PURPOSEThe National Surgical Adjuvant Breast and Bowel Project trial C-08 was designed to investigate the safety and efficacy of adding bevacizumab to fluorouracil, leucovorin, and oxaliplatin (FOLFOX6) for the adjuvant treatment of patients with stage 2-3 colon cancer. Our report summarizes the primary and secondary end points of disease-free and overall survival, respectively, with 5 years median follow-up time.Patients And methodsPatients received modified FOLFOX6 once every 2 weeks for a 6-month period (control group) or modified FOLFOX6 for 6 months plus bevacizumab (5 mg/kg) once every 2 weeks for a 12-month period (experimental group). The primary end point of the study was disease-free survival (DFS) and overall survival (OS) was a secondary end point.ResultsOf 2,673 analyzed patients, demographic factors were well-balanced by treatment. With a median follow-up of 5 years, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.93; 95% CI, 0.81 to 1.08; P = .35). Exploratory analyses found that the effect of bevacizumab on DFS was different before and after a 1.25-year landmark (time-by-treatment interaction P value <.0001). The secondary end point of OS was no different between the two study arms for all patients (HR, 0.95; 95% CI, 0.79 to 1.13; P = .56) and for those with stage 3 disease (HR, 1.0; 95% CI, 0.83 to 1.21; P = .99). CONCLUSION
Bevacizumab for 1 year with modified FOLFOX6 does not significantly prolong DFS or OS in stage 2-3 colon cancer. We observed no evidence of a detrimental effect of exposure to bevacizumab. A transient effect on disease-free survival was observed during bevacizumab exposure in the study's experimental arm.
"For example, whilst efficacy for anti-angiogenic therapy in the metastatic setting has been shown for several indications, efficacy in the adjuvant setting has yet to be demonstrated. Findings indicating that bevacizumab is effective in the metastatic setting in colorectal cancer , but ineffective in the adjuvant setting for the same disease [56, 57], may have important consequences. Many trials of anti-angiogenic agents in the adjuvant setting are currently underway. "
[Show abstract][Hide abstract] ABSTRACT: Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies.
"However, as co-opted vessels are also important in early stage of tumor development it would be of interest to know whether vessel co-option partly may be one of the reasons why antiangiogenic treatment has not succeeded so far in an adjuvant setting 46,47. "
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis has been regarded as essential for tumor growth and progression. Studies of many human tumors, however, suggest that their microcirculation may be provided by nonsprouting vessels and that a variety of tumors can grow and metastasize without angiogenesis. Vessel co-option, where tumor cells migrate along the preexisting vessels of the host organ, is regarded as an alternative tumor blood supply. Vessel co-option may occur in many malignancies, but so far mostly reported in highly vascularized tissues such as brain, lung, and liver. In primary and metastatic lung cancer and liver metastasis from different primary origins, as much as 10–30% of the tumors are reported to use this alternative blood supply. In addition, vessel co-option is introduced as a potential explanation of antiangiogenic drug resistance, although the impact of vessel co-option in this clinical setting is still to be further explored. In this review we discuss tumor vessel co-option with specific examples of vessel co-option in primary and secondary tumors and a consideration of the clinical implications of this alternative tumor blood supply.
Both primary and metastatic tumors use preexisting host tissue vessels as their blood supply. Tumors may grow to a clinically detectable size without angiogenesis and makes them less likely to respond to drugs designed to target the abnormal vasculature produced by angiogenesis, but further studies to explore the biological and clinical implication of these co-opted vessels is needed.
Cancer Medicine 08/2013; 2(4):427-36. DOI:10.1002/cam4.105 · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer (CRC) places a considerable burden on individuals and society in Europe, being the second most common cause of cancer-related death in the region. While earlier diagnosis and advances in treatment have considerably improved survival in recent years, further progress is needed. One of the greatest challenges associated with the treatment of CRC is the fact that current therapies for advanced disease are not curative, necessitating treatment for many years and placing a significant healthcare burden on society. To reduce the burden of CRC, care delivery must be more efficient and cost-effective. In particular, development of adequate screening programmes is needed, along with chemo-preventative strategies and newer, more active therapies. Further challenges include the lack of optimal selection of patients for adjuvant therapy, identification of the most appropriate target populations for current treatments and the optimum sequence for new molecular targeted agents. This article outlines current developments and unmet needs in CRC, and provides a detailed vision for improvements in the management of the disease. Implementation of some of these strategies will go some way to improving outcomes for patients with CRC.
European journal of cancer (Oxford, England: 1990) 04/2013; 49(11). DOI:10.1016/j.ejca.2013.03.026 · 5.42 Impact Factor
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