Chemotherapy in rectal cancer]

Until mid-1990s, fluorouracil was the only chemotherapeutic agent available for the treatment of colorectal cancer. The treatment of advanced colorectal cancer has evolved considerably over the last decade. Considerable improvements in survival as well as quality of life have been achieved with the application of oxaliplatin and irinotecan with fluoropyrimidine as a first and subsequent line therapy for colorectal cancer. Development of oral fluoropyrimidines as an alternative to intravenous administration provides an additional option for combination cytotoxic therapy, which is currently being assessed in phase III trials in advanced settings. The appearance of biologic agents in mid-2000s, namely cetuximab and bevacizumab, and their integration with conventional cytotoxic therapy for the treatment of colorectal cancer has additionally expanded the options for the treatment. Their dramatic success has led to further clinical studies of targeted therapy in colorectal cancer, making it one of the most promising areas of cancer research. Although considerable improvement was achieved by incorporating oxaliplatin in adjuvant chemotherapy for the treatment of colon cancer, there has been no phase III trial incorporating new agents in adjuvant setting for rectal cancer. However, many phase II trials on the efficacy of new agents in the setting of concurrent chemoradiation are in progress. Based on their results, randomized phase III clinical trials evaluating new agents in preoperative or postoperative setting will be carried out.     

The treatment of advanced colorectal cancer: where are we now and where do we go?

The treatment of patients with metastatic colorectal cancer has changed dramatically over recent years. The more optimal use of 5-fluorouracil (5-FU) in association with folinic acid (FA), the development of new drugs such as irinotecan and oxaliplatin and of the oral fluoropyrimidines, capecitabine and UFT, have contributed to increased therapeutic options and to the improved outcome of patients with metastatic colorectal cancer. It is shown that combination therapy with 5-FU/FA and irinotecan or oxaliplatin is more active than 5-FU/FA in the first-line treatment of advanced colorectal cancer. Irinotecan and oxaliplatin are also active in the second-line treatment of colorectal cancer. The oral fluoropyrimidines seem to have an activity comparable to that of intravenous 5-FU/FA in the first-line treatment of metastatic colorectal cancer.New agents acting on novel targets are under development: epidermal growth factor inhibitors, vascular endothelial growth inhibitors, COX-2 inhibitors and farnesyl transferase inhibitors might play a role in the future in the treatment of colon cancer.     

Neoadjuvant and adjuvant therapy in relation to surgery for colorectal liver metastases

Liver resection is associated with prolonged survival in patients with colorectal liver metastases. At diagnosis, 15-20% of patients have resectable colorectal liver metastases whereas other patients have too advanced disease to enable surgical treatment and receive chemotherapy. In patients undergoing resection of colorectal liver metastases, disease relapse occurs in up to 70%. Therefore, a combined approach including preoperative or postoperative chemotherapy or both has been tested to improve outcome after surgery. In patients with unresectable colorectal liver metastases, chemotherapy is initially the sole treatment option. The considerable improvement of the efficacy of anticancer agents has contributed to increase the response rate in patients with advanced colorectal cancer. In case of major response to chemotherapy, surgery with curative intent can be offered to patients with initially unresectable liver metastases.     

New developments in systemic chemotherapy in advanced colorectal cancer

BACKGROUND: The majority of patients with newly diagnosed colorectal cancer who present with concurrent metastases are considered to be incurable from the disease. For their treatment, these patients depend on systemic anticancer therapy and supportive care. METHODS: This article reviews recent developments in systemic treatment of disseminated colorectal cancer. RESULTS: Until recently, the fluoropyrimidines were the only cytotoxic drugs available, but during recent years three other classes of active conventional cytotoxic drugs and a new class of target-directed drugs have become available. New cytotoxic drug therapies include raltitrexed, irinotecan and oxaliplatin. Patients receiving irinotecan experience a better quality of life than those treated with best supportive care alone. Irinotecan or oxaliplatin in combination with 5-fluoro-uracil (5-FU) and leucovorin are currently the most active treatment regimens. Oral prodrugs of 5-FU, such as capecitabine and uracil, have been developed in order to mimic the protracted infusion schedule of 5-FU, and these drugs may change the daily practice of palliative chemotherapy for colorectal cancer in the coming years. Therapeutic agents that target specific molecular processes that promote proliferation, vascularization and metastasis, and inhibit apoptosis, are being designed and may offer a rational approach to anticancer therapy. Examples of this novel approach are monoclonal antibodies and small molecules adhering to the epithelial growth factor receptor and vascular endothelial growth factor receptor in order to inhibit growth stimulation and angiogenesis. CONCLUSION: The current debate is no longer whether to use palliative chemotherapy in metastatic colorectal, but which patient will benefit from which combination and in what sequence.     

Chemotherapy of nonoperable colorectal liver metastases.

Biomodulated 5-fluorouracil-based therapy is the mainstay of treatment for advanced colorectal cancer. Patients with advanced disease do better with chemotherapy than they do without, but the overall survival in these patients is still poor. Combination of infusional and bolus 5-fluorouracil/folinic acid (leucovorin) regimens with newer agents, such as CPT-11 and oxaliplatin, in the fist-line treatment of patients with advanced colorectal cancer, has yielded increased response rates and progression-free survivals. In the case of CPT-11 this has also led to an increase in overall survival. Improved therapy combinations and the delivery of the therapy directly to the liver by hepatic arterial infusion, either alone or in combination with intravenous delivery, all herald an improvement in the clinical outcome of patients with nonoperable liver metastases. These patients should be offered the best chemotherapy option available coupled, where appropriate, with liver resection.     

Oral fluoropyrimidines in colorectal cancer: a door open to the future?

Since its first use 40 years ago, 5-fluorouracil (5-FU) has become an unquestionable component of colorectal cancer treatment. It is also now well established that infusional 5-FU administration, in combination with leucovorin, is associated with better tolerance and at least equal efficacy than bolus administration. However, requiring catheter and infusion pumps, infusional 5-FU administration is costly, rather inconvenient for patients and potentially associated with morbidity, initiating subsequent oral chemotherapy development. To address intravenous 5-FU related issues, oral fluoropyrimidines have been developed such as capecitabine, preferentially converted to 5-FU into tumour cells, and UFT, able of bypassing intestinal dihydropyrimidine dehydrogenase. We discuss in this article current oral fluoropyrimidines achievements in colorectal cancer management.     

丹皮酚对人大肠癌HT-29细胞增殖的抑制作用

目的探讨中药丹皮酚(Pae)对人大肠癌HT-29细胞增殖的抑制作用及其与多种化疗药物的协同作用.方法应用MTT法(噻唑蓝比色试验)检测不同浓度的丹皮酚和5-氟脲嘧啶(5-FU)、丝裂霉素(MMC)、顺铂(DDP)对体外培养的人大肠癌HT-29细胞增殖的抑制作用,同时观察低浓度的Pae与化疗药物的协同作用.结果 Pae可抑制HT-29细胞增殖,并且与药物浓度及作用时间呈正相关关系.低浓度的Pae与化疗药物协同可产生较强的抑制细胞增殖作用.结论 Pae具有直接的抗肿瘤作用,并且具有增强化疗药物作用的功效.     

Management of liver metastases from colorectal cancer

About 50% of colorectal cancer patients develop liver metastasis, and liver resection is considered the only curative therapy. However, the rate of recurrence is high, which contributes to poor prognosis. Since surgical resection coverage has increased because of improved hepatectomy including portal vein embolization, tumors shrink because of the effectiveness of recent chemotherapy, such as FOLFOX and FOLFIRI, and it has become possible for many patients whose cancer was judged unresectable before to undergo resection. Improvement of new anticancer drugs such as molecularly targeted biologics is greatly changing therapeutic systems of metastatic colorectal cancer, and it is time for us to innovate stage IV therapy. In this report, we will review new treatment strategies for metastatic liver cancer from colorectal cancer, clinical trials of new anticancer drugs for liver metastasis, surgery and ablation as local therapy, and further clarify complex therapeutic systems for metastatic liver tumors from colorectal cancer.     

Predictive factors for response to chemotherapy in colorectal cancer patients

Colorectal cancer represents a major health problem in the western world. A lot of drugs have been employed in treatment of this disease, but only few data are available about predictive factors for response to anticancer treatments in colorectal cancer. Aim of this paper is to review the main data about this investigation field. Using a Medline database search (1966-2003) we reviewed all the relevant papers that investigate clinical and molecular predictors for response to the main drugs used in the treatment of colorectal cancer patients, both in adjuvant and in advanced setting. Moreover we comprehensively reviewed all the data published in abstract form during the most significant international meetings. Our review put in evidence the most important predictive factors for response in colorectal cancer patients treated with anticancer chemotherapy both in adjuvant and in advanced setting. The predictive factors are clustered on the basis of the different anticancer drugs. The results of this review provide the rationale basis for personalizing anticancer treatment in colorectal cancer patients by molecular and clinical features, aiming to improve response rate and reduce toxicities.     

Non-platinum-based chemotherapy for treatment of advanced gastric cancer:5-fluorouracil,taxanes,and irinotecan

Despite numerous advances in treatment options,advanced gastric cancer(AGC)remains a major public health issue and the leading cause of cancer-related deaths.Cisplatin is one of the most effective broadspectrum anticancer drugs for AGC and a doublet combination regimen of either cisplatin-based or 5-fluorouracil(5FU)-based chemotherapy is generally used for treatment of patients with AGC.However,there is still no consensus on the best regimen for treating AGC.Recently,various new chemotherapeutic agents,including oral 5FU,taxanes,and irinotecan,have been identified as improving the outcomes for AGC when used as a single agent or in combination with nonplatinum chemotherapy.Nonetheless,it is still unclear whether non-platinum-based chemotherapy is a viable treatment option for patients with AGC.Accordingly,this review focuses on the efficacy and tolerability of non-platinum-based chemotherapy for patients with AGC.     

Targeting mTOR network in colorectal cancer therapy

The mechanistic target of rapamycin(mTOR)integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth,proliferation and survival.A regulatory network with multiple feedback loops has evolved to ensure the exquisite regulation of cell growth and division.Colorectal cancer is the most intensively studied cancer because of its high incidence and mortality rate.Multiple genetic alterations are involved in colorectal carcinogenesis,including oncogenic Ras activation,phosphatidylinositol 3-kinase pathway hyperactivation,p 53 mutation,and dysregulation of wnt pathway.Many oncogenic pathways activate the mTOR pathway.mTOR has emerged as an effective target for colorectal cancer therapy.In vitro and preclinical studies targeting the mTOR pathway for colorectal cancer chemotherapy have provided promising perspectives.However,the overall objective response rates in major solid tumors achieved with single-agent rapalog therapy have been modest,especially in advanced metastatic colorectal cancer.Combination regimens of mTOR inhibitor with agents such as cytotoxic chemotherapy,inhibitors of vascular endothelial growth factor,epidermal growth factor receptor and Mitogen-activated protein kinase kinase(MEK)inhibitors are being intensively studied and appear to be promising.Further understanding of the molecular mechanism in mTOR signaling network is needed to develop optimized therapeutic regimens.In this paper,oncogenic gene alterations in colorectal cancer,as well as their interaction with the mTOR pathway,are systematically summarized.The most recent preclinical and clinical anticancer therapeutic endeavors are reviewed.New players in mTOR signaling pathway,such as nonsteroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here.     

Chemotherapy in metastatic colorectal cancer

The treatment of patients with metastatic colorectal cancer (MCRC) has changed dramatically over the years. 5-Fluorouracil (5FU)-based therapies have been routinely included in treatment regimens for colorectal cancer for the past 40 years. A number of options are available to clinicians for the treatment of patients relapsing after surgical excision of their primary tumour, such as 5FU in association with FA, the new drugs such as irinotecan and oxaliplatin and the oral fluoropyrimidines: capecitabine and uracil/tegafur (UFT). It has been shown that combination therapy with 5FU/FA and irinotecan or oxaliplatin is more active than 5FU/FA in the first line of treatment in MCRC. New agents acting on novel targets are under development such as epidermal growth factor inhibitors, vascular endothelial growth factor inhibitors and cyclooxygenase 2 inhibitors.     

术后腹腔化疗对老年结直肠癌患者生存质量的影响

目的评价老年结直肠癌患者手术后腹腔化疗对生存质量的影响。方法调查1998年1月至2002年12月期间52例60岁以上进行术后腹腔化疗的患者的生存质量GLQI指数,并与同期、同年龄段44例静脉化疗患者和40名健康老年对照组进行比较。所有病人于术前和术后6个月期间调查患者的生存质量。结果老年结直肠癌患者手术前的生存质量GLQI指数明显低于正常老年人群(P<0.05)。而两组患者手术前的生存质量GLQI指数无显著差异(P>0.05)。腹腔化疗组患者手术后6个月期间的生存质量GLQI指数高于静脉化疗组患者,其差异存在统计学意义(P<0.05)。腹腔化疗组患者手术后3月、4月、5月和6月的生存质量GLQI指数与正常老年人群无显著差异(P>0.05);而静脉化疗组患者手术后3月、4月、5月和6月的生存质量GLQI指数仍低于正常老年人群(P<0.05)。结论针对老年结直肠癌患者的生理特点,手术后采用腹腔化疗,不仅有利于提高手术后的生存期;而且有助于提高患者的生存质量,是老年结直肠癌患者手术后首选的理想化疗方式。     

Management of chemotherapy induced diarrhea

Chemotherapy-induced diarrhea (CID) became first apparent during clinical studies on the combination of 5-FU with leucovorin and, furthermore, with irinotecan in the treatment of metastatic colorectal carcinoma. Bowel dysfunctions, such as diarrhea and constipation, can be a disturbing side effect in chemotherapy that may result not only in significant physical and emotional distress for the patients and care givers, but also in diminished therapeutic efficacy due to dose limitations and treatment interruptions. Besides leucocytopenia, granulocytopenia and thrombocytopenia, CID is considered one of the main dose-limiting toxicities associated with chemotherapy agents, especially in treatment regimens for colorectal cancer and can even be life-threatening. Early recognition and treatment can prevent the morbidity and mortality associated with CID. The most commonly used assessment tool is the National Cancer Institute Common Toxicity Criteria for Grading the Severity of Diarrhea. In this review, we will concentrate on the modern management of CID. Traditional pharmacological management of CID has included mainly non-specific agents. For patients who are refractory to non-specific therapy, there are more sophisticated, specific therapeutic agents available.     

Role of pomegranate and citrus fruit juices in colon cancer prevention

Colorectal cancer is the second leading cause of cancer-related deaths in the United States.Recent studies prove that though chemotherapeutic agents are being used for the treatment of colon cancer,they become non-effective when the cancer progresses to an invasive stage.Since consumption of certain dietary agents has been linked with various cancers,fruit juices have been investigated for their consistently protective effect against colon cancer.The unique biochemical composition of fruit juices is responsible for their anticancer properties.In this review,the chemo-preventive effect of fruit juices such as pomegranate and citrus juices against colon cancer are discussed.For this purpose,the bioavailability,in vitro and in vivo effects of these fruit juices on colorectal cancer are highlighted.Moreover,there is a scarcity of studies involving human trials to estimate the preventive nature of these juices against colon cancer.This review will support the need for more preclinical tests with these crude juices and their constituents in different colorectal cancer cell lines and also some epidemiological studies in order to have a better understanding and promote pomegranate and citrus juices as crusaders against colon cancer.     

Long-term survivors of colorectal cancer with unresectable hepatic metastases

Five patients with colorectal cancer and unresectable synchronous liver metastases have survived for over five years at this writing. Four of the five had multiple metastases over both lobes, as diagnosed preoperatively, and the other had multiple metastases in the right lobe not evident preoperatively. The primary foci were excised completely in four patients. For one patient with multiple metastases limited to the right lobe, the postoperative cancer chemotherapy prescribed was intravenous mitomycin C (MMC; 12 mg) and oral ftorafur (a derivative of 5-FU) for a total dose of 291 gm over 63 weeks. The remaining four patients underwent postoperative intra-arterial infusion therapy with the average total dose of 20.5 mg of MMC plus 5600 mg of 5-FU; subsequently, they received protracted chemotherapy with oral ftorafur of 354 gm as an average, with little or no side effects. In these four patients, duration of intra-arterial treatment was an average of 3.2 weeks, and the subsequent oral treatment continued for an average of 85 weeks. Recent hepatic echography and CEA determinations show these patients to be free from intrahepatic metastasis.     

Therapeutic strategies for hepatic metastasis of colorectal cancer: overview

To determine the treatment strategy for hepatic metastases of colorectal cancer, it is important to take into account whether metastases are still localized in the liver, or whether the tumor has metastasized throughout the body. For liver-limited metastasis, hepatectomy is the therapeutic strategy that offers the best prospect of improving a patient's prognosis if the case is deemed resectable. In cases when surgery is not indicated for hepatic metastases of colorectal cancer, chemotherapy is the first-choice treatment. Chemotherapy for colorectal cancer has made vast strides in recent years through advances such as the development of molecular targeted drugs. In cases where chemotherapy is effective and surgical resection becomes possible (conversion chemotherapy), the long-term prognosis may be good. The value of preoperative chemotherapy in resectable cases (neoadjuvant chemotherapy) has also been reported. The improvement in prognosis achieved by eradicating tiny latent metastases is important in conversion therapy, as well as in neoadjuvant chemotherapy. It will be important to achieve further improvements in the prognoses of patients with hepatic metastases of colorectal cancer through a combination of advances in diagnostic imaging, improvements in surgical techniques, and more effective chemotherapy treatments.     

Systemic treatment of colorectal cancer

Colorectal cancer is the fourth most common noncutaneous malignancy in the United States and the second most frequent cause of cancer-related death. Over the past 12 years, significant progress has been made in the systemic treatment of this malignant condition. Six new chemotherapeutic agents have been introduced, increasing median overall survival for patients with metastatic colorectal cancer from less than 9 months with no treatment to approximately 24 months. For patients with stage III (lymph node positive) colon cancer, an overall survival benefit for fluorouracil-based chemotherapy has been firmly established, and recent data have shown further efficacy for the inclusion of oxaliplatin in such adjuvant treatment programs. For patients with stage II colon cancer, the use of adjuvant chemotherapy remains controversial, but may be appropriate in a subset of individuals at higher risk for disease recurrence. Ongoing randomized clinical trials are evaluating how best to combine currently available therapies, while smaller studies are evaluating new agents, with the goal of continued progress in prolonging life among patients with metastatic colorectal cancer and increasing cure rates among those with resectable disease.     

EGFR-Targeted Therapies in Colorectal Cancer

The management of colorectal cancer relies heavily on the combination of the pyrimidine analog antimetabolite 5-fluorouracil with the platinum-based drug oxaliplatin or the topoisomerase inhibitor irinotecan. Optimization of dosing and scheduling of these agents to improve response and survival continues to evolve. Meanwhile, the rational targeting of molecular signaling pathways that are involved in the etiology of malignancies is currently one of the most promising strategies in novel anticancer drug development. New classes of drugs that target the epidermal growth factor receptor are among the most clinically advanced molecular-targeted therapies and have shown efficacy in colorectal cancer. The current status of epidermal growth factor receptor-targeted therapeutic agents is reviewed, with emphasis on their role in the management of colorectal cancer.     

Treatment of venous thrombosis in the cancer patient

Venous thromboembolism is a common complication in patients with cancer. The management of deep vein thrombosis and pulmonary embolism can be a considerable challenge in patients with cancer. The cancer itself and associated treatments contribute to an ongoing thrombogenic stimulus, while cancer patients are thought to be at increased risk for anticoagulant-induced bleeding. Initial treatment of acute thromboembolism is with intravenous unfractionated heparin or subcutaneous low molecular weight heparin. Treatment at home with low molecular weight heparin is an attractive option in patients with malignant disease. Long-term treatment of acute venous thromboembolism has traditionally been with oral anticoagulants. However, the inconvenience and narrow therapeutic window of oral anticoagulants make such therapy unattractive and problematic in cancer patients. Low molecular weight heparins are being evaluated as an alternative for long-term therapy because their anticoagulant effects are more predictable and laboratory monitoring is unnecessary. Although many clinical issues remain unresolved in the treatment of cancer patients with venous thromboembolism, the future holds much promise as new antithrombotic agents, including factor Xa antagonists and oral thrombin inhibitors, are being tested in clinical trials.