Adjuvant Treatment Of Colon Cancer Research Articles

Adjuvant Chemotherapy Using the FOLFOX Regimen in Colon Cancer

PurposeGreat progress has been made in the adjuvant treatment of colon cancer. The aim of this study was to evaluate the efficacy of postoperative adjuvant chemotherapy using the FOLFOX regimen in patients with stage III and high-risk stage II colon cancer.MethodsEighty-two patients who underwent a potentially curative resection for stage III or high-risk stage II colon cancer were enrolled in this retrospective study. They received FOLFOX4 or modified FOLFOX6. The primary endpoint was disease-free survival.ResultsDuring the median follow-up of 37 months (range, 21 to 61 months), 14 patients experienced disease relapse. The disease-free survival rate at 3 years was 82.9%: 84.6% for stage II and 82.6% for stage III. At the time of the analysis, 8 patients were dead from recurrence. The probability of overall survival at 5 years was 74.5%: 90% for stage II and 74.6% for stage III. Grade 3 or 4 hematologic adverse events included neutropenia (40.2%), anemia (2.4%), and thrombocytopenia (1.2%). Gastrointestinal toxicities included grade 3 or 4 nausea (4.9%) and stomatitis (2.4%). Peripheral sensory neuropathy was observed in 81.7% of the patients during treatment. Of the 11 patients (13.4%) who had grade 3 peripheral sensory neuropathy during treatment, grade 3 symptoms were persistent in 3 patients with gait disturbance at the time of analysis. No treatment-related deaths were recorded.ConclusionPostoperative chemotherapy using the FOLFOX regimen, oxaliplatin in combination with 5-fluorouracil and leucovorin, is effective and tolerable in patients with stage III and high-risk stage II colon cancer.

Oxaliplatin-Induced Neuropathy in Colorectal Cancer

Oxaliplatin use in palliative and adjuvant treatment of colon cancer is frequently limited by cumulative neurotoxicity, leading to reduced quality of life and decreased dose. The mechanism of this neurotoxicity is unclear, but may relate to neuronal voltage-gated sodium channels involving calcium chelation by a metabolite of the drug. Various preventative measures have been tested to reduce the incidence of neurotoxicity, including calcium and magnesium infusions, dose interruption of the drug, and prophylactic neuromodulatory agents. Despite the promising efficacy of these measures, they are not universally accepted. Less is known about the best way to treat established neurotoxicity, which is permanent in some patients, although venlafaxine has shown promise in small clinical trials. This paper analyzes the extent, cause and risk factors for neuropathy, and the potential preventative and therapeutic treatments for oxaliplatin-induced neuropathy.

Advances in research on capecitabine as adjuvant treatment for colon cancer after radical resection

结直肠癌是最常见的恶性肿瘤之一,据统计,2007年全球新发病例120万,居恶性肿瘤第3位,同年死亡病例为60万.手术切除是治愈结直肠癌最好的手段,而术后辅助化疗能减少复发和转移风险,进一步提高疗效.除传统药物5-氟尿嘧啶（5-Fu）外,近年来,出现了很多被证明对结肠癌有确实疗效的药物,如卡培他滨、伊立替康和奥沙利铂,这些药物都在全球范围内进行并完成了结肠癌的临床试验,其中卡培他滨和奥沙利铂被证明应用于辅助治疗有效.这些循证医学的证据使得结肠癌的辅助化疗发生了很大的变化,并趋于规范.本文在循证医学证据的基础上,就结肠癌的辅助治疗,尤其是卡培他滨应用方面的进展进行回顾.

SEOM clinical guidelines for the adjuvant treatment of colorectal cancer

Colorectal cancer is the third most common malignant neoplasm and the second cause of death by cancer in western countries. In this manuscript, the clinical guidelines of the Spanish Society of Medical Oncology (SEOM) for diagnosis and adjuvant treatment of colon cancer and rectal cancer are reported.

The Annual Meeting of the American Society of Clinical Oncology

The current standard of care for stage III resected colon cancer is 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (FOLFOX) chemotherapy, based on significant improvements in disease-free survival (DFS) compared to 5-FU/LV in the MOSAIC (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) and National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 phase III trials. 1 Andre T Boni C Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009; 27: 3109-3116 Crossref PubMed Scopus (1712) Google Scholar , 2 Kuebler JP Wieand HS O'Connell MJ et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007; 25: 2198-2204 Crossref PubMed Scopus (871) Google Scholar The addition of biologic agents, such as those targeting the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), to chemotherapy has significantly improved clinical outcome in the metastatic setting and is now under investigation in earlier stages of disease.

Adjuvant therapy in colorectal cancer – studies of the FOGT group

The FOGT (Study Group for GI-Oncology) was formed among clinicians and scientists with the aim of testing innovative scientific concepts in gastrointestinal tumors, especially colorectal cancers, within controlled clinical studies. In the FOGT-1 trial (n=813stage III or II(T4N0) colon cancer patients) the effect on recurrence-free and overall survivalwas tested by an adjuvant chemotherapy protocol with double-modulation of 5-fluorouracil (5-FU) and levamisole (LEV) with either folinic acid (FA) or interferon-alpha (IFNa) in a three arm randomized trial within 60 German cancer centers. In parallel, in the FOGT-2 trial stage II or III rectal cancer patients (n = 796 pts.) were treated with additional postoperative radiochemotherapy (50,4 Gy). The most effective arm of these trials was tested as control arm versus a 5-FU/FA/irinotecan (FOLFIRI) protocol in the two-arm FOGT-4 trial (n = 281stage III or II(T4N0) colon cancer pts.) for adjuvant therapy in colon cancer. In the FOGT-1 trial, we found a 11% overall survival (OAS) benefit in patients who were treated for one year adjuvantly with 5-FU plus FA (77% OAS), compared to treatment with either 5-FU or 5-FU plus interferon-alpha (each 66% OAS). This effect was statistically significant for colon cancer patients (FOGT-1), but not for rectal cancer patients (FOGT-2). In rectal cancer, the 5-FU plus FA arm showed this effect with a 12% survival benefit only in the stage II subgroup. The FA modulation of 5-FU was safe and cost-effective. The modulation with IFNa was less effective and caused more toxicity, mainly diarrhea in rectal cancer patients. When the 5FU/FA protocol was slightly modulated (treatment for 6 months, no LEV) and compared to the FOLFIRI protocol (FOGT-4), survival and toxicity in the 5FU/FA arm was similar to the toxicity observed in the earlier studies, and the FOLFIRI arm was significantly more toxic (40% vs. 14% grade III/IV toxicity) without any benefit in recurrence rates (25% vs. 23% local/systemic recurrence) or survival. The FOGT-4 study confirms three other studies that – in contrast to palliative treatment protocols – did not find any benefit for the role of irinotecan in the adjuvant treatment of colon cancer. In conclusion, by conducting the three FOGT-studies with more than 1800 patients, we identified a safe and effective treatment protocol for adjuvant therapy in colon cancer, consisting of infusional 5-fluorouracil and folinic acid, given for at least six months, and well combinable with additional postoperative radiotherapy. This protocol was not improved by addition of irinotecan in colon cancer patients.

Hepatic steatosis secondary to capecitabine: a case report

IntroductionThere are no known case reports of hepatic steatosis caused by oral fluoropyrimidines such as capecitabine. With increasing use of capecitabine since its approval for the treatment of metastatic colon cancer in 2001, and more recently for adjuvant treatment of colon cancer and treatment of metastatic breast cancer, we can anticipate increased recognition of potential toxicities associated with this 5-fluorouracil derivative.Case presentationWe report the case of a 74-year-old Armenian woman who received capecitabine as adjuvant treatment for colon cancer and subsequently developed abnormal liver biochemical tests and radiographic findings in keeping with hepatic steatosis. There was complete reversal of liver enzyme abnormalities with discontinuation of the drug and this patient represents a case of reversible liver injury due to capecitabine.ConclusionIn this original case report, capecitabine use was associated with hepatic steatosis. It is important for clinicians to recognize and monitor for this potential toxicity, which may be a cause of abnormal liver enzymes in this patient population.

Evaluation of Bevacizumab in the Adjuvant Treatment of Colon Cancer

Evaluation of Bevacizumab in the Adjuvant Treatment of Colon Cancer

Incidence and evolution of oxaliplatin-induced peripheral sensory neuropathy in diabetic patients with colorectal cancer: a pooled analysis of three phase III studies

BackgroundThe purpose of this study was to determine whether the presence of diabetes mellitus (DM) influences the incidence, severity, and/or course of peripheral sensory neuropathy (PSN) after oxaliplatin (FOLFOX) therapy in patients with colorectal cancer (CRC). MethodsA retrospective pooled analysis incorporating three phase III studies was conducted: Multicenter International Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) (adjuvant treatment; stage II/III colon cancer), EFC4584 (second-line treatment; metastatic CRC), and EFC2962 (first-line treatment; metastatic CRC). Patients were ineligible for the studies if they had known PSN (EFC4584) or PSN grade ≥1 (MOSAIC and EFC2962) at baseline. The incidence of PSN was evaluated retrospectively in patient subgroups with or without DM at baseline that received FOLFOX. Kaplan–Meier curves were used to assess the probability of PSN with increasing cumulative oxaliplatin dose. ResultsOf 1587 patients enrolled across the three studies, 135 (8.5%) had DM at baseline. The incidence of PSN (non-DM/DM) was 45.0%/46.7% (grade 1), 28.6%/26.7% (grade 2), and 13.0%/12.6% (grade 3). The probability of PSN by cumulative dose of oxaliplatin was similar in DM and non-DM patients. ConclusionsThis retrospective analysis indicates that oxaliplatin-based therapy does not influence the incidence, severity, or time to onset of PSN in asymptomatic DM patients with CRC who meet eligibility criteria for clinical trials.

Prognostic and Predictive Biomarkers in Resected Colon Cancer: Current Status and Future Perspectives for Integrating Genomics into Biomarker Discovery

The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era.

Irinotecan in the Adjuvant Treatment of Colon Cancer: Is the Story Finished or Does Personalized Therapy Open New Opportunities?

Irinotecan in the Adjuvant Treatment of Colon Cancer: Is the Story Finished or Does Personalized Therapy Open New Opportunities?

Cost-Effectiveness of Oxaliplatin in the Adjuvant Treatment of Colon Cancer in Canada

The cost-effectiveness of oxaliplatin in combination with 5-fluorouracil/leucovorin (5FU/LV)-the FOLFOX regimen-was compared with that of 5FU/LV alone as adjuvant therapy for patients with stage III colon cancer, from the perspective of the Cancer Care Ontario New Drug Funding Program. In the mosaic (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) trial, the FOLFOX regimen significantly improved disease-free survival. The mosaic trial formed the basis of the present analysis. Extrapolated patient-level data from the mosaic trial were used to model patient outcomes from treatment until death. Utilities were obtained from the literature. Resource utilization data were derived from the mosaic trial and supplemented with data from the literature. Unit costs were obtained from the Ontario Ministry of Health and Long-Term Care, the London Health Sciences Centre, and the literature. Lifetime incremental cost-effectiveness ratios for FOLFOX compared with 5fu/lv were CA$14,266 per disease-free year, CA$23,598 per life-year saved, and CA$24,104 per quality adjusted life-year (QALY) gained, discounting costs and outcomes at 5% per annum. These results were stable for a wide range of inputs; only utility values associated with relapse seemed to influence the cost-effectiveness ratios observed. With an incremental cost of CA$24,104 per QALY gained, FOLFOX is a cost-effective adjuvant treatment for stage iii colon cancer. Compared with 5fu/lv alone, this regimen offers better clinical outcomes and provides good value for money.

Preference values associated with stage III colon cancer and adjuvant chemotherapy

To elicit preference values for health states associated with Stage III colon cancer (CRC) and to explore the effect of neuropathy associated with current adjuvant treatment. We used time trade-off (TTO) techniques to elicit preferences from 49 CRC patients and 49 community members. We elicited preferences for 7 health states: remission; adjuvant therapy with no, mild, moderate, and severe neuropathy; metastatic stable; and metastatic progressive disease. Mean TTO values were adjusted for the covariates age, education, and current health. Patients' adjusted mean TTO value for remission was 0.83; adjuvant chemotherapy health states ranged from 0.48 to 0.61. Significant differences were observed for both patient and community groups between TTO for remission and all adjuvant health states (P < 0.001), and between adjuvant therapy with no neuropathy and metastatic health states (P < or = 0.001). Across all health states, patients' values were on average 0.12 higher than community members (P < 0.05). The findings highlight the trade-offs between the disutility of adjuvant treatment, the higher utility of remission, and the severe utility loss during metastatic disease. The preference values obtained from this study will be useful for informing patients' treatment decisions and payer cost-utility analyses of adjuvant treatment for colon cancer.

Oncologic Outcome after Cessation or Dose Reduction of Capecitabine in Patients with Colon Cancer

PurposeOral capecitabine has been used as adjuvant therapy for colorectal cancer patients since the 1990s. Patient-initiated cessation or reduced use of capecitabine occurs widely for various reasons, yet the consequences of these actions are unclear. The present study sought to clarify treatment outcomes in such patients.MethodsThe study included 173 patients who had been diagnosed with stage II or III colon cancer according to the pathologic report after radical surgery at Samsung Medical Center from May 2005 to June 2007 and who had received capecitabine as adjuvant therapy. The patients were divided into groups according to whether the dose was reduced (I, dose maintenance; II, dose reduction) or stopped (A, cycle completion; B, cycle cessation). Recurrence and disease-free survival rates between the two groups each were analyzed.ResultsOf the 173 patients, 128 (74.6%) experienced complications, most frequently hand-foot syndrome (n = 114). Reduction (n = 35) or cessation (n = 18) of medication was most commonly due to complications. Concerning reduced dosage, both groups displayed no statistically significant differences in recurrence rate and 3-year disease-free survival rate. Concerning discontinued medication use, the cycle completion group showed an improved recurrence rate (P = 0.048) and 3-year disease-free survival rate (P = 0.028).ConclusionThe results demonstrate that maintaining compliance with capecitabine as an adjuvant treatment for colon cancer to preventing complications positively affects patient prognosis.

Cost-Effectiveness Analysis of Capecitabine Compared with Bolus 5-Fluorouracil/l-Leucovorin for the Adjuvant Treatment of Colon Cancer in Japan

A cost-effectiveness analysis of oral capecitabine versus intravenous bolus 5-fluorouracil/l-leucovorin (FU/LV) as adjuvant therapy in patients with stage 3 colon cancer was performed from a Japanese healthcare payer perspective. Adjuvant therapy comprised 24 weeks of treatment with either oral capecitabine 1250 mg/m(2) twice daily on days 1-14 of a 21-day cycle or intravenous bolus FU 500 mg/m(2) and LV 250 mg/m(2) weekly for 6 weeks of an 8-week cycle (Roswell Park regimen). The analysis comprised short-term (1 year after initiation of adjuvant therapy) and long-term (up to 15 years) components. The long-term analysis involved a three-state (disease-free, recurrence and death) Markov model. Estimates for transition probabilities, costs and utilities were derived from the X-ACT trial, a Japanese phase II trial, and other published sources. Cost estimates were considered from the perspective of a healthcare payer. Costs were expressed in Japanese Yen (yen), year 2007 values. A discount rate of 3% was applied to costs and outcomes. Cost effectiveness was expressed as a cost per QALY. The effects of uncertainty were explored through one-way and probabilistic sensitivity analyses. In the 1-year analysis, direct costs were yen440,000 ($US4000) less per patient with capecitabine than with FU/LV. In the long-term analysis, differences between treatments in direct medical costs ranged from yen470,000 ($US4300) to yen580,000 ($US5300) depending on the time horizon used. Capecitabine was also projected to increase the number of QALYs compared with FU/LV. The sensitivity analysis suggested that the model outcome was robust. The probabilistic sensitivity analysis estimate of capecitabine being the dominant regimen was 96.6% at a zero willingness to pay. Direct costs remained lower with capecitabine if the price of generic LV was >OR=50% of the branded product. This analysis suggests that capecitabine improves health outcomes and lowers direct costs compared with bolus FU/LV (i.e. dominant treatment strategy) when used as adjuvant therapy in patients with stage 3 colon cancer in Japan.

Safety and tolerability of FOLFOX4 in the adjuvant treatment of colon cancer in Asian patients: The MASCOT study

Aims: The MOSAIC trial showed that FOLFOX4 improves overall survival as compared to 5-FU/LV and is feasible and safe in early stage colon cancer patients worldwide. Based on these positive results, the present study MASCOT (Multicenter Asia Study in adjuvant treatment of Colon cancer with Oxalipla Tin/5-FU/LV), aimed to evaluate the safety and tolerability of FOLFOX4 in postoperative adjuvant treatment of colon cancer in Asian patients. Methods: In this open-label, non-randomized, single arm feasibility study, stage II/III colon cancer patients who had undergone complete resection of a primary tumor were treated using the FOLFOX4 regimen (2 weeks/cycle, 12 cycles) and followed up for 12 months. Results: A total of 159 patients (28.3% stage II and 71.7% stage III) from 17 hospitals in five Asian countries were included in the study. Overall 130 (81.8%) patients completed all 12 planned treatment cycles. There were 60% and 11% patients who experienced ≥ grade 3 pre-listed and non pre-listed toxicities, respectively. The incidences of grade 3 and 4 neuropathy were 5.7% and 0%, respectively. A total of 25 serious adverse events (SAE) were experienced by 21 (13%) patients, with one life-threatening SAE. At 12 months follow-up two patients were known to be dead due to disease relapse or recurrence. Conclusion: The MASCOT study demonstrates a favorable safety profile of FOLFOX4 in Asian patients. Based on these results and the safety and efficacy results from MOSAIC, FOLFOX4 may be considered a standard for the adjuvant treatment of colon cancer in the Asian population.

Primary colon cancer: ESMO Clinical Recommendations for diagnosis, adjuvant treatment and follow-up

Staging provides essential prognostic information relevant for choosing adequate therapy and should also identify patients with resectable distant metastases. Preoperative staging consists of clinical examination, blood counts, liver and renal function tests, carcino-embryonic antigen (CEA), chest X-ray or preferably chest CT-scan, CT scan of the abdomen including the pelvis and a colonoscopy of the entire large bowel, i.e. with postoperative repeat colonoscopy if proximal parts of the colon were not accessible preoperatively. Pathologic staging should be done according to the 2002TNM system with optional listing of the modified Dukes stage, as described in Table 1. Risk factors for colorectal cancer are: family history, familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) syndromes, hereditary non-polyposis colorectal cancer (HNPCC) syndrome, past history of colorectal cancer or adenoma, chronic ulcerative colitis and Crohn’s disease. prognosis

The role of meta-analysis in cancer clinical trials

Meta-analysis of randomized controlled trials is considered to be the methodology that provides the most solid scientific basis for constructing clinical guidelines. It involves systematically collecting the results of similar studies that were conducted to verify similar medical hypotheses and combining these results statistically. In meta-analysis, targeting only those randomized controlled trials with good comparability also provides the meta-analysis with comparability. With the combining of multiple studies and the increased sample size, meta-analysis provides results with higher clarity than those obtained from a single study. In conventional meta-analyses, in addition to estimating the combined effect, the cause of heterogeneity of the effects among studies is usually explored. If multiple studies reveal homogeneous effects, the overall effect is interpretable and generalizability can be suggested; that is, the results can be reproducible even when the study conditions are slightly modified. On the other hand, if the effect cannot be viewed as homogeneous among the studies, it is difficult to interpret the overall effect obtained from a meta-analysis. From the viewpoints of clarity, comparability, and generalizability, meta-analysis and large-scale clinical trials can provide the most valuable evidence among several possible study designs. In this article, the role of meta-analysis in cancer clinical trials is illustrated with the example of adjuvant therapy with UFT in patients with curatively resected rectal cancer, compared with the example of a large-scale clinical trial using oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.

Effects of oxaliplatin and 5-fluorouracil on the healing of colon anastomoses

Oxaliplatin (OX) and 5-fluorouracil (5-FU) are the most widely used chemotherapeutic agents in the adjuvant treatment of colon cancer. Although the early initiation of adjuvant chemotherapy can improve the outcome of surgery, it carries potentially fatal risks. This experimental study investigates the effects of 5-FU and OX on colon anastomoses. We used 60 rats, divided into six groups. After being subjected to bowel resection and anastomosis, the rats were given 5-FU on days 1-3, or OX 130 mg/m(2) on days 1 or 5, or 5% dextrose as a control. The bursting pressures and hydroxyproline content of the anastomoses were measured, and complications and adhesions were recorded. There were no major complications in the treatment groups. The bursting pressures of the 5-FU group were significantly lower than those of the control and OX groups. The bursting pressures of the OX groups were not significantly different from those of the control groups. The hydroxyproline levels of the rats treated with OX on day 1 were significantly lower than those of the rats treated with OX on day 5 and the 5-FU groups. Oxaliplatin and 5-FU did not compromise wound healing of the colon significantly. Our results indicate that OX is less detrimental to the healing of colonic anastomoses, when administered on days 1 and 5 after resection, than 5-FU.

Targeted therapies in the management of colorectal carcinoma: role of bevacizumab

Colorectal cancer continues to be an important public health concern, despite improvements in screening and better systemic chemotherapy. The integration of targeted therapies in the treatment of colon cancer has resulted in significant improvements in efficacy outcomes. Angiogenesis is important for tumor growth and metastasis and is an important target for new biological agents. Bevacizumab is a humanized recombinant antibody that prevents vascular endothelial growth factor (VEGF) receptor binding, and inhibits angiogenesis and tumor growth. The addition of bevacizumab to fluoropyrimidine-based chemotherapy, with or without irinotecan or oxaliplatin, in both the first- and second-line treatment of metastatic colorectal cancer, significantly increased median progression-free survival and overall survival in select randomized phase III studies. Ongoing studies are evaluating the role of bevacizumab in the adjuvant treatment of colon cancer. Common toxicities associated with bevacizumab include hypertension, bleeding episodes, and thrombotic events. This review will focus on the integration of bevacizumab in the treatment paradigm of colon cancer and the management of its side effects.