Thymidylate synthase haplotype is associated with tumor recurrence in stage II and stage III colon cancer

BACKGROUND: Tumor recurrence after curative resection is a major problem in the management of colon cancer therapy. Identifying molecular markers for tumor recurrence is critical for successfully selecting patients who are more likely to benefit from adjuvant chemotherapy. We analyzed the value of thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms as a prognostic marker in stage II and stage III colon cancer patients treated with 5-fluorouracil-based adjuvant chemotherapy. METHODS: Between 1987 and 2007, blood samples were obtained from 197 patients with stage II or stage III colon cancer at medical facilities at the University of Southern California. DNA was extracted from peripheral blood, and the genotypes were analyzed using PCR-restriction fragment length polymorphism technique. RESULTS: Patients harboring the TS 3RG/+6-bp haplotype were at greatest risk to develop tumor recurrence [relative risk (RR): 2.25; 95% confidence interval (CI): 1.04-4.85; adjusted P value=0.032]. TS enhancer region 3RG alone (RR: 3.48 years; 95% CI: 1.61-7.54; adjusted P value=0.013) or in combination with TS 1494del6 bp (RR: 3.41 years; 95% CI: 1.33-8.75; adjusted P value=0.044) proved to be adverse prognostic markers in both univariate and multivariable analysis. CONCLUSION: 'High-expression' variants of TS 2R/3R repeat, TS enhancer region 3R G/C, TS 1494del6 bp, and TS haplotype analysis might help to identify stage II and stage III colon cancer patients who are at great risk of developing tumor recurrence, and also those who are more likely to benefit from 5-fluorouracil-based adjuvant chemotherapy. Larger, independent, prospective studies are, however, needed to confirm and validate our preliminary findings.     

Risk-adapted adjuvant chemotherapy after concomitant fluoropyrimidine-radiotherapy neoadjuvant treatment for patients with resectable cT3-4 or N+ rectal cancer

Adjuvant chemotherapy in rectal cancer is not well defined.After neoadjuvant chemoradiation and surgery, at least a short period of treatment with 5-fluorouracil is recommended, and some investigators claim a more aggressive approach, in particular, for those patients with a high risk of systemic relapse. Nevertheless, there are few studies about adjuvant combination therapy tolerance and efficacy, and no randomized trials have been conducted comparing fluoropyrimidines versus combination therapy such as folinic acid plus 5-fluorouracil plus oxaliplatin(FOLFOX), considered the standard of care in stage IIIcolon cancer. We present an institutional series of risk adapted adjuvant therapy. Sixty evaluable patients who had received treatment with neoadjuvant fluoropyrimidine radiotherapy and surgery now received adjuvant fluoropyrimidines in the case of pT0-2N0 or oxaliplatin based combination in the case of pT3-4 or N+ . Overall, 33 patients experienced downstaging to pT2-0N0 (55%) and27 patients were restaged as pT3-4 or N+ (45%) after surgery. Local recurrence rate was 5% (three patients), one local and one local plus systemic in the adjuvant single agent group and one local plus systemic in the adjuvant FOLFOX group. Systemic relapse occurred in 14 patients(23.3%), five (15%) in the single-agent group and nine(33.3%) in the FOLFOX group. Disease-free survival at 3 years for patients in the good prognostic group(pT0-2N0) and poor prognostic group (pT3-4 or N+ ) were 78.7 and 62.2%, respectively. Severe diarrhoea was more frequent with fluoropyrimidines and neutropenia, mucositis and peripheral neuropathy were more common with FOLFOX. There were no toxic deaths. A risk-adapted adjuvant therapeutic decision is feasible with an acceptable safety profile even with the use of oxaliplatin based combinations. Three-year disease-free survival compares favourably with historical controls, especially in those patients with high risk factors for relapse.Phase III controlled trials are needed.     

Recent advances in the treatment of gastric cancer

Gastric cancer is one of the most common cancers in the world. The prognosis of the disease is poor, with only 40% of patients eligible to undergo potentially curative surgery. Even for those patients who undergo a complete resection, the rate of recurrence is very high. Extensive studies of multidisciplinary adjuvant treatment have been conducted seeking to improve the cure rates in the past two decades. The benefit of D2 dissection is still controversial and is undergoing prospective evaluation. Preliminary results from the United States Gastrointestinal Intergroup study, a well designed trial, have shown overall survival benefit of postoperative chemoradiation therapy. Neoadjuvant chemotherapy or chemoradiation is under active study in order to increase the number of patients to undergo potential curative surgery. Although many chemotherapy regimens have been developed recently, only modest clinical efficacy has been demonstrated for advanced metastatic disease. So far, there is no single regimen considered to be standard.     

Neoadjuvant chemotherapy and chemoradiotherapy for non-small cell lung cancer: current status and future prospects

Of the patients with non-small cell lung cancer, 60% present with localised or locally advanced disease. Although they may be considered potentially curable, the vast majority will die, usually from systemic disease. So far, adjuvant (postoperative) therapy has failed to demonstrate benefit. In contrast, chemotherapy has demonstrated clear advantages when administered prior to, or concurrently with radiotherapy in Stage III disease or prior to surgery in Stage III disease. Chemotherapy administered prior to surgery, termed neoadjuvant therapy, in Stage I and II disease has been demonstrated to be feasible. Several trials employing currently available agents have yielded promising results. Whether these regimens will result in an unequivocal benefit is the subject of several ongoing studies in the US and Europe. Current research is focusing on the role of newer drugs including novel antitubulin agents, growth factor receptor antagonists, eicosanoid modulators and various other agents.     

Neoadjuvant chemotherapy and chemoradiotherapy for non-small cell lung cancer: current status and future prospects

Of the patients with non-small cell lung cancer, 60% present with localised or locally advanced disease. Although they may be considered potentially curable, the vast majority will die, usually from systemic disease. So far, adjuvant (postoperative) therapy has failed to demonstrate benefit. In contrast, chemotherapy has demonstrated clear advantages when administered prior to, or concurrently with radiotherapy in Stage III disease or prior to surgery in Stage III disease. Chemotherapy administered prior to surgery, termed neoadjuvant therapy, in Stage I and II disease has been demonstrated to be feasible. Several trials employing currently available agents have yielded promising results. Whether these regimens will result in an unequivocal benefit is the subject of several ongoing studies in the US and Europe. Current research is focusing on the role of newer drugs including novel antitubulin agents, growth factor receptor antagonists, eicosanoid modulators and various other agents.     

结直肠癌术后局部复发因素的研究

目的 研究导致结直肠癌术后局部复发的可能因素。方法 将结直肠癌术后局部复发18例与无复发21例的临床及病理资料进行对比分析。结果 直肠癌局部复发12例,占68％(P<0.05)。Miles术后局部复发3例占25％,Dixon术后复发9例占75％(P<0.01)。术后正规化学药物治疗或放射治疗与非治疗者比较差异有显著意义。结论 结直肠癌发生的部位、手术方式、淋巴结清扫程度及术后正规化学药物治疗或放射治疗是影响其术后局部复发的因素。     

Tailoring treatment of rectal adenocarcinoma: immunohistochemistry for predictive biomarkers

Over the past couple of decades, multimodality treatment for the management of resectable rectal cancer has substantially improved the outcome of affected patients. However, the broad and unpredictable response to tumor of patients with rectal cancer treated with preoperative chemoradiotherapeutic interventions shows that our understanding of the molecular events leading to radioresistance in patients affected with this malignancy remains sparse. Multiple attempts by individual molecular markers in gene array and tissue microarray studies have emerged with the goal of identifying predictors of a response to chemoradiation in patients with rectal cancer. In this report, we discuss the status of the markers currently available in an attempt to tailor specific targeted therapies for rectal cancer in the neoadjuvant setting.     

Extended adjuvant endocrine therapy of early breast cancer

Women who are diagnosed with early breast cancer remain at considerable risk of recurrence over the next several decades, even if their tumors were small and lymph nodes were negative, and despite receiving standard adjuvant therapy. A majority of breast cancers are hormone (estrogen) receptor-positive and amenable to endocrine therapy, and for those women five years of the selective estrogen receptor modulator tamoxifen is standard therapy. Longer treatment of node-negative patients with tamoxifen may reduce survival benefits, however, possibly due to tamoxifen resistance and emerging receptor agonist activity of that drug. Aromatase inhibitors, which indirectly prevent estrogen stimulation of breast cancer by suppressing whole-body estrogen synthesis in post-menopausal women, are being investigated as alternative, or complementary, therapy to adjuvant tamoxifen in those women: as an alternative to five years of tamoxifen, sequenced with two to three years of tamoxifen, or following five years of tamoxifen. The strategy to extend the benefits of adjuvant therapy beyond a standard course of tamoxifen, using the aromatase inhibitor letrozole, was explored in a large trial, MA.17. Compared with women who received placebo, those who were treated with letrozole experienced a significant 43% reduction in their residual risk of recurrence. This effect was seen regardless of nodal status. Based on the long-term risk of most women with early breast cancer and the MA.17 trial results, the extended adjuvant letrozole may benefit many of those women who are disease-free after five years of tamoxifen. This review is based on a literature search of databases including MEDLINE/PubMed, San Antonio Breast Cancer Symposium, and the Annual Meeting of the American Society of Clinical Oncology, up to and including August 2005, with information selected for its relevance to adjuvant therapy of breast cancer with endocrine therapy only.     

Phase I study of oral uracil and Tegafur plus leucovorin and pelvic radiation in patients with recurrent rectal cancer

Continuous 5-fluorouracil (5-FU) infusion during radiation therapy is superior to the application of bolus 5-FU schedules. As an oral therapy, that provides prolonged fluoropyrimidine exposure, uracil and Tegafur (UFT) plus leucovorin (LV) has shown favorable activity with only moderate toxicity in colorectal cancer. The present study was designed to evaluate the safety of UFT+LV combined with pelvic radiation to determine the maximum-tolerated dose (MTD) in recurrent rectal cancer. Patients with recurrent rectal cancer received escalating doses of UFT (starting at 250 mg/m /day with 50 mg/m /day increments between consecutive cohorts) and fixed doses of LV (90 mg). The UFT+LV combination was given 5 days per week simultaneously to a 5-week course of irradiation up to a total dose of 50.4 Gy, 1.8 Gy daily fractions followed by a boost of 5.4 or 9.0 Gy to the gross tumor volume. Nineteen patients were treated and 14 received the full chemotherapy with delivery of all planned radiotherapy. The MTD of UFT was 400 mg/m /day due to the occurrence of dose-limiting diarrhea and emesis. Toxicities were mild and manageable on the lower dose levels. Treatment was feasible mainly on an outpatient base. We conclude that combined chemoradiation with oral UFT+LV is feasible and well tolerated for recurrent rectal cancer patients undergoing pelvic radiation. The safety profile appears comparable to that of i.v. dosing without requiring any i.v. port systems. The recommended doses for further phase II chemoradiation trials are 350 mg/m /day UFT+90 mg LV.     

Information from US FDA——Impact of Severe Weather Conditions on Biological Products & FDA Drug Safety Communication: FDA review finds additional data supports the potential for increased long-term risks with antibiotic clarithromycin (Biaxin) in patients with heart disease

The U.S. Food and Drug Administration today approved Imfinzi (durvalumab) for the treatment of patients with stage III non-small cell lung cancer (NSCLC) whose tumors are not able to be surgically removed (unresectable) and whose cancer has not progressed after treatment with chemotherapy and radiation (chemoradiation). “This is the first treatment approved for stage III unresectable non-small cell lung cancer to reduce the risk of the cancer progressing, when the cancer has not worsened after chemoradiation,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “For patients with stage III lung cancer that cannot be removed surgically, the current approach to prevent progression is chemoradiation. Although a small number of patients may be cured with the chemoradiation, the cancer may eventually progress. Patients now have an approved therapy that has been shown to keep the cancer from progressing for a longer time after chemoradiation.”     

肿瘤体积对局部晚期非小细胞肺癌三维立体放疗预后的影响

目的回顾分析肿瘤体积对ⅢA期和ⅢB期非小细胞肺癌患者三维立体适形放疗预后的影响。方法 2002～2009年间64例患者入组分析。23例采用单独放疗、23例采用同步放化疗、18例序贯放化疗。放疗的中位剂量是60（50～78）Gy。结果全组1、3、5年总生存率和中位生存期分别是69.7%,22.7%和10.4%,18.6个月,1、3、5年肿瘤专项生存率依次为73.8%,29.7%和15.8%。单因素分析提示近期疗效、纵隔淋巴结预防照射、放疗总剂量、肿瘤体积与总生存率及肿瘤专项生存率有显著相关性;多因素分析表明肿瘤体积和近期疗效是总生存及肿瘤专项生存的最重要的影响因素。评价预后的最佳肿瘤体积分界值可能是80cm3。结论三维立体适形放疗治疗不能手术的局部晚期非小细胞肺癌时,肿瘤体积和近期疗效是显著影响总生存和肿瘤专项生存的两个因素。80cm3可能是影响预后的最佳肿瘤体积分界点。     

透明细胞型肝癌患者术后复发和生存状况研究

目的：探究原发性透明细胞型肝细胞肝癌（PCCCL）患者术后复发和生存状况。方法选取2010年1月—2013年1月期间该院接收治疗的原发性透明细胞型肝癌患者226例,分析患者的临床资料和术后随访资料。根据治疗方法将226例患者分为两组,对照组有113例患者,采用根治性手术治疗。观察组有113例患者,采用根治性手术＋术后化疗进行治疗。患者在术后1年或者1年内复发为早期复发,在术后1年以上复发为晚期复发。分析两组患者的术后复发率和生存率,探究影响透明细胞型肝癌术后复发的相关因素。结果226例患者中有45例术后复发,其中早期复发患者15例,晚期复发患者30例。观察组患者在术后1、2、3年内的总生存较对照组无明显差异（P＞0．05）。观察组患者在术后1、2、3年内的总复发率较对照组患者无明显差异,比较两组差异不具有统计学意义（P＞0．05）。多因素分析两组患者术后复发因素,讨论得出年龄是PC-CCL患者术后晚期复发惟一的独立危险因素。血管侵犯、肿瘤＞5 cm、血清谷丙转氨酶（ALT）＞40 U·L－1和丙氨酯转氨酶水平是PCCCL患者术后早期复发的独立危险因素。结论明确PCCCL患者晚期复发和早期复发的各种危险因素,可以及时发现患者的术后复发,提高患者术后生存率。     

Emerging drugs for esophageal cancer

Background: Cancer of the esophagus and gastro-esophageal junction is a disorder with a poor prognosis and increasing incidence. Objective: To provide a critical evaluation of current treatment strategies and new developments including targeted therapy for esophageal cancer. Methods: Published clinical trials as well as abstracts were selected regarding chemoradiation or targeted therapy for esophageal cancer. Results/conclusions: Preoperative chemotherapy may offer a survival advantage compared to surgery alone, but the evidence is inconclusive. For preoperative chemoradiation, only 2 of 10 randomized trials showed advanced survival compared to surgery alone, and, therefore, more Phase III trials and, consequently, meta-analyses are needed. Until now, for palliative chemotherapy, no survival benefit has been shown. This is largely due to a lack of studies and difficulties in performing randomized trials. The application of targeted therapy is widespread and reported for several tumor types. For esophageal cancer, most studies have been performed with EGFR inhibitors, including cetuximab, gefitinib, erlotinib and trastuzumab. Limited experience is available with angiogenesis inhibitors, apoptosis inhibitors and COX-2 inhibitors. As yet, targeted therapies are proven to be safe often in combination with chemoradiation, but modestly effective for esophageal cancer. Phase III trials have not been published yet and, therefore, for targeted therapies also, possibly using new concepts, more studies are needed.     

Cellular therapy for ovarian cancer: experimental and clinical perspectives

Ovarian cancer is the leading cause of death among gynecologic malignancies and the 5th leading cause of cancer deaths for women in the United States. Two-thirds of patients present with advanced-stage disease (Stage III and IV) and the majority will suffer recurrence of disease, require ongoing treatment, and eventually succumb to chemotherapy-resistant disease. To potentially circumvent chemo-resistance in recurrent ovarian cancer, immunotherapy is being explored as a novel treatment option. Our laboratory findings demonstrate that immune effector cells from healthy donors elicit a significant cytotoxic response in the presence of IL-2 and IFN alpha- 2b against ovarian cancer in vitro; however, peripheral blood mononuclear cells (PBMC) isolated from ovarian cancer patients fail to elicit a similar response. A major obstacle to immunotherapy is the immunosuppressive environment supported by tumors, which limits the immune system's ability to fight the tumor. Myeloid-derived suppressor cells are an immature population of myeloid cells, which have recently been implicated to play a major role in immunosuppression and tumor evasion. In addition to novel immunotherapies, new diagnostic and prognostic markers are being identified through applying molecular tools/approaches in clinical and pathological analyses of this malignancy, which will provide additional therapeutic targets. To test these experimental therapeutic options, pre-clinical murine models of ovarian cancer are being developed. Ultimately, treatment of ovarian cancer will benefit from the careful alignment of appropriate target, drug, patient, and trial design. This article provides an objective overview of cellular therapy (the use of immune cells to elicit an anti-tumor response) for ovarian cancer highlighting both experimental and clinical perspectives.     

Gene-expression assays: new tools to individualize treatment of early-stage breast cancer.

PURPOSE: The clinical and economic data for the two currently available gene-expression assays are reviewed. SUMMARY: Two gene-expression assays, used to determine the risk of breast cancer recurrence in patients with stage I or II node-negative breast cancer, are currently available. Oncotype DX is an assay performed on RNA extracted from paraffin-embedded tumor tissue. It analyzes the expression of 21 genes: 16 cancer-related genes and 5 reference genes. The results are used to calculate a recurrence score to identify the likelihood of cancer recurrence in patients treated with tamoxifen. The results of two studies evaluating the ability of Oncotype DX to predict the risk of breast cancer recurrence suggest that patients with ER-positive, node-negative breast cancer and a low recurrence score may need only adjuvant treatment with tamoxifen, while intermediate- and high-risk patients may require additional treatment with adjuvant chemotherapy. MammaPrint, an oligonucleotide microassay performed on fresh-frozen tumor samples, analyzes the expression of 70 genes. Studies have found that MammaPrint allows young patients (<61 years) with early-stage breast cancer to be categorized as having a high or low risk of distant metastasis. High-risk patients may then be managed with more aggressive therapy. CONCLUSION: Two gene-expression assays, Oncotype DX and MammaPrint, have been developed to determine the risk of breast cancer recurrence in patients with stage I or II node-negative breast cancer. In the future, these tests may be useful in determining the need for systemic adjuvant therapy in such patients.     

Extended adjuvant endocrine therapy of early breast cancer

ABSTRACT

Women who are diagnosed with early breast cancer remain at considerable risk of recurrence over the next several decades, even if their tumors were small and lymph nodes were negative, and despite receiving standard adjuvant therapy. A majority of breast cancers are hormone (estrogen) receptor-positive and amenable to endocrine therapy, and for those women five years of the selective estrogen receptor modulator tamoxifen is standard therapy. Longer treatment of node-negative patients with tamoxifen may reduce survival benefits, however, possibly due to tamoxifen resistance and emerging receptor agonist activity of that drug. Aromatase inhibitors, which indirectly prevent estrogen stimulation of breast cancer by suppressing whole-body estrogen synthesis in post-menopausal women, are being investigated as alternative, or complementary, therapy to adjuvant tamoxifen in those women: as an alternative to five years of tamoxifen, sequenced with two to three years of tamoxifen, or following five years of tamoxifen. The strategy to extend the benefits of adjuvant therapy beyond a standard course of tamoxifen, using the aromatase inhibitor letrozole, was explored in a large trial, MA.17. Compared with women who received placebo, those who were treated with letrozole experienced a significant 43% reduction in their residual risk of recurrence. This effect was seen regardless of nodal status. Based on the long-term risk of most women with early breast cancer and the MA.17 trial results, the extended adjuvant letrozole may benefit many of those women who are disease-free after five years of tamoxifen.

This review is based on a literature search of databases including MEDLINE/PubMed, San Antonio Breast Cancer Symposium, and the Annual Meeting of the American Society of Clinical Oncology, up to and including August 2005, with information selected for its relevance to adjuvant therapy of breast cancer with endocrine therapy only.     

126例低位直肠癌的保肛治疗

目的:探讨低位直肠癌的保肛治疗.方法:分析126例低位直肠癌保肛治疗的临床资料. 结果:126位保肛治疗病例,局部复发率14%,1年、3年、5年生存率分别为100%、90%、72%.结论:对符合保肛条件者行保肛治疗,对远期生存率和局部复发率无不良影响,提高了生存质量.     

Adjuvant therapy of colorectal cancer: the next step forward

Adjuvant therapy for colorectal cancer includes chemotherapy, radiotherapy and immunotherapy. It is advocated in patients who are at significant risk of developing recurrence. We review recent advances in adjuvant treatment for colorectal cancer. Although colorectal cancer is often considered as a single entity, it is being increasingly recognised that colon and rectal cancers are distinct disease groups and separate therapeutic strategies should be considered for each. In colonic cancer, 5-fluorouracil is used, with or without other agents. Both preoperative radiotherapy and postoperative chemoradiotherapy have been used in rectal cancer. The development of oral chemotherapeutic agents has been a significant step in the management of colorectal cancer, while newer agents have been introduced with good results. Targeting the immune response and genetic manipulations are being developed as innovative management strategies. Although adjuvant therapy has improved outcome in colorectal cancer, stress should be laid on identifying patients who need adjuvant therapy, permitting individualisation of treatment strategy. Apart from including survival and local recurrence as outcome measures, new therapeutic approaches should be assessed in terms of quality of life of the patient.     

Locally advanced rectal cancer: a comparison of management strategies

Traditionally, there has been a high local recurrence rate in rectal cancer and 10-40% of patients require a permanent stoma. Both short-course preoperative radiotherapy (SCPRT) and long-course preoperative chemoradiation (CRT) are used to reduce the risk of local recurrence and enable a curative resection. Total mesorectal excision has reduced the rate of local recurrence (even without radiotherapy) to below 10%, but has highlighted a high risk of metastatic disease in 30-40% of patients. Current trials suggest that in resectable cancers, where the preoperative magnetic resonance imaging (MRI) suggests the circumferential resection margin (CRM) is not potentially involved, then SCPRT and CRT are equivalent in terms of outcomes such as local recurrence, disease-free survival (DFS) and overall survival (OS). For patients with more advanced disease, where the CRM is breached or threatened according to the MRI, the integration of more active chemotherapy and biological agents into chemoradiation is an attractive strategy because of the high risk of metastases. However, in none of the trials published in the last decade has chemoradiation impacted on DFS or OS. We examine the strategies of neoadjuvant, concurrent, consolidation (after chemoradiation and before surgery) and postoperative adjuvant chemotherapy with cytotoxic agents, and the integration of biological agents for future potential strategies of treatment. We also compare the trials and compare the different strategies of long-course preoperative radiotherapy and SCPRT; the intensification of preoperative radiation and chemoradiation with dose escalation of external beam radiotherapy, using brachytherapy, intra-operative radiotherapy, hyperfractionation, and various available techniques such as intensity-modulated radiotherapy. We recommend examining dose escalation of radiotherapy to the primary tumour where MRI predicts a threatened CRM. Of the potential treatment strategies involving cytotoxic agents, such as neoadjuvant, concurrent, consolidation and postoperative adjuvant chemotherapy, the most promising would appear to be consolidation chemotherapy following chemoradiation in locally advanced disease, and neoadjuvant chemotherapy in MRI-selected patients who do not require radiation. Improvement in the quality of surgery is also an important future goal.