Therapy For Advanced Colorectal Cancer Research Articles

Combination Biologic Therapy in Advanced Colorectal Cancer

Combination Biologic Therapy in Advanced Colorectal Cancer

Cetuximab inhibits thymidylate synthase in colorectal cells expressing epidermal growth factor receptor

The monoclonal antibody cetuximab directed against the epidermal growth factor receptor (EGFR) is an attractive agent for targeted therapy in advanced colorectal cancer (CRC), especially when combined with 5-fluorouracil (5-FU)-based chemotherapy. However, the mechanisms of cetuximab activity as chemosensitizer remain poorly understood. Using proteome-fluorescence-based technology, we found that cetuximab is able to suppress the expression of thymidylate synthase (TS), which is involved in the mechanism of 5-FU action. Caco-2, HRT-18, HT-29, WiDr and SW-480 CRC cells were found to express EGFR. SW-620 was used as EGFR-negative cell line. Only in EGFR-expressing cells cetuximab is able to inhibit TS expression. Combined treatment with cetuximab and 5-FU revealed a synergistic anti-tumor response that is closely correlated with functional activity of EGFR/mitogen-activated protein kinase (MAPK) pathway. Moreover, no correlation was seen between constitutive TS protein expression, level of cetuximab-induced TS down-regulation and response either to 5-FU alone or in combination with cetuximab. We demonstrated that only EGFR expression with high functional activity of EGFR/MAPK pathway is important for the synergistic effects between cetuximab and 5-FU in the investigated cell lines.

Activity of the combination of bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin (CapOx/Bev) in advanced colorectal cancer (ACRC): A randomized phase II study of the AIO Colorectal Study Group (AIO trial 0604)

4030 Background: The combination of Bev with 5-FU/FA and irinotecan or oxaliplatin is highly active in ACRC. A recent phase III trial demonstrated that infusional 5-FU and capecitabine (cape) have comparable efficacy when combined with oxaliplatin and Bev (Cassidy et al. 2007). In contrast, data are heterogeneous for cape/irinotecan combinations. This randomized phase II trial compared safety and efficacy of Bev with either CapOx or CapIri as first line therapy in ACRC. Methods: Prerequisites were: untreated ACRC, ECOG PS≤2, measurable lesion(s), adequate hematologic and organ functions. Primary endpoint in this non- comparative design was progression-free survival (PFS) rate after 6 months (mos). Regimen: Bev 7.5 mg/kg day (d)1 with either oxaliplatin (130 mg/m2 d1)/cape (1,000 mg/m2 bid d1–14; CapOx/Bev, arm A) or irinotecan (200 mg/m2 d1)/cape (800 mg/m2 bid d 1–14; CapIri/Bev, arm B), all q d22. Arm B doses were reduced by 20% for both, cape and irinotecan, compared to previous trials reporting unacceptable GI toxicity (Köhne et al., Ann Oncol 2007; Fuchs et al., J Clin Oncol 2007). Results: From July 2005 to Oct 2006, 255 patients (pts) were randomised. Patient characteristics (arm A/B): Median age 64/65 yrs, male 67%/68%, ECOG 0/1/2 52/45/3% and 52/45/2%, colon 60%/64%, rectum 40%/36%, respectively. Data are available for 244 (124/120) pts. Treatment characteristics (arm A/B): A total of 965/1069 cycles (median 8/9 cycles) have been administered. For 198 pts the end of treatment has been documented: 34% (30%/38%) due to progression, 29% (41%/18%) due to toxicity, 20% (16%/24%) because of pts´ decision. Most common CTC gr. 3/4 toxicities of pts, arm A/B: Diarrhea 19%/15%, hand-foot-syndrome 10%/7%, peripheral neuropathy 23%/0% Tumor response rates (CR+PR) were 54%/55%, tumor control rates (incl. SD) were 79%/80%. PFS rate at 6 mos were 78%/84%, median PFS 9.9/12.5 mos. Conclusions: Both regimen are highly active and safe. The absense of neuropathy favours the CapIri/Bev combination. Interestingly, the dose reduction of CapIri seemingly improves tolerability without compromising efficacy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Pharma, sanofi-aventis Merck, Roche Pharma, sanofi-aventis GmbH Merck, Roche Pharma, sanofi-aventis GmbH Roche Pharma GmbH, sanofi-aventis GmbH

Who can benefit from chemotherapy holidays after first-line therapy for advanced colorectal cancer? A GERCOR study

4037 Background: Chemotherapy free-intervals (CFI) in patients with advanced colorectal cancer who benefit from improved therapy are frequently done. However, early CFI after 6 cycles of first-line FOLFOX could negatively affect overall survival (Optimox 2 study, ASCO 2007, abs 4013). The ongoing study was performed to determine the best time to stop therapy and the predictive factors for a prolonged CFI. Methods: All patients who had a 3-months CFI in the two optimox studies (N=822) were studied according to the time to CFI. Patients who had R0 or R1 metastase resection after 3 months of CFI were censored at time of surgery, patients who had surgery before 3 months of CFI or with progressive disease at time of CFI were excluded. Additionally, patients were individually matched with patients who did not stop chemotherapy, had a PFS at least 3 months longer than time to CFI, and similar baseline features (PS, LDH, ALP, number of metastatic sites, adjuvant chemotherapy, primary and age). Results: 31% of the...

Pharmacogenetic (PGx) analysis of toxicity after oxaliplatin (Ox), capecitabine (Cap), bevacizumab (Bev) and cetuximab (Cet) therapy for advanced colorectal cancer (ACC): First results from the Dutch Colorectal Cancer Group (DCCG)-CAIRO2 trial

2574 Background: In the CAIRO2 study the addition of Cet to the combination Cap, Ox and Bev for patients with untreated ACC is investigated. The aim of this side study is to evaluate predictive PGx factors for toxicity for Cet and Cap in the EGFR/FCGR pathway and thymidylate synthase (TYMS) gene, respectively. Methods: Treatment was administered q3wk until progression: Ox 130 mg/m2 iv cycle 1–6, Cap 1,000 mg/m2 orally bid on day 1–14 (1,250 mg/m2 after 6 cycles) and Bev 7.5 mg/kg iv on day 1 (arm A) with the addition of Cet 400 mg/m2 iv on day 1 of cycle 1, thereafter weekly 250 mg/m2 (arm B). Toxicity (NCI-CTC v3) was evaluated in the first 400 patients. Cet and Cap related toxicities were evaluated and DNA was isolated from peripheral blood after informed consent. Genotype of FCGR2A His131Arg (n=259), FCGR3A Phe158Val (n=253), EGF 61A>G (n=217) and CCND1 870G>A (n=273) were analyzed with Taqman, EGFR CA-repeat (n=221; both alleles <20 vs. any allele >/=20 repeats) was analyzed with fragment analysis and TYMS 2/3C/3G (n=255) was analyzed with direct sequencing. Multivariate logistic regression was performed with gender, age, performance status, treatment arm and number of affected organs as confounders. Results: Germline DNA from 299 (arm A: 153; arm B: 146) eligible patients was available. The FCGR2A polymorphism was associated with grade 3–4 acneiform skin reaction and/or nail changes (ASR/NC) (P=0.037). Carriage of the FCGR2A-His allele (n=199/259) was associated with an increased risk of grade 3–4 ASR/NC (OR=3.85; 95%CI=1.02–14.29). The FCGR3A, EGF, CCND1 and EGFR polymorphisms were not associated with grade 3–4 ASR/NC. Non-carriage of the TYMS-3G allele (n=156/255) was associated with an increased risk of grade 2–4 hand-foot syndrome (HFS) (OR=1.82; 95%CI=1.03–3.23) but not with the risk of grade 3–4 diarrhea. Conclusions: These results indicate that the FCGR2A His131Arg and TYMS-3G polymorphisms may be useful markers for predicting ASR/NC after Cet treatment and HFS after Cap treatment, respectively. No significant financial relationships to disclose.

A Four-Arm, Randomized, Multicenter Phase II Trial of Oxaliplatin Combined with Varying Schedules of 5-Fluorouracil as First-line Therapy in Previously Untreated Advanced Colorectal Cancer

Oxaliplatin combined with 5-fluorouracil (5-FU), with or without leucovorin (LV), is effective and well tolerated for first-line therapy of advanced colorectal cancer (CRC). However, there is no consensus as to which oxaliplatin/5-FU-containing regimen is superior in the first-line setting. This randomized, multicenter phase II trial was designed to evaluate and compare the efficacy of 4 different oxaliplatin/5-FU regimens. Patients with previously untreated metastatic CRC (mCRC; n = 129) were randomized to 1 of 4 treatment regimens: (1) continuous 5-FU infusion plus oxaliplatin (n = 23); (2) weekly 5-FU bolus with LV plus oxaliplatin (n = 40); (3) oxaliplatin with 2-day infusion 5-FU/LV (FOLFOX4, n = 41); and (4) chronomodulated 5-FU plus oxaliplatin (n = 25). Overall response rates, after expert assessment, ranged from 24% to 34%, and median progression-free survival (PFS) ranged from 6 months to 8 months. Although no significant differences in efficacy were detected in pairwise comparisons of the 4 different regimens, patients randomized to FOLFOX4 had the highest response rate and longest PFS. The FOLFOX4 regimen was also associated with the lowest incidence of severe (grade 3/4) toxicity, with the exception of cumulative peripheral neurotoxicity. This randomized phase II trial provides evidence that oxaliplatin/5-FU regimens are effective and well tolerated for first-line therapy of previously untreated mCRC. The FOLFOX regimens are now an established standard for CRC.

Toward Progression-Free Survival As a Primary End Point in Advanced Colorectal Cancer

In this issue of the Journal of Clinical Oncology, Buyse et al evaluate progression-free survival (PFS) as a surrogate end point for overall survival (OS) in advanced colorectal cancer (CRC). They employ a general methodology for validating surrogate end points across multiple trials, as proposed by Buyse et al in 2000. They considered trials where leucovorin-modulated fluorouracil (FU) was compared with either FU without leucovorin or with raltitrexed. In these trials, they were able to show modest correlation between the proportion alive and progression free at 6 months and the proportion alive at 12 months, as well as good correlation when data across all time were considered. More importantly, they showed that the effect of treatment on each of these end points was highly correlated both when data across all time were considered and when the PFS and OS data were censored at 6 and 12 months, respectively. This latter step is an important advance over previous attempts to establish surrogacy. The model relating treatment effects between the PFS and OS end points was validated on a set of three contemporary trials in which leucovorin-modulated FU was compared with regimens that added irinotecan or oxaliplatin. The model was used to predict the treatment effect on OS given the observed treatment effect on PFS. The observed treatment effect on OS for the validation trials fell within the prediction limits for all three trials. The authors conclude that PFS is an acceptable surrogate for OS in advanced CRC and provide a surrogate threshold effect (STE), which is the treatment effect size for PFS which, if exceeded, would rule out equivalence with 95% confidence for the OS end point based on the model’s prediction limits. PFS has now been validated as a surrogate end point for OS in advanced CRC, but OS is not a perfect end point for this disease. In advanced CRC, the goal of therapy in order of desirability of outcome is to eliminate cancer, reduce cancer burden, stabilize cancer, or slow cancer progression. Prolongation of life is secondary to the goal of therapy. As more and better options for secondand third-line therapies in advanced CRC become available, the relevance of OS as the primary end point is increasingly coming into question. Let’s take a moment to compare and contrast the virtues of PFS and OS as potential primary end points for first-line treatment of metastatic CRC. OS is usually defined as time to death from any cause and may be considered a composite end point based on the cause of death where the event is the first of death related to the same cancer, death related to another cancer, death related to treatment, or death resulting from other causes. PFS is a composite end point where the event is the first of progression resulting from increasing size of tumor, progression resulting from formation of a new tumor, death related to the same cancer, death related to another cancer, death related to treatment, or death resulting from other causes. The component events are listed in Table 1 for the PFS and OS end points along with their relationship to the disease process under study or the therapies being studied. Events related to the disease process under study or to treatment toxicity provide important information for comparing potential therapies. Events that are unrelated to the disease process under study or to treatment toxicity are essentially background noise and provide little useful information for comparing potential therapies. We don’t want to ignore these likely irrelevant events, because sometimes treatments have unintended consequences. The underlying rates of these so-called background events should be equivalent on the treatment arms, because they are by definition unrelated to the disease process or treatments. Some desirable attributes for a primary end point in advanced CRC are listed in Table 2. Event status determination is extremely reliable in OS. The difficulties associated with determining

The Impact of the Introduction of Irinotecan and Oxaliplatin on the Outcome of Patients with Advanced Colorectal Cancer

The effectiveness of oxaliplatin and irinotecan in advanced colorectal cancer therapy has been shown by many randomized clinical trials. We developed a retrospective study on patients treated in the clinical practice. The main inclusion criteria were: diagnosis of unresectable colorectal adenocarcinoma and having undergone chemotherapy. Univariate and multivariate analyses were performed to identify the prognostic factors of survival. The study included 286 consecutive patients. Three factors were associated with worse survival: high CA19-9 levels (p=0.003), schedules without new regimens (p=0.031) and weight loss (p=0.070). The use of new regimens was associated with a significant improvement in median survival (15 to 10 months, p<0.001). Although the new regimens improved survival in clinical practice, the median gain is smaller than that reported in randomized trials. The palliative intent of these therapies should not be forgotten in order to improve quality of life rather than absolute survival.

Third-line therapy for metastatic colorectal cancer

The past years' therapy for colorectal cancer has evolved rapidly with the introduction of novel cytotoxic agents such as irinotecan, capecitabine and oxaliplatin. Further advances have been achieved with the integration of targeted agents such as bevacizumab, cetuximab and recently, panitumumab. As a result, third-line treatment is now a necessary step in the optimal treatment of patients with metastatic colorectal cancer (MCRC). We conducted a literature review of English language publications on third-line therapy for MCRC from January 2000 to April 2007. Data on median overall survival (mOS), median time to progression (mTTP) and response rate were recorded. We found 27 articles and 22 abstracts to fulfil the criteria. Patients who received regimens containing oxaliplatin and infusional 5-fluorouracil (5-FU) demonstrated mTTP up to 7 months and a mOS of 16 months. With irinotecan and 5-FU, mOS around 8 months were reported and with cetuximab combined with irinotecan, the highest mOS was 9.8 months. Third-line therapy in advanced colorectal cancer may improve mOS for patients with MCRC. Therefore, randomized studies should be conducted in the future.

A phase II study of irinotecan, high-dose 24-h continuous intravenous infusion of floxuridine and leucovorin (IFLUX) for advanced, previously untreated colorectal cancer

Our objectives were to determine response rate, time to progression, overall survival and tolerability of novel combination chemotherapy, consisting of irinotecan, high-dose 24-h continuous intravenous infusion of floxuridine and leucovorin in advanced previously untreated colorectal cancer. Thirty-eight patients with advanced colorectal cancer were treated at Sylvester Comprehensive Cancer Center, University of Miami, from 2000 to 2004, and received weekly intravenous infusion of irinotecan at 110 mg/m with a combination of 120 mg/kg floxuridine and 500 mg/m leucovorin administered as a 24-h continuous intravenous infusion. The treatment cycle consisted of 4 weeks of consecutive therapy followed by 2 weeks of rest. Five (13%) patients achieved complete response, 10 (26%) patients achieved partial response, 17 (45%) patients attained stable disease and six (16%) patients progressed. The overall response rate was 39% in this study. This chemotherapy regiment was well tolerated; the most common grade 3 toxicities were neutropenia (16%), anemia (16%), vomiting (24%), diarrhea (16%), and hand-and-foot syndrome (26%). The median time to progression was 11.5 months (347.5 days) with 95% confidence intervals of 6.8-12.9 months (206-389 days). The time to progression ranged from 1.8 to 34 months. The median survival of the patients in this trial was 31.28 months (952 days) with a confidence interval of 20.9-38.0 months (629-1141 days). Intravenous infusion of floxuridine and leucovorin is beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged time to progression and overall survival with acceptable tolerability and manageable toxicity profile.

Oxaliplatin and Fixed-Rate Infusional Gemcitabine in the Second-Line Treatment of Patients with Metastatic Colon Cancer: Final Results of a Phase II Trial Prematurely Closed as a Result of Poor Accrual

Second-line therapy of advanced colorectal cancer (CRC) after failure of a combination of irinotecan, a fluoropyrimidine, and bevacizumab includes the use of oxaliplatin and a fluoropyrimidine. In animal models, synergistic effects of gemcitabine and platinum agents have been established. Additionally, superior antitumor activity of prolonged administration of gemcitabine compared with bolus administration has been demonstrated in vivo against murine colon tumors. A 2-stage phase II trial was developed to assess the efficacy (primary endpoint: response rate) and safety of gemcitabine 1000 mg/m(2) over 100 minutes on days 1 and 15 in combination with oxaliplatin 100 mg/m(2) over 2 hours on days 2 and 16, every 4 weeks. Patients with metastatic CRC in whom irinotecan and a fluoropyrimidine treatment had failed were enrolled. Calcium and magnesium infusion was routinely given before and after oxaliplatin administration. Because of slow accrual as a result of oxaliplatin becoming more commonly used in first-line treatment, the trial was stopped with only 10 patients enrolled. Eight were men and 2 were women. Median age was 58.5 years (range, 47-72 years). Nine patients had an Eastern Cooperative Oncology Group performance status of 0/1. A median of 3.5 cycles was administered (range, 1-9; total, 42). Six patients had stable disease and 1 had progressive disease. Two patients had confirmed partial responses, and 1 patient had a partial response but developed necrotizing fasciitis, declined surgical treatment, and died before a confirmatory scan could be performed. The regimen was otherwise well tolerated: 1 patient developed grade 3 neutropenia. With a median follow-up of 5.5 months, 4 patients have died. The time to treatment failure was 3.7 months. Despite premature study closure because of poor accrual, oxaliplatin in combination with fixed-rate infusional gemcitabine seems to be a safe and potentially effective regimen in the treatment of CRC. Further studies should be considered with the addition of targeted therapy.

Targeted therapy in advanced colorectal cancer, an update

The introduction of inhibitors of signal transduction pathways has increased the therapeutic arsenal for patients with advanced colorectal cancer (ACC). Bevacizumab, a monoclonal vascular endothelial growth factor antibody, is currently part of the standard first-line treatment in combination with fluoropyrimidine-based chemotherapy. Cetuximab, a chimeric monoclonal antibody against the epidermal growth factor receptor, has shown efficacy in irinotecan-refractory ACC patients. Several experimental targeted agents, including small molecules that inhibit receptor tyrosine kinase activity, are currently being tested. We review the mechanism of action as well as the current status of targeted therapy in ACC.

Waterfall plots provide detailed information on magnitude of response to conventional chemotherapy in advanced colorectal cancer (ACRC) - lessons learned from N9741

4080 Background: Waterfall plots have been used to capture the anti-tumor efficacy of both biologic agents (Ratain JCO 2006), which mainly exhibit a cytostatic effect, but also of chemotherapeutic agents. We are not aware of an application to therapeutic studies in CRC. We conducted waterfall plot analyses on the data of N9741 which compared IFL, FOLFOX4, and IROX as first-line therapy in ACRC (Goldberg JCO 2004). Methods: 634 (IFL 215, FOLFOX 215, IROX 204) of the 795 pts presented in the published analysis had measurable disease, and are included. The percentage change in tumor measurements from baseline to 12 wks was calculated, allowing for a time window of assessment from 6 to 20 wks for those without a 12 wk measurement. Pts with progression before the 12 wk assessment were assigned a 100% increase. The average reduction in tumor burden (ARTB) was calculated as difference in waterfall AUC divided by the number of pts. ARTB captures the average percentage reduction in tumor measurements at 12 wks for a patient entering the trial. Results: Waterfall plot analysis demonstrated some tumor growth at 12 wks in 23.7% (IFL), 15.8% (FOLFOX), and 26.9% (IROX) of pts. In contrast, tumor shrinkage was observed in 67.9% (IFL), 71.6% (FOLFOX), and 61.4% (IROX) of pts. Total differential AUC was -34.4 (IFL), -61.6 (FOLFOX), and -30.4 (IROX) resulting in an ARTB of 16.0% (95% Confidence Interval (CI) (23.7%, 8.2%)) for IFL, 28.7% (35.1%, 22.2%) for FOLFOX, and 14.9% (22.5%, 7.3%) for IROX. Conclusions: Waterfall plot analyses are feasible in this and likely other CRC trials using conventional chemotherapy. Our analysis confirms the published results of N9741, but suggests a larger degree of benefit for individuals based on anti-tumor activity than captured by conventional response analysis. Waterfall plots provide a potentially useful new efficacy metric, the average reduction of tumor burden per pt, which should be validated in future trials. No significant financial relationships to disclose.

A systematic review of economic analyses of pharmaceutical therapies for advanced colorectal cancer

Colorectal cancer is one of the most common causes of cancer in the Western world. New drugs in the treatment of advanced colorectal cancer, such as irinotecan and oxaliplatin, have substantially increased the cost of treatment. A systematic literature review on the cost (-effectiveness) of pharmaceutical therapies for advanced colorectal cancer was conducted, in which 13 articles were included. The main topics were: orally versus intravenously administered fluoropyrimidine, raltitrexed, irinotecan and oxaliplatin. Additional information was collected on the cost (-effectiveness) of the monoclonal antibodies, cetuximab and bevacizumab. Only five articles had taken the societal perspective, in most articles no data on quality of life was presented, and only two reported the cost per quality-adjusted life year. As only a limited amount of information is available on the cost-effectiveness of pharmaceutical therapies for advanced colorectal cancer, there is a need for more cost-effectiveness studies. These studies are preferably performed by taking a societal perspective and including quality of life outcomes.

Surrogate biomarkers for anti-angiogenic therapy for advanced colorectal cancer

Vascular endothelial growth factor (VEGF)—over-expressed in colorectal cancer—is associated with disease progression and inferior survival. Based on successful, randomized, phase III trials, anti-VEGF therapeutics have entered clinical practice. Bevacizumab, a VEGF-specific antibody, was the first anti-angiogenic agent to be approved by the Food and Drug Administration to be used in combination with standard chemotherapy in the first and second line of treatment in metastatic colorectal cancer. VEGF-targeted therapy may lead to indirect killing of cancer cells by damaging tumor blood vessels and may increase the radiosensitivity of tumor-associated endothelial cells. VEGF blockade can also normalize tumor vasculature thereby leading to greater tumor oxygenation (a known radiosensitizer) and drug penetration. A dose-escalation phase I trial has demonstrated that the combination of bevacizumab at the 5-mg/kg dose with radiochemotherapy was well tolerated by patients with rectal cancers. In addition, results from an array of correlative studies have demonstrated that bevacizumab has antivascular effects and supported the normalization hypothesis. The ongoing phase II study will further elucidate the mechanisms of action and efficacy of bevacizumab in locally advanced rectal cancer.

Efficacy and safety of bevacizumab in combination with oxaliplatin, irinotecan and fluoropyrimidine-based therapy in advanced colorectal cancer

Background: Bevacizumab is an anti-VEGF, humanized mAb that is the most advanced agent of its class in clinical development. Several studies have examined bevacizumab in combination with chemotherapy in the first- and second-line settings in patients with metastatic CRC. Despite of that, there is lack of information concerning the extent to which bevacizumab can be used to treat metastatic CRC. We still need more evidence related to efficacy and safety of bevacizumab in different settings, or sequential treatments. The aim of this study was to investigate efficacy and safety of bevacizumab added to different chemotherapy in patients with metastatic CRC. Methods: This was a controlled, prospective, multicentre, cohort study. Thirty patients with advanced colorectal cancer were enrolled into this study. Bevacizumab was applied with oxaliplatin-, irinotecan-, 5FU- or capecitabine -based chemotherapy in the first-, second- or third-therapy lines. Totally 261 cycles were applied. The median number of applied cycles per patient was 8 (range 2-16). Results: Objective tumor response (RR) was seen in 11 patients 37% (95%CI 19-69%) calculated on an intention-to-treat basis. The median duration of response was 12 months. Three of 11 patients (27%) with PR had secondary surgery. RR was seen in 9 of 16 patients (56%) who received bevacizumab in the first-line treatment and in 2 of 14 patients (14%) who received therapy in the second+ lines (p=0.02). Clinical benefit (PR+SD) was seen in 22 (74%) patients. 75% of patients achieved clinical benefit in the first-line and 74% in the second+ chemotherapy lines. The median time to progression (TTP) of the patients is was 9 + months (95%CI 7 - + ?) at the moment of this analysis. The median TTP of patients who received bevacizumab in the first line was 11 months (95%CI 8 - + ?). The median TTP of patients who received bevacizumab in the second+ lines was 5.5 months (95%CI 4 - + ?) (p=0.015). The median survival time (OS) for all patients was 9 + months (95%CI 7 - + ?). The median OS at the moment of analysis was 11 months (95%CI 9 - + ?) for patients receiving bevacizumab in the first line, and 7 months for patients receiving the drug in the second+ lines (95%CI 6 - + ?) (p=0.024). The incidence of any toxicity grade 3-4 was less than 10%. Bevacizumab associated incidence of grade 3-4 side effects did not exceed 5%. Hypertension 5% and thromboembolism 5% were the most frequent events. Gastrointestinal perforation did not occur. There was one toxic death due to sepsis and not directly associated with bevacizumab toxicity. Conclusion: Bevacizumab can safely be added to different chemotherapeutic regimens in first- and second+ line. The conferred benefit in overall survival, TTP and response rate obviously requires randomized trials.

Modified Irinotecan/5FU/Leucovorin therapy in advanced colorectal cancer and predicting therapeutic efficacy by expression of tumor-related enzymes

Objective. To evaluate the efficacy and safety of a regimen using Irinotecan, 5FU and Leucovorin for patients with advanced or recurrent colorectal cancer. Material and methods. Irinotecan (75 mg/m2) was administered biweekly, while 5FU (600 mg/m2) and Leucovorin (250 mg/m2) were administered weekly, for 6 weeks. Results. The 21 consecutive patients subjected to this regimen showed a good response rate (43%) with minimal toxicity (incidence of grade 3/4: leukopenia and neutropenia, 5%, respectively, and vomiting, 10%). The mean survival time of all 21 patients was 15.7 months. This regimen could be a valid option for patients with advanced colorectal cancer, especially those seeking a good QoL (quality of life) for the remainder of their lives. We evaluated the expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT) mRNAs, and sialyl Lewis X on formalin-fixed, paraffin-embedded colorectal tumor samples. Expression of TS mRNA or sialyl Lewis X was negatively correlated with the response from chemotherapy. Patients with low DPD mRNA expression in the tumor showed a significant longer survival than those with high expression. In patients with high TP mRNA expression, there was a tendency towards a high incidence of leukopenia. Conclusions. Some predictive factors elucidated in this study could contribute to the progress of the tumor-biology based, individualized chemotherapy for colorectal cancer patients.

Role of Oxaliplatin Combined with 5-Fluorouracil and Folinic Acid in the First- and Second-Line Treatment of Advanced Colorectal Cancer

Question: What is the role of oxaliplatin combined with 5-fluorouracil (5-fu) and folinic acid (FA) in the first- and second-line treatment of advanced (unresectable locally advanced or metastatic) colorectal cancer? Perspectives: Evidence was selected and reviewed by two members of the Gastrointestinal Cancer Disease Site Group (GI DSG) of Cancer Care Ontario’s Program in Evidence- Based Care (PEBC) and by a methodologist. The resulting practice guideline report has been reviewed and approved by the GI DSG, which comprises medical and radiation oncologists, surgeons, a pathologist, and patient representatives. External review by Ontario practitioners was obtained through a mailed survey. Final approval of the original guideline report was obtained from the Practice Guidelines Coordinating Committee. Outcomes: Outcomes of interest were 1-year survival, response rates, and quality of life. Methodology: The MEDLINE, CANCERLIT, EMBASE, Guidelines International Network, and Cochrane Library databases were systematically searched for relevant studies. Recommendations were formed based on the evidence reviewed. Through a survey, these recommendations were appraised by Ontario clinicians; the recommendations were then revised by the GI DSG. The systematic review and modified recommendations were approved by a review body within PEBC. Results: The literature review found twenty-one randomized controlled trials and two meta-analyses. Evidence on first-line treatment found infusional 5-FU/FA/oxaliplatin (FOLFOX) to be superior to bolus 5-FU/FA/irinotecan (IFL) for rates of median survival and tumour response, with lower incidences of most adverse effects except peripheral neuropathy. For second-line treatment after fluoropyrimidine monotherapy, FOLFOX is a reasonable alternative for patients with contraindications to second- line irinotecan. After progression on infusional 5-FU/FA/irinotecan (FOLFIRI), FOLFIRI is the preferred therapy. Evidence from a single randomized trial suggests that additional benefits can be expected with the addition of bevacizumab to the FOLFOX regimen in second- line treatment. Practice Guideline: These recommendations apply to adult patients with advanced colorectal cancer who have high performance status (Eastern Cooperative Oncology Group score 0–2). Refer to Appendix A for available treatment options and to Appendix B for recommended dosages and schedules. The FOLFOX regimen is an important component of therapy for advanced colorectal cancer. First-line Therapy In one trial, FOLFOX was shown to be superior to IFL. The FOLFOX regimen has superior rates of median survival and tumour response. Compared with IFL, FOLFOX has lower incidences of severe nausea, vomiting, diarrhea, and febrile neutropenia, but a higher incidence of peripheral neuropathy. Short-term infusional 5-FU/FA in combination with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are both acceptable alternatives for fit patients when combination therapy is the preferred treatment. Choice of first-line therapy may rely on patient factors and preferences—for example, less neuropathy with irinotecan versus less alopecia with oxaliplatin. Second-line Therapy After progression on first-line anti-thymidylate synthase monotherapy (for example, 5-FU/FA, capecitabine), irinotecan is standard secondline therapy. The FOLFOX regimen is a reasonable alternative for patients with contraindications to the use of second-line irinotecan. After progression on both irinotecan and an antithymidylate synthase agent, FOLFOX is the preferred therapy. Recent trials suggest that, as compared with FOLFOX alone, FOLFOX combined with bevacizumab provides additional survival benefits. Qualifying Statements: The role of radiation therapy, either alone or in combination with chemotherapy, for locally advanced unresectable colorectal cancer is not addressed in this guideline. Use of chronomodulated regimens is a topic that intersects with the use of oxaliplatin/5-FU combinations, particularly chronomodulation of 5-FU in these combinations. Chronomodulation of oxaliplatin has not been extensively studied, and the topic of chronomodulation is beyond the scope of this guideline and is not addressed. Although data exist to support the use of bevacizumab in combination with FOLFOX in second-line treatment, no first-line treatment data are available on which to make a recommendation.

Tegafur combined with oxaliplatin and 5-FU versus FOLFOX4 for advanced colorectal cancer: a randomized controlled study

13566 Background: To determine the activity and side-effect of tegarfur injection combined with L-OHP and 5-FU, comparing with FOLFOX4 as the therapy for advanced colorectal cancer. Methods: 60 patients, proved pathologically, were divided into 2 groups at random. Group A received the intravenous administration of tegafur(800mg/m2 IV 3hrs qd d1–5),leucovorin(100mg/m2 IV 2hrs qd d1–5) and L-OHP(130mg/m2 IV 2hrs d1) every 21 days. FOLFOX4 was applied in the group B. The endpoint included response rate (RR), progression free survival (PFS), overall survival(OS) and quality of life(QOL). Results: The response rate was 39.3% in the group A, while median time to progression was 9.5 months with median survival time of 11.6 months. In the group B, the response rate was 48.1% and median time to progression was 9.4 months with median survival time of 12.1 months. No significant differences were found between treatment arms in curative effect, survival time and side effect(P&gt;0.05). With respect to QOL, the group A achieved higher PS than B during treatment (P&lt;0.001). Conclusions: The intravenous administration of tegafur, leucovorin and L-OHP is a well-tolerated, effective, and feasible schedule for advanced colorectal cancer that yields comparable efficacy and side effect compared with FOLFOX4. Meanwhile, the former achieves the better QOL. No significant financial relationships to disclose.

A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the eastern cooperative oncology group study E2200

Patients with untreated advanced colorectal cancer were enrolled to this single arm phase II multi-center cooperative group trial of bevacizumab combined with IFL. The first 20 patients received irinotecan (125 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and leucovorin (20 mg/m(2)) weekly for four of six weeks and high-dose bevacizumab (10 mg/kg) every other week. Following a toxicity review of other trials using IFL, subsequent patients were enrolled at reduced doses of irinotecan (100 mg/m(2)) and 5-fluorouracil (400 mg/m(2)). Of the 92 patients accrued to the study, toxicity data are available for 87 patients and efficacy data for 81 patients. At a median follow-up of 37.5 months, median overall survival is 26.3 months, median progression free survival is 10.7 months and 1-year survival is 85%. The overall response rate is 49.4% (6.2% complete responses). A reduction in the starting doses of irinotecan and 5-fluorouracil decreased the occurrence of vomiting, diarrhea and neutropenia related complications. Bleeding occurred in 37 patients; all events but two were grade 1 or grade 2. There were nine reports of grade 3 or grade 4 thrombo-embolic events. Hypertension of any grade occurred in 13% of patients and proteinuria was infrequent. High-dose bevacizumab added to IFL is a well-tolerated and highly active regimen in patients with previously untreated metastatic colorectal cancer.