to-severe reactions to oxaliplatin, reexposure is not usually considered. However, a need to use first-line therapy when there is recurrence of the cancer has encouraged the development of rapid desensitization procedures which allow patients to be treated with medications to which they have previously shown hypersensitivity reactions. A combination of premedication using intravenous dexamethasone and a desensitization regimen was designed which was used successfully to increase concentrations and flow rates of oxaliplatin. CONCLUSIONS: Hypersensitivity reactions to oxaliplatin are not rare and physicians need to be aware of these. When substitution of another antineoplastic drug is not feasible, oxaliplatin desensitization should be considered even when hypersensitivity reactions to oxaliplatin are severe.     

Chemotherapy of metastatic colorectal cancer: fluorouracil plus folinic acid and irinotecan or oxaliplatin

(1) Following the recent introduction of several new cytotoxic agents, a new look at the role of chemotherapy in metastatic colorectal cancer is needed. (2) In one clinical trial of first-line treatment, fluorouracil + folinic acid infusion, after an initial bolus (LV-5FU2 protocol), was more effective and better tolerated than bolus administration alone (Mayo Clinic protocol). (3) Five comparative trials failed to show that raltitrexed was more effective than fluorouracil + folinic acid in first-line treatment, and it has more serious adverse effects. (4) There are no comparative trials of capecitabine or tegafur + uracil versus fluorouracil + folinic acid (LV-5FU2 protocol) in first-line treatment. (5) In three comparative randomised trials involving previously untreated patients, adjunction of oxaliplatin to the fluorouracil + folinic acid combination (FOLFOX protocol) increased both tumour response rate and progression-free survival (by about 2 months), but it also caused more neuropathies, severe diarrhea and severe neutropenia. (6) In two comparative trials of first-line treatment, adjunction of irinotecan to fluorouracil + folinic acid (FOLFIRI protocol) increased the median survival time by about 3 months, to 15-17 months, but increased the incidence of diarrhea, neutropenia, serious cardiovascular disorders and severe thrombosis. (7) In second-line treatment, irinotecan is the only properly assessed drug with a positive impact, prolonging survival compared with appropriate palliative care (34 months after diagnosis, versus 27 months). (8) In one comparative trial, first-line treatment with the FOLFOX protocol, followed by the FOLFIRI protocol, resulted in the same median survival time (21 months) as the reverse sequence. (9) In practice, the first-line treatment for metastatic colorectal cancer appears to be the fluorouracil + folinic acid combination (LV-5FU2 protocol) plus either oxaliplatin (FOLFOX protocol) or irinotecan (FOLFIRI protocol). The reference second-line treatment is the FOLFIRI protocol (or the FOLFOX protocol if the FOLFIRI protocol has already been used). These treatments were associated with the longest survival in one trial.     

Oxaliplatin: in operable colorectal cancer

Oxaliplatin is available in numerous countries for the treatment of metastatic colorectal cancer (in conjunction with fluoropyrimidine therapy). The activity of oxaliplatin in advanced disease has led to investigation of its potential in operable disease. The addition of oxaliplatin to adjuvant therapy with fluorouracil and folinic acid (FOLFOX4 regimen) is associated with a significantly greater disease-free survival at 3 years (78% vs 73%; p = 0.002), according to results of the MOSAIC (Multicenter International Study of Oxaliplatin/5FU/Leucovorin [folinic acid] in the Adjuvant Treatment of Colon Cancer) trial, a study in 2246 patients with stage II or III colon cancer. In addition, a 23% reduction in the risk of disease recurrence after surgery was seen with FOLFOX4 compared with fluorouracil/folinic acid in the MOSAIC trial. Results from several phase I/II studies suggest that the addition of oxaliplatin to preoperative radiochemotherapy may be of benefit in patients with locally advanced lower rectal cancer in terms of disease downstaging and sphincter preservation. Oxaliplatin was generally well tolerated in the MOSAIC trial and neuro- and myelotoxicity with FOLFOX4 were manageable.     

奥沙利铂和氟尿嘧啶及甲酰四氢叶酸钙联合应用治疗晚期大肠癌的护理

目的观察临床护理对使用奥沙利铂联合氟尿嘧啶、甲酰四氢叶酸钙方案化疗晚期大肠癌患者的影响。方法 75例晚期大肠癌患者,使用奥沙利铂联合氟尿嘧啶、甲酰四氢叶酸钙方案化疗,从护理学角度,在化疗前和化疗中加强对病人全身状况的评估及相关护理知识的教育,观察疗效及不良反应。结果通过有力的护理措施,所有病人按预期完成治疗计划,近期疗效好,总有效率为72.5%,无严重不良反应发生。结论奥沙利铂联合氟尿嘧啶、甲酰四氢叶酸钙方案治疗晚期大肠癌,做好化疗前护理,用药中加强对药物不良反应观察与护理,能有效避免相关不良反应,改善患者生活质量,提高治疗疗效。     

Oxaliplatin. A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies

Oxaliplatin is a platinum compound that inhibits DNA synthesis, primarily by causing intrastrand cross-links in DNA. Oxaliplatin has a broad spectrum of antineoplastic activity and has demonstrated a lack of cross-resistance with other platinum compounds. In patients with metastatic colorectal cancer, intravenous oxaliplatin has been trialled as a monotherapy and in combination with other agents. The highest response rates were achieved when oxaliplatin was used in combination with fluorouracil/folinic acid (leucovorin; calcium folinate), typically > or = 50% in the first-line setting and 13 to 45% as a second-line therapy. First-line triple therapy with oxaliplatin and fuorouracil/folinic acid achieved significantly higher response rates and longer median progression-free survival than fluorouracil/folinic acid therapy alone. However, no significant difference in the median duration of overall survival was found. This may be a consequence of the subsequent use of oxaliplatin and/or surgery after disease progression in patients who relapsed after fluorouracil/folinic acid therapy alone. Neoadjuvant therapy with oxaliplatin/fluorouracil/folinic acid has proven beneficial in enabling surgical removal of previously unresectable liver metastases. In 2 studies, surgery with curative intent was performed in 16 and 51% of patients with initially unresectable liver metastases following oxaliplatin/fluorouracil/folinic acid therapy; the 5-year survival rates were 40 and 50%, respectively. In patients with advanced ovarian cancer, first-line therapy with oxaliplatin/cyclophosphamide achieved an objective response rate which did not differ significantly from that of cisplatin/cyclophosphamide (33 vs 42%). In addition, oxaliplatin has shown efficacy in patients with platinum-pretreated ovarian cancer and achieved objective response rates similar to paclitaxel in this setting (16 vs 17%). Promising results have also been found with oxaliplatin in patients with non-Hodgkin's lymphoma, breast cancer, mesothelioma and non-small cell lung cancer. Reversible, cumulative, peripheral sensory neuropathy is the principle dose-limiting factor of oxaliplatin therapy. Haematological and gastrointestinal toxicities occur frequently but are generally mild to moderate in intensity. CONCLUSION: Oxaliplatin in combination with fluorouracil/folinic acid is an effective treatment option for patients with metastatic colorectal cancer, both as a first-line therapy and in patients refractory to previous chemotherapy. Although preliminary results failed to show any overall survival advantage of this regimen over fluorouracil/folinic acid alone, this may be a consequence of trial design and requires further examination. Additional clinical investigation of oxaliplatin in patients with other cancers is warranted given the promising results achieved in early trials, most notably in patients with platinum-pretreated ovarian cancer.     

国产和进口奥沙利铂的临床疗效及不良反应比较

目的:比较国产奥沙利铂(商品名为艾恒)和进口奥沙利铂(商品名为乐沙定)的不良反应和近期疗效。方法:共68例晚期结肠癌患者,男性42例,女26例;年龄32～62岁,平均53.2岁。使用FOLFOX4方案化疗,采用随机单盲方法,分为2组:国产奥沙利铂50 mg(艾恒组,n=35)和进口奥沙利铂50 mg(乐沙定组,n=32),观察分析2组的不良反应及近期临床疗效的差异。结果:2组患者不良反应的无明显差异(P>0.05),近期疗效也无显著性差异。结论:国产药艾恒抗肿瘤疗效及不良反应与进口药乐沙定相近。     

Adjuvant chemotherapy of colon cancer: lymph node involvement without metastases

(1) The standard treatment for colon cancer is surgical excision, but without additional treatment nearly 50% of surgically treated patients die from relapse and metastatic disease progression. Adjuvant chemotherapy is designed to reduce the risk of post-surgical relapse. (2) The standard adjuvant chemotherapy is a combination of fluorouracil + folinic acid administered intravenously for 6 months (de Gramont protocol). (3) In patients with stage III disease (corresponding to Dukes stage C: lymph node involvement but no metastases), the 5-year survival rate after a 6-month course of fluorouracil + folinic acid is significantly higher than with placebo (63% versus 51%). The efficacy of this treatment has not been established in patients with stage II disease (no lymph node involvement or metastases), for whom the overall 5-year survival rate is about 80%. (4) In one trial a combination of oxaliplatin + fluorouracil + folinic acid (FOLFOX 4 protocol) failed to increase the overall 3-year survival rate more than the fluorouracil + folinic acid combination. It increased the event-free survival rate (72.2% versus 65.3%) but had more severe adverse effects, including: neuropathies (in about 12% of patients), neutropenia (41%), and gastrointestinal disturbances (5% to 10% of patients had nausea, vomiting and diarrhoea). (5) Capecitabine, a fluorouracil precursor, does not appear to be more effective than fluorouracil, but it does provide an alternative oral treatment with a slightly different profile of adverse effects (more frequent erythrodysesthesia, etc.). (6) In practice, adjuvant treatment with fluorouracil + folinic acid should be offered to patients with surgically treated stage-III colonic cancer.     

Cetuximab: new drug. Metastatic colorectal cancer: an inappropriate evaluation

(1) In patients with metastatic colorectal cancer initially treated with irinotecan combination therapy, second-line therapy with a combination of fluorouracil, folinic acid and oxaliplatin resulted in a median survival time of 21 months after the start of first-line chemotherapy, in one clinical trial. (2) Cetuximab, an antibody directed against the epidermal growth factor receptor (EGFR), is indicated for patients with EGF-expressing metastatic colorectal cancer, after failure of irinotecan-based chemotherapy. (3) A comparative trial involving 329 patients showed that the cetuximab + irinotecan combination was more effective than cetuximab monotherapy in terms of progression-free survival time (4.1 versus 1.5 months). Three non comparative trials did not show that adding cetuximab to irinotecan improved the efficacy of irinotecan. (4) Nearly 90% of patients taking cetuximab developed cutaneous adverse effects (usually acne), which were severe in about 15% of cases. About 5% of cetuximab infusions were associated with occasionally severe hypersensitivity reactions. (5) More pertinent comparative trials are underway, but no detailed results were available on 29 April 2005. (6) The cetuximab packaging is somewhat impractical. (7) In practice, given its known toxicity and unproven efficacy, cetuximab currently has no place in the second-line treatment of colorectal cancer.     

Cost considerations in the treatment of colorectal cancer

Colorectal cancer is among the most common malignancies in developed countries. Screening can reduce mortality significantly, although the most appropriate method is still under debate. Observational studies have revealed that lifestyle measures may also be beneficial for prevention of colorectal cancer. Surgery is still the most effective treatment modality for colorectal cancer. The survival benefits of chemotherapy are only modest. For nearly 5 decades, 5-fluorouracil (5-FU) has been the main cytotoxic agent for treatment of colorectal cancer. In the last decade, the new cytotoxic agents raltitrexed, irinotecan and oxaliplatin have been introduced, next to the oral 5-FU analogues capecitabine and tegafur in combination with uracil (UFT). Moreover, the immunotherapeutics bevacizumab and cetuximab have become approved for treatment of metastatic colorectal cancer. The economic implications of colorectal cancer treatment are substantial. The costs of treatment are mainly attributable to the early and terminal stage of the disease (i.e. surgery, hospitalisation, chemo- and immunotherapy and supportive care). The introduction of new chemo- and immunotherapeutics has caused a continuing increase of treatment expenditures. Therefore, comparative costs and cost effectiveness are important for assessing the value of new treatment regimens. The available study results suggest that addition of irinotecan or oxaliplatin to 5-FU/folinic acid dosage regimens is cost effective. Also, capecitabine is calculated to be cost effective when compared with 5-FU/folinic acid. For UFT, no comparative studies of cost effectiveness were found. Since raltitrexed and 5-FU/folinic acid have shown equal efficacy in terms of survival, cost-effectiveness analysis is considered not to be applicable and cost-minimisation analysis may be sufficient. At present, pharmacoeconomic analyses of combination treatment with the immunotherapeutics bevacizumab or cetuximab are not available, except for recent cost-effectiveness considerations by the UK National Institute for Health and Clinical Excellence with negative recommendations for both agents in the treatment of metastatic colorectal cancer. Given the high treatment costs, substantial toxicity and relatively limited efficacy of the fast changing chemo- and immunotherapeutic combinations for colorectal cancer, examination of cost-effectiveness studies should be conducted on a routine basis along with determination of clinical benefits.     

Synergistic antitumour effect of raltitrexed and 5-fluorouracil plus folinic acid combination in human cancer cells

5-Fluorouracil, usually in combination with folinic acid, is widely used in the treatment of both colorectal and head and neck squamous cell cancer patients. Since 5-fluorouracil plus folinic acid and the antifolate thymidylate synthase inhibitor; raltitrexed have distinct mechanisms of action and toxicity profiles, we have evaluated the potential synergistic antitumor interaction between these two agents combined with a sequential schedule of administration in KB (wt-p53) and Cal27 (mut-p53) head and neck squamous cell carcinomas, and LoVo (wt-p53) and HT29 (mut-p53) colorectal cell lines. The combination between a 24-h exposure to raltitrexed followed by a 4-h exposure to 5-fluorouracil plus folinic acid was globally synergistic, as assessed by the median effect principle and combination index. A specific contribution of folinic acid to the cytotoxic effect of the raltitrexed/5-fluorouracil combination was clearly demonstrated by the evaluation of the potentiation factor. In all cell lines, a 1.5- up to 17-fold reduction in the IC50 of both raltitrexed and 5-fluorouracil plus folinic acid was observed in the combination setting compared with the concentrations of the each drug used alone. Moreover, we demonstrated that raltitrexed/5-fluorouracil plus folinic acid induced a distinct S-phase block of the cell cycle, as well as a potentiation of the apoptotic cell death, compared with 5-fluorouracil plus folinic acid or raltitrexed/5-fluorouracil combination. This preclinical work represents, at least to our knowledge, the first demonstration of a synergistic interaction between raltitrexed and 5-fluorouracil modulated by folinic acid, and could represent a rationale for further clinical investigation of raltitrexed/5-fluorouracil plus folinic acid combination.     

大肠癌患者使用奥沙利铂联合化疗的护理体会

目的大肠癌患者联合化疗过程中有效预防/治疗不良反应的护理措施。方法34例中、晚期大肠癌患者给予奥沙利铂（130mg/m2静脉滴注4h,化疗第1天,）,第1～5天5-氟尿嘧啶（450mg/m2静脉滴注,4h滴完）和亚叶酸钙（0.2静脉滴注,5-氟尿嘧啶前）联合治疗,21d重复疗程,每例患者完成至少2个周期。结果34例患者完全缓解（CR）2例,部分缓解（PR）18例,总有效率为%,有效的护理干预能减少不良反应的发生,使患者配合治疗,提高生存率。结论奥沙利铂联合化疗存在不同程度的毒副反应,治疗过程中做好心理护理,注意观察,及时处理,能减轻毒副反应,提高生存质量。     

Capecitabine, alone and in combination, in the management of patients with colorectal cancer: a review of the evidence

Capecitabine, an oral prodrug of fluorouracil (5FU), has shown efficacy in terms of progression-free and overall survival at least equivalent to standard folinic acid (leucovorin)-modulated intravenous 5FU bolus regimens in patients with metastatic colorectal cancer. Moreover, capecitabine has demonstrated a better tolerability profile, producing a significantly lower occurrence of severe stomatitis than 5FU plus folinic acid regimens, making this drug particularly attractive for treating elderly patients. In addition, capecitabine can be combined with other active drugs such as irinotecan or oxaliplatin. Indeed, the combination of capecitabine plus oxaliplatin (XELOX regimen) now represents a new standard of care for the metastatic disease and is also under evaluation in the adjuvant setting. The combination of new biological drugs, such as bevacizumab, with the XELOX regimen was shown to further prolong the time to progression of metastatic disease, and might reduce the risk of recurrence for those with resected colon cancer with poor risk factors. Cost-effectiveness analyses have demonstrated that, despite higher acquisition costs, capecitabine appears to be more cost effective than standard treatments for the management of colorectal cancer patients.     

Rapid desensitization of hypersensitivity reactions to chemotherapy agents

All chemotherapy agents can cause hypersensitivity reactions, which have limited the used of critical drugs in very sick patients for fear of inducing a more severe reaction and possibly death. The choice of an alternative chemotherapy regimen is often limited by tumor sensitivity and, because of the increasing number of cancer survivors, exposure to multiple courses of the same or similar chemotherapy agents. Increased exposures lead to sensitization and to hypersensitivity reactions in an increasing patient population. The need to offer first line therapy after cancer recurrence has spurred the clinical development of rapid desensitizations, which allow patients to be treated with medications to which they have presented hypersensitivity reactions. Desensitization protocols are available to treat hypersensitivity reactions to most chemotherapy agents including taxenes, platinums, doxorubicin, monoclonal antibodies and others, by gradual re-introduction of small amounts of drug antigens up to full therapeutic doses. Candidate patients include those who present mild to severe type I hypersensitivity, mast cell/IgE dependent, reactions during the chemotherapy infusion or shortly after. Symptoms include pruritus, flushing, urticaria, angioedema, respiratory and gastrointestinal distress, changes in blood pressure including hypotension, and shock with anaphylaxis. Associated musculoskeletal symptoms and pain can be present in patients reacting to taxenes as in anaphylactoid reactions, in which mast cell/IgE mechanisms cannot be demonstrated. There is now strong evidence that anaphylactoid reactions are amendable to treatment with the same rapid desensitization protocols as for type I hypersensitivity reactions. Initial rapid desensitizations should only be performed in settings with one on one nurse-patient care and where resuscitation personnel and resources are readily available. Temporary tolerization is achieved in a few hours. After the first desensitization, standard protocols are available for safe, repeated desensitizations in outpatient settings with similar conditions, which not only provides flexibility, but allows patients to remain in clinical studies. Breakthrough symptoms are less severe than the initial hypersensitivity reaction in all series reviewed, and deaths have not been reported. The aim of this review is to familiarize the medical community with the type of hypersensitivity reactions amendable to rapid desensitization and to review protocols for chemotherapy desensitization that can be used for most chemotherapy agents. Few studies have measured the cancer response to the chemotherapy agents delivered through rapid desensitizations. One patient population in which 26 patients were desensitized to carboplatin and 16 to paclitaxel had similar rates of remission as for non-desensitized patients. Education of nurses, pharmacists, oncology and allergy specialists will lead to the universal use of rapid desensitization protocols for all cancer patients with hypersensitivity reactions to chemotherapy agents. Basic research is needed to uncover the cellular and molecular mechanisms underlying the temporary tolerization induced by rapid desensitization, so that pharmacological interventions can improve its safety and efficacy.     

奥沙利铂、5-氟尿嘧啶、甲酰亚叶酸钙联合化疗治疗晚期结直肠癌的临床疗效与耐受性的随机对照观察

目的观察奥沙利铂、5-氟尿嘧啶、亚叶酸钙联合方案治疗晚期结直肠癌的临床疗效与耐受性,优化晚期直肠癌的化疗方案。方法将符合入组标准的80例晚期结直肠癌随机分为观察组40例和对照组40例,对照组给予顺铂、5-氟尿嘧啶、甲酰亚叶酸钙联合化疗治疗,观察组给予奥沙利铂、5-氟尿嘧啶、甲酰亚叶酸钙联合化疗治疗,28d为1个周期,治疗4个周期,治疗前后进行实验室辅助检查,评价两组临床近期疗效与远期疗效,记录实验过程中的不良反应。结果①观察组的总有效率为52.5%,对照组的总有效率为30%,观察组的总有效率明显高于对照组,差异具有统计学意义,χ2=8.182,P<0.05;观察组的1年生存率为87.5%,明显高于对照组,χ2=6.667,P<0.05;观察组的3年生存率为62.5%,明显高于对照组,χ2=5.000,P<0.05;②两组患者治疗过程出现的不良反应有贫血、白细胞减少、血小板减少、恶心呕吐、腹泻、口腔炎、脱发、肝损害,观察组出现贫血、白细胞减少、腹泻的几率明显低于对照组,差异具有统计学意义,均P<0.05。结论奥沙利铂、5-氟尿嘧啶、亚叶酸钙联合方案近期疗效、远期疗效及安全性均明显优于顺铂、5-氟尿嘧啶、亚叶酸钙,明显改善患者生活质量,值得临床广泛推广运用。     

Hypersensitivity reactions to oxaliplatin: a case report and the success of a continuous infusional desensitization schedule

Oxaliplatin is a third-generation platinum analog that is used mainly to treat advanced colorectal cancer. The reported incidence of hypersensitivity reactions to oxaliplatin, especially after multiple cycles of therapy, is less than 1%. We report a patient with metastatic colon cancer who developed a hypersensitivity reaction to oxaliplatin during the sixth cycle of combination chemotherapy with oxaliplatin, high-dose 5-fluorouracil and leucovorin. The same reaction occurred again after re-exposure to oxaliplatin 2 weeks later even with prophylactic administration of steroids and H1 antihistamines. After failing third-line treatment with oral tegafur-uracil, we desensitized the patient by using a fixed-rate 24-h continuous infusion of dilute oxaliplatin (0.15 mg/ml), in addition to steroids and H1 antihistamines. He had no hypersensitivity reaction during or after that infusion or when the same concentration was infused in the same way 2 weeks later. Because his condition subsequently deteriorated and the cancer progressed, no further oxaliplatin was given. Our experience does demonstrate, however, that a fixed-rate 24-h continuous infusion of oxaliplatin in a low concentration may prevent a hypersensitivity reaction in a previously sensitized patient.     

Chemotherapy of metastatic colorectal cancer

Without treatment, patients with inoperable or metastatic colorectal cancer have a median life expectancy of about 8 months. The following article is an update of our 2005 review of chemotherapy regimens used in metastatic colorectal cancer, based on the standard Prescrire methodology. In 2005, the de Gramont protocol, based on fluorouracil (always combined with folinic acid) plus either oxaliplatin (Folfox protocol) or irinotecan (Folfiri protocol), was the standard first-line chemotherapy in this setting. Four trials comparing monotherapy versus combination therapy in previously untreated patients showed that initial fluorouracil (or fluorouracil precursor) monotherapy, followed by the Folfox or Folfiri protocol in case of failure, was not associated with shorter overall survival. Two trials compared first-line treatment with the Folfiri regimen versus the Folfoxiri regimen (fluorouracil + oxaliplatin + irinotecan). One of these studies showed an increase in median survival with the Folfoxiri protocol (24 versus 17 months), but at a cost of greater neurotoxicity. The only tangible advantage of capecitabine and tegafur, two oral fluorouracil precursors, is their convenience of use. Pemetrexed was less effective and more toxic than the Folfiri protocol in one trial. Bevacizumab and panitumumab have yielded disappointing results in previously untreated patients. Neither of these monoclonal antibodies has yet been shown to improve overall survival. Three trials have assessed the addition of cetuximab to combinations consisting of fluorouracil or capecitabine plus oxaliplatin or irinotecan. In two of these trials, the median survival time of patients whose tumours carried the wild-type KRAS gene was about 3 months longer in the cetuximab arms, although the increase was statistically significant in only one trial. Cetuximab had no impact on survival time in the third trial. In two trials, an anti-EGFR antibody (panitumumab or cetuximab) reduced median survival when added to bevacizumab in previously untreated patients. When progression occurs after treatment with the Folfiri protocol (or equivalent), a combination of the Folfox protocol and bevacizumab seems to increase median survival time by about 2 months versus Folfox alone, but it is also more toxic. In patients who progress after receiving the fluorouracil + oxaliplatin combination (Folfox) or the fluorouracil+ irinotecan combination (Folfiri), neither panitumumab nor cetuximab has been shown to provide a clinically meaningful increase in overall survival. It remains to be shown whether these drugs are more effective in patients with the wild-type KRAS gene than in patients with KRAS mutations. In early 2010, the standard cytotoxic drugs for treatment of metastatic colorectal cancer are fluorouracil (combined with folinic acid), oxaliplatin and irinotecan. Initial combination therapy may be beneficial when the metastases are borderline operable. When the metastases are inoperable and are unlikely to become operable after chemotherapy, it seems best to begin treatment with single-agent fluorouracil (+ folinic acid) or capecitabine. The use of monoclonal antibodies in first-line treatment of patients with colorectal cancer is not justified. Further trials of these drugs are warranted as second-line treatment for patients with KRAS wild-type tumours.     

奥沙利铂致过敏危险因素分析

目的分析奥沙利铂致结直肠癌患者过敏的危险因素。方法回顾分析185例接受奥沙利铂化疗的结直肠癌患者,分析人口学特征,既往过敏史,实验室检查,化疗方案和抗过敏预防措施的使用等。结果奥沙利铂所致过敏反应者23例,其中17例患者发生Ⅰ/Ⅱ度过敏反应,6例患者发生Ⅲ/Ⅳ度过敏反应。与无过敏反应组相比,过敏反应组患者奥沙利铂化疗间断率高,其中Ⅰ/Ⅱ度过敏反应组患者化疗次数较多。结论化疗次数增多和奥沙利铂化疗曾有间断与发生过敏反应相关。