结肠癌全身辅助化疗的进展

Ⅲ期结肠癌的术后辅助化疗具有明显的生存效益,主要采用以5-FU为基础的全身化疗方案,包括5-FU/Lev、Mayo(FU/LV)方案、持续小剂量灌注(PVI)5-FU、口服氟尿嘧啶类抗癌药(UFT、Xeloda)等;5-FU合用草酸铂可以进一步提高疗效,与依立替康合用的疗效有待于进一步研究。Ⅱ期结肠癌术后辅助化疗的生存效益目前尚有争议,对高危Ⅱ期肠癌患者也应考虑行术后辅助化疗。本文综述了近年来结肠癌术后辅助化疗的进展。     

基于循证医学依据的结肠癌辅助化疗

目前,氟尿嘧啶仍是结肠癌辅助化疗的基本药物,含5-FU/LV/奥沙利铂(FOLFOX或FLOX)的方案是结肠癌辅助化疗的新标准,对部分患者也可以考虑选用5-FU/LV(Mayo,Roswell Park,LV5 FU2)、卡培他滨等单药辅助化疗;目前没有证据表明辅助化疗中使用伊立替康能带来额外的获益,反而会增加化疗毒性的风险,因此,不建议在结肠癌辅助化疗中使用含伊立替康的方案。Ⅲ期结肠癌是辅助化疗的主要适应证,而"高危Ⅱ期"结肠癌也应该在患者充分知情后给予辅助化疗,高危因素包括T4肿瘤、伴有肠梗阻、穿孔、肿瘤分化差、伴有神经脉管浸润以及切除或送检淋巴结<12枚。其他的Ⅱ期结肠癌不应该常规行辅助化疗。只要身体状况允许,年龄不应该是选择辅助化疗的禁忌;结肠癌辅助化疗建议在术后8周内开始,目前的标准疗程是为期6个月。     

The role of adjuvant chemotherapy in colon cancer

Surgical resection of the primary and regional lymph nodes is still, at this time, the standard treatment of colon cancer. However, the risk of recurrence is still high in many patients. Efforts of the past decades have proved the role of systemic chemotherapy in the adjuvant setting in improving the curative rates. The combination of 5-fluorouracil (5-FU)and leucovorin (LV) remains the cornestorne of colon cancer chemotherapy worldwide. The addition of Oxaliplatin to infusional 5FU/LV has been shown to prolong significantly disease-free survival and capecitabine may be considered as an alternative to 5-FU/LV in the adjuvant therapy of stage III colon cancer. Novel molecular and biological-oriented agents are being studied, with promising date.     

Timing of adjuvant chemotherapy initiation after surgery for stage III colon cancer

BACKGROUND: An important advance in medical oncology has been the use of adjuvant chemotherapy for lymph node-positive colon cancer. However, to the authors' knowledge, the effect of the interval between surgery and the initiation of chemotherapy on survival has not been investigated. METHODS: The authors analyzed predictors and outcomes of time intervals to treatment after surgery among patients older than 65 years who were diagnosed with stage III colon cancer between 1992 and 1999 using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Linear and logistic regression analyses were used to model predictors of delay, and Cox proportional hazards models were used to analyze the impact of treatment timing on survival. RESULTS: Among 4382 patients with colon cancer, 1122 patients (26%) began adjuvant chemotherapy within 1 month, 2391 patients (55%) began adjuvant chemotherapy in 1 to 2 months, 454 patients (10%) began adjuvant chemotherapy in 2 to 3 months, and 415 patients (9%) began adjuvant chemotherapy >/=3 months after surgery. Intervals of >/=3 months (delay) were associated with older age, increased comorbid conditions, well/moderately differentiated grade, and being unmarried. Colon cancer-specific mortality was associated with a delay in the initiation of chemotherapy (hazards ratio [HR], 1.48; 95% confidence interval [95% CI], 1.15-1.92), advanced age, increased comorbidity, poorly differentiated tumor grade, the presence of >/=4 positive lymph nodes, and undergoing surgery in a nonteaching hospital. All-cause mortality was associated with intervals >2 months between surgery and chemotherapy (2 to 3 months: HR, 1.41; 95% CI, 1.15-1.74; >/=3 months: HR, 1.62; 95% CI, 1.31-1.99) compared with <1 month. CONCLUSIONS: In the older population that was studied, only 9% of patients initiated adjuvant chemotherapy >3 months after the date of curative surgery. However, delay in initiation was associated with both cancer-specific and all-cause mortality. Determining whether these results were because of chemotherapy timing or other associated factors will require further study.     

An overview of randomised controlled trials of adjuvant chemotherapy in head and neck cancer.

Meta-analysis of the published results from 54 randomised controlled trials of adjuvant chemotherapy in head and neck cancer suggests that chemotherapy might increase absolute survival by 6.5% (95% confidence interval 3.1-9.9%). The odds ratio in favour of chemotherapy is 1.37 (95% confidence interval 1.24-1.5). Single-agent chemotherapy given synchronously with radiotherapy increased survival by 12.1% (95% confidence interval 5-19%). The benefit from neoadjuvant chemotherapy was less: a rate difference of 3.7% (95% confidence interval 0.9-6.5%). The results suggest that the investigation of optimal agents and scheduling for synchronous radiotherapy and chemotherapy might still be important in clinical trials in head and neck cancer.     

An overview of 48 elderly-specific clinical trials of systemic chemotherapy for advanced non-small cell lung cancer

PURPOSE: The aim of the present study was to identify elderly-specific clinical trials for advanced non-small cell lung cancer (NSCLC) and to clarify the study design and patient characteristics entered of each of these trials. METHODS: We used the MEDLINE database to select prospective clinical trials evaluating the efficacy of chemotherapy in elderly patients with advanced NSCLC. RESULTS: Our literature search yielded 48 prospective clinical trials between 1990 and 2003, involving a total of 2648 elderly patients with advanced NSCLC. The median number of patients treated per trial was 36. In 23 (48%) of the 48 trials, only the abstract was available. In 44 trials (92%), elderly patients were defined using their calendar age, and the age of 70 years was the most frequently used lower limit for inclusion. Vinorelbine was the most widely studied chemotherapy agent in elderly patients. CONCLUSIONS: Our review revealed that (i) the definition of "elderly" varied from trial to trial, and elderly patients were simply defined using calendar age in the clinical trials; (ii) the quality of elderly-specific trials were generally poor, mainly because of their small sample size.     

Age and adjuvant chemotherapy use after surgery for stage III colon cancer

BACKGROUND: Randomized trials have established that 5-fluorouracil-based adjuvant chemotherapy following resection of stage III colon cancer reduces subsequent mortality by as much as 30%. However, the extent to which adjuvant therapy is used outside the clinical trial setting, particularly among the elderly, is unknown. METHODS: A retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results/Medicare-linked database identified 6262 patients aged 65 years and older with resected stage III colon cancer. The primary outcome was chemotherapy use within 3 months of surgery, as ascertained from Medicare claims. We examined the extent to which age at diagnosis was associated with adjuvant chemotherapy usage, and we adjusted for potential confounding based on differences in other patient characteristics with the use of multiple logistic regression. All P values were two-sided. RESULTS: Age at diagnosis was the strongest determinant of chemotherapy: 78% of patients aged 65-69 years, 74% of those aged 70-74 years, 58% of those aged 75-79 years, 34% of those aged 80-84 years, and 11% of those aged 85-89 years received postoperative chemotherapy. The age trend remained pronounced after adjustment for potential confounding based on variation in patients' demographic and clinical characteristics and after exclusion of patients with any evident comorbidity (all P values <.001). CONCLUSIONS: Adjuvant chemotherapy for stage III colon cancer is used extensively, especially for patients under the age of 75 years. However, treatment rates decline dramatically with chronologic age. Because patients in their 70s and even 80s have a reasonable life expectancy, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding this potentially curative treatment.     

From chemotherapy to targeted therapy in adjuvant treatment for stage III colon cancer

Colorectal cancer represents a major public health problem due to its frequency and mortality rate. Adjuvant chemotherapy has improved the prognosis of colon cancer. Six months of oxaliplatin and fluoropyrimidine in combination is the standard adjuvant treatment in stage III patients. Ongoing trials are evaluating the optimal duration of chemotherapy. A critical issue, which needs to be specifically addressed, is the role of adjuvant therapy in elderly patients. Preliminary results of trials evaluating targeted therapies in combination with chemotherapy have shown disappointing results. The monoclonal antibodies bevacizumab, targeting vascular endothelial growth factor (VEGF) and cetuximab, targeting epidermal growth factor receptor (EGFR)/HER1, which improved survival in patients with metastatic colorectal cancer, could even induce chemotherapy resistance in a significant number of patients in the adjuvant setting. A major challenge is emerging to understand the mechanism leading to this effect and to multi-target the tumor cell proliferation and survival network. Clarity regarding the clinical signal needed before launching a phase III study and optimized designs adapted to multiple agents are urgently needed for new trials.     

Palliative oxaliplatin-based chemotherapy after exposure to oxaliplatin in the adjuvant setting for colon cancer

Background

Little is known regarding the efficacy of oxaliplatin-based chemotherapy for metastatic colon cancer patients who have already received adjuvant oxaliplatin-based chemotherapy.

Methods

We retrospectively reviewed 22 consecutive patients who developed recurrence after adjuvant oxaliplatin-based chemotherapy for stage III colon cancer and received another course of oxaliplatin-based chemotherapy for their metastatic disease. The main endpoint was progression-free survival (PFS).

Results

A total of 635 patients received oxaliplatin-based chemotherapy for stage III colon cancer at the British Columbia Cancer Agency from 2006 to 2011. A total of 176 patients recurred, 22 (12.5%) of whom were re-exposed to oxaliplatin in the metastatic scenario. Oxaliplatin in combination with fluoropyrimidine was given as first, second and third line in in 3 (13.6%), 14 (63.6%), and 5 (22.7%) patients respectively. Median time from the last cycle of adjuvant oxaliplatin-based chemotherapy to the first cycle of palliative oxaliplatin-based chemotherapy was 44.3 months. Median PFS and overall survival (OS) were 3.3 (95% CI, 1.4-5.1) and 10.0 months (95% CI, 5.3-14.6), respectively. There was no difference in PFS for patients re-exposed to oxaliplatin less than 36 months compared to longer (3.6 versus 3.1 months, P=0.793, HR =0.88).

Conclusions

In this population-based study, only a small proportion of pts who recurred after oxaliplatin-based adjuvant therapy received oxaliplatin in the metastatic setting. Re-exposure of oxaliplatin in combination with fluoropyrimidine is associated with only modest PFS benefit. Larger studies evaluating the role of oxaliplatin re-exposure are needed.     

Adjuvant chemotherapy for colon cancer

Colon cancer remains the third most common cancer, and cause of cancer-related death in the United States. Greater public awareness and acceptance of screening programs have contributed significantly to increasingly earlier detection of colon cancer and decreased mortality. Advances made in the understanding of this disease, both in terms of its clinical behavior and molecular pathogenesis, have translated into major improvements in its therapy. Several large randomized trials during the last two decades have helped the oncology community forge a successful multi-modality treatment strategy against colon cancer. These studies have defined the role of adjuvant therapy for colon cancer after curative surgery. Despite all the advances, a large number of patients continue to succumb to this disease, and the search for better therapies is still necessary. In this article, we discuss the evolution and the current state of adjuvant chemotherapy in colon cancer and briefly review new developments.     

Guides for adjuvant treatment of colon cancer

The choice of the most suitable chemotherapy schedule for the adjuvant treatment of colon cancer has been reviewed by the TTD group, as well as the principles of risk assessment for patients with stage II disease. In the light of data now available, oxaliplatin-based schedules (FOLFOX4 or FLOX) are recommended. Alternatives in special situations are monotherapy with capecitabine, UFT/LV, or 5-FU/LV in infusion. In patients with stage II disease, the indication of chemotherapy must be individualized and based on the patient’s risk of recurrence (perforation, obstruction, peritumoral lymphovascular involvement, poorly differentiated histology, number of lymph nodes examined ≤11, pre-surgical CEA), and comorbidities that can compromise the safety of treatment or survival of the patient.     

Risk assessment and adjuvant systemic therapy in resected stage II colon cancer

Adjuvant chemotherapy following surgical resection of stage III colon cancer has become the standard of care based on numerous large randomized trials that have demonstrated benefit in overall survival. For patients with stage II colon cancer, the picture is more uncertain. Although clinical trials have not reported a significant survival benefit for adjuvant chemotherapy in stage II disease, patients with certain high-risk clinical and pathologic features may warrant postoperative treatment. Molecular markers, such as 18q loss of heterozygosity and mi crosatellite instability, may also help to prognosticate patients with stage II colon cancer, although data supporting their role have been largely retrospective. The role of these markers in stage II disease is being prospectively investigated. Continued enrollment in clinical trials and further risk stratification will help clarify the optimal management of patients with stage II colon cancer.